Submitting a successful National Institutes of Health career development award for the vascular surgeon scientist.

Obtaining a career development award from the National Institutes of Health (K award) is often an important step in establishing a career as a vascular surgeon scientist. The application and review process is competitive, involves many steps, and may be confusing to the prospective applicant. Further, there are requirements involving mentors and the applicant's institution. This article, authored completely by vascular surgeons with active K awards, is intended for potential applicants and personnel at their institution and reviews relevant information including strategies for a successful application.

IL-4-STAT6 axis amplifies histamine-induced vascular endothelial dysfunction and hypovolemic shock.

BACKGROUND: Mast cell (MC)-derived mediators induce vasodilatation and fluid extravasation, leading to cardiovascular failure in severe anaphylaxis. We have previously revealed a synergistic interaction between the cytokine IL-4 and the MC-derived mediator histamine in modulating vascular endothelial (VE) dysfunction and severe anaphylaxis. The mechanism by which IL-4 exacerbates histamine-induced VE dysfunction and severe anaphylaxis are unknown. OBJECTIVE: To identify the IL-4-induced molecular processes regulating the amplification of histamine-induced VE barrier dysfunction and the severity of IgE-mediated anaphylaxic reactions. METHODS: RNAseq, Western blot, Ca2+ imaging and barrier functional analyses on the vascular endothelial cell line (EA.hy926). Pharmacologic degraders (selective PROTAC (proteolysis-targeting chimera) and genetic (lentiviral shRNA) inhibitors were used to determine the roles of STAT3 and STAT6 in conjunction with in vivo model systems of histamine-induced hypovolemic shock. RESULTS: IL-4 enhancement of histamine-induced VE barrier dysfunction was associated with increased VE-Cadherin degradation, intracellular calcium flux, phospho-Src levels and required transcription and de novo protein synthesis. RNAseq analyses of IL-4 stimulated VE cells identified dysregulation of genes involved in cell proliferation, cell development, and cell growth and transcription factor motif analyses revealed a significant enrichment of differential expressed genes (DEGs) with putative STAT3 and STAT6 motif. IL-4 stimulation in EA.hy926 cells induced both STAT3Y705 and STAT3S727 phosphorylation. Genetic and pharmacologic ablation of VE STAT3 activity revealed a role for STAT3 in basal VE barrier function, however IL-4 enhancement and histamine-induced VE barrier dysfunction was predominantly STAT3-independent. In contrast, IL-4 enhancement and histamine-induced VE barrier dysfunction was STAT6-dependent. Consistent with this finding, pharmacologic knockdown of STAT6 abrogated IL-4-mediated amplification of histamine-induced hypovolemia. CONCLUSIONS: These studies unveil a novel role of the IL-4/ STAT6 signaling axis in the priming of VE cells predisposing to exacerbation of histamine-induced anaphylaxis.

Comparative evaluation of transcutaneous oxygen tension vs ankle-brachial index as predictors of reoperation following below-knee amputation.

OBJECTIVE: Decision-making regarding level of lower extremity amputation is sometimes challenging. Selecting an appropriate anatomic level for major amputation requires consideration of tradeoffs between postoperative function and risk of wound complications that may require additional operations, including debridement and/or conversion to above-knee amputation (AKA). We evaluated the utility of common, non-invasive diagnostic tests used in clinical practice to predict the need for reoperations among patients undergoing primary, elective, below knee-amputations (BKAs) by vascular surgeons. METHODS: Patients undergoing elective BKA over a 5-year period were identified using Current Procedural Terminology codes. Medical records were reviewed to characterize demographics, pre-amputation testing transcutaneous oxygen tension (TcPO2), and ankle-brachial index (ABI). The need for ipsilateral post-BKA reoperation (including BKA revision and/or conversion to AKA) regardless of indication was the primary outcome. Associations were evaluated using univariable and multivariable logistic regression models. Cutpoints for TcPO2 values associated with amputation reoperation were evaluated using receiver operating characteristic curves. RESULTS: We identified 175 BKAs, of which 46 (26.3%) required ipsilateral reoperation (18.9% BKA revisions and 14.3% conversions to AKA). The mean age was 63.3 ± 14.8 years. Most patients were male (65.1%) and White (72.0%). Mean pre-amputation calf TcPO2 was 40.0 ± 20.5 mmHg, and mean ABI was 0.64 ± 0.45. In univariable models, post-BKA reoperation was associated with calf TcPO2 (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.94-0.99; P = .013) but not ABI (OR, 0.53; 95% CI, 0.19-1.46; P = .217). Univariable associations with reoperation were also identified for age (OR, 0.97; 95% CI, 0.94-0.990; P = .003) and diabetes (OR, 0.43; 95% CI, 0.21-0.87; P = .019). No associations with amputation revision were identified for gender, race, end-stage renal disease, or preoperative antibiotics. Calf TcPO2 remained associated with post-BKA reoperation in a multivariable model (OR, 0.97; 95% CI, 0.94-0.99; P = .022) adjusted for age (OR, 0.98; 95% CI, 0.94-1.01; P = .222) and diabetes (OR, 0.98; 95% CI, 0.94-1.01; P = .559). Receiver operating characteristic analysis suggested a TcPO2 ≥38 mmHg as an appropriate cut-point for assessing risk for BKA revision (area under the curve = 0.682; negative predictive value, 0.91). CONCLUSIONS: Reoperation after BKA is common, and reoperation risk was associated with pre-amputation TcPO2. For patients undergoing elective BKA, higher risk of reoperation should be discussed with patients with an ipsilateral TcPO2 <38 mmHg.

