Risk of acute pancreatitis among new users of empagliflozin compared to sulfonylureas in patients with type 2 diabetes: A post-authorization safety study.

PURPOSE: This study was undertaken to evaluate the potential risk of acute pancreatitis with empagliflozin in patients with type 2 diabetes (T2D) newly initiating empagliflozin. METHODS: Data from two large US claims databases were analyzed in an observational study of patients with T2D receiving metformin who were newly prescribed empagliflozin versus sulfonylurea (SU). Because dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have been associated with the risk of acute pancreatitis in some studies, patients on these agents were excluded. Using pooled analyses of data from the two databases (2014-2021), patients initiating empagliflozin were matched 1:1 within database to patients initiating SU using propensity scores (PS) that incorporated relevant demographic and clinical characteristics. Prespecified sensitivity analyses were performed for design parameters. RESULTS: The analyses identified 72 661 new users of empagliflozin and 422 018 new users of SUs, with both patient groups on concurrent metformin therapy. Baseline characteristics within treatment groups appeared to be similar across the 72 621 matched pairs. After mean follow-up of ~6 months, incidence rates of acute pancreatitis in the pooled matched cohort were 10.30 (95% confidence interval [CI] 9.29-11.39) events per 1000 patient-years (PY) for empagliflozin and 11.65 (95% CI 10.59-12.77) events per 1000 PY for SUs. On a background of metformin, patients newly initiating empagliflozin did not have an increased risk of acute pancreatitis compared with those initiating an SU (pooled PS matched hazard ratio 0.88 [0.76-1.02]) across 75621.42 PY of follow-up. CONCLUSIONS: The results of this voluntary post-approval safety study provide additional evidence that the use of empagliflozin for the treatment of T2D is not associated with an increased risk of acute pancreatitis.

A digital approach to asthma self-management in adults: Protocol for a pragmatic randomized controlled trial.

Asthma self-management can improve symptom control, but adherence to established self-management behaviors is often poor. With adult asthma uncontrolled in over 60% of U.S. cases, there is a need for scalable, cost-effective tools to improve asthma outcomes. Here we describe a protocol for the Asthma Digital Study, a 24-month, decentralized, pragmatic, open-label, randomized controlled trial investigating the impact of a digital asthma self-management (DASM) program on asthma outcomes in adults. The program leverages consumer-grade devices with a smartphone app to provide "smart nudges," symptom logging, trigger tracking, and other features. Participants are recruited (target N = 900) from throughout the U.S., and randomized to a DASM or control arm (1:1). Co-primary outcomes at one year are a) asthma-associated costs for acute care and b) change from baseline in Asthma Control Test™ scores. Findings may inform decisions around adoption of digital tools for asthma self-management. Trial registration:clinicaltrials.gov identifier: NCT04609644. Registered: Oct 30, 2020.

Examining implicit bias of physicians who care for individuals with spinal cord injury: A pilot study and future directions.

CONTEXT: Despite evidence that healthcare providers have implicit biases that can impact clinical interactions and decisions, implicit bias among physicians caring for individuals with spinal cord injury (SCI) has not been examined. OBJECTIVE: Conduct a pilot study to examine implicit racial bias of SCI physicians and its association with functioning and wellbeing for individuals with SCI. DESIGN: Combined data from cross-sectional surveys of individuals with SCI and their SCI physicians. SETTING: Four national SCI Model Systems sites. PARTICIPANTS: Individuals with SCI (N = 162) and their SCI physicians (N = 14). OUTCOME MEASURES: SCI physicians completed online surveys measuring implicit racial (pro-white/anti-black) bias. Individuals with SCI completed questionnaires assessing mobility, physical independence, occupational functioning, social integration, self-reported health, depression, and life satisfaction. We used multilevel regression analyses to examine the associations of physician bias and outcomes of individuals with SCI. RESULTS: Physicians had a mean bias score of 0.62 (SD = 0.35), indicating a strong pro-white/anti-black bias. Greater physician bias was associated with disability among individuals with SCI in the domain of social integration (odds ratio = 4.80, 95% confidence interval (CI) = 1.44, 16.04), as well as higher depression (B = 3.24, 95% CI = 1.06, 5.41) and lower life satisfaction (B = -4.54, 95% CI= -8.79, -0.28). CONCLUSION: This pilot study indicates that SCI providers are susceptible to implicit racial bias and provides preliminary evidence that greater implicit racial bias of physicians is associated with poorer psychosocial health outcomes for individuals with SCI. It demonstrates the feasibility of studying implicit bias among SCI providers and provides guidance for future research on physician bias and patient outcomes.

The influence of genetic variants on striatal dopamine transporter and D2 receptor binding after TBI.

Dopamine (DA) neurotransmission influences cognition and recovery after traumatic brain injury (TBI). We explored whether functional genetic variants affecting the DA transporter (DAT) and D2 receptor (DRD2) impacted in vivo dopaminergic binding with positron emission tomography (PET) using [(11)C]ßCFT and [(11)C]raclopride. We examined subjects with moderate/severe TBI (N=12) ∼1 year post injury and similarly matched healthy controls (N=13). The variable number of tandem repeat polymorphism within the DAT gene and the TaqI restriction fragment length polymorphism near the DRD2 gene were assessed. TBI subjects had age-adjusted DAT-binding reductions in the caudate, putamen, and ventral striatum, and modestly increased D2 binding in ventral striatum versus controls. Despite small sample sizes, multivariate analysis showed lower caudate and putamen DAT binding among DAT 9-allele carriers and DRD2 A2/A2 homozygotes with TBI versus controls with the same genotype. Among TBI subjects, 9-allele carriers had lower caudate and putamen binding than 10/10 homozygotes. This PET study suggests a hypodopaminergic environment and altered DRD2 autoreceptor DAT interactions that may influence DA transmission after TBI. Future work will relate these findings to cognitive performance; future studies are required to determine how DRD2/DAT1 genotype and DA-ligand binding are associated with neurostimulant response and TBI recovery.

The Stroke Assessment of Fall Risk (SAFR): predictive validity in inpatient stroke rehabilitation.

OBJECTIVE: To evaluate relative accuracy of a newly developed Stroke Assessment of Fall Risk (SAFR) for classifying fallers and non-fallers, compared with a health system fall risk screening tool, the Fall Harm Risk Screen. DESIGN AND SETTING: Prospective quality improvement study conducted at an inpatient stroke rehabilitation unit at a large urban university hospital. PARTICIPANTS: Patients admitted for inpatient stroke rehabilitation (N = 419) with imaging or clinical evidence of ischemic or hemorrhagic stroke, between 1 August 2009 and 31 July 2010. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Sensitivity, specificity, and area under the curve for Receiver Operating Characteristic Curves of both scales' classifications, based on fall risk score completed upon admission to inpatient stroke rehabilitation. RESULTS: A total of 68 (16%) participants fell at least once. The SAFR was significantly more accurate than the Fall Harm Risk Screen (p < 0.001), with area under the curve of 0.73, positive predictive value of 0.29, and negative predictive value of 0.94. For the Fall Harm Risk Screen, area under the curve was 0.56, positive predictive value was 0.19, and negative predictive value was 0.86. Sensitivity and specificity of the SAFR (0.78 and 0.63, respectively) was higher than the Fall Harm Risk Screen (0.57 and 0.48, respectively). CONCLUSIONS: An evidence-derived, population-specific fall risk assessment may more accurately predict fallers than a general fall risk screen for stroke rehabilitation patients. While the SAFR improves upon the accuracy of a general assessment tool, additional refinement may be warranted.

Cerebrospinal fluid cortisol and progesterone profiles and outcomes prognostication after severe traumatic brain injury.

Despite significant advances in the management of head trauma, there remains a lack of pharmacological treatment options for traumatic brain injury (TBI). While progesterone clinical trials have shown promise, corticosteroid trials have failed. The purpose of this study was to (1) characterize endogenous cerebrospinal fluid (CSF) progesterone and cortisol levels after TBI, (2) determine relationships between CSF and serum profiles, and (3) assess the utility of these hormones as predictors of long-term outcomes. We evaluated 130 adults with severe TBI. Serum samples (n=538) and CSF samples (n=746) were collected for 6 days post-injury, analyzed for cortisol and progesterone, and compared with healthy controls (n=13). Hormone data were linked with clinical data, including Glasgow Outcome Scale (GOS) scores at 6 and 12 months. Group based trajectory (TRAJ) analysis was used to develop temporal hormone profiles delineating distinct subpopulations. Compared with controls, CSF cortisol levels were significantly and persistently elevated during the first week after TBI, and high CSF cortisol levels were associated with poor outcome. As a precursor to cortisol, progesterone mediated these effects. Serum and CSF levels for both cortisol and progesterone were strongly correlated after TBI relative to controls, possibly because of blood-brain barrier disruption. Also, differentially impaired hormone transport and metabolism mechanisms after TBI, potential de novo synthesis of steroids within the brain, and the complex interplay of cortisol and pro-inflammatory cytokines may explain these acute hormone profiles and, when taken together, may help shed light on why corticosteroid trials have previously failed and why progesterone treatment after TBI may be beneficial.

Neuroprotective, neuroplastic, and neurobehavioral effects of daily treatment with levetiracetam in experimental traumatic brain injury.

BACKGROUND: Prophylactic treatment with antiepileptic drugs (AEDs) has been recommended to prevent early seizure onset in patients with traumatic brain injury (TBI). However, the potential neuroprotective and/or detrimental effects of prophylactic AED treatment on behavioral and cognitive function after TBI are not well studied. OBJECTIVE: To investigate the effects of a novel AED, levitiracetam (LEV), on behavioral and cognitive function after experimental TBI in rats. METHODS: Adult male rats were administered LEV (intraperitoneal 50 mg/kg) or vehicle (saline; SL) daily for 20 days beginning 1 day after controlled cortical impact (CCI; 2.8 mm; 4 m/s) or sham surgery. Beam performance (days 1-6), Y-maze (day 7), and Morris water maze (days 14-19) postinjury testing was assessed. RESULTS: Daily LEV treatment improved motor function, increased novel arm exploration in the Y-maze, elicited greater hippocampal cell sparing, and decreased contusion volumes compared with CCI/SL rats. Daily LEV administration also reversed a TBI-induced decrease in regional glutamate transporter expression and neuroplastic marker proteins present 20 days post-CCI. Also, daily LEV treatment decreased regional IL-1ß expression after TBI. CONCLUSIONS: These results suggest that daily LEV treatment has beneficial effects on histological, molecular, and behavioral elements of neurological recovery after TBI, in part, via modulation of neuroinflammatory and excitatory pathways.

Non-spatial pre-training in the water maze as a clinically relevant model for evaluating learning and memory in experimental TBI.

Explicit and implicit learning and memory networks exist where each network can facilitate or inhibit cognition. Clinical evidence suggests that implicit networks are relatively preserved after traumatic brain injury (TBI). Non-spatial pre-training (NSPT) in the Morris Water Maze (MWM) provides the necessary behavioral components to complete the task, while limiting the formation of spatial maps. Our study utilized NSPT in the MWM to assess implicit and explicit learning and memory system deficits in the controlled cortical impact (CCI) model of TBI. 76 adult male Sprague-Dawley rats were divided: CCI vs. sham surgery, NSPT vs. No-NSPT, and cued vs. non-cued groups. NSPT occurred for 4d prior to surgery (dynamic hidden platform location, extra-maze cues covered, static pool entry point). Acquisition (d14-18), Probe/Visible Platform (d19), and Reversal (d20-21) trials were conducted with or without extra-maze cues. Novel time allocation and search strategy selection metrics were utilized. Results indicated implicit and explicit learning/memory networks are distinguishable in the MWM. In the cued condition, NSPT reduced thigmotaxis, improved place learning, and largely eliminated the apparent injury-induced deficits typically observed between untrained CCI and sham rats. However, among NSPT groups, incorporation of cues into search strategy selection for CCI rats was relatively impaired compared to shams. Non-cued condition performance showed sham/NSPT and CCI/NSPT rats perform similarly, suggesting implicit memory networks are largely intact 2weeks after CCI. Place learning differences between CCI/NSPT and sham/NSPT rats more accurately reflect spatial deficits in our CCI model compared to untrained controls. These data suggest NSPT as a clinically relevant construct for evaluating potential neurorestorative and neuroprotective therapies. These findings also support development of non-spatial cognitive training paradigms for evaluating rehabilitation relevant combination therapies.

Impact of aromatase genetic variation on hormone levels and global outcome after severe TBI.

