Exploratory assessment of the effect of systemic administration of soluble glycoprotein 130 on cognitive performance and chemokine levels in a mouse model of experimental traumatic brain injury.

Uncontrolled neuroinflammation mediates traumatic brain injury (TBI) pathology and impairs recovery. Interleukin-6 (IL-6), a pleiotropic inflammatory regulator, is associated with poor clinical TBI outcomes. IL-6 operates via classical-signaling through membrane-bound IL-6 receptor (IL-6R) and trans-signaling through soluble IL-6 receptor (s)IL-6R. IL-6 trans-signaling specifically contributes to neuropathology, making it a potential precision therapeutic TBI target. Soluble glycoprotein 130 (sgp130) prevents IL-6 trans-signaling, sparing classical signaling, thus is a possible treatment. Mice received either controlled cortical impact (CCI) (6.0 ± 0.2 m/s; 2 mm; 50-60ms) or sham procedures. Vehicle (VEH) or sgp130-Fc was subcutaneously administered to sham (VEH or 1 µg) and CCI (VEH, 0.25 µg or 1 µg) mice on days 1, 4, 7, 10 and 13 post-surgery to assess effects on cognition [Morris Water Maze (MWM)] and ipsilateral hemisphere IL-6 related biomarkers (day 21 post-surgery). CCI + sgp130-Fc groups (0.25 µg and 1 µg) were combined for analysis given similar behavior/biomarker outcomes. CCI + VEH mice had longer latencies and path lengths to the platform and increased peripheral zone time versus Sham + VEH and Sham + sgp130-Fc mice, suggesting injury-induced impairments in learning and anxiety. CCI + sgp130-Fc mice had shorter platform latencies and path lengths and had decreased peripheral zone time, indicating a therapeutic benefit of sgp130-Fc after injury on learning and anxiety. Interestingly, Sham + sgp130-Fc mice had shorter platform latencies, path lengths and peripheral zone times than Sham + VEH mice, suggesting a beneficial effect of sgp130-Fc, independent of injury. CCI + VEH mice had increased brain IL-6 and decreased sgp130 levels versus Sham + VEH and Sham + sgp130-Fc mice. There was no treatment effect on IL-6, sIL6-R or sgp130 in Sham + VEH versus Sham + sgp130-Fc mice. There was also no treatment effect on IL-6 in CCI + VEH versus CCI + sgp130-Fc mice. However, CCI + sgp130-Fc mice had increased sIL-6R and sgp130 versus CCI + VEH mice, demonstrating sgp130-Fc treatment effects on brain biomarkers. Inflammatory chemokines (MIP-1ß, IP-10, MIG) were increased in CCI + VEH mice versus Sham + VEH and Sham + sgp130-Fc mice. However, CCI + sgp130-Fc mice had decreased chemokine levels versus CCI + VEH mice. IL-6 positively correlated, while sgp130 negatively correlated, with chemokine levels. Overall, we found that systemic sgp130-Fc treatment after CCI improved learning, decreased anxiety and reduced CCI-induced brain chemokines. Future studies will explore sex-specific dosing and treatment mechanisms for sgp130-Fc therapy.

Temporal Profile of Serum Neurofilament Light (NF-L) and Heavy (pNF-H) Level Associations With 6-Month Cognitive Performance in Patients With Moderate-Severe Traumatic Brain Injury.

OBJECTIVE: Identification of biomarkers of cognitive recovery after traumatic brain injury (TBI) will inform care and improve outcomes. This study assessed the utility of neurofilament (NF-L and pNF-H), a marker of neuronal injury, informing cognitive performance following moderate-to-severe TBI (msTBI). SETTING: Level 1 trauma center and outpatient via postdischarge follow-up. PARTICIPANTS: N = 94. Inclusion criteria: Glasgow Coma Scale score less than 13 or 13-15 with clinical evidence of moderate-to-severe injury traumatic brain injury on clinical imaging. Exclusion criteria: neurodegenerative condition, brain death within 3 days after injury. DESIGN: Prospective observational study. Blood samples were collected at several time points post-injury. Cognitive testing was completed at 6 months post-injury. MAIN MEASURES: Serum NF-L (Human Neurology 4-Plex B) pNF-H (SR-X) as measured by SIMOA Quanterix assay. Divided into 3 categorical time points at days post-injury (DPI): 0-15 DPI, 16-90 DPI, and >90 DPI. Cognitive composite comprised executive functioning measures derived from 3 standardized neuropsychological tests (eg, Delis-Kaplan Executive Function System: Verbal Fluency, California Verbal Learning Test, Second Edition, Wechsler Adult Intelligence Scale, Third Edition). RESULTS: pNF-H at 16-90 DPI was associated with cognitive outcomes including a cognitive-executive composite score at 6 months (ß = -.430, t34 = -3.190, P = .003). CONCLUSIONS: Results suggest that "subacute" elevation of serum pNF-H levels may be associated with protracted/poor cognitive recovery from msTBI and may be a target for intervention. Interpretation is limited by small sample size and including only those who were able to complete cognitive testing.