A comparative study of altered hemodynamics in iliac vein compression syndrome.

Introduction: Iliac vein compression syndrome (IVCS) is present in over 20% of the population and is associated with left leg pain, swelling, and thrombosis. IVCS symptoms are thought to be induced by altered pelvic hemodynamics, however, there currently exists a knowledge gap on the hemodynamic differences between IVCS and healthy patients. To elucidate those differences, we carried out a patient-specific, computational modeling comparative study. Methods: Computed tomography and ultrasound velocity and area data were used to build and validate computational models for a cohort of IVCS (N = 4, Subject group) and control (N = 4, Control group) patients. Flow, cross-sectional area, and shear rate were compared between the right common iliac vein (RCIV) and left common iliac vein (LCIV) for each group and between the Subject and Control groups for the same vessel. Results: For the IVCS patients, LCIV mean shear rate was higher than RCIV mean shear rate (550 ± 103 s-1 vs. 113 ± 48 s-1, p = 0.0009). Furthermore, LCIV mean shear rate was higher in the Subject group than in the Control group (550 ± 103 s-1 vs. 75 ± 37 s-1, p = 0.0001). Lastly, the LCIV/RCIV shear rate ratio was 4.6 times greater in the Subject group than in the Control group (6.56 ± 0.9 vs. 1.43 ± 0.6, p = 0.00008). Discussion: Our analyses revealed that IVCS patients have elevated shear rates which may explain a higher thrombosis risk and suggest that their thrombus initiation process may share aspects of arterial thrombosis. We have identified hemodynamic metrics that revealed profound differences between IVCS patients and Controls, and between RCIV and LCIV in the IVCS patients. Based on these metrics, we propose that non-invasive measurement of shear rate may aid with stratification of patients with moderate compression in which treatment is highly variable. More investigation is needed to assess the prognostic value of shear rate and shear rate ratio as clinical metrics and to understand the mechanisms of thrombus formation in IVCS patients.

Effect of junctional reflux on the venous clinical severity score in patients with insufficiency of the great saphenous vein (JURY study).

OBJECTIVE: Effective treatment options are available for chronic venous insufficiency associated with superficial venous reflux. Although many patients with C2 and C3 disease based on the CEAP (Clinical-Etiological-Anatomical-Pathophysiological) classification have combined great saphenous vein (GSV) and saphenofemoral junction (SFJ) reflux, some may not have concomitant SFJ reflux. Several payors have determined that symptom severity in patients without SFJ reflux does not warrant treatment. In patients planned for venous ablation, we tested whether Venous Clinical Severity Scores (VCSS) are equivalent in those with GSV reflux alone compared with those with both GSV and SFJ reflux. METHODS: This cross-sectional study was conducted at 10 centers. Inclusion criteria were: candidate for endovenous ablation as determined by treating physician; 18 to 80 years of age; GSV reflux with or without SFJ reflux on ultrasound; and C2 or C3 disease. Exclusion criteria were prior deep vein thrombosis; prior vein ablation on the index limb; ilio-caval obstruction; and renal, hepatic, or heart failure requiring prior hospitalization. An a priori sample size was calculated. We used multiple linear regression (adjusted for patient characteristics) to compare differences in VCSS scores of the two groups at baseline, and to test whether scores were equivalent using a priori equivalence boundaries of +1 and -1. In secondary analyses, we tested differences in VCSS scores in patients with C2 and C3 disease separately. RESULTS: A total of 352 patients were enrolled; 64.2% (n = 226) had SFJ reflux, and 35.8% (n = 126) did not. The two groups did not differ by major clinical characteristics. The mean age of the cohort was 53.9 ± 14.3 years; women comprised 74.2%; White patients 85.8%; and body mass index was 27.8 ± 6.1 kg/m2. The VCSS scores in patients with and without SFJ reflux were found to be equivalent; SFJ reflux was not a significant predictor of VCSS score; and mean VCSS scores did not differ significantly (6.4 vs 6.6, respectively, P = .40). In secondary subset analyses, VCSS scores were equivalent between C2 patients with and without SFJ reflux, and VCSS scores of C3 patients with SFJ reflux were lower than those without SFJ reflux. CONCLUSIONS: Symptom severity is equivalent in patients with GSV reflux with or without SFJ reflux. The absence of SFJ reflux alone should not determine the treatment paradigm in patients with symptomatic chronic venous insufficiency. Patients with GSV reflux who meet clinical criteria for treatment should have equivalent treatment regardless of whether or not they have SFJ reflux.

A comparison of below-knee vs above-knee endovenous ablation of varicose veins.

OBJECTIVE: Varicose veins have a significant impact on quality of life and can commonly occur in the thigh and calves. However, there has been no large-scale investigation examining the relationship between anatomic distribution and outcomes after varicose vein treatment. This study sought to compare below-the-knee (BTK) and above-the-knee (ATK) varicose vein treatment outcomes. METHODS: Employing the Vascular Quality Initiative Varicose Vein Registry, 13,731 patients undergoing varicose vein ablation for either BTK or ATK lesions were identified. Outcomes were assessed using patient-reported outcomes (PROs) and the Venous Clinical Severity Score (VCSS). Continuous variables were compared using the t-test, and categorical variables were analyzed using the χ2 test. Multivariable logistic regression was used to estimate the odds of improvement after intervention. The multivariable model controlled for age, gender, race, preoperative VCSS composite score, and history of deep vein thrombosis. RESULTS: Patients who received below-knee treatment had a lower preoperative VCSS composite (7.0 ± 3.3 vs 7.7 ± 3.3; P < .001) and lower PROs composite scores (11.1 ± 6.4 vs 13.0 ± 6.6; P < .001) compared with those of patients receiving above-knee treatment. However, on follow-up, patients receiving below-knee intervention had a higher postoperative VCSS composite score (4.4 ± 3.3 vs 3.9 ± 3.5; P < .001) and PROs composite score (6.1 ± 4.4 vs 5.8 ± 4.5; P = .007), the latter approaching statistical significance. Patients receiving above-knee interventions also demonstrated more improvement in both composite VCSS (3.8 ± 4.0 vs 2.9 ± 3.7; P < .001) and PROs (7.1 ± 6.8 vs 4.8 ± 6.6; P < .001). Multivariable logistic regression analysis similarly revealed that patients receiving above-knee treatment had significantly higher odds of improvement in VCSS composite in both the unadjusted (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.28-1.65; P < .001 and adjusted (OR, 1.31; 95% CI, 1.14-1.50; P < .001) models. Patients receiving above-knee treatment also had a significantly higher odds of reporting improvement in PROs composite in both the unadjusted (OR, 1.85; 95% CI, 1.64-2.11; P < .001) and adjusted (OR, 1.65; 95% CI, 1.45-1.88; P < .001) models. CONCLUSIONS: Treatment region has a significant association with PROs and VCSS composite scores after varicose vein interventions. Preoperatively, there were significant differences in the composite scores of VCSS and PROs with patients receiving BTK treatment exhibiting less severe symptoms. Yet, the association appeared to reverse postoperatively, with those receiving BTK treatments exhibiting worse PROs, worse VCSS composites scores, and less improvement in VCSS composite scores. Therefore, BTK interventions pose a unique challenge compared with ATK interventions in ensuring commensurate clinical improvement after treatment.

The 2023 Society for Vascular Surgery, American Venous Forum, and American Vein and Lymphatic Society clinical practice guidelines for the management of varicose veins of the lower extremities. Part II: Endorsed by the Society of Interventional Radiology and the Society for Vascular Medicine.

The Society for Vascular Surgery, the American Venous Forum, and the American Vein and Lymphatic Society recently published Part I of the 2022 clinical practice guidelines on varicose veins. Recommendations were based on the latest scientific evidence researched following an independent systematic review and meta-analysis of five critical issues affecting the management of patients with lower extremity varicose veins, using the patients, interventions, comparators, and outcome system to answer critical questions. Part I discussed the role of duplex ultrasound scanning in the evaluation of varicose veins and treatment of superficial truncal reflux. Part II focuses on evidence supporting the prevention and management of varicose vein patients with compression, on treatment with drugs and nutritional supplements, on evaluation and treatment of varicose tributaries, on superficial venous aneurysms, and on the management of complications of varicose veins and their treatment. All guidelines were based on systematic reviews, and they were graded according to the level of evidence and the strength of recommendations, using the GRADE method. All ungraded Consensus Statements were supported by an extensive literature review and the unanimous agreement of an expert, multidisciplinary panel. Ungraded Good Practice Statements are recommendations that are supported only by indirect evidence. The topic, however, is usually noncontroversial and agreed upon by most stakeholders. The Implementation Remarks contain technical information that supports the implementation of specific recommendations. This comprehensive document includes a list of all recommendations (Parts I-II), ungraded consensus statements, implementation remarks, and best practice statements to aid practitioners with appropriate, up-to-date management of patients with lower extremity varicose veins.

The oxylipin analog CS585 prevents platelet activation and thrombosis through activation of the prostacyclin receptor.

Cardiovascular disease remains the primary cause of morbidity and mortality globally. Platelet activation is critical for maintaining hemostasis and preventing the leakage of blood cells from the vessel. There has been a paucity in the development of new drugs to target platelet reactivity. Recently, the oxylipin 12(S)-hydroxy-eicosatrienoic acid (12-HETrE), which is produced in platelets, was shown to limit platelet reactivity by activating the prostacyclin receptor. Here, we demonstrated the synthesis of a novel analog of 12-HETrE, known as CS585. Human blood and mouse models of hemostasis and thrombosis were assessed for the ability of CS585 to attenuate platelet activation and thrombosis without increasing the risk of bleeding. Human platelet activation was assessed using aggregometry, flow cytometry, western blot analysis, total thrombus formation analysis system, microfluidic perfusion chamber, and thromboelastography. Hemostasis, thrombosis, and bleeding assays were performed in mice. CS585 was shown to potently target the prostacyclin receptor on the human platelet, resulting in a highly selective and effective mechanism for the prevention of platelet activation. Furthermore, CS585 was shown to inhibit platelet function in human whole blood ex vivo, prevent thrombosis in both small and large vessels in mouse models, and exhibit long-lasting prevention of clot formation. Finally, CS585 was not observed to perturb coagulation or increase the risk of bleeding in the mouse model. Hence, CS585 represents a new validated target for the treatment of thrombotic diseases without the risk of bleeding or off-target activation observed with other prostaglandin receptor agonists.

An ultrasound imaging and computational fluid dynamics protocol to assess hemodynamics in iliac vein compression syndrome.

OBJECTIVE: Elevated shear rates are known to play a role in arterial thrombosis; however, shear rates have not been thoroughly investigated in patients with iliac vein compression syndrome (IVCS) owing to imaging limitations and assumptions on the low shear nature of venous flows. This study was undertaken to develop a standardized protocol that quantifies IVCS shear rates and can aid in the diagnosis and treatment of patients with moderate yet symptomatic compression. METHODS: Study patients with and without IVCS had their iliac vein hemodynamics measured via duplex ultrasound (US) at two of the following three vessel locations: infrarenal inferior vena cava (IVC), right common iliac vein, and left common iliac vein, in addition to acquiring data at the right and left external iliac veins. US velocity spectra were multiplied by a weighted cross-sectional area calculated from US and computed tomography (CT) data to create flow waveforms. Flow waveforms were then scaled to enforce conservation of flow across the IVC and common iliac veins. A three-dimensional (3D), patient-specific model of the iliac vein anatomy was constructed from CT and US examination. Flow waveforms and the 3D model were used as a basis to run a computational fluid dynamics (CFD) simulation. Owing to collateral vessel flow and discrepancies between CT and US area measurements, flows in internal iliac veins and cross-sectional areas of the common iliac veins were calibrated iteratively against target common iliac flow. Simulation results on mean velocity were validated against US data at measurement locations. Simulation results were postprocessed to derive spatial and temporal values of quantities such as velocity and shear rate. RESULTS: Using our modeling protocol, we were able to build CFD models of the iliac veins that matched common iliac flow splits within 2% and measured US velocities within 10%. Proof-of-concept analyses (1 subject, 1 control) have revealed that patients with IVCS may experience elevated shear rates in the compressed left common iliac vein, more typical of the arterial rather than the venous circulation. These results encourage us to extend this protocol to a larger group of patients with IVCS and controls. CONCLUSIONS: We developed a protocol that obtains hemodynamic measurements of the IVC and iliac veins from US, creates patient-specific 3D reconstructions of the venous anatomy using CT and US examinations, and computes shear rates using calibrated CFD methods. Proof-of-concept results have indicated that patients with IVCS may experience elevated shear rates in the compressed left common iliac vein. Larger cohorts are needed to assess the relationship between venous compression and shear rates in patients with IVCS as compared with controls with noncompressed iliac veins. Further studies using this protocol may also give promising insights into whether or not to treat patients with moderate, yet symptomatic compression.

