Publications by authors named "Ben E Biesterveld"

41 Publications

Valproic Acid Protects Against Acute Kidney Injury in Hemorrhage and Trauma.

J Surg Res 2021 May 20;266:222-229. Epub 2021 May 20.

Department of Surgery, University of Michigan, Ann Arbor, MI; Department of Surgery, Northwestern University, Chicago, IL.

Introduction: Trauma is the leading cause of death among young people. These patients have a high incidence of kidney injury, which independently increases the risk of mortality. As valproic acid (VPA) treatment has been shown to improve survival in animal models of lethal trauma, we hypothesized that it would also attenuate the degree of acute kidney injury.

Methods: We analyzed data from two separate experiments where swine were subjected to lethal insults.  Model 1: hemorrhage (50% blood volume hemorrhage followed by 72-h damage control resuscitation). Model 2: polytrauma (traumatic brain injury, 40% blood volume hemorrhage, femur fracture, rectus crush and grade V liver laceration). Animals were resuscitated with normal saline (NS) +/- VPA 150 mg/kg after a 1-h shock phase in both models (n = 5-6/group). Serum samples were analyzed for creatinine (Cr) using colorimetry on a Liasys 330 chemistry analyzer. Proteomic analysis was performed on kidney tissue sampled at the time of necropsy.

Results: VPA treatment significantly (P < 0.05) improved survival in both models. (Model 1: 80% vs 20%; Model 2: 83% vs. 17%). Model 1 (Hemorrhage alone): Cr increased from a baseline of 1.2 to 3.0 in NS control animals (P < 0.0001) 8 h after hemorrhage, whereas it rose only to 2.1 in VPA treated animals (P = 0.004). Model 2 (Polytrauma): Cr levels increased from baseline of 1.3 to 2.5 mg/dL (P = 0.01) in NS control animals 4 h after injury but rose to only 1.8 in VPA treated animals (P = 0.02). Proteomic analysis of kidney tissue identified metabolic pathways were most affected by VPA treatment.

Conclusions: A single dose of VPA (150 mg/kg) offers significant protection against acute kidney injury in swine models of polytrauma and hemorrhagic shock.
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http://dx.doi.org/10.1016/j.jss.2021.04.014DOI Listing
May 2021

Delay in Hip Fracture Repair in the Elderly: A Missed Opportunity Towards Achieving Better Outcomes.

J Surg Res 2021 May 11;266:142-147. Epub 2021 May 11.

Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan. Electronic address:

Background: Hip fractures are a major cause of morbidity and mortality in the elderly. The American Academy of Orthopedic Surgeons (AAOS) recommends surgical repair within 48 hours of admission, as this is associated with lower postoperative mortality and complications. This study demonstrates the association between patient demographics, level of care, and hospital region to delay in hip fracture repair in the elderly.

Methods: The National Trauma Data Bank (NTDB) was queried for elderly patients (age >65 years) who underwent proximal femoral fracture repair. Identified patients were subcategorized into two groups: hip fracture repair in <48 hours, and hip fracture repair > 48 hours after admission. Patient and hospital characteristics were collected. Outcome variables were timed from the day of admission to surgery and inpatient mortality.

Results: Out of 69,532 patients, 28,031 were included after inclusion criteria were applied. 23,470 (83.7%) patients underwent surgical repair within 48 hours. The overall median time to procedure was 21 (interquartile range [IQR] 7-38) hours. Females were less likely to undergo a delay in hip fracture repair (odds ratio [OR; 95% confidence interval {CI}]: 0.82 [0.76-0.88], P< 0.05), and patients with higher Injury Severity Score (ISS ≥25) had higher odds of delay in surgical repair (OR; 95% CI: 1.56 [1.07-2.29], P< 0.05). Patients treated at hospitals in the Western regions of the United States had lower odds of delay, and those treated in the Northeast and the South had higher odds of delay compared to the hospitals in the Midwest (taken as standard). There was no association between trauma level designation and odds of undergoing delay in hip fracture repair.

Conclusion: Variables related to patient demographic and hospital characteristics are associated with delay in hip fracture repair in the elderly. This study delineates key determinants of delay in hip fracture repair in the elderly patients.
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http://dx.doi.org/10.1016/j.jss.2021.03.027DOI Listing
May 2021

Assessment of the Cytoprotective Effects of High-Dose Valproic Acid Compared to a Clinically Used Lower Dose.

J Surg Res 2021 May 11;266:125-141. Epub 2021 May 11.

Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan; Department of Surgery, Feinberg School of Medicine/Northwestern University, Chicago, Illinois. Electronic address:

Objective: Valproic acid (VPA) treatment improves survival in animal models of injuries on doses higher than those allowed by Food and Drug Administration (FDA). We investigated the proteomic alterations induced by a single high-dose (140mg/kg) of VPA (VPA140) compared to the FDA-approved dose of 30mg/kg (VPA30) in healthy humans. We also describe the proteomic and transcriptomic changes induced by VPA140 in an injured patient. We hypothesized that VPA140 would induce cytoprotective changes in the study participants.

Methods: Serum samples were obtained from healthy subjects randomized to two groups; VPA140 and VPA30 at 3 timepoints: 0h(baseline), 2h, and 24h following infusion(n = 3/group). Samples were also obtained from an injured patient that received VPA140 at 0h, 6h and 24h following infusion. Proteomic analyses were performed using liquid chromatography-mass spectrometry (LC-MS/MS), and transcriptomic analysis was performed using RNA-sequencing. Differentially expressed (DE) proteins and genes were identified for functional annotation and pathway analysis using iPathwayGuide and gene set enrichment analysis (GSEA), respectively.

Results: For healthy individuals, a dose comparison was performed between VPA140 and VPA30 groups at 2 and 24 h. Functional annotation showed that top biological processes in VPA140 versus VPA30 analysis at 2 h included regulation of fatty acid (P = 0.002) and ATP biosynthesis (P = 0.007), response to hypoxia (P = 0.017), cell polarity regulation (P = 0.031), and sequestration of calcium ions (P = 0.031). Top processes at 24 h in VPA140 versus VPA30 analysis included amino acid metabolism (P = 0.023), collagen catabolism (P = 0.023), and regulation of protein breakdown (P = 0.023). In the injured patient, annotation of the DE proteins in the serum showed that top biological processes at 2 h included neutrophil chemotaxis (P = 0.002), regulation of cellular response to heat (P = 0.008), regulation of oxidative stress (P = 0.008) and regulation of apoptotic signaling pathway (P = 0.008). Top biological processes in the injured patient at 24 h included autophagy (P = 0.01), glycolysis (P = 0.01), regulation of apoptosis (P = 0.01) and neuron apoptotic processes (P = 0.02).

