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Item Acute White-Matter Abnormalities in Sports-Related Concussion: A Diffusion Tensor Imaging Study from the NCAA-DoD CARE Consortium(Mary Ann Liebert, 2018-11-15) Mustafi, Sourajit Mitra; Harezlak, Jaroslaw; Koch, Kevin M.; Nencka, Andrew S.; Meier, Timothy B.; West, John D.; Giza, Christopher C.; DiFiori, John P.; Guskiewicz, Kevin M.; Mihalik, Jason P.; LaConte, Stephen M.; Duma, Stefan M.; Broglio, Steven P.; Saykin, Andrew J.; McCrea, Michael; McAllister, Thomas W.; Wu, Yu-Chien; Radiology and Imaging Sciences, School of MedicineSports-related concussion (SRC) is an important public health issue. Although standardized assessment tools are useful in the clinical management of acute concussion, the underlying pathophysiology of SRC and the time course of physiological recovery after injury remain unclear. In this study, we used diffusion tensor imaging (DTI) to detect white matter alterations in football players within 48 h after SRC. As part of the NCAA-DoD CARE Consortium study of SRC, 30 American football players diagnosed with acute concussion and 28 matched controls received clinical assessments and underwent advanced magnetic resonance imaging scans. To avoid selection bias and partial volume effects, whole-brain skeletonized white matter was examined by tract-based spatial statistics to investigate between-group differences in DTI metrics and their associations with clinical outcome measures. Mean diffusivity was significantly higher in brain white matter of concussed athletes, particularly in frontal and subfrontal long white matter tracts. In the concussed group, axial diffusivity was significantly correlated with the Brief Symptom Inventory and there was a similar trend with the symptom severity score of the Sport Concussion Assessment Tool. In addition, concussed athletes with higher fractional anisotropy performed better on the cognitive component of the Standardized Assessment of Concussion. Overall, the results of this study are consistent with the hypothesis that SRC is associated with changes in white matter tracts shortly after injury, and these differences are correlated clinically with acute symptoms and functional impairments.Item Are EPB41 and alpha-synuclein diagnostic biomarkers of sport-related concussion? Findings from the NCAA and Department of Defense CARE Consortium(Elsevier, 2023) Vorn, Rany; Devoto, Christina; Meier, Timothy B.; Lai, Chen; Yun, Sijung; Broglio, Steven P.; Mithani, Sara; McAllister, Thomas W.; Giza, Christopher C.; Kim, Hyung-Suk; Huber, Daniel; Harezlak, Jaroslaw; Cameron, Kenneth L.; McGinty, Gerald; Jackson, Jonathan; Guskiewicz, Kevin M.; Mihalik, Jason P.; Brooks, Alison; Duma, Stefan; Rowson, Steven; Nelson, Lindsay D.; Pasquina, Paul; McCrea, Michael A.; Gill, Jessica M.; CARE Consortium Investigators; Psychiatry, School of MedicineBackground: Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion. Therefore, more accurate diagnostic markers are needed for sport-related concussion. Methods: This was a multicenter, prospective, case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the National Collegiate Athletic Association-Department of Defense Concussion Assessment, Research, and Education Consortium conducted between 2015 and 2019. The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints. Athletes with concussion were divided into 6 h post-injury (0-6 h post-injury) and after 6 h post-injury (7-48 h post-injury) groups. We applied a highly multiplexed proteomic technique that used a DNA aptamers assay to target 1305 proteins in plasma samples from athletes with and without sport-related concussion. Results: A total of 140 athletes with concussion (79.3% males; aged 18.71 ± 1.10 years, mean ± SD) and 21 non-concussed athletes (76.2% males; 19.14 ± 1.10 years) were included in this study. We identified 338 plasma proteins that significantly differed in abundance (319 upregulated and 19 downregulated) in concussed athletes compared to non-concussed athletes. The top 20 most differentially abundant proteins discriminated concussed athletes from non-concussed athletes with an area under the curve (AUC) of 0.954 (95% confidence interval: 0.922‒0.986). Specifically, after 6 h of injury, the individual AUC of plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein (SNCA) were 0.956 and 