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Mycotic aneurysms are exceedingly rare in the pediatric population. The optimal surgical treatment for children with this disease is unclear as aneurysm resection and vascular reconstruction are uncommonly performed in young children. We present a unique case of a 21-month-old child with a complex cardiac history who presented with limb ischemia and was discovered to have thrombosis of the common femoral and superficial femoral artery. Groin exploration revealed a left common femoral and superficial femoral artery mycotic aneurysm that was successfully repaired with excision of the mycotic aneurysm, external iliac to profunda femoral artery vascular bypass using cryopreserved arterial allograft and femoral vein reconstruction. This case demonstrates successful vascular reconstruction can be performed in a young child with an Aspergillus mycotic aneurysm using cadaveric arterial allograft.

INTRODUCTION: The molecular transformation of the human preaccess vein after arteriovenous fistula (AVF) creation is poorly understood. This limits our ability to design efficacious therapies to improve maturation outcomes. METHODS: Bulk RNA sequencing (RNA-seq) followed by paired bioinformatic analyses and validation assays were performed in 76 longitudinal vascular biopsies (veins and AVFs) from 38 patients with stage 5 chronic kidney disease or end-stage kidney disease undergoing surgeries for 2-stage AVF creation (19 matured, 19 failed). RESULTS: A total of 3637 transcripts were differentially expressed between veins and AVFs independent of maturation outcomes, with 80% upregulated in fistulas. The postoperative transcriptome demonstrated transcriptional activation of basement membrane and interstitial extracellular matrix (ECM) components, including preexisting and novel collagens, proteoglycans, hemostasis factors, and angiogenesis regulators. A postoperative intramural cytokine storm involved >80 chemokines, interleukins, and growth factors. Postoperative changes in ECM expression were differentially distributed in the AVF wall, with proteoglycans and fibrillar collagens predominantly found in the intima and media, respectively. Interestingly, upregulated matrisome genes were enough to make a crude separation of AVFs that failed from those with successful maturation. We identified 102 differentially expressed genes (DEGs) in association with AVF maturation failure, including upregulation of network collagen VIII in medial smooth muscle cells (SMCs) and downregulation of endothelial-predominant transcripts and ECM regulators. CONCLUSION: This work delineates the molecular changes that characterize venous remodeling after AVF creation and those relevant to maturation failure. We provide an essential framework to streamline translational models and our search for antistenotic therapies.

Objective General surgery resident (GSR) 5-year attrition rates of 12% to 20% are currently reported. This study explores the impact of full-time surgery faculty (FSF) diversity on GSR attrition. Design Deidentified data were obtained from the Association of American Medical Colleges (AAMC) for FSF at US Liaison Committee on Medical Education (LCME)-accredited medical schools and GSR at the affiliated general surgery residency programs (2001-2016). Data included annual GSR attrition rate and the number, gender, and race of FSF and GSR. Data were analyzed using linear and logarithmic regression. Setting The study was conducted at the University of Miami Leonard M. Miller School of Medicine in Miami, Florida. Participants The data obtained included FSF from US LCME-accredited medical schools and GSR from those residency programs affiliated with US LCME-accredited medical schools. Data were included only if available for both FSF and GSR at a single institution. There were 107,300 annual FSF positions and 39,504 annual GSR positions from 61 U.S. LCME-accredited medical schools included in the analysis. Results Data included 107,300 FSF positions (26% non-white; 20% female) and 39,504 GSR positions (41% non-white; 33% female) summed across 1034 institution years. Increased female FSF is associated with decreased GSR attrition (R2 = 0.009, p = 0.002, Fig. 1 ). For every 1% increase in female FSF, GSR programs were 4% less likely to have an attrition rate in the top quartile (odds ratio 0.96, confidence interval 0.94-0.98). Conclusions Gender diversity of FSF has an impact on GSR attrition; more female FSF correlates with lower GSR attrition rates.

Background and aims Increased receptor tyrosine kinase (RTK) activity has been historically linked to atherosclerosis. Paradoxically, we recently found that global deficiency in c-Kit function increased atherosclerosis in hyperlipidemic mice. This study aimed to investigate if such unusual atheroprotective phenotype depends upon c-Kit's function in smooth muscle cells (SMC). Methods We studied atherosclerosis in a SMC-specific conditional knockout mice (KitSMC) and control littermate. Tamoxifen (TAM) and vehicle treated mice were fed high fat diet for 16 weeks before atherosclerosis assessment in the whole aorta using oil red staining. Smooth muscle cells were traced within the aortic sinus of conditional c-Kit tracing mice (KitSMC eYFP) and their control littermates (KitWT eYFP) by immunofluorescent confocal microscopy. We then performed RNA sequencing on primary SMC from c-Kit deficient and control mice, and identified significantly altered genes and pathways as a result of c-Kit deficiency in SMC. Results Atherosclerosis significantly increased in KitSMC mice with respect to control groups. In addition, the loss of c-Kit in SMC increased plaque size and necrotic core area in the aortic sinus of hyperlipidemic mice. Smooth muscle cells from KitSMC eYFP mice were more prone to migrate and express foam cell markers (e.g., Mac2 and MCAM) than those from control littermate animals. RNAseq analysis showed a significant upregulation in genes associated with cell proliferation, migration, lipid metabolism, and inflammation secondary to the loss of Kit function in primary SMCs. Conclusions Loss of c-Kit increases SMC migration, proliferation, and expression of foam cell markers in atherosclerotic plaques from hyperlipidemic mice.

Pharmacological activation of integrin CD11b/CD18 (αMβ2, Mac-1, and CR3) shows anti-inflammatory benefits in a variety of animal models of human disease, and it is a novel therapeutic strategy. Reasoning that genetic models can provide an orthogonal and direct system for the mechanistic study of CD11b agonism, we present in this study, to our knowledge, a novel knock-in model of constitutive active CD11b in mice. We genetically targeted the Itgam gene (which codes for CD11b) to introduce a point mutation that results in the I332G substitution in the protein. The I332G mutation in CD11b promotes an active, higher-affinity conformation of the ligand-binding I/A-domain (CD11b αA-domain). In vitro, this mutation increased adhesion of knock-in neutrophils to fibrinogen and decreased neutrophil chemotaxis to a formyl–Met–Leu–Phe gradient. In vivo, CD11bI332G animals showed a reduction in recruitment of neutrophils and macrophages in a model of sterile peritonitis. This genetic activation of CD11b also protected against development of atherosclerosis in the setting of hyperlipidemia via reduction of macrophage recruitment into atherosclerotic lesions. Thus, our animal model of constitutive genetic activation of CD11b can be a useful tool for the study of integrin activation and its potential contribution to modulating leukocyte recruitment and alleviating different inflammatory diseases.

