Torsion pendulum facility for direct force measurements of LISA GRS related disturbances

A four mass torsion pendulum facility for testing of the LISA GRS is under development in Trento. With a LISA-like test mass suspended off-axis with respect to the pendulum fiber, the facility allows for a direct measurement of surface force disturbances arising in the GRS. We present here results with a prototype pendulum integrated with very large-gap sensors, which allows an estimate of the intrinsic pendulum noise floor in the absence of sensor related force noise. The apparatus has shown a torque noise near to its mechanical thermal noise limit, and would allow to place upper limits on GRS related disturbances with a best sensitivity of 300 fN/Hz^(1/2) at 1mHz, a factor 50 from the LISA goal. Also, we discuss the characterization of the gravity gradient noise, one environmental noise source that could limit the apparatus performances, and report on the status of development of the facility.Comment: Submitted to Proceedings of the 6th International LISA Symposium, AIP Conference Proceedings 200

Proliferation of cerebellar precursor cells is negatively regulated by nitric oxide in newborn rat.

The diffusible messenger, nitric oxide plays multiple roles in neuroprotection, neurodegeneration and brain plasticity. Its involvement in neurogenesis has been disputed, on the basis of results on models in vivo and in culture. We report here that pharmacological blockade of nitric oxide production in rat pups resulted, during a restricted time window of the first three postnatal days, in increased cerebellar proliferation rate, as assessed through tritiated thymidine or BrdU incorporation into DNA. This was accompanied by increased expression of Myc, a transcription factor essential for cerebellar development, and of the cell cycle regulating gene, cyclin D1. These effects were mediated downstream by the nitric oxide-dependent second messenger, cGMP. Schedules of pharmacological NO deprivation targeted to later developmental stages (from postnatal day 3 to 7), no longer increased proliferation, probably because of partial escape of the cGMP level from nitric oxide control. Though limited to a brief temporal window, the proliferative effect of neonatal nitric oxide deprivation could be traced into adulthood. Indeed, the number of BrdU-labeled surviving cells, most of which were of neuronal phenotype, was larger in the cerebellum of 60-day-old rats that had been subjected to NO deprivation during the first three postnatal days than in control rats. Experiments on cell cultures from neonatal cerebellum confirmed that nitric oxide deprivation stimulated proliferation of cerebellar precursor cells and that this effect was not additive with the proliferative action of sonic hedgehog peptide. The finding that nitric oxide deprivation during early cerebellar neurogenesis, stimulates a brief increase in cell proliferation may contribute to a better understanding of the controversial role of nitric oxide in brain development

Meta-analyses of randomized controlled trials show suboptimal validity of surrogate outcomes for overall survival in advanced colorectal cancer

Comparative StudyMeta-AnalysisReviewValidation StudiesThis is the final version of the article. Available from Elsevier via the DOI in this record.OBJECTIVES: To quantify and compare the treatment effects on three surrogate end points, progression-free survival (PFS), time to progression (TTP), and tumor response rate (TR) vs. overall survival (OS) based on a meta-analysis of randomized controlled trials (RCTs) of drug interventions in advanced colorectal cancer (aCRC). STUDY DESIGN AND SETTING: We systematically searched for RCTs of pharmacologic therapies in aCRC between 2003 and 2013. Trial characteristics, risk of bias, and outcomes were recorded based on a predefined form. Univariate and multivariate random-effects meta-analyses were used to estimate pooled summary treatment effects. The ratio of hazard ratios (HRs)/odds ratios (ORs) and difference in medians were used to quantify the degree of difference in treatment effects on the surrogate end points and OS. Spearman ρ, surrogate threshold effect (STE), and R(2) were also estimated across predefined trial-level covariates. RESULTS: We included 101 RCTs. In univariate and multivariate meta-analyses, we found larger treatment effects for the surrogates than for OS. Compared with OS, treatment effects were on average 13% higher when HRs were measured and 3% to 45% higher when ORs were considered; differences in median PFS/TTP were higher than on OS by an average of 0.5 month. Spearman ρ ranged from 0.39 to 0.80, mean R(2) from 0.06 to 0.65, and STE was 0.8 for HRPFS, 0.64 for HRTTP, or 0.28 for ORTR. The stratified analyses revealed high variability across all strata. CONCLUSION: None of the end points in this study were found to achieve the level of evidence (ie, mean R(2)trial > 0.60) that has been set to select high or excellent correlation levels by common surrogate evaluation tools. Previous surrogacy relationships observed between PFS and TTP vs. OS in selected settings may not apply across other classes or lines of therapy

Trans-arterial radioembolization in intermediate-advanced hepatocellular carcinoma: systematic review and meta-analyses.

