Showing papers by "University of York published in 2011"

Overview of the CCP4 suite and current developments.

Abstract: The CCP4 (Collaborative Computational Project, Number 4) software suite is a collection of programs and associated data and software libraries which can be used for macromolecular structure determination by X-ray crystallography. The suite is designed to be flexible, allowing users a number of methods of achieving their aims. The programs are from a wide variety of sources but are connected by a common infrastructure provided by standard file formats, data objects and graphical interfaces. Structure solution by macromolecular crystallo­graphy is becoming increasingly automated and the CCP4 suite includes several automation pipelines. After giving a brief description of the evolution of CCP4 over the last 30 years, an overview of the current suite is given. While detailed descriptions are given in the accompanying articles, here it is shown how the individual programs contribute to a complete software package.

REFMAC5 for the refinement of macromolecular crystal structures

Abstract: This paper describes various components of the macromolecular crystallographic refinement program REFMAC5, which is distributed as part of the CCP4 suite. REFMAC5 utilizes different likelihood functions depending on the diffraction data employed (amplitudes or intensities), the presence of twinning and the availability of SAD/SIRAS experimental diffraction data. To ensure chemical and structural integrity of the refined model, REFMAC5 offers several classes of restraints and choices of model parameterization. Reliable models at resolutions at least as low as 4 A can be achieved thanks to low-resolution refinement tools such as secondary-structure restraints, restraints to known homologous structures, automatic global and local NCS restraints, `jelly-body' restraints and the use of novel long-range restraints on atomic displacement parameters (ADPs) based on the Kullback–Leibler divergence. REFMAC5 additionally offers TLS parameterization and, when high-resolution data are available, fast refinement of anisotropic ADPs. Refinement in the presence of twinning is performed in a fully automated fashion. REFMAC5 is a flexible and highly optimized refinement package that is ideally suited for refinement across the entire resolution spectrum encountered in macromolecular crystallography.

Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L)

Abstract: This article introduces the new 5-level EQ-5D (EQ-5D-5L) health status measure. EQ-5D currently measures health using three levels of severity in five dimensions. A EuroQol Group task force was established to find ways of improving the instrument's sensitivity and reducing ceiling effects by increasing the number of severity levels. The study was performed in the United Kingdom and Spain. Severity labels for 5 levels in each dimension were identified using response scaling. Focus groups were used to investigate the face and content validity of the new versions, including hypothetical health states generated from those versions. Selecting labels at approximately the 25th, 50th, and 75th centiles produced two alternative 5-level versions. Focus group work showed a slight preference for the wording 'slight-moderate-severe' problems, with anchors of 'no problems' and 'unable to do' in the EQ-5D functional dimensions. Similar wording was used in the Pain/Discomfort and Anxiety/Depression dimensions. Hypothetical health states were well understood though participants stressed the need for the internal coherence of health states. A 5-level version of the EQ-5D has been developed by the EuroQol Group. Further testing is required to determine whether the new version improves sensitivity and reduces ceiling effects.

Rapid Range Shifts of Species Associated with High Levels of Climate Warming

Abstract: The distributions of many terrestrial organisms are currently shifting in latitude or elevation in response to changing climate Using a meta-analysis, we estimated that the distributions of species have recently shifted to higher elevations at a median rate of 110 meters per decade, and to higher latitudes at a median rate of 169 kilometers per decade These rates are approximately two and three times faster than previously reported The distances moved by species are greatest in studies showing the highest levels of warming, with average latitudinal shifts being generally sufficient to track temperature changes However, individual species vary greatly in their rates of change, suggesting that the range shift of each species depends on multiple internal species traits and external drivers of change Rapid average shifts derive from a wide diversity of responses by individual species