Although experimental traumatic brain injury (TBI) studies support estradiol as a neuroprotectant and potent stimulator of neuroplasticity, clinical studies suggest a negative association between endogenous estradiol profiles and mortality/poor outcomes. However, no studies have evaluated associations with cerebral spinal fluid (CSF) hormone profiles and aromatase gene (cytochrome P450 [CYP]19A1) variability on clinical TBI outcomes. We evaluated 110 adults with severe TBI. Average and daily estradiol, testosterone, and estradiol/testosterone ratios (E2:T) were measured using CSF and serum samples and compared to healthy controls. Eighteen tagging and four functional single-nucleotide polymorphisms (SNPs) for CYP19A1 were genotyped and compared to hormones, acute mortality, and Glasgow Outcome Scale (GOS) scores 6 months post-TBI. TBI subjects had lower CSF estradiol over time versus controls. CSF testosterone was initially high, but declined over time. E2/T ratios were initially low, compared to controls, but rose over time. Higher mean E2/T ratio in bivariate analysis was associated with lower mortality (p=0.019) and better GOS-6 scores (p=0.030). rs2470152 influenced CSF E2/T ratio and also serum and CSF testosterone (p≤0.05 all comparisons). Multiple-risk SNPs rs2470152, rs4646, and rs2470144 were associated with worse GOS-6 scores (p≤0.05, all comparisons), and those with>1 risk SNP variant had a higher risk for poor outcome, compared with those with ≤1 risk variant. TBI results in low CSF estradiol and dynamic CSF testosterone and E2/T ratio. In contrast to clinical serum hormone studies, higher CSF E2/T ratio was associated with better outcome. Further, genetic variation in CYP19A1 influences both hormone dynamics and outcome post-TBI.

Group-based trajectory analysis applications for prognostic biomarker model development in severe TBI: a practical example.

Over the last decade, biomarker research has identified potential biomarkers for the diagnosis, prognosis, and management of traumatic brain injury (TBI). Several cerebrospinal fluid (CSF) and serum biomarkers have shown promise in predicting long-term outcome after severe TBI. Despite this increased focus on identifying biomarkers for outcome prognostication after a severe TBI, several challenges still exist in effectively modeling the significant heterogeneity observed in TBI-related pathology, as well as the biomarker-outcome relationships. Biomarker data collected over time are usually summarized into single-point estimates (e.g., average or peak biomarker levels), which are, in turn, used to examine the relationships between biomarker levels and outcomes. Further, many biomarker studies to date have focused on the prediction power of biomarkers without controlling for potential clinical and demographic confounders that have been previously shown to affect long-term outcome. In this article, we demonstrate the application of a practical approach to delineate and describe distinct subpopulations having similar longitudinal biomarker profiles and to model the relationships between these biomarker profiles and outcomes while taking into account potential confounding factors. As an example, we demonstrate a group-based modeling technique to identify temporal S100 calcium-binding protein B (S100b) profiles, measured from CSF over the first week post-injury, in a sample of adult subjects with TBI, and we use multivariate logistic regression to show that the prediction power of S100b biomarker profiles can be superior to the prediction power of single-point estimates.

Unique contribution of fatigue to disability in community-dwelling adults with traumatic brain injury.

OBJECTIVE: To examine the unique contribution of fatigue to self-reported disability in community-dwelling adults with traumatic brain injury (TBI). DESIGN: A cross-sectional cohort design. SETTING: Community dwellings. PARTICIPANTS: Adults (N=50) with a history of mild to severe TBI were assessed. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: This study assessed the contribution of fatigue (Modified Fatigue Impact Scale) to disability (Mayo-Portland Adaptability Inventory), controlling for executive functions (Frontal Systems Behavior Scale), depression status (major depression in partial remission/current major depression/depressive symptoms or no history of depression), and initial injury severity (uncomplicated mild, complicated mild, moderate, or severe). RESULTS: Fatigue was found to contribute uniquely to the variance in self-reported disability (ß=.47, P<.001) after controlling for injury severity, executive functions, and depression status. The overall model was significant (F(4,45)=17.32, P<.001) and explained 61% of the variance in self-reported disability, with fatigue alone accounting for 12% of the variance in self-reported disability (F(1,45)=13.97, P<.001). CONCLUSIONS: Fatigue contributes uniquely to disability status among community-dwelling adults with chronic TBI, independent of injury severity, executive functions, and depression. Addressing fatigue through targeted interventions may help to improve self-perceived disability in this population.

S100b as a prognostic biomarker in outcome prediction for patients with severe traumatic brain injury.

