Purpose Evaluate the discriminatory ability of two clinical measures and one device-based measure of gait and balance for concussed youth. Methods We enrolled 81 cases and 90 controls age 14-18 yr old from August 2017 to June 2018. Controls were recruited from a suburban high school, and cases were recruited from the concussion program of an academic pediatric tertiary care center. Tests included two clinical measures: 1) complex tandem gait, scored as sway/errors walking forward and backward eyes open and closed; 2) Modified Balance Error Scoring System (mBESS), scored as total number of errors on three standing tasks; and one device-based measure; 3) Modified Clinical Test of Sensory Interaction and Balance (mCTSIB) using the Biodex Biosway Balance System, scored as a sway index. Sensitivity, specificity, ideal cutpoint, and area under the receiver operating characteristic curve (AUC) were calculated for all test components. Results Ideal cutpoint for total number of sway/errors for tandem gait = 5, sensitivity 41%, specificity 90%. Ideal cutpoint for total mBESS errors = 4, sensitivity 55%, specificity 75%. Ideal cutpoint for mCTSIB = 1.37, sensitivity 37%, specificity 88%. Among each test, some individual components outperformed overall composites, in particular tandem gait (specificity forward eyes open = 99%, sensitivity backward eyes closed = 81%). Among the 40 cases and 65 controls with all three assessments, AUC (95% CI) for tandem gait = 0.63 (0.52,0.75), mBESS = 0.70 (0.60,0.81), and mCTSIB = 0.54 (0.42,0.66). Conclusions A device-based measure of balance did not produce better discriminatory ability than two clinical assessments. Complex tandem gait has the additional benefit of being an easy-to-perform and graded test with highly sensitive and specific individual components.

Background: Passive auditory oddball tests are effort independent assessments that evaluate auditory processing and are suitable for paediatric patient groups. Our goal was to develop a two-tone auditory oddball test protocol and use this clinical assessment in an immature large animal model. Event-related potentials captured middle latency P1, N1, and P2 responses in 4-week old (N = 16, female) piglets using a custom piglet 32- electrode array on 3 non-consecutive days. The effect of target tone frequency (250 Hz and 4000 Hz) on middle latency responses were tested in a subset of animals. Results: Results show that infrequent target tone pulses elicit greater N1 amplitudes than frequent standard tone pulses. There was no effect of day. Electrodes covering the front of the head tend to elicit greater waveform responses. P2 amplitudes increased for higher frequency target tones (4000 Hz) than the regular 1000 Hz target tones (p < 0.05). Conclusions: Two-tone auditory oddball tests produced consistent responses day-to-day. This clinical assessment was successful in the immature large animal model.

Background Nordihydroguaiaretic acid (NDGA) is a plant extract that has been shown to act as a free radical scavenger and pluripotent inhibitor of pro-inflammatory cytokines, two major cellular processes involved in the pathophysiology of sepsis. We investigated whether NDGA would improve markers of organ injury as well as survival in a rodent model of sepsis. Methods Abdominal sepsis was induced by cecal ligation and double puncture (CLP) in male Sprague- Dawley rats. NDGA was administered either at the time of injury (pre-) or 6 hours later (post-treatment). A sham surgery group and a vehicle only group were also followed as controls. Blood and lung tissue were collected 24 h after CLP. Lung tissue was used for histopathologic analysis and to measure pulmonary edema. Arterial oxygenation was measured directly to generate PaO2/FiO2, and markers of renal injury (blood urea nitrogen), liver injury (alanine aminotransferase), and tissue hypoxia (lactate) were measured. In a separate set of animals consisting of the same treatment groups, animals were followed for up to 36 hours for survival. Results NDGA pre-treatment resulted in improved oxygenation, less lung edema, lower lactate, lower BUN, and reduced histologic lung injury. NDGA post-treatment resulted in less lung edema, lower lactate, lower BUN, and less histologic lung injury, but did not significantly change oxygenation. None of the NDGA treatment groups statistically affected ALT or creatinine. NDGA pre-treatment showed improved survival compared with control CLP animals at 36 hours, while post-treatment did not. Conclusions NDGA represents a novel pleiotropic anti-inflammatory agent with potential clinical utility for modulation of organ injury secondary to sepsis.

Some patients infected with the Coronavirus Disease 2019 (COVID-19) require endotracheal intubation, an aerosol-generating procedure that is believed to result in viral transmission to personnel performing the procedure. Additionally, donning and doffing personal protective equipment can be time consuming. In particular, doffing requires strict protocol adherence to avoid exposure. We describe the Emory Healthcare intubation team approach during the COVID-19 pandemic. This structure resulted in only 1 team member testing positive for COVID-19 despite 253 patient intubations over a 6-week period with 153 anesthesia providers on service.

