Feasibility studies are increasingly undertaken in preparation for randomised controlled trials in order to explore uncertainties and enable trialists to optimise the intervention or the conduct of the trial. Qualitative research can be used to examine and address key uncertainties prior to a full trial. We present guidance that researchers, research funders and reviewers may wish to consider when assessing or undertaking qualitative research within feasibility studies for randomised controlled trials. The guidance consists of 16 items within five domains: research questions, data collection, analysis, teamwork and reporting. Appropriate and well conducted qualitative research can make an important contribution to feasibility studies for randomised controlled trials. This guidance may help researchers to consider the full range of contributions that qualitative research can make in relation to their particular trial. The guidance may also help researchers and others to reflect on the utility of such qualitative research in practice, so that trial teams can decide when and how best to use these approaches in future studies.

Rationale: Atheroprogression is a consequence of nonresolved inflammation, and currently a comprehensive overview of the mechanisms preventing resolution is missing. However, in acute inflammation, resolution is known to be orchestrated by a switch from inflammatory to resolving lipid mediators. Therefore, we hypothesized that lesional lipid mediator imbalance favors atheroprogression. Objective: To understand the lipid mediator balance during atheroprogression and to establish an interventional strategy based on the delivery of resolving lipid mediators. Methods and Results: Aortic lipid mediator profiling of aortas from Apoe −/− mice fed a high-fat diet for 4 weeks, 8 weeks, or 4 months revealed an expansion of inflammatory lipid mediators, Leukotriene B4 and Prostaglandin E2, and a concomitant decrease of resolving lipid mediators, Resolvin D2 (RvD2) and Maresin 1 (MaR1), during advanced atherosclerosis. Functionally, aortic Leukotriene B4 and Prostaglandin E2 levels correlated with traits of plaque instability, whereas RvD2 and MaR1 levels correlated with the signs of plaque stability. In a therapeutic context, repetitive RvD2 and MaR1 delivery prevented atheroprogression as characterized by halted expansion of the necrotic core and accumulation of macrophages along with increased fibrous cap thickness and smooth muscle cell numbers. Mechanistically, RvD2 and MaR1 induced a shift in macrophage profile toward a reparative phenotype, which secondarily stimulated collagen synthesis in smooth muscle cells. Conclusions: We present evidence for the imbalance between inflammatory and resolving lipid mediators during atheroprogression. Delivery of RvD2 and MaR1 successfully prevented atheroprogression, suggesting that resolving lipid mediators potentially represent an innovative strategy to resolve arterial inflammation.

Background The CXCL12/CXCR4 chemokine ligand/receptor axis controls (progenitor) cell homeostasis and trafficking. So far, an atheroprotective role of CXCL12/CXCR4 has only been implied through pharmacological intervention, particularly as the somatic deletion of the CXCR4 gene in mice is embryonically lethal. Moreover, cell-specific effects of CXCR4 in the arterial wall and underlying mechanisms remain elusive, prompting us to investigate the relevance of CXCR4 in vascular cell types for atheroprotection. Methods We examined the role of vascular CXCR4 in atherosclerosis and plaque composition by inducing an endothelial cell (EC, BmxCreERT2-driven)-specific or smooth muscle cell (SMC, SmmhcCreERT2- or TaglnCre-driven)-specific-deficiency of CXCR4 in an apolipoprotein E-deficient mouse model. To identify underlying mechanisms for effects of CXCR4, we studied endothelial permeability, intravital leukocyte adhesion, involvement of the Akt/WNT/β-catenin signaling pathway and relevant phosphatases in VE-cadherin expression and function, vascular tone in aortic rings, cholesterol efflux from macrophages, and expression of SMC phenotypic markers. Finally, we analyzed associations of common genetic variants at the CXCR4 locus with the risk for coronary heart disease, along with CXCR4 transcript expression in human atherosclerotic plaques. Results The cell-specific deletion of CXCR4 in arterial ECs (n=12-15) or SMCs (n=13-24) markedly increased atherosclerotic lesion formation in hyperlipidemic mice. Endothelial barrier function was promoted by CXCL12/CXCR4, which triggered Akt/WNT/β-catenin-signaling to drive VE-cadherin expression and stabilized junctional VE-cadherin complexes through associated phosphatases. Conversely, endothelial CXCR4-deficiency caused arterial leakage and inflammatory leukocyte recruitment during atherogenesis. In arterial SMCs, CXCR4 sustained normal vascular reactivity and contractile responses, whereas CXCR4-deficiency favored a synthetic phenotype, the occurrence of macrophage-like SMCs in the lesions, and impaired cholesterol efflux. Regression analyses in humans (n=259,796) identified the C-allele at rs2322864 within the CXCR4 locus to be associated with increased risk for coronary heart disease. In line, C/C risk genotype carriers showed reduced CXCR4 expression in carotid artery plaques (n=188), which was furthermore associated with symptomatic disease. Conclusions Our data clearly establish that vascular CXCR4 limits atherosclerosis by maintaining arterial integrity, preserving endothelial barrier function, and a normal contractile SMC phenotype. Enhancing these beneficial functions of arterial CXCR4 by selective modulators might open novel therapeutic options in atherosclerosis.