As an astrocytic protein specific to the central nervous system, S100b is a potentially useful marker in outcome prediction after traumatic brain injury (TBI). Some studies have questioned the validity of S100b, citing the extracerebral origins of the protein as reducing the specificity of the marker. This study evaluated S100b as a prognostic biomarker in adult subjects with severe TBI (sTBI) by comparing outcomes with S100b temporal profiles generated from both cerebrospinal fluid (CSF) (n = 138 subjects) and serum (n = 80 subjects) samples across a 6-day time course. Long-bone fracture, Injury Severity Score (ISS), and isolated head injury status were variables used to assess extracerebral sources of S100b in serum. After TBI, CSF and serum S100b levels were increased over healthy controls across the first 6 days post-TBI (p ≤ 0.005 and p ≤ 0.031). Though CSF and serum levels were highly correlated during early time points post-TBI, this association diminished over time. Bivariate analysis showed that subjects who had temporal CSF profiles with higher S100b concentrations had higher acute mortality (p < 0.001) and worse Glasgow Outcome Scale (GOS; p = 0.002) and Disability Rating Scale (DRS) scores (p = 0.039) 6 months post-injury. Possibly as a result of extracerebral sources of S100b in serum, as represented by high ISS scores (p = 0.032), temporal serum profiles were associated with acute mortality (p = 0.015). High CSF S100b levels were observed in women (p = 0.022) and older subjects (p = 0.004). Multivariate logistic regression confirmed CSF S100b profiles in predicting GOS and DRS and showed mean and peak serum S100b as acute mortality predictors after sTBI.

Elimination of dysphagia using ultrasound guidance for botulinum toxin injections in cervical dystonia.

INTRODUCTION: Dysphagia is a common side effect after botulinum toxin injections for cervical dystonia, with an incidence of 10-40%, depending upon the study and dose used. METHODS: Our study consisted of 5 preselected women who met criteria for cervical dystonia and subsequent dysphagia after electromyography (EMG)-guided injections. Injections were performed with ultrasound (US) imaging, and the effects on swallowing were examined. Separately, sternocleidomastoid (SCM) thickness in healthy controls and treated patients was measured. RESULTS: There were 34 episodes of dysphagia over 98 injection sessions using EMG guidance for a cumulative rate of 34.7%. Using US plus EMG guidance, there was 0% dysphagia across 27 injection sessions. SCM thickness was <1.1 cm. CONCLUSION: US combined with EMG guidance eliminated recurrent dysphagia after botulinum toxin treatment, possibly by keeping the injectate within the SCM.

Association of KIBRA rs17070145 polymorphism and episodic memory in individuals with severe TBI.

BACKGROUND: Studies implicate single nucleotide polymorphism (SNP) rs17070145, a common T → C polymorphism on the KIBRA gene, in mediating differences in episodic memory. In healthy adults, T-allele carriers perform better than non-carriers on episodic memory measures. However, this association is reversed in adults with subjective memory complaints and populations vulnerable to memory deficits, a problem common in traumatic brain injury (TBI). METHODS: This study assessed associations between variation in the KIBRA gene and cognitive function in 129 adults with severe TBI. In addition to other executive functioning and functional/global outcomes, the Buschke Selective Reminding Test (SRT), Rey-Osterrieth Complex Figure Test and California Verbal Learning Test-II (CVLT-II) were administered 6 and 12 months post-injury. RESULTS: T-allele non-carriers performed better than carriers on multiple episodic memory measures. At 6 months, T-allele non-carriers performed better for delayed recall measures on the SRT. At 12 months, T-allele non-carriers performed better on multiple SRT measures and on List-B learning with CVLT-II. No associations occurred with executive function or global outcome measures. CONCLUSION: These results suggest that rs17070145 T-allele effects are specific to episodic memory and support the hypothesis that associations between rs17070145 variation and memory are disparate between healthy and impaired populations.

Persistent hypogonadism influences estradiol synthesis, cognition and outcome in males after severe TBI.

