Top research priorities in healthcare-associated infection in the UK

Background: There is a mismatch between research questions which are considered to be important by patients, carers and healthcare professionals and the research performed in many fields of medicine. No relevant studies which have assessed research priorities in healthcare-associated infection (HCAI) that have involved patients' and carers' opinions were identified in the literature. / Aim: The Healthcare-Associated Infections Priority Setting Partnership was established to identify the top research priorities in the prevention, diagnosis and treatment of HCAI in the UK, considering the opinions of all these groups. / Methods: The methods broadly followed the principles of the James Lind Alliance (JLA) priority setting activity. / Findings: In total, 259 unique valid research questions were identified from 221 valid responses to a consultation of patients, carers and healthcare professionals after seeking their opinions for research priorities. The steering committee of the priority setting partnership rationalized these to 50 unique questions. A literature review established that for these questions there were no recent high-quality systematic reviews, high-quality systematic reviews which concluded that further studies were necessary, or the steering committee considered that further research was required despite the conclusions of recent systematic reviews. An interim survey ranked the 50 questions, and the 10 main research priorities were identified from the top 32 questions by consensus at a final priority setting workshop of patients, carers and healthcare professionals using group discussions. / Conclusions: A priority setting process using JLA methods and principles involving patients, carers and healthcare professionals was used to identify the top 10 priority areas for research related to HCAI. Basic, translational, clinical and public health research would be required to address these uncertainties

Extensive conservation of ancient microsynteny across metazoans due to cis-regulatory constraints

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date; after six months, it is available under a Creative Commons License.-- et al.The order of genes in eukaryotic genomes has generally been assumed to be neutral, since gene order is largely scrambled over evolutionary time. Only a handful of exceptional examples are known, typically involving deeply conserved clusters of tandemly duplicated genes (e.g., Hox genes and histones). Here we report the first systematic survey of microsynteny conservation across metazoans, utilizing 17 genome sequences. We identified nearly 600 pairs of unrelated genes that have remained tightly physically linked in diverse lineages across over 600 million years of evolution. Integrating sequence conservation, gene expression data, gene function, epigenetic marks, and other genomic features, we provide extensive evidence that many conserved ancient linkages involve (1) the coordinated transcription of neighboring genes, or (2) genomic regulatory blocks (GRBs) in which transcriptional enhancers controlling developmental genes are contained within nearby bystander genes. In addition, we generated ChIP-seq data for key histone modifications in zebrafish embryos, which provided further evidence of putative GRBs in embryonic development. Finally, using chromosome conformation capture (3C) assays and stable transgenic experiments, we demonstrate that enhancers within bystander genes drive the expression of genes such as Otx and Islet, critical regulators of central nervous system development across bilaterians. These results suggest that ancient genomic functional associations are far more common than previously thought—involving ∼12% of the ancestral bilaterian genome—and that cis-regulatory constraints are crucial in determining metazoan genome architecture.M.I., M.S.A., S.W.R., and H.B.F. were funded by NIH grant 1R21HG005240-01A1. H.B.F. is an Alfred P. Sloan Fellow and Pew Scholar in the Biomedical Sciences. J.J.T., A.F-M., O.B., E.C-M., and J.L.G-S. were funded by grants BFU2010-14839, CSD2007-00008, and Proyecto de Excelencia CVI-3488.Peer reviewe

Topological Defects in Nematic Droplets of Hard Spherocylinders

Using computer simulations we investigate the microscopic structure of the singular director field within a nematic droplet. As a theoretical model for nematic liquid crystals we take hard spherocylinders. To induce an overall topological charge, the particles are either confined to a two-dimensional circular cavity with homeotropic boundary or to the surface of a three-dimensional sphere. Both systems exhibit half-integer topological point defects. The isotropic defect core has a radius of the order of one particle length and is surrounded by free-standing density oscillations. The effective interaction between two defects is investigated. All results should be experimentally observable in thin sheets of colloidal liquid crystals.Comment: 13 pages, 16 figures, Phys. Rev.

What are the most important unanswered research questions in trial retention? A James Lind Alliance Priority Setting Partnership: the PRioRiTy II (Prioritising Retention in Randomised Trials) study

Background One of the top three research priorities for the UK clinical trial community is to address the gap in evidence-based approaches to improving participant retention in randomised trials. Despite this, there is little evidence supporting methods to improve retention. This paper reports the PRioRiTy II project, a Priority Setting Partnership (PSP) that identified and prioritised unanswered questions and uncertainties around trial retention in collaboration with key stakeholders. Methods This PSP was conducted in collaboration with the James Lind Alliance, a non-profit making initiative, to support key stakeholders (researchers, patients, and the public) in jointly identifying and agreeing on priority research questions. There were three stages. (1) First an initial online survey was conducted consisting of six open-ended questions about retention in randomised trials. Responses were coded into thematic groups to create a longlist of questions. The longlist of questions was checked against existing evidence to ensure that they had not been answered by existing research. (2) An interim stage involved a further online survey where stakeholders were asked to select questions of key importance from the longlist. (3) A face-to-face consensus meeting was held, where key stakeholder representatives agreed on an ordered list of 21 unanswered research questions for methods of improving retention in randomised trials. Results A total of 456 respondents yielded 2431 answers to six open-ended questions, from which 372 questions specifically about retention were identified. Further analysis included thematically grouping all data items within answers and merging questions in consultation with the Steering Group. This produced 27 questions for further rating during the interim survey. The top 21 questions from the interim online survey were brought to a face-to-face consensus meeting in which key stakeholder representatives prioritised the order. The ‘Top 10’ of these are reported in this paper. The number one ranked question was ’What motivates a participant’s decision to complete a clinical trial?’ The entire list will be available at www.priorityresearch.ie. Conclusion The Top 10 list can inform the direction of future research on trial methods and be used by funders to guide projects aiming to address and improve retention in randomised trials

Distinct molecular programs regulate synapse specificity in cortical inhibitory circuits

How neuronal connections are established and organized into functional networks determines brain function. In the mammalian cerebral cortex, different classes of GABAergic interneurons exhibit specific connectivity patterns that underlie their ability to shape temporal dynamics and information processing. Much progress has been made toward parsing interneuron diversity, yet the molecular mechanisms by which interneuron-specific connectivity motifs emerge remain unclear. In this study, we investigated transcriptional dynamics in different classes of interneurons during the formation of cortical inhibitory circuits in mouse. We found that whether interneurons form synapses on the dendrites, soma, or axon initial segment of pyramidal cells is determined by synaptic molecules that are expressed in a subtype-specific manner. Thus, cell-specific molecular programs that unfold during early postnatal development underlie the connectivity patterns of cortical interneurons

Distinct molecular programs regulate synapse specificity in cortical inhibitory circuits

How neuronal connections are established and organized into functional networks determines brain function. In the mammalian cerebral cortex, different classes of GABAergic interneurons exhibit specific connectivity patterns that underlie their ability to shape temporal dynamics and information processing. Much progress has been made toward parsing interneuron diversity, yet the molecular mechanisms by which interneuron-specific connectivity motifs emerge remain unclear. In this study, we investigated transcriptional dynamics in different classes of interneurons during the formation of cortical inhibitory circuits in mouse. We found that whether interneurons form synapses on the dendrites, soma, or axon initial segment of pyramidal cells is determined by synaptic molecules that are expressed in a subtype-specific manner. Thus, cell-specific molecular programs that unfold during early postnatal development underlie the connectivity patterns of cortical interneurons