Publications by authors named "Mitri K Khoury"

18 Publications

  • Page 1 of 1

Cardiac transplantation in adults with congenital heart disease: A single center case series.

Clin Transplant 2021 Jul 20. Epub 2021 Jul 20.

Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Background: Adult congenital heart disease (CHD) transplant recipients historically experienced worse survival early after transplantation. We aim to review updated trends in adult CHD transplantation.

Methods: We performed a single center case series of adult cardiac transplants from January 2013 through July 2020. Outcomes of patients with CHD were compared to non-CHD. The primary outcome was overall survival. Secondary outcomes included a variety of post-operative complications.

Results: 18/262 (7%) transplants were CHD recipients. CHD patients were younger with median age 41 (32-47) versus 58 (48-65) (P < .001). Fontan circulation for single ventricle physiology was present in 4/18 (22%) of CHD recipients, while 16/18 (89%) had systemic right ventricles. CHD recipients had higher rates of previous cardiovascular operations (94% vs. 51%, P < .001). 9/18 (50%) of CHD patients required reconstructive procedures at the time of transplant. Operative and cardiopulmonary bypass times were longer for the CHD cohort (7.5 h [6.6-8.5] vs. 5.6 h [4.6-7] P < .001) and (197 min [158-240] vs. 130 [105-167] P < .001), respectively. There were no differences in operative complications or survival between CHD and non-CHD recipients.

Conclusions: These data highlight the added technical challenges of performing adult CHD transplants. However, similar outcomes can be achieved as for non-CHD recipients.

Summary: Modern advances in palliation of congenital heart defects (CHD) has led to increased survival into adulthood. Many of these patients require heart transplantation as adults. There are limited data on adult CHD transplantation. Historically, these patients have had worse perioperative outcomes with improved long-term survival. We retrospectively analyzed 262 heart transplants at a single center, 18 of which were for adult CHD. Here, we report our series of 18 CHD recipients. We detail the palliative history of all CHD patients and highlight the added technical challenges for each of the 18 patients at transplant. In our analysis, CHD patients had more prior cardiovascular surgeries as well as longer transplant operative and bypass times. Despite this, there were no differences in perioperative and long-term outcomes. We have added patient and institution specific data for transplanting patients with adult CHD. We hope that our experience will add to the growing body of literature on adult CHD transplantation.
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http://dx.doi.org/10.1111/ctr.14430DOI Listing
July 2021

Trainee Reliance on Public Service Loan Forgiveness.

J Surg Educ 2021 Jul 12. Epub 2021 Jul 12.

University of Wisconsin, Madison; Department of Surgery; Madison, Wisconsin.

Objective: The Public Service Loan Forgiveness (PSLF) program is an option to trainees to help alleviate federal education debt. The prevalence of PSLF utilization and how this may impact career decisions of trainees is unknown. The purpose of this study was to understand the prevalence, impact, and understanding of PSLF participation on trainees.

Design: IRB-approved anonymous survey asking study subjects to report demographics, financial status, and reliance on PSLF. In addition, study subjects were asked to report their participation in PSLF, the possible impact of PSLF participation on career decisions, and to identify the qualifications needed to complete PSLF.

Setting: Online anonymous survey.

Participants: The survey was offered to all physician trainees in all specialties at the University of Texas, Southwestern, University of Wisconsin, Madison, and University of Michigan, Ann Arbor.

Results: There were 934 respondents, yielding a 37.6% response rate. A total of 416/934 (44.5%) respondents were actively or planning on participating in the PSLF program with 175/934 (18.7%) belonging to a surgical specialty. Those belonging to a surgical specialty were more likely to be PSLF participants compared to medical specialties (53.1% versus 42.6%, p = 0.01). For those participating in PSLF, 82/416 (19.7%) stated this participation impacted career decisions. A total of 275/934 (29.4%) respondents obtained and 437/934 (46.8%) wanted to receive formal training/lectures in regards to the PSLF program. Of those actively or planning on participating in the PSLF program, only 58/416 (13.9%) were able to correctly identify all of the qualifications/criteria to complete the program.

