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Few studies have analyzed the Sport Concussion Assessment Tool's (SCAT) utility among athletes whose concussion assessment is challenging. Using a previously published algorithm, we identified possible and probable concussions at

Introduction: Sport is very important in the lives of children and adolescents, as it brings countless benefits at the physical, psychological and social levels. Objective: The aim of the study was to investigate the effects on physical fitness of an exercise program for overweight and obese female adolescents, with an emphasis on teaching volleyball. Methods: Twenty-five volunteers participated, aged between 13 and 14 years, of which 11 were overweight or obese for statistical analysis. Anthropometric and physical capacity assessments were performed, before and after 12 weeks, through activities related to volleyball. Results: There was an increase in height and span and a reduction in waist circumference, with no significant differences in body weight, BMI, arm circumference and triceps skinfold thickness; there was an increase in the sit-and-reach test, in the number of sit-ups and in the distance of the horizontal jump. There was a decrease in the time in the square test and the 20-meter run, with no significant differences in the medicine ball throw and in the 6-minute run test. Conclusion: It is concluded that the volleyball teaching program provided benefits for the physical fitness of overweight and obese adolescents. Level of evidence II; Lower quality RCT (example

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.

Sport-related concussion is recognized as a significant injury with variable recovery rates. This study defined the acute natural history of sport concussion in male and female collegiate athletes participating in a broad array of sports. We conducted a prospective, longitudinal investigation among collegiate student athletes (n = 34,709) from 30 academic institutions. Primary outcomes included the time (days) from injury until initiation of a return to participation (RTP) protocol and time from injury until medical clearance for unrestricted RTP. Concussed athletes (n = 1751, 19.2 years, 63.2% male) participating in 22 different sports began the RTP protocol in a median 6.4 (IQR 3.7–11.8) days. Time to initiate the RTP protocol was lengthened by less frequent post-injury assessments, greater initial post-injury symptom severity, limited contact sports participation, practice/training injuries, and three or more prior concussions. The median total RTP duration was 12.8 (IQR 8.7–20.1) days. Total RTP duration was shorter with ADHD medication usage, males, and greater assessment frequency; while greater initial post-injury symptom severity, practice-/training-related injuries, and three or more prior concussions had longer recoveries. Although median recovery times are consistent with previous guidelines, it was not until 1 month post-injury that a preponderance of collegiate athletes were cleared to begin the RTP protocol (92%) or cleared for unrestricted sport participation (85%). Intrinsic and extrinsic factors had a small effect, altering recovery trajectories by up to 2 days, suggesting a largely unified approach to post-injury monitoring and management across all athletes. These data represent a shift from previous classification parameters of normal clinical recovery.

The purpose of this study was to describe the mechanism of injury (MOI) and examine factors associated with greater risk for specific MOIs involving concussions in collegiate soccer players.Participants included 3,288 collegiate soccer players from 28 institutions across four competitive seasons, 2014-17. MOIs were documented for 262 soccer-related concussions during the study and placed into one of four categories: collisions, unintentional contact, aerial challenges, and others.70% of the concussions occurred in DI soccer players. Collisions and unintentional contact were the MOIs that resulted in 66.5% of all concussions. DI and DIII soccer players sustained more concussions by unintentional contact versus collisions and aerial challenges when compared to their DII counterparts. Defenders were more likely than midfielders to sustain concussions by aerial challenges than collisions. As expected, the field players experienced more concussions as a result of collisions, unintentional contact, and aerial challenges when compared to goalkeepers.Future research should explore preventive strategies for decreasing collisions, especially during aerial challenges while heading the soccer ball, and unintentional contacts from errant balls in soccer in order to decrease concussion risk.

A Bayesian adaptive design is proposed for a clinical trial in Duchenne muscular dystrophy. The trial was designed to demonstrate treatment efficacy on an ambulatory-based clinical endpoint and to identify early success on a biomarker (dystrophin protein levels) that can serve as a basis for accelerated approval in the United States. The trial incorporates placebo augmentation using placebo data from past clinical trials. A thorough simulation study was conducted to understand the operating characteristics of the trial. This trial design was selected for the US FDA Complex Innovative Trial Design Pilot Meeting Program and the experience in that program is summarized.

Concussion is a growing public health concern and generating concussion prevention programs depends on identifying high-risk sports and characteristics. Identifying the roles of sport, sex, and participation level (e.g., high school versus collegiate athletics) in concussion risk would facilitate more informed decision-making regarding sports participation and generate better targeted prevention strategies. The current study’s objectives were to: (1) determine the magnitude and hierarchy of sports-related concussion (SRC) risk across an array of events and (2) evaluate the modifying roles of sex, participation level, and session type on SRC rates. A literature search was conducted on PubMed, searching concussion studies published between 2001 and December 2019. Inclusion criteria for studies required: (1) concussion occurred during sport, (2) that the SRC was clinically diagnosed, and (3) athlete exposures and concussions could be extracted or estimated. A study was excluded if it: (1) was not an original research article, (2) was not written in English language, (3) was an animal study, (4) did not have enough data to calculate SRC rates, (5) included professional or youth sample, and/or (6) contained data collected prior to 2001. The meta-analysis and meta-regression analyses were fit using a random effects model. Search results returned 2695 unique research articles, with 83 studies included in analyses. Sport, sex, participation level, and session type all significantly influenced SRC rates. Overall, rugby had the highest concussion rate and was classified as the highest risk sport (28.25 concussions per 10,000 athlete exposures). Overall, females had a higher concussion rate than males. Only lacrosse demonstrated a higher concussion rate for males compared to females. Collegiate athletes had higher concussion rates than high school athletes. Games were associated with 2.01 more concussions per 10,000 AEs than practices. This meta-analysis demonstrated rugby has the highest concussion risk, followed by American Football, ice hockey, and wrestling. Concussion risk was influenced by sport, sex, participation, and session. Identifying the factors and environments that influence concussion risk can facilitate risk reduction and prevention strategies.

Highlights • Previous concussion was associated with 2 times increased odds of incident concussion, while wearing a mouthguard was protective against incident concussion, reducing odds by 57%. • Overall, concussion mechanisms did not significantly differ between sexes. • Females took significantly longer to reach asymptomatic and return-to-play clearance. Within the first 2 weeks post-concussion, 86.11% of males reached asymptomatic, while only 45.50% of females reached the same phase of recovery. • Most males (91.67%) were cleared for return-to-play within 3 weeks of their concussion, compared to less than one-half (45.50%) of females., Objective Since concussion is the most common injury in ice hockey, the objective of the current study was to elucidate risk factors, specific mechanisms, and clinical presentations of concussion in men's and women's ice hockey. Methods Ice hockey players from 5 institutions participating in the Concussion Assessment, Research, and Education Consortium were eligible for the current study. Participants who sustained a concussion outside of this sport were excluded. There were 332 (250 males, 82 females) athletes who participated in ice hockey, and 47 (36 males, 11 females) who sustained a concussion. Results Previous concussion (odds ratio (OR) = 2.00; 95% confidence interval (95% CI): 1.02‒3.91) was associated with increased incident concussion odds, while wearing a mouthguard was protective against incident concussion (OR = 0.43; 95%CI: 0.22‒0.85). Overall, concussion mechanisms did not significantly differ between sexes. There were specific differences in how concussions presented clinically across male and female ice hockey players, however. Females (9.09%) were less likely than males (41.67%) to have a delayed symptom onset (p = 0.045). Additionally, females took significantly longer to reach asymptomatic (p = 0.015) and return-to-play clearance (p = 0.005). Within the first 2 weeks post-concussion, 86.11% of males reached asymptomatic, while only 45.50% of females reached the same phase of recovery. Most males (91.67%) were cleared for return to play within 3 weeks of their concussion, compared to less than half (45.50%) of females. Conclusion The current study proposes possible risk factors, mechanisms, and clinical profiles to be validated in future concussions studies with larger female sample sizes. Understanding specific risk factors, concussion mechanisms, and clinical profiles of concussion in collegiate ice hockey may generate ideas for future concussion prevention or intervention studies., Graphical Abstract Image, graphical abstract

