Publications by authors named "Michael Kemp"

188 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

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

Physician Heal Thyself: A Call to Action for Prioritizing Trainee Health.

Ann Surg 2021 Apr 21. Epub 2021 Apr 21.

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

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http://dx.doi.org/10.1097/SLA.0000000000004918DOI Listing
April 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

A narrative review on the epidemiology, prevention, and treatment of venous thromboembolic events in the context of chronic venous disease.

J Vasc Surg Venous Lymphat Disord 2021 Apr 16. Epub 2021 Apr 16.

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

Objective: Chronic venous disease (CVD) describes a spectrum of conditions associated with venous hypertension. The association between various CVD etiologies and the subsequent risk of venous thromboembolism (VTE), such as deep vein thrombosis or pulmonary embolism, is a topic of considerable clinical interest. The aims of the present review were to characterize the risk of VTE according to the CVD etiology and to determine the optimal anticoagulation strategy for the treatment or prevention of VTE in patients with CVD.

Methods: An extensive search of the available surgical and medical data was conducted in PubMed and Google Scholar. We searched for the following terms and other related terms to identify relevant studies: CVD, chronic venous insufficiency, varicose veins, post-thrombotic syndrome (PTS), anticoagulation, venous thromboembolism, and venous disease scoring systems (eg, CEAP [clinical, etiology, anatomic, pathophysiology], Villalta, Ginsberg, venous clinical severity score). The identified studies included randomized control trials, retrospective and prospective observational studies, narrative and systematic reviews, case reports, and case series that contributed to the proposed aims. The ClinicalTrials.gov database was also queried to identify any relevant ongoing clinical trials.

Results: Congenital CVD carries a heightened risk of VTE, although few higher level studies are available to inform on this topic or on the appropriate anticoagulation strategies for these patients. Noncongenital CVD seems to carry a heightened risk of VTE, although few studies have adequately differentiated between primary and secondary etiologies. Varicose veins are a risk factor for primary VTE but might not be associated with an increased risk of recurrent VTE. In the hospital setting, patients with varicosities should be provided thromboprophylaxis. In the setting of varicose vein intervention, high-risk patients should be identified using risk assessment models and receive thromboprophylaxis. The risk of recurrent VTE in the setting of PTS is unclear but indefinite anticoagulation is not currently indicated. For patients with PTS, residual vein thrombosis might be an indicator of when anticoagulation can be safely stopped, although practical limitations to its application exist.

Conclusions: CVD is associated with an increased risk of VTE. Few studies have differentiated between classes of CVD using a standardized method and have assessed the efficacy of anticoagulation prophylaxis against or treatment of VTE. Additional studies are needed to determine the optimal therapy for preventing and treating VTE in patients with active concurrent CVD.
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http://dx.doi.org/10.1016/j.jvsv.2021.03.018DOI Listing
April 2021

Not Just Bystanders: A Qualitative Study on the Vicarious Effects of Surgical Training on the Wellness of Support Persons for Trainees.

Ann Surg 2021 Apr 7. Epub 2021 Apr 7.

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

Objective: To obtain insights into the effects of surgical training on the well-being of support persons.

Summary Background Data: Surgical trainee wellness is a critical priority among surgical educators and leaders. The impact of surgical training on the wellness of loved ones who support trainees has not been previously studied.

Methods: This qualitative study employs semi-structured interviews of 32 support persons of surgical trainees at a single tertiary care center with multiple surgical specialty training programs. Interviews focused on perceptions about supporting a surgical trainee. Transcripts underwent thematic analysis with semantic and conceptual coding. Key themes regarding the effects that caring for a trainee has on support persons are reported.

Results: Three key themes were identified: (1) Sacrifices-support persons report significant tangible and intangible sacrifices, (2) Delaying life-life is placed on hold to prioritize training, and (3) A disconnect-there is a disconnect and a lack of recognition of support person needs that require greater awareness and targeted interventions.

Conclusions: The impact of surgical training can extend beyond trainees and can affect the wellness of their support persons who endure the effects of training alongside trainees. Programs should be aware of these effects and develop meaningful strategies to aid trainees and their support persons.
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http://dx.doi.org/10.1097/SLA.0000000000004890DOI Listing
April 2021

Keratinocyte-derived microvesicle particles mediate ultraviolet B radiation-induced systemic immunosuppression.

J Clin Invest 2021 May;131(10)

Department of Pharmacology and Toxicology.

A complete carcinogen, ultraviolet B (UVB) radiation (290-320 nm), is the major cause of skin cancer. UVB-induced systemic immunosuppression that contributes to photocarcinogenesis is due to the glycerophosphocholine-derived lipid mediator platelet-activating factor (PAF). A major question in photobiology is how UVB radiation, which only absorbs appreciably in the epidermal layers of skin, can generate systemic effects. UVB exposure and PAF receptor (PAFR) activation in keratinocytes induce the release of large numbers of microvesicle particles (MVPs; extracellular vesicles ranging from 100 to 1000 nm in size). MVPs released from skin keratinocytes in vitro in response to UVB (UVB-MVPs) are dependent on the keratinocyte PAFR. Here, we used both pharmacologic and genetic approaches in cells and mice to show that both the PAFR and enzyme acid sphingomyelinase (aSMase) were necessary for UVB-MVP generation. Our discovery that the calcium-sensing receptor is a keratinocyte-selective MVP marker allowed us to determine that UVB-MVPs leaving the keratinocyte can be found systemically in mice and humans following UVB exposure. Moreover, we found that UVB-MVPs contained bioactive contents including PAFR agonists that allowed them to serve as effectors for UVB downstream effects, in particular UVB-mediated systemic immunosuppression.
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http://dx.doi.org/10.1172/JCI144963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121517PMC
May 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

Age and insulin-like growth factor-1 impact PCNA mono-ubiquitination in UVB-irradiated human skin.

J Biol Chem 2021 Mar 19:100570. Epub 2021 Mar 19.

Departments of Pharmacology and Toxicology. Electronic address:

Non-melanoma skin cancers occur primarily in individuals over the age of 60 and are characterized by an abundance of ultraviolet (UV) signature mutations in keratinocyte DNA. Though geriatric skin removes UV photoproducts from DNA less efficiently than young adult skin, it is not known whether the utilization of other pro-survival but potentially mutagenic DNA damage tolerance systems such as translesion synthesis (TLS) is altered in older individuals. Using mono-ubiquitination of the replicative DNA polymerase clamp protein PCNA (proliferating cell nuclear antigen) as a biochemical marker of TLS pathway activation, we find that UVB exposure of skin from individuals over the age of 65 results in a higher level of PCNA mono-ubiquitination than in the skin of young adults. Furthermore, based on previous reports showing a role for deficient insulin-like growth factor-1 (IGF-1) signaling in altered UVB DNA damage responses in geriatric human skin, we find that both pharmacological inhibition of the IGF-1 receptor (IGF-1R) and deprivation of IGF-1 potentiates UVB-induced PCNA mono-ubiquitination in both human skin ex vivo and keratinocytes in vitro. Interestingly, though the TLS DNA polymerase Pol eta can accurately replicate the major photoproducts induced in DNA by UV radiation, we find that it fails to accumulate on chromatin in the absence of IGF-1R signaling and that this phenotype is correlated with increased mutagenesis in keratinocytes in vitro. Thus, altered IGF-1/IGF-1R signaling in geriatric skin may predispose epidermal keratinocytes to carry out a more mutagenic form of DNA synthesis following UVB exposure.
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http://dx.doi.org/10.1016/j.jbc.2021.100570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065225PMC
March 2021

Using core genome multilocus sequence typing (cgMLST) for vancomycin-resistant Enterococcus faecium isolates to guide infection control interventions and end an outbreak.

J Glob Antimicrob Resist 2021 Mar 19;24:418-423. Epub 2021 Feb 19.

Research Unit for Department of Clinical Microbiology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.

Objectives: Until July 2016, vancomycin-resistantEnterococcus faecium (VREfm) was sporadically detected in Odense University Hospital, Denmark. After July 2016, the number of VREfm cases increased. This study aimed to apply a core genome multilocus sequence typing (cgMLST) scheme for E. faecium to type and analyse VREfm isolates collected at a single Danish hospital and to compare the results with cgMLST data from other regions of Denmark to trace transmission.

Methods: A total of 38 VREfm clinical isolates from inpatients at the hospital in the period January 2014 through June 2017 were included in the study and analysed using whole-genome sequencing. Use of SeqSphere + software was initiated from the beginning of June 2017 to obtain MLST, cgMLST and epi curves. Admission histories were incorporated and national surveillance data on cgMLST were used to identify transmission routes.

