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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.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.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 completed3 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).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.

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.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.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; plt; 0.001).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.

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.

Popliteal vein aneurysms are a rare vascular anomaly first reported in the 1980s. Degeneration of elastic fibers and smooth muscle cell reduction, possibly secondary to inflammation, are implicated as integral steps in the development of these aneurysms. Given the rarity of this clinical entity, significant controversy exists regarding ideal treatment strategies, including the role of observation, medical management with anticoagulation, and surgical intervention. Retrospective reviews have demonstrated a failure rate of40% with anticoagulation alone, with patients often presenting with pulmonary embolism. This has prompted our institutional preference for surgical management once the aneurysm is identified. Surgical management involves tangential repair with lateral venorrhaphy most commonly, followed in prevalence by aneurysm resection and end-to-end anastomosis either primarily or with vein interposition. Herein, we report our results with venous plications, through both closed and open techniques.We performed a retrospective review of prospectively collected data for 10 patients undergoing popliteal vein plication for treatment of popliteal vein aneurysms. Patient-level characteristics and operative details were examined from periprocedural and follow-up records.We identified 10 patients undergoing popliteal vein plication, including 9 closed plications and 1 open plication. The average aneurysm size at presentation was 2.35 ± 0.69 cm for closed plication and 4.74 cm for the one open plication. After treatment, the average popliteal vein size was significantly reduced to 1.12 ± 0.45 cm for the closed plications (P .001 from preprocedural size) and 1.13 cm for the open plication with 100% primary patency. Average follow-up for patients treated with closed plication was 35.0 ± 25.2 months, during which seven (78%) patients had a stable, normal popliteal vein size. One patient with recurrence was diagnosed with Klippel-Trénaunay syndrome. The other had degeneration of the popliteal vein cranial to the previous repair at 39 months after the original operation that required additional plication. The open plication patient experienced a hematoma requiring washout and resulting in a transient peroneal mononeuropathy. There was one case of cellulitis after closed plication but no hematomas within this group.Closed plication demonstrated favorable primary patency rates and low recurrence rates, avoiding technical issues or need for early institution of systemic anticoagulation associated with tangential repair and venorrhaphy or resection methods. Closed plication represents an attractive option in patients without luminal thrombus to limit the risk of these postoperative complications and obviates the need for bypass conduit and postoperative anticoagulation.

Objectives: Coronavirus associated coagulopathy (CAC) is postulated to be driven by systemic macrophage activation after SARS-CoV-2 infection and presents with elevated risk of thrombogenesis and hyperfibrinolysis. Previous work shows that the histone methyltransferase KMT2A/MLL1 is a key mediator of inflammatory signaling in monocytes and macrophages (Mo/Mϕs). In this study, we sought to identify the regulation of factors important in CAC by MLL1. Methods: Mice with myeloid specific knockout of MLL1 (Cre+) and littermate controls (Cre-) underwent intranasal inoculation of 2 x 10 5 pfu of the murine coronavirus MHVA59, an established model which phenocopies SARS-CoV-2 infection. Splenic Mϕs (surrogate for circulating Mo/Mϕs) were isolated and RNA and protein levels of urokinase (Plau; profibrinolytic), urokinase receptor (Plaur; profibrinolytic), and tissue factor (F3/TF; procoagulant) were analyzed using qRT-PCR and ELISA, respectively. Thromboelastography (TEG) on whole blood and urokinase activity assays from mouse plasma were performed. Urokinase and TF activity assays were performed on plasma from human samples. Results: RNA (top panel) and protein (bottom) levels of Plau, Plaur, and F3 were suppressed in the Splenic Mϕs harvested from sham (intranasal PBS) and infected Cre+ animals (white bars) compared to Splenic Mϕs harvested from Cre- animals (blue bars; Fig. 1A). Cre- mice displayed a shortened R-time (reaction time) as measured by TEG (Fig. 1B) and elevated plasma urokinase activity levels (not shown). Hospitalized COVID-positive patients (hCOV+) displayed elevated plasma urokinase and TF activity levels (Fig. 1C). Conclusions: We identify a role for MLL1 for basal expression and for coronavirus-mediated induction of factors important for fibrinolysis and coagulation in murine Mo/Mϕs and in driving coagulopathy. Our results suggest that MLL1 blockade may be an attractive strategy to combat coronavirus associated coagulopathy.