Symptom resolution is a key marker in determining fitness for return to activity following concussion, but in some cases, distinguishing persistent symptoms due to concussion versus symptoms related to other factors can be challenging. To determine base rates of postconcussional syndrome (PCS) diagnostic categorization in healthy cadets and student athletes with no recent concussion. 13,009 cadets and 21,006 student athletes completed baseline preseason testing. After inclusion/exclusion criteria were applied, the final sample included 12,039 cadets [9123 men (75.8%); 2916 women (24.2%)] and 18,548 student athletes [10,192 men (54.9%); 8356 women (45.1%)]. Participants completed the Sport Concussion Assessment Tool–3rd Edition (SCAT3) symptom evaluation as part of baseline preseason testing. The PCS diagnostic categorization was classified by the International Classification of Diseases, 10th Revision (ICD-10) symptom criteria for PCS. In the absence of recent concussion, subgroups of cadets (17.8% of men; 27.6% of women) and student athletes (11.4% of men; 20.0% of women) reported a cluster of symptoms that would meet the ICD-10 symptom criteria for PCS. Participants with insufficient sleep and/or preexisting conditions (e.g., mental health problems), freshmen cadets, and cadets at the U.S. Coast Guard Academy and at the U.S. Air Force Academy (freshmen were tested during basic cadet training) were more likely to report a cluster of symptoms that would meet the ICD-10 symptom criteria for PCS. The ICD-10 symptom criteria for PCS can be mimicked by preexisting conditions, insufficient sleep, and/or stress. Findings support person-specific assessment and management of symptoms following concussion.

Objective: As part of an initiative led by the Brain Injury Special Interest Group Mild Traumatic Brain Injury (TBI) Task Force of the American Congress of Rehabilitation Medicine (ACRM) to update the 1993 ACRM definition of mild TBI, the present study aimed to characterize current expert opinion on diagnostic considerations. Design: Cross-sectional web-based survey. Setting: Not applicable. Participants: An international, interdisciplinary group of clinician-scientists (N=31) with expertise in mild TBI completed the survey by invitation between May and July 2019 (100% completion rate). Interventions: Not applicable. Main Outcome Measures: Ratings of agreement with statements related to the diagnosis of mild TBI and ratings of the importance of various clinical signs, symptoms, test findings, and contextual factors for increasing the likelihood that the individual sustained a mild TBI, on a scale ranging from 1 (“not at all important”) to 10 (“extremely important”). Results: Men (n=25; 81%) and Americans (n=21; 68%) were over-represented in the sample. The survey revealed areas of expert agreement (eg, acute symptoms are diagnostically useful) and disagreement (eg, whether mild TBI with abnormal structural neuroimaging should be considered the same diagnostic entity as “concussion”). Observable signs were generally rated as more diagnostically important than subjective symptoms (Wilcoxon signed ranks test, Z=3.77; P

To develop a predictive model for sport-related concussion in collegiate athletes and military service academy cadets using baseline data collecting during the pre-participation examination. Baseline assessments were performed in 15,682 participants from 21 US academic institutions and military service academies participating in the CARE Consortium Study during the 2015–2016 academic year. Participants were monitored for sport-related concussion during the subsequent season. 176 baseline covariates mapped to 957 binary features were used as input into a support vector machine model with the goal of learning to stratify participants according to their risk for sport-related concussion. Performance was evaluated in terms of area under the receiver operating characteristic curve (AUROC) on a held-out test set. Model inputs significantly associated with either increased or decreased risk were identified. 595 participants (3.79%) sustained a concussion during the study period. The predictive model achieved an AUROC of 0.73 (95% confidence interval 0.70–0.76), with variable performance across sports. Features with significant positive and negative associations with subsequent sport-related concussion were identified. This predictive model using only baseline data identified athletes and cadets who would go on to sustain sport-related concussion with comparable accuracy to many existing concussion assessment tools for identifying concussion. Furthermore, this study provides insight into potential concussion risk and protective factors.

To optimally care for concussed individuals, a multi-dimensional approach is critical and a key component of this assessment in the athletic environment is computer-based neurocognitive testing. However, there continues to be concerns about the reliability and validity of these testing tools. The purpose of this study was to determine the sensitivity and specificity of three common computer-based neurocognitive tests (Immediate Post-Concussion Assessment and Cognitive Testing [ImPACT], CNS Vital Signs, and CogState Computerized Assessment Tool [CCAT]), to provide guidance on their clinical utility. This study analyzed assessments from a cohort of collegiate athletes and non-varsity cadets from the NCAA-DoD CARE Consortium. The data were collected from 2014–2018. Study participants were divided into two testing groups [concussed, n = 1414 (baseline/24–48 h) and healthy, n = 8305 (baseline/baseline)]. For each test type, change scores were calculated for the components of interest. Then, the Normative Change method, which used normative data published in a similar cohort, and the Reliable Change Index (RCI) method were used to determine if the change scores were significant. Using the Normative Change method, ImPACT performed best with an 87.5%-confidence interval and 1 number of components failed (NCF; sensitivity = 0.583, specificity = 0.625, F1 = 0.308). CNS Vital Signs performed best with a 90%-confidence interval and 1 NCF (sensitivity = 0.587, specificity = 0.532, F1 = 0.314). CCAT performed best when using a 75%-confidence interval and 2 NCF (sensitivity = 0.513, specificity = 0.715, F1 = 0.290). When using the RCI method, ImPACT performed best with an 87.5%-confidence interval and 1 NCF (sensitivity = 0.626, specificity = 0.559, F1 = 0.297). When considering all three computer-based neurocognitive tests, the overall low sensitivity and specificity results provide additional evidence for the use of a multi-dimensional assessment for concussion diagnosis, including symptom evaluation, postural control assessment, neuropsychological status, and other functional assessments.

OBJECTIVEPrevious studies have shown that clinically asymptomatic high-acceleration head impacts (HHIs) may be associated with neuronal and axonal injury, as measured by advanced imaging and biomarkers. Unfortunately, these methods of measurement are time-consuming, invasive, and costly. A quick noninvasive measurement tool is needed to aid studies of head injury and its biological impact. Quantitative pupillometry is a potential objective, rapid, noninvasive measurement tool that may be used to assess the neurological effects of HHIs. In this study, the authors investigated the effect of HHIs on pupillary metrics, as measured using a pupillometer, in the absence of a diagnosed concussion.METHODSA prospective observational cohort study involving 18 high school football athletes was performed. These athletes were monitored for both the frequency and magnitude of head impacts that they sustained throughout a playing season by using the Head Impact Telemetry System. An HHI was defined as an impact exceeding 95g linear acceleration and 3760 rad/sec2 rotational acceleration. Pupillary assessments were performed at baseline, midseason, after occurrence of an HHI, and at the end of the season by using the NeurOptics NPi-200 pupillometer. The Sport Concussion Assessment Tool, 5th Edition (SCAT5), was also used at each time point. Comparisons of data obtained at the various time points were calculated using a repeated-measures analysis of variance and a t-test.RESULTSSeven athletes sustained HHIs without a related diagnosed concussion. Following these HHIs, the athletes demonstrated decreases in pupil dilation velocity (mean difference 0.139 mm/sec; p = 0.048), percent change in pupil diameter (mean difference 3.643%; p = 0.002), and maximum constriction velocity (mean difference 0.744 mm/sec; p = 0.010), compared to measurements obtained at the athletes’ own midseason evaluations. No significant changes occurred between the SCAT5 subtest scores calculated at midseason and those after a high impact, although the effect sizes (Cohen’s d) on individual components ranged from 0.41 to 0.65.CONCLUSIONSMeasurable changes in pupil response were demonstrated following an HHI. These results suggest that clinically asymptomatic HHIs may affect brain reflex pathways, reflecting a biological injury previously seen when more invasive methods were applied.

Introduction Increased risk of musculoskeletal (MSK) injury post-concussion has been reported in collegiate athletes, yet it is unknown if professional football athletes are at the same risk of secondary injury. The objective of this study was to determine if the risk of MSK injury in National Football League (NFL) athletes increases after concussion. Methods NFL injury reports from 2013 to 2017 were collected from public websites. Concussed athletes (n=91) were equally matched to a non-injured control and an athlete with an incident of musculoskeletal (MSK) injury. Results Following their return to sport, concussed athletes were 2.35 times more likely to have a subsequent MSK injury relative to non-injured controls (95% CI: 2.35 [1.25, 4.44], P = 0.01), but were no more likely than athletes with an incident MSK injury (P = 0.55). Likewise, athletes with an incident MSK injury were no more likely to have a subsequent MSK injury than controls (P = 0.08). Discussion Increased odds of MSK injury in the 12-week period following a concussion in professional football athletes warrants future research on the acute effects of concussion and the relationship to MSK injury risk.