Conclusions: VPA140 induces cytoprotective changes in human proteome not observed in VPA30. These changes may be responsible for its protective effects in response to injuries.
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http://dx.doi.org/10.1016/j.jss.2021.03.025DOI Listing
May 2021

Brain proteomic changes by histone deacetylase inhibition after traumatic brain injury.

Trauma Surg Acute Care Open 2021 24;6(1):e000682. Epub 2021 Mar 24.

Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.

Background: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality. There are currently no cytoprotective treatments for TBI. There is growing evidence that the histone deacetylase inhibitor valproic acid (VPA) may be beneficial in the treatment of TBI associated with hemorrhagic shock and in isolation. We sought to further evaluate the mechanistic underpinnings of this demonstrated efficacy via proteomic analysis of injured brain tissue.

Methods: Swine were subjected to TBI via controlled cortical impact, randomized to treatment with VPA or control and observed for 6 hours. The brains of the pigs were then sectioned, and tissue was prepared and analyzed for proteomic data, including gene ontology (GO), gene-set enrichment analysis and enrichment mapping, and network mapping.

Results: Proteomic analysis demonstrated differential expression of hundreds of proteins in injured brain tissue after treatment with VPA. GO analysis and network analyses revealed groups of proteins and processes that are known to modulate injury response after TBI and impact cell fate. Processes affected included protein targeting and transport, cation and G-protein signaling, metabolic response, neurotransmitter response and immune function.

Discussion: This proteomic analysis provides initial mechanistic insight into the observed rescue of injured brain tissue after VPA administration in isolated TBI.

Level Of Evidence: Not applicable (animal study).
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http://dx.doi.org/10.1136/tsaco-2021-000682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993337PMC
March 2021

Validation of intraosseous delivery of valproic acid in a swine model of polytrauma.

Trauma Surg Acute Care Open 2021 17;6(1):e000683. Epub 2021 Mar 17.

Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.

Background: Intraosseous (IO) drug delivery may be necessary in emergency situations when intravenous access is unattainable. Valproic acid (VPA) is a histone deacetylase inhibitor that has previously been shown to improve survival in preclinical models of lethal polytrauma. In this study, we sought to compare serum levels of intravenously and IO-delivered VPA, and to analyze the effect of IO-delivered VPA.

Methods: Swine were subjected to 40% blood volume hemorrhage, brain injury, femur fracture, rectus crush injury and liver laceration. After 1 hour of shock, animals were randomized (n=3/group) to receive normal saline resuscitation (control), normal saline+intravenous VPA 150 mg/kg (intravenous group) or normal saline +IO VPA 150 mg/kg (IO group). Serum levels of VPA were assessed between groups, and proteomics analyses were performed on IO and control groups on heart, lung and liver samples.

Results: Intravenous and IO serum VPA levels were similar at 1, 3, 5 and 7 hours after starting the infusion (p>0.05). IO-delivered VPA induced significant proteomics changes in the heart, lung and liver, which were most pronounced in the lung. Biologic processes affected included inflammation, metabolism and transcriptional & translational machinery. The control group had 0% survival, and the intravenous and IO group both had 100% survival to the end of the experiment (p<0.05).

Discussion: IO-delivered VPA is noninferior to intravenous administration and is a viable option in emergent situations when intravenous access is unattainable.

Level Of Evidence: Not applicable (animal study).
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http://dx.doi.org/10.1136/tsaco-2021-000683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978107PMC
March 2021

Multimodal tensor-based method for integrative and continuous patient monitoring during postoperative cardiac care.

Artif Intell Med 2021 03 11;113:102032. Epub 2021 Feb 11.

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, United States; Michigan Institute for Data Science (MIDAS), University of Michigan, Ann Arbor, MI 48109, United States. Electronic address:

Patients recovering from cardiovascular surgeries may develop life-threatening complications such as hemodynamic decompensation, making the monitoring of patients for such complications an essential component of postoperative care. However, this need has given rise to an inexorable increase in the number and modalities of data points collected, making it challenging to effectively analyze in real time. While many algorithms exist to assist in monitoring these patients, they often lack accuracy and specificity, leading to alarm fatigue among healthcare practitioners. In this study we propose a multimodal approach that incorporates salient physiological signals and EHR data to predict the onset of hemodynamic decompensation. A retrospective dataset of patients recovering from cardiac surgery was created and used to train predictive models. Advanced signal processing techniques were employed to extract complex features from physiological waveforms, while a novel tensor-based dimensionality reduction method was used to reduce the size of the feature space. These methods were evaluated for predicting the onset of decompensation at varying time intervals, ranging from a half-hour to 12 h prior to a decompensation event. The best performing models achieved AUCs of 0.87 and 0.80 for the half-hour and 12-h intervals respectively. These analyses evince that a multimodal approach can be used to develop clinical decision support systems that predict adverse events several hours in advance.
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http://dx.doi.org/10.1016/j.artmed.2021.102032DOI Listing
March 2021

Development of a large animal model of lethal polytrauma and intra-abdominal sepsis with bacteremia.

Trauma Surg Acute Care Open 2021 1;6(1):e000636. Epub 2021 Feb 1.

Surgery, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Background: Trauma and sepsis are individually two of the leading causes of death worldwide. When combined, the mortality is greater than 50%. Thus, it is imperative to have a reproducible and reliable animal model to study the effects of polytrauma and sepsis and test novel treatment options. Porcine models are more translatable to humans than rodent models due to the similarities in anatomy and physiological response. We embarked on a study to develop a reproducible model of lethal polytrauma and intra-abdominal sepsis, which was lethal, though potentially salvageable with treatment.

Methods: Our laboratory has a well-established porcine model that was used as the foundation. Animals were subjected to a rectus crush injury, long bone fracture, liver and spleen laceration, traumatic brain injury and hemorrhage that was used as a foundation. We tested various colon injuries to create intra-abdominal sepsis. All animals underwent injuries followed by a period of shock, then subsequent resuscitation.

Results: All animals had blood culture-proven sepsis. Attempts at long-term survival of animals after injury were ceased because of poor appetite and energy. We shifted to an 8-hour endpoint. The polytrauma injury pattern remained constant and the colon injury pattern changed with the intention of creating a model that was ultimately lethal but potentially salvageable with a therapeutic drug. An uncontrolled cecal injury (n=4) group resulted in very early deaths. A controlled cecal injury (CCI; n=4) group had prolonged time prior to mortality with one surviving to the endpoint. The sigmoid injury (n=5) produced a similar survival curve to CCI but no animals surviving to the endpoint.

Conclusion: We have described a porcine model of polytrauma and sepsis that is reproducible and may be used to investigate novel treatments for trauma and sepsis.

Level Of Evidence: Not applicable. Animal study.
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http://dx.doi.org/10.1136/tsaco-2020-000636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852924PMC
February 2021

A novel partial resuscitative endovascular balloon aortic occlusion device that can be deployed in zone 1 for more than 2 hours with minimal provider titration.

J Trauma Acute Care Surg 2021 03;90(3):426-433

From the Department of Surgery (M.T.K., G.K.W., A.M.W., B.E.B., R.L.O., C.A.V., K.C., H.B.A.), University of Michigan, Ann Arbor, Michigan; Department of Surgery (R.M.R.), UC Davis Medical Center, Sacramento; US Air Force Medical Corps, 60th Medical Group (R.M.R.), Travis AFB, Fairfield, California; and Department of Surgery (H.B.A.), Northwestern University, Chicago, Illinois.

Background: Hemorrhage is a leading cause of mortality in trauma. Resuscitative endovascular balloon occlusion of the aorta (REBOA) can control hemorrhage, but distal ischemia, subsequent reperfusion injury, and the need for frequent balloon titration remain problems. Improved device design can allow for partial REBOA (pREBOA) that may provide hemorrhage control while also perfusing distally without need for significant provider titration.

Methods: Female Yorkshire swine (N = 10) were subjected to 40% hemorrhagic shock for 1 hour (mean arterial pressure [MAP], 28-32 mm Hg). Animals were then randomized to either complete aortic occlusion (ER-REBOA) or partial occlusion (novel pREBOA-PRO) without frequent provider titration or distal MAP targets. Detection of a trace distal waveform determined partial occlusion in the pREBOA-PRO arm. After 2 hours of zone 1 occlusion, the hemorrhaged whole blood was returned. After 50% autotransfusion, the balloon was deflated over a 10-minute period. Following transfusion, the animals were survived for 2 hours while receiving resuscitation based on objective targets: lactated Ringer's fluid boluses (goal central venous pressure, ≥ 6 mm Hg), a norepinephrine infusion (goal MAP, 55-60 mm Hg), and acid-base correction (goal pH, >7.2). Hemodynamic variables, arterial lactate, lactate dehydrogenase, aspartate aminotransferase, and creatinine levels were measured.

Results: All animals survived throughout the experiment, with similar increase in proximal MAPs in both groups. Animals that underwent partial occlusion had slightly higher distal MAPs. At the end of the experiment, the partial occlusion group had lower end levels of serum lactate (p = 0.006), lactate dehydrogenase (p = 0.0004) and aspartate aminotransferase (p = 0.004). Animals that underwent partial occlusion required less norepinephrine (p = 0.002), less bicarbonate administration (p = 0.006), and less fluid resuscitation (p = 0.042).

Conclusion: Improved design for pREBOA can decrease the degree of distal ischemia and reperfusion injury compared with complete aortic occlusion, while providing a similar increase in proximal MAPs. This can allow pREBOA zone-1 deployment for longer periods without the need for significant balloon titration.
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http://dx.doi.org/10.1097/TA.0000000000003042DOI Listing
March 2021

Surgery Provider Perceptions on Telehealth Visits During the COVID-19 Pandemic: Room for Improvement.

J Surg Res 2021 04 13;260:300-306. Epub 2020 Nov 13.

Department of Surgery, University of Michigan, Ann Arbor, Michigan. Electronic address:

Background: COVID-19 has mandated rapid adoption of telehealth for surgical care. However, many surgical providers may be unfamiliar with telehealth. This study evaluates the perspectives of surgical providers practicing telehealth care during COVID-19 to help identify targets for surgical telehealth optimization.

Materials And Methods: At a single tertiary care center with telehealth capabilities, all department of surgery providers (attending surgeons, residents, fellows, and advanced practice providers) were emailed a voluntary survey focused on telehealth during the pandemic. Descriptive statistics and Mann-Whitney U analyses were performed as appropriate on responses. Text responses were thematically coded to identify key concepts.

Results: The completion rate was 41.3% (145/351). Providers reported increased telehealth usage relative to the pandemic (P < 0.001). Of respondents, 80% (116/145) had no formal telehealth training. Providers estimated that new patient video visits required less time than traditional visits (P = 0.001). Satisfaction was high for several aspects of video visits. Comparatively lower satisfaction scores were reported for the ability to perform physical exams (sensitive and nonsensitive) and to break bad news. The largest barriers to effective video visits were limited physical exams (55.6%; 45/81) and lack of provider or patient internet access/equipment/connection (34.6%; 28/81). Other barriers included ineffective communication and difficulty with fostering rapport. Concerns regarding video-to-telephone visit conversion were loss of physical exam/visual cues (34.3%; 24/70), less personal interactions (18.6%; 13/70), and reduced efficiency (18.6%; 13/70).

Conclusions: Telehealth remains a new experience for surgical providers despite its expansion. Optimization strategies should target technology barriers and include specialized virtual exam and communication training.
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http://dx.doi.org/10.1016/j.jss.2020.11.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664345PMC
April 2021

Administration of valproic acid in clinically approved dose improves neurologic recovery and decreases brain lesion size in swine subjected to hemorrhagic shock and traumatic brain injury.

J Trauma Acute Care Surg 2021 02;90(2):346-352

From the Department of Surgery (G.K.W., B.E.B., M.T.K., R.L.O., A.M.W., K.C., A.Z.S., U.F.B., C.A.V., H.B.A.), Department of Clinical Pharmacy (M.P.P.), and Section of Neuroradiology, Department of Radiology (A.S.), Michigan Medicine, University of Michigan, Ann Arbor, Michigan.