Published onlineJournal ArticleThis is the final version of the article. Available from Impact Journals via the DOI in this record.Trans-arterial radioembolization (TARE) is a recognized, although not explicitly recommended, experimental therapy for unresectable hepatocellular carcinoma (HCC).A systematic literature review was performed to identify published studies on the use of TARE in intermediate and advanced stages HCC exploring the efficacy and safety of this innovative treatment.Twenty-one studies reporting data on overall survival (OS) and time to progression (TTP), were included in a meta-analysis. The pooled post-TARE OS was 63% (95% CI: 56-70%) and 27% (95% CI: 21-33%) at 1- and 3-years respectively in intermediate stage HCC, whereas OS was 37% (95% CI: 26-50%) and 13% (95% CI: 9-18%) at the same time intervals in patients with sufficient liver function (Child-Pugh A-B7) but with an advanced HCC because of the presence of portal vein thrombosis. When an intermediate and advanced case-mix was considered, OS was 58% (95% CI: 48-67%) and 17% (95% CI: 12-23%) at 1- and 3-years respectively. As for TTP, only four studies reported data: the observed progression probability was 56% (95% CI: 41-70%) and 73% (95% CI: 56-87%) at 1 and 2 years respectively. The safety analysis, focused on the risk of liver decompensation after TARE, revealed a great variability, from 0-1% to more than 36% events, influenced by the number of procedures, patient Child-Pugh stage and treatment duration.Evidence supporting the use of radioembolization in HCC is mainly based on retrospective and prospective cohort studies. Based on this evidence, until the results of the ongoing randomized trials become available, radioembolization appears to be a viable treatment option for intermediate-advanced stage HCC.The present study was funded by ASBM Srl through an unrestricted grant to CERGAS, Bocconi University, Via Roentgen 1, 20136 Milan, Italy

Genotyping-by-sequencing of a melon (Cucumis melo L.) germplasm collection from a secondary center of diversity highlights patterns of genetic variation and genomic features of different gene pool.

Melon (Cucumis melo L.) is one of the most important horticultural species, which includes several taxonomic groups. With the advent of next-generation sequencing, single nucleotide polymorphism (SNP) markers are widely used in the study of genetic diversity and genomics. Results: We report the first successful application of genotyping-by-sequencing (GBS) technology in melon. We detected 25,422 SNPs by the analysis of 72 accessions collected in Apulia, a secondary centre of diversity in Southern Italy. Analyses of genetic structure, principal components, and hierarchical clustering support the identification of three distinct subpopulations. One of them includes accessions known with the folk name of 'carosello', referable to the chate taxonomic group. This is one of the oldest domesticated forms of C. melo, once widespread in Europe and now exposed to the risk of genetic erosion. The second subpopulation contains landraces of 'barattiere', a regional vegetable production that was never characterized at the DNA level and we show was erroneously considered another form of chate melon. The third subpopulation includes genotypes of winter melon (C. melo var. inodorus). Genetic analysis within each subpopulation revealed patterns of diversity associated with fruit phenotype and geographical origin. We used SNP data to describe, for each subpopulation, the average linkage disequilibrium (LD) decay, and to highlight genomic regions possibly resulting from directional selection and associated with phenotypic variation. Conclusions: We used GBS to characterize patterns of genetic diversity and genomic features within C. melo. We provide useful information to preserve endangered gene pools and to guide the use of germplasm in breeding. Finally, our findings lay a foundation for molecular breeding approaches and the identification of genes underlying phenotypic traits

Exercise training for chronic heart failure (ExTraMATCH II): individual participant data meta-analysis of randomised controlled trials

This is the author accepted manuscript. The final version is available from NIHR Journals Library via the DOI in this record.Background: Current national and international guidelines on the management of heart failure (HF) recommend exercise-based cardiac rehabilitation (ExCR), but do not differentiate this recommendation according to patient subgroups. Objective(s): (1) to obtain definitive estimates of the impact of ExCR interventions versus control (no exercise intervention) on mortality, hospitalisation, exercise capacity, and health-related quality of life (HRQoL) in HF patients; (2) to determine the differential (subgroup) effects of ExCR in HF patients according to their age, gender, ejection fraction, aetiology, New York Heart Association (NYHA) class, and baseline exercise capacity; (3) to assess whether the change in exercise capacity mediates for the impact of the ExCR on final outcomes (mortality, hospitalisation, and HRQoL) and is an acceptable surrogate endpoint. Design: Individual participant data (IPD) meta-analysis Setting: An international literature review Participants: HF patients in randomised controlled trials (RCTs) of ExCR Interventions: ExCR for at least 3 weeks compared with no exercise control with 6 months follow-up Main outcome measures: mortality (all cause and HF-specific), hospitalisation (all-cause & HF-specific), exercise capacity, and HRQoL Data sources: Individual participant data from eligible RCTs 3 Review methods: RCTs from ExTraMATCH IPD meta-analysis and 2014 Cochrane systematic review of ExCR Results: Out of the 23 eligible RCTs (4,398 patients), 19 RCTs (3,990 patients) contributed data to this IPD meta-analysis. There was a wide variation in exercise programme prescriptions across included studies. Compared with control, there was no statistically significant difference in pooled time to event estimates in favour of ExCR although confidence intervals were wide: all-cause mortality: hazard ratio (HR) 0.83 (95% confidence interval (CI): 0.67 to 1.04), HF-related mortality: HR 0.84 (95% CI: 0.49 to 1.46), all-cause hospitalisation: HR 0.90 (95% CI: 0.76 to 1.06), and HF-related hospitalisation: HR 0.98 (95% CI: 0.72 to 1.35). There was a statistically significant difference in favour of ExCR for exercise capacity and HRQoL. Compared to control, at 12-months follow-up, improvements were seen in the six-minute walk test (6MWT) (mean: 21.0 metres, 95% CI: 1.57 to 40.4, and Minnesota Living with HF Questionnaire score (mean: -5.94, 95% CI: -1.0 to -10.9, lower scores indicate improved HRQoL). No strong evidence for differential intervention effects across patient characteristics was found for any outcomes. Moderate to good levels of correlation (R2 trial>50% & ρ>0.50) between peak oxygen uptake (VO2peak) or 6MWT with mortality and HRQoL were seen. Estimated surrogate threshold effect (STE) was an increase of 1.6 to 4.6 ml/kg/min for VO2peak. Limitations: Lack consistency in how included RCTs defined and collected the outcomes; we were unable to obtain IPD from all includable trials for all outcomes; and we did not seek patient level on exercise adherence. . Conclusions: In comparison to no exercise control, participation in ExCR improves the exercise and HRQoL in HF patients but appears to have no effect on their mortality or hospitalisation. No strong evidence was found of differential intervention effects of ExCR across patient characteristics. VO2peak and 6MWT may be suitable surrogate endpoints for the treatment effect of ExCR on mortality and HRQoL in HF.NIHR Health Technology Assessment programm

Demographic genetics of the endangered Amiata donkey breed

The demogenetic structure of the Amiata donkey, an endangered breed from Central Italy, was investigated using information from pedigrees. Genealogical data of 602 donkeys reared in Tuscany were recorded in a database and analysed by the computer package ENDOG. Population size increased from 89 subjects in 1995 to 503 (129 males and 374 females) in 2005. Animals were distributed among 152 herds, but the effective number of herds was 21, suggesting that a small number of herds provided stallions for the entire breed. The maximum number of traced generation was 4, the mean maximum generation was 1.14, the mean com- plete generation was 0.53, and the mean equivalent generation was 0.78. The average relatedness coeffi- cient (AR) in the 503 alive animals was 0.94% while the mean F was 0.29% so the effective population size was 172.41. Among 24 animals with a 4-generation history, 3 (12.5%) were 25% inbred. Although the incompleteness of genealogical information did not permit accurate inference of the current values of popu- lation genetic parameters, the present work represents a first step towards an efficient management of the breed

Gas damping force noise on a macroscopic test body in an infinite gas reservoir

We present a simple analysis of the force noise associated with the mechanical damping of the motion of a test body surrounded by a large volume of rarefied gas. The calculation is performed considering the momentum imparted by inelastic collisions against the sides of a cubic test mass, and for other geometries for which the force noise could be an experimental limitation. In addition to arriving at an accurated estimate, by two alternative methods, we discuss the limits of the applicability of this analysis to realistic experimental configurations in which a test body is surrounded by residual gas inside an enclosure that is only slightly larger than the test body itself.Comment: 8 pages. updated with correct translational damping coefficient for cylinder on axis. added cylinder orthogonal to symmetry axis, force and torque. slightly edited throughou