Design, recruitment, logistics, and data management of the GEHA (Genetics of Healthy Ageing) project

In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90 years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75 years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7 years the number of families with all participating siblings aged 95 years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.

Distinct CCK-2 Receptor Conformations Associated with β-Arrestin-2 Recruitment or Phospholipase-C Activation Revealed by a Biased Antagonist

Seven-transmembrane receptors (7TMRs), also termed G protein-coupled receptors (GPCRs), form the largest class of cell surface membrane receptors, involving several hundred members in the human genome. Near 30% of marketed pharmacological agents target 7TMRs. 7TMRs adopt multiple conformations upon agonist binding. Biased agonists, in contrast to non-biased agonists, are believed to stabilize conformations preferentially activating either G-protein- or ß-arrestin-dependent signalling pathways. However, proof that cognate conformations of receptors display structural differences within their binding site where biased agonism initiates, are still lacking. Here, we show that a non-biased agonist, cholecystokinin (CCK) induces conformational states of the CCK2R activating Gq-protein-dependent pathway (CCK2RG) or recruiting ß-arrestin2 (CCK2Rß) that are pharmacologically and structurally distinct. Two structurally unrelated antagonists competitively inhibited both pathways. A third ligand (GV150,013X), acted as a high affinity competitive antagonist on CCK2RG but was nearly inefficient as inhibitor of CCK2Rß. Several structural elements on both GV150,013X and in CCK2R binding cavity, which hinder binding of GV150,013X only to the CCK2Rß were identified. At last, proximity between two conserved amino acids from transmembrane helices 3 and 7 interacting through sulphur-aromatic interaction was shown to be crucial for selective stabilization of the CCK2Rß state. These data establish structural evidences for distinct conformations of a 7TMR associated with ß-arrestin-2 recruitment or G-protein coupling and validate relevance of the design of biased ligands able to selectively target each functional conformation of 7TMRs.

Community convergence and recruitment of keystone species as performance indicators of artificial reefs

An experimental artificial reefwas constructed in Strangford Lough, Northern Ireland as part of trials to regenerate damaged biogenic reefs formed by the horse mussel Modiolus modiolus. Experimental reef plots were constructed using Pecten maximus shell as cultch. Clumps of live adult M. modiolus were translocated from nearby natural reefs into cultchwith a high profile (elevated cultch), cultch with a lowprofile (flattened cultch), as well as directly into the seafloor. The aim of the study was to test the hypothesis that translocated mussel clumps would increase habitat complexity thus accelerating community succession and enhancing natural recruitment of M. modiolus spat. These effects were predicted to be greater on elevated cultch due to greater protection from
predators and increased accessibility to food resources. Within the artificial reef array the translocated clumps had a significant positive effect on recruitment compared to cultch without mussels with average densities of spat settled on the translocated M. modiolus clumps ranging from 100 to 200 individuals m-2 compared to 4 to 52 spat m-2 on cultch without mussels. Recruitment of M. modiolus spat was also significantly higher on translocated horse mussels when compared to natural reefs where densities of 8–36 spat m-2 were recorded.
Reef elevation appeared to provide some degree of protection from predators but differences in translocated M. modiolus survival on the different elevation treatments were not significant. In total, 223 taxa were recorded 12 months after reef construction. The presence of translocated clumps ofM. modiolus was the main driver of the increases in faunal diversity and species abundance. Application of objective criteria to assess the performance of artificial reefs suggested that translocation of M. modiolus clumps alone achieved most of the restoration objectives. Consequently this pilot study demonstrates a straightforward and realistic intervention technique that could be used to kick start the regeneration and expansion of impacted mussel and similar biogenic reefs elsewhere.

Stock-recruitment relations controlled by feeding interactions alone

Stock-recruitment (S-R) relationships are the centrepiece of fisheries management aimed at achieving maximum sustainable yield (MSY). Here we consider the possibility that the density dependence evident in S-R relations is controlled by feeding interactions alone. We simulate a food-web model with dynamic representations of intra- and interspecific size structure and a linear relation between food intake and hatchling production of adults. Population sizes of individual stocks are modified by imposing additional mortality. The predominant functional forms and the steepness of resulting S-R relationships agree well with observations. We conclude that recruitment is plausibly regulated by feeding interactions alone.

SWAT 1:what effects do site visits by the principal investigator have on recruitment in a multicentre randomized trial?

The SWAT (Study Within A Trial) programme has been established to develop a series of studies that would embed research within research, so as to resolve uncertainties about the effects of different ways of designing, conducting, analyzing and interpreting evaluations of health and social care. It was described in an Education piece in the Journal of Evidence-Based Medicine in 2012. We have now prepared the first example of the design summary for a SWAT, using the template that will be used for other SWAT. This is presented in this article.

Survey of challenges and best practice strategies for participant recruitment to research projects in northern ireland

Participant recruitment is understood to be one of the most difficult aspects of the research process. Researchers are now devoting increasing amounts of time and resources to understand how participants decide to take part in research and what researchers can do to make their work appeal to potential participants. The purpose of the study is to assess the problems experienced by researchers in Northern Ireland when recruiting human participants into trials and studies and to gain insight into how researchers handle and overcome these issues. The main research question being addressed by this research is to develop an understanding of the problems experienced by staff when recruiting human participants to research projects. Methods used to increase study recruitment were also examined. The participants in this research are investigators and other associated staff on research studies based in Northern Ireland. Potential participants were identified through contacts with research active organizations such as the academic researchers in Queen’s University Belfast and research physicians and clinical trialists employed by the Belfast Health and Social Care Trust. Each organization forwarded on the survey request via email or newsletters. Researchers willing to take part accessed the questionnaire through the Survey Monkey website. This study utilised a cross-sectional questionnaire design.

SWAT-1: The effectiveness of a 'site visit' intervention on recruitment rates in a multi-centre randomised trial

Background: Recruitment rates in multi-centre randomised trials often fall below target recruitment rates, causing problems for study outcomes. The Studies Within A Trial (SWAT) Programme, established by the All-Ireland Hub for Trials Methodology Research in collaboration with the Medical Research Council Network of Hubs in the United Kingdom and others, is developing methods for evaluating aspects of trial methodology through the conduct of research within research. A recently published design for a SWAT-1 provides a protocol for evaluating the effect of a site visit by the principal investigator on recruitment in multi-centre trials.

Methods: Using the SWAT-1 design, the effect of a site visit, with the sole purpose of discussing trial recruitment, on recruitment rates in a large multicentre trial in the Republic of Ireland was evaluated. A controlled before and after intervention comparison was used, where the date of the site visit provides the time point for the intervention, and for the comparison to control sites. Site A received the intervention. Site B and Site C acted as the controls. Z-scores for proportions were calculated to determine within site recruitment differences. Odds ratios and 95% confidence intervals were calculated to determine between site recruitment differences.

Results: Recruitment rates were increased in Site A post-intervention (17% and 14% percentage point increases at 1 and 3 months, respectively). No differences in recruitment occurred in Site B or in Site C. Comparing between site differences, at 3 months post-intervention, a statistically significant difference was detected in favour of higher recruitment in Site A (34% versus 25%; odds ratio 1.57, 95% confidence interval 1.09 to 2.26).

Conclusions: This is the first reported example of a study in the SWAT programme.. It provides evidence that a site visit, combined with a scheduled meeting, increases recruitment in a clinical trial. Using this example, other researchers might be encouraged to consider conducting a similar study, allowing the findings of future SWAT-1s to be compared and combined, so that higher level evidence on the effect of a site visit by the principal investigator can be obtained.

Relative toxicity of arsenite and arsenate on germination and early seedling growth of rice (Oryza sativa L.)

Elevated soil arsenic levels resulting from long-term use of arsenic contaminated ground for irrigation in Bangladesh may inhibit seed germination and seedling establishment of rice, the country's main food crop. A germination study on rice seeds and a short-term toxicity experiment with different concentrations of arsenite and arsenate on rice seedlings were conducted. Percent germination over control decreased significantly with increasing concentrations of arsenite and arsenate. Arsenite was found to be more toxic than arsenate for rice seed germination. There were varietal differences among the test varieties in response to arsenite and arsenate exposure. The performance of the dry season variety Purbachi was the best among the varieties. Germination of Purbachi was not inhibited at all up to 4 mg l^-1 arsenite and 8 mg l^-1 arsenate treatment. Root tolerance index (RTI) and relative shoot height (RSH) for rice seedlings decreased with increasing concentrations of arsenite and arsenate. Reduction of RTI caused by arsenate was higher than that of arsenite. In general, dry season varieties have more tolerance to arsenite or arsenate than the wet season varieties.