Protective Role for Smooth Muscle Cell Hepcidin in Abdominal Aortic Aneurysm.

BACKGROUND: Hepcidin is a liver-derived hormone that controls systemic iron homeostasis, by inhibiting the iron exporter ferroportin in the gut and spleen, respective sites of iron absorption and recycling. Hepcidin is also expressed ectopically in the context of cardiovascular disease. However, the precise role of ectopic hepcidin in underlying pathophysiology is unknown. In patients with abdominal aortic aneurysm (AAA), hepcidin is markedly induced in smooth muscle cells (SMCs) of the aneurysm wall and inversely correlated with the expression of LCN2 (lipocalin-2), a protein implicated in AAA pathology. In addition, plasma hepcidin levels were inversely correlated with aneurysm growth, suggesting hepcidin has a potential disease-modifying role. METHODS: To probe the role of SMC-derived hepcidin in the setting of AAA, we applied AngII (Angiotensin-II)-induced AAA model to mice harbouring an inducible, SMC-specific deletion of hepcidin. To determine whether SMC-derived hepcidin acted cell-autonomously, we also used mice harboring an inducible SMC-specific knock-in of hepcidin-resistant ferroportinC326Y. The involvement of LCN2 was established using a LCN2-neutralizing antibody. RESULTS: Mice with SMC-specific deletion of hepcidin or knock-in of hepcidin-resistant ferroportinC326Y had a heightened AAA phenotype compared with controls. In both models, SMCs exhibited raised ferroportin expression and reduced iron retention, accompanied by failure to suppress LCN2, impaired autophagy in SMCs, and greater aortic neutrophil infiltration. Pretreatment with LCN2-neutralizing antibody restored autophagy, reduced neutrophil infiltration, and prevented the heightened AAA phenotype. Finally, plasma hepcidin levels were consistently lower in mice with SMC-specific deletion of hepcidin than in controls, indicating that SMC-derived hepcidin contributes to the circulating pool in AAA. CONCLUSIONS: Hepcidin elevation in SMCs plays a protective role in the setting of AAA. These findings are the first demonstration of a protective rather than deleterious role for hepcidin in cardiovascular disease. They highlight the need to further explore the prognostic and therapeutic value of hepcidin outside disorders of iron homeostasis.

Twelve tips for designing and implementing peer-led assessment writing schemes in health professions education.

Peer-led assessment (PLA) has gained increasing prominence within health professions education as an effective means of engaging learners in the process of assessment writing and practice. Involving students in various stages of the assessment lifecycle, including item writing, quality assurance, and feedback, not only facilitates the creation of high-quality item banks with minimal faculty input but also promotes the development of students' assessment literacy and fosters their growth as teachers. The advantages of involving students in the generation of assessments are evident from a pedagogical standpoint, benefiting both students and faculty. However, faculty members may face uncertainty when it comes to implementing such approaches effectively. To address this concern, this paper presents twelve tips that offer guidance on important considerations for the successful implementation of peer-led assessment schemes in the context of health professions education.

Prediction of Abdominal Aortic Aneurysm Growth Using Geometric Assessment of Computerized Tomography Images Acquired During the Aneurysm Surveillance Period.

OBJECTIVE: We investigated the utility of geometric features for future AAA growth prediction. BACKGROUND: Novel methods for growth prediction of AAA are recognized as a research priority. Geometric feature have been used to predict cerebral aneurysm rupture, but not examined as predictor of AAA growth. METHODS: Computerized tomography (CT) scans from patients with infra-renal AAAs were analyzed. Aortic volumes were segmented using an automated pipeline to extract AAA diameter (APD), undulation index (UI), and radius of curvature (RC). Using a prospectively recruited cohort, we first examined the relation between these geometric measurements to patients' demographic features (n = 102). A separate 192 AAA patients with serial CT scans during AAA surveillance were identified from an ongoing clinical database. Multinomial logistic and multiple linear regression models were trained and optimized to predict future AAA growth in these patients. RESULTS: There was no correlation between the geometric measurements and patients' demographic features. APD (Spearman r = 0.25, P < 0.05), UI (Spearman r = 0.38, P < 0.001) and RC (Spearman r =-0.53, P < 0.001) significantly correlated with annual AAA growth. Using APD, UI, and RC as 3 input variables, the area under receiver operating characteristics curve for predicting slow growth (<2.5 mm/yr) or fast growth (>5 mm/yr) at 12 months are 0.80 and 0.79, respectively. The prediction or growth rate is within 2 mm error in 87% of cases. CONCLUSIONS: Geometric features of an AAA can predict its future growth. This method can be applied to routine clinical CT scans acquired from patients during their AAA surveillance pathway.

