OBJECTIVE:The purpose of this study was to measure the efficacy of a novel faculty and resident educational bundle focused on development of faculty-resident behaviors and entrustment in the operating room. SUMMARY BACKGROUND DATA:As surgical training environments are orienting to entrustable professional activities (EPAs), successful transitions to this model will require significant faculty and resident development. Identifying an effective educational initiative which prepares faculty and residents for optimizing assessment, teaching, learning, and interacting in this model is critical. METHODS:From September 2015 to June 2017, an experimental study was conducted in the Department of Surgery at the University of Michigan Health System (UMHS). Case observations took place across general, plastic, thoracic, and vascular surgical specialties. A total of 117 operating room observations were conducted during Phase I of the study and 108 operating room observations were conducted during Phase II following the educational intervention. Entrustment behaviors were rated for 56 faculty and 73 resident participants using OpTrust, a validated intraoperative entrustment instrument. RESULTS:Multiple regression analysis showed a significant increase in faculty entrustment (Phase I = 2.32 vs Phase II = 2.56, P < 0.027) and resident entrustability (Phase I = 2.16 vs Phase II = 2.40, P < 0.029) scores following exposure to the educational intervention. CONCLUSIONS:Our study shows improved intraoperative entrustment following implementation of faculty and resident development, indicating the efficacy of this innovative educational bundle. This represents a crucial component in the implementation of a competency-based assessment framework like EPAs.

Traumatic brain injury (TBI) is a heterogeneous injury that is a major cause of morbidity and mortality worldwide. Epigenetic modulation through the alteration of cellular acetylation by valproic acid (VPA) administration has shown promise as a novel pharmacological treatment for TBI. It improves clinical outcomes through multiple mechanisms, many of which are still poorly understood. In recent years, omics technologies have emerged as a promising strategy to detect molecular changes at the cellular level. This review highlights the use of these high throughput technologies in advancing the understanding of epigenetic modulation by VPA in TBI. It also describes the future role of omics techniques in developing a point of care test to guide patient selection for VPA administration.

Cystic duct stump leak remains a difficult clinical problem despite advancements in endoscopic techniques. When these minimally invasive strategies fail, patients are often subject to high morbidity and mortality associated with open surgical exploration. We report the successful treatment of persistent biliary leak from the cystic duct stump following cholecystectomy using percutaneous transabdominal access of the cystic duct and coil embolization.

BACKGROUND:Longitudinal contact between faculty and residents facilitates greater faculty entrustment. The purpose of this study is to assess the relationship between faculty familiarity with residents and faculty entrustment. MATERIALS AND METHODS:Researchers observed and rated entrustment behaviors using OpTrust, September 2015-June 2017 at Michigan Medicine. Faculty familiarity with resident was measured on a 1-4 scale (1 = not familiar, 4 = extremely familiar). ANOVA and Sidak adjusted multiple comparisons were used to assess the relationship between faculty familiarity and faculty entrustment. RESULTS:56 faculty and 73 residents were observed across 225 surgical cases. Faculty entrustment scores increased to 2.48 when resident familiarity was reported as "slightly familiar". Faculty entrustment scores for "moderately familiar" increased to 2.57. Faculty entrustment scores for "extremely familiar" increased to 2.84. CONCLUSIONS:We found a positive relationship between faculty familiarity and entrustment. These findings support greater continuity in faculty/resident relationships. Longitudinal contact allows learners to be granted progressive entrustment. SUMMARY:This study demonstrates a positive relationship between faculty familiarity with residents and an increase in intraoperative entrustment. These findings support greater continuity in faculty/resident relationships.

Purpura fulminans (PF) is a rare but serious complication of septic shock in adults. The complex disease course makes it challenging to manage the condition. Here, we present the case of a healthy young woman who presented with sepsis and new-onset erythematous lesions 4days after the vaginal delivery of a healthy baby. The infectious source could not be identified, and the patient was started on antibiotics and resuscitated. However, her condition worsened, and she developed disseminated intravascular coagulation and PF. The septic episode slowly decreased in severity, but she sustained extensive ischaemic injuries to her extremities, for which she underwent four-limb amputation.

Bhatti, Umar F. MD; Williams, Aaron M. MD; Nikolian, Vahagn C. MD; Dennahy, Isabel S. MD; Weykamp, Michael MD; Georgoff, Patrick E. MD; Biesterveld, Ben E. MD; Tagett, Rebecca MS, PhD; Li, Yongqing MD, PhD; Alam, Hasan B. MD, FACS Author Information

OBJECTIVE To determine the association between intraoperative entrustment and personality alignment. SUMMARY BACKGROUND DATA For surgical residents, achieving operative autonomy has become increasingly difficult. The impact of faculty-resident operative interactions in accomplishing this goal is not well understood. We hypothesized that if operative dyads (faculty and resident) had personality alignment or congruency, then resident entrustment in the operating room would increase. METHODS We completed a retrospective analysis of 63 operations performed from September 2015 to August 2016. Operations were scored using OpTrust, a validated tool that assesses progressive entrustment of responsibility to surgical residents in the operating room. All dyads were classified as having congruent or incongruent personality alignment as measured by promotion or prevention orientation using the regulatory focus questionnaire. The association between personality congruence and OpTrust scores was identified using multivariable linear regression. RESULTS A total of 35 congruent dyads and 28 incongruent dyads were identified. Congruent dyads had a higher percentage of "very difficult" cases (33.3 vs. 7.4%, P = 0.017), female residents (37.1 vs. 14.3%, P = 0.042) and faculty with fewer years of experience (10.4 vs. 14.8%, P = 0.028) than incongruent dyads. In addition to post-graduate year level, dyad congruency was independently associated with a 0.88 increase (95% CI [0.27-1.49], P = 0.006) in OpTrust scores (overall range 2-8), after adjusting for case difficulty, faculty experience, and post-graduate year. CONCLUSIONS Congruent operative dyads are associated with increased operative entrustment as demonstrated by increased OpTrust scores. Developing awareness and strategies for addressing incongruence in personality in the operative dyad is needed.

BACKGROUND Early treatment with valproic acid (VPA) has demonstrated benefit in preclinical models of traumatic brain injury, including smaller brain lesion size, decreased edema, reduced neurologic disability, and faster recovery. Mechanisms underlying these favorable outcomes are not fully understood. We hypothesized that VPA treatment would upregulate genes involved in cell survival and proliferation and downregulate those associated with cell death and the inflammatory response. METHODS Ten female swine were subjected to a protocol of traumatic brain injury and hemorrhagic shock. They were assigned to two groups (n = 5): normal saline (NS; 3× volume of shed blood), or NS + VPA (150 mg/kg). Following 6 hours of observation, brain tissue was harvested to evaluate lesion size and edema. Brain tissue was processed for RNA sequencing. Gene set enrichment and pathway analysis was performed to determine the differential gene expression patterns following injury. RESULTS Animals treated with VPA were noted to have a 46% reduction in brain lesion size and a 57% reduction in ipsilateral brain edema. Valproic acid significantly upregulated genes involved in morphology of the nervous system, neuronal development and neuron quantity. The VPA treatment downregulated pathways related to apoptosis, glial cell proliferation, and neuroepithelial cell differentiation. Ingenuity Pathway Analysis identified VPA as the top upstream regulator of activated transcription, supporting it as a direct cause of these transcriptional changes. Master transcriptional regulator NEUROD1 was also significantly upregulated, suggesting that VPA may induce additional transcription factors. CONCLUSION Administration of VPA attenuated brain lesion size, reduced brain edema, and induced significant changes in the transcriptome of injured brain within 6 hours. Patterns of differential expression were consistent with the proposed neurogenic and prosurvival effects of VPA treatment.

Background: Optimizing intraoperative education is critical for development of autonomous residents. Faculty decisions concerning intraoperative entrustment determine the degree to which a resident gains intraoperative responsibility. Accordingly, residents exhibit entrustable behaviors that further faculty entrustment in the operating room. Little empiric evidence exists evaluating how the sex of a resident influences faculty-resident decisions of entrustment. Studies involving perception-based measurements of autonomy report inequities for women residents. We sought to assess faculty behaviors in entrustment in relation to resident sex using OpTrust, a third-party objective measurement tool. Methods: From September 2015 to June 2017 at the University of Michigan, surgical cases were observed and entrustment behaviors were rated using OpTrust. Critical case sampling was used to generate variation in operation type, case difficulty, faculty-resident pairings, faculty experience, and the level of the resident's training. Independent sample t-tests were conducted to compare faculty entrustment scores, as well as resident entrustability scores. Results: A total of 56 faculty and 73 residents were observed across 223 surgical cases from 4 surgical specialties: general, plastic, thoracic, and vascular. There was no difference in faculty entrustment or entrustability scores between women and men (2.54 vs 2.35, P=.117 and 2.32 vs 2.22, P=.393, respectively). Conclusion: Using OpTrust scores, we found that a resident's sex does not appear to influence faculty entrustment in the OR. Faculty entrustment scores for women and men residents are similar across cases. This observation suggests that during the intraoperative interaction, faculty are not extending entrustment or opportunities for autonomy differently to women or men. Future research is needed to identify and measure perioperative elements that inform resident autonomy, which may contribute to inequities for women residents. Published by Elsevier Inc.

