Integrating workplace exposure databases for occupational medicine services and epidemiologic studies at a former nuclear weapons facility

We outline methods for integrating epidemiologic and industrial hygiene data systems for the purpose of exposure estimation, exposure surveillance, worker notification, and occupational medicine practice. We present examples of these methods from our work at the Rocky Flats Plant?a former nuclear weapons facility that fabricated plutonium triggers for nuclear weapons and is now being decontaminated and decommissioned. The weapons production processes exposed workers to plutonium, gamma photons, neutrons, beryllium, asbestos, and several hazardous chemical agents, including chlorinated hydrocarbons and heavy metals. We developed a job exposure matrix (JEM) for estimating exposures to 10 chemical agents in 20 buildings for 120 different job categories over a production history spanning 34 years. With the JEM, we estimated lifetime chemical exposures for about 12,000 of the 16,000 former production workers. We show how the JEM database is used to estimate cumulative exposures over different time periods for epidemiological studies and to provide notification and determine eligibility for a medical screening program developed for former workers. We designed an industrial hygiene data system for maintaining exposure data for current cleanup workers. We describe how this system can be used for exposure surveillance and linked with the JEM and databases on radiation doses to develop lifetime exposure histories and to determine appropriate medical monitoring tests for current cleanup workers. We also present time-line-based graphical methods for reviewing and correcting exposure estimates and reporting them to individual workers

The Association Between Persistent White-Matter Abnormalities and Repeat Injury After Sport-Related Concussion

Objective: 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

Longitudinal white-matter abnormalities in sports-related concussion: A diffusion MRI study

Objective To study longitudinal recovery trajectories of white matter after sports-related concussion (SRC) by performing diffusion tensor imaging (DTI) on collegiate athletes who sustained SRC. Methods Collegiate 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. Results In 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. Conclusions Changes 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 tim

EGFR amplification and classical subtype are associated with a poor response to bevacizumab in recurrent glioblastoma

Purpose The highly vascular malignant brain tumor glioblastoma (GBM) appears to be an ideal target for anti-angiogenic therapy; however, clinical trials to date suggest the VEGF antibody bevacizumab affects only progression-free survival. Here we analyze a group of patients with GBM who received bevacizumab treatment at recurrence and are stratified according to tumor molecular and genomic profile (TCGA classification), with the goal of identifying molecular predictors of the response to bevacizumab. Methods We performed a retrospective review of patients with a diagnosis of glioblastoma who were treated with bevacizumab in the recurrent setting at our hospital, from 2006 to 2014. Treatment was discontinued by the treating neuro-oncologists, based on clinical and radiographic criteria. Pre- and post-treatment imaging and genomic subtype were available on 80 patients. We analyzed time on bevacizumab and time to progression. EGFR gene amplification was determined by FISH. Results Patients with classical tumors had a significantly shorter time on bevacizumab than mesenchymal, and proneural patients (2.7 vs. 5.1 vs. 6.4 and 6.0 months respectively, p = 0.011). Classical subtype and EGFR gene amplification were significantly associated with a shorter time to progression both in univariate (p < 0.001 and p = 0.007, respectively) and multivariate analysis (both p = 0.010). Conclusion EGFR gene amplification and classical subtype by TCGA analysis are associated with significantly shorter time to progression for patients with recurrent GBM when treated with bevacizumab. These findings can have a significant impact on decision-making and should be further validated prospectively

Cerebral blood flow in acute concussion: preliminary ASL findings from the NCAA-DoD CARE consortium

Sport-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

Recovery After Mild Traumatic Brain Injury in Patients Presenting to US Level I Trauma Centers: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study

Question How common are persistent, injury-related functional limitations following mild traumatic brain injury vs orthopedic trauma? Findings In this cohort study of 1154 patients with mild traumatic brain injury and 299 patients with orthopedic trauma serving as controls, 53% of participants with mild traumatic brain injury reported impairment 12 months postinjury vs 38% of those with orthopedic trauma. Patients with intracranial abnormalities had the poorest outcomes; however, patients without abnormalities also reported problems at 12 months. Meaning Many patients who present to level I trauma centers with mild traumatic brain injury experience difficulties at 12 months postinjury, suggesting that this injury is not always benign; better follow-up and treatment appear to be needed

Validity of the Brief Test of Adult Cognition by Telephone in Level 1 Trauma Center Patients Six Months Post-Traumatic Brain Injury: A TRACK-TBI Study

Our objective was to examine the construct validity of the Brief Test of Adult Cognition by Telephone (BTACT) and its relationship to traumatic brain injury (TBI) of differing severities. Data were analyzed on 1422 patients with TBI and 170 orthopedic trauma controls (OTC) from the multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Participants were assessed at 6 months post-injury with the BTACT and an in-person neuropsychological battery. We examined the BTACT's factor structure, factorial group invariance, convergent and discriminant validity, and relationship to TBI and TBI severity. Confirmatory factor analysis supported both a 1-factor model and a 2-factor model comprising correlated Episodic Memory and Executive Function (EF) factors. Both models demonstrated strict invariance across TBI severity and OTC groups. Correlations between BTACT and criterion measures suggested that the BTACT memory indices predominantly reflect verbal episodic memory, whereas the BTACT EF factor correlated with a diverse range of cognitive tests. Although the EF factor and other BTACT indices showed significant relationships with TBI and TBI severity, some group effect sizes were larger for more comprehensive in-person cognitive tests than the BTACT. The BTACT is a promising, brief, phone-based cognitive screening tool for patients with TBI. Although the BTACT's memory items appear to index verbal Episodic Memory, items that purport to assess EFs may reflect a broader array of cognitive domains. The sensitivity of the BTACT to TBI severity is lower than domain-specific neuropsychological measures, suggesting it should not be used as a substitute for comprehensive, in-person cognitive testing at 6 months post-TBI

Repetitive Head Impact Exposure in College Football Following an NCAA Rule Change to Eliminate Two-A-Day Preseason Practices: A Study from the NCAA-DoD CARE Consortium

Repetitive head impact exposure sustained by athletes of contact sports has been hypothesized to be a mechanism for concussion and a possible explanation for the high degree of variability in sport-related concussion biomechanics. In an attempt to limit repetitive head impact exposure during the football preseason, the NCAA eliminated two-a-day practices in 2017, while maintaining the total number of team practice sessions. The objective of this study was to quantify head impact exposure during the preseason and regular season in Division I college football athletes to determine whether the 2017 NCAA ruling decreased head impact exposure. 342 unique athletes from five NCAA Division I Football Bowl Subdivision (FBS) programs were consented and enrolled. Head impacts were recorded using the Head Impact Telemetry (HIT) System during the entire fall preseasons and regular seasons in 2016 and 2017. Despite the elimination of two-a-day practices, the number of preseason contact days increased in 2017, with an increase in average hourly impact exposure (i.e., contact intensity), resulting in a significant increase in total head impact burden (+ 26%) for the 2017 preseason. This finding would indicate that the 2017 NCAA ruling was not effective at reducing the head impact burden during the football preseason. Additionally, athletes sustained a significantly higher number of recorded head impacts per week (+ 40%) during the preseason than the regular season, implicating the preseason as a time of elevated repetitive head impact burden. With increased recognition of a possible association between repetitive head impact exposure and concussion, increased preseason exposure may predispose certain athletes to a higher risk of concussion during the preseason and regular season. Accordingly, efforts at reducing concussion incidence in contact sports should include a reduction in overall head impact exposure