The impact of pneumolysin on the macrophage response to Streptococcus pneumoniae is strain-dependent

Streptococcus pneumoniae is the world's leading cause of pneumonia, bacteremia, meningitis and otitis media. A major pneumococcal virulence factor is the cholesterol-dependent cytolysin, which has the defining property of forming pores in cholesterol-containing membranes. In recent times a clinically significant and internationally successful serotype 1 ST306 clone has been found to express a non-cytolytic variant of Ply (Ply306). However, while the pneumococcus is a naturally transformable organism, strains of the ST306 clonal group have to date been virtually impossible to transform, severely restricting efforts to understand the role of non-cytolytic Ply in the success of this clone. In this study isogenic Ply mutants were constructed in the D39 background and for the first time in the ST306 background (A0229467) to enable direct comparisons between Ply variants for their impact on the immune response in a macrophage-like cell line. Strains that expressed cytolytic Ply were found to induce a significant increase in IL-1β release from macrophage-like cells compared to the non-cytolytic and Ply-deficient strains in a background-independent manner, confirming the requirement for pore formation in the Ply-dependent activation of the NLRP3 inflammasome. However, cytolytic activity in the D39 background was found to induce increased expression of the genes encoding GM-CSF (CSF2), p19 subunit of IL-23 (IL23A) and IFNβ (IFNB1) compared to non-cytolytic and Ply-deficient D39 mutants, but had no effect in the A0229467 background. The impact of Ply on the immune response to the pneumococcus is highly dependent on the strain background, thus emphasising the importance of the interaction between specific virulence factors and other components of the genetic background of this organism

Isolation site influences virulence phenotype of serotype 14 Streptococcus pneumoniae strains belonging to multilocus sequence type 15

Streptococcus pneumoniae is a diverse species causing invasive as well as localized infections that result in massive global morbidity and mortality. Strains vary markedly in pathogenic potential, but the molecular basis is obscured by the diversity and plasticity of the pneumococcal genome. We have previously reported that S. pneumoniae serotype 3 isolates belonging to the same multilocus sequence type (MLST) differed markedly in in vitro and in vivo phenotypes, in accordance with the clinical site of isolation, suggesting stable niche adaptation within a clonal lineage. In the present study, we have extended our analysis to serotype 14 clinical isolates from cases of sepsis or otitis media that belong to the same MLST (ST15). In a murine intranasal challenge model, five ST15 isolates (three from blood and two from ears) colonized the nasopharynx to similar extents. However, blood and ear isolates exhibited significant differences in bacterial loads in other host niches (lungs, ear, and brain) at both 24 and 72 h postchallenge. In spite of these differences, blood and ear isolates were present in the lungs at similar levels at 6 h postchallenge, suggesting that early immune responses may underpin the distinct virulence phenotypes. Transcriptional analysis of lung tissue from mice infected for 6 h with blood isolates versus ear isolates revealed 8 differentially expressed genes. Two of these were exclusively expressed in response to infection with the ear isolate. These results suggest a link between the differential capacities to elicit early innate immune responses and the distinct virulence phenotypes of clonally related S. pneumoniae strains

Can oral healthcare for older people be embedded into routine community aged care practice? A realist evaluation using normalisation process theory

This author accepted manuscript is made available following 12 month embargo from date of publication (December 2018) in accordance with the publisher’s archiving policyBackground An intervention ‘Better Oral Health in Home Care’ was introduced (2012–2014) to improve the oral health of older people receiving community aged care services. Implementation of the intervention was theoretically framed by the Promoting Action on Research Implementation in Health Services framework. Process outcomes demonstrated significant improvements in older people’s oral health. Objective To evaluate the extent to which the intervention has been embedded and sustained into routine community aged care practice 3 years after the initial implementation project. Design A Realist Evaluation applying Normalisation Process Theory within a single case study setting. Setting Community aged care (home care) provider in South Australia, Australia. Participants Purposeful sampling was undertaken. Twelve staff members were recruited from corporate, management and direct care positions. Two consumers representing high and low care recipients also participated. Methods Qualitative methods were applied in two subcases, reflecting different contextual settings. Data were collected via semi-structured interviews and analysed deductively by applying the Normalisation Process Theory core constructs (with the recommended phases of the Realist Evaluation cycle). Retrospective and prospective analytic methods investigated how the intervention has been operationalised by comparing two timeframes: Time 1 (Implementation June 2012–December 2014) and Time 2 (Post-implementation July 2017–July 2018). Results At Time 1, the initial program theory proposed that multi-level facilitation contributed to a favourable context that triggered positive mechanisms supportive of building organisational and workforce oral healthcare capacity. At Time 2, an alternative program theory of how the intervention has unfolded in practice described a changed context following the withdrawal of the project facilitation processes with the triggering of alternative mechanisms that have made it difficult for staff to embed sustainable practice. Conclusion Findings concur with the literature that successful implementation outcomes do not necessarily guarantee sustainability. The study has provided a deeper explanation of how contextual characteristics have contributed to the conceptualisation of oral healthcare as a low priority, basic work-ready personal care task and how this, in turn, hindered the embedding of sustainable oral healthcare into routine community aged care practice. This understanding can be used to better inform the development of strategies, such as multi-level facilitation, needed to navigate contextual barriers so that sustainable practice can be achieved

The variable region of the pneumococcal pathogenicity island 1 is responsible for the unusually high virulence of a serotype 1 isolate

Streptococcus pneumoniae is the leading infectious cause of death in children in the world. However, the mechanisms that drive the progression from asymptomatic colonization to disease are poorly understood. Two virulence-associated genomic accessory regions (ARs) were deleted in a highly virulent serotype 1 clinical isolate (strain 4496) and examined for their contribution to pathogenesis. Deletion of a prophage encoding a platelet-binding protein (PblB) resulted in reduced adherence, biofilm formation, reduced initial infection within the lungs, and a reduction in the number of circulating platelets in infected mice. However, the region’s overall contribution to the survival of mice was not significant. In contrast, deletion of the variable region of pneumococcal pathogenicity island 1 (vPPI1) was also responsible for a reduction in adherence and biofilm formation but also reduced survival and invasion of the pleural cavity, blood, and lungs. While the 4496�PPI1 strain induced higher expression of the genes encoding interleukin-10 (IL-10) and CD11b in the lungs of challenged mice than the wild-type strain, very few other genes exhibited altered expression. Moreover, while the level of IL-10 protein was increased in the lungs of 4496�PPI1 mutant-infected mice compared to strain 4496-infected mice, the levels of gamma interferon (IFN-�), CXCL10, CCL2, and CCL4 were not different in the two groups. However, the 4496�PPI1 mutant was found to be more susceptible than the wild type to phagocytic killing by a macrophage-like cell line. Therefore, our data suggest that vPPI1 may be a major contributing factor to the heightened virulence of certain serotype 1 strains, possibly by influencing resistance to phagocytic killing

The behaviour of dark matter associated with 4 bright cluster galaxies in the 10kpc core of Abell 3827

Galaxy cluster Abell 3827 hosts the stellar remnants of four almost equally bright elliptical galaxies within a core of radius 10kpc. Such corrugation of the stellar distribution is very rare, and suggests recent formation by several simultaneous mergers. We map the distribution of associated dark matter, using new Hubble Space Telescope imaging and VLT/MUSE integral field spectroscopy of a gravitationally lensed system threaded through the cluster core. We find that each of the central galaxies retains a dark matter halo, but that (at least) one of these is spatially offset from its stars. The best-constrained offset is 1.62+/-0.48kpc, where the 68% confidence limit includes both statistical error and systematic biases in mass modelling. Such offsets are not seen in field galaxies, but are predicted during the long infall to a cluster, if dark matter self-interactions generate an extra drag force. With such a small physical separation, it is difficult to definitively rule out astrophysical effects operating exclusively in dense cluster core environments - but if interpreted solely as evidence for self-interacting dark matter, this offset implies a cross-section sigma/m=(1.7+/-0.7)x10^{-4}cm^2/g x (t/10^9yrs)^{-2}, where t is the infall duration.Comment: 15 pages, 9 figure

CoCREATE: Collaborative Curriculum Reimagining and Enhancement Aiming to Transform Education

The establishment of TU Dublin in January 2019 provided a unique opportunity to create a bespoke curriculum framework for students, staff and stakeholders of TU Dublin, produced by the students, staff and stakeholders of TU Dublin. A curriculum framework is a set of guiding values that inform the design of teaching and learning activities within TU Dublin. A Teaching Fellowship Team, comprising eighteen teaching academics from across the three TU Dublin campuses and supported extensively by the Learning Teaching and Technology Centre (LTTC), was formed to collaboratively craft, in partnership with all stakeholders, a curriculum framework for TU Dublin. Working collaboratively under the project name CoCREATE (Collaborative Curriculum Reimagining and Enhancement Aiming to Transform Education) the Teaching Fellowship Team developed TU Dublin’s CoCREATED Curriculum Framework over eighteen months. The design and development of the CoCREATED Curriculum Framework was informed by consultation with all key stakeholders across all campuses, examination and synthesis of local, national and international best practice and policy, as well as relevant scholarly literature. The framework is underpinned by the core values and mission of TU Dublin, as well as local and national strategic plans. It provides a distinctive but tangible learning philosophy for all at TU Dublin. The framework is both considered, flexible and progressive so as to adapt to the diversity within TU Dublin, including accredited programmes, and is inclusive of all learners across the university. The four curriculum values of the TU Dublin CoCREATED Curriculum Framework are: Step forward and try new things Use all of our talents; everyone has something to learn and something to teach Make our learning experience active, useful and related to the world Create the space and time to do work that matters This new, dynamic and evolving TU Dublin CoCREATED Curriculum Framework characterises an innovative, responsive and caring learning environment for the diversity of our university’s student population across all programme levels. Simultaneously, it developed a synergy between staff, students, professional bodies, industry and community partners through a collaborative design process. It is as inspiring, distinctive and pioneering as Ireland’s first Technological University. The CoCREATED Curriculum Framework will support staff and students to develop a unique approach to teaching and learning, which will characterise a TU Dublin teaching and learning experience, and ultimately a TU Dublin graduate, in a competitive national and international higher education space. Going forward, the TU Dublin CoCREATED Curriculum Framework will empower the judicious creation of rich and diverse curricula across all disciplines and levels within TU Dublin, from apprenticeship, through undergraduate, to structured PhD

Bike skills training for children with cerebral palsy: protocol for a randomised controlled trial

INTRODUCTION: Two-wheel bike riding can be a goal for children with cerebral palsy (CP) and a means of participating in physical activity. It is possible for some children with CP to ride a two-wheel bike; however, currently far fewer can ride compared with their typically developing peers. Evidence supports training targeted towards goals of the child with CP and their family; yet there is little evidence to guide best-practice bike skills training. Task-specific training may lead to attainment of two-wheel bike-specific goals. This study aims to determine if a novel task-specific approach to training two-wheel bike skills is more effective than a parent-led home programme for attaining individualised two-wheel bike-specific goals in independently ambulant children with CP aged 6-15 years. METHODS AND ANALYSIS: Sixty eligible children with CP (Gross Motor Function Classification System levels I-II) aged 6-15 years with goals relating to riding a two-wheel bike will be randomised to either a novel task-specific centre-based group programme (intervention) or a parent-led home-based programme (comparison), both involving a 1-week intervention period. The primary outcome is goal attainment in the week following the intervention period (T1). Secondary outcomes include: goal attainment and participation in physical activity at 3&thinsp;months postintervention (T2) and bike skills, attendance and involvement in bike riding, self-perception and functional skills at T1 and T2. Economic appraisal will involve cost-effectiveness and cost-utility analyses. Adherence of clinicians and parents to the intervention and comparison protocols will be assessed. Linear and logistic regression will be used to assess the effect of the intervention, adjusted for site as used in the randomisation process. ETHICS AND DISSEMINATION: This study was approved by the Human Research and Ethics Committees at The Royal Children\u27s Hospital (#36209). Results will be disseminated via peer-reviewed publications and conference presentations.<br /

