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Traumatic brain injury (TBI) affects millions of Americans each year and has been shown to disproportionately impact those subject to greater disparities in health. Female sex is one factor that has been associated with disparities in health outcomes, including in TBI, but sex differences in biomarker levels and behavioral outcomes after TBI are underexplored. This study included participants with both blunt and blast TBI with majority rating their TBI as mild. Time since injury was 5.4 (2.0, 15.5) years for females and 6.8 (2.4, 11.3) years for males. The aim of this cross sectional study is to investigate the relationship between postconcussive, depression, and post-traumatic stress disorder (PTSD) symptoms, as well as health related quality of life (HRQOL), and the levels of glial fibrillary acidic protein (GFAP), total tau (t-tau), neurofilament light chain (NfL), and ubiquitin C-terminal hydrolase-L1 (UCH-L1). Behavioral outcomes were evaluated with the Neurobehavioral Symptom Inventory (NSI), Patient Health Questionnaire-9 (PHQ-9), PTSD Checklist- Civilian Version (PCL-C), short form (SF)-36, and plasma levels of total tau, GFAP, NfL, and UCHL-1 measured with the Simoa-HDX. We observed that females had significantly higher levels of GFAP and tau ( ps < 0.05), and higher PHQ-9 scores, NSI total scores, NSI- vestibular, NSI-somatosensory, NSI-affective sub-scale scores ( ps < 0.05)), than males. In addition, females had lower scores in HRQOL outcomes of role limitations due to emotional problems, vitality, emotional well-being, social functioning, and pain compared to males ( ps < 0.05). Correlation analysis showed positive associations between levels of tau and the NSI-total and NSI-cognitive sub-scale scores ( ps < 0.05) in females. No significant associations were found for NfL or GFAP with NSI scores. For female participants, negative correlations were observed between tau and NfL concentrations and the SF-36 physical function subscale ( ps < 0.05), as well as tau and the social function subscale ( p < 0.001), while GFAP levels positively correlated with role limitations due to emotional problems ( p = 0.004). No significant associations were observed in males. Our findings suggest that sex differences exist in TBI-related behavioral outcomes, as well as levels of biomarkers associated with brain injury, and that the relationship between biomarker levels and behavioral outcomes is more evident in females than males. Future studies are warranted to corroborate these results, and to determine the implications for prognosis and treatment. The identification of candidate TBI biomarkers may lead to development of individualized treatment guidelines.

Traumatic brain injuries (TBI) and posttraumatic stress disorder (PTSD) are commonly observed comorbid occurrences among military service members and veterans (SMVs). In this cross-sectional study, SMVs with a history of TBI were stratified into symptomatic and asymptomatic PTSD groups based on posttraumatic stress checklist-civilian (PCL-C) total scores. Blood-based biomarkers were assessed, and significant differential markers were associated with scores from multiple neurobehavioral self-report assessments. PCL-C cutoffs were total scores >50 (PTSD symptomatic) and <25 (asymptomatic). Cytokines IL6, IL8, TNFα, and IL10 were significantly elevated (p < 0.05–0.001) in the TBI+/PTSD symptomatic group compared to the TBI+/asymptomatic group. Cytokine levels of IL8, TNFα, and IL10 were strongly associated with PCL-C scores (0.356 < r > 0.624 for all, p < 0.01 for all), while TNFα and IL10 were additionally associated with NSI totals (r = 0.285 and r = 0.270, p < 0.05, respectively). This is the first study focused on PTSD symptom severity to report levels of circulating pro-inflammatory IL8, specifically in SMVs with TBI. These data suggest that within the military TBI population, there are unique cytokine profiles that relate to neurobehavioral outcomes associated with TBI and PTSD.

Abstract Study Objectives Posttraumatic stress disorder (PTSD) is a common condition for military personnel and veterans. PTSD has been shown to impact gene expression, however, to date no study has examined comorbid conditions which may also impact gene expression, for example, excessive daytime sleepiness (EDS). As such, this study sought to examine gene expression using RNA sequencing across three group comparisons of military personnel and veterans: (1) PTSD with EDS (PTSDwEDS) versus PTSD without EDS (PTSDw/outEDS), (2) Controls (no PTSD or EDS) versus PTSDwEDS, and (3) Controls versus PTSDw/outEDS. Methods We performed experimental RNA-seq using Illumina’s HiSeq 2500 Sequencing System. We also used Ingenuity Pathway Analysis (IPA), a bioinformatics application, to identify gene pathways and networks which may be disrupted. Results There were only two genes that were significantly dysregulated between the Controls and PTSDw/outEDS, therefore IPA analysis was not conducted. However, comparisons revealed that there was significant gene dysregulation between Controls and the PTSDwEDS (251 genes), and the PTSDwEDS versus the PTSDw/outEDS (1,873 genes) groups. Four candidate networks were identified via the IPA software for analysis. Significantly dysregulated genes across the four candidate networks were associated with sleep and circadian function, metabolism, mitochondrial production and function, ubiquitination, and the glutamate system. Conclusions These results suggest that PTSD with concurrent EDS is associated with gene dysregulation. This dysregulation may present additional biological and health consequences for these military personnel and veterans. Further research, to track these gene changes over time and to determine the cause of the EDS reported, is vital.

Recruitment of participants for traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) studies is a major challenge, causing delays in study timelines and even study failures. To address this challenge, the Center for Neuroscience and Regenerative Medicine (CNRM) Recruitment Core developed procedures for identification, screening, and referral of participants from screening studies to a broad range of TBI and PTSD studies. Participants were recruited from civilian hospitals, Military Treatment Facilities, and through various events and presentations. Enrolled participants were referred to other studies during initial enrollment, follow-up visits, or ad hoc as new CNRM studies became active. A centralized online database was used to streamline the eligibility and referral process. As of October 25, 2016, 1,040 enrolled participants from the two screening studies have been assessed for eligibility for active CNRM studies. Referrals have led to 197 total enrollments into other CNRM studies. Common reasons for exclusion from studies included age, date of injury, injury severity, contraindication to Magnetic Resonance Imaging, state of residence, and military status. Collaborative work with multiple disciplines and institutions, and the use of diverse media, was critical to augmenting participant enrollment, and significantly diversified the demographics of the participant population. Streamlining the referral process helps studies meet their timelines and target enrollment.

Background Trainees in graduate medical education are affected by burnout at disproportionate rates. Trainees experience tremendous growth in clinical skills and reasoning, however little time is dedicated to metacognition to process their experiences or deliberate identity formation to create individualized definitions of success and wellbeing. The purpose of this study was to understand the perspectives and experiences of trainees who participated in a 6-month, web-based, group coaching program for women residents in training. Methods Better Together Physician Coaching is a six-month, self-paced, online, asynchronous, coaching program with multiple components including live coaching calls, unlimited written coaching, and self-study modules. Semi-structured interviews of seventeen participants of Better Together from twelve GME programs within a single institution in Colorado were conducted from May to June of 2021. All identified as women and had participated in a 6-month coaching program. Both inductive and deductive methods were used in collecting and analyzing the data with an aim to understand learners’ perceptions of the coaching program, including “how and why” the coaching program affected training experiences and wellbeing. Results Three main themes emerged as benefits to the coaching program from the data: 1) practicing metacognition as a tool for healthy coping 2) building a sense of community, and 3) the value of a customizable experience. Conclusions Female trainees who participated in a group coaching program expressed that they found value in learning how to cope with stressors through metacognition-focused coaching. They also described that building a community and being able to customize the experience were positive aspects of the program. Trial registration ClinicalTrials.gov Identifier: NCT05280964 . Date of registration: March 15th 2022. Retrospectively registered. URL of trial registry record.

Physician burnout disproportionately affects women physicians and begins in training. Professional coaching may improve well-being, but generalizable evidence is lacking. To assess the generalizability of a coaching program (Better Together Physician Coaching) in a national sample of women physician trainees. A randomized clinical trial involving trainees in 26 graduate medical education institutions in 19 states was conducted between September 1, 2022, and December 31, 2022. Eligible participants included physician trainees at included sites who self-identified as a woman (ie, self-reported their gender identity as woman, including those who reported woman if multiple genders were reported). A 4-month, web-based, group coaching program. The primary outcomes were change in burnout (measured using subscales for emotional exhaustion, depersonalization, and personal achievement from the Maslach Burnout Inventory). Secondary outcomes included changes in impostor syndrome, moral injury, self-compassion, and flourishing, which were assessed using standardized measures. A linear mixed model analysis was performed on an intent-to-treat basis. A sensitivity analysis was performed to account for the missing outcomes. Among the 1017 women trainees in the study (mean [SD] age, 30.8 [4.0] years; 540 White participants [53.1%]; 186 surgical trainees [18.6%]), 502 were randomized to the intervention group and 515 were randomized to the control group. Emotional exhaustion decreased by an estimated mean (SE) -3.81 (0.73) points in the intervention group compared with a mean (SE) increase of 0.32 (0.57) points in the control group (absolute difference [SE], -4.13 [0.92] points; 95% CI, -5.94 to -2.32 points; P < .001). Depersonalization decreased by a mean (SE) of -1.66 (0.42) points in the intervention group compared with a mean (SE) increase of 0.20 (0.32) points in the control group (absolute difference [SE], -1.87 [0.53] points; 95%CI, -2.91 to -0.82 points; P < .001). Impostor syndrome decreased by a mean (SE) of -1.43 (0.14) points in the intervention group compared with -0.15 (0.11) points in the control group (absolute difference [SE], -1.28 (0.18) points; 95% CI -1.63 to -0.93 points; P < .001). Moral injury decreased by a mean (SE) of -5.60 (0.92) points in the intervention group compared with -0.92 (0.71) points in the control group (absolute difference [SE], -4.68 [1.16] points; 95% CI, -6.95 to -2.41 points; P < .001). Self-compassion increased by a mean (SE) of 5.27 (0.47) points in the intervention group and by 1.36 (0.36) points in the control group (absolute difference [SE], 3.91 [0.60] points; 95% CI, 2.73 to 5.08 points; P < .001). Flourishing improved by a mean (SE) of 0.48 (0.09) points in the intervention group vs 0.09 (0.07) points in the control group (absolute difference [SE], 0.38 [0.11] points; 95% CI, 0.17 to 0.60 points; P < .001). The sensitivity analysis found similar findings. The findings of this randomized clinical trial suggest that web-based professional group-coaching can improve outcomes of well-being and mitigate symptoms of burnout for women physician trainees. ClinicalTrials.gov Identifier: NCT05222685.