Historically, carotid procedures incur a readmission rate of approximately 6%; however, these studies are not nationally representative and are limited to tracking only the index hospitals. We sought to evaluate a nationally representative database for readmission rates (including different hospitals) after both carotid endarterectomy (CEA) and carotid artery stenting (CAS) and determine risk factors for poor outcomes including postoperative mortality and myocardial infarction.This study was a retrospective analysis utilizing the 2010-2014 Nationwide Readmissions Database to query patients aged18 years undergoing CEA or CAS. Outcomes included initial admission mortality, and 30-day readmission, including mortality and myocardial infarction (MI). Univariable analysis of 39 demographic, clinical, and hospital variables was conducted with significance set at P 0.05. Significant variables were included in a multivariable logistic regression to identify independent risk factors for readmission. Results were weighted for national estimates.There were 527,622 patients undergoing carotid procedures and 13% (n = 69,187) underwent CAS. The 30-day readmission rate was 7% (n = 35,782), and of those, 25% (n = 8,862) were readmitted to a different hospital. When controlling for other factors, CAS was a risk factor for mortality at both index admission (odds ratio [OR] 2.29 [2.11-2.49]) and 30-day readmission (OR 1.48 [1.3-1.69]) and 30-day readmissions at both index hospital (OR 1.11 [1.07-1.14]) and different hospital (OR 1.38 [1.29-1.48]). Readmission to a different hospital increased mortality risk (OR 1.45 [1.29-1.63]) but did not have an effect on MI. Postoperative infections comprised 15% of readmissions while 6% of all readmissions were for stroke.Previously unreported, one in 4 readmissions after carotid procedures occur at a different hospital and this fragmentation of care could increase mortality risk after carotid procedures particularly for CAS which was also an independent risk factor for postoperative mortality and readmissions. Further validation is required to decrease unnecessary hospital after carotid procedures.

The intrahepatic milieu is inhospitable to intraportal islet allografts1–3, limiting their applicability for the treatment of type 1 diabetes. Although the subcutaneous space represents an alternate, safe and easily accessible site for pancreatic islet transplantation, lack of neovascularization and the resulting hypoxic cell death have largely limited the longevity of graft survival and function and pose a barrier to the widespread adoption of islet transplantation in the clinic. Here we report the successful subcutaneous transplantation of pancreatic islets admixed with a device-free islet viability matrix, resulting in long-term euglycaemia in diverse immune-competent and immuno-incompetent animal models. We validate sustained normoglycaemia afforded by our transplantation methodology using murine, porcine and human pancreatic islets, and also demonstrate its efficacy in a non-human primate model of syngeneic islet transplantation. Transplantation of the islet–islet viability matrix mixture in the subcutaneous space represents a simple, safe and reproducible method, paving the way for a new therapeutic paradigm for type 1 diabetes. Yu et al. report a preparation that enables transplantation of pancreatic islets underneath the skin and achieves long-term euglycaemia in several preclinical models of type 1 diabetes, thus providing a simple method that might enable a more widespread adoption of islet transplantation in the clinic.

In the era of subspecialization and duty-hour restrictions, many General Surgery residents desire additional training in their future subspecialty areas. This study examines the relationship between case distributions performed by General Surgery residents and their chosen future subspecialty.A retrospective review of Accreditation Council for Graduate Medical Education case logs of 101 graduated General Surgery residents at a single academic institution (2002-2018) was performed. The total number of operative cases performed during General Surgery residency overall and in Accreditation Council for Graduate Medical Education-defined categories were compared between residents with differing areas of future subspecialization.Residents pursuing surgical fellowships in Endocrine, Cardiothoracic, Vascular, and Trauma/Critical Care Surgery logged respectively more endocrine (63 [11] vs 32 [13]; P.001), thoracic (61 [15] vs 41 [13]; P.001), vascular (225 [38] vs 162 [38]; P.001), and operative trauma (83 [29] vs 71 [25]; P = .045) cases, compared with program average. Residents pursuing General Surgery (no fellowship) performed significantly more endoscopies (131 [47] vs 105 [28]; P = .029) than peers. Residents pursuing Breast, Oncology, Colorectal, and Pediatric Surgery fellowships performed numerically (non-significantly) more breast (94 [16] vs 78 [20]; P = .180), liver/pancreas (39 [3.1] vs 33 [8.0]; P = .173), large intestinal (132 [30] vs 125 [24]; P = .507), and pediatric (173 [27] vs 155 [37]; P = .832) cases, respectively, compared with peers. The majority of these additional cases were performed in postgraduate years 3 to 5.In this single-institution study, many General Surgery residents perform more cases than peers in respective areas of future subspecialization. This may reflect residents at the reporting institution, and similar large, university-based programs seeking focused training in preparation for fellowship while still meeting case-volume minimums in all Accreditation Council for Graduate Medical Education-defined categories.

Shunt placement during carotid endarterectomy (CEA) has often been advocated to protect the ischemic penumbra in patients with symptomatic carotid stenosis. In the present study, we assessed the effect of shunt placement during CEA on postoperative stroke risk in symptomatic patients.We queried the American College of Surgeons National Surgical Quality Improvement Program database (2016-2019) for CEA cases with complete CEA procedure-targeted data available. Symptomatic patients were identified as those with a preoperative diagnosis of stroke on presentation (DS), transient ischemic attack, amaurosis fugax, or temporary monocular blindness. The DS patients were further analyzed according to the severity of their stroke using the modified Rankin scale scores. To better assess the effect of shunt placement on the stroke rate, we compared cases of CEA with the patch angioplasty technique stratified by the use of an intraoperative shunt. Patients who had undergone carotid eversion or primary closure were excluded. The baseline demographics and perioperative outcomes were compared using the χWe identified 4652 cases of CEA with patch angioplasty in symptomatic patients, including 1889 with (40.6%) and 2763 without (59.4%) shunt placement. The distribution of age, race, and sex was similar for both procedures. Compared with patients without a shunt, those with a shunt had significantly higher rates of emergency surgery (9.1% vs 7.0%; P = .010), nonelective surgery (40.3% vs 37.2%; P = .035), general anesthesia (97.0% vs 86.3%; P .001), and bleeding disorders (27.2% vs 22.7%; P .001). The 30-day incidence of postoperative stroke was similar between the patients with (3.2%) and without (2.6%) shunt placement (P = .219). Additionally, a subgroup analysis failed to show any benefit from shunt placement on the incidence of postoperative stroke, regardless of the preoperative symptoms or neurologic disability. In contrast, shunt placement was associated with an increased rate of cranial nerve injury (4.1% vs 2.4%; P = .001). Multivariate analysis revealed that nonelective surgery (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.36-2.91; P .001) and DS (vs transient ischemic attack, amaurosis fugax, or temporary monocular blindness; OR, 1.64; 95% CI, 1.12-2.41; P = .012) were predictive of 30-day postoperative stroke. After adjusting for confounders, shunt placement had no effect on stroke risk at 30 days but remained an independent risk factor for cranial nerve injury (adjusted OR, 1.87; 95% CI, 1.32-2.64; P .001).For symptomatic patients undergoing CEA with patch angioplasty, shunt placement was associated with an increased risk of cranial nerve injury without a reduction in postoperative stroke risk.

In the present study, we used a national database to identify racial differences in the presentation and outcomes for patients undergoing endovascular abdominal aortic aneurysm (AAA) repair (EVAR) and identified areas for improving their care.We queried the EVAR-targeted National Surgical Quality Improvement Program database (2016-2019) to identify patients who had undergone EVAR for both ruptured and nonruptured AAAs. The patients were categorized according to race (White, Black, and Asian). Patients with a history of abdominal aortic surgery or an indication other than AAAs were excluded. The data was analyzed using the χWe identified 3629 patients (16.6% female), including 3312 White (91.3%), 248 Black (6.8%), and 69 Asian (1.9%) patients. Black patients were more frequently women (27.0%) compared with White patients (15.9%) and were younger (median age, 71 years; IQR, 64-77 years) than White (median age, 73 years; IQR, 67-79 years) and Asian (median age, 76 years; IQR, 67-81 years) patients (P .001 for both). The incidence of smoking, congestive heart failure, and dialysis dependency was highest for Black patients, and the incidence of obesity was lowest for Asian patients. The AAAs in Black patients extended more frequently beyond the aortic bifurcation (P = .047). In Asian patients, the internal iliac arteries were more involved (P = .040). For Black patients, 29.8% of the EVARs were performed in a nonelective setting compared with 20.2% for the White and 15.9% for the Asian patients (P .001). The aneurysm diameter, nonruptured symptomatic rate, and rupture rate were similar across the groups (P = .807). The operative time was prolonged for Black (median, 128 minutes; IQR, 96-177 minutes) compared with White (median, 114 minutes; IQR, 84-162 minutes) patients (P .001). Postoperatively, Black patients were more likely to require blood transfusion (16.5%) and had prolonged length of hospital stay (median, 2 days; IQR, 1-4 days) compared with White (10.0%; median, 1 day; IQR, 1-3 days) and Asian (4.3%; median, 1 day; IQR, 1-3 days) patients (P = .001 and P .001, respectively). Black patients also had a higher 30-day readmission rate (P = .038). On multivariate analysis, Black race was an independent factor for length of stay1 day after both elective and nonelective EVAR and 30-day readmission for elective EVAR, but not 30-day mortality after elective and nonelective EVAR.In the present nationwide sample of EVAR cases, Black patients were more often women and younger. Despite similar rates of symptomatic and ruptured AAAs at presentation and 30-day mortality, Black patients more often presented and were treated during the same nonelective admission; they also had associated increased length of hospital stay and readmission. These findings signal a missed opportunity to diagnose, optimize, and treat this particular group of patients in an elective setting.

Peripheral arterial disease (PAD) is a significant cause of morbidity resulting from chronic exposure to atherosclerotic risk factors. Patients suffering from its most severe form, chronic limb-threatening ischemia (CLTI), face substantial impairments to daily living, including chronic pain, limited walking distance without pain, and nonhealing wounds. Preclinical models have been developed in various animals to study PAD, but mouse hindlimb ischemia remains the most widely used. There can be significant variation in response to ischemic insult in these models depending on the mouse strain used and the site, number, and means of arterial disruption. This protocol describes a unique method combining femoral artery and vein electrocoagulation with the administration of a nitric oxide synthase (NOS) inhibitor to reliably induce footpad gangrene in Friend Virus B (FVB) mice that resembles the tissue loss of CLTI. While traditional means of assessing reperfusion such as laser Doppler perfusion imaging (LDPI) are still recommended, intracardiac perfusion of the lipophilic dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) is used to label the vasculature. Subsequent whole-mount confocal laser scanning microscopy allows for high-resolution, three-dimensional (3D) reconstruction of footpad vascular networks that complements traditional means of assessing reperfusion in hindlimb ischemia models.

Objective: Monocytes, which play an important role in arteriogenesis, can build immunologic memory by a functional reprogramming that modifies their response to a second challenge. This process, called trained immunity, is evoked by insults that shift monocyte metabolism, increasing HIF (hypoxia-inducible factor)-1α levels. Since ischemia enhances HIF-1α, we evaluate whether ischemia can lead to a functional reprogramming of monocytes, which would contribute to arteriogenesis after hindlimb ischemia. Methods and Results: Mice exposed to ischemia by 24 hours (24h) of femoral artery occlusion (24h trained) or sham were subjected to hindlimb ischemia one week later; the 24h trained mice showed significant improvement in blood flow recovery and arteriogenesis after hindlimb ischemia. Adoptive transfer using bone marrow-derived monocytes (BM-Mono) from 24h trained or sham donor mice, demonstrated that recipients subjected to hindlimb ischemia who received 24h ischemic-trained monocytes had remarkable blood flow recovery and arteriogenesis. Further, ischemic-trained BM-Mono had increased HIF-1α and GLUT-1 (glucose transporter-1) gene expression during femoral artery occlusion. Circulating cytokines and GLUT-1 were also upregulated during femoral artery occlusion.Transcriptomic analysis and confirmatory qPCR performed in 24h trained and sham BM-Mono revealed that among the 15 top differentially expressed genes, 4 were involved in lipid metabolism in the ischemic-trained monocytes. Lipidomic analysis confirmed that ischemia training altered the cholesterol metabolism of these monocytes. Further, several histone-modifying epigenetic enzymes measured by qPCR were altered in mouse BM-Mono exposed to 24h hypoxia. Conclusions: Ischemia training in BM-Mono leads to a unique gene profile and improves blood flow and arteriogenesis after hindlimb ischemia.

AimsNovel cell-based therapeutic angiogenic treatments for patients with critical limb ischemia may afford limb salvage. Mesenchymal stem cells (MSCs) do not overexpress E-selectin; however, we have previously demonstrated the cell-adhesion molecule's vital role in angiogenesis and wound healing. Thus, we created a viral vector to overexpress E-selectin on MSCs to increase their therapeutic profile.Methods and ResultsFemoral artery ligation induced hind limb ischemia in mice and intramuscular injections were administered of vehicle or syngeneic donor MSCs, transduced ex vivo with an adeno-associated viral vector to express either GFP+ (MSCGFP) or E-selectin-GFP+ (MSCE−selectin−GFP). Laser Doppler Imaging demonstrated significantly restored reperfusion in MSCE−selectin−GFP-treated mice vs. controls. After 3 weeks, the ischemic limbs in mice treated with MSCE−selectin−GFP had increased footpad blood vessel density, hematoxylin and eosin stain (H&E) ischemic calf muscle sections revealed mitigated muscular atrophy with restored muscle fiber size, and mice were able to run further before exhaustion. PCR array-based gene profiling analysis identified nine upregulated pro-angiogenic/pro-repair genes and downregulated Tumor necrosis factor (TNF) gene in MSCE−selectin−GFP-treated limb tissues, indicating that the therapeutic effect is likely achieved via upregulation of pro-angiogenic cytokines and downregulation of inflammation.ConclusionThis innovative cell therapy confers increased limb reperfusion, neovascularization, improved functional recovery, decreased muscle atrophy, and thus offers a potential therapeutic method for future clinical studies.