Parallel Cerebrospinal Fluid and Serum Temporal Profile Assessment of Axonal Injury Biomarkers Neurofilament-Light Chain and Phosphorylated Neurofilament-Heavy Chain: Associations With Patient Outcome in Moderate-Severe Traumatic Brain Injury.

Neurofilament-light chain (NF-L) and phosphorylated neurofilament-heavy chain (pNF-H) are axonal proteins that have been reported as potential diagnostic and prognostic biomarkers in traumatic brain injury (TBI). However, detailed temporal profiles for these proteins in blood, and interrelationships in the acute and chronic time periods post-TBI have not been established. Our objectives were: 1) to characterize acute-to-chronic serum NF-L and pNF-H profiles after moderate-severe TBI, as well as acute cerebrospinal fluid (CSF) levels; 2) to evaluate CSF and serum NF-L and pNF-H associations with each other; and 3) to assess biomarker associations with global patient outcome using both the Glasgow Outcome Scale-Extended (GOS-E) and Disability Rating Scale (DRS). In this multi-cohort study, we measured serum and CSF NF-L and pNF-H levels in samples collected from two clinical cohorts (University of Pittsburgh [UPITT] and Baylor College of Medicine [BCM]) of individuals with moderate-severe TBI. The UPITT cohort includes 279 subjects from an observational cohort study; we obtained serum (n = 277 unique subjects) and CSF (n = 95 unique subjects) daily for 1 week, and serum every 2 weeks for 6 months. The BCM cohort included 103 subjects from a previous randomized clinical trial of erythropoietin and blood transfusion threshold after severe TBI, which showed no effect on neurological outcome between treatment arms; serum (n = 99 unique subjects) and CSF (n = 54 unique subjects) NF-L and pNF-H levels were measured at least daily during Days (D) 0-10 post-injury. GOS-E and DRS were assessed at 6 months (both cohorts) and 12 months (UPITT cohort only). Results show serum NF-L and pNF-H gradually rise during the first 10 days and peak at D20-30 post-injury. In the UPITT cohort, acute (D0-6) NF-L and pNF-H levels correlate within CSF and serum (Spearman r = 0.44-0.48; p < 0.05). In the UPITT cohort, acute NF-L CSF and serum levels, as well as chronic (Months [M]2-6) serum NF-L levels, were higher among individuals with unfavorable GOS-E and worse DRS at 12 months (p < 0.05, all comparisons). In the BCM cohort, higher acute serum NF-L levels were also associated with unfavorable GOS-E. Higher pNF-H serum concentrations (D0-6 and M2-6), but not CSF pNF-H, were associated with unfavorable GOS-E and worse DRS (p < 0.05, all comparisons) in the UPITT cohort. Relationships between biomarker levels and favorable outcome persisted after controlling for age, sex, and Glasgow Coma Scale. This study shows for the first time that serum levels of NF-L and pNF-H peak at D20-30 post-TBI. Serum NF-L levels, and to a lesser extent pNF-H levels, are robustly associated with global patient outcomes and disability after moderate-severe TBI. Further studies on clinical utility as prognosis and treatment-response indicators are needed.

Differential Effects of Targeted Temperature Management on Sex-Dependent Outcomes After Experimental Asphyxial Cardiac Arrest.

Asphyxial cardiac arrest (ACA) survivors face lasting neurological disability from hypoxic ischemic brain injury. Sex differences in long-term outcomes after cardiac arrest (CA) are grossly understudied and underreported. We used rigorous targeted temperature management (TTM) to understand its influence on survival and lasting sex-specific neurological and neuropathological outcomes in a rodent ACA model. Adult male and female rats underwent either sham or 5-minute no-flow ACA with 18 hours TTM at either ∼37°C (normothermia) or ∼36°C (mild hypothermia). Survival, temperature, and body weight (BW) were recorded over the 14-day study duration. All rats underwent neurological deficit score (NDS) assessment on days 1-3 and day 14. Hippocampal pathology was assessed for cell death, degenerating neurons, and microglia on day 14. Although ACA females were less likely to achieve return of spontaneous circulation (ROSC), post-ROSC physiology and biochemical profiles were similar between sexes. ACA females had significantly greater 14-day survival, NDS, and BW recovery than ACA males at normothermia (56% vs. 29%). TTM at 36°C versus 37°C improved 14-day survival in males, producing similar survival in male (63%) versus female (50%). There were no sex or temperature effects on CA1 histopathology. We conclude that at normothermic conditions, sex differences favoring females were observed after ACA in survival, NDS, and BW recovery. We achieved a clinically relevant ACA model using TTM at 36°C to improve long-term survival. This model can be used to more fully characterize sex differences in long-term outcomes and test novel acute and chronic therapies.

