Blood biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have recently been Food and Drug Administration approved as predictors of intracranial ...lesions on CT after mild traumatic brain injury (mTBI). However, most cases with mTBI are CT negative, and no biomarkers are approved to assist diagnosis in these individuals. In this study, we aimed to determine the optimal combination of blood biomarkers to assist mTBI diagnosis in otherwise healthy adults younger than 50 years presenting to an emergency department within 6 hours of injury. To further understand the utility of biomarkers, we assessed how biological sex, presence or absence of loss of consciousness and/or post-traumatic amnesia (LOC/PTA), and delayed presentation affected classification performance.
Blood samples, symptom questionnaires, and cognitive tests were prospectively conducted for participants with mTBI recruited from The Alfred Hospital Level 1 Emergency & Trauma Center and uninjured controls. Follow-up testing was conducted at 7 days. Simoa quantified plasma GFAP, UCH-L1, tau, neurofilament light chain (NfL), interleukin (IL)-6, and IL-1β. Area under the receiver operating characteristic (AUC) analysis assessed classification accuracy for diagnosed mTBI, and logistic regression models identified optimal biomarker combinations.
Plasma IL-6 (AUC 0.91, 95% CI 0.86-0.96), GFAP (AUC 0.85, 95% CI 0.78-0.93), and UCH-L1 (AUC 0.79, 95% CI 0.70-0.88) best differentiated mTBI (n = 74) from controls (n = 44) acutely (<6 hours), with NfL (AUC 0.81, 95% CI 0.72-0.90) the only marker to have such utility subacutely (7 days). Biomarker performance was similar between sexes and for participants with and without LOC/PTA, with the exception at 7 days, where GFAP and IL-6 retained some utility in female participants (GFAP: AUC 0.71, 95% CI 0.55-0.88; IL-6: AUC 0.71, 95% CI 0.55-0.87) and in those with LOC/PTA (GFAP: AUC 0.73, 95% CI 0.59-0.86; IL-6: AUC 0.71, 95% CI 0.57-0.84). Acute IL-6 (
= 0.50, 95% CI 0.34-0.64) outperformed GFAP and UCH-L1 combined (
= 0.35, 95% CI 0.17-0.50), with the best acute model featuring GFAP and IL-6 (
= 0.54, 95% CI 0.34-0.68).
These findings indicate that adding IL-6 to a panel of brain-specific proteins such as GFAP and UCH-L1 might assist in the acute diagnosis of mTBI in adults younger than 50 years. Multiple markers had high classification accuracy in participants without LOC/PTA. When compared with the best-performing acute markers, subacute measures of plasma NfL resulted in minimal reduction in classification accuracy. Future studies will investigate the optimal time frame over which plasma IL-6 might assist diagnostic decisions and how extracranial trauma affects utility.
A history of mild traumatic brain injury (mTBI) is linked to a number of chronic neurological conditions, however there is still much unknown about the underlying mechanisms. To provide new insights, ...this study used a clinically relevant model of repeated mTBI in rats to characterize the acute and chronic neuropathological and neurobehavioral consequences of these injuries. Rats were given four sham-injuries or four mTBIs and allocated to 7-day or 3.5-months post-injury recovery groups. Behavioral analysis assessed sensorimotor function, locomotion, anxiety, and spatial memory. Neuropathological analysis included serum quantification of neurofilament light (NfL), mass spectrometry of the hippocampal proteome, and ex vivo magnetic resonance imaging (MRI). Repeated mTBI rats had evidence of acute cognitive deficits and prolonged sensorimotor impairments. Serum NfL was elevated at 7 days post injury, with levels correlating with sensorimotor deficits; however, no NfL differences were observed at 3.5 months. Several hippocampal proteins were altered by repeated mTBI, including those associated with energy metabolism, neuroinflammation, and impaired neurogenic capacity. Diffusion MRI analysis at 3.5 months found widespread reductions in white matter integrity. Taken together, these findings provide novel insights into the nature and progression of repeated mTBI neuropathology that may underlie lingering or chronic neurobehavioral deficits.
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•Repeat mTBI in rats resulted in prolonged sensorimotor deficits.•Serum NfL was elevated at 7d, with levels correlating with sensorimotor deficits.•Diffusion MRI revealed chronic widespread reductions in white matter integrity.•Mass spectroscopy revealed acute and chronic alterations in hippocampal proteins.
Biomarkers that can objectively guide the diagnosis of sports-related concussion, and consequent return-to-play decisions, are urgently needed. In this study, we aimed to determine the temporal ...profile and diagnostic ability of serum levels of neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), glial fibrillary acidic protein (GFAP), and tau in concussed male and female Australian footballers.