Thromboembolic outcomes are decreased with the use of a standardized venous thromboembolism risk assessment and prophylaxis protocol for patients undergoing superficial venous procedures.

OBJECTIVE: Patients with venous insufficiency can be treated with ablation or phlebectomy, or both. Patients undergoing superficial venous procedures have an elevated risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). At our institution, we initiated a standardized protocol in which patients with a Caprini score (2005 version) of ≥8 are treated with 1 week of prophylactic anticoagulation after the procedure. Duplex ultrasound was performed at 1 week and then within 90 days after the procedure. This aim of the present study was to determine the thrombotic and clinical outcomes after superficial vein procedures using a standardized protocol for DVT/PE risk assessment and prophylaxis. METHODS: We performed a retrospective analysis of prospectively collected data of superficial vein procedures from 2015 to 2021 at a single center. The patient demographics, CEAP (Clinical-Etiology-Anatomy-Pathophysiology) clinical class, venous clinical severity score, patient-reported outcomes, treatment type, Caprini scores, pre- and postoperative anticoagulation use, and outcomes were collected. Descriptive statistics were used for the patient demographics, procedure details, and unadjusted surgical outcomes. Multivariable logistic regression was used to evaluate the relationship between procedure type and DVT and PE after adjusting for patient characteristics, disease severity, periprocedural anticoagulation, and Caprini score. RESULTS: A total of 1738 limbs were treated with ablation (n = 820), phlebectomy (n = 181), or ablation and phlebectomy (n = 737). More patients were women (67.1%) and White (90.9%). The overall incidence of DVT/PE was 1.4%. Patients undergoing ablation with phlebectomy had higher rates of DVT/PE (2.7%) than those undergoing ablation (0.2%) or phlebectomy alone (1.7%; P < .01). However, only 30% of DVTs were above the knee. On multivariate analysis, only the procedure type predicted for DVT/PE. However, patients undergoing ablation and phlebectomy achieved better patient-reported outcomes (Caprini score, 5.9) compared with those undergoing ablation (Caprini score, 7.2) or phlebectomy (Caprini score, 7.9) alone (P < .01). The best improvement in the venous clinical severity score was seen with phlebectomy alone. CONCLUSIONS: The expected difference in the DVT/PE rates between high- and low-risk groups did not materialize in our patients, perhaps secondary to the additional chemoprophylaxis prescribed for the high-risk cohort (Caprini score, ≥8). These results call for a randomized trial to assess the efficacy of a standardized protocol in the reduction of DVT/PE after superficial vein procedures.

Experimental venous thrombus resolution is driven by IL-6 mediated monocyte actions.

