Protocol for the PINCER trial: a cluster randomised trial comparing the effectiveness of a pharmacist-led IT-based intervention with simple feedback in reducing rates of clinically important errors in medicines management in general practices

Background: Medication errors are an important cause of morbidity and mortality in primary care. The aims of this study are to determine the effectiveness, cost effectiveness and acceptability of a pharmacist-led information-technology-based complex intervention compared with simple feedback in reducing proportions of patients at risk from potentially hazardous prescribing and medicines management in general (family) practice. Methods: Research subject group: "At-risk" patients registered with computerised general practices in two geographical regions in England. Design: Parallel group pragmatic cluster randomised trial. Interventions: Practices will be randomised to either: (i) Computer-generated feedback; or (ii) Pharmacist-led intervention comprising of computer-generated feedback, educational outreach and dedicated support. Primary outcome measures: The proportion of patients in each practice at six and 12 months post intervention: - with a computer-recorded history of peptic ulcer being prescribed non-selective non-steroidal anti-inflammatory drugs - with a computer-recorded diagnosis of asthma being prescribed beta-blockers - aged 75 years and older receiving long-term prescriptions for angiotensin converting enzyme inhibitors or loop diuretics without a recorded assessment of renal function and electrolytes in the preceding 15 months. Secondary outcome measures; These relate to a number of other examples of potentially hazardous prescribing and medicines management. Economic analysis: An economic evaluation will be done of the cost per error avoided, from the perspective of the UK National Health Service (NHS), comparing the pharmacist-led intervention with simple feedback. Qualitative analysis: A qualitative study will be conducted to explore the views and experiences of health care professionals and NHS managers concerning the interventions, and investigate possible reasons why the interventions prove effective, or conversely prove ineffective. Sample size: 34 practices in each of the two treatment arms would provide at least 80% power (two-tailed alpha of 0.05) to demonstrate a 50% reduction in error rates for each of the three primary outcome measures in the pharmacist-led intervention arm compared with a 11% reduction in the simple feedback arm. Discussion: At the time of submission of this article, 72 general practices have been recruited (36 in each arm of the trial) and the interventions have been delivered. Analysis has not yet been undertaken.

Binocular coordination of the eyes during reading

Saccadic eye movements and fixations are the behavioral means by which we visually sample text during reading. Human oculomotor control is governed by a complex neurophysiological system involving the brain stem, superior colliculus, and several cortical areas [1, 2]. A very widely held belief among researchers investigating primate vision is that the oculomotor system serves to orient the visual axes of both eyes to fixate the same target point in space. It is argued that such precise positioning of the eyes is necessary to place images on corresponding retinal locations, such that on each fixation a single, nondiplopic, visual representation is perceived [3]. Vision works actively through a continual sampling process involving saccades and fixations [4]. Here we report that during normal reading, the eyes do not always fixate the same letter within a word. We also demonstrate that saccadic targeting is yoked and based on a unified cyclopean percept of a whole word since it is unaffected if different word parts are delivered exclusively to each eye via a dichoptic presentation technique. These two findings together suggest that the visual signal from each eye is fused at a very early stage in the visual pathway, even when the fixation disparity is greater than one character (0.29 deg), and that saccade metrics for each eye are computed on the basis of that fused signal.

Semantic organization to enhance active learning based on distributed multimedia educational resources

In order to organize distributed educational resources efficiently, to provide active learners an integrated, extendible and cohesive interface to share the dynamically growing multimedia learning materials on the Internet, this paper proposes a generic resource organization model with semantic structures to improve expressiveness, scalability and cohesiveness. We developed an active learning system with semantic support for learners to access and navigate through efficient and flexible manner. We learning resources in an efficient and flexible manner. We provide facilities for instructors to manipulate the structured educational resources via a convenient visual interface. We also developed a resource discovering and gathering engine based on complex semantic associations for several specific topics.

Norms-based simulation for personalised service provision

User interfaces have the primary role of enabling access to information meeting individual users' needs. However, the user-systems interaction is still rigid, especially in support of complex environments where various types of users are involved. Among the approaches for improving user interface agility, we present a normative approach to the design interfaces of web applications, which allow delivering users personalized services according to parameters extracted from the simulation of norms in the social context. A case study in an e-Government context is used to illustrate the implications of the approach.

Fully complex-valued radial basis function networks: orthogonal least squares regression and classification

We consider a fully complex-valued radial basis function (RBF) network for regression and classification applications. For regression problems, the locally regularised orthogonal least squares (LROLS) algorithm aided with the D-optimality experimental design, originally derived for constructing parsimonious real-valued RBF models, is extended to the fully complex-valued RBF (CVRBF) network. Like its real-valued counterpart, the proposed algorithm aims to achieve maximised model robustness and sparsity by combining two effective and complementary approaches. The LROLS algorithm alone is capable of producing a very parsimonious model with excellent generalisation performance while the D-optimality design criterion further enhances the model efficiency and robustness. By specifying an appropriate weighting for the D-optimality cost in the combined model selecting criterion, the entire model construction procedure becomes automatic. An example of identifying a complex-valued nonlinear channel is used to illustrate the regression application of the proposed fully CVRBF network. The proposed fully CVRBF network is also applied to four-class classification problems that are typically encountered in communication systems. A complex-valued orthogonal forward selection algorithm based on the multi-class Fisher ratio of class separability measure is derived for constructing sparse CVRBF classifiers that generalise well. The effectiveness of the proposed algorithm is demonstrated using the example of nonlinear beamforming for multiple-antenna aided communication systems that employ complex-valued quadrature phase shift keying modulation scheme. (C) 2007 Elsevier B.V. All rights reserved.

Classification-based probabilistic modeling of texture transition for fast line search tracking and delineation

We introduce a classification-based approach to finding occluding texture boundaries. The classifier is composed of a set of weak learners, which operate on image intensity discriminative features that are defined on small patches and are fast to compute. A database that is designed to simulate digitized occluding contours of textured objects in natural images is used to train the weak learners. The trained classifier score is then used to obtain a probabilistic model for the presence of texture transitions, which can readily be used for line search texture boundary detection in the direction normal to an initial boundary estimate. This method is fast and therefore suitable for real-time and interactive applications. It works as a robust estimator, which requires a ribbon-like search region and can handle complex texture structures without requiring a large number of observations. We demonstrate results both in the context of interactive 2D delineation and of fast 3D tracking and compare its performance with other existing methods for line search boundary detection.

An ontological modelling of user requirements for personalised information provision

The knowledge economy offers opportunity to a broad and diverse community of information systems users to efficiently gain information and know-how for improving qualifications and enhancing productivity in the work place. Such demand will continue and users will frequently require optimised and personalised information content. The advancement of information technology and the wide dissemination of information endorse individual users when constructing new knowledge from their experience in the real-world context. However, a design of personalised information provision is challenging because users’ requirements and information provision specifications are complex in their representation. The existing methods are not able to effectively support this analysis process. This paper presents a mechanism which can holistically facilitate customisation of information provision based on individual users’ goals, level of knowledge and cognitive styles preferences. An ontology model with embedded norms represents the domain knowledge of information provision in a specific context where users’ needs can be articulated and represented in a user profile. These formal requirements can then be transformed onto information provision specifications which are used to discover suitable information content from repositories and pedagogically organise the selected content to meet the users’ needs. The method is provided with adaptability which enables an appropriate response to changes in users’ requirements during the process of acquiring knowledge and skills.

