ABSTRACT
Purpose
There is limited understanding of factors affecting concussion diagnosis status using large sample sizes. The study objective was to identify factors that can accurately classify ...previous concussion diagnosis status among collegiate student-athletes and service academy cadets with concussion history.
Methods
This retrospective study used support vector machine, Gaussian Naïve Bayes, and decision tree machine learning techniques to identify individual (e.g., sex) and institutional (e.g., academic caliber) factors that accurately classify previous concussion diagnosis status (all diagnosed vs 1+ undiagnosed) among Concussion Assessment, Research, and Education Consortium participants with concussion histories (
n
= 7714).
Results
Across all classifiers, the factors examined enable >50% classification between previous diagnosed and undiagnosed concussion histories. However, across 20-fold cross validation, ROC-AUC accuracy averaged between 56% and 65% using all factors. Similar performance is achieved considering individual risk factors alone. By contrast, classifications with institutional risk factors typically did not distinguish between those with all concussions diagnosed versus 1+ undiagnosed; average performances using only institutional risk factors were almost always <58%, including confidence intervals for many groups <50%. Participants with more extensive concussion histories were more commonly classified as having one or more of those previous concussions undiagnosed.
Conclusions
Although the current study provides preliminary evidence about factors to help classify concussion diagnosis status, more work is needed given the tested models’ accuracy. Future work should include a broader set of theoretically indicated factors, at levels ranging from individual behavioral determinants to features of the setting in which the individual was injured.
•Feasibility of multiplexed blood-based protein levels in sport-related concussion.•Identify novel blood-based biomarkers for concussed athletes.•Dysregulation of blood-based proteins provides a ...better understanding of human response to injury.•EPB41 and alpha synuclein distinguish concussed athletes from non-concussed athletes.
Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion. Therefore, more accurate diagnostic markers are needed for sport-related concussion.
This was a multicenter, prospective, case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the National Collegiate Athletic Association–Department of Defense Concussion Assessment, Research, and Education Consortium conducted between 2015 and 2019. The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints. Athletes with concussion were divided into 6 h post-injury (0–6 h post-injury) and after 6 h post-injury (7–48 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.
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.
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.
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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.
Campylobacter fetus
is commonly associated with venereal disease and abortions in cattle and sheep, and can also cause intestinal or systemic infections in humans that are immunocompromised, elderly, ...or exposed to infected livestock. It is also believed that
C. fetus
infection can result from the consumption or handling of contaminated food products, but
C. fetus
is rarely detected in food since isolation methods are not suited for its detection and the physiology of the organism makes culturing difficult. In the related species,
Campylobacter jejuni
, the ability to colonize the host has been linked to N-linked protein glycosylation with quantitative proteomics demonstrating that glycosylation is interconnected with cell physiology. Using label-free quantitative (LFQ) proteomics, we found more than 100 proteins significantly altered in expression in two
C. fetus
subsp.
fetus
protein glycosylation (
pgl
) mutants (
pglX
and
pglJ
) compared to the wild-type. Significant increases in the expression of the (NiFe)-hydrogenase HynABC, catalyzing H
2
-oxidation for energy harvesting, correlated with significantly increased levels of cellular nickel, improved growth in H
2
and increased hydrogenase activity, suggesting that N-glycosylation in
C. fetus
is involved in regulating the HynABC hydrogenase and nickel homeostasis. To further elucidate the function of the
C. fetus pgl
pathway and its enzymes, heterologous expression in
Escherichia coli
followed by mutational and functional analyses revealed that PglX and PglY are novel glycosyltransferases involved in extending the
C. fetus
hexasaccharide beyond the conserved core, while PglJ and PglA have similar activities to their homologs in
C. jejuni
. In addition, the
pgl
mutants displayed decreased motility and ethidium bromide efflux and showed an increased sensitivity to antibiotics. This work not only provides insight into the unique protein N-glycosylation pathway of
C. fetus
, but also expands our knowledge on the influence of protein N-glycosylation on
Campylobacter
cell physiology.
