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Item Association of Blood Biomarkers of Inflammation With Acute Concussion in Collegiate Athletes and Military Service Academy Cadets(Wolters Kluwer, 2024) Meier, Timothy B.; Huber, Daniel L.; Goeckner, Bryna D.; Gill, Jessica M.; Pasquina, Paul; Broglio, Steven P.; McAllister, Thomas W.; Harezlak, Jaroslaw; McCrea, Michael A.; CARE Consortium Investigators; Psychiatry, School of MedicineBackground and objectives: The objective was to characterize the acute effects of concussion (a subset of mild traumatic brain injury) on serum interleukin (IL)-6 and IL-1 receptor antagonist (RA) and 5 additional inflammatory markers in athletes and military service academy members from the Concussion Assessment, Research, and Education Consortium and to determine whether these markers aid in discrimination of concussed participants from controls. Methods: Athletes and cadets with concussion and matched controls provided blood at baseline and postinjury visits between January 2015 and March 2020. Linear models investigated changes in inflammatory markers measured using Meso Scale Discovery assays across time points (baseline and 0-12, 12-36, 36-60 hours). Subanalyses were conducted in participants split by sex and injury population. Logistic regression analyses tested whether acute levels of IL-6 and IL-1RA improved discrimination of concussed participants relative to brain injury markers (glial fibrillary acidic protein, tau, neurofilament light, ubiquitin c-terminal hydrolase-L1) or clinical data (Sport Concussion Assessment Tool-Third Edition, Standardized Assessment of Concussion, Balance Error Scoring System). Results: Participants with concussion (total, N = 422) had elevated IL-6 and IL-1RA at 0-12 hours vs controls (n = 345; IL-6: mean difference [MD] (standard error) = 0.701 (0.091), p < 0.0001; IL-1RA: MD = 0.283 (0.042), p < 0.0001) and relative to baseline (IL-6: MD = 0.656 (0.078), p < 0.0001; IL-1RA: MD = 0.242 (0.038), p < 0.0001), 12-36 hours (IL-6: MD = 0.609 (0.086), p < 0.0001; IL-1RA: MD = 0.322 (0.041), p < 0.0001), and 36-60 hours (IL-6: MD = 0.818 (0.084), p < 0.0001; IL-1RA: MD = 0.317 (0.040), p < 0.0001). IL-6 and IL-1RA were elevated in participants with sport (IL-6: MD = 0.748 (0.115), p < 0.0001; IL-1RA: MD = 0.304 (0.055), p < 0.0001) and combative-related concussions (IL-6: MD = 0.583 (0.178), p = 0.001; IL-1RA: MD = 0.312 (0.081), p = 0.0001). IL-6 was elevated in male (MD = 0.734 (0.105), p < 0.0001) and female participants (MD = 0.600 (0.177), p = 0.0008); IL-1RA was only elevated in male participants (MD = 0.356 (0.047), p < 0.0001). Logistic regression showed the inclusion of IL-6 and IL-1RA at 0-12 hours improved the discrimination of participants with concussion from controls relative to brain injury markers (χ2(2) = 17.855, p = 0.0001; area under the receiver operating characteristic curve [AUC] 0.73 [0.66-0.80] to 0.78 [0.71-0.84]), objective clinical measures (balance and cognition; χ2(2) = 40.661, p < 0.0001; AUC 0.81 [0.76-0.86] to 0.87 [0.83-0.91]), and objective and subjective measures combined (χ2(2) = 13.456, p = 0.001; AUC 0.97 [0.95-0.99] to 0.98 [0.96-0.99]), although improvement in AUC was only significantly relative to objective clinical measures. Discussion: IL-6 and IL-1RA (male participants only) are elevated in the early-acute window postconcussion and may aid in diagnostic decisions beyond traditional blood markers and common clinical measures. IL-1RA results highlight sex differences in the immune response to concussion which should be considered in future biomarker work.Item Removing the COVID-19 Vaccination Requirement for the Military Increases the United States’ National Security Concerns(Society of Teachers of Family Medicine, 2023) Seehusen, Dean A.; Silver, Sabrina L.; Stephens, Mark B.; Wilkins, Thad; Medicine, School of MedicineItem Service Dogs for Veterans and Military Members With Posttraumatic Stress Disorder: A Nonrandomized Controlled Trial(American Medical Association, 2024-06-03) Leighton, Sarah C.; Rodriguez, Kerri E.; Jensen, Clare L.; MacLean, Evan L.; Davis, Louanne W.; Ashbeck, Erin L.; Bedrick, Edward J.; O'Haire, Marguerite E.; Psychiatry, School of MedicineImportance: Military members and veterans (hereafter, veterans) with posttraumatic stress disorder (PTSD) increasingly seek psychiatric service dogs as a complementary intervention, yet the effectiveness of service dogs is understudied. Objective: To estimate the associations between psychiatric service dog partnership and self-reported and clinician-rated PTSD symptom severity, depression, anxiety, and psychosocial functioning after 3 months of intervention among veterans. Design, setting, and participants: This nonrandomized controlled trial used standardized and validated assessment instruments completed by participants and administered by blinded clinicians. Recruitment, eligibility screening, and enrollment were conducted between August 2017 and December 2019. Veterans were recruited using the database of an accredited nonprofit service dog organization with constituents throughout the US. Participants were veterans with a PTSD diagnosis; they were allocated to either the intervention group (n = 81) or control group (n = 75). Outcome assessments were performed at baseline and at the 3-month follow-up. Data analyses were completed in October 2023. Interventions: Participants allocated to the intervention group received a psychiatric service dog for PTSD, whereas those allocated to the control group remained on the waiting list based on the date of application submitted to the service dog organization. Both groups had unrestricted access to usual care. Main outcomes and measures: The primary outcomes were PTSD symptom severity, depression, and anxiety after 3 months, and the secondary outcomes were psychosocial functioning, such as quality of life and social health. The self-reported PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) was used to measure symptom severity, and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) was used to assess PTSD diagnosis (score range for both instruments: 0-80, with higher scores indicating greater PTSD symptoms). Results: The 156 participants included in the trial had a mean (SD) age of 37.6 (8.3) years and included 117 males (75%), 17 Black or African American individuals (11%), 30 Hispanic individuals (19%), and 117 White individuals (76%). Compared with the control group, the intervention group had significantly lower PTSD symptom severity based on the PTSD Checklist for DSM-5 mean (SD) score (41.9 [16.9] vs 51.7 [16.1]; difference in means, -11.5 [95% CI, -16.2 to -6.6]; P < .001) and the CAPS-5 mean (SD) score (30.2 [10.2] vs 36.9 [10.2]; difference in means, -7.0 [95% CI, -10.8 to -4.5]; P < .001) at 3 months. The intervention group also had significantly lower depression scores (odds ratio [OR], 0.45 [95% CI, 0.23-0.86]; difference in means, -3.3 [95% CI, -6.8 to -0.6]), anxiety (OR, 0.25 [95% CI, 0.13-0.50]; difference in means, -4.4 [95% CI, -6.9 to -2.1]), and most areas of psychosocial functioning (eg, social isolation: OR, 0.34 [95% CI, 0.18-0.64]). Conclusions and relevance: This nonrandomized controlled trial found that compared with usual care alone, partnership with a trained psychiatric service dog was associated with lower PTSD symptom severity and higher psychosocial functioning in veterans. Psychiatric service dogs may be an effective complementary intervention for military service-related PTSD.Item Sex Differences Across Concussion Characteristics in US Service Academy Cadets: A CARE Consortium Study(Springer, 2024) Kelly, Louise A.; Caccese, J. B.; Jain, D.; Master, C. L.; Lempke, L.; Memmini, A. K.; Buckley, T. A.; Clugston, J. R.; Mozel, A.; Eckner, J. T.; Susmarski, A.; Ermer, E.; Cameron, K. L.; Chrisman, S.; Pasquina, P.; Broglio, S. P.; McAllister, T. W.; McCrea, M.; Esopenko, C.; CARE Consortium Investigators; Psychiatry, School of MedicineObjective: To describe sex differences in concussion characteristics in US Service Academy cadets. Design: Descriptive epidemiology study. Setting: Four US service academies. Participants: 2209 cadets (n = 867 females, n = 1342 males). Independent variable: Sex. Outcome measures: Injury proportion ratios (IPR) compared the proportion of injuries by sex (females referent) for injury situation, certainty of diagnosis, prolonged recovery, recurrent injuries, mental status alterations, loss of consciousness (LOC), posttraumatic amnesia (PTA), retrograde amnesia (RGA), motor impairments, delayed symptom presentation, and immediate reporting. Main results: Concussions from varsity/intercollegiate sports [IPR of 1.73, 95% confidence interval (CI) 1.43-2.10] and intramurals (IPR of 1.53, 95% CI 1.02-2.32) accounted for a larger proportion in males, whereas concussions outside of sport and military activities accounted for a smaller proportion among males (IPR of 0.70, 95% CI 0.58-0.85). The proportion of concussions with prolonged recovery was lower among males (IPR of 0.69, 95% CI 0.60-0.78), while concussions with altered mental status (IPR of 1.23, 95% CI 1.09-1.38), LOC (IPR of 1.67, 95% CI 1.17-2.37), PTA (IPR of 1.94, 95% CI 1.43-2.62), and RGA (IPR of 2.14, 95% CI 1.38-3.31) accounted for a larger proportion among males. A larger proportion of concussions that were immediately reported was observed in males (IPR of 1.15, 95% CI 1.00-2.31). Proportions of other characteristics (e.g., recurrent injuries) were not different between sexes. Conclusions: A higher proportion of concussions occurred outside of sport and military training for female cadets, who also displayed proportionally longer recovery times than males, despite males demonstrating a higher proportion of LOC, PTA, and RGA. Possible factors may include different mechanisms of injury outside of sport and military training, different biopsychosocial states associated with sex or injury context, and delayed injury reporting when outside of an observed environment, possibly secondary to perceived stigma about reporting injuries.