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Three articles deal with primary school English instruction. W. J. Jackson examines some possible sets of objectives for a language arts program--e.g., development through language of creative and reasoning faculties, awareness of language characteristics and of writing models useful in contemporary society, achievement of expected terminal and intermediate behavioral goals, and development of the componential parts of particular language arts skills, such as reading for comprehension. He also offers thoughts on setting up programs to highlight critical language areas. J. Tosh describes an approach to language and grammar that involves teachers in three stages: (1) determining whether children can recognize various uses of language; (2) determining whether the students were able or could be taught to describe the uses; and (3) encouraging students to produce varieties of language appropriate to certain purposes. M. Cook and D. Valentine describe their experience using a children's novel, "Carrigmore Castle," as a basis for class discussion, composition, dramatic interpretation, and supplementary reading. (LH)

Wiseman et al. show that triplication of genes other than APP is sufficient to exacerbate Aβ deposition and associated cognitive changes in a mouse model of Down syndrome – Alzheimer’s disease. This occurs independently of changes to γ-secretase but results from a novel mechanism that lowers the soluble Aβ40/42 ratio., Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer’s disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer’s disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer’s disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer’s disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer’s disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration.

© Queen’s Printer and Controller of HMSO 2014 Background: The National Institute for Health and Care Excellence recommends the use of generic preference-based measures (GPBMs) of health for its Health Technology Assessments (HTAs). However, these data may not be available or appropriate for all health conditions. Objectives: To determine whether GPBMs are appropriate for some key conditions and to explore alternative methods of utility estimation when data from GPBMs are unavailable or inappropriate. Design: The project was conducted in three stages: (1) A systematic review of the psychometric properties of three commonly used GPBMs [EQ-5D, SF-6D and Health Utilities Index Mark 3 (HUI3)] in four broadly defined conditions: visual impairment, hearing impairment, cancer and skin conditions. (2) Potential modelling approaches to ‘map’ EQ-5D values from condition-specific and clinical measures of health [European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) and Functional Assessment of Cancer Therapy – General Scale (FACT-G)] are compared for predictive ability and goodness of fit using two separate data sets. (3) Three potential extensions to the EQ-5D are developed as ‘bolt-on’ items relating to hearing, tiredness and vision. They are valued using the time trade-off method. A second valuation study is conducted to fully value the EQ-5D with and without the vision bolt-on item in an additional sample of 300 people. Main outcome measures: Comparisons of EQ-5D, SF-6D and HUI3 in four conditions with various generic and condition-specific measures. Mapping functions were estimated between EORTC QLQ-C30 and FACT-G with EQ-5D. Three bolt-ons to the EQ-5D were developed: EQ + hearing/vision/tiredness. A full valuation study was conducted for the EQ + vision. Results: (1) EQ-5D was valid and responsive for skin conditions and most cancers; in vision, its performance varied according to aetiology; and performance was poor for hearing impairments. The HUI3 performed well for hearing and vision disorders. It also performed well in cancers although evidence was limited and there was no evidence in skin conditions. There were limited data for SF-6D in all four conditions and limited evidence on reliability of all instruments. (2) Mapping algorithms were estimated to predict EQ-5D values from alternative cancer-specific measures of health. Response mapping using all the domain scores was the best performing model for the EORTC QLQ-C30. In an exploratory analysis, a limited dependent variable mixture model performed better than an equivalent linear model. In the full analysis for the FACT-G, linear regression using ordinary least squares gave the best predictions followed by the tobit model. (3) The exploratory valuation study found that bolt-on items for vision, hearing and tiredness had a significant impact on values of the health states, but the direction and magnitude of differences depended on the severity of the health state. The vision bolt-on item had a statistically significant impact on EQ-5D health state values and a full valuation model was estimated. Conclusions: EQ-5D performs well in studies of cancer and skin conditions. Mapping techniques provide a solution to predict EQ-5D values where EQ-5D has not been administered. For conditions where EQ-5D was found to be inappropriate, including some vision disorders and for hearing, bolt-ons provide a promising solution. More primary research into the psychometric properties of the generic preference-based measures is required, particularly in cancer and for the assessment of reliability. Further research is needed for the development and valuation of bolt-ons to EQ-5D. UK Medical Research Council (MRC) as part of the MRC-NIHR methodology research programme (reference G0901486)

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As part of the co-coordinated strategy for health research under the Office for Strategic Coordination of Health Research (OSCHR), the Medical Research Council (MRC) is the lead organisation for methodological research in the UK. The National Institute for Health and Clinical Excellence (NICE) is an important public stakeholder in this research area, and it has faced a range of challenges in the selection and specification of research methods employed in the production of its guidance for the NHS.

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