STUDY OBJECTIVE:To determine the diagnostic accuracy of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) for detecting clinically significant acute traumatic intracranial lesions in emergency department patients who undergo brain computed tomography (CT) after blunt trauma. METHODS:We conducted a retrospective study of 1,867 patients aged more than or equal to 18 years, who presented with trauma-related complaints, underwent brain CT, and had residual samples collected less than or equal to 24 hours postinjury. We evaluated the diagnostic accuracy of GFAP and UCH-L1 using the Abbott i-STAT TBI Plasma test. Additionally, we assessed diagnostic accuracy within key clinical subgroups to define a proposed implementation cohort and assessed the diagnostic accuracy of the biomarkers within this cohort. RESULTS:Among 1,867 patients, 49 (2.6%) had clinically significant traumatic intracranial lesions. Elevated GFAP or UCH-L1 demonstrated 96% sensitivity (95% confidence interval [CI] 86% to 99%), 30% specificity (95% CI 28% to 32%), positive likelihood ratio (LR+) of 1.38 (95% CI 1.29 to 1.47), and negative likelihood ratio (LR-) of 0.13 (95% CI 0.03 to 0.53). Two patients had clinically significant CT lesions without elevated GFAP or UCH-L1. In the proposed implementation cohort of adults aged more than or equal to 18 years without coagulopathy elevated GFAP or UCH-L1 had a sensitivity of 100% (95% CI 86% to 100%), specificity of 33% (95% CI 31% to 36%), LR+ of 1.50 (95% CI 1.44 to 1.56), and LR- of 0.00 (95% CI 0.00 to 0.95). CONCLUSION:Plasma GFAP and UCH-L1 in combination, measured ≤24 hours postinjury, demonstrated high sensitivity for clinically significant acute traumatic intracranial lesions. Further research is needed to determine whether deploying these biomarkers in the proposed implementation cohort decreases avoidable brain CT scans.

BACKGROUND:Acute intoxication is common in patients evaluated for traumatic brain injury (TBI). However, the effect of elevated blood alcohol levels (BALs) on the diagnostic accuracy of FDA-cleared biomarkers for evaluating traumatic intracranial injury on computed tomography (CT) scan, namely, glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), has not been well studied. METHODS:We investigated the effect of significantly elevated (>300 mg/dL) and modestly elevated BAL (81-300 mg/dL) at emergency department presentation on the diagnostic accuracy of GFAP and UCH-L1 for predicting a positive CT in patients presenting to 18 U.S. Level I trauma centers within 24 h of TBI as part of the prospective, Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Plasma GFAP and UCH-L1 were measured using Abbott i-STAT Alinity and ARCHITECT assays. Discrimination was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS:Of 2320 TRACK-TBI participants studied, 54 (2.3%), 332 (14.3%), 1209 (52.1%), and 725 (31.3%) had significantly elevated BAL, modestly elevated BAL, nonelevated BAL (0-80 mg/dL), and no BAL available, respectively; 48.3% of the cohort had a positive brain CT. Those with significantly elevated and modestly elevated BAL were more likely to have positive CT (61.1% and 60.5% vs. 46.9% and 44.0%) and had higher plasma GFAP and UCH-L1 levels than those with nonelevated BAL and no BAL available. The AUC of GFAP and UCH-L1 combined for predicting CT positivity was higher in those with significantly elevated BAL (0.949) than those with modestly elevated BAL (0.858), nonelevated BAL (0.849), and no BAL available (0.883). CONCLUSIONS:Modestly and significantly elevated BAL does not lower the diagnostic accuracy of GFAP and UCH-L1 for predicting traumatic intracranial injury on CT. These biomarkers may be useful in decreasing avoidable brain CT imaging in persons with acute alcohol intoxication.

Introduction: After out-of-hospital cardiac arrest (OHCA) with return of spontaneous circulation (ROSC), hypoxic-ischemic brain injury is the leading cause of severe disability and death, but accurate, early prognostication and selection for neuroprotective therapies remains challenging. Additional early biomarkers could improve post-arrest care. Glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) are proteins associated with glial and neuronal injury. This study aimed to determine whether early blood levels of GFAP and UCH-L1 are associated with neurologic outcome. Methods: We retrospectively analyzed OHCA patients transported to a single urban academic ED over 15 months. Exclusions included traumatic arrests, prisoners, and pregnant patients. Blood samples were collected within 12 hours of ED arrival, and plasma was analyzed for GFAP and UCH-L1 using Abbott Alinity i system (Abbott Laboratories, Abbott Park, IL). Clinical and outcome data were obtained from the EMR and EMS registry. Neurologic outcome at discharge was assessed using the Cerebral Performance Category (CPC), with CPC 1–2 defined as neurologically intact. Biomarker concentrations were log-2 transformed and grouped using k-medians clustering to categorize data points with greater similarity within than between clusters to improve interpretability. Associations between biomarker clusters and outcomes were evaluated using covariate-adjusted logistic regression. Results: 171 patients were included. Median age was 53 years (IQR 41–54), and 72% were male. Most arrests were non-shockable (81%) and 47% were witnessed. Overall, 33% survived to discharge, and 28% were neurologically intact. Median time to sample collection was 6 hours (IQR 3–9). GFAP levels ranged from 0.9 to >50,000 pg/ml; UCH-L1 from 95.8 to >25,000 pg/ml. Results from covariate-adjusted analyses suggested dose-dependent associations between higher GFAP and UCH-L1 levels and decreased neurologically intact survival. Effects were most pronounced in the highest GFAP cluster (>895 pg/ml; aOR 0.11, 95% CI = 0.02–0.64) and highest UCH-L1 cluster (>9,947 pg/ml; aOR 0.21, 95% CI = 0.04–1.09). Conclusion: In this retrospective study, higher concentrations of early GFAP and UCH-L1 levels were associated with poorer neurologic outcomes at discharge. These biomarkers show promise and warrant further study for early prognostication and potential selection for early neuroprotective therapies.

Systemic and neuroinflammatory responses mediate secondary injuries after traumatic brain injury (TBI), which lead to adverse outcomes. Identifying biomarkers of secondary injury may enable early recognition of patients at risk of clinical decline and delineate targets for therapeutic modulation. The 18-center TRACK-TBI Study (years 2014-2018) enrolled patients who received head CT within 24-hours of TBI. In 394 TBI patients, 100 orthopedic trauma controls (OCs), and 67 healthy controls (HCs) with plasma biomarkers within 24-hours (MesoScale Diagnostics) and 6-month outcome, biomarker levels were compared between CT-positive/CT-negative TBI, Glasgow Coma Scale (GCS)=3-12/13-15, and unfavorable/favorable outcome (Glasgow Outcome Sale-Extended=1-4/5-8). Differences between medians (fold-change) and discrimination (AUC) were reported. Significance threshold p<0.002 (0.05÷26 biomarkers). Comparisons reported at p<0.0001(*) unless denoted. Eleven biomarkers differentiated TBI/HC, TBI/OC, TBI severity, and 6-month outcome. Fold-changes and AUCs were consistent across severity comparisons (CT+/CT-, GCS=3-12/13-15, respectively): interleukin-10 (IL-10; 6.4-fold*/7.6-fold*; AUC=0.81/0.89), IL-6 (4.6*/3.7*; AUC=0.82/0.87), IL-2 (3.3*/4.1*; AUC=0.82/0.85), tumor necrosis factor-alpha (TNFa; 2.3*/3.0*; AUC=0.81/0.85), IL-15 (1.4*/1.5*; AUC=0.77/0.85), c-reactive protein (CRP; 8.8*/10.2*; AUC=0.79/0.81), serum amyloid A (SAA; 19.8*/18.6*; AUC=0.78/0.0.80), IL-1b (3.4*/4.3*; AUC=0.76/0.83), IL-4 (3.4*/3.9*; AUC=0.74/0.79), IL-17a (1.7*/2.0*; AUC=0.69/0.74), IL-12p70 (1.4*/1.6*; AUC=0.65/0.70). Fold-changes and AUCs were consistent for unfavorable outcome: IL-10 (5.6-fold*/AUC=0.83), IL-6 (1.5*/AUC=0.75), IL-2 (3.9*/AUC=0.81), TNFa (2.8*/AUC=0.77), IL-15 (1.6*/AUC=0.79), CRP (4.9*/AUC=0.71), SAA (4.1*/AUC=0.67), IL-1b (2.7*/AUC=0.74), IL-4 (2.5*/AUC=0.73), IL-17a (2.1*/AUC=0.73), IL-12p70 (1.7*/AUC=0.70). Bivariate correlations (Spearman’s ρ>0.7) emerged amongst IL-1b, IL-2, IL-4, TNFa (with several other markers), and between CRP/SAA. We identified 11 blood-based inflammatory proteins with diagnostic and prognostic relevance (CRP, SAA, IL-1b, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-15, IL-17a, TNFa). These biomarkers distinguished TBI severity and 6-month unfavorable outcome with consistent magnitudes of association.

Introduction: For the 240,000 patients presenting to the emergency department (ED) annually with transient ischemic attack (TIA), a resource-intensive multimodal evaluation and possible admission to the hospital may help prevent a subsequent stroke. Multiple strategies to approach the location and timing of these evaluations exist. Using a nationally representative data source, we evaluated variation and trends in ED practices for patients with suspected TIA. Methods: Retrospective cross-sectional study of ED visits using the 2013-2021 National Emergency Department Sample, a 20% sample of ED encounters in the United States maintained by the Healthcare Cost and Utilization Project (HCUP). TIA diagnosis was determined by first-listed ICD-9 or -10 code. Imaging utilization was determined in discharged ED patients by CPT code for TIA related modalities. Factors associated with discharge from the ED in a TIA encounter were evaluated with a multivariable logistic regression. Results: Percentage of ED TIA patients discharged from the ED increased from 47% (95%CI 46-49) to 68% (95% CI 66-69) between 2013 and 2021. Average cost per discharged TIA encounter increased from $1559 (95% CI 1482-1635) to $2753 (95% CI 2649-2857). Imaging utilization in discharged TIA patients increased markedly between 2013 and 2021. In 2013, 3.6% (95% CI 2.8-4.4) of discharged TIA patients received a CTA Head during their evaluation, while in 2021 this had increased to 44%(95% CI 42-46). Logistic regression analysis for factors associated with discharge in ED TIA encounters in 2021 showed patients from rural areas were more likely to be discharged (OR 2.95 (95% CI 2.42-3.59) than those in densely populated areas (OR 0.68 (95% CI 0.54-0.86). Conclusion: Discharge rates for patients with TIA increased between 2013 and 2021, with a parallel increase in the ED charges for patients discharged with TIA. Utilization of imaging in the ED increased during the time interval and may explain some of this increased cost. This may suggest a shifting of previously inpatient TIA evaluations to the non-admitted ED setting. Likelihood of discharge with a TIA was inversely related with population density of the patient’s location. More resources should be focused on optimizing ED evaluation and follow up of TIA patients in non-urban areas.

BACKGROUND: Management of diabetic ketoacidosis (DKA) requires frequent point-of-care blood glucose (POCBG) measurements, often necessitating ICU admission and incurring substantial costs. Replacing hourly POCBG measurements with continuous glucose monitoring (CGM) could optimize DKA management by minimizing resource use and detecting hypoglycemic events earlier. However, the accuracy of CGM in DKA is not well established. RESEARCH QUESTION: What is the clinical and analytical accuracy of CGM in adults with DKA? STUDY DESIGN AND METHODS: This was a prospective observational study at a single academic medical center emergency department. Adults older than 18 years with DKA were included. Glucose was measured every 5 minutes via Dexcom G6 CGM and compared with hourly POCBG measurements until resolution of DKA. The primary outcome was proportion of paired CGM and POCBG values in Clarke error grid zones A and B. Additional outcomes included level of agreement via Bland-Altman plot, mean absolute relative difference, and time of first detection of glucose < 150 mg/dL. RESULTS: Twenty adult patients with DKA were studied. Mean age was 42 years, 60% were female, 70% had type I diabetes, and mean presenting pH was 7.17. Three hundred thirtyfour paired measurements from CGM and POCBG measurements were analyzed. Clarke error grid analysis revealed 97.0% of readings to be within zones A and B. Bland-Altman analysis showed the average difference between CGM and POCBG measurement was 26.0 mg/dL (95% limits of agreement, -70.7 to 122.6). Mean absolute relative difference was 28.6% (95% CI, 26.5%-30.6%). The first incidence of glucose < 150 mg/dL (n 1/4 14) was detected 28.9 minutes earlier by CGM than POCBG measurements. INTERPRETATION: In this study, CGM provided accurate measurements of blood glucose and identified missed opportunities for earlier intervention in adults with DKA. Future interventional trials can assess the impact of CGM-guided DKA management on patient outcomes, patient experience, and resource use.

Background/Objectives: Traumatic brain injury (TBI) is a complex condition and a leading cause of injury-related disability and death, with significant impacts on patient outcomes. Extracranial organ involvement plays a critical role in the outcome of patients following TBI. Method: This review aims to provide a comprehensive overview of the pathophysiology, clinical presentation, and challenges in diagnosing patients with autonomic dysfunction after TBI. The databases used in this review include PubMed/MEDLINE, Cochrane Central Register, and Scopus. Results: Of 172 articles identified for screening, 98 were ultimately included in the review. Conclusion: This review summarized the current evidence on the pathophysiology, clinical presentation, and diagnosis of early autonomic dysfunction. It also emphasizes the effects of autonomic dysfunction on end-organ damage. These insights aim to guide clinicians and researchers toward improving the care for and understanding of autonomic dysfunction in TBI patients, while underscoring the need for further research in this area.

We examined innate and antibody responses in C3PO clinical trial participants of coronavirus disease 2019 (COVID-19) convalescent plasma to identify predictors of disease progression. We found severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viremia in 64% of participants at enrollment, and we could also quantify viremia in approximately half of those samples using an RT-PCR assay. Viremia was associated with increased risk of disease progression (OR, 3.0; 95% CI, 1.7-5.0). Participants with viremia at baseline had lower SARS-CoV-2 binding antibody levels and higher proinflammatory cytokine levels, including IP-10 (CXCL10), TNF-α, calprotectin, and CRP. Disease progression correlated with extracellular vesicle levels from multiple cell types in the convalescent but not acute phase of the disease. Male sex predicted worse disease outcome and was associated with higher baseline levels of several proinflammatory cytokines. Viremia's strong predictive value for disease progression argues for further study of its use to predict which patients with COVID-19 might require more intensive therapy or monitoring.

BACKGROUND:Accrual of participants into clinical trials is a fundamental and important aspect for the management of trial progress. Monitoring of trial accrual often provides insight into the potential timing of key study events, such as interim analysis, as well as the feasibility of the overall trial to enroll the projected sample size in the original estimated timeline. METHODS:A Bayesian first order simple dynamic linear model with weakly informative priors is utilized to characterize enrollment rates temporally within pre-defined time windows (quarterly) for the duration of a trial. RESULTS:Application of the model to three ongoing clinical trials demonstrates the utility of the model to characterize the observed accrual patterns. Additionally, the applications demonstrate the flexibility of the model to react to variable accrual patterns without overreacting to the variability of accrual within a trial due to expected causes, such as seasonal variability in disease incidence, or unexpected causes, such as a global pandemic. CONCLUSIONS:Much statistical literature has been dedicated to predicting when key study events are likely to occur by utilizing current estimated rates of participant accrual; however, study teams, sponsors, and funding agencies have interest in the previous trends in participant accrual. This work presents an addition to the literature which allows parties interested in assessing trial progress to do so by providing a flexible framework for the standardized characterization of trial accrual which is not overly sensitive to the expected variability of trial accrual.

OBJECTIVE:Mild traumatic brain injury (mTBI) can lead to psychiatric and somatic symptoms for some patients, including posttraumatic headache (PTH) and depression. This study attempted to further establish the relationship between PTH and depression following mTBI and investigate whether the presence of PTH immediately following injury can identify patients at risk for developing depressive symptoms up to 6 months later. METHODS:This study was a secondary analysis of data from Head Injury Serum Markers for Assessing Response to Trauma (HeadSMART), a prospective study of adult patients in the emergency department with head injury. Participants included 265 patients who met criteria for mTBI and completed the Rivermead Post-Concussion Symptoms Questionnaire, to identify PTH within 24 hours after injury, and the Patient Health Questionnaire-9, to assess depressive symptoms during follow-up. Measures were completed at the initial visit immediately after the injury in the emergency department and at 1-, 3-, and 6-month follow-up visits. RESULTS:Patients with acute PTH (aPTH) at time of injury were more likely to report PTH at 1, 3, and 6 months. They also had more severe depressive symptoms and a greater likelihood of clinically significant depression at all time points. CONCLUSIONS:Patients with aPTH within 24 hours after injury were more likely to report continued symptoms of PTH and clinically significant depression at 1, 3, and 6 months. These findings provide support for using the presence of aPTH in the emergency department following mTBI as an indicator for monitoring persistent PTH and depressive symptoms in the postacute recovery period.