O-GlcNAc regulates anti-fibrotic genes in lung fibroblasts through EZH2.

Epigenetic modifications are involved in fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), and contribute to the silencing of anti-fibrotic genes. H3K27me3, a key repressive histone mark, is catalysed by the methyltransferase enhancer of Zeste homologue 2 (EZH2), which is regulated by the post-translational modification, O-linked N-Acetylglucosamine (O-GlcNAc). In this study, we explored the effects of O-GlcNAc and EZH2 on the expression of antifibrotic genes, cyclooxygenase-2 (Cox2) and Heme Oxygenase (Homx1). The expression of Cox2 and Hmox1 was examined in primary IPF or non-IPF lung fibroblasts with or without EZH2 inhibitor EZP6438, O-GlcNAc transferase (OGT) inhibitor (OSMI-1) or O-GlcNAcase (OGA) inhibitor (thiamet G). Non-IPF cells were also subjected to TGF-ß1 with or without OGT inhibition. The reduced expression of Cox2 and Hmox1 in IPF lung fibroblasts is restored by OGT inhibition. In non-IPF fibroblasts, TGF-ß1 treatment reduces Cox2 and Hmox1 expression, which was restored by OGT inhibition. ChIP assays demonstrated that the association of H3K27me3 is reduced at the Cox2 and Hmox1 promoter regions following OGT or EZH2 inhibition. EZH2 levels and stability were decreased by reducing O-GlcNAc. Our study provided a novel mechanism of O-GlcNAc modification in regulating anti-fibrotic genes in lung fibroblasts and in the pathogenesis of IPF.

Impact of socioeconomic status on presentation, care quality and outcomes of patients attended by emergency medical services for dyspnoea: a population-based cohort study.

BACKGROUND: Low socioeconomic status (SES) has been linked to poor outcomes in many conditions. It is unknown whether these disparities extend to individuals presenting with dyspnoea. We aimed to evaluate the relationship between SES and incidence, care quality and outcomes among patients attended by emergency medical services (EMS) for dyspnoea. METHODS: This population-based cohort study included consecutive patients attended by EMS for dyspnoea between 1 January 2015 and 30 June 2019 in Victoria, Australia. Data were obtained from individually linked ambulance, hospital and mortality datasets. Patients were stratified into SES quintiles using a composite census-derived index. RESULTS: A total of 262 412 patients were included. There was a stepwise increase in the age-adjusted incidence of EMS attendance for dyspnoea with increasing socioeconomic disadvantage (lowest SES quintile 2269 versus highest quintile 889 per 100 000 person years, ptrend<0.001). Patients of lower SES were younger and more comorbid, more likely to be from regional Victoria or of Aboriginal or Torres Strait Islander heritage and had higher rates of respiratory distress. Despite this, lower SES groups were less frequently assigned a high acuity EMS transport or emergency department (ED) triage category and less frequently transported to tertiary centres or hospitals with intensive care unit facilities. In multivariable models, lower SES was independently associated with lower acuity EMS and ED triage, ED length of stay>4 hours and increased 30-day EMS reattendance and mortality. CONCLUSION: Lower SES was associated with a higher incidence of EMS attendances for dyspnoea and disparities in several metrics of care and clinical outcomes.

The cost-effectiveness of semaglutide in reducing cardiovascular risk among people with overweight and obesity and existing cardiovascular disease, but without diabetes.

BACKGROUND AND AIMS: The Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial demonstrated significant reductions in cardiovascular outcomes in people with cardiovascular disease (CVD) and overweight or obesity (but without diabetes). However, the cost of the medication has raised concerns about its financial viability and accessibility within healthcare systems. This study explored whether use of semaglutide for the secondary prevention of CVD in overweight or obesity is cost-effective from the Australian healthcare perspective. METHODS: A Markov model was developed based on the SELECT trial to model the clinical outcomes and costs of a hypothetical population treated with semaglutide versus placebo, in addition to standard care, and followed up over 20 years. With each annual cycle, subjects were at risk of having non-fatal CVD events or dying. Model inputs were derived from SELECT and published literature. Costs were obtained from Australian sources. All outcomes were discounted by 5% annually. The main outcome of interest was the incremental cost-effectiveness ratio (ICER) in terms of cost per year of life saved (YoLS) and cost per quality-adjusted life year (QALY) gained. RESULTS: With an annual estimated cost of semaglutide of A${\$}$4175, the model resulted in ICERs of A${\$}$99 853 (US${\$}$143 504; £40 873) per YoLS and A${\$}$96 055 (US${\$}$138 046; £39 318) per QALY gained. CONCLUSIONS: Assuming a willingness-to-pay threshold of A${\$}$50 000, semaglutide is not considered cost-effective at the current price. A price of ≤ A${\$}$2000 per year or more targeted use in high-risk patients would be needed for it to be considered cost-effective in the Australian setting.