A modeling approach on why simple central pattern generators are built of irregular neurons.

PubMed

Reyes, Marcelo Bussotti; Carelli, Pedro Valadão; Sartorelli, José Carlos; Pinto, Reynaldo Daniel

2015-01-01

The crustacean pyloric Central Pattern Generator (CPG) is a nervous circuit that endogenously provides periodic motor patterns. Even after about 40 years of intensive studies, the rhythm genesis is still not rigorously understood in this CPG, mainly because it is made of neurons with irregular intrinsic activity. Using mathematical models we addressed the question of using a network of irregularly behaving elements to generate periodic oscillations, and we show some advantages of using non-periodic neurons with intrinsic behavior in the transition from bursting to tonic spiking (as found in biological pyloric CPGs) as building components. We studied two- and three-neuron model CPGs built either with Hindmarsh-Rose or with conductance-based Hodgkin-Huxley-like model neurons. By changing a model's parameter we could span the neuron's intrinsic dynamical behavior from slow periodic bursting to fast tonic spiking, passing through a transition where irregular bursting was observed. Two-neuron CPG, half center oscillator (HCO), was obtained for each intrinsic behavior of the neurons by coupling them with mutual symmetric synaptic inhibition. Most of these HCOs presented regular antiphasic bursting activity and the changes of the bursting frequencies was studied as a function of the inhibitory synaptic strength. Among all HCOs, those made of intrinsic irregular neurons presented a wider burst frequency range while keeping a reliable regular oscillatory (bursting) behavior. HCOs of periodic neurons tended to be either hard to change their behavior with synaptic strength variations (slow periodic burster neurons) or unable to perform a physiologically meaningful rhythm (fast tonic spiking neurons). Moreover, 3-neuron CPGs with connectivity and output similar to those of the pyloric CPG presented the same results.

Flight and Walking in Locusts–Cholinergic Co-Activation, Temporal Coupling and Its Modulation by Biogenic Amines

PubMed Central

Rillich, Jan; Stevenson, Paul A.; Pflueger, Hans-Joachim

2013-01-01

Walking and flying in locusts are exemplary rhythmical behaviors generated by central pattern generators (CPG) that are tuned in intact animals by phasic sensory inputs. Although these two behaviors are mutually exclusive and controlled by independent CPGs, leg movements during flight can be coupled to the flight rhythm. To investigate potential central coupling between the underlying CPGs, we used the muscarinic agonist pilocarpine and the amines octopamine and tyramine to initiate fictive flight and walking in deafferented locust preparations. Our data illustrate that fictive walking is readily evoked by comparatively lower concentrations of pilocarpine, whereas higher concentrations are required to elicit fictive flight. Interestingly, fictive flight did not suppress fictive walking so that the two patterns were produced simultaneously. Frequently, leg motor units were temporally coupled to the flight rhythm, so that each spike in a step cycle volley occurred synchronously with wing motor units firing at flight rhythm frequency. Similarly, tyramine also induced fictive walking and flight, but mostly without any coupling between the two rhythms. Octopamine in contrast readily evoked fictive flight but generally failed to elicit fictive walking. Despite this, numerous leg motor units were recruited, whereby each was temporarily coupled to the flight rhythm. Our results support the notion that the CPGs for walking and flight are largely independent, but that coupling can be entrained by aminergic modulation. We speculate that octopamine biases the whole motor machinery of a locust to flight whereas tyramine primarily promotes walking. PMID:23671643

Development of clinical practice guidelines.

PubMed

Hollon, Steven D; Areán, Patricia A; Craske, Michelle G; Crawford, Kermit A; Kivlahan, Daniel R; Magnavita, Jeffrey J; Ollendick, Thomas H; Sexton, Thomas L; Spring, Bonnie; Bufka, Lynn F; Galper, Daniel I; Kurtzman, Howard

2014-01-01

Clinical practice guidelines (CPGs) are intended to improve mental, behavioral, and physical health by promoting clinical practices that are based on the best available evidence. The American Psychological Association (APA) is committed to generating patient-focused CPGs that are scientifically sound, clinically useful, and informative for psychologists, other health professionals, training programs, policy makers, and the public. The Institute of Medicine (IOM) 2011 standards for generating CPGs represent current best practices in the field. These standards involve multidisciplinary guideline development panels charged with generating recommendations based on comprehensive systematic reviews of the evidence. The IOM standards will guide the APA as it generates CPGs that can be used to inform the general public and the practice community regarding the benefits and harms of various treatment options. CPG recommendations are advisory rather than compulsory. When used appropriately, high-quality guidelines can facilitate shared decision making and identify gaps in knowledge.

Preclinical evidence supporting the clinical development of central pattern generator-modulating therapies for chronic spinal cord-injured patients

PubMed Central

2014-01-01

Ambulation or walking is one of the main gaits of locomotion. In terrestrial animals, it may be defined as a series of rhythmic and bilaterally coordinated movement of the limbs which creates a forward movement of the body. This applies regardless of the number of limbs—from arthropods with six or more limbs to bipedal primates. These fundamental similarities among species may explain why comparable neural systems and cellular properties have been found, thus far, to control in similar ways locomotor rhythm generation in most animal models. The aim of this article is to provide a comprehensive review of the known structural and functional features associated with central nervous system (CNS) networks that are involved in the control of ambulation and other stereotyped motor patterns—specifically Central Pattern Generators (CPGs) that produce basic rhythmic patterned outputs for locomotion, micturition, ejaculation, and defecation. Although there is compelling evidence of their existence in humans, CPGs have been most studied in reduced models including in vitro isolated preparations, genetically-engineered mice and spinal cord-transected animals. Compared with other structures of the CNS, the spinal cord is generally considered as being well-preserved phylogenetically. As such, most animal models of spinal cord-injured (SCI) should be considered as valuable tools for the development of novel pharmacological strategies aimed at modulating spinal activity and restoring corresponding functions in chronic SCI patients. PMID:24910602

Epigenome-wide DNA methylation analysis in siblings and monozygotic twins discordant for sporadic Parkinson's disease revealed different epigenetic patterns in peripheral blood mononuclear cells.

PubMed

Kaut, Oliver; Schmitt, Ina; Tost, Jörg; Busato, Florence; Liu, Yi; Hofmann, Per; Witt, Stephanie H; Rietschel, Marcella; Fröhlich, Holger; Wüllner, Ullrich

2017-01-01

Numerous studies have elucidated the genetics of Parkinson's disease; however, the aetiology of the majority of sporadic cases has not yet been resolved. We hypothesized that epigenetic variations could be associated with PD and evaluated the DNA methylation pattern in PD patients compared to brothers or twins without PD. The methylation of DNA from peripheral blood mononuclear cells of 62 discordant siblings including 24 monozygotic twins was characterized with Illumina DNA Methylation 450K bead arrays and subsequently validated in two independent cohorts: 221 PD vs. 227 healthy individuals (cohort 1) applying Illumina's VeraCode and 472 PD patients vs. 487 controls (cohort 2) using pyrosequencing. We choose a delta beta of >15 % and selected 62 differentially methylated CpGs in 51 genes from the discordant siblings. Among them, three displayed multiple CpGs per gene: microRNA 886 (MIR886, 10 CpGs), phosphodiesterase 4D (PDE4D, 2 CpGs) and tripartite motif-containing 34 (TRIM34, 2 CpGs). PDE4D was confirmed in both cohorts (p value 2.44e-05). In addition, for biomarker construction, we used the penalized logistic regression model, resulting in a signature of eight CpGs with an AUC of 0.77. Our findings suggest that a distinct level of PD susceptibility stems from individual, epigenetic modifications of specific genes. We identified a signature of CpGs in blood cells that could separate control from disease with a reasonable discriminatory power, holding promise for future epigenetically based biomarker development.

Comparison of extrinsic and intrinsic neuromodulation in two central pattern generator circuits in invertebrates.

PubMed

Katz, P S

1998-05-01

There are many sources of modulatory input to CPGs and other types of neuronal circuits. These inputs can change the properties of cells and synapses and dramatically alter the production of motor patterns. Sometimes this enables the production of motor patterns by the circuit. At other times, the modulation allows alternate motor patterns to be produced by a single circuit. Modulatory neurones have fast as well as slow actions. In some cases, such as with GPR, the two types of effects are due to the release of co-transmitters. In other cases, such as with the DSIs, a single substance can act at different receptors to cause fast and slow postsynaptic actions. The effect of a neuromodulatory neurone is determined by the type of receptor on the target neurone. Thus a single modulatory neurone evokes a suite of actions in a circuit and thereby produces a co-ordinated output. Extrinsic and intrinsic sources of neuromodulation have different sets of constraints acting upon them. For example, extrinsic neuromodulation can easily be used for motor pattern selection; a different pattern is produced depending upon which modulatory inputs are active. However, intrinsic neuromodulation is not well suited to that task. Instead, it is useful for self-organizing properties and experience-dependent effects. One clear conclusion from this work and other work in the field is that neuromodulation by neurones intrinsic and extrinsic to CPGs is not uncommon (Katz, 1995; Katz & Frost, 1996). It is part of the normal process of motor pattern generation. As such, it needs to be considered when discussing mechanisms for neuronal circuit actions.

Computer simulations of neural mechanisms explaining upper and lower limb excitatory neural coupling

PubMed Central

2010-01-01

Background When humans perform rhythmic upper and lower limb locomotor-like movements, there is an excitatory effect of upper limb exertion on lower limb muscle recruitment. To investigate potential neural mechanisms for this behavioral observation, we developed computer simulations modeling interlimb neural pathways among central pattern generators. We hypothesized that enhancement of muscle recruitment from interlimb spinal mechanisms was not sufficient to explain muscle enhancement levels observed in experimental data. Methods We used Matsuoka oscillators for the central pattern generators (CPG) and determined parameters that enhanced amplitudes of rhythmic steady state bursts. Potential mechanisms for output enhancement were excitatory and inhibitory sensory feedback gains, excitatory and inhibitory interlimb coupling gains, and coupling geometry. We first simulated the simplest case, a single CPG, and then expanded the model to have two CPGs and lastly four CPGs. In the two and four CPG models, the lower limb CPGs did not receive supraspinal input such that the only mechanisms available for enhancing output were interlimb coupling gains and sensory feedback gains. Results In a two-CPG model with inhibitory sensory feedback gains, only excitatory gains of ipsilateral flexor-extensor/extensor-flexor coupling produced reciprocal upper-lower limb bursts and enhanced output up to 26%. In a two-CPG model with excitatory sensory feedback gains, excitatory gains of contralateral flexor-flexor/extensor-extensor coupling produced reciprocal upper-lower limb bursts and enhanced output up to 100%. However, within a given excitatory sensory feedback gain, enhancement due to excitatory interlimb gains could only reach levels up to 20%. Interconnecting four CPGs to have ipsilateral flexor-extensor/extensor-flexor coupling, contralateral flexor-flexor/extensor-extensor coupling, and bilateral flexor-extensor/extensor-flexor coupling could enhance motor output up to 32%. Enhancement observed in experimental data exceeded 32%. Enhancement within this symmetrical four-CPG neural architecture was more sensitive to relatively small interlimb coupling gains. Excitatory sensory feedback gains could produce greater output amplitudes, but larger gains were required for entrainment compared to inhibitory sensory feedback gains. Conclusions Based on these simulations, symmetrical interlimb coupling can account for much, but not all of the excitatory neural coupling between upper and lower limbs during rhythmic locomotor-like movements. PMID:21143960

Identifying CpG sites associated with eczema via random forest screening of epigenome-scale DNA methylation.

PubMed

Quraishi, B M; Zhang, H; Everson, T M; Ray, M; Lockett, G A; Holloway, J W; Tetali, S R; Arshad, S H; Kaushal, A; Rezwan, F I; Karmaus, W

2015-01-01

The prevalence of eczema is increasing in industrialized nations. Limited evidence has shown the association of DNA methylation (DNA-M) with eczema. We explored this association at the epigenome-scale to better understand the role of DNA-M. Data from the first generation (F1) of the Isle of Wight (IoW) birth cohort participants and the second generation (F2) were examined in our study. Epigenome-scale DNA methylation of F1 at age 18 years and F2 in cord blood was measured using the Illumina Infinium HumanMethylation450 Beadchip. A total of 307,357 cytosine-phosphate-guanine sites (CpGs) in the F1 generation were screened via recursive random forest (RF) for their potential association with eczema at age 18. Functional enrichment and pathway analysis of resulting genes were carried out using DAVID gene functional classification tool. Log-linear models were performed in F1 to corroborate the identified CpGs. Findings in F1 were further replicated in F2. The recursive RF yielded 140 CpGs, 88 of which showed statistically significant associations with eczema at age 18, corroborated by log-linear models after controlling for false discovery rate (FDR) of 0.05. These CpGs were enriched among many biological pathways, including pathways related to creating transcriptional variety and pathways mechanistically linked to eczema such as cadherins, cell adhesion, gap junctions, tight junctions, melanogenesis, and apoptosis. In the F2 generation, about half of the 83 CpGs identified in F1 showed the same direction of association with eczema risk as in F1, of which two CpGs were significantly associated with eczema risk, cg04850479 of the PROZ gene (risk ratio (RR) = 15.1 in F1, 95 % confidence interval (CI) 1.71, 79.5; RR = 6.82 in F2, 95 % CI 1.52, 30.62) and cg01427769 of the NEU1 gene (RR = 0.13 in F1, 95 % CI 0.03, 0.46; RR = 0.09 in F2, 95 % CI 0.03, 0.36). Via epigenome-scaled analyses using recursive RF followed by log-linear models, we identified 88 CpGs associated with eczema in F1, of which 41 were replicated in F2. Several identified CpGs are located within genes in biological pathways relating to skin barrier integrity, which is central to the pathogenesis of eczema. Novel genes associated with eczema risk were identified (e.g., the PROZ and NEU1 genes).

Leveraging workflow control patterns in the domain of clinical practice guidelines.

PubMed

Kaiser, Katharina; Marcos, Mar

2016-02-10

Clinical practice guidelines (CPGs) include recommendations describing appropriate care for the management of patients with a specific clinical condition. A number of representation languages have been developed to support executable CPGs, with associated authoring/editing tools. Even with tool assistance, authoring of CPG models is a labor-intensive task. We aim at facilitating the early stages of CPG modeling task. In this context, we propose to support the authoring of CPG models based on a set of suitable procedural patterns described in an implementation-independent notation that can be then semi-automatically transformed into one of the alternative executable CPG languages. We have started with the workflow control patterns which have been identified in the fields of workflow systems and business process management. We have analyzed the suitability of these patterns by means of a qualitative analysis of CPG texts. Following our analysis we have implemented a selection of workflow patterns in the Asbru and PROforma CPG languages. As implementation-independent notation for the description of patterns we have chosen BPMN 2.0. Finally, we have developed XSLT transformations to convert the BPMN 2.0 version of the patterns into the Asbru and PROforma languages. We showed that although a significant number of workflow control patterns are suitable to describe CPG procedural knowledge, not all of them are applicable in the context of CPGs due to their focus on single-patient care. Moreover, CPGs may require additional patterns not included in the set of workflow control patterns. We also showed that nearly all the CPG-suitable patterns can be conveniently implemented in the Asbru and PROforma languages. Finally, we demonstrated that individual patterns can be semi-automatically transformed from a process specification in BPMN 2.0 to executable implementations in these languages. We propose a pattern and transformation-based approach for the development of CPG models. Such an approach can form the basis of a valid framework for the authoring of CPG models. The identification of adequate patterns and the implementation of transformations to convert patterns from a process specification into different executable implementations are the first necessary steps for our approach.

Mapping the zebrafish brain methylome using reduced representation bisulfite sequencing

PubMed Central

Chatterjee, Aniruddha; Ozaki, Yuichi; Stockwell, Peter A; Horsfield, Julia A; Morison, Ian M; Nakagawa, Shinichi

2013-01-01

Reduced representation bisulfite sequencing (RRBS) has been used to profile DNA methylation patterns in mammalian genomes such as human, mouse and rat. The methylome of the zebrafish, an important animal model, has not yet been characterized at base-pair resolution using RRBS. Therefore, we evaluated the technique of RRBS in this model organism by generating four single-nucleotide resolution DNA methylomes of adult zebrafish brain. We performed several simulations to show the distribution of fragments and enrichment of CpGs in different in silico reduced representation genomes of zebrafish. Four RRBS brain libraries generated 98 million sequenced reads and had higher frequencies of multiple mapping than equivalent human RRBS libraries. The zebrafish methylome indicates there is higher global DNA methylation in the zebrafish genome compared with its equivalent human methylome. This observation was confirmed by RRBS of zebrafish liver. High coverage CpG dinucleotides are enriched in CpG island shores more than in the CpG island core. We found that 45% of the mapped CpGs reside in gene bodies, and 7% in gene promoters. This analysis provides a roadmap for generating reproducible base-pair level methylomes for zebrafish using RRBS and our results provide the first evidence that RRBS is a suitable technique for global methylation analysis in zebrafish. PMID:23975027

Food and dietary pattern-based recommendations: an emerging approach to clinical practice guidelines for nutrition therapy in diabetes.

PubMed

Sievenpiper, John L; Dworatzek, Paula D N

2013-02-01

Clinical practice guidelines (CPGs) for the nutritional management of diabetes mellitus have evolved considerably over the last 25 years. As major diabetes associations have focussed on the individualization of nutrition therapy, there has been a move toward a broader more flexible macronutrient distribution that emphasizes macronutrient quality over quantity. There is now a call for the integration of food- and dietary pattern-based approaches into diabetes association CPGs. The main argument has been that an approach that focuses on nutrients alone misses important nutrient interactions oversimplifying the complexity of foods and dietary patterns, both of which have been shown to have a stronger influence on disease risk than nutrients alone. Although cancer and heart associations have begun to integrate this approach into their dietary guidelines, diabetes associations have not yet adopted this approach. We provide a rationale for the adoption of this approach for The Canadian Diabetes Association (CDA) 2013 CPGs for nutrition therapy. The systematic review for the development of these guidelines revealed emerging evidence to support the use of vegetarian, Mediterranean, and Dietary Approaches to Stop Hypertension (DASH) dietary patterns as well as specific foods such as dietary pulses and nuts in people with diabetes. Popular and conventional weight loss diets were also found to have similar advantages in people with diabetes, although poor dietary adherence remains an issue with these diets. The CDA 2013 CPGs will support an even greater individualization of nutrition therapy for people with diabetes and appeal to a broader range of practice styles of health professionals. Copyright © 2013 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

Physical activity, sedentary behaviour and sleep in COPD guidelines: A systematic review.

PubMed

Lewthwaite, Hayley; Effing, Tanja W; Olds, Timothy; Williams, Marie T

2017-08-01

Physical activity, sedentary and sleep behaviours have strong associations with health. This systematic review aimed to identify how clinical practice guidelines (CPGs) for the management of chronic obstructive pulmonary disease (COPD) report specific recommendations and strategies for these movement behaviours. A systematic search of databases (Medline, Scopus, CiNAHL, EMbase, Clinical Guideline), reference lists and websites identified current versions of CPGs published since 2005. Specific recommendations and strategies concerning physical activity, sedentary behaviour and sleep were extracted verbatim. The proportions of CPGs providing specific recommendations and strategies were reported. From 2370 citations identified, 35 CPGs were eligible for inclusion. Of these, 21 (60%) provided specific recommendations for physical activity, while none provided specific recommendations for sedentary behaviour or sleep. The most commonly suggested strategies to improve movement behaviours were encouragement from a healthcare provider (physical activity n = 20; sedentary behaviour n = 2) and referral for a diagnostic sleep study (sleep n = 4). Since optimal physical activity, sedentary behaviour and sleep durations and patterns are likely to be associated with mitigating the effects of COPD, as well as with general health and well-being, there is a need for further COPD-specific research, consensus and incorporation of recommendations and strategies into CPGs.

Fast Dynamical Coupling Enhances Frequency Adaptation of Oscillators for Robotic Locomotion Control

PubMed Central

Nachstedt, Timo; Tetzlaff, Christian; Manoonpong, Poramate

2017-01-01

Rhythmic neural signals serve as basis of many brain processes, in particular of locomotion control and generation of rhythmic movements. It has been found that specific neural circuits, named central pattern generators (CPGs), are able to autonomously produce such rhythmic activities. In order to tune, shape and coordinate the produced rhythmic activity, CPGs require sensory feedback, i.e., external signals. Nonlinear oscillators are a standard model of CPGs and are used in various robotic applications. A special class of nonlinear oscillators are adaptive frequency oscillators (AFOs). AFOs are able to adapt their frequency toward the frequency of an external periodic signal and to keep this learned frequency once the external signal vanishes. AFOs have been successfully used, for instance, for resonant tuning of robotic locomotion control. However, the choice of parameters for a standard AFO is characterized by a trade-off between the speed of the adaptation and its precision and, additionally, is strongly dependent on the range of frequencies the AFO is confronted with. As a result, AFOs are typically tuned such that they require a comparably long time for their adaptation. To overcome the problem, here, we improve the standard AFO by introducing a novel adaptation mechanism based on dynamical coupling strengths. The dynamical adaptation mechanism enhances both the speed and precision of the frequency adaptation. In contrast to standard AFOs, in this system, the interplay of dynamics on short and long time scales enables fast as well as precise adaptation of the oscillator for a wide range of frequencies. Amongst others, a very natural implementation of this mechanism is in terms of neural networks. The proposed system enables robotic applications which require fast retuning of locomotion control in order to react to environmental changes or conditions. PMID:28377710

Optimization of stable quadruped locomotion using mutual information

NASA Astrophysics Data System (ADS)

Silva, Pedro; Santos, Cristina P.; Polani, Daniel

2013-10-01

Central Pattern Generators (CPG)s have been widely used in the field of robotics to address the task of legged locomotion generation. The adequate configuration of these structures for a given platform can be accessed through evolutionary strategies, according to task dependent selection pressures. Information driven evolution, accounts for information theoretical measures as selection pressures, as an alternative to a fully task dependent selection pressure. In this work we exploit this concept and evaluate the use of mean Mutual Information, as a selection pressure towards a CPG configuration capable of faster, yet more coordinated and stabler locomotion than when only a task dependent selection pressure is used.

FPGA implementation of a configurable neuromorphic CPG-based locomotion controller.

PubMed

Barron-Zambrano, Jose Hugo; Torres-Huitzil, Cesar

2013-09-01

Neuromorphic engineering is a discipline devoted to the design and development of computational hardware that mimics the characteristics and capabilities of neuro-biological systems. In recent years, neuromorphic hardware systems have been implemented using a hybrid approach incorporating digital hardware so as to provide flexibility and scalability at the cost of power efficiency and some biological realism. This paper proposes an FPGA-based neuromorphic-like embedded system on a chip to generate locomotion patterns of periodic rhythmic movements inspired by Central Pattern Generators (CPGs). The proposed implementation follows a top-down approach where modularity and hierarchy are two desirable features. The locomotion controller is based on CPG models to produce rhythmic locomotion patterns or gaits for legged robots such as quadrupeds and hexapods. The architecture is configurable and scalable for robots with either different morphologies or different degrees of freedom (DOFs). Experiments performed on a real robot are presented and discussed. The obtained results demonstrate that the CPG-based controller provides the necessary flexibility to generate different rhythmic patterns at run-time suitable for adaptable locomotion. Copyright © 2013 Elsevier Ltd. All rights reserved.

Physical activity, sedentary behaviour and sleep in COPD guidelines: A systematic review

PubMed Central

Effing, Tanja W; Olds, Timothy; Williams, Marie T

2017-01-01

Objectives: Physical activity, sedentary and sleep behaviours have strong associations with health. This systematic review aimed to identify how clinical practice guidelines (CPGs) for the management of chronic obstructive pulmonary disease (COPD) report specific recommendations and strategies for these movement behaviours. Methods: A systematic search of databases (Medline, Scopus, CiNAHL, EMbase, Clinical Guideline), reference lists and websites identified current versions of CPGs published since 2005. Specific recommendations and strategies concerning physical activity, sedentary behaviour and sleep were extracted verbatim. The proportions of CPGs providing specific recommendations and strategies were reported. Results: From 2370 citations identified, 35 CPGs were eligible for inclusion. Of these, 21 (60%) provided specific recommendations for physical activity, while none provided specific recommendations for sedentary behaviour or sleep. The most commonly suggested strategies to improve movement behaviours were encouragement from a healthcare provider (physical activity n = 20; sedentary behaviour n = 2) and referral for a diagnostic sleep study (sleep n = 4). Conclusion: Since optimal physical activity, sedentary behaviour and sleep durations and patterns are likely to be associated with mitigating the effects of COPD, as well as with general health and well-being, there is a need for further COPD-specific research, consensus and incorporation of recommendations and strategies into CPGs. PMID:28774202

CPG-inspired workspace trajectory generation and adaptive locomotion control for quadruped robots.

PubMed

Liu, Chengju; Chen, Qijun; Wang, Danwei

2011-06-01

This paper deals with the locomotion control of quadruped robots inspired by the biological concept of central pattern generator (CPG). A control architecture is proposed with a 3-D workspace trajectory generator and a motion engine. The workspace trajectory generator generates adaptive workspace trajectories based on CPGs, and the motion engine realizes joint motion imputes. The proposed architecture is able to generate adaptive workspace trajectories online by tuning the parameters of the CPG network to adapt to various terrains. With feedback information, a quadruped robot can walk through various terrains with adaptive joint control signals. A quadruped platform AIBO is used to validate the proposed locomotion control system. The experimental results confirm the effectiveness of the proposed control architecture. A comparison by experiments shows the superiority of the proposed method against the traditional CPG-joint-space control method.

Multifunctional Nanostructured Conductive Polymer Gels: Synthesis, Properties, and Applications

DOE PAGES

Zhao, Fei; Shi, Ye; Pan, Lijia; ...

2017-06-26

Conductive polymers have attracted significant interest over the past few decades because they synergize the advantageous features of conventional polymeric materials and organic conductors. With rationally designed nanostructures, conductive polymers can further exhibit exceptional mechanical, electrical, and optical properties because of their confined dimensions at the nanoscale level. Among various nanostructured conductive polymers, conductive polymer gels (CPGs) with synthetically tunable hierarchical 3D network structures show great potential for a wide range of applications, such as bioelectronics, and energy storage/conversion devices owing to their structural features. CPGs retain the properties of nanosized conductive polymers during the assembly of the nanobuilding blocksmore » into a monolithic macroscopic structure while generating structure-derived features from the highly cross-linked network. In this Account, we review our recent progress on the synthesis, properties, and novel applications of dopant cross-linked CPGs. We first describe the synthetic strategies, in which molecules with multiple functional groups are adopted as cross-linkers to cross-link conductive polymer chains into a 3D molecular network. These cross-linking molecules also act as dopants to improve the electrical conductivity of the gel network. The microstructure and physical/chemical properties of CPGs can be tuned by controlling the synthetic conditions such as species of monomers and cross-linkers, reaction temperature, and solvents. By incorporating other functional polymers or particles into the CPG matrix, hybrid gels have been synthesized with tailored structures. These hybrid gel materials retain the functionalities from each component, as well as enable synergic effects to improve mechanical and electrical properties of CPGs. We then introduce the unique structure-derived properties of the CPGs. The network facilitates both electronic and ionic transport owing to the continuous pathways for electrons and hierarchical pores for ion diffusion. CPGs also provide high surface area and solvent compatibility, similar to natural gels. With these improved properties, CPGs have been explored to enable novel conceptual devices in diverse applications from smart electronics and ultrasensitive biosensors, to energy storage and conversion devices. CPGs have also been adopted for developing hybrid materials with multifunctionalities, such as stimuli responsiveness, self-healing properties, and super-repellency to liquid. With synthetically tunable physical/chemical properties, CPGs emerge as a unique material platform to develop novel multifunctional materials that have the potential to impact electronics, energy, and environmental technologies. Our hope is that this Account promotes further efforts toward synthetic control, fundamental investigation, and application exploration of CPGs.« less

Multifunctional Nanostructured Conductive Polymer Gels: Synthesis, Properties, and Applications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, Fei; Shi, Ye; Pan, Lijia

Conductive polymers have attracted significant interest over the past few decades because they synergize the advantageous features of conventional polymeric materials and organic conductors. With rationally designed nanostructures, conductive polymers can further exhibit exceptional mechanical, electrical, and optical properties because of their confined dimensions at the nanoscale level. Among various nanostructured conductive polymers, conductive polymer gels (CPGs) with synthetically tunable hierarchical 3D network structures show great potential for a wide range of applications, such as bioelectronics, and energy storage/conversion devices owing to their structural features. CPGs retain the properties of nanosized conductive polymers during the assembly of the nanobuilding blocksmore » into a monolithic macroscopic structure while generating structure-derived features from the highly cross-linked network. In this Account, we review our recent progress on the synthesis, properties, and novel applications of dopant cross-linked CPGs. We first describe the synthetic strategies, in which molecules with multiple functional groups are adopted as cross-linkers to cross-link conductive polymer chains into a 3D molecular network. These cross-linking molecules also act as dopants to improve the electrical conductivity of the gel network. The microstructure and physical/chemical properties of CPGs can be tuned by controlling the synthetic conditions such as species of monomers and cross-linkers, reaction temperature, and solvents. By incorporating other functional polymers or particles into the CPG matrix, hybrid gels have been synthesized with tailored structures. These hybrid gel materials retain the functionalities from each component, as well as enable synergic effects to improve mechanical and electrical properties of CPGs. We then introduce the unique structure-derived properties of the CPGs. The network facilitates both electronic and ionic transport owing to the continuous pathways for electrons and hierarchical pores for ion diffusion. CPGs also provide high surface area and solvent compatibility, similar to natural gels. With these improved properties, CPGs have been explored to enable novel conceptual devices in diverse applications from smart electronics and ultrasensitive biosensors, to energy storage and conversion devices. CPGs have also been adopted for developing hybrid materials with multifunctionalities, such as stimuli responsiveness, self-healing properties, and super-repellency to liquid. With synthetically tunable physical/chemical properties, CPGs emerge as a unique material platform to develop novel multifunctional materials that have the potential to impact electronics, energy, and environmental technologies. Our hope is that this Account promotes further efforts toward synthetic control, fundamental investigation, and application exploration of CPGs.« less

Multifunctional Nanostructured Conductive Polymer Gels: Synthesis, Properties, and Applications.

PubMed

Zhao, Fei; Shi, Ye; Pan, Lijia; Yu, Guihua

2017-07-18

Conductive polymers have attracted significant interest over the past few decades because they synergize the advantageous features of conventional polymeric materials and organic conductors. With rationally designed nanostructures, conductive polymers can further exhibit exceptional mechanical, electrical, and optical properties because of their confined dimensions at the nanoscale level. Among various nanostructured conductive polymers, conductive polymer gels (CPGs) with synthetically tunable hierarchical 3D network structures show great potential for a wide range of applications, such as bioelectronics, and energy storage/conversion devices owing to their structural features. CPGs retain the properties of nanosized conductive polymers during the assembly of the nanobuilding blocks into a monolithic macroscopic structure while generating structure-derived features from the highly cross-linked network. In this Account, we review our recent progress on the synthesis, properties, and novel applications of dopant cross-linked CPGs. We first describe the synthetic strategies, in which molecules with multiple functional groups are adopted as cross-linkers to cross-link conductive polymer chains into a 3D molecular network. These cross-linking molecules also act as dopants to improve the electrical conductivity of the gel network. The microstructure and physical/chemical properties of CPGs can be tuned by controlling the synthetic conditions such as species of monomers and cross-linkers, reaction temperature, and solvents. By incorporating other functional polymers or particles into the CPG matrix, hybrid gels have been synthesized with tailored structures. These hybrid gel materials retain the functionalities from each component, as well as enable synergic effects to improve mechanical and electrical properties of CPGs. We then introduce the unique structure-derived properties of the CPGs. The network facilitates both electronic and ionic transport owing to the continuous pathways for electrons and hierarchical pores for ion diffusion. CPGs also provide high surface area and solvent compatibility, similar to natural gels. With these improved properties, CPGs have been explored to enable novel conceptual devices in diverse applications from smart electronics and ultrasensitive biosensors, to energy storage and conversion devices. CPGs have also been adopted for developing hybrid materials with multifunctionalities, such as stimuli responsiveness, self-healing properties, and super-repellency to liquid. With synthetically tunable physical/chemical properties, CPGs emerge as a unique material platform to develop novel multifunctional materials that have the potential to impact electronics, energy, and environmental technologies. We hope that this Account promotes further efforts toward synthetic control, fundamental investigation, and application exploration of CPGs.

First-order logic theory for manipulating clinical practice guidelines applied to comorbid patients: a case study.

PubMed

Michalowski, Martin; Wilk, Szymon; Tan, Xing; Michalowski, Wojtek

2014-01-01

Clinical practice guidelines (CPGs) implement evidence-based medicine designed to help generate a therapy for a patient suffering from a single disease. When applied to a comorbid patient, the concurrent combination of treatment steps from multiple CPGs is susceptible to adverse interactions in the resulting combined therapy (i.e., a therapy established according to all considered CPGs). This inability to concurrently apply CPGs has been shown to be one of the key shortcomings of CPG uptake in a clinical setting1. Several research efforts are underway to address this issue such as the K4CARE2 and GuideLine INteraction Detection Assistant (GLINDA)3 projects and our previous research on applying constraint logic programming to developing a consistent combined therapy for a comorbid patient4. However, there is no generalized framework for mitigation that effectively captures general characteristics of the problem while handling nuances such as time and ordering requirements imposed by specific CPGs. In this paper we propose a first-order logic-based (FOL) approach for developing a generalized framework of mitigation. This approach uses a meta-algorithm and entailment properties to mitigate (i.e., identify and address) adverse interactions introduced by concurrently applied CPGs. We use an illustrative case study of a patient suffering from type 2 diabetes being treated for an onset of severe rheumatoid arthritis to show the expressiveness and robustness of our proposed FOL-based approach, and we discuss its appropriateness as the basis for the generalized theory.

A systematic critical appraisal of non-pharmacological management of rheumatoid arthritis with Appraisal of Guidelines for Research and Evaluation II.

PubMed

Brosseau, Lucie; Rahman, Prinon; Poitras, Stéphane; Toupin-April, Karine; Paterson, Gail; Smith, Christine; King, Judy; Casimiro, Lynn; De Angelis, Gino; Loew, Laurianne; Cavallo, Sabrina; Ewan, Jessica Mc

2014-01-01

Clinical practice guidelines (CPGs) have been developed to summarize evidence about the management of rheumatoid arthritis (RA) and facilitate the uptake of evidence-based knowledge by consumers, health professionals, health administrators and policy makers. The objectives of this review was to assess the quality of CPGS on non-pharmacological management of RA with a standardized and validated instrument--the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool and summarize the key recommendations from these CPGs. Scientific literature databases from 2001 to 2013 were systematically searched and a total of 13 CPGs for RA was identified. Only a minority of AGREE II domains were effectively addressed by the CPGS. Scope and purpose was effectively addressed in 10 out of 13 CPGs, stakeholder involvement in 11 CPGs, rigor of development in 6 CPGs, clarity/presentation in 9 CPGs, editorial independence in 1 CPGs, and applicability in none of the CPGs. The overall quality of the included CPGs according to the 7-point AGREE II scoring system was 4.8 ± 1.04. Patient education/self-management, aerobic, dynamic and stretching exercises were the commonly recommended for the non-pharmacological management of RA by the high-quality CPGs. The general clinical management recommendations tended to be similar among high-quality CPGs. Non-pharmacological management interventions were superficially addressed in more than half of the selected CPGs. CPGs creators should use the AGREE II criteria when developing guidelines. Innovative and effective methods of CPGs implementation to users are needed to ultimately enhance the quality of life of arthritic individuals. In addition, it was difficult to establish between strongly recommended, recommended and weakly recommended, as there is no consensus between the strength of the recommendations between the appraised CPGs.