Deep venous thrombosis and residual thrombus burden correlates with circulating IL-6 levels in humans. To investigate the cellular source and role of IL-6 in thrombus resolution, Wild type C57BL/6J (WT), and IL-6-/- mice underwent induction of VT via inferior vena cava (IVC) stenosis or stasis. Vein wall (VW) and thrombus were analyzed by western blot, immunohistochemistry, and flow cytometry. Adoptive transfer of WT bone marrow derived monocytes was performed into IL6-/- mice to assess for rescue. Cultured BMDMs from WT and IL-6-/- mice underwent quantitative real time PCR and immunoblotting for fibrinolytic factors and matrix metalloproteinase activity. No differences in baseline coagulation function or platelet function were found between WT and IL-6-/- mice. VW and thrombus IL-6 and IL-6 leukocyte-specific receptor CD126 were elevated in a time-dependent fashion in both VT models. Ly6Clo Mo/MØ were the predominant leukocyte source of IL-6. IL-6-/- mice demonstrated larger, non-resolving stasis thrombi with less neovascularization, despite a similar number of monocytes/macrophages (Mo/MØ). Adoptive transfer of WT BMDM into IL-6-/- mice undergoing stasis VT resulted in phenotype rescue. Human specimens of endophlebectomized tissue showed co-staining of Monocyte and IL-6 receptor. Thrombosis matrix analysis revealed significantly increased thrombus fibronectin and collagen in IL-6-/- mice. MMP9 activity in vitro depended on endogenous IL-6 expression in Mo/MØ, and IL-6-/- mice exhibited stunted matrix metalloproteinase activity. Lack of IL-6 signaling impairs thrombus resolution potentially via dysregulation of MMP-9 leading to impaired thrombus recanalization and resolution. Restoring or augmenting monocyte-mediated IL-6 signaling in IL-6 deficient or normal subjects, respectively, may represent a non-anticoagulant target to improve thrombus resolution.

The 2022 Society for Vascular Surgery, American Venous Forum, and American Vein and Lymphatic Society clinical practice guidelines for the management of varicose veins of the lower extremities. Part I. Duplex Scanning and Treatment of Superficial Truncal Reflux: Endorsed by the Society for Vascular Medicine and the International Union of Phlebology.

The Society for Vascular Surgery, American Venous Forum, and American Vein and Lymphatic Society collaborated to update the 2011 Society for Vascular Surgery/American Venous Forum clinical practice guidelines and provide new evidence-based recommendations on critical issues affecting the care of patients with varicose veins. Each recommendation is based on a recent, independent systematic review and meta-analysis of the diagnostic tests and treatments options for patients with lower extremity varicose veins. Part I of the guidelines includes evidence-based recommendations for the evaluation of patients with CEAP (Clinical Class, Etiology, Anatomy, Pathology) class 2 varicose vein using duplex ultrasound scanning and other diagnostic tests, open surgical treatment (ligation and stripping) vs endovenous ablation techniques, thermal vs nonthermal ablation of the superficial truncal veins, and management of incompetent perforating veins in CEAP class 2 disease. We have also made recommendations on the concomitant vs staged treatment of varicose tributaries using phlebectomy or liquid or foam sclerotherapy (with physician-compounded foam or commercially prepared polidocanol endovenous microfoam) for patients undergoing ablation of incompetent superficial truncal veins.

The histone methyltransferase MLL1/KMT2A in monocytes drives coronavirus-associated coagulopathy and inflammation.

Coronavirus-associated coagulopathy (CAC) is a morbid and lethal sequela of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. CAC results from a perturbed balance between coagulation and fibrinolysis and occurs in conjunction with exaggerated activation of monocytes/macrophages (MO/Mφs), and the mechanisms that collectively govern this phenotype seen in CAC remain unclear. Here, using experimental models that use the murine betacoronavirus MHVA59, a well-established model of SARS-CoV-2 infection, we identify that the histone methyltransferase mixed lineage leukemia 1 (MLL1/KMT2A) is an important regulator of MO/Mφ expression of procoagulant and profibrinolytic factors such as tissue factor (F3; TF), urokinase (PLAU), and urokinase receptor (PLAUR) (herein, "coagulopathy-related factors") in noninfected and infected cells. We show that MLL1 concurrently promotes the expression of the proinflammatory cytokines while suppressing the expression of interferon alfa (IFN-α), a well-known inducer of TF and PLAUR. Using in vitro models, we identify MLL1-dependent NF-κB/RelA-mediated transcription of these coagulation-related factors and identify a context-dependent, MLL1-independent role for RelA in the expression of these factors in vivo. As functional correlates for these findings, we demonstrate that the inflammatory, procoagulant, and profibrinolytic phenotypes seen in vivo after coronavirus infection were MLL1-dependent despite blunted Ifna induction in MO/Mφs. Finally, in an analysis of SARS-CoV-2 positive human samples, we identify differential upregulation of MLL1 and coagulopathy-related factor expression and activity in CD14+ MO/Mφs relative to noninfected and healthy controls. We also observed elevated plasma PLAU and TF activity in COVID-positive samples. Collectively, these findings highlight an important role for MO/Mφ MLL1 in promoting CAC and inflammation.

