Characterization of the plasma metabolome and lipidome in response to sleeve gastrectomy and gastric bypass surgeries reveals molecular patterns of surgical weight loss.

OBJECTIVES: Bariatric surgery improves metabolic health, but the underlying mechanisms are not fully understood. We analyzed the effects of two types of bariatric surgery, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), on the plasma metabolome and lipidome. METHODS: We characterized the plasma metabolome (1268 metabolites) and lipidome (953 lipids) pre-operatively and at 3 and 12 months post-operatively in 104 obese adults who were previously recruited to a prospective cohort of bariatric surgery. The metabolomic and lipidomic responses to bariatric surgery over time were analyzed using multivariable linear mixed-effects models. RESULTS: There were significant changes in multiple metabolites and lipids, including rapid early changes in amino acid and peptide metabolites, including decreases in branched-chain amino acids (BCAAs), aromatic AAs, alanine and aspartate, and increases in glycine, serine, arginine and citrulline. There were also significant decreases in many triglyceride species, with increases in phosphatidylcholines and phosphatidylethanolamines. There were significant changes in metabolites related to energy metabolism that were apparent only after 12 months. We observed differences by bariatric surgery type in the changes in a small number of primary and secondary bile acids, including glycohyocholate and glyco-beta-muricholate. CONCLUSIONS: Our findings highlight the comprehensive changes in metabolites and lipids that occur over the 12 months following bariatric surgery. While both SG and RYGB caused profound changes in the metabolome and lipidome, RYGB was characterized by greater increases in bile acids following surgery.

Safety and Efficacy of Percutaneous Translumbar Inferior Vena Cava Catheters: A Systematic Review and Meta-Analysis.

PURPOSE: To examine the reported adverse events associated with inferior vena cava (IVC) catheterization and investigate the reasons for discrepancies between reports. MATERIALS AND METHODS: Cochrane Library trials register, PubMed, Embase, and Scopus databases were systematically searched for studies that included any terms of IVC and phrases related to catheters or central access. Of the 5,075 searched studies, 137 were included in the full-text evaluation. Of these, 37 studies were included in the systematic review, and the adverse events reported in 16 of these 37 identified studies were analyzed. An inverse-variance random-effects model was used to conduct the meta-analysis. Outcomes were summarized by the incidence rate (IR) and 95% CI. RESULTS: Compared with that of catheters <10 F in size (IR, 0.08; 95% CI, 0.03-0.12), the incidence of catheter-related infections per 100 catheter days was 0.2 more for catheters ≥10 F in size (IR, 0.28; 95% CI, 0.25-0.31). In addition, dual-lumen catheters showed 0.13 more malfunction per 100 catheter days (IR, 0.27; 95% CI, 0.16-0.37) than that shown by single-lumen catheters (IR, 0.14; 95% CI, 0.09-0.19). Both differences were statistically significant. Other adverse events were malposition (IR, 0.04; 95% CI, 0.04-0.05), fracture (IR, 0.01; 95% CI, 0.00-0.02), kinking (IR, 0.01; 95% CI, 0.00-0.01), replaced catheter (IR, 0.2; 95% CI, 0.1-0.31), removal (IR, 0.13; 95% CI, 0.1-0.16), IVC thrombosis (IR, 0.01; 95% CI, 0.00-0.03), and retroperitoneal hematoma (IR, 0.01; 95% CI, 0.00-0.01), all per 100 catheter days. CONCLUSIONS: Translumbar IVC access is an option for patients with exhausted central veins. Small-caliber catheters cause fewer catheter-related infections, and single-lumen catheters function longer.

A systematic review of routine post operative screening duplex ultrasound after thermal and non-thermal endovenous ablation.