Concussion tolerance and head impact exposure are highly variable among football players. Recent findings highlight that head impact data analyses need to be performed at the subject level. In this paper, we describe a method of characterizing concussion risk between individuals using a new survival analysis technique developed with real-world head impact data in mind. Our approach addresses the limitations and challenges seen in previous risk analyses of football head impact data. Specifically, this demonstrative analysis appropriately models risk for a combination of left-censored recurrent events (concussions) and right-censored recurrent non-events (head impacts without concussion). Furthermore, the analysis accounts for uneven impact sampling between players. In brief, we propose using the Consistent Threshold method to develop subject-specific risk curves and then determine average risk point estimates between subjects at injurious magnitude values. We describe an approach for selecting an optimal cumulative distribution function to model risk between subjects by minimizing injury prediction error. We illustrate that small differences in distribution fit can result in large predictive errors. Given the vast amounts of on-field data researchers are collecting across sports, this approach can be applied to develop population-specific risk curves that can ultimately inform interventions that reduce concussion incidence.

Purpose In patients with obesity, micronutrient deficiencies have been reported both before and after bariatric surgery (BS). Obesity is a chronic pro-inflammatory status, and inflammation increases the risk of micronutrient malnutrition. Our objective was to assess in pre-BS patients the prevalence of micronutrient deficiencies and their correlation with blood values of C-reactive protein (CRP). Methods Anthropometric data, instrumental examinations, and blood variables were centrally measured in the first 200 patients undergoing a pre-BS evaluation at the “Città della Salute e della Scienza” Hospital of Torino, starting from January 2018. Results At least one micronutrient deficiency was present in 85.5% of pre-BS patients. Vitamin D deficiency was the most prevalent (74.5%), followed by folate (33.5%), iron (32%), calcium (13%), vitamin B12 (10%), and albumin (5.5%) deficiency. CRP values were high (> 5 mg/L) in 65% of the patients. These individuals showed increased rate of iron, folate, vitamin B12 deficiency, and a higher number of micronutrient deficiencies. In a multiple logistic regression model, increased CRP levels were significantly associated with deficiencies of vitamin B12 (OR = 5.84; 95% CI 1.25–27.2; p = 0.024), folate (OR = 4.02; 1.87–8.66; p p = 0.01). Conclusions Micronutrient deficiencies are common in patients with severe obesity undergoing BS, especially when inflammation is present. In the presence of increased CRP values before surgery, it might be advisable to search for possible multiple micronutrient deficiencies.

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.

ObjectiveTo study longitudinal recovery trajectories of white matter after sports-related concussion (SRC) by performing diffusion tensor imaging (DTI) on collegiate athletes who sustained SRC.MethodsCollegiate athletes (n = 219, 82 concussed athletes, 68 contact-sport controls, and 69 non–contact-sport controls) were included from the Concussion Assessment, Research and Education Consortium. The participants completed clinical assessments and DTI at 4 time points: 24 to 48 hours after injury, asymptomatic state, 7 days after return-to-play, and 6 months after injury. Tract-based spatial statistics was used to investigate group differences in DTI metrics and to identify white-matter areas with persistent abnormalities. Generalized linear mixed models were used to study longitudinal changes and associations between outcome measures and DTI metrics. Cox proportional hazards model was used to study effects of white-matter abnormalities on recovery time.ResultsIn the white matter of concussed athletes, DTI-derived mean diffusivity was significantly higher than in the controls at 24 to 48 hours after injury and beyond the point when the concussed athletes became asymptomatic. While the extent of affected white matter decreased over time, part of the corpus callosum had persistent group differences across all the time points. Furthermore, greater elevation of mean diffusivity at acute concussion was associated with worse clinical outcome measures (i.e., Brief Symptom Inventory scores and symptom severity scores) and prolonged recovery time. No significant differences in DTI metrics were observed between the contact-sport and non–contact-sport controls.ConclusionsChanges in white matter were evident after SRC at 6 months after injury but were not observed in contact-sport exposure. Furthermore, the persistent white-matter abnormalities were associated with clinical outcomes and delayed recovery time.

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled “a randomized embedded multifactorial adaptive platform.” The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas. Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Context Assessments of the duration of concussion recovery have primarily been limited to sport-related concussions and male contact sports. Furthermore, whereas durations of symptoms and return-to-activity (RTA) protocols encompass total recovery, the trajectory of each duration has not been examined separately. Objective To identify individual (eg, demographics, medical history), initial concussion injury (eg, symptoms), and external (eg, site) factors associated with symptom duration and RTA-protocol duration after concussion. Design Cohort study. Setting Three US military service academies. Patients or Other Participants A total of 10 604 cadets at participating US military service academies enrolled in the study and completed a baseline evaluation and up to 5 postinjury evaluations. A total of 726 cadets (451 men, 275 women) sustained concussions during the study period. Main Outcome Measure(s) Number of days from injury (1) until the participant became asymptomatic and (2) to complete the RTA protocol. Results Varsity athlete cadets took less time than nonvarsity cadets to become asymptomatic (hazard ratio [HR] = 1.75, 95% confidence interval = 1.38, 2.23). Cadets who reported less symptom severity on the Sport Concussion Assessment Tool, third edition (SCAT3), within 48 hours of concussion had 1.45 to 3.77 times shorter symptom-recovery durations than those with more symptom severity. Similar to symptom duration, varsity status was associated with a shorter RTA-protocol duration (HR = 1.74, 95% confidence interval = 1.34, 2.25), and less symptom severity on the SCAT3 was associated with a shorter RTA-protocol duration (HR range = 1.31 to 1.47). The academy that the cadet attended was associated with the RTA-protocol duration (P < .05). Conclusions The initial total number of symptoms reported and varsity athlete status were strongly associated with symptom and RTA-protocol durations. These findings suggested that external (varsity status and academy) and injury (symptom burden) factors influenced the time until RTA.

With morbidity and mortality related to opioid use continuing to increase, clinicians need to better understand the risk for opioid misuse in patient populations. Screening for opioid misuse risk has not been routinely adopted as a standard practice in clinical settings. A pilot study was performed to determine the feasibility of screening for future opioid misuse risk using the Opioid Risk Tool (ORT) in an ambulatory oncology clinic. Twelve patients in this sample scored in the moderate- to high-risk range for aberrant behavior, and 8 patients reported a personal history of substance abuse, indicating a need for opioid misuse risk screening in populations of patients with cancer. Because it is easy and quick to use, the ORT may be a feasible tool to incorporate into standard practice.

BackgroundHypercortisolism accounts for relevant morbidity and mortality and is often a diagnostic challenge for clinicians. A prompt diagnosis is necessary to treat Cushing’s syndrome as early as possible.ObjectiveThe aim of this study was to develop and validate a clinical model for the estimation of pre-test probability of hypercortisolism in an at-risk population.DesignWe conducted a retrospective multicenter case-control study, involving five Italian referral centers for Endocrinology (Turin, Messina, Naples, Padua and Rome). One hundred and fifty patients affected by Cushing’s syndrome and 300 patients in which hypercortisolism was excluded were enrolled. All patients were evaluated, according to current guidelines, for the suspicion of hypercortisolism.ResultsThe Cushing score was built by multivariable logistic regression, considering all main features associated with a clinical suspicion of hypercortisolism as possible predictors. A stepwise backward selection algorithm was used (final model AUC=0.873), then an internal validation was performed through ten-fold cross-validation. Final estimation of the model performance showed an average AUC=0.841, thus reassuring about a small overfitting effect. The retrieved score was structured on a 17.5-point scale: low-risk class (score value: ≤5.5, probability of disease=0.8%); intermediate-low-risk class (score value: 6-8.5, probability of disease=2.7%); intermediate-high-risk class (score value: 9-11.5, probability of disease=18.5%) and finally, high-risk class (score value: ≥12, probability of disease=72.5%).ConclusionsWe developed and internally validated a simple tool to determine pre-test probability of hypercortisolism, the Cushing score, that showed a remarkable predictive power for the discrimination between subjects with and without a final diagnosis of Cushing’s syndrome.