Plasmacytoid dendritic cells (pDCs) are first responders to tissue damage and interact with wound CD4 T-cells to orchestrate tissue repair. In diabetes, the role of pDCs and their subsequent influence on wound CD4 T-cells and inflammation during tissue repair is unknown. Using human diabetic wound single cell sequencing, we identified that human wound CD4 T cells are primarily the Th17 phenotype. Thus, we hypothesized that pDCs in the wounds may regulate this inflammatory T cell phenotype, contributing to chronic inflammation. Although pDCs exist in low numbers in the wounds, we isolated wound pDCs from diabetic and control mice and examined them for inflammatory cytokine expression. We found that diabetic pDC produced significantly more IL6 (amongst other inflammatory cytokines) compared to controls. This is important as IL6 has been shown to skew CD4 T-cells towards a Th17 phenotype in tissues. Upon co-culture of diabetic pDCs with naïve CD4 T-cells, a significant increase in Th17 cells was observed by intracellular flow cytometry analysis. In order to examine the increased IL6 from diabetic pDCs we isolated diabetic and control wound pDCs and performed an epigenetic superarray. We identified that histone demethylase Jarid1C was significantly decreased in diabetic pDCs compared to controls. We then isolated diabetic pDCs and performed a ChIP analysis on the IL6 NFkB binding sites in the promoter and identified an increase in tri-methylated lysine 4 on histone 3 (H3K4me3), a marker regulated by Jarid 1C and consistent with increased transcription of IL6. Taken together, this data suggests that in diabetes, pDCs are epigenetically altered to produce increased IL6 and contribute to increased Th17 and inflammation in diabetic wounds.

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.

This retrospective cohort study analyzes venous thromboembolism (VTE) incidence, morbidity, and mortality amongst postsurgical patients with and without VTE chemoprophylaxis within a quality collaborative. Postoperative thromboprophylaxis was broadly applied, yet was associated with no decrease in VTE, without affecting transfusion or mortality. Predictors of breakthrough VTE development despite evidence-based thromboprophylaxis are identified.We hypothesized that a high rate of prescription of VTE chemoprophylaxis would be associated with decreased VTE incidence and mortality.Recommendations for VTE prevention in surgical patients include chemoprophylaxis based upon preoperative risk stratification.This retrospective cohort study analyzed VTE incidence, morbidity, and mortality amongst postsurgical patients with and without VTE chemoprophylaxis between April 2013 and September 2017 from 63 hospitals within the Michigan Surgical Quality Collaborative. A VTE risk assessment survey was distributed to providers. Bivariate and multivariate comparisons were made, as well as using propensity score matched cohorts to determine if VTE chemoprophylaxis was associated with decreased VTE events. Hospitals were compared using risk-reliability adjusted VTE prophylaxis and postoperative VTE event rates.Within the registry, 80% of practitioners reported performing formal VTE risk assessment. Amongst 32,856 operations, there were 480 (1.46%) postoperative VTE, and an overall mortality of 609 (1.85%) patients. Using a propensity matched cohort, we found that rates of VTE were similar in those receiving unfractionated heparin or low molecular weight heparin compared to those not receiving chemoprophylaxis (1.22 vs 1.13%, P = 0.57). When stratified further by VTE risk scoring, even the highest risk patients did not have an associated lower VTE rate (3.68 vs 4.22% P = 0.092). Postoperative transfusion (8.28 vs 7.50%, P = 0.057) and mortality (2.00% vs 1.62%, P = 0.064) rates were similar amongst those receiving and those not receiving chemoprophylaxis. No correlation was found between postoperative VTE chemoprophylaxis application and hospital specific risk adjusted postoperative VTE rates.In modern day postsurgical care, VTE remains a significant occurrence, despite wide adoption of VTE risk assessment. Although postoperative VTE chemoprophylaxis was broadly applied, after adjusting for confounders, no reduction in VTE was observed in at-risk surgical patients.