Results: Six different sequence types (STs) were identified, the most frequent being ST80, ST117 and ST203. cgMLST subdivided the 38 isolates into 18 different complex types (CTs) with 13 isolates (34%) belonging to ST80-CT993. Epi curves indicated transmission of ST80-CT993 in several departments. Transmission from patients transferred from other hospitals was not identifiable. Infection control interventions launched in one department ended the outbreak.

Conclusion: The high resolution of cgMLST allowed for detailed interpretation with evidence of nosocomial transmission of specific CTs. cgMLST made it easy to compare our local isolates with national findings, thereby clarifying transmission routes. Supplemented with admission histories, cgMLST targeted the epidemiological investigation and delineated the expensive and time-consuming infection control interventions.
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http://dx.doi.org/10.1016/j.jgar.2021.02.007DOI 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

What's New in Shock? January 2021.

Shock 2021 01;55(1):1-4

Department of Surgery, Northwestern University, Chicago, Illinois.

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http://dx.doi.org/10.1097/SHK.0000000000001697DOI Listing
January 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

Trainee Wellness and Safety in the Context of COVID-19: The Experience of One Institution.

Acad Med 2021 05;96(5):655-660

D.M. Coleman is associate professor of surgery, Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan.

The COVID-19 pandemic has had significant ramifications for provider well-being. During these unprecedented and challenging times, one institution's Department of Surgery put in place several important initiatives for promoting the well-being of trainees as they were redeployed to provide care to COVID-19 patients. In this article, the authors describe these initiatives, which fall into 3 broad categories: redeploying faculty and trainees, ensuring provider safety, and promoting trainee wellness. The redeployment initiatives are the following: reframing the team mindset, creating a culture of grace and forgiveness, establishing a multidisciplinary wellness committee, promoting centralized leadership, providing clear communication, coordinating between departments and programs, implementing phased restructuring of the department's services, establishing scheduling flexibility and redundancy, adhering to training regulations, designating a trainee ombudsperson, assessing physical health risks for high-risk individuals, and planning for structured deimplementation. Initiatives specific to promoting provider safety are appointing a trainee safety advocate, guaranteeing personal protective equipment and relevant information about these materials, providing guidance regarding safe practices at home, and offering alternative housing options when necessary. Finally, the initiatives put in place to directly promote trainee wellness are establishing an environment of psychological safety, providing mental health resources, maintaining the educational missions, solidifying a sense of community by showing appreciation, being attentive to childcare, and using social media to promote community morale. The initiatives to carry out the department's strategy presented in this article, which were well received by both faculty and trainee members of the authors' community, may be employed in other departments and even outside the context of COVID-19. The authors hope that colleagues at other institutions and departments, independent of specialty, will find the initiatives described here helpful during, and perhaps after, the pandemic as they develop their own institution-specific strategies to promote trainee wellness.
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http://dx.doi.org/10.1097/ACM.0000000000003853DOI Listing
May 2021

Twelve tips for the integration of medical students into telemedicine visits.

Med Teach 2020 Nov 15:1-7. Epub 2020 Nov 15.

Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.

The use of telemedicine in clinical care has grown significantly in the last few years and has only increased during the COVID-19 pandemic. Given that many physicians will be expected to deliver virtual care moving forward, it is important for medical students to gain exposure via this modality during their clinical training. Many medical schools are actively working to integrate students into telemedicine. This article aims to provide guidance for readers incorporating medical students in telemedicine visits at an institutional or departmental level. This article covers essential topics such as coordinating key stakeholders, conducting needs assessments, addressing technological or software considerations, and creating appropriate workflows for students and physicians.
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http://dx.doi.org/10.1080/0142159X.2020.1844877DOI Listing
November 2020

High vs. low entrustment behaviors in the operating room.

Am J Surg 2021 May 16;221(5):973-979. Epub 2020 Sep 16.

Department of Surgery, Michigan Medicine, Ann Arbor, MI, 48109, USA. Electronic address:

Background: Operative experience with an appropriate degree of supervised autonomy is critical to resident training. Progressively greater intraoperative entrustment has been associated with gradually higher levels of resident autonomy. This study attempts to identify consistently observed intraoperative behaviors that are linked with higher resident entrustment.

Methods: This qualitative study analyzed observational notes recorded by trained raters who provided entrustment scores for 204 surgical cases at Michigan Medicine from 2015 to 2017. Notes were coded in NVivo12. Thematic analysis was used to identify themes and patterns within the data.

Results: The analysis generated 144 codes. Codes were clustered into 10 themes. These themes manifested differently in intraoperative behaviors strongly associated with high entrustment versus low entrustment.

Conclusion: This study demonstrates key differences in intraoperative behaviors exhibited by residents and faculty in high and low entrustment interactions. Awareness of behaviors that enhance entrustment can help faculty augment resident learning and enable higher resident operative autonomy.
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http://dx.doi.org/10.1016/j.amjsurg.2020.09.015DOI Listing
May 2021

An invited commentary on "Outcomes' Predictors in Post-cardiac Surgery Extracorporeal Life Support. An Observational Prospective Cohort Study" (Int J Surg 2020; epub ahead of print).

Int J Surg 2020 11 25;83:176-177. Epub 2020 Sep 25.

Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ijsu.2020.09.041DOI Listing
November 2020

Invited commentary on "Impact of hyperglycemia on neuronal apoptosis after subarachnoid hemorrhage in rodent brain: An experimental research".

Int J Surg 2020 11 11;83:141-142. Epub 2020 Sep 11.

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

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http://dx.doi.org/10.1016/j.ijsu.2020.09.002DOI Listing
November 2020

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

Calcineurin inhibitor (CNI)-associated skin cancers: New insights on exploring mechanisms by which CNIs downregulate DNA repair machinery.

Photodermatol Photoimmunol Photomed 2020 Nov 27;36(6):433-440. Epub 2020 Aug 27.

Department of Neuroscience, Cell Biology & Physiology, College of Science and Mathematics, Wright State University Boonshoft School of Medicine, Dayton, Ohio, USA.

The use of the calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus remains a cornerstone in post-transplantation immunosuppression. Although these immunosuppressive agents have revolutionized the field of transplantation medicine, its increased skin cancer risk poses a major concern. A key contributor to this phenomenon is a reduced capacity to repair DNA damage caused by exposure to ultraviolet (UV) wavelengths of sunlight. CNIs decrease DNA repair by mechanisms that remain to be fully explored. Though CsA is known to decrease the abundance of key DNA repair enzymes, less is known about how tacrolimus yields this effect. CNIs hold the capacity to inhibit both of the main catalytic calcineurin isoforms (CnAα and CnAβ). However, it is unknown which isoform regulates UV-induced DNA repair, which is the focus of this review. It is with hope that this insight spurs investigative efforts that conclusively addresses these gaps in knowledge. Additionally, this research also raises the possibility that newer CNIs can be developed that effectively blunt the immune response while mitigating the incidence of skin cancers with immunosuppression.
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http://dx.doi.org/10.1111/phpp.12600DOI Listing
November 2020

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

Perspectives From Rising Fourth Year Medical Students Regarding Strategies to Counteract the Effects of COVID-19 on Medical Education.

J Med Educ Curric Dev 2020 Jan-Dec;7:2382120520940659. Epub 2020 Jul 13.

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

The COVID-19 pandemic has put those who oversee medical education in a challenging position. Medical school administrators, students, and national governing bodies have been forced to make difficult decision as a result of public health concerns and government-enforced restrictions. We, as rising fourth-year medical students, would like to shed light upon the hard work that many of those in leadership positions have done as well as lay out some concerns that medical students who are preparing to apply to residency have. Additionally, we would like to suggest several potential approaches that attempt to address some of the problems arising from the pandemic. Continuing to balance education with the hurdles presented by COVID-19 will require a multi-faceted and coordinated approach. We believe that implementing virtual rotations, delaying the opening of the application, decentralizing clinical skills evaluations, and modifying graduation requirements are possible options among many that could aid in addressing some of the current challenges presented by COVID-19.
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http://dx.doi.org/10.1177/2382120520940659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359646PMC
July 2020

The Potential Impact of COVID-19 on the Medical School Application.

J Med Educ Curric Dev 2020 Jan-Dec;7:2382120520940666. Epub 2020 Jul 8.

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

The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on the medical community. It is suspected that the pandemic will impact the medical school application process due to effects on standardized testing, performance measures, financial burdens, and interview strategies. It is important to consider these issues early to optimize success of future strategies and mitigate the impact of COVID-19 on the application cycle.
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http://dx.doi.org/10.1177/2382120520940666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346688PMC
July 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