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.

Development and single laboratory validation of an optical biosensor assay for tetrodotoxin detection as a tool to combat emerging risks in European seafood

Tetrodotoxin (TTX) is a potent neurotoxin emerging in European waters due to increasing ocean temperatures. Its detection in seafood is currently performed as a consequence of using the Association of Analytical Communities (AOAC) mouse bioassay (MBA) for paralytic shellfish poisoning (PSP) toxins, but TTX is not monitored routinely in Europe. Due to ethical and performance-related issues associated with this bioassay, the European Commission has recently published directives extending procedures that may be used for official PSP control. An AOAC-accredited high-performance liquid chromatography (HPLC) method has now been accepted by the European Union as a first action screening method for PSP toxins to replace the MBA. However, this AOAC HPLC method is not capable of detecting TTX, so this potent toxin would be undetected; thereby, a separate method of analysis is required. Surface plasmon resonance (SPR) optical biosensor technology has been proven as a potential alternative screening method to detect PSP toxins in seafood. The addition of a similar SPR inhibition assay for TTX would complement the PSP assay in removing the MBA. The present report describes the development and single laboratory validation in accordance with AOAC and IUPAC guidelines of an SPR method to be used as a rapid screening tool to detect TTX in the sea snail Charonia lampas lampas, a species which has been implicated in 2008 in the first case of human TTX poisoning in Europe. As no current regulatory limits are set for TTX in Europe, single laboratory validation was undertaken using those for PSP toxins at 800 µg/kg. The decision limit (CCa) was 100 µg/kg, with the detection capability (CCß) found to be =200 µg/kg. Repeatability and reproducibility were assessed at 200, 400, and 800 µg/kg and showed relative standard deviations of 8.3, 3.8, and 5.4 % and 7.8, 8.3, and 3.7 % for both parameters at each level, respectively. At these three respective levels, the recovery of the assay was 112, 98, and 99 %.

Development and validation of the first high performance-lateral flow immunoassay (HP-LFIA) for the rapid screening of domoic acid from shellfish extracts

A lateral flow immunoassay (LFIA) has been developed and fully validated to detect the primary amnesic shellfish poisoning (ASP) toxin, domoic acid (DA). The performance characteristics of two versions of the test were investigated using spiked and naturally contaminated shellfish (mussels, scallops, oysters, clams, and cockles). The tests provide a qualitative result, to indicate the absence or presence of DA in extracts of shellfish tissues, at concentrations that are relevant to regulatory limits. The new rapid assay (LFIA version 2) was designed to overcome the performance limitations identified in the first version of the assay. The improved test uses an electronic reader to remove the subjective nature of the generated results, and the positive cut-off for screening of DA in shellfish was increased from 10 ppm (version 1) to 17.5 ppm (version 2). A simple extraction and test procedure was employed, which required minimal equipment and materials; results were available 15 min after sample preparation. Stability of the aqueous extracts at room temperature (22 C) at four time points (up to 245 min after extraction) and across a range of DA concentrations was 100.3±1.3% and 98.8±2.4% for pre- and post-buffered extracts, respectively. The assay can be used both within laboratory settings and in remote locations. The accuracy of the new assay, to indicate negative results at or below 10 ppm DA, and positive results at or above 17.5 ppm, was 99.5% (n=216 tests). Validation data were obtained from a 2-day, randomised, blind study consisting of multiple LFIA lots (n=3), readers (n=3) and operators (n=3), carrying out multiple extractions of mussel tissue (n=3) at each concentration (0, 10, 17.5, and 20 ppm). No matrix effects were observed on the performance of the assay with different species (mussels, scallops, oysters, clams, and cockles). There was no impact on accuracy or interference from other phycotoxins, glutamic acid or glutamine with various strip incubations (8, 10, and 12 min). The accuracy of the assay, using naturally contaminated samples to indicate negative results at or below 12.5 ppm and positive results at or above 17.5 ppm, was 100%. Variability between three LFIA lots across a range of DA concentrations, expressed as coefficient of variation (% CV), was 1.1±0.4% (n=2 days) based on quantitative readings from the electronic reader. During an 8 week stability study, accuracy of the method with test strips stored at various temperatures (6, 22, 37 and 50 C) was 100%. Validation for both versions included comparisons with results obtained using reference LC-UV methods. © 2013 Elsevier B.V.

