Osteopontin Activation and Microcalcification in Venous Grafts Can Be Modulated by Dexamethasone.

BACKGROUND: Osteopontin has been implicated in vascular calcification formation and vein graft intimal hyperplasia, and its expression can be triggered by pro-inflammatory activation of cells. The role of osteopontin and the temporal formation of microcalcification in vein grafts is poorly understood with a lack of understanding of the interaction between haemodynamic changes and the activation of osteopontin. METHODS: We used a porcine model of vein interposition grafts, and human long saphenous veins exposed to ex vivo perfusion, to study the activation of osteopontin using polymerase chain reaction, immunostaining, and 18F-sodium fluoride autoradiography. RESULTS: The porcine model showed that osteopontin is active in grafts within 1 week following surgery and demonstrated the presence of microcalcification. A brief pretreatment of long saphenous veins with dexamethasone can suppress osteopontin activation. Prolonged culture of veins after exposure to acute arterial haemodynamics resulted in the formation of microcalcification but this was suppressed by pretreatment with dexamethasone. 18F-sodium fluoride uptake was significantly increased as early as 1 week in both models, and the pretreatment of long saphenous veins with dexamethasone was able to abolish its uptake. CONCLUSIONS: Osteopontin is activated in vein grafts and is associated with microcalcification formation. A brief pretreatment of veins ex vivo with dexamethasone can suppress its activation and associated microcalcification.

The Role of Preservation Solutions upon Saphenous Vein Endothelial Integrity and Function: Systematic Review and UK Practice Survey.

The long saphenous vein is the most used conduit in cardiac surgery, but its long-term patency is limited by vein graft disease (VGD). Endothelial dysfunction is a key driver of VGD; its aetiology is multi-factorial. However emerging evidence identifies vein conduit harvest technique and preservation fluids as causal in their onset and propagation. This study aims to comprehensively review published data on the relationship between preservation solutions, endothelial cell integrity and function, and VGD in human saphenous veins harvested for CABG. The review was registered with PROSPERO (CRD42022358828). Electronic searches of Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE databases were undertaken from inception until August 2022. Papers were evaluated in line with registered inclusion and exclusion criteria. Searches identified 13 prospective, controlled studies for inclusion in the analysis. All studies used saline as a control solution. Intervention solutions included heparinised whole blood and saline, DuraGraft, TiProtec, EuroCollins, University of Wisconsin (UoW), buffered, cardioplegic and Pyruvate solutions. Most studies demonstrated that normal saline appears to have negative effects on venous endothelium and the most effective preservation solutions identified in this review were TiProtec and DuraGraft. The most used preservation solutions in the UK are heparinised saline or autologous whole blood. There is substantial heterogeneity both in practice and reporting of trials evaluating vein graft preservation solutions, and the quality of existing evidence is low. There is an unmet need for high quality trials evaluating the potential for these interventions to improve long-term patency in venous bypass grafts.

Large animal model of vein grafts intimal hyperplasia: A systematic review.

Coronary artery bypass grafting remains the treatment of choice for a large cohort of patients with significant coronary disease. Despite the increased use of arterial grafts, the long saphenous vein remains the most commonly used conduit. Long-term graft patency continues to be the Achilles heel of saphenous vein grafts. This is due to the development of intimal hyperplasia, a chronic inflammatory disease that results in the narrowing and occlusion of a significant number of vein grafts. Research models for intimal hyperplasia are essential for a better understanding of pathophysiological processes of this condition. Large animal models resemble human anatomical structures and have been used as a surrogate to study disease development and prevention over the years. In this paper, we systematically review all published studies that utilized large animal models of vein graft disease with a focus on the type of model and any therapeutic intervention, specifically the use of external stents/mesh.

The Role of Endothelial Cells in the Onset, Development and Modulation of Vein Graft Disease.

Endothelial cells comprise the intimal layer of the vasculature, playing a crucial role in facilitating and regulating aspects such nutrient transport, vascular homeostasis, and inflammatory response. Given the importance of these cells in maintaining a healthy haemodynamic environment, dysfunction of the endothelium is central to a host of vascular diseases and is a key predictor of cardiovascular risk. Of note, endothelial dysfunction is believed to be a key driver for vein graft disease-a pathology in which vein grafts utilised in coronary artery bypass graft surgery develop intimal hyperplasia and accelerated atherosclerosis, resulting in poor long-term patency rates. Activation and denudation of the endothelium following surgical trauma and implantation of the graft encourage a host of immune, inflammatory, and cellular differentiation responses that risk driving the graft to failure. This review aims to provide an overview of the current working knowledge regarding the role of endothelial cells in the onset, development, and modulation of vein graft disease, as well as addressing current surgical and medical management approaches which aim to beneficially modulate endothelial function and improve patient outcomes.

