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Current pharmacologic treatments for atherosclerosis do not completely protect patients; additional protection can be achieved by dietary modifications, such as a low-cholesterol/low-fat diet (LCLFD), that mediate plaque stabilization and inflammation reduction. However, this lifestyle modification can be challenging for patients. Unfortunately, incomplete understanding of the underlying mechanisms has thwarted efforts to mimic the protective effects of a LCLFD. Here, we report that the tricarboxylic acid cycle intermediate itaconate (ITA), produced by plaque macrophages, is key to diet-induced plaque resolution. ITA is produced by immunoresponsive gene 1 (IRG1), which we observe is highly elevated in myeloid cells of vulnerable plaques and absent from early or stable plaques in mice and humans. We additionally report development of an ITA-conjugated lipid nanoparticle that accumulates in plaque and bone marrow myeloid cells, epigenetically reduces inflammation via H3K27ac deacetylation, and reproduces the therapeutic effects of LCLFD-induced plaque resolution in multiple atherosclerosis models. [Display omitted] • Itaconate (ITA) mediates diet-driven plaque resolution in ASCVD • ITA-bearing lipid nanoparticles (ITA-LNPs) target plaque and bone marrow myeloid cells • ITA-LNP treatment recapitulates LCLFD-induced atherosclerotic plaque resolution • ITA-LNP treatment downregulates inflammatory genes via H3K27ac deacetylation Hong et al. report that the tricarboxylic acid cycle metabolite itaconate (ITA) mediates low-cholesterol/low-fat-diet-induced atherosclerotic plaque resolution. Additionally, administration of nanoparticle-based ITA therapy induces plaque resolution in several models of atherosclerosis via multiple mechanisms, including epigenetic immunomodulation via H3K27ac deacetylation. [ABSTRACT FROM AUTHOR]

Red Blood Cell Distribution Width (RDW), a measure of variability in size of circulating red blood cells and is a marker of inflammation. We sought to test the hypothesis that RDW reflects an inflammatory milieu permissive for cardiac fibrosis in those with Heart Failure and preserved ejection fraction (HFpEF). We analyzed the association between RDW and fibrosis in two separate cohorts. Cohort 1 (n = 200) was a retrospective analysis of blood biomarkers measured in the RELAX trial (Clinicaltrials.gov NCT00763867) and Cohort 2 (n = 160) included a single center cohort of patients with preserved ventricular function referred for cardiac magnetic resonance imaging (cMRI). Linear regression was used to adjust for potential confounders, and a mediation analysis used to explore relationships with exercise intolerance (peak VO2 max). Within Cohort 1, anisocytosis (RDW > 14.5) was prevalent (49.5%) and was associated with greater baseline clinical comorbidities, a lower Peak VO2 and more frequent heart failure hospitalizations. The RDW was associated with biomarkers of inflammation and cardiac fibrosis. In Cohort 2, RDW was associated with cMRI myocardial fibrosis (extracellular volume; Spearman's rho=0.38, P <0.001) which was independent of age, sex, LV ejection fraction, and hematocrit (P = 0.026). Individuals with both anisocytosis and myocardial fibrosis identified a subgroup of at high risk for 2-year mortality (HR 16.28 [4.30–61.66], P <0.001). In two independent cohorts of patients with HFpEF, elevated RDW is associated reduced exercise capacity and greater fibrosis as measured by serum biomarkers and cMRI. Additional studies are needed to validate this novel relationship. [ABSTRACT FROM AUTHOR]

The authors found that growing up in rural New Zealand presents a multiplicity of possible identities rather than a generalized conceptualization of 'rural life.' Comparisons are made between Pakeha and Maori societies, and the different linguistic and cultural resources used to articulate relationships to identity and place.

If, as is normally assumed, the future has yet to happen and is dependent upon preceding events and choices it remains uncertain and alternative futures possible. This appears to make the future plural and different from the past and present, which are usually considered to be singular. The role of Futures Research, in an uncertain future, is not to predict but to assist in making informed choices about issues of significance to the future in the changing present. Effective management of change requires the adoption of a learning approach to the future, some of the characteristics of which are explored. (Reprinted by permission of the publisher.)

Urban planning is concerned with issues which require a longer-term view than most. Even if forecasting is not explicitly carried out, planners nevertheless take a view about and influence the future. This article argues that planning, forecasting and monitoring should all be continuous, interlinked operations. Bearing this in mind, future planning issues are identified - renewal, technology and greening the city.(Reprinted by permission of the publisher.)