TRY - a global database of plant traits

Abstract: Plant traits – the morphological, anatomical, physiological, biochemical and phenological characteristics of plants and their organs – determine how primary producers respond to environmental factors, affect other trophic levels, influence ecosystem processes and services and provide a link from species richness to ecosystem functional diversity. Trait data thus represent the raw material for a wide range of research from evolutionary biology, community and functional ecology to biogeography. Here we present the global database initiative named TRY, which has united a wide range of the plant trait research community worldwide and gained an unprecedented buy-in of trait data: so far 93 trait databases have been contributed. The data repository currently contains almost three million trait entries for 69 000 out of the world's 300 000 plant species, with a focus on 52 groups of traits characterizing the vegetative and regeneration stages of the plant life cycle, including growth, dispersal, establishment and persistence. A first data analysis shows that most plant traits are approximately log-normally distributed, with widely differing ranges of variation across traits. Most trait variation is between species (interspecific), but significant intraspecific variation is also documented, up to 40% of the overall variation. Plant functional types (PFTs), as commonly used in vegetation models, capture a substantial fraction of the observed variation – but for several traits most variation occurs within PFTs, up to 75% of the overall variation. In the context of vegetation models these traits would better be represented by state variables rather than fixed parameter values. The improved availability of plant trait data in the unified global database is expected to support a paradigm shift from species to trait-based ecology, offer new opportunities for synthetic plant trait research and enable a more realistic and empirically grounded representation of terrestrial vegetation in Earth system models.

American College of Rheumatology/European League Against Rheumatism Provisional Definition of Remission in Rheumatoid Arthritis for Clinical Trials

Abstract: Objective Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used defi nition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a defi nition. Methods A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecifi ed analyses from RA clinical trials. The committee requested a stringent defi nition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to defi ne remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate defi nitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as defi nitions using disease activity indexes. To select a defi nition of remission, trial data were analysed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes. Results Survey results for the defi nition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (eg, tender and swollen joint counts, C reactive protein (CRP) level, and global assessments on a 0–10 scale). Analyses suggested the need to include a patientreported measure. Examination of 2-year follow-up data suggested that many candidate defi nitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score–based measures of remission did not

Presenting your structures: the CCP4mg molecular-graphics software.

Abstract: CCP4mg is a molecular-graphics program that is designed to give rapid access to both straightforward and complex static and dynamic representations of macromolecular structures. It has recently been updated with a new interface that provides more sophisticated atom-selection options and a wizard to facilitate the generation of complex scenes. These scenes may contain a mixture of coordinate-derived and abstract graphical objects, including text objects, arbitrary vectors, geometric objects and imported images, which can enhance a picture and eliminate the need for subsequent editing. Scene descriptions can be saved to file and transferred to other molecules. Here, the substantially enhanced version 2 of the program, with a new underlying GUI toolkit, is described. A built-in rendering module produces publication-quality images.

A survey of hard real-time scheduling for multiprocessor systems

Abstract: This survey covers hard real-time scheduling algorithms and schedulability analysis techniques for homogeneous multiprocessor systems. It reviews the key results in this field from its origins in the late 1960s to the latest research published in late 2009. The survey outlines fundamental results about multiprocessor real-time scheduling that hold independent of the scheduling algorithms employed. It provides a taxonomy of the different scheduling methods, and considers the various performance metrics that can be used for comparison purposes. A detailed review is provided covering partitioned, global, and hybrid scheduling algorithms, approaches to resource sharing, and the latest results from empirical investigations. The survey identifies open issues, key research challenges, and likely productive research directions.

Insights into the oxidative degradation of cellulose by a copper metalloenzyme that exploits biomass components

Abstract: The enzymatic degradation of recalcitrant plant biomass is one of the key industrial challenges of the 21st century. Accordingly, there is a continuing drive to discover new routes to promote polysaccharide degradation. Perhaps the most promising approach involves the application of “cellulase-enhancing factors,” such as those from the glycoside hydrolase (CAZy) GH61 family. Here we show that GH61 enzymes are a unique family of copper-dependent oxidases. We demonstrate that copper is needed for GH61 maximal activity and that the formation of cellodextrin and oxidized cellodextrin products by GH61 is enhanced in the presence of small molecule redox-active cofactors such as ascorbate and gallate. By using electron paramagnetic resonance spectroscopy and single-crystal X-ray diffraction, the active site of GH61 is revealed to contain a type II copper and, uniquely, a methylated histidine in the copper's coordination sphere, thus providing an innovative paradigm in bioinorganic enzymatic catalysis.

