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Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1ß cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasome-dependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.
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INTRODUCTION: Major organ-based in vitro diagnostic (IVD) tests like ALT/AST for the liver and cardiac troponins for the heart are established, but an approved IVD blood test for the brain has been missing, highlighting a gap in medical diagnostics. AREAS COVERED: In response to this need, Abbott Diagnostics secured FDA clearance in 2021 for the i-STAT Alinity™, a point-of-care plasma blood test for mild traumatic brain injury (TBI). BioMerieux VIDAS, also approved in Europe, utilizes two brain-derived protein biomarkers: neuronal ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP). These biomarkers, which are typically present in minimal amounts in healthy individuals, are instrumental in diagnosing mild TBI with potential brain lesions. The study explores how UCH-L1 and GFAP levels increase significantly in the bloodstream following traumatic brain injury, aiding in early and accurate diagnosis. EXPERT OPINION: The introduction of the i-STAT Alinity™ and the Biomerieux VIDAS TBI blood tests mark a groundbreaking development in TBI diagnosis. It paves the way for the integration of TBI biomarker tools into clinical practice and therapeutic trials, enhancing the precision medicine approach by generating valuable data. This advancement is a critical step in addressing the long-standing gap in brain-related diagnostics and promises to revolutionize the management and treatment of mild TBI.
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Brain Concussion , Brain Injuries, Traumatic , Humans , Glial Fibrillary Acidic Protein , Ubiquitin Thiolesterase , Brain Injuries, Traumatic/diagnosis , Biomarkers , Hematologic Tests , Diagnostic Tests, RoutineABSTRACT
INTRODUCTION: Traumatic brain injury (TBI) is a major global health issue, resulting in debilitating consequences to families, communities, and health-care systems. Prior research has found that biomarkers aid in the pathophysiological characterization and diagnosis of TBI. Significantly, the FDA has recently cleared both a bench-top assay and a rapid point-of-care assays of tandem biomarker (UCH-L1/GFAP)-based blood test to aid in the diagnosis mTBI patients. With the global necessity of TBI biomarkers research, several major consortium multicenter observational studies with biosample collection and biomarker analysis have been created in the USA, Europe, and Canada. As each geographical region regulates its data and findings, the International Initiative for Traumatic Brain Injury Research (InTBIR) was formed to facilitate data integration and dissemination across these consortia. AREAS COVERED: This paper covers heavily investigated TBI biomarkers and emerging non-protein markers. Finally, we analyze the regulatory pathways for converting promising TBI biomarkers into approved in-vitro diagnostic tests in the United States, European Union, and Canada. EXPERT OPINION: TBI biomarker research has significantly advanced in the last decade. The recent approval of an iSTAT point of care test to detect mild TBI has paved the way for future biomarker clearance and appropriate clinical use across the globe.
Subject(s)
Brain Injuries, Traumatic , Biological Assay , Biomarkers , Brain Injuries, Traumatic/diagnosis , Europe , Humans , Point-of-Care Systems , United StatesABSTRACT
Traumatic brain injury (TBI) is a major cause of mortality and morbidity affecting all ages. It remains to be a diagnostic and therapeutic challenge, in which, to date, there is no Food and Drug Administration-approved drug for treating patients suffering from TBI. The heterogeneity of the disease and the associated complex pathophysiology make it difficult to assess the level of the trauma and to predict the clinical outcome. Current injury severity assessment relies primarily on the Glasgow Coma Scale score or through neuroimaging, including magnetic resonance imaging and computed tomography scans. Nevertheless, such approaches have certain limitations when it comes to accuracy and cost efficiency, as well as exposing patients to unnecessary radiation. Consequently, extensive research work has been carried out to improve the diagnostic accuracy of TBI, especially in mild injuries, because they are often difficult to diagnose. The need for accurate and objective diagnostic measures led to the discovery of biomarkers significantly associated with TBI. Among the most well-characterized biomarkers are ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein. The current review presents an overview regarding the structure and function of these distinctive protein biomarkers, along with their clinical significance that led to their approval by the US Food and Drug Administration to evaluate mild TBI in patients.
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INTRODUCTION: The Advanced Cardiac Life Support (ACLS) Clinical Decision Display System (CDDS) is a novel application designed to optimize team organization and facilitate decision-making during ACLS resuscitations. We hypothesized that resuscitation teams would more consistently adhere to ACLS guideline time intervals in simulated resuscitation scenarios with the CDDS compared to without. METHODS: We conducted a simulation-based, non-blinded, randomized, crossover-design study with resuscitation teams comprised of Emergency Medicine physicians, registered nurses, critical care technicians, and paramedics. Each team performed 4 ACLS scenarios in randomized sequences, half with the CDDS and half without. We analyzed the resuscitations and recorded the times of interventions that have defined intervals by ACLS: rhythm checks, epinephrine administration, and shock delivery. In addition, we surveyed each resuscitation team regarding their experience using the CDDS. RESULTS: On average, teams performed rhythm checks 4.9 s closer to ACLS guidelines with the CDDS (p = 0.0358). Teams were also more consistent; on average, teams reduced the variation of time between consecutive doses of epinephrine by 45% (p = 0.0001) and defibrillation by 47% (p < 0.0001). Ninety-eight percent of participants indicated they would use the CDDS if available in real cardiac arrests. CONCLUSIONS: This study demonstrates that the CDDS improves the accuracy and precision of timed ACLS interventions in a simulated setting. Resuscitation teams were strongly in favor of utilizing the CDDS in clinical practice. Further investigations of the introduction of the platform into real time clinical environments will be needed to assess true efficacy and patient outcomes.
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Advanced Cardiac Life Support/standards , Decision Support Systems, Clinical , Emergency Medicine/standards , Guideline Adherence , Cross-Over Studies , Heart Arrest/therapy , HumansABSTRACT
BACKGROUND: Research based on emergency departments (EDs) primarily focuses on medical conditions. There is limited research that investigates patients who willingly participate in research. This current study explored ED super-utilizers' (SUs') and nonsuper-utilizers' (NSUs') attitudes toward research. OBJECTIVE: The study assesses the willingness of SUs to participate in research. We hypothesize that the SU population will be as interested as nonutilizers in participating in medical research. METHODS: This prospective observational study stratified participants into SU and NSU cohorts based on their self-reported number of ED visits within 6 months. Surveys were captured in a secured database and analyzed using SAS 9.4. RESULTS: 7,481 completed questionnaires. SUs were more interested in participating in all types of research compared to NSUs. Both groups were most willing to participate in surveys. Neither group was particularly interested in studies that required medications. SUs were not more willing to participate in studies without payment than NSUs. Both groups trusted researchers at the same rates. CONCLUSION: Although rarely included in medical research, SUs were more willing to participate in nearly all types of research and expressed a similar trust in medical research when compared to nonsuper-utilizers.
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Objectives. To assess the health impact of Hurricane Irma and Hurricane Maria on St Thomas, US Virgin Islands.Methods. We collected data from interviews conducted 6 and 9 months after the hurricanes, a review of 597 randomly selected emergency department (ED) encounters, and administrative records from 10 716 ED visits 3 months before, between, and 3 months after the hurricanes.Results. Informants described damaged hospital infrastructure, including flooding, structural damage, and lost staff. The greatest public health impact was on the elderly and persons with chronic diseases. In the setting of loss of the electronic medical record system, ED chart reviews were limited by problems with missing data. ED administrative data demonstrated that posthurricane patients, compared with prehurricane patients, were older and had less severe complaints. There was a significant increase in patients being seen for diabetes-related and respiratory complaints, especially asthma. Suboptimal recordkeeping for medical evacuees limited the ability to assess outcomes for patients with severe illnesses.Conclusions. Hurricanes Irma and Maria caused major disruptions to health care on St Thomas. Emphasis should be given to building a resilient health care system that will optimally respond to future hurricanes.
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Cyclonic Storms , Delivery of Health Care/organization & administration , Emergency Service, Hospital/statistics & numerical data , Public Health , Age Factors , Delivery of Health Care/standards , Humans , Interviews as Topic , Personnel Administration, Hospital , Personnel, Hospital/statistics & numerical data , Severity of Illness Index , United States Virgin IslandsABSTRACT
INTRODUCTION: Traumatic brain injury (TBI) is a major worldwide neurological disorder of epidemic proportions. To date, there are still no FDA-approved therapies to treat any forms of TBI. Encouragingly, there are emerging data showing that biofluid-based TBI biomarker tests have the potential to diagnose the presence of TBI of different severities including concussion, and to predict outcome. Areas covered: The authors provide an update on the current knowledge of TBI biomarkers, including protein biomarkers for neuronal cell body injury (UCH-L1, NSE), astroglial injury (GFAP, S100B), neuronal cell death (αII-spectrin breakdown products), axonal injury (NF proteins), white matter injury (MBP), post-injury neurodegeneration (total Tau and phospho-Tau), post-injury autoimmune response (brain antigen-targeting autoantibodies), and other emerging non-protein biomarkers. The authors discuss biomarker evidence in TBI diagnosis, outcome prognosis and possible identification of post-TBI neurodegernative diseases (e.g. chronic traumatic encephalopathy and Alzheimer's disease), and as theranostic tools in pre-clinical and clinical settings. Expert commentary: A spectrum of biomarkers is now at or near the stage of formal clinical validation of their diagnostic and prognostic utilities in the management of TBI of varied severities including concussions. TBI biomarkers could serve as a theranostic tool in facilitating drug development and treatment monitoring.
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Biomarkers , Brain Injuries, Traumatic/diagnosis , Brain Injuries, Traumatic/metabolism , Brain Injuries, Traumatic/drug therapy , Brain Injuries, Traumatic/mortality , Humans , Liquid Biopsy , Neuroimaging/methods , Prognosis , Severity of Illness IndexABSTRACT
Cervical acceleration/deceleration or whiplash injuries are a common cause of cervical spine trauma. Cervical acceleration/deceleration can result in vertebral fractures, subluxations, and ligamentous and other soft tissue injuries. Severe injuries are often evidenced by increased prevertebral swelling on lateral X-ray. Assessment of the prevertebral space on lateral cervical spine films is an essential component for identifying potential traumatic neck injuries. We describe a case in which an 84-year-old man on coumadin presented to the emergency department after a low-impact motor vehicle crash. The patient initially complained of neck and shoulder pain which subsequently progressed to hoarseness, dysphagia, and dyspnea. Imaging studies revealed significant prevertebral tissue swelling with anterior compression of his airway that required airway stabilization via awake fiber-optic intubation and reversal of his anticoagulation therapy.
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Objective. To study the impact of helmet use on outcomes after recreational vehicle accidents. Methods. This is an observational cohort of adult and pediatric patients who sustained a TBI while riding a recreational vehicle. Recreational vehicles included bicycles, motorcycles, and all-terrain vehicles (ATVs), as well as a category for other vehicles such as skateboards and scooters. Results. Lack of helmet use was significantly associated with having a more severe traumatic brain injury and being admitted to the hospital. Similarly, 25% of those who did wearing a helmet were admitted to the ICU versus 36% of those who did not (P = 0.0489). The hospital length of stay was significantly greater for patients who did not use helmets. Conclusion. Lack of helmet use is significantly correlated with abnormal neuroimaging and admission to the hospital and ICU; these data support a call for action to implement more widespread injury prevention and helmet safety education and advocacy.
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INTRODUCTION: Early antibiotic administration is recommended in newborns presenting with febrile illness to emergency departments (ED) to avert the sequelae of serious bacterial infection. Although ED crowding has been associated with delays in antibiotic administration in a dedicated pediatric ED, the majority of children that receive emergency medical care in the United States present to EDs that treat both adult and pediatric emergencies. The purpose of this study was to examine the relationship between time to antibiotic administration in febrile newborns and crowding in a general ED serving both an adult and pediatric population. METHODS: We conducted a retrospective chart review of 159 newborns presenting to a general ED between 2005 and 2011 and analyzed the association between time to antibiotic administration and ED occupancy rate at the time of, prior to, and following infant presentation to the ED. RESULTS: We observed delayed and variable time to antibiotic administration and found no association between time to antibiotic administration and occupancy rate prior to, at the time of, or following infant presentation (p>0.05). ED time to antibiotic administration was not associated with hospital length of stay, and there was no inpatient mortality. CONCLUSION: Delayed and highly variable time to antibiotic treatment in febrile newborns was common but unrelated to ED crowding in the general ED study site. Guidelines for time to antibiotic administration in this population may reduce variability in ED practice patterns.
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BACKGROUND: To characterize the patterns of presentation of adults with head injury to the Emergency Department. METHODS: This is a cohort study that sought to collect injury and outcome variables with the goal of characterizing the very early natural history of traumatic brain injury in adults. This IRB-approved project was conducted in collaboration with our Institution's Center for Translational Science Institute. Data were entered in REDCap, a secure database. Statistical analyses were performed using JMP 10.0 pro for Windows. RESULTS: The cohort consisted of 2,394 adults, with 40% being women and 79% Caucasian. The most common mechanism was fall (47%) followed by motor vehicle collision (MVC) (36%). Patients sustaining an MVC were significantly younger than those whose head injury was secondary to a fall (P < 0.0001). Ninety-one percent had CT imaging; hemorrhage was significantly more likely with worse severity as measured by the Glasgow Coma Score (chi-square, P < 0.0001). Forty-four percent were admitted to the hospital, with half requiring ICU admission. In-hospital death was observed in 5.4%, while neurosurgical intervention was required in 8%. For all outcomes, worse TBI severity per GCS was significantly associated with worse outcomes (logistic regression, P < 0.0001, adjusted for age). CONCLUSION: These cohort data highlight the burden of TBI in the Emergency Department and provide important demographic trends for further research.