Unusual presentation of distal ICA aneurysm in relation to dental abscess.

Mycotic extracranial carotid artery aneurysms are a rare vascular phenomenon with a number of implicated pathogens, most commonly Staphylococcus aureus and Salmonella. Presentation of a mycotic extracranial carotid artery aneurysm after dental abscess or procedure is similarly not frequently described in the literature. We present a unique case of a large, distal mycotic internal carotid artery aneurysm, which developed secondary to Haemophilus parainfluenzae infection and dental abscess.

Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair.

Macrophage plasticity is critical for normal tissue repair following injury. In pathologic states such as diabetes, macrophage plasticity is impaired, and macrophages remain in a persistent proinflammatory state; however, the reasons for this are unknown. Here, using single-cell RNA sequencing of human diabetic wounds, we identified increased JMJD3 in diabetic wound macrophages, resulting in increased inflammatory gene expression. Mechanistically, we report that in wound healing, JMJD3 directs early macrophage-mediated inflammation via JAK1,3/STAT3 signaling. However, in the diabetic state, we found that IL-6, a cytokine increased in diabetic wound tissue at later time points post-injury, regulates JMJD3 expression in diabetic wound macrophages via the JAK1,3/STAT3 pathway and that this late increase in JMJD3 induces NFκB-mediated inflammatory gene transcription in wound macrophages via an H3K27me3 mechanism. Interestingly, RNA sequencing of wound macrophages isolated from mice with JMJD3-deficient myeloid cells (Jmjd3f/fLyz2Cre+) identified that the STING gene (Tmem173) is regulated by JMJD3 in wound macrophages. STING limits inflammatory cytokine production by wound macrophages during healing. However, in diabetic mice, its role changes to limit wound repair and enhance inflammation. This finding is important since STING is associated with chronic inflammation, and we found STING to be elevated in human and murine diabetic wound macrophages at late time points. Finally, we demonstrate that macrophage-specific, nanoparticle inhibition of JMJD3 in diabetic wounds significantly improves diabetic wound repair by decreasing inflammatory cytokines and STING. Taken together, this work highlights the central role of JMJD3 in tissue repair and identifies cell-specific targeting as a viable therapeutic strategy for nonhealing diabetic wounds.

Use of Direct Oral Anticoagulant and Associated Bleeding and Thrombotic Complication after Lower Extremity Bypass.

BACKGROUND: Therapeutic anticoagulation with either a vitamin K antagonist (VKA) or direct anticoagulant (DOAC) is often newly prescribed to patients undergoing lower extremity bypass (LEB) to aid in graft patency when risk factors for thrombosis are present or to treat postoperative venous thromboembolism or atrial fibrillation. There is a gap in knowledge as to how DOAC usage impacts postoperative outcomes compared with the standard-of-care VKAs. STUDY DESIGN: To determine temporal trends in DOAC prescription after infrainguinal LEB, impact on length of stay (LOS), and associated bleeding and thrombotic complications, patients undergoing elective LEB were identified from the Vascular Quality Initiative between January 2013 and May 2019. Postoperative bleeding, LOS, and graft occlusion for patients receiving VKA compared with DOAC were evaluated. RESULTS: A total of 24,459 LEBs were performed during the study period. Among 2,656 patients newly prescribed an anticoagulant, 78.0% (n = 2,072) received VKA and 22.0% (n = 584) received a DOAC, with DOAC use increasing throughout the study period. There was no significant difference in postoperative bleeding (VKA 2.3%, DOAC 1.7%, p = 0.413) or graft occlusion (VKA 1.2%, DOAC 1.4%, p = 0.762) between the anticoagulant classes. LOS was shorter in the DOAC group than in the VKA group (5.7 vs 6.8 days; p < 0.001). CONCLUSIONS: This analysis demonstrates that DOAC use is increasing with time in Vascular Quality Initiative centers. DOACs are a safe and comparable alternative to VKAs in the postoperative setting with similar rates of bleeding complications and early graft patency and are associated with a reduced postoperative LOS.

Women benefit from endovenous ablation with fewer complications: Analysis of the Vascular Quality Initiative Varicose Vein Registry.

