Sharing data from clinical trials: the rationale for a controlled access approach.

The move towards increased transparency around clinical trials is welcome. Much focus has been on under-reporting of trials and access to individual patient data to allow independent verification of findings. There are many other good reasons for data sharing from clinical trials. We describe some key issues in data sharing, including the challenges of open access to data. These include issues in consent and disclosure; risks in identification, including self-identification; risks in distorting data to prevent self-identification; and risks in analysis. These risks have led us to develop a controlled access policy, which safeguards the rights of patients entered in our trials, guards the intellectual property rights of the original researchers who designed the trial and collected the data, provides a barrier against unnecessary duplication, and ensures that researchers have the necessary resources and skills to analyse the data

Changing platforms without stopping the train: experiences of data management and data management systems when adapting platform protocols by adding and closing comparisons.

Background There is limited research and literature on the data management challenges encountered in multi-arm, multi-stage platform and umbrella protocols. These trial designs allow both (1) seamless addition of new research comparisons and (2) early stopping of accrual to individual comparisons that do not show sufficient activity. FOCUS4 (colorectal cancer) and STAMPEDE (prostate cancer), run from the Medical Research Council Clinical Trials Unit (CTU) at UCL, are two leading UK examples of clinical trials implementing adaptive platform protocol designs. To date, STAMPEDE has added five new research comparisons, closed two research comparisons following pre-planned interim analysis (lack of benefit), adapted the control arm following results from STAMPEDE and other relevant trials, and completed recruitment to six research comparisons. FOCUS4 has closed one research comparison following pre-planned interim analysis (lack of benefit) and added one new research comparison, with a number of further comparisons in the pipeline. We share our experiences from the operational aspects of running these adaptive trials, focusing on data management.Methods We held discussion groups with STAMPEDE and FOCUS4 CTU data management staff to identify data management challenges specific to adaptive platform protocols. We collated data on a number of case report form (CRF) changes, database amendments and database growth since each trial began.Discussion We found similar adaptive protocol-specific challenges in both trials. Adding comparisons to and removing them from open trials provides extra layers of complexity to CRF and database development. At the start of an adaptive trial, CRFs and databases must be designed to be flexible and scalable in order to cope with the continuous changes, ensuring future data requirements are considered where possible. When adding or stopping a comparison, the challenge is to incorporate new data requirements while ensuring data collection within ongoing comparisons is unaffected. Some changes may apply to all comparisons; others may be comparison-specific or applicable only to patients recruited during a specific time period. We discuss the advantages and disadvantages of the different approaches to CRF and database design we implemented in these trials, particularly in relation to use and maintenance of generic versus comparison-specific CRFs and databases. The work required to add or remove a comparison, including the development and testing of changes, updating of documentation, and training of sites, must be undertaken alongside data management of ongoing comparisons. Adequate resource is required for these competing data management tasks, especially in trials with long follow-up. A plan is needed for regular and pre-analysis data cleaning for multiple comparisons that could recruit at different rates and periods of time. Data-cleaning activities may need to be split and prioritised, especially if analyses for different comparisons overlap in time.Conclusions Adaptive trials offer an efficient model to run randomised controlled trials, but setting up and conducting the data management activities in these trials can be operationally challenging. Trialists and funders must plan for scalability in data collection and the resource required to cope with additional competing data management tasks