Despite recent advances, median survival for patients with resectable glioblastoma multiforme (GBM) is only 12 to 15 months. We previously observed minimal toxicity and a 9.0-month median survival ...after treatment with intralesional autologous lymphokine-activated killer (LAK) cells in 40 patients with recurrent GBM. In this study, GBM patients were treated with adjuvant intralesional LAK cells. Eligible patients had completed primary therapy for GBM without disease progression. LAK cells were produced by incubating autologous peripheral blood mononuclear cells with interleukin-2 for 3 to 7 days and then placed into the surgically exposed tumor cavity by a neurosurgeon. The 19 men and 14 women had a median age of 57 years. Prior therapy included surgical resection (97%), partial brain irradiation (97%), gamma knife radiosurgery (97%), and temozolomide chemotherapy (70%). Median time from diagnosis to LAK cell therapy was 5.3 months (range: 3.0 to 11.1 mo). LAK cell treatment was well tolerated; average length of hospitalization was 3 days. At the time of this analysis, 27 patients have died; the median survival from the date of original diagnosis is 20.5 months with a 1-year survival rate of 75%. In subset analyses, superior survival was observed for patients who received higher numbers of CD3+/CD16+/CD56+ (T-LAK) cells in the cell products, which was associated with not taking corticosteroids in the month before leukopheresis. Intralesional LAK cell therapy is safe and the survival sufficiently encouraging to warrant further evaluation in a randomized phase 2 trial of intralesional therapies with LAK or carmustine-impregnated wafers.
There is potential scientific and clinical value in validation of objective biomarkers for sport-related concussion (SRC).
To investigate the association of acute-phase blood biomarker levels with ...SRC in collegiate athletes.
This multicenter, prospective, case-control study was conducted by the National Collegiate Athletic Association (NCAA) and the US Department of Defense Concussion Assessment, Research, and Education (CARE) Consortium from February 20, 2015, to May 31, 2018, at 6 CARE Advanced Research Core sites. A total of 504 collegiate athletes with concussion, contact sport control athletes, and non-contact sport control athletes completed clinical testing and blood collection at preseason baseline, the acute postinjury period, 24 to 48 hours after injury, the point of reporting being asymptomatic, and 7 days after return to play. Data analysis was conducted from March 1 to November 30, 2019.
Glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light chain, and tau were quantified using the Quanterix Simoa multiplex assay. Clinical outcome measures included the Sport Concussion Assessment Tool-Third Edition (SCAT-3) symptom evaluation, Standardized Assessment of Concussion, Balance Error Scoring System, and Brief Symptom Inventory 18.
A total of 264 athletes with concussion (mean SD age, 19.08 1.24 years; 211 79.9% male), 138 contact sport controls (mean SD age, 19.03 1.27 years; 107 77.5% male), and 102 non-contact sport controls (mean SD age, 19.39 1.25 years; 82 80.4% male) were included in the study. Athletes with concussion had significant elevation in GFAP (mean difference, 0.430 pg/mL; 95% CI, 0.339-0.521 pg/mL; P < .001), UCH-L1 (mean difference, 0.449 pg/mL; 95% CI, 0.167-0.732 pg/mL; P < .001), and tau levels (mean difference, 0.221 pg/mL; 95% CI, 0.046-0.396 pg/mL; P = .004) at the acute postinjury time point compared with preseason baseline. Longitudinally, a significant interaction (group × visit) was found for GFAP (F7,1507.36 = 16.18, P < .001), UCH-L1 (F7,1153.09 = 5.71, P < .001), and tau (F7,1480.55 = 6.81, P < .001); the interaction for neurofilament light chain was not significant (F7,1506.90 = 1.33, P = .23). The area under the curve for the combination of GFAP and UCH-L1 in differentiating athletes with concussion from contact sport controls at the acute postinjury period was 0.71 (95% CI, 0.64-0.78; P < .001); the acute postinjury area under the curve for all 4 biomarkers combined was 0.72 (95% CI, 0.65-0.79; P < .001). Beyond SCAT-3 symptom score, GFAP at the acute postinjury time point was associated with the classification of athletes with concussion from contact controls (β = 12.298; 95% CI, 2.776-54.481; P = .001) and non-contact sport controls (β = 5.438; 95% CI, 1.676-17.645; P = .005). Athletes with concussion with loss of consciousness or posttraumatic amnesia had significantly higher levels of GFAP than athletes with concussion with neither loss of consciousness nor posttraumatic amnesia at the acute postinjury time point (mean difference, 0.583 pg/mL; 95% CI, 0.369-0.797 pg/mL; P < .001).