OBJECTIVE: The Society of Vascular Surgery and the American Venous Forum recommend duplex ultrasound (DUS) following endovenous ablation. However, this screening may not be cost-effective or clinically indicated. The most common abnormal finding, endovenous heat-induced thrombosis (EHIT level 1-2), represents extension of thrombus from the saphenous <50% across the femoral or popliteal vein, which is thought to have a benign course regardless of intervention. The likelihood of venous thromboembolism (VTE) after thermal and non-thermal ablations was explored to determine the utility of routine postoperative DUS. METHODS: This is an updated and expanded systematic review including data from randomized trials and large observational studies (≥150 patients) of thermal and non-thermal ablations, examining the incidence of VTE. Using PubMed and EMBASE, 4584 publications were screened from 2000 through 2020. After applying inclusion and exclusion criteria, 72 studies were included. Random effects DerSimonian-Laird method was conducted to obtain the pooled incidence. We calculated the number of tests needed to detect one VTE, and the cost was derived from Center for Medicare Services tables. RESULTS: A total of 31,663 patients were included. The pooled incidence of EHIT II-IV, deep venous thrombosis (DVT), and pulmonary embolism (PE) was 1.32% (95% confidence interval [CI], 0.75%-2.02%); DVT (excluding EHIT), 0.20% (95% CI, 0.0%-0.2%); EHIT (I-IV), 2.51% (95% CI, 1.54%-3.68%); and EHIT (II-IV), 1.00% (95% CI, 0.51%-1.61%). There was no mortality. There was a lower DVT rate in thermal vs non-thermal ablations (0.23% vs 0.43%; P = .02); however, for all VTE (EHIT I-IV + DVT + PE), thermal techniques had more thrombosis (2.5% vs 0.5%; P <.001). When clinical significance is defined as DVT + EHIT (II-IV), 175 studies are needed to identify one VTE, costing $21,813 per "significant VTE." Patients receiving pharmacological prophylaxis had less EHIT I-IV compared with those who did not (3.04% vs 1.63%; P < .001); those who received DUS during the first post-op week had three times higher EHIT incidence compared with those whose first DUS was >7 days postoperative (6.6% vs 2.4%; P < .001). CONCLUSIONS: For thermal and non-thermal endovenous ablations, the incidence of VTE diagnosed with routine DUS is small and without clear clinical significance but caries a high cost. The Society of Vascular Surgery and the American Venous Forum recommendation to perform DUS within 72 hours is not justified by these data. We recommend a more targeted post-ablation scanning protocol including symptomatic patients and those at high risk.

The American Venous Forum, American Vein and Lymphatic Society and the Society for Vascular Medicine expert opinion consensus on lymphedema diagnosis and treatment.

BACKGROUND: Lymphedema imposes a significant economic and social burden in modern societies. Controversies about its risk factors, diagnosis, and treatment permeate the literature. The goal of this study was to assess experts' opinions on the available literature on lymphedema while following the Delphi methodology. METHODS: In December of 2019, the American Venous Forum created a working group tasked to develop a consensus statement regarding current practices for the diagnosis and treatment of lymphedema. A panel of experts was identified by the working group. The working group then compiled a list of clinical questions, risk factors, diagnosis and evaluation, and treatment of lymphedema. Fifteen questions that met the criteria for consensus were included in the list. Using a modified Delphi methodology, six questions that received between 60% and 80% of the votes were included in the list for the second round of analysis. Consensus was reached whenever >70% agreement was achieved. RESULTS: The panel of experts reached consensus that cancer, infection, chronic venous disease, and surgery are risk factors for secondary lymphedema. Consensus was also reached that clinical examination is adequate for diagnosing lymphedema and that all patients with chronic venous insufficiency (C3-C6) should be treated as lymphedema patients. No consensus was reached regarding routine clinical practice use of radionuclide lymphoscintigraphy as a mandatory diagnostic tool. However, the panel came to consensus regarding the importance of quantifying edema in all patients (93.6% in favor). In terms of treatment, consensus was reached favoring the regular use of compression garments to reduce lymphedema progression (89.4% in favor, 10.6% against; mean score of 79), but the use of Velcro devices as the first line of compression therapy did not reach consensus (59.6% in favor vs 40.4% against; total score of 15). There was agreement that sequential pneumatic compression should be considered as adjuvant therapy in the maintenance phase of treatment (91.5% in favor vs. 8.5% against; mean score of 85), but less so in its initial phases (61.7% in favor vs. 38.3% against; mean score of 27). Most of the panel agreed that manual lymphatic drainage should be a mandatory treatment modality (70.2% in favor), but the panel was split in half regarding the proposal that reductive surgery should be considered for patients with failed conservative treatment. CONCLUSION: This consensus process demonstrated that lymphedema experts agree on the majority of the statements related to risk factors for lymphedema, and the diagnostic workup for lymphedema patients. Less agreement was demonstrated on statements related to treatment of lymphedema. This consensus suggests that variability in lymphedema care is high even among the experts. Developers of future practice guidelines for lymphedema should consider this information, especially in cases of low-level evidence that supports practice patterns with which the majority of experts disagree.

An Analysis of Guideline Consensus for the Prevention, Diagnosis, and Management of Diabetic Foot Ulcers.