Post-thrombotic syndrome (PTS) is an end stage manifestation of deep vein thrombosis. This is an inherently inflammatory process, with consequent fibrosis. Multiple cellular types are involved, and are likely driven by leukocytes. Herein, we review the current gaps in therapy, and insights from rodent models of venous thrombosis that suggest possible targets to treat and prevent PTS.

Objective Venous thromboembolism (VTE) is a common disease with potentially devastating and long-term sequelae, such as pulmonary embolism and post-thrombotic syndrome (PTS). Given the mortality risk, prevalence of VTE, and limited access to diagnostic imaging, clinically relevant biomarkers for diagnosis and prognostication are needed. Therefore, this review aimed to summarize the data on clinically applicable biomarkers that best indicate acute VTE and chronic PTS. Methods We reviewed the medical and scientific literature from 2001 to 2019 for VTE biomarkers. Randomized controlled trials, meta-analyses, and review articles were included. Primary basic research papers with no clinical applicability, opinion papers, institutional guidelines, and case reports were excluded. Results We highlight the diagnostic value of D-dimer alongside other promising biomarkers, including cellular adhesion molecules, P-selectin, cytokines (interleukins 6 and 10), fibrin monomer complexes, and coagulation factors (factor VIII). Conclusions High-sensitivity D-dimer remains the most clinically established VTE biomarker. Current research endeavors are under way to identify more precise biomarkers of VTE and PTS.

Objectives: Men are disproportionately affected by the coronavirus disease-2019 (COVID-19) and experience higher mortality as compared to women. Endothelial dysfunction has been proposed as a major inciting factor of pro-inflammatory and thrombotic changes in COVID-19 infection. The vascular effects of androgen signaling and inflammatory cytokines in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated endothelial damage are not defined. Methods: Here, we determined the effects of SARS-CoV-2 spike protein-mediated endothelial damage under conditions of exposure to androgens and TNF-α. We tested the therapeutic effects of approved drugs: angiotensin receptor blockade by valsartan and mineralocorticoid receptor antagonism by spironolactone. Circulating endothelial injury markers VCAM-1 and E-selectin were measured in the plasma from men and women diagnosed with COVID-19. Results: Exposure of endothelial cells (ECs) in vitro to androgen dihydrotestosterone (DHT) exacerbated spike protein S1-mediated endothelial injury transcripts for cell adhesion molecules E-selectin, VCAM-1, and ICAM-1 and anti-fibrinolytic PAI-1 (P Conclusions: Androgen exposure promoted spike protein-mediated endothelial injury by increasing markers of inflammation and thrombosis. A beneficial therapeutic effect of the FDA-approved drug spironolactone was observed, supporting a rationale for further evaluation as an adjunct treatment in COVID-19.

Significance The COVID-19 pandemic has disproportionately affected patients with comorbidities, namely, obesity and type 2 diabetes. Macrophages (Mφs) are a key innate immune cell primarily responsible for the harmful, hyperinflammatory “cytokine storm” in patients that develop severe COVID-19. We describe a mechanism for this Mφ-mediated cytokine storm in response to coronavirus. In response to coronavirus infection, expression of the chromatin-modifying enzyme, SETDB2, decreases in Mφs, leading to increased transcription of inflammatory cytokines. Further, we find SETDB2 is regulated by an interferon beta (IFNβ)/JaK/STAT3 mechanism, and that exogenous administration of IFNβ can reverse inflammation, particularly in diabetic Mφs via an increase in SETDB2. Together, these results suggest therapeutic targeting of the IFNβ/SETDB2 axis in diabetic patients with COVID-19 may decrease pathologic inflammation., COVID-19 induces a robust, extended inflammatory “cytokine storm” that contributes to an increased morbidity and mortality, particularly in patients with type 2 diabetes (T2D). Macrophages are a key innate immune cell population responsible for the cytokine storm that has been shown, in T2D, to promote excess inflammation in response to infection. Using peripheral monocytes and sera from human patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a murine hepatitis coronavirus (MHV-A59) (an established murine model of SARS), we identified that coronavirus induces an increased Mφ-mediated inflammatory response due to a coronavirus-induced decrease in the histone methyltransferase, SETDB2. This decrease in SETDB2 upon coronavirus infection results in a decrease of the repressive trimethylation of histone 3 lysine 9 (H3K9me3) at NFkB binding sites on inflammatory gene promoters, effectively increasing inflammation. Mφs isolated from mice with a myeloid-specific deletion of SETDB2 displayed increased pathologic inflammation following coronavirus infection. Further, IFNβ directly regulates SETDB2 in Mφs via JaK1/STAT3 signaling, as blockade of this pathway altered SETDB2 and the inflammatory response to coronavirus infection. Importantly, we also found that loss of SETDB2 mediates an increased inflammatory response in diabetic Mϕs in response to coronavirus infection. Treatment of coronavirus-infected diabetic Mφs with IFNβ reversed the inflammatory cytokine production via up-regulation of SETDB2/H3K9me3 on inflammatory gene promoters. Together, these results describe a potential mechanism for the increased Mφ-mediated cytokine storm in patients with T2D in response to COVID-19 and suggest that therapeutic targeting of the IFNβ/SETDB2 axis in T2D patients may decrease pathologic inflammation associated with COVID-19.