The results suggest that blood biomarkers can be used as research tools to inform the underlying pathophysiological mechanism of concussion and provide additional support for future studies to optimize and validate biomarkers for potential clinical use in SRC.
The absence of evidence-based guidelines make medical disqualification (MDQ) following concussion one of the most challenging decision-making processes faced by sports medicine professionals.
We ...aimed to compare premorbid and postmorbid factors between student-athletes that were and were not medically disqualified from sport following a concussion.
Among 1832 student-athletes diagnosed with concussion within the CARE Consortium, 53 (2.9%) were medically disqualified (MDQ +) and 1779 (97.1%) were not medically disqualified (MDQ-). We used contingency tables and descriptive statistics for an initial evaluation of a broad list of premorbid and postmorbid factors. For those factors showing association with MDQ status, we calculated odds ratios and 95% confidence intervals for the odds of being MDQ + in the presence of the identified factor.
History of 2 (OR: 3.2, 95% CI 1.5, 6.9) or 3 + (OR: 7.4, 95% CI 3.4, 15.9) previous concussions; 1 + headaches in past 3 months (OR: 1.8, 95% CI 1.0, 3.2); immediate removal from play (OR: 2.4, 95% CI 1.2, 4.9); alcohol (OR: 2.6, 95% CI 1.2, 5.4), tobacco (OR: 3.3, 95% CI 1.1, 9.5), or marijuana use since injury (OR: 5.4, 95% CI 1.5, 19.0); as well as prolonged recovery due to mental health alterations (OR: 5.3, 95% CI 2.0, 14.1) or motivation/malingering (OR: 7.5, 95% CI 3.3, 17.0) increased odds of being MDQ + . The MDQ + group took longer to become asymptomatic relative to the MDQ- group (MDQ + : 23.5 days, 95% CI 15.8, 31.2; MDQ-: 10.6 days, 95% CI 9.5, 11.6; p < 0.001).
MDQ following concussion was relatively rare. We identified three patterns related to MDQ following concussion: (1) concussion and headache history were the only premorbid factors that differed (2) initial concussion presentation was more severe and more immediate in the MDQ + group, and (3) post-concussion recovery outcomes expressed the greatest differences between groups.
Sport-related concussions can result from a single high magnitude impact that generates concussive symptoms, repeated subconcussive head impacts aggregating to generate concussive symptoms, or a ...combined effect from the two mechanisms. The array of symptoms produced by these mechanisms may be clinically interpreted as a sport-related concussion. It was hypothesized that head impact exposure resulting in concussion is influenced by severity, total number, and frequency of subconcussive head impacts. The influence of total number and magnitude of impacts was previously explored, but frequency was investigated to a lesser degree. In this analysis, head impact frequency was investigated over a new metric called ‘time delta’, the time difference from the first recorded head impact of the day until the concussive impact. Four exposure metrics were analyzed over the time delta to determine whether frequency of head impact exposure was greater for athletes on their concussion date relative to other dates of contact participation. Those metrics included head impact frequency, head impact accrual rate, risk weighted exposure (RWE), and RWE accrual rate. Athletes experienced an elevated median number of impacts, RWE, and RWE accrual rate over the time delta on their concussion date compared to non-injury sessions. This finding suggests elevated frequency of head impact exposure on the concussion date compared to other dates that may precipitate the onset of concussion.
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