An In-Vitro Comparison of Steady State Leakage Rates through Introducer Sheaths Used for Fenestrated Endovascular Aortic Aneurysm Repair.

BACKGROUND: Fenestrated Endovascular Aneurysm Repair (fEVAR) involves deploying a covered stent into the aorta followed by multiple visceral stents through fenestrations in the main body of graft. The most commonly used large sheaths for cannulation of visceral vessels are the Gore DrySeal Flex, Cook Performer Check-Flo, and Medtronic Sentrant. None of these sheaths were designed for the insertion of multiple sheaths, and so a slow but steady leakage of blood occurs during the procedure. The aim of this paper is to assess in an in vitro setting which large bore sheath has the best valve for use when multiple smaller sheaths are inserted through it. METHODS: Three large bore introducer sheaths (LBISs) were used for this study, The Gore DrySeal Flex LBIS, Medtronic Sentrant LBIS and Cook Performer Check-Flo LBIS. A test rig was constructed, made of an 18-liter fluid reservoir mounted vertically and receiving a constant supply of water from a domestic water supply which flowed into the reservoir and out of an overflow. The reservoir was connected to the LBIS by a vertical plastic pipe with an internal diameter of 40 mm and an isolation valve. The LBIS was connected to the isolation valve by inserting the LBIS up a flexible silicone tube connected to the isolation valve. The LBIS was subject to a constant column/pressure of water and fluid leakage from the LBIS was collected in a plastic pot/tray placed underneath the LBIS. The leakage rates through each LBIS were determined for the following smaller diameter sheath combinations inserted through the valve, one 6 French Sheath, two 6 French Sheaths, two 6 French Sheaths and one 7 French Sheath. This was done to closely mimic a fEVAR procedure in vitro. The procedure was to insert different sheath combinations through the nonreturn valves in the LBIS and measure the volume of fluid that leaked through the valves. The leaked fluid was weighed, and the weight was converted to volume using the density of water (1 g/ml). RESULTS: The average (mean) leakage rates for each LBIS and each sheath combination showed that leakage rates when only one sheath was inserted were very low. For all 3 LBIS's tested, the leakage rates increased dramatically when multiple sheaths were inserted. The Medtronic LBIS leaked the most, followed by Cook, followed by Gore. For the Cook LBIS, the leakage rates exhibited with 2 × 6 French sheaths were approx. 106 times greater than those for the Gore LBIS and 5 times greater for the 2 × 6 French +1 × 7 French sheath combination. A similar comparison for the Medtronic LBIS versus the Gore LBIS yields factors of 132 and 8. CONCLUSIONS: Leakage rates increase significantly when multiple sheaths are inserted and the Gore LBIS demonstrates significantly lower leakage than both the Cook and Medtronic during procedures that require simultaneous, multiple insertions of smaller sheaths. Although the Gore Dryseal has by far the lowest leakage rate when 3 small diameter sheaths are inserted (just under 1 ml/s), depending on the duration of the procedure this could still result in significant blood loss.

Novel Glycomimetics Protect against Glycated Low-Density Lipoprotein-Induced Vascular Calcification In Vitro via Attenuation of the RAGE/ERK/CREB Pathway.

Heparan sulphate (HS) can act as a co-receptor on the cell surface and alterations in this process underpin many pathological conditions. We have previously described the usefulness of mimics of HS (glycomimetics) in protection against ß-glycerophosphate-induced vascular calcification and in the restoration of the functional capacity of diabetic endothelial colony-forming cells in vitro. This study aims to investigate whether our novel glycomimetic compounds can attenuate glycated low-density lipoprotein (g-LDL)-induced calcification by inhibiting RAGE signalling within the context of critical limb ischemia (CLI). We used an established osteogenic in vitro vascular smooth muscle cell (VSMC) model. Osteoprotegerin (OPG), sclerostin and glycation levels were all significantly increased in CLI serum compared to healthy controls, while the vascular calcification marker osteocalcin (OCN) was down-regulated in CLI patients vs. controls. Incubation with both CLI serum and g-LDL (10 µg/mL) significantly increased VSMC calcification vs. controls after 21 days, with CLI serum-induced calcification apparent after only 10 days. Glycomimetics (C2 and C3) significantly inhibited g-LDL and CLI serum-induced mineralisation, as shown by a reduction in alizarin red (AR) staining and alkaline phosphatase (ALP) activity. Furthermore, secretion of the osteogenic marker OCN was significantly reduced in VSMCs incubated with CLI serum in the presence of glycomimetics. Phosphorylation of cyclic AMP response element-binding protein (CREB) was significantly increased in g-LDL-treated cells vs. untreated controls, which was attenuated with glycomimetics. Blocking CREB activation with a pharmacological inhibitor 666-15 replicated the protective effects of glycomimetics, evidenced by elevated AR staining. In silico molecular docking simulations revealed the binding affinity of the glycomimetics C2 and C3 with the V domain of RAGE. In conclusion, these findings demonstrate that novel glycomimetics, C2 and C3 have potent anti-calcification properties in vitro, inhibiting both g-LDL and CLI serum-induced VSMC mineralisation via the inhibition of LDLR, RAGE, CREB and subsequent expression of the downstream osteogenic markers, ALP and OCN.

Staphylococcus aureus surgical site infection rates in 5 European countries.

OBJECTIVE: To determine the overall and procedure-specific incidence of surgical site infections (SSI) caused by Staphylococcus aureus (S. aureus) as well as risk factors for such across all surgical disciplines in Europe. METHODS: This is a retrospective cohort of patients with surgical procedures performed at 14 European centres in 2016, with a nested case-control analysis. S. aureus SSI were identified by a semi-automated crossmatching bacteriological and electronic health record data. Within each surgical procedure, cases and controls were matched using optimal propensity score matching. RESULTS: A total of 764 of 178 902 patients had S. aureus SSI (0.4%), with 86.0% of these caused by methicillin susceptible and 14% by resistant pathogens. Mean S. aureus SSI incidence was similar for all surgical specialties, while varying by procedure. CONCLUSIONS: This large procedure-independent study of S. aureus SSI proves a low overall infection rate of 0.4% in this cohort. It provides proof of principle for a semi-automated approach to utilize big data in epidemiological studies of healthcare-associated infections. Trials registration The study was registered at clinicaltrials.gov under NCT03353532 (11/2017).

Personalised nitinol stent for focal plaques: Design and evaluation.

The purpose of this study is to develop personalised nitinol stents for arteries with one and two opposite focal plaques. Novel designs are evaluated through comparison with a commercial stent design, in terms of lumen gain and shape as well as stress levels in the media layer after stenting. METHODS: Personalised stents are developed for arteries with one and two opposite focal plaques, based on medical imaging of patients and computer simulations. In silico analysis is then carried out for assessment of stent performance in the diseased arteries. RESULTS: Personalised designs significantly increase the lumen gain, reduce the stresses in the media layer, and improve the lumen shape compared to the commercial nitinol stent. CONCLUSION: The personalised designs show outstanding performance compared to the commercial stent. SIGNIFICANCE: This pilot study proves that personalised nitinol stents are able to deliver desirable treatment outcomes.

Loss of SIRT1 in diabetes accelerates DNA damage-induced vascular calcification.

AIMS: Vascular calcification is a recognized predictor of cardiovascular risk in the diabetic patient, with DNA damage and accelerated senescence linked to oxidative stress-associated pathological calcification. Having previously shown that systemic SIRT1 is reduced in diabetes, the aim was to establish whether SIRT1 is protective against a DNA damage-induced senescent and calcified phenotype in diabetic vascular smooth muscle cells (vSMCs). METHODS AND RESULTS: Immunohistochemistry revealed decreased SIRT1 and increased DNA damage marker expression in diabetic calcified arteries compared to non-diabetic and non-calcified controls, strengthened by findings that vSMCs isolated from diabetic patients show elevated DNA damage and senescence, assessed by the Comet assay and telomere length. Hyperglycaemic conditions were used and induced DNA damage and enhanced senescence in vSMCs in vitro. Using H2O2 as a model of oxidative stress-induced DNA damage, pharmacological activation of SIRT1 reduced H2O2 DNA damage-induced calcification, prevented not only DNA damage, as shown by reduced comet tail length, but also decreased yH2AX foci formation, and attenuated calcification. While Ataxia Telanglectasia Mutated (ATM) expression was reduced following DNA damage, in contrast, SIRT1 activation significantly increased ATM expression, phosphorylating both MRE11 and NBS1, thus allowing formation of the MRN complex and increasing activation of the DNA repair pathway. CONCLUSION: DNA damage-induced calcification is accelerated within a diabetic environment and can be attenuated in vitro by SIRT1 activation. This occurs through enhancement of the MRN repair complex within vSMCs and has therapeutic potential within the diabetic patient.

Numerical simulations of patient-specific models with multiple plaques in human peripheral artery: a fluid-structure interaction analysis.

Atherosclerotic plaque in the femoral is the leading cause of peripheral artery disease (PAD), the worse consequence of which may lead to ulceration and gangrene of the feet. Numerical studies on fluid-structure interactions (FSI) of atherosclerotic femoral arteries enable quantitative analysis of biomechanical features in arteries. This study aims to investigate the hemodynamic performance and its interaction with femoral arterial wall based on the patient-specific model with multiple plaques (calcified and lipid plaques). Three types of models, calcification-only, lipid-only and calcification-lipid models, are established. Hyperelastic material coefficients of the human femoral arteries obtained from experimental studies are employed for all simulations. Oscillation of WSS is observed in the healthy downstream region in the lipid-only model. The pressure around the plaques in the two-plaque model is lower than that in the corresponding one-plaque models due to the reduction of blood flow domain, which consequently diminishes the loading forces on both plaques. Therefore, we found that stress acting on the plaques in the two-plaque model is lower than that in the corresponding one-plaque models. This finding implies that the lipid plaque, accompanied by the calcified plaque around, might reduce its risk of rupture due to the reduced the stress acting on it.

A Literature Review and Case Series of DVT Patients with Absent IVC Treated with Thrombolysis.

BACKGROUND: Congenital absence of the inferior vena cava is related to deep venous thrombosis (DVT) in 5% of cases with no other risk factors. DVT is normally diagnosed by Duplex, whereas computerized tomography or magnetic resonance imaging is required to visualize this absence, and so, it is often missed but ought to be considered in young patients. There are many existing cases in the literature illustrating this link, but these patients were often managed conservatively with anticoagulation. CASE SERIES: We report five cases presenting with a DVT who were found to have an absent inferior vena cava after imaging and were treated successfully with thrombolysis and consequently managed with lifelong anticoagulation, between January 2014 and January 2019. CONCLUSIONS: Anomalies of the inferior vena cava can cause unprovoked DVT. These anomalies are often incidental findings after CT but could change the management plan in these patients. Treatment can be with anticoagulants only, thrombolysis, thrombectomy, balloon angioplasty or stents, and long-term or lifelong anticoagulation to prevent DVT recurrence.

Generation of Human-Induced Pluripotent Stem Cells From Anterior Cruciate Ligament.

Human-induced pluripotent stem cells (hiPSCs) are reprogrammed somatic cells and are an excellent cell source for tissue engineering applications, disease modeling, and for understanding human development. HiPSC lines have now been generated from a diverse range of somatic cell types and have been reported to retain an epigenetic memory of their somatic origin. To date, the reprogramming of a true ligament has not been reported. The aim of this study is to generate iPSCs from human anterior cruciate ligament (ACL) cells. ACL cells from three above-knee amputation donors, with donor matched dermal fibroblasts (DFs) were tested for reprogramming using an existing DF reprogramming protocol. ACL cells were, however, more sensitive than donor matched DF to transforming growth factor-ß (TGF-ß); displaying marked contraction, increased proliferation and increased TNC and COMP expression in vitro, which hindered reprogramming to iPSCs. Modification of the protocol by scoring the cell monolayer or by removal of TGF-ß during ACL reprogramming resulted in emerging colonies being easier to identify and extract, increasing reprogramming efficiency. Following 30 passages in culture, the generated ACL derived iPSCs displayed pluripotency markers, normal karyotype and can successfully differentiate to cells of the three embryonic germ layers. This study illustrates it is possible to generate hiPSCs from ligament and identifies optimized ligament reprogramming conditions. ACL derived iPSCs may provide a promising cell source for ligament and related tissue engineering applications. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society J Orthop Res 38:92-104, 2020.

Stratification of knee osteoarthritis: two major patient subgroups identified by genome-wide expression analysis of articular cartilage.

INTRODUCTION: Osteoarthritis (OA) is a heterogeneous and complex disease. We have used a network biology approach based on genome-wide analysis of gene expression in OA knee cartilage to seek evidence for pathogenic mechanisms that may distinguish different patient subgroups. METHODS: Results from RNA-Sequencing (RNA-Seq) were collected from intact knee cartilage at total knee replacement from 44 patients with OA, from 16 additional patients with OA and 10 control patients with non-OA. Results were analysed to identify patient subsets and compare major active pathways. RESULTS: The RNA-Seq results showed 2692 differentially expressed genes between OA and non-OA. Analysis by unsupervised clustering identified two distinct OA groups: Group A with 24 patients (55%) and Group B with 18 patients (41%). A 10 gene subgroup classifier was validated by RT-qPCR in 16 further patients with OA. Pathway analysis showed increased protein expression in both groups. PhenomeExpress analysis revealed group differences in complement activation, innate immune responses and altered Wnt and TGFß signalling, but no activation of inflammatory cytokine expression. Both groups showed suppressed circadian regulators and whereas matrix changes in Group A were chondrogenic, in Group B they were non-chondrogenic with changes in mechanoreceptors, calcium signalling, ion channels and in cytoskeletal organisers. The gene expression changes predicted 478 potential biomarkers for detection in synovial fluid to distinguish patients from the two groups. CONCLUSIONS: Two subgroups of knee OA were identified by network analysis of RNA-Seq data with evidence for the presence of two major pathogenic pathways. This has potential importance as a new basis for the stratification of patients with OA for drug trials and for the development of new targeted treatments.

Giant Hepatic Aneurysm Presenting With Hematemesis Successfully Treated With an Endovascular Technique.

Hepatic artery aneurysms are uncommon visceral aneurysms that are usually found incidentally on imaging. We present a case of large common hepatic aneurysm presenting with life-threatening hematemesis due to duodenal erosion, in a 66-year-old man, treated by embolization with Onyx and coils while preserving hepatic perfusion.

Elevated levels of endothelial-derived microparticles, and serum CXCL9 and SCGF-ß are associated with unstable asymptomatic carotid plaques.

Endothelial microparticles (EMPs) are released from dysfunctional endothelial cells. We hypothesised that patients with unstable carotid plaque have higher levels of circulating microparticles compared to patients with stable plaques, and may correlate with serum markers of plaque instability and inflammation. Circulating EMPs, platelet MPs (PMPs) and inflammatory markers were measured in healthy controls and patients undergoing carotid endarterectomy. EMP/PMPs were quantified using flow cytometry. Bioplex assays profiled systemic inflammatory and bone-related proteins. Immunohistological analysis detailed the contribution of differentially-regulated systemic markers to plaque pathology. Alizarin red staining showed calcification. EMPs and PMPs were significantly higher in patients with carotid stenosis (≥ 70%) compared to controls, with no differences between asymptomatic vs symptomatic patients. Asymptomatic patients with unstable plaques exhibited higher levels of EMPs, CXCL9 and SCGF-ß compared to those with stable plaques. CXCL9, and SCGF-ß were detected within all plaques, suggesting a contribution to both localised and systemic inflammation. Osteopontin and osteoprotegerin were significantly elevated in the symptomatic vs asymptomatic group, while osteocalcin was higher in asymptomatic patients with stable plaque. All plaques exhibited calcification, which was significantly greater in asymptomatic patients. This may impact on plaque stability. These data could be important in identifying patients at most benefit from intervention.

Popliteal artery pseudoaneurysm treated with covered stent placement and thrombolysis: a case report.

Pseudoaneurysms of the popliteal artery are a rare clinical entity, accounting for <4% of all popliteal aneurysms. Accurate diagnosis and effective intervention is required to prevent potentially limb-threatening complications. We present the case of a 37-year-old man with acute limb ischaemia due to distal calf vessel thrombosis secondary to a popliteal pseudoaneurysm that was managed with covered stent placement and thrombolysis.

Novel methods for accurate identification, isolation, and genomic analysis of symptomatic microenvironments in atherosclerotic arteries.

A challenge facing surgeons is identification and selection of patients for carotid endarterectomy or coronary artery bypass/surgical intervention. While some patients with atherosclerosis develop unstable plaques liable to undergo thrombosis, others form more stable plaques and are asymptomatic. Identification of the cellular signaling mechanisms associated with production of the inflammatory, hemorrhagic lesions of mature heterogenic plaques will help significantly in our understanding of the differences in microenvironment associated with development of regions susceptible to rupture and thrombosis and may help to predict the risk of plaque rupture and guide surgical intervention to patients who will most benefit. Here, we demonstrate detailed and novel methodologies for successful and, more importantly, accurate and reproducible extraction, sampling, and analysis of micro-regions in stable and unstable coronary/carotid arteries. This information can be applied to samples from other origins and so should be useful for scientists working with micro-isolation techniques in all fields of biomedical science.

Endovascular repair of aortic arch false aneurysm with branched endograft.

This case report describes the use of a customized branched device for the treatment of a distal anastomotic false aneurysm in an ascending to descending interposition graft in a 34-year-old Jehovah's Witness with congenital aortic arch interruption. A single branched customized stent graft device was used to successfully exclude the false aneurysm. The procedure was challenging due to the abnormal congenital anatomy. The planning, operative technique, and successful execution are described in this case report.

Treatment of aortoiliac aneurysms with the iliac bifurcated device for preservation of internal iliac artery flow.

INTRODUCTION: The iliac bifurcated device (IBD) is an innovative endovascular device for aortoiliac aneurysm repair. The objective of this study is to provide further evidence on the efficacy and safety of the device. STUDY DESIGN: Case series study with retrospective analysis of prospectively collected nonrandomized data. METHODS: Between 2007 and 2010, all consecutive IBD placements were analyzed. The main outcomes included (1) technical failure; (2) morbidity and mortality; and (3) late outcomes. Prospective follow-up was performed by interval computed tomography scanning. RESULTS: In all, 27 consecutive patients had elective placement of 28 IBDs. Mean operating time was 251.1 ± 65.4 minutes, mean fluoroscopy time was 63.9 ± 27.2 minutes, and mean contrast volume used was 186.2 ± 106.7 mL. Periprocedural type I endoleak occurred in 2 patients. No aneurysm-related adverse events were recorded. CONCLUSION: We demonstrate that IBDs can be used in patients with aortoiliac aneurysms and are associated with satisfactory medium-term results as expressed by high patency and low reintervention rates.

Endovascular aortic repair with the chimney technique using the ultra low-profile Ovation stent-graft for juxtarenal aneurysms having small iliac access vessels.

PURPOSE: To report the first experience using the chimney technique in combination with the latest-generation low-profile stent-graft to seal abdominal aortic aneurysms having a very short neck (proximal sealing zone) and difficult access due to very small iliac vessels. MATERIALS AND METHODS: Use of an ultra low-profile 14F delivery aortic stent-graft system (Ovation; Trivascular, Santa Rosa, CA) with chimneys to the lowermost renal arteries in two patients who were not anatomically suitable for endovascular aortic aneurysm repair (EVAR) and too frail for open surgery. RESULTS: Implantation of stent-grafts and chimneys was technically successful without endoleak or other postinterventional complications. Follow-up after >1 year confirmed complete aneurysm exclusion, shrinkage of the aneurysm sac, and patent renal perfusion by way of the chimney. CONCLUSION: Ultra low-profile aortic stent-graft systems are particularly helpful in case of inadequate small iliac access vessels and allow EVAR for short-necked aortic aneurysms if technical contraindications obviate FEVAR and physical impairment discourages open surgical repair.

Meta-analysis of outcomes of endovascular treatment of infrapopliteal occlusive disease with drug-eluting stents.

PURPOSE: To review emerging evidence regarding the use of bare metal (BMS) vs. drug-eluting stents (DES) in the treatment of infrapopliteal occlusive disease. METHODS: A systematic review of the literature was undertaken to identify all studies comparing stent treatments of infragenicular vessels in patients with chronic lower limb ischemia. Validated methods to assess the methodological quality of the included studies were applied. Outcome data were pooled, and combined overall effect sizes were calculated using fixed or random effects models. The search identified 4 randomized clinical trials and 2 observational studies reporting on 544 patients (287 treated with DES and 257 treated with BMS). Data are presented as the odds ratio (OR) with 95% confidence interval (CI) and the number-needed-to-treat (NNT). RESULTS: Primary patency, freedom from target lesion revascularization, and clinical improvement at 1 year were significantly higher in the DES recipients compared to patients treated with BMS (OR 4.511, 95% CI 2.897 to 7.024, p<0.001, NNT 3.5; OR 3.238, 95% CI 2.019 to 5.192, p<0.001, NNT 6.0; and OR 1.792, 95% CI 1.039 to 3.090, p=0.036, NNT 7.3, respectively). No significant differences in limb salvage and overall survival at 1 year were identified between the groups (OR 2.008, 95% CI 0.722 to 5.585, p=0.181; OR 1.262, 95% CI 0.605 to 2.634, p=0.535, respectively). Sensitivity analyses investigating the potential effects of study design and type of DES on the combined outcome estimates validated the results. CONCLUSION: Our analysis has demonstrated superior short-term results with DES compared with BMS, expressed by increased patency and freedom from target lesion revascularization. The influence of this finding on clinical surrogate endpoints, such as limb salvage, remains unknown.