Diverging volumetric trajectories following pediatric traumatic brain injury.

Traumatic brain injury (TBI) is a significant public health concern, and can be especially disruptive in children, derailing on-going neuronal maturation in periods critical for cognitive development. There is considerable heterogeneity in post-injury outcomes, only partially explained by injury severity. Understanding the time course of recovery, and what factors may delay or promote recovery, will aid clinicians in decision-making and provide avenues for future mechanism-based therapeutics. We examined regional changes in brain volume in a pediatric/adolescent moderate-severe TBI (msTBI) cohort, assessed at two time points. Children were first assessed 2-5 months post-injury, and again 12 months later. We used tensor-based morphometry (TBM) to localize longitudinal volume expansion and reduction. We studied 21 msTBI patients (5 F, 8-18 years old) and 26 well-matched healthy control children, also assessed twice over the same interval. In a prior paper, we identified a subgroup of msTBI patients, based on interhemispheric transfer time (IHTT), with significant structural disruption of the white matter (WM) at 2-5 months post injury. We investigated how this subgroup (TBI-slow, N = 11) differed in longitudinal regional volume changes from msTBI patients (TBI-normal, N = 10) with normal WM structure and function. The TBI-slow group had longitudinal decreases in brain volume in several WM clusters, including the corpus callosum and hypothalamus, while the TBI-normal group showed increased volume in WM areas. Our results show prolonged atrophy of the WM over the first 18 months post-injury in the TBI-slow group. The TBI-normal group shows a different pattern that could indicate a return to a healthy trajectory

Functional Brain Hyperactivations Are Linked to an Electrophysiological Measure of Slow Interhemispheric Transfer Time after Pediatric Moderate/Severe Traumatic Brain Injury.

Increased task-related blood oxygen level dependent (BOLD) activation is commonly observed in functional magnetic resonance imaging (fMRI) studies of moderate/severe traumatic brain injury (msTBI), but the functional relevance of these hyperactivations and how they are linked to more direct measures of neuronal function remain largely unknown. Here, we investigated how working memory load (WML)-dependent BOLD activation was related to an electrophysiological measure of interhemispheric transfer time (IHTT) in a sample of 18 msTBI patients and 26 demographically matched controls from the UCLA RAPBI (Recovery after Pediatric Brain Injury) study. In the context of highly similar fMRI task performance, a subgroup of TBI patients with slow IHTT had greater BOLD activation with higher WML than both healthy control children and a subgroup of msTBI patients with normal IHTT. Slower IHTT treated as a continuous variable was also associated with BOLD hyperactivation in the full TBI sample and in controls. Higher WML-dependent BOLD activation was related to better performance on a clinical cognitive performance index, an association that was more pronounced within the patient group with slow IHTT. Our previous work has shown that a subgroup of children with slow IHTT after pediatric msTBI has increased risk for poor white matter organization, long-term neurodegeneration, and poor cognitive outcome. BOLD hyperactivations after msTBI may reflect neuronal compensatory processes supporting higher-order capacity demanding cognitive functions in the context of inefficient neuronal transfer of information. The link between BOLD hyperactivations and slow IHTT adds to the multi-modal validation of this electrophysiological measure as a promising biomarker

Association of Blood Biomarkers With Acute Sport-Related Concussion in Collegiate Athletes: Findings From the NCAA and Department of Defense CARE Consortium

Importance: There is potential scientific and clinical value in validation of objective biomarkers for sport-related concussion (SRC). Objective: To investigate the association of acute-phase blood biomarker levels with SRC in collegiate athletes. Design, Setting, and Participants: 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. Main Outcomes and Measures: 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. Results: 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). Conclusions and Relevance: 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

Environmental Effects of Hydrokinetic Turbines on Fish: Desktop and Laboratory Flume Studies

