Effects of study design and allocation on participant behaviour-ESDA: study protocol for a randomized controlled trial

Background: What study participants think about the nature of a study has been hypothesised to affect subsequent behaviour and to potentially bias study findings. In this trial we examine the impact of awareness of study design and allocation on participant drinking behaviour. Methods/Design: A three-arm parallel group randomised controlled trial design will be used. All recruitment, screening, randomisation, and follow-up will be conducted on-line among university students. Participants who indicate a hazardous level of alcohol consumption will be randomly assigned to one of three groups. Group A will be informed their drinking will be assessed at baseline and again in one month (as in a cohort study design). Group B will be told the study is an intervention trial and they are in the control group. Group C will be told the study is an intervention trial and they are in the intervention group. All will receive exactly the same brief educational material to read. After one month, alcohol intake for the past 4 weeks will be assessed. Discussion: The experimental manipulations address subtle and previously unexplored ways in which participant behaviour may be unwittingly influenced by standard practice in trials. Given the necessity of relying on self-reported outcome, it will not be possible to distinguish true behaviour change from reporting artefact. This does not matter in the present study, as any effects of awareness of study design or allocation involve bias that is not well understood. There has been little research on awareness effects, and our outcomes will provide an indication of the possible value of further studies of this type and inform hypothesis generation

Elucidating the aetiology of human Campylobacter coli infections

Peer reviewedPublisher PD

Mobility promotes and jeopardizes biodiversity in rock-paper-scissors games

Biodiversity is essential to the viability of ecological systems. Species diversity in ecosystems is promoted by cyclic, non-hierarchical interactions among competing populations. Such non-transitive relations lead to an evolution with central features represented by the `rock-paper-scissors' game, where rock crushes scissors, scissors cut paper, and paper wraps rock. In combination with spatial dispersal of static populations, this type of competition results in the stable coexistence of all species and the long-term maintenance of biodiversity. However, population mobility is a central feature of real ecosystems: animals migrate, bacteria run and tumble. Here, we observe a critical influence of mobility on species diversity. When mobility exceeds a certain value, biodiversity is jeopardized and lost. In contrast, below this critical threshold all subpopulations coexist and an entanglement of travelling spiral waves forms in the course of temporal evolution. We establish that this phenomenon is robust, it does not depend on the details of cyclic competition or spatial environment. These findings have important implications for maintenance and evolution of ecological systems and are relevant for the formation and propagation of patterns in excitable media, such as chemical kinetics or epidemic outbreaks.Comment: Final submitted version; the printed version can be found at http://dx.doi.org/10.1038/nature06095 Supplementary movies are available at http://www.theorie.physik.uni-muenchen.de/lsfrey/images_content/movie1.AVI and http://www.theorie.physik.uni-muenchen.de/lsfrey/images_content/movie2.AV

The SAR11 Group of Alpha-Proteobacteria Is Not Related to the Origin of Mitochondria

Although free living, members of the successful SAR11 group of marine alpha-proteobacteria contain a very small and A+T rich genome, two features that are typical of mitochondria and related obligate intracellular parasites such as the Rickettsiales. Previous phylogenetic analyses have suggested that Candidatus Pelagibacter ubique, the first cultured member of this group, is related to the Rickettsiales+mitochondria clade whereas others disagree with this conclusion. In order to determine the evolutionary position of the SAR11 group and its relationship to the origin of mitochondria, we have performed phylogenetic analyses on the concatenation of 24 proteins from 5 mitochondria and 71 proteobacteria. Our results support that SAR11 group is not the sistergroup of the Rickettsiales+mitochondria clade and confirm that the position of this group in the alpha-proteobacterial tree is strongly affected by tree reconstruction artefacts due to compositional bias. As a consequence, genome reduction and bias toward a high A+T content may have evolved independently in the SAR11 species, which points to a different direction in the quest for the closest relatives to mitochondria and Rickettsiales. In addition, our analyses raise doubts about the monophyly of the newly proposed Pelagibacteraceae family

Exploring the evidence base for how people with dementia and their informal carers manage their medication in the community:a mixed studies review

BACKGROUND: Little is known about the general medicines management issues for people with dementia living in the community. This review has three aims: firstly to explore and evaluate the international literature on how people with dementia manage medication; assess understanding of medicines management from an informal carers perspective; and lastly to understand the role that healthcare professionals play in assisting this population with medicines management. METHODS: A mixed studies review was conducted. Web of Knowledge, PubMed and Cochrane Library were searched post-1999 for studies that explored medicines management in people with dementia dwelling in the community, and the role healthcare professionals play in supporting medicines management in people with dementia. Following screening, nine articles were included. Data from included studies were synthesised using a convergent synthesis approach and analysed thematically to combine findings from studies using a range of methods (qualitative, quantitative and mixed methods). RESULTS: Four themes were generated from the synthesis: The nature of the disease and the effects this had on medicines management; the additional responsibilities informal carers have; informal caregivers' knowledge of the importance of managing medication and healthcare professionals' understanding of medicines management in people with dementia. Consequently, these were found to affect management of medication, in particular adherence to medication. CONCLUSIONS: This review has identified that managing medication for people with dementia dwelling in the community is a complex task with a frequently associated burden on their informal caregivers. Healthcare professionals can be unaware of this burden. The findings warrant the need for healthcare professionals to undergo further training in supporting medicines management for people with dementia in their own homes

Phylogenetic Beta Diversity Metrics, Trait Evolution and Inferring the Functional Beta Diversity of Communities

The beta diversity of communities along gradients has fascinated ecologists for decades. Traditionally such studies have focused on the species composition of communities, but researchers are becoming increasingly interested in analyzing the phylogenetic composition in the hope of achieving mechanistic insights into community structure. To date many metrics of phylogenetic beta diversity have been published, but few empirical studies have been published. Further inferences made from such phylogenetic studies critically rely on the pattern of trait evolution. The present work provides a study of the phylogenetic dissimilarity of 96 tree communities in India. The work compares and contrasts eight metrics of phylogenetic dissimilarity, considers the role of phylogenetic signal in trait data and shows that environmental distance rather than spatial distance is the best correlate of phylogenetic dissimilarity in the study system

Unsuspected and extensive transmission of a drug-susceptible Mycobacterium tuberculosis strain

<p>Abstract</p> <p>Background</p> <p>A large and unsuspected tuberculosis outbreak involving 18.7% of the total of the tuberculosis cases studied, was detected in a population-based molecular epidemiological study performed in Zaragoza (Spain) from 2001 to 2004.</p> <p>Methods</p> <p>The <it>Mycobacterium tuberculosis </it>drug-susceptible strain, named <it>MTZ </it>strain, was genetically characterized by IS<it>6110</it>-RFLP, Spoligotyping and by MIRU-VNTR typing and the genetic patterns obtained were compared with those included in international databases. The characteristics of the affected patients, in an attempt to understand why the <it>MTZ </it>strain was so highly transmitted among the population were also analyzed.</p> <p>Results</p> <p>The genetic profile of the <it>MTZ </it>strain was rare and not widely distributed in our area or elsewhere. The patients affected did not show any notable risk factor for TB.</p> <p>Conclusion</p> <p>The <it>M. tuberculosis </it>strain <it>MTZ</it>, might have particular transmissibility or virulence properties, and we believe that greater focus should be placed on stopping its widespread dissemination.</p

Simulating Food Web Dynamics along a Gradient: Quantifying Human Influence

Realistically parameterized and dynamically simulated food-webs are useful tool to explore the importance of the functional diversity of ecosystems, and in particular relations between the dynamics of species and the whole community. We present a stochastic dynamical food web simulation for the Kelian River (Borneo). The food web was constructed for six different locations, arrayed along a gradient of increasing human perturbation (mostly resulting from gold mining activities) along the river. Along the river, the relative importance of grazers, filterers and shredders decreases with increasing disturbance downstream, while predators become more dominant in governing eco-dynamics. Human activity led to increased turbidity and sedimentation which adversely impacts primary productivity. Since the main difference between the study sites was not the composition of the food webs (structure is quite similar) but the strengths of interactions and the abundance of the trophic groups, a dynamical simulation approach seemed to be useful to better explain human influence. In the pristine river (study site 1), when comparing a structural version of our model with the dynamical model we found that structurally central groups such as omnivores and carnivores were not the most important ones dynamically. Instead, primary consumers such as invertebrate grazers and shredders generated a greater dynamical response. Based on the dynamically most important groups, bottom-up control is replaced by the predominant top-down control regime as distance downstream and human disturbance increased. An important finding, potentially explaining the poor structure to dynamics relationship, is that indirect effects are at least as important as direct ones during the simulations. We suggest that our approach and this simulation framework could serve systems-based conservation efforts. Quantitative indicators on the relative importance of trophic groups and the mechanistic modeling of eco-dynamics could greatly contribute to understanding various aspects of functional diversity