Epigenetic Signatures of Cigarette Smoking

PubMed Central

Joehanes, Roby; Just, Allan C.; Marioni, Riccardo E.; Pilling, Luke C.; Reynolds, Lindsay M.; Mandaviya, Pooja R.; Guan, Weihua; Xu, Tao; Elks, Cathy E.; Aslibekyan, Stella; Moreno-Macias, Hortensia; Smith, Jennifer A.; Brody, Jennifer A.; Dhingra, Radhika; Yousefi, Paul; Pankow, James S.; Kunze, Sonja; Shah, Sonia; McRae, Allan F.; Lohman, Kurt; Sha, Jin; Absher, Devin M.; Ferrucci, Luigi; Zhao, Wei; Demerath, Ellen W.; Bressler, Jan; Grove, Megan L.; Huan, Tianxiao; Liu, Chunyu; Mendelson, Michael M.; Yao, Chen; Kiel, Douglas P.; Peters, Annette; Wang-Sattler, Rui; Visscher, Peter M.; Wray, Naomi R.; Starr, John M.; Ding, Jingzhong; Rodriguez, Carlos J.; Wareham, Nicholas J.; Irvin, Marguerite R.; Zhi, Degui; Barrdahl, Myrto; Vineis, Paolo; Ambatipudi, Srikant; Uitterlinden, André G.; Hofman, Albert; Schwartz, Joel; Colicino, Elena; Hou, Lifang; Vokonas, Pantel S.; Hernandez, Dena G.; Singleton, Andrew B.; Bandinelli, Stefania; Turner, Stephen T.; Ware, Erin B.; Smith, Alicia K.; Klengel, Torsten; Binder, Elisabeth B.; Psaty, Bruce M.; Taylor, Kent D.; Gharib, Sina A.; Swenson, Brenton R.; Liang, Liming; DeMeo, Dawn L.; O'Connor, George T.; Herceg, Zdenko; Ressler, Kerry J.; Conneely, Karen N.; Sotoodehnia, Nona; Kardia, Sharon L. R.; Melzer, David; Baccarelli, Andrea A.; van Meurs, Joyce B. J.; Romieu, Isabelle; Arnett, Donna K.; Ong, Ken K.; Liu, Yongmei; Waldenberger, Melanie; Deary, Ian J.; Fornage, Myriam; Levy, Daniel; London, Stephanie J.

2016-01-01

Background DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. Methods and Results To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15,907 blood derived DNA samples from participants in 16 cohorts (including 2,433 current, 6,518 former, and 6,956 never smokers). Comparing current versus never smokers, 2,623 CpG sites (CpGs), annotated to 1,405 genes, were statistically significantly differentially methylated at Bonferroni threshold of p<1×10−7 (18,760 CpGs at False Discovery Rate (FDR)<0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant p<1×10−7 (2,623 CpGs at FDR<0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. Conclusions Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biologic effects of smoking, and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke. PMID:27651444

Epigenetic Signatures of Cigarette Smoking.

PubMed

Joehanes, Roby; Just, Allan C; Marioni, Riccardo E; Pilling, Luke C; Reynolds, Lindsay M; Mandaviya, Pooja R; Guan, Weihua; Xu, Tao; Elks, Cathy E; Aslibekyan, Stella; Moreno-Macias, Hortensia; Smith, Jennifer A; Brody, Jennifer A; Dhingra, Radhika; Yousefi, Paul; Pankow, James S; Kunze, Sonja; Shah, Sonia H; McRae, Allan F; Lohman, Kurt; Sha, Jin; Absher, Devin M; Ferrucci, Luigi; Zhao, Wei; Demerath, Ellen W; Bressler, Jan; Grove, Megan L; Huan, Tianxiao; Liu, Chunyu; Mendelson, Michael M; Yao, Chen; Kiel, Douglas P; Peters, Annette; Wang-Sattler, Rui; Visscher, Peter M; Wray, Naomi R; Starr, John M; Ding, Jingzhong; Rodriguez, Carlos J; Wareham, Nicholas J; Irvin, Marguerite R; Zhi, Degui; Barrdahl, Myrto; Vineis, Paolo; Ambatipudi, Srikant; Uitterlinden, André G; Hofman, Albert; Schwartz, Joel; Colicino, Elena; Hou, Lifang; Vokonas, Pantel S; Hernandez, Dena G; Singleton, Andrew B; Bandinelli, Stefania; Turner, Stephen T; Ware, Erin B; Smith, Alicia K; Klengel, Torsten; Binder, Elisabeth B; Psaty, Bruce M; Taylor, Kent D; Gharib, Sina A; Swenson, Brenton R; Liang, Liming; DeMeo, Dawn L; O'Connor, George T; Herceg, Zdenko; Ressler, Kerry J; Conneely, Karen N; Sotoodehnia, Nona; Kardia, Sharon L R; Melzer, David; Baccarelli, Andrea A; van Meurs, Joyce B J; Romieu, Isabelle; Arnett, Donna K; Ong, Ken K; Liu, Yongmei; Waldenberger, Melanie; Deary, Ian J; Fornage, Myriam; Levy, Daniel; London, Stephanie J

2016-10-01

DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10 -7 (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10 -7 (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke. © 2016 American Heart Association, Inc.

A Systematic Critical Appraisal for Non-Pharmacological Management of Osteoarthritis Using the Appraisal of Guidelines Research and Evaluation II Instrument

PubMed Central

Brosseau, Lucie; Rahman, Prinon; Toupin-April, Karine; Poitras, Stéphane; King, Judy; De Angelis, Gino; Loew, Laurianne; Casimiro, Lynn; Paterson, Gail; McEwan, Jessica

2014-01-01

Clinical practice CPGs (CPGs) have been developed to summarize evidence related to the management of osteoarthritis (OA). CPGs facilitate uptake of evidence-based knowledge by consumers, health professionals, health administrators and policy makers. The objectives of the present review were: 1) to assess the quality of the CPGs on non-pharmacological management of OA; using a standardized and validated instrument - the Appraisal of Guidelines Research and Evaluation (AGREE II) tool - by three pairs of trained appraisers; and 2) to summarize the recommendations based on only high-quality existing CPGs. Scientific literature databases from 2001 to 2013 were systematically searched for the state of evidence, with 17 CPGs for OA being identified. Most CPGs effectively addressed only a minority of AGREE II domains. Scope and purpose was effectively addressed in 10 CPGs on the management of OA, stakeholder involvement in 12 CPGs, rigour of development in 10 CPGs, clarity/presentation in 17 CPGs, editorial independence in 2 CPGs, and applicability in none of the OA CPGs. The overall quality of the included CPGs, according to the 7-point AGREE II scoring system, is 4.8±0.41 for OA. Therapeutic exercises, patient education, transcutaneous electrical nerve stimulation, acupuncture, orthoses and insoles, heat and cryotherapy, patellar tapping, and weight control are commonly recommended for the non-pharmacological management of OA by the high-quality CPGs. The general clinical management recommendations tended to be similar among high-quality CPGs, although interventions addressed varied. Non-pharmacological management interventions were superficially addressed in more than half of the selected CPGs. For CPGs to be standardized uniform creators should use the AGREE II criteria when developing CPGs. Innovative and effective methods of CPG implementation to users are needed to ultimately enhance the quality of life of arthritic individuals. PMID:24427268

A systematic critical appraisal for non-pharmacological management of osteoarthritis using the appraisal of guidelines research and evaluation II instrument.

PubMed

Brosseau, Lucie; Rahman, Prinon; Toupin-April, Karine; Poitras, Stéphane; King, Judy; De Angelis, Gino; Loew, Laurianne; Casimiro, Lynn; Paterson, Gail; McEwan, Jessica

2014-01-01

Clinical practice CPGs (CPGs) have been developed to summarize evidence related to the management of osteoarthritis (OA). CPGs facilitate uptake of evidence-based knowledge by consumers, health professionals, health administrators and policy makers. The objectives of the present review were: 1) to assess the quality of the CPGs on non-pharmacological management of OA; using a standardized and validated instrument--the Appraisal of Guidelines Research and Evaluation (AGREE II) tool--by three pairs of trained appraisers; and 2) to summarize the recommendations based on only high-quality existing CPGs. Scientific literature databases from 2001 to 2013 were systematically searched for the state of evidence, with 17 CPGs for OA being identified. Most CPGs effectively addressed only a minority of AGREE II domains. Scope and purpose was effectively addressed in 10 CPGs on the management of OA, stakeholder involvement in 12 CPGs, rigour of development in 10 CPGs, clarity/presentation in 17 CPGs, editorial independence in 2 CPGs, and applicability in none of the OA CPGs. The overall quality of the included CPGs, according to the 7-point AGREE II scoring system, is 4.8 ± 0.41 for OA. Therapeutic exercises, patient education, transcutaneous electrical nerve stimulation, acupuncture, orthoses and insoles, heat and cryotherapy, patellar tapping, and weight control are commonly recommended for the non-pharmacological management of OA by the high-quality CPGs. The general clinical management recommendations tended to be similar among high-quality CPGs, although interventions addressed varied. Non-pharmacological management interventions were superficially addressed in more than half of the selected CPGs. For CPGs to be standardized uniform creators should use the AGREE II criteria when developing CPGs. Innovative and effective methods of CPG implementation to users are needed to ultimately enhance the quality of life of arthritic individuals.

A model-based exploration of the role of pattern generating circuits during locomotor adaptation.

PubMed

Marjaninejad, Ali; Finley, James M

2016-08-01

In this study, we used a model-based approach to explore the potential contributions of central pattern generating circuits (CPGs) during adaptation to external perturbations during locomotion. We constructed a neuromechanical modeled of locomotion using a reduced-phase CPG controller and an inverted pendulum mechanical model. Two different forms of locomotor adaptation were examined in this study: split-belt treadmill adaptation and adaptation to a unilateral, elastic force field. For each simulation, we first examined the effects of phase resetting and varying the model's initial conditions on the resulting adaptation. After evaluating the effect of phase resetting on the adaptation of step length symmetry, we examined the extent to which the results from these simple models could explain previous experimental observations. We found that adaptation of step length symmetry during split-belt treadmill walking could be reproduced using our model, but this model failed to replicate patterns of adaptation observed in response to force field perturbations. Given that spinal animal models can adapt to both of these types of perturbations, our findings suggest that there may be distinct features of pattern generating circuits that mediate each form of adaptation.

Diabetic Retinopathy Clinical Practice Guidelines: Customized for Iranian Population

PubMed Central

Rajavi, Zhale; Safi, Sare; Javadi, Mohammad Ali; Azarmina, Mohsen; Moradian, Siamak; Entezari, Morteza; Nourinia, Ramin; Ahmadieh, Hamid; Shirvani, Armin; Shahraz, Saeid; Ramezani, Alireza; Dehghan, Mohammad Hossein; Shahsavari, Mohsen; Soheilian, Masoud; Nikkhah, Homayoun; Ziaei, Hossein; Behboudi, Hasan; Farrahi, Fereydoun; Falavarjani, Khalil Ghasemi; Parvaresh, Mohammad Mehdi; Fesharaki, Hamid; Abrishami, Majid; Shoeibi, Nasser; Rahimi, Mansour; Javadzadeh, Alireza; Karkhaneh, Reza; Riazi-Esfahani, Mohammad; Manaviat, Masoud Reza; Maleki, Alireza; Kheiri, Bahareh; Golbafian, Faegheh

2016-01-01

Purpose: To customize clinical practice guidelines (CPGs) for management of diabetic retinopathy (DR) in the Iranian population. Methods: Three DR CPGs (The Royal College of Ophthalmologists 2013, American Academy of Ophthalmology [Preferred Practice Pattern 2012], and Australian Diabetes Society 2008) were selected from the literature using the AGREE tool. Clinical questions were designed and summarized into four tables by the customization team. The components of the clinical questions along with pertinent recommendations extracted from the above-mentioned CPGs; details of the supporting articles and their levels of evidence; clinical recommendations considering clinical benefits, cost and side effects; and revised recommendations based on customization capability (applicability, acceptability, external validity) were recorded in 4 tables, respectively. Customized recommendations were sent to the faculty members of all universities across the country to score the recommendations from 1 to 9. Results: Agreed recommendations were accepted as the final recommendations while the non-agreed ones were approved after revision. Eventually, 29 customized recommendations under three major categories consisting of screening, diagnosis and treatment of DR were developed along with their sources and levels of evidence. Conclusion: This customized CPGs for management of DR can be used to standardize the referral pathway, diagnosis and treatment of patients with diabetic retinopathy. PMID:27994809

Temperature-dependent regulation of vocal pattern generator.

PubMed

Yamaguchi, Ayako; Gooler, David; Herrold, Amy; Patel, Shailja; Pong, Winnie W

2008-12-01

Vocalizations of Xenopus laevis are generated by central pattern generators (CPGs). The advertisement call of male X. laevis is a complex biphasic motor rhythm consisting of fast and slow trills (a train of clicks). We found that the trill rate of these advertisement calls is sensitive to temperature and that this rate modification of the vocal rhythms originates in the central pattern generators. In vivo the rates of fast and slow trills increased linearly with an increase in temperature. In vitro a similar linear relation between temperature and compound action potential frequency in the laryngeal nerve was found when fictive advertisement calls were evoked in the isolated brain. Temperature did not limit the contractile properties of laryngeal muscles within the frequency range of vocalizations. We next took advantage of the temperature sensitivity of the vocal CPG in vitro to localize the source of the vocal rhythms. We focused on the dorsal tegmental area of the medulla (DTAM), a brain stem nucleus that is essential for vocal production. We found that bilateral cooling of DTAM reduced both fast and slow trill rates. Thus we conclude that DTAM is a source of biphasic vocal rhythms.

Does Epileptiform Activity Represent a Failure of Neuromodulation to Control Central Pattern Generator-Like Neocortical Behavior?

PubMed Central

Traub, Roger D.; Whittington, Miles A.; Hall, Stephen P.

2017-01-01

Rhythmic motor patterns in invertebrates are often driven by specialized “central pattern generators” (CPGs), containing small numbers of neurons, which are likely to be “identifiable” in one individual compared with another. The dynamics of any particular CPG lies under the control of modulatory substances, amines, or peptides, entering the CPG from outside it, or released by internal constituent neurons; consequently, a particular CPG can generate a given rhythm at different frequencies and amplitudes, and perhaps even generate a repertoire of distinctive patterns. The mechanisms exploited by neuromodulators in this respect are manifold: Intrinsic conductances (e.g., calcium, potassium channels), conductance state of postsynaptic receptors, degree of plasticity, and magnitude and kinetics of transmitter release can all be affected. The CPG concept has been generalized to vertebrate motor pattern generating circuits (e.g., for locomotion), which may contain large numbers of neurons – a construct that is sensible, if there is enough redundancy: that is, the large number of neurons consists of only a small number of classes, and the cells within any one class act stereotypically. Here we suggest that CPG and modulator ideas may also help to understand cortical oscillations, normal ones, and particularly transition to epileptiform pathology. Furthermore, in the case illustrated, the mechanism of the transition appears to be an exaggerated form of a normal modulatory action used to influence sensory processing. PMID:29093667

Towards symbiosis in knowledge representation and natural language processing for structuring clinical practice guidelines.

PubMed

Weng, Chunhua; Payne, Philip R O; Velez, Mark; Johnson, Stephen B; Bakken, Suzanne

2014-01-01

The successful adoption by clinicians of evidence-based clinical practice guidelines (CPGs) contained in clinical information systems requires efficient translation of free-text guidelines into computable formats. Natural language processing (NLP) has the potential to improve the efficiency of such translation. However, it is laborious to develop NLP to structure free-text CPGs using existing formal knowledge representations (KR). In response to this challenge, this vision paper discusses the value and feasibility of supporting symbiosis in text-based knowledge acquisition (KA) and KR. We compare two ontologies: (1) an ontology manually created by domain experts for CPG eligibility criteria and (2) an upper-level ontology derived from a semantic pattern-based approach for automatic KA from CPG eligibility criteria text. Then we discuss the strengths and limitations of interweaving KA and NLP for KR purposes and important considerations for achieving the symbiosis of KR and NLP for structuring CPGs to achieve evidence-based clinical practice.

Support of personalized medicine through risk-stratified treatment recommendations - an environmental scan of clinical practice guidelines

PubMed Central

2013-01-01

Background Risk-stratified treatment recommendations facilitate treatment decision-making that balances patient-specific risks and preferences. It is unclear if and how such recommendations are developed in clinical practice guidelines (CPGs). Our aim was to assess if and how CPGs develop risk-stratified treatment recommendations for the prevention or treatment of common chronic diseases. Methods We searched the United States National Guideline Clearinghouse for US, Canadian and National Institute for Health and Clinical Excellence (United Kingdom) CPGs for heart disease, stroke, cancer, chronic obstructive pulmonary disease and diabetes that make risk-stratified treatment recommendations. We included only those CPGs that made risk-stratified treatment recommendations based on risk assessment tools. Two reviewers independently identified CPGs and extracted information on recommended risk assessment tools; type of evidence about treatment benefits and harms; methods for linking risk estimates to treatment evidence and for developing treatment thresholds; and consideration of patient preferences. Results We identified 20 CPGs that made risk-stratified treatment recommendations out of 133 CPGs that made any type of treatment recommendations for the chronic diseases considered in this study. Of the included 20 CPGs, 16 (80%) used evidence about treatment benefits from randomized controlled trials, meta-analyses or other guidelines, and the source of evidence was unclear in the remaining four (20%) CPGs. Nine CPGs (45%) used evidence on harms from randomized controlled trials or observational studies, while 11 CPGs (55%) did not clearly refer to harms. Nine CPGs (45%) explained how risk prediction and evidence about treatments effects were linked (for example, applying estimates of relative risk reductions to absolute risks), but only one CPG (5%) assessed benefit and harm quantitatively and three CPGs (15%) explicitly reported consideration of patient preferences. Conclusions Only a small proportion of CPGs for chronic diseases make risk-stratified treatment recommendations with a focus on heart disease and stroke prevention, diabetes and breast cancer. For most CPGs it is unclear how risk-stratified treatment recommendations were developed. As a consequence, it is uncertain if CPGs support patients and physicians in finding an acceptable benefit- harm balance that reflects both profile-specific outcome risks and preferences. PMID:23302096

Comparative whole genome DNA methylation profiling of cattle sperm and somatic tissues reveals striking hypomethylated patterns in sperm

USDA-ARS?s Scientific Manuscript database

Using whole-genome bisulfite sequencing (WGBS), we profiled the DNA methylome of cattle sperms through comparison with three bovine somatic tissues (mammary grand, brain and blood). Large differences between them were observed in the methylation patterns of global CpGs, pericentromeric satellites, p...

The tools of an evidence-based culture: implementing clinical-practice guidelines in an Israeli HMO.

PubMed

Kahan, Natan R; Kahan, Ernesto; Waitman, Dan-Andrei; Kitai, Eliezer; Chintz, David P

2009-09-01

Although clinical-practice guidelines (CPGs) are implemented on the assumption that they will improve the quality, efficiency, and consistency of health care, they generally have limited effect in changing physicians' behavior. The purpose of this study was to design and implement an effective program for formulating, promulgating, and implementing CPGs to foster the development of an evidence-based culture in an Israeli HMO. The authors implemented a four-stage program of stepwise collaborative efforts with academic institutions composed of developing quantitative tools to evaluate prescribing patterns, updating CPGs, collecting MDs' input via focus groups and quantitative surveys, and conducting a randomized controlled trial of a two-stage, multipronged intervention. The test case for this study was the development, dissemination, and implementation of CPG for the treatment of acute uncomplicated cystitis in adult women. Interventions in the form of a lecture at a conference and a letter with personalized feedback were implemented, both individually and combined, to improve physicians' rates of prescribing the first-line drug, nitrofurantoin, and, in the absence of nitrofurantoin, adhering to the recommended duration of three days of treatment with ofloxacin. The tools and data-generating capabilities designed and constructed in Stage I of the project were integral components of all subsequent stages of the program. Personalized feedback alone was sufficient to improve the rate of adherence to the guidelines by 19.4% (95% CI = 16.7, 22.1). This study provides a template for introducing the component of experimentation essential for cultivating an evidence-based culture. This process, composed of collaborative efforts between academic institutions and a managed care organization, may be beneficial to other health care systems.

Neuromodulation intrinsic to the central pattern generator for escape swimming in Tritonia.

PubMed

Katz, P S

1998-11-16

Extrinsic neuromodulatory inputs to central pattern generators (CPGs) can alter the properties and synaptic interactions of neurons in those circuits and thereby modify the output of the CPG. Recent work in a number of systems has now demonstrated that neurons intrinsic to CPG can also evoke neuromodulatory actions on other members of the CPG. Such "intrinsic neuromodulation" plays a role in controlling the CPG underlying the escape swim response of the nudibrach mollusc, Tritonia diomedea. The dorsal swim interneurons (DSIs) are a bilaterally represented set of three serotonergic neurons that participate in the generation of the rhythmic swim motor program. Serotonin released from these CPG neurons functions both as a fast neurotransmitter and as a slower neuromodulator. In its modulatory role, serotonin enhances the release of neurotransmitter from another CPG neuron, C2, and also increases C2 excitability by decreasing spike frequency adaptation. These neuromodulatory actions intrinsic to the CPG may be important for the initial self-configuration of the system into a function CPG and for experience-dependent changes in the output such as behavioral sensitization and habituation.

Determining coding CpG islands by identifying regions significant for pattern statistics on Markov chains.

PubMed

Singer, Meromit; Engström, Alexander; Schönhuth, Alexander; Pachter, Lior

2011-09-23

Recent experimental and computational work confirms that CpGs can be unmethylated inside coding exons, thereby showing that codons may be subjected to both genomic and epigenomic constraint. It is therefore of interest to identify coding CpG islands (CCGIs) that are regions inside exons enriched for CpGs. The difficulty in identifying such islands is that coding exons exhibit sequence biases determined by codon usage and constraints that must be taken into account. We present a method for finding CCGIs that showcases a novel approach we have developed for identifying regions of interest that are significant (with respect to a Markov chain) for the counts of any pattern. Our method begins with the exact computation of tail probabilities for the number of CpGs in all regions contained in coding exons, and then applies a greedy algorithm for selecting islands from among the regions. We show that the greedy algorithm provably optimizes a biologically motivated criterion for selecting islands while controlling the false discovery rate. We applied this approach to the human genome (hg18) and annotated CpG islands in coding exons. The statistical criterion we apply to evaluating islands reduces the number of false positives in existing annotations, while our approach to defining islands reveals significant numbers of undiscovered CCGIs in coding exons. Many of these appear to be examples of functional epigenetic specialization in coding exons.

Quality assessment of recent evidence-based clinical practice guidelines for management of type 2 diabetes mellitus in adults using the AGREE II instrument.

PubMed

Anwer, Muhammad A; Al-Fahed, Ousama B; Arif, Samir I; Amer, Yasser S; Titi, Maher A; Al-Rukban, Mohammed O

2018-02-01

Type 2 diabetes mellitus (T2DM) is a worldwide and national public health problem that has a great impact on the population in Saudi Arabia. High-quality clinical practice guidelines (CPGs) are cornerstones in improving the health care provided for patients with diabetes. This study evaluated the methodological rigour, transparency, and applicability of recently published CPGs. Our group conducted a systematic search for recently published CPGs for T2DM. The searching and screening for Source CPGs were guided by tools from the ADAPTE methods with specific inclusion/exclusion criteria. Five reviewers using the second version of the Appraisal of Guidelines for Research and Evaluation (AGREE II) Instrument independently assessed the quality of the retrieved Source CPGs. Domains of Scope and purpose and Clarity of presentation received the highest scores in all CPGs. Most of the assessed CPGs (86%) were considered with high overall quality and were recommended for use. Rigour of development and applicability domains were together highest in 3 CPGs (43%). The overall high quality of DM CPGs published in the last 3 years demonstrated the continuous development and improvement in CPG methodologies and standards. Health care professionals should consider the quality of any CPG for T2DM before deciding to use it in their daily clinical practice. Three CPGs have been identified, using the AGREE criteria, as high-quality and trustworthy. Ideally, the resources provided by the AGREE trust including the AGREE II Instrument should be used by a clinician to scan through the large number of published T2DM CPGs to identify the CPGs with high methodological quality and applicability. © 2017 John Wiley & Sons, Ltd.

CpG Methylation Signature Predicts Recurrence in Early-Stage Hepatocellular Carcinoma: Results From a Multicenter Study.

PubMed

Qiu, Jiliang; Peng, Baogang; Tang, Yunqiang; Qian, Yeben; Guo, Pi; Li, Mengfeng; Luo, Junhang; Chen, Bin; Tang, Hui; Lu, Canliang; Cai, Muyan; Ke, Zunfu; He, Wei; Zheng, Yun; Xie, Dan; Li, Binkui; Yuan, Yunfei

2017-03-01

Purpose Early-stage hepatocellular carcinoma (E-HCC) is being diagnosed increasingly, and in one half of diagnosed patients, recurrence will develop. Thus, it is urgent to identify recurrence-related markers. We investigated the effectiveness of CpG methylation in predicting recurrence for patients with E-HCCs. Patients and Methods In total, 576 patients with E-HCC from four independent centers were sorted by three phases. In the discovery phase, 66 tumor samples were analyzed using the Illumina Methylation 450k Beadchip. Two algorithms, Least Absolute Shrinkage and Selector Operation and Support Vector Machine-Recursive Feature Elimination, were used to select significant CpGs. In the training phase, penalized Cox regression was used to further narrow CpGs into 140 samples. In the validation phase, candidate CpGs were validated using an internal cohort (n = 141) and two external cohorts (n = 191 and n =104). Results After combining the 46 CpGs selected by the Least Absolute Shrinkage and Selector Operation and the Support Vector Machine-Recursive Feature Elimination algorithms, three CpGs corresponding to SCAN domain containing 3, Src homology 3-domain growth factor receptor-bound 2-like interacting protein 1, and peptidase inhibitor 3 were highlighted as candidate predictors in the training phase. On the basis of the three CpGs, a methylation signature for E-HCC (MSEH) was developed to classify patients into high- and low-risk recurrence groups in the training cohort ( P < .001). The performance of MSEH was validated in the internal cohort ( P < .001) and in the two external cohorts ( P < .001; P = .002). Furthermore, a nomogram comprising MSEH, tumor differentiation, cirrhosis, hepatitis B virus surface antigen, and antivirus therapy was generated to predict the 5-year recurrence-free survival in the training cohort, and it performed well in the three validation cohorts (concordance index: 0.725, 0.697, and 0.693, respectively). Conclusion MSEH, a three-CpG-based signature, is useful in predicting recurrence for patients with E-HCC.

Reinforcement learning for a biped robot based on a CPG-actor-critic method.

PubMed

Nakamura, Yutaka; Mori, Takeshi; Sato, Masa-aki; Ishii, Shin

2007-08-01

Animals' rhythmic movements, such as locomotion, are considered to be controlled by neural circuits called central pattern generators (CPGs), which generate oscillatory signals. Motivated by this biological mechanism, studies have been conducted on the rhythmic movements controlled by CPG. As an autonomous learning framework for a CPG controller, we propose in this article a reinforcement learning method we call the "CPG-actor-critic" method. This method introduces a new architecture to the actor, and its training is roughly based on a stochastic policy gradient algorithm presented recently. We apply this method to an automatic acquisition problem of control for a biped robot. Computer simulations show that training of the CPG can be successfully performed by our method, thus allowing the biped robot to not only walk stably but also adapt to environmental changes.

Development of Quality Management Systems for Clinical Practice Guidelines in Korea.

PubMed

Jo, Heui-Sug; Kim, Dong Ik; Chang, Sung-Goo; Shin, Ein-Soon; Oh, Moo-Kyung

2015-11-01

This study introduces the Clinical practice guidelines (CPGs) appraisal system by the Korean Academy of Medical Sciences (KAMS). Quality management policies for CPGs vary among different countries, which have their own cultures and health care systems. However, supporting developers in guideline development and appraisals using standardized tools are common practices. KAMS, an organization representing the various medical societies of Korea, has been striving to establish a quality management system for CPGs, and has established a CPGs quality management system that reflects the characteristics of the Korean healthcare environment and the needs of its users. KAMS created a foundation for the development of CPGs, set up an independent appraisal organization, enacted regulations related to the appraisals, and trained appraisers. These efforts could enhance the ability of each individual medical society to develop CPGs, to increase the quality of the CPGs, and to ultimately improve the quality of the information available to decision-makers.

Identification of critical paralog groups with indispensable roles in the regulation of signaling flow

PubMed Central

Modos, Dezso; Brooks, Johanne; Fazekas, David; Ari, Eszter; Vellai, Tibor; Csermely, Peter; Korcsmaros, Tamas; Lenti, Katalin

2016-01-01

Extensive cross-talk between signaling pathways is required to integrate the myriad of extracellular signal combinations at the cellular level. Gene duplication events may lead to the emergence of novel functions, leaving groups of similar genes - termed paralogs - in the genome. To distinguish critical paralog groups (CPGs) from other paralogs in human signaling networks, we developed a signaling network-based method using cross-talk annotation and tissue-specific signaling flow analysis. 75 CPGs were found with higher degree, betweenness centrality, closeness, and ‘bowtieness’ when compared to other paralogs or other proteins in the signaling network. CPGs had higher diversity in all these measures, with more varied biological functions and more specific post-transcriptional regulation than non-critical paralog groups (non-CPG). Using TGF-beta, Notch and MAPK pathways as examples, SMAD2/3, NOTCH1/2/3 and MEK3/6-p38 CPGs were found to regulate the signaling flow of their respective pathways. Additionally, CPGs showed a higher mutation rate in both inherited diseases and cancer, and were enriched in drug targets. In conclusion, the results revealed two distinct types of paralog groups in the signaling network: CPGs and non-CPGs. Thus highlighting the importance of CPGs as compared to non-CPGs in drug discovery and disease pathogenesis. PMID:27922122

Homology and homoplasy of swimming behaviors and neural circuits in the Nudipleura (Mollusca, Gastropoda, Opisthobranchia)

PubMed Central

Newcomb, James M.; Sakurai, Akira; Lillvis, Joshua L.; Gunaratne, Charuni A.; Katz, Paul S.

2012-01-01

How neural circuit evolution relates to behavioral evolution is not well understood. Here the relationship between neural circuits and behavior is explored with respect to the swimming behaviors of the Nudipleura (Mollusca, Gastropoda, Opithobranchia). Nudipleura is a diverse monophyletic clade of sea slugs among which only a small percentage of species can swim. Swimming falls into a limited number of categories, the most prevalent of which are rhythmic left–right body flexions (LR) and rhythmic dorsal–ventral body flexions (DV). The phylogenetic distribution of these behaviors suggests a high degree of homoplasy. The central pattern generator (CPG) underlying DV swimming has been well characterized in Tritonia diomedea and in Pleurobranchaea californica. The CPG for LR swimming has been elucidated in Melibe leonina and Dendronotus iris, which are more closely related. The CPGs for the categorically distinct DV and LR swimming behaviors consist of nonoverlapping sets of homologous identified neurons, whereas the categorically similar behaviors share some homologous identified neurons, although the exact composition of neurons and synapses in the neural circuits differ. The roles played by homologous identified neurons in categorically distinct behaviors differ. However, homologous identified neurons also play different roles even in the swim CPGs of the two LR swimming species. Individual neurons can be multifunctional within a species. Some of those functions are shared across species, whereas others are not. The pattern of use and reuse of homologous neurons in various forms of swimming and other behaviors further demonstrates that the composition of neural circuits influences the evolution of behaviors. PMID:22723353

Clinical practice guidelines for fertility preservation in young women undergoing gonadotoxic treatment: an overview and critical appraisal of methodological quality and content.

PubMed

Baysal, Özlem; Hamilton, Jozefien A M; Hamilton, Carl J C M; Braat, Didi D M; Beerendonk, Catharina C M; Nelen, Willianne L D M

2018-04-13

What is the methodological quality and content of internationally available clinical practice guidelines (CPGs) on fertility preservation (FP) care in adult women? Internationally available CPGs on FP care in adult women were identified after conducting an extensive literature search and consulting (inter)national key experts. The methodological quality of the CPGs was appraised by an (inter)national panel of experts using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. The content of the best CPGs, scoring ≥60% for the domain 'Rigour of development' of the AGREE II instrument, was extracted and categorized according to their topic. Thirty of the 1808 documents found were included. After consulting (inter)national key experts, 30 CPGs were included, six of which scored ≥60% for their 'Rigour of development'. The number of FP-related topics discussed by these six CPGs ranged from 4 to 12. The number of recommendations provided by the CPGs on these topics varied. The number of topics to which ≥5 recommendations were dedicated ranged from 0 to 4 between CPGs. CPGs on the subject of FP care are available, but there is room for improvement in quality and content. Although written for use in daily practice, the CPGs can also be used to develop quality indicators to monitor the quality of current FP care or to evaluate future improvement initiatives. Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

How current Clinical Practice Guidelines for low back pain reflect Traditional Medicine in East Asian Countries: a systematic review of Clinical Practice Guidelines and systematic reviews.

PubMed

Cho, Hyun-Woo; Hwang, Eui-Hyoung; Lim, Byungmook; Heo, Kwang-Ho; Liu, Jian-Ping; Tsutani, Kiichiro; Lee, Myeong Soo; Shin, Byung-Cheul

2014-01-01

The aims of this study were to investigate whether there is a gap between evidence of traditional medicine (TM) interventions in East-Asian countries from the current Clinical Practice Guidelines (CPGs) and evidence from current systematic reviews and meta-analyses (SR-MAs) and to analyze the impact of this gap on present CPGs. We examined 5 representative TM interventions in the health care systems of East-Asian countries. We searched seven relevant databases for CPGs to identify whether core CPGs included evidence of TM interventions, and we searched 11 databases for SR-MAs to re-evaluate current evidence on TM interventions. We then compared the gap between the evidence from CPGs and SR-MAs. Thirteen CPGs and 22 SR-MAs met our inclusion criteria. Of the 13 CPGs, 7 CPGs (54%) mentioned TM interventions, and all were for acupuncture (only one was for both acupuncture and acupressure). However, the CPGs did not recommend acupuncture (or acupressure). Of 22 SR-MAs, 16 were for acupuncture, 5 for manual therapy, 1 for cupping, and none for moxibustion and herbal medicine. Comparing the evidence from CPGs and SR-MAs, an underestimation or omission of evidence for acupuncture, cupping, and manual therapy in current CPGs was detected. Thus, applying the results from the SR-MAs, we moderately recommend acupuncture for chronic LBP, but we inconclusively recommend acupuncture for (sub)acute LBP due to the limited current evidence. Furthermore, we weakly recommend cupping and manual therapy for both (sub)acute and chronic LBP. We cannot provide recommendations for moxibustion and herbal medicine due to a lack of evidence. The current CPGs did not fully reflect the evidence for TM interventions. As relevant studies such as SR-MAs are conducted and evidence increases, the current evidence on acupuncture, cupping, and manual therapy should be rigorously considered in the process of developing or updating the CPG system.