This collection of three reports describes desktop and laboratory flume studies that provide information to support assessment of the potential for injury and mortality of fish that encounter hydrokinetic turbines of various designs installed in tidal and river environments. Behavioral responses to turbine exposure also are investigated to support assessment of the potential for disruptions to upstream and downstream movements of fish. The studies: (1) conducted an assessment of potential injury mechanisms using available data from studies with conventional hydro turbines; (2) developed theoretical models for predicting blade strike probabilities and mortality rates; and (3) performed flume testing with three turbine designs and several fish species and size groups in two laboratory flumes to estimate survival rates and document fish behavior. The project yielded three reports which this document comprises. The three constituent documents are addressed individually below Fish Passage Through Turbines: Application of Conventional Hydropower Data to Hydrokinetic Technologies Fish passing through the blade sweep of a hydrokinetic turbine experience a much less harsh physical environment than do fish entrained through conventional hydro turbines. The design and operation of conventional turbines results in high flow velocities, abrupt changes in flow direction, relatively high runner rotational and blade speeds, rapid and significant changes in pressure, and the need for various structures throughout the turbine passageway that can be impacted by fish. These conditions generally do not occur or are not significant factors for hydrokinetic turbines. Furthermore, compared to conventional hydro turbines, hydrokinetic turbines typically produce relatively minor changes in shear, turbulence, and pressure levels from ambient conditions in the surrounding environment. Injuries and mortality from mechanical injuries will be less as well, mainly due to low rotational speeds and strike velocities, and an absence of structures that can lead to grinding or abrasion injuries. Additional information is needed to rigorously assess the nature and magnitude of effects on individuals and populations, and to refine criteria for design of more fish-friendly hydrokinetic turbines. Evaluation of Fish Injury and Mortality Associated with Hydrokinetic Turbines Flume studies exposed fish to two hydrokinetic turbine designs to determine injury and survival rates and to assess behavioral responses. Also, a theoretical model developed for predicting strike probability and mortality of fish passing through conventional hydro turbines was adapted for use with hydrokinetic turbines and applied to the two designs evaluated during flume studies. The flume tests were conducted with the Lucid spherical turbine (LST), a Darrieus-type (cross flow) turbine, and the Welka UPG, an axial flow propeller turbine. Survival rates for rainbow trout tested with the LST were greater than 98% for both size groups and approach velocities evaluated. Turbine passage survival rates for rainbow trout and largemouth bass tested with the Welka UPG were greater than 99% for both size groups and velocities evaluated. Injury rates of turbine-exposed fish were low with both turbines and generally comparable to control fish. Video observations of the LST demonstrated active avoidance of turbine passage by a large proportion fish despite being released about 25 cm upstream of the turbine blade sweep. Video observations from behavior trials indicated few if any fish pass through the turbines when released farther upstream. The theoretical predictions for the LST indicated that strike mortality would begin to occur at an ambient current velocity of about 1.7 m/s for fish with lengths greater than the thickness of the leading edge of the blades. As current velocities increase above 1.7 m/s, survival was predicted to decrease for fish passing through the LST, but generally remained high (greater than 90%) for fish less than 200 mm in length. Strike mortality was not predicted to occur during passage through a Welka UPG turbine at ambient current velocities less than about 2.5 m/s. Survival and Behavior of Juvenile Atlantic Salmon and Adult American Shad on Exposure to a Hydrokinetic Turbine This report describes a series of experiments designed to measure the effect of exposure to a full-scale, vertical axis hydrokinetic turbine on downstream migrating juvenile Atlantic salmon and upstream migrating adult American shad. Studies were performed in a large-scale, open-channel flume, and all individuals approached the turbine under volitional control. No injuries were observed, and there was no measurable increase in mortality associated with turbine passage. Exposure to the turbine elicited behavioral responses from both species, however, with salmon passing primarily over the downrunning blades. Shad movement was impeded in the presence of the device, as indicated by fewer attempts of shorter duration and reduced distance of ascent up the flume. More work should be performed in both laboratory and field conditions to determine the extent to which observed effects are likely to influence fish in riverine environments. Analysis is needed to assess the potential for multiple units to lead to greater mortality rates or impacts on fish movements and migrations. Additionally, future research should focus on expanding the existing data by developing better estimates of encounter and avoidance probabilities

Environmental Effects of Hydrokinetic Turbines on Fish: Desktop and Laboratory Flume Studies

This collection of three reports describes desktop and laboratory flume studies that provide information to support assessment of the potential for injury and mortality of fish that encounter hydrokinetic turbines of various designs installed in tidal and river environments. Behavioral responses to turbine exposure also are investigated to support assessment of the potential for disruptions to upstream and downstream movements of fish. The studies: (1) conducted an assessment of potential injury mechanisms using available data from studies with conventional hydro turbines; (2) developed theoretical models for predicting blade strike probabilities and mortality rates; and (3) performed flume testing with three turbine designs and several fish species and size groups in two laboratory flumes to estimate survival rates and document fish behavior. The project yielded three reports which this document comprises. The three constituent documents are addressed individually below Fish Passage Through Turbines: Application of Conventional Hydropower Data to Hydrokinetic Technologies Fish passing through the blade sweep of a hydrokinetic turbine experience a much less harsh physical environment than do fish entrained through conventional hydro turbines. The design and operation of conventional turbines results in high flow velocities, abrupt changes in flow direction, relatively high runner rotational and blade speeds, rapid and significant changes in pressure, and the need for various structures throughout the turbine passageway that can be impacted by fish. These conditions generally do not occur or are not significant factors for hydrokinetic turbines. Furthermore, compared to conventional hydro turbines, hydrokinetic turbines typically produce relatively minor changes in shear, turbulence, and pressure levels from ambient conditions in the surrounding environment. Injuries and mortality from mechanical injuries will be less as well, mainly due to low rotational speeds and strike velocities, and an absence of structures that can lead to grinding or abrasion injuries. Additional information is needed to rigorously assess the nature and magnitude of effects on individuals and populations, and to refine criteria for design of more fish-friendly hydrokinetic turbines. Evaluation of Fish Injury and Mortality Associated with Hydrokinetic Turbines Flume studies exposed fish to two hydrokinetic turbine designs to determine injury and survival rates and to assess behavioral responses. Also, a theoretical model developed for predicting strike probability and mortality of fish passing through conventional hydro turbines was adapted for use with hydrokinetic turbines and applied to the two designs evaluated during flume studies. The flume tests were conducted with the Lucid spherical turbine (LST), a Darrieus-type (cross flow) turbine, and the Welka UPG, an axial flow propeller turbine. Survival rates for rainbow trout tested with the LST were greater than 98% for both size groups and approach velocities evaluated. Turbine passage survival rates for rainbow trout and largemouth bass tested with the Welka UPG were greater than 99% for both size groups and velocities evaluated. Injury rates of turbine-exposed fish were low with both turbines and generally comparable to control fish. Video observations of the LST demonstrated active avoidance of turbine passage by a large proportion fish despite being released about 25 cm upstream of the turbine blade sweep. Video observations from behavior trials indicated few if any fish pass through the turbines when released farther upstream. The theoretical predictions for the LST indicated that strike mortality would begin to occur at an ambient current velocity of about 1.7 m/s for fish with lengths greater than the thickness of the leading edge of the blades. As current velocities increase above 1.7 m/s, survival was predicted to decrease for fish passing through the LST, but generally remained high (greater than 90%) for fish less than 200 mm in length. Strike mortality was not predicted to occur during passage through a Welka UPG turbine at ambient current velocities less than about 2.5 m/s. Survival and Behavior of Juvenile Atlantic Salmon and Adult American Shad on Exposure to a Hydrokinetic Turbine This report describes a series of experiments designed to measure the effect of exposure to a full-scale, vertical axis hydrokinetic turbine on downstream migrating juvenile Atlantic salmon and upstream migrating adult American shad. Studies were performed in a large-scale, open-channel flume, and all individuals approached the turbine under volitional control. No injuries were observed, and there was no measurable increase in mortality associated with turbine passage. Exposure to the turbine elicited behavioral responses from both species, however, with salmon passing primarily over the downrunning blades. Shad movement was impeded in the presence of the device, as indicated by fewer attempts of shorter duration and reduced distance of ascent up the flume. More work should be performed in both laboratory and field conditions to determine the extent to which observed effects are likely to influence fish in riverine environments. Analysis is needed to assess the potential for multiple units to lead to greater mortality rates or impacts on fish movements and migrations. Additionally, future research should focus on expanding the existing data by developing better estimates of encounter and avoidance probabilities

Plasma Biomarker Concentrations Associated With Return to Sport Following Sport-Related Concussion in Collegiate Athletes—A Concussion Assessment, Research, and Education (CARE) Consortium Study

Importance: Identifying plasma biomarkers associated with the amount of time an athlete may need before they return to sport (RTS) following a sport-related concussion (SRC) is important because it may help to improve the health and safety of athletes. Objective: To examine whether plasma biomarkers can differentiate collegiate athletes who RTS in less than 14 days or 14 days or more following SRC. Design, Setting, and Participants: This multicenter prospective diagnostic study, conducted by the National Collegiate Athletics Association–Department of Defense Concussion Assessment, Research, and Education Consortium, included 127 male and female athletes who had sustained an SRC while enrolled at 6 Concussion Assessment, Research, and Education Consortium Advanced Research Core sites as well as 2 partial–Advanced Research Core military service academies. Data were collected between February 2015 and May 2018. Athletes with SRC completed clinical testing and blood collection at preseason (baseline), postinjury (0-21 hours), 24 to 48 hours postinjury, time of symptom resolution, and 7 days after unrestricted RTS. Main Outcomes and Measures: A total of 3 plasma biomarkers (ie, total tau protein, glial fibrillary acidic protein [GFAP], and neurofilament light chain protein [Nf-L]) were measured using an ultrasensitive single molecule array technology and were included in the final analysis. RTS was examined between athletes who took less than 14 days vs those who took 14 days or more to RTS following SRC. Linear mixed models were used to identify significant interactions between period by RTS group. Area under the receiver operating characteristic curve analyses were conducted to examine whether these plasma biomarkers could discriminate between RTS groups. Results: The 127 participants had a mean (SD) age of 18.9 (1.3) years, and 97 (76.4%) were men; 65 (51.2%) took less than 14 days to RTS, and 62 (48.8%) took 14 days or more to RTS. Linear mixed models identified significant associations for both mean (SE) plasma total tau (24-48 hours postinjury, <14 days RTS vs ≥14 days RTS: −0.65 [0.12] pg/mL vs −0.14 [0.14] pg/mL; P = .008) and GFAP (postinjury, 14 days RTS vs ≥14 days RTS: 4.72 [0.12] pg/mL vs 4.39 [0.11] pg/mL; P = .04). Total tau at the time of symptom resolution had acceptable discrimination power (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.63-0.86; P < .001). We also examined a combined plasma biomarker panel that incorporated Nf-L, GFAP, and total tau at each period to discriminate RTS groups. Although the analyses did reach significance at each time period when combined, results indicated that they were poor at distinguishing the groups (area under the receiver operating characteristic curve, <0.7). Conclusions and Relevance: The findings of this study suggest that measures of total tau and GFAP may identify athletes who will require more time to RTS. However, further research is needed to improve our ability to determine recovery following an SRC.This publication was made possible with support from the Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium, funded, in part by the NCAA and the Department of Defense. The US Army Medical Research Acquisition Activity, 820 Chandler St, Ft Detrick, MD 21702, is the awarding and administering acquisition office. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Psychological Health and Traumatic Brain Injury Program under award No. W81XWH-14-2-0151

A microfluidic-FCS platform for investigation on the dissociation of Sp1-DNA complex by doxorubicin

The transcription factor (TF) Sp1 is a well-known RNA polymerase II transcription activator that binds to GC-rich recognition sites in a number of essential cellular and viral promoters. In addition, direct interference of Sp1 binding to DNA cognate sites using DNA-interacting compounds may provide promising therapies for suppression of cancer progression and viral replication. In this study, we present a rapid, sensitive and cost-effective evaluation of a GC intercalative drug, doxorubicin (DOX), in dissociating the Sp1–DNA complex using fluorescence correlation spectroscopy (FCS) in a microfluidic system. FCS allows assay miniaturization without compromising sensitivity, making it an ideal analytical method for integration of binding assays into high-throughput, microfluidic platforms. A polydimethylsiloxane (PDMS)-based microfluidic chip with a mixing network is used to achieve specific drug concentrations for drug titration experiments. Using FCS measurements, the IC(50) of DOX on the dissociation of Sp1–DNA complex is estimated to be 0.55 μM, which is comparable to that measured by the electrophoretic mobility shift assay (EMSA). However, completion of one drug titration experiment on the proposed microfluidic-FCS platform is accomplished using only picograms of protein and DNA samples and less than 1 h total assay time, demonstrating vast improvements over traditional ensemble techniques

Consensus statement on concussion in sport—the 5 th international conference on concussion in sport held in Berlin, October 2016

The 2017 Concussion in Sport Group (CISG) consensus statement is designed to build on the principles outlined in the previous statements1–4 and to develop further conceptual understanding of sport-related concussion (SRC) using an expert consensus-based approach. This document is developed for physicians and healthcare providers who are involved in athlete care, whether at a recreational, elite or professional level. While agreement exists on the principal messages conveyed by this document, the authors acknowledge that the science of SRC is evolving and therefore individual management and return-to-play decisions remain in the realm of clinical judgement. This consensus document reflects the current state of knowledge and will need to be modified as new knowledge develops. It provides an overview of issues that may be of importance to healthcare providers involved in the management of SRC. This paper should be read in conjunction with the systematic reviews and methodology paper that accompany it. First and foremost, this document is intended to guide clinical practice; however, the authors feel that it can also help form the agenda for future research relevant to SRC by identifying knowledge gaps

The ENIGMA sports injury working group - an international collaboration to further our understanding of sport-related brain injury

Sport-related brain injury is very common, and the potential long-term effects include a wide range of neurological and psychiatric symptoms, and potentially neurodegeneration. Around the globe, researchers are conducting neuroimaging studies on primarily homogenous samples of athletes. However, neuroimaging studies are expensive and time consuming, and thus current findings from studies of sport-related brain injury are often limited by small sample sizes. Further, current studies apply a variety of neuroimaging techniques and analysis tools which limit comparability among studies. The ENIGMA Sports Injury working group aims to provide a platform for data sharing and collaborative data analysis thereby leveraging existing data and expertise. By harmonizing data from a large number of studies from around the globe, we will work towards reproducibility of previously published findings and towards addressing important research questions with regard to diagnosis, prognosis, and efficacy of treatment for sport-related brain injury. Moreover, the ENIGMA Sports Injury working group is committed to providing recommendations for future prospective data acquisition to enhance data quality and scientific rigor