OBJECTIVE: Acute hypogonadotropic hypogonadism (AHH) occurs frequently after TBI, as does chronic hypogonadotropic hypogonadism. However, AHH and persistent hypogonadotropic hypogonadism (PHH) after TBI are not well studied. The objective of this study was to characterize longitudinal hormone profiles and the impact of AHH and PHH on outcome. METHODS: In this prospective cohort study, men with severe TBI (n = 38) had serum gonadal and gonadotropic hormones measured during weeks 1-52 post-injury. AHH, PHH and/or early resolving hypogonadotropic hypogonadism (ERHH) were based on temporal hormone assessments. PHH and hormone profiles were then compared to multiple outcome measures 6-12 months post-TBI. RESULTS: AHH affected 100% of the population, while 37% subsequently developed PHH. Acute testosterone (TEST) and estradiol/testosterone (E2/TEST) ratios were associated with PHH and outcome. Over time, post-acute TEST and E2 levels for the ERHH group approached normal range, while levels for the PHH group remained low. Post-acute gonadotrophin levels were within the normal range for both groups. PHH, along with lower post-acute TEST and E2 profiles, was associated with worse functional and cognitive outcomes at 6 and 12 months post-injury. CONCLUSIONS: These results support screening for post-acute secondary hypogonadism and further research to assess the mechanisms underlying PHH and associated functional and cognitive deficits.

Quantitative electromyography improves prediction in vocal fold paralysis.

OBJECTIVES: Quantitative laryngeal electromyography (LEMG) using turns analysis can differentiate acute vocal fold paralysis from normal controls. The objective of this study is to determine if using both traditional qualitative LEMG measurements in addition to turns analysis improves prognostic accuracy in patients with acute vocal fold paralysis who demonstrate voluntary motor activity. STUDY DESIGN: Retrospective review of LEMG data (qualitative and quantitative) and charts of patients with vocal fold paralysis on flexible laryngoscopy, recurrent laryngeal neuropathy, and varying degrees of motor unit recruitment. METHODS: Laryngeal EMG using a standardized protocol involving qualitative (evaluation of recruitment, motor unit configuration, detection of fibrillations, synkinesis) and quantitative (turns analysis) measurements was performed. Prognosis was correlated with vocal fold motion recovery status (minimum of 6 months following onset) using positive and negative predictive values (PPV, NPV). RESULTS: Twenty-three patients underwent LEMG for acute recurrent laryngeal neuropathy. All four patients with excellent LEMG prognosis recovered motion, whereas 17/19 patients with fair/poor LEMG prognosis were without motion at least 6 months following onset, resulting in a 100% PPV and 89.5% NPV. CONCLUSIONS: Integrating both qualitative and quantitative LEMG data improves prognostic accuracy in vocal fold paralysis patients who demonstrate voluntary motor unit activity.

Acute serum hormone levels: characterization and prognosis after severe traumatic brain injury.

Experimental traumatic brain injury (TBI) studies report the neuroprotective effects of female sex steroids on multiple mechanisms of injury, with the clinical assumption that women have hormonally mediated neuroprotection because of the endogenous presence of these hormones. Other literature indicates that testosterone may exacerbate injury. Further, stress hormone abnormalities that accompany critical illness may both amplify or blunt sex steroid levels. To better understand the role of sex steroid exposure in mediating TBI, we 1) characterized temporal profiles of serum gonadal and stress hormones in a population with severe TBI during the acute phases of their injury; and 2) used a biological systems approach to evaluate these hormones as biomarkers predicting global outcome. The study population was 117 adults (28 women; 89 men) with severe TBI. Serum samples (n=536) were collected for 7 days post-TBI for cortisol, progesterone, testosterone, estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Hormone data were linked with clinical data, including acute care mortality and Glasgow Outcome Scale (GOS) scores at 6 months. Hormone levels after TBI were compared to those in healthy controls (n=14). Group based trajectory analysis (TRAJ) was used to develop temporal hormone profiles that delineate distinct subpopulations in the cohort. Structural equations models were used to determine inter-relationships between hormones and outcomes within a multivariate model. Compared to controls, acute serum hormone levels were significantly altered after severe TBI. Changes in the post-TBI adrenal response and peripheral aromatization influenced hormone TRAJ profiles and contributed to the abnormalities, including increased estradiol in men and increased testosterone in women. In addition to older age and greater injury severity, increased estradiol and testosterone levels over time were associated with increased mortality and worse global outcome for both men and women. These findings represent a paradigm shift when thinking about the role of sex steroids in neuroprotection clinically after TBI.

CSF Bcl-2 and cytochrome C temporal profiles in outcome prediction for adults with severe TBI.

