Pre-validation methods for developing a patient reported outcome instrument

BACKGROUND: Measures that reflect patients' assessment of their health are of increasing importance as outcome measures in randomised controlled trials. The methodological approach used in the pre-validation development of new instruments (item generation, item reduction and question formatting) should be robust and transparent. The totality of the content of existing PRO instruments for a specific condition provides a valuable resource (pool of items) that can be utilised to develop new instruments. Such 'top down' approaches are common, but the explicit pre-validation methods are often poorly reported. This paper presents a systematic and generalisable 5-step pre-validation PRO instrument methodology.

METHODS: The method is illustrated using the example of the Aberdeen Glaucoma Questionnaire (AGQ). The five steps are: 1) Generation of a pool of items; 2) Item de-duplication (three phases); 3) Item reduction (two phases); 4) Assessment of the remaining items' content coverage against a pre-existing theoretical framework appropriate to the objectives of the instrument and the target population (e.g. ICF); and 5) qualitative exploration of the target populations' views of the new instrument and the items it contains.

RESULTS: The AGQ 'item pool' contained 725 items. Three de-duplication phases resulted in reduction of 91, 225 and 48 items respectively. The item reduction phases discarded 70 items and 208 items respectively. The draft AGQ contained 83 items with good content coverage. The qualitative exploration ('think aloud' study) resulted in removal of a further 15 items and refinement to the wording of others. The resultant draft AGQ contained 68 items.

CONCLUSIONS: This study presents a novel methodology for developing a PRO instrument, based on three sources: literature reporting what is important to patient; theoretically coherent framework; and patients' experience of completing the instrument. By systematically accounting for all items dropped after the item generation phase, our method ensures that the AGQ is developed in a transparent, replicable manner and is fit for validation. We recommend this method to enhance the likelihood that new PRO instruments will be appropriate to the research context in which they are used, acceptable to research participants and likely to generate valid data.

Cast Offs (Touchstones in Practice)

The working process of an architect is not often shown publicly, as the finished buildings, more particularly images and publications on them tend to dominate how architecture is communicated. In this there is something lost. The experience of the building, which is its most valuable aspect, is only possible by being there physically. Photography and other means of representation of architecture can tend to an overly perfected and artificial read of both the building and how the design was produced. In truth the design process for a building is a complex one, full of chance discoveries, multiple abandoned ideas, and refinement which is lateral as well as rational.

When we were asked to exhibit it struck us that we should address this deficit in some small way. These are models made as part of the design process for four projects (an arts centre, a womens refuge, a villa and four artists studios). An important part of our work method is to try to explore the material qualities of the buildings we are working on. To advance this we commonly make models to allow us to make discoveries and to advance the project so that the finished building is imbued with material and spatial character. These models are not made to show the final design of the building but to highlight an aspect that we are interested in exploring, in some cases this is about a space, in others about texture and its relationship to form. We chose these four models as all in some way allowed us to make discoveries about the project being explored. This discovery, once made, is what we value. The model itself serves only to produce this, and once made we can cast off the model and move on. We show them, not as architecture, but as touchstones for ideas out of which architecture may come.

A Neutron Diffraction and Molecular Dynamics Investigation of Acetate-based Ionic Liquids as Solvents for Glucose

The liquid state structure of the ionic liquid, 1-ethyl-3-methylimidazolium acetate, and the solute/solvent structure of glucose dissolved in the ionic liquid at a 1: 6 molar ratio have been investigated at 323 K by molecular dynamics simulations and neutron diffraction experiments using H/D isotopically substituted materials. Interactions between hydrogen-bond donating cation sites and polar, directional hydrogen-bond accepting acetate anions are examined. Ion-ion radial distribution functions for the neat ionic liquid, calculated from both MD and derived from the empirical potential structure refinement model to the experimental data, show the alternating shell-structure of anions around the cation, as anticipated. Spatial probability distributions reveal the main anion-to-cation features as in-plane interactions of anions with imidazolium ring hydrogens and cation-cation planar stacking. Interestingly, the presence of the polarised hydrogen-bond acceptor anion leads to increased anion-anion tail-tail structuring within each anion shell, indicating the onset of hydrophobic regions within the anion regions of the liquid.

Structure of molten 1,3-dimethylimidazolium chloride using neutron diffraction

The model room temperature ionic liquid, 1,3-dimethylimidazolium chloride, has been studied by neutron diffraction for the first time. The diffraction data are used to derive a structural model of this liquid using Empirical Potential Structure Refinement. The model obtained indicates that significant charge ordering is present in the liquid salt and that the local order in this liquid closely resembles that found in the solid state. As in the crystal structure, hydrogen-bonding interactions between the ring hydrogens and the chloride dominate the structure. The model is compared with the data reported previously for both simple alkyl substituted imidazolium halides and binary mixtures with AlCl3. (C) 2003 American Institute of Physics.

Deriving the Edge: What's in a phase?

This article offers a critical conceptual discussion and refinement of Chomsky’s (2000, 2001, 2007, 2008) phase system, addressing many of the problematic aspects highlighted in the critique of Boeckx & Grohmann (2007) and seeking to resolve these issues, in particular the stipulative and arbitrary properties of phases and phase edges encoded in the (various versions of the) Phase Impenetrability Condition (PIC). Chomsky’s (2000) original conception of phases as lexical subarrays is demonstrated to derive these properties straightforwardly once a single assumption about the pairwise composition of phases is made, and the PIC is reduced to its necessary core under the Strong Minimalist Thesis (SMT)—namely, the provision of an edge. Finally, a comparison is undertaken of the lexical-subarray conception of phases with the feature-inheritance system of Chomsky 2007, 2008, in which phases are simply the locus of uninterpretable features (probes). Both conceptions are argued to conform to the SMT, and both converge on a pairwise composition of phases. However, the two conceptions of phases are argued to be mutually incompatible in numerous fundamental ways, with no current prospect of unification. The lexical-subarray conception of phases is then to be preferred on grounds of greater empirical adequacy.

Combination of CFD and DOE to analyse solid particle erosion in elbows

Solid particle erosion is a major concern in the engineering industry, particularly where transport of slurry flow is involved. Such flow regimes are characteristic of those in alumina refinement plants. The entrainment of particulate matter, for example sand, in the Bayer liquor can cause severe erosion in pipe fittings, especially in those which redirect the flow. The considerable costs involved in the maintenance and replacement of these eroded components led to an interest in research into erosion prediction by numerical methods at Rusal Aughinish alumina refinery, Limerick, Ireland, and the University of Limerick. The first stage of this study focused on the use of computational fluid dynamics (CFD) to simulate solid particle erosion in elbows. Subsequently an analysis of the factors that affect erosion of elbows was performed using design of experiments (DOE) techniques. Combining CFD with DOE harnesses the computational power of CFD in the most efficient manner for prediction of elbow erosion. An analysis of the factors that affect the erosion of elbows was undertaken with the intention of producing an erosion prediction model. © 2009 Taylor & Francis.

Addressing potentially inappropriate prescribing in older patients: development and pilot study of an intervention in primary care (the OPTI-SCRIPT study)

Background: Potentially inappropriate prescribing (PIP) in older people is common in primary care and can result in increased morbidity, adverse drug events, hospitalizations and mortality. The prevalence of PIP in Ireland is estimated at 36% with an associated expenditure of over [euro sign]45 million in 2007. The aim of this paper is to describe the application of the Medical Research Council (MRC) framework to the development of an intervention to decrease PIP in Irish primary care.

Methods: The MRC framework for the design and evaluation of complex interventions guided the development of the study intervention. In the development stage, literature was reviewed and combined with information obtained from experts in the field using a consensus based methodology and patient cases to define the main components of the intervention. In the pilot stage, five GPs tested the proposed intervention. Qualitative interviews were conducted with the GPs to inform the development and implementation of the intervention for the main randomised controlled trial.

Results: The literature review identified PIP criteria for inclusion in the study and two initial intervention components - academic detailing and medicines review supported by therapeutic treatment algorithms. Through patient case studies and a focus group with a group of 8 GPs, these components were refined and a third component of the intervention identified - patient information leaflets. The intervention was tested in a pilot study. In total, eight medicine reviews were conducted across five GP practices. These reviews addressed ten instances of PIP, nine of which were addressed in the form of either a dose reduction or a discontinuation of a targeted medication. Qualitative interviews highlighted that GPs were receptive to the intervention but patient preference and time needed both to prepare for and conduct the medicines review, emerged as potential barriers. Findings from the pilot study allowed further refinement to produce the finalised intervention of academic detailing with a pharmacist, medicines review with web-based therapeutic treatment algorithms and tailored patient information leaflets.

Conclusions: The MRC framework was used in the development of the OPTI-SCRIPT intervention to decrease the level of PIP in primary care in Ireland. Its application ensured that the intervention was developed using the best available evidence, was acceptable to GPs and feasible to deliver in the clinical setting. The effectiveness of this intervention is currently being tested in a pragmatic cluster randomised controlled trial.

Trial registration: Current controlled trials ISRCTN41694007.© 2013 Clyne et al.; licensee BioMed Central Ltd.

Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements

Retinitis pigmentosa (RP) is a devastating form of retinal degeneration, with significant social and professional consequences. Molecular genetic information is invaluable for an accurate clinical diagnosis of RP due to its high genetic and clinical heterogeneity. Using a gene capture panel that covers 163 of the currently known retinal disease genes, including 48 RP genes, we performed a comprehensive molecular screening in a collection of 123 RP unsettled probands from a wide variety of ethnic backgrounds, including 113 unrelated simplex and 10 autosomal recessive RP (arRP) cases. As a result, 61 mutations were identified in 45 probands, including 38 novel pathogenic alleles. Interestingly, we observed that phenotype and genotype were not in full agreement in 21 probands. Among them, eight probands were clinically reassessed, resulting in refinement of clinical diagnoses for six of these patients. Finally, recessive mutations in CLN3 were identified in five retinal degeneration patients, including four RP probands and one cone-rod dystrophy patient, suggesting that CLN3 is a novel non-syndromic retinal disease gene. Collectively, our results underscore that, due to the high molecular and clinical heterogeneity of RP, comprehensive screening of all retinal disease genes is effective in identifying novel pathogenic mutations and provides an opportunity to discover new genotype-phenotype correlations. Information gained from this genetic screening will directly aid in patient diagnosis, prognosis, and treatment, as well as allowing appropriate family planning and counseling.

Dose, dose-rate and field size effects on cell survival following exposure to non-uniform radiation fields

For the delivery of intensity-modulated radiation therapy (IMRT), highly modulated fields are used to achieve dose conformity across a target tumour volume. Recent in vitro evidence has demonstrated significant alterations in cell survival occurring out-of-field which cannot be accounted for on the basis of scattered dose. The radiobiological effect of area, dose and dose-rate on out-of-field cell survival responses following exposure to intensity-modulated radiation fields is presented in this study. Cell survival was determined by clonogenic assay in human prostate cancer (DU-145) and primary fibroblast (AG0-1522) cells following exposure to different modulated field configurations delivered using a X-Rad 225 kVp x-ray source. Uniform survival responses were compared to in- and out-of-field responses in which 25-99% of the cell population was shielded. Dose delivered to the out-of-field region was varied from 1.6-37.2% of that delivered to the in-field region using different levels of brass shielding. Dose rate effects were determined for 0.2-4 Gy min⁻¹ for uniform and modulated exposures with no effect seen in- or out-of-field. Survival responses showed little dependence on dose rate and area in- and out-of-field with a trend towards increased survival with decreased in-field area. Out-of-field survival responses were shown to scale in proportion to dose delivered to the in-field region and also local dose delivered out-of-field. Mathematical modelling of these findings has shown survival response to be highly dependent on dose delivered in- and out-of-field but not on area or dose rate. These data provide further insight into the radiobiological parameters impacting on cell survival following exposure to modulated irradiation fields highlighting the need for refinement of existing radiobiological models to incorporate non-targeted effects and modulated dose distributions.

Microstructure and microtexture evolution of aluminum alloy 3003 under ultrasonic welding process for embedding SiC fibre

Ultrasonic welding process can be used for bonding metal foils which is the fundament of ultrasonic consolidation (UC). UC process can be used to embed reinforcement fibres such as SiC fibres within an aluminum matrix materials. In this research we are investigating the phenomena occurring in the microstructure of the parts during ultrasonic welding process to obtain better understanding about how and why the process works. High-resolution electron backscatter diffraction (EBSD) is used to study the effects of the vibration on the evolution of microstructure in AA3003. The inverse pole figures (IPF) and the correlated misorientation angle distribution of the mentioned samples are obtained. The characteristics of the crystallographic orientation, the grain structure and the grain boundary are analyzed to find the effect of ultrasonic vibration on the microstructure and microtexture of the bond. The ultrasonic vibration will lead to exceptional refinement of grains to a micron level along the bond area and affect the crystallographic orientation. Ultrasonic vibration results in a very weak texture. Plastic flow occurs in the grain after welding process and there is additional plastic flow around the fibre which leads to the fibre embedding. © 2009 Editorial Board of CHINA WELDING.

