The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers

There remain many treatment uncertainties in cystic fibrosis (CF). With limited resources, research should focus on questions which are most important to the CF community. We conducted a James Lind Alliance Priority Setting Partnership in CF. Research questions were elicited and then prioritised in successive surveys. A workshop agreed the final top 10. Online methods avoided cross infection and widened participation. The elicitation survey had 482 respondents (1080 questions) and prioritisation survey 677 respondents. Participants were drawn equally from the patient and clinical communities globally. We have achieved a consensus on 10 research priorities which will be attractive to funders

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Endomorphin-1 induced desensitization and down-regulation of the recombinant μ-opioid receptor

1. Endomorphin-1 (E1) is a peptide with high affinity and selectivity for the μ-opioid receptor. The aim of this study was to determine if endomorphin-1 caused desensitization and down-regulation of the μ-opioid receptor expressed in Chinese hamster ovary cells. 2. Following 10 μM E1 pre-treatment, desensitization was assessed by measuring cyclic AMP inhibition, down-regulation was assessed by [(3)H]-diprenorphine ([(3)H]-DPN) binding and immunoblotting. 3. Pre-treatment of CHOμ cells with 10 μM E1 for 11 and 18 h caused significant reduction in cyclic AMP inhibition. (11 h=39.0±16.7%, 18 h 47.0±11.1% reduction). 4. At 18 h E1 pre-treatment there was an enhancement (4.5 fold) of cyclic AMP production under forskolin stimulated conditions accompanied by a small rightward shift in the concentration-response curve (pEC(50) control=7.8±0.3, pEC(50) E1=7.3±0.2) when cells were re-challenged with E1. 5. In membranes prepared from untreated and 0.5 h E1 pre-treated cells, addition of GTPγS produced a significant rightward shift in the concentration response curves for E1 displacement of [(3)H]-DPN (0 h K(i) control=7.86±0.11, GTPγS=7.37±0.15; 0.5 h K(i) control=7.92±0.12, GTPγS=7.36±0.08) This was not observed in membranes prepared from cells that had been treated with E1 for 18 h (18 h K(i) control=7.69±0.11, GTPγS=7.75±0.08). 6. In whole cells E1 treatment caused a rapid loss of cell surface receptors such that at 0.5 h there was a 30.5±1.5 reduction (this was unchanged for 18 h). In crude membranes a loss of receptors was also observed using radioligand binding or immuno-blotting protocols. 7. These data show that E1 causes desensitization and down-regulation of the rat μ-opioid receptor expressed in CHO cells. However, these two responses appear temporally distinct

Work-life balance and parenthood:a comparative review of definitions, equity and enrichment

This review investigates the problems of definition and inequity with which the literature on parenthood and work–life balance is beset. It analyses research trajectories first within the established disciplines of organizational psychology and the sociologies of work and family practices, and then within the newer field of management studies. Gender, class and difference are singled out as troubling themes, especially in relation to fathers and impoverished parents. A tendency towards mono-disciplinarity is observed within organizational psychology and sociologies of work and family practices. The review offers explanations for the historic but narrow definition within organizational psychology and sociologies of work and family practices of work–life balance as affecting mainly heterosexual dual-career parent couples. The authors show how this narrow definition has led to inequities within research. They further identify as limiting the definition of work–life balance to be always ‘problematic’, rather than enriching, among employed parents. Consequently, a three-factor framework is recommended, through which future studies may address the problems of definition and equity in work–life balance literature, including: a broader definition of work–life balance to include marginalized parents; the defining of parenting and employment as potentially life-enriching; and a commendation of the transdisciplinary approach within management studies as poised to move debate forward