The biochemical cascades associated with cell death after traumatic brain injury (TBI) involve both pro-survival and pro-apoptotic proteins. We hypothesized that elevated cerebrospinal fluid (CSF) Bcl-2 and cytochrome C (CytoC) levels over time would reflect cellular injury response and predict long-term outcomes after TBI. Cerebrospinal fluid Bcl-2 and CytoC levels were measured for 6 days after injury for adults with severe TBI (N=76 subjects; N=277 samples). Group-based trajectory analysis was used to generate distinct temporal biomarker profiles that were compared with Glasgow Outcome Scale (GOS) and Disability Rating Scale (DRS) scores at 6 and 12 months after TBI. Subjects with persistently elevated temporal Bcl-2 and CytoC profiles compared with healthy controls had the worst outcomes at 6 and 12 months (P≤0.027). Those with CytoC profiles near controls had better long-term outcomes, and those with declining CytoC levels over time had intermediate outcomes. Subjects with Bcl-2 profiles that remained near controls had better outcomes than those with consistently elevated Bcl-2 profiles. However, subjects with Bcl-2 values that started near controls and steadily rose over time had 100% good outcomes by 12 months after TBI. These results show the prognostic value of Bcl-2 and CytoC profiles and suggest a dynamic apoptotic and pro-survival response to TBI.

Alterations in gene expression in response to compression of nucleus pulposus cells.

BACKGROUND CONTEXT: It is clear that mechanical forces are involved in initiating disc degeneration but also have the potential to exert beneficial effects. However, the signaling pathways initiated by mechanical stress and thresholds for these responses have not been elucidated. We have developed a metabolically active compression system with the advantages of having the ability to test cells in vitro as well as within their native matrix and control exposure to environmental factors. We hypothesized that nucleus pulposus cells would respond to compressive stress with different thresholds for alterations in catabolic and anabolic gene expression. PURPOSE: The purpose of the study was to establish the utility of a novel compression chamber and examine the effects of various magnitudes and durations of compression on nucleus pulposus inflammatory, catabolic, and anabolic gene expression. STUDY DESIGN: In vitro controlled examination of intervertebral disc cell responses to compression. METHODS: A chamber capable of imparting 0 to 20 MPa of hydrostatic compression onto nucleus pulposus cells was fabricated. Healthy rabbit nucleus pulposus cells were cultured in alginate beads and exposed to static compression at 0.7, 2, and 4 MPa for 4 or 24 hours. Gene expression analysis (real-time polymerase chain reaction) was performed to compare markers of inflammation (inducible nitric oxide synthase, cyclooxygenase-2), matrix catabolism (matrix metalloproteinase-3), and anticatabolic/anabolic metabolism (tissue inhibitor of metalloproteinase-1, aggrecan) in control and compressed cells. RESULTS: Compression resulted in magnitude- and duration-dependent changes in gene expression. Increasing magnitudes showed more anticatabolic gene expression changes, whereas increasing duration resulted in increases in procatabolic gene expression. CONCLUSION: These data demonstrate favorable effects of compression in relation to genes involved in matrix homeostasis and procatabolic gene expression in response to sustained loading levels, consistent with traumatic effects. These data provide an improved understanding of how compression affects cell signaling, which has the potential to be exploited to initiate repair and prevent matrix breakdown.

APOE genetic associations with seizure development after severe traumatic brain injury.

PRIMARY OBJECTIVE: The purpose of the current study is to assess the role of the APOE genotype in post-traumatic seizure (PTS) development. RESEARCH DESIGN: A retrospective study of 322 adult Caucasians with a severe TBI and APOE genotype. METHODS AND PROCEDURES: Medical records were searched for PTS. Time to first seizure was categorized as early, late or delayed-onset PTS. Potential PTS associations by genotype, grouped genotype and allele were investigated. MAIN OUTCOME AND RESULTS: No statistically significant associations were found. However, two out of the four individuals (50%) with the E4/E4 genotype had late/delayed-onset PTS. Furthermore, none with a E2/E2 or E2/E4 genotype seized in the late periods. CONCLUSIONS: The results of this study may suggest 4/4 as a risk genotype for late/delayed onset PTS and a potential neuroprotective role of the E2 allele. However, this study did not definitively support a role for the APOE genotype in PTS susceptibility and indicates that larger populations are needed to fully evaluate the potential impact of APOE on PTS.