On the Role of Sensory Feedbacks in Rowat–Selverston CPG to Improve Robot Legged Locomotion

PubMed Central

Amrollah, Elmira; Henaff, Patrick

2010-01-01

This paper presents the use of Rowat and Selverston-type of central pattern generator (CPG) to control locomotion. It focuses on the role of afferent exteroceptive and proprioceptive signals in the dynamic phase synchronization in CPG legged robots. The sensori-motor neural network architecture is evaluated to control a two-joint planar robot leg that slips on a rail. Then, the closed loop between the CPG and the mechanical system allows to study the modulation of rhythmic patterns and the effect of the sensing loop via sensory neurons during the locomotion task. Firstly simulations show that the proposed architecture easily allows to modulate rhythmic patterns of the leg, and therefore the velocity of the robot. Secondly, simulations show that sensori-feedbacks from foot/ground contact of the leg make the hip velocity smoother and larger. The results show that the Rowat–Selverston-type CPG with sensory feedbacks is an effective choice for building adaptive neural CPGs for legged robots. PMID:21228904

Predicting neural network firing pattern from phase resetting curve

NASA Astrophysics Data System (ADS)

Oprisan, Sorinel; Oprisan, Ana

2007-04-01

Autonomous neural networks called central pattern generators (CPG) are composed of endogenously bursting neurons and produce rhythmic activities, such as flying, swimming, walking, chewing, etc. Simplified CPGs for quadrupedal locomotion and swimming are modeled by a ring of neural oscillators such that the output of one oscillator constitutes the input for the subsequent neural oscillator. The phase response curve (PRC) theory discards the detailed conductance-based description of the component neurons of a network and reduces them to ``black boxes'' characterized by a transfer function, which tabulates the transient change in the intrinsic period of a neural oscillator subject to external stimuli. Based on open-loop PRC, we were able to successfully predict the phase-locked period and relative phase between neurons in a half-center network. We derived existence and stability criteria for heterogeneous ring neural networks that are in good agreement with experimental data.

The Sea Slug, Pleurobranchaea californica: A Signpost Species in the Evolution of Complex Nervous Systems and Behavior.

PubMed

Gillette, Rhanor; Brown, Jeffrey W

2015-12-01

How and why did complex brain and behavior evolve? Clues emerge from comparative studies of animals with simpler morphology, nervous system, and behavioral economics. The brains of vertebrates, arthropods, and some annelids have highly derived executive structures and function that control downstream, central pattern generators (CPGs) for locomotion, behavioral choice, and reproduction. For the vertebrates, these structures-cortex, basal ganglia, and hypothalamus-integrate topographically mapped sensory inputs with motivation and memory to transmit complex motor commands to relay stations controlling CPG outputs. Similar computations occur in the central complex and mushroom bodies of the arthropods, and in mammals these interactions structure subjective thought and socially based valuations. The simplest model systems available for comparison are opisthobranch molluscs, which have avoided selective pressure for complex bodies, brain, and behavior through potent chemical defenses. In particular, in the sea-slug Pleurobranchaea californica the functions of vertebrates' olfactory bulb and pallium are performed in the peripheral nervous system (PNS) of the chemotactile oral veil. Functions of hypothalamus and basal ganglia are combined in Pleurobranchaea's feeding motor network. The actions of basal ganglia on downstream locomotor regions and spinal CPGs are analogous to Pleurobranchaea's feeding network actions on CPGs for agonist and antagonist behaviors. The nervous systems of opisthobranch and pulmonate gastropods may conserve or reflect relations of the ancestral urbilaterian. Parallels and contrasts in neuronal circuits for action selection in Pleurobranchaea and vertebrates suggest how a basic set of decision circuitry was built upon in evolving segmentation, articulated skeletons, sociality, and highly invested reproductive strategies. They suggest (1) an origin of olfactory bulb and pallium from head-region PNS; (2) modularization of an ancestral feeding network into discrete but interacting executive modules for incentive comparison and decision (basal ganglia), and homeostatic functions (hypothalamus); (3) modification of a multifunctional premotor network for turns and locomotion, and its downstream targets for mid-brain and hind-brain motor areas and spinal CPGs; (4) condensation of a distributed serotonergic network for arousal into the raphe nuclei, with superimposed control by a peptidergic hypothalamic network mediating appetite and arousal; (5) centralization and condensation of the dopaminergic sensory afferents of the PNS, and/or the disperse dopaminergic elements of central CPGs, into the brain nuclei mediating valuation, reward, and motor arousal; and (6) the urbilaterian possessed the basic circuit relations integrating sensation, internal state, and learning for cost-benefit approach-avoidance decisions. © The Author 2015. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

Systematic Review and Quality Appraisal of Practice Guidelines for Self-Harm in Children and Adolescents.

PubMed

Courtney, Darren B; Duda, Stephanie; Szatmari, Peter; Henderson, Joanna; Bennett, Kathryn

2018-05-02

This study aimed to systematically identify and appraise clinical practice guidelines (CPGs) relating to the assessment and management of suicide risk and self-harm in children and adolescents. Our research question is as follows: For young people (under 18 years old) presenting to clinical care with suicide ideation or a history of self-harm, what is the quality of up-to-date CPGs? Using the PRISMA format, we systematically identified CPGs meeting our inclusion and exclusion criteria. Subsequently, two independent raters conducted appraisals of the eligible CPGs using the Appraisal of Guidelines for Research and Evaluation II instrument. CPGs were then classified as "poor quality," "minimum quality," and "high quality" using operationally defined criteria developed a priori. We identified 10 eligible CPGs published or renewed between 2005 and May 2017. Only the long-term management of self-harm CPGs produced by the National Institute for Health and Care Excellence met "high-quality" criteria. Despite multiple options of CPGs published to choose from, only one was identified as "high quality," where bias is adequately minimized. Clinicians are advised to direct resources to implementing the "high-quality" CPG. © 2018 The American Association of Suicidology.

Quality assessment of osteoporosis clinical practice guidelines for physical activity and safe movement: an AGREE II appraisal.

PubMed

Armstrong, James Jacob; Rodrigues, Isabel Braganca; Wasiuta, Tom; MacDermid, Joy C

2016-01-01

Many osteoporosis clinical practice guidelines are published, and the extent to which physical activity and safe movement is addressed varies. To better inform clinical decision-making, a quality assessment and structured analysis of recommendations was undertaken. Guideline quality varied substantially, and improvement is necessary in physical activity and safe movement recommendations. The purpose of the present study is to survey available osteoporosis clinical practice guidelines (CPGs) containing physical activity and safe movement recommendations in order to assess the methodological quality with which they were developed. An analysis of the various physical activity and safe movement recommendations was conducted to determine variability between CPGs. An online literature search revealed 19 CPGs meeting our inclusion criteria. Three independent scorers evaluated CPG quality using the Appraisal of Guidelines for Research and Evaluation version II (AGREE II) instrument. Two separate individuals used a standard table to extract relevant recommendations. Intra-reviewer AGREE II score agreement ranged from fair to good (intra-class correlation coefficient (ICC) = 0.34 to 0.65). The quality of the 19 included CPGs was variable (AGREE sub-scores: 14 to 100%). CPGs scored higher in the "scope and purpose" and "clarity of presentation" domains. They scored the lowest in "applicability" and "editorial independence." Four CPGs were classified as high quality, ten average quality, and five low quality. Most CPGs recommended weight-bearing, muscle-strengthening, and resistance exercises. Information on exercise dosage, progression, and contraindications was often absent. Immobility and movements involving spinal flexion and/or torsion were discouraged. There were several high-quality CPGs; however, variability in quality and lack of specific parameters for implementation necessitates caution and critical examination by readers. CPG development groups should pay special attention to the clinical applicability of their CPGs as well as fully disclosing conflicts of interest. CPGs were in general an agreement regarding safe physical activity and safe movement recommendations. However, recommendations were often vague and the more specific recommendations were inconsistent between CPGs.

Neonatal testosterone suppresses a neuroendocrine pulse generator required for reproduction

NASA Astrophysics Data System (ADS)

Israel, Jean-Marc; Cabelguen, Jean-Marie; Le Masson, Gwendal; Oliet, Stéphane H.; Ciofi, Philippe

2014-02-01

The pituitary gland releases hormones in a pulsatile fashion guaranteeing signalling efficiency. The determinants of pulsatility are poorly circumscribed. Here we show in magnocellular hypothalamo-neurohypophyseal oxytocin (OT) neurons that the bursting activity underlying the neurohormonal pulses necessary for parturition and the milk-ejection reflex is entirely driven by a female-specific central pattern generator (CPG). Surprisingly, this CPG is active in both male and female neonates, but is inactivated in males after the first week of life. CPG activity can be restored in males by orchidectomy or silenced in females by exogenous testosterone. This steroid effect is aromatase and caspase dependent, and is mediated via oestrogen receptor-α. This indicates the apoptosis of the CPG network during hypothalamic sexual differentiation, explaining why OT neurons do not burst in adult males. This supports the view that stereotypic neuroendocrine pulsatility is governed by CPGs, some of which are subjected to gender-specific perinatal programming.

Perception, attitude, and satisfaction of paediatric physicians and nurses towards clinical practice guidelines at a university teaching hospital.

PubMed

Amer, Yasser Sami; Al Nemri, Abdulrahman; Osman, Mohamed Elfaki; Saeed, Elshazaly; Assiri, Asaad Mohamed; Mohamed, Sarar

2018-04-03

To explore perception, attitude, and satisfaction of paediatric clinicians, trainees, and nurses at King Khalid University Hospital towards clinical practice guidelines (CPGs) including the locally adapted diabetic ketoacidosis CPG (DKA-CPG). A cross-sectional survey was distributed to 260 doctors and nurses working in the paediatrics department. The response rate was 95.4%. The respondents had a positive perception and attitude towards general CPGs and specifically for the DKA-CPG; 98.7% thought CPGs were useful sources of advice, improved safety, and decreased risk, and reduced variation in practice. A total of 99.2% thought CPGs were good clinical tools, 98.3% satisfied with, had confidence in well-developed CPGs, and would recommend them to their colleagues to use, and 94.6% agreed they were cost-effective. The preferred format for CPGs was paper (46.6%) and electronic (42.9%). The DKA-CPG helped in managing patients and respondents were all satisfied and had confidence with it (100%). The rationale and objectives of the DKA-CPG were clear for 99.25%; 98.5% thought the layout was clear and well organized and user-friendly (96.2%). Compared with nurses, physicians had a higher perception towards CPGs in general (P < .05) and the DKA-CPG (P < .05). The paediatric doctors, and nurses have a great perception and satisfaction and positive attitude towards CPGs in general, towards the paediatric diabetic ketoacidosis CPG in particular, which in turn had a positive impact on the acceptability and implementation of the CPGs. These findings could help in sustaining a safe and high-quality health care environment through implementation of evidence-based CPGs. © 2018 John Wiley & Sons, Ltd.

Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies.

PubMed

Hedman, Åsa K; Mendelson, Michael M; Marioni, Riccardo E; Gustafsson, Stefan; Joehanes, Roby; Irvin, Marguerite R; Zhi, Degui; Sandling, Johanna K; Yao, Chen; Liu, Chunyu; Liang, Liming; Huan, Tianxiao; McRae, Allan F; Demissie, Serkalem; Shah, Sonia; Starr, John M; Cupples, L Adrienne; Deloukas, Panos; Spector, Timothy D; Sundström, Johan; Krauss, Ronald M; Arnett, Donna K; Deary, Ian J; Lind, Lars; Levy, Daniel; Ingelsson, Erik

2017-01-01

Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications. To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage ( P <1.08E-07) and replicated 33 (at Bonferroni-corrected P <0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglycerides and high-density lipoprotein cholesterol (HDL-C; cg27243685; P =8.1E-26 and 9.3E-19) was associated with cis -expression of a reverse cholesterol transporter ( ABCG1; P =7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38; 95% confidence interval, 1.15-1.66; P =0.0007). We found significant cis -methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels ( P TC =0.004, P HDL-C =0.008 and P triglycerides =0.00003) and coronary heart disease ( P =0.0007). For example, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at APOB were cis -methylation quantitative trait loci for a low-density lipoprotein cholesterol-related differentially methylated locus. We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events. © 2017 The Authors.

Variation in motor output and motor performance in a centrally generated motor pattern

PubMed Central

Norris, Brian J.; Doloc-Mihu, Anca; Calabrese, Ronald L.

2014-01-01

Central pattern generators (CPGs) produce motor patterns that ultimately drive motor outputs. We studied how functional motor performance is achieved, specifically, whether the variation seen in motor patterns is reflected in motor performance and whether fictive motor patterns differ from those in vivo. We used the leech heartbeat system in which a bilaterally symmetrical CPG coordinates segmental heart motor neurons and two segmented heart tubes into two mutually exclusive coordination modes: rear-to-front peristaltic on one side and nearly synchronous on the other, with regular side-to-side switches. We assessed individual variability of the motor pattern and the beat pattern in vivo. To quantify the beat pattern we imaged intact adults. To quantify the phase relations between motor neurons and heart constrictions we recorded extracellularly from two heart motor neurons and movement from the corresponding heart segments in minimally dissected leeches. Variation in the motor pattern was reflected in motor performance only in the peristaltic mode, where larger intersegmental phase differences in the motor neurons resulted in larger phase differences between heart constrictions. Fictive motor patterns differed from those in vivo only in the synchronous mode, where intersegmental phase differences in vivo had a larger front-to-rear bias and were more constrained. Additionally, load-influenced constriction timing might explain the amplification of the phase differences between heart segments in the peristaltic mode and the higher variability in motor output due to body shape assumed in this soft-bodied animal. The motor pattern determines the beat pattern, peristaltic or synchronous, but heart mechanics influence the phase relations achieved. PMID:24717348

Using AGREE II to Evaluate the Quality of Traditional Medicine Clinical Practice Guidelines in China.

PubMed

Deng, Wei; Li, Le; Wang, Zixia; Chang, Xiaonan; Li, Rui; Fang, Ziye; Wei, Dang; Yao, Liang; Wang, Xiaoqin; Wang, Qi; An, Guanghui

2016-03-15

To evaluate/assess the quality of the Clinical Practice Guidelines (CPGs) of traditional medicine in China. We systematically searched the literature databases WanFang Data, VIP, CNKI and CBM for studies published between 1978 and 2012 to identify and select CPGs of traditional medicine. We used the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument to evaluate these guidelines. A total of 75 guidelines were included, of which 46 guidelines (62%) were on Traditional Chinese Medicine, 19 (25%) on Chinese Integrated Medicine, and 10 (13%) on Uyghur Medicine. Most traditional medicine CPGs published in domestic journals scored <20% (range: 0-63%). Eleven (14%) CPGs were developed following the methodology of evidence-based medicine. In each domain of AGREE II, traditional Medicine CPGs performed clearly better than international CPGs. The same trend was seen in guidelines of Modern Medicine. An increasing amount of CPGs are being published, but their quality is low. Referring to the key points of international guidelines development, supervision through AGREE II, cooperating with international groups and exploring the strategy of guideline development could improve the quality of CPGs on traditional medicine. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Neural control and adaptive neural forward models for insect-like, energy-efficient, and adaptable locomotion of walking machines

PubMed Central

Manoonpong, Poramate; Parlitz, Ulrich; Wörgötter, Florentin

2013-01-01

Living creatures, like walking animals, have found fascinating solutions for the problem of locomotion control. Their movements show the impression of elegance including versatile, energy-efficient, and adaptable locomotion. During the last few decades, roboticists have tried to imitate such natural properties with artificial legged locomotion systems by using different approaches including machine learning algorithms, classical engineering control techniques, and biologically-inspired control mechanisms. However, their levels of performance are still far from the natural ones. By contrast, animal locomotion mechanisms seem to largely depend not only on central mechanisms (central pattern generators, CPGs) and sensory feedback (afferent-based control) but also on internal forward models (efference copies). They are used to a different degree in different animals. Generally, CPGs organize basic rhythmic motions which are shaped by sensory feedback while internal models are used for sensory prediction and state estimations. According to this concept, we present here adaptive neural locomotion control consisting of a CPG mechanism with neuromodulation and local leg control mechanisms based on sensory feedback and adaptive neural forward models with efference copies. This neural closed-loop controller enables a walking machine to perform a multitude of different walking patterns including insect-like leg movements and gaits as well as energy-efficient locomotion. In addition, the forward models allow the machine to autonomously adapt its locomotion to deal with a change of terrain, losing of ground contact during stance phase, stepping on or hitting an obstacle during swing phase, leg damage, and even to promote cockroach-like climbing behavior. Thus, the results presented here show that the employed embodied neural closed-loop system can be a powerful way for developing robust and adaptable machines. PMID:23408775

Adherence to treatment guidelines for primary sarcomas affects patient survival: a side study of the European CONnective TIssue CAncer NETwork (CONTICANET).

PubMed

Rossi, C R; Vecchiato, A; Mastrangelo, G; Montesco, M C; Russano, F; Mocellin, S; Pasquali, S; Scarzello, G; Basso, U; Frasson, A; Pilati, P; Nitti, D; Lurkin, A; Ray-Coquard, I

2013-06-01

The impact of adherence to clinical practice guidelines (CPGs) for loco-regional treatment (i.e. surgery and radiotherapy) and chemotherapy on local disease control and survival in sarcoma patients was investigated in a European study conducted in an Italian region (Veneto). The completeness of the adherence to the Italian CPGs for sarcomas treatment was assessed by comparing the patient's charts and the CPGs. Propensity score-adjusted multivariate survival analysis was used to assess the impact of CPGs adherence on patient clinical outcomes. A total of 151 patients were included. Adherence to CPGs for loco-regional therapy and chemotherapy was observed in 106 out of 147 (70.2%) and 129 out of 139 (85.4%) patients, respectively. Non-adherence to CPGs for loco-regional treatment was independently associated with AJCC stage III disease [odds ratio (OR) 1.77, P = 0.011] and tumor-positive excision margin (OR 3.55, P = 0.003). Patients not treated according to the CPGs were at a higher risk of local recurrence [hazard ratio (HR) 5.4, P < 0.001] and had a shorter sarcoma-specific survival (HR 4.05, P < 0.001), independently of tumor stage. Incomplete adherence to CPGs for loco-regional treatment of sarcomas was associated with worse prognosis in patients with non-metastatic tumors.

Curricula for teaching clinical practice guidelines in US psychiatry residency and child and adolescent fellowship programs: a survey study.

PubMed

Bannister, Elizabeth; Nakonezny, Paul; Byerly, Matthew

2014-04-01

To determine the characteristics of curricula for teaching the content of clinical practice guidelines (CPGs) in psychiatric residency and child and adolescent fellowship programs as well as to determine if and how the learning of CPG content is applied in clinical care settings. We conducted a national online survey of directors of general psychiatry residency and child and adolescent fellowship programs in the USA. The survey questionnaire included 13 brief questions about the characteristics used to teach CPGs in the programs, as well as two demographic questions about each program and director. Descriptive statistics were reported for each questionnaire item by program classification (i.e., child and adolescent vs. general psychiatry). The survey response rate was 49.8% (146 out of 293). Just 23% of programs reported having written goals and objectives related to teaching CPGs. The most frequently taught aspect of CPGs was their content (72% of programs). Didactic sessions were the most frequently employed teaching strategy (79% of programs). Regarding the application of CPG learning in treatment care settings, just 16% of programs applied algorithms in care settings, and 15% performed evaluations to determine consistency between CPG recommendations and care delivery. Only 8% of programs utilized audit and feedback to residents about their adherence to CPGs. Faculty time constraints and insufficient interest were the leading barriers (39% and 33% of programs, respectively) to CPG teaching, although 38% reported no barriers. However, child and adolescent programs less commonly identified insufficient interest among faculty as a barrier to teaching CPGs compared to general programs (20% vs. 43%). Moreover, compared to general programs, child and adolescent fellowship programs taught more aspects of CPGs, used more educational activities to teach the content of specific CPGs, and used more methods to evaluate the teaching of CPGs. Although the majority of programs provided some teaching of CPGs, the rigorousness of the teaching approaches was limited, especially attempts to evaluate the extent and effectiveness of their use in clinical care. Child and adolescent fellowship programs provided more extensive teaching and evaluation related to CPGs.

Fertility preservation in children, adolescents, and young adults with cancer: Quality of clinical practice guidelines and variations in recommendations.

PubMed

Font-Gonzalez, Anna; Mulder, Renée L; Loeffen, Erik A H; Byrne, Julianne; van Dulmen-den Broeder, Eline; van den Heuvel-Eibrink, Marry M; Hudson, Melissa M; Kenney, Lisa B; Levine, Jennifer M; Tissing, Wim J E; van de Wetering, Marianne D; Kremer, Leontien C M

2016-07-15

Fertility preservation care for children, adolescents, and young adults (CAYAs) with cancer is not uniform among practitioners. To ensure high-quality care, evidence-based clinical practice guidelines (CPGs) are essential. The authors identified existing CPGs for fertility preservation in CAYAs with cancer, evaluated their quality, and explored differences in recommendations. A systematic search in PubMed (January 2000-October 2014); guideline databases; and Web sites of oncology, pediatric, and fertility organizations was performed. Two reviewers evaluated the quality of the identified CPGs using the Appraisal of Guidelines for Research and Evaluation II Instrument (AGREE II). From high-quality CPGs, the authors evaluated concordant and discordant areas among the recommendations. A total of 25 CPGs regarding fertility preservation were identified. The average AGREE II domain scores (scale of 0%-100%) varied from 15% on applicability to 100% on clarity of presentation. The authors considered 8 CPGs (32%) to be of high quality, which was defined as scores ≥60% in any 4 domains. Large variations in the recommendations of the high-quality CPGs were observed, with 87.2% and 88.6%, respectively, of discordant guideline areas among the fertility preservation recommendations for female and male patients with cancer. Only approximately one-third of the identified CPGs were found to be of sufficient quality. Of these CPGs, the fertility preservation recommendations varied substantially, which can be a reflection of inadequate evidence for specific recommendations, thereby hindering the ability of providers to deliver high-quality care. CPGs including a transparent decision process for fertility preservation can help health care providers to deliver optimal and uniform care, thus improving the quality of life of CAYAs with cancer and cancer survivors. Cancer 2016;122:2216-23. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

dbCPG: A web resource for cancer predisposition genes.

PubMed

Wei, Ran; Yao, Yao; Yang, Wu; Zheng, Chun-Hou; Zhao, Min; Xia, Junfeng

2016-06-21

Cancer predisposition genes (CPGs) are genes in which inherited mutations confer highly or moderately increased risks of developing cancer. Identification of these genes and understanding the biological mechanisms that underlie them is crucial for the prevention, early diagnosis, and optimized management of cancer. Over the past decades, great efforts have been made to identify CPGs through multiple strategies. However, information on these CPGs and their molecular functions is scattered. To address this issue and provide a comprehensive resource for researchers, we developed the Cancer Predisposition Gene Database (dbCPG, Database URL: http://bioinfo.ahu.edu.cn:8080/dbCPG/index.jsp), the first literature-based gene resource for exploring human CPGs. It contains 827 human (724 protein-coding, 23 non-coding, and 80 unknown type genes), 637 rats, and 658 mouse CPGs. Furthermore, data mining was performed to gain insights into the understanding of the CPGs data, including functional annotation, gene prioritization, network analysis of prioritized genes and overlap analysis across multiple cancer types. A user-friendly web interface with multiple browse, search, and upload functions was also developed to facilitate access to the latest information on CPGs. Taken together, the dbCPG database provides a comprehensive data resource for further studies of cancer predisposition genes.

Developing prehospital clinical practice guidelines for resource limited settings: why re-invent the wheel?

PubMed

McCaul, Michael; de Waal, Ben; Hodkinson, Peter; Pigoga, Jennifer L; Young, Taryn; Wallis, Lee A

2018-02-05

Methods on developing new (de novo) clinical practice guidelines (CPGs) have received substantial attention. However, the volume of literature is not matched by research into alternative methods of CPG development using existing CPG documents-a specific issue for guideline development groups in low- and middle-income countries. We report on how we developed a context specific prehospital CPG using an alternative guideline development method. Difficulties experienced and lessons learnt in applying existing global guidelines' recommendations to a national context are highlighted. The project produced the first emergency care CPG for prehospital providers in Africa. It included > 270 CPGs and produced over 1000 recommendations for prehospital emergency care. We encountered various difficulties, including (1) applicability issues: few pre-hospital CPGs applicable to Africa, (2) evidence synthesis: heterogeneous levels of evidence classifications and (3) guideline quality. Learning points included (1) focusing on key CPGs and evidence mapping, (2) searching other resources for CPGs, (3) broad representation on CPG advisory boards and (4) transparency and knowledge translation. Re-inventing the wheel to produce CPGs is not always feasible. We hope this paper will encourage further projects to use existing CPGs in developing guidance to improve patient care in resource-limited settings.

National Priority Setting of Clinical Practice Guidelines Development for Chronic Disease Management.

PubMed

Jo, Heui-Sug; Kim, Dong Ik; Oh, Moo-Kyung

2015-12-01

By November 2013, a total of 125 clinical practice guidelines (CPGs) have been developed in Korea. However, despite the high burden of diseases and the clinical importance of CPGs, most chronic diseases do not have available CPGs. Merely 83 CPGs are related to chronic diseases, and only 40 guidelines had been developed in the last 5 yr. Considering the rate of the production of new evidence in medicine and the worsening burden from chronic diseases, the need for developing CPGs for more chronic diseases is becoming increasingly pressing. Since 2011, the Korean Academy of Medical Sciences and the Korea Centers for Disease Control and Prevention have been jointly developing CPGs for chronic diseases. However, priorities have to be set and resources need to be allocated within the constraint of a limited funding. This study identifies the chronic diseases that should be prioritized for the development of CPGs in Korea. Through an objective assessment by using the analytic hierarchy process and a subjective assessment with a survey of expert opinion, high priorities were placed on ischemic heart disease, cerebrovascular diseases, Alzheimer's disease and other dementias, osteoarthritis, neck pain, chronic kidney disease, and cirrhosis of the liver.

Relationship Between Using Clinical Practice Guidelines for Pain Treatment and Physicians' Training and Attitudes Toward Patients and the Effects on Patient Care.

PubMed

Dueñas, María; Salazar, Alejandro; Sánchez, Modesto; De Sola, Helena; Ojeda, Begoña; Failde, Inmaculada

2018-01-01

To determine the use of clinical practice guidelines (CPGs) for chronic pain (CP) management; analyze the effects of training in pain and the attitudes of physicians toward pain and CP patients on the adherence to these CPGs; and assess the impact of adherence to CPGs on patient care. This was a cross-sectional study in a sample of physicians involved in CP patient management. Information on the use of CPGs for CP management, their training in pain, and their attitudes toward pain, patients, and patient care was collected. Descriptive and bivariate analyses were performed, and a multinomial logistic regression model was constructed to analyze factors associated with the use of CPGs. Of the 257 physicians surveyed, 46.6% were physiatrists, 26.7% were general practitioners, and 26.7% were medical oncologists. Although 96.5% claimed to have received training in pain, only 10.1% had received college training, and 76.3% expressed having gaps in their knowledge; 53.9% stated they applied CPGs often/always, and 12.5% rarely/never. Limited knowledge on pain, reduced involvement in training activities, more negative attitudes toward patients, and having experienced CP were the factors related to reduced adherence to CPGs, especially among the youngest respondents. The greater the use of CPGs, the better the patient care was. Access to scientific information and specialized training are factors related to the use of CPGs for pain treatment. Therefore, the inclusion of CP training in university and during medical specialty training will be essential measures to improve adherence to CPG, thereby improving patient care and pain control. © 2017 World Institute of Pain.

Genome-wide DNA methylation at birth in relation to in utero arsenic exposure and the associated health in later life.

PubMed

Kaushal, Akhilesh; Zhang, Hongmei; Karmaus, Wilfried J J; Everson, Todd M; Marsit, Carmen J; Karagas, Margaret R; Tsai, Shih-Fen; Wen, Hui-Ju; Wang, Shu-Li

2017-05-30

In utero arsenic exposure may alter fetal developmental programming by altering DNA methylation, which may result in a higher risk of disease in later life. We evaluated the association between in utero arsenic exposure and DNA methylation (DNAm) in cord blood and its influence in later life. Genome-wide DNA methylation in cord blood from 64 subjects in the Taiwanese maternal infant and birth cohort was analyzed. Robust regressions were applied to assess the association of DNA methylation with in utero arsenic exposure. Multiple testing was adjusted by controlling false discovery rate (FDR) of 0.05. The DAVID bioinformatics tool was implemented for functional annotation analyses on the detected CpGs. The identified CpGs were further tested in an independent cohort. For the CpGs replicated in the independent cohort, linear mixed models were applied to assess the association of DNA methylation with low-density lipoprotein (LDL) at different ages (2, 5, 8, 11 and 14 years). In total, 579 out of 385,183 CpGs were identified after adjusting for multiple testing (FDR = 0.05), of which ~60% were positively associated with arsenic exposure. Functional annotation analysis on these CpGs detected 17 KEGG pathways (FDR = 0.05) including pathways for cardiovascular diseases (CVD) and diabetes mellitus. In the independent cohort, about 46% (252 out of 553 CpGs) of the identified CpGs showed associations consistent with those in the study cohort. In total, 11 CpGs replicated in the independent cohort were in the pathways related to CVD and diabetes mellitus. Via longitudinal analyses, we found at 5 out of the 11 CpGs methylation was associated with LDL over time and interactions between DNA methylation and time were observed at 4 of the 5 CpGs, cg25189764 (coeff = 0.157, p-value = 0.047), cg04986899 (coeff. For interaction [coeff.int] = 0.030, p-value = 0.024), cg04903360 (coeff.int = 0.026, p-value = 0.032), cg08198265 (coeff.int = -0.063, p-value = 0.0021), cg10473311 (coeff.int = -0.021, p-value = 0.027). In utero arsenic exposure was associated with cord blood DNA methylation at various CpGs. The identified CpGs may help determine pathological epigenetic mechanisms linked to in utero arsenic exposure. Five CpGs (cg25189764, cg04986899, cg04903360, cg08198265 and cg10473311) may serve as epigenetic markers for changes in LDL later in life.

[Clinical practice guidelines in Peru: evaluation of its quality using the AGREE II instrument].

PubMed

Canelo-Aybar, Carlos; Balbin, Graciela; Perez-Gomez, Ángela; Florez, Iván D

2016-01-01

To evaluate the methodological quality of clinical practice guidelines (CPGs) put into practice by the Peruvian Ministry of Health (MINSA), 17 CPGs from the ministry, published between 2009 and 2014, were independently evaluated by three methodologic experts using the AGREE II instrument. The score of AGREE II domains was low and very low in all CPGs: scope and purpose (medium, 44%), clarity of presentation (medium, 47%), participation of decision-makers (medium, 8%), methodological rigor (medium, 5%), applicability (medium, 5%), and editorial independence (medium, 8%). In conclusion, the methodological quality of CPGs implemented by the MINSA is low. Consequently, its use could not be recommended. The implementation of the methodology for the development of CPGs described in the recentlypublished CPG methodological preparation manual in Peru is a pressing need.

dbCPG: A web resource for cancer predisposition genes

PubMed Central

Wei, Ran; Yao, Yao; Yang, Wu; Zheng, Chun-Hou; Zhao, Min; Xia, Junfeng

2016-01-01

Cancer predisposition genes (CPGs) are genes in which inherited mutations confer highly or moderately increased risks of developing cancer. Identification of these genes and understanding the biological mechanisms that underlie them is crucial for the prevention, early diagnosis, and optimized management of cancer. Over the past decades, great efforts have been made to identify CPGs through multiple strategies. However, information on these CPGs and their molecular functions is scattered. To address this issue and provide a comprehensive resource for researchers, we developed the Cancer Predisposition Gene Database (dbCPG, Database URL: http://bioinfo.ahu.edu.cn:8080/dbCPG/index.jsp), the first literature-based gene resource for exploring human CPGs. It contains 827 human (724 protein-coding, 23 non-coding, and 80 unknown type genes), 637 rats, and 658 mouse CPGs. Furthermore, data mining was performed to gain insights into the understanding of the CPGs data, including functional annotation, gene prioritization, network analysis of prioritized genes and overlap analysis across multiple cancer types. A user-friendly web interface with multiple browse, search, and upload functions was also developed to facilitate access to the latest information on CPGs. Taken together, the dbCPG database provides a comprehensive data resource for further studies of cancer predisposition genes. PMID:27192119

Competing interests in development of clinical practice guidelines for diabetes management: Report from a multidisciplinary workshop

PubMed Central

Sawka, Anna M; Magalhães, Lilian; Gafni, Amiram; Lewis, Gary F

2008-01-01

Objective To explore the complex issue of competing interests (CIs) in development of clinical practice guidelines (CPGs) in diabetes with stakeholders. Methods A multidisciplinary panel of 26 health, methodological, legal, and bioethical experts, trainees, and lay people from across Canada participated in a workshop on CIs in CPGs. Mixed methods were used such that qualitative themes were extracted from the discussions and quantitative survey data were collected. Results In the discussions, participants acknowledged that potential competing interests were not uncommon among sponsoring organizations and authors of CPGs. Avoidance of all potential CIs in development of CPGs was emulated as ideal, but considered probably unrealistic, given the paucity of peer-reviewed funding opportunities for development of evidence-informed CPGs and the scarcity of knowledgeable authors without CIs. An optimal approach for management of CIs in CPGs could not be agreed upon by participants. Full disclosure of any financial CIs for authors and sponsoring organizations as well as discouragement of external financial contributors from writing involvement, were endorsed by participants in the workshop and a subsequent survey. Conclusions Complete disclosure of financial CIs of sponsoring organizations and authors of CPGs is essential, yet the optimal approach to management of potential CIs is currently undefined. PMID:21197330

Transgenerational effects of the endocrine disruptor vinclozolin on the methylation pattern of imprinted genes in the mouse sperm.

