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Aim: Ileus is characterized by a period of intestinal dysmotility after surgery, leading to vomiting and constipation. In preclinical models, vagus nerve stimulation reduces intestinal inflammation and prevents smooth muscle dysfunction, accelerating the return of gut function. This study explored the feasibility of a definitive trial of non‐invasive vagus nerve stimulation (nVNS) along with an early assessment of efficacy. Method: A multicentre, randomized feasibility trial (IDEAL Stage 2B) of self‐administered nVNS was performed. Patients undergoing colorectal surgery were randomized to nVNS or sham before and after surgery. Feasibility outcomes comprised assessments of recruitment, compliance, blinding and attrition. Clinical outcomes were measures of intestinal function and adverse events. All participants were followed up for 30 days. Interviews with patients and health professionals explored barriers to feasibility and perspectives around implementation. Results: In all, 125 patients were approached about the study and 97 (77.6%) took part. Across all randomized groups, the median compliance to treatment was 19 out of 20 stimulations (interquartile range 17–20). The incidence of adverse events was similar across groups. In this unpowered feasibility study, the time taken for the return of gut function (such as first passage of stool) was similar between nVNS and sham treatments. According to interviews, patients were highly motivated to use the device because it provided them with an opportunity to engage actively in their care. Health professionals were highly driven to tackle the problem of ileus. Conclusion: Powered assessments of clinical efficacy are required to confirm or refute the promise of nVNS, as already demonstrated in preclinical models. This feasibility study concludes that a definitive randomized assessment of the clinical benefits of nVNS is desired and feasible. [ABSTRACT FROM AUTHOR]

Abstract Background Exploring barriers to the uptake of research based recommendations into practice is an important part of the development of implementation programmes. Techniques to identify barriers can include use of theory-informed questionnaires and qualitative interviews. Conceptualising and measuring theory-informed factors, and engaging health professionals’ to uncover all potential barriers, can be a difficult task. This paper presents a case study of the process of trying to identify, systematically, the key factors influencing health professionals’ referrals for women diagnosed with mild to moderate postnatal depression for psychological treatment. The paper illustrates how the factors were conceptualised and measured and explores the real world challenges experienced, with implications for future implementation studies. Methods Theory-informed factors were conceptualised and measured using a questionnaire and interviews. The questionnaire was piloted, before being administered to general practitioners, practice nurses and health visitors working in general practices in one area of the UK NHS. The interviews were conducted with a small sample of general practitioners who had not completed the questionnaire, further exploring factors influencing their referral decisions in the local context. Results The response rate to the questionnaire was low (19%), despite selecting the recommendation to target through engagement with local stakeholders and surveying local health professionals, and despite using two reminders, an incentive prize, and phone calls to practice managers to bolster response rates. Conclusions Two significant challenges to achieving higher response rates and successfully exploring local context were identified: the difficulties of developing a robust- but feasible- questionnaire to explore theory-informed factors, and targeting recommendations that are important to policy makers, but which health professionals view as unimportant. This case study highlights the “trade-off” between scientifically rigorous collection of data against the pragmatism and flexibility requirements of “real world” implementation. Future implementation studies should explore different ways of identifying factors influencing the adoption of recommendations to bridge this gulf.

Background: Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy. Methodology/Principal Findings: Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent. Conclusions/Significance: Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings. Further study in larger patient populations will be necessary to fully characterize and validate the clinical impact of polymorphisms in SLCO1B1 and other transporter and metabolizing enzyme genes on outcomes from flavopiridol therapy. [ABSTRACT FROM AUTHOR]