ObjectiveSingle cases and small series of Guillain-Barré syndrome (GBS) have been reported during the SARS-CoV-2 outbreak worldwide. We evaluated incidence and clinical features of GBS in a cohort of patients from two regions of northern Italy with the highest number of patients with COVID-19.MethodsGBS cases diagnosed in 12 referral hospitals from Lombardy and Veneto in March and April 2020 were retrospectively collected. As a control population, GBS diagnosed in March and April 2019 in the same hospitals were considered.ResultsIncidence of GBS in March and April 2020 was 0.202/100 000/month (estimated rate 2.43/100 000/year) vs 0.077/100 000/month (estimated rate 0.93/100 000/year) in the same months of 2019 with a 2.6-fold increase. Estimated incidence of GBS in COVID-19-positive patients was 47.9/100 000 and in the COVID-19-positive hospitalised patients was 236/100 000. COVID-19-positive patients with GBS, when compared with COVID-19-negative subjects, showed lower MRC sum score (26.3±18.3 vs 41.4±14.8, p=0.006), higher frequency of demyelinating subtype (76.6% vs 35.3%, p=0.011), more frequent low blood pressure (50% vs 11.8%, p=0.017) and higher rate of admission to intensive care unit (66.6% vs 17.6%, p=0.002).ConclusionsThis study shows an increased incidence of GBS during the COVID-19 outbreak in northern Italy, supporting a pathogenic link. COVID-19-associated GBS is predominantly demyelinating and seems to be more severe than non-COVID-19 GBS, although it is likely that in some patients the systemic impairment due to COVID-19 might have contributed to the severity of the whole clinical picture.

Context Preseason testing can be time intensive and cost prohibitive. Therefore, using normative data for postconcussion interpretation in lieu of preseason testing is desirable. Objective To establish the recovery trajectory for clinical reaction time (RTclin) and assess the usefulness of changes from baseline (comparison of postconcussion scores with individual baseline scores) and norm-based cutoff scores (comparison of postconcussion scores with a normative mean) for identifying impairments postconcussion. Design Case-control study. Setting Multisite clinical setting. Patients or Other Participants An overlapping sample of 99 participants (age = 19.0 ± 1.1 years) evaluated within 6 hours postconcussion, 176 participants (age = 18.9 ± 1.1 years) evaluated at 24 to 48 hours postconcussion, and 214 participants (age = 18.9 ± 1.1 years) evaluated once they were cleared to begin a return-to-play progression were included. Participants with concussion were compared with 942 control participants (age = 19.0 ± 1.0 years) who did not sustain a concussion during the study period but completed preseason baseline testing at 2 points separated by 1 year (years 1 and 2). Main Outcome Measure(s) At each time point, follow-up RTclin (ie, postconcussion or year 2) was compared with the individual year 1 preseason baseline RTclin and normative baseline data (ie, sex and sport specific). Receiver operating characteristic curves were calculated to compare the sensitivity and specificity of RTclin change from baseline and norm-based cutoff scores. Results Clinical reaction time performance declined within 6 hours (18 milliseconds, 9.2% slower than baseline). The decline persisted at 24 to 48 hours (15 milliseconds, 7.6% slower than baseline), but performance recovered by the time of return-to-play initiation. Within 6 hours, a change from baseline of 16 milliseconds maximized combined sensitivity (52%) and specificity (79%, area under the curve [AUC] = 0.702), whereas a norm-based cutoff score of 19 milliseconds maximized combined sensitivity (46%) and specificity (86%, AUC = 0.700). At 24 to 48 hours, a change from baseline of 2 milliseconds maximized combined sensitivity (64%) and specificity (61%, AUC = 0.666), whereas a norm-based cutoff score of 0 milliseconds maximized combined sensitivity (63%) and specificity (62%, AUC = 0.647). Conclusions Norm-based cutoff scores can be used for interpreting RTclin scores postconcussion in collegiate athletes when individual baseline data are not available, although low sensitivity and specificity limit the use of RTclin as a stand-alone test.

Context Comprehensive assessments are recommended to evaluate sport-related concussion (SRC). The degree to which the King-Devick (KD) test adds novel information to an SRC evaluation is unknown. Objective To describe relationships at baseline among the KD and other SRC assessments and explore whether the KD provides unique information to a multimodal baseline concussion assessment. Design Cross-sectional study. Setting Five National Collegiate Athletic Association institutions participating in the Concussion Assessment, Research and Education (CARE) Consortium. Patients or Other Participants National Collegiate Athletic Association student-athletes (N = 2258, age = 20 ± 1.5 years, 53.0% male, 68.9% white) in 11 men's and 13 women's sports. Main Outcome Measure(s) Participants completed baseline assessments on the KD and (1) the Symptom Inventory of the Sport Concussion Assessment Tool–3rd edition, (2) the Brief Symptom Inventory-18, (3) the Balance Error Scoring System, (4) the Standardized Assessment of Concussion (SAC), (5) the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) test battery, and (6) the Vestibular/Ocular Motor Screening tool during their first year in CARE. Correlation coefficients between the KD and the 6 other concussion assessments in isolation were determined. Assessments with ρ magnitude >0.1 were included in a multivariate linear regression analysis to evaluate their relative association with the KD. Results Scores for SAC concentration, ImPACT visual motor speed, and ImPACT reaction time were correlated with the KD (ρ = −0.216, −0.276, and 0.164, respectively) and were thus included in the regression model, which explained 16.8% of the variance in baseline KD time (P < .001, Cohen f2 = 0.20). Better SAC concentration score (β = −.174, P < .001), ImPACT visual motor speed (β = −.205, P < .001), and ImPACT reaction time (β = .056, P = .020) were associated with faster baseline KD performance, but the effect sizes were small. Conclusions Better performance on cognitive measures involving concentration, visual motor speed, and reaction time was weakly associated with better baseline KD performance. Symptoms, psychological distress, balance, and vestibular-oculomotor provocation were unrelated to KD performance at baseline. The findings indicate limited overlap at baseline among the CARE SRC assessments and the KD.

Background: Sport-related concussions (SRCs) are associated with short-term disablement, characterized as increased concussion symptoms and lower health-related quality of life (HRQoL). However, there are limited longitudinal data detailing how an SRC affects disablement beyond short-term injury recovery. Purpose: To longitudinally assess the effect of SRCs on symptoms and HRQoL in high school athletes through the 12 months after injury. Study Design: Cohort study; Level of evidence, 2. Methods: The 125 participants included high school athletes who sustained an SRC (female patients, 36%; mean ± SD age, 15.9 ± 1.1 years). The Post-concussion Symptom Scale (PCSS) from the Sport Concussion Assessment Tool–3 and the Pediatric Quality of Life Inventory 4.0 (PedsQL) were completed at enrollment and repeated at 24 to 72 hours (onset) and at 7 days (D7) after the SRC; on the date of return to play (RTP); and at 3, 6, and 12 months (M12) after the SRC. Scores at each time point were compared with the athletes’ own baseline via linear mixed models for repeated measures, controlling for age, sex, and history of previous SRC and with patient as a random effect. Results: Relative to baseline, female patients reported higher PCSS symptom and severity scores at onset ( P < .001) and D7 ( P < .001), while scores were not higher ( P > .05) for RTP through M12. As compared with baseline, male patients reported higher PCSS scores at onset ( P < .001) and D7 ( P = .003) and severity scores at onset ( P < .001) and D7 ( P = .016), while the symptom and severity scores were not higher ( P > .05) at RTP through M12. Female participants reported lower PedsQL physical scores at onset ( P = .006), while scores were not lower ( P > .05) from D7 through M12. Female psychosocial scores were not lower ( P > .05) at any time after the SRC, while the total PedsQL score was lower at onset ( P = .05) but not from D7 through M12. Male physical scores were lower at onset ( P < .001) and D7 ( P = .001) but not lower ( P > .05) from RTP through M12. Male psychosocial and PedsQL scores were unchanged ( P > .05) from baseline at onset through M12. Conclusion: After an SRC, high school athletes reported initial disablement (increased symptoms and lower HRQoL) through their RTP. However, after RTP, no similar disablement was detected through 12 months after injury.

The aim of our study was to estimate the overall rate of first hospitalizations for diabetic foot (DF) regardless of the outcome in amputations, as well as the mortality rate with their determinants in the period 2012–2016 in Piedmont Region in Italy. The study included all the subjects registered in the Regional Diabetes Registry and alive as at January 1, 2012. DF cases were identified by record linkage with the regional hospital discharge database. Incident cases of diabetic foot were followed up for mortality. The 5-year rates were 1762, 324, and 343 × 100,000 patients for first hospitalization without amputations, with major amputations, and with minor amputations, respectively. Patients not undergoing amputations were more than 70% of the cohort. Patients with the more severe stages of diabetes and those with low education were at higher risk of each type of hospitalization. The risk of death during a mean follow-up of 2.5 years was about 16, 18, and 30% among patients without amputations, with major amputations, and with minor amputations, respectively. Males, insulin-treated patients, those affected with severe diabetes complications, particularly on dialysis, and those with lower levels of education were at higher risk. The heavier burden of DF on hospitalizations is due to cases without amputation, a condition that is seldom considered in the diabetes literature. The severity of diabetes, preexisting complications, and low educational levels are associated with both first hospitalization and subsequent survival at any level of severity of DF.

Researchers have been collecting head impact data from instrumented football players to characterize the biomechanics of concussion for the past 15 years, yet the link between biomechanical input and clinical outcome is still not well understood. We have previously shown that even though concussive biomechanics might be unremarkable in large datasets of head impacts, the impacts causing injury are of high magnitude for the concussed individuals relative to their impact history. This finding suggests a need to account for differences in tolerance at the individual level. In this study, we identified control subjects for our concussed subjects who demonstrated traits we believed were correlated to factors thought to affect injury tolerance, including height, mass, age, race, and concussion history. A total of 502 college football players were instrumented with helmet-mounted accelerometer arrays and provided complete baseline assessment data, 44 of which sustained a total of 49 concussion. Biomechanical measures quantifying impact frequency and acceleration magnitude were compared between groups. On average, we found that concussed subjects experienced 93.8 more head impacts (p = 0.0031), 10.2 more high magnitude impacts (p = 0.0157), and 1.9 × greater risk-weighted exposure (p = 0.0175) than their physically matched controls. This finding provides further evidence that head impact data need to be considered at the individual level and that cohort wide assessments may be of little value in the context of concussion. Published version

Kutcher and Giza suggested incorporating levels of certainty in concussion diagnosis decisions. These guidelines were based on clinical experience rather than objective data. Therefore, we combined data-driven optimization with predictive modeling to identify which athletes are unlikely to have concussion and to classify remaining athletes as having possible, probable, or definite concussion with diagnostic certainty. We developed and validated our framework using data from the Concussion Assessment, Research, and Education (CARE) Consortium. Acute concussions had assessments at6 h (

ObjectiveWe compared data from the National Collegiate Athletic Association (NCAA) Concussion Study (1999–2001) and the NCAA-Department of Defense Concussion Assessment, Research and Education (CARE) Consortium (2014–2017) to examine how clinical management, return to play (RTP) and risk of repeat concussion in collegiate football players have changed over the past 15 years.MethodsWe analysed data on reported duration of symptoms, symptom-free waiting period (SFWP), RTP and occurrence of within-season repeat concussion in collegiate football players with diagnosed concussion from the NCAA Study (n=184) and CARE (n=701).ResultsCARE athletes had significantly longer symptom duration (CARE median=5.92 days, IQR=3.02–9.98 days; NCAA median=2.00 days, IQR=1.00–4.00 days), SFWP (CARE median=6.00 days, IQR=3.49–9.00 days; NCAA median=0.98 days, IQR=0.00–4.00 days) and RTP (CARE median=12.23 days, IQR=8.04–18.92 days; NCAA median=3.00 days, IQR=1.00–8.00 days) than NCAA Study athletes (all pConclusionOur findings indicate that concussion in collegiate football is managed more conservatively than 15 years ago. These changes in clinical management appear to have reduced the risk of repetitive concussion during the critical period of cerebral vulnerability after sport-related concussion (SRC). These data support international guidelines recommending additional time for brain recovery before athletes RTP after SRC.

Background Concussion, or mild traumatic brain injury, is a major public health concern affecting 42 million individuals globally each year. However, little is known regarding concussion risk factors across all concussion settings as most concussion research has focused on only sport-related or military-related concussive injuries. Methods The current study is part of the Concussion, Assessment, Research, and Education (CARE) Consortium, a multi-site investigation on the natural history of concussion. Cadets at three participating service academies completed annual baseline assessments, which included demographics, medical history, and concussion history, along with the Sport Concussion Assessment Tool (SCAT) symptom checklist and Brief Symptom Inventory (BSI-18). Clinical and research staff recorded the date and injury setting at time of concussion. Generalized mixed models estimated concussion risk with service academy as a random effect. Since concussion was a rare event, the odds ratios were assumed to approximate relative risk. Results Beginning in 2014, 10,604 (n = 2421, 22.83% female) cadets enrolled over 3 years. A total of 738 (6.96%) cadets experienced a concussion, 301 (2.84%) concussed cadets were female. Female sex and previous concussion were the most consistent estimators of concussion risk across all concussion settings. Compared to males, females had 2.02 (95% CI: 1.70–2.40) times the risk of a concussion regardless of injury setting, and greater relative risk when the concussion occurred during sport (Odds Ratio (OR): 1.38 95% CI: 1.07–1.78). Previous concussion was associated with 1.98 (95% CI: 1.65–2.37) times increased risk for any incident concussion, and the magnitude was relatively stable across all concussion settings (OR: 1.73 to 2.01). Freshman status was also associated with increased overall concussion risk, but was driven by increased risk for academy training-related concussions (OR: 8.17 95% CI: 5.87–11.37). Medical history of headaches in the past 3 months, diagnosed ADD/ADHD, and BSI-18 Somatization symptoms increased overall concussion risk. Conclusions Various demographic and medical history factors are associated with increased concussion risk. While certain factors (e.g. sex and previous concussion) are consistently associated with increased concussion risk, regardless of concussion injury setting, other factors significantly influence concussion risk within specific injury settings. Further research is required to determine whether these risk factors may aid in concussion risk reduction or prevention. Electronic supplementary material The online version of this article (10.1186/s40621-018-0178-3) contains supplementary material, which is available to authorized users.

For monitoring of concussion, brain function, organ condition and other medical applications, what is needed is a non-invasive method of monitoring tissue metabolism. MRI-based functional imaging technology detects changes in blood oxygenation, a correlate of neural activity, and thus may offer a prediction of prognosis in cases of concussion and other cerebral traumas. Yet, potential relationships between perturbations to cerebral metabolism and patient outcomes cannot be effectively exploited clinically because we lack a practical, low-cost, non-invasive means to monitor cerebral oxygenation and metabolism in the emergency department, operating room, or medical facilities. We have developed a device to optically assay the redox state of Cytochrome-C-Oxidase (CCO), the mitochondrial enzyme responsible for the last step of the electron transport chain. Changes in CCO redox reflect changes in respiratory flux, and thus changes in the rate of oxidative adenosine triphosphate (ATP) synthesis. In other words, changes in CCO reflect brain cell’s metabolic activity more directly than the traditional blood oxygenation measurement methods. To non-invasively measure changes in CCO as well as blood oxygenation, we have developed a Super-Continuum Infrared Spectroscopy of Cytochrome-C-Oxidase (SCISCCO) system that uses an all-fiber integrated, super-continuum light source to simultaneously measure both of the new (CCO) and the traditional (blood oxygenation) markers of neural metabolism. The SCISCCO system is validated by confirming the near-infrared spectrum of CCO in vitro. To demonstrate in vivo feasibility, the measured responses of oxygenation and CCO responses to acute ischemia (e.g., blood pressure tests) in human participants are compared to data from the literature. Furthermore, we show that the new device’s measurements of oxygenated (HbO) and deoxygenated (HbR) hemoglobin in response to breath hold challenges are principled and consistent with previously reported findings. The validated SCISCCO system is finally applied to measure cerebral oxygenation and the redox state of CCO in participants during an attention test protocol. Twenty-five healthy adults completed an attention task that included nine 60-second periods of attention task, interleaved with 60-s periods of resting baseline. It has been well established that the frontal lobe of the human brain is active during tasks of attention. We therefore predicted that attention task should elicit an increase in HbO concentration accompanied by a decrease in redox state of CCO (e.g., ratio of oxidized CCO to reduced CCO) in frontal lobe brain regions as measured with the SCISCCO system. Our findings are consistent with our predictions: HbO concentration increases while CCO concentration decreases during the attention blocks relative to the resting baseline, thereby indicating an increase in oxidative metabolism of the frontal lobe brain regions of interest. Our systematic, multi-method approach thus validates the new device as well as the validity of the metabolic biomarkers that it measures. The SCISCCO system could be a new tool for monitoring brain and organ metabolism, which could be invaluable for screening concussion patients or use in an operating or emergency room to gauge patient’s organ response to treatments.