Background: Traumatic brain injury (TBI) and hemorrhage remain the leading causes of death after trauma. We have previously shown that a dose of valproic acid (VPA) at (150 mg/kg) can decrease brain lesion size and hasten neurologic recovery. The current Food and Drug Administration-approved dose of VPA is 60 mg/kg. We evaluate neurologic outcomes and brain lesion size of a single dose of VPA at a level currently within Food and Drug Administration-approved dose in swine subjected to TBI and hemorrhagic shock.

Methods: Swine (n = 5/group) were subjected to TBI and 40% blood volume hemorrhage. Animals remained in shock for 2 hours before randomization to normal saline (NS) resuscitation alone (control), NS-VPA 150 mg/kg (VPA 150), or NS-VPA 50 mg/kg (VPA 50). Neurologic severity scores (range, 0-32) were assessed daily for 14 days, and brain lesion size was measured via magnetic resonance imaging on postinjury day (PID) 3.

Results: Shock severity and laboratory values were similar in all groups. Valproic acid-treated animals demonstrated significantly less neurologic impairment on PID 1 and returned to baseline faster (PID 1 mean neurologic severity score, control = 22 ± 3 vs. VPA 150 mg/kg = 8 ± 7 or VPA 50 mg/kg = 6 ± 6; p = 0.02 and 0.003). Valproic acid-treated animals had significantly smaller brain lesion sizes (mean volume in mm3, control = 1,268.0 ± 241.2 vs. VPA 150 mg/kg = 620.4 ± 328.0 or VPA 50 mg/kg = 438.6 ± 234.8; p = 0.007 and 0.001).

Conclusion: In swine subjected to TBI and hemorrhagic shock, VPA treatment, in a dose that is approved for clinical use, decreases brain lesion size and reduces neurologic impairment compared with resuscitation alone.
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http://dx.doi.org/10.1097/TA.0000000000003036DOI Listing
February 2021

Pharmacologic modulation of brain metabolism by valproic acid can induce a neuroprotective environment.

J Trauma Acute Care Surg 2021 03;90(3):507-514

From the Department of Surgery (U.F.B., I.S.D., A.M.W., V.C.N., B.E.B., A.S., R.L.O., B.L., Y.L., H.B.A.), University of Michigan, Ann Arbor, Michigan; Department of Surgery (U.F.B.), Washington University, St. Louis, Missouri; Department of Surgery (H.B.A.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Computational Medicine and Bioinformatics (A.K.), and Michigan Regional Comprehensive Metabolomics Resource Core (M.K.), University of Michigan Health System, Ann Arbor, Michigan.

Objective: Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality. Valproic acid (VPA) has been shown to attenuate brain lesion size and swelling within the first few hours following TBI. Because injured neurons are sensitive to metabolic changes, we hypothesized that VPA treatment would alter the metabolic profile in the perilesional brain tissues to create a neuroprotective environment.

Methods: We subjected swine to combined TBI (12-mm cortical impact) and hemorrhagic shock (40% blood volume loss and 2 hours of hypotension) and randomized them to two groups (n = 5/group): (1) normal saline (NS; 3× hemorrhage volume) and (2) NS-VPA (NS, 3× hemorrhage volume; VPA, 150 mg/kg). After 6 hours, brains were harvested, and 100 mg of the perilesional tissue was used for metabolite extraction. Samples were analyzed using reversed-phase liquid chromatography-mass spectrometry in positive and negative ion modes, and data were analyzed using MetaboAnalyst software (McGill University, Quebec, Canada).

Results: In untargeted reversed-phase liquid chromatography-mass spectrometry analysis, we detected 3,750 and 1,955 metabolites in positive and negative ion modes, respectively. There were no significantly different metabolites in positive ion mode; however, 167 metabolite features were significantly different (p < 0.05) in the negative ion mode, which included VPA derivates. Pathway analysis showed that several pathways were affected in the treatment group, including the biosynthesis of unsaturated fatty acids (p = 0.001). Targeted amino acid analysis on glycolysis/tricarboxylic acid (TCA) cycle revealed that VPA treatment significantly decreased the levels of the excitotoxic amino acid serine (p = 0.001).

Conclusion: Valproic acid can be detected in perilesional tissues in its metabolized form. It also induces metabolic changes in the brains within the first few hours following TBI to create a neuroprotective environment.
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http://dx.doi.org/10.1097/TA.0000000000003026DOI Listing
March 2021

Modulation of Brain Transcriptome by Combined Histone Deacetylase Inhibition and Plasma Treatment Following Traumatic Brain Injury and Hemorrhagic Shock.

Shock 2021 01;55(1):110-120

Department of Surgery, University of Michigan, Ann Arbor, Michigan.

Introduction: We previously showed that the addition of valproic acid (VPA), a histone deacetylase inhibitor, to fresh frozen plasma (FFP) resuscitation attenuates brain lesion size and swelling following traumatic brain injury (TBI) and hemorrhagic shock (HS). The goal of this study was to use computational biology tools to investigate the effects of FFP+VPA on the brain transcriptome following TBI+HS.

Methods: Swine underwent TBI+HS, kept in shock for 2 h, and resuscitated with FFP or FFP + VPA (n = 5/group). After 6 h of observation, brain RNA was isolated and gene expression was analyzed using a microarray. iPathwayGuide, Gene Ontology (GO), Gene-Set Enrichment Analysis, and Enrichment Mapping were used to identify significantly impacted genes and transcriptomic networks.

Results: Eight hundred differentially expressed (DE) genes were identified out of a total of 9,118 genes. Upregulated genes were involved in promotion of cell division, proliferation, and survival, while downregulated genes were involved in autophagy, cell motility, neurodegenerative diseases, tumor suppression, and cell cycle arrest. Seven hundred ninety-one GO terms were significantly enriched. A few major transcription factors, such as TP53, NFKB3, and NEUROD1, were responsible for modulating hundreds of other DE genes. Network analysis revealed attenuation of interconnected genes involved in inflammation and tumor suppression, and an upregulation of those involved in cell proliferation and differentiation.