BACKGROUND: Multiple organizations have issued guidelines to address the prevention, diagnosis, and management of diabetic foot ulcers (DFUs) based on evidence review and expert opinion. We reviewed these guidelines to identify consensus (or lack thereof) on the nature of these recommendations, the strength of the recommendations, and the level of evidence. METHODS: Ovid, PubMed, Web of Science, Cochrane Library, and Embase were searched in October 2018 using the MESH term diabetic foot, the key word diabetic foot, and the filters guideline or practice guideline. To minimize recommendations based on older literature, guidelines published before 2012 were excluded. Articles without recommendations characterized by strength of recommendation and level of evidence related specifically to DFU were also excluded. A manual search for societal recommendations yielded no further documents. Recommendations were ultimately extracted from 12 articles. Strength of evidence and strength of recommendation were noted for each guideline recommendation using the Grading of Recommendations Assessment, Development, and Evaluation system or the Centre for Evidence-Based Medicine system. To address disparate grading systems, we mapped the perceived level of evidence and strength of recommendations onto the American Heart Association guideline classification schema. RESULTS: Recommendations found in two or more guidelines were collected into a clinical checklist characterized by strength of evidence and strength of recommendation. Areas for future research were identified among recommendations based on minimal evidence, areas of controversy, or areas of clinical care without recommendations. CONCLUSIONS: Through this work we developed a multidisciplinary set of DFU guidelines stratified by strength of recommendation and quality of evidence, created a clinical checklist for busy practitioners, and identified areas for future focused research. This work should be of value to clinicians, guideline-issuing bodies, and researchers. We also formulated a method for the review and integration of guidelines issued by multiple professional bodies.

Private payers' varicose vein policies are inaccurate, disparate, and not evidence based, which mandates a proposal for a reasonable and responsible policy for the treatment of venous disease.

Varicose veins afflict more than one in five Americans, and although varicose veins may be an asymptomatic cosmetic concern in some, many others experience symptoms of pain, aching, heaviness, itching, and swelling. More advanced venous disease can result from untreated venous insufficiency. The complications of chronic venous disease, including bleeding, thrombosis, and ulceration, are seen in up to 2 million Americans annually. Numerous reports have documented venous disease adversely affects quality of life and that treatment of venous disease can improve quality of life. It has previously been documented that private insurers, and Centers for Medicare & Medicaid Services subcontractors for that matter, have disparate policies that in many instances are self-serving, contain mistakes, use outdated evidence, and disregard evidence-based guidelines. The two leading venous medical societies, the American Venous Forum and the American Venous and Lymphatic Society, have come together to review the varicose vein coverage policies of seven major U.S. private medical insurance carriers whose policies cover more than 150 million Americans. The authors reviewed the policies for venous disease and, if significant gaps or inconsistencies are found, we hope to point them out, and, finally, to propose a thoughtful and reasonable policy based on the best available evidence.

A systematic review of the quality of cardiovascular surgery studies that extracted data from the MAUDE database.

OBJECTIVE: To investigate opportunities and limitations of using the Manufacturer and User Facility Device Experience (MAUDE) database for cardiovascular surgery research, we analyzed the quality of studies having ever used MAUDE, in the field of cardiovascular surgery. METHODS: We systematically searched the Cochrane Library, PubMed, EMBASE, and Google Scholar for randomized and nonrandomized studies, from inception to July 2019. Two authors evaluated the quality of the retrieved observational studies, according to the National Institutes of Health quality assessment tool for either case series or cross-sectional studies. These tools quantify the quality of case series and cohorts/cross-sectional studies, respectively, with nine and 14 queries. RESULTS: Fifty-eight studies were included in the final qualitative review. Of 58 identified studies, 32 were case series, 8 were abstracts of case series, and 13 were reviews or case discussion with an included series from MAUDE. Also, five articles were cross-sectional studies. Of the 32 formal case series, 26 (81%) were found to have poor quality. The most common reasons for a poor quality designation included a lack of consecutive participants, undetermined comparability of participants, and undetermined follow-up adequacy. Only one out of five cross-sectional studies had fair quality; four others were evaluated as poor quality studies. CONCLUSIONS: Cardiovascular surgery studies using the MAUDE database, whether case series or cross-sectional design, are mostly of poor quality. Their low quality is partly caused by poor study design, but mainly by intrinsic limitations to the MAUDE database: cases recruited are not consecutive; patient characteristics are not detailed enough to allow a meaningful comparison of patient characteristics between different patient entries; outcome measures are unclear; there is a limited follow-up; and time-to-event data are lacking. We conclude that the quality of cardiovascular surgery publications that rely on data from MAUDE could be improved if investigators were to extract all relevant data points from MAUDE entries, then apply standard quality assessment tools in compiling and reporting the data. MAUDE might be improved if it used medical case report standards during the process of reporting and indexing adverse events. To calculate the incidence rate of any adverse event, all event-free cases, as well as all adverse events in patients using a device, are required. Neither of these two variables is available in the MAUDE at the time of writing.

Correlation of disease comorbidity with prescribed treatment among insured U.S. lymphedema patients.