First development and characterisation of polyclonal and monoclonal antibodies to the emerging fresh water toxin cylindrospermopsin

As increasing incidences in the occurrence of cylindrospermopsin (CYN) appear, in addition to further research on its toxicological nature, improved rapid methods to detect this toxin are required. Antibody based assays are renowned for their ability to provide rapid, portable, simple to use tests. As yet however there are no publications outlining how an antibody to CYN can be produced. A range of chemical approaches was investigated to synthesise CYN immunogens for antibody production but failed to generate a response. Finally, a modified Mannich reaction for immunogen synthesis was employed to couple the toxin to two carrier proteins. Both protein conjugates were successfully used to raise both polyclonal and monoclonal antibodies of high sensitivity to CYN. These antibodies were characterised employing competitive indirect ELISA and an optical biosensor assay. By ELISA the sensitivity achieved ranged from 27 to 131. pg/mL and by SPR 4.4 to 11.1. ng/mL thus demonstrating that the selection of immunoassay platform is important for the detection level required by the end user for their application. Low cross-reactivity to the much less toxic metabolite deoxyCYN was observed. This is the first reported production of antibodies to this toxin. © 2013 Elsevier B.V.

Lovastatin biosynthesis depends on the carbon-nitrogen proportion: model development and controller design

Lovastatin biosynthesis depends on the relative concentrations of dissolved oxygen and the carbon and nitrogen resources. An elucidation of the underlying relationship would facilitate the derivation of a controller for the improvement of lovastatin yield in bioprocesses. To achieve this goal, batch submerged cultivation experiments of lovastatin production by Aspergillus flavipus BICC 5174, using both lactose and glucose as carbon sources, were performed in a 7 liter bioreactor and the data used to determine how the relative concentrations of lactose, glucose, glutamine and oxygen affected lovastatin yield. A model was developed based on these results and its prediction was validated using an independent set of batch data obtained from a 15-liter bioreactor using five statistical measures, including the Willmott index of agreement. A nonlinear controller was designed considering that dissolved oxygen and lactose concentrations could be measured online, and using the lactose feed rate and airflow rate as process inputs. Simulation experiments were performed to demonstrate that a practical implementation of the nonlinear controller would result in satisfactory outcomes. This is the first model that correlates lovastatin biosynthesis to carbon-nitrogen proportion and possesses a structure suitable for implementing a strategy for controlling lovastatin production.

Development and validation of a rapid multiplex ELISA for pyrrolizidine alkaloids and their N-oxides in honey and feed Rapid Detection in Food and Feed

Pyrrolizidine alkaloids (PAs) are a group of plant secondary metabolites with carcinogenic and hepatotoxic properties. When PA-producing plants contaminate crops, toxins can be transferred through the food chain and cause illness in humans and animals, most notably hepatic veno-occlusive disease. Honey has been identified as a direct risk of human exposure. The European Food Safety Authority has recently identified four groups of PAs that are of particular importance for food and feed: senecionine-type, lycopsamine-type, heliotrine-type and monocrotaline-type. Liquid or gas chromatography methods are currently used to detect PAs but there are no rapid screening assays available commercially. Therefore, the aim of this study was to develop a rapid multiplex ELISA test for the representatives of three groups of alkaloids (senecionine, lycopsamine and heliotrine types) that would be used as a risk-management tool for the screening of these toxic compounds in food and feed. The method was validated for honey and feed matrices and was demonstrated to have a detection capability less than 25 µg/kg for jacobine, lycopsamine, heliotrine and senecionine. The zinc reduction step introduced to the extraction procedure allows for the additional detection of the presence of N-oxides of PAs. This first multiplex immunoassay for PA detection with N-oxide reduction can be used for the simultaneous screening of 21 samples for >12 PA analytes. Honey samples (n?=?146) from various origins were analysed for PA determination. Six samples were determined to contain measurable PAs >25 µg/kg by ELISA which correlated to >10 µg/kg by LC-MS/MS.

Development and assessment of a robust optimization metric for WAMPAC modeling

A PMU based WAMS is to be placed on a weakly coupled section of distribution grid, with high levels of distributed generation. In anticipation of PMU data a Siemens PSS/E model of the electrical environment has been used to return similar data to that expected from the WAMS. This data is then used to create a metric that reflects optimization, control and protection in the region. System states are iterated through with the most desirable one returning the lowest optimization metric, this state is assessed against the one returned by PSS/E under normal circumstances. This paper investigates the circumstances that trigger SPS in the region, through varying generation between 0 and 110% and compromising the network through line loss under summer minimum and winter maximum conditions. It is found that the optimized state can generally tolerate an additional 2 MW of generation (3% of total) before encroaching the same thresholds and in one instance moves the triggering to 100% of generation output.

Microstructural analysis of non-woven fabrics using scanning electron microscopy and image processing. Part 1:Development and verification of the methods

This paper reports image analysis methods that have been developed to study the microstructural changes of non-wovens made by the hydroentanglement process. The validity of the image processing techniques has been ascertained by applying them to test images with known properties. The parameters in preprocessing of the scanning electron microscope (SEM) images used in image processing have been tested and optimized. The fibre orientation distribution is estimated using fast Fourier transform (FFT) and Hough transform (HT) methods. The results obtained using these two methods are in good agreement. The HT method is more demanding in computational time compared with the Fourier transform (FT) method. However, the advantage of the HT method is that the actual orientation of the lines can be concluded directly from the result of the transform without the need for any further computation. The distribution of the length of the straight fibre segments of the fabrics is evaluated by the HT method. The effect of curl of the fibres on the result of this evaluation is shown.

Production of a broad specificity antibody for the development and validation of an optical SPR screening method for free and intracellular microcystins and nodularin in cyanobacteria cultures

A highly sensitive broad specificity monoclonal antibody was produced and characterised for microcystin detection through the development of a rapid surface plasmon resonance (SPR) optical biosensor based immunoassay. The antibody displayed the following cross-reactivity: MC-LR 100%; MC-RR 108%; MC-YR 68%; MC-LA 69%; MC-LW 71%; MC-LF 68%; and Nodularin 94%. Microcystin-LR was covalently attached to a CM5 chip and with the monoclonal antibody was employed in a competitive 4min injection assay to detect total microcystins in water samples below the WHO recommended limit (1µg/L). A 'total microcystin' level was determined by measuring free and intracellular concentrations in cyanobacterial culture samples as this toxin is an endotoxin. Glass bead beating was used to lyse the cells as a rapid extraction procedure. This method was validated according to European Commission Decision 96/23/EC criteria. The method was proven to measure intracellular microcystin levels, the main source of the toxin, which often goes undetected by other analytical procedures and is advantageous in that it can be used for the monitoring of blooms to provide an early warning of toxicity. It was shown to be repeatable and reproducible, with recoveries from spiked samples ranging from 74 to 123%, and had % CVs below 10% for intra-assay analysis and 15% for inter-assay analysis. The detection capability of the assay was calculated as 0.5ng/mL for extracellular toxins and 0.05ng/mL for intracellular microcystins. A comparison of the SPR method with LC-MS/MS was achieved by testing six Microcystis aeruginosa cultures and this study yielded a correlation R(2) value of 0.9989.

Lifelong learning:Reflections of a junior doctor

Purpose - The aim of this paper is investigate the importance of lifelong learning in the area of medicine. Design/methodology/approach - The paper examines changes in methods of learning and challenges to educators today. Findings - The paper finds that today there is a pressure for the formalized accounting of education with a few high profile cases of negligent medical care which have perhaps created the belief that recording learning for all may catch errant doctors in the future. It is suggested that learning risks becoming an exercise in meeting demands, but inspiring the desire to learn is also crucial. Originality/value - The paper provides a useful opinion on lifelong learning for the medical profession. © Emerald Group Publishing Limited.

Sustainable Technoscientific Development and the Innovator Citizen

Sustainable development could provide a critical foil for individual
and especially collective reflection on the normative
direction, ends and means employed by societies, particularly
around the economy, its technology and resource-intensive
orientation and configuration with ecosystems. However,
although sustainable development is a constitutional objective
of the EU, its implementation in strategies and policies reveals
a much narrower meaning. By framing sustainable development
as ecological modernisation on the basis of technoscientific
innovation, and by imagining citizens as entrepreneurs in a
knowledge-based European economy, openings for democratic
experimentation and social innovation are limited and even
forestalled. In addition, the disruptive and transformational
potential of citizenship is stymied. Still, sustainable development
has resonance within citizenship and human rights
discourses that provide important resources for the fashioning
of common understanding. These are valuable supplements to
the repertoire of European citizenship that could help to embed
sustainable development in the social fabric and generate
alternative imaginaries and futures of a sustainable Europe.

Attention during social interaction in children with autism: Comparison to specific language impairment, typical development, and links to cognition

Eye-tracking studies have shown how people with autism spend significantly less time looking at socially relevant information on-screen compared to those developing typically. This has been suggested to impact on the development of socio-cognitive skills in autism. We present novel evidence of how attention atypicalities in children with autism extend to real-life interaction, in comparison to typically developing (TD) children and children with specific language impairment (SLI). We explored the allocation of attention during social interaction with an interlocutor, and how aspects of attention (awareness checking) related to traditional measures of social cognition (false belief attribution). We found divergent attention allocation patterns across the groups in relation to social cognition ability. Even though children with autism and SLI performed similarly on the socio- cognitive tasks, there were syndrome-specific atypicalities of their attention patterns. Children with SLI were most similar to TD children in terms of prioritising attention to socially pertinent information (eyes, face, awareness checking). Children with autism showed reduced attention to the eyes and face, and slower awareness checking. This study provides unique and timely insight into real-world social gaze (a)typicality in autism, SLI and typical development, its relationship to socio-cognitive ability, and raises important issues for intervention.