0.875, respectively. The combination of EPB41 and SNCA provided the best AUC (1.000), which suggests this combination of candidate plasma biomarkers is the best for diagnosing concussion in athletes after 6 h of injury. Conclusion: Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and SNCA is the most predictive biomarker of concussion after 6 h of injury.Item Assessment of Blood Biomarker Profile After Acute Concussion During Combative Training Among US Military Cadets(JAMA, 2021-02) Giza, Christopher C.; McCrea, Michael; Huber, Daniel; Cameron, Kenneth L.; Houston, Megan N.; Jackson, Jonathan C.; McGinty, Gerald; Pasquina, Paul; Broglio, Steven P.; Brooks, Alison; DiFiori, John; Duma, Stefan; Harezlak, Jaroslaw; Goldman, Joshua; Guskiewicz, Kevin; McAllister, Thomas W.; McArthur, David; Meier, Timothy B.; Mihalik, Jason P.; Nelson, Lindsay D.; Rowson, Steven; Gill, Jessica; Foroud, Tatiana; Katz, Barry; Saykin, Andrew; Campbell, Darren E.; Svoboda, Steven; Psychiatry, School of MedicineImportance: 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 (<6 hours), the 24- to 48-hour postinjury point, the asymptomatic postinjury point (defined as the point at which the cadet reported being asymptomatic and began the return-to-activity protocol), and 7 days after return to activity. Biomarker levels and estimated mean differences in biomarker levels were natural log (ln) transformed to decrease the skewness of their distributions. Data were collected from August 1, 2016, to May 31, 2018, and analyses were conducted from March 1, 2019, to January 14, 2020. Exposure: Concussion incurred during combative training. Main outcomes and measures: Proteins examined included glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, neurofilament light chain, and tau. Quantification was conducted using a multiplex assay (Simoa; Quanterix Corp). Clinical measures included the Sport Concussion Assessment Tool-Third Edition symptom severity evaluation, the Standardized Assessment of Concussion, the Balance Error Scoring System, and the 18-item Brief Symptom Inventory. Results: Among 103 military service academy cadets, 67 cadets incurred concussions during combative training, and 36 matched cadets who engaged in the same training exercises did not incur concussions. The mean (SD) age of cadets in the concussion group was 18.6 (1.3) years, and 40 cadets (59.7%) were male. The mean (SD) age of matched cadets in the contact-control group was 19.5 (1.3) years, and 25 cadets (69.4%) were male. Compared with cadets in the contact-control group, those in the concussion group had significant increases in glial fibrillary acidic protein (mean difference in ln values, 0.34; 95% CI, 0.18-0.50; P < .001) and ubiquitin C-terminal hydrolase-L1 (mean difference in ln values, 0.97; 95% CI, 0.44-1.50; P < .001) levels at the acute postinjury point. The glial fibrillary acidic protein level remained high in the concussion group compared with the contact-control group at the 24- to 48-hour postinjury point (mean difference in ln values, 0.22; 95% CI, 0.06-0.38; P = .007) and the asymptomatic postinjury point (mean difference in ln values, 0.21; 95% CI, 0.05-0.36; P = .01). The area under the curve for all biomarkers combined, which was used to differentiate cadets in the concussion and contact-control groups, was 0.80 (95% CI, 0.68-0.93; P < .001) at the acute postinjury point. Conclusions and relevance: This study's findings indicate that blood biomarkers have potential for use as research tools to better understand the pathobiological changes associated with concussion and to assist with injury identification and recovery from combative training-associated concussions among military service academy cadets. These results extend the previous findings of studies of collegiate athletes with sport-associated concussions.Item Association between concussion and mental health in former collegiate athletes(Springer, 2014-12) Kerr, Zachary Y.; Evenson, Kelly R.; Rosamond, Wayne D.; Mihalik, Jason P.; Guskiewicz, Kevin M.; Marshall, Stephen W.; Department of Social and Behavioral Sciences, Richard M. Fairbanks School of Public HealthBACKGROUND: The existing research on the association between concussion and mental health outcomes is largely limited to former professional athletes. This cross-sectional study estimated the association between recurrent concussion and