A Deep Learning Approach to Visualize Aortic Aneurysm Morphology Without the Use of Intravenous Contrast Agents.

BACKGROUND: Intravenous contrast agents are routinely used in CT imaging to enable the visualization of intravascular pathology, such as with abdominal aortic aneurysms. However, the injection is contraindicated in patients with iodine allergy and is associated with renal complications. OBJECTIVES: In this study, we investigate if the raw data acquired from a noncontrast CT image contains sufficient information to differentiate blood and other soft tissue components. A deep learning pipeline underpinned by generative adversarial networks was developed to simulate contrast enhanced CTA images using noncontrast CTs. METHODS AND RESULTS: Two generative models (cycle- and conditional) are trained with paired noncontrast and contrast enhanced CTs from seventy-five patients (total of 11,243 pairs of images) with abdominal aortic aneurysms in a 3-fold cross-validation approach with a training/testing split of 50:25 patients. Subsequently, models were evaluated on an independent validation cohort of 200 patients (total of 29,468 pairs of images). Both deep learning generative models are able to perform this image transformation task with the Cycle-generative adversarial network (GAN) model outperforming the Conditional-GAN model as measured by aneurysm lumen segmentation accuracy (Cycle-GAN: 86.1% ± 12.2% vs Con-GAN: 85.7% ± 10.4%) and thrombus spatial morphology classification accuracy (Cycle-GAN: 93.5% vs Con-GAN: 85.7%). CONCLUSION: This pipeline implements deep learning methods to generate CTAs from noncontrast images, without the need of contrast injection, that bear strong concordance to the ground truth and enable the assessment ofimportant clinical metrics. Our pipeline is poised to disrupt clinical pathways requiring intravenous contrast.

CD200 Limits Monopoiesis and Monocyte Recruitment in Atherosclerosis.

[Figure: see text].

A Deep Learning Pipeline to Automate High-Resolution Arterial Segmentation With or Without Intravenous Contrast.

BACKGROUND: Existing methods to reconstruct vascular structures from a computerized tomography (CT) angiogram rely on contrast injection to enhance the radio-density within the vessel lumen. However, pathological changes in the vasculature may be present that prevent accurate reconstruction. In aortic aneurysmal disease, a thrombus adherent to the aortic wall within the expanding aneurysmal sac is present in >90% of cases. These deformations prevent the automatic extraction of vital clinical information by existing image reconstruction methods. AIM: In this study, a deep learning architecture consisting of a modified U-Net with attention-gating was implemented to establish a high-throughput and automated segmentation pipeline of pathological blood vessels in CT images acquired with or without the use of a contrast agent. METHODS AND RESULTS: Seventy-Five patients with paired noncontrast and contrast-enhanced CT images were randomly selected from an ongoing study (Ethics Ref 13/SC/0250), manually annotated and used for model training and evaluation. Data augmentation was implemented to diversify the training data set in a ratio of 10:1. The performance of our Attention-based U-Net in extracting both the inner (blood flow) lumen and the wall structure of the aortic aneurysm from CT angiograms was compared against a generic 3-D U-Net and displayed superior results. Implementation of this network within the aortic segmentation pipeline for both contrast and noncontrast CT images has allowed for accurate and efficient extraction of the morphological and pathological features of the entire aortic volume. CONCLUSIONS: This extraction method can be used to standardize aneurysmal disease management and sets the foundation for complex geometric and morphological analysis. Furthermore, this pipeline can be extended to other vascular pathologies.

