No abstract

“Treatable traits” have been proposed as a new paradigm for the management of airway diseases, particularly complex disease, which aims to apply personalised medicine to each individual to improve outcomes. Moving new treatment approaches from concepts to practice is challenging, but necessary. In an effort to accelerate progress in research and practice relating to the treatable traits approach, the Treatable Traits Down Under International Workshop was convened in Melbourne, Australia in May 2018. Here, we report the key concepts and research questions that emerged in discussions during the meeting. We propose a programme of research that involves gaining international consensus on candidate traits, recognising the prevalence of traits, and identifying a potential hierarchy of traits based on their clinical impact and responsiveness to treatment. We also reflect on research methods and designs that can generate new knowledge related to efficacy of the treatable traits approach and consider multidisciplinary models of care that may aid its implementation into practice.

Background: Whether blood eosinophil counts and exhaled nitric oxide (FeNO) are associated with important outcomes in mild asthma is unclear. Methods: This question was explored in a pre-specified analysis of a 52week, open-label, randomized, parallel-group trial in patients with mild asthma receiving only reliever inhalers, comparing salbutamol 200µg asneeded, maintenance budesonide 200µg twice-daily with salbutamol as needed, and budesonide/formoterol 200/6µg as-needed. Outcomes were compared between patients with blood eosinophils of <0.15, 0.15-<0.3 and ≥0.3x109/L; FeNO of <20, 20-50 and >50ppb; and a composite score based on both. Results: The proportion of patients randomised to as-needed salbutamol having a severe exacerbation increased progressively with increasing blood eosinophil sub-group (4.1%, 6.5% and 19.5%; p=0.014). There were no significant interactions between either biomarker and the effect of as-needed budesonide/formoterol compared with as-needed salbutamol for either exacerbations or severe exacerbations. However, there were significant interactions between blood eosinophil sub-groups and the effect of maintenance budesonide compared with as needed salbutamol for exacerbations (p<0.001) and severe exacerbations (p<0.001). Maintenance budesonide was more effective than as-needed salbutamol in patients with eosinophils ≥0.3x109/L for exacerbations (odds ratio 0.13; 95% CI 0.05-0.33) and severe exacerbations (0.11; 0.03-0.45). This was not the case for eosinophils <0.15x109/L (odds ratio for exacerbations 1.15; 0.51-1.28 and severe exacerbations 5.72; 0.97-33.6). There was no consistent interaction between treatment response and FeNO or the composite score. Conclusions: In patients with mild asthma the effects of as-needed budesonide/formoterol on exacerbations are independent of biomarker profile, whereas the benefits of maintenance inhaled budesonide are greater in patients with high blood eosinophil counts.

Background We investigated the effects of cardiopulmonary bypass (CPB) on peripheral arteriolar reactivity and associated signaling pathways in poorly controlled (UDM), controlled (CDM), and case-matched non-diabetic (ND) patients undergoing coronary artery bypass grafting. Methods and Results Skeletal muscle arterioles were harvested pre- and post-CPB from the UDM patients (hemoglobin A1c [HbA1c] = 9.0 ± 0.3), the CDM patients (HbA1c = 6.3 ± 0.15) and the ND patients (HbA1c = 5.2 ± 0.1) undergoing CABG surgery (n = 10/group). In vitro relaxation responses of pre-contracted arterioles to endothelium-dependent vasodilators adenosine 5’-diphosphate (ADP) and substance P and the endothelium-independent vasodilator sodium nitroprusside (SNP) were examined. The baseline responses to ADP, substance P and SNP of arterioles from the UDM patients were decreased as compared to microvessels from the ND or CDM patients (P <0.05). The post-CPB relaxation responses to ADP and substance P were significantly decreased in all three groups compared to pre-CPB responses (P <0.05). However, these decreases were more pronounced in the UDM group (P <0.05). The post-CPB response to SNP was significantly decreased only in the UDM group, not in the other two groups compared to pre-CPB. The expression of PKC-α, PKC-β, protein oxidation and nitrotyrosine in the skeletal muscle were significantly increased in the UDM group as compared with those of ND or CDM groups (P<0.05). Conclusion Poorly controlled diabetes results in impaired arteriolar function before and after CPB. These alterations are associated with the increased expression/activation of PKC-α and PKC-β, and enhanced oxidative and nitrosative stress.