Conclusion: Overall, these results suggest that VPA treatment creates an environment that favors production of new neurons, removal of damaged cells, and attenuation of inflammation, which could explain its previously observed neuroprotective effects.
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http://dx.doi.org/10.1097/SHK.0000000000001605DOI Listing
January 2021

Factors Associated with Increased Risk of Patient No-Show in Telehealth and Traditional Surgery Clinics.

J Am Coll Surg 2020 12 3;231(6):695-702. Epub 2020 Sep 3.

Department of Surgery, University of Michigan, Ann Arbor, MI. Electronic address:

Background: With the growing use of telehealth, understanding factors affecting patient follow-up in traditional and telehealth settings is important. Few data exist examining the use of telehealth compared with traditional settings. Bridging this gap is critical to optimizing telehealth use and reducing barriers.

Study Design: This is a retrospective cohort study of return and postoperative (electronic video [eClinic] and traditional) visits from January 2018 to March 2020 at single tertiary care center. There were 12,359 unique first-encounter patients with 903 eClinic and 11,456 traditional visits; 11,547 patients completed visits, while 812 patients did not show up. Multivariable logistic regression modeling was performed to identify factors associated with no-show. County-level mapping was used to identify patterns in no-show rates.

Results: Patients from the eClinic had twice the odds of no-show compared with those from a traditional clinic (p < 0.001). Age was inversely proportional to odds of no-show, with each additional decade associated with a 16% decrease in these odds (p < 0.001). African-American patients had greater odds of no-show compared to Caucasian patients (odds ratio [OR] 2.47; 95% CI 1.95-3.13, p < 0.001). Marital statuses of single and legal separation were associated with higher odds of no-show compared with married marital status (p < 0.001 and p = 0.04, respectively). Minimally invasive and endocrine surgery clinics had lower odds of no-show compared with acute care surgery clinic (p < 0.001 for both). County-level no-show rates demonstrate similar patterns between clinic settings.

Conclusions: Several factors are associated with increased odds of no-show, including the visit being in eClinic. County-level analysis suggests no-show variation is not dependent on geographic location. Understanding these patterns allows for prospective identification of barriers and development of interventions to optimize access and patient care.
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http://dx.doi.org/10.1016/j.jamcollsurg.2020.08.760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470818PMC
December 2020

Valproic acid treatment rescues injured tissues after traumatic brain injury.

J Trauma Acute Care Surg 2020 12;89(6):1156-1165

From the Department of Surgery (B.E.B., L.P., A.I., A.A.S., A.Z.S., R.L.O., G.K.W., M.T.K., A.M.W., H.B.A.), Department of Biological Chemistry (H.A.R.), and Department of Clinical Pharmacy (M.P.P.), University of Michigan, Ann Arbor, Michigan.

Background: No agents that are specifically neuroprotective are currently approved to emergently treat patients with traumatic brain injury (TBI). The histone deacetylase inhibitor, high-dose valproic acid (VPA) has been shown to have cytoprotective potential in models of combined TBI and hemorrhagic shock, but it has not been tested in an isolated TBI model. We hypothesized that VPA, administered after isolated TBI, will penetrate the injured brain, attenuate the lesion size, and activate prosurvival pathways.

Methods: Yorkshire swine were subjected to severe TBI by cortical impact. One hour later, animals were randomized to VPA treatment (150 mg/kg delivered intravenously for 1 hour; n = 4) or control (saline vehicle; n = 4) groups. Seven hours after injury, animals were sacrificed, and brain lesion size was measured. Mass spectrometry imaging was used to visualize and quantitate brain tissue distribution of VPA. Sequential serum samples were assayed for key biomarkers and subjected to proteomic and pathway analysis.

Results: Brain lesion size was 50% smaller (p = 0.01) in the VPA-treated animals (3,837 ± 948 mm) compared with the controls (1,900 ± 614 mm). Endothelial regions had eightfold higher VPA concentrations than perivascular regions by mass spectrometry imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared with the control animals (p < 0.05). More than 500 proteins were differentially expressed in the brain, and pathway analysis revealed that VPA affected critical modulators of TBI response including calcium signaling pathways, mitochondria metabolism, and biosynthetic machinery.

Conclusion: Valproic acid penetrates injured brain tissues and exerts neuroprotective and prosurvival effects that resulted in a significant reduction in brain lesion size after isolated TBI. Levels of serum biomarkers reflect these changes, which could be useful for monitoring the response of TBI patients during clinical studies.
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http://dx.doi.org/10.1097/TA.0000000000002918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830776PMC
December 2020

Cl-Amidine Improves Survival and Attenuates Kidney Injury in a Rabbit Model of Endotoxic Shock.

Surg Infect (Larchmt) 2021 May 20;22(4):421-426. Epub 2020 Aug 20.

Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.

Sepsis causes millions of deaths on a global scale annually. Activation of peptidylarginine deiminase (PAD) enzymes in sepsis causes citrullination of histones, which results in neutrophil extracellular trap formation and sepsis progression. This study evaluates pan-PAD inhibitor, Cl-amidine, in a model of lipopolysaccharide (LPS)-induced endotoxic shock in rabbits. We hypothesized that Cl-amidine would improve survival and attenuate kidney injury. In the survival model, rabbits were injected injected intravenously with 1 mg/kg of LPS, and then randomly assigned either to receive dimethyl sulfoxide (DMSO; 1 mcL/g) or Cl-amidine (10 mg/kg diluted in 1 mcL/g DMSO). They were then monitored for 14 days to evaluate survival. In the non-survival experiment, the same insult and treatment were administered, however; the animals were euthanized 12 hours after LPS injection for kidney harvest. Acute kidney injury (AKI) scoring was performed by a histopathologist who was blinded to the group assignment. Serial blood samples were also collected and compared. Rabbits that received Cl-amidine had a higher survival (72%) compared with the rabbits that received DMSO (14%; p < 0.05). Cl-amidine-treated rabbits had lower (p < 0.05) histopathologic AKI scores, as well as plasma creatinine and blood urea nitrogen (BUN) levels 12 hours after insult. Pan-PAD inhibitor Cl-amidine improves survival and attenuates kidney injury in LPS-induced endotoxic shock in rabbits.
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http://dx.doi.org/10.1089/sur.2020.189DOI Listing
May 2021

Barriers associated with failed completion of an acute care general surgery telehealth clinic visit.

Surgery 2020 Nov 8;168(5):851-858. Epub 2020 Aug 8.