OBJECTIVE: The objective of this study was to define the current forms of treatment in a contemporary population of lymphedema (LED) patients for LED related to breast cancer, the most prevalently diagnosed LED comorbidity in Western countries, and phlebolymphedema with venous leg ulcer (PLEDU), a sequela of chronic venous disease. The goals of LED therapy are to reduce edema, thereby improving function and related symptoms, and to improve skin integrity to prevent development of infection. Treatment is generally nonsurgical: conservative care, including complex physical therapy, manual lymphatic drainage, and compression bandaging; or pneumatic compression device (PCD) therapy by a simple nonprogrammable device or an advanced programmable device. METHODS: To determine the frequency of individual types of treatment for LED and their relationship to breast cancer-related lymphedema (BCRL) and PLEDU, we queried claims from a deidentified Health Insurance Portability and Accountability Act-compliant commercial administrative insurance database with >165 million members. A total of 26,902 patients identified with LED who had been enrolled with continuous medical benefits for 12 months before and after the index date for the complete years 2012 through 2016 were separated into four treatment categories: no treatment, conservative care, simple PCD (SPCD), and advanced PCD. LED treatment was related to the BCRL and PLEDU comorbidities. RESULTS: BCRL patients, who represented 32.1% of all study patients, made up 41% of all patients receiving conservative care and 24% of patients receiving PCD therapy. By contrast, PLEDU patients (9.6% of study patients) were proportionally under-represented in the conservative care group (7.8%) but composed a disproportionately high share of the PCD therapy group (17.7%). PLEDU patients represented 23.5% of all LED patients prescribed SPCD therapy, whereas BCRL patients composed 10.3% of total LED patient SPCD prescriptions (P < .001). CONCLUSIONS: Our analysis of a large health care administrative database showed clear differences between the way BCRL and PLEDU patients are treated. Compared with BCRL patients, PLEDU patients were less likely to receive conservative care and more likely to be prescribed SPCDs for pneumatic compression therapy. These differences suggest that lymphatic therapy may be undervalued for treatment of chronic venous swelling and prevention and treatment of PLEDU.

The Dynamic Platelet Transcriptome in Obesity and Weight Loss.

OBJECTIVE: Adiposity is associated with oxidative stress, inflammation, and glucose intolerance. Previous data suggest that platelet gene expression is associated with key cardiometabolic phenotypes, including body mass index but stable in healthy individuals over time. However, modulation of gene expression in platelets in response to metabolic shifts (eg, weight reduction) is unknown and may be important to defining mechanism. Approach and Results: Platelet RNA sequencing and aggregation were performed from 21 individuals with massive weight loss (>45 kg) following bariatric surgery. Based on RNA sequencing data, we measured the expression of 67 genes from isolated platelet RNA using high-throughput quantitative reverse transcription quantitative PCR in 1864 FHS (Framingham Heart Study) participants. Many transcripts not previously studied in platelets were differentially expressed with bariatric surgical weight loss, appeared specific to platelets (eg, not differentially expressed in leukocytes), and were enriched for a nonalcoholic fatty liver disease pathway. Platelet aggregation studies did not detect alteration in platelet function after significant weight loss. Linear regression models demonstrated several platelet genes modestly associated with cross-sectional cardiometabolic phenotypes, including body mass index. There were no associations between studied transcripts and incident diabetes or cardiovascular end points. CONCLUSIONS: In summary, while there is no change in platelet aggregation function after significant weight loss, the human platelet experiences a dramatic transcriptional shift that implicates pathways potentially relevant to improved cardiometabolic risk postweight loss (eg, nonalcoholic fatty liver disease). Further studies are needed to determine the mechanistic importance of these observations.

Distal perfusion cannulae reduce extracorporeal membrane oxygenation-related limb ischemia.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a means of providing cardiopulmonary support that is being increasingly used in patients with acute heart failure. When ECMO cannulae are placed peripherally, their large diameters pose a risk of limb ischemia. Distal perfusion cannulae (DPC) have been proposed as means to reduce risk, but their use is not recommended by the most recent ECMO guidelines. We sought to establish their utility at our institution. METHODS: We performed a retrospective review of of all patients treated with peripheral VA-ECMO at our institution from 2013-2018. During the first 2 years, DPC were not routinely placed, whereas in the final 4 years, DPC were recommended as part of the ECMO cannulation routine. RESULTS: One hundred and one patients were treated with peripheral VA-ECMO, with an overall mortality of 61%. By univariate analysis, obesity (47% vs. 75%, P<0.01) and limb ischemia (57% vs. 83%, P<0.05) were associated with increased mortality. DPC were placed prophylactically in 49% of patients. Prophylactic placement of a DPC at the time of cannulation significantly reduced the incidence of limb ischemia (2% vs. 32%, P<0.05), but did not impact mortality (53% vs. 69%, P=0.0953). In patients who did not have a DPC placed during ECMO cannulation and subsequently developed limb ischemia, late DPC placement for limb salvage did not impact mortality. CONCLUSIONS: Limb ischemia portends a poor outcome in VA-ECMO patients, and prophylactic DPC placement significantly reduces the risk of limb ischemia. We propose prophylactic DPC placement be considered in patients requiring peripheral VA-ECMO.

A systematic review of guidelines for lymphedema and the need for contemporary intersocietal guidelines for the management of lymphedema.

OBJECTIVE: Lymphedema (LED) affects an estimated 35 million patients in the United States and a staggering 140,200 million people worldwide, yet LED is the forgotten vascular disease. Whereas the diagnosis and treatment of arterial and venous diseases have been strengthened by the development of clinical practice guidelines (CPGs), few CPGs are available for LED. Moreover, for CPGs to have their greatest impact, they should be both of high quality and developed using the most rigorous evidence-based methods. We performed a systematic review of the available CPGs for LED, which were assessed for breadth of content and methodologic strength. METHODS: A literature search was conducted from National Guideline Clearinghouse (www. GUIDELINES: gov), BMJ Clinical Evidence (http://clinicalevidence.bmj.com), and National Institute for Health and Care Excellence (http://www.nice.org.uk) as well as from MEDLINE and Google, which selected 245 documents. After a horizon scan that identified 13 potential CPGs, 4 satisfied the criteria for LED. These were analyzed for inclusion of key elements of diagnosis and treatment. RESULTS: A horizon scan (abstract review) of the 245 documents identified 10 potential CPGs. Of the 10 documents, 6 claimed to be CPGs, but 2 were limited in scope (rehabilitation or compression only), 2 were consensus statements, 1 was a position statement, and 1 was a systematic review. This process yielded four CPGs: Lymphedema Framework Best Practice for the Management of Lymphedema; Japanese Lymphedema Study Group-A Practice Guideline for the Management of Lymphedema; Clinical Resource Efficiency Support Team Guidelines for the Diagnosis, Assessment and Management of Lymphedema; and Guidelines of the American Venous Forum. Only one of four CPGs was based on a contemporary systematic review (2016 end date of references), whereas the remainder had older systematic reviews (end dates of 2005, 2007, and 2007). Several areas of contemporary diagnosis, treatment, and monitoring of LED were absent. CONCLUSIONS: This systematic review of available LED CPGs demonstrates a limited number of guidelines. The four CPGs identified lack contemporary references while demonstrating low overall study quality. Therefore, it is imperative for our vascular societies to develop contemporary high-quality evidence-based CPGs for LED, as they have for other vascular diseases.

A systematic review of the quality of clinical practice guidelines for lymphedema, as assessed using the Appraisal of Guidelines for Research and Evaluation II instrument.

OBJECTIVE: We assessed the quality of current clinical practice guidelines (CPGs) for lymphedema using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. CPGs provide recommendations for the management of medical conditions such as lymphedema. However, their evidentiary quality and methodology should determine their reliability. The AGREE II instrument was developed to externally and objectively evaluate the quality of CPGs and has been used to assess other nonvascular CPGs. A systematic review identified four CPGs for lymphedema of varying content: Lymphedema Framework's Best Practice for the Management of Lymphedema (LED F); Japanese Lymphedema Study Group-A Practice Guideline for the Management of Lymphedema (J LED); Clinical Resource Efficiency Support Team (CREST) Guidelines for the Diagnosis, Assessment and Management of Lymphedema; and Guidelines of the American Venous Forum (AVF). The quality of these CPGs appeared to vary. METHODS: The four CPGs were analyzed using the AGREE II instrument by three independent graders, who were unaware of each other's scores. Six domains with 23 items were graded using a Likert scale (1, strongly disagree; to 7, strongly agree) regarding whether the CPG had satisfied the requirements of each item. The score for each domain was calculated by summing the scores for each item in that domain and scaling the total as a percentage of the maximum possible score for that domain (ie, obtained score - minimum score/maximum possible score - minimum possible score × 100 = percentage). RESULTS: CREST had the highest overall score (66.8%), as an average of all domains, and J LED had the lowest (37%). CREST also had five of five domains rated >50%. In contrast, J LED had only one and AVF had only two domains that scored >50%. Although two domains, rigor of development and applicability, scored low, with only one CPG scoring >50%, the editorial independence domain scored the lowest of all six domains. CONCLUSIONS: In addition to limitations in content and the lack of contemporary references, the four CPGs studied were judged objectively to be of low quality using the AGREE II instrument. A contemporary CPG for lymphedema, guided by the AGREE II requirements, is needed.