ImportanceBayesian adaptive trial design has the potential to create more efficient clinical trials. However, one of the barriers to the uptake of Bayesian adaptive designs for confirmatory trials is limited experience with how they may perform compared to a frequentist design.ObjectiveCompare the performance of a Bayesian and a frequentist adaptive clinical trial design.DesignProspective observational study comparing two trial designs using individual patient level data from a completed stroke trial, including the timing and order of enrollments and outcome ascertainment. The implemented frequentist design had group sequential boundaries for efficacy and futility interim analyses when 90-days post-randomization was met for 500, 700, 900, and 1,100 patients. The Bayesian alternative utilized predictive probability of trial success to govern early termination for efficacy and futility with a first interim analysis at 500 randomized patients, and subsequent interims after every 100 randomizations.SettingMulti-center, acute stroke study conducted within a National Institutes of Health neurological emergencies clinical trials network.ParticipantsPatient level data from 1,151 patients randomized in a clinical trial comparing intensive insulin therapy to standard in acute stroke patients with hyperglycemia.Main Outcome(s) and Measure(s)Sample size at end of study. This was defined as the sample size at which each of the studies stopped accrual of patients.ResultsAs conducted, the frequentist design passed the futility boundary after 936 participants were randomized. Using the same sequence and timing of randomization and outcome data, the Bayesian alternative crossed the futility boundary about 3 months earlier after 800 participants were randomized.Conclusions and RelevanceBoth trial designs stopped for futility prior to reaching the planned maximum sample size. In both cases, the clinical community and patients would benefit from learning the answer to the trial’s primary question earlier. The common feature across the two designs was frequent interim analyses to stop early for efficacy or for futility. Differences between how this was implemented between the two trials resulted in the differences in early stopping.Trial RegistrationThe SHINE trial was registered and results are reported on clinicaltrials.gov under identifier: NCT01369069

Concussion pre-injury (i.e., baseline) assessments serve as a benchmark comparison point in the event an individual sustains a concussion and allows clinicians to compare to post-injury measures. However, baseline assessments must reflect the individual’s true and most optimized performance to serve as a useful comparison. Mental fatigue and motivation throughout baseline testing may alter individual assessment performance, indicating an order of administration (OoA) may play an influential role in assessment outcomes. To examine the influence concussion baseline battery OoA has on symptom, postural stability, cognitive screening, and computerized neurocognitive test outcomes. We employed a retrospective observational cohort study to examine healthy collegiate student-athletes and military cadets (n = 2898, 19.0 ± 1.4 years, 66.1% male, 75.6% white, 54.4% Division-I) baseline assessment performance on the Sport Concussion Assessment Tool (SCAT; total symptom number and severity), Balance Error Scoring System (BESS; total error scores), Standardized Assessment of Concussion (SAC; total score), and Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) domain scores (verbal and visual memory, visual-motor speed, reaction time). Assessments were binned to beginning, middle, or end tertiles based upon OoA. We used one-way ANOVAs with Tukey post-hoc t tests, 95% confidence intervals (CI), and Cohen’s d effect sizes for significant models (α = 0.05). SCAT total symptom number (mean difference = 2.23; 95% CI 1.76–2.70; d = 0.49, p

Background: Vestibular and ocular motor screening tools, such as the Vestibular/Ocular Motor Screening (VOMS), are recognized as important components of a multifaceted evaluation of sport-related concussion. Previous research has supported the predictive utility of the VOMS in identifying concussion, but researchers have yet to examine the predictive utility of the VOMS among collegiate athletes in the first few days after injury. Purpose: To determine the discriminative validity of individual VOMS item scores and an overall VOMS score for identifying collegiate athletes with an acute sport-related concussion (≤72 hours) from healthy controls matched by age, sex, and concussion history. Study Design: Case-control study; Level of evidence, 3. Methods: Participants (N = 570) aged 17 to 25 years were included from 8 institutions of the National Collegiate Athletic Association–Department of Defense CARE Consortium (Concussion Assessment, Research, and Education): 285 athletes who were concussed (per current consensus guidelines) and 285 healthy controls matched by age, sex, and concussion history. Participants completed the VOMS within 3 days of injury (concussion) or during preseason (ie, baseline; control). Symptoms are totaled for each VOMS item for an item score (maximum, 40) and totaled across items for an overall score (maximum, 280), and distance (centimeters) for near point of convergence (NPC) is averaged across 3 trials. Receiver operating characteristic analysis of the area under the curve (AUC) was performed on cutoff scores using Youden index ( J) for each VOMS item, overall VOMS score, and NPC distance average. A logistic regression was conducted to identify which VOMS scores identified concussed status. Results: A symptom score ≥1 on each VOMS item and horizontal vestibular/ocular reflex ≥2 significantly discriminated concussion from control (AUC, 0.89-0.90). NPC distance did not significantly identify concussion from control (AUC, 0.51). The VOMS overall score had the highest accuracy (AUC, 0.91) for identifying sport-related concussion from control. Among the individual items, vertical saccades ≥1 and horizontal vestibular/ocular reflex ≥2 best discriminated concussion from control. Conclusion: The findings indicate that individual VOMS items and overall VOMS scores are useful in identifying concussion in collegiate athletes within 3 days of injury. Clinicians can use the cutoffs from this study to help identify concussion in collegiate athletes.

Sport-related concussion (SRC) is a significant public health problem. Understanding the behavioral and personal factors that influence risk and incidence of SRC is critically important for appropriate care and management. Sensation-seeking and impulsivity have been posited to be two such factors that may be significantly associated with SRC. We performed a focused review of recent evidence of the relationships between sensation-seeking and impulsivity in athletes with SRC. While the research is relatively limited, extant findings demonstrate a significant relationship between sensation-seeking and contact sport participation and risk of prior and future SRC. Impulsivity appears to be common among athletes competing in high contact sports and may contribute to neural and functional brain changes following SRC; however, causal relationships between impulsivity, contact sport participation, and SRC have not been demonstrated. Both sensation-seeking and impulsivity are significantly associated with SRC in collegiate athletes. Interventions designed to ameliorate high levels of these constructs may prove to be beneficial avenues to reducing SRC risk and improving patient care and outcomes.

Aim: The underlying neurophysiological effects of concussion often result in attenuated cognitive and cortical function. To understand the relation between cognition and brain injury, we investigated the effects of concussion on attentional networks using functional near-infrared spectroscopy (fNIRS). Materials & methods: Healthy controls and concussed patients, tested within 72 h from injury (T1) and after symptoms resolved (T2) completed a computerized attention task during fNIRS imaging. Results: T1 patients exhibited slower reaction times and reduced brain activation pattern relative to healthy controls. Interestingly, the cortical oxygenation hemoglobin response at T2 was greater relative to T1 and healthy controls, while reaction time was normative. Conclusion: The exploratory findings of this study suggest once asymptomatic, a compensatory hemodynamic response may support the restoration of reaction time despite ongoing physiological recovery.