Transient ferromagnetic-like state mediating ultrafast reversal of antiferromagnetically coupled spins

Abstract: The dynamics of spin ordering in magnetic materials is of interest for both fundamental understanding and progress in information-processing and recording technology. Radu et al. study spin dynamics in a ferrimagnetic gadolinium–iron–cobalt (GdFeCo) alloy that is optically excited at a timescale shorter than the characteristic magnetic exchange interaction between the Gd and Fe spins. Using element-specific X-ray magnetic circular dichroism spectroscopy, they show that the Gd and Fe spins switch directions at very different timescales. As a consequence, an unexpected transient ferromagnetic state emerges. These surprising observations, supported by simulations, provide a possible new concept of manipulating magnetic order on a timescale of the exchange interaction. Ferromagnetic or antiferromagnetic spin ordering is governed by the exchange interaction, the strongest force in magnetism1,2,3,4. Understanding spin dynamics in magnetic materials is an issue of crucial importance for progress in information processing and recording technology. Usually the dynamics are studied by observing the collective response of exchange-coupled spins, that is, spin resonances, after an external perturbation by a pulse of magnetic field, current or light. The periods of the corresponding resonances range from one nanosecond for ferromagnets down to one picosecond for antiferromagnets. However, virtually nothing is known about the behaviour of spins in a magnetic material after being excited on a timescale faster than that corresponding to the exchange interaction (10–100 fs), that is, in a non-adiabatic way. Here we use the element-specific technique X-ray magnetic circular dichroism to study spin reversal in GdFeCo that is optically excited on a timescale pertinent to the characteristic time of the exchange interaction between Gd and Fe spins. We unexpectedly find that the ultrafast spin reversal in this material, where spins are coupled antiferromagnetically, occurs by way of a transient ferromagnetic-like state. Following the optical excitation, the net magnetizations of the Gd and Fe sublattices rapidly collapse, switch their direction and rebuild their net magnetic moments at substantially different timescales; the net magnetic moment of the Gd sublattice is found to reverse within 1.5 picoseconds, which is substantially slower than the Fe reversal time of 300 femtoseconds. Consequently, a transient state characterized by a temporary parallel alignment of the net Gd and Fe moments emerges, despite their ground-state antiferromagnetic coupling. These surprising observations, supported by atomistic simulations, provide a concept for the possibility of manipulating magnetic order on the timescale of the exchange interaction.

Signal integration in the control of shoot branching.

Abstract: Shoot branching is a highly plastic developmental process in which axillary buds are formed in the axil of each leaf and may subsequently be activated to give branches. Three classes of plant hormones, auxins, cytokinins and strigolactones (or strigolactone derivatives) are central to the control of bud activation. These hormones move throughout the plant forming a network of systemic signals. The past decade brought great progress in understanding the mechanisms of shoot branching control. Biological and computational studies have led to the proposal of two models, the auxin transport canalization-based model and the second messenger model, which provide mechanistic explanations for apical dominance.

Species-specific responses of Late Quaternary megafauna to climate and humans

Abstract: Despite decades of research, the roles of climate and humans in driving the dramatic extinctions of large-bodied mammals during the Late Quaternary period remain contentious. Here we use ancient DNA, species distribution models and the human fossil record to elucidate how climate and humans shaped the demographic history of woolly rhinoceros, woolly mammoth, wild horse, reindeer, bison and musk ox. We show that climate has been a major driver of population change over the past 50,000 years. However, each species responds differently to the effects of climatic shifts, habitat redistribution and human encroachment. Although climate change alone can explain the extinction of some species, such as Eurasian musk ox and woolly rhinoceros, a combination of climatic and anthropogenic effects appears to be responsible for the extinction of others, including Eurasian steppe bison and wild horse. We find no genetic signature or any distinctive range dynamics distinguishing extinct from surviving species, emphasizing the challenges associated with predicting future responses of extant mammals to climate and human-mediated habitat change.

Short-Term Music Training Enhances Verbal Intelligence and Executive Function

Abstract: Researchers have designed training methods that can be used to improve mental health and to test the efficacy of education programs. However, few studies have demonstrated broad transfer from such training to performance on untrained cognitive activities. Here we report the effects of two interactive computerized training programs developed for preschool children: one for music and one for visual art. After only 20 days of training, only children in the music group exhibited enhanced performance on a measure of verbal intelligence, with 90% of the sample showing this improvement. These improvements in verbal intelligence were positively correlated with changes in functional brain plasticity during an executive-function task. Our findings demonstrate that transfer of a high-level cognitive skill is possible in early childhood.

Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network.

Abstract: Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network

Height-diameter allometry of tropical forest trees

Abstract: . Tropical tree height-diameter (H:D) relationships may vary by forest type and region making large-scale estimates of above-ground biomass subject to bias if they ignore these differences in stem allometry. We have therefore developed a new global tropical forest database consisting of 39 955 concurrent H and D measurements encompassing 283 sites in 22 tropical countries. Utilising this database, our objectives were: 1. to determine if H:D relationships differ by geographic region and forest type (wet to dry forests, including zones of tension where forest and savanna overlap). 2. to ascertain if the H:D relationship is modulated by climate and/or forest structural characteristics (e.g. stand-level basal area, A). 3. to develop H:D allometric equations and evaluate biases to reduce error in future local-to-global estimates of tropical forest biomass. Annual precipitation coefficient of variation (PV), dry season length (SD), and mean annual air temperature (TA) emerged as key drivers of variation in H:D relationships at the pantropical and region scales. Vegetation structure also played a role with trees in forests of a high A being, on average, taller at any given D. After the effects of environment and forest structure are taken into account, two main regional groups can be identified. Forests in Asia, Africa and the Guyana Shield all have, on average, similar H:D relationships, but with trees in the forests of much of the Amazon Basin and tropical Australia typically being shorter at any given D than their counterparts elsewhere. The region-environment-structure model with the lowest Akaike's information criterion and lowest deviation estimated stand-level H across all plots to within amedian −2.7 to 0.9% of the true value. Some of the plot-to-plot variability in H:D relationships not accounted for by this model could be attributed to variations in soil physical conditions. Other things being equal, trees tend to be more slender in the absence of soil physical constraints, especially at smaller D. Pantropical and continental-level models provided less robust estimates of H, especially when the roles of climate and stand structure in modulating H:D allometry were not simultaneously taken into account.

Habitat microclimates drive fine‐scale variation in extreme temperatures

Abstract: Most multicellular terrestrial organisms experience climate at scales of millimetres to metres, yet most species-climate associations are analysed at resolutions of kilometres or more. Because individuals experience heterogeneous microclimates in the landscape, species sometimes survive where the average background climate appears unsuitable, and equally may be eliminated from sites within apparently suitable grid cells where microclimatic extremes are intolerable. Local vegetation structure and topography can be important determinants of fine-resolution microclimate, but a literature search revealed that the vast majority of bioclimate studies do not include fine-scale habitat information, let alone a representation of how habitat affects microclimate. In this paper, we show that habitat type (grassland, heathland, deciduous woodland) is a major modifier of the temperature extremes experienced by organisms. We recorded differences among these habitats of more than 5°C in monthly temperature maxima and minima, and of 10°C in thermal range, on a par with the level of warming expected for extreme future climate change scenarios. Comparable differences were found in relation to variation in local topography (slope and aspect). Hence, we argue that the microclimatic effects of habitat and topography must be included in studies if we are to obtain sufficiently detailed projections of the ecological impacts of climate change to develop detailed adaptation strategies for the conservation of biodiversity.

Strigolactones Are Transported through the Xylem and Play a Key Role in Shoot Architectural Response to Phosphate Deficiency in Nonarbuscular Mycorrhizal Host Arabidopsis

Abstract: The biosynthesis of the recently identified novel class of plant hormones, strigolactones, is up-regulated upon phosphate deficiency in many plant species. It is generally accepted that the evolutionary origin of strigolactone up-regulation is their function as a rhizosphere signal that stimulates hyphal branching of arbuscular mycorrhizal fungi. In this work, we demonstrate that this induction is conserved in Arabidopsis (Arabidopsis thaliana), although Arabidopsis is not a host for arbuscular mycorrhizal fungi. We demonstrate that the increase in strigolactone production contributes to the changes in shoot architecture observed in response to phosphate deficiency. Using high-performance liquid chromatography, column chromatography, and multiple reaction monitoring-liquid chromatography-tandem mass spectrometry analysis, we identified two strigolactones (orobanchol and orobanchyl acetate) in Arabidopsis and have evidence of the presence of a third (5-deoxystrigol). We show that at least one of them (orobanchol) is strongly reduced in the putative strigolactone biosynthetic mutants more axillary growth1 (max1) and max4 but not in the signal transduction mutant max2. Orobanchol was also detected in xylem sap and up-regulated under phosphate deficiency, which is consistent with the idea that root-derived strigolactones are transported to the shoot, where they regulate branching. Moreover, two additional putative strigolactone-like compounds were detected in xylem sap, one of which was not detected in root exudates. Together, these results show that xylem-transported strigolactones contribute to the regulation of shoot architectural response to phosphate-limiting conditions.

Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes.

Abstract: Brain glucose metabolism is impaired in Alzheimer's disease (AD), the most common form of dementia. Type 2 diabetes mellitus (T2DM) is reported to increase the risk for dementia, including AD, but the underlying mechanism is not understood. Here, we investigated the brain insulin-PI3K-AKT signalling pathway in the autopsied frontal cortices from nine AD, 10 T2DM, eight T2DM-AD and seven control cases. We found decreases in the levels and activities of several components of the insulin-PI3K-AKT signalling pathway in AD and T2DM cases. The deficiency of insulin-PI3K-AKT signalling was more severe in individuals with both T2DM and AD (T2DM-AD). This decrease in insulin-PI3K-AKT signalling could lead to activation of glycogen synthase kinase-3β, the major tau kinase. The levels and the activation of the insulin-PI3K-AKT signalling components correlated negatively with the level of tau phosphorylation and positively with protein O-GlcNAcylation, suggesting that impaired insulin-PI3K-AKT signalling might contribute to neurodegeneration in AD through down-regulation of O-GlcNAcylation and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration. The decrease in brain insulin-PI3K-AKT signalling also correlated with the activation of calpain I in the brain, suggesting that the decrease might be caused by calpain over-activation. Our findings provide novel insight into the molecular mechanism by which type 2 diabetes mellitus increases the risk for developing cognitive impairment and dementia in Alzheimer's disease.

The Neural Organization of Semantic Control: TMS Evidence for a Distributed Network in Left Inferior Frontal and Posterior Middle Temporal Gyrus

Abstract: Assigning meaning to words, sounds, and objects requires stored conceptual knowledge plus executive mechanisms that shape semantic retrieval according to the task or context. Despite the essential role of control in semantic cognition, its neural basis remains unclear. Neuroimaging and patient research has emphasized the importance of left inferior frontal gyrus (IFG)—however, impaired semantic control can also follow left temporoparietal lesions, suggesting that this function may be underpinned by a large-scale cortical network. We used repetitive transcranial magnetic stimulation in healthy volunteers to disrupt processing within 2 potential sites in this network—IFG and posterior middle temporal cortex. Stimulation of both sites selectively disrupted executively demanding semantic judgments: semantic decisions based on strong automatic associations were unaffected. Performance was also unchanged in nonsemantic tasks—irrespective of their executive demands—and following stimulation of a control site. These results reveal that an extended network of prefrontal and posterior temporal regions underpins semantic control.

Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review

Abstract: Non-opioid analgesics, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), or cyclo-oxygenase 2 (COX-2) inhibitors are often given along with morphine as part of multimodal analgesia after major surgery. We have undertaken a systematic review and a mixed treatment comparison (MTC) analysis in order to determine explicitly which class of non-opioid analgesic, paracetamol, NSAIDs, or COX-2 inhibitors is the most effective in reducing morphine consumption and morphine-related adverse effects. Sixty relevant studies were identified. The MTC found that when paracetamol, NSAIDs, or COX-2 inhibitors were added to patient-controlled analgesia (PCA) morphine, there was a statistically significant reduction in morphine consumption: paracetamol [mean difference (MD) -6.34 mg; 95% credibility interval (CrI) -9.02, -3.65], NSAIDs (MD -10.18; 95% CrI -11.65, -8.72), and COX-2 inhibitors (MD -10.92; 95% CrI -12.77, -9.08). There was a significant reduction in nausea and postoperative nausea and vomiting with NSAIDs compared with placebo (odds ratio 0.70; 95% CrI 0.53, 0.88) but not for paracetamol or COX-2 inhibitors, nor for NSAIDs compared with paracetamol or COX-2 inhibitors. There was no statistically significant difference in sedation between any intervention and comparator. On the basis of six trials (n=695), 2.4% of participants receiving an NSAID experienced surgical-related bleeding compared with 0.4% with placebo. The MTC found that there is a decrease in 24 h morphine consumption when paracetamol, NSAID, or COX-2 inhibitors are given in addition to PCA morphine after surgery, with no clear difference between them. Similarly, the benefits in terms of reduction in morphine-related adverse effects do not strongly favour one of the three non-opioid analgesics.

Distinct seasonal assemblages of arbuscular mycorrhizal fungi revealed by massively parallel pyrosequencing

Abstract: • Understanding the dynamics of rhizosphere microbial communities is essential for predicting future ecosystem function, yet most research focuses on either spatial or temporal processes, ignoring combined spatio-temporal effects. • Using pyrosequencing, we examined the spatio-temporal dynamics of a functionally important community of rhizosphere microbes, the arbuscular mycorrhizal (AM) fungi. We sampled AM fungi from plant roots growing in a temperate grassland in a spatially explicit manner throughout a year. • Ordination analysis of the AM fungal assemblages revealed significant temporal changes in composition and structure. Alpha and beta diversity tended to be negatively correlated with the climate variables temperature and sunshine hours. Higher alpha diversity during colder periods probably reflects more even competitive interactions among AM fungal species under limited carbon availability, a conclusion supported by analysis of beta diversity which highlights how resource limitation may change localized spatial dynamics. • Results reveal distinct AM fungal assemblages in winter and summer at this grassland site. A seasonally changing supply of host-plant carbon, reflecting changes in temperature and sunshine hours, may be the driving force in regulating the temporal dynamics of AM fungal communities. Climate change effects on seasonal temperatures may therefore substantially alter future AM fungal community dynamics and ecosystem functioning.

C-F and C-H bond activation of fluorobenzenes and fluoropyridines at transition metal centers: how fluorine tips the scales.

Abstract: In this Account, we describe the transition metal-mediated cleavage of C−F and C−H bonds in fluoroaromatic and fluoroheteroaromatic molecules.The simplest reactions of perfluoroarenes result in C−F oxida tive addition, but C−H activation competes with C−F activation for partially fluorinated molecules. We first consider the reactivity of the fluoroaromatics toward nickel and platinum complexes, but extend to rhenium and rhodium where they give special insight. Sections on spectroscopy and molecular structure are followed by discussions of energetics and mechanism that incorporate experimental and computational results. We highlight special characteristics of the metal−fluorine bond and the influence of the fluorine substituents on energetics and mechanism.Fluoroaromatics reacting at an ML2 center initially yield η2-arene complexes, followed usually by oxidative addition to generate MF(ArF)(L)2 or MH(ArF)(L)2 (M is Ni, Pd, or Pt; L is trialkylphosphine). The outcome of competition between C−F and C−H bond ...

An overview of reviews evaluating the effectiveness of financial incentives in changing healthcare professional behaviours and patient outcomes

Abstract: Background There is considerable interest in the effectiveness of financial incentives in the delivery of health care. Incentives may be used in an attempt to increase the use of evidence-based treatments among healthcare professionals or to stimulate health professionals to change their clinical behaviour with respect to preventive, diagnostic and treatment decisions, or both. Financial incentives are an extrinsic source of motivation and exist when an individual can expect a monetary transfer which is made conditional on acting in a particular way. Since there are numerous reviews performed within the healthcare area describing the effects of various types of financial incentives, it is important to summarise the effectiveness of these in an overview to discern which are most effective in changing health professionals' behaviour and patient outcomes. Objectives To conduct an overview of systematic reviews that evaluates the impact of financial incentives on healthcare professional behaviour and patient outcomes. Methods We searched the Cochrane Database of Systematic Reviews (CDSR) (The Cochrane Library); Database of Abstracts of Reviews of Effectiveness (DARE); TRIP; MEDLINE; EMBASE; Science Citation Index; Social Science Citation Index; NHS EED; HEED; EconLit; and Program in Policy Decision-Making (PPd) (from their inception dates up to January 2010). We searched the reference lists of all included reviews and carried out a citation search of those papers which cited studies included in the review. We included both Cochrane and non-Cochrane reviews of randomised controlled trials (RCTs), controlled clinical trials (CCTs), interrupted time series (ITSs) and controlled before and after studies (CBAs) that evaluated the effects of financial incentives on professional practice and patient outcomes, and that reported numerical results of the included individual studies. Two review authors independently extracted data and assessed the methodological quality of each review according to the AMSTAR criteria. We included systematic reviews of studies evaluating the effectiveness of any type of financial incentive. We grouped financial incentives into five groups: payment for working for a specified time period; payment for each service, episode or visit; payment for providing care for a patient or specific population; payment for providing a pre-specified level or providing a change in activity or quality of care; and mixed or other systems. We summarised data using vote counting. Main results We identified four reviews reporting on 32 studies. Two reviews scored 7 on the AMSTAR criteria (moderate, score 5 to 7, quality) and two scored 9 (high, score 8 to 11, quality). The reported quality of the included studies was, by a variety of methods, low to moderate. Payment for working for a specified time period was generally ineffective, improving 3/11 outcomes from one study reported in one review. Payment for each service, episode or visit was generally effective, improving 7/10 outcomes from five studies reported in three reviews; payment for providing care for a patient or specific population was generally effective, improving 48/69 outcomes from 13 studies reported in two reviews; payment for providing a pre-specified level or providing a change in activity or quality of care was generally effective, improving 17/20 reported outcomes from 10 studies reported in two reviews; and mixed and other systems were of mixed effectiveness, improving 20/31 reported outcomes from seven studies reported in three reviews. When looking at the effect of financial incentives overall across categories of outcomes, they were of mixed effectiveness on consultation or visit rates (improving 10/17 outcomes from three studies in two reviews); generally effective in improving processes of care (improving 41/57 outcomes from 19 studies in three reviews); generally effective in improving referrals and admissions (improving 11/16 outcomes from 11 studies in four reviews); generally ineffective in improving compliance with guidelines outcomes (improving 5/17 outcomes from five studies in two reviews); and generally effective in improving prescribing costs outcomes (improving 28/34 outcomes from 10 studies in one review). Authors' conclusions Financial incentives may be effective in changing healthcare professional practice. The evidence has serious methodological limitations and is also very limited in its completeness and generalisability. We found no evidence from reviews that examined the effect of financial incentives on patient outcomes.

A first-principles predictive model of the pedestal height and width: development, testing and ITER optimization with the EPED model

Abstract: We develop and test a model, EPED1.6, for the H-mode pedestal height and width based upon two fundamental and calculable constraints: (1) onset of non-local peeling–ballooning modes at low to intermediate mode number, (2) onset of nearly local kinetic ballooning modes at high mode number. Calculation of these two constraints allows a unique, predictive determination of both pedestal height and width. The present version of the model is first principles, in that no parameters are fit to observations, and includes important non-ideal effects. Extensive successful comparisons with existing experiments on multiple tokamaks, including experiments where predictions were made prior to the experiment, are presented, and predictions for ITER are discussed.

Response-Time Analysis for Mixed Criticality Systems

Abstract: Many safety-critical embedded systems are subject to certification requirements. However, only a subset of the functionality of the system may be safety-critical and hence subject to certification, the rest of the functionality is non safety-critical and does not need to be certified, or is certified to a lower level. The resulting mixed criticality system offers challenges both for static schedulability analysis and run-time monitoring. This paper considers a novel implementation scheme for fixed priority uniprocessor scheduling of mixed criticality systems. The scheme requires that jobs have their execution times monitored (as is usually the case in high integrity systems). An optimal priority assignment scheme is derived and sufficient response-time analysis is provided. The new scheme formally dominates those previously published. Evaluations illustrate the benefits of the scheme.

Impacts of anthropogenic activity on the ecology of class 1 integrons and integron-associated genes in the environment

Abstract: The impact of human activity on the selection for antibiotic resistance in the environment is largely unknown, although considerable amounts of antibiotics are introduced through domestic wastewater and farm animal waste. Selection for resistance may occur by exposure to antibiotic residues or by co-selection for mobile genetic elements (MGEs) which carry genes of varying activity. Class 1 integrons are genetic elements that carry antibiotic and quaternary ammonium compound (QAC) resistance genes that confer resistance to detergents and biocides. This study aimed to investigate the prevalence and diversity of class 1 integron and integron-associated QAC resistance genes in bacteria associated with industrial waste, sewage sludge and pig slurry. We show that prevalence of class 1 integrons is higher in bacteria exposed to detergents and/or antibiotic residues, specifically in sewage sludge and pig slurry compared with agricultural soils to which these waste products are amended. We also show that QAC resistance genes are more prevalent in the presence of detergents. Studies of class 1 integron prevalence in sewage sludge amended soil showed measurable differences compared with controls. Insertion sequence elements were discovered in integrons from QAC contaminated sediment, acting as powerful promoters likely to upregulate cassette gene expression. On the basis of this data, >1 × 1019 bacteria carrying class 1 integrons enter the United Kingdom environment by disposal of sewage sludge each year.