Evolution of the elaborate male intromittent organ of Xiphophorus fishes

Internally fertilizing animals show a remarkable diversity in male genital morphology that is associated with sexual selection, and these traits are thought to be evolving particularly rapidly. Male fish in some internally fertilizing species have “gonopodia,” highly modified anal fins that are putatively important for sexual selection. However, our understanding of the evolution of genital diversity remains incomplete. Contrary to the prediction that male genital traits evolve more rapidly than other traits, here we show that gonopodial traits and other nongonopodial traits exhibit similar evolutionary rates of trait change and also follow similar evolutionary models in an iconic genus of poeciliid fish (Xiphophorus spp.). Furthermore, we find that both mating and nonmating natural selection mechanisms are unlikely to be driving the diverse Xiphophorus gonopodial morphology. Putative holdfast features of the male genital organ do not appear to be influenced by water flow, a candidate selective force in aquatic habitats. Additionally, interspecific divergence in gonopodial morphology is not significantly higher between sympatric species, than between allopatric species, suggesting that male genitals have not undergone reproductive character displacement. Slower rates of evolution in gonopodial traits compared with a subset of putatively sexually selected nongenital traits suggest that different selection mechanisms may be acting on the different trait types. Further investigations of this elaborate trait are imperative to determine whether it is ultimately an important driver of speciation

Actin polymerization driven by WASH causes V-ATPase retrieval and vesicle neutralization before exocytosis

WASH coats mature lysosomes and is required for exocytosis of indigestible material

Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial.

BACKGROUND: STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). METHODS AND FINDINGS: Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. CONCLUSIONS: Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. TRIAL REGISTRATION: ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544

An Indirect Cue of Predation Risk Counteracts Female Preference for Conspecifics in a Naturally Hybridizing Fish Xiphophorus birchmanni

Mate choice is context dependent, but the importance of current context to interspecific mating and hybridization is largely unexplored. An important influence on mate choice is predation risk. We investigated how variation in an indirect cue of predation risk, distance to shelter, influences mate choice in the swordtail Xiphophorus birchmanni, a species which sometimes hybridizes with X. malinche in the wild. We conducted mate choice experiments to determine whether females attend to the distance to shelter and whether this cue of predation risk can counteract female preference for conspecifics. Females were sensitive to shelter distance independent of male presence. When conspecific and heterospecific X. malinche males were in equally risky habitats (i.e., equally distant from shelter), females associated primarily with conspecifics, suggesting an innate preference for conspecifics. However, when heterospecific males were in less risky habitat (i.e., closer to shelter) than conspecific males, females no longer exhibited a preference, suggesting that females calibrate their mate choices in response to predation risk. Our findings illustrate the potential for hybridization to arise, not necessarily through reproductive “mistakes”, but as one of many potential outcomes of a context-dependent mate choice strategy

FYVE-Dependent Endosomal Targeting of an Arrestin-Related Protein in Amoeba

International audienceBACKGROUND: Visual and β-arrestins are scaffolding proteins involved in the regulation of receptor-dependent intracellular signaling and their trafficking. The arrestin superfamilly includes several arrestin domain-containing proteins and the structurally related protein Vps26. In Dictyostelium discoideum, the arrestin-domain containing proteins form a family of six members, namely AdcA to -F. In contrast to canonical arrestins, Dictyostelium Adc proteins show a more complex architecture, as they possess, in addition to the arrestin core, other domains, such as C2, FYVE, LIM, MIT and SAM, which potentially mediate selective interactions with either lipids or proteins. METHODOLOGY AND PRINCIPAL FINDINGS: A detailed analysis of AdcA has been performed. AdcA extends on both sides of the arrestin core, in particular by a FYVE domain which mediates selective interactions with PI(3)P, as disclosed by intrinsic fluorescence measurements and lipid overlay assays. Localization studies showed an enrichment of tagged- and endogenous AdcA on the rim of early macropinosomes and phagosomes. This vesicular distribution relies on a functional FYVE domain. Our data also show that the arrestin core binds the ADP-ribosylation factor ArfA, the unique amoebal Arf member, in its GDP-bound conformation. SIGNIFICANCE: This work describes one of the 6 arrestin domain-containing proteins of Dictyostelium, a novel and atypical member of the arrestin clan. It provides the basis for a better understanding of arrestin-related protein involvement in trafficking processes and for further studies on the expanding roles of arrestins in eukaryotes

Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial

BACKGROUND: STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). METHODS AND FINDINGS: Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p &lt; 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p &lt; 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. CONCLUSIONS: Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. TRIAL REGISTRATION: ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544

Cichlid biogeography: comment and review

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72313/1/j.1467-2979.2004.00148.x.pd