Blood was collected from 28 Australian rules footballers (20 males, 8 females) at 2-, 6-, and 13-days after a diagnosed concussion for comparison to their levels at baseline (i.e. pre-season), and with 27 control players (19 males, 8 females) without a diagnosis of concussion. Serum concentrations of protein markers associated with damage to neurons (UCHL1), axons (NfL, tau), and astrocytes (GFAP) were quantified using a Simoa HD-X Analyzer. Biomarker levels for concussed players were compared over time and between sex using generalised linear mixed effect models, and diagnostic performance was assessed using area under the receiver operating characteristic curve (AUROC) analysis.
Serum NfL was increased from baseline in male footballers at 6- and 13-days post-concussion. GFAP and tau were increased in male footballers with concussion at 2- and 13-days respectively. NfL concentrations discriminated between concussed and non-concussed male footballers at all time-points (AUROC: 2d = 0.73, 6d = 0.85, 13d = 0.79), with tau also demonstrating utility at 13d (AUROC = 0.72). No biomarker differences were observed in female footballers after concussion.
Serum NfL may be a useful biomarker for the acute and sub-acute diagnosis of concussion in males, and could inform neurobiological recovery and return-to-play decisions. Future adequately powered studies are still needed to investigate biomarker changes in concussed females.
An increasing number of centers are using active rehabilitation and ambulation for critically ill patients on extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation. This ...investigation assessed the economic impact at a single center of ambulatory versus non-ambulatory ECMO strategies as a bridge to lung transplantation.
We conducted a single-center retrospective cohort analysis of all subjects supported with ECMO as a bridge to lung transplantation (N = 9) from 2007 to 2012. Subjects who were rehabilitated while supported with ECMO before lung transplantation were compared with those who were not rehabilitated during ECMO. Hospital cost data for the month before transplantation through 12 months after the initial post-transplant hospital discharge were compared.
The median cost (interquartile range IQR) in the 30 d before transplant for the ambulatory cohort was $88,137 (IQR $38,589-$122,111) compared with $52,124 (IQR $23,824-$69,929) for the non-ambulatory cohort (P = .08). The median post-transplant ICU cost for the ambulatory cohort was $38,468 (IQR $23,611-$64,126) compared with $143,407 (IQR $112,199-$168,993) for the non-ambulatory cohort (P = .01). The median total hospital cost for subjects supported with ambulatory ECMO was $213,086 (IQR $166,767-$264,536) compared with $273,291 (IQR $237,299-$374,175) for non-ambulatory ECMO subjects (P = .05). The median total cost for the ambulatory cohort was $268,194 (IQR $219,972-$517,320) compared with $300,307 (IQR $274,262-$394,913) for the non-ambulatory cohort (P = .14).
Subjects supported with ambulatory ECMO had a 22% ($60,204) reduction in total hospital cost, 73% ($104,939) reduction in post-transplant ICU cost, and 11% ($32,133) reduction in total cost compared with non-ambulatory ECMO subjects. This analysis demonstrates the potential economic benefit of rehabilitation and ambulation during ECMO compared with a traditional strategy.
Abstract
The rate at which the coronavirus disease (COVID-19) spread required a rapid response across many, if not all, industries. Academic medical centers had to rapidly evaluate, prioritize, and ...coordinate the multiple requests for clinical trial participation. This involved redirecting resources and developing a collaborative system for assessment, decision making, and implementation. Our institution formed a team with diverse representation from multiple stakeholders to review and prioritize all research protocols related to COVID-19. To accomplish this, a prioritization matrix was developed to help determine the order in which the protocols should be placed for consideration by the treating clinician. The purpose of the team was to review the COVID-19 clinical trials in the pipeline, prioritize those trials that best met the needs of our patients, oversee training and resource needs, and lead the formulation of procedures for integration with clinical care. Resources from the Clinical Research Unit were then allocated to support the swift execution of such studies. This manuscript describes that process, the challenges encountered, and the lessons learned on how to make all clinical trials more successful in a complex and dynamic environment.
There is a widely recognized need for blood biomarkers to assist clinical decisions surrounding mild traumatic brain injury (mTBI). Serum neurofilament light (NfL), an indicator of neuroaxonal ...damage, is one such candidate, with early mTBI clinical investigations demonstrating significant promise. To facilitate the translation of pre-clinical mTBI findings, clinically relevant outcomes should be integrated into animal studies wherever possible. Despite this, the temporal profile and potential utility of NfL as a blood biomarker in pre-clinical mTBI is poorly understood. Here, we quantified serum NfL at 2-h, 1-, 3-, 7- and 14-days following mTBI in rats and compared these to pre-injury levels. We also investigated cumulative effects of repeat-mTBI by delivering 0, 1 or 5 mTBIs separated by 24 h. Sensorimotor performance was evaluated with the beam task at 1- and 4-h after mTBI, and serum was collected 1-day after the final procedure. We found that serum NfL levels were substantially elevated at all acute and sub-acute time-points after a single-mTBI, peaked at 1-day, and remained elevated 14-days post-injury. An mTBI dose-dependent effect on serum NfL levels was also observed, with substantially higher NfL levels found at 1-day post repeat-mTBI when compared to single-mTBI and sham-injured rats. Furthermore, NfL levels were found to be greatest in rats with the highest degree of sensorimotor impairment. In conclusion, these findings have described the temporal profile of serum NfL elevations following a single-mTBI in rats, and indicate a profile with some similarities and differences to that seen in the clinical condition. Moreover, we found that serum NfL levels were potentiated by repeat-mTBI, and that this biomarker may have utility as an indicator of injury severity. As such, future pre-clinical TBI studies may benefit from incorporating measures of serum NfL as an objective injury outcome.