Background Recent advances in technology have enabled the development of head impact sensors, which provide a unique opportunity for sports medicine researchers to study head kinematics in contact sports. Studies have suggested that video or observer confirmation of head impact sensor data is required to remove false positives. In addition, manufacturer filtering algorithms may be ineffective in identifying true positives and removing true negatives. Purpose To (1) identify the percentage of video-confirmed events recorded by headband-mounted sensors in high school soccer through video analysis, overall and by sex; (2) compare video-confirmed events with the classification by the manufacturer filtering algorithms; and (3) quantify and compare the kinematics of true- and false-positive events. Study Design Cohort study; Level of evidence, 2. Methods Adolescent female and male soccer teams were instrumented with headband-mounted impact sensors (SIM-G; Triax Technologies) during games over 2 seasons of suburban high school competition. Sensor data were sequentially reduced to remove events recorded outside of game times, associated with players not on the pitch (ie, field) and players outside the field of view of the camera. With video analysis, the remaining sensor-recorded events were identified as an impact event, trivial event, or nonevent. The mechanisms of impact events were identified. The classifications of sensor-recorded events by the SIM-G algorithm were analyzed. Results A total of 6796 sensor events were recorded during scheduled varsity game times, of which 1893 (20%) were sensor-recorded events associated with players on the pitch in the field of view of the camera during verified game times. Most video-confirmed events were impact events (n = 1316, 70%), followed by trivial events (n = 396, 21%) and nonevents (n = 181, 10%). Female athletes had a significantly higher percentage of trivial events and nonevents with a significantly lower percentage of impact events. Most impact events were head-to-ball impacts (n = 1032, 78%), followed by player contact (n = 144, 11%) and falls (n = 129, 10%) with no significant differences between male and female teams. The SIM-G algorithm correctly identified 70%, 52%, and 66% of video-confirmed impact events, trivial events, and nonevents, respectively. Conclusion Video confirmation is critical to the processing of head impact sensor data. Percentages of video-confirmed impact events, trivial events, and nonevents vary by sex in high school soccer. Current manufacturer filtering algorithms and magnitude thresholds are ineffective at correctly classifying sensor-recorded events and should be used with caution.

Traumatic brain injury (TBI) can cause biochemical and metabolomic alterations in the brain tissue and serum. These alterations can be used for diagnosis and prognosis of TBI. Here, the serum concentrations of seventeen amino acids (AA) were studied for their potential utility as biomarkers of TBI. Twenty-five female, 4-week-old piglets received diffuse (n = 13) or focal (n = 12) TBI. Blood samples were obtained both pre-injury and at either 24-h or 4-days post-TBI. To find a robust panel of biomarkers, the results of focal and diffuse TBIs were combined and multivariate logistic regression analysis, coupled with the best subset selection technique and repeated k-fold cross-validation method, was used to perform a thorough search of all possible subsets of AAs. The combination of serum glycine, taurine, and ornithine was optimal for TBI diagnosis, with 80% sensitivity and 86% overall prediction rate, and showed excellent TBI diagnostic performance, with 100% sensitivity and 78% overall prediction rate, on a separate validation dataset including four uninjured and five injured animals. We found that combinations of biomarkers outperformed any single biomarker. We propose this 3-AA serum biomarker panel to diagnose mild-to-moderate focal/diffuse TBI. The systematic approaches implemented herein can be used for combining parameters from various TBI assessments to develop/evaluate optimal multi-factorial diagnostic/prognostic TBI metrics.

Skull fractures are common injuries in young children, typically caused by accidental falls and child abuse. The paucity of detailed biomechanical data from real-world trauma in children has hampered development of biomechanical thresholds for skull fracture in infants. The objectives of this study were to identify biomechanical metrics to predict skull fracture, determine threshold values associated with fracture, and develop skull fracture risk curves for low-height falls in infants. To achieve these objectives, we utilized an integrated approach consisting of case evaluation, anthropomorphic reconstruction, and finite element simulation. Four biomechanical candidates for predicting skull fracture were identified (first principal stress, first principal strain, shear stress, and von Mises stress) and evaluated against well-witnessed falls in infants (0–6 months). Among the predictor candidates, first principal stress and strain correlated best with the occurrence of parietal skull fracture. The principal stress and strain thresholds associated with 50 and 95% probability of parietal skull fracture were 25.229 and 36.015 MPa and 0.0464 and 0.0699, respectively. Risk curves using these predictors determined that infant falls from 0.3 m had a low probability (0–54%) to result in parietal skull fracture, particularly with carpet impact (0–1%). Head-first falls from 0.9 m had a high probability of fracture (86–100%) for concrete impact and a moderate probability (34–81%) for carpet impact. Probabilities of fracture in 0.6 m falls were dependent on impact surface. Occipital impacts from 0.9 m onto the concrete also had the potential (27–90% probability) to generate parietal skull fracture. These data represent a multi-faceted biomechanical assessment of infant skull fracture risk and can assist in the differential diagnosis for head trauma in children.