Mono- and heterodimetallic FeII and RuII complexes based on a novel heteroditopic 4′-{bis(phosphanyl)aryl}-2,2′:6′,2″-terpyridine ligand

In the search for a versatile building block that allows the preparation of heteroditopic tpy-pincer bridging ligands, the synthon 14'-[C6H3(CH2Br)(2)-3,5]-2,2':6',2 ''-terpyridine was synthesized. Facile introduction of diphenylphosphanyl groups in this synthon gave the ligand 14'-[C6H3(CH2PPh2)2-3,5]-2,2':6',2"-terpyridine) ([tpyPC(H)Pj). The asymmetric mononuclear complex [Fe(tpy){tpyPC(H)P}](PF6)(2), prepared by selective coordination of [Fe(tpy)Cl-3] to the tpy moiety of [tpyPC(H)P], was used for the synthesis of the heterodimetallic complex [Fe(tpy)(tpyPCP)Ru(tpy)](PFC,)3, which applies the "complex as ligand" approach. Coordination of the ruthenium centre at the PC(H)P-pincer moiety of [Fe(tpy){tpyPC(H)P}](PF6)(2) has been achieved by applying a transcyclometallation procedure. The ground-state electronic properties of both complexes, investigated by cyclic and square-wave voltammetries and UV/Vis spectroscopy, are discussed and compared with those of [Fe(tPY)(2)](PF6)(2) and [Ru(PCP)(tpy)]Cl, which represent the mononuclear components of the heterodinuclear species. An in situ UV/Vis spectroelectrochemical study was performed in order to localize the oxidation and reduction steps and to gain information about the Fe-II-Ru-II communication in the heterodimetallic system [Fe(tpy)(tpyPCP)Ru(tpy)](PF6)(3) mediated by the bridging ligand [tpyPCP]. Both the voltammetric and spectroelectrochemical results point to only very limited electronic interaction between the metal centres in the ground state.

Syntheses, x-ray structures, photochemistry, redox properties, and DFT calculations of interconvertible fac- and mer-[Mn(SPS)(CO)3] isomers containing a flexible SPS-based pincer ligand

The lithium salt of the anionic SPS pincer ligand composed of a central hypervalent lambda(4)-phosphinine ring bearing two ortho-positioned diphenylphosphine sulfide side arms reacts with [Mn(CO)(5)Br] to give fac-[Mn(SPS)(CO)(3)], This isomer can be converted photochemicaily to mer-[Mn(SPS)(CO)(3)], with a very high quantum yield (0.80 +/- 0.05). The thermal backreaction is slow (taking ca. 8 h at room temperature), in contrast to rapid electrodecatalyzed mer-to-fac isomerization triggered by electrochemical reduction of mer-[Mn(SPS)(CO)(3)]. Both geometric isomers of [Mn(SPS)(CO)(3)] have been characterized by X-ray crystallography. Both isomers show luminescence from a low-lying (IL)-I-3 (SPS-based) excited state. The light emission of fac-[Mn(SPS)(CO)(3)] is largely quenched by the efficient photoisomerization occurring probably from a low-lying Mn-CO dissociative excited state. Density functional theory (DFT) and time-dependent DFT calculations describe the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of fac- and mer-[Mn(CO)(3)(SPS)] as ligand-centered orbitals, largely localized on the phosphinine ring of the SPS pincer ligand. In line with the ligand nature of its frontier orbitals, fac-[Mn(SPS)(CO)(3)] is electrochemically reversibly oxidized and reduced to the corresponding radical cation and anion, respectively. The spectroscopic (electron paramagnetic resonance, IR, and UV-vis) characterization of the radical species provides other evidence for the localization of the redox steps on the SIPS ligand. The smaller HOMO-LUMO energy difference in the case of mer-[Mn(CO)(3)(SPS)], reflected in the electronic absorption and emission spectra, corresponds with its lower oxidation potential compared to that of the fac isomer. The thermodynamic instability of mer-[Mn(CO)(3)(SPS)], confirmed by the DFT calculations, increases upon one-electron reduction and oxidation of the complex.