Hypercoagulability and thrombotic complications seen in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as the associated pathophysiology, have been reported extensively. However, there is limited information regarding the factors related to this phenomenon and its association with the Coronavirus disease 2019 (COVID-19) Delta variant.A retrospective review including patients admitted to a tertiary center with a COVID-19 positive test and at least one acute thrombotic event confirmed by imaging between June 2020 and August 2021 was performed. We compared the rates of thrombotic events in patients with COVID-19 before and during the Delta peak. We also analyzed the association of the thrombotic complications with demographic characteristics, comorbidities, anticoagulation strategies, and prothrombotic markers while describing other complications secondary to COVID-19 infection.Of 964 patients admitted with COVID-19 diagnosis, 26.5% (n = 256) had a thrombotic event evidenced by ultrasound or computed tomography scan. Venous thromboembolism was found in 60% (n = 153), arterial thrombosis in 23% (n = 60), and both venous and arterial thromboses in 17% (n = 17) of the study cohort. Of all patients, 94% were not vaccinated. Delta variant wave (DW) patients had thrombotic episodes in 34.7% (n = 50/144) of cases compared with 25% (n = 206/820) of non-Delta wave (NDW) patients, posing an estimated risk 1.36 times higher in patients infected with COVID-19 during the DW than NDW. Overall, DW subjects were significantly younger (P .001) with lower body mass index (P = .021) compared with NDW patients. Statistical analyses showed African American patients were more likely to have arterial thrombosis compared with the other groups when testing positive for COVID-19 (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.04-3.05; P = .035, whereas immunosuppressed patients had less risk of arterial thrombosis (OR, 0.38; 95% CI, 0.15-0.96; P = .042). Female gender (OR, 2.15; 95% CI, 1.20-3.85; P = .009) and patients with active malignancy (OR, 5.99; 95% CI, 2.14-16.78; P = .001) had an increased risk of having multiple thrombotic events at different locations secondary to COVID-19.COVID-19 infection is associated with elevated rates of thrombotic complications and an especially higher risk in patients infected during the Delta variant peak. We highlight the importance of vaccination and the development of new anticoagulation strategies for patients with COVID-19 with additional hypercoagulable risk factors to prevent thrombotic complications caused by this disease.

Peripheral Arterial Disease (PAD) is a progressive, atherosclerotic disease that at its end stage, Critical Limb Ischemia (CLI), results in severely diminished limb perfusion and causes leg pain at rest, non-healing ulcers, and tissue gangrene. Many patients with CLI fail current medical and surgical therapies and thus are deemed "no option" and require limb amputation. Novel therapies to attempt limb salvage in these "no option" patients are needed. Stem cell therapy is one therapeutic angiogenic avenue that has been tested over the last 20 years. To date, clinical trials have shown promise but with only modest improvement and none demonstrated a significant decrease in amputation rates in those treated with stem cell therapy. Thus, recent investigations into improving stem cell therapy have been the focus of our laboratory and many others. This review aims to describe recent advances in increasing the therapeutic potential of stem cell therapies for CLI.

Background and objectives:The venous vasa vasorum is the mesh of microvessels that provide oxygen and nutrients to the walls of large veins. Whether changes to the vasa vasorum have any effects on human arteriovenous fistula outcomes remains undetermined. In this study, we challenged the hypothesis that inadequate vascularization of the arteriovenous fistula wall is associated with maturation failure.Design, setting, participants, and measurements:This case–control pilot study includes pre-access veins and arteriovenous fistula venous samples (i.e. tissue pairs) from 30 patients undergoing two-stage arteriovenous fistula creation (15 matured and 15 failed to mature). Using anti-CD31 immunohistochemistry, we quantified vasa vasorum density and luminal area (vasa vasorum area) in the intima, media, and adventitia of pre-access veins and fistulas. We evaluated the association of pre-existing and postoperative arteriovenous fistula vascularization with maturation failure and with postoperative morphometry.Results:Vascularization of veins and arteriovenous fistulas was predominantly observed in the outer media and adventitia. Only the size of the microvasculature (vasa vasorum area), but not the number of vessels (vasa vasorum density), increased after arteriovenous fistula creation in the adventitia (median vasa vasorum area 1366 µm2/mm2(interquartile range 495–2582) in veins versus 3077 µm2/mm2(1812–5323) in arteriovenous fistulas, p Conclusion:The lack of change in intimal and medial vascularization after arteriovenous fistula creation argues against higher oxygen demand in the inner walls of the fistula during the vein to arteriovenous fistula transformation. Postoperative intimal hyperplasia in the arteriovenous fistula wall appears to thrive under hypoxic conditions. Vasa vasorum density and area by themselves are not predictive of maturation outcomes.

In response to the growing opioid crisis, Florida recently implemented a law restricting the duration of opioid prescriptions for acute pain. Little is known about the impact of such legislation on opioid prescription practices at the time of discharge after surgery. The objective of this study was to determine whether Florida's new legislation changed opioid prescription practices for analgesia after surgery.Adults 18 years of age and older undergoing cholecystectomy, appendectomy, hernia repair, hysterectomy, mastectomy, or lymph node dissection were included in this retrospective cohort study at a large public university-affiliated hospital. We analyzed opioid prescriptions on discharge after these common outpatient surgical procedures between June 1, 2017, and December 31, 2018. Florida House Bill 21 was passed on March 2, 2018, and subsequent implementation of this law took place on July 1, 2018. The law restricts the duration of opioid prescriptions for acute pain to 3 days, which can be extended up to a maximum of 7 days with additional documentation. The outcomes studied included the following: the proportion of patients receiving opioid prescriptions on discharge, total opioid dose prescribed, daily opioid dose prescribed, and the proportion of patients receiving more than a 3-day supply of opioids. We colledted data on emergency department cumulative visits within 7 and 30 days after discharge. Drug doses were converted to morphine milligram equivalents and calculated for each selected procedure.A total of 1,467 surgical encounters were included. The cohort was predominantly female (963 [65.6%]) with a mean (SD) age of 49.6 (14.4) years. At 6 months after implementation of HB 21, the proportion of patients receiving opioid prescriptions decreased by 21% (95% CI 16.8% to 25.3%, P.001), mean total opioid dose prescribed decreased by 64.2 morphine milligram equivalents (95% CI 54.7 to 73.7, P.001) from a baseline mean (SD) of 172.5 (78.9) morphine milligram equivalents. The mean daily opioid dose prescribed increased by 3.5 morphine milligram equivalents (95% CI 1.8 to 5.1, P.001) from a baseline mean (SD) of 30.5 (9.4) morphine milligram equivalents. The proportion of patients receiving opioid prescriptions for longer than a 3-day supply decreased by 68% (95% CI 63.4% to 72.7%, P.001). We observed no change in the number of postoperative emergency department visits before and after implementation of the law.Opioid prescriptions for patients undergoing common outpatient surgical procedures at a large public university-affiliated hospital in Florida were substantially reduced within 6 months after implementation of state legislation limiting the duration of opioid prescriptions. This reduction was not associated with an increase in the number of postoperative emergency department visits. The legislation should significantly decrease the amount of unused opioid pills potentially available for diversion and abuse. Secondary effects from the enactment of this law remain to be evaluated.

Introduction There remains a paucity of novel therapeutics for limb salvage in patients with critical limb ischemia (CLI) for whom revascularization procedures have failed and amputation is imminent. We have shown that E-selectin+/Mesenchymal Stem Cell (MSC) injections into the ischemic limb tissue of a CLI mouse model improves revascularization and limb function. Thus, we sought to determine a mechanism of action for E-selectin+/MSC’s pro-angiogenic and tissue salvage properties. Methods MSC were extracted from donor mice bone marrow and subsequently engineered via viral transduction with E-selectin-ires-GFP/AAV and GFP/AAV (control) to create E-selectin-GFP+/MSC vs GFP+/MSC. Intramuscular injections of E-selectin-GFP+/MSC, GFP+/MSC, or PBS were performed in a mouse model of hindlimb ischemia. Laser doppler imaging (LDI), confocal laser microscopy, and treadmill exhaustion test were utilized to determine neovascularization and limb function. RNA extraction from engineered MSC (E-selectin-GFP+/MSC vs GFP+/MSC) and ischemic hindlimb tissues treated with E-selectin-GFP+/MSC vs GFP+/MSC was performed, followed by RT2 Profiler PCR Array analysis of 84 genes involved in angiogenesis. GFP+/MSC treated hindlimb tissue served as control. Student’s t-test or ANOVA was utilized to compare means and significance set at P Results Compared with GFP+/MSC and PBS, treatment with E-selectin-GFP+/MSC increased ischemic leg LDI reperfusion (54% vs. 39% vs. 22%, P Conclusion Stem cell therapy using E-selectin-GFP+/MSC, in a murine model of CLI, confers both augmented postnatal neovascularization and increased limb function. The pro-angiogenic and pro-repair effects are likely mediated by upregulation of a panel of chemokines/cytokines and down-regulation of TNF in ischemic tissues treated with E-selectin-GFP+/MSC.

Background The arteriovenous fistula (AVF) is the preferred hemodialysis access for end-stage renal disease (ESRD) patients. Yet, establishment of a functional AVF presents a challenge, even for the most experienced surgeons, since postoperative stenosis frequently occludes the AVF. Stenosis results from the loss of compliance in fibrotic areas of the fistula which turns intimal hyperplasia into an occlusive feature. Fibrotic remodeling depends on deposition and crosslinking of collagen by lysyl oxidase (LOX), an enzyme that catalyzes the deamination of lysine and hydroxylysine residues, facilitating intra/intermolecular covalent bonds. We postulate that pharmacological inhibition of lysyl oxidase (LOX) increases postoperative venous compliance and prevents stenosis in a rat AVF model. Methods LOX gene expression and vascular localization were assayed in rat AVFs and human pre-access veins, respectively. Collagen crosslinking was measured in humans AVFs that matured or failed, and in rat AVFs treated with β-aminopropionitrile (BAPN), an irreversible LOX inhibitor. BAPN was either injected systemically or delivered locally around rat AVFs using nanofiber scaffolds. The major endpoints were AVF blood flow, wall fibrosis, collagen crosslinking, and vascular distensibility. Results Non-maturation of human AVFs was associated with higher LOX deposition in pre-access veins (N=20, P=0.029), and increased trivalent crosslinks (N=18, P=0.027) in human AVF tissues. Systemic and local inhibition of LOX increased AVF distensibility, while reducing wall fibrosis and collagen crosslinking in rat fistulas. Conclusions Our results demonstrate that BAPN-mediated inhibition of LOX significantly improves vascular remodeling in experimental fistulas.

Introduction & Objective Mycotic aneurysms are exceedingly rare in the pediatric population. The optimal surgical treatment for children with this disease is unclear as aneurysm resection and vascular reconstruction are uncommonly performed in young children. We present the unique case of a21-month-old child with a complex cardiac history who presented with leg ischemia and a femoral mycotic aneurysm that was successfully repaired with an external iliac to profunda femoris artery vascular bypass with cryopreserved arterial allograft and femoral vein reconstruction. Case Report Our patient presented with leg ischemia and blood cultures positive for Aspergillus, with CT angiography demonstrating complete occlusion of the left common femoral artery and proximal superficial femoral artery ( Figure 1 Download : Download high-res image (117KB) Download : Download full-size image Figure 1 . Axial computed tomography shows large left common femoral artery mycotic aneurysm with dense inflammatory reaction. ). Upon operative exploration, there was an extremely dense inflammatory response with purulent material extruding from the region and bulky reactive lymphadenopathy ( Figure 2A Download : Download high-res image (399KB) Download : Download full-size image Figure 2 . A-B. (A) Intraoperative photograph demonstrating large mycotic aneurysm involving the femoral artery. (B) Intraoperative photograph demonstrating the completed anastomosis between the left common iliac artery and the profunda femoris artery, along with femoral vein reconstruction. ) with extension of thrombosis from the external iliac artery immediately at the inguinal ligament to the superficial femoral artery. The 2 mm profunda arterywas the remaining outflow to the lower extremity. A 6 mm cryopreserved artery allograft (CryoArtery) was used to perform the vascular bypass between the external iliac artery and the profunda femoris artery in an end-to-side fashion. The mycotic aneurysm and underlying vesselswere dissected and resected from the external iliac artery to the proximal superficial femoral artery. As the femoral vein was densely adherent to the inflammatory mass, a segment was removed and reconstructed in a similar fashion with CryoArtery. Completed anastomosis is shown in Figure 2B. At the conclusion of the procedure, the patient had biphasic doppler signal in the dorsalis pedis artery. Conclusions Successful vascular reconstruction can be performed in a young child with an Aspergillus mycotic aneurysm using cadaveric arterial allograft. For our patient, a cryopreserved artery allograft was used as the iliofemoral bypass conduit. Although an autologous conduit would have been the preferred bypass method, it was not possible in this case owing to the patients immaturevenous system and prior surgical manipulation. Not only is restoring flow to the distal extremity of the utmost importance in young pediatric patients to avoid future limb-length discrepancies, but flow must also be maintained in the bypass conduit postoperatively without conduit occlusion. Our patient received intravenous heparin in the immediate postoperative period and was bridged to prophylactic enoxaparin for three months and aspirin indefinitely. If the use of an autologous conduit is not possible, we show here that a cadaveric arterial allograft can be a suitable and durable alternative and report the successful vascular reconstruction of a 20-month-old with an Aspergillus mycotic aneurysm using cadaveric arterial allograft and no limb-length discrepancy as of thirty-six months follow-up.

Introduction: Recent studies have shown that innate response can build immunological memory. This process called “trained immunity” is an epigenetic reprogramming of the monocytes driven by a metabolism shift towards glycolysis. Hypothesis: Since HIF-1a is a major player in monocytes activation and also targets some epigenetic enzymes, we hypothesize that hypoxia/ischemia can lead to “trained immunity” improving arteriogenesis in a mouse model of hindlimb ischemia. Methods: Mice subjected to a unilateral single ischemia insult for 24hours (24h group: femoral artery ligation for 24 h) or by ischemia reperfusion cycles (Cycle group: ischemia-reperfusion in 4 cycles of 5 minutes) or non-ischemia (sham group), were used as donors in the monocyte transfer experiment. Recipient mice underwent to permanent hindlimb ischemia one day prior the tail vein injection of bone marrow (BM) monocytes from the ischemic leg. Laser Doppler assessed blood flow recovery before and after hindlimb ischemia. Arteriogenesis was quantified on recipient mice by assessing the diameter of gracilis collaterals. A 24h group monocytes from ischemia and non-ischemia leg was used as donors to test the systemic vs. local effect of the ischemic-trained monocytes. Lin- cells were used as a control. Cultured human monocytes were subjected to 24h hypoxia and gene expression for epigenetic enzymes was performed by real time rt-PCR Results: Blood flow recovery in recipients who received ischemic-trained monocytes (24h and cycle) improved overtime compared to sham. Arteriogenesis was significant greater in 24h group compared to sham. Surprisingly, the improvement in blood flow recovery was abolished using combined monocytes from ischemic and non-sichemic, suggesting that ischemia training has a local effect in the monocytes. The Lin- experiment confirmed that the ischemia training is monocyte specific. Moreover, hypoxia regulated epigenetic enzymes responsible for histones methylation in human monocytes. Conclusions: Monocytes can be trained by previous ischemia/hypoxia insult and improve arteriogenesis during hindlimb ischemia. The molecular mechanisms that lead the trained immunity by hypoxia still unknown, however epigenetic modifications might play a role in this process.

Introduction: Bronchopulmonary dysplasia (BPD) or chronic lung injury of newborn is a life-threatening condition in preterm infants with few effective therapies. Mesenchymal stem cells (MSC) are a promising therapeutic strategy for BPD. The ideal MSC source for BPD prevention is however unknown. Umbilical cord tissue (UCT) MSC may potentially have more anti-inflammatory and pro-angiogenic properties. Hypothesis: We hypothesized that the UCT-MSC will have superior lung regenerative effect in BPD owing to superior anti-inflammatory and pro-angiogenic properties as compared to BM-MSC. Methods: Newborn rats (n=10-12/group) were randomly assigned to normoxia or hyperoxia (85% O 2 ) from postnatal day (P) 1 to 21 were given intra-tracheal (IT) BM or UCT-MSC (1 x 10 6 cells/50 μl), or placebo (PL) on P3. Results: Hyperoxia PL-treated pups had marked alveolar simplification, vascular rarefaction, remodeling and lung inflammation. Administration of both BM-MSC and UCT-MSC significantly improved alveolar structure, vascular density, pulmonary hypertension, vascular remodeling and lung inflammation. However, the improvement in alveolar structure and lung inflammation was more marked in hyperoxic pups who received UCT-MSC. In vitro studies demonstrated greater TSG-6 and IL-10 expression in UCT-MSC as compared to BM-MSC. Moreover, lung epithelial cells incubated with UCT-MSC conditioned media had greater wound healing following scratch injury. Conclusion: These findings demonstrate that while both BM and UCT-MSC have lung regenerative effects, UCT-MSC have greater anti-inflammatory and alveolar protective effects in experimental BPD. These findings have significant implications for cellular therapy in BPD, as it suggests that UCT-MSC are a superior cellular source for preterm lung protection.

Bronchopulmonary dysplasia (BPD) is a life-threatening condition in preterm infants with few effective therapies. Mesenchymal stem or stromal cells (MSCs) are a promising therapeutic strategy for BPD. The ideal MSC source for BPD prevention is however unknown. The objective of this study was to compare the regenerative effects of MSC obtained from bone marrow (BM) and umbilical cord tissue (UCT) in an experimental BPD model. In vitro, UCT-MSC demonstrated greater proliferation and expression of anti-inflammatory cytokines as compared to BM-MSC. Lung epithelial cells incubated with UCT-MSC conditioned media (CM) had better-wound healing following scratch injury. UCT-MSC CM and BM-MSC CM had similar pro-angiogenic effects on hyperoxia-exposed pulmonary microvascular endothelial cells. In vivo, newborn rats exposed to normoxia or hyperoxia (85% O2) from postnatal day (P) 1 to 21 were given intra-tracheal (IT) BM or UCT-MSC (1 × 106 cells/50 μL), or placebo (PL) on P3. Hyperoxia PL-treated rats had marked alveolar simplification, reduced lung vascular density, pulmonary vascular remodeling, and lung inflammation. In contrast, administration of both BM-MSC and UCT-MSC significantly improved alveolar structure, lung angiogenesis, pulmonary vascular remodeling, and lung inflammation. UCT-MSC hyperoxia-exposed rats however had greater improvement in some morphometric measures of alveolarization and less lung macrophage infiltration as compared to the BM-MSC-treated group. Together, these findings suggest that BM-MSC and UCT-MSC have significant lung regenerative effects in experimental BPD but UCT-MSC suppresses lung macrophage infiltration and promotes lung epithelial cell healing to a greater degree.

Notch1 signaling determines the plasticity and function of fibroblasts in diabetic wounds and may serve as a potential target for therapeutic intervention in diabetic wound healing., Fibroblasts play a pivotal role in wound healing. However, the molecular mechanisms determining the reparative response of fibroblasts remain unknown. Here, we identify Notch1 signaling as a molecular determinant controlling the plasticity and function of fibroblasts in modulating wound healing and angiogenesis. The Notch pathway is activated in fibroblasts of diabetic wounds but not in normal skin and non-diabetic wounds. Consistently, wound healing in the FSP-1+/−;ROSALSL-N1IC+/+ mouse, in which Notch1 is activated in fibroblasts, is delayed. Increased Notch1 activity in fibroblasts suppressed their growth, migration, and differentiation into myofibroblasts. Accordingly, significantly fewer myofibroblasts and less collagen were present in granulation tissues of the FSP-1+/−;ROSALSL-N1IC+/+ mice, demonstrating that high Notch1 activity inhibits fibroblast differentiation. High Notch1 activity in fibroblasts diminished their role in modulating the angiogenic response. We also identified that IL-6 is a functional Notch1 target and involved in regulating angiogenesis. These findings suggest that Notch1 signaling determines the plasticity and function of fibroblasts in wound healing and angiogenesis, unveiling intracellular Notch1 signaling in fibroblasts as potential target for therapeutic intervention in diabetic wound healing.

Background Common measures of evaluating surgical resident progression include American Board of Surgery In-Training Exam scores and Accreditation Council for Graduate Medical Education operative case logs. This study evaluates the relationship between operative cases performed and American Board of Surgery In-Training Exam scores in general surgery residents. Methods A retrospective review of American Board of Surgery In-Training Exam scores and operative case logs was performed for postgraduate year 1–5 general surgery residents at a single academic institution (2008–2017). For each resident, the total number of operative cases logged from the start of their postgraduate year 1 until the end of each academic year was calculated and compared to their American Board of Surgery In-Training Exam scores for that corresponding year. Results At all postgraduate-year levels, there was a positive linear relationship between the number of cases logged and American Board of Surgery In-Training Exam percentile (slope, m = 0.23–5.2, R2 .01–.17) and scaled (m = 0.29–5.3, R2 .13–.37) scores. At the postgraduate year 1, 2, 3, and 5 levels, and with all residents combined, residents in the top quartile of cases logged performed significantly better on the American Board of Surgery In-Training Exam than those in the bottom quartile (P Conclusion Surgical residents who perform more operative cases do significantly better on the American Board of Surgery In-Training Exam than their peers. This association may be due to increased clinical experience, exposure to pathology, and/or individual resident motivation.