OBJECTIVE: To evaluate the association between gender and long-term clinician-reported and patient-reported outcomes after endovenous ablation procedures. METHODS: This retrospective cohort study of prospectively collected data from the Vascular Quality Initiative's Varicose Vein Registry included patients undergoing endovenous ablation procedures on truncal veins with or without treatment of perforating veins between 2015 and 2019. A univariate analysis included comparisons of preprocedural, postprocedural, and periprocedural change in Venous Clinical Severity Score (VCSS) and total symptom score by gender. Rates of complications including deep vein thrombosis, endovenous heat-induced thrombosis, leg pigmentation, blistering, paresthesia, incisional infection, and any postprocedural complications were reported by gender. Multivariable analysis leveraged linear regression to examine how gender affected the relationships between patient characteristics, complication rates, and periprocedural change in VCSS score and total symptom score. RESULTS: Of 9743 patients who met the inclusion criteria, 3090 (31.7%) were men and 6653 (68.2%) were women. The perioperative change in VCSS score was greater for men than women (average -4.46 for men vs -4.13 for women; P < .0001). Perioperative change in total symptom score was greater for women than for men (average -10.64 for women vs -9.64 for men; P < .0001). Women had lower incidence of any leg complication (6.1% vs 8.6%; P = .001) endovenous heat-induced thrombosis (1.1% vs 2.2%; P = .002), and infection (0.4% vs 0.7%; P = .001). In multivariable analysis, among patients with a body mass index of more than 40, presence of deep reflux, and preoperative Clinical, Etiologic, Anatomic, and Physiologic classification of 2, women had a greater periprocedural change in VCSS score than men. CONCLUSIONS: Women benefited from endovenous ablation similarly as men, with a lower incidence of postprocedural complications. Gender may be useful for patient selection and counseling for endovenous ablation, with particular usefulness among patients with a high body mass index, presence of deep reflux, and preoperative Clinical, Etiologic, Anatomic, and Physiologic classification of 2.

Treatment and contemporary outcomes associated with adjunct tourniquet use during phlebectomy of complex, voluminous truncular varicosities.

OBJECTIVE: Phlebectomy of large voluminous varicose veins comes with a risk of substantial blood loss. The purpose of the present study was to investigate the outcomes associated with the use of an adjunct tourniquet during varicose vein surgery of complex and large truncular varicosities. METHODS: The prospectively collected registry data included anatomic and outcomes details for patients who presented with complex and large truncular varicosities with a CEAP clinical class of C2, or higher (indicating more serious venous disease) from December 2014 to December 2021. Of all patients, those treated with an adjunct tourniquet for large complex varicosities (largest diameter varicosity ≥1 cm by visual inspection) were selected for analysis. The venous clinical severity scores (VCSSs) and patient-reported outcomes (PROs) were obtained. Additional parameters, including operative time, tourniquet time, and blood loss, were obtained retrospectively via a review of the medical records. Univariate descriptive statistics of the demographic and procedural data were performed pre- and postoperatively, with comparisons performed using the Student two-tailed t test. RESULTS: The data from 19 patients (22 limbs; 7 women and 12 men) were analyzed. Of the 22 limbs, 11 (50%) had advanced venous disease of C4 or higher preoperatively. A review of the preoperative duplex ultrasound scans confirmed the presence of large varicosities (average, 1.0 ± 0.54 cm; n = 18). All the limbs were treated using radiofrequency ablation of axial reflux and phlebectomy (a combination of powered and stab) under tourniquet control (82%) or phlebectomy under tourniquet control alone (18%). The average tourniquet time was 40 ± 12 minutes, with a median blood loss of 50 mL (interquartile range, 30-100 mL). The average follow-up was 332 ± 422 days after 19 procedures for 16 patients (2 patients moved out of state during the immediate postoperative period and 1 patient was lost to follow-up). Of the patients who completed >3 months of follow-up, 14 limbs experienced improvement in the CEAP class, 5 limbs had no change, and 3 were limbs of patients who moved or were lost to follow-up. The VCSSs significantly improved (8.8 ± 2.8 vs 3.9 ± 1.9; P < .0001). The PROs also improved significantly (16.1 ± 5.0 vs 2.2 ± 2.3; P < .0001). CONCLUSIONS: Tourniquet use in the treatment of varicosities has only been described in the setting of high ligation and stripping. Our data suggest that in the modern era of minimally invasive endovenous treatment of axial reflux and phlebectomy, adjunct tourniquet use during the treatment of large complex varicosities can result in significant improvements in the VCSSs and PROs, with minimal blood loss.