Background: Changes in the surgical training landscape have sparked an interest in developing new educational models anchored on entrustment assessment. We sought to optimize the validated OpTrust entrustment assessment tool by comparing ratings from short-course video reviews to previously validated intraoperative assessments. Methods: Entrustment assessment scores for video-based and 1-h (short-course) observations were compared to previously validated intraoperative assessment scores. Faculty and residents were surveyed for their perceptions related to operative observation. Results: There was a strong association between entrustment scores when comparing in-person to video-based observations (R-2 = 0.76-0.84, p < 0.01) as well as short-course to full-duration observations (R-2 = 0.65-0.76, p < 0.01). The majority of faculty and residents (>97%) felt observation did not negatively impact operative experience. Conclusions: Assessment of entrustment behaviors using short-course video review provides a feasible approach to intraoperative assessment. This latest application of OpTrust allows for the tool to be incorporated into surgical training programs across a variety of environments. (C) 2017 Elsevier Inc. All rights reserved.

Background: Histone deacetylase inhibitors such as valproic acid (VPA) improve survival in lethal models of hemorrhagic shock and polytrauma. Although VPA is known to modulate transcription, its ability to reduce mortality within minutes of administration suggests involvement of a rapid, posttranslational mechanism. We hypothesized that VPA treatment would cause proteomic changes within minutes of treatment including quantitative and/or posttranslational differences in structural and/or effector proteins. Materials and methods: We used a porcine model of traumatic brain injury (computercontrolled cortical impact, 12 mm depth) and hemorrhagic shock (40% hemorrhage). Animals were kept in shock for 2 h and randomized to two groups (n = 3): normal saline (volume = 3:1 hemorrhage volume) or normal saline + VPA (150 mg/kg, single dose). Peripheral blood mononuclear cells were collected at baseline, postshock, and postresuscitation. Intracellular protein profiles were assessed using 1 dimensional gel electrophoresis, liquid chromatography, mass spectrometry, and analyzed with Ingenuity Pathway Analysis software. Results: Animals treated with VPA demonstrated significant proteomic changes. Quantitative differences were found in over 200 proteins including effector, regulatory, and structural proteins in critical cell signaling pathways. Posttranslational modification analysis demonstrated differential VPA-induced acetylation of lysine residues in histone and nonhistone proteins. Pathway analysis correlated these changes with significant increases in numerous prosurvival and cytoskeletal intracellular pathways, including Rho GTPase signaling (P = 1.66E-11), integrin signaling (P = 4.19E-21), and a decrease in Rho guanosine nucleotide dissociation inhibitor signaling (P = 4.83E-12). Conclusions: In a porcine model of severe injuries, a single dose of VPA is associated with protective changes in the proteome that are measurable within minutes of treatment. (C) 2018 Elsevier Inc. All rights reserved.

Objective: Combined traumatic brain injury and hemorrhagic shock are highly lethal. Following injuries, the integrity of the blood-brain barrier can be impaired, contributing to secondary brain insults. The status of the blood-brain barrier represents a potential factor impacting long-term neurologic outcomes in combined injuries. Treatment strategies involving plasma-based resuscitation and valproic acid therapy have shown efficacy in this setting. We hypothesize that a component of this beneficial effect is related to blood-brain barrier preservation. Design: Following controlled traumatic brain injury, hemorrhagic shock, various resuscitation and treatment strategies were evaluated for their association with blood-brain barrier integrity. Analysis of gene expression profiles was performed using Porcine Gene ST 1.1 microarray. Pathway analysis was completed using network analysis tools (Gene Ontology, Ingenuity Pathway Analysis, and Parametric Gene Set Enrichment Analysis). Subjects: Female Yorkshire swine were subjected to controlled traumatic brain injury and 2 hours of hemorrhagic shock (40% blood volume, mean arterial pressure 30-35 mmHg). Interventions: Subjects were resuscitated with 1) normal saline, 2) fresh frozen plasma, 3) hetastarch, 4) fresh frozen plasma + valproic acid, or 5) hetastarch + valproic acid (n = 5 per group). After 6 hours of observation, brains were harvested for evaluation. Measurements and Main Results: Immunofluoroscopic evaluation of the traumatic brain injury site revealed significantly increased expression of tight-junction associated proteins (zona occludin-1, claudin-5) following combination therapy (fresh frozen plasma + valproic acid and hetastarch + valproic acid). The extracellular matrix protein laminin was found to have significantly improved expression with combination therapies. Pathway analysis indicated that valproic acid significantly modulated pathways involved in endothelial barrier function and cell signaling. Conclusions: Resuscitation with fresh frozen plasma results in improved expression of proteins essential for blood-brain barrier integrity. The addition of valproic acid provides significant improvement to these protein expression profiles. This is likely secondary to activation of key pathways related to endothelial functions.

BACKGROUND Valproic acid (VPA) is a histone deacetylase inhibitor that improves outcomes in large animal models of trauma. However, its protective mechanism of action is not completely understood. We sought to characterize the genetic changes induced by VPA treatment following traumatic injuries. METHODS Six female Yorkshire swine were subjected to traumatic brain injury (controlled cortical impact), polytrauma (liver and splenic laceration, rib fracture, rectus crush), and hemorrhagic shock (HS, 40% total blood volume). Following 2 hours of HS, animals were randomized to resuscitation with normal saline (NS) or NS + 150 mg/kg of intravenous VPA (n = 3/cohort, 18 samples total). Blood samples were collected for isolation of peripheral blood mononuclear cells at three distinct time points: baseline, 6 hours following injuries, and on postinjury day 1. RNA was extracted from peripheral blood mononuclear cells and sequenced. Differential expression analysis (false discovery rate < 0.001 and p value <0.001) and gene set enrichment (Panther Gene Ontology and Ingenuity Pathway Analysis) was used to compare VPA to non–VPA-treated animals. RESULTS A total of 628 differentially expressed RNA transcripts were identified, 412 of which were used for analysis. There was no difference between treatment groups at baseline. The VPA-induced genetic changes were similar at 6 hours and on postinjury day 1. Upregulated genes were associated with gene expression ( p 2.13E-34), cellular development (1.19E-33), cellular growth and proliferation (1.25E-30), and glucocorticoid receptor signaling (8.6E-21). Downregulated genes were associated with cell cycle checkpoint regulation (3.64E-22), apoptosis signaling (6.54E-21), acute phase response signaling (5.84E-23), and the inflammasome pathway (1.7E-19). CONCLUSION In injured swine, VPA increases the expression of genes associated with cell survival, proliferation, and differentiation and decreases those associated with cell death and inflammation. These genetic changes could explain the superior clinical outcomes in VPA-treated animals, including smaller brain lesion size and improved neurologic recovery.

Background: Faculty entrustment decisions affect resident entrustability behaviors and surgical autonomy. The relationship between entrustability and autonomy is not well understood. This pilot study explores that relationship. Methods: 108 case observations were completed. Entrustment behaviors were rated using OpTrust. Residents completed a Zwisch self-assessment to measure surgical autonomy. Resident perceived autonomy was collected for 67 cases used for this pilot study. Results: Full entrustability was observed in 5 of the 108 observed cases. Residents in our study did not report full autonomy. Spearman's rank correlation coefficient identified that resident entrustability was positively correlated with perceived resident autonomy (r = 0.66, p < 0.05). Ordinal logistic regression assessed the relationship between resident entrustability and autonomy. The relationship persisted while controlling for PGY level, gender, and case complexity (OR = 8.42, SEM = 4.54, p < 0.000). Conclusions: Resident entrustability is positively associated with perceived autonomy, yet full entrustability is not translating to the perception of full autonomy for residents. (C) 2018 Elsevier Inc. All rights reserved.

OBJECTIVE: Feedback is critical to the development of medical students. To enhance feedback, we created a web application, the Minute Feedback System (MFS). This app allows students to request precise, timely, written feedback from residents and staff without the burden of vague, end-of-rotation surveys. In this study, we investigate variations in response rates and feedback fatigue based on sex and rank (resident/fellow vs. faculty). DESIGN: Data were collected from May 2015-October 2016. The MFS stores student requests for feedback along with faculty responses allowing for analysis of feedback response rate as well as sex and rank identification. Variation in response rate was analyzed using Chi-square and log-rank testing. Feedback fatigue was assessed using Cox regression modeling. SETTING: University Affiliated, Tertiary Care Center. PARTICIPANTS: Medical Students, Residents and Faculty. RESULTS: About 98.6% of students (138 women, 140 men) used the MFS on their surgery clerkship. They requested feedback from 159 trainees (residents or fellows) and 114 surgical faculty. Feedback was requested more from faculty (26.3 requests per individual) compared to trainees (16.4 requests per individual). The overall evaluator response rate was 60%. Male students were 13% less likely to receive feedback than female students. There was a higher prevalence of feedback fatigue among female faculty (11% less likely to respond) and residents (23% less likely to respond). Regression analysis showed that the overall hazard of nonresponse over time was 1.05, indicative of overall feedback fatigue among all respondents. CONCLUSIONS: The MFS is a novel tool for feedback used by nearly all M3 students during their surgery clerkship at our institution. Evaluation of response rates demonstrated feedback fatigue, especially among women faculty and residents. Feedback fatigue was more likely to affect male students, although the reason for this is unclear. Further analysis is necessary to understand this sex-associated response disparity and its effect on student feedback in the learning environment. (C) 2018 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

Objective: Venous thromboembolism (VTE) is reported to occur in up to 33% of patients undergoing major vascular surgery. Despite this high incidence, patients inconsistently receive timely VTE chemoprophylaxis. The true incidence of VTE among patients receiving delayed VTE chemoprophylaxis is unknown. We sought to identify the association of VTE chemoprophylaxis timing on VTE risk, postoperative transfusion rates, and 30-day mortality and morbidity in patients undergoing major open vascular surgery. Methods: Patients undergoing major open vascular surgery (open abdominal aortic aneurysm[oAAA] repair, aortofemoral bypass, and lower extremity infrainguinal bypass [LEB]) were identified using the Michigan Surgical Quality Collaborative (MSQC) between July 2012 and June 2015. The VTE rate was compared between patients receiving early versus delayed VTE chemoprophylaxis. VTE chemoprophylaxis delay was defined as therapy initiation more than 24 hours after surgery. The risk-adjusted association of the chemoprophylaxis timing and VTE development was determined using multivariable logistic regression. Blood transfusion rates, 30-day mortality, and postoperative complications were compared across groups. Results: A total of 2421 patients underwent major open vascular surgery, including 196 oAAA repair, 259 aortofemoral bypass, and 1966 LEB. The overall incidence of 30-day VTE was 1.40%, ranging from 1.12% for LEB to 3.57% for oAAA repair. Among patients receiving early VTE chemoprophylaxis, the rate of VTE was 0.78% versus 2.26% among those with a delay in VTE chemoprophylaxis (P = .002). When accounting for the preoperative risk of VTE, delayed chemoprophylaxis was associated with a significantly higher risk of VTE (odds ratio, 2.38; 95% confidence interval, 1.12-5.06; P = .024). The early VTE chemoprophylaxis group was associated with a significantly decreased risk of bleeding compared with those with a delay (14.31% vs 18.90%; P = .002). Overall 30-day mortality and postoperative complications were similar with the exception of an associated higher rate of infectious complications in the delayed VTE chemoprophylaxis group, including superficial surgical site infection (6.00% vs 4.06%; P = .028), pneumonia (3.25% vs 1.85%; P = .028), urinary tract infection (2.95% vs 1.57%; P = .020), and severe sepsis (3.05% vs 1.71%; P = .029). Conclusions: Although patients undergoing major open vascular surgery have a low risk of VTE at baseline, there is a significantly greater risk of developing VTE among patients who have a delay in the administration of VTE chemoprophylaxis. Postoperative transfusion rates were significantly lower among patients receiving early chemoprophylaxis. There were no differences in the 30-day mortality and postoperative complications, except for infectious complications. Given these findings, surgeons should consider early chemoprophylaxis in the postoperative setting after major open vascular surgery without contraindication.

Hemorrhage is a common cause of death in the battlefield. Valproic acid (VPA) has been associated with improved outcomes in multiple models of trauma, when combined with isotonic fluid resuscitation. However, isotonic fluid administered in this setting is logistically impractical and may be associated with complications. In this study, we sought to evaluate the feasibility and immunologic impact of combining VPA treatment with low-volume hypertonic saline (HTS). In vivo: female Yorkshire swine were subjected to hemorrhage (40% total blood volume) and polytrauma (rib fracture and delayed liver injury). Animals were kept in shock for 30 minutes and resuscitated with (1) normal saline (NS, 3× hemorrhaged volume), (2) HTS (7.5% saline, 4 mL/kg), or (3) HTS + VPA (4 mg/kg; 150 mg/kg; n = 3/cohort). After 18 hours of observation, animals were euthanized and the lungs evaluated for acute injury and expression of myeloperoxidase (MPO) and caveolin-1 (Cav-1). In vitro: human umbilical vein endothelial cells (HUVECs) were exposed to anoxic conditions (5% CO2, 95% N2) for 16 hours in (1) normosmotic, (2) hyperosmotic (400 mOsm), or (3) hyperosmotic + VPA (4 mM) media. Immunohistochemistry and Western blots were performed to determine Cav-1 expression. Lungs from VPA-treated animals demonstrated decreased acute injury, MPO expression, and endothelial expression of Cav-1 when compared to lungs from animals resuscitated with NS or HTS alone. Similarly, HUVECs cultured in hyperosmotic media containing VPA demonstrated decreased expression of Cav-1. This study demonstrates that combined treatment with VPA and HTS is a viable strategy in hemorrhagic shock and polytrauma. Attenuation of lung injury following VPA treatment may be related to modulation of the inflammatory response.

The pharmacoepigenome can be defined as the active, noncoding province of the genome including canonical spatial and temporal regulatory mechanisms of gene regulation that respond to xenobiotic stimuli. Many psychotropic drugs that have been in clinical use for decades have ill-defined mechanisms of action that are beginning to be resolved as we understand the transcriptional hierarchy and dynamics of the nucleus. In this review, we describe spatial, temporal and biomechanical mechanisms mediated by psychotropic medications. Focus is placed on a bioinformatics pipeline that can be used both for detection of pharmacoepigenomic variants that discretize drug response and adverse events to improve pharmacogenomic testing, and for the discovery of novel CNS therapeutics. This approach integrates the functional topology and dynamics of the transcriptional hierarchy of the pharmacoepigenome, gene variant-driven identification of pharmacogenomic regulatory domains, and mesoscale mapping for the discovery of novel CNS pharmacodynamic pathways in human brain. Examples of the application of this pipeline are provided, including the discovery of valproic acid (VPA) mediated transcriptional reprogramming of neuronal cell fate following injury, and mapping of a CNS pathway glutamatergic pathway for the mood stabilizer lithium. These examples in regulatory pharmacoepigenomics illustrate how ongoing research using the 4D nucleome provides a foundation to further insight into previously unrecognized psychotropic drug pharmacodynamic pathways in the human CNS.

Objectives To determine the mechanism of action of valproic acid (VPA) in the adult central nervous system (CNS) following traumatic brain injury (TBI) and hemorrhagic shock (HS). Methods Data were analyzed from different sources, including experiments in a porcine model, data from postmortem human brain, published studies, public and commercial databases. Results The transcriptional program in the CNS following TBI, HS, and VPA treatment includes activation of regulatory pathways that enhance neurogenesis and suppress gliogenesis. Genes which encode the transcription factors (TFs) that specify neuronal cell fate, including MEF2D, MYT1L, NEUROD1, PAX6 and TBR1, and their target genes, are induced by VPA. VPA represses genes responsible for oligodendrogenesis, maintenance of white matter, T-cell activation, angiogenesis, and endothelial cell proliferation, adhesion and chemotaxis. NEUROD1 has regulatory interactions with 38% of the genes regulated by VPA in a swine model of TBI and HS in adult brain. Hi-C spatial mapping of a VPA pharmacogenomic SNP in the GRIN2B gene shows it is part of a transcriptional hub that contacts 12 genes that mediate chromatin-mediated neurogenesis and neuroplasticity. Conclusions Following TBI and HS, this study shows that VPA administration acts in the adult brain through differential activation of TFs responsible for neurogenesis, genes responsible for neuroplasticity, and repression of TFs that specify oligodendrocyte cell fate, endothelial cell chemotaxis and angiogenesis. Short title: Mechanism of action of valproic acid in traumatic brain injury

Valproic acid, a histone deacetylase inhibitor, has beneficial effects in the setting of cancer, neurologic diseases, and traumatic injuries. In animal models of traumatic injury, a single dose of valproic acid has been shown to reduce mortality. The purpose of this trial was to determine the maximum tolerated single dose of intravenous valproic acid in healthy humans.