depression, impulsivity, and aggression in former collegiate athletes. METHODS: Former collegiate athletes who played between 1987-2012 at a Division I university completed an online questionnaire. The main exposure, total number of self-recalled concussions (sport-related and non-sport-related), were categorized as: zero (referent), one, two, or three or more concussions. The main outcomes were the depression module of The Patient Health Questionnaire (PHQ-9), the Short Form of the Barratt Impulsiveness scale (BIS15); and the 12-item Short Form of the Buss-Perry Aggression Questionnaire (BPAQ-SF). Depression was categorized into a binomial severity classification that differentiated between no or mild depression (PHQ-9 scores <10) and moderate to severe depression (PHQ-9 scores ≥10). Impulsivity and aggression were kept as continuous outcomes. Binomial regression estimated adjusted prevalence ratios (PR). Linear regression estimated adjusted mean differences (MD). RESULTS: Of the 797 respondents with complete data (21.9% completion rate), 38.8% reported at least one concussion. Controlling for alcohol dependence and family history of depression, the prevalence of moderate to severe depression among former collegiate athletes reporting three or more concussions in total was 2.4 times that of those reporting zero concussions [95% Confidence Interval (CI): 1.0, 5.7]. Controlling for alcohol dependence, family history of anxiety, relationship status, obtaining a post-graduate degree, and playing primary college sport professionally, former collegiate athletes reporting two or more concussions in total had higher mean scores for impulsivity, compared to those reporting no concussions (2 concussions MD = 2.7; 95% CI: 1.2, 4.1; 3+ concussions MD = 1.9; 95% CI: 0.6, 3.2). Controlling for alcohol dependence, sex, and relationship status, former collegiate athletes reporting three or more concussions in total had a higher mean score for aggression, compared to those reporting no concussions (MD = 3.0; 95% CI: 1.4, 4.7). CONCLUSIONS: Our study found an association between former concussion and greater risk of severe depression and higher levels of impulsivity and aggression among former collegiate athletes. Additional prospective studies better addressing causality and ascertaining valid lifetime concussion histories and medical histories are needed.Item The Association Between Persistent White-Matter Abnormalities and Repeat Injury After Sport-Related Concussion(Frontiers Media, 2020-01-21) Brett, Benjamin L.; Wu, Yu-Chien; Mustafi, Sourajit M.; Saykin, Andrew J.; Koch, Kevin M.; Nencka, Andrew S.; Giza, Christopher C.; Goldman, Joshua; Guskiewicz, Kevin M.; Mihalik, Jason P.; Duma, Stefan M.; Broglio, Steven P.; McAllister, Thomas W.; McCrea, Michael A.; Meier, Timothy B.; Radiology and Imaging Sciences, School of MedicineObjective: A recent systematic review determined that the physiological effects of concussion may persist beyond clinical recovery. Preclinical models suggest that ongoing physiological effects are accompanied by increased cerebral vulnerability that is associated with risk for subsequent, more severe injury. This study examined the association between signal alterations on diffusion tensor imaging following clinical recovery of sport-related concussion in athletes with and without a subsequent second concussion. Methods: Average mean diffusivity (MD) was calculated in a region of interest (ROI) in which concussed athletes (n = 82) showed significantly elevated MD acutely after injury (<48 h), at an asymptomatic time point, 7 days post-return to play (RTP), and 6 months relative to controls (n = 69). The relationship between MD in the identified ROI and likelihood of sustaining a subsequent concussion over a 1-year period was examined with a binary logistic regression (re-injured, yes/no). Results: Eleven of 82 concussed athletes (13.4%) sustained a second concussion within 12 months of initial injury. Mean MD at 7 days post-RTP was significantly higher in those athletes who went on to sustain a repeat concussion within 1 year of initial injury than those who did not (p = 0.048; d = 0.75). In this underpowered sample, the relationship between MD at 7 days post-RTP and likelihood of sustaining a secondary injury approached significance [χ2 (1) = 4.17, p = 0.057; B = 0.03, SE = 0.017; OR = 1.03, CI = 0.99, 