Microstrcutural evolution of SiC fibre embedded AA6061 matrix induced by ultrasonic consolidation

Ultrasonic consolidation (UC) uses high frequency (20-40KHz) mechanical vibrations to produce a solid-state metallurgical bond (weld) between metal foils. UC as a novel layered manufacturing technique is used in this research to embed reinforcing members such as silicon carbide fibers into the aluminium alloy 6061's matrices. It is known that UC induce volume and surface effect in the material it is acting on. Both effects are employed in embedding active/passive elements in the metal matrix. Whilst the process and the two effects are used and identified at macro level, what is happening at micro level is unknown and hardly studied. In this research we are investigating the phenomena occurring in the microstructure of the parts during UC process to obtain better understanding about how and why the process works. In this research, high-resolution electron backscatter diffraction is used to study the effects of the UC process on the evolution of microstructure in AA6061 with and without fibre elements. The inverse pole figures (IPF), pole figures (PF) and the correlated misorientation angle distribution of the mentioned samples are obtained. The characteristics of the crystallographic orientation, the grain structure and the grain boundary are analysed to find the effect of ultrasonic vibration and embedding fibre on the microstructure and texture of the bond. The ultrasonic vibration will lead to exceptional refinement of grains to a micron level along the bond area and affect the crystallographic orientation. Additional plastic flow occurs around the fibre which leads to the fibre embedding. © 2008 Materials Research Society.

Numerical Study of Wave Slamming on an Oscillating Flap

Bottom hinged Oscillating Wave Surge Converters (OWSCs) are efficient devices for extracting power from ocean waves. There is limited knowledge about wave slamming on such devices. This paper deals with numerical studies of wave slamming on an oscillating flap to investigate the mechanism of slamming events. In our model, the Navier–Stokes equations are discretized using the Finite Volume method with the Volume of Fluid (VOF) approach for interface capturing. Waves are generated by a flaptype wave maker in the numerical wave tank, and the dynamic mesh method is applied to model the motion of the oscillating flap. Basic mesh and time step refinement studies are performed. The flow characteristics in a slamming event are analysed based on numerical results. Various simulations with different flap densities, water depths and wave amplitudes are performed for a better understanding of the slamming.

The changing university business model: a stakeholder perspective

Universities are in a current state of transition, whereby they are expected to develop a wide range of relationships with stakeholders in order to enhance regional innovation systems. However, despite external environmental pressures commonly regarded as one of the main drivers of business model evolution, there is a lack of studies that explore business model innovation as a result of multiple stakeholder influences. Accordingly, the aim of this paper is to examine the changing university business model within a region of the United Kingdom, using a stakeholder perspective that will aid theoretical development and refinement in both the business model and stakeholder fields. This examination is aided by consideration of the university business model as an activity system. Repeat interviews, combined with stakeholder theory, have been used to show how the changing university business model–stakeholder relationship has progressed through different stakeholder stages with resultant changes in content, structure and governance. Furthermore, conflicting objectives between each of the stakeholder groups (i.e. academics, industry liaison staff, technology transfer office staff and government support agency representatives) have led to the university business model evolving not as a process of co-creation but rather in a series of transitions whereby multiple stakeholders are continually shaping the university business model through strategies that are dependent upon their salience. Finally, this paper contributes to the development and refinement of business model innovation research, in that the use of stakeholder constructs can illustrate the impact of multiple stakeholders' power and influence on business model innovation.

The establishment of a 3D breast photography service in medical illustration

This paper aims to describe the development of a 3D breast photography service managed by the Medical Illustration Department, in the Belfast Health and Social Care Trust, Northern Ireland. Dedicated 3D breast photography equipment was installed in Medical Illustration for 18 months. Women were referred for a variety of indications including pre- and post-surgical assessment. A dedicated 3D breast photography protocol was developed locally and this requires further refinement to allow reproducibility in other centres. There are image/data artefacts associated with this technology and special techniques are required to reduce these. Specialist software is necessary for clinicians and scientists to use 3D breast photography data in surgical planning and measurement of surgical outcome.

Adding metadata to Orc to support reasoning about grid programs

Following earlier work demonstrating the utility of Orc as a means of specifying and reasoning about grid applications we propose the enhancement of such specifications with metadata that provide a means to extend an Orc specification with implementation oriented information. We argue that such specifications provide a useful refinement step in allowing reasoning about implementation related issues ahead of actual implementation or even prototyping. As examples, we demonstrate how such extended specifications can be used for investigating security related issues and for evaluating the cost of handling grid resource faults. The approach emphasises a semi-formal style of reasoning that makes maximum use of programmer domain knowledge and experience.