Our results demonstrate a functional role for the commensal microbiota in atherothrombosis. In a ferric chloride injury model of the carotid artery, GF C57BL/6J mice had increased occlusion times compared to colonized controls. Interestingly, in late atherosclerosis, HFD-fed GF Ldlr−/− mice had reduced plaque rupture-induced thrombus growth in the carotid artery and diminished ex vivo thrombus formation under arterial flow conditions.

Genome-wide association studies (GWAS) have established a link between the genomic locus 10q11, which hosts the CXCL12 gene, and the risk for coronary artery disease (CAD) (1). CAD risk alleles downstream of CXCL12 have been associated with plasma levels of the chemokine CXCL12 (2); however, the nature and directionality of this association remain elusive. Recently, a Mendelian randomization study identifying genetic determinants of biomarkers in the populations of ORIGIN and CARDIoGRAM revealed CXCL12 as a causal mediator of CAD, supported by epidemiological analysis showing a 15% higher risk for cardiovascular events per SD of increased CXCL12 plasma levels in ORIGIN (3). To detail the association between CXCL12 and CAD, we conducted a meta-analysis of GWAS performed in the EPIC-Norfolk and PROMIS cohorts (n=12,657; filters: INFO≥0.5, MAF≥0.01, HWE≥1×10 −6 , only SNPs appearing in both cohorts). The study was approved by an institutional review committee and subjects gave informed consent. Applying conditional analysis, we newly identified rs2802492, an intergenic SNP near CXCL12, to be independently associated with CXCL12 plasma levels (β=0.016, P=3.24×10 −8) as determined by ELISA (α-isoform, R&D Systems Quantikine kit) (2) and with increased risk for CAD (OR 1.047, P=1.27×10 −6), corroborating CXCL12 as a driver of CAD. No linkage disequilibrium (r 2 >0.8) was found between rs2802492 and the CAD-associated SNPs rs1746048 (1) and intergenic rs1482478 (3). Notably, when specifically tested for

Cite this article as: O'Cathain et al.: Maximising the impact of qualitative research in feasibility studies for randomised controlled trials: guidance for researchers. Trials 2015 16(Suppl 2):O88.

BackgroundElectronic health (eHealth) solutions are considered to relieve current and future pressure on the sustainability of primary health care systems. However, evidence of the effectiveness of eHealth in daily practice is missing. Furthermore, eHealth solutions are often not implemented structurally after a pilot phase, even if successful during this phase. Although many studies on barriers and facilitators were published in recent years, eHealth implementation still progresses only slowly. To further unravel the slow implementation process in primary health care and accelerate the implementation of eHealth, a 3-year Living Lab project was set up. In the Living Lab, called eLabEL, patients, health care professionals, small- and medium-sized enterprises (SMEs), and research institutes collaborated to select and integrate fully mature eHealth technologies for implementation in primary health care. Seven primary health care centers, 10 SMEs, and 4 research institutes participated.ObjectiveThis viewpoint paper aims to show the process of adoption of eHealth in primary care from the perspective of different stakeholders in a qualitative way. We provide a real-world view on how such a process occurs, including successes and failures related to the different perspectives.MethodsReflective and process-based notes from all meetings of the project partners, interview data, and data of focus groups were analyzed systematically using four theoretical models to study the adoption of eHealth in primary care.ResultsThe results showed that large-scale implementation of eHealth depends on the efforts of and interaction and collaboration among 4 groups of stakeholders: patients, health care professionals, SMEs, and those responsible for health care policy (health care insurers and policy makers). These stakeholders are all acting within their own contexts and with their own values and expectations. We experienced that patients reported expected benefits regarding the use of eHealth for self-management purposes, and health care professionals stressed the potential benefits of eHealth and were interested in using eHealth to distinguish themselves from other care organizations. In addition, eHealth entrepreneurs valued the collaboration among SMEs as they were not big enough to enter the health care market on their own and valued the collaboration with research institutes. Furthermore, health care insurers and policy makers shared the ambition and need for the development and implementation of an integrated eHealth infrastructure.ConclusionsFor optimal and sustainable use of eHealth, patients should be actively involved, primary health care professionals need to be reinforced in their management, entrepreneurs should work closely with health care professionals and patients, and the government needs to focus on new health care models stimulating innovations. Only when all these parties act together, starting in local communities with a small range of eHealth tools, the potential of eHealth will be enforced.

Pragmatic trials seem to be oxymoronic. Although the pragmatic trial methodology establishes the effectiveness of interventions under natural, non-experimental conditions, no pragmatic fit is allowed. Qualitative research's contribution to the development of tailor-made community-based interventions lies in providing ongoing evaluations of the dilemmas faced in pragmatic trials and allowing for the development of true tailor-made interventions.