The optimal medical management of patients following endovascular deep venous interventions remains ill-defined. As such, the Society of Interventional Radiology Foundation (SIRF) convened a multidisciplinary group of experts in a virtual Research Consensus Panel (RCP) to develop a prioritized research agenda regarding antithrombotic therapy following deep venous interventions. The panelists presented the gaps in knowledge followed by discussion and ranking of research priorities based on clinical relevance, overall impact, and technical feasibility. The following research topics were identified as high priority: 1) characterization of biological processes leading to in-stent stenosis/rethrombosis; 2) identification and validation of methods to assess venous flow dynamics and their effect on stent failure; 3) elucidation of the role of inflammation and anti-inflammatory therapies; and 4) clinical studies to compare antithrombotic strategies and improve venous outcome assessment. Collaborative, multicenter research is necessary to answer these questions and thereby enhance the care of patients with venous disease.

Background The CAVA (Ultrasound‐Accelerated Catheter‐Directed Thrombolysis Versus Anticoagulation for the Prevention of Post‐Thrombotic Syndrome) trial did not show a reduction of post‐thrombotic syndrome (PTS) after additional ultrasound‐accelerated catheter‐directed thrombolysis in patients with acute iliofemoral deep vein thrombosis at 1‐year follow‐up. This prespecified analysis of the CAVA trial aimed to determine the impact of additional thrombolysis on outcomes of PTS at long‐term follow‐up. Methods and Results Patients aged 18 to 85 years with a first‐time acute iliofemoral deep vein thrombosis were included and randomly assigned (1:1) to either standard treatment plus ultrasound‐accelerated catheter‐directed thrombolysis or standard treatment alone. The primary outcome was the proportion of PTS (Villalta score ≥5 on 2 occasions ≥3 months apart or venous ulceration) at the final follow‐up visit. Additionally, PTS according to the International Society on Thrombosis and Haemostasis (ISTH) consensus definition was assessed to allow external comparability. Major bleedings were the main safety outcome. At a median follow‐up of 39.0 months (interquartile range, 23.3–63.8), 120 patients (79.8%) participated in the final follow‐up visit: 62 from the intervention group and 58 from the standard treatment group. PTS developed in 19 (30.6%) versus 26 (44.8%) patients, respectively (odds ratio [OR], 0.54; 95% CI, 0.26 to 1.15 [P=0.11]), with an absolute difference between groups of −14.2% (95% CI, −32.0% to 4.8%). Using the ISTH consensus definition, a significant reduction in PTS was observed (29 [46.8%] versus 40 [69.0%]) (OR, 0.40; 95% CI, 0.19–0.84 [P=0.01]) with an absolute difference between groups of −22.2% (95% CI, −39.8% to −2.8%). No new major bleedings occurred following the 12‐month follow‐up. Conclusions The impact of additional ultrasound‐accelerated catheter‐directed thrombolysis on the prevention of PTS was found to increase with time. Although this study was limited by its sample size, the overall findings indicate a reduction of mild PTS without impact on quality of life. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00970619.