A neural network enhanced generalized minimum variance self-tuning proportional, integral and derivative control algorithm for complex dynamic systems

A neural network enhanced proportional, integral and derivative (PID) controller is presented that combines the attributes of neural network learning with a generalized minimum-variance self-tuning control (STC) strategy. The neuro PID controller is structured with plant model identification and PID parameter tuning. The plants to be controlled are approximated by an equivalent model composed of a simple linear submodel to approximate plant dynamics around operating points, plus an error agent to accommodate the errors induced by linear submodel inaccuracy due to non-linearities and other complexities. A generalized recursive least-squares algorithm is used to identify the linear submodel, and a layered neural network is used to detect the error agent in which the weights are updated on the basis of the error between the plant output and the output from the linear submodel. The procedure for controller design is based on the equivalent model, and therefore the error agent is naturally functioned within the control law. In this way the controller can deal not only with a wide range of linear dynamic plants but also with those complex plants characterized by severe non-linearity, uncertainties and non-minimum phase behaviours. Two simulation studies are provided to demonstrate the effectiveness of the controller design procedure.

A very rare hydrogen-bridged hexanuclear CuII complex containing a triangular Cu3O core capped by an unusual triply coordinated perchlorate anion

An unusual hexanuclear Cu-II complex, [{[Cu(NHDEPO)](3)(mu(3)-O)(O3ClO)}(2)(mu-H)]center dot 7ClO(4)center dot 4H(2)O (1) was prepared starting from Cu(ClO4)(2)center dot 6H(2)O and the oxime-based Schiff base ligand NHDEPO (= 3-[3-(diethylamino)propylimino]butan-2-one oxime). Structural characterization of the complex reveals that it consists of two triangular Cu3O units, the copper ions being at the corners of an equilateral triangle, separated by an O center dot center dot center dot O distance of 2,447(5) angstrom, held together solely by a proton. In each triangle, the copper atoms are in square-pyramid environments. The equatorial plane consists of the bridging oxygen of the central OH-(O2-) group together with three atoms (N, N, O) of the Schiff base. All Unusual triply coordinated perchlorate ion (mu(3)-kappa O:kappa O':kappa O '') interacts in axial position with the three copper ions, Variable-temperature (2-300 K) magnetic susceptibility measurements show that complex 1 is antiferromagnetically Coupled (J = -148 cm(1-)). The EPR data at low temperature clearly indicates the presence of spin frustration phenomenon in the complex.

Fast regridding of large, complex geospatial datasets

In the earth sciences, data are commonly cast on complex grids in order to model irregular domains such as coastlines, or to evenly distribute grid points over the globe. It is common for a scientist to wish to re-cast such data onto a grid that is more amenable to manipulation, visualization, or comparison with other data sources. The complexity of the grids presents a significant technical difficulty to the regridding process. In particular, the regridding of complex grids may suffer from severe performance issues, in the worst case scaling with the product of the sizes of the source and destination grids. We present a mechanism for the fast regridding of such datasets, based upon the construction of a spatial index that allows fast searching of the source grid. We discover that the most efficient spatial index under test (in terms of memory usage and query time) is a simple look-up table. A kd-tree implementation was found to be faster to build and to give similar query performance at the expense of a larger memory footprint. Using our approach, we demonstrate that regridding of complex data may proceed at speeds sufficient to permit regridding on-the-fly in an interactive visualization application, or in a Web Map Service implementation. For large datasets with complex grids the new mechanism is shown to significantly outperform algorithms used in many scientific visualization packages.