It is increasingly reported that a history of concussion may be associated with chronic deleterious consequences. While the pathophysiology that contributes to these consequences is not well ...understood, neuroinflammation is postulated to be critical. Activation of multi-protein complexes termed inflammasomes, a key component of this inflammatory response, has been reported in more severe TBIs; however, it has not been investigated in milder TBIs, such as concussion. This study investigated serum levels of interleukin (IL)-1β and IL-18 (key proteins activated downstream of these inflammasomes) at acute, sub-acute, and chronic time-points post-concussion. We recruited 105 Australian footballers (65 male, 40 female) during the pre-season, then prospectively followed these players for the occurrence of concussion during the season. At baseline, 58 footballers reported a previous concussion history, and 47 reported no previous concussion history. Additionally, 25 players sustained a mid-season concussion and were sampled at 2, 6, and 13 days post-concussion. Serum levels of IL-1β and IL-18 were quantified using highly sensitive Simoa HD-X Analyzer assays. At baseline, IL-1β levels were higher in male, but not female, footballers with a previous concussion history compared with footballers with no concussion history. There was also a positive correlation between years of collision sport participation and IL-18 levels in males. No evidence was found in males or females to indicate that IL-1β or IL-18 levels differed at 2, 6, or 13 days post-concussion. These findings provide novel insights into potential sex-specific physiological consequences of concussion, and suggest that neuroinflammation may be persistent chronically following concussion in male athletes.
Extracorporeal membrane oxygenation (ECMO) use in poisoned patients is increasing, but is rare post cardiac arrest. We report a case of ECMO use with complete recovery in a patient who arrested twice ...after a cardiotoxicant overdose. A 17-year-old male presented after an unknown overdose. He rapidly became hypotensive and bradycardic and received aggressive supportive care without improvement. He was transferred to our institution and suffered a cardiac arrest shortly after arrival. Six minutes of advanced cardiac life support resulted in return of spontaneous circulation. High-dose insulin, lipid emulsion, and ECMO were initiated. While awaiting ECMO deployment, he again became pulseless. Compressions resumed, and after 30 min, ROSC was achieved, and he was cannulated for veno-arterial ECMO. Within 48 h, he was decannulated, and then weaned off epinephrine 2 days later. Upon extubation, he was neurologically intact. Amlodipine and metoprolol were later confirmed in serum. Adolescent poisoned patients represent an ideal population for ECMO due to lack of comorbidities. As experience with ECMO in overdose increases, additional research is needed to determine appropriate indications and timing for its use. ECMO is an option for patients poisoned with a cardiotoxicant drug, even following witnessed cardiac arrest.
A second mild traumatic brain injury (mTBI) sustained prior to neuropathological recovery can lead to exacerbated effects. Without objective indicators of this neuropathology, individuals may return ...to activities at risk of mTBI when their brain is still vulnerable. With axonal injury recognized as a neuropathological hallmark of mTBI, we hypothesized that serum levels of neurofilament light (NfL), a highly sensitive biomarker of axonal injury, may be predictive of vulnerability to worse outcomes in the event of a second mTBI. Given this hypothesis is difficult to test clinically, we used a two-hit model of mTBI in rats and staggered inter-injury intervals by 1-, 3-, 7-, or 14-days. Repeat-mTBI rats were dichotomized into NfLhigh (NfL>median at the time of re-injury) and NfLlow (NfL<median) groups, with behavior and NfL levels analyzed throughout the 28-days, followed by ex vivo diffusion tensor imaging. NfL levels at the time of the second mTBI were found to be predictive of vulnerability to re-injury, with NfLhigh rats displaying more neurological signs and a greater potentiation of NfL levels after the second mTBI. Importantly, this potentiation phenomenon remained even when limiting analyses to rats with longer inter-injury intervals, providing evidence that vulnerability to re-injury may not be exclusively dependent on inter-injury interval. Finally, NfL levels correlated with, and were predictive of, the severity of neurological signs following the second mTBI. These findings provide evidence that measurement of NfL during mTBI recovery may be reflective of the vulnerability to a second mTBI, and as such may have utility to assist return to sport, duty and work decisions.
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