Venous thromboembolism (VTE) is a significant cause of mortality1, yet its genetic determinants remain incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank testing ~13 million DNA sequence variants for association with VTE (26,066 cases; 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 VTE cases and 167,295 controls. We identified 22 novel loci, bringing the total number of VTE-associated loci to 33 and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for VTE that identifies 5% of the population at equivalent incident VTE risk to carriers of the established F5 Leiden (p.R506Q) and prothrombin G20210A mutations. Our data provide new mechanistic insights into the genetic epidemiology of VTE and suggest a greater overlap among venous and arterial cardiovascular disease than previously suggested., Editorial summary Genome-wide analysis of venous thromboembolism identifies 22 new risk loci and facilitates construction of a polygenic risk score. Comparison to arterial vascular disease highlights shared pathophysiology and potential therapeutic strategies.

Myeloid cells are critical for orchestrating regulated inflammation during wound healing. TLRs, particularly TLR4, and its downstream-signaling MyD88 pathway play an important role in regulating myeloid-mediated inflammation. Because an initial inflammatory phase is vital for tissue repair, we investigated the role of TLR4-regulated, myeloid-mediated inflammation in wound healing. In a cutaneous tissue injury murine model, we found that TLR4 expression is dynamic in wound myeloid cells during the course of normal wound healing. We identified that changes in myeloid TLR4 during tissue repair correlated with increased expression of the histone methyltransferase, mixed-lineage leukemia 1 (MLL1), which specifically trimethylates the histone 3 lysine 4 (H3K4me3) position of the TLR4 promoter. Furthermore, we used a myeloid-specific Mll1 knockout (Mll1f/fLyz2Cre+) to determine MLL1 drives Tlr4 expression during wound healing. To understand the critical role of myeloid-specific TLR4 signaling, we used mice deficient in Tlr4 (Tlr4−/−), Myd88 (Myd88−/−), and myeloid-specific Tlr4 (Tlr4f/fLyz2Cre+) to demonstrate delayed wound healing at early time points postinjury. Furthermore, in vivo wound myeloid cells isolated from Tlr4−/− and Myd88−/− wounds demonstrated decreased inflammatory cytokine production. Importantly, adoptive transfer of monocyte/macrophages from wild-type mice trafficked to wounds with restoration of normal healing and myeloid cell function in Tlr4-deficient mice. These results define a role for myeloid-specific, MyD88-dependent TLR4 signaling in the inflammatory response following cutaneous tissue injury and suggest that MLL1 regulates TLR4 expression in wound myeloid cells.

Abdominal aortic aneurysms (AAAs) are a life-threatening disease characterized by macrophage infiltration contributing to pathological vascular remodeling. Herein, we demonstrate that the histone demethylase JMJD3 is a critical regulator of inflammation during AAA development and cell-specific inhibition reduces AAA progression., Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte/macrophages resulting in up-regulation of an inflammatory immune response. Mechanistically, we report that interferon-β regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-κB–mediated inflammatory gene transcription in infiltrating aortic macrophages. In vivo targeted inhibition of JMJD3 with myeloid-specific genetic depletion (JMJD3f/fLyz2Cre+) or pharmacological inhibition in the elastase or angiotensin II–induced AAA model preserved the repressive H3K27me3 on inflammatory gene promoters and markedly reduced AAA expansion and attenuated macrophage-mediated inflammation. Together, our findings suggest that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA expansion., Graphical Abstract

To evaluate the association between gender and long-term clinician-reported and patient-reported outcomes after endovenous ablation procedures.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.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.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.

Objective Chronic venous disease (CVD) describes a spectrum of conditions associated with venous hypertension. The association between various CVD etiologies and the subsequent risk of venous thromboembolism (VTE), such as deep vein thrombosis or pulmonary embolism, is a topic of considerable clinical interest. The aims of the present review were to characterize the risk of VTE according to the CVD etiology and to determine the optimal anticoagulation strategy for the treatment or prevention of VTE in patients with CVD. Methods An extensive search of the available surgical and medical data was conducted in PubMed and Google Scholar. We searched for the following terms and other related terms to identify relevant studies: CVD, chronic venous insufficiency, varicose veins, post-thrombotic syndrome (PTS), anticoagulation, venous thromboembolism, and venous disease scoring systems (eg, CEAP [clinical, etiology, anatomic, pathophysiology], Villalta, Ginsberg, venous clinical severity score). The identified studies included randomized control trials, retrospective and prospective observational studies, narrative and systematic reviews, case reports, and case series that contributed to the proposed aims. The ClinicalTrials.gov database was also queried to identify any relevant ongoing clinical trials. Results Congenital CVD carries a heightened risk of VTE, although few higher level studies are available to inform on this topic or on the appropriate anticoagulation strategies for these patients. Noncongenital CVD seems to carry a heightened risk of VTE, although few studies have adequately differentiated between primary and secondary etiologies. Varicose veins are a risk factor for primary VTE but might not be associated with an increased risk of recurrent VTE. In the hospital setting, patients with varicosities should be provided thromboprophylaxis. In the setting of varicose vein intervention, high-risk patients should be identified using risk assessment models and receive thromboprophylaxis. The risk of recurrent VTE in the setting of PTS is unclear but indefinite anticoagulation is not currently indicated. For patients with PTS, residual vein thrombosis might be an indicator of when anticoagulation can be safely stopped, although practical limitations to its application exist. Conclusions CVD is associated with an increased risk of VTE. Few studies have differentiated between classes of CVD using a standardized method and have assessed the efficacy of anticoagulation prophylaxis against or treatment of VTE. Additional studies are needed to determine the optimal therapy for preventing and treating VTE in patients with active concurrent CVD.

Macrophages are a primary immune cell involved in inflammation, and their cell plasticity allows for transition from an inflammatory to a reparative phenotype and is critical for normal tissue repair following injury. Evidence suggests that epigenetic alterations play a critical role in establishing macrophage phenotype and function during normal and pathologic wound repair. Here, we find in human and murine wound macrophages that cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) is elevated in diabetes and regulates downstream macrophage-mediated inflammation and host defense. Using single-cell RNA sequencing of human wound tissue, we identify increased NF-κB–mediated inflammation in diabetic wounds and show increased COX-2/PGE2 in diabetic macrophages. Further, we identify that COX-2/PGE2 production in wound macrophages requires epigenetic regulation of 2 key enzymes in the cytosolic phospholipase A2/COX-2/PGE2 (cPLA2/COX-2/PGE2) pathway. We demonstrate that TGF-β–induced miRNA29b increases COX-2/PGE2 production via inhibition of DNA methyltransferase 3b–mediated hypermethylation of the Cox-2 promoter. Further, we find mixed-lineage leukemia 1 (MLL1) upregulates cPLA2 expression and drives COX-2/PGE2. Inhibition of the COX-2/PGE2 pathway genetically (Cox2fl/fl Lyz2Cre+) or with a macrophage-specific nanotherapy targeting COX-2 in tissue macrophages reverses the inflammatory macrophage phenotype and improves diabetic tissue repair. Our results indicate the epigenetically regulated PGE2 pathway controls wound macrophage function, and cell-targeted manipulation of this pathway is feasible to improve diabetic wound repair., Epigenetic modification of the COX-2/PGE2 pathway modulates diabetic macrophage phenotype, and cell-targeted manipulation improves diabetic tissue repair.

A markedly increased demand for vascular ultrasound laboratory and other imaging studies in COVID-19-positive patients has occurred, due to most of these patients having a markedly elevated D-dimer and a presumed prothrombotic state in many of the very ill patients. In the present report, we have summarized a broad institutional consensus focusing on evaluation and recommended empirical therapy for COVID-19-positive patients. We recommend following the algorithms with the idea that as more data becomes available these algorithms may well change.

OBJECTIVE: Many insurance payers are hesitating to cover interventional treatments in patients with isolated symptomatic varicose veins. In this study, we sought to determine the outcomes of patients with varicose veins who were treated with venous ablation alone or ablation plus phlebectomy using the Vascular Quality Initiative Varicose Vein Registry. METHODS: Using data from the Varicose Vein Registry between January 2015 and March 2019, we investigated immediate postoperative as well as long-term clinical and patient-reported outcomes among patients with documented symptomatic C2 disease undergoing truncal endovenous ablations alone and combined ablation and phlebectomy. Preprocedural and postprocedural comparisons were performed using t-test, χ(2) test, or nonparametric tests when appropriate. Multivariable ordinal logistic regression was performed on ordinal outcome variables. RESULTS: Among 3375 patients with symptomatic C2 disease, 40.1% of patients (1376) underwent isolated truncal ablation and 59.9% (1999) underwent ablation and phlebectomy. Complications overall were low (8.6%) and varied between 8.4% and 8.7% in patients undergoing ablation alone and ablation plus phlebectomy, respectively (P = .820). The most common complication noted was paresthesia, 3.4% overall, which occurred more commonly after ablation and phlebectomy (4.5%) than after ablation alone (1.3%; P < .001). An improvement in Venous Clinical Severity Score (VCSS) was experienced by 87.4% of patients; median change in VCSS was 4 points (interquartile range [IQR], 2–5 points), with an improvement of 3 points among patients undergoing ablation alone (IQR, 1–5 points) and 5 points among patients undergoing ablation and phlebectomy (IQR, 3–5 points; P < .001). An improvement in overall symptoms was experienced by 94.4% of patients (median improvement, 11 points; (maximum, 30 points), with more significant decreases among patients undergoing ablation and phlebectomy (median, 12 points; IQR, 8–17 points) compared with ablation alone (median, 9 points; IQR, 5–13 points; P < .001). CONCLUSIONS: Among patients with isolated symptomatic varicose veins (C2 disease), ablation and ablation with phlebectomy are safe and effective in improving both patient-reported outcomes and clinical severity (VCSS). Given these data, payers should continue to cover these treatments.

OBJECTIVE: Venous insufficiency is commonly bilateral, and patients often prefer single-episode care compared with staged procedures. Few studies have investigated clinical outcomes after unilateral vs bilateral venous ablation procedures or between staged and concurrent bilateral procedures. Here, we report data from the Vascular Quality Initiative regarding truncal venous ablation for chronic venous insufficiency. METHODS: Using data from the Vascular Quality Initiative, we investigated immediate postoperative as well as long-term clinical and patient-reported outcomes of patients undergoing unilateral vs bilateral truncal endovenous ablation from 2015 to 2019. We further investigated outcomes between staged bilateral and concurrent bilateral ablations. Preprocedural and postprocedural comparisons were performed using t-test, χ(2) test, or their nonparametric counterpart when appropriate. Multivariable ordinal logistic regression was performed on ordinal outcome variables. RESULTS: A total of 5029 patients were included, of whom 3782 (75.2%) underwent unilateral procedures. Median follow-up was 227 days (interquartile range [IQR], 55–788 days). Unilateral patients were less likely to be female (67.0% vs 70.3%; P = .031) and white (86.3% vs 91.2%; P < .001) and had lower body mass index (30.3 ± 7.3 kg/m(2) vs 31.8 ± 7.6 kg/m(2); P < .001) compared with patients undergoing bilateral procedures. In addition, unilateral patients had fewer prior varicose vein treatments (23.0% vs 15.7%; P < .001) and had higher median preprocedural Venous Clinical Severity Score (VCSS; 8 [IQR, 6–10] vs 7 [IQR, 5.5–9]; P < .001). No difference was seen in complications (6.9% vs 8.2%; P = .292), and systemic complications were rare in both groups. No difference was seen in VCSS improvement after treatment (median, 3 [IQR, 1–6] for unilateral; median, 3 [IQR 1–5] for bilateral; P = .055). In comparing staged with concurrent bilateral procedures, there was no difference in overall complications (7.5% vs 12.2%; P = .144). Staged bilateral patients were older (56.9 ± 13.3 years vs 54.2 ± 12.9 years; P = .002), less likely to have had prior varicose vein treatment (14.3% vs 19.8%; P = .020), and more likely to be therapeutically anticoagulated (10.8% vs 6.5%; P = .028) compared with concurrent bilateral patients. Staged patients also have higher preprocedural VCSS compared with concurrent patients (median, 8 [IQR, 6–10] vs 7 [IQR, 5.5–9]; P < .001). In multivariable analysis, there was no difference in the likelihood of VCSS improvement for concurrent compared with staged procedures (odds ratio, 0.70; 95% confidence interval, 0.40–1.24; P = .226). CONCLUSIONS: Concurrent bilateral truncal endovenous ablation can be performed safely without increased morbidity compared with staged bilateral or unilateral ablations.

The Intersocietal Accreditation Commission of vein centers was instituted in 2014, yet data regarding impact of accreditation on patients undergoing superficial vein interventions are lacking. This study was undertaken to identify differences in patient outcomes and utilization index as a measure of appropriate use in accredited compared with nonaccredited centers.This study was performed with a matched control design using prospectively collected data from two major U.S.-based venous registries: the Society for Vascular Surgery Vascular Quality Initiative Varicose Vein Registry and the American VeinLymphatic Society PRO Venous Registry.A total of 39,001 patients treated between 2015 and 2018 in 192 centers were included in the study. The Vascular Quality Initiative Varicose Vein Registry provided information on 19,810 (50.8%) patients, and the American VeinLymphatic Society PRO Venous Registry provided information on 19,191 (49.2%) patients. Accredited centers were significantly more likely to treat patients with advanced venous disease as characterized by trophic skin changes (C4-C6, 38.1% vs 25.2%; P .001). Percentage of patients treated 2 standard deviations above the Medicare-reported mean (3.4 utilization index) was significantly higher among patients treated at nonaccredited centers (3.3% vs 0.1%; P .001). Venous Clinical Severity Score of those who were assessed between 1 month and 1 year after ablation decreased by 4.98 ± 4.01 in nonaccredited centers compared with 5.61 ± 3.64 in accredited centers (P .001). Complications were low in both cohorts (nonaccredited centers, 71 [0.4%]; accredited centers, 17 [0.1%]; P .001). One-year clinical follow-up was higher in nonaccredited centers (76.4% vs 31.5%; P .001).Venous registries are a powerful tool for capturing and identifying significant variations in procedure utilization and complications in low-risk procedures. Intersocietal Accreditation Commission accreditation was associated with reduced use of endovenous therapies, slightly lower complication rates, lower 1-year follow up, and greater improvement in Venous Clinical Severity Score.

The leap from graduating chief resident or fellow to attending physician is one of the most critical and daunting times in a surgeon’s career. Here, we have outlined key “must dos” in the first year to ensure that milestones are reached and the research mission and personal/family life does not suffer during the course of building an academic clinical practice. This includes identifying requirements for board certification early and planning backwards from these dates; developing a strategic debt management plan, retirement and insurance plan; keeping a case log and identifying clinical mentors. The basics of laboratory set up including how to leverage mentors’ experience when hiring laboratory staff, negotiating research regulations, and curating a reputation are emphasized.

Background: Men are disproportionately affected by the coronavirus disease-2019 (COVID-19) and experience higher mortality as compared to women. The vascular effects of androgen signaling and inflammatory cytokines in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated endothelial damage are not defined. Methods: Here, we determined the effects of SARS-CoV-2 spike protein-mediated endothelial damage under conditions of exposure to androgens and TNF-α. We tested the therapeutic effects of approved drugs: angiotensin receptor blockade by valsartan and mineralocorticoid receptor antagonism by spironolactone. Circulating endothelial injury markers VCAM-1 and E-selectin were measured in the plasma from men and women diagnosed with COVID-19. Findings: Exposure of endothelial cells (ECs) in vitro to androgen dihydrotestosterone (DHT) exacerbated spike protein S1-mediated endothelial injury transcripts for cell adhesion molecules E-selectin, VCAM-1, and ICAM-1 and anti-fibrinolytic PAI-1 (P