B-spline neural network based digital baseband predistorter solution using the inverse of De Boor algorithm

In this paper a new nonlinear digital baseband predistorter design is introduced based on direct learning, together with a new Wiener system modeling approach for the high power amplifiers (HPA) based on the B-spline neural network. The contribution is twofold. Firstly, by assuming that the nonlinearity in the HPA is mainly dependent on the input signal amplitude the complex valued nonlinear static function is represented by two real valued B-spline neural networks, one for the amplitude distortion and another for the phase shift. The Gauss-Newton algorithm is applied for the parameter estimation, in which the De Boor recursion is employed to calculate both the B-spline curve and the first order derivatives. Secondly, we derive the predistorter algorithm calculating the inverse of the complex valued nonlinear static function according to B-spline neural network based Wiener models. The inverse of the amplitude and phase shift distortion are then computed and compensated using the identified phase shift model. Numerical examples have been employed to demonstrate the efficacy of the proposed approaches.

Technologies for biological containment of GM and Non-GM crops

International Perspective The development of GM technology continues to expand into increasing numbers of crops and conferred traits. Inevitably, the focus remains on the major field crops of soybean, maize, cotton, oilseed rape and potato with introduced genes conferring herbicide tolerance and/or pest resistance. Although there are comparatively few GM crops that have been commercialised to date, GM versions of 172 plant species have been grown in field trials in 31 countries. European Crops with Containment Issues Of the 20 main crops in the EU there are four for which GM varieties are commercially available (cotton, maize for animal feed and forage, and oilseed rape). Fourteen have GM varieties in field trials (bread wheat, barley, durum wheat, sunflower, oats, potatoes, sugar beet, grapes, alfalfa, olives, field peas, clover, apples, rice) and two have GM varieties still in development (rye, triticale). Many of these crops have hybridisation potential with wild and weedy relatives in the European flora (bread wheat, barley, oilseed rape, durum wheat, oats, sugar beet and grapes), with escapes (sunflower); and all have potential to cross-pollinate fields non-GM crops. Several fodder crops, forestry trees, grasses and ornamentals have varieties in field trials and these too may hybridise with wild relatives in the European flora (alfalfa, clover, lupin, silver birch, sweet chestnut, Norway spruce, Scots pine, poplar, elm, Agrostis canina, A. stolonifera, Festuca arundinacea, Lolium perenne, L. multiflorum, statice and rose). All these crops will require containment strategies to be in place if it is deemed necessary to prevent transgene movement to wild relatives and non-GM crops. Current Containment Strategies A wide variety of GM containment strategies are currently under development, with a particular focus on crops expressing pharmaceutical products. Physical containment in greenhouses and growth rooms is suitable for some crops (tomatoes, lettuce) and for research purposes. Aquatic bioreactors of some non-crop species (algae, moss, and duckweed) expressing pharmaceutical products have been adopted by some biotechnology companies. There are obvious limitations of the scale of physical containment strategies, addressed in part by the development of large underground facilities in the US and Canada. The additional resources required to grow plants underground incurs high costs that in the long term may negate any advantage of GM for commercial productioNatural genetic containment has been adopted by some companies through the selection of either non-food/feed crops (algae, moss, duckweed) as bio-pharming platforms or organisms with no wild relatives present in the local flora (safflower in the Americas). The expression of pharmaceutical products in leafy crops (tobacco, alfalfa, lettuce, spinach) enables growth and harvesting prior to and in the absence of flowering. Transgenically controlled containment strategies range in their approach and degree of development. Plastid transformation is relatively well developed but is not suited to all traits or crops and does not offer complete containment. Male sterility is well developed across a range of plants but has limitations in its application for fruit/seed bearing crops. It has been adopted in some commercial lines of oilseed rape despite not preventing escape via seed. Conditional lethality can be used to prevent flowering or seed development following the application of a chemical inducer, but requires 100% induction of the trait and sufficient application of the inducer to all plants. Equally, inducible expression of the GM trait requires equally stringent application conditions. Such a method will contain the trait but will allow the escape of a non-functioning transgene. Seed lethality (‘terminator’ technology) is the only strategy at present that prevents transgene movement via seed, but due to public opinion against the concept it has never been trialled in the field and is no longer under commercial development. Methods to control flowering and fruit development such as apomixis and cleistogamy will prevent crop-to-wild and wild-to-crop pollination, but in nature both of these strategies are complex and leaky. None of the genes controlling these traits have as yet been identified or characterised and therefore have not been transgenically introduced into crop species. Neither of these strategies will prevent transgene escape via seed and any feral apomicts that form are arguably more likely to become invasives. Transgene mitigation reduces the fitness of initial hybrids and so prevents stable introgression of transgenes into wild populations. However, it does not prevent initial formation of hybrids or spread to non-GM crops. Such strategies could be detrimental to wild populations and have not yet been demonstrated in the field. Similarly, auxotrophy prevents persistence of escapes and hybrids containing the transgene in an uncontrolled environment, but does not prevent transgene movement from the crop. Recoverable block of function, intein trans-splicing and transgene excision all use recombinases to modify the transgene in planta either to induce expression or to prevent it. All require optimal conditions and 100% accuracy to function and none have been tested under field conditions as yet. All will contain the GM trait but all will allow some non-native DNA to escape to wild populations or to non-GM crops. There are particular issues with GM trees and grasses as both are largely undomesticated, wind pollinated and perennial, thus providing many opportunities for hybridisation. Some species of both trees and grass are also capable of vegetative propagation without sexual reproduction. There are additional concerns regarding the weedy nature of many grass species and the long-term stability of GM traits across the life span of trees. Transgene stability and conferred sterility are difficult to trial in trees as most field trials are only conducted during the juvenile phase of tree growth. Bio-pharming of pharmaceutical and industrial compounds in plants Bio-pharming of pharmaceutical and industrial compounds in plants offers an attractive alternative to mammalian-based pharmaceutical and vaccine production. Several plantbased products are already on the market (Prodigene’s avidin, β-glucuronidase, trypsin generated in GM maize; Ventria’s lactoferrin generated in GM rice). Numerous products are in clinical trials (collagen, antibodies against tooth decay and non-Hodgkin’s lymphoma from tobacco; human gastric lipase, therapeutic enzymes, dietary supplements from maize; Hepatitis B and Norwalk virus vaccines from potato; rabies vaccines from spinach; dietary supplements from Arabidopsis). The initial production platforms for plant-based pharmaceuticals were selected from conventional crops, largely because an established knowledge base already existed. Tobacco and other leafy crops such as alfalfa, lettuce and spinach are widely used as leaves can be harvested and no flowering is required. Many of these crops can be grown in contained greenhouses. Potato is also widely used and can also be grown in contained conditions. The introduction of morphological markers may aid in the recognition and traceability of crops expressing pharmaceutical products. Plant cells or plant parts may be transformed and maintained in culture to produce recombinant products in a contained environment. Plant cells in suspension or in vitro, roots, root cells and guttation fluid from leaves may be engineered to secrete proteins that may be harvested in a continuous, non-destructive manner. Most strategies in this category remain developmental and have not been commercially adopted at present. Transient expression produces GM compounds from non-GM plants via the utilisation of bacterial or viral vectors. These vectors introduce the trait into specific tissues of whole plants or plant parts, but do not insert them into the heritable genome. There are some limitations of scale and the field release of such crops will require the regulation of the vector. However, several companies have several transiently expressed products in clinical and pre-clinical trials from crops raised in physical containment.

A comparative study of multilayered and single layered neural network based predictive controllers

The authors compare the performance of two types of controllers one based on the multilayered network and the other based on the single layered CMAC network (cerebellar model articulator controller). The neurons (information processing units) in the multi-layered network use Gaussian activation functions. The control scheme which is considered is a predictive control algorithm, along the lines used by Willis et al. (1991), Kambhampati and Warwick (1991). The process selected as a test bed is a continuous stirred tank reactor. The reaction taking place is an irreversible exothermic reaction in a constant volume reactor cooled by a single coolant stream. This reactor is a simplified version of the first tank in the two tank system given by Henson and Seborg (1989).