PubMed

Stouder, Christelle; Paoloni-Giacobino, Ariane

2010-02-01

Endocrine-disrupting chemicals (EDCs), among which is the antiandrogen vinclozolin (VCZ), have been reported to affect the male reproductive system. In this study, VCZ was administered to pregnant mice at the time of embryo sex determination, and its possible effects on the differentially methylated domains (DMDs) of two paternally (H19 and Gtl2) and three maternally (Peg1, Snrpn, and Peg3) imprinted genes were tested in the male offspring. The CpGs methylation status within the five gene DMDs was analyzed in the sperm, tail, liver, and skeletal muscle DNAs by pyrosequencing. In the sperm of controls, the percentages of methylated CpGs were close to the theoretical values of 100 and 0% in paternally or maternally imprinted genes respectively. VCZ decreased the percentages of methylated CpGs of H19 and Gtl2 (respective values 83.1 and 91.5%) and increased those of Peg1, Snrpn, and Peg3 (respective values 11.3, 18.3, and 11.2%). The effects of VCZ were transgenerational, but they disappeared gradually from F1 to F3. The mean sperm concentration of the VCZ-administered female offspring was only 56% of that of the controls in the F1 offspring, and it was back to normal values in the F2 and F3 offspring. In the somatic cells of controls, the percentages of methylated CpGs were close to the theoretical value of 50% and, surprisingly, VCZ altered the methylation of Peg3. We propose that the deleterious effects of VCZ on the male reproductive system are mediated by imprinting defects in the sperm. The reported effects of EDCs on human male spermatogenesis might be mediated by analogous imprinting alterations.

A simple rule for quadrupedal gait generation determined by leg loading feedback: a modeling study

PubMed Central

Fukuoka, Yasuhiro; Habu, Yasushi; Fukui, Takahiro

2015-01-01

We discovered a specific rule for generating typical quadrupedal gaits (the order of the movement of four legs) through a simulated quadrupedal locomotion, in which unprogrammed gaits (diagonal/lateral sequence walks, left/right-lead canters, and left/right-lead transverse gallops) spontaneously emerged because of leg loading feedbacks to the CPGs hard-wired to produce a default trot. Additionally, all gaits transitioned according to speed, as seen in animals. We have therefore hypothesized that various gaits derive from a trot because of posture control through leg loading feedback. The body tilt on the two support legs of each diagonal pair during trotting was classified into three types (level, tilted up, or tilted down) according to speed. The load difference between the two legs led to the phase difference between their CPGs via the loading feedbacks, resulting in nine gaits (32: three tilts to the power of two diagonal pairs) including the aforementioned. PMID:25639661

Critical Appraisal of International Clinical Practice Guidelines in Kidney Transplantation Using the Appraisal of Guidelines for Research and Education (AGREE) II Tool: A Systematic Review.

PubMed

OʼDonoghue, Katriona Jane Marie; Reed, Rhiannon D; Knight, Simon R; O'Callaghan, John M; Ayaz-Shah, Anam A; Hassan, Sevda; Weissenbacher, Annemarie; Morris, Peter J; Pengel, Liset H M

2018-05-22

Whilst Clinical Practice Guidelines (CPGs) are used for the development of local protocols in kidney transplantation (Ktx), the quality of their methodology is variable. This systematic review aimed to critically appraise international CPGs in all aspects of Ktx using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool. CPGs in Ktx and donation published between 2010 and 2017 were identified from MEDLINE, Embase, National Guideline Clearinghouse, NHS and NICE Evidence Searches, and the websites of transplant societies. Using AGREE II, 3 appraisers assessed the quality of CPGs. Interrater reliability was measured using the intraclass correlation coefficient (ICC). Searches identified 3,168 records and 115 CPGs were included. The highest scoring AGREE II domain was 'Scope and Purpose' (80%; Range 30-100%), followed by 'Clarity of Presentation' (77%; Range 43-98%), 'Editorial independence' (52%; Range 0-94%), 'Rigour of Development' (47%; Range 6-97%) and 'Stakeholder Involvement' (41%; Range 11-85%). The poorest scoring domain was 'Applicability' (31%; Range 3-74%). Most CPGs were recommended for future use either with (63%) or without modifications (18%). A small number were not recommended for future use (14%) or reviewers did not agree on recommending the CPG (5%). The overall mean CPG quality score was 4 out of 7 (Range 2-7). The mean ICC of 0.74 indicated substantial agreement between reviewers. The quality of international CPGs in Ktx was variable, and most CPGs lacked key aspects of methodological robustness and transparency. Improvements in methodology, patient involvement and strategies for implementation are required.

A systematic review and quality appraisal of international guidelines for early breast cancer systemic therapy: Are recommendations sensitive to different global resources?

PubMed

Gandhi, S; Verma, S; Ethier, J-L; Simmons, C; Burnett, H; Alibhai, S M H

2015-08-01

The breast cancer incidence in low and middle income countries (LMCs) is increasing globally, and patient outcomes are generally worse in these nations compared to high income countries (HICs). This is partly due to resource constraints associated with implementing recommended breast cancer therapies. Clinical practice guideline (CPG) adherence can improve breast cancer outcomes, however, many CPGs are created in HICs, and include costly recommendations that may not be feasible in LMCs. In addition, the quality of CPGs can be variable. The aim of this study was to perform a systematic review of CPGs on early breast cancer systemic therapy with potential international impact, to evaluate their content, quality, and resource sensitivity. A MEDLINE and gray literature search was completed for English language CPGs published between 2005 and 2010, and then updated to July 2014. Extracted guidelines were evaluated using the AGREE 2 instrument. Guidelines were specifically analyzed for resource sensitivity. Most of the extracted CPGs had similar recommendations with regards to systemic therapy. However, only one, the Breast Health Global Initiative, made recommendations with consideration of different global resources. Overall, the CPGs were of variable quality, and most scored poorly in the quality domain evaluating implementation barriers such as resources. Published CPGs for early breast cancer are created in HICs, have similar recommendations, and are generally resource-insensitive. Given the visibility and influence of these CPGs on LMCs, efforts to create higher quality, resource-sensitive guidelines with less redundancy are needed. Copyright © 2014 Elsevier Ltd. All rights reserved.

A Systematic Review and Appraisal of Clinical Practice Guidelines for Musculoskeletal Soft Tissue Injuries and Conditions.

PubMed

Pincus, Daniel; Kuhn, John E; Sheth, Ujash; Rizzone, Katie; Colbenson, Kristi; Dwyer, Tim; Karpinos, Ashley; Marks, Paul H; Wasserstein, David

2017-05-01

Clinical practice guidelines (CPGs) are published by several sports medicine institutions. A systematic evaluation can help identify the highest quality CPGs for clinical use and identify any deficiencies that remain. To identify and appraise CPGs relevant to clinical sports medicine professionals. Systematic review. Predetermined selection criteria were utilized by 2 reviewers who independently identified published CPGs before January 1, 2014. CPGs were excluded if they focused on injured workers, radiological criteria, medical pathology, or the axial skeleton (back/neck). The remaining guidelines were scored by 6 reviewers with different clinical backgrounds using the Appraisal of Guidelines for Research and Evaluation II (AGREE II). Scores lower than 50% indicated deficiency. Scores were also stratified by the publishing institution and anatomic location and compared using Kruskal-Wallis tests. The Spearman correlation coefficient was used to assess the range of interobserver agreement between the evaluators. Seventeen CPGs met the inclusion criteria. The majority of guidelines pertained to the knee, ankle, or shoulder. Interobserver agreement was strong ( r = 0.548-0.740), and mean total scores between nonsurgical (107.8) and surgical evaluators (109.3) were not statistically different. Overall guideline quality was variable but not deficient for 16 of 17 guidelines (>50%), except regarding clinical "applicability" and "editorial independence." No difference was found between CPGs of the knee, shoulder, foot/ankle, or chronic conditions. However, CPG publishing institutions had significantly different scores; the American Academy of Orthopaedic Surgeons (AAOS) guidelines scored significantly higher (141.4) than the total mean score (108.0). The overall quality of sports medicine CPGs was variable but generally not deficient, except regarding applicability and editorial independence. Bias through poor editorial independence is a concern. To improve future guideline quality, authors should pay particular attention to these areas and use existing highest quality guidelines, or the AGREE II instrument, as templates. CPGs dedicated to anatomic areas other than the knee, ankle, and shoulder are needed.

Quality and consistency of guidelines for the management of mild traumatic brain injury in the emergency department.

PubMed

Tavender, Emma J; Bosch, Marije; Green, Sally; O'Connor, Denise; Pitt, Veronica; Phillips, Kate; Bragge, Peter; Gruen, Russell L

2011-08-01

The objective was to provide an overview of the recommendations and quality of evidence-based clinical practice guidelines (CPGs) for the emergency management of mild traumatic brain injury (mTBI), with a view to informing best practice and improving the consistency of recommendations. Electronic searches of health databases (MEDLINE, EMBASE, The Cochrane Library, PsycINFO), CPG clearinghouse websites, CPG developer websites, and Internet search engines up to January 2010 were conducted. CPGs were included if 1) they were published in English and freely accessible, 2) their scope included the management of mTBI in the emergency department (ED), 3) the date of last search was within the past 10 years (2000 onward), 4) systematic methods were used to search for evidence, and 5) there was an explicit link between the recommendations and the supporting evidence. Four authors independently assessed the quality of the included CPGs using the Appraisal of Guidelines, Research and Evaluation (AGREE) Instrument. The authors extracted and categorized recommendations according to initial clinical assessment, imaging, management, observation, discharge planning, and patient information and follow-up. The search identified 18 potential CPGs, of which six met the inclusion criteria. The included CPGs varied in scope, target population, size, and guideline development processes. Four CPGs were assessed as "strongly recommended." The majority of CPGs did not provide information about the level of stakeholder involvement (mean AGREE standardized domain score = 57%, range = 25% to 81%), nor did they address the organizational/cost implications of applying the recommendations or provide criteria for monitoring and review of recommendations in practice (mean AGREE standardized domain score = 46.6%, range = 19% to 94%). Recommendations were mostly consistent in terms of the use of the Glasgow Coma Scale (GCS) score (adult and pediatric) to assess the level of consciousness, initial assessment criteria, the use of computed tomography (CT) scanning as imaging investigation of choice, and the provision of patient information. The CPGs defined mTBI in a variety of ways and described different rules to determine the need for CT scanning and therefore used different criteria to identify high-risk patients. Higher-quality CPGs for mTBI are consistent in their recommendations about assessment, imaging, and provision of patient information. There is not, however, an agreed definition of mTBI, and the quality of future CPGs could be improved with better reporting of stakeholder involvement, procedures for updating, and greater consideration of the applicability of the recommendations (cost implications, monitoring procedures). Nevertheless, guideline developers may benefit from adapting existing CPGs to their local context rather than investing in developing CPGs de novo. © 2011 by the Society for Academic Emergency Medicine.

Kinematic control of walking.

PubMed

Lacquaniti, F; Ivanenko, Y P; Zago, M

2002-10-01

The planar law of inter-segmental co-ordination we described may emerge from the coupling of neural oscillators between each other and with limb mechanical oscillators. Muscle contraction intervenes at variable times to re-excite the intrinsic oscillations of the system when energy is lost. The hypothesis that a law of coordinative control results from a minimal active tuning of the passive inertial and viscoelastic coupling among limb segments is congruent with the idea that movement has evolved according to minimum energy criteria (1, 8). It is known that multi-segment motion of mammals locomotion is controlled by a network of coupled oscillators (CPGs, see 18, 33, 37). Flexible combination of unit oscillators gives rise to different forms of locomotion. Inter-oscillator coupling can be modified by changing the synaptic strength (or polarity) of the relative spinal connections. As a result, unit oscillators can be coupled in phase, out of phase, or with a variable phase, giving rise to different behaviors, such as speed increments or reversal of gait direction (from forward to backward). Supra-spinal centers may drive or modulate functional sets of coordinating interneurons to generate different walking modes (or gaits). Although it is often assumed that CPGs control patterns of muscle activity, an equally plausible hypothesis is that they control patterns of limb segment motion instead (22). According to this kinematic view, each unit oscillator would directly control a limb segment, alternately generating forward and backward oscillations of the segment. Inter-segmental coordination would be achieved by coupling unit oscillators with a variable phase. Inter-segmental kinematic phase plays the role of global control variable previously postulated for the network of central oscillators. In fact, inter-segmental phase shifts systematically with increasing speed both in man (4) and cat (38). Because this phase-shift is correlated with the net mechanical power output over a gait cycle (3, 4), phase control could be used for limiting the overall energy expenditure with increasing speed (22). Adaptation to different walking conditions, such as changes in body posture, body weight unloading and backward walk, also involves inter-segmental phase tuning, as does the maturation of limb kinematics in toddlers.

Central pattern generation involved in oral and respiratory control for feeding in the term infant

PubMed Central

Barlow, Steven M.

2009-01-01

Purpose of review Drinking and eating are essential skills for survival and benefit from the coordination of several pattern generating networks and their musculoskeletal effectors to achieve safe swallows. Oral-pharyngo-esophageal motility develops during infancy and early childhood, and is influenced by various factors, including neuromuscular maturation, dietary and postural habits, arousal state, ongoing illnesses, congenital anomalies, and the effects of medical or surgical interventions. Gastroesophageal reflux is frequent in neonates and infants, and its role in neonatal morbidity including dysphagia, chronic lung disease, or apparent life-threatening events is not well understood. This review highlights recent studies aimed at understanding the development of oral feeding skills, and cross-system interactions among the brainstem, spinal, and cerebral networks involved in feeding. Recent Findings Functional linkages between suck-swallow and swallow-respiration manifest transitional forms during late gestation through the first year of life which can be delayed or modified by sensory experience and/or disease processes. Relevant central pattern generator (CPG) networks and their neuromuscular targets attain functional status at different rates, which ultimately influences cross-system CPG interactions. Entrainment of trigeminal primary afferents accelerates pattern genesis for the suck CPG and transition-to-oral feed in the RDS preterm infant. Summary The genesis of within-system CPG control for rate and amplitude scaling matures differentially for suck, mastication, swallow, and respiration. Cross-system interactions among these CPGs represent targets of opportunity for new interventions which optimize experience-dependent mechanisms to promote safe swallows among newborn and pediatric patients. PMID:19417662

A survey on selection, use, maintenance, and management of chemical protective gloves at workplaces in Japan.

PubMed

Kabe, Isamu; Tsuruoka, Hiroko; Kochi, Takeshi; Koga, Yasuo; Eguchi, Masafumi; Matsui, Tomomi; Ito, Rie; Tokujitani, Yoko; Miyauchi, Hiroyuki; Tanaka, Shigeru

2017-10-05

The aim of this study was to survey the selection, use, and maintenance of chemical protective gloves (CPGs) at real workplaces. Subjects comprised 817 workers using CPGs at seven domestic manufacturing plants in Japan. We administered an anonymous questionnaire survey comprising the following aspect related to CPGs: environment of use, conditions of use, method of selection, knowledge/awareness pertaining to their use, method of use, precautionary measures associated with their use, maximum time of use, and maintenance. We compared responses provided by management staff and field workers. Chi square test was used for the analysis. Respondents included 661 (80.9%) manufacturing workers, 121 (14.8%) managers or supervisors, and 35 (4.3%) others. In total, 70.5% organic solvents, 28.9% acid or/and alkali, 18.1% dust, and 10.3% carcinogenic substances were the chemical substances handled using CPGs. The reason for deciding to wear CPGs was "the use of chemical substances" for 46.5%, "notice in safety data sheet (SDS) " for 29.8%, and "management staffs' guidance" for 21.4% respondents. "The grasp of chemical substances" was 70.1% (91.1% excluding "not applicable" ). "Warning of caution on skin and eyes" was indicated by 69.5% (91.0%) and "educational reasons for use of CPGs" was accepted by 68.1% (90.7%) respondents. On the other hand, the rate of responses such as "obtaining permeability test results of target substances" and "mixed substances are selected considering substances with short permeation time" was 25.2% (38.4%) and 29.2% (48.4%), respectively. The rate of "yes" as a response in the item concerning "permeation test" was low. On comparing the response provided by the management staff and field workers, the rate of "the permeation test result of the target substance was obtained" was 27.7% for management staff and 41.2% for field workers (p = 0.022). Regarding the cuffs of CPGs, the rate of "to fold back and to prevent sagging" and "mounted with tape" were 30.5% and 21.8% for management staff and 50.2% and 42.2% for field workers (p = 0.001 and p = 0.001), respectively. This survey results suggested that the knowledge of "permeation test" of CPGs was not yet popular at industrial workplaces. It is necessary to disseminate knowledge related to "permeation test" to the users from manufacturers of CPGs. Additionally, the employer should appoint an administrator to ensure that CPGs are worn and increase the understanding of correct knowledge and usage of CPGs among workers.

Methodological quality of systematic reviews referenced in clinical practice guidelines for the treatment of opioid use disorder.

PubMed

Ross, Andrew; Rankin, Justin; Beaman, Jason; Murray, Kelly; Sinnett, Philip; Riddle, Ross; Haskins, Jordan; Vassar, Matt

2017-01-01

With efforts to combat opioid use disorder, there is an increased interest in clinical practice guidelines (CPGs) for opioid use disorder treatments. No literature exists examining the quality of systematic reviews used in opioid use disorder CPGs. This study aims to describe the methodological quality and reporting clarity of systematic reviews (SRs) used to create CPGs for opioid use disorder. From June to July 2016 guideline clearinghouses and medical literature databases were searched for relevant CPGs used in the treatment of opioid use disorder. Included CPGs must have been recognized by a national organization. SRs from the reference section of each CPG was scored by using AMSTAR (a measurement tool to assess the methodological quality of systematic reviews) tool and PRISMA (preferred reporting items for systematic reviews and meta-analyses) checklist. Seventeen CPGs from 2006-2016 were included in the review. From these, 57 unique SRs were extracted. SRS comprised 0.28% to 17.92% of all references found in the CPGs. All SRs obtained moderate or high methodological quality score on the AMSTAR tool. All reviews met at least 70% of PRISMA criteria. In PRISMA, underperforming areas included accurate title labeling, protocol registration, and risk of bias. Underperforming areas in AMSTAR included conflicts of interest, funding, and publication bias. A positive correlation was found between AMSTAR and PRISMA scores (r = .79). Although the SRs in the CPGs were of good quality, there are still areas for improvement. Systematic reviewers should consult PRISMA and AMSTAR when conducting and reporting reviews. It is important for CPG developers to consider methodological quality as a factor when developing CPG recommendations, recognizing that the quality of systematic reviews underpinning guidelines does not necessarily correspond to the quality of the guideline itself.

Is traditional Chinese medicine recommended in Western medicine clinical practice guidelines in China? A systematic analysis

PubMed Central

Ren, Jun; Li, Xun; Sun, Jin; Han, Mei; Yang, Guo-Yan; Li, Wen-Yuan; Robinson, Nicola; Lewith, George; Liu, Jian-Ping

2015-01-01

Background Evidence-based medicine promotes and relies on the use of evidence in developing clinical practice guidelines (CPGs). The Chinese healthcare system includes both traditional Chinese medicine (TCM) and Western medicine, which are expected to be equally reflected in Chinese CPGs. Objective To evaluate the inclusion of TCM-related information in Western medicine CPGs developed in China and the adoption of high level evidence. Methods All CPGs were identified from the China Guideline Clearinghouse (CGC), which is the main Chinese organisation maintaining the guidelines issued by the Ministry of Health of China, the Chinese Medical Association and the Chinese Medical Doctors’ Association. TCM-related contents were extracted from all the CPGs identified. Extracted information comprised the institution issuing the guideline, date of issue, disease, recommendations relating to TCM, evidence level of the recommended content and references supporting the recommendations. Results A total of 604 CPGs were identified, only a small number of which (74/604; 12%) recommended TCM therapy and only five guidelines (7%) had applied evidence grading. The 74 CPGs involved 13 disease systems according to the International Classification of Diseases 10th edition. TCM was mainly recommended in the treatment part of the guidelines (73/74, 99%), and more than half of the recommendations (43/74, 58%) were related to Chinese herbal medicine (single herbs or herbal treatment based on syndrome differentiation). Conclusions Few Chinese Western medicine CPGs recommend TCM therapies and very few provide evidence grading for the TCM recommendation. We suggest that future guideline development should be based on systematic searches for evidence to support CPG recommendations and involve a multidisciplinary approach including TCM expertise. PMID:26041487

Is traditional Chinese medicine recommended in Western medicine clinical practice guidelines in China? A systematic analysis.

PubMed

Ren, Jun; Li, Xun; Sun, Jin; Han, Mei; Yang, Guo-Yan; Li, Wen-Yuan; Robinson, Nicola; Lewith, George; Liu, Jian-Ping

2015-06-03

Evidence-based medicine promotes and relies on the use of evidence in developing clinical practice guidelines (CPGs). The Chinese healthcare system includes both traditional Chinese medicine (TCM) and Western medicine, which are expected to be equally reflected in Chinese CPGs. To evaluate the inclusion of TCM-related information in Western medicine CPGs developed in China and the adoption of high level evidence. All CPGs were identified from the China Guideline Clearinghouse (CGC), which is the main Chinese organisation maintaining the guidelines issued by the Ministry of Health of China, the Chinese Medical Association and the Chinese Medical Doctors' Association.TCM-related contents were extracted from all the CPGs identified. Extracted information comprised the institution issuing the guideline, date of issue, disease, recommendations relating to TCM, evidence level of the recommended content and references supporting the recommendations. A total of 604 CPGs were identified, only a small number of which (74/604; 12%) recommended TCM therapy and only five guidelines (7%) had applied evidence grading. The 74 CPGs involved 13 disease systems according to the International Classification of Diseases 10th edition. TCM was mainly recommended in the treatment part of the guidelines (73/74, 99%), and more than half of the recommendations (43/74, 58%) were related to Chinese herbal medicine (single herbs or herbal treatment based on syndrome differentiation). Few Chinese Western medicine CPGs recommend TCM therapies and very few provide evidence grading for the TCM recommendation. We suggest that future guideline development should be based on systematic searches for evidence to support CPG recommendations and involve a multidisciplinary approach including TCM expertise. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Inhibitory and modulatory inputs to the vocal central pattern generator of a teleost fish

PubMed Central

Rosner, Elisabeth; Rohmann, Kevin N.; Bass, Andrew H.

2018-01-01

Abstract Vocalization is a behavioral feature that is shared among multiple vertebrate lineages, including fish. The temporal patterning of vocal communication signals is set, in part, by central pattern generators (CPGs). Toadfishes are well‐established models for CPG coding of vocalization at the hindbrain level. The vocal CPG comprises three topographically separate nuclei: pre‐pacemaker, pacemaker, motor. While the connectivity between these nuclei is well understood, their neurochemical profile remains largely unexplored. The highly vocal Gulf toadfish, Opsanus beta, has been the subject of previous behavioral, neuroanatomical and neurophysiological studies. Combining transneuronal neurobiotin‐labeling with immunohistochemistry, we map the distribution of inhibitory neurotransmitters and neuromodulators along with gap junctions in the vocal CPG of this species. Dense GABAergic and glycinergic label is found throughout the CPG, with labeled somata immediately adjacent to or within CPG nuclei, including a distinct subset of pacemaker neurons co‐labeled with neurobiotin and glycine. Neurobiotin‐labeled motor and pacemaker neurons are densely co‐labeled with the gap junction protein connexin 35/36, supporting the hypothesis that transneuronal neurobiotin‐labeling occurs, at least in part, via gap junction coupling. Serotonergic and catecholaminergic label is also robust within the entire vocal CPG, with additional cholinergic label in pacemaker and prepacemaker nuclei. Likely sources of these putative modulatory inputs are neurons within or immediately adjacent to vocal CPG neurons. Together with prior neurophysiological investigations, the results reveal potential mechanisms for generating multiple classes of social context‐dependent vocalizations with widely divergent temporal and spectral properties. PMID:29424431

Clinical practice guidelines consistency for patients with multimorbidity: a case-study in the management of type 2 diabetes and hypertension.

PubMed

Galopin, Alexandre; Bouaud, Jacques; Pereira, Suzanne; Séroussi, Brigitte

2015-01-01

Decision support for the guideline-based management of patients with multimorbidity is a challenge since it relies on the combination of single-disease clinical practice guidelines (CPGs). The aim of this work is to present a framework to check, at the modelling level, whether two CPGs overlap and are potentially inconsistent, thus requiring further reconciliation. The method relies on an ontological comparison of the patient profiles covered by CPGs and the recommended actions attached. It was applied to check the consistency of CPGs for the management of arterial hypertension and for the management of type 2 diabetes. Results showed that the two CPGs had only one common patient profile, although more profiles were impacted through profile subsumption. In this specific case, recommended actions were not found inconsistent since antihypertensive and anti-diabetic drugs could be combined in an additive way.

A glycine receptor is involved in the organization of swimming movements in an invertebrate chordate.

PubMed

Nishino, Atsuo; Okamura, Yasushi; Piscopo, Stefania; Brown, Euan R

2010-01-19

Rhythmic motor patterns for locomotion in vertebrates are generated in spinal cord neural networks known as spinal Central Pattern Generators (CPGs). A key element in pattern generation is the role of glycinergic synaptic transmission by interneurons that cross the cord midline and inhibit contralaterally-located excitatory neurons. The glycinergic inhibitory drive permits alternating and precisely timed motor output during locomotion such as walking or swimming. To understand better the evolution of this system we examined the physiology of the neural network controlling swimming in an invertebrate chordate relative of vertebrates, the ascidian larva Ciona intestinalis. A reduced preparation of the larva consisting of nerve cord and motor ganglion generates alternating swimming movements. Pharmacological and genetic manipulation of glycine receptors shows that they are implicated in the control of these locomotory movements. Morphological molecular techniques and heterologous expression experiments revealed that glycine receptors are inhibitory and are present on both motoneurones and locomotory muscle while putative glycinergic interneurons were identified in the nerve cord by labeling with an anti-glycine antibody. In Ciona intestinalis, glycine receptors, glycinergic transmission and putative glycinergic interneurons, have a key role in coordinating swimming movements through a simple CPG that is present in the motor ganglion and nerve cord. Thus, the strong association between glycine receptors and vertebrate locomotory networks may now be extended to include the phylum chordata. The results suggest that the basic network for 'spinal-like' locomotion is likely to have existed in the common ancestor of extant chordates some 650 M years ago.

A glycine receptor is involved in the organization of swimming movements in an invertebrate chordate

PubMed Central

2010-01-01

Background Rhythmic motor patterns for locomotion in vertebrates are generated in spinal cord neural networks known as spinal Central Pattern Generators (CPGs). A key element in pattern generation is the role of glycinergic synaptic transmission by interneurons that cross the cord midline and inhibit contralaterally-located excitatory neurons. The glycinergic inhibitory drive permits alternating and precisely timed motor output during locomotion such as walking or swimming. To understand better the evolution of this system we examined the physiology of the neural network controlling swimming in an invertebrate chordate relative of vertebrates, the ascidian larva Ciona intestinalis. Results A reduced preparation of the larva consisting of nerve cord and motor ganglion generates alternating swimming movements. Pharmacological and genetic manipulation of glycine receptors shows that they are implicated in the control of these locomotory movements. Morphological molecular techniques and heterologous expression experiments revealed that glycine receptors are inhibitory and are present on both motoneurones and locomotory muscle while putative glycinergic interneurons were identified in the nerve cord by labeling with an anti-glycine antibody. Conclusions In Ciona intestinalis, glycine receptors, glycinergic transmission and putative glycinergic interneurons, have a key role in coordinating swimming movements through a simple CPG that is present in the motor ganglion and nerve cord. Thus, the strong association between glycine receptors and vertebrate locomotory networks may now be extended to include the phylum chordata. The results suggest that the basic network for 'spinal-like' locomotion is likely to have existed in the common ancestor of extant chordates some 650 M years ago. PMID:20085645

Assessing the Methodological Quality of Glaucoma Clinical Practice Guidelines and Their Recommendations on Microinvasive Glaucoma Surgery: A Systematic Review.

PubMed

Michaelov, Evan; Armstrong, James J; Nguyen, Mary; Instrum, Bridget; Lam, Tracey; Denstedt, James; Hutnik, Cindy M L

2018-02-01

Clinical practice guidelines (CPG) are regarded by many as critical communications providing guidance within specific medical fields. Over a decade ago, the first microinvasive glaucoma surgical (MIGS) procedures were introduced. Since then, a number of these novel intraocular pressure controlling surgical options have been approved worldwide. Governing bodies and health care administration often utilize CPGs when considering funding for newer technologies. This highlights the importance of well-written, accurate, and up-to-date CPGs in the rapidly evolving field of MIGS. If CPGs are unable to fill this role, their use in treatment decision-making is doing a disservice to patients, who will be denied currently available and potentially superior care. To determine the overall value of a CPG, the methodological quality with which it was developed, in addition to the current relevance and appropriateness of its recommendations, should be evaluated. The objective of the present study was to assess the methodological quality of currently available international glaucoma CPGs, as well as their coverage of MIGS as a surrogate marker of relevance and appropriateness to policy-makers and ophthalmologists alike. To identify potentially relevant CPGs, a predefined search strategy was used to search the following databases: Medline, EMBASE, BIOSIS, and Web of Science. All CPGs related to adult glaucoma and published in English were included. CPG methodological quality was assessed by 3 individuals using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. Studies were then assessed for coverage of MIGS devices and procedures. Search strategy and subsequent screening identified 11 CPGs for analysis. Eight were of high quality according to the AGREE II criteria. Three included basic information on MIGS, but none provided specific recommendations regarding their indications or which patient populations would benefit most. Many international glaucoma CPGs are of high methodological quality. However, coverage of MIGS is sparse, nonspecific and in many instances, absent. This causes CPGs to be a suboptimal source in guiding physicians and health policy-makers in areas characterized by novel and/or rapidly evolving technologies. Mechanisms to incorporate updated evidence in CPGs would have to be considered before they can be used as a source of contemporary clinical decision-making.

Proprioceptive coupling within motor neurons drives C. elegans forward locomotion

PubMed Central

Wen, Quan; Po, Michelle; Hulme, Elizabeth; Chen, Sway; Liu, Xinyu; Kwok, Sen Wai; Gershow, Marc; Leifer, Andrew M; Butler, Victoria; Fang-Yen, Christopher; Kawano, Taizo; Schafer, William R; Whitesides, George

2012-01-01

Summary Locomotion requires coordinated motor activity throughout an animal’s body. In both vertebrates and invertebrates, chains of coupled Central Pattern Generators (CPGs) are commonly evoked to explain local rhythmic behaviors. In C. elegans, we report that proprioception within the motor circuit is responsible for propagating and coordinating rhythmic undulatory waves from head to tail during forward movement. Proprioceptive coupling between adjacent body regions transduces rhythmic movement initiated near the head into bending waves driven along the body by a chain of reflexes. Using optogenetics and calcium imaging to manipulate and monitor motor circuit activity of moving C. elegans held in microfluidic devices, we found that the B-type cholinergic motor neurons transduce the proprioceptive signal. In C. elegans, a sensorimotor feedback loop operating within a specific type of motor neuron both drives and organizes body movement. PMID:23177960

How equity is addressed in clinical practice guidelines: a content analysis

PubMed Central

Shi, Chunhu; Tian, Jinhui; Wang, Quan; Petkovic, Jennifer; Ren, Dan; Yang, Kehu; Yang, Yang

2014-01-01

Objectives Considering equity into guidelines presents methodological challenges. This study aims to qualitatively synthesise the methods for incorporating equity in clinical practice guidelines (CPGs). Setting Content analysis of methodological publications. Eligibility criteria for selecting studies Methodological publications were included if they provided checklists/frameworks on when, how and to what extent equity should be incorporated in CPGs. Data sources We electronically searched MEDLINE, retrieved references, and browsed guideline development organisation websites from inception to January 2013. After study selection by two authors, general characteristics and checklists items/framework components from included studies were extracted. Based on the questions or items from checklists/frameworks (unit of analysis), content analysis was conducted to identify themes and questions/items were grouped into these themes. Primary outcomes The primary outcomes were methodological themes and processes on how to address equity issues in guideline development. Results 8 studies with 10 publications were included from 3405 citations. In total, a list of 87 questions/items was generated from 17 checklists/frameworks. After content analysis, questions were grouped into eight themes (‘scoping questions’, ‘searching relevant evidence’, ‘appraising evidence and recommendations’, ‘formulating recommendations’, ‘monitoring implementation’, ‘providing a flow chart to include equity in CPGs’, and ‘others: reporting of guidelines and comments from stakeholders’ for CPG developers and ‘assessing the quality of CPGs’ for CPG users). Four included studies covered more than five of these themes. We also summarised the process of guideline development based on the themes mentioned above. Conclusions For disadvantaged population-specific CPGs, eight important methodological issues identified in this review should be considered when including equity in CPGs under the guidance of a scientific guideline development manual. PMID:25479795

Barriers and enablers for the development and implementation of allied health clinical practice guidelines in South African primary healthcare settings: a qualitative study.

PubMed

Dizon, J M; Grimmer, K; Louw, Q; Machingaidze, S; Parker, H; Pillen, H

2017-09-15

The South African allied health (AH) primary healthcare (PHC) workforce is challenged with the complex rehabilitation needs of escalating patient numbers. The application of evidence-based care using clinical practice guidelines (CPGs) is one way to make efficient and effective use of resources. Although CPGs are common for AH in high-income countries, there is limited understanding of how to do this in low- to middle-income countries. This paper describes barriers and enablers for AH CPG uptake in South African PHC. Semi-structured individual interviews were undertaken with 25 South African AH managers, policymakers, clinicians and academics to explore perspectives on CPGs. Interviews were conducted by researcher dyads, one being familiar with South African AH PHC practice and the other with CPG expertise. Rigour and transparency of data collection was ensured. Interview transcripts were analysed by structuring content into codes, categories and themes. Exemplar quotations were extracted to support themes. CPGs were generally perceived to be relevant to assist AH providers to address the challenges of consistently providing evidence-based care in South African PHC settings. CPGs were considered to be tools for managing clinical, social and economic complexities of AH PHC practice, particularly if CPG recommendations were contextusalised. CPG uptake was one way to deal with increasing pressures to make efficient use of scarce financial resources, and to demonstrate professional legitimacy. Themes comprised organisational infrastructures and capacities for CPG uptake, interactions between AH actors and interaction with broader political structures, the nature of AH evidence in CPGs, and effectively implementing CPGs into practice. CPGs contextualised to local circumstances offer South African PHC AH services with an efficient vehicle for putting evidence into practice. There are challenges to doing this, related to local barriers such as geography, AH training, workforce availability, scarce resources, an escalating number of patients requiring complex rehabilitation, and local knowledge. Concerted attempts to implement locally relevant CPGs for AH primary care in South Africa are required to improve widespread commitment to evidence-based care, as well as to plan efficient and effective service delivery models.

Dietary vitamin A impacts DNA methylation patterns of adipogenesis-related genes in suckling rats.

PubMed

Arreguín, A; Ribot, J; Mušinović, H; von Lintig, J; Palou, A; Bonet, M L

2018-05-11

We previously showed that vitamin A supplementation in early life impacts white adipose tissue (WAT) biology. We here studied the vitamin's effects on DNA methylation of genes crucial for WAT cell development, determination and metabolism. CpG promoter methylation and mRNA expression of Pparg, Zfp423, Pcna, and Rbp4 was compared in inguinal WAT of 21-day-old rats supplemented during the suckling period with vehicle (controls) or an emulsion of vitamin A as retinyl ester (RE) or β-carotene (BC). The methylation profile of promoters was affected by vitamin A supplementation with pronounced differences between the RE and BC groups. In the RE group, hypermethylation of the Rbp4 (at multiple CpGs) and the Pparg2 (at a specific CpG) promoters and hypomethylation of the Pcna promoter (at multiple CpGs) was observed, together with inverse changes in gene expression levels. In the BC group, hypomethylation of the Rbp4 and hypermethylation of the Pcna promoter at distinct CpGs was observed, with no effects on gene expression. In both supplemention groups, hypomethylation and increased expression was found for Zfp423. Thus, modest vitamin A supplementation in early postnatal life impacts methylation marks in developing WAT. Differential epigenetic effects of RE and BC in early life may affect adipose tissue programming activity. Copyright © 2018 Elsevier Inc. All rights reserved.

The use of lithium for the treatment of bipolar disorder: Recommendations from clinical practice guidelines.

PubMed

Malhi, Gin S; Gessler, Danielle; Outhred, Tim

2017-08-01

Lithium is an effective mood stabilizer that is used principally for the management of bipolar disorder (BD). Its administration is complex and often requires sophisticated management and assiduous monitoring. When considering the use of lithium therapy for bipolar disorder, clinicians are advised to refer to recommendations outlined in clinical practice guidelines (CPGs); but because of varying emphases placed by different international CPGs, recommendations addressing the practical use of lithium lack consistency. In order to inform clinicians of optimal lithium therapy for bipolar disorder, we compared and synthesized recommendations for the treatment of bipolar disorder made by recognized CPGs internationally. We conducted a search of the literature and extracted guidance across multiple clinical issues, including clinical indications, disorder subtypes, additional uses, special populations, practical aspects, and side effects. Collectively, CPGs consider lithium most robustly as a first-line intervention for maintenance treatment of bipolar disorder and strongly for the treatment of mania, with relatively modest support for the management of acute bipolar depression. Additionally, there is consensus across the CPGs that lithium tangibly reduces the risk of suicide. Generally, CPGs provide guidance on the many facets of initiating and maintaining patients on lithium therapy, but individually the CPGs varied in terms of depth and practical guidance they provide across these areas. However, consensus was established across many key areas of practice such as the ideal lithium plasma concentration for maintenance and monitoring (0.6-0.8mmol/L), along with the need for regular monitoring of renal and endocrine function. However, with more complex aspects (e.g., atypical presentations) and in special populations (e.g., youth; pregnancy and post-partum; older adults), guidance varied considerably and clear consensus recommendations were more difficult to achieve. In younger adults desirable plasma lithium levels of 0.6-0.8mmol/L can perhaps be achieved with comparatively lower doses and in the very elderly it may be prudent to target lower plasma levels in the first instance. These are important practical points for consideration that, along with many others offered throughout the article, should assist clinicians in dissecting the more complex aspects of management with greater precision. This review was limited to CPGs written in English. CPGs are themselves limited by reliance on evidence that often has little resemblance to real-world presentations. An important area that is not sufficiently addressed in the CPGs is clear guidance on the cessation of lithium therapy. Further research is needed on many aspects of lithium therapy and this alongside existing knowledge needs to be used more consistently to inform CPGs, which should also incorporate empirical evidence and clinical experience. The recommendations in this paper provide a useful synthesis of guidance available currently. Copyright © 2017 Elsevier B.V. All rights reserved.

An educational game for teaching clinical practice guidelines to Internal Medicine residents: development, feasibility and acceptability

PubMed Central

Akl, Elie A; Mustafa, Reem; Slomka, Thomas; Alawneh, Alia; Vedavalli, Abhishek; Schünemann, Holger J

2008-01-01

Background Adherence to Clinical Practice Guidelines (CPGs) remains suboptimal among internal medicine trainees. Educational games are of growing interest and have the potential to improve adherence to CPGs. The objectives of this study were to develop an educational game to teach CPGs in Internal Medicine residency programs and to evaluate its feasibility and acceptability. Methods We developed the Guide-O-Game© in the format of a TV game show with questions based on recommendations of CPGs. The development of the Guide-O-Game© consisted of the creation of a multimedia interactive tool, the development of recommendation-based questions, and the definition of the game's rules. We evaluated its feasibility through pilot testing and its acceptability through a qualitative process. Results The multimedia interactive tool uses a Macromedia Flash web application and consists of a manager interface and a user interface. The user interface allows the choice of two game styles. We created so far 16 sets of questions relating to 9 CPGs. The pilot testing proved that the game was feasible. The qualitative evaluation showed that residents considered the game to be acceptable. Conclusion We developed an educational game to teach CPGs to Internal Medicine residents that is both feasible and acceptable. Future work should evaluate its impact on educational outcomes. PMID:19017400

Korean Clinical Practice Guidelines for Aneurysmal Subarachnoid Hemorrhage

PubMed Central

Cho, Won-Sang; Park, Sukh Que; Ko, Jun Kyeung; Kim, Dae-Won; Park, Jung Cheol; Yeon, Je Young; Chung, Seung Young; Chung, Joonho; Joo, Sung-Pil; Hwang, Gyojun; Kim, Deog Young; Chang, Won Hyuk; Choi, Kyu-Sun; Lee, Sung Ho; Sheen, Seung Hun; Kang, Hyun-Seung; Kim, Byung Moon; Bae, Hee-Joon; Oh, Chang Wan; Park, Hyeon Seon

2018-01-01

Despite advancements in treating ruptured cerebral aneurysms, an aneurysmal subarachnoid hemorrhage (aSAH) is still a grave cerebrovascular disease associated with a high rate of morbidity and mortality. Based on the literature published to date, worldwide academic and governmental committees have developed clinical practice guidelines (CPGs) to propose standards for disease management in order to achieve the best treatment outcomes for aSAHs. In 2013, the Korean Society of Cerebrovascular Surgeons issued a Korean version of the CPGs for aSAHs. The group researched all articles and major foreign CPGs published in English until December 2015 using several search engines. Based on these articles, levels of evidence and grades of recommendations were determined by our society as well as by other related Quality Control Committees from neurointervention, neurology and rehabilitation medicine. The Korean version of the CPGs for aSAHs includes risk factors, diagnosis, initial management, medical and surgical management to prevent rebleeding, management of delayed cerebral ischemia and vasospasm, treatment of hydrocephalus, treatment of medical complications and early rehabilitation. The CPGs are not the absolute standard but are the present reference as the evidence is still incomplete, each environment of clinical practice is different, and there is a high probability of variation in the current recommendations. The CPGs will be useful in the fields of clinical practice and research. PMID:29526058

An epigenetic aging clock for dogs and wolves.

PubMed

Thompson, Michael J; vonHoldt, Bridgett; Horvath, Steve; Pellegrini, Matteo

2017-03-28

Several articles describe highly accurate age estimation methods based on human DNA-methylation data. It is not yet known whether similar epigenetic aging clocks can be developed based on blood methylation data from canids. Using Reduced Representation Bisulfite Sequencing, we assessed blood DNA-methylation data from 46 domesticated dogs ( Canis familiaris ) and 62 wild gray wolves ( C. lupus ). By regressing chronological dog age on the resulting CpGs, we defined highly accurate multivariate age estimators for dogs (based on 41 CpGs), wolves (67 CpGs), and both combined (115 CpGs). Age related DNA methylation changes in canids implicate similar gene ontology categories as those observed in humans suggesting an evolutionarily conserved mechanism underlying age-related DNA methylation in mammals.

An epigenetic aging clock for dogs and wolves

PubMed Central

Thompson, Michael J.; vonHoldt, Bridgett; Horvath, Steve; Pellegrini, Matteo

2017-01-01

Several articles describe highly accurate age estimation methods based on human DNA-methylation data. It is not yet known whether similar epigenetic aging clocks can be developed based on blood methylation data from canids. Using Reduced Representation Bisulfite Sequencing, we assessed blood DNA-methylation data from 46 domesticated dogs (Canis familiaris) and 62 wild gray wolves (C. lupus). By regressing chronological dog age on the resulting CpGs, we defined highly accurate multivariate age estimators for dogs (based on 41 CpGs), wolves (67 CpGs), and both combined (115 CpGs). Age related DNA methylation changes in canids implicate similar gene ontology categories as those observed in humans suggesting an evolutionarily conserved mechanism underlying age-related DNA methylation in mammals. PMID:28373601

Diethylstilbestrol (DES)-stimulated hormonal toxicity is mediated by ERα alteration of target gene methylation patterns and epigenetic modifiers (DNMT3A, MBD2, and HDAC2) in the mouse seminal vesicle.

PubMed

Li, Yin; Hamilton, Katherine J; Lai, Anne Y; Burns, Katherine A; Li, Leping; Wade, Paul A; Korach, Kenneth S

2014-03-01

Diethylstilbestrol (DES) is a synthetic estrogen associated with adverse effects on reproductive organs. DES-induced toxicity of the mouse seminal vesicle (SV) is mediated by estrogen receptor α (ERα), which alters expression of seminal vesicle secretory protein IV (Svs4) and lactoferrin (Ltf) genes. We examined a role for nuclear receptor activity in association with DNA methylation and altered gene expression. We used the neonatal DES exposure mouse model to examine DNA methylation patterns via bisulfite conversion sequencing in SVs of wild-type (WT) and ERα-knockout (αERKO) mice. The DNA methylation status at four specific CpGs (-160, -237, -306, and -367) in the Svs4 gene promoter changed during mouse development from methylated to unmethylated, and DES prevented this change at 10 weeks of age in WT SV. At two specific CpGs (-449 and -459) of the Ltf gene promoter, DES altered the methylation status from methylated to unmethylated. Alterations in DNA methylation of Svs4 and Ltf were not observed in αERKO SVs, suggesting that changes of methylation status at these CpGs are ERα dependent. The methylation status was associated with the level of gene expression. In addition, gene expression of three epigenetic modifiers-DNMT3A, MBD2, and HDAC2-increased in the SV of DES-exposed WT mice. DES-induced hormonal toxicity resulted from altered gene expression of Svs4 and Ltf associated with changes in DNA methylation that were mediated by ERα. Alterations in gene expression of DNMT3A, MBD2, and HDAC2 in DES-exposed male mice may be involved in mediating the changes in methylation status in the SV. Li Y, Hamilton KJ, Lai AY, Burns KA, Li L, Wade PA, Korach KS. 2014. Diethylstilbestrol (DES)-stimulated hormonal toxicity is mediated by ERα alteration of target gene methylation patterns and epigenetic modifiers (DNMT3A, MBD2, and HDAC2) in the mouse seminal vesicle. Environ Health Perspect 122:262-268; http://dx.doi.org/10.1289/ehp.1307351.

Computational Modeling Approach in Probing the Effects of Cytosine Methylation on the Transcription Factor Binding to DNA.

PubMed

Tenayuca, John; Cousins, Kimberley; Yang, Shumei; Zhang, Lubo

2017-01-01

Cytosine methylation at CpG dinucleotides is a chief mechanism in epigenetic modification of gene expression patterns. Previous studies demonstrated that increased CpG methylation of Sp1 sites at -268 and -346 of protein kinase C ε promoter repressed the gene expression. The present study investigated the impact of CpG methylation on the Sp1 binding via molecular modeling and electrophoretic mobility shift assay. Each of the Sp1 sites contain two CpGs. Methylation of either CpG lowered the binding affinity of Sp1, whereas methylation of both CpGs produced a greater decrease in the binding affinity. Computation of van der Waals (VDW) energy of Sp1 in complex with the Sp1 sites demonstrated increased VDW values from one to two sites of CpG methylation. Molecular modeling indicated that single CpG methylation caused underwinding of the DNA fragment, with the phosphate groups at C1, C4 and C5 reoriented from their original positions. Methylation of both CpGs pinched the minor groove and increased the helical twist concomitant with a shallow, hydrophobic major groove. Additionally, double methylation eliminated hydrogen bonds on recognition helix residues located at positions -1 and 1, which were essential for interaction with O6/N7 of G-bases. Bonding from linker residues Arg565, Lys595 and Lys596 were also reduced. Methylation of single or both CpGs significantly affected hydrogen bonding from all three Sp1 DNA binding domains, demonstrating that the consequences of cytosine modification extend beyond the neighboring nucleotides. The results indicate that cytosine methylation causes subtle structural alterations in Sp1 binding sites consequently resulting in inhibition of side chain interactions critical for specific base recognition and reduction of the binding affinity of Sp1. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Prevention of venous thromboembolism in long term care: results of a multicenter educational intervention using clinical practice guidelines: part 2 of 2 (an AMDA Foundation project).

PubMed

Dharmarajan, T S; Nanda, Aman; Agarwal, Bikash; Agnihotri, Parag; Doxsie, G L; Gokula, Murthy; Javaheri, Ashkan; Kanagala, M; Lebelt, Anna S; Madireddy, Prasuna; Mahapatra, Sourya; Murakonda, P; Muthavarapu, S Ram Rao; Patel, Mennakshi; Patterson, Christopher; Soch, Kathleen; Troncales, Anna; Yaokim, Kamal; Kroft, Robin; Norkus, Edward P

2012-03-01

Implementation of prophylaxis for venous thomboembolism (VTE) through risk assessment based on clinical practice guidelines (CPGs) is variably adopted in long term care facilities (LTCF). Current guidelines recommend venous thromboembolism prophylaxis (VTE-P) following risk assessment, individualized to patient status. In LTCF, differing comorbidity, life-expectancy, ethical, and quality-of-life issues may warrant a unique approach. This article examines VTE-P practices in LTCF before and after educational intervention to bring practice patterns consistent with CPGs. Phase 1 (preceding article in this issue) identified current practice to assess risk and implement VTE-P (17 geographically diverse LTCFs, 3260 total beds). Phase 2 (educational intervention using CPGs) and Phase 3 (outcomes) reexamined VTE-P at the same 17 centers. The frequency of indications for VTE-P and contraindications to anticoagulation were similar during Phases 1 and 3 (all P > .05). In Phase 3, use of aspirin alone decreased more than 50% (P < .0005), whereas use of compression devices increased (P < .0005). Regression models predicted no relationship between any indication or contraindication and VTE-P in Phase 1 (all P > .05) but identified significant relationships between indication and contraindications and VTE-P in Phase 3 (P = .022 to P < .0005), suggesting adequate understanding of current CPGs following education as the basis for improved VTE-P. The study confirms the presence of significant comorbidity in LTC residents, many with indications for VTE-P, some with contraindications for anticoagulation. Following educational intervention, more residents received VTE-P, influenced by risk-benefit ratio favoring treatment. These findings suggest that even a modest educational intervention significantly improves provider knowledge pertinent to risk assessment consistent with CPG and more appropriate VTE-P. Copyright © 2012 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.

A novel approach to locomotion learning: Actor-Critic architecture using central pattern generators and dynamic motor primitives.

PubMed

Li, Cai; Lowe, Robert; Ziemke, Tom

2014-01-01

In this article, we propose an architecture of a bio-inspired controller that addresses the problem of learning different locomotion gaits for different robot morphologies. The modeling objective is split into two: baseline motion modeling and dynamics adaptation. Baseline motion modeling aims to achieve fundamental functions of a certain type of locomotion and dynamics adaptation provides a "reshaping" function for adapting the baseline motion to desired motion. Based on this assumption, a three-layer architecture is developed using central pattern generators (CPGs, a bio-inspired locomotor center for the baseline motion) and dynamic motor primitives (DMPs, a model with universal "reshaping" functions). In this article, we use this architecture with the actor-critic algorithms for finding a good "reshaping" function. In order to demonstrate the learning power of the actor-critic based architecture, we tested it on two experiments: (1) learning to crawl on a humanoid and, (2) learning to gallop on a puppy robot. Two types of actor-critic algorithms (policy search and policy gradient) are compared in order to evaluate the advantages and disadvantages of different actor-critic based learning algorithms for different morphologies. Finally, based on the analysis of the experimental results, a generic view/architecture for locomotion learning is discussed in the conclusion.

A novel approach to locomotion learning: Actor-Critic architecture using central pattern generators and dynamic motor primitives

PubMed Central

Li, Cai; Lowe, Robert; Ziemke, Tom

2014-01-01

In this article, we propose an architecture of a bio-inspired controller that addresses the problem of learning different locomotion gaits for different robot morphologies. The modeling objective is split into two: baseline motion modeling and dynamics adaptation. Baseline motion modeling aims to achieve fundamental functions of a certain type of locomotion and dynamics adaptation provides a “reshaping” function for adapting the baseline motion to desired motion. Based on this assumption, a three-layer architecture is developed using central pattern generators (CPGs, a bio-inspired locomotor center for the baseline motion) and dynamic motor primitives (DMPs, a model with universal “reshaping” functions). In this article, we use this architecture with the actor-critic algorithms for finding a good “reshaping” function. In order to demonstrate the learning power of the actor-critic based architecture, we tested it on two experiments: (1) learning to crawl on a humanoid and, (2) learning to gallop on a puppy robot. Two types of actor-critic algorithms (policy search and policy gradient) are compared in order to evaluate the advantages and disadvantages of different actor-critic based learning algorithms for different morphologies. Finally, based on the analysis of the experimental results, a generic view/architecture for locomotion learning is discussed in the conclusion. PMID:25324773

Intra- and intersegmental influences among central pattern generating networks in the walking system of the stick insect.

PubMed

Mantziaris, Charalampos; Bockemühl, Till; Holmes, Philip; Borgmann, Anke; Daun, Silvia; Büschges, Ansgar

2017-10-01

To efficiently move around, animals need to coordinate their limbs. Proper, context-dependent coupling among the neural networks underlying leg movement is necessary for generating intersegmental coordination. In the slow-walking stick insect, local sensory information is very important for shaping coordination. However, central coupling mechanisms among segmental central pattern generators (CPGs) may also contribute to this. Here, we analyzed the interactions between contralateral networks that drive the depressor trochanteris muscle of the legs in both isolated and interconnected deafferented thoracic ganglia of the stick insect on application of pilocarpine, a muscarinic acetylcholine receptor agonist. Our results show that depressor CPG activity is only weakly coupled between all segments. Intrasegmental phase relationships differ between the three isolated ganglia, and they are modified and stabilized when ganglia are interconnected. However, the coordination patterns that emerge do not resemble those observed during walking. Our findings are in line with recent studies and highlight the influence of sensory input on coordination in slowly walking insects. Finally, as a direct interaction between depressor CPG networks and contralateral motoneurons could not be observed, we hypothesize that coupling is based on interactions at the level of CPG interneurons. NEW & NOTEWORTHY Maintaining functional interleg coordination is vitally important as animals locomote through changing environments. The relative importance of central mechanisms vs. sensory feedback in this process is not well understood. We analyzed coordination among the neural networks generating leg movements in stick insect preparations lacking phasic sensory feedback. Under these conditions, the networks governing different legs were only weakly coupled. In stick insect, central connections alone are thus insufficient to produce the leg coordination observed behaviorally. Copyright © 2017 the American Physiological Society.

Changes in DNA Methylation from Age 18 to Pregnancy in Type 1, 2, and 17 T Helper and Regulatory T-Cells Pathway Genes

PubMed Central

Iqbal, Sabrina; Lockett, Gabrielle A.; Arshad, S. Hasan; Zhang, Hongmei; Kaushal, Akhilesh; Tetali, Sabarinath R.; Mukherjee, Nandini

2018-01-01

To succeed, pregnancies need to initiate immune biases towards T helper 2 (Th2) responses, yet little is known about what establishes this bias. Using the Illumina 450 K platform, we explored changes in DNA methylation (DNAm) of Th1, Th2, Th17, and regulatory T cell pathway genes before and during pregnancy. Female participants were recruited at birth (1989), and followed through age 18 years and their pregnancy (2011–2015). Peripheral blood DNAm was measured in 245 girls at 18 years; from among these girls, the DNAm of 54 women was repeatedly measured in the first (weeks 8–21, n = 39) and second (weeks 22–38, n = 35) halves of pregnancy, respectively. M-values (logit-transformed β-values of DNAm) were analyzed: First, with repeated measurement models, cytosine–phosphate–guanine sites (CpGs) of pathway genes in pregnancy and at age 18 (nonpregnant) were compared for changes (p ≤ 0.05). Second, we tested how many of the 348 pathway-related CpGs changed compared to 10 randomly selected subsets of all other CpGs and compared to 10 randomly selected subsets of other CD4+-related CpGs (348 in each subset). Contrasted to the nonpregnant state, 27.7% of Th1-related CpGs changed in the first and 36.1% in the second half of pregnancy. Among the Th2 pathway CpGs, proportions of changes were 35.1% (first) and 33.8% (second half). The methylation changes suggest involvement of both Th1 and Th2 pathway CpGs in the immune bias during pregnancy. Changes in regulatory T cell and Th17 pathways need further exploration. PMID:29415463

Dissemination of Clinical Practice Guidelines: A Content Analysis of Patient Versions.

PubMed

Santesso, Nancy; Morgano, Gian Paolo; Jack, Susan M; Haynes, R Brian; Hill, Sophie; Treweek, Shaun; Schünemann, Holger J

2016-08-01

Clinical practice guidelines (CPGs) are typically written for health care professionals but are meant to assist patients with health care decisions. A number of guideline producers have started to develop patient versions of CPGs to reach this audience. To describe the content and purpose of patient versions of CPGs and compare with patient and public views of CPGs. A descriptive qualitative study with a directed content analysis of a sample of patient versions of CPGs published and freely available in English from 2012 to 2014. We included 34 patient versions of CPGs from 17 guideline producers. Over half of the patient versions were in dedicated patient sections of national/professional agency websites. There was essentially no information about how to manage care in the health care system. The most common purpose was to equip people with information about disease, tests or treatments, and recommendations, but few provided quantitative data about benefits and harms of treatments. Information about beliefs, values and preferences, accessibility, costs, or feasibility of the interventions was rarely addressed. Few provided personal stories or scenarios to personalize the information. Three versions described the strength of the recommendation or the level of evidence. Our search for key institutions that produce patient versions of guidelines was comprehensive, but we only included English and freely available versions. Future work will include other languages. This review describes the current landscape of patient versions of CPGs and suggests that these versions may not address the needs of their targeted audience. Research is needed about how to personalize information, provide information about factors contributing to the recommendations, and provide access. © The Author(s) 2016.

A Critical Review of the Quality of Cough Clinical Practice Guidelines.

PubMed

Jiang, Mei; Guan, Wei-Jie; Fang, Zhang-Fu; Xie, Yan-Qing; Xie, Jia-Xing; Chen, Hao; Wei, Dang; Lai, Ke-Fang; Zhong, Nan-Shan

2016-10-01

Clinical practice guidelines (CPGs) have been developed to provide health-care practitioners with the best possible evidence, but the quality of these CPGs varies greatly. The goal of this study was to systematically evaluate the quality of cough CPGs and identify gaps limiting evidence-based practice. Systematic searches were conducted to identify cough CPGs in guideline databases, developers' Websites, and Medline. Four reviewers independently evaluated eligible guidelines by using the Appraisal of Guidelines for Research and Evaluation II assessment tool. Agreement among reviewers was measured by using the intraclass correlation coefficient. The number of recommendations, strength of recommendation, and levels of evidence were determined. Fifteen cough CPGs were identified. An overall high degree of agreement among reviewers was observed (intraclass correlation coefficient, 0.82 [95% CI, 0.79-0.85]). The quality ranged from good to acceptable in the scope and purpose (mean, 72%; range, 54%-93%) and clarity and presentation (mean, 68%; range, 50%-90%) domains but not in stakeholder involvement (mean, 36%; range, 18%-90%), rigor of development (mean, 36%; range, 9%-93%), applicability (mean, 23%; range, 9%-83%), and editorial independence domains (mean, 24%; range, 0-96%). Seven guidelines (46.7%) were considered "strongly recommended" or "recommended with modifications" for clinical practice. More than 70% of recommendations were based on nonrandomized studies (Level C, 30.4%) and expert opinion (Level D, 41.3%). The quality of cough CPGs is variable, and recommendations are largely based on low-quality evidence. There is significant room for improvement to develop high-quality guidelines, which urgently warrants first-class research to minimize the vital gaps in the evidence for formulation of cough CPGs. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Coupling computer-interpretable guidelines with a drug-database through a web-based system – The PRESGUID project

PubMed Central

Dufour, Jean-Charles; Fieschi, Dominique; Fieschi, Marius

2004-01-01

Background Clinical Practice Guidelines (CPGs) available today are not extensively used due to lack of proper integration into clinical settings, knowledge-related information resources, and lack of decision support at the point of care in a particular clinical context. Objective The PRESGUID project (PREScription and GUIDelines) aims to improve the assistance provided by guidelines. The project proposes an online service enabling physicians to consult computerized CPGs linked to drug databases for easier integration into the healthcare process. Methods Computable CPGs are structured as decision trees and coded in XML format. Recommendations related to drug classes are tagged with ATC codes. We use a mapping module to enhance computerized guidelines coupling with a drug database, which contains detailed information about each usable specific medication. In this way, therapeutic recommendations are backed up with current and up-to-date information from the database. Results Two authoritative CPGs, originally diffused as static textual documents, have been implemented to validate the computerization process and to illustrate the usefulness of the resulting automated CPGs and their coupling with a drug database. We discuss the advantages of this approach for practitioners and the implications for both guideline developers and drug database providers. Other CPGs will be implemented and evaluated in real conditions by clinicians working in different health institutions. PMID:15053828

Plasticity of spinal centers in spinal cord injury patients: new concepts for gait evaluation and training.

PubMed

Scivoletto, Giorgio; Ivanenko, Yuri; Morganti, Barbara; Grasso, Renato; Zago, Mirka; Lacquaniti, Francesco; Ditunno, John; Molinari, Marco

2007-01-01

Recent data on spinal cord plasticity after spinal cord injury (SCI) were reviewed to analyze the influence of training on the neurophysiological organization of locomotor spinal circuits in SCI patients. In particular, the authors studied the relationship between central pattern generators (CPGs) and motor neuron pool activation during gait. An analysis of the relations between locomotor recovery and compensatory mechanisms focuses on the hierarchical organization of gait parameters and allows characterizing kinematic parameters that are highly stable during different gait conditions and in recovered gait after SCI. The importance of training characteristics and the use of robotic/automated devices in gait recovery is analyzed and discussed. The role of CPG in defining kinematic gait parameters is summarized, and spatio-temporal maps of EMG activity during gait are used to clarify the role of CPG plasticity in sustaining gait recovery.

A UML approach to process modelling of clinical practice guidelines for enactment.

PubMed

Knape, T; Hederman, L; Wade, V P; Gargan, M; Harris, C; Rahman, Y

2003-01-01

Although clinical practice guidelines (CPGs) have been suggested as a means of encapsulating best practice in evidence-based medical treatment, their usage in clinical environments has been disappointing. Criticisms of guideline representations have been that they are predominantly narrative and are difficult to incorporate into clinical information systems. This paper analyses the use of UML process modelling techniques for guideline representation and proposes the automated generation of executable guidelines using XMI. This hybrid UML-XMI approach provides flexible authoring of guideline decision and control structures whilst integrating appropriate data flow. It also uses an open XMI standard interface to allow the use of authoring tools and process control systems from multiple vendors. The paper first surveys CPG modelling formalisms followed by a brief introduction to process modelling in UMI. Furthermore, the modelling of CPGs in UML is presented leading to a case study of encoding a diabetes mellitus CPG using UML.

An Evaluation of Web-Based Clinical Practice Guidelines for Managing Problems Associated with Cannabis Use

PubMed Central

Turner, Michael W; Rooke, Sally E; Langton, Julia M; Gates, Peter J

2012-01-01

Background Cannabis is the most widely used illicit substance, and multiple treatment options and avenues exist for managing its use. There has been an increase in the development of clinical practice guidelines (CPGs) to improve standards of care in this area, many of which are disseminated online. However, little is known about the quality and accessibility of these online CPGs. Objective The purpose of study 1 was to determine the extent to which cannabis-related CPGs disseminated online adhere to established methodological standards. The purpose of study 2 was to determine if treatment providers are familiar with these guidelines and to assess their perceived quality of these guidelines. Methods Study 1 involved a systematic search using the Google Scholar search engine and the National Drugs Sector Information Service (NDSIS) website of the Alcohol and Other Drugs Council of Australia (ADCA) to identify CPGs disseminated online. To be included in the current study, CPGs needed to be free of charge and provide guidance on psychological interventions for reducing cannabis use. Four trained reviewers independently assessed the quality of the 7 identified guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. Study 2 assessed 166 Australian cannabis-use treatment providers’ (mean age = 45.47 years, SD 12.14) familiarity with and opinions of these 7 guidelines using an online survey. Treatment providers were recruited using online advertisements that directed volunteers to a link to complete the survey, which was posted online for 6 months (January to June 2012). Primary study outcomes included quality scores and rates of guideline familiarity, guideline use, and discovery methods. Results Based on the AGREE II, the quality of CPGs varied considerably. Across different reporting domains, adherence to methodological standards ranged from 0% to 92%. Quality was lowest in the domains of rigor of development (50%), applicability (46%), and editorial independence (30%). Although examination of AGREE II domain scores demonstrated that the quality of the 7 guidelines could be divided into 3 categories (high quality, acceptable to low quality, and very low quality), review of treatment providers’ quality perceptions indicated all guidelines fell into 1 category (acceptable quality). Based on treatment providers’ familiarity with and usage rates of the CPGs, a combination of peer/colleagues, senior professionals, workshops, and Internet dissemination was deemed to be most effective for promoting cannabis use CPGs. Lack of time, guideline length, conflicts with theoretical orientation, and prior content knowledge were identified as barriers to guideline uptake. Conclusions Developers of CPGs should improve their reporting of development processes, conflicts of interest, and CPGs’ applicability to practice, while remaining cognizant that long guidelines may deter implementation. Treatment providers need to be aware that the quality of cannabis-related CPGs varies substantially. PMID:23249447

Natural variation in maternal care and cross-tissue patterns of oxytocin receptor gene methylation in rats.

PubMed

Beery, Annaliese K; McEwen, Lisa M; MacIsaac, Julia L; Francis, Darlene D; Kobor, Michael S

2016-01-01

This article is part of a Special Issue "Parental Care". Since the first report of maternal care effects on DNA methylation in rats, epigenetic modifications of the genome in response to life experience have become the subject of intense focus across many disciplines. Oxytocin receptor expression varies in response to early experience, and both oxytocin signaling and methylation status of the oxytocin receptor gene (Oxtr) in blood have been related to disordered social behavior. It is unknown whether Oxtr DNA methylation varies in response to early life experience, and whether currently employed peripheral measures of Oxtr methylation reflect variation in the brain. We examined the effects of early life rearing experience via natural variation in maternal licking and grooming during the first week of life on behavior, physiology, gene expression, and epigenetic regulation of Oxtr across blood and brain tissues (mononucleocytes, hippocampus, striatum, and hypothalamus). Rats reared by "high" licking-grooming (HL) and "low" licking-grooming (LL) rat dams exhibited differences across study outcomes: LL offspring were more active in behavioral arenas, exhibited lower body mass in adulthood, and showed reduced corticosterone responsivity to a stressor. Oxtr DNA methylation was significantly lower at multiple CpGs in the blood of LL versus HL males, but no differences were found in the brain. Across groups, Oxtr transcript levels in the hypothalamus were associated with reduced corticosterone secretion in response to stress, congruent with the role of oxytocin signaling in this region. Methylation of specific CpGs at a high or low level was consistent across tissues, especially within the brain. However, individual variation in DNA methylation relative to these global patterns was not consistent across tissues. These results suggest that blood Oxtr DNA methylation may reflect early experience of maternal care, and that Oxtr methylation across tissues is highly concordant for specific CpGs, but that inferences across tissues are not supported for individual variation in Oxtr methylation. Copyright © 2015 Elsevier Inc. All rights reserved.

Natural variation in maternal care and cross-tissue patterns of oxytocin receptor gene methylation in rats

PubMed Central

Beery, Annaliese K.; McEwen, Lisa M.; MacIsaac, Julia L; Francis, Darlene D.; Kobor, Michael S.

2015-01-01

Since the first report of maternal care effects on DNA methylation in rats, epigenetic modifications of the genome in response to life experience have become the subject of intense focus across many disciplines. Oxytocin receptor expression varies in response to early experience, and both oxytocin signaling and methylation status of the oxytocin receptor gene (Oxtr) in blood have been related to disordered social behavior. It is unknown whether Oxtr methylation varies in response to early life experience, and whether currently employed peripheral measures of Oxtr methylation reflect variation in the brain. We examined the effects of early life rearing experience via natural variation in maternal licking and grooming during the first week of life on behavior, physiology, gene expression, and epigenetic regulation of Oxtr across blood and brain tissues (mononucleocytes, hippocampus, striatum, and hypothalamus). Rats reared by “high” licking-grooming (HL) and “low” licking-grooming (LL) rat dams exhibited differences across study outcomes: LL offspring were more active in behavioral arenas, exhibited lower body mass in adulthood, and showed reduced corticosterone responsivity to a stressor. Oxtr methylation was significantly lower at multiple CpGs in the blood of LL versus HL rats, but no differences were found in the brain. Across groups, Oxtr transcript levels in the hypothalamus were associated with reduced corticosterone secretion in response to stress, congruent with the role of oxytocin signaling in this region. Methylation of specific CpGs at a high or low level was consistent across tissues, especially within the brain. However, individual variation in methylation relative to these global patterns was not consistent across tissues. These results suggest that blood Oxtr methylation may reflect early experience of maternal care, and that Oxtr methylation across tissues is highly concordant for specific CpGs, but that inferences across tissues are not supported for individual variation in Oxtr methylation. PMID:26122287

Do Clinical Practice Guidelines Improve Quality?

PubMed

Baldassari, Cristina M

2017-07-01

Controversy exists surrounding how to best define and assess quality in the health care setting. Clinical practice guidelines (CPGs) have been developed to improve the quality of medical care by highlighting key clinical recommendations based on recent evidence. However, data linking CPGs to improvements in outcomes in otolaryngology are lacking. Numerous barriers contribute to difficulties in translating CPGs to improvements in quality. Future initiatives are needed to improve CPG adherence and define the impact of CPG recommendations on the quality of otolaryngologic care provided to our patients.

Developing evidence-based physical therapy clinical practice guidelines.

PubMed

Kaplan, Sandra L; Coulter, Colleen; Fetters, Linda

2013-01-01

Recommended strategies for developing evidence-based clinical practice guidelines (CPGs) are provided. The intent is that future CPGs developed with the support of the Section on Pediatrics of the American Physical Therapy Association would consistently follow similar developmental processes to yield consistent quality and presentation. Steps in the process of developing CPGs are outlined and resources are provided to assist CPG developers in carrying out their task. These recommended processes may also be useful to CPG developers representing organizations with similar structures, objectives, and resources.

Development of quadruped walking locomotion gait generator using a hybrid method

NASA Astrophysics Data System (ADS)

Jasni, F.; Shafie, A. A.

2013-12-01

The earth, in many areas is hardly reachable by the wheeled or tracked locomotion system. Thus, walking locomotion system is becoming a favourite option for mobile robot these days. This is because of the ability of walking locomotion to move on the rugged and unlevel terrains. However, to develop a walking locomotion gait for a robot is not a simple task. Central Pattern Generator (CPGs) method is a biological inspired method that is introduced as a method to develop the gait for the walking robot recently to tackle the issue faced by the conventional method of pre-designed trajectory based method. However, research shows that even the CPG method do have some limitations. Thus, in this paper, a hybrid method that combines CPG and the pre-designed trajectory based method is introduced to develop a walking gait for quadruped walking robot. The 3-D foot trajectories and the joint angle trajectories developed using the proposed method are compared with the data obtained via the conventional method of pre-designed trajectory to confirm the performance.

Australian general practitioner attitudes to clinical practice guidelines and some implications for translating osteoarthritis care into practice.

PubMed

Basedow, Martin; Runciman, William B; Lipworth, Wendy; Esterman, Adrian

2016-11-01

Clinical practice guidelines (CPGs) have been shown to improve processes of care and health outcomes, but there is often a discrepancy between recommendations for care and clinical practice. This study sought to explore general practitioner (GP) attitudes towards CPGs, in general and specifically for osteoarthritis (OA), with the implications for translating OA care into practice. A self-administered questionnaire was conducted in January 2013 with a sample of 228 GPs in New South Wales and South Australia. Seventy-nine GPs returned questionnaires (response rate 35%). Nearly all GPs considered that CPGs support decision-making in practice (94%) and medical education (92%). Very few respondents regarded CPGs as a threat to clinical autonomy, and most recognised that individual patient circumstances must be taken into account. Shorter CPG formats were preferred over longer and more comprehensive formats, with preferences being evenly divided among respondents for short, 2-3-page summaries, flowcharts or algorithms and single page checklists. GPs considered accessibility to CPGs to be important, and electronic formats were popular. Familiarity and use of The Royal Australian College of General Practitioners OA Guideline was poor, with most respondents either not aware of it (30%; 95% confidence interval (CI) 27 - 41%), had never used it (19%; 95% CI 12 - 29%) or rarely used it (34%; 95% CI 25-45%). If CPGs are to assist with the translation of evidence into practice, they must be easily accessible and in a format that encourages use.

An Interdisciplinary Education Initiative to Promote Blood Conservation in Cardiac Surgery.

PubMed

Goda, Tamara S; Sherrod, Brad; Kindell, Linda

Transfusion practices vary extensively for patients undergoing cardiac surgical procedures, leading to high utilization of blood products despite evidence that transfusions negatively impact outcomes. An important factor affecting transfusion practice is recognition of the importance of teams in cardiac surgery care delivery. This article reports an evidenced-based practice (EBP) initiative constructed using the Society of Thoracic Surgery (STS) 2011 Blood Conservation Clinical Practice Guidelines (CPGs) to standardize transfusion practice across the cardiac surgery team at a large academic medical center. Project outcomes included: a) Improvement in clinician knowledge related to the STS Blood Conservation CPGs; and b) Decreased blood product utilization for patients undergoing cardiac surgical procedures. Participants' scores reflected an improvement in the overall knowledge of the STS CPGs noting a 31.1% (p = 0.012) increase in the number of participants whose practice reflected the Blood Conservation CPGs post intervention. Additionally, there was a reduction in overall blood product utilization for all patients undergoing cardiac surgery procedures post intervention (p = 0.005). Interdisciplinary education based on the STS Blood Conservation CPGs is an effective way to reduce transfusion practice variability and decrease utilization of blood products during cardiac surgery.

'How to know what you need to do': a cross-country comparison of maternal health guidelines in Burkina Faso, Ghana and Tanzania.

PubMed

Baker, Ulrika; Tomson, Göran; Somé, Mathias; Kouyaté, Bocar; Williams, John; Mpembeni, Rose; Massawe, Siriel; Blank, Antje; Gustafsson, Lars L; Eriksen, Jaran

2012-04-13

Initiatives to raise the quality of care provided to mothers need to be given priority in Sub Saharan Africa (SSA). The promotion of clinical practice guidelines (CPGs) is a common strategy, but their implementation is often challenging, limiting their potential impact. Through a cross-country perspective, this study explored CPGs for maternal health in Burkina Faso, Ghana, and Tanzania. The objectives were to compare factors related to CPG use including their content compared with World Health Organization (WHO) guidelines, their format, and their development processes. Perceptions of their availability and use in practice were also explored. The overall purpose was to further the understanding of how to increase CPGs' potential to improve quality of care for mothers in SSA. The study was a multiple case study design consisting of cross-country comparisons using document review and key informant interviews. A conceptual framework to aid analysis and discussion of results was developed, including selected domains related to guidelines' implementability and use by health workers in practice in terms of usability, applicability, and adaptability. The study revealed few significant differences in content between the national guidelines for maternal health and WHO recommendations. There were, however, marked variations in the format of CPGs between the three countries. Apart from the Ghanaian and one of the Tanzanian CPGs, the levels of both usability and applicability were assessed as low or medium. In all three countries, the use of CPGs by health workers in practice was perceived to be limited. Our cross-country study suggests that it is not poor quality of content or lack of evidence base that constitute the major barrier for CPGs to positively impact on quality improvement in maternal care in SSA. It rather emphasises the need to prioritise the format of guidelines to increase their usability and applicability and to consider these attributes together with implementation strategies as integral to their development processes.

Supplementation with N-3 Long-Chain Polyunsaturated Fatty Acids or Olive Oil in Men and Women with Renal Disease Induces Differential Changes in the DNA Methylation of FADS2 and ELOVL5 in Peripheral Blood Mononuclear Cells

PubMed Central

Hoile, Samuel P.; Clarke-Harris, Rebecca; Huang, Rae-Chi; Calder, Philip C.; Mori, Trevor A.; Beilin, Lawrence J.; Lillycrop, Karen A.; Burdge, Graham C.

2014-01-01

Background Studies in animal models and in cultured cells have shown that fatty acids can induce alterations in the DNA methylation of specific genes. There have been no studies of the effects of fatty acid supplementation on the epigenetic regulation of genes in adult humans. Methods and Results We investigated the effect of supplementing renal patients with 4 g daily of either n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) or olive oil (OO) for 8 weeks on the methylation status of individual CpG loci in the 5′ regulatory region of genes involved in PUFA biosynthesis in peripheral blood mononuclear cells from men and women (aged 53 to 63 years). OO and n-3 LCPUFA each altered (>10% difference in methylation) 2/22 fatty acid desaturase (FADS)-2 CpGs, while n-3 LCPUFA, but not OO, altered (>10%) 1/12 ELOVL5 CpGs in men. OO altered (>6%) 8/22 FADS2 CpGs and (>3%) 3/12 elongase (ELOVL)-5 CpGs, while n-3 LCPUFA altered (>5%) 3/22 FADS2 CpGs and 2/12 (>3%) ELOVL5 CpGs in women. FADS1 or ELOVL2 methylation was unchanged. The n-3 PUFA supplementation findings were replicated in blood DNA from healthy adults (aged 23 to 30 years). The methylation status of the altered CpGs in FADS2 and ELOVL5 was associated negatively with the level of their transcripts. Conclusions These findings show that modest fatty acid supplementation can induce altered methylation of specific CpG loci in adult humans, contingent on the nature of the supplement and on sex. This has implications for understanding the effect of fatty acids on PUFA metabolism and cell function. PMID:25329159

Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation.

PubMed

Teschendorff, Andrew E; Jones, Allison; Fiegl, Heidi; Sargent, Alexandra; Zhuang, Joanna J; Kitchener, Henry C; Widschwendter, Martin

2012-03-27

Recently, it has been proposed that epigenetic variation may contribute to the risk of complex genetic diseases like cancer. We aimed to demonstrate that epigenetic changes in normal cells, collected years in advance of the first signs of morphological transformation, can predict the risk of such transformation. We analyzed DNA methylation (DNAm) profiles of over 27,000 CpGs in cytologically normal cells of the uterine cervix from 152 women in a prospective nested case-control study. We used statistics based on differential variability to identify CpGs associated with the risk of transformation and a novel statistical algorithm called EVORA (Epigenetic Variable Outliers for Risk prediction Analysis) to make predictions. We observed many CpGs that were differentially variable between women who developed a non-invasive cervical neoplasia within 3 years of sample collection and those that remained disease-free. These CpGs exhibited heterogeneous outlier methylation profiles and overlapped strongly with CpGs undergoing age-associated DNA methylation changes in normal tissue. Using EVORA, we demonstrate that the risk of cervical neoplasia can be predicted in blind test sets (AUC = 0.66 (0.58 to 0.75)), and that assessment of DNAm variability allows more reliable identification of risk-associated CpGs than statistics based on differences in mean methylation levels. In independent data, EVORA showed high sensitivity and specificity to detect pre-invasive neoplasia and cervical cancer (AUC = 0.93 (0.86 to 1) and AUC = 1, respectively). We demonstrate that the risk of neoplastic transformation can be predicted from DNA methylation profiles in the morphologically normal cell of origin of an epithelial cancer. Having profiled only 0.1% of CpGs in the human genome, studies of wider coverage are likely to yield improved predictive and diagnostic models with the accuracy needed for clinical application. The ARTISTIC trial is registered with the International Standard Randomised Controlled Trial Number ISRCTN25417821.

Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation

PubMed Central

2012-01-01

Background Recently, it has been proposed that epigenetic variation may contribute to the risk of complex genetic diseases like cancer. We aimed to demonstrate that epigenetic changes in normal cells, collected years in advance of the first signs of morphological transformation, can predict the risk of such transformation. Methods We analyzed DNA methylation (DNAm) profiles of over 27,000 CpGs in cytologically normal cells of the uterine cervix from 152 women in a prospective nested case-control study. We used statistics based on differential variability to identify CpGs associated with the risk of transformation and a novel statistical algorithm called EVORA (Epigenetic Variable Outliers for Risk prediction Analysis) to make predictions. Results We observed many CpGs that were differentially variable between women who developed a non-invasive cervical neoplasia within 3 years of sample collection and those that remained disease-free. These CpGs exhibited heterogeneous outlier methylation profiles and overlapped strongly with CpGs undergoing age-associated DNA methylation changes in normal tissue. Using EVORA, we demonstrate that the risk of cervical neoplasia can be predicted in blind test sets (AUC = 0.66 (0.58 to 0.75)), and that assessment of DNAm variability allows more reliable identification of risk-associated CpGs than statistics based on differences in mean methylation levels. In independent data, EVORA showed high sensitivity and specificity to detect pre-invasive neoplasia and cervical cancer (AUC = 0.93 (0.86 to 1) and AUC = 1, respectively). Conclusions We demonstrate that the risk of neoplastic transformation can be predicted from DNA methylation profiles in the morphologically normal cell of origin of an epithelial cancer. Having profiled only 0.1% of CpGs in the human genome, studies of wider coverage are likely to yield improved predictive and diagnostic models with the accuracy needed for clinical application. Trial registration The ARTISTIC trial is registered with the International Standard Randomised Controlled Trial Number ISRCTN25417821. PMID:22453031

Quality Assessment of Clinical Practice Guidelines Developed by Professional Societies in Turkey.

PubMed

Yaşar, Ilknur; Kahveci, Rabia; Baydar Artantaş, Aylin; Ayhan Başer, Duygu; Gökşin Cihan, Fatma; Şencan, Irfan; Koç, Esra Meltem; Özkara, Adem

2016-01-01

Clinical practice guidelines (CPGs) are systematically developed statements to assist practitioner and patient decisions about appropriate healthcare for specific clinical circumstances. There is a limited number of studies on guidelines in Turkey. The quality of Ministry of Health guidelines have formerly been assessed whereas there is no information on the other guidelines developed in the country. This study aims to assess the quality of CPGs that are developed by professional societies that work for the health sector in Turkey, and compare the findings with international guidelines. Professional societies that work for the health sector were determined by using the data obtained from the Ministry of Internal Affairs. Inclusion and exclusion criteria were defined for selecting the CPGs. Guidelines containing recommendations about disease management to the doctors, accessible online, developed within the past 5 years, citing references for recommendations, about the diseases over 1% prevalence according to the "Statistical Yearbook of Turkey 2012" were included in the study. The quality of CPGs were assessed with the AGREE II instrument, which is an internationally recognized tool for this purpose. Four independent reviewers, who did not participate in the development of the selected guidelines and were trained in CPG appraisal, used the AGREE instrument for assessment of the selected guidelines. 47 professional societies were defined which provided access to CPGs in their websites; 3 of them were only open to members so these could not be reached. 8 CPGs from 7 societies were selected from a total of 401 CPGs from 44 societies. The mean scores of the domains of the guidelines which were assessed by the AGREE II tool were; 64%, stakeholder involvement: 37.9%, rigour of development: 35.3%, clarity and presentation: 77.9%, applicability: 49.0% and editorial independence: 46.0%. This is the first study in Turkey regarding quality appraisal of guidelines developed by the local professional societies. It adds to the limited amount of information in the literature that comes from Turkey as well as other developing countries.

DNA methylation signatures of educational attainment

NASA Astrophysics Data System (ADS)

van Dongen, Jenny; Bonder, Marc Jan; Dekkers, Koen F.; Nivard, Michel G.; van Iterson, Maarten; Willemsen, Gonneke; Beekman, Marian; van der Spek, Ashley; van Meurs, Joyce B. J.; Franke, Lude; Heijmans, Bastiaan T.; van Duijn, Cornelia M.; Slagboom, P. Eline; Boomsma, Dorret I.; BIOS consortium

2018-03-01

Educational attainment is a key behavioural measure in studies of cognitive and physical health, and socioeconomic status. We measured DNA methylation at 410,746 CpGs (N = 4152) and identified 58 CpGs associated with educational attainment at loci characterized by pleiotropic functions shared with neuronal, immune and developmental processes. Associations overlapped with those for smoking behaviour, but remained after accounting for smoking at many CpGs: Effect sizes were on average 28% smaller and genome-wide significant at 11 CpGs after adjusting for smoking and were 62% smaller in never smokers. We examined sources and biological implications of education-related methylation differences, demonstrating correlations with maternal prenatal folate, smoking and air pollution signatures, and associations with gene expression in cis, dynamic methylation in foetal brain, and correlations between blood and brain. Our findings show that the methylome of lower-educated people resembles that of smokers beyond effects of their own smoking behaviour and shows traces of various other exposures.

Osteoarthritis guidelines: Barriers to implementation and solutions.

PubMed

Ferreira de Meneses, Sarah; Rannou, Francois; Hunter, David J

2016-06-01

Osteoarthritis (OA) is a leading cause of disability worldwide. Clinical practice guidelines (CPGs) have been developed to facilitate improved OA management. Scientific communities worldwide have proposed CPGs for OA treatment. Despite the number of highly prominent guidelines available and their remarkable consistency, their uptake has been suboptimal. Possibly because of the multitude of barriers related to the implementation of CPGs. For example, different guidelines show contradictions, some lack evidence, and they lack a hierarchy or tools to facilitate their translation and application. Also, the guidelines do not acknowledge the effect of comorbidities on choosing the treatments. Finally, poor integration of multidisciplinary services within and across healthcare settings is a major barrier to the effective implementation of management guidelines. Here we describe the main problems related to the OA guidelines and some solutions so as to offer some guidance on the elaboration of future CPGs and their implementation in primary care. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Evaluation and management of combat-related spinal injuries: a review based on recent experiences.

PubMed

Schoenfeld, Andrew J; Lehman, Ronald A; Hsu, Joseph R

2012-09-01

The current approach to the evaluation and treatment of military casualties in the Global War on Terror is informed by medical experience from prior conflicts and combat encounters from the last 10 years. In an effort to standardize the care provided to military casualties in the ongoing conflicts, the Department of Defense (DoD) has published Clinical Practice Guidelines (CPGs) that deal specifically with the combat casualty sustaining a spinal injury. However, the combat experience with spine injuries in the present conflicts remains incompletely described. To describe the CPGs for the care of the combat casualty with suspected spine injuries and discuss them in light of the published military experience with combat-related spinal trauma. Literature review. A literature review was conducted regarding published works that discussed the incidence, epidemiology, and management of combat-related spinal trauma. The CPGs, established by the DoD, are discussed in light of actual military experiences with spine trauma, the present situation in the forward surgical teams and combat support hospitals treating casualties in theater, and recent publications in the field of spine surgery. In the conventional wars fought by the United States between 1950 and 1991 (Korea, Vietnam, Gulf War I), the incidence of spine injuries remained close to 1% of all combat casualties. However, in the Global War on Terror, the enemy has relied on implements of asymmetric warfare, including sniper attacks, ambush, roadside bombs, and improvised explosive devices. The increase in explosive mechanisms of injury has elevated the number of soldiers exposed to blunt force trauma and, consequently, recent publications reported the highest incidence of combat-related spinal injuries in American military history. Wounded soldiers are expeditiously evacuated through the echelons of care but typically do not receive surgical management in theater. The current CPGs for the care of soldiers with combat-related spinal injuries should be re-examined in light of data regarding the increasing number of spine injuries, new injury patterns, such as lumbosacral dissociation and low lumbar burst fractures, and recent reports within the field of spine surgery as a whole. American and coalition forces are sustaining the highest spine combat casualty rates in recorded history and previously unseen injuries are being encountered with increased frequency. While the CPGs provide useful direction in terms of the evaluation and management of combat casualties with spine injuries, such recommendations may warrant periodic re-evaluation in light of recent combat experiences and evolving scientific evidence within the spine literature. Published by Elsevier Inc.

Speech pathologists' experiences with stroke clinical practice guidelines and the barriers and facilitators influencing their use: a national descriptive study.

PubMed

Hadely, Kathleen A; Power, Emma; O'Halloran, Robyn

2014-03-06

Communication and swallowing disorders are a common consequence of stroke. Clinical practice guidelines (CPGs) have been created to assist health professionals to put research evidence into clinical practice and can improve stroke care outcomes. However, CPGs are often not successfully implemented in clinical practice and research is needed to explore the factors that influence speech pathologists' implementation of stroke CPGs. This study aimed to describe speech pathologists' experiences and current use of guidelines, and to identify what factors influence speech pathologists' implementation of stroke CPGs. Speech pathologists working in stroke rehabilitation who had used a stroke CPG were invited to complete a 39-item online survey. Content analysis and descriptive and inferential statistics were used to analyse the data. 320 participants from all states and territories of Australia were surveyed. Almost all speech pathologists had used a stroke CPG and had found the guideline "somewhat useful" or "very useful". Factors that speech pathologists perceived influenced CPG implementation included the: (a) guideline itself, (b) work environment, (c) aspects related to the speech pathologist themselves, (d) patient characteristics, and (e) types of implementation strategies provided. There are many different factors that can influence speech pathologists' implementation of CPGs. The factors that influenced the implementation of CPGs can be understood in terms of knowledge creation and implementation frameworks. Speech pathologists should continue to adapt the stroke CPG to their local work environment and evaluate their use. To enhance guideline implementation, they may benefit from a combination of educational meetings and resources, outreach visits, support from senior colleagues, and audit and feedback strategies.

Clinical practice guidelines in breast cancer

PubMed Central

Tyagi, N. Kumar; Dhesy-Thind, S.

2018-01-01

Background A number of clinical practice guidelines (cpgs) concerning breast cancer (bca) screening and management are available. Here, we review the strengths and weaknesses of cpgs from various professional organizations and consensus groups with respect to their methodologic quality, recommendations, and implementability. Methods Guidelines from four groups were reviewed with respect to two clinical scenarios: adjuvant ovarian function suppression (ofs) in premenopausal women with early-stage estrogen receptor–positive bca, and use of sentinel lymph node biopsy (slnb) after neoadjuvant chemotherapy (nac) for locally advanced bca. Guidelines from the American Society of Clinical Oncology (asco); Cancer Care Ontario’s Program in Evidence Based Care (cco’s pebc); the U.S. National Comprehensive Cancer Network (nccn); and the St. Gallen International Breast Cancer Consensus Conference were reviewed by two independent assessors. Guideline methodology and applicability were evaluated using the agree ii tool. Results The quality of the cpgs was greatest for the guidelines developed by asco and cco’s pebc. The nccn and St. Gallen guidelines were found to have lower scores for methodologic rigour. All guidelines scored poorly for applicability. The recommendations for ofs were similar in three guidelines. Recommendations by the various organizations for the use of slnb after nac were contradictory. Conclusions Our review demonstrated that cpgs can be heterogeneous in methodologic quality. Low-quality cpg implementation strategies contribute to low uptake of, and adherence to, bca cpgs. Further research examining the barriers to recommendations—such as intrinsic guideline characteristics and the needs of end users—is required. The use of bca cpgs can improve the knowledge-to-practice gap and patient outcomes.

Early- and late-onset preeclampsia and the DNA methylation of circadian clock and clock-controlled genes in placental and newborn tissues.

PubMed

van den Berg, C B; Chaves, I; Herzog, E M; Willemsen, S P; van der Horst, G T J; Steegers-Theunissen, R P M

2017-01-01

The placenta is important in providing a healthy environment for the fetus and plays a central role in the pathophysiology of preeclampsia (PE). Fetal and placental developments are influenced by epigenetic programming. There is some evidence that PE is controlled to an altered circadian homeostasis. In a nested case-control study embedded in the Rotterdam Periconceptional Cohort, we obtained placental tissue, umbilical cord leukocytes (UCL), and human umbilical venous endothelial cells of 13 early-onset PE, 16 late-onset PE and 83 controls comprising 36 uncomplicated and 47 complicated pregnancies, i.e. 27 fetal growth restricted and 20 spontaneous preterm birth. To investigate the associations between PE and the epigenetics of circadian clock and clock-controlled genes in placental and newborn tissues, genome-wide DNA methylation analysis was performed using the Illumina HumanMethylation450K BeadChip and a candidate-gene approach using ANCOVA was applied on 939 CpGs of 39 circadian clock and clock-controlled genes. DNA methylation significantly differed in early-onset PE compared with spontaneous preterm birth at 6 CpGs in placental tissue (3.73 E-5 ≤ p ≤ 0.016) and at 21 CpGs in UCL (1.09 E-5 ≤ p ≤ 0.024). In early-onset PE compared with fetal growth restriction 2 CpGs in placental tissue (p < 0.05) and 8 CpGs in uncomplicated controls (4.78 E-5 ≤ p ≤ 0.049) were significantly different. Moreover, significantly different DNA methylation in early-onset PE compared with uncomplicated controls was shown at 6 CpGs in placental tissue (1.36 E-4 ≤ p ≤ 0.045) and 11 CpGs in uncomplicated controls (2.52 E-6 ≤ p ≤ 0.009). No significant associations were shown with late-onset PE between study groups or tissues. The most differentially methylated CpGs showed hypomethylation in placental tissue and hypermethylation in uncomplicated controls. In conclusion, DNA methylation of circadian clock and clock-controlled genes demonstrated most differences in UCL of early-onset PE compared with spontaneous preterm birth. Implications of the tissue-specific variations in epigenetic programming for circadian performance and long-term health need further investigation.

Pregnancy exposure to atmospheric pollution and meteorological conditions and placental DNA methylation.

PubMed

Abraham, Emilie; Rousseaux, Sophie; Agier, Lydiane; Giorgis-Allemand, Lise; Tost, Jörg; Galineau, Julien; Hulin, Agnès; Siroux, Valérie; Vaiman, Daniel; Charles, Marie-Aline; Heude, Barbara; Forhan, Anne; Schwartz, Joel; Chuffart, Florent; Bourova-Flin, Ekaterina; Khochbin, Saadi; Slama, Rémy; Lepeule, Johanna

2018-06-19

Air pollution exposure represents a major health threat to the developing foetus. DNA methylation is one of the most well-known molecular determinants of the epigenetic status of cells. Blood DNA methylation has been proven sensitive to air pollutants, but the molecular impact of air pollution on new-borns has so far received little attention. We investigated whether nitrogen dioxide (NO 2 ), particulate matter (PM 10 ), temperature and humidity during pregnancy are associated with differences in placental DNA methylation levels. Whole-genome DNA-methylation was measured using the Illumina's Infinium HumanMethylation450 BeadChip in the placenta of 668 newborns from the EDEN cohort. We designed an original strategy using a priori biological information to focus on candidate genes with a specific expression pattern in placenta (active or silent) combined with an agnostic epigenome-wide association study (EWAS). We used robust linear regression to identify CpGs and differentially methylated regions (DMR) associated with each exposure during short- and long-term time-windows. The candidate genes approach identified nine CpGs mapping to 9 genes associated with prenatal NO 2 and PM 10 exposure [false discovery rate (FDR) p < 0.05]. Among these, the methylation level of 2 CpGs located in ADORA2B remained significantly associated with NO 2 exposure during the 2nd trimester and whole pregnancy in the EWAS (FDR p < 0.05). EWAS further revealed associations between the environmental exposures under study and variations of DNA methylation of 4 other CpGs. We further identified 27 DMRs significantly (FDR p < 0.05) associated with air pollutants exposure and 13 DMRs with meteorological conditions. The methylation of ADORA2B, a gene whose expression was previously associated with hypoxia and pre-eclampsia, was consistently found here sensitive to atmospheric pollutants. In addition, air pollutants were associated to DMRs pointing towards genes previously implicated in preeclampsia, hypertensive and metabolic disorders. These findings demonstrate that air pollutants exposure at levels commonly experienced in the European population are associated with placental gene methylation and provide some mechanistic insight into some of the reported effects of air pollutants on preeclampsia. Copyright © 2018 Elsevier Ltd. All rights reserved.

Impacts of Chromatin States and Long-Range Genomic Segments on Aging and DNA Methylation

PubMed Central

Sun, Dan; Yi, Soojin V.

2015-01-01

Understanding the fundamental dynamics of epigenome variation during normal aging is critical for elucidating key epigenetic alterations that affect development, cell differentiation and diseases. Advances in the field of aging and DNA methylation strongly support the aging epigenetic drift model. Although this model aligns with previous studies, the role of other epigenetic marks, such as histone modification, as well as the impact of sampling specific CpGs, must be evaluated. Ultimately, it is crucial to investigate how all CpGs in the human genome change their methylation with aging in their specific genomic and epigenomic contexts. Here, we analyze whole genome bisulfite sequencing DNA methylation maps of brain frontal cortex from individuals of diverse ages. Comparisons with blood data reveal tissue-specific patterns of epigenetic drift. By integrating chromatin state information, divergent degrees and directions of aging-associated methylation in different genomic regions are revealed. Whole genome bisulfite sequencing data also open a new door to investigate whether adjacent CpG sites exhibit coordinated DNA methylation changes with aging. We identified significant ‘aging-segments’, which are clusters of nearby CpGs that respond to aging by similar DNA methylation changes. These segments not only capture previously identified aging-CpGs but also include specific functional categories of genes with implications on epigenetic regulation of aging. For example, genes associated with development are highly enriched in positive aging segments, which are gradually hyper-methylated with aging. On the other hand, regions that are gradually hypo-methylated with aging (‘negative aging segments’) in the brain harbor genes involved in metabolism and protein ubiquitination. Given the importance of protein ubiquitination in proteome homeostasis of aging brains and neurodegenerative disorders, our finding suggests the significance of epigenetic regulation of this posttranslational modification pathway in the aging brain. Utilizing aging segments rather than individual CpGs will provide more comprehensive genomic and epigenomic contexts to understand the intricate associations between genomic neighborhoods and developmental and aging processes. These results complement the aging epigenetic drift model and provide new insights. PMID:26091484

Genetic and epigenetic profiling of CLL disease progression reveals limited somatic evolution and suggests a relationship to memory-cell development.

PubMed

Smith, E N; Ghia, E M; DeBoever, C M; Rassenti, L Z; Jepsen, K; Yoon, K-A; Matsui, H; Rozenzhak, S; Alakus, H; Shepard, P J; Dai, Y; Khosroheidari, M; Bina, M; Gunderson, K L; Messer, K; Muthuswamy, L; Hudson, T J; Harismendy, O; Barrett, C L; Jamieson, C H M; Carson, D A; Kipps, T J; Frazer, K A

2015-04-10

We examined genetic and epigenetic changes that occur during disease progression from indolent to aggressive forms of chronic lymphocytic leukemia (CLL) using serial samples from 27 patients. Analysis of DNA mutations grouped the leukemia cases into three categories: evolving (26%), expanding (26%) and static (47%). Thus, approximately three-quarters of the CLL cases had little to no genetic subclonal evolution. However, we identified significant recurrent DNA methylation changes during progression at 4752 CpGs enriched for regions near Polycomb 2 repressive complex (PRC2) targets. Progression-associated CpGs near the PRC2 targets undergo methylation changes in the same direction during disease progression as during normal development from naive to memory B cells. Our study shows that CLL progression does not typically occur via subclonal evolution, but that certain CpG sites undergo recurrent methylation changes. Our results suggest CLL progression may involve developmental processes shared in common with the generation of normal memory B cells.

Systematic Review of Clinical Practice Guidelines for Failed Antidepressant Treatment Response in Major Depressive Disorder, Dysthymia, and Subthreshold Depression in Adults.

PubMed

MacQueen, Glenda; Santaguida, Pasqualina; Keshavarz, Homa; Jaworska, Natalia; Levine, Mitchell; Beyene, Joseph; Raina, Parminder

2017-01-01

This systematic review critically evaluated clinical practice guidelines (CPGs) for treating adults with major depressive disorder, dysthymia, or subthreshold or minor depression for recommendations following inadequate response to first-line treatment with selective serotonin reuptake inhibitors (SSRIs). Searches for CPGs (January 2004 to November 2014) in English included 7 bibliographic databases and grey literature sources using CPG and depression as the keywords. Two raters selected CPGs on depression with a national scope. Data extraction included definitions of adequate response and recommended treatment options. Two raters assessed quality using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. From 46,908 citations, 3167 were screened at full text. From these 21 CPG were applicable to adults in primary care and outpatient settings. Five CPGs consider patients with dysthymia or subthreshold or minor depression. None provides recommendations for those who do not respond to first-line SSRI treatment. For adults with MDD, most CPGs do not define an "inadequate response" or provide specific suggestions regarding how to choose alternative medications when switching to an alternative antidepressant. There is variability between CPGs in recommending combination strategies. AGREE II ratings for stakeholder involvement in CPG development, editorial independence, and rigor of development are domains in which depression guidelines are often less robust. About half of patients with depression require second-line treatment to achieve remission. Consistency and clarity in guidelines for second-line treatment of depression are therefore important for clinicians but lacking in most current guidelines. This may reflect a paucity of primary studies upon which to base conclusions.

Failure Mode and Effect Analysis (FMEA) may enhance implementation of clinical practice guidelines: An experience from the Middle East.

PubMed

Babiker, Amir; Amer, Yasser S; Osman, Mohamed E; Al-Eyadhy, Ayman; Fatani, Solafa; Mohamed, Sarar; Alnemri, Abdulrahman; Titi, Maher A; Shaikh, Farheen; Alswat, Khalid A; Wahabi, Hayfaa A; Al-Ansary, Lubna A

2018-02-01

Implementation of clinical practice guidelines (CPGs) has been shown to reduce variation in practice and improve health care quality and patients' safety. There is a limited experience of CPG implementation (CPGI) in the Middle East. The CPG program in our institution was launched in 2009. The Quality Management department conducted a Failure Mode and Effect Analysis (FMEA) for further improvement of CPGI. This is a prospective study of a qualitative/quantitative design. Our FMEA included (1) process review and recording of the steps and activities of CPGI; (2) hazard analysis by recording activity-related failure modes and their effects, identification of actions required, assigned severity, occurrence, and detection scores for each failure mode and calculated the risk priority number (RPN) by using an online interactive FMEA tool; (3) planning: RPNs were prioritized, recommendations, and further planning for new interventions were identified; and (4) monitoring: after reduction or elimination of the failure mode. The calculated RPN will be compared with subsequent analysis in post-implementation phase. The data were scrutinized from a feedback of quality team members using a FMEA framework to enhance the implementation of 29 adapted CPGs. The identified potential common failure modes with the highest RPN (≥ 80) included awareness/training activities, accessibility of CPGs, fewer advocates from clinical champions, and CPGs auditing. Actions included (1) organizing regular awareness activities, (2) making CPGs printed and electronic copies accessible, (3) encouraging senior practitioners to get involved in CPGI, and (4) enhancing CPGs auditing as part of the quality sustainability plan. In our experience, FMEA could be a useful tool to enhance CPGI. It helped us to identify potential barriers and prepare relevant solutions. © 2017 John Wiley & Sons, Ltd.

The "ABCs of AD": A pilot test of an online educational module to increase use of the autonomic dysreflexia clinical practice guidelines among paramedic and nurse trainees.

PubMed

Tomasone, Jennifer R; Martin Ginis, Kathleen A; Pulkkinen, Wayland; Krassioukov, Andrei

2014-09-01

Despite availability of clinical practice guidelines (CPGs), gaps in autonomic dysreflexia (AD) knowledge and practice persist. A free, online educational module, the "ABCs of AD", was developed to improve knowledge of the AD-CPGs among emergency healthcare personnel. We examine short-term changes in paramedic and nurse trainees' knowledge of, and social cognitions towards using, the AD-CPGs following module completion. Pre-post. Thirty-four paramedic and nurse trainees from two training programs in Canada completed measures immediately before and after viewing the online "ABCs of AD" module. AD knowledge test; Theory of Planned Behavior social cognition questionnaire; module feedback survey. Paired samples t-tests revealed significant increases in participants' AD knowledge test scores (M ± SDpre = 9.00 ± 2.46, M ± SDpost = 12.03 ± 4.07, P < 0.001; d = 0.84). Prior to viewing the module, participants reported positive social cognitions for using the AD-CPGs (all Ms ≥ 4.84 out of 7). From pre- to post-module, no significant changes were seen in participants' social cognitions for using the AD-CPGs. Participants' average module viewing time was 36.73 ± 24.17 minutes (range 8-90 minutes). There was a decline in viewing from the first to the last module sections, with only half of participants viewing all six sections. Knowledge alone is insufficient for clinical behavior change; as such, social cognitive determinants of behavior should be explicitly targeted in future iterations of the module to increase the likelihood of increased use of the AD-CPGs. To engage viewers across all module sections, the "ABCs of AD" module should include supplementary learning strategies, such as interactive quizzes and peer-to-peer interaction.

Adapting evidence-based clinical practice guidelines at university teaching hospitals: A model for the Eastern Mediterranean Region.

PubMed

Amer, Yasser S; Wahabi, Hayfaa A; Abou Elkheir, Manal M; Bawazeer, Ghada A; Iqbal, Shaikh M; Titi, Maher A; Ekhzaimy, Aishah; Alswat, Khalid A; Alzeidan, Rasmieh A; Al-Ansary, Lubna A

2018-04-24

Clinical practice guidelines (CPGs) are significant tools for evidence-based health care quality improvement. The CPG program at King Saud University was launched as a quality improvement program to fulfil the international accreditation standards. This program was a collaboration between the Research Chair for Evidence-Based Healthcare and Knowledge Translation and the Quality Management Department. This study aims to develop a fast-track method for adaptation of evidence-based CPGs and describe results of the program. Twenty-two clinical departments participated in the program. Following a CPGs awareness week directed to all health care professionals (HCPs), 22 teams were trained to set priorities, search, screen, assess, select, and customize the best available CPGs. The teams were technically supported by the program's CPG advisors. To address the local health care context, a modified version of the ADAPTE was used where recommendations were either accepted or rejected but not changed. A strict peer-review process for clinical content and methodology was employed. In addition to raising awareness and building capacity, 35 CPGs were approved for implementation by March 2018. These CPGs were integrated with other existing projects such as accreditation, electronic medical records, performance management, and training and education. Preliminary implementation audits suggest a positive impact on patient outcomes. Leadership commitment was a strength, but the high turnover of the team members required frequent and extensive training for HCPs. This model for CPG adaptation represents a quick, practical, economical method with a sense of ownership by staff. Using this modified version can be replicated in other countries to assess its validity. © 2018 John Wiley & Sons, Ltd.

Mapping of Variable DNA Methylation Across Multiple Cell Types Defines a Dynamic Regulatory Landscape of the Human Genome.

PubMed

Gu, Junchen; Stevens, Michael; Xing, Xiaoyun; Li, Daofeng; Zhang, Bo; Payton, Jacqueline E; Oltz, Eugene M; Jarvis, James N; Jiang, Kaiyu; Cicero, Theodore; Costello, Joseph F; Wang, Ting

2016-04-07

DNA methylation is an important epigenetic modification involved in many biological processes and diseases. Many studies have mapped DNA methylation changes associated with embryogenesis, cell differentiation, and cancer at a genome-wide scale. Our understanding of genome-wide DNA methylation changes in a developmental or disease-related context has been steadily growing. However, the investigation of which CpGs are variably methylated in different normal cell or tissue types is still limited. Here, we present an in-depth analysis of 54 single-CpG-resolution DNA methylomes of normal human cell types by integrating high-throughput sequencing-based methylation data. We found that the ratio of methylated to unmethylated CpGs is relatively constant regardless of cell type. However, which CpGs made up the unmethylated complement was cell-type specific. We categorized the 26,000,000 human autosomal CpGs based on their methylation levels across multiple cell types to identify variably methylated CpGs and found that 22.6% exhibited variable DNA methylation. These variably methylated CpGs formed 660,000 variably methylated regions (VMRs), encompassing 11% of the genome. By integrating a multitude of genomic data, we found that VMRs enrich for histone modifications indicative of enhancers, suggesting their role as regulatory elements marking cell type specificity. VMRs enriched for transcription factor binding sites in a tissue-dependent manner. Importantly, they enriched for GWAS variants, suggesting that VMRs could potentially be implicated in disease and complex traits. Taken together, our results highlight the link between CpG methylation variation, genetic variation, and disease risk for many human cell types. Copyright © 2016 Gu et al.

Systematic Review of Clinical Practice Guidelines for Failed Antidepressant Treatment Response in Major Depressive Disorder, Dysthymia, and Subthreshold Depression in Adults

PubMed Central

MacQueen, Glenda; Santaguida, Pasqualina; Keshavarz, Homa; Jaworska, Natalia; Levine, Mitchell; Beyene, Joseph

2016-01-01

Objective: This systematic review critically evaluated clinical practice guidelines (CPGs) for treating adults with major depressive disorder, dysthymia, or subthreshold or minor depression for recommendations following inadequate response to first-line treatment with selective serotonin reuptake inhibitors (SSRIs). Method: Searches for CPGs (January 2004 to November 2014) in English included 7 bibliographic databases and grey literature sources using CPG and depression as the keywords. Two raters selected CPGs on depression with a national scope. Data extraction included definitions of adequate response and recommended treatment options. Two raters assessed quality using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. Results: From 46,908 citations, 3167 were screened at full text. From these 21 CPG were applicable to adults in primary care and outpatient settings. Five CPGs consider patients with dysthymia or subthreshold or minor depression. None provides recommendations for those who do not respond to first-line SSRI treatment. For adults with MDD, most CPGs do not define an “inadequate response” or provide specific suggestions regarding how to choose alternative medications when switching to an alternative antidepressant. There is variability between CPGs in recommending combination strategies. AGREE II ratings for stakeholder involvement in CPG development, editorial independence, and rigor of development are domains in which depression guidelines are often less robust. Conclusions: About half of patients with depression require second-line treatment to achieve remission. Consistency and clarity in guidelines for second-line treatment of depression are therefore important for clinicians but lacking in most current guidelines. This may reflect a paucity of primary studies upon which to base conclusions. PMID:27554483

Speech pathologists’ experiences with stroke clinical practice guidelines and the barriers and facilitators influencing their use: a national descriptive study

PubMed Central

2014-01-01

Background Communication and swallowing disorders are a common consequence of stroke. Clinical practice guidelines (CPGs) have been created to assist health professionals to put research evidence into clinical practice and can improve stroke care outcomes. However, CPGs are often not successfully implemented in clinical practice and research is needed to explore the factors that influence speech pathologists’ implementation of stroke CPGs. This study aimed to describe speech pathologists’ experiences and current use of guidelines, and to identify what factors influence speech pathologists’ implementation of stroke CPGs. Methods Speech pathologists working in stroke rehabilitation who had used a stroke CPG were invited to complete a 39-item online survey. Content analysis and descriptive and inferential statistics were used to analyse the data. Results 320 participants from all states and territories of Australia were surveyed. Almost all speech pathologists had used a stroke CPG and had found the guideline “somewhat useful” or “very useful”. Factors that speech pathologists perceived influenced CPG implementation included the: (a) guideline itself, (b) work environment, (c) aspects related to the speech pathologist themselves, (d) patient characteristics, and (e) types of implementation strategies provided. Conclusions There are many different factors that can influence speech pathologists’ implementation of CPGs. The factors that influenced the implementation of CPGs can be understood in terms of knowledge creation and implementation frameworks. Speech pathologists should continue to adapt the stroke CPG to their local work environment and evaluate their use. To enhance guideline implementation, they may benefit from a combination of educational meetings and resources, outreach visits, support from senior colleagues, and audit and feedback strategies. PMID:24602148

Variable methodological quality and use found in systematic reviews referenced in STEMI clinical practice guidelines.

PubMed

Scott, Jared; Howard, Benjamin; Sinnett, Philip; Schiesel, Michael; Baker, Jana; Henderson, Patrick; Vassar, Matt

2017-12-01

The objective of this study was to assess the methodological quality and clarity of reporting of the systematic reviews (SRs) supporting clinical practice guideline (CPG) recommendations in the management of ST-elevation myocardial infarction (STEMI) across international CPGs. We searched 13 guideline clearinghouses including the National Guideline Clearinghouse and Guidelines International Network (GIN). To meet inclusion criteria CPGs must be pertinent to the management of STEMI, endorsed by a governing body or national organization, and written in English. We retrieved SRs from the reference sections using a combination of keywords and hand searching. Two investigators scored eligible SRs using AMSTAR and PRISMA. We included four CPGs. We extracted 71 unique SRs. These SRs received AMSTAR scores ranging from 1 (low) to 9 (high) on an 11-point scale. All CPGs consistently underperformed in areas including disclosure of funding sources, risk of bias, and publication bias according to AMSTAR. PRISMA checklist completeness ranged from 44% to 96%. The PRISMA scores indicated that SRs did not provide a full search strategy, study protocol and registration, assessment of publication bias or report funding sources. Only one SR was referenced in all four CPGs. All CPGs omitted a large subset of available SRs cited by other guidelines. Our study demonstrates the variable quality of SRs used to establish recommendations within guidelines included in our sample. Although guideline developers have acknowledged this variability, it remains a significant finding that needs to be addressed further. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Copyright © 2017 Elsevier Inc. All rights reserved.

Analysis of evidence within the AUA's clinical practice guidelines.

PubMed

Antoine, Samuel G; Small, Alexander C; McKiernan, James M; Shah, Ojas

2018-02-01

Surgical subspecialty societies release clinical practice guidelines (CPGs) to provide topic-specific recommendations to healthcare providers. We hypothesize that there may be significant differences in statement strength and evidence quality both within the American Urological Association (AUA) guidelines and compared to those published by the American Academy of Orthopedic Surgeons (AAOS) and American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS). CPGs issued through 2017 were extracted from the AUAnet.org. Statements were characterized by evidence basis, strength, and evidence quality. CPGs were compared among urologic subspecialties and to those from the AAOS and AAO-HNS. Analysis used Fisher's exact tests and Student's t-tests with significance p < 0.05. A total of 25 AUA CPGs (672 statements) were reviewed and 34.6% were non-evidence based with the highest proportions in pediatrics (47.5%) and sexual medicine (46.5%). The AUA has published over twice as many statements as the AAOS and quadruple that of the AAO-HNS. A smaller proportion of the AUA statements were evidence-based (65.4%) compared to the AAOS (80.5%, p < 0.001) and AAO-HNS (99.8%, p < 0.001), and fewer used "high" quality evidence (AUA 7.2% versus AAOS 21.2%, p < 0.001; versus AAO-HNS 16.1%, p < 0.001). The AUA has published broad CPGs that far exceed those from the AAOS and AAO-HNS. The AUA has utilized extensive resources to provide guidance to help standardize care among urologists. The AAOS and AAO-HNS may not provide guidelines when evidence is limited. With the continued increase of high quality clinical trials, the AUA will be able to continue improving its robust set of evidence-based CPGs.

Online training improves paramedics' knowledge of autonomic dysreflexia management guidelines.

PubMed

Martin Ginis, K A; Tomasone, J R; Welsford, M; Ethans, K; Sinden, A R; Longeway, M; Krassioukov, A

2017-02-01

Single-group pre-/post-test with 3- and 6-month follow-ups. To test the effects of the 'ABCs of AD' educational module on immediate and longer-term changes in paramedics' knowledge and beliefs about using the autonomic dysreflexia clinical practice guidelines (AD-CPGs). Canada. A total of 119 paramedics completed an AD knowledge test and measures of attitudes, perceived control, self-efficacy, social pressure from patients and health-care professionals, and intentions to use the AD-CPGs before and 1 week, 3 months and 6 months after viewing 'ABCs of AD'. There were significant improvements in AD knowledge, attitudes and social pressure from patients to use the AD-CPGs from baseline to 1 week, 3 months and 6 months post viewing (all P<0.001). Self-efficacy and intentions increased 1 week post viewing (P<0.001), but returned to baseline levels at 3 and 6 months (P>0.05). There was no change in perceived control or social pressure from health-care professionals. AD knowledge and beliefs explained 50-61% of the variance in intentions to use the AD-CPGs. Attitudes, social pressure from patients and perceived behavioural control were significant unique predictors of intentions at all time points (P<0.05); AD knowledge was a significant predictor at 6 months only (P=0.048). No other predictors were significant. 'ABCs of AD' has immediate and sustained effects on paramedics' knowledge of attitudes toward and perceived pressure from patients to use the AD-CPGs. Updates to paramedic patient care guidelines and standards are needed to increase paramedics' perceived control and self-efficacy to implement the guidelines, and their intentions to use the AD-CPGs. Canadian Institutes of Health Research (2011-CIHR- 260877).

Transformation of the Air Force Medical Service -The Right Medicine

DTIC Science & Technology

2003-04-17

to clinical practice guidelines (CPGs)/ evidence - based medicine . These areas have been transformed using this technology combined with a changing...and the central databases can e-mail the answers. Clinical Practice Guidelines (CPGs) and Evidence Based Medicine have been derived from expert

AGREEing on Canadian cardiovascular clinical practice guidelines.

PubMed

Stone, James A; Austford, Leslie; Parker, John H; Gledhill, Norm; Tremblay, Guy; Arthur, Heather M

2008-10-01

The use of clinical practice guidelines (CPGs), particularly the routine implementation of evidence-based cardiovascular health maintenance and disease management recommendations, affords both expert and nonexpert practitioners the opportunity to achieve better, and at least theoretically similar, patient outcomes. However, health care practitioners are often stymied in their efforts to follow even well-researched and well-written CPGs as a consequence of contradictory information. The purposeful integration and harmonization of Canadian cardiovascular CPGs, regardless of their specific risk factor or clinical management focus, is critical to their widespread acceptance and implementation. This level of cooperation and coordination among CPG groups and organizations would help to ensure that their clinical practice roadmaps (ie, best practice recommendations) contain clear, concise and complementary, rather than contradictory, patient care information. Similarly, the application of specific tools intended to improve the quality of CPGs, such as the Appraisal of Guidelines for Research and Evaluation (AGREE) assessment tool, may also lead to improvements in CPG quality and potentially enhance their acceptance and implementation.

Quality Assessment of Clinical Practice Guidelines Developed by Professional Societies in Turkey

PubMed Central

Yaşar, Ilknur; Kahveci, Rabia; Baydar Artantaş, Aylin; Ayhan Başer, Duygu; Gökşin Cihan, Fatma; Şencan, Irfan; Koç, Esra Meltem; Özkara, Adem

2016-01-01

Background Clinical practice guidelines (CPGs) are systematically developed statements to assist practitioner and patient decisions about appropriate healthcare for specific clinical circumstances. There is a limited number of studies on guidelines in Turkey. The quality of Ministry of Health guidelines have formerly been assessed whereas there is no information on the other guidelines developed in the country. Aim This study aims to assess the quality of CPGs that are developed by professional societies that work for the health sector in Turkey, and compare the findings with international guidelines. Methodology Professional societies that work for the health sector were determined by using the data obtained from the Ministry of Internal Affairs. Inclusion and exclusion criteria were defined for selecting the CPGs. Guidelines containing recommendations about disease management to the doctors, accessible online, developed within the past 5 years, citing references for recommendations, about the diseases over 1% prevalence according to the “Statistical Yearbook of Turkey 2012” were included in the study. The quality of CPGs were assessed with the AGREE II instrument, which is an internationally recognized tool for this purpose. Four independent reviewers, who did not participate in the development of the selected guidelines and were trained in CPG appraisal, used the AGREE instrument for assessment of the selected guidelines. Findings 47 professional societies were defined which provided access to CPGs in their websites; 3 of them were only open to members so these could not be reached. 8 CPGs from 7 societies were selected from a total of 401 CPGs from 44 societies. The mean scores of the domains of the guidelines which were assessed by the AGREE II tool were; Scope and purpose: 64%, stakeholder involvement: 37.9%, rigour of development: 35.3%, clarity and presentation: 77.9%, applicability: 49.0% and editorial independence: 46.0%. Conclusion This is the first study in Turkey regarding quality appraisal of guidelines developed by the local professional societies. It adds to the limited amount of information in the literature that comes from Turkey as well as other developing countries. PMID:27295303

Sensory-evoked perturbations of locomotor activity by sparse sensory input: a computational study

PubMed Central

Brownstone, Robert M.

2015-01-01

Sensory inputs from muscle, cutaneous, and joint afferents project to the spinal cord, where they are able to affect ongoing locomotor activity. Activation of sensory input can initiate or prolong bouts of locomotor activity depending on the identity of the sensory afferent activated and the timing of the activation within the locomotor cycle. However, the mechanisms by which afferent activity modifies locomotor rhythm and the distribution of sensory afferents to the spinal locomotor networks have not been determined. Considering the many sources of sensory inputs to the spinal cord, determining this distribution would provide insights into how sensory inputs are integrated to adjust ongoing locomotor activity. We asked whether a sparsely distributed set of sensory inputs could modify ongoing locomotor activity. To address this question, several computational models of locomotor central pattern generators (CPGs) that were mechanistically diverse and generated locomotor-like rhythmic activity were developed. We show that sensory inputs restricted to a small subset of the network neurons can perturb locomotor activity in the same manner as seen experimentally. Furthermore, we show that an architecture with sparse sensory input improves the capacity to gate sensory information by selectively modulating sensory channels. These data demonstrate that sensory input to rhythm-generating networks need not be extensively distributed. PMID:25673740

Overlap in drug-disease associations between clinical practice guidelines and drug structured product label indications.

PubMed

Leung, Tiffany I; Dumontier, Michel

2016-06-08

Clinical practice guidelines (CPGs) recommend pharmacologic treatments for clinical conditions, and drug structured product labels (SPLs) summarize approved treatment indications. Both resources are intended to promote evidence-based medical practices and guide clinicians' prescribing decisions. However, it is unclear how well CPG recommendations about pharmacologic therapies match SPL indications for recommended drugs. In this study, we perform text mining of CPG summaries to examine drug-disease associations in CPG recommendations and in SPL treatment indications for 15 common chronic conditions. We constructed an initial text corpus of guideline summaries from the National Guideline Clearinghouse (NGC) from a set of manually selected ICD-9 codes for each of the 15 conditions. We obtained 377 relevant guideline summaries and their Major Recommendations section, which excludes guidelines for pediatric patients, pregnant or breastfeeding women, or for medical diagnoses not meeting inclusion criteria. A vocabulary of drug terms was derived from five medical taxonomies. We used named entity recognition, in combination with dictionary-based and ontology-based methods, to identify drug term occurrences in the text corpus and construct drug-disease associations. The ATC (Anatomical Therapeutic Chemical Classification) was utilized to perform drug name and drug class matching to construct the drug-disease associations from CPGs. We then obtained drug-disease associations from SPLs using conditions mentioned in their Indications section in SIDER. The primary outcomes were the frequency of drug-disease associations in CPGs and SPLs, and the frequency of overlap between the two sets of drug-disease associations, with and without using taxonomic information from ATC. Without taxonomic information, we identified 1444 drug-disease associations across CPGs and SPLs for 15 common chronic conditions. Of these, 195 drug-disease associations overlapped between CPGs and SPLs, 917 associations occurred in CPGs only and 332 associations occurred in SPLs only. With taxonomic information, 859 unique drug-disease associations were identified, of which 152 of these drug-disease associations overlapped between CPGs and SPLs, 541 associations occurred in CPGs only, and 166 associations occurred in SPLs only. Our results suggest that CPG-recommended pharmacologic therapies and SPL indications do not overlap frequently when identifying drug-disease associations using named entity recognition, although incorporating taxonomic relationships between drug names and drug classes into the approach improves the overlap. This has important implications in practice because conflicting or inconsistent evidence may complicate clinical decision making and implementation or measurement of best practices.

Aligning Documentation With Congenital Muscular Torticollis Clinical Practice Guidelines: Administrative Case Report.

PubMed

Gutierrez, Dennis; Kaplan, Sandra L

2016-01-01

A hospital-based pediatric outpatient center, wanting to weave evidence into practice, initiated an update of knowledge, skills, and documentation patterns with its staff physical therapists and occupational therapists who treat people with congenital muscular torticollis (CMT). This case report describes 2 cycles of implementation: (1) the facilitators and barriers to implementation and (2) selected quality improvement outcomes aligned with published clinical practice guidelines (CPGs). The Pediatric Therapy Services of St Joseph's Regional Medical Center in New Jersey has 4 full-time, 1 part-time, and 3 per diem staff. Chart audits in 2012 revealed variations in measurement, interventions, and documentation that led to quality improvement initiatives. An iterative process, loosely following the knowledge-to-action cycle, included a series of in-service training sessions to review the basic anatomy, pathokinesiology, and treatment strategies for CMT; reading assignments of the available CPGs; journal review; documentation revisions; and training on the recommended measurements to implement 2 published CPGs and measure outcomes. A previous 1-page generic narrative became a 3-page CMT-specific form aligned with the American Physical Therapy Association Section on Pediatrics CMT CPG recommendations. Staff training on the Face, Legs, Activity, Cry, Consolability (FLACC) pain scale, classification of severity, type of CMT, prognostication, measures of cervical range of motion, and developmental progression improved documentation consistency from 0% to 81.9% to 100%. Clinicians responded positively to using the longer initial evaluation form. Successful implementation of both clinical and documentation practices were facilitated by a multifaceted approach to knowledge translation that included a culture supportive of evidence-based practice, administrative support for training and documentation redesign, commitment by clinicians to embrace changes aimed at improved care, and clinical guidelines that provide implementable recommendations. © 2016 American Physical Therapy Association.

A JAVA-based multimedia tool for clinical practice guidelines.

PubMed

Maojo, V; Herrero, C; Valenzuela, F; Crespo, J; Lazaro, P; Pazos, A

1997-01-01

We have developed a specific language for the representation of Clinical Practice Guidelines (CPGs) and Windows C++ and platform independent JAVA applications for multimedia presentation and edition of electronically stored CPGs. This approach facilitates translation of guidelines and protocols from paper to computer-based flowchart representations. Users can navigate through the algorithm with a friendly user interface and access related multimedia information within the context of each clinical problem. CPGs can be stored in a computer server and distributed over the World Wide Web, facilitating dissemination, local adaptation, and use as a reference element in medical care. We have chosen the Agency for Health Care and Policy Research's heart failure guideline to demonstrate the capabilities of our tool.

Guidance for updating clinical practice guidelines: a systematic review of methodological handbooks.

PubMed

Vernooij, Robin W M; Sanabria, Andrea Juliana; Solà, Ivan; Alonso-Coello, Pablo; Martínez García, Laura

2014-01-02

Updating clinical practice guidelines (CPGs) is a crucial process for maintaining the validity of recommendations. Methodological handbooks should provide guidance on both developing and updating CPGs. However, little is known about the updating guidance provided by these handbooks. We conducted a systematic review to identify and describe the updating guidance provided by CPG methodological handbooks and included handbooks that provide updating guidance for CPGs. We searched in the Guidelines International Network library, US National Guidelines Clearinghouse and MEDLINE (PubMed) from 1966 to September 2013. Two authors independently selected the handbooks and extracted the data. We used descriptive statistics to analyze the extracted data and conducted a narrative synthesis. We included 35 handbooks. Most handbooks (97.1%) focus mainly on developing CPGs, including variable degrees of information about updating. Guidance on identifying new evidence and the methodology of assessing the need for an update is described in 11 (31.4%) and eight handbooks (22.8%), respectively. The period of time between two updates is described in 25 handbooks (71.4%), two to three years being the most frequent (40.0%). The majority of handbooks do not provide guidance for the literature search, evidence selection, assessment, synthesis, and external review of the updating process. Guidance for updating CPGs is poorly described in methodological handbooks. This guidance should be more rigorous and explicit. This could lead to a more optimal updating process, and, ultimately to valid trustworthy guidelines.

Microarray-Based Analysis of Methylation of 1st Trimester Trisomic Placentas from Down Syndrome, Edwards Syndrome and Patau Syndrome.

PubMed

Hatt, Lotte; Aagaard, Mads M; Bach, Cathrine; Graakjaer, Jesper; Sommer, Steffen; Agerholm, Inge E; Kølvraa, Steen; Bojesen, Anders

2016-01-01

Methylation-based non-invasive prenatal testing of fetal aneuploidies is an alternative method that could possibly improve fetal aneuploidy diagnosis, especially for trisomy 13(T13) and trisomy 18(T18). Our aim was to study the methylation landscape in placenta DNA from trisomy 13, 18 and 21 pregnancies in an attempt to find trisomy-specific methylation differences better suited for non-invasive prenatal diagnosis. We have conducted high-resolution methylation specific bead chip microarray analyses assessing more than 450,000 CpGs analyzing placentas from 12 T21 pregnancies, 12 T18 pregnancies and 6 T13 pregnancies. We have compared the methylation landscape of the trisomic placentas to the methylation landscape from normal placental DNA and to maternal blood cell DNA. Comparing trisomic placentas to normal placentas we identified 217 and 219 differentially methylated CpGs for CVS T18 and CVS T13, respectively (delta β>0.2, FDR<0.05), but only three differentially methylated CpGs for T21. However, the methylation differences was only modest (delta β<0.4), making them less suitable as diagnostic markers. Gene ontology enrichment analysis revealed that the gene set connected to theT18 differentially methylated CpGs was highly enriched for GO terms related to"DNA binding" and "transcription factor binding" coupled to the RNA polymerase II transcription. In the gene set connected to the T13 differentially methylated CpGs we found no significant enrichments.

Microarray-Based Analysis of Methylation of 1st Trimester Trisomic Placentas from Down Syndrome, Edwards Syndrome and Patau Syndrome

PubMed Central

Hatt, Lotte; Aagaard, Mads M.; Bach, Cathrine; Graakjaer, Jesper; Sommer, Steffen; Agerholm, Inge E.; Bojesen, Anders

2016-01-01

Methylation-based non-invasive prenatal testing of fetal aneuploidies is an alternative method that could possibly improve fetal aneuploidy diagnosis, especially for trisomy 13(T13) and trisomy 18(T18). Our aim was to study the methylation landscape in placenta DNA from trisomy 13, 18 and 21 pregnancies in an attempt to find trisomy–specific methylation differences better suited for non-invasive prenatal diagnosis. We have conducted high-resolution methylation specific bead chip microarray analyses assessing more than 450,000 CpGs analyzing placentas from 12 T21 pregnancies, 12 T18 pregnancies and 6 T13 pregnancies. We have compared the methylation landscape of the trisomic placentas to the methylation landscape from normal placental DNA and to maternal blood cell DNA. Comparing trisomic placentas to normal placentas we identified 217 and 219 differentially methylated CpGs for CVS T18 and CVS T13, respectively (delta β>0.2, FDR<0.05), but only three differentially methylated CpGs for T21. However, the methylation differences was only modest (delta β<0.4), making them less suitable as diagnostic markers. Gene ontology enrichment analysis revealed that the gene set connected to theT18 differentially methylated CpGs was highly enriched for GO terms related to”DNA binding” and “transcription factor binding” coupled to the RNA polymerase II transcription. In the gene set connected to the T13 differentially methylated CpGs we found no significant enrichments. PMID:27490343

Inclusion of ethical issues in dementia guidelines: a thematic text analysis.

PubMed

Knüppel, Hannes; Mertz, Marcel; Schmidhuber, Martina; Neitzke, Gerald; Strech, Daniel

2013-08-01

Clinical practice guidelines (CPGs) aim to improve professionalism in health care. However, current CPG development manuals fail to address how to include ethical issues in a systematic and transparent manner. The objective of this study was to assess the representation of ethical issues in general CPGs on dementia care. To identify national CPGs on dementia care, five databases of guidelines were searched and national psychiatric associations were contacted in August 2011 and in June 2013. A framework for the assessment of the identified CPGs' ethical content was developed on the basis of a prior systematic review of ethical issues in dementia care. Thematic text analysis and a 4-point rating score were employed to assess how ethical issues were addressed in the identified CPGs. Twelve national CPGs were included. Thirty-one ethical issues in dementia care were identified by the prior systematic review. The proportion of these 31 ethical issues that were explicitly addressed by each CPG ranged from 22% to 77%, with a median of 49.5%. National guidelines differed substantially with respect to (a) which ethical issues were represented, (b) whether ethical recommendations were included, (c) whether justifications or citations were provided to support recommendations, and (d) to what extent the ethical issues were explained. Ethical issues were inconsistently addressed in national dementia guidelines, with some guidelines including most and some including few ethical issues. Guidelines should address ethical issues and how to deal with them to help the medical profession understand how to approach care of patients with dementia, and for patients, their relatives, and the general public, all of whom might seek information and advice in national guidelines. There is a need for further research to specify how detailed ethical issues and their respective recommendations can and should be addressed in dementia guidelines. Please see later in the article for the Editors' Summary.

Inclusion of Ethical Issues in Dementia Guidelines: A Thematic Text Analysis

PubMed Central

Knüppel, Hannes; Schmidhuber, Martina; Neitzke, Gerald

2013-01-01

Background Clinical practice guidelines (CPGs) aim to improve professionalism in health care. However, current CPG development manuals fail to address how to include ethical issues in a systematic and transparent manner. The objective of this study was to assess the representation of ethical issues in general CPGs on dementia care. Methods and Findings To identify national CPGs on dementia care, five databases of guidelines were searched and national psychiatric associations were contacted in August 2011 and in June 2013. A framework for the assessment of the identified CPGs' ethical content was developed on the basis of a prior systematic review of ethical issues in dementia care. Thematic text analysis and a 4-point rating score were employed to assess how ethical issues were addressed in the identified CPGs. Twelve national CPGs were included. Thirty-one ethical issues in dementia care were identified by the prior systematic review. The proportion of these 31 ethical issues that were explicitly addressed by each CPG ranged from 22% to 77%, with a median of 49.5%. National guidelines differed substantially with respect to (a) which ethical issues were represented, (b) whether ethical recommendations were included, (c) whether justifications or citations were provided to support recommendations, and (d) to what extent the ethical issues were explained. Conclusions Ethical issues were inconsistently addressed in national dementia guidelines, with some guidelines including most and some including few ethical issues. Guidelines should address ethical issues and how to deal with them to help the medical profession understand how to approach care of patients with dementia, and for patients, their relatives, and the general public, all of whom might seek information and advice in national guidelines. There is a need for further research to specify how detailed ethical issues and their respective recommendations can and should be addressed in dementia guidelines. Please see later in the article for the Editors' Summary PMID:23966839

Providers' perceptions of spinal cord injury pressure ulcer guidelines.

PubMed

Thomason, Susan S; Evitt, Celinda P; Harrow, Jeffrey J; Love, Linda; Moore, D Helen; Mullins, Maria A; Powell-Cope, Gail; Nelson, Audrey L

2007-01-01

Pressure ulcers are a serious complication for people with spinal cord injury (SCI). The Consortium for Spinal Cord Medicine (CSCM) published clinical practice guidelines (CPGs) that provided guidance for pressure ulcer prevention and treatment after SCI. The aim of this study was to assess providers' perceptions for each of the 32 CPG recommendations regarding their agreement with CPGs, degree of CPG implementation, and CPG implementation barriers and facilitators. This descriptive mixed-methods study included both qualitative (focus groups) and quantitative (survey) data collection approaches. The sample (n = 60) included 24 physicians and 36 nurses who attended the 2004 annual national conferences of the American Paraplegia Society or American Association of Spinal Cord Injury Nurses. This sample drew from two sources: a purposive sample from a list of preregistered participants and a convenience sample of conference attendee volunteers. We analyzed quantitative data using descriptive statistics and qualitative data using a coding scheme to capture barriers and facilitators. The focus groups agreed unanimously on the substance of 6 of the 32 recommendations. Nurse and physician focus groups disagreed on the degree of CGP implementation at their sites, with nurses as a group perceiving less progress in implementation of the guideline recommendations. The focus groups identified only one recommendation, complications of surgery, as being fully implemented at their sites. Categories of barriers and facilitators for implementation of CPGs that emerged from the qualitative analysis included (a) characteristics of CPGs: need for research/evidence, (b) characteristics of CPGs: complexity of design and wording, (c) organizational factors, (d) lack of knowledge, and (e) lack of resources. Although generally SCI physicians and nurses agreed with the CPG recommendations as written, they did not feel these recommendations were fully implemented in their respective clinical settings. The focus groups identified multiple barriers to the implementation of the CPGs and suggested several facilitators/solutions to improve implementation of these guidelines in SCI. Participants identified organizational factors and the lack of knowledge as the most substantial systems/issues that created barriers to CPG implementation.

Integration of clinical practice guidelines into a distributed regional electronic patient record for tumour-patients using XML: a means for standardization of the treatment processes.

PubMed

Mludek, V; Wolff, A C; Drings, P; van der Haak, M; Haux, R; Wannenmacher, M; Zierhut, D

2001-01-01

With the rising efforts to guarantee a high quality treatment in medicine and to reduce the costs in the health care system, Clinical Practice Guidelines (CPG) have developed into a very important reference in medicine. CPGs are especially useful for the standardization of multi-professional treatment processes like the care for patients with malignant diseases. The Tumour-Centre Heidelberg/Mannheim (Germany) leads a project to build up a regional, virtual distributed Electronic Patient Record (EPR) for patients with malignant diseases in the Rhein-Neckar-Area. Aims of the first stages of the project are the introduction of the distributed EPR to two co-operating pilot-clinics. In this context we intend to provide access for medical professionals not only to the data of the jointly treated patients, but also to relevant existing CPGs and other medical knowledge sources like Medline and Cochrane-Library. Knowledge and Patient data should be interlinked to offer patient-specific views on the CPG-information. As all professions have different information needs, this views should be presented individualized according to the demands of the users. We analysed three relevant CPGs and defined a meta-structure that will be refined to a common meta-structure for CPGs in Oncology. CPGs as well as structured patient-documents will be implemented in the Extensible Markup Language (XML), as this platform-independent technology seems to suit our needs for data exchange and presentation purposes best. The implementation process will be accompanied tightly with evaluations to gain experience for further expansions of the EPR. The vision of the project is, that by integrating CPGs in a shared distributed EPR, the way towards standardized treatment processes in a local, but multi-professional setting, and the efforts to guarantee a high quality treatment in Oncology can sufficiently be supported.

Mapping South African allied health primary care clinical guideline activity: establishing a stakeholder reference sample.

PubMed

Dizon, Janine Margarita; Grimmer, Karen; Machingaidze, Shingai; McLaren, Pam; Louw, Quinette

2016-10-10

Little is known about allied health (AH) clinical practice guideline (CPG) activity in South Africa, and particularly in relation to primary health care (PHC). This paper reports on a scoping study undertaken to establish a reference framework, from which a comprehensive maximum variation sample could be selected. This was required to underpin robust sampling for a qualitative study aimed at understanding South African primary care AH therapy CPG activities. This paper builds on findings from the South African Guidelines Evaluation (Project SAGE) Flagship grant. South African government websites were searched for structures of departments and portfolios, and available CPGs. Professional AH association websites were searched for CPGs, purposively-identified key informants were interviewed, and CPGs previously identified for priority South African primary care conditions were critiqued for AH therapy involvement. Key informants described potentially complex relationships between players who may be engaged in South African AH CPGs, in both public and private sectors. There were disability/rehabilitation portfolios at national and provincial governments, but no uniformity in provincial government organisation of, or support for, PHC AH services. There were no AH primary care therapy CPGs on government websites, although there was 'clinical guidance' in various forms on professional association websites. Only two CPGs of priority South African PHC conditions included mention of any AH therapy (physiotherapy for adult asthma and chronic obstructive pulmonary disease). A comprehensive and wide-reaching stakeholder reference framework would be required in order to capture the heterogeneity of AH primary care CPG activity in South Africa. This should involve the voices of national and purposively-selected provincial governments, academic institutions, consultants, public sector managers and clinicians, private practitioners, professional associations, and private sector insurers. Provincial governments should be selected to reflect heterogeneity in local economics, population demographics and availability of university AH training programs. This investigation should aim to determine the areas of PHC in which AH are engaged.

The “ABCs of AD”: A pilot test of an online educational module to increase use of the autonomic dysreflexia clinical practice guidelines among paramedic and nurse trainees

PubMed Central

Tomasone, Jennifer R.; Martin Ginis, Kathleen A.; Pulkkinen, Wayland; Krassioukov, Andrei

2014-01-01

Context/Objective Despite availability of clinical practice guidelines (CPGs), gaps in autonomic dysreflexia (AD) knowledge and practice persist. A free, online educational module, the “ABCs of AD”, was developed to improve knowledge of the AD-CPGs among emergency healthcare personnel. We examine short-term changes in paramedic and nurse trainees’ knowledge of, and social cognitions towards using, the AD-CPGs following module completion. Design Pre–post. Methods Thirty-four paramedic and nurse trainees from two training programs in Canada completed measures immediately before and after viewing the online “ABCs of AD” module. Outcome measures AD knowledge test; Theory of Planned Behavior social cognition questionnaire; module feedback survey. Results Paired samples t-tests revealed significant increases in participants’ AD knowledge test scores (M ± SDpre = 9.00 ± 2.46, M ± SDpost = 12.03 ± 4.07, P < 0.001; d = 0.84). Prior to viewing the module, participants reported positive social cognitions for using the AD-CPGs (all Ms ≥ 4.84 out of 7). From pre- to post-module, no significant changes were seen in participants’ social cognitions for using the AD-CPGs. Participants’ average module viewing time was 36.73 ± 24.17 minutes (range 8–90 minutes). There was a decline in viewing from the first to the last module sections, with only half of participants viewing all six sections. Conclusion Knowledge alone is insufficient for clinical behavior change; as such, social cognitive determinants of behavior should be explicitly targeted in future iterations of the module to increase the likelihood of increased use of the AD-CPGs. To engage viewers across all module sections, the “ABCs of AD” module should include supplementary learning strategies, such as interactive quizzes and peer-to-peer interaction. PMID:25055849

Development of clinical practice guidelines for supportive care in childhood cancer--prioritization of topics using a Delphi approach.