Importance Validation of protein biomarkers for concussion diagnosis and management in military combative training is important, as these injuries occur outside of traditional health care settings and are generally difficult to diagnose. Objective To investigate acute blood protein levels in military cadets after combative training-associated concussions. Design, Setting, and Participants This multicenter prospective case-control study was part of a larger cohort study conducted by the National Collegiate Athletic Association and the US Department of Defense Concussion Assessment Research and Education (CARE) Consortium from February 20, 2015, to May 31, 2018. The study was performed among cadets from 2 CARE Consortium Advanced Research Core sites: the US Military Academy at West Point and the US Air Force Academy. Cadets who incurred concussions during combative training (concussion group) were compared with cadets who participated in the same combative training exercises but did not incur concussions (contact-control group). Clinical measures and blood sample collection occurred at baseline, the acute postinjury point (

Context Concussion may negatively influence cardiovascular function and the autonomic nervous system, defined by alteration in heart rate variability (HRV). Differences in HRV most commonly emerge during a physical challenge, such as the final steps of the return-to-sport progression. Objective To assess the effect of concussion history on aspects of cardio-autonomic function during recovery from a bout of submaximal exercise in adolescent male hockey athletes. Design Case-control study. Setting Research laboratory. Patients or Other Participants Thirty-three male athletes participating in Midget-AAA hockey were divided into those with (n = 15; age = 16 ± 1 years, height = 1.78 ± 0.06 m, mass = 73.9 ± 7.4 kg, 10.5 ± 1.6 years of sport experience, 25.2 ± 18.3 months since last injury) or without (n = 18; age = 16 ± 1 years, height = 1.78 ± 0.05 m, mass = 74.8 ± 7.6 kg, 10.6 ± 1.9 years of sport experience) a concussion history. Those with a concussion history were binned on total count: 1 concussion or 2 or more concussions. Intervention(s) All athletes underwent 5 minutes of resting HRV assessment, followed by 20 minutes of aerobic exercise at 60% to 70% of their maximal target heart rate and a 9-minute, postexercise HRV assessment. Main Outcome Measure(s) Heart rate variability measures of mean NN interval, root mean square of successive differences, and standard deviation of NN interval (SDNN). Results Group demographic characteristics were not different. When the control and concussed groups were compared, group and time main effects for heart rate recovery, root mean square of successive differences, and SDNN (P values < .01), and an interaction effect for SDNN (P < .05) were demonstrated. Recovery trends for each group indicated that a history of 2 or more concussions may negatively affect cardio-autonomic recovery postexercise. Conclusions Our findings suggest that those with more than 1 previous concussion may be associated with a greater risk for long-term dysautonomia. Future use of HRV may provide clinicians with objective guidelines for concussion-management and safe return-to-participation protocols.

Context: Pre-season testing is often used to establish baseline scores for post-concussion interpretation. However, pre-season testing can be time-intensive and cost-prohibitive, in which case normative data may be used for post-injury interpretation. Objective: To compare change from baseline and normative-based cutoff scores in interpreting clinical reaction time (RTclin) following concussion. Design: Prospective case-control study. Setting: Multi-site study with testing completed in university athletic training rooms. Patients or Other Participants: An overlapping sample of 99 participants (age=19.0±1.1 years) evaluated within 6 hours post injury, 176 participants (age 18.9±1.1 years) evaluated 24–48 hours post injury, and 214 participants (18.9±1.1 years) evaluated at the time they were cleared to begin a return-to-play progression. Concussion participants were compared to 942 control participants (age=19.0±1.0 years) who did not sustain a concussion during the study period but completed preseason baseline testing one year apart. Main Outcome Measures: At each time point, follow-up RTclin (i.e., post injury or year 2) was compared to individualized year 1 preseason baseline RTclin and to normative baseline data (i.e., sex- and sport-specific). Receiver operating characteristic curves were used to compare sensitivity and specificity of RTclin change from baseline and normative-based cutoff scores. Results: Within 6h, change from baseline of 16ms maximized combined sensitivity (52%) and specificity (78%, AUC=0.702), while normative-based cutoff scores of 19ms maximized combined sensitivity (45%) and specificity (86%, AUC=0.700). At 24–48h, change from baseline of 2ms maximized combined sensitivity (64%) and specificity (61%, AUC=0.666), while normative-based cutoff scores of 0ms maximized combined sensitivity (63%) and specificity (62%, AUC=0.647). Conclusions: Normative-based cutoff scores can be used for interpreting RTclin scores following concussion when individualized baseline data is not available, although low sensitivity and specificity may limit clinical use as a stand-alone test.

ObjectivesTo examine sex differences in sport-related concussion (SRC) across comparable sports.MethodsProspective cohort of collegiate athletes enrolled between 2014 and 2017 in the Concussion Assessment, Research and Education Consortium study.ResultsAmong 1071 concussions (females=615; 57.4%), there was no difference in recovery (median days to full return to play) (females=13.5 (IQR 9.0, 23.1) vs males=11.8 (IQR 8.1, 19.0), p=0.96). In subgroup analyses, female recovery was longer in contact (females=12.7 days (IQR 8.8, 21.4) vs males=11.0 days (IQR 7.9, 16.2), p=0.0021), while male recovery was longer in limited contact sports (males=16.9 days (IQR 9.7, 101.7) vs females=13.8 days (IQR 9.1, 22.0), pConclusionOverall, no difference in recovery between sexes across comparable women’s and men’s sports in this collegiate cohort was found. However, females in contact and males in limited contact sports experienced longer recovery times, while females had longer recovery times at the Division II/III level. These disparate outcomes indicate that, while intrinsic biological sex differences in concussion recovery may exist, important, modifiable extrinsic factors may play a role in concussion outcomes.

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest (OHCA) is promising but unproven. We developed a concept for a randomized Bayesian adaptive clinical trial to define the interval after arrest during which patients derive benefit. Hypotheses: We hypothesized that the simulated design characteristics of the adaptive design would efficiently confirm or refute the existence of a therapeutic window for ECPR in a future trial. Methods: Through iterative simulation and design modification, we developed a Bayesian adaptive trial of ECPR for adults with OHCA. The goals of the trial design were to address the uncertainty surrounding the OHCA-to-ECPR interval within which clinical benefit might be preserved and the difference in prognosis between patients with non-shockable vs shockable rhythms. The treatment effect was defined as the mean 90-day utility-weighted Modified Rankin Scale (uwmRS) for each rhythm subgroup and estimated CA-to-ECPR interval. The trial adaptively lengthens or contracts the estimated CA-to-ECPR eligibility window depending on the probability of benefit from ECPR. We simulated trial performance under six potential ECPR efficacy scenarios. We compared the adaptive design to a fixed design. Results: The trial had 91-100% power to detect a benefit from ECPR for non-shockable rhythms and 69-98% power for shockable rhythms under the scenarios simulated (figure). The design had a high probability of identifying the maximum CA-to-ECPR interval within which ECPR produces a clinically significant benefit of 0.2 on the uwMRS. In null scenarios, the 97-99% of the simulated trials ended early declaring futility. Conclusions: The adaptive trial design helps to ensure the patient population most likely to benefit from treatment—as defined by rhythm subgroup and estimated CA-to-ECPR interval—are enrolled. The design also promotes early termination of the trial if continuation is likely to be futile.

Context Football is the most popular sport among US high school students and among the highest for sport-related concussion (SRC) incidence. Limited data detail how SRCs affect high school football players' psychosocial and health status beyond short-term injury recovery. Objective To longitudinally assess how SRCs affected symptoms, depression, and health-related quality of life (HRQoL) in high school football players up to 12 months after SRC. Design Prospective cohort study. Setting Thirty-one Wisconsin high schools. Patients or Other Participants A total of 1176 interscholastic football players (age = 16.0 ± 1.2 years). Main Outcome Measure(s) Participants completed the Post-concussion Symptom Scale (PCSS) from the Sport Concussion Assessment Tool 3 (SCAT3), Patient Health Questionnaire-9 (PHQ-9) for depression, and Pediatric Quality of Life Inventory 4.0 (PedsQL) for HRQoL at enrollment. Participants who sustained an SRC repeated each measure within 72 hours of their injury (onset) and at 7 days (D7), return to play (RTP), and 3 months (M3), 6 months (M6), and 12 months (M12) after SRC. Scores at each time point were compared with each participant's baseline using linear mixed models for repeated measures while controlling for age and previous SRC with participant as a random effect. Results Sixty-two participants sustained an SRC. Participants reported a higher number of PCSS symptoms, greater symptom severity, and lower PedsQL physical summary scores at onset and D7. From RTP through M12, PCSS symptoms, PCSS severity scores, PedsQL total scores, physical summary, and psychosocial summary were unchanged or improved relative to baseline. The PHQ-9 scores were not higher than baseline at any post-SRC interval. Conclusions High school football players in this study who sustained an SRC described no sustained adverse health outcomes (increased PCSS symptoms or symptom severity, increased depression symptoms, or lower HRQoL) after their RTP through M12 after injury.

