Use of drug therapy in the management of symptomatic ureteric stones in hospitalized adults (SUSPEND), a multicentre, placebo-controlled, randomized trial of a calcium-channel blocker (nifedipine) and an α-blocker (tamsulosin) : study protocol for a randomized controlled trial

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The clinical and cost effectiveness of surgical interventions for stones in the lower pole of the kidney : the percutaneous nephrolithotomy, flexible ureterorenoscopy and extracorporeal shockwave lithotripsy for lower pole kidney stones randomised controlled trial (PUrE RCT) protocol

PUrE is a UK Collaborative Trial funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project no. 13/152/02). The Health Services Research Unit is funded by the Chief Scientists Office of the Scottish Government Health Directorates. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Health Technology Assessment Programme, the National Institute of Health Research, the National Health Service or the Department of Health. The funder (through their peer-review and funding board review process) approved the study proposal but had no role in the collection, analysis or interpretation of data or writing of the report.Peer reviewedPublisher PD

Shockwave lithotripsy compared with ureteroscopic stone treatment for adults with ureteric stones : the TISU non-inferiority RCT

Acknowledgements The authors wish to thank the patients who participated in the TISU trial.We also thank Stanley Coutts (patient representative) and Charles Clark (patient representative and co-applicant) for their contribution to the design of the participant-facing documents (patient information sheet and questionnaires); Sharon Wren for her secretarial support and data management; previous data co-ordinators, Jessica Wood and Margery Heath, for their data and trial management support; the CHaRT programming team led by Gladys McPherson (to 2016) and Mark Forrest (2016–present); other staff within CHaRT and the HSRU for their assistance with the trial (Cynthia Fraser); members of the PMG for their ongoing advice and support of the trial, plus the independent members of the TSC and DMC; and the staff at the recruitment sites who facilitated the recruitment, treatment and follow-up of trial participants (all listed below); and, finally, we would like to thank the National Institute for Health Research and the Health Technology Assessment programme for funding the TISU trial. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 19. See the NIHR Journals Library website for further project information.Peer reviewedPublisher PD

Cost−utility analysis of shockwave lithotripsy vs ureteroscopic stone treatment in adults

Objectives: To assess the cost‐effectiveness, resource use implications, quality‐adjusted life‐years (QALYs) and cost per QALY of care pathways starting with either extracorporeal shockwave lithotripsy (SWL) or with ureteroscopic retrieval (ureteroscopy [URS]) for the management of ureteric stones. Patients and Methods: Data on quality of life and resource use for 613 patients, collected prospectively in the Therapeutic Interventions for Stones of the Ureter (TISU) randomized controlled trial (ISRCTN 92289221), were used to assess the cost‐effectiveness of two care pathways, SWL and URS. A health provider (UK National Health Service) perspective was adopted to estimate the costs of the interventions and subsequent resource use. Quality‐of‐life data were calculated using a generic instrument, the EuroQol EQ‐5D‐3L. Results are expressed as incremental cost‐effectiveness ratios and cost‐effectiveness acceptability curves. Results: The mean QALY difference (SWL vs URS) was −0.021 (95% confidence interval [CI] −0.033 to −0.010) and the mean cost difference was −£809 (95% CI −£1061 to −£551). The QALY difference translated into approximately 10 more healthy days over the 6‐month period for the patients on the URS care pathway. The probabaility that SWL is cost‐effective is 79% at a society's willingness to pay (WTP) threshold for 1 QALY of £30,000 and 98% at a WTP threshold of £20,000. Conclusion: The SWL pathway results in lower QALYs than URS but costs less. The incremental cost per QALY is £39 118 cost saving per QALY lost, with a 79% probability that SWL would be considered cost‐effective at a WTP threshold for 1 QALY of £30 000 and 98% at a WTP threshold of £20 000. Decision‐makers need to determine if costs saved justify the loss in QALYs

TISU: Extracorporeal shockwave lithotripsy, as first treatment option, compared with direct progression to ureteroscopic treatment, for ureteric stones : study protocol for a randomised controlled trial

This project is funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number 10/137/01) and will be published in full in Health Technology Assessment. The Health Services Research Unit of the University of Aberdeen iscore funded by the Chief Scientist Office (CSO) of the Scottish Government Health and Social Care Directorates. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the CSO, HTA programme, NIHR, NHS or the Department of Health.Peer reviewedPublisher PD

Regulation of skeletal muscle oxidative capacity and insulin signaling by the Mitochondrial Rhomboid Protease PARL

Type 2 diabetes mellitus (T2DM) and aging are characterized by insulin resistance and impaired mitochondrial energetics. In lower organisms, remodeling by the protease pcp1 (PARL ortholog) maintains the function and lifecycle of mitochondria. We examined whether variation in PARL protein content is associated with mitochondrial abnormalities and insulin resistance. PARL mRNA and mitochondrial mass were both reduced in elderly subjects and in subjects with T2DM. Muscle knockdown of PARL in mice resulted in malformed mitochondrial cristae, lower mitochondrial content, decreased PGC1&alpha; protein levels, and impaired insulin signaling. Suppression of PARL protein in healthy myotubes lowered mitochondrial mass and insulin-stimulated glycogen synthesis and increased reactive oxygen species production. We propose that lower PARL expression may contribute to the mitochondrial abnormalities seen in aging and T2DM.<br /

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

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe