Reducing alcohol intake.

Alcohol is second in importance only to smoking as a proved cause of cancer. The risk associated with excessive alcohol consumption can be reduced by adopting national and local population based policies. The population approach is aimed at reducing the level of consumption across the whole population, which contains many modest drinkers. Underlying this approach is the fact that a larger proportion of the total morbidity and mortality attributed to alcohol in a population occurs in modest drinkers, even though individually they are at lower risk. This approach should be complemented by risk reduction initiatives in primary care, focused on high risk individuals. Several studies have shown the efficacy of brief interventions by general practitioners in patients with excessive alcohol consumption. Brief interventions, taking 5 to 10 minutes, use simple assessments to identify those at risk and provide information and advice. Evidence exists that general practitioners underuse opportunities to identify and advise patients about excessive drinking.     

A cluster randomized controlled trial aimed at implementation of local quality improvement collaboratives to improve prescribing and test ordering performance of general practitioners: Study Protocol

Background

The use of guidelines in general practice is not optimal. Although evidence-based methods to improve guideline adherence are available, variation in physician adherence to general practice guidelines remains relatively high. The objective for this study is to transfer a quality improvement strategy based on audit, feedback, educational materials, and peer group discussion moderated by local opinion leaders to the field. The research questions are: is the multifaceted strategy implemented on a large scale as planned?; what is the effect on general practitioners' (GPs) test ordering and prescribing behaviour?; and what are the costs of implementing the strategy?

Methods

In order to evaluate the effects, costs and feasibility of this new strategy we plan a multi-centre cluster randomized controlled trial (RCT) with a balanced incomplete block design. Local GP groups in the south of the Netherlands already taking part in pharmacotherapeutic audit meeting groups, will be recruited by regional health officers. Approximately 50 groups of GPs will be randomly allocated to two arms. These GPs will be offered two different balanced sets of clinical topics. Each GP within a group will receive comparative feedback on test ordering and prescribing performance. The feedback will be discussed in the group and working agreements will be created after discussion of the guidelines and barriers to change. The data for the feedback will be collected from existing and newly formed databases, both at baseline and after one year.

Discussion

We are not aware of published studies on successes and failures of attempts to transfer to the stakeholders in the field a multifaceted strategy aimed at GPs' test ordering and prescribing behaviour. This pragmatic study will focus on compatibility with existing infrastructure, while permitting a certain degree of adaptation to local needs and routines.

Trial registration

Nederlands Trial Register ISRCTN40008171     

Signs of stabilisation and stable coexistence

Many empirical studies motivated by an interest in stable coexistence have quantified negative density dependence, negative frequency dependence, or negative plant–soil feedback, but the links between these empirical results and ecological theory are not straightforward. Here, we relate these analyses to theoretical conditions for stabilisation and stable coexistence in classical competition models. By stabilisation, we mean an excess of intraspecific competition relative to interspecific competition that inherently slows or even prevents competitive exclusion. We show that most, though not all, tests demonstrating negative density dependence, negative frequency dependence, and negative plant–soil feedback constitute sufficient conditions for stabilisation of two‐species interactions if applied to data for per capita population growth rates of pairs of species, but none are necessary or sufficient conditions for stable coexistence of two species. Potential inferences are even more limited when communities involve more than two species, and when performance is measured at a single life stage or vital rate. We then discuss two approaches that enable stronger tests for stable coexistence‐invasibility experiments and model parameterisation. The model parameterisation approach can be applied to typical density‐dependence, frequency‐dependence, and plant–soil feedback data sets, and generally enables better links with mechanisms and greater insights, as demonstrated by recent studies.     

Program and feedback in the systems organization of a motor act

After simultaneous visual dereceptation, aimed jumps in cats, reinforced by electric shocks, are restored, while those with food reward are irreversibly lost. Yet, after a two-stage dereceptation, the aimed jumps reappeared even in case when they had food reinforcement. The adequacy of their performance depended on the stability of the distance between the starting sites. The possibility of local cortical control of motor units was demonstrated which is considered as a component of the general mechanism of urgent identification of the motor system state, via somatic afferent pathways. The ablation of their higher link (the medial lemniscus) at the level where it enters the thalamus, disturbs the biomechanics of the aimed jump, increasing the number of multisensory responses of single sensorimotor cortical units. It is suggested that the motivation and the program of the movement corrected by feedback, provide for its adaptive character.     