Background: Acute respiratory distress syndrome (ARDS) is a severe form of lung injury characterized by damage to the epithelial barrier with subsequent pulmonary edema and hypoxic respiratory failure. ARDS is a significant medical problem in intensive care units with associated high care costs. There are many potential causes of ARDS; however, alveolar injury associated with mechanical ventilation, termed ventilator-induced lung injury (VILI), remains a well-recognized contributor. It is thus critical to understand the mechanism of VILI. Based on our published preliminary data, we hypothesized that the endoplasmic reticulum (ER) stress response molecule Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) plays a role in transmitting mechanosensory signals the alveolar epithelium. Methods: ER stress signal responses to mechanical stretch were studied in ex-vivo ventilated pig lungs. To explore the effect of PERK inhibition on VILI, we ventilated live rats and compared lung injury parameters to non-ventilated controls. The effect of stretch-induced epithelial ER Ca2+signaling on PERK was studied in stretched alveolar epithelial monolayers. To confirm the activation of PERK in human disease, ER stress signaling was compared between ARDS and non-ARDS lungs. Results: Our studies revealed increased PERK-specific ER stress signaling in response to overstretch. PERK inhibition resulted in dose-dependent improvement of alveolar inflammation and permeability. Our data indicate that stretch-induced epithelial ER Ca2+release is an activator of PERK. Experiments with human lung tissue confirmed PERK activation by ARDS. Conclusion: Our study provides evidences that PERK is a mediator stretch signals in the alveolar epithelium.

Mechanical ventilation can be damaging, and can cause or exacerbate ventilator-induced lung injury (VILI). The human epidermal growth factor receptor (HER) ligand neuregulin-1 (NRG1) activates HER2 heterodimerization with HER3, and has been implicated in inflammatory injuries. We hypothesized that HER2 activation contributes to VILI.We analyzed a database of differentially expressed genes between cyclically stretched and unstretched rat alveolar epithelial cells (RAEC) for HER ligands and validated the differential expression. The effect of the ligand and HER2 inhibition on RAEC permeability was tested, and in vivo relevance was assessed in a rat model of VILI. Analysis of our expression array revealed the upregulation of NRG1 and amphiregulin (AREG) with stretch. NRG1 protein, but not AREG, increased after stretch in culture media. Treatment with an NRG1-cleavage inhibitor (TAPI2) or an inhibitor of NRG1-binding (anti-HER3 antibody) reduced HER2 phosphorylation and partially mitigated stretch-induced permeability, with the upregulation of claudin-7. The results were reproduced by treatment with a direct inhibitor of HER2 phosphorylation (AG825). The transfection of microRNA miR-15b, predicted to negatively regulate NRG1, also attenuated stretch-induced permeability, and was associated with lower NRG1 mRNA levels. In rats ventilated at damaging tidal volumes, AG825 partly attenuated VILI.We concluded that cyclic stretch activates HER2 via the HER3 ligand NRG1, leading to increased permeability. Outcomes were mitigated by the downregulation of NRG1, prevention of NRG1 binding, and most strongly by the direct inhibition of HER2. In vivo HER2 inhibition also attenuated VILI. Ligand-dependent HER2 activation is a potential target for reducing VILI.

With the growing rate of traumatic brain injury (TBI), there is an increasing interest in validated tools to predict and prevent brain injuries. Finite element models (FEM) are valuable tools to estimate tissue responses, predict probability of TBI, and guide the development of safety equipment. In this study, we developed and validated an anisotropic pig brain multi-scale FEM by explicitly embedding the axonal tract structures and utilized the model to simulate experimental TBI in piglets undergoing dynamic head rotations. Binary logistic regression, survival analysis with Weibull distribution, and receiver operating characteristic curve analysis, coupled with repeated k-fold cross-validation technique, were used to examine 12 FEM-derived metrics related to axonal/brain tissue strain and strain rate for predicting the presence or absence of traumatic axonal injury (TAI). All 12 metrics performed well in predicting of TAI with prediction accuracy rate of 73–90%. The axonal-based metrics outperformed their rival brain tissue-based metrics in predicting TAI. The best predictors of TAI were maximum axonal strain times strain rate (MASxSR) and its corresponding optimal fraction-based metric (AF-MASxSR7.5) that represents the fraction of axonal fibers exceeding MASxSR of 7.5 s−1. The thresholds compare favorably with tissue tolerances found in in–vitro/in–vivo measurements in the literature. In addition, the damaged volume fractions (DVF) predicted using the axonal-based metrics, especially MASxSR (DVF = 0.05–4.5%), were closer to the actual DVF obtained from histopathology (AIV = 0.02–1.65%) in comparison with the DVF predicted using the brain-related metrics (DVF = 0.11–41.2%). The methods and the results from this study can be used to improve model prediction of TBI in humans.