Conclusions: A large proportion of trainees rely on the PSLF program for education loan forgiveness with approximately 20% reporting participation impacted career decisions. Additionally, the majority may not fully understand PSLF criteria. Programs should strongly consider providing a formal education regarding PSLF to their trainees.
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http://dx.doi.org/10.1016/j.jsurg.2021.06.015DOI Listing
July 2021

Long-term survival after descending thoracic and thoracoabdominal aortic aneurysm repair.

J Vasc Surg 2021 Mar 25. Epub 2021 Mar 25.

University of Wisconsin, Madison; Department of Surgery; Division of Vascular and Endovascular Surgery; Madison, WI. Electronic address:

Objective: Patients with descending thoracic or thoracoabdominal aortic aneurysms (dTAA or TAAA) often have a variety of medical comorbidities. Those that are deemed acceptable for intervention undergo complicated repairs with good early outcomes. The purpose of this study was to identify variables that were associated with mortality over time.

Methods: This was a retrospective review of a prospectively maintained database at our institution from 1983-2015. Patients were included if they underwent open or endovascular repair for dTAAs and TAAAs. Patients were excluded if they were intervened on for traumatic transections. The primary outcome for the study was long-term survival. Secondary outcomes included aortic-related mortality. We had mortality/survival data on all patients.

Results: A total of 946 patients met our study criteria with a median follow-up of 102.8 months [IQR 58.9-148.2 months]. The median age of the cohort was 71 years [IQR 63-77 years] with the majority of patients being male (58.1%). The extent of TAAA pathology was as follows: Type I (14.2%), Type II (21.2%), Type III (17.1%), Type IV (26.2%), and dTAA (21.2%). A total of 147 (15.5%) patients had a prior dissection. The median diameter of aneurysm was 6.4cm [IQR 6.0-7.0cm]. A total of 158 (16.7%) patients underwent endovascular repair over the study period. Variables associated with mortality over time were: age, surgical era, acute pathology, dissection, preoperative creatinine, and Type IV TAAAs. In addition, experiencing the following complications in the postoperative period was associated with mortality over time: neurological, cardiac, and pulmonary. Aortic related mortality was 2.1% (n=20) over the study period. Patients that underwent endovascular repair for acute conditions had better long-term survival when compared to open. However, there were no differences in long-term survival between open and endovascular repair for non-acute cases. In addition, repair in the more modern era was associated with improved survival.

Conclusion: TAAAs can be repaired with reasonable perioperative mortality rates. Once patients undergo repair of their aneurysm, aortic-related mortality remains low. The addition of endovascular options has dramatically changed management of patients with dTAAs and TAAAs. Further, endovascular repair was associated with reduced perioperative mortality and significantly increased long-term survival in acute patients. Patients undergoing TAAA repair are generally considered high-risk and therefore require extensive long-term follow-up for management of their comorbidities and complications as these are the main contributors to mortality over time.
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http://dx.doi.org/10.1016/j.jvs.2021.02.048DOI Listing
March 2021

GSK2593074A blocks progression of existing abdominal aortic dilation.

JVS Vasc Sci 2020 28;1:123-135. Epub 2020 Jul 28.

Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison.

Objective: Receptor interacting proteins kinase 1 and 3 (RIPK1 and RIPK3) have been shown to play essential roles in the pathogenesis of abdominal aortic aneurysms (AAAs) by mediating necroptosis and inflammation. We previously discovered a small molecular inhibitor GSK2593074A (GSK'074) that binds to both RIPK1 and RIPK3 with high affinity and prevents AAA formation in mice. In this study, we evaluated whether GSK'074 can attenuate progression of existing AAA in the calcium phosphate model.

Methods: C57BL6/J mice were subjected to the calcium phosphate model of aortic aneurysm generation. Mice were treated with either GSK'074 (4.65 mg/kg/day) or dimethylsulfoxide (DMSO) controls starting 7 days after aneurysm induction. Aneurysm growth was monitored via ultrasound imaging every 7 days until harvest on day 28. Harvested aortas were examined via immunohistochemistry. The impact of GSK'074 on vascular smooth muscle cells and macrophages were evaluated via flow cytometry and transwell migration assay.

Results: At the onset of treatment, mice in both the control (DMSO) and GSK'074 groups showed similar degree of aneurysmal expansion. The weekly ultrasound imaging showed a steady aneurysm growth in DMSO-treated mice. The aneurysm growth was attenuated by GSK'074 treatment. At humane killing, GSK'074-treated mice had significantly reduced progression in aortic diameter from baseline as compared with the DMSO-treated mice (83.2% ± 13.1% [standard error of the mean] vs 157.2% ± 32.0% [standard error of the mean]; < .01). In addition, the GSK'074-treated group demonstrated reduced macrophages (F4/80, CD206, MHCII), less gelatinase activity, a higher level of smooth muscle cell-specific myosin heavy chain, and better organized elastin fibers within the aortic walls compared with DMSO controls. In vitro, GSK'074 inhibited necroptosis in mouse aortic smooth muscle cells; whereas, it was able to prevent macrophage migration without affecting and expression.

Conclusions: GSK'074 is able to attenuate aneurysm progression in the calcium phosphate model. The ability to inhibit both vascular smooth muscle cell necroptosis and macrophage migration makes GSK'074 an attractive drug candidate for pharmaceutical treatment of aortic aneurysms.

Clinical Relevance: Previous clinical trials evaluating pharmaceutical treatments in blocking aneurysm progression have failed. However, most agents used in those trials focused on inhibiting only one mechanism that contributes to aneurysm pathogenesis. In this study, we found GSK'074 is able to attenuate aneurysm progression in the calcium phosphate model by inhibiting both vascular smooth muscle cell necroptosis and macrophage migration, which are both key processes in the pathogenesis of aneurysm progression. The ability of GSK'0474 to inhibit multiple key pathologic mechanisms makes it an attractive therapeutic candidate for aneurysm progression.
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http://dx.doi.org/10.1016/j.jvssci.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872141PMC
July 2020

Macrophage Biology in Cardiovascular Diseases.

Arterioscler Thromb Vasc Biol 2021 02 15;41(2):e77-e81. Epub 2020 Oct 15.

Division of Vascular and Endovascular Surgery, Department of Surgery, University of Wisconsin, Madison.

Macrophages have a key functional role in the pathogenesis of various cardiovascular diseases, such as atherosclerosis and aortic aneurysms. Their accumulation within the vessel wall leads to sustained local inflammatory responses characterized by secretion of chemokines, cytokines, and matrix protein degrading enzymes. Here, we summarize some recent findings on macrophage contribution to cardiovascular disease. We focus on the origin, survival/death, and phenotypic switching of macrophages within vessel walls.
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http://dx.doi.org/10.1161/ATVBAHA.120.313584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046835PMC
February 2021

Pathophysiology of Aortic Aneurysms: Insights from Animal Studies.

Cardiol Cardiovasc Med 2020 Aug 31;4(4):498-514. Epub 2020 Aug 31.

Department of Surgery, Division of Vascular Surgery, University of Wisconsin-Madison, WI, United States.

Aortic aneurysms are defined as dilations of the aorta greater than 50 percent. Currently, the only effective treatment for aortic aneurysms is surgical repair, which is recommended only to those that meet criteria. There is no available pharmaceutical therapy to slow aneurysm growth and thus prevent lethal rupture. The development of a number of murine models has allowed in depth studies of various cellular and extracellular components of aneurysm pathophysiology. The identification of key therapeutic targets has resulted in several clinical trials evaluating pharmaceutical candidates to treat aneurysm progression. In this review, we focus on providing recent updates on developments in murine models of aortic aneurysm. In addition, we discuss recent studies of the various cellular and extracellular components of the aorta along with the abutting aortic structures that contribute to aneurysm development and progression.
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http://dx.doi.org/10.26502/fccm.92920146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508467PMC
August 2020

Risk Factors for Nonhome Discharge After Esophagectomy for Neoplastic Disease.

Ann Thorac Surg 2021 04 28;111(4):1118-1124. Epub 2020 Aug 28.

Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.

Background: Esophagectomies are known to be technically challenging operations that create significant physiologic changes. These patients often require assisted care postoperatively that necessitates a nonhome discharge. The purpose of this study was to assess factors associated with nonhome discharge after esophagectomy for neoplastic disease.

Methods: The 2016 to 2017 American College of Surgeons National Surgical Quality Improvement Program Esophagectomy database was queried to identify patients who underwent esophagectomy for a neoplasm. Patients were excluded if they died within 30 days of their operation, the index operation was considered emergent, or had missing data for the variables of interest. Multivariable analysis was performed to identify which factors were predictive of nonhome discharge.

Results: One thousand seven patients were included. Of those, 121 (12.0%) had a nonhome discharge. Multivariable analysis showed that the following factors were associated with nonhome discharge: Modified Charlson comorbidity index (adjusted odds ratio [aOR], 2.04; 95% confidence interval [CI], 1.49-2.86), partially dependent preoperative functional status (aOR, 13.18; 95% CI, 1.07-315.67), urinary tract infection (aOR, 5.25; 95% CI, 1.32-20.41), and length of stay (aOR, 1.12; 95% CI, 1.08-1.16).

Conclusions: We identified various factors associated with nonhome discharge. Early identification of patients who are at risk for nonhome discharge is important for early discharge planning, which may decrease nonmedical delays and healthcare costs.
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http://dx.doi.org/10.1016/j.athoracsur.2020.06.066DOI Listing
April 2021

Antifungal Therapy in Fungal Necrotizing Soft Tissue Infections.

J Surg Res 2020 12 22;256:187-192. Epub 2020 Jul 22.

Division of General and Acute Care Surgery, Department of Surgery, UT Southwestern Medical Center, Dallas, Texas. Electronic address:

Background: Necrotizing soft tissue infections (NSTIs) are life-threatening surgical emergencies associated with high morbidity and mortality. Fungal NSTIs are considered rare and have been largely understudied. The purpose of this study was to study the impact of fungal NSTIs and antifungal therapy on mortality after NSTIs.

Methods: A retrospective chart review was performed on patients with NSTIs from 2012 to 2018. Patient baseline characteristics, microbiologic data, antimicrobial therapy, and clinical outcomes were collected. Patients were excluded if they had comfort care before excision. The primary outcome measured was in-hospital mortality.

Results: A total of 215 patients met study criteria with a fungal species identified in 29 patients (13.5%). The most prevalent fungal organism was Candida tropicalis (n = 11). Fungal NSTIs were more prevalent in patients taking immunosuppressive medications (17.2% versus 3.2%, P = 0.01). A fungal NSTI was significantly associated with in-hospital mortality (odds ratio, 3.13; 95% confidence interval, 1.16-8.40; P = 0.02). Furthermore, fungal NSTI patients had longer lengths of stay (32 d [interquartile range, 16-53] versus 19 d [interquartile range, 11-31], P < 0.01), more likely to require initiation of renal replacement therapy (24.1% versus 8.6%, P = 0.02), and more likely to require mechanical ventilation (64.5% versus 42.0%, P = 0.02). Initiation of antifungals was associated with a significantly lower rate of in-hospital mortality (6.7% versus 57.1%, P = 0.01).

Conclusions: Fungal NSTIs are more common in patients taking immunosuppressive medications and are significantly associated with in-hospital mortality. Antifungal therapy is associated with decreased in-hospital mortality in those with fungal NSTIs. Consideration should be given to adding antifungals in empiric treatment regimens, especially in those taking immunosuppressive medications.
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http://dx.doi.org/10.1016/j.jss.2020.06.013DOI Listing
December 2020

Acute Kidney Injury in Patients Undergoing Cardiopulmonary Bypass for Lung Transplantation.

J Surg Res 2020 11 26;255:332-338. Epub 2020 Jun 26.

Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.

Background: Cardiopulmonary bypass (CPB) is often used to support patients undergoing lung transplantation who are intolerant of anatomic manipulation or single lung ventilation during the procedure. However, CPB may be associated with adverse outcomes. We evaluated the hypothesis that CPB is associated with increased acute kidney injury (AKI) and postoperative mortality after lung transplantation.