A systematic review and meta-analysis of predilation and postdilation in transfemoral carotid artery stenting.

OBJECTIVE: In this review, we evaluate the short-term impact of different ballooning combinations on hemodynamic instability neurologic events, and mortality associated with carotid artery stenting. METHODS: We used a search strategy to identify studies in the Cochrane Library trials register, PubMed, EMBASE, Google Scholar, and the US National Library of Medicine clinical trial databases up to May 2019. Studies reporting either hemodynamic instability, neurologic events, or mortality were included according to the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-analysis. Fixed and random models were used to summarize the effects. RESULTS: Of seven included cohort studies for qualitative review, six were selected for meta-analysis. Patients without postdilation had significantly less hemodynamic instability in the random effects model (risk ratio, 0.53; 95% confidence interval, 0.37-0.77; P = .001). Regardless of the dilation type, the overall summary effect in the fixed model showed a significant decrease in the risk of developing short-term neurologic events (risk ratio, 0.67; 95% confidence interval, 0.47-0.97; P = .03). Last, the exclusion of either of the two dilation techniques had no significant effect on mortality. CONCLUSIONS: Avoiding postdilation reduces perioperative hemodynamic instability and this benefit lasts at least up to 30 days. Regardless of the type, fewer dilations during carotid artery stenting possibly decreases the neurologic events during and 30 days after the procedure. The data also suggest that the residual stenoses above current practiced standard may provide a safer threshold to prompt postdilation. Statements about the long-term effects of dilation techniques requires more study.

Proteins Altered by Surgical Weight Loss Highlight Biomarkers of Insulin Resistance in the Community.

Objective- Mechanisms of early and late improvements in cardiovascular risk after bariatric surgery and applicability to larger, at-risk populations remain unclear. We aimed to identify proteins altered after bariatric surgery and their relations to metabolic syndrome and diabetes mellitus. Approach and Results- We identified 19 proteins altered in 32 nonfasting plasma samples from a study of patients undergoing bariatric surgery who were evaluated preoperatively (visit 1) versus both early (visit 2; ≈3 months) and late (visit 3; ≈12 months) postoperative follow-up using predefined protein panels (Olink). Using in silico methods and publicly available gene expression repositories, we found that genes encoding 8 out of 19 proteins had highest expression in liver relative to other assayed tissues, with the top biological and disease processes, including major obesity-related vascular diseases. Of 19 candidate proteins in the surgical cohort, 6 were previously measured in >3000 FHS (Framingham Heart Study) participants (IGFBP [insulin-like growth factor binding protein]-1, IGFBP-2, P-selectin, CD163, LDL (low-density lipoprotein)-receptor, and PAI [plasminogen activator inhibitor]-1). A higher concentration of IGFBP-2 at baseline was associated with a lower risk of incident metabolic syndrome (odds ratio per log-normal unit, 0.45; 95% CI, 0.32-0.64; P=7.7×10-6) and diabetes mellitus (odds ratio, 0.63; 95% CI, 0.49-0.79; P=0.0001) after multivariable adjustment. Conclusions- Using a directed protein quantification platform (Olink), we identified known and novel proteins altered after surgical weight loss, including IGFBP-2. Future efforts in well-defined obesity intervention settings may further define and validate novel targets for the prevention of vascular disease in obesity.

Risk factors associated with the venous leg ulcer that fails to heal after 1 year of treatment.

BACKGROUND: Despite regular treatment of venous leg ulcers (VLUs), some fail to heal. Although several risk factors have previously been identified to be associated with the failure of VLUs to heal, the majority of studies are limited to <24-week follow-up. METHODS: A retrospective cohort study was performed at an academic vascular and wound center. A total of 65 patients with VLUs who were observed for a year or more were identified. These patients underwent a variety of treatments following the Society for Vascular Surgery and American Venous Forum VLU guidelines. Risk factors, which were based on previously defined elements for failure of VLUs to heal after a period of treatment, were examined. Both univariate (unadjusted) and multivariate (adjusted) logistic regression analyses were used to assess the magnitude of effect that a given risk factor had on healing. RESULTS: Of 65 patients treated for a minimum of 52 weeks, 19 (29%) remained unhealed. By univariate analysis, deep venous disease (P = .01; odds ratio [OR], 5.82; 95% confidence interval [CI], 1.49-22.72), history of deep venous thrombosis (P < .001; OR, 14.06; 95% CI, 3.77-52.39), and depression (P = .04; OR, 3.89; 95% CI, 1.10-13.80) were all shown to be significant risk factors for nonhealing. The patient's race (ie, being nonwhite; P = .02; OR, 103.45; 95% CI, 1.94-5.53 × 103), deep venous disease (P = .05; OR, 37.0; 95% CI, 1.05-1.31 × 103), and history of deep venous thrombosis (P = .01; OR, 122.4; 95% CI, 3.09-4.84 × 103), however, were all shown to be significant for nonhealing under multivariate analysis. In addition, identification of an incompetent perforator (P = .02; OR, 0.006; 95% CI, 9.27 × 10-5-0.44) was conversely shown to be a good prognostic factor for healing. CONCLUSIONS: This study confirmed that risk factors known to be associated with the failure of a VLU to heal-deep venous disease and post-thrombotic etiology-were significant at 52 weeks, whereas depression and race (nonwhite) are novel risk factors. An analysis of markers of access to care showed no difference between white and nonwhite, suggesting other factors as a cause. The predominance of deep venous disease in the unhealed vs healed cohort (84% vs 48%) highlights the need for a viable treatment option for deep venous disease due to reflux. Overall, this study emphasizes the need to consider all risk factors when evaluating a patient for VLU to coordinate an effective treatment plan and to identify gaps in our treatment.

Venography versus intravascular ultrasound for diagnosing and treating iliofemoral vein obstruction.

OBJECTIVE: The Venogram vs IVUS for Diagnosing Iliac vein Obstruction (VIDIO) trial was designed to compare the diagnostic efficacy of intravascular ultrasound (IVUS) with multiplanar venography for iliofemoral vein obstruction. METHODS: During a 14-month period beginning July 2014, 100 patients with chronic Clinical, Etiologic, Anatomic, and Pathophysiologic clinical class C4 to C6 venous disease and suspected iliofemoral vein obstruction were enrolled at 11 U.S. and 3 European sites. The inferior vena cava and common iliac, external iliac, and common femoral veins were imaged. Venograms were measured for vein diameter; IVUS provided diameter and area measurements. Multiplanar venograms included three views: anteroposterior and 30-degree right and left anterior oblique views. A core laboratory evaluated the deidentified images, determining stenosis severity as the ratio between minimum luminal diameter and reference vessel diameter, minimal luminal area, and reference vessel area. A 50% diameter stenosis by venography and a 50% cross-sectional area reduction by IVUS were considered significant. Analyses assessed change in procedures performed on the basis of imaging method and concordance of measurements between each imaging method. RESULTS: Venography identified stenotic lesions in 51 of 100 subjects, whereas IVUS identified lesions in 81 of 100 subjects. Compared with IVUS, the diameter reduction was on average 11% less for venography (P < .001). The intraclass correlation coefficient was 0.505 for vein diameter stenosis calculated with the two methods. IVUS identified significant lesions not detected with three-view venography in 26.3% of patients. Investigators revised the treatment plan in 57 of 100 cases after IVUS, most often because of failure of venography to detect a significant lesion (41/57 [72%]). IVUS led to an increased number of stents in 13 of 57 subjects (23%) and the avoidance of an endovascular procedure in 3 of 57 subjects (5%). Overall, IVUS imaging changed the treatment plan in 57 patients; 54 patients had stents placed on the basis of IVUS detection of significant iliofemoral vein obstructive lesions not appreciated with venography, whereas 3 patients with significant lesions on venography had no stent placed on the basis of IVUS. CONCLUSIONS: IVUS is more sensitive for assessing treatable iliofemoral vein stenosis compared with multiplanar venography and frequently leads to revised treatment plans and the potential for improved clinical outcome.

Histology and Biaxial Mechanical Behavior of Abdominal Aortic Aneurysm Tissue Samples.

Abdominal aortic aneurysms (AAAs) represent permanent, localized dilations of the abdominal aorta that can be life-threatening if progressing to rupture. Evaluation of risk of rupture depends on understanding the mechanical behavior of patient AAA walls. In this project, a series of patient AAA wall tissue samples have been evaluated through a combined anamnestic, mechanical, and histopathologic approach. Mechanical properties of the samples have been characterized using a novel, strain-controlled, planar biaxial testing protocol emulating the in vivo deformation of the aorta. Histologically, the tissue ultrastructure was highly disrupted. All samples showed pronounced mechanical stiffening with stretch and were notably anisotropic, with greater stiffness in the circumferential than the axial direction. However, there were significant intrapatient variations in wall stiffness and stress. In biaxial tests in which the longitudinal stretch was held constant at 1.1 as the circumferential stretch was extended to 1.1, the maximum average circumferential stress was 330 ± 70 kPa, while the maximum average axial stress was 190 ± 30 kPa. A constitutive model considering the wall as anisotropic with two preferred directions fit the measured data well. No statistically significant differences in tissue mechanical properties were found based on patient gender, age, maximum bulge diameter, height, weight, body mass index, or smoking history. Although a larger patient cohort is merited to confirm these conclusions, the project provides new insight into the relationships between patient natural history, histopathology, and mechanical behavior that may be useful in the development of accurate methods for rupture risk evaluation.

