The IRG1-itaconate axis protects from cholesterol-induced inflammation and atherosclerosis.

Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches to reverse atherosclerotic inflammation are needed to address the rising global burden of cardiovascular disease (CVD). Recently, metabolites have gained attention for their immunomodulatory properties, including itaconate, which is generated from the tricarboxylic acid-intermediate cis-aconitate by the enzyme Immune Responsive Gene 1 (IRG1/ACOD1). Here, we tested the therapeutic potential of the IRG1-itaconate axis for human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), we found that IRG1 is up-regulated in human coronary atherosclerotic lesions compared to patient-matched healthy vasculature, and in mouse models of atherosclerosis, where it is primarily expressed by plaque monocytes, macrophages, and neutrophils. Global or hematopoietic Irg1-deficiency in mice increases atherosclerosis burden, plaque macrophage and lipid content, and expression of the proatherosclerotic cytokine interleukin (IL)-1ß. Mechanistically, absence of Irg1 increased macrophage lipid accumulation, and accelerated inflammation via increased neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3-inflammasome in macrophages, resulting in increased IL-1ß release. Conversely, supplementation of the Irg1-itaconate axis using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques and reduced lesional IL-1ß levels in mice. To investigate the effects of 4-OI in humans, we leveraged an ex vivo systems-immunology approach for CVD drug discovery. Using CyTOF and scRNA-seq of peripheral blood mononuclear cells treated with plasma from CVD patients, we showed that 4-OI attenuates proinflammatory phospho-signaling and mediates anti-inflammatory rewiring of macrophage populations. Our data highlight the relevance of pursuing IRG1-itaconate axis supplementation as a therapeutic approach for atherosclerosis in humans.

Patients' experiences of medication management while navigating ongoing care between outpatient services: A qualitative case study of patients on hemodialysis.

Background: Patients on hemodialysis have complex medical diagnoses and medication regimens, requiring access to numerous health services and consultation with various healthcare providers. While interprofessional collaboration can optimize care among hemodialysis patients, these patients commonly experience medication-related problems and frequent hospitalizations resulting from miscommunications and mismanagement of medications. Objectives: This study aims to capture the lived experiences of patients on hemodialysis to reveal their medication management needs as they navigate ongoing care between various outpatient services. Methods: A qualitative methodology was used to explore the perspectives of hemodialysis patients. One-on-one, in-person, semi-structured interviews were conducted at an outpatient hemodialysis clinic located inside an urban teaching hospital. English-speaking adults 18 years and older who have been followed at the clinic for at least three months were selected through random, convenience sampling. Interviews were recorded and transcribed verbatim. Patients were recruited and data were collected iteratively and continued until data saturation was reached. Data was analyzed through the lens of the Picker Principles of Patient Centered Care using a general inductive approach. Results: A total of nine interviews were conducted. Two major themes, medication management and care navigation, were identified. Though patients had a wealth of knowledge about their medications, and they were motivated to self-manage their medications to enhance their well-being, they experienced barriers with medication management. Patients further expressed challenges with navigating care and spoke of the importance of having good rapport with healthcare providers who are attentive to their needs. Conclusions: The results revealed a need for improved support for self-care and interprofessional collaboration to possibly reduce the burden of medications and care fragmentation experienced by patients and improve continuity of care for patients.

Barriers and facilitators to using a clinical decision support tool for the management of osteoarthritis pain in patients undergoing hemodialysis: a qualitative study.

BACKGROUND: While osteoarthritis is a significant issue within the hemodialysis population and contributes to reduced quality of life, pain related to osteoarthritis is poorly managed by healthcare professionals (HCPs) in hemodialysis settings due to the absence of clinical guidance applicable to this population. The purpose of this study was to explore the perceptions of HCPs on the barriers and facilitators to using a clinical decision support tool for osteoarthritis pain management in the hemodialysis setting. METHODS: A qualitative descriptive study was conducted. Purposeful and snowball sampling techniques were used to recruit hemodialysis clinicians from academic and community settings across multiple Canadian provinces. One-to-one interviews were conducted with clinicians using a semi-structured, open ended interview guide informed by the Theoretical Domains Framework, a behavior change framework. A general inductive approach was applied to identify the main themes of barriers and facilitators. RESULTS: A total of 11 interviews were completed with 3 nephrologists, 2 nurse practitioners and 6 pharmacists. Findings revealed 6 main barriers and facilitators related to the use of the clinical decision support tool. Alignment of the tool with practice roles emerged as a key barrier and facilitator. Other barriers included challenges related to the dialysis environment, varying levels of clinician comfort with pain medications, and limited applicability of the tool due to patient factors. An important facilitator was the intrinsic motivation among clinicians to use the tool. CONCLUSIONS: Most participants across the included hemodialysis settings expressed satisfaction with the clinical decision support tool and acknowledged its overall potential for improving osteoarthritis pain management among patients on hemodialysis. Future implementation of the tool may be limited by existing roles and practices at different institutions. Increased collaboration among hemodialysis and primary care teams may promote uptake of the tool.