1.07]. Conclusions: These preliminary findings raise the hypothesis that persistent signal abnormalities in diffusion imaging metrics at RTP following concussion may be predictive of a repeat concussion. This may reflect a window of cerebral vulnerability or increased susceptibility following concussion, though understanding the clinical significance of these findings requires further study.Item Association between Preseason/Regular Season Head Impact Exposure and Concussion Incidence in NCAA Football(ACSM, 2022-06) Stemper, Brian D.; Harezlak, Jaroslaw; Shah, Alok S.; Rowson, Steven; Mihalik, Jason P.; Riggen, Larry; Duma, Stefan; Pasquina, Paul; Broglio, Steven P.; Mcallister, Thomas W.; Mccrea, Michael A.; CARE Consortium Investigators; Psychiatry, School of MedicinePurpose Contact sport athletes are exposed to a unique environment where they sustain repeated head impacts throughout the season and can sustain hundreds of head impacts over a few months. Accordingly, recent studies outlined the role that head impact exposure (HIE) has in concussion biomechanics and in the development of cognitive and brain-based changes. Those studies focused on time-bound effects by quantifying exposure leading up to the concussion, or cognitive changes after a season in which athletes had high HIE. However, HIE may have a more prolonged effect. This study identified associations between HIE and concussion incidence during different periods of the college football fall season. Methods This study included 1120 athlete seasons from six National Collegiate Athletic Association Division I football programs across 5 yr. Athletes were instrumented with the Head Impact Telemetry System to record daily HIE. The analysis quantified associations of preseason/regular season/total season concussion incidence with HIE during those periods. Results Strong associations were identified between HIE and concussion incidence during different periods of the season. Preseason HIE was associated with preseason and total season concussion incidence, and total season HIE was associated with total season concussion incidence. Conclusions These findings demonstrate a prolonged effect of HIE on concussion risk, wherein elevated preseason HIE was associated with higher concussion risk both during the preseason and throughout the entire fall season. This investigation is the first to provide evidence supporting the hypothesis of a relationship between elevated HIE during the college football preseason and a sustained decreased tolerance for concussion throughout that season.Item Association of Alzheimer’s disease polygenic risk score with concussion severity and recovery metrics(Wiley, 2025-01-09) Dybing, Kaitlyn M.; McAllister, Thomas W.; Wu, Yu-Chien; McDonald, Brenna C.; McCrea, Michael A.; Broglio, Steven P.; Pasquina, Paul F.; Brooks, M. Alison; Mihalik, Jason P.; Guskiewicz, Kevin M.; Giza, Christopher C.; Goldman, Joshua; Duma, Stefan; Rowson, Steve; Svoboda, Steven; Cameron, Kenneth L.; Houston, Megan N.; Campbell, Darren E.; McGinty, Gerald; Jackson, Jonathan; Risacher, Shannon L.; Saykin, Andrew J.; Nudelman, Kelly N.; Radiology and Imaging Sciences, School of MedicineBackground: Shared genetic risk between Alzheimer’s disease (AD) and concussion may help explain the association between concussion and elevated risk for dementia. However, there has been little investigation into whether AD risk genes also associate with concussion severity/recovery, and the limited findings are mixed. We used AD polygenic risk scores (PRS) and APOE genotypes to investigate associations between AD genetic risk and concussion severity/recovery in the NCAA‐DoD Grand Alliance CARE Consortium (CARE) dataset. Method: There were 1,917 injuries in the dataset upon project initiation. After removing repeated injuries, related participants, and those without genetic/outcome data, we had 931 participants. Outcomes were number of days to return to play (RTP) as a recovery measure, and four severity measures (scores on SAC and BESS, SCAT symptom severity and total number of symptoms). We calculated PRS using a published score (de Rojas et al., 2021) and performed a linear regression (MLR) of RTP by PRS in normal (<24 days) and long (>24 days) RTP subgroups. We then compared severity measures by PRS using MLR. Next, we used t‐tests to examine outcomes by APOE genotype in military and civilian subgroups. We also performed chi‐squared tests of RTP category (normal vs. long) by APOE genotype. Finally, we analyzed outcomes by PRS in European or African genetic ancestry subgroups using MLR. Result: Higher PRS was associated with longer injury to RTP interval in the normal RTP (<24 days) subgroup (estimate = 0.0412, SE = 0.182, p = 0.0237). 