Developing a Task Switching Training Game for Children With a Rare Genetic Syndrome Linked to Intellectual Disability

Background. The ability to rapidly switch between tasks is important in a variety of contexts. Training in task switching may be particularly valuable for children with intellectual disability (ID), specifically ID linked to genetic syndromes such as Prader-Willi syndrome (PWS). We have developed a cognitive training game for children with PWS and performed a pilot evaluation of the programme to inform future game development. Here, we describe and critically reflect on the development and pilot evaluation process.Methods. Several novel aspects of our approach are highlighted in this paper, including the involvement (in various roles) of children with a rare genetic syndrome (PWS) in the development and evaluation of the software (participatory design) and the development of a matched control, or placebo version of the game for use in the pilot evaluation.Results.Children with PWS were capable of contributing to the design and development of a cognitive training game in various roles. In the subsequent pilot evaluation, playing the active version of the game was associated with greater improvement in task switching performance than playing the matched control (placebo) version of the game. However, attrition was an issue during both the design phase and the pilot evaluation.Conclusions. The lessons learned from our work have relevance in a wide range of contexts, such as the development of future cognitive training games; the evaluation of serious games in general; and the involvement of end-users with cognitive disabilities and/or rare syndromes in the design and development of software

Pedagogy and Culture: An Educational Initiative in Supporting UAE Nursing Graduates Prepare for a High-stakes Nurse Licensing Examination

Graduates of an Abu Dhabi transnational nursing degree struggled with the mandatory national licensing examination. Poor pass rates undermine graduate career futures and impact on the workforce capacity building contributions of the partnering transnational educational providers. This paper describes how the design and delivery of an intensive examination preparation program dramatically reversed this trend. The objectives of this educational initiative involved the design, delivery and evaluation of a program that would align with cultural learning preferences and which improve the success rates of graduates attempting the national nurse licensing examination. To achieve these objectives, the program combined a range of teaching and assessment strategies developed to reflect the specific needs of Arabic learners, build on their existing knowledge and help them engage more effectively in the learning processes required for successful performance in a high stakes examination. Analysis of data collected during program evaluation provides useful insights into the preference and experiences of nursing graduates in the UAE Emirate of Abu Dhabi. The lessons learned are applicable to Arabic learners both regionally and globally

Reenvisioning an Energy Strategy for Manitoba: Planning for 2030 and Beyond

On March 10, 2020 the Re-envisioning an Energy Strategy for Manitoba: Planning for 2030 and Beyond workshop was held at The University of Winnipeg. The purpose of the event was to initiate a discussion amongst Manitobans about energy in the province. In doing so, it brought together people with a variety of energy-based perspectives and interests, including consumers, researchers, students, Indigenous peoples, energy providers, entrepreneurs, decision-makers, and members of the public interested in the future of energy use in Manitoba. This event was organized by The Community Appropriate Sustainable Energy Security (CASES) Partnership, the Manitoba Branch of The Consumers’ Association of Canada (CAC), The Public Interest Law Centre (PILC), and Amanda Gelfant.Community Appropriate Sustainable Energy Security (CASES); Consumers' Association of Canada – Manitoba; Public Interest Law Centr

Recipient mucosal-associated invariant T cells control GVHD within the colon

Mucosal-associated invariant T (MAIT) cells are a unique innate-like T cell subset that responds to a wide array of bacteria and yeast through recognition of riboflavin metabolites presented by the MHC class I–like molecule MR1. Here, we demonstrate using MR1 tetramers that recipient MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT). Consistent with their preferential juxtaposition to microbial signals in the colon, recipient MAIT cells generate large amounts of IL-17A, promote gastrointestinal tract integrity, and limit the donor alloantigen presentation that in turn drives donor Th1 and Th17 expansion specifically in the colon after BMT. Allogeneic BMT recipients deficient in IL-17A also develop accelerated GVHD, suggesting MAIT cells likely regulate GVHD, at least in part, by the generation of this cytokine. Indeed, analysis of stool microbiota and colon tissue from IL-17A–/– and MR1–/– mice identified analogous shifts in microbiome operational taxonomic units (OTU) and mediators of barrier integrity that appear to represent pathways controlled by similar, IL-17A–dependent mechanisms. Thus, MAIT cells act to control barrier function to attenuate pathogenic T cell responses in the colon and, given their very high frequency in humans, likely represent an important population in clinical BMT

Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies

Dominant mutations in the skeletal muscle ryanodine receptor (RYR1) gene are well-recognized causes of both malignant hyperthermia susceptibility (MHS) and central core disease (CCD). More recently, recessive RYR1 mutations have been described in few congenital myopathy patients with variable pathology, including multi-minicores. Although a clinical overlap between patients with dominant and recessive RYR1 mutations exists, in most cases with recessive mutations the pattern of muscle weakness is remarkably different from that observed in dominant CCD. In order to characterize the spectrum of congenital myopathies associated with RYR1 mutations, we have investigated a cohort of 44 patients from 28 families with clinical and/or histopathological features suggestive of RYR1 involvement. We have identified 25 RYR1 mutations, 9 of them novel, including 12 dominant and 13 recessive mutations. With only one exception, dominant mutations were associated with a CCD phenotype, prominent cores and predominantly occurred in the RYR1 C-terminal exons 101 and 102. In contrast, the 13 recessive RYR1 mutations were distributed evenly along the entire RYR1 gene and were associated with a wide range of clinico-pathological phenotypes. Protein expression studies in nine cases suggested a correlation between specific mutations, RyR1 protein levels and resulting phenotype: in particular, whilst patients with dominant or recessive mutations associated with typical CCD phenotypes appeared to have normal RyR1 expression, individuals with more generalized weakness, multi-minicores and external ophthalmoplegia had a pronounced depletion of the RyR1 protein. The phenomenon of protein depletion was observed in some patients compound heterozygous for recessive mutations at the genomic level and silenced another allele in skeletal muscle, providing additional information on the mechanism of disease in these patients. Our data represent the most extensive study of RYR1-related myopathies and indicate complex genotype-phenotype correlations associated with mutations differentially affecting assembly and function of the RyR1 calcium release channe

Interdisciplinary Collaboration to Integrate Inquiry-Oriented Learning in Undergraduate Science Practicals

The benefits of inquiry-oriented learning (IOL) in undergraduate science courses have been validated through a considerable range of studies incorporating observation and examination data, as well as qualitative and quantitative feedback from students and employers. However, IOL initiatives often occur in single subject or discipline areas, meaning that students may experience IOL in isolated or disjunct forms, without the synergies made possible through interdisciplinary collaboration by educators. This paper reports on the progress of an interdisciplinary approach to develop, implement and evaluate IOL practicals in first year biology, chemistry and physics laboratory teaching programs. This initiative, founded on principles of collegiality and mentorship among the team members, has involved professional development of teaching associates (aka demonstrators), collaboration in the design and branding of inquiry-oriented practicals, and a degree of interdisciplinary alignment of practical assessments. The initiative has generated a more student-centred and coherent approach to enhancement of scientific literacy and a range of associated skills, provided greater clarity and transparency for students, and scaffolded inquiry-oriented approaches throughout the degree

AMP-activated protein kinase activator A-769662 increases intracellular calcium and ATP release from astrocytes in an AMPK-independent manner

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordAim To test the hypothesis that, given the role of AMP‐activated protein kinase (AMPK) in regulating intracellular ATP levels, AMPK may alter ATP release from astrocytes, the main sources of extracellular ATP (eATP) within the brain. Materials and Methods Measurements of ATP release were made from human U373 astrocytoma cells, primary mouse hypothalamic (HTAS) and cortical astrocytes (CRTAS) and wild‐type and AMPK α1/α2 null mouse embryonic fibroblasts (MEFs). Cells were treated with drugs known to modulate AMPK activity: A‐769662, AICAR and metformin, for up to 3 hours. Intracellular calcium was measured using Fluo4 and Fura‐2 calcium‐sensitive fluorescent dyes. Results In U373 cells, A‐769662 (100 μM) increased AMPK phosphorylation, whereas AICAR and metformin (1 mM) induced a modest increase or had no effect, respectively. Only A‐769662 increased eATP levels, and this was partially blocked by AMPK inhibitor Compound C. A‐769662‐induced increases in eATP were preserved in AMPK α1/α2 null MEF cells. A‐769662 increased intracellular calcium in U373, HTAS and CRTAS cells and chelation of intracellular calcium using BAPTA‐AM reduced A‐769662‐induced eATP levels. A‐769662 also increased ATP release from a number of other central and peripheral endocrine cell types. Conclusions AMPK is required to maintain basal eATP levels but is not required for A‐769662‐induced increases in eATP. A‐769662 (>50 μM) enhanced intracellular calcium levels leading to ATP release in an AMPK and purinergic receptor independent pathway.This study was funded by: Diabetes UK RD Lawrence Fellowship (13/0004647 to C. B.), the British Society for Neuroendocrinology, the Society for Endocrinology, Mary Kinross Charitable Trust and Tenovus Scotland

Socioeconomic inequalities in attitudes towards cancer: An international cancer benchmarking partnership study

Socioeconomic status (SES) differences in attitudes towards cancer have been implicated in the differential screening uptake and the timeliness of symptomatic presentation. However, the predominant emphasis of this work has been on cancer fatalism, and many studies focus on specific community subgroups. This study aimed to assess SES differences in positive and negative attitudes towards cancer in UK adults. A population-based sample of UK adults (n=6965, age≥50 years) completed the Awareness and Beliefs about Cancer scale, including six belief items: three positively framed (e.g. 'Cancer can often be cured') and three negatively framed (e.g. 'A cancer diagnosis is a death sentence'). SES was indexed by education. Analyses controlled for sex, ethnicity, marital status, age, self-rated health, and cancer experience. There were few education-level differences for the positive statements, and overall agreement was high (all&gt;90%). In contrast, there were strong differences for negative statements (all Ps&lt;0.001). Among respondents with lower education levels, 57% agreed that 'treatment is worse than cancer', 27% that cancer is 'a death sentence' and 16% 'would not want to know if I have cancer'. Among those with university education, the respective proportions were 34, 17 and 6%. Differences were not explained by cancer experience or health status. In conclusion, positive statements about cancer outcomes attract near-universal agreement. However, this optimistic perspective coexists alongside widespread fears about survival and treatment, especially among less-educated groups. Health education campaigns targeting socioeconomically disadvantaged groups might benefit from a focus on reducing negative attitudes, which is not necessarily achieved by promoting positive attitudes.</p

Delayed neutrophil apoptosis enhances NET formation in cystic fibrosis

BackgroundCystic fibrosis (CF) lung disease is defined by large numbers of neutrophils and associated damaging products in the airway. Delayed neutrophil apoptosis is described in CF although it is unclear whether this is a primary neutrophil defect or a response to chronic inflammation. Increased levels of neutrophil extracellular traps (NETs) have been measured in CF and we aimed to investigate the causal relationship between these phenomena and their potential to serve as a driver of inflammation. We hypothesised that the delay in apoptosis in CF is a primary defect and preferentially allows CF neutrophils to form NETs, contributing to inflammation.MethodsBlood neutrophils were isolated from patients with CF, CF pigs and appropriate controls. Neutrophils were also obtained from patients with CF before and after commencing ivacaftor. Apoptosis was assessed by morphology and flow cytometry. NET formation was determined by fluorescent microscopy and DNA release assays. NET interaction with macrophages was examined by measuring cytokine generation with ELISA and qRT-PCR.ResultsCF neutrophils live longer due to decreased apoptosis. This was observed in both cystic fibrosis transmembrane conductance regulator (CFTR) null piglets and patients with CF, and furthermore was reversed by ivacaftor (CFTR potentiator) in patients with gating (G551D) mutations. CF neutrophils formed more NETs and this was reversed by cyclin-dependent kinase inhibitor exposure. NETs provided a proinflammatory stimulus to macrophages, which was enhanced in CF.ConclusionsCF neutrophils have a prosurvival phenotype that is associated with an absence of CFTR function and allows increased NET production, which can in turn induce inflammation. Augmenting neutrophil apoptosis in CF may allow more appropriate neutrophil disposal, decreasing NET formation and thus inflammation.</jats:sec