Confidence from uncertainty - A multi-target drug screening method from robust control theory

<p>Abstract</p> <p>Background</p> <p>Robustness is a recognized feature of biological systems that evolved as a defence to environmental variability. Complex diseases such as diabetes, cancer, bacterial and viral infections, exploit the same mechanisms that allow for robust behaviour in healthy conditions to ensure their own continuance. Single drug therapies, while generally potent regulators of their specific protein/gene targets, often fail to counter the robustness of the disease in question. Multi-drug therapies offer a powerful means to restore disrupted biological networks, by targeting the subsystem of interest while preventing the diseased network from reconciling through available, redundant mechanisms. Modelling techniques are needed to manage the high number of combinatorial possibilities arising in multi-drug therapeutic design, and identify synergistic targets that are robust to system uncertainty.</p> <p>Results</p> <p>We present the application of a method from robust control theory, Structured Singular Value or μ- analysis, to identify highly effective multi-drug therapies by using robustness in the face of uncertainty as a new means of target discrimination. We illustrate the method by means of a case study of a negative feedback network motif subject to parametric uncertainty.</p> <p>Conclusions</p> <p>The paper contributes to the development of effective methods for drug screening in the context of network modelling affected by parametric uncertainty. The results have wide applicability for the analysis of different sources of uncertainty like noise experienced in the data, neglected dynamics, or intrinsic biological variability.</p

NF-κB2 signalling in enteroids modulates enterocyte responses to secreted factors from bone marrow-derived dendritic cells

Alternative pathway NF-κB signalling regulates susceptibility towards developing inflammatory bowel disease (IBD), colitis-associated cancer and sepsis-associated intestinal epithelial cell apoptosis and shedding. However, the cell populations responsible for the perturbed alternative pathway NF-κB signalling in intestinal mucosal pathology remain unclear. In order to investigate the contribution of the epithelial compartment, we have tested whether NF-κB2 regulated transcription in intestinal epithelial cells controls the intestinal epithelial response to cytokines that are known to disrupt intestinal barrier permeability. Enteroids were generated from the proximal, middle and distal regions of small intestine (SI) from C57BL/6J wild-type mice and displayed region-specific morphology that was maintained during sub-culture. Enteroids treated with 100 ng/mL TNF were compared with corresponding regions of SI from C57BL/6J mice treated systemically with 0.33 mg/kg TNF for 1.5 h. TNF-induced apoptosis in all regions of the intestine in vitro and in vivo but resulted in Paneth cell degranulation only in proximal tissue-derived SI and enteroids. TNF also resulted in increased enteroid sphericity (quantified as circularity from two-dimensional bright field images). This response was dose and time-dependent and correlated with active caspase-3 immunopositivity. Proximal tissue-derived enteroids generated from Nfκb2−/− mice showed a significantly blunted circularity response following the addition of TNF, IFNγ, lipopolysaccharide (LPS) activated C57BL/6J-derived bone marrow-derived dendritic cells (BMDC) and secreted factors from LPS-activated BMDCs. However, Nfκb1−/− mouse-derived enteroids showed no significant changes in response to these stimuli. In conclusion, the selection of SI region is important when designing enteroid studies as region-specific identity and response to stimuli such as TNF are maintained in culture. Intestinal epithelial cells are at least partially responsible for regulating their own fate by modulating NF-κB2 signalling in response to stimuli known to be involved in multiple intestinal and systemic diseases. Future studies are warranted to investigate the therapeutic potential of intestinal epithelial NF-κB2 inhibition