BACKGROUND:We conducted a systematic review and network meta-analysis to examine comparative efficacy and tolerability of pharmacologic interventions for pulmonary arterial hypertension (PAH). METHODS:MEDLINE, the Cochrane Register, EMBASE, CINAHL, and clinicaltrials.gov were searched (January 1, 1990 to March 3, 2016). Randomized controlled trials (RCTs) studying the approved pharmacologic agents endothelin receptor antagonists (ERA), phosphodiesterase inhibitors (PDE5i), the oral/inhaled (PO/INH) and IV/subcutaneous (SC) prostanoids, and riociguat and selexipag, alone or in combination, for pulmonary arterial hypertension (PAH) and reporting at least one efficacy outcome were selected. RESULTS:Thirty-one RCTs with 6,565 patients were selected. In network meta-analysis, when compared with a median placebo rate of 14.5%, clinical worsening was estimated at 2.8% with riociguat (risk ratio [RR], 0.19; 95% CI, 0.05-0.76); at 3.9% with ERA + PDE5i (RR, 0.27; 95% CI, 0.14-0.52), and at 5.7% with PDE5i (RR, 0.39; 95% CI, 0.24-0.62). For improvement in functional status, when compared with 16.2% in the placebo group, improvement in at least one New York Heart Association/World Health Organization (NYHA/WHO) functional class was estimated at 81.8% with IV/SC prostanoids (RR, 5.06; 95% CI, 2.3211.04), at 28.3% with ERA + PDE5i (RR, 1.75; 95% CI, 1.05-2.92), and at 25.2% with ERA (RR, 1.56; 95% CI, 1.22-2.00). Differences in mortality were not significant. Adverse events leading to discontinuation of therapy were highest with the PO/INH prostanoids (RR, 2.92; 95% CI, 1.68-5.06) and selexipag (RR, 2.06; 95% CI, 1.04-3.88) compared with placebo. CONCLUSIONS:Currently approved pharmacologic agents have varying effects on morbidity and functional status in patients with PAH. Future comparative effectiveness trials are warranted with a focus on a patient-centered approach to therapy. REGISTRATION:PROSPERO CRD42016036803.

Rationale: Cigarette smoking is a leading cause of both emphysema and lung cancer, yet the mechanism of how smoking drives disease is unclear. Alveolar macrophages are key players in the development of smoking-related diseases. One important, but little studied, regulator of macrophage function is epigenetic modification of gene expression. Methods: Smokers with and without emphysema, and nonsmokers, underwent bronchoscopy with bronchoalveolar lavage to obtain alveolar macrophages. DNA and RNA were isolated using the Qiagen DNeasy kit (Qiagen, Valencia, CA) and MirVana kit (Life Technologies, Grand Island, NY) methods, respectively. Genome-wide methylation status of the samples was determined using Illumina Infinium 27K HumanMethylation array (Illumina, San Diego, CA). Macrophage mRNA expression was analyzed using GeneChip Human Exon 1.0 ST Arrays (Affymetrix, Santa Clara, CA). Results: The distribution of methylation in these probes differed significantly with respect to smoking status. There is enrichment of differential methylation in genes from inflammatory pathways. Consistent with recent findings, significant methylation changes were particularly enriched in the areas flanking CpG islands. Analysis of matching gene expression data demonstrated a parallel enrichment for changes in inflammatory pathways. Conclusion: The alveolar macrophage data obtained from smokers, patients with emphysema, and nonsmokers demonstrates methylation changes that track with smoke exposure. The affected genes cluster in inflammation-linked pathways, and a significant number of the genes with differential methylation also have altered gene expression. This discovery suggests that epigenetic modification of alveolar macrophages contributes to smoking-related lung disease.

The aim of the ETAMI project is to provide pre-hospital triage of patients with chest pain to expedite revascularisation. During the first 22 months of the trial, the Regional Heart Centre (RHC) in Western Sydney treated 300 patients with acute ST elevation myocardial infarction. We divided these patients into 3 groups: 96 presented to the RHC, 128 to the 3 district hospitals (DH), and 76 were triaged pre-hospital to the cardiac catheterisation laboratory using the ETAMI model. There was a median reduction in door to table time in the ETAMI group of 71 min compared to the DH patients, and 32 min compared to the RHC patients (p < 0.01). Table to open artery (TIMI-3) times were similar. Left ventricular ejection fraction (LVEF) was measured by Gated Isotope Scanning at a mean of 4 days post infarct. The median LVEF was 54% in the ETAMI group, 51% in the RHC group and 48.5% in the DH group (p = 0.02). There was a difference in all cause mortality at 30 days, with 7 deaths in the RHC group, 5 deaths in the DH group, and no deaths in the ETAMI group (p = 0.015). At 12 months follow up there were 11 deaths in the RHC group, 7 deaths in the DH group, and 4 deaths in the ETAMI group (p = 0.19). The combined 12 month mortality for the 3 groups was 7.3%. The ETAMI model is safe, reduces revascularisations times, and improves LV function and mortality in an Australian metropolitan population with RHC and DH structure.