Background Intimal hyperplasia has been historically associated with improper venous remodeling and stenosis after creation of an arteriovenous fistula. Recently, however, we showed that intimal hyperplasia by itself does not explain the failure of maturation of 2-stage arteriovenous fistulas. We seek to evaluate whether intimal hyperplasia plays a role in the development of focal stenosis of an arteriovenous fistula. Methods This study compares intimal hyperplasia lesions in stenotic and nearby nonstenotic segments collected from the same arteriovenous fistula. Focal areas of stenosis were detected in the operating room in patients (n = 14) undergoing the second-stage vein transposition procedure. The entire vein was inspected, and areas of stenosis were visually located with the aid of manual palpation and hemodynamic changes in the vein peripheral and central to the narrowing. Stenotic and nonstenotic segments were documented by photography before tissue collection (14 tissue pairs). Intimal area and thickness, intima-media thickness, and intima to media area ratio were measured in hematoxylin and eosin stained cross-sections followed by pairwise statistical comparisons. Results The intimal area in stenotic and nonstenotic segments ranged from 1.25 to 11.61 mm2 and 1.29 to 5.81 mm2, respectively. There was no significant difference between these 2 groups (P = .26). Maximal intimal thickness (P = .22), maximal intima-media thickness (P = .13), and intima to media area ratio (P = .73) were also similar between both types of segments. Conclusion This preliminary study indicates that postoperative intimal hyperplasia by itself is not associated with the development of focal venous stenosis in 2-stage fistulas.

Thromboangiitis obliterans, also known as Buerger’s disease, is a rare inflammatory vasculitis that predominantly develops in smokers and characteristically affects the small- and medium-sized peripheral arteries and veins. Patients typically present with extremity claudication, but symptoms may progress to rest pain and tissue loss, especially in those unable to abstain from tobacco use. Unfortunately, traditional medical treatments are largely ineffective and due to the small caliber of affected vessels and lack of suitable distal targets or venous conduits, endovascular and open surgical approaches are often not possible. Eventually, a significant number of patients require major amputation. For these reasons, much research effort has been made in developing techniques of therapeutic angiogenesis to improve limb perfusion, both for atherosclerotic peripheral arterial disease and the smaller subset of patients with critical limb ischemia due to Buerger’s disease. Neovascularization in response to ischemia relies on a complex interplay between the local tissue microenvironment and circulating stem and progenitor cells. To date, studies of therapeutic angiogenesis have therefore focused on exploiting known angiogenic factors and stem cells to induce neovascularization in ischemic tissues. This review summarizes the available clinical data regarding the safety and efficacy of various angiogenic therapies, notably injection of naked DNA plasmids, viral gene constructs, and cell-based preparations, and describes techniques for potentiating in vivo efficacy of gene- and cell-based therapies as well as ongoing developments in exosome-based cell-free approaches for therapeutic angiogenesis. Plain Language Title and Summary A review of available and emerging treatments for improving blood flow and wound healing in patients with Buerger’s disease, a rare disorder of blood vessels Buerger’s disease is a rare disorder of the small- and medium-sized blood vessels in the arms and legs that almost exclusively develops in young smokers. Buerger’s disease causes inflammation in arteries and veins, which leads to blockage of these vessels and reduces blood flow to and from the extremities. Decreased blood flow to the arms and legs can lead to development of nonhealing wounds and infection for which some patients may eventually require amputation. Unfortunately, traditional medical and surgical treatments are not effective in Buerger’s disease, so other methods for improving blood flow are needed for these patients. There are several different ways to stimulate new blood vessel formation, both in humans and animal models. The most common treatments involve injection of DNA or viruses that express genes related to blood vessel formation or, alternatively, stem cell–based treatments that help regenerate blood vessels and repair wound tissue. This review explores how safe and effective these various treatments are and describes recent research developments that may lead to better therapies for patients with Buerger’s disease and other vascular disorders.

Supplemental oxygen (O2) therapy in preterm infants impairs lung development, but the impact of O2 on long‐term systemic vascular structure and function has not been well‐explored. The present study tested the hypothesis that neonatal O2 therapy induces long‐term structural and functional alterations in the systemic vasculature, resulting in vascular stiffness observed in children and young adults born preterm. Newborn Sprague‐Dawley rats were exposed to normoxia (21% O2) or hyperoxia (85% O2) for 1 and 3 weeks. A subgroup exposed to 3 weeks hyperoxia was recovered in normoxia for an additional 3 weeks. Aortic stiffness was assessed by pulse wave velocity (PWV) using Doppler ultrasound and pressure myography. Aorta remodeling was assessed by collagen deposition and expression. Left ventricular (LV) function was assessed by echocardiography. We found that neonatal hyperoxia exposure increased vascular stiffness at 3 weeks, which persisted after normoxic recovery at 6 weeks of age. These findings were accompanied by increased PWV, aortic remodeling, and altered LV function as evidenced by decreased ejection fraction, cardiac output, and stroke volume. Importantly, these functional changes were associated with increased collagen deposition in the aorta. Together, these findings demonstrate that neonatal hyperoxia induces early and sustained biomechanical alterations in the systemic vasculature and impairs LV function. Early identification of preterm infants who are at risk of developing systemic vascular dysfunction will be crucial in developing targeted prevention strategies that may improve the long‐term cardiovascular outcomes in this vulnerable population., Prolonged neonatal oxygen exposure causes persistent aortic structural and biomechanical alterations, which was even more pronounced after recovery in normoxia. This was accompanied by a marked impairment in left ventricular function. These findings have important implications as it suggests that premature babies exposed to oxygen may be predisposed to vascular dysfunction, leading to increased risk of cardiovascular disease in later life. As this affected population begins to age, there will be a critical need to identify the underlying pathophysiological mechanisms for these vascular morbidities in preterm survivors.

Atherosclerosis is the most common underlying cause of cardiovascular morbidity and mortality worldwide. c-Kit (CD117) is a member of the receptor tyrosine kinase family, which regulates differentiation, proliferation, and survival of multiple cell types. Recent studies have shown that c-Kit and its ligand stem cell factor (SCF) are present in arterial endothelial cells and smooth muscle cells (SMCs). The role of c-Kit in cardiovascular disease remains unclear. The aim of the current study is to determine the role of c-Kit in atherogenesis. For this purpose, atherosclerotic plaques were quantified in c-Kit-deficient mice (KitMut) after they were fed a high-fat diet (HFD) for 16 wk. KitMutmice demonstrated substantially greater atherosclerosis compared with control (KitWT) littermates ( P < 0.01). Transplantation of c-Kit-positive bone marrow cells into KitMutmice failed to rescue the atherogenic phenotype, an indication that increased atherosclerosis was associated with reduced arterial c-Kit. To investigate the mechanism, SMC organization and morphology were analyzed in the aorta by histopathology and electron microscopy. SMCs were more abundant, disorganized, and vacuolated in aortas of c-Kit mutant mice compared with controls ( P < 0.05). Markers of the “contractile” SMC phenotype (calponin, SM22α) were downregulated with pharmacological and genetic c-Kit inhibition ( P < 0.05). The absence of c-Kit increased lipid accumulation and significantly reduced the expression of the ATP-binding cassette transporter G1 (ABCG1) necessary for lipid efflux in SMCs. Reconstitution of c-Kit in cultured KitMutSMCs resulted in increased spindle-shaped morphology, reduced proliferation, and elevated levels of contractile markers, all indicators of their restored contractile phenotype ( P < 0.05).NEW & NOTEWORTHY This study describes the novel vasculoprotective role of c-Kit against atherosclerosis and its function in the preservation of the SMC contractile phenotype.

Background The Clinical PeRformancE of the Valiant Thoracic Stent Graft with Capitvia Delivery System for the EndovaSCUlar treatment of Blunt Thoracic Aortic Injuries (RESCUE) study evaluating thoracic endovascular repair using the Valiant Captivia endograft for blunt thoracic aortic injury reported promising 30-day outcomes. We now describe 5 years of follow-up of this cohort. Methods Fifty patients (mean age 40.7 ± 17.4 years, 76% male, mean injury severity score 38 ± 14.4) were treated for blunt thoracic aortic injury (2010 to 2012) with this endograft. Seventy percent (n = 35) of blunt thoracic aortic injury extent was grade III or higher. Extent of arch repair required full (40%) or partial (18%) left subclavian artery coverage. At 5 years, clinical and imaging compliance was 90.3% (28 of 31) and 67.7% (21 of 31), respectively. Results Thirty-day mortality was 8%. Three additional patients died of non–device-related causes (respiratory failure, infection, metastatic cancer) through 5-year follow-up, yielding a Kaplan-Meier survival of 85.2% through 5 years. Neither stroke nor spinal cord ischemia was observed at 5 years. Two type II endoleaks seen at 30 days resolved spontaneously, and no additional endoleaks were described in the study cohort through 5 years. No secondary endovascular procedures or conversion to open surgery were reported through 5 years. Four subjects underwent left subclavian revascularization for symptomatic indications. Finally, complete exclusion of the traumatic injury was maintained with no incidences of stent graft kinking, fracture, loss of patency, or migration through 5 years in all patients. Conclusions This multicenter clinical trial describes excellent 5-year outcomes and durable exclusion of blunt thoracic aortic injury using a novel stent graft system. Thoracic endovascular repair with this endograft appears to be a safe and effective treatment option for patients with blunt thoracic aortic injury.

Background The contribution of intimal hyperplasia (IH) to arteriovenous fistula (AVF) failure is uncertain. This observational study assessed the relationship between pre-existing, postoperative, and change in IH over time and AVF outcomes. Study Design Prospective cohort study with longitudinal assessment of IH at the time of AVF creation (pre-existing) and transposition (postoperative). Patients were followed up for up to 3.3 years. Setting & Participants 96 patients from a single center who underwent AVF surgery initially planned as a 2-stage procedure. Veins and AVF samples were collected from 66 and 86 patients, respectively. Matched-pair tissues were available from 56 of these patients. Predictors Pre-existing, postoperative, and change in IH over time. Outcomes Anatomic maturation failure was defined as an AVF that never reached a diameter > 6mm. Primary unassisted patency was defined as the time elapsed from the second-stage surgery to the first intervention. Measurements Maximal intimal thickness in veins and AVFs and change in intimal thickness over time. Results Pre-existing IH (>0.05mm) was present in 98% of patients. In this group, the median intimal thickness increased 4.40-fold (IQR, 2.17- to 4.94-fold) between AVF creation and transposition. However, this change was not associated with pre-existing thickness ( r 2 =0.002; P =0.7). Ten of 96 (10%) AVFs never achieved maturation, whereas 70% of vascular accesses remained patent at the end of the observational period. Postoperative IH was not associated with anatomic maturation failure using univariate logistic regression. Pre-existing, postoperative, and change in IH over time had no effects on primary unassisted patency. Limitations The small number of patients from whom longitudinal tissue samples were available and low incidence of anatomic maturation failure, which decreased the statistical power to find associations between end points and IH. Conclusions Pre-existing, postoperative, and change in IH over time were not associated with 2-stage AVF outcomes.

Supplemental material, Supplementary_tables_JVA for Vascularization of the arteriovenous fistula wall and association with maturation outcomes by Juan C Duque, Laisel Martinez, Marwan Tabbara, Punam Parikh, Angela Paez, Guillermo Selman, Loay H Salman, Omaida C Velazquez and Roberto I Vazquez-Padron in The Journal of Vascular Access

Supplemental material, VV_Figure_S1_082118 for Vascularization of the arteriovenous fistula wall and association with maturation outcomes by Juan C Duque, Laisel Martinez, Marwan Tabbara, Punam Parikh, Angela Paez, Guillermo Selman, Loay H Salman, Omaida C Velazquez and Roberto I Vazquez-Padron in The Journal of Vascular Access

Improving arteriovenous fistula (AVF) outcomes requires better understanding of the biology underlying maturation or failure. Our current knowledge of maturation relies on extrapolation from other vascular pathologies, which does not incorporate unique aspects of AVF remodeling. This study compares the RNA expression of pre-access (native) veins and AVFs with distinct maturation outcomes.Case-control study.64 patients undergoing 2-stage AVF surgeries at a single center. 19 native veins and 19 AVF samples were analyzed using RNA sequencing (RNA-seq). 58 native veins were studied using real-time polymerase chain reaction; 45, using immunohistochemistry; and 19, using Western blot analysis.RNA expression in native veins and AVFs.Anatomic nonmaturation, defined as an AVF that never achieved an internal diameter ≥ 6mm.Pre-access native veins and AVF samples were obtained from patients undergoing 2-stage AVF creation. Veins that subsequently matured or failed after access creation were analyzed using RNA-seq to search for genes associated with maturation failure. Genes associated with nonmaturation were confirmed using real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis. In addition, the association between pre-access gene expression and postoperative morphology was evaluated. RNA-seq was also performed on AVFs to search for transcriptional differences between AVFs that matured and those that failed at the time of transposition.Pro-inflammatory genes (CSF3R, FPR1, S100A8, S100A9, and VNN2) were upregulated in pre-access veins that failed (false discovery rate 0.05), and their expression colocalized to smooth muscle cells. Expression of S100A8 and S100A9 correlated with postoperative intimal hyperplasia and the product of medial fibrosis and intimal hyperplasia (r=0.32-0.38; P0.05). AVFs that matured or failed were transcriptionally similar at the time of transposition.Small sample size, analysis of only upper-arm veins and transposed fistulas.Increased expression of proinflammatory genes in pre-access veins appears to be associated with greater risk for AVF nonmaturation.