Integrated Plasma and Tissue Proteomics Reveals Attractin Release by Intraluminal Thrombus of Abdominal Aortic Aneurysms and Improves Aneurysm Growth Prediction in Humans.

OBJECTIVE: Discovery of novel biomarkers for AAA growth prediction. BACKGROUND: Novel biomarker of AAA growth is a recognized priority in research. Our prior work implicated intraluminal thrombus (ILT) in AAAs to be a potential source of systemic mediators during AAA progression. Here we applied a mass spectrometry proteomics pipeline to discover novel biomarkers for AAA growth prediction. METHODS: Patients were prospectively recruited. Plasma samples were collected at baseline (n = 62). AAA growth was recorded at 12 months. In Experiment 1, plasma samples from the fastest and slowest growth patients (n = 10 each) were compared. In Experiment 2, plasma samples were collected before and at 10-12 weeks after surgery (n = 29). In Experiment 3, paired ILT and omental biopsies were collected intra-operatively during open surgical repair (n = 3). In Experiment 4, tissue secretome was obtained from ex-vivo culture of these paired tissue samples. Samples were subjected to a liquid chromatography tandem mass spectrometry workflow to discover novel biomarkers. RESULTS: We discovered 3 proteins that are: (i) present in ILT; (ii) released by ILT; (iii) reduced in circulation after AAA surgery; (iv) differs between fast and slow growth AAAs. One of these is Attractin. Plasma Attractin correlates significantly with future AAA growth (Spearman r = 0.35, P < 0.005). Using Attractin and AAA diameter as input variables, the area under receiver operating characteristics for predicting no growth and fast growth or AAA at 12 months is 85% and 76%, respectively. CONCLUSION: We show that ILT of AAAs releases mediators during the natural history of AAA growth. These are novel biomarkers for AAA growth prediction in humans.

The role of dipeptidyl peptidase-IV in abdominal aortic aneurysm pathogenesis: A systematic review.

Abdominal aortic aneurysm (AAA) is an important vascular disease carrying significant mortality implications due to the risk of aneurysm rupture. Current management relies exclusively on surgical repair as there is no effective medical therapy. A key element of AAA pathogenesis is the chronic inflammation mediated by inflammatory cells releasing proteases, including the enzyme dipeptidyl peptidase IV (DPP-IV). This review sought to recapitulate available evidence on the involvement of DPP-IV in AAA development. Further, we assessed the experimental use of currently available DPP-IV inhibitors for AAA management in murine models. Embase, Medline, PubMed, and Web of Science databases were utilised to access the relevant studies. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). A narrative synthesis approach was used. Sixty-four studies were identified from the searched databases; a final 11 were included in the analysis. DPP-IV was reported to be significantly increased in both AAA tissue and plasma of patients and correlated with AAA growth. DPP-IV inhibitors (sitagliptin, vildagliptin, alogliptin, and teneligliptin) were all shown to attenuate AAA formation in murine models by reducing monocyte differentiation, the release of reactive oxygen species (ROS), and metalloproteinases (MMP-2 and MMP-9). DPP-IV seems to play a role in AAA pathogenesis by propagating the inflammatory microenvironment. This is supported by observations of decreased AAA formation and reduction in macrophage infiltration, ROS, matrix MMPs, and interleukins following the use of DPP-IV inhibitors in murine models. There is an existing translational gap from preclinical observations to clinical trials in this important and novel mechanism of AAA pathogenesis. This prior literature highlights the need for further research on molecular targets involved in AAA formation.

Use of deep learning for detection, characterisation and prediction of metastatic disease from computerised tomography: a systematic review.

CT is widely used for diagnosis, staging and management of cancer. The presence of metastasis has significant implications on treatment and prognosis. Deep learning (DL), a form of machine learning, where layers of programmed algorithms interpret and recognise patterns, may have a potential role in CT image analysis. This review aims to provide an overview on the use of DL in CT image analysis in the diagnostic evaluation of metastatic disease. A total of 29 studies were included which could be grouped together into three areas of research: the use of deep learning on the detection of metastatic disease from CT imaging, characterisation of lesions on CT into metastasis and prediction of the presence or development of metastasis based on the primary tumour. In conclusion, DL in CT image analysis could have a potential role in evaluating metastatic disease; however, prospective clinical trials investigating its clinical value are required.

Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity.

Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high mortality and limited treatment options. How blood lipids regulate AAA development is unknown. Here lipidomics and genetic models demonstrate a central role for procoagulant enzymatically oxidized phospholipids (eoxPL) in regulating AAA. Specifically, through activating coagulation, eoxPL either promoted or inhibited AAA depending on tissue localization. Ang II administration to ApoE-/- mice increased intravascular coagulation during AAA development. Lipidomics revealed large numbers of eoxPL formed within mouse and human AAA lesions. Deletion of eoxPL-generating enzymes (Alox12 or Alox15) or administration of the factor Xa inhibitor rivaroxaban significantly reduced AAA. Alox-deficient mice displayed constitutively dysregulated hemostasis, including a consumptive coagulopathy, characterized by compensatory increase in prothrombotic aminophospholipids (aPL) in circulating cell membranes. Intravenously administered procoagulant PL caused clotting factor activation and depletion, induced a bleeding defect, and significantly reduced AAA development. These data suggest that Alox deletion reduces AAA through diverting coagulation away from the vessel wall due to eoxPL deficiency, instead activating clotting factor consumption and depletion in the circulation. In mouse whole blood, ∼44 eoxPL molecular species formed within minutes of clot initiation. These were significantly elevated with ApoE-/- deletion, and many were absent in Alox-/- mice, identifying specific eoxPL that modulate AAA. Correlation networks demonstrated eoxPL belonged to subfamilies defined by oxylipin composition. Thus, procoagulant PL regulate AAA development through complex interactions with clotting factors. Modulation of the delicate balance between bleeding and thrombosis within either the vessel wall or circulation was revealed that can either drive or prevent disease development.

The Spatial Morphology of Intraluminal Thrombus Influences Type II Endoleak after Endovascular Repair of Abdominal Aortic Aneurysms.

INTRODUCTION: Type 2 endoleaks (T2Es) after endovascular repair (EVAR) of abdominal aortic aneurysm (AAA) can lead to sac expansion or failure of sac regression, and often present as a management dilemma. The intraluminal thrombus (ILT) may influence the likelihood of endoleaks after EVAR and can be characterized using routine preoperative imaging. We examined the relationship between preoperative spatial morphology of ILT and the incidence of postoperative T2E. METHODS: All patients who underwent EVAR at the John Radcliffe Hospital (Oxford, UK) were prospectively entered in a clinical database. Computed tomography angiograms (CTAs) were performed as part of routine clinical care. The ILT morphology of each patient was determined using the preoperative CTA. Arterial phase cross-sectional images of the AAA were analyzed according to the presence and morphology of the thrombus in each quadrant. The overall ILT morphology was defined by measurements obtained over a 4-cm segment of the AAA. The diagnosis of T2Es during EVAR surveillance was confirmed by CTAs. The relation between the ILT morphology and T2E was assessed using logistic regression. RESULTS: Between September 2009 and July 2016, 271 patients underwent EVAR for infrarenal AAAs (male: 241, age = 79 ± 7). The ILT was present in 265 (98%) of AAAs. Mean follow-up was 1.9 ± 1.6 years. The T2E was observed in 77 cases. Sixty-one percent of T2Es were observed within the first week after surgery. The T2E was observed in 50% (3/6) of cases without the ILT (no-ILT). Compared with no-ILT, the presence of circumferential or posterolateral ILTs was protective from T2Es (odds ratio = 0.33 and 0.37; P = 0.002 and P = 0.047, respectively). CONCLUSIONS: The spatial ILT morphology on routine preoperative CTA imaging can be a biomarker for post-EVAR T2Es. ILTs that cover the posterolateral aspects of the lumen, or circumferential ILTs, are protective of T2Es. This information can be useful in the preoperative planning of EVARs.

Augmented reality in surgical training: a systematic review.

The aim of this systematic review is to provide an update on the current state of augmented reality (AR) in surgical training and to further report on any described benefits compared with traditional techniques. A PICO (Population, Intervention, Comparison, Outcome) strategy was adopted to formulate an appropriate research question and define strict search terms to be entered into MEDLINE, CENTRAL and Google Scholar. The search was returned on 12/09/2019. All returned results were screened first by title and then abstract. The systematic search returned a total of 236 results, of which 18 were selected for final inclusion. Studies covered the full range of surgical disciplines and reported on outcomes including operative duration, accuracy and postoperative complication rates. Due to the heterogeneity of the collected data, no meta-analysis was possible. Outcome measures of competency, surgical opinion and postoperative complication rate were in favour of AR technology while operative duration appears to increase.

Values-based interprofessional education: how interprofessional education and values- based practice interrelate and are vehicles for the benefit of patients and health and social care professionals.

The 2016 All Together Better Health VIII Oxford conference brought together interprofessional education (IPE) and values-based practice (VBP) communities. As there is a paucity of research and publications in the area, following the event a working party consisting of representatives from both communities continued to meet and has developed a joint community of practice. This report describes the work achieved by the group so far and is intended for those involved in the planning and implementation of IPE and collaborative working. The authors consider that incorporating principles of VBP within a framework of IPE can provide a different perspective and understanding of the complexities involved in delivering realistic, student centered learning for collaborative practice, relevant in the 21st century workplace. In particular the authors suggest that using the principles of values and VBP in this way can inform the transition between IPE and collaborative practice facilitating effective person centered collaborative care. This process will require not only the incorporation of these principles within IPE sessions, but also incorporation within the training and support of new and established teachers involved in IPE.

Differential Gene Expression in Macrophages From Human Atherosclerotic Plaques Shows Convergence on Pathways Implicated by Genome-Wide Association Study Risk Variants.

Objective- Plaque macrophages are intricately involved in atherogenesis and plaque destabilization. We sought to identify functional pathways in human plaque macrophages that are differentially regulated in respect of (1) plaque stability and (2) lipid content. We hypothesized that differentially regulated macrophage gene sets would relate to genome-wide association study variants associated with risk of acute complications of atherosclerosis. Approach and Results- Forty patients underwent carotid magnetic resonance imaging for lipid quantification before endarterectomy. Carotid plaque macrophages were procured by laser capture microdissection from (1) lipid core and (2) cap region, in 12 recently symptomatic and 12 asymptomatic carotid plaques. Applying gene set enrichment analysis, a number of gene sets were found to selectively upregulate in symptomatic plaque macrophages, which corresponded to 7 functional pathways: inflammation, lipid metabolism, hypoxic response, cell proliferation, apoptosis, antigen presentation, and cellular energetics. Predicted upstream regulators included IL-1ß, TNF-α, and NF-κB. In vivo lipid quantification by magnetic resonance imaging correlated most strongly with the upregulation of genes of the IFN/ STAT1 pathways. Cross-interrogation of gene set enrichment analysis and meta-analysis gene set enrichment of variant associations showed lipid metabolism pathways, driven by genes coding for APOE and ABCA1/G1 coincided with known risk-associated SNPs (single nucleotide polymorphisms) from genome-wide association studies. Conclusions- Macrophages from recently symptomatic carotid plaques show differential regulation of functional gene pathways. There were additional quantitative relationships between plaque lipid content and key gene sets. The data show a plausible mechanism by which known genome-wide association study risk variants for atherosclerotic complications could be linked to (1) a relevant cellular process, in (2) the key cell type of atherosclerosis, in (3) a human disease-relevant setting.

Length Redundancy and Twist Improve the Biomechanical Properties of Polytetrafluoroethylene Bypass Grafts.

BACKGROUND: The iliofemoropopliteal artery significantly changes path length during normal hip and knee flexion. Prosthetic bypass grafts, such as polytetrafluoroethylene (PTFE) grafts, are relatively stiff and thus can subject graft anastomoses to high tension when the path length increases. The aim of this study was to examine the influence of length redundancy and twist on the biomechanical properties of PTFE bypass grafts. METHODS: Unreinforced and ring-reinforced PTFE grafts were loaded in an axial mechanical testing machine to measure the tensile and compressive axial forces with varying levels of length redundancy and axial twist. RESULTS: Adding 5-15% length redundancy to a graft decreases the force to cause 5% extension by > 90% without substantially increasing shortening forces. Adding 4.5°/cm of axial twist imparts a corkscrew shape to the graft without increasing extension or shortening forces in the presence of length redundancy. Ring-reinforced PTFE grafts require more length redundancy to experience these reductions in forces especially in the presence of axial twist. CONCLUSIONS: A modest amount of length redundancy and twist (i.e., a cork-screw condition) confers improved biomechanical properties in a PTFE graft, especially in ring-reinforced grafts. This should be taken into consideration when fashioning an arterial bypass graft in the iliofemoropopliteal segment.

Between the Reasonable and the Particular: Deflating Autonomy in the Legal Regulation of Informed Consent to Medical Treatment.

The law of informed consent to medical treatment has recently been extensively overhauled in England. The 2015 Montgomery judgment has done away with the long-held position that the information to be disclosed by doctors when obtaining valid consent from patients should be determined on the basis of what a reasonable body of medical opinion agree ought to be disclosed in the circumstances. The UK Supreme Court concluded that the information that is material to a patient's decision should instead be judged by reference to a new two-limbed test founded on the notions of the 'reasonable person' and the 'particular patient'. The rationale outlined in Montgomery for this new test of materiality, and academic comment on the ruling's significance, has focused on the central ethical importance that the law now (rightfully) accords to respect for patient autonomy in the process of obtaining consent from patients. In this paper, we dispute the claim that the new test of materiality articulated in Montgomery equates with respect for autonomy being given primacy in re-shaping the development of the law in this area. We also defend this position, arguing that our revised interpretation of Montgomery's significance does not equate with a failure by the courts to give due legal consideration to what is owed to patients as autonomous decision-makers in the consent process. Instead, Montgomery correctly implies that doctors are ethically (and legally) obliged to attend to a number of relevant ethical considerations in framing decisions about consent to treatment, which include subtle interpretations of the values of autonomy and well-being. Doctors should give appropriate consideration to how these values are fleshed out and balanced in context in order to specify precisely what information ought to be disclosed to a patient as a requirement of obtaining consent, and as a core component of shared decision-making within medical encounters more generally.

'The House of God': reflections 40 years on, in conversation with author Samuel Shem.

The House of God is a seminal work of medical satire based on the gruelling internship experiences of Samuel Shem at the Beth Israel Hospital. Thirteen 'Laws' were offered to rationalise the seemingly chaotic patient management and flow. There have been large shifts in the healthcare landscape and practice since, so we consider whether these medical truisms are still applicable to contemporary National Health Service practice and propose updates where necessary:People are sometimes allowed to die.GOMERs (Get Out of My Emergency Room) still go to ground.Master yourself, join the multidisciplinary team.The patient is the one with the disease, but not the only one suffering.Placement (discharge planning) comes first.There is no body cavity that cannot be reached with a gentle arm and good interventional radiologists.Fit the rule to the patient rather than the patient to the rule.They can always pay you less.The only bad admission is a futile one.If you don't take a temperature you can't find a fever and if you are not going to act on it, don't do the test.Show me a BMS (best medical student) who ONLY triples my work, and I'll show you a future Foundation Year 1 doctor (FY1) who is an asset to the firm.Interpret radiology freely, but share your clinical findings with the radiologist and in a timely fashion.Doing nothing can be a viable option. These were developed in conversation with Samuel Shem, who also offers further insight on the creation of the original laws.

Quick reference guide to the new oral anticoagulants.

After the commissioning of new oral anticoagulants for the treatment and prevention of thrombosis, these medications are now widely used within clinical settings. Increasing numbers of patients present to the health services on anticoagulant medications, and it is therefore imperative for surgeons to be aware of the new therapeutic treatments available and how patients will benefit from such interventions. This review highlights the most pertinent learning points for surgeons regarding the indications, pharmacokinetics, and perioperative management of these new oral medications, as a quick reference guide.