Cost analysis and implications of routine deep venous thrombosis duplex ultrasound scanning after endovenous ablation.

BACKGROUND: Duplex ultrasound (DUS) is performed by the majority of physicians after endovenous ablation (EVA) of the great saphenous vein to screen for endovenous heat-induced thrombosis (EHIT) at the saphenofemoral junction extending into the femoral vein. Several factors should be considered in assessing the value and cost of routine DUS after EVA: the natural history of EHIT is poorly defined, the incidence appears low, and the majority are both asymptomatic and Kabnick type 2 (projecting only slightly into the femoral vein). Moreover, routine postoperative DUS screening is not recommended for procedures with higher thromboembolic complication rates, such as joint replacement or bariatric surgery. METHODS: Data on the incidence of death, EHIT, and deep venous thrombosis (DVT) were derived from a systematic review after either radiofrequency or laser ablation of the saphenous vein from two sources: (1) EVA randomized controlled trials (N = 1482) and a (2) large (>150 patients) EVA case series (N = 12,363). The number of tests required to detect one case of EHIT/DVT was calculated from the incidence in the EVA and case series data bases; the cost to detect a case was estimated using the 2013 Medicare global fee schedule for the cost of a unilateral venous DUS study. RESULTS: This analysis included 13,845 EVA-treated limbs. There were no reported deaths. The incidence of DUS-detected venous thromboembolism after EVA is 0.7%. The cost of unilateral DUS according to the Medicare global reimbursement fee for office-based studies is $106.71. The total cost of performing DUS in this study population is estimated to be at least $1,477,399, and the amount of dollars expended per venous thromboembolism detected is $14,667. CONCLUSIONS: The current Society for Vascular Surgery/American Venous Forum recommendation is to perform screening DUS after EVA within 72 hours postoperatively with a weak level of recommendation (grade 2C). The current analysis demonstrates a low incidence of EHIT/DVT with a corresponding high cost to detect each case with routine DUS screening. These data combined with the unclear clinical significance of EHIT suggest that the policy of universal post-EVA screening should be revised in the near future.

Matrix- and plasma-derived peptides promote tissue-specific injury responses and wound healing in diabetic swine.

BACKGROUND: Non-healing wounds are a major global health concern and account for the majority of non-traumatic limb amputations worldwide. However, compared to standard care practices, few advanced therapeutics effectively resolve these injuries stemming from cardiovascular disease, aging, and diabetes-related vasculopathies. While matrix turnover is disrupted in these injuries, debriding enzymes may promote healing by releasing matrix fragments that induce cell migration, proliferation, and morphogenesis, and plasma products may also stimulate these processes. Thus, we created matrix- and plasma-derived peptides, Comb1 and UN3, which induce cellular injury responses in vitro, and accelerate healing in rodent models of non-healing wounds. However, the effects of these peptides in non-healing wounds in diabetes are not known. Here, we interrogated whether these peptides stimulate healing in a diabetic porcine model highly reminiscent of human healing impairments in type 1 and type 2-diabetes. METHODS: After 3-6 weeks of streptozotocin-induced diabetes, full-thickness wounds were surgically created on the backs of adult female Yorkshire swine under general anesthesia. Comb1 and UN3 peptides or sterile saline (negative control) were administered to wounds daily for 3-7 days. Following sacrifice, wound tissues were harvested, and quantitative histological and immunohistochemical analyses were performed for wound closure, angiogenesis and granulation tissue deposition, along with quantitative molecular analyses of factors critical for angiogenesis, epithelialization, and dermal matrix remodeling. RESULTS: Comb1 and UN3 significantly increase re-epithelialization and angiogenesis in diabetic porcine wounds, compared to saline-treated controls. Additionally, fluorescein-conjugated Comb1 labels keratinocytes, fibroblasts, and vascular endothelial cells in porcine wounds, and Far western blotting reveals these cell populations express multiple fluorescein-Comb1-interacting proteins in vitro. Further, peptide treatment increases mRNA expression of several pro-angiogenic, epithelializing, and matrix-remodeling factors, importantly including balanced inductions in matrix metalloproteinase-2, -9, and tissue inhibitor of metalloproteinases-1, lending further insight into their mechanisms. CONCLUSIONS: Comb1 and UN3 stimulate wound resolution in diabetic Yorkshire swine through upregulation of multiple reparative growth factors and cytokines, especially matrix metalloproteinases and inhibitors that may aid in reversing the proteolytic imbalance characteristic of chronically inflamed non-healing wounds. Together, these peptides should have great therapeutic potential for all patients in need of healing, regardless of injury etiology.