Group adaptation, formal darwinism and contextual analysis

We consider the question: under what circumstances can the concept of adaptation be applied to groups, rather than individuals? Gardner and Grafen (2009, J. Evol. Biol. 22 : 659–671) develop a novel approach to this question, building on Grafen's ‘formal Darwinism’ project, which defines adaptation in terms of links between evolutionary dynamics and optimization. They conclude that only clonal groups, and to a lesser extent groups in which reproductive competition is repressed, can be considered as adaptive units. We re‐examine the conditions under which the selection–optimization links hold at the group level. We focus on an important distinction between two ways of understanding the links, which have different implications regarding group adaptationism. We show how the formal Darwinism approach can be reconciled with G.C. Williams’ famous analysis of group adaptation, and we consider the relationships between group adaptation, the Price equation approach to multi‐level selection, and the alternative approach based on contextual analysis.     

How valuable is feedback of information on hospital referral patterns?

OBJECTIVES--To determine general practitioners'' responses to and explanations for variation in rates of referral to hospital and how feedback of data on rates of referral could be used to facilitate practices in auditing their own referral behaviour. DESIGN--Visits by audit facilitators to general practices after feedback of details of rates of referral to hospital derived from annual reports in general practice. SETTING--92 general practices in East Anglia. RESULTS--General practitioners judged that access to specialist care, the individual skill of general practitioners, patient demand, and fear of litigation were major determinants of referral behaviour. Because there was widespread scepticism about the accuracy of the data on which the feedback was based and because there is no clear relation between rates of referral and quality of care, it was extremely difficult to encourage doctors to use the feedback as a basis for auditing their own hospital referrals. CONCLUSION--If general practitioners are to contribute meaningfully to monitoring future changes in referral patterns it will be essential to develop reliable information systems in which doctors have confidence. Furthermore, audits need to be based on analysis of clinical cases rather than on rates of referral.     

Effect of feedback on test ordering behaviour of general practitioners.

OBJECTIVE--To assess the effect of feedback on the test ordering behaviour of general practitioners. DESIGN--Comparison of requests at two diagnostic centres, and internal comparison between tests which were discussed in feedback and tests which were not. SETTING--A diagnostic centre in Maastricht giving feedback and another elsewhere in the Netherlands (laboratory A) not giving feedback. SUBJECTS--All 85 general practitioners in the region of Maastricht, and all general practitioners in the region of laboratory A. MAIN OUTCOME MEASURES--Numbers of tests requested by general practitioners. RESULTS--Requests at the Maastricht diagnostic centre decreased soon after the onset of feedback whereas there was a persistent increase in requests at laboratory A. Tests that were discussed showed the strongest decrease (maximum 40%), though tests that were not discussed decreased as well (maximum 27%). CONCLUSIONS--Feedback on diagnostic requests may exert a strong influence on request behaviour. Four years after the onset of feedback the effects were still noticeable.     

Large-scale network models of IL-1 and IL-6 signalling and their hepatocellular specification

The pro-inflammatory cytokines interleukin 1 (IL-1) and 6 (IL-6) are crucially involved in the regulation of a multitude of physiological processes, in particular coordinating the immune response upon bacterial infection and tissue injury. Both interleukins induce complex signalling cascades and trigger the production of mitogenic, pro-proliferative, anti-apoptotic, chemotactic, and pro-angiogenic factors thereby affecting the delicate balance between regeneration vs. invasive growth, tumourigenesis and metastasis. Moreover, several links to insulin resistance have been found within their associated signalling networks. Focusing on this from a systems biology perspective, we introduce comprehensive large-scale network models of IL-1 and IL-6 signalling which are based on a logical modelling approach and reflect the current biological knowledge. Theoretical network analysis enabled us to uncover general topological features and to make testable predictions on the stimulus-response behaviour of the networks. In this context, non-intuitive network-wide species dependencies as well as structures of regulatory feedback and feed-forward mechanisms could be characterised. By integrating high-throughput phosphoproteomic data from primary human hepatocytes we optimised the model structures to obtain models with high prediction accuracy for hepatocytes. Our model-based data analysis, for instance, suggested model modifications regarding (i) Akt contribution to IL-1-stimulated p38 MAPK activation and (ii) insignificant p38 MAPK activation in response to IL-6. In light of the presented results and in conjunction with the detailed model documentations, both models hold great potential for theoretical studies and practical applications.     

Formulating variable carrying capacity by exploring a resource dynamics-based feedback mechanism underlying the population growth models

Most of the population growth models comprise the concept of carrying capacity presume that a stable population would have a saturation level characteristic. This indicates that the population growth models have a common implicit feature of resource-limited growth, which contributes at a later stage of population growth by forming a numerical upper bound on the population size. However, a general underlying resource dynamics of the models has not been previously explored, which is the focus of present study. In this paper, we found that there exists a conservation of energy relationship comprising the terms of available resource and population density, jointly interpreted here as total available vital energy in a confined environment. We showed that this relationship determines a density-dependent functional form of relative population growth rate and consequently the parametric equations are in the form depending upon the population density, resource concentration, and time. Thus, the derived form of relative population growth rate is essentially a feedback type, i.e., updating parametric values for the corresponding population density. This resource dynamics-based feedback approach has been implemented for formulating variable carrying capacity in a confined environment. Particularly, at a constant resource replenishment rate, a density-dependent population growth equation similar to the classic logistic equation is derived, while one of the regulating factors of the underlying resource dynamics is that the resource consumption rate is directly proportional to the resource concentration. Likewise two other population growth equations similar to two known popular growth equations are derived based on this resource dynamics-based feedback approach. Using microcosm-derived data of fungus T. virens, we fitted one derived population growth model against the datasets, and concluded that this approach is practically implementable for studying a single population growth regulation in a confined environment.     

Dynamic model development for a continuous culture of Saccharomyces cerevisiae

The problem of dynamically modeling a chemostat is addressed. Using the results of continuous culture experiments for the growth of a strain of Saccharomyces cerevisiae on a glucose-limited medium, a general approach to developing dynamic models is discussed. The approach to develop and verify the model involves three different types of experiments: steady-state, dynamic step response, and feedback identification.     

Multiscale modeling of macromolecular conformational changes combining concepts from rigidity and elastic network theory

The development of a two-step approach for multiscale modeling of macromolecular conformational changes is based on recent developments in rigidity and elastic network theory. In the first step, static properties of the macromolecule are determined by decomposing the molecule into rigid clusters by using the graph-theoretical approach FIRST and an all-atom representation of the protein. In this way, rigid clusters are not limited to consist of residues adjacent in sequence or secondary structure elements as in previous studies. Furthermore, flexible links between rigid clusters are identified and can be modeled as such subsequently. In the second step, dynamical properties of the molecule are revealed by the rotations-translations of blocks approach (RTB) using an elastic network model representation of the coarse-grained protein. In this step, only rigid body motions are allowed for rigid clusters, whereas links between them are treated as fully flexible. The approach was tested on a data set of 10 proteins that showed conformational changes on ligand binding. For efficiency, coarse-graining the protein results in a remarkable reduction of memory requirements and computational times by factors of 9 and 27 on average and up to 25 and 125, respectively. For accuracy, directions and magnitudes of motions predicted by our approach agree well with experimentally determined ones, despite embracing in extreme cases >50% of the protein into one rigid cluster. In fact, the results of our method are in general comparable with when no or a uniform coarse-graining is applied; and the results are superior if the movement is dominated by loop or fragment motions. This finding indicates that explicitly distinguishing between flexible and rigid regions is advantageous when using a simplified protein representation in the second step. Finally, motions of atoms in rigid clusters are also well predicted by our approach, which points to the need to consider mobile protein regions in addition to flexible ones when modeling correlated motions.     

Detection of Deregulated Modules Using Deregulatory Linked Path

The identification of deregulated modules (such as induced by oncogenes) is a crucial step for exploring the pathogenic process of complex diseases. Most of the existing methods focus on deregulation of genes rather than the links of the path among them. In this study, we emphasize on the detection of deregulated links, and develop a novel and effective regulatory path-based approach in finding deregulated modules. Observing that a regulatory pathway between two genes might involve in multiple rather than a single path, we identify condition-specific core regulatory path (CCRP) to detect the significant deregulation of regulatory links. Using time-series gene expression, we define the regulatory strength within each gene pair based on statistical dependence analysis. The CCRPs in regulatory networks can then be identified using the shortest path algorithm. Finally, we derive the deregulated modules by integrating the differential edges (as deregulated links) of the CCRPs between the case and the control group. To demonstrate the effectiveness of our approach, we apply the method to expression data associated with different states of Human Epidermal Growth Factor Receptor 2 (HER2). The experimental results show that the genes as well as the links in the deregulated modules are significantly enriched in multiple KEGG pathways and GO biological processes, most of which can be validated to suffer from impact of this oncogene based on previous studies. Additionally, we find the regulatory mechanism associated with the crucial gene SNAI1 significantly deregulated resulting from the activation of HER2. Hence, our method provides not only a strategy for detecting the deregulated links in regulatory networks, but also a way to identify concerning deregulated modules, thus contributing to the target selection of edgetic drugs.     

Immunological characterization of multipotent mesenchymal stromal cells—The International Society for Cellular Therapy (ISCT) working proposal

Cultured mesenchymal stromal cells (MSCs) possess immune regulatory properties and are already used for clinical purposes, although preclinical data (both in vitro and in vivo in animal models) are not always homogeneous and unequivocal. However, the various MSC-based clinical approaches to treat immunological diseases would be significantly validated and strengthened by using standardized immune assays aimed at obtaining shared, reproducible and consistent data. Thus, the MSC Committee of the International Society for Cellular Therapy has decided to put forward for general discussion a working proposal for a standardized approach based on a critical view of literature data.     

The agro-production chain environmental management in the agricultural production-consumption chain

After promoting environmental certification of companies in a chain perspective (Udo de Haes & De Snoo, 1996) now the agro-production chain is worked out as a case study. The role of the different links in the chain, such as agricultural producers, processing industry, wholesale companies and retailers is discussed. Also the role of consumers and authorities is described. For every company in the chain the advantages of a company based approach will be a better image and a guaranteed-sale and/or supply. In comparison with a product based approach (ecolabelling) the steering forces in the agro-production chain will be the retailers and not the consumers. Because consumers only get information at company level the approach is less dependent on consumers behaviour in the shop.     

Linking genotypes to phenotypes and fitness: how mechanistic biology can inform molecular ecology

The accessibility of new genomic resources, high‐throughput molecular technologies and analytical approaches such as genome scans have made finding genes contributing to fitness variation in natural populations an increasingly feasible task. Once candidate genes are identified, we argue that it is necessary to take a mechanistic approach and work up through the levels of biological organization to fully understand the impacts of genetic variation at these candidate genes. We demonstrate how this approach provides testable hypotheses about the causal links among levels of biological organization, and assists in designing relevant experiments to test the effects of genetic variation on phenotype, whole‐organism performance capabilities and fitness. We review some of the research programs that have incorporated mechanistic approaches when examining naturally occurring genetic and phenotypic variation and use these examples to highlight the value of developing a comprehensive understanding of the relationship between genotype and fitness. We give suggestions to guide future research aimed at uncovering and understanding the genetic basis of adaptation and argue that further integration of mechanistic approaches will help molecular ecologists better understand the evolution of natural populations.     

Moving beyond the guild concept: developing a practical functional trait framework for terrestrial beetles

1. New logical and analytical frameworks for studying functional traits have led to major advances in plant and freshwater ecology at local and global scales. The ecological and taxonomic diversity of terrestrial adult beetles (Coleoptera) means that functional trait approaches should have considerable power to illuminate the function not only of these animals but also of the ecosystems in which they occur. 2. Even though the functional trait concept is not new in ecology, it is still plagued with inconsistencies in methodology and terminology. Plant‐based studies have shown that an integrated and relatively consistent functional trait approach facilitates comparisons between studies, and allows the full utility and predictive capacity of trait‐based approaches to be realised. 3. This review outlines a logical framework for adult beetle functional trait studies using uniform terminology and methodology similar to those used by plant ecologists. Beetle life‐history and ecomorphological trait studies are synthesised and it is shown that a combination of both is analogous to the functional trait approach. A general functional trait list for beetles and potential functional links is outlined, as are potential analysis approaches. A consistent functional trait approach, coupled with advances in molecular techniques, has the capability to provide deeper insights into beetle community assembly and how beetles impact ecosystems and will enable worldwide comparisons and predictions to be made.     