The behaviour of dark matter associated with four bright cluster galaxies in the 10kpc core of Abell 3827

Galaxy cluster Abell 3827 hosts the stellar remnants of four almost equally bright elliptical galaxies within a core of radius 10kpc. Such corrugation of the stellar distribution is very rare, and suggests recent formation by several simultaneous mergers. We map the distribution of associated dark matter, using new Hubble Space Telescope imaging andVery Large Telescope/Multi-Unit Spectroscopic Explorer integral field spectroscopy of a gravitationally lensed system threaded through the cluster core. We find that each of the central galaxies retains a dark matter halo, but that (at least) one of these is spatially offset from its stars. The best-constrained offset is $1.62^{+0.47}_{-0.49}$kpc, where the 68 per cent confidence limit includes both statistical error and systematic biases in mass modelling. Such offsets are not seen in field galaxies, but are predicted during the long infall to a cluster, if dark matter self-interactions generate an extra drag force. With such a small physical separation, it is difficult to definitively rule out astrophysical effects operating exclusively in dense cluster core environments - but if interpreted solely as evidence for self-interacting dark matter, this offset implies a cross-section σDM/m∼(1.7±0.7)×10−4cm2g−1×(tinfall/109 yr)−2, where tinfall is the infall duratio

EURRECA-Evidence-Based Methodology for Deriving Micronutrient Recommendations

The EURopean micronutrient RECommendations Aligned (EURRECA) Network of Excellence explored the process of setting micronutrient recommendations to address the variance in recommendations across Europe. Work centered upon the transparent assessment of nutritional requirements via a series of systematic literature reviews and meta-analyses. In addition, the necessity of assessing nutritional requirements and the policy context of setting micronutrient recommendations was investigated. Findings have been presented in a framework that covers nine activities clustered into four stages: stage one Defining the problem describes Activities 1 and 2: Identifying the nutrition-related health problem and Defining the process; stage two Monitoring and evaluating describes Activities 3 and 7: Establishing appropriate methods, and Nutrient intake and status of population groups; stage three Deriving dietary reference values describes Activities 4, 5, and 6: Collating sources of evidence, Appraisal of the evidence, and Integrating the evidence; stage four Using dietary reference values in policy making describes Activities 8 and 9: Identifying policy options, and Evaluating policy implementation. These activities provide guidance on how to resolve various issues when deriving micronutrient requirements and address the methodological and policy decisions, which may explain the current variation in recommendations across Europe. [Supplementary materials are available for this article. Go to the publisher's online edition of Critical Reviews in Food Science and Nutrition for the following free supplemental files: Additional text, tables, and figures.]This is the peer-reviewed version of the article: Dhonukshe-Rutten Rosalie, Bouwman Jildau, Brown Kerry A., Cavelaars Adrienne E., Collings Rachel, Grammatikaki Evangelia, de Groot Lisette, Gurinović Mirjana A., Harvey Linda, Hermoso Maria, Hurst Rachel, Kremer Bas, Ngo Joy, Novaković Romana, Raats Monique M., Rollin Fanny, Serra-Majem Lluis, Souverein Olga W., Timotijević Lada, van't Veer Pieter, "EURRECA-Evidence-Based Methodology for Deriving Micronutrient Recommendations" 53, no. 10 (2013):999-1040, [https://doi.org/10.1080/10408398.2012.749209