Department of Surgery, University of Michigan, Ann Arbor, MI. Electronic address:

Background: A form of telehealth, a surgical electronic clinic (E-clinic, video or telephone visit) is a safe and efficient way for delivering care; however, factors leading to poor clinic utilization are not well-described. This study was performed to gather electronic clinic utilization data and to better define barriers to visit completion.

Methods: A retrospective review of 199 patients cared for by a general surgery service with subsequent referral to the electronic clinic (January 2019 to June 2019) was performed. Data regarding demographics, medical characteristics, travel distance, and postoperative complications were collected. Patients were categorized based upon visit completion. The χ and Fisher exact analyses were performed as appropriate. Reasons for cancellations were categorized.

Results: More than 1/5 of all patients (21.6%) failed to complete the visit. No differences were observed in completion rates according to the type of operation, American Society of Anesthesiologists classification, and age. The failed-completion group had a significantly (P < .05) higher proportion of non-Caucasian patients and those with a marital status of single. Travel distance had no impact. Complication rates were low. Pre-clinic readmission within 30 days contributed to failed completion. Reasons for cancellation included medical issues, technical difficulties, and patient preference to have no follow-up in the electronic clinic.

Conclusion: Several factors contribute to a patient's failure to complete an electronic clinic visit including marital status, medical complications, technical issues, and patient preference. Electronic clinic utilization patterns also demonstrate racial disparities. Successful electronic clinic program implementation requires understanding the factors that contribute to failed visits to address them and improve access.
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http://dx.doi.org/10.1016/j.surg.2020.06.029DOI Listing
November 2020

Early treatment with exosomes following traumatic brain injury and hemorrhagic shock in a swine model promotes transcriptional changes associated with neuroprotection.

J Trauma Acute Care Surg 2020 09;89(3):536-543

From the Department of Surgery (A.M.W., U.F.B., B.E.B., S.E.D., R.G.K., Y.T., Z.W., M.T.K., G.K.W., B.L., Y.L., H.B.A.), Department of Computational Medicine and Bioinformatics (G.A.H.), University of Michigan, Ann Arbor; and Department of Neurology (B.B.), Henry Ford Hospital, Detroit, Michigan.

Background: We have shown that administration of mesenchymal stem cell-derived exosomes (single dose given within 1 hour) in models of traumatic brain injury (TBI) and hemorrhagic shock is neuroprotective. The precise mechanisms responsible for the neuroprotection are not fully understood. This study was designed to investigate the transcriptomic changes in the brain that are associated with this treatment strategy.

Methods: Yorkshire swine (40-45 kg) were subjected to a severe TBI (12-mm cortical impact) and hemorrhagic shock (40% estimated total blood volume). One hour into shock, animals were randomized (n = 5/cohort) to receive either lactated Ringer's (LR; 5 mL) or exosomes suspended in LR (LR + EXO; 1 × 10 exosome particles in 5 mL LR). Animals then underwent additional shock (1 hour) followed by normal saline resuscitation. After 6 hours of observation, brain swelling (% increase compared with the uninjured side) and lesion size (mm) were assessed. Periinjured brain tissue was processed for RNA sequencing, analyzed with high through-put RNA sequencing data analysis, and results compared between control and experimental groups.

Results: Exosome treatment significantly increased (p < 0.005) gene expression associated with neurogenesis, neuronal development, synaptogenesis, and neuroplasticity. It also significantly reduced (p < 0.005) genes associated with stroke, neuroinflammation, neuroepithelial cell proliferation, and nonneuronal cell proliferation contributing to reactive gliosis. Exosome treatment also significantly increased (p < 0.005) the genes that are associated with stability of blood-brain barrier.

Conclusions: Administration of a single dose of exosomes induces transcriptomic changes suggestive of neuroprotection. Their use as a treatment for TBI is promising and requires further investigation for human translation.
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http://dx.doi.org/10.1097/TA.0000000000002815DOI Listing
September 2020

Valproic acid decreases resuscitation requirements after hemorrhage in a prolonged damage-control resuscitation model.

J Trauma Acute Care Surg 2020 10;89(4):752-760

From the Department of Surgery, University of Michigan, Ann Arbor, Michigan.

Background: Hemorrhage is the leading cause of preventable death in trauma. Future military conflicts are likely to be in austere environments, where prolonged damage-control resuscitation (p-DCR) may be required for 72 hours before evacuation. There is a need to demonstrate that p-DCR is feasible and to optimize its logistics. Dried plasma (DP) is a practical alternative to conventional blood products in austere settings, and valproic acid (VPA) improves survival in preclinical models of trauma and hemorrhage. We performed the current experiment to study the synergistic effects of VPA and DP and hypothesized that VPA treatment would decrease the fluid resuscitation requirements in p-DCR.

Methods: Female swine were subjected to 50% hemorrhage (associated with 20% survival using non-plasma-based p-DCR) and left unresuscitated for 1 hour to simulate medic response time. They were then randomized to receive VPA (150 mg/kg + DP 250 mL; DP-VPA group; n = 5) or DP alone (DP group; n = 6). All animals were resuscitated to a systolic blood pressure of 80 mm Hg with lactated Ringer according to the Tactical Combat Casualty Care Guidelines for 72 hours, after which packed red blood cells were transfused to simulate evacuation to higher levels of care.

Results: The DP-VPA group needed significantly (p = 0.002) less volume of lactated Ringer to reach and maintain the target systolic blood pressure. This would translate to a 4.3 L volume sparing effect for a 70-kg person.

Conclusion: Addition of a single dose of VPA significantly decreases the volume of resuscitation required in a p-DCR model.
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http://dx.doi.org/10.1097/TA.0000000000002876DOI Listing
October 2020

Higher Long-Term Quality of Life Metrics After VATS Lobectomy Compared to Robotic-Assisted Lobectomy.

Ann Thorac Surg 2020 Jun 26. Epub 2020 Jun 26.

University of Michigan Medical School, Ann Arbor, MI, USA; Section of Thoracic Surgery, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Background: Robotic-assisted thoracic surgery (RATS) lung lobectomy has emerged as an alternative approach to video-assisted thoracoscopic surgery (VATS). Patient-reported outcomes (PROs) comparing these approaches have been limited.