Next-Generation and Single-Cell Sequencing Approaches to Study Atherosclerosis and Vascular Inflammation Pathophysiology: A Systematic Review.

Background and Aims: Atherosclerosis is a chronic inflammatory disease that remains the leading cause of morbidity and mortality worldwide. Despite decades of research into the development and progression of this disease, current management and treatment approaches remain unsatisfactory and further studies are required to understand the exact pathophysiology. This review aims to provide a comprehensive assessment of currently published data utilizing single-cell and next-generation sequencing techniques to identify key cellular and molecular contributions to atherosclerosis and vascular inflammation. Methods: Electronic searches of Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE databases were undertaken from inception until February 2022. A narrative synthesis of all included studies was performed for all included studies. Quality assessment and risk of bias analysis was evaluated using the ARRIVE and SYRCLE checklist tools. Results: Thirty-four studies were eligible for narrative synthesis, with 16 articles utilizing single-cell exclusively, 10 utilizing next-generation sequencing and 8 using a combination of these approaches. Studies investigated numerous targets, ranging from exploratory tissue and plaque analysis, cell phenotype investigation and physiological/hemodynamic contributions to disease progression at both the single-cell and whole genome level. A significant area of focus was placed on smooth muscle cell, macrophage, and stem/progenitor contributions to disease, with little focus placed on contributions of other cell types including lymphocytes and endothelial cells. A significant level of heterogeneity exists in the outcomes from single-cell sequencing of similar samples, leading to inter-sample and inter-study variation. Conclusions: Single-cell and next-generation sequencing methodologies offer novel means of elucidating atherosclerosis with significantly higher resolution than previous methodologies. These approaches also show significant potential for translatability into other vascular disease states, by facilitating cell-specific gene expression profiles between disease states. Implementation of these technologies may offer novel approaches to understanding the disease pathophysiology and improving disease prevention, management, and treatment.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021229960, identifier: CRD42021229960.

Acute shear stress and vein graft disease.

The long saphenous vein is commonly used in cardiac surgery to bypass occluded coronary arteries. Its use is complicated by late stenosis and occlusion due to the development of intimal hyperplasia. It is accepted that intimal hyperplasia is a multifactorial inflammatory process that starts immediately after surgery. The role of acute changes in haemodynamic conditions when the vein is implanted into arterial circulation, especially shear stress, is not fully appreciated. This review provides an overview of intimal hyperplasia and the effect of acute shear stress changes on the activation of pro-inflammatory mediators.

Fostering healthcare innovation in public hospitals: the Queensland experience.

Faced with scarce resources and a demand for health care that exceeds supply, health policy makers at all levels of government need to adopt some form of rationing when deciding which health services should be funded in the public health system. With a relatively small investment, programs such as Queensland Health's New Technology Funding Evaluation Program (NTFEP) fosters innovation by providing funding and pilot studies for new and innovative healthcare technologies. The NTFEP assists policy makers to make informed decisions regarding investments in new safe and effective technologies based on available evidence gathered from real-world settings relevant to Queensland patients and clinicians. In addition, the NTFEP allows appropriate patient access, especially in rural and remote locations, to potentially beneficial technologies and acts a gatekeeper, protecting them from technologies that may be detrimental or harmful.

Multicriteria decision analysis (MCDA) for health technology assessment: the Queensland Health experience.