Materials And Methods: This was a retrospective review of our institutional lung transplant database at the University of Texas Southwestern Medical Center from 2012 to 2018. Patients were grouped based on their need for CPB. The primary outcome was AKI within 48 h of transplantation, which was defined as Kidney Disease Improving Global Outcomes stage 1 or greater. Secondary outcomes included all-cause mortality.

Results: A total of 426 patients underwent lung transplantation with 39.0% (n = 166) requiring CPB. There were no differences in demographics and comorbidities, including baseline renal function, between CPB and no CPB. CPB use was higher in recipients with interstitial lung diseases and primary pulmonary hypertension. Median lung allocation score was higher in those needing CPB (47 [interquartile range, 40-59] versus 39 [interquartile range, 35-47]). Patients requiring CPB were significantly more likely to experience AKI (61.44% versus 36.5.3%, P < 0.01) and postoperative hemodialysis (6.6% versus 0.4%, P < 0.01). On multivariable analysis, CPB was significantly associated with postoperative AKI (odds ratio, 1.66; 95% CI, 1.01-2.75; P = 0.04). Thirty-day mortality was higher in patients undergoing CPB (4.2% versus 0.8%, P = 0.03).

Conclusions: CPB for lung transplantation is associated with a higher incidence of AKI, renal failure requiring hemodialysis, and 30-d mortality. CPB should be used selectively for lung transplantation.
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http://dx.doi.org/10.1016/j.jss.2020.05.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541654PMC
November 2020

Regarding "Long-term survival after endovascular and open repair in patients with anatomy outside instructions for use criteria for endovascular repair".

J Vasc Surg 2020 06;71(6):2187

Division of Vascular Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisc.

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http://dx.doi.org/10.1016/j.jvs.2020.02.034DOI Listing
June 2020

Outcomes after Open Lower Extremity Revascularization in Patients with Critical Limb Ischemia.

Ann Vasc Surg 2020 Aug 24;67:417-424. Epub 2020 Apr 24.

Division of Vascular and Endovascular Surgery, Department of Surgery, Southwestern Medical Center, University of Texas, Dallas, TX; Department of Surgery, Dallas Veterans Affairs Medical Center, Dallas, TX. Electronic address:

Background: For decades, open intervention was the treatment of choice in patients requiring lower extremity revascularization. In the endovascular era, however, open and endovascular revascularization are options. The implications of prior revascularization on the outcomes for subsequent revascularization are not known. In the present study, we evaluated 30-day outcomes after open lower extremity revascularization for critical limb ischemia (CLI) in those who had previous interventions.

Methods: The 2012-2017 open lower extremity bypass Participant User Data Files from the National Surgical Quality Improvement Program were used to identify a cohort of patients with CLI. Patients whose operation was considered emergent were excluded from the analysis. Patients were stratified on whether they had a previous open or endovascular intervention or undergoing a primary revascularization. The primary outcome measure was 30-day major adverse limb events (MALEs). Secondary outcomes included major adverse cardiac events (MACEs) and wound complications.

Results: A total of 12,668 patients met study criteria with 59.6% (n = 7,549) undergoing a primary open revascularization, 22.4% (n = 2,839) having a prior endovascular intervention, and 18.0% (n = 2,280) having a prior open revascularization. There were notable differences in the baseline characteristics between the 3 groups. In addition, there were differences in the reason for intervention (rest pain versus tissue loss), type of revascularization, and type of conduit used between the 3 groups. After adjustment, a prior open revascularization was significantly associated with 30-day MALE when compared with a primary revascularization (adjusted odds ratio, 1.69; 95% confidence interval, 1.47-1.94; P < 0.001) and prior endovascular intervention (adjusted odds ratio, 1.76; 95% confidence interval, 1.46-2.12; P < 0.001). There were no differences in outcomes between primary revascularization and prior endovascular patients. There were no differences between MACEs or wound complications between the 3 groups.

Conclusions: A prior endovascular intervention does not seem to accrue any additional short-term risk when compared with primary revascularization, suggesting an endovascular-first approach may be a safe strategy in patients with CLI. However, a prior open intervention is significantly associated with 30-day MALE in patients undergoing redo open revascularization, which may be related to the rapid decline in patients once they have exhausted their best open revascularization option.
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http://dx.doi.org/10.1016/j.avsg.2020.04.023DOI Listing
August 2020

Fenestrated-branched endovascular aortic repair in patients with chronic kidney disease.

J Vasc Surg 2020 07 13;72(1):66-72. Epub 2020 Feb 13.

Division of Vascular and Endovascular Surgery, Department of Surgery, UT Southwestern Medical Center, Dallas, Tex. Electronic address:

Objective: Renal function impairment is a common complication after open repair of complex abdominal aortic aneurysms and thoracoabdominal aortic aneurysms (TAAAs). The purpose of this study was to assess renal perioperative outcomes and renal function deterioration after fenestrated-branched endovascular aneurysm repair (F/BEVAR) in patients with chronic kidney disease (CKD).

Methods: The study included 186 patients who underwent F/BEVAR between 2013 and 2018 for suprarenal, juxtarenal, and type I to type IV TAAAs. Glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease (MDRD) study equation. Postoperative acute kidney injury (AKI) and CKD were defined using RIFLE criteria (Risk, Injury, Failure, Loss, and End-stage renal disease) and CKD staging system (stage ≥3, GFR <60 mL/min/1.73 m), respectively. For those without baseline CKD, renal decline was defined as a drop in GFR <60 mL/min/1.73 m (ie, progression to CKD stage 3 or higher). For patients with baseline renal dysfunction, GFR decline ≥20% or progression in CKD stage (ie, from stage 3 to stage 4) was considered renal decline.

Results: CKD was present in 83 patients (44.6%). Postoperative AKI was diagnosed in 27 patients (14.5%); 13 (48.1%) had history of CKD and 14 (51.9%) had adequate renal function preoperatively (P = .8). None of these patients required permanent renal replacement therapy. Intraoperative technical success was 100%. Overall 30-day mortality was 1.1%. There was no difference in 30-day mortality in patients with (1.2%) and without (1.0%) CKD (P = .5). During a median follow-up time of 12 months (interquartile range, 6-23 months), renal decline was observed in 21 patients (25.3%) with previous CKD and in 11 patients (10.6%) without CKD (P = .01). Among patients with previous CKD, 18 patients (9%) progressed from stage 3 CKD to stage 4. In patients with progression in CKD stage, two (5%) had renal stent stenosis requiring restenting. Among patients with renal decline, 13 had juxtarenal aneurysms (21.3%), 27 had suprarenal aneurysms (44.3%), and 21 had TAAAs (34.3%; P = .4). Subset analysis of patients who developed AKI in the immediate postoperative period found that patients with a history of CKD were less likely to experience freedom from renal decline.

Conclusions: F/BEVAR is an effective and safe procedure for patients with complex abdominal aortic aneurysms and TAAAs, even among patients with CKD. The frequency of AKI was not affected by pre-existing CKD. Midterm outcomes demonstrated that progression of CKD was more frequent among patients with pre-existing CKD, but permanent renal replacement therapy was not required. Anatomic extent of aneurysms did not affect CKD progression. CKD patients are susceptible to renal decline over time if they experience AKI in the postoperative period. Therefore, preventing AKI in the postoperative period should be regarded as a priority. Long-term effects of CKD after F/BEVAR remain to be elucidated.
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http://dx.doi.org/10.1016/j.jvs.2019.09.035DOI Listing
July 2020

Necroptosis in the Pathophysiology of Disease.

Am J Pathol 2020 02 26;190(2):272-285. Epub 2019 Nov 26.

Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin. Electronic address:

Over the past 15 years, elegant studies have demonstrated that in certain conditions, programed cell death resembles necrosis and depends on a unique molecular pathway with no overlap with apoptosis. This form of regulated necrosis is represented by necroptosis, in which the receptor-interacting protein kinase-3 and its substrate mixed-lineage kinase domain-like protein play a crucial role. With the development of knockout mouse models and molecular inhibitors unique to necroptotic proteins, this cell death has been found to occur in virtually all tissues and diseases evaluated. There are different immunologic consequences depending on whether cells die through apoptosis or necroptosis. Therefore, distinguishing between these two forms of cell death may be crucial during pathologic evaluations. In this review, we provide an understanding of necroptotic cell-death and highlight diseases in which necroptosis has been found to play a role. We also discuss the inhibitors of necroptosis and the ways these inhibitors have been used in preclinical models of diseases. These two discussions offer an understanding of the role of necroptosis in diseases and will foster efforts to pharmacologically target this unique yet pervasive form of programed cell death in the clinic.
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http://dx.doi.org/10.1016/j.ajpath.2019.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983729PMC
February 2020

Invited commentary.

J Vasc Surg 2019 11;70(5):1668

Madison, Wisc.

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http://dx.doi.org/10.1016/j.jvs.2019.01.031DOI Listing
November 2019

Transfer Is Associated with a Higher Mortality Rate in Necrotizing Soft Tissue Infections.

Surg Infect (Larchmt) 2020 Mar 26;21(2):136-142. Epub 2019 Aug 26.

Department of Surgery; Division of General and Acute Care Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.

Necrotizing soft tissue infections (NSTI) are a surgical emergency with significant morbidity and mortality rates. It has been thought that NSTIs are best treated in large tertiary centers. However, the effect of transfer has been under-studied. We examined whether transfer status is associated with a higher mortality rate in NSTIs. We conducted a retrospective review of patients with an International Classification of Disease (ICD) code associated with NSTI seen from 2012-2015 at two tertiary care institutions. Patients transferred to a tertiary center (T-NSTI) were compared with those who were treated initially at a tertiary center (P-NSTI). The primary endpoint was in-hospital death. A total of 138 patients with NSTI met our study criteria, 39 transfer patients (28.0%) and 99 (72.0%) who were treated primarily at our institutions. The mortality rate was significantly higher for T-NSTI patients than P-NSTI patients (35.9% versus 14.1%; p < 0.01) with an adjusted odds ratio of 5.33 (95% confidence interval 1.02-28.30; p = 0.04). The need for hemodialysis was an independent predictor of in-hospital death. Treatment at a Level 1 trauma center and current smoking status were independent protectors???? of in-hospital death. For the transfer patients, the timing of transfer and debridement status were not different in survivors and non-survivors. However, there was a trend toward a lower in-hospital mortality rate if patients were transferred early without prior debridement than in all other transfers (21.4% versus 40.0%; p = 0.21). The in-hospital mortality rate was significantly lower at the Level 1 trauma center than at the non-trauma tertiary center (15.5% versus 34.3%; p = 0.02). Transfer status is an independent predictor of in-hospital death in patients with NSTI. Larger, multi-institutional studies are needed to elucidate further what factors contribute to the higher mortality rate in these patients.
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http://dx.doi.org/10.1089/sur.2019.091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133432PMC
March 2020

Visceral stent patency after fenestrated endovascular aneurysm repair using bare-metal stent extensions versus covered stents only.

J Vasc Surg 2020 01 4;71(1):23-29. Epub 2019 Jul 4.

Division of Vascular and Endovascular Surgery, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Tex. Electronic address:

Objective: Fenestrated endovascular aneurysm repair (FEVAR) is an alternative to treat complex abdominal aortic aneurysms. Patency of visceral vessels remains high when covered stents are used. The use of distal uncovered stents to prevent kinking has been associated with loss of branch patency. The aim of this study was to evaluate branch-related outcomes of FEVAR using covered stents only vs the use of uncovered stents distal to covered stents.

Methods: During a 4-year period, 142 patients underwent FEVAR. Patients with suprarenal, juxtarenal, and type IV thoracoabdominal aneurysms were included. Patients treated with side branch devices were excluded. Covered iCAST (Maquet, Hudson, NH) stents were used as bridging stents in all cases. The primary end point was primary patency, defined as the absence of stenosis or occlusion that required intervention. Secondary end points included secondary patency, branch-related outcomes (kidney injury and gastrointestinal complications), branch instability, and mortality rates.

Results: A total of 442 target vessels were incorporated (49 scallops and 393 fenestrations). Uncovered stents were used in 38 (9.6%) visceral vessels. Median follow-up time was 11 (interquartile range, 6-13) months. Overall, visceral vessel primary patency was 91% at 12 and 24 months. The overall primary patency rate was 86% in the distal extension group vs 93% when only covered stents were used at 12 and 24 months (P = .8). Similarly, the rate of branch-related reinterventions at 12 months was 9% and 15% for each group, respectively, and 22% vs 32% at 24 months, respectively (P = .5). Overall, freedom from branch instability was 87% at 12 months and 81% at 24 months. Freedom from branch instability in the distal extension group was 82% at 12 and 24 months vs 89% at 12 months and 81% at 24 months when only covered stents were used (P =. 08). Mortality rate at 24 months was 15% for the bare-metal stent extension group vs 14% for the covered stent only group (P = .4). We found no statistical difference in acute kidney injury at any Kidney Disease: Improving Global Outcomes stage (P = 1.0) or gastrointestinal complications (P = 1.0) between the groups.

Conclusions: The use of distal uncovered stents to prevent kinks was not associated with decreased early branch patency. The long-term outcomes of bare-metal stents remain to be determined. For now, the use of uncovered stents distal to covered stents may be considered to prevent kinks in complex anatomy.
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http://dx.doi.org/10.1016/j.jvs.2019.03.054DOI Listing
January 2020

Isoaspartate accumulation in mouse brain is associated with altered patterns of protein phosphorylation and acetylation, some of which are highly sex-dependent.

PLoS One 2013 5;8(11):e80758. Epub 2013 Nov 5.

Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, California, United States of America.

Isoaspartate (isoAsp) formation is a major source of protein damage that is kept in check by the repair function of protein L-isoaspartyl methyltransferase (PIMT). Mice deficient in PIMT accumulate isoAsp-containing proteins, resulting in cognitive deficits, abnormal neuronal physiology and cytoarchitecture, and fatal epileptic seizures 30-60 days after birth. Synapsins I and II, dynamin-1, collapsin response mediator protein 2 (CRMP2), and α/β-tubulin are major targets of PIMT in brain. To investigate links between isoAsp accumulation and the neurological phenotype of the KO mice, we used Western blotting to compare patterns of in vivo phosphorylation or acetylation of the major PIMT targets listed above. Phosphorylations of synapsins I and II at Ser-9 were increased in female KO vs. WT mice, and acetylation of tubulin at Lys-40 was decreased in male KO vs. WT mice. Average levels of dynamin-1 phosphorylation at Ser-778 and Ser-795 were higher in male KO vs. WT mice, but the statistical significance (P>0.1) was low. No changes in phosphorylation were found in synapsins I and II at Ser-603, in CRMP2 at Ser-522 or Thr-514, in DARPP-32 at Thr-34, or in PDK1 at Ser-241. General levels of phosphorylation assessed with Pro-Q Diamond stain, or an anti-phosphotyrosine antibody, appeared similar in the WT and KO mice. We conclude that isoAsp accumulation is associated with altered functional status of several neuronal proteins that are highly susceptible to this type of damage. We also uncovered unexpected differences in how male and female mice respond to isoAsp accumulation in the brain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080758PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818261PMC
June 2014

Acquisition of chemiluminescent signals from immunoblots with a digital single-lens reflex camera.

Anal Biochem 2010 Feb 27;397(1):129-31. Epub 2009 Sep 27.

Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA.

We found that certain mid-range consumer-level digital single-lens reflex (SLR) cameras using full-frame complementary metal oxide semiconductor (CMOS) sensors outperform X-ray film in acquiring signals from immunoblots that use enhanced chemiluminescence for detection. These cameras exhibit a sensitivity comparable to X-ray film, yet they provide a 3-fold increase in linear dynamic range and substantial cost savings over time, are more convenient to use, and eliminate the chemical waste associated with processing film.
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http://dx.doi.org/10.1016/j.ab.2009.09.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808431PMC
February 2010
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