Serial Measurements of Serum Glial Fibrillary Acidic Protein in Moderate-Severe Traumatic Brain Injury: Potential Utility in Providing Insights into Secondary Insults and Long-Term Outcome.

In patients with traumatic brain injury (TBI), serum biomarkers may have utility in assessing the evolution of secondary brain injury. A panel of nine brain-injury- associated biomarkers was measured in archived serum samples over 10 days post-injury from 100 patients with moderate-severe TBI. Among the biomarkers evaluated, serum glial fibrillary acidic protein (GFAP) had the strongest associations with summary measures of acute pathophysiology, including intracranial pressure (ICP), cerebral perfusion pressure (CPP), and brain tissue pO2 (PbtO2). Group based trajectory (TRAJ) analysis was used to identify three distinct GFAP subgroups. The low TRAJ group (n = 23) had peak levels of 9.4 + 1.2 ng/mL that declined rapidly. The middle TRAJ group (n = 48) had higher peak values (31.5 + 5.0 ng/mL) and a slower decline over time. The high TRAJ group (n = 26) had very high, sustained peak values (59.6 + 12.5 ng/mL) that even rose among some patients over 10 days. Patients in the high TRAJ group had significantly higher mortality rate than patients in low and middle TRAJ groups (26.9% vs. 7.0%, p = 0.028). The frequency of poor neurological outcome (Glasgow Outcome Score Extended [GOS-E] 1-4) was 88.5% in the high TRAJ group, 54.2% in the middle TRAJ group, and 30.4% in the low TRAJ group (p < 0.001). ICP was highest in the high TRAJ group (median 17.6 mm Hg), compared with 14.4 mmHg in the low and 15.9 mm Hg in middle TRAJ groups (p = 0.002). High TRAJ patients spent the longest time with ICP >25 mm Hg, median 23 h, compared with 2 and 6 h in the low and middle TRAJ groups (p = 0.006), and the longest time with ICP >30 mm Hg, median 5 h, compared with 0 and 1 h in the low and middle TRAJ groups, respectively (p = 0.013). High TRAJ group patients more commonly required tier 2 or 3 treatment to control ICP. The high TRAJ group had the longest duration when CPP was <50 mm Hg (p = 0.007), and PbtO2 was <10 mm Hg (p = 0.002). Logistical regression was used to study the relationship between temporal serum GFAP patterns and 6-month GOS-E. Here, the low and middle TRAJ groups were combined to form a low-risk group, and the high TRAJ group was designated the high-risk group. High TRAJ group patients had a greater chance of a poor 6-month GOS-E (p < 0.0001). When adjusting for baseline injury characteristics, GFAP TRAJ group membership remained associated with GOS-E (p = 0.003). When an intensive care unit (ICU) injury burden score, developed to quantify physiological derangements, was added to the model, GFAP TRAJ group membership remained associated with GOS-E (p = 0.014). Mediation analysis suggested that ICU burden scores were in the causal pathway between TRAJ group and 6-month mortality or GOS-E. Our results suggest that GFAP may be useful to monitor serially in moderate-severe TBI patients. Future studies in larger cohorts are needed to confirm these results.

Temporal Profiles of P-Tau, T-Tau, and P-Tau:Tau Ratios in Cerebrospinal Fluid and Blood from Moderate-Severe Traumatic Brain Injury Patients and Relationship to 6-12 Month Global Outcomes.

Traumatic brain injury (TBI) can initiate progressive injury responses, which are linked to increased risk of neurodegenerative diseases known as "tauopathies." Increased post-TBI tau hyperphosphorylation has been reported in brain tissue and biofluids. Acute-to-chronic TBI total (T)-tau and phosphorylated (P)-tau temporal profiles in the cerebrospinal fluid (CSF) and serum and their relationship to global outcome is unknown. Our multi-site longitudinal study examines these concurrent profiles acutely (CSF and serum) and also characterizes the acute- to-chronic serum patterns. Serial serum and CSF samples from individuals with moderate-to-severe TBI were obtained from two cohorts (acute, subacute, and chronic samples from University of Pittsburgh [UPitt] [n = 286 unique subjects] and acute samples from Baylor College of Medicine [BCM] [n = 114 unique subjects]) and assayed for T-tau and P-tau using the Rolling Circle Amplification-Surround Optical Fiber ImmunoAssay platform. Biokinetic analyses described serum T-tau and P-tau temporal patterns. T-tau and P-tau levels are compared with those in healthy controls (n = 89 for both CSF and serum), and univariate/multivariable associations are made with global outcome, including the Disability Rating Scale (DRS) and the Glasgow Outcome Scale-Extended (GOS-E) scores at 3 and 6 months post-TBI (BCM cohort) and at 6 and 12 months post-TBI (UPitt cohort). For both the UPitt and BCM cohorts, temporal increases in median serum and CSF T-tau and P-tau levels occurred over the first 5 days post-injury, while the initial increases of P-tau:T-tau ratio plateaued by day 4 post-injury (UPitt: n = 99, BCM: n = 48). Biokinetic analyses with UPitt data showed novel findings that T-tau (n = 74) and P-tau (n = 87) reached delayed maximum levels at 4.5 and 5.1 days, while exhibiting long serum half-lives (152 and 123 days), respectively. The post-TBI rise in acute (days 2-6) serum P-tau (up to 276-fold) far outpaced that of T-tau (7.3-fold), leading to a P-tau:T-tau increase of up to 267-fold, suggesting a shift toward tau hyperphosphorylation. BCM analyses showed that days 0-6 mean CSF T-tau and P-tau levels and P-tau:T-tau ratios were associated with greater disability (DRS) (n = 48) and worse global outcome (GOS-E) (n = 48) 6 months post-injury. Days 0-6 mean serum T-tau, P-tau, and P-tau:T-tau ratio were not associated with outcome in either cohort (UPitt: n = 145 [DRS], n = 154 [GOS-E], BCM: n = 99 [DRS and GOS-E]). UPitt multivariate models showed that higher chronic (months 1-6) mean P-tau levels and P-tau:T-tau ratio, but not T-tau levels, are associated with greater disability (DRS: n = 119) and worse global outcomes (GOS-E: n = 117) 12 months post-injury. This work shows the potential importance of monitoring post-TBI T-tau and P-tau levels over time. This multi-site longitudinal study features concurrent acute TBI T-tau and P-tau profiles in CSF and serum, and also characterizes acute-to-chronic serum profiles. Longitudinal profiles, along with no temporal concordance between trajectory groups over time, imply a sustained post-TBI shift in tau phosphorylation dynamics that may favor tauopathy development chronically.

Using Machine Learning to Examine Suicidal Ideation After Traumatic Brain Injury: A Traumatic Brain Injury Model Systems National Database Study.

OBJECTIVE: The aim of the study was to predict suicidal ideation 1 yr after moderate to severe traumatic brain injury. DESIGN: This study used a cross-sectional design with data collected through the prospective, longitudinal Traumatic Brain Injury Model Systems network at hospitalization and 1 yr after injury. Participants who completed the Patient Health Questionnaire-9 suicide item at year 1 follow-up ( N = 4328) were included. RESULTS: A gradient boosting machine algorithm demonstrated the best performance in predicting suicidal ideation 1 yr after traumatic brain injury. Predictors were Patient Health Questionnaire-9 items (except suicidality), Generalized Anxiety Disorder-7 items, and a measure of heavy drinking. Results of the 10-fold cross-validation gradient boosting machine analysis indicated excellent classification performance with an area under the curve of 0.882. Sensitivity was 0.85 and specificity was 0.77. Accuracy was 0.78 (95% confidence interval, 0.77-0.79). Feature importance analyses revealed that depressed mood and guilt were the most important predictors of suicidal ideation, followed by anhedonia, concentration difficulties, and psychomotor disturbance. CONCLUSIONS: Overall, depression symptoms were most predictive of suicidal ideation. Despite the limited clinical impact of the present findings, machine learning has potential to improve prediction of suicidal behavior, leveraging electronic health record data, to identify individuals at greatest risk, thereby facilitating intervention and optimization of long-term outcomes after traumatic brain injury.

Developing a National Trauma Research Action Plan: Results from the long-term outcomes research gap Delphi survey.

BACKGROUND: In the National Academies of Sciences, Engineering, and Medicine 2016 report on trauma care, the establishment of a National Trauma Research Action Plan to strengthen and guide future trauma research was recommended. To address this recommendation, the Department of Defense funded the Coalition for National Trauma Research to generate a comprehensive research agenda spanning the continuum of trauma and burn care. We describe the gap analysis and high-priority research questions generated from the National Trauma Research Action Plan panel on long-term outcomes. METHODS: Experts in long-term outcomes were recruited to identify current gaps in long-term trauma outcomes research, generate research questions, and establish the priority for these questions using a consensus-driven, Delphi survey approach from February 2021 to August 2021. Panelists were identified using established Delphi recruitment guidelines to ensure heterogeneity and generalizability including both military and civilian representation. Panelists were encouraged to use a PICO format to generate research questions: Patient/Population, Intervention, Compare/Control, and Outcome model. On subsequent surveys, panelists were asked to prioritize each research question on a 9-point Likert scale, categorized to represent low-, medium-, and high-priority items. Consensus was defined as ≥60% of panelists agreeing on the priority category. RESULTS: Thirty-two subject matter experts generated 482 questions in 17 long-term outcome topic areas. By Round 3 of the Delphi, 359 questions (75%) reached consensus, of which 107 (30%) were determined to be high priority, 252 (70%) medium priority, and 0 (0%) low priority. Substance abuse and pain was the topic area with the highest number of questions. Health services (not including mental health or rehabilitation) (64%), mental health (46%), and geriatric population (43%) were the topic areas with the highest proportion of high-priority questions. CONCLUSION: This Delphi gap analysis of long-term trauma outcomes research identified 107 high-priority research questions that will help guide investigators in future long-term outcomes research. LEVEL OF EVIDENCE: Diagnostic Tests or Criteria; Level IV.

Proceedings of the Second Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness.

This proceedings article presents actionable research targets on the basis of the presentations and discussions at the 2nd Curing Coma National Institutes of Health (NIH) symposium held from May 3 to May 5, 2021. Here, we summarize the background, research priorities, panel discussions, and deliverables discussed during the symposium across six major domains related to disorders of consciousness. The six domains include (1) Biology of Coma, (2) Coma Database, (3) Neuroprognostication, (4) Care of Comatose Patients, (5) Early Clinical Trials, and (6) Long-term Recovery. Following the 1st Curing Coma NIH virtual symposium held on September 9 to September 10, 2020, six workgroups, each consisting of field experts in respective domains, were formed and tasked with identifying gaps and developing key priorities and deliverables to advance the mission of the Curing Coma Campaign. The highly interactive and inspiring presentations and panel discussions during the 3-day virtual NIH symposium identified several action items for the Curing Coma Campaign mission, which we summarize in this article.

Relations Among Suicidal Ideation, Depressive Symptoms, and Functional Independence During the 10 Years After Traumatic Brain Injury: A Model Systems Study.

OBJECTIVE: To investigate relative causality in relations among suicidal ideation (SI), depressive symptoms, and functional independence over the first 10 years after traumatic brain injury (TBI). DESIGN: Prospective longitudinal design with data collected through the Traumatic Brain Injury Model Systems (TBIMS) network at acute rehabilitation hospitalization as well as 1, 2, 5, and 10 years after injury. SETTING: United States Level I/II trauma centers and inpatient rehabilitation centers with telephone follow-up. PARTICIPANTS: Individuals enrolled into the TBIMS National Database (N=9539) with at least 1 SI score at any follow-up data collection (72.1% male; mean age, 39.39y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patient Health Questionnaire-9 and FIM at years 1, 2, 5, and 10 post injury. RESULTS: A cross-lagged panel structural equation model, which is meant to indirectly infer causality through longitudinal correlational data, suggested that SI, depressive symptoms, and functional independence each significantly predicted themselves over time. Within the model, bivariate correlations among variables were all significant within each time point. Between years 1 and 2 and between years 2 and 5, depressive symptoms had a larger effect on SI than SI had on depressive symptoms. Between years 5 and 10, there was reciprocal causality between the 2 variables. Functional independence more strongly predicted depressive symptoms than the reverse between years 1 and 2 as well as years 2 and 5, but its unique effects on SI over time were extremely marginal or absent after controlling for depressive symptoms. CONCLUSIONS: A primary goal for rehabilitation and mental health providers should be to monitor and address elevated symptoms of depression as quickly as possible before they translate into SI, particularly for individuals with TBI who have reduced functional independence. Doing so may be a key to breaking the connection between low functional independence and SI.

Identifying group-based patterns of suicidal ideation over the first 10 years after moderate-to-severe TBI.

OBJECTIVE: To identify group-based patterns in suicidal ideation (SI) over the first 10 years after traumatic brain injury (TBI). METHODS: Participants included 9539 individuals in the TBI Model Systems National Database who responded to Patient Health Questionnaire-9 Item 9 assessing SI at 1, 2, 5, and/or 10 years post-injury. A k-means cluster analysis was conducted to determine group-based patterns of SI, and pre-injury variables were compared with ANOVAs and chi-square tests. RESULTS: SI and attempts decreased over time. Four group-based patterns emerged: Low, increasing, moderate, and decreasing SI. The low SI group comprised 89% of the sample, had the highest pre-injury employment, fewer mental health vulnerabilities, least severe injuries, and were oldest. The increasing SI group had the most severe TBIs, were youngest, and disproportionately Black or Asian/Pacific Islander. CONCLUSION: These findings reinforce the importance of mental health and suicide risk assessment during chronic recovery from TBI.

Acute Cortisol Profile Associations With Cognitive Impairment After Severe Traumatic Brain Injury.

BACKGROUND: Cognitive impairments commonly occur after traumatic brain injury (TBI) and affect daily functioning. Cortisol levels, which are elevated during acute hospitalization for most individuals after severe TBI, can influence cognition, but this association has not been studied previously in TBI. OBJECTIVE: We hypothesized that serum and cerebral spinal fluid (CSF) cortisol trajectories over days 0-5 post-injury are associated with cognition 6-month post-injury. METHODS: We examined 94 participants with severe TBI, collected acute serum and/or CSF samples over days 0-5 post-injury, and compared cortisol levels to those in 17 healthy controls. N = 88 participants had serum, and n = 84 had CSF samples available for cortisol measurement and had neuropsychological testing 6 months post-injury. Group based trajectory analysis (TRAJ) was used to generate temporal serum and CSF cortisol profiles which were examined for associations with neuropsychological performance. We used linear regression to examine relationships between cortisol TRAJ groups and both overall and domain-specific cognition. RESULTS: TRAJ analysis identified a high group and a decliner group for serum and a high group and low group for CSF cortisol. Multivariable analysis showed serum cortisol TRAJ group was associated with overall cognitive composites scores (P = .024) and with executive function (P = .039) and verbal fluency (P = .029) domain scores. CSF cortisol TRAJ group was associated with overall cognitive composite scores (P = .021) and domain scores for executive function (P = .041), verbal fluency (P = .031), and attention (P = .034). CONCLUSIONS: High acute cortisol trajectories are associated with poorer cognition 6 months post-TBI.

Early chronic systemic inflammation and associations with cognitive performance after moderate to severe TBI.

BACKGROUND: Cognitive dysfunction adversely effects multiple functional outcomes and social roles after TBI. We hypothesize that chronic systemic inflammation exacerbates cognitive deficits post-injury and diminishes functional cognition and quality of life (QOL). Yet few studies have examined relationships between inflammation and cognition after TBI. Associations between early chronic serum inflammatory biomarker levels, cognitive outcomes, and QOL 6-months and 12-months after moderate-to-severe TBI were identified using unweighted (uILS) and weighted (wILS) inflammatory load score (ILS) formation. METHODS: Adults with moderate-to-severe TBI (n â€‹= â€‹157) completed neuropsychological testing, the Functional Impairment Measure Cognitive Subscale (FIM-Cog) and self-reported Percent Back to Normal scale 6 months (n â€‹= â€‹139) and 12 months (n â€‹= â€‹136) post-injury. Serial serum samples were collected 1-3 months post-TBI. Cognitive composite scores were created as equally weighted means of T-scores derived from a multidimensional neuropsychological test battery. Median inflammatory marker levels associated with 6-month and 12-month cognitive composite T-scores (p â€‹< â€‹0.10) were selected for ILS formation. Markers were quartiled, and quartile ranks were summed to generate an uILS. Marker-specific ß-weights were derived using penalized ridge regression, multiplied by standardized marker levels, and summed to generate a wILS. ILS associations with cognitive composite scores were assessed using multivariable linear regression. Structural equation models assessed ILS influences on functional cognition and QOL using 12-month FIM-Cog and Percent Back to Normal scales. RESULTS: ILS component markers included: IL-1ß, TNF-α, sIL-4R, sIL-6R, RANTES, and MIP-1ß. Increased sIL-4R levels were positively associated with overall cognitive composite T-scores in bivariate analyses, while remaining ILS markers were negatively associated with cognition. Multivariable receiver operator curves (ROC) showed uILS added 14.98% and 31.93% relative improvement in variance captured compared to the covariates only base model (age, sex, education, Glasgow Coma Scale score) when predicting cognitive composite scores at 6 and 12 months, respectively; wILS added 33.99% and 36.87% relative improvement in variance captured. Cognitive composite mediated wILS associations with FIM-Cog scores at 12 months, and both cognitive composite and FIM-Cog scores mediated wILS associations with QOL. CONCLUSIONS: Early chronic inflammatory burden is associated with cognitive performance post-TBI. wILS explains greater variance in cognitive composite T-scores than uILS. Linking inflammatory burden associated with cognitive deficits to functional outcome post-TBI demonstrates the potential impact of immunotherapy interventions aimed at improving cognitive recovery post-TBI.

Research Needs for Prognostic Modeling and Trajectory Analysis in Patients with Disorders of Consciousness.

BACKGROUND: The current state of the science regarding the care and prognosis of patients with disorders of consciousness is limited. Scientific advances are needed to improve the accuracy, relevance, and approach to prognostication, thereby providing the foundation to develop meaningful and effective interventions. METHODS: To address this need, an interdisciplinary expert panel was created as part of the Coma Science Working Group of the Neurocritical Care Society Curing Coma Campaign. RESULTS: The panel performed a gap analysis which identified seven research needs for prognostic modeling and trajectory analysis ("recovery science") in patients with disorders of consciousness: (1) to define the variables that predict outcomes; (2) to define meaningful intermediate outcomes at specific time points for different endotypes; (3) to describe recovery trajectories in the absence of limitations to care; (4) to harness big data and develop analytic methods to prognosticate more accurately; (5) to identify key elements and processes for communicating prognostic uncertainty over time; (6) to identify health care delivery models that facilitate recovery and recovery science; and (7) to advocate for changes in the health care delivery system needed to advance recovery science and implement already-known best practices. CONCLUSION: This report summarizes the current research available to inform the proposed research needs, articulates key elements within each area, and discusses the goals and advances in recovery science and care anticipated by successfully addressing these needs.

Plasma 1,3-ß-d-glucan levels predict adverse clinical outcomes in critical illness.

BACKGROUNDThe fungal cell wall constituent 1,3-ß-d-glucan (BDG) is a pathogen-associated molecular pattern that can stimulate innate immunity. We hypothesized that BDG from colonizing fungi in critically ill patients may translocate into the systemic circulation and be associated with host inflammation and outcomes.METHODSWe enrolled 453 mechanically ventilated patients with acute respiratory failure (ARF) without invasive fungal infection and measured BDG, innate immunity, and epithelial permeability biomarkers in serially collected plasma samples.RESULTSCompared with healthy controls, patients with ARF had significantly higher BDG levels (median [IQR], 26 pg/mL [15-49 pg/mL], P < 0.001), whereas patients with ARF with high BDG levels (≥40 pg/mL, 31%) had higher odds for assignment to the prognostically adverse hyperinflammatory subphenotype (OR [CI], 2.88 [1.83-4.54], P < 0.001). Baseline BDG levels were predictive of fewer ventilator-free days and worse 30-day survival (adjusted P < 0.05). Integrative analyses of fungal colonization and epithelial barrier disruption suggested that BDG may translocate from either the lung or gut compartment. We validated the associations between plasma BDG and host inflammatory responses in 97 hospitalized patients with COVID-19.CONCLUSIONBDG measurements offered prognostic information in critically ill patients without fungal infections. Further research in the mechanisms of translocation and innate immunity recognition and stimulation may offer new therapeutic opportunities in critical illness.FUNDINGUniversity of Pittsburgh Clinical and Translational Science Institute, COVID-19 Pilot Award and NIH grants (K23 HL139987, U01 HL098962, P01 HL114453, R01 HL097376, K24 HL123342, U01 HL137159, R01 LM012087, K08HK144820, F32 HL142172, K23 GM122069).

Effect of CHRFAM7A Δ2bp gene variant on secondary inflammation after spinal cord injury.

The α7 neuronal nicotinic acetylcholine receptors (α7nAChRs) are essential for anti-inflammatory responses. The human-specific CHRFAM7A gene and its 2bp deletion polymorphism (Δ2bp variant) encodes a structurally-deficient α7nAChRs that may impact the anti-inflammatory function. We studied 45 spinal cord injury (SCI) patients for up to six weeks post SCI to investigate the role of the Δ2bp variant on multiple circulating inflammatory mediators and two outcome measures (neuropathic pain and risk of pressure ulcers). The patient's SCI were classified as either severe or mild. Missing values were imputed. Overall genetic effect was conducted with independent sample t-test and corrected with false discovery rate (FDR). Univariate analysis and regression analysis were applied to evaluate the Δ2bp effects on temporal variation of inflammatory mediators post SCI and their interaction with outcome measures. In severe SCI, the Δ2bp carriers showed higher levels of circulating inflammatory mediators than the Δ2bp non-carriers in TNF-α (FDR = 9.6x10-4), IFN-γ (FDR = 1.3x10-3), IL-13 (FDR = 1.6x10-3), CCL11 (FDR = 2.1x10-3), IL-12p70 (FDR = 2.2x10-3), IL-8 (FDR = 2.2x10-3), CXCL10 (FDR = 3.1x10-3), CCL4 (FDR = 5.7x10-3), IL-12p40 (FDR = 7.1x10-3), IL-1b (FDR = 0.014), IL-15 (FDR = 0.024), and IL-2 (FDR = 0.037). IL-8 and CCL2 were negatively associated with days post injury (DPI) for the Δ2bp carriers (P = 2x10-7 and P = 2x10-8, respectively) and IL-5 was positively associated with DPI for the Δ2bp non-carriers (P = 0.015). Neuropathic pain was marginally positively associated with IL-13 for the Δ2bp carriers (P = 0.056). In mild SCI, the Δ2bp carriers had lower circulating levels of IL-15 (FDR = 0.04) than the Δ2bp non-carriers. Temporal variation of inflammatory mediators post SCI was not associated with the Δ2bp variant. For the mild SCI Δ2bp carriers, risk of pressure ulcers was positively associated with circulating levels of IFN-γ, CXCL10, and CCL4 and negatively associated with circulating levels of IL-12p70. These findings support an important role for the human-specific CHRFAM7A Δ2bp gene variant in modifying anti-inflammatory function of α7nAChRs following SCI.

Serum Biomarkers of Regeneration and Plasticity are Associated with Functional Outcome in Pediatric Neurocritical Illness: An Exploratory Study.

BACKGROUND/OBJECTIVE: Pediatric neurocritical care survivorship is frequently accompanied by functional impairments. Lack of prognostic biomarkers is a barrier to early identification and management of impairment. We explored the association between blood biomarkers and functional impairment in children with acute acquired brain injury. METHODS: This study is a secondary analysis of a randomized control trial evaluating early versus usual care rehabilitation in the pediatric intensive care unit (PICU). Forty-four children (17 [39%] female, median age 11 [interquartile range 6-13] years) with acute acquired brain injury admitted to the PICU were studied. A single center obtained serum samples on admission days 0, 1, 3, 5, and the day closest to hospital discharge. Biomarkers relevant to brain injury (neuron specific enolase [NSE], S100b), inflammation (interleukin [IL-6], C-reactive protein), and regeneration (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor [VEGF]) were collected. Biomarkers were analyzed using a Luminex® bioassay. Functional status scale (FSS) scores were abstracted from the medical record. New functional impairment was defined as a (worse) FSS score at hospital discharge compared to pre-PICU (baseline). Individual biomarker fluorescence index (FI) values for each sample collection day were correlated with new functional impairment using Spearman rank correlation coefficient (ρ). Trends in repeated measures of biomarker FI over time were explored graphically, and the association between repeated measures of biomarker FI and new functional impairment was analyzed using covariate adjusted linear mixed-effect models. RESULTS: Functional impairment was inversely correlated with markers of regeneration and plasticity including BDNF at day 3 (ρ = - 0.404, p = .015), day 5 (ρ = - 0.549, p = 0.005) and hospital discharge (ρ = - 0.420, p = 0.026) and VEGF at day 1 (ρ = - 0.282, p = 0.008) and hospital discharge (ρ = - 0.378, p = 0.047), such that lower levels of both markers at each time point were associated with greater impairment. Similarly, repeated measures of BDNF and VEGF were inversely correlated with new functional impairment (B = - 0.001, p = 0.001 and B = - 0.001, p = 0.003, respectively). NSE, a biomarker of acute brain injury, showed a positive correlation between day 0 levels and new functional impairment (ρ = 0.320, p = 0.044). CONCLUSIONS: Blood-based biomarkers of regeneration and plasticity may hold prognostic utility for functional impairment among pediatric patients with neurocritical illness and warrant further investigation.

Effects of an acute care brain injury medicine continuity consultation service on health care utilization and rehabilitation outcomes.

INTRODUCTION: Although general physiatry acute-care consultation services are commonplace and improve length of stay (LOS), the benefits of a subspecialty physiatric continuity consultation service targeting patients with severe brain injury have not been reported. OBJECTIVES: Our primary objective was to characterize patient care recommendations from a Brain Injury Medicine (BIM) Continuity Consult Service, and to investigate the effects on acute-care LOS relative to brain injury patients receiving General Physical Medicine & Rehabilitation (PM&R) Consult Services. Our secondary objectives were to examine inpatient rehabilitation (IPR) health care utilization metrics and costs between groups and evaluate clinical improvements during IPR and discharge disposition. DESIGN: Retrospective cohort comparison study. SETTING: Academic medical center with level 1 trauma center. PARTICIPANTS: Adults with severe brain injury admitted to a single-site acute-care facility and subsequently admitted to a single inpatient brain injury rehabilitation unit over the same time period. PHYSIATRIC CARE MODELS: BIM Continuity Consult Service versus General PM&R Consult Service. MAIN OUTCOME MEASURES: Acute-care LOS; unplanned discharges to acute-care. RESULTS: Despite no major demographic or clinical group differences, the BIM Consult Service had more patient comorbidities than General PM&R Consult Service (17.5±5.3 versus 16±5.1;P = .04). BIM Consult Service patients spent fewer days in acute care (30±11.8 versus 36±22.8; P = .008), and early BIM consult (≤7 days after admission) was associated with shorter acute-care LOS (P < .002). IPR LOS was similar between groups when considering unplanned transfers. Unplanned transfers among General PM&R Consult Service patients occurred twice as frequently as in BIM Consult Service patients; average readmission costs were $2778 per patient on the BIM Consult Service and $6702 per patient on the General PM&R Consult Service. More BIM Consult Service (85.7%) than General PM&R Consult Service (27.3%) patients emerged from disorders of consciousness during IPR (P = .02). CONCLUSIONS: BIM Continuity Consultation Services were associated with shorter acute-care LOS, fewer unplanned acute-care transfers, and an increased likelihood of emerging from a minimally conscious state during IPR.