Objectives In determining whether new health technologies should be funded, health technology assessment (HTA) committees prefer explicit to implicit methods of analysis in enhancing transparency and consistency of decision making. The aim of this study was to develop and pilot a multicriteria decision analysis (MCDA) framework for the Queensland Department of Health HTA program committee, which weighted decision making criteria according to their perceived importance as determined by group consensus. Methods The criteria used in the MCDA framework were identified by reviewing the five unweighted criteria used in the existing process, consultation with committee members and literature review. Criteria were clearly defined and ordinal categories of lowest to highest preferred were assigned against which technology submissions would be rated. Criteria weights were determined through a discrete choice experiment (DCE) survey of committee members using validated software. Mean weighted technology scores were then used to guide deliberative discussions in determining final funding decisions. Results The MCDA framework created one additional criterion to the previous five. The criteria and their mean weights identified through the DCE survey were clinical benefit and safety (27.2%), quality of evidence (19.2%), implementation capacity (16.9%), innovation (15.4%), burden of disease and clinical need (13.3%) and societal and ethical values (8.0%). Criterion weights varied considerably between individual committee members, with one criterion having a difference of 36.9% between the highest and lowest preference weights. Following deliberative discussions, all but one of 10 submissions were awarded funding. The submission not supported received the third lowest score through the MCDA model. Conclusions This pilot application of an MCDA framework, as a complement to committee deliberation, conferred greater transparency and objectivity on HTA assessment of technologies. The framework converted an implicit, unweighted review process to one that is more explicit, flexible in weighting importance and pragmatic. What is known about the topic? HTA programs involve complex decision-making processes requiring the consideration of multiple criteria. Explicit methods of analysis that use weighted criteria according to their relative importance enhance transparency and consistency of decision making by HTA committees, and are preferred to implicit reviews using unweighted criteria. What does this paper add? This article describes the development and piloting of an MCDA framework that aims to improve transparency, objectivity and consistency of funding decisions of the Queensland HTA committee. Criteria were identified through a review of current processes, committee discussions and a literature review, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) quality of evidence system. Criteria were weighted using a discrete choice experiment involving committee members. Using weighted criteria, mean technology scores were calculated and incorporated into deliberative discussions to determine funding decisions. What are the implications for practitioners? The MCDA framework described here converted a more implicit, unweighted process to one that was more pragmatic, explicit and flexible in scoring HTA submissions. This framework may be useful to other HTA programs and could be expanded to resource allocation decision making in many other healthcare settings.

Evidence-based medicine and clinical fluorodeoxyglucose PET/MRI in oncology.

Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) is a hybrid of two technologies each with its own evidence for clinical effectiveness. This article amalgamates evidence for clinical effectiveness of fluorodeoxyglucose (FDG) PET/CT and MRI as separate modalities with current evidence for hybrid PET/MRI and considers whether such an approach might provide a stronger case for the clinical use of PET/MRI at an earlier stage.Because links between diagnostic accuracy and health outcomes have already been established for FDG-PET/CT in the investigation of suspected residual or recurrent malignancies, evidence showing improved diagnostic performance and therapeutic impact from the use of PET/MRI as an alternative would imply clinical effectiveness of this modality for this application. A meta-analysis of studies comparing FDG-PET/CT to MRI in patients with suspected residual disease or recurrence of tumours indicates complementary roles for these modalities. PET demonstrates greater sensitivity for recurrence within lymph nodes whereas MRI is more effective that PET/CT in the detection of skeletal and hepatic recurrence. A review of studies assessing therapeutic impact of PET/MRI suggests a greater likelihood for change in clinical management when PET/MRI is used for assessment of suspected residual or recurrent disease rather than tumour staging.Supplementing the evidence-base for FDG-PET/MRI with studies that compare the components of this hybrid technology deployed separately indicates that FDG-PET/MRI is likely to be clinical effective for the investigation of patients with a range of suspected residual or recurrent cancers. This indication should therefore be prioritised for further health technology assessment.

Workforce profile for allied health professions in Queensland Public Health cancer care services with linear accelerators.

PURPOSE: This article profiles staffing levels for all allied health professionals in Queensland Public Health cancer care services to determine whether linear accelerator hours per clinical day are a potentially useful predictor of workforce requirements. Currently, radiation therapists and radiation oncology medical physicists have developed professional guidelines for calculating staffing full-time equivalents (FTEs) related to linear accelerator hours per clinical day. METHODS: Queensland Public Health service managers were surveyed using a self-reported standardized data collection tool, requesting the FTE allied health staff provided for a number of services, including cancer care. Linear accelerator hours per clinical day were also collected. A linear regression model was employed to determine the relationship with the allied health workforce FTEs at linear accelerator sites. RESULTS: High correlations existed between linear accelerator hours per clinical day and radiation therapists (0.99), radiation oncology medical physicists (0.95), pharmacy services (pharmacists and assistants combined; 0.91), and rehabilitation allied health staff (> 0.95). A linear regression model was employed to determine the allied health pharmacy service and rehabilitation workforce FTEs. CONCLUSION: In the four Queensland Public Health cancer care services with linear accelerators, radiation therapists, radiation oncology medical physicists, pharmacy services, and rehabilitation allied health staff, cancer care staff are highly correlated with linear accelerator hours per clinical day. The findings support identifying and establishing alternative denominators for allied health workforce requirements in cancer care beyond those of expert knowledge, opinion, and consensus.