1 SD increase in PRS resulted in a 0.412 day (9.89 hours) increase to the interval. This may be clinically meaningful in the collegiate athlete environment. We did not identify any other significant differences. Conclusion: Our preliminary results provide limited evidence for an impact of AD PRS on concussion recovery, though the pattern was inconsistent and its clinical significance is uncertain. Future studies should attempt to replicate these findings in larger samples with longer follow‐up using PRS calculated from multiple/diverse populations, which will be especially relevant for diverse datasets like CARE.Item Association of Premorbid Anxiety and Depression Symptoms in Concussion Recovery in Collegiate Student-Athletes(Sage, 2024-06-04) Sawlani, Sabrina P.; Goldman, Joshua T.; Babikian, Talin; McArthur, David L.; Polster, Douglas; McCrea, Michael; McAllister, Thomas; Giza, Christopher C.; CARE Consortium; CARE Consortium Investigators; Ortega, Justus D.; Port, Nicholas; Putukian, Margot; McDevitt, Jane; Giza, Christopher C.; Goldman, Joshua T.; Benjamin, Holly J.; Buckley, Thomas; Kaminski, Thomas W.; Clugston, James R.; Feigenbaum, Luis A.; Eckner, James T.; Mihalik, Jason P.; Anderson, Scott; Master, Christina L.; Kontos, Anthony P.; Chrisman, Sara P. O.; Cameron, Kenneth; Duma, Stefan; Miles, Christopher M.; Psychiatry, School of MedicineBackground: Mental health disorders are linked to prolonged concussion symptoms. However, the association of premorbid anxiety/depression symptoms with postconcussion return-to-play timelines and total symptom burden is unclear. Objective: To examine the association of self-reported premorbid anxiety/depression symptoms in collegiate student-athletes with (1) recovery times until asymptomatic, (2) return-to-play, and (3) postconcussion symptom burden. Study design: Athletes in the Concussion Assessment, Research and Education Consortium completed baseline concussion assessments (Sport Concussion Assessment Tool [SCAT3] and Brief Symptom Inventory-18 [BSI-18]). Athletes were tested postinjury at <6 hours, 24 to 48 hours, time of asymptomatic and start of return-to-play protocol, unrestricted return-to-play, and 6 months after injury. Injured athletes were categorized into 4 groups based on BSI-18 scores: (1) B-ANX, elevated anxiety symptoms only; (2) B-DEP, elevated depression symptoms only; (3) B-ANX&DEP, elevated anxiety and depression symptoms; and (4) B-NEITHER, no elevated anxiety or depression symptoms. Relationship between age, sex, BSI-18 group, SCAT3 total symptom and severity scores, and time to asymptomatic status and return-to-play was assessed with Pearson's chi-squared test and robust analysis of variance. Level of evidence: Level 3. Results: Among 1329 athletes with 1352 concussions, no respondents had a self-reported premorbid diagnosis of anxiety/depression. There was no difference in time until asymptomatic or time until return-to-play between BSI-18 groups (P = 0.15 and P = 0.11, respectively). B-ANX, B-DEP, and B-ANX&DEP groups did not have higher total symptom or severity scores postinjury compared with the B-NEITHER group. Conclusion: Baseline anxiety/depression symptoms in collegiate student-athletes without a mental health diagnosis are not associated with longer recovery times until asymptomatic, longer time to return-to-play, or higher postconcussion total symptom and severity scores compared with athletes without baseline symptoms. Clinical relevance: Anxiety and depression symptoms without a clear mental health diagnosis should be considered differently from other comorbidities when discussing prolonged recovery in collegiate student-athletes.Item Cerebral blood flow in acute concussion: preliminary ASL findings from the NCAA-DoD CARE consortium(Springer, 2019-10-01) Wang, Yang; Nencka, Andrew S.; Meier, Timothy B.; Guskiewicz, Kevin; Mihalik, Jason P.; Alison Brooks, M.; Saykin, Andrew J.; Koch, Kevin M.; Wu, Yu-Chien; Nelson, Lindsay D.; McAllister, Thomas W.; Broglio, Steven P.; McCrea, Michael A.; Radiology and Imaging Sciences, School of MedicineSport-related concussion (SRC) has become a major health problem, affecting millions of athletes each year. Despite the increasing occurrence and prevalence of SRC, its underlying mechanism and recovery course have yet to be fully elucidated. The National Collegiate Athletic Association–Department of Defense Grand Alliance: Concussion Assessment, Research and Education (CARE) Consortium is a large-scale, multisite study of the natural history of concussion across multiple sports. The Advanced Research Core (ARC) of CARE is focused on the advanced biomarker assessment of a reduced subject cohort. This paper reports findings from two ARC sites to evaluate cerebral blood flow (CBF) changes in acute SRC, as measured using advanced arterial spin labeling (ASL) magnetic resonance imaging (MRI). We compared relative CBF maps assessed in 24 concussed contact sport athletes obtained at 24–48 h after injury to those of a control group of 24 matched contact sport players. Significantly less CBF was detected in several brain regions in concussed athletes, while clinical assessments also indicated clinical symptom and performance impairments in SRC patients. Correlations were found between decreased CBF in acute SRC and clinical assessments, including Balance Error Scoring System total score and Immediate Post-Concussion Assessment and Cognitive Test memory composite and impulse control composite scores, as well as days from injury to asymptomatic. Although using different ASL MRI sequences, our preliminary results from two sites are consistent with previous reports and suggest that advanced ASL MRI methods might be useful for detecting acute neurobiological changes in acute SRC.Item Comparison of Head Impact Exposure Between Concussed Football Athletes and Matched Controls: Evidence for a Possible Second Mechanism of Sport-Related Concussion(Springer, 2018) Stemper, Brian D.; Shah, Alok S.; Harezlak, Jaroslaw; Rowson, Steven; Mihalik, Jason P.; Duma, Stefan M.; Riggen, Larry D.; Brooks, Alison; Cameron, Kenneth L.; Campbell, Darren; DiFiori, John P.; Giza, Christopher C.; Guskiewicz, Kevin M.; Jackson, Jonathan; McGinty, Gerald T.; Svoboda, Steven J.; McAllister, Thomas W.; Broglio, Steven P.; McCrea, Michael; Psychiatry, School of MedicineStudies of football athletes have implicated repetitive head impact exposure in the onset of cognitive and brain structural changes, even in the absence of diagnosed concussion. Those studies imply accumulating damage from successive head impacts reduces tolerance and increases risk for concussion. Support for this premise is that biomechanics of head impacts resulting in concussion are often not remarkable when compared to impacts sustained by athletes without diagnosed concussion. Accordingly, this analysis quantified repetitive head impact exposure in a cohort of 50 concussed NCAA Division I FBS college football athletes compared to controls that were matched for team and position group. The analysis quantified the number of head impacts and risk weighted exposure both on the day of injury and for the season to the date of injury. 43% of concussed athletes had the most severe head impact exposure on the day of injury compared to their matched control group and 46% of concussed athletes had the most severe head impact exposure for the season to the date of injury compared to their matched control group. When accounting for date of injury or season to date of injury, 72% of all concussed athletes had the most or second most severe head impact exposure compared to their matched control group. These trends associating cumulative head impact exposure with concussion onset were stronger for athletes that participated in a greater number of contact activities. For example, 77% of athletes that participated in ten or more days of contact activities had greater head impact exposure than their matched control group. This unique analysis provided further evidence for the role of repetitive head impact exposure as a predisposing factor for the onset of concussion. The clinical implication of these findings supports contemporary trends of limiting head impact exposure for college football athletes during practice activities in an effort to also reduce risk of concussive injury.
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