Is the attenuation effect on the ankle muscles activity from the EMG biofeedback generalized to – or compensated by – other lower limb muscles during standing?

Biofeedback based on electromyograms (EMGs) has been recently proposed to reduce exaggerated postural activity. Whether the effect of EMG biofeedback on the targeted muscles generalizes to – or is compensated by – other muscles is still an open question we address here. Fourteen young individuals were tested in three 60 s standing trials, without and with EMG-audio feedback: (i) collectively from soleus and medial gastrocnemius and (ii) from medial gastrocnemii. The Root Mean Square (RMS) of bipolar EMGs sampled from postural muscles bilaterally was computed to assess the degree of activity and postural sway was assessed from the center of pressure (CoP). In relation to standing at naturally, EMG-audio feedback from soleus and medial gastrocnemii decreased plantar flexors’ activity (∼10 %) but at the cost of increased amplitude of tibialis anterior (∼5%) and vasti muscles (∼20 %) accompanied by a posterior shift of the mean CoP position. However, EMG-audio feedback from medial gastrocnemii reduced only plantar flexors’ activity (∼5%) when compared to standing at naturally. Current results suggest the EMG biofeedback has the potential to reduce calf muscles’ activity without loading other postural muscles especially when using medial gastrocnemii as feedback source, with implications on postural training aimed at assisting individuals in activating more efficiently postural muscles during standing.     

Impact of Alien Plant Invaders on Pollination Networks in Two Archipelagos

Mutualistic interactions between plants and animals promote integration of invasive species into native communities. In turn, the integrated invaders may alter existing patterns of mutualistic interactions. Here we simultaneously map in detail effects of invaders on parameters describing the topology of both plant-pollinator (bi-modal) and plant-plant (uni-modal) networks. We focus on the invader Opuntia spp., a cosmopolitan alien cactus. We compare two island systems: Tenerife (Canary Islands) and Menorca (Balearic Islands). Opuntia was found to modify the number of links between plants and pollinators, and was integrated into the new communities via the most generalist pollinators, but did not affect the general network pattern. The plant uni-modal networks showed disassortative linkage, i.e. species with many links tended to connect to species with few links. Thus, by linking to generalist natives, Opuntia remained peripheral to network topology, and this is probably why native network properties were not affected at least in one of the islands. We conclude that the network analytical approach is indeed a valuable tool to evaluate the effect of invaders on native communities.     

Spatial guilds in the Serengeti food web revealed by a Bayesian group model

Food webs, networks of feeding relationships in an ecosystem, provide fundamental insights into mechanisms that determine ecosystem stability and persistence. A standard approach in food-web analysis, and network analysis in general, has been to identify compartments, or modules, defined by many links within compartments and few links between them. This approach can identify large habitat boundaries in the network but may fail to identify other important structures. Empirical analyses of food webs have been further limited by low-resolution data for primary producers. In this paper, we present a Bayesian computational method for identifying group structure using a flexible definition that can describe both functional trophic roles and standard compartments. We apply this method to a newly compiled plant-mammal food web from the Serengeti ecosystem that includes high taxonomic resolution at the plant level, allowing a simultaneous examination of the signature of both habitat and trophic roles in network structure. We find that groups at the plant level reflect habitat structure, coupled at higher trophic levels by groups of herbivores, which are in turn coupled by carnivore groups. Thus the group structure of the Serengeti web represents a mixture of trophic guild structure and spatial pattern, in contrast to the standard compartments typically identified. The network topology supports recent ideas on spatial coupling and energy channels in ecosystems that have been proposed as important for persistence. Furthermore, our Bayesian approach provides a powerful, flexible framework for the study of network structure, and we believe it will prove instrumental in a variety of biological contexts.