PubMed

Loeffen, E A H; Mulder, R L; Kremer, L C M; Michiels, E M C; Abbink, F C H; Ball, L M; Segers, H; Mavinkurve-Groothuis, A M C; Smit, F J; Vonk, I J M; Vd Wetering, M D; Tissing, W J E

2015-07-01

Currently, very few guidelines for supportive care for children with cancer exist. In the Netherlands, nationwide guidelines are over 10 years old and mostly based on expert opinion. Consequently, there is growing support and need for clinical practice guidelines (CPGs), which ought to be developed with a well-defined methodology and include a systematic search of literature, evidence summaries, and a transparent description of the decision process for the final recommendations. Development of CPGs is time consuming; therefore, it is important to prioritize topics for which there is the greatest clinical demand. This study aims to prioritize childhood cancer supportive care topics for development of CPGs. A Delphi survey consisting of two rounds was conducted to prioritize relevant childhood cancer supportive care topics for the development of CPGs. A group of experts comprising 15 pediatric oncologists, 15 pediatric oncology nurses, and 15 general pediatricians involved in care for childhood cancer patients were invited to participate. All relevant supportive care topics in childhood cancer were rated. In both rounds, 36 panellists (82%) responded. Agreement between panellists was very good, with an intraclass correlation coefficient of 0.918 (95% confidence interval (CI) = 0.849-0.966, p < 0.001) in round 2. The ten topics with the highest score in the final round were infection, sepsis, febrile neutropenia, pain, nausea/vomiting, restrictions in daily life and activities, palliative care, procedural sedation, terminal care, and oral mucositis. We successfully used a Delphi survey to prioritize childhood cancer supportive care topics for the development of CPGs. This is a first step towards uniform and evidence-based Dutch guidelines in supportive care in childhood cancer. Even though performed nationally, we believe that this study can also be regarded as an example starting point for international development of CPGs in the field of supportive care in cancer or any other field for that matter.

DNA methylation signature of human fetal alcohol spectrum disorder.

PubMed

Portales-Casamar, Elodie; Lussier, Alexandre A; Jones, Meaghan J; MacIsaac, Julia L; Edgar, Rachel D; Mah, Sarah M; Barhdadi, Amina; Provost, Sylvie; Lemieux-Perreault, Louis-Philippe; Cynader, Max S; Chudley, Albert E; Dubé, Marie-Pierre; Reynolds, James N; Pavlidis, Paul; Kobor, Michael S

2016-01-01

Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America. While the underlying mechanisms of alcohol's effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of symptoms observed in children with fetal alcohol spectrum disorder (FASD). Thus, we investigated the effects of prenatal alcohol exposure on genome-wide DNA methylation in the NeuroDevNet FASD cohort, the largest cohort of human FASD samples to date. Genome-wide DNA methylation patterns of buccal epithelial cells (BECs) were analyzed using the Illumina HumanMethylation450 array in a Canadian cohort of 206 children (110 FASD and 96 controls). Genotyping was performed in parallel using the Infinium HumanOmni2.5-Quad v1.0 BeadChip. After correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns. Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders. These findings suggested that prenatal alcohol exposure is associated with distinct DNA methylation patterns in children and adolescents, raising the possibility of an epigenetic biomarker of FASD.

Peripheral oxygen-sensing cells directly modulate the output of an identified respiratory central pattern generating neuron.

PubMed

Bell, Harold J; Inoue, Takuya; Shum, Kelly; Luk, Collin; Syed, Naweed I

2007-06-01

Breathing is an essential homeostatic behavior regulated by central neuronal networks, often called central pattern generators (CPGs). Despite ongoing advances in our understanding of the neural control of breathing, the basic mechanisms by which peripheral input modulates the activities of the central respiratory CPG remain elusive. This lack of fundamental knowledge vis-à-vis the role of peripheral influences in the control of the respiratory CPG is due in large part to the complexity of mammalian respiratory control centres. We have therefore developed a simpler invertebrate model to study the basic cellular and synaptic mechanisms by which a peripheral chemosensory input affects the central respiratory CPG. Here we report on the identification and characterization of peripheral chemoreceptor cells (PCRCs) that relay hypoxia-sensitive chemosensory information to the known respiratory CPG neuron right pedal dorsal 1 in the mollusk Lymnaea stagnalis. Selective perfusion of these PCRCs with hypoxic saline triggered bursting activity in these neurons and when isolated in cell culture these cells also demonstrated hypoxic sensitivity that resulted in membrane depolarization and spiking activity. When cocultured with right pedal dorsal 1, the PCRCs developed synapses that exhibited a form of short-term synaptic plasticity in response to hypoxia. Finally, osphradial denervation in intact animals significantly perturbed respiratory activity compared with their sham counterparts. This study provides evidence for direct synaptic connectivity between a peripheral regulatory element and a central respiratory CPG neuron, revealing a potential locus for hypoxia-induced synaptic plasticity underlying breathing behavior.

Nucleosome dynamics and maintenance of epigenetic states of CpG islands

NASA Astrophysics Data System (ADS)

Sneppen, Kim; Dodd, Ian B.

2016-06-01

Methylation of mammalian DNA occurs primarily at CG dinucleotides. These CpG sites are located nonrandomly in the genome, tending to occur within high density clusters of CpGs (islands) or within large regions of low CpG density. Cluster methylation tends to be bimodal, being dominantly unmethylated or mostly methylated. For CpG clusters near promoters, low methylation is associated with transcriptional activity, while high methylation is associated with gene silencing. Alternative CpG methylation states are thought to be stable and heritable, conferring localized epigenetic memory that allows transient signals to create long-lived gene expression states. Positive feedback where methylated CpG sites recruit enzymes that methylate nearby CpGs, can produce heritable bistability but does not easily explain that as clusters increase in size or density they change from being primarily methylated to primarily unmethylated. Here, we show that an interaction between the methylation state of a cluster and its occupancy by nucleosomes provides a mechanism to generate these features and explain genome wide systematics of CpG islands.

Acceleration of Age-Associated Methylation Patterns in HIV-1-Infected Adults

PubMed Central

Sehl, Mary; Sinsheimer, Janet S.; Hultin, Patricia M.; Hultin, Lance E.; Quach, Austin; Martínez-Maza, Otoniel; Horvath, Steve; Vilain, Eric; Jamieson, Beth D.

2015-01-01

Patients with treated HIV-1-infection experience earlier occurrence of aging-associated diseases, raising speculation that HIV-1-infection, or antiretroviral treatment, may accelerate aging. We recently described an age-related co-methylation module comprised of hundreds of CpGs; however, it is unknown whether aging and HIV-1-infection exert negative health effects through similar, or disparate, mechanisms. We investigated whether HIV-1-infection would induce age-associated methylation changes. We evaluated DNA methylation levels at >450,000 CpG sites in peripheral blood mononuclear cells (PBMC) of young (20-35) and older (36-56) adults in two separate groups of participants. Each age group for each data set consisted of 12 HIV-1-infected and 12 age-matched HIV-1-uninfected samples for a total of 96 samples. The effects of age and HIV-1 infection on methylation at each CpG revealed a strong correlation of 0.49, p<1 x10-200 and 0.47, p<1x10-200. Weighted gene correlation network analysis (WGCNA) identified 17 co-methylation modules; module 3 (ME3) was significantly correlated with age (cor=0.70) and HIV-1 status (cor=0.31). Older HIV-1+ individuals had a greater number of hypermethylated CpGs across ME3 (p=0.015). In a multivariate model, ME3 was significantly associated with age and HIV status (Data set 1: βage= 0.007088, p=2.08 x 10-9; βHIV= 0.099574, p=0.0011; Data set 2: βage= 0.008762, p=1.27x 10-5; βHIV= 0.128649, p= 0.0001). Using this model, we estimate that HIV-1 infection accelerates age-related methylation by approximately 13.7 years in data set 1 and 14.7 years in data set 2. The genes related to CpGs in ME3 are enriched for polycomb group target genes known to be involved in cell renewal and aging. The overlap between ME3 and an aging methylation module found in solid tissues is also highly significant (Fisher-exact p=5.6 x 10-6, odds ratio=1.91). These data demonstrate that HIV-1 infection is associated with methylation patterns that are similar to age-associated patterns and suggest that general aging and HIV-1 related aging work through some common cellular and molecular mechanisms. These results are an important first step for finding potential therapeutic targets and novel clinical approaches to mitigate the detrimental effects of both HIV-1-infection and aging. PMID:25807146

Neuromolecular Imaging Shows Temporal Synchrony Patterns between Serotonin and Movement within Neuronal Motor Circuits in the Brain.

PubMed

Broderick, Patricia A

2013-06-21

The present discourse links the electrical and chemical properties of the brain with neurotransmitters and movement behaviors to further elucidate strategies to diagnose and treat brain disease. Neuromolecular imaging (NMI), based on electrochemical principles, is used to detect serotonin in nerve terminals (dorsal and ventral striata) and somatodendrites (ventral tegmentum) of reward/motor mesocorticolimbic and nigrostriatal brain circuits. Neuronal release of serotonin is detected at the same time and in the same animal, freely moving and unrestrained, while open-field behaviors are monitored via infrared photobeams. The purpose is to emphasize the unique ability of NMI and the BRODERICK PROBE® biosensors to empirically image a pattern of temporal synchrony, previously reported, for example, in Aplysia using central pattern generators (CPGs), serotonin and cerebral peptide-2. Temporal synchrony is reviewed within the context of the literature on central pattern generators, neurotransmitters and movement disorders. Specifically, temporal synchrony data are derived from studies on psychostimulant behavior with and without cocaine while at the same time and continuously, serotonin release in motor neurons within basal ganglia, is detected. The results show that temporal synchrony between the neurotransmitter, serotonin and natural movement occurs when the brain is NOT injured via, e.g., trauma, addictive drugs or psychiatric illness. In striking contrast, in the case of serotonin and cocaine-induced psychostimulant behavior, a different form of synchrony and also asynchrony can occur. Thus, the known dysfunctional movement behavior produced by cocaine may well be related to the loss of temporal synchrony, the loss of the ability to match serotonin in brain with motor activity. The empirical study of temporal synchrony patterns in humans and animals may be more relevant to the dynamics of motor circuits and movement behaviors than are studies of static parameters currently relied upon within the realms of science and medicine. There are myriad applications for the use of NMI to discover clinically relevant diagnoses and treatments for brain disease involving the motor system.

Neuromolecular Imaging Shows Temporal Synchrony Patterns between Serotonin and Movement within Neuronal Motor Circuits in the Brain

PubMed Central

Broderick, Patricia A.

2013-01-01

The present discourse links the electrical and chemical properties of the brain with neurotransmitters and movement behaviors to further elucidate strategies to diagnose and treat brain disease. Neuromolecular imaging (NMI), based on electrochemical principles, is used to detect serotonin in nerve terminals (dorsal and ventral striata) and somatodendrites (ventral tegmentum) of reward/motor mesocorticolimbic and nigrostriatal brain circuits. Neuronal release of serotonin is detected at the same time and in the same animal, freely moving and unrestrained, while open-field behaviors are monitored via infrared photobeams. The purpose is to emphasize the unique ability of NMI and the BRODERICK PROBE® biosensors to empirically image a pattern of temporal synchrony, previously reported, for example, in Aplysia using central pattern generators (CPGs), serotonin and cerebral peptide-2. Temporal synchrony is reviewed within the context of the literature on central pattern generators, neurotransmitters and movement disorders. Specifically, temporal synchrony data are derived from studies on psychostimulant behavior with and without cocaine while at the same time and continuously, serotonin release in motor neurons within basal ganglia, is detected. The results show that temporal synchrony between the neurotransmitter, serotonin and natural movement occurs when the brain is NOT injured via, e.g., trauma, addictive drugs or psychiatric illness. In striking contrast, in the case of serotonin and cocaine-induced psychostimulant behavior, a different form of synchrony and also asynchrony can occur. Thus, the known dysfunctional movement behavior produced by cocaine may well be related to the loss of temporal synchrony, the loss of the ability to match serotonin in brain with motor activity. The empirical study of temporal synchrony patterns in humans and animals may be more relevant to the dynamics of motor circuits and movement behaviors than are studies of static parameters currently relied upon within the realms of science and medicine. There are myriad applications for the use of NMI to discover clinically relevant diagnoses and treatments for brain disease involving the motor system. PMID:24961434

Perceptions and attitudes of clinicians in Spain toward clinical practice guidelines and grading systems: a protocol for a qualitative study and a national survey

PubMed Central

2010-01-01

Background Clinical practice guidelines (CPGs) have become a very popular tool for decision making in healthcare. While there is some evidence that CPGs improve outcomes, there are numerous factors that influence their acceptability and use by healthcare providers. While evidence of clinicians' knowledge, perceptions and attitudes toward CPGs is extensive, results are still disperse and not conclusive. Our study will evaluate these issues in a large and representative sample of clinicians in Spain. Methods/Design A mixed-method design combining qualitative and quantitative research techniques will evaluate general practitioners (GPs) and hospital-based specialists in Spain with the objective of exploring attitudes and perceptions about CPGs and evidence grading systems. The project will consist of two phases: during the first phase, group discussions will be carried out to gain insight into perceptions and attitudes of the participants, and during the second phase, this information will be completed by means of a survey, reaching a greater number of clinicians. We will explore these issues in GPs and hospital-based practitioners, with or without previous experience in guideline development. Discussion Our study will identify and gain insight into the perceived problems and barriers of Spanish practitioners in relation to guideline knowledge and use. The study will also explore beliefs and attitudes of clinicians towards CPGs and evidence grading systems used to rate the quality of the evidence and the strength of recommendations. Our results will provide guidance to healthcare researchers and healthcare decision makers to improve the use of guidelines in Spain and elsewhere. PMID:21129195

Clinical Practice Guidelines for Prevention, Diagnosis and Management of Early and Delayed-onset Ocular Injuries Due to Mustard Gas Exposure

PubMed Central

Rajavi, Zhale; Safi, Sare; Javadi, Mohammad Ali; Jafarinasab, Mohammad Reza; Feizi, Sepehr; Moghadam, Mohammadreza Sedighi; Jadidi, Khosrow; Babaei, Mahmoud; Shirvani, Armin; Baradaran-Rafii, Alireza; Mohammad-Rabei, Hossein; Ziaei, Hossein; Ghassemi-Broumand, Mohammad; Baher, Siamak Delfaza; Naderi, Mostafa; Panahi-Bazaz, Mahmoodreza; Zarei-Ghanavati, Siamak; Hanjani, Shahriar; Ghasemi, Hassan; Salouti, Ramin; Pakbin, Mojgan; Kheiri, Bahareh

2017-01-01

Purpose: To develop clinical practice guidelines (CPGs) for prevention, diagnosis, treatment and follow-up of ocular injuries caused by exposure to mustard gas. Methods: The clinical questions were designed by the guideline team. Websites and databases including National Guidelines Clearinghouse, National Institute for Clinical Excellence, Cochrane, and PubMed were searched to find related CPGs and explore possible answers to the clinical questions. Since there were no relevant CPGs in the literature, related articles in Persian and English languages were extracted. Each article along with its level of evidence was summarized. Additionally, hand search was performed by looking the reference list of each article. Consequently, recommendations were developed considering the clinical benefits and side effects of each therapeutic modality. The recommendations were re-evaluated in terms of customization criteria. All recommendations along with the related evidence were scored from 1 to 9 by experts from all medical universities of Iran. The level of agreement among the experts was evaluated by analyzing the given scores. Results: The agreement was achieved for all recommendations. The experts suggested a number of minor modifications which were applied to the recommendations. Finally, CPGs were developed with 98 recommendations under three major domains including prevention of injury, diagnosis and management of the acute and delayed-onset mustard gas ocular injuries. Conclusion: Considering the lack of CPGs for the prevention, diagnosis, and management of mustard gas-induced keratitis, these recommendations would be useful to prevent the serious ocular complications of mustard gas and standardize eye care services to the affected individuals. PMID:28299009

Clinical Practice Guidelines for Prevention, Diagnosis and Management of Early and Delayed-onset Ocular Injuries Due to Mustard Gas Exposure.

PubMed

Rajavi, Zhale; Safi, Sare; Javadi, Mohammad Ali; Jafarinasab, Mohammad Reza; Feizi, Sepehr; Moghadam, Mohammadreza Sedighi; Jadidi, Khosrow; Babaei, Mahmoud; Shirvani, Armin; Baradaran-Rafii, Alireza; Mohammad-Rabei, Hossein; Ziaei, Hossein; Ghassemi-Broumand, Mohammad; Baher, Siamak Delfaza; Naderi, Mostafa; Panahi-Bazaz, Mahmoodreza; Zarei-Ghanavati, Siamak; Hanjani, Shahriar; Ghasemi, Hassan; Salouti, Ramin; Pakbin, Mojgan; Kheiri, Bahareh

2017-01-01

To develop clinical practice guidelines (CPGs) for prevention, diagnosis, treatment and follow-up of ocular injuries caused by exposure to mustard gas. The clinical questions were designed by the guideline team. Websites and databases including National Guidelines Clearinghouse, National Institute for Clinical Excellence, Cochrane, and PubMed were searched to find related CPGs and explore possible answers to the clinical questions. Since there were no relevant CPGs in the literature, related articles in Persian and English languages were extracted. Each article along with its level of evidence was summarized. Additionally, hand search was performed by looking the reference list of each article. Consequently, recommendations were developed considering the clinical benefits and side effects of each therapeutic modality. The recommendations were re-evaluated in terms of customization criteria. All recommendations along with the related evidence were scored from 1 to 9 by experts from all medical universities of Iran. The level of agreement among the experts was evaluated by analyzing the given scores. The agreement was achieved for all recommendations. The experts suggested a number of minor modifications which were applied to the recommendations. Finally, CPGs were developed with 98 recommendations under three major domains including prevention of injury, diagnosis and management of the acute and delayed-onset mustard gas ocular injuries. Considering the lack of CPGs for the prevention, diagnosis, and management of mustard gas-induced keratitis, these recommendations would be useful to prevent the serious ocular complications of mustard gas and standardize eye care services to the affected individuals.

Quality assessment of clinical practice guidelines for integrative medicine in China: A systematic review.

PubMed

Yao, Sha; Wei, Dang; Chen, Yao-Long; Wang, Qi; Wang, Xiao-Qin; Zeng, Zhao; Li, Hui

2017-05-01

To assess the quality of integrative medicine clinical practice guidelines (CPGs) published before 2014. A systematic search of the scientific literature published before 2014 was conducted to select integrative medicine CPGs. Four major Chinese integrated databases and one guideline database were searched: the Chinese Biomedical Literature Database (CBM), the China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Wanfang Data, and the China Guideline Clearinghouse (CGC). Four reviewers independently assessed the quality of the included guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE) II Instrument. Overall consensus among the reviewers was assessed using the intra-class correlation coefficient (ICC). A total of 41 guidelines published from 2003 to 2014 were included. The overall consensus among the reviewers was good [ICC: 0.928; 95% confifi dence interval (CI): 0.920 to 0.935]. The scores on the 6 AGREE domains were: 17% for scope and purpose (range: 6% to 32%), 11% for stakeholder involvement (range: 0 to 24%), 10% for rigor of development (range: 3% to 22%), 39% for clarity and presentation (range: 25% to 64%), 11% for applicability (range: 4% to 24%), and 1% for editorial independence (range: 0 to 15%). The quality of integrative medicine CPGs was low, the development of integrative medicine CPGs should be guided by systematic methodology. More emphasis should be placed on multi-disciplinary guideline development groups, quality of evidence, management of funding and conflfl icts of interest, and guideline updates in the process of developing integrative medicine CPGs in China.

Management of Low Back Pain by Physical Therapists in Quebec: How Are We Doing?

PubMed Central

Derghazarian, Tamar

2011-01-01

ABSTRACT Purpose: In this study, we characterized physiotherapists' attitudes and beliefs about the bio-psychosocial problem of low back pain (LBP), their use of clinical practice guidelines (CPGs), and the extent to which their advice and treatment is in line with best-evidence CPGs. Methods: One hundred eight physiotherapists completed an online survey that included questionnaires exploring the strength of physiotherapists' biomedical and bio-psychosocial orientations toward the management of LBP: the Pain Attitudes and Beliefs Scale for Physiotherapists and the Attitudes to Back Pain Scale for musculoskeletal practitioners. In addition, participants responded to questions about treatment recommendations for patients in two vignettes. Results: Only 12% of respondents were aware of CPGs. Physiotherapists with a stronger biomedical orientation scored the severity of spinal pathology higher in the patient vignettes. A stronger biomedical orientation was also associated with disagreement with recommendations to return to usual activity or work. Conclusions: The results suggest limited awareness by physiotherapists of best-evidence CPGs and contemporary understandings of LBP that support early activation and self-management. Research to better understand and facilitate the implementation of best-evidence professional education and clinical practice is an urgent priority. PMID:22942525

Hebbian Plasticity in CPG Controllers Facilitates Self-Synchronization for Human-Robot Handshaking.

PubMed

Jouaiti, Melanie; Caron, Lancelot; Hénaff, Patrick

2018-01-01

It is well-known that human social interactions generate synchrony phenomena which are often unconscious. If the interaction between individuals is based on rhythmic movements, synchronized and coordinated movements will emerge from the social synchrony. This paper proposes a plausible model of plastic neural controllers that allows the emergence of synchronized movements in physical and rhythmical interactions. The controller is designed with central pattern generators (CPG) based on rhythmic Rowat-Selverston neurons endowed with neuronal and synaptic Hebbian plasticity. To demonstrate the interest of the proposed model, the case of handshaking is considered because it is a very common, both physically and socially, but also, a very complex act in the point of view of robotics, neuroscience and psychology. Plastic CPGs controllers are implemented in the joints of a simulated robotic arm that has to learn the frequency and amplitude of an external force applied to its effector, thus reproducing the act of handshaking with a human. Results show that the neural and synaptic Hebbian plasticity are working together leading to a natural and autonomous synchronization between the arm and the external force even if the frequency is changing during the movement. Moreover, a power consumption analysis shows that, by offering emergence of synchronized and coordinated movements, the plasticity mechanisms lead to a significant decrease in the energy spend by the robot actuators thus generating a more adaptive and natural human/robot handshake.

1-CMDb: A Curated Database of Genomic Variations of the One-Carbon Metabolism Pathway.

PubMed

Bhat, Manoj K; Gadekar, Veerendra P; Jain, Aditya; Paul, Bobby; Rai, Padmalatha S; Satyamoorthy, Kapaettu

2017-01-01

The one-carbon metabolism pathway is vital in maintaining tissue homeostasis by driving the critical reactions of folate and methionine cycles. A myriad of genetic and epigenetic events mark the rate of reactions in a tissue-specific manner. Integration of these to predict and provide personalized health management requires robust computational tools that can process multiomics data. The DNA sequences that may determine the chain of biological events and the endpoint reactions within one-carbon metabolism genes remain to be comprehensively recorded. Hence, we designed the one-carbon metabolism database (1-CMDb) as a platform to interrogate its association with a host of human disorders. DNA sequence and network information of a total of 48 genes were extracted from a literature survey and KEGG pathway that are involved in the one-carbon folate-mediated pathway. The information generated, collected, and compiled for all these genes from the UCSC genome browser included the single nucleotide polymorphisms (SNPs), CpGs, copy number variations (CNVs), and miRNAs, and a comprehensive database was created. Furthermore, a significant correlation analysis was performed for SNPs in the pathway genes. Detailed data of SNPs, CNVs, CpG islands, and miRNAs for 48 folate pathway genes were compiled. The SNPs in CNVs (9670), CpGs (984), and miRNAs (14) were also compiled for all pathway genes. The SIFT score, the prediction and PolyPhen score, as well as the prediction for each of the SNPs were tabulated and represented for folate pathway genes. Also included in the database for folate pathway genes were the links to 124 various phenotypes and disease associations as reported in the literature and from publicly available information. A comprehensive database was generated consisting of genomic elements within and among SNPs, CNVs, CpGs, and miRNAs of one-carbon metabolism pathways to facilitate (a) single source of information and (b) integration into large-genome scale network analysis to be developed in the future by the scientific community. The database can be accessed at http://slsdb.manipal.edu/ocm/. © 2017 S. Karger AG, Basel.

An Algorithm Using Twelve Properties of Antibiotics to Find the Recommended Antibiotics, as in CPGs.

PubMed

Tsopra, R; Venot, A; Duclos, C

2014-01-01

Clinical Decision Support Systems (CDSS) incorporating justifications, updating and adjustable recommendations can considerably improve the quality of healthcare. We propose a new approach to the design of CDSS for empiric antibiotic prescription, based on implementation of the deeper medical reasoning used by experts in the development of clinical practice guidelines (CPGs), to deduce the recommended antibiotics. We investigated two methods ("exclusion" versus "scoring") for reproducing this reasoning based on antibiotic properties. The "exclusion" method reproduced expert reasoning the more accurately, retrieving the full list of recommended antibiotics for almost all clinical situations. This approach has several advantages: (i) it provides convincing explanations for physicians; (ii) updating could easily be incorporated into the CDSS; (iii) it can provide recommendations for clinical situations missing from CPGs.

Systematic and transparent inclusion of ethical issues and recommendations in clinical practice guidelines: a six-step approach.

PubMed

Mertz, Marcel; Strech, Daniel

2014-12-04

Clinical practice guidelines (CPGs), a core tool to foster medical professionalism, differ widely in whether and how they address disease-specific ethical issues (DSEIs), and current manuals for CPG development are silent on this issue. The implementation of an explicit method faces two core challenges: first, it adds further complexity to CPG development and requires human and financial resources. Second, in contrast to the in-depth treatment of ethical issues that is standard in bioethics, the inclusion of DSEIs in CPGs need to be more pragmatic, reductive, and simplistic, but without rendering the resulting recommendations useless or insufficiently justified. This paper outlines a six-step approach, EthicsGuide, for the systematic and transparent inclusion of ethical issues and recommendations in CPGs. The development of EthicsGuide is based on (a) methodological standards in evidence-based CPG development, (b) principles of bioethics, (c) research findings on how DSEIs are currently addressed in CPGs, and (d) findings from two proof-of-concept analyses of the EthicsGuide approach. The six steps are 1) determine the DSEI spectrum and the need for ethical recommendations; 2) develop statements on which to base ethical recommendations; 3) categorize, classify, condense, and paraphrase the statements; 4) write recommendations in a standard form; 5) validate and justify recommendations, making any necessary modifications; and 6) address consent. All six steps necessarily come into play when including DSEIs in CPGs. If DSEIs are not explicitly addressed, they are unavoidably dealt with implicitly. We believe that as ethicists gain greater involvement in decision-making about health, personal rights, or economic issues, they should make their methods transparent and replicable by other researchers; and as ethical issues become more widely reflected in CPGs, CPG developers have to learn how to address them in a methodologically adequate way. The approach proposed should serve as a basis for further discussion on how to reach these goals. It breaks open the black box of what ethicists implicitly do when they develop recommendations. Further, interdisciplinary discussion and pilot tests are needed to explore the minimal requirements that guarantee a simplified procedure which is still acceptable and does not become mere window dressing.

Information to cerebellum on spinal motor networks mediated by the dorsal spinocerebellar tract

PubMed Central

Stecina, Katinka; Fedirchuk, Brent; Hultborn, Hans

2013-01-01

The main objective of this review is to re-examine the type of information transmitted by the dorsal and ventral spinocerebellar tracts (DSCT and VSCT respectively) during rhythmic motor actions such as locomotion. Based on experiments in the 1960s and 1970s, the DSCT was viewed as a relay of peripheral sensory input to the cerebellum in general, and during rhythmic movements such as locomotion and scratch. In contrast, the VSCT was seen as conveying a copy of the output of spinal neuronal circuitry, including those circuits generating rhythmic motor activity (the spinal central pattern generator, CPG). Emerging anatomical and electrophysiological information on the putative subpopulations of DSCT and VSCT neurons suggest differentiated functions for some of the subpopulations. Multiple lines of evidence support the notion that sensory input is not the only source driving DSCT neurons and, overall, there is a greater similarity between DSCT and VSCT activity than previously acknowledged. Indeed the majority of DSCT cells can be driven by spinal CPGs for locomotion and scratch without phasic sensory input. It thus seems natural to propose the possibility that CPG input to some of these neurons may contribute to distinguishing sensory inputs that are a consequence of the active locomotion from those resulting from perturbations in the external world. PMID:23613538

Mitigation of adverse interactions in pairs of clinical practice guidelines using constraint logic programming.

PubMed

Wilk, Szymon; Michalowski, Wojtek; Michalowski, Martin; Farion, Ken; Hing, Marisela Mainegra; Mohapatra, Subhra

2013-04-01

We propose a new method to mitigate (identify and address) adverse interactions (drug-drug or drug-disease) that occur when a patient with comorbid diseases is managed according to two concurrently applied clinical practice guidelines (CPGs). A lack of methods to facilitate the concurrent application of CPGs severely limits their use in clinical practice and the development of such methods is one of the grand challenges for clinical decision support. The proposed method responds to this challenge. We introduce and formally define logical models of CPGs and other related concepts, and develop the mitigation algorithm that operates on these concepts. In the algorithm we combine domain knowledge encoded as interaction and revision operators using the constraint logic programming (CLP) paradigm. The operators characterize adverse interactions and describe revisions to logical models required to address these interactions, while CLP allows us to efficiently solve the logical models - a solution represents a feasible therapy that may be safely applied to a patient. The mitigation algorithm accepts two CPGs and available (likely incomplete) patient information. It reports whether mitigation has been successful or not, and on success it gives a feasible therapy and points at identified interactions (if any) together with the revisions that address them. Thus, we consider the mitigation algorithm as an alerting tool to support a physician in the concurrent application of CPGs that can be implemented as a component of a clinical decision support system. We illustrate our method in the context of two clinical scenarios involving a patient with duodenal ulcer who experiences an episode of transient ischemic attack. Copyright © 2013 Elsevier Inc. All rights reserved.

Quality Assessment of Clinical Practice Guidelines for Respiratory Diseases in China: A Systematic Appraisal.

PubMed

Jiang, Mei; Liao, Li-Yue; Liu, Xiao-Qing; He, Wei-Qun; Guan, Wei-Jie; Chen, Hao; Li, Yi-Min

2015-09-01

There has been a significant increase in the publication of clinical practice guidelines (CPGs) for respiratory diseases in China. However, little is known about the quality and potential impacts of these CPGs. Our objective was to critically evaluate the quality of Chinese CPGs for respiratory diseases that were published in peer-reviewed medical journals. A systematic search of scientific literature published between 1979 and 2013 was undertaken to identify and select CPGs that were related to respiratory diseases. Four Chinese databases (the Chinese Biomedical Literature database [CBM], the China National Knowledge Infrastructure [CNKI], the VIP database, and the WANFANG database) were used. The quality of eligible guidelines was assessed independently by four reviewers using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. The overall agreement among reviewers was evaluated using an intraclass correlation coefficient. A total of 109 guidelines published in 27 medical journals from 1979 to 2013 were evaluated. The overall agreement among reviewers was considered good (intraclass correlation coefficient, 0.838; 95% CI, 0.812-0.862). The scores of the six AGREE domains were low: 57.3% for scope and purpose (range, 4.2%-80.5%), 23.8% for stakeholder involvement (range, 2.8%-54.2%), 7.7% for rigor of development (range, 0%-27.1%), 59.8% for clarity and presentation (range, 22.2%-80.6%), 10.9% for applicability (range, 0%-22.9%), and 0.6% for editorial independence (range, 0%-16.7%). Scores for all guidelines were below 60%, and only three guidelines (2.8%) were recommended for clinical practice with modifications. The quality of the guidelines was low, and stakeholder involvement, rigor of development, applicability, and editorial independence should be considered in the future development of CPGs for respiratory diseases in China.

DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis

PubMed Central

Joubert, Bonnie R.; Felix, Janine F.; Yousefi, Paul; Bakulski, Kelly M.; Just, Allan C.; Breton, Carrie; Reese, Sarah E.; Markunas, Christina A.; Richmond, Rebecca C.; Xu, Cheng-Jian; Küpers, Leanne K.; Oh, Sam S.; Hoyo, Cathrine; Gruzieva, Olena; Söderhäll, Cilla; Salas, Lucas A.; Baïz, Nour; Zhang, Hongmei; Lepeule, Johanna; Ruiz, Carlos; Ligthart, Symen; Wang, Tianyuan; Taylor, Jack A.; Duijts, Liesbeth; Sharp, Gemma C.; Jankipersadsing, Soesma A.; Nilsen, Roy M.; Vaez, Ahmad; Fallin, M. Daniele; Hu, Donglei; Litonjua, Augusto A.; Fuemmeler, Bernard F.; Huen, Karen; Kere, Juha; Kull, Inger; Munthe-Kaas, Monica Cheng; Gehring, Ulrike; Bustamante, Mariona; Saurel-Coubizolles, Marie José; Quraishi, Bilal M.; Ren, Jie; Tost, Jörg; Gonzalez, Juan R.; Peters, Marjolein J.; Håberg, Siri E.; Xu, Zongli; van Meurs, Joyce B.; Gaunt, Tom R.; Kerkhof, Marjan; Corpeleijn, Eva; Feinberg, Andrew P.; Eng, Celeste; Baccarelli, Andrea A.; Benjamin Neelon, Sara E.; Bradman, Asa; Merid, Simon Kebede; Bergström, Anna; Herceg, Zdenko; Hernandez-Vargas, Hector; Brunekreef, Bert; Pinart, Mariona; Heude, Barbara; Ewart, Susan; Yao, Jin; Lemonnier, Nathanaël; Franco, Oscar H.; Wu, Michael C.; Hofman, Albert; McArdle, Wendy; Van der Vlies, Pieter; Falahi, Fahimeh; Gillman, Matthew W.; Barcellos, Lisa F.; Kumar, Ashish; Wickman, Magnus; Guerra, Stefano; Charles, Marie-Aline; Holloway, John; Auffray, Charles; Tiemeier, Henning W.; Smith, George Davey; Postma, Dirkje; Hivert, Marie-France; Eskenazi, Brenda; Vrijheid, Martine; Arshad, Hasan; Antó, Josep M.; Dehghan, Abbas; Karmