Publications by authors named "Aaron M Williams"

80 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

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

Acute hemorrhagic cholecystitis with gallbladder rupture and massive intra-abdominal hemorrhage.

Autops Case Rep 2021 Jan 28;11:e2020232. Epub 2021 Jan 28.

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

Acute hemorrhagic cholecystitis is a rare, life-threatening condition that can be further complicated by perforation of the gallbladder. We describe a patient with clinical and radiologic findings of acute cholecystitis with a gallbladder rupture and massive intra-abdominal bleeding. Our patient is a 67-year-old male who presented with an ischemic stroke and was treated with early tissue plasminogen activator. His hospital course was complicated by a fall requiring posterior spinal fusion surgery. He recovered well, but several days later developed subxiphoid and right upper quadrant pain and an episode of hemobilia and melena. A computed tomography scan revealed an inflamed, distended gallbladder with indistinct margins and a large hematoma in the gallbladder fossa extending to the right paracolic gutter. The patient also developed hemodynamic instability concerning for hemorrhagic shock. He underwent an emergent laparoscopic converted to open subtotal fenestrating cholecystectomy with abdominal washout for management of his acute hemorrhagic cholecystitis with massive intra-abdominal hemorrhage. Prompt recognition of this lethal condition in high-risk patients is crucial for optimizing patient care.
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http://dx.doi.org/10.4322/acr.2020.232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020585PMC
January 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

Patient and Surgeon Predictors of Mitral and Tricuspid Valve Repair for Infective Endocarditis.

Semin Thorac Cardiovasc Surg 2021 Apr 15. Epub 2021 Apr 15.

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

Mitral repair (MVr) is superior to replacement for degenerative disease; however, its benefit is less established for endocarditis. We report outcomes of repair or replacement for mitral/tricuspid endocarditis and identify predictors of MVr. Patients undergoing first-time surgery for mitral (n = 260) or tricuspid (n = 71) endocarditis between 1992 to 2018 were identified. Patients with aortic endocarditis were excluded. Primary outcome was all-cause mortality and secondary outcome was MVr. Patients were stratified into active and treated endocarditis separately for mitral and tricuspid groups. Predictors of MVr were assessed through multivariable logistic regression and adjusted likelihood of MVr through marginal effects estimates. A mitral specialist was defined by performing ≥25 annual degenerative MVr. Among 331 patients, 70% (181/260) of those with mitral valve endocarditis and 52% (37/71) of those with tricuspid endocarditis underwent repair. The MVr group compared with replacement had a higher proportion of elective acuity and less diabetes, hypertension, active endocarditis, cardiogenic shock, and dialysis. Estimated 5-year survival did not differ between repair versus replacement for active mitral (68 ± 14% vs 60 ± 14%, P = 0.34) or tricuspid endocarditis (60 ± 17% vs 61 ± 19%, P = 0.67), but was superior after repair for treated mitral endocarditis (86 ± 7% vs 51 ± 24%, P = 0.014). Independent predictors of mortality included dialysis for active and treated mitral endocarditis, and mitral replacement (vs MVr) for treated mitral endocarditis. The likelihood of MVr was 82 ± 5% for mitral specialists and 47 ± 9% for non-specialists (P < 0.001). MVr for endocarditis should be pursued, if feasible. Importantly, achieving MVr was driven not only by patient factors, but also surgeon experience.
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http://dx.doi.org/10.1053/j.semtcvs.2021.03.017DOI 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

Commentary: Preoperative pulmonary artery size: A new risk stratification for morbidity following pulmonary lobectomy?

J Thorac Cardiovasc Surg 2021 Mar 11. Epub 2021 Mar 11.

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

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http://dx.doi.org/10.1016/j.jtcvs.2021.03.027DOI Listing
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

Similar Quality of Life After Conventional and Robotic Transhiatal Esophagectomy.

Ann Thorac Surg 2021 Mar 18. Epub 2021 Mar 18.

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

Background: Patient-reported outcomes (PROs) for minimally invasive esophagectomy (MIE) have demonstrated benefits compared to open transthoracic or 3-hole esophagectomy. PROs including quality of life (QoL) and fear of recurrence (FoR) comparing open transhiatal esophagectomy (THE) and transhiatal robotic-assisted MIE (Th-RAMIE) have been limited.

Methods: At a single, high-volume academic center, patients undergoing THE and Th-RAMIE with gastric conduit for clinical stage I-III esophageal cancer from 2013 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 Esophageal Cancer (QLQ-OES18), and FoR survey were administered preoperatively, and at 1, 6- and 12-months post-operatively. Linear mixed-effects models were used for QoL and FoR score comparisons. Perioperative outcomes were also compared.

Results: 309 patients (212 THE and 97 Th-RAMIE) were included. The Th-RAMIE cohort had a significantly higher number of lymph nodes harvested (14 ±0.8 vs. 11.2 ±0.4; p = 0.01), shorter length of stay (days, 10.0 ± 6.7 vs. 12.1 ±7.0; p = 0.03), lower rates of postoperative ileus (5% vs. 15%; p = 0.02), and had fewer opioids prescribed at discharge (71% vs. 85%; p = 0.03). After adjustment, there were no significant differences in QLQ-C30, QLQ-OES18, and FoR scores between groups out to 1 year following surgery.

Conclusions: There were no clear patient-reported benefits of Th-RAMIE over THE for esophageal cancer. However, Th-RAMIE conferred a number of perioperative benefits.
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http://dx.doi.org/10.1016/j.athoracsur.2021.03.018DOI Listing
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

Wandering spleen leading to splenic torsion with gastric and pancreatic volvulus.

BMJ Case Rep 2021 Jan 28;14(1). Epub 2021 Jan 28.

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

This case highlights a 37-year-old woman with primary sclerosing cholangitis awaiting liver transplantation who presented with torsion of a wandering spleen with associated gastric and pancreatic volvulus. The patient underwent emergent exploratory laparotomy with splenectomy. She had an uncomplicated postoperative course and recovered well.
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http://dx.doi.org/10.1136/bcr-2020-235918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845679PMC
January 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

Pre-Clinical Common Data Elements for Traumatic Brain Injury Research: Progress and Use Cases.

J Neurotrauma 2021 May 24;38(10):1399-1410. Epub 2021 Feb 24.

National Institutes of Health, Bethesda, Maryland, USA.

Traumatic brain injury (TBI) is an extremely complex condition due to heterogeneity in injury mechanism, underlying conditions, and secondary injury. Pre-clinical and clinical researchers face challenges with reproducibility that negatively impact translation and therapeutic development for improved TBI patient outcomes. To address this challenge, TBI Pre-clinical Working Groups expanded upon previous efforts and developed common data elements (CDEs) to describe the most frequently used experimental parameters. The working groups created 913 CDEs to describe study metadata, animal characteristics, animal history, injury models, and behavioral tests. Use cases applied a set of commonly used CDEs to address and evaluate the degree of missing data resulting from combining legacy data from different laboratories for two different outcome measures (Morris water maze [MWM]; RotorRod/Rotarod). Data were cleaned and harmonized to Form Structures containing the relevant CDEs and subjected to missing value analysis. For the MWM dataset (358 animals from five studies, 44 CDEs), 50% of the CDEs contained at least one missing value, while for the Rotarod dataset (97 animals from three studies, 48 CDEs), over 60% of CDEs contained at least one missing value. Overall, 35% of values were missing across the MWM dataset, and 33% of values were missing for the Rotarod dataset, demonstrating both the feasibility and the challenge of combining legacy datasets using CDEs. The CDEs and the associated forms created here are available to the broader pre-clinical research community to promote consistent and comprehensive data acquisition, as well as to facilitate data sharing and formation of data repositories. In addition to addressing the challenge of standardization in TBI pre-clinical studies, this effort is intended to bring attention to the discrepancies in assessment and outcome metrics among pre-clinical laboratories and ultimately accelerate translation to clinical research.
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http://dx.doi.org/10.1089/neu.2020.7328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082734PMC
May 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

Functional tricuspid regurgitation: indications, techniques, and outcomes.

Indian J Thorac Cardiovasc Surg 2020 Jan 9;36(Suppl 1):131-139. Epub 2020 Jan 9.

Department of Cardiac Surgery, University of Michigan, Frankel Cardiovascular Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109 USA.

Functional tricuspid regurgitation (TR) results from asymmetric dilation of the tricuspid valve annulus. This often occurs due to right ventricular enlargement and dysfunction as a consequence of myocardial or valvular abnormalities of the left heart. Even mild TR at the time of left-sided valvular surgery may worsen postoperatively, which carries poor prognostic implications. In spite of data revealing poor outcomes associated with residual TR, surgery for functional TR remains underutilized. Surgical repair techniques for TR include placement of a rigid or semi-rigid tricuspid annular ring, which has been shown to provide superior longevity compared with suture and flexible band repair techniques. Additionally, emerging percutaneous annuloplasty techniques to correct functional TR can expand interventional treatment options to patients who would otherwise carry prohibitive operative risk.
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http://dx.doi.org/10.1007/s12055-019-00915-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525406PMC
January 2020

Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis.

JCI Insight 2020 10 15;5(20). Epub 2020 Oct 15.

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

Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes that are involved in a variety of human disorders, including cancer and autoimmune diseases. Although targeting PAD4 has shown no benefit in sepsis, the role of PAD2 remains unknown. Here, we report that PAD2 is engaged in sepsis and sepsis-induced acute lung injury in both human patients and mice. Pad2-/- or selective inhibition of PAD2 by a small molecule inhibitor increased survival and improved overall outcomes in mouse models of sepsis. Pad2 deficiency decreased neutrophil extracellular trap (NET) formation. Importantly, Pad2 deficiency inhibited Caspase-11-dependent pyroptosis in vivo and in vitro. Suppression of PAD2 expression reduced inflammation and increased macrophage bactericidal activity. In contrast to Pad2-/-, Pad4 deficiency enhanced activation of Caspase-11-dependent pyroptosis in BM-derived macrophages and displayed no survival improvement in a mouse sepsis model. Collectively, our findings highlight the potential of PAD2 as an indicative marker and therapeutic target for sepsis.
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http://dx.doi.org/10.1172/jci.insight.138873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605547PMC
October 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

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

Virtual volunteers: the importance of restructuring medical volunteering during the COVID-19 pandemic.

Med Humanit 2020 Dec 20;46(4):537-540. Epub 2020 Aug 20.

Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA

Healthcare systems have postponed medical volunteering services in response to the COVID-19 pandemic. However, much of the aid provided by these volunteers is crucial to patient care and hospital functioning in the American healthcare system. The adoption of online video conferencing platforms in healthcare-telehealth-offers a novel solution for volunteering during this pandemic. Virtual volunteering can alleviate pressures on medical workers, enhance patient experiences, reduce the risk of viral infection and provide a sense of normalcy for patients and families. Although further study is required, this should be an avenue considered by health systems.
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http://dx.doi.org/10.1136/medhum-2020-011956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445098PMC
December 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

Peptidylarginine Deiminases 2 Mediates Caspase-1-Associated Lethality in Pseudomonas aeruginosa Pneumonia-Induced Sepsis.

J Infect Dis 2021 Mar;223(6):1093-1102

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

Background: Pseudomonas aeruginosa (PA) is a pathogenic bacterium that causes severe pneumonia in critically ill and immunocompromised patients. Peptidylarginine deiminase (PAD) 2, PAD4, and caspase-1 are important enzymes in mediating host response to infection. The goal of this study was to determine the interplay between PAD2, PAD4, and caspase-1 in PA pneumonia-induced sepsis.

Methods: Pneumonia was produced in wild-type, Pad2-/-, and Pad4-/- mice by intranasal inoculation of PA (2.5 × 106 colony-forming units per mouse), and survival (n = 15/group) was monitored for 10 days. Bone marrow-derived macrophages (BMDMs) were isolated for in vitro studies. Samples were collected at specific timepoints for Western blot, bacterial load determination, and flow cytometry analysis.

Results: Caspase-1-dependent inflammation was diminished in PA-inoculated Pad2-/- mice, contributing to reduced macrophage death and enhanced bacterial clearance. In addition, Pad2-/- mice exhibited improved survival and attenuated acute lung injury after PA infection. In contrast, Pad4-/- mice did not display diminished caspase-1 activation, altered bacterial loads, or improved survival.

Conclusions: Peptidylarginine deiminase 2 plays an essential role in the pathogenesis of pulmonary sepsis by mediating caspase-1 activation. This goes against previous findings of PAD4 in sepsis. Our study suggests that PAD2 is a potential therapeutic target of PA pneumonia-induced sepsis.
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http://dx.doi.org/10.1093/infdis/jiaa475DOI Listing
March 2021