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

ObjectivesTo determine the acute and early long-term associations of sport-related concussion (SRC) and subcortical and cortical structures in collegiate contact sport athletes.MethodsAthletes with a recent SRC (n=99) and matched contact (n=91) and non-contact sport controls (n=95) completed up to four neuroimaging sessions from 24 to 48 hours to 6 months postinjury. Subcortical volumes (amygdala, hippocampus, thalamus and dorsal striatum) and vertex-wise measurements of cortical thickness/volume were computed using FreeSurfer. Linear mixed-effects models examined the acute and longitudinal associations between concussion and structural metrics, controlling for intracranial volume (or mean thickness) and demographic variables (including prior concussions and sport exposure).ResultsThere were significant group-dependent changes in amygdala volumes across visits (p=0.041); this effect was driven by a trend for increased amygdala volume at 6 months relative to subacute visits in contact controls, with no differences in athletes with SRC. No differences were observed in any cortical metric (ie, thickness or volume) for primary or secondary analyses.ConclusionA single SRC had minimal associations with grey matter structure across a 6-month time frame.

Context With growing awareness of and advocacy for including individuals with disabilities in sport, implementation of concussion-assessment and -management strategies is warranted. Limited research is available on concussion assessment in adapted wheelchair sport athletes. Objective To examine baseline symptom reporting, computerized neurocognitive testing, and a modified balance scoring system in adapted athletes. A secondary objective was to provide preliminary normative data for this population. Design Cross-sectional study. Setting University athletic training room and computer laboratory. Patients or Other Participants Twenty-one athletes (age = 22.1 ± 3.0 years) from 1 institution's collegiate adapted athletics program. Main Outcome Measure(s) Athletes completed baseline Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) and the Wheelchair Error Scoring System (WESS) before the start of their respective seasons. Symptom reporting variables consisted of total symptoms, symptom severity scores, and baseline symptom factors (eg, vestibular-somatic, sleep arousal, cognitive-sensory, and affective). We analyzed ImPACT composite scores of verbal memory, visual memory, visual motor processing speed, and reaction time and impulse control to determine neurocognitive function. Balance performance was quantified using the WESS condition and overall errors. Results Compared with normative reference values, 17 (81%) of adapted athletes reported greater symptoms and 20 (95%) performed at or below average on at least 1 neurocognitive composite score. Mean errors on the WESS were 3.14 ± 2.9, with 81% committing ≥1 error. Sex differences were not present for symptoms, neurocognitive testing, or balance measures. Conclusions Our findings provide context for baseline performance in adapted athletes and help to further develop the WESS as an assessment of balance in these athletes.

BACKGROUND Extracorporeal cardiopulmonary resuscitation (ECPR) is a promising therapy for out-of-hospital cardiac arrest (OHCA) that is refractory to standard therapy, but no multicenter randomized clinical trials have been conducted to establish its efficacy. We report the design and operating characteristics of a proposed randomized Bayesian adaptive “enrichment” clinical trial designed to determine whether ECPR is effective for refractory OHCA and, if effective, to define the interval after arrest during which patients derive benefit. METHODS Through iterative trial simulation and trial design modification, we developed a Bayesian adaptive trial of ECPR for adults who experience non-traumatic out-of-hospital cardiac arrest. Our proposed trial design addresses the threats to trial success identified during the design process, which were (1) the uncertainty surrounding the cardiac arrest (CA)-to-ECPR interval within which clinical benefit might be preserved (2) the difference in prognosis between patients with an initial rhythm that is non-shockable vs. shockable. Trial subjects will be randomized 1:1 to receive either standard care or expedited transport to a hospital for potential ECPR. The CA-to-ECPR interval will be estimated in real time based on the sum of the estimated paramedic response time (911 call to scene arrival), paramedic scene time, and transport time to hospital. A Bayesian decreasing step function will be used to estimate the efficacy of the treatment with an outcome of the 90-day utility-weighted Modified Rankin Scale (uwmRS) for each rhythm subgroup and estimated CA-to-ECPR interval at pre-specified interims. The trial will adaptively lengthen the estimated CA-to-ECPR eligibility window if the treatment appears effective at the upper limit of initial eligibility window. If ECPR appears ineffective at longer estimated CA-to-ECPR intervals, the upper limit of the window for enrollment eligibility will be shortened. The analysis will be stratified by rhythm subgroup. RESULTS With a maximum total sample size of 400, and a cap on the maximum sample size of 300 for the non-shockable rhythm subgroup, the trial design has power ranging from 91–100% to detect a benefit from ECPR for non-shockable rhythms under the various efficacy scenarios simulated and power ranging from 69–98% for shockable rhythms under the same scenarios. The trial design also has a high probability of correctly identifying the maximum CA-to-ECPR interval within which ECPR produces a clinically significant benefit of 0.2 on the uwMRS. If ECPR is equivalent to standard CA care, the type I error is 2.5% with a 99% probability of stopping enrollment early for futility in the non-shockable subgroup and a 97% probability of stopping enrollment early for futility in the shockable subgroup. CONCLUSION This proposed adaptive trial design helps to ensure the population of patients who are most likely to benefit from treatment—as defined both by rhythm subgroup and estimated CA-to-ECPR interval—is enrolled. The design promotes early termination of the trial if continuation is likely to be futile.

Introduction Regulatory efforts toward reducing concussion risk have begun to focus on decreasing the number of head impacts (i.e., head impact burden) sustained by athletes in contact sports. To that end, in 2018, the NCAA decreased the number of preseason on-field team activities for Division I teams from 29 to 25. The objective of the current study was to quantify changes in practice schedule and head impact exposure between the 2017 and 2018 football preseasons. Methods Athletes from five NCAA Division I football teams (n = 426) were consented and enrolled. Results On average, athletes participated in 10% fewer contact practices in 2018. However, the effect of this ruling on preseason head impact burden was mixed. Across all athletes, the total preseason head impact burden was essentially the same from 2017 to 2018. However, this study revealed significant team-by-team differences in preseason head impact burden, with one team demonstrating a 35% increase in the average number of recorded head impacts from 2017 to 2018, despite a modest decrease in the number of contact practices. Other teams had similar or decreased head impact burden. Conclusions Team-based differences in total preseason head impact burden were attributable to changes in daily practice schedule, with longer practice durations and more intense contact practice sessions contributing to increases in daily head impact exposure that, in turn, led to greater preseason head impact burden. Results of this study have highlighted the difficulty in decreasing contact sport head impact exposure through rule changes targeted at limiting on-field team activities. Future efforts aimed specifically at contact practice duration, daily head impact exposure, or limiting time in specific drills may be more effective at reducing total preseason head impact burden.

Objective:In response to advancing clinical practice guidelines regarding concussion management, service members, like athletes, complete a baseline assessment prior to participating in high-risk activities. While several studies have established test stability in athletes, no investigation to date has examined the stability of baseline assessment scores in military cadets. The objective of this study was to assess the test–retest reliability of a baseline concussion test battery in cadets at U.S. Service Academies.Methods:All cadets participating in the Concussion Assessment, Research, and Education (CARE) Consortium investigation completed a standard baseline battery that included memory, balance, symptom, and neurocognitive assessments. Annual baseline testing was completed during the first 3 years of the study. A two-way mixed-model analysis of variance (intraclass correlation coefficent (ICC)3,1) and Kappa statistics were used to assess the stability of the metrics at 1-year and 2-year time intervals.Results:ICC values for the 1-year test interval ranged from 0.28 to 0.67 and from 0.15 to 0.57 for the 2-year interval. Kappa values ranged from 0.16 to 0.21 for the 1-year interval and from 0.29 to 0.31 for the 2-year test interval. Across all measures, the observed effects were small, ranging from 0.01 to 0.44.Conclusions:This investigation noted less than optimal reliability for the most common concussion baseline assessments. While none of the assessments met or exceeded the accepted clinical threshold, the effect sizes were relatively small suggesting an overlap in performance from year-to-year. As such, baseline assessments beyond the initial evaluation in cadets are not essential but could aid concussion diagnosis.