Methods: At a single, high-volume academic center, patients undergoing VATS and RATS lobectomies for Stage I and II non-small cell lung cancer from 2014 to 2018 were evaluated. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), EORTC Quality of Life Questionnaire in Lung Cancer (QLQ-LC13), and Fear of Recurrence (FoR) survey were administered preoperatively, and at 1, 6 and 12 months post-operation. Raw scores underwent linear transformation (0-100 scale). Linear mixed-effects models were used for QoL and FoR score comparisons.

Results: 219 patients (139 VATS and 80 RATS) were included. RATS patients had longer (p < 0.05) operative times and a higher incidence (p < 0.05) of postoperative myocardial infarction compared to VATS patients. VATS patients reported higher (p < 0.05) QLQ-C30 summary scores postoperatively and at 12 months, including higher (p < 0.05) Social Functioning and Cognitive scores, and less (p < 0.05) appetite loss. VATS patients also reported decreased (p < 0.05) QLQ-LC13 symptom summary scores at 6 months postoperatively, including decreased (p < 0.05) dyspnea, neuropathy, and pain compared to RATS patients. VATS patients also reported lower (p < 0.05) FoR summary scores at 6 months post-operation.

Conclusions: VATS patients report improvement in select QoL and FoR measures following lobectomy. Further study comparing these two approaches is required.
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http://dx.doi.org/10.1016/j.athoracsur.2020.05.033DOI Listing
June 2020

Evidence-Based Management of Calculous Biliary Disease for the Acute Care Surgeon.

Surg Infect (Larchmt) 2021 Mar 29;22(2):121-130. Epub 2020 May 29.

Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.

Gallstones and cholecystitis are common clinical problems. There is a wide spectrum of disease severity, from rare symptoms of biliary colic to severe cholecystitis with marked gallbladder infection and inflammation that can cause life-threatening sepsis. The care of such patients is similarly varied and multi-disciplinary. Despite the prevalence of cholecystitis, there remain questions about how to manage patients appropriately. A multi-disciplinary team created institutional cholecystitis guidelines, and supporting evidence was compiled for review. Even in "routine" cholecystitis, patient triage and work-up can be variable, resulting in unnecessary tests and delay to cholecystectomy. Beyond this, there are new treatment options available that may serve special populations particularly well, although the appropriate pattern of emerging endoscopic and percutaneous treatment modalities is not well defined. This review outlines evidence-based management of cholecystitis from diagnosis to treatment with a focused discussion of special populations and emerging therapies.
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http://dx.doi.org/10.1089/sur.2020.110DOI Listing
March 2021

Hey Doctor! Did You Wash Your Smartphone?

J Gen Intern Med 2020 07 20;35(7):2193-2194. Epub 2020 Apr 20.

Department of Surgery, University of Michigan, 1500 E Medical Center Dr., Ann Arbor, MI, 48109, USA.

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http://dx.doi.org/10.1007/s11606-020-05847-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170536PMC
July 2020

Not Dying Alone - Modern Compassionate Care in the Covid-19 Pandemic.

N Engl J Med 2020 Jun 14;382(24):e88. Epub 2020 Apr 14.

From the Department of Surgery, University of Michigan , Ann Arbor.

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http://dx.doi.org/10.1056/NEJMp2007781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768603PMC
June 2020

Early single-dose exosome treatment improves neurologic outcomes in a 7-day swine model of traumatic brain injury and hemorrhagic shock.

J Trauma Acute Care Surg 2020 08;89(2):388-396

From the Department of Surgery (A.M.W., Z.W., U.F.B., B.E.B., M.T.K., G.K.W., C.A.V., K.C., A.Z.S., Z.P., S.E.D., Y.T., B.L., Y.L., H.B.A.), University of Michigan, Ann Arbor, Michigan; Xiangya 2nd Hospital of Central South University (Z.W.), Changsha, Hunan, China; and Department of Neurology (B.B.), Henry Ford Health System, Detroit, Michigan.

Background: Early single-dose treatment with human mesenchymal stem cell-derived exosomes promotes neuroprotection and promotes blood-brain barrier integrity in models of traumatic brain injury (TBI) and hemorrhagic shock (HS) in swine. The impact of an early single dose of exosomes on late survival (7 days), however, remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on neurologic outcomes, brain lesion size, inflammatory cytokines, apoptotic markers, and mediators of neural plasticity in a 7-day survival model.

Methods: Yorkshire swine were subjected to a severe TBI (8-mm cortical impact) and HS (40% estimated total blood volume). After 1 hour of shock, animals were randomized (n = 4/cohort) to receive either lactated Ringer's (5 mL) or lactated Ringer's with exosomes (1 × 10 exosome particles). After an additional hour of shock, animals were resuscitated with normal saline. Daily neurologic severity scores were compared. At 7 days following injury, lesion size, inflammatory markers, and mediators of inflammation (NF-κB), apoptosis (BAX), and neural plasticity (brain-derived neurotrophic factor) in brain tissue were compared between groups.

Results: Exosome-treated animals had significantly lower neurologic severity scores (first 4 days; p < 0.05) and faster neurologic recovery. At 7 days, exosome-treated animals had significantly smaller (p < 0.05) brain lesion sizes. Exosome-treated animals also had significantly lower levels of inflammatory markers (interleukin [IL]-1, IL-6, IL-8, and IL-18) and higher granulocyte-macrophage colony-stimulating factor levels compared with the control animals, indicating specific impacts on various cytokines. The BAX and NF-κB levels were significantly lower (p < 0.05) in exosome-treated animals, while brain-derived neurotrophic factor levels were significantly higher (p < 0.05) in the exosome-treated animals.

Conclusion: In a large animal model of TBI and HS, early single-dose exosome treatment attenuates neurologic injury, decreases brain lesion size, inhibits inflammation and apoptosis, and promotes neural plasticity over a 7-day period.
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http://dx.doi.org/10.1097/TA.0000000000002698DOI Listing
August 2020

Histone deacetylase 6 inhibition improves survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia.

J Trauma Acute Care Surg 2020 11;89(5):932-939

From the Department of Surgery (B.E.B., G.K.W., M.T.K., A.M.W., A.S., R.L.O., A.Z.S., K.C., U.F.B., Y.L., H.B.A.), University of Michigan, Ann Arbor, Michigan.

Background: Trauma is the leading cause of death for young Americans. Nonspecific histone deacetylase inhibitors, such as valproic acid, have been shown to improve survival in preclinical models of lethal trauma, hemorrhage, and sepsis. The doses needed to achieve a survival benefit are higher than Food and Drug Administration-approved doses, and the nonspecificity raises concerns about unintended adverse effects. The isoform-specific histone deacetylase 6 inhibitor, ACY-1083, has been found to be as efficacious as valproic acid in a rodent model of hemorrhagic shock. We hypothesized that ACY-1083 treatment would improve survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia.

Methods: Swine were subjected to 45% blood volume hemorrhage, brain injury, femur fracture, rectus crush, splenic and liver lacerations, and colon injury. After 1 hour of shock (mean arterial pressure, 30-35 mm Hg), animals were randomized to normal saline resuscitation (control) or normal saline plus ACY-1083 30 mg/kg treatment (n = 5/group). After 3 hours (simulating delayed evacuation), packed red blood cells and antibiotics were administered, the colon injury was repaired, and the abdomen was closed. Animals were then monitored for another 4 hours. Survival was assessed using Kaplan-Meier and log-rank test.

Results: This combination of injuries was lethal. All animals became bacteremic, in addition to the severe hemorrhagic shock. Survival in the control group was 0%, and ACY-1083 treatment increased survival to 80% (p = 0.019). There was no difference in the brain lesion size between the groups.

Conclusion: A single dose of ACY-1083 markedly improves survival in an otherwise lethal model of polytrauma, hemorrhagic shock, and bacteremia.
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http://dx.doi.org/10.1097/TA.0000000000002677DOI Listing
November 2020

Early single-dose treatment with exosomes provides neuroprotection and improves blood-brain barrier integrity in swine model of traumatic brain injury and hemorrhagic shock.

J Trauma Acute Care Surg 2020 Feb;88(2):207-218

From the Department of Surgery (A.M.W., U.F.B., J.F.B., B.E.B., R.G.K., N.J.G., K.C., A.Z.S., S.E.D., zH.B.A.), Department of Neuropathology (A.A.), and Department of Bioinformatics and Computational Medicine (G.A.H.), University of Michigan, Ann Arbor; and Department of Neurology (B.B.), Henry Ford Health System, Detroit, Michigan.

Background: Administration of human mesenchymal stem cell (MSC)-derived exosomes can enhance neurorestoration in models of traumatic brain injury (TBI) and hemorrhagic shock (HS). The impact of early treatment with MSC-derived exosomes on brain injury in a large animal model remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on brain swelling and lesion size, blood-based cerebral biomarkers, and blood-brain barrier (BBB) integrity.

Methods: Female Yorkshire swine were subjected to a severe TBI (12-mm cortical impact) and HS (40% estimated total blood volume). One hour into shock, animals were randomized (n = 5/cohort) to receive either lactated Ringer's (LR; 5 mL) or LR + exosomes (1 × 10 exosome particles in 5 mL LR). Animals then underwent additional shock (1 hour) followed by normal saline resuscitation. After 6 hours of observation, brain swelling (% increase compared with the uninjured side) and lesion size (mm) were assessed. Cerebral hemodynamics and blood-based biomarkers of brain injury were compared. Immunofluorescence and RNA sequencing with differential gene expression and pathway analysis were used to assess the integrity of the perilesion BBB.

Results: Exosome-treated animals had significantly less (p < 0.05) brain swelling and smaller lesion size. They also had significantly decreased (p < 0.05) intracranial pressures and increased cerebral perfusion pressures. Exosome-treated animals had significantly decreased (p < 0.05) albumin extravasation and significantly higher (p < 0.05) laminin, claudin-5, and zonula occludens 1 levels. Differential gene expression and pathway analysis confirmed these findings. Serum glial fibrillary acidic protein levels were also significantly lower (p < 0.05) in the exosome-treated cohort at the end of the experiment.

Conclusion: In a large animal model of TBI and HS, early treatment with a single dose of MSC-derived exosomes significantly attenuates brain swelling and lesion size, decreases levels of blood-based cerebral biomarkers, and improves BBB integrity.
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http://dx.doi.org/10.1097/TA.0000000000002563DOI Listing
February 2020

Frailty Is Associated With Increased Rates of Acute Cellular Rejection Within 3 Months After Liver Transplantation.

Liver Transpl 2020 04 20;26(4):606-607. Epub 2019 Dec 20.

Transplant Research Education and Enthusiasm, University of Michigan, Ann Arbor, MI.

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http://dx.doi.org/10.1002/lt.25690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790166PMC
April 2020

Peptidylarginine Deiminase 2 Knockout Improves Survival in hemorrhagic shock.

Shock 2020 10;54(4):458-463

Department of Surgery, University of Michigan, Ann Arbor, Michigan.

Background: The peptidylarginine deiminase (PAD) family converts arginine into citrulline through protein citrullination. PAD2 and PAD4 inhibitors can improve survival in hemorrhagic shock (HS). However, the impact of isoform-specific PAD inhibition in improving survival has not been studied. In this study, we utilize selective Pad2 knockout mice to elucidate loss of function of PAD2 leads to pro-survival effect in HS.

Methods: HS: Pad2 and wild-type (WT) mice (n = 5/group) were subjected to lethal HS (55% volume hemorrhage). Survival was monitored over 7 days. Myocardial infarction (MI): Pad2 and WT mice (n = 9/group) were subjected to MI by permanent LAD ligation to examine the effect of ischemia on the heart. After 24 h cardiac function and infarct size were measured.

Results: HS: Pad2 mice demonstrated 100% survival compared with 0% for WT mice (P = 0.002). In a sub-lethal HS model, cardiac β-catenin levels were higher in Pad2 compared with WT after 24 h. MI: WT mice demonstrated larger MI (75%) compared with Pad2 (60%) (P < 0.05). Pad2 had significantly higher ejection fraction and fractional shortening compared with WT (P < 0.05).

Conclusions: Pad2 improves survival in lethal HS. Possible mechanisms by which loss of PAD2 function improves survival include the activation of cell survival pathways, improved tolerance of cardiac ischemia, and improved cardiac function during ischemia. PAD2 is promising as a future therapeutic target for the treatment of HS and cardiac ischemia.
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http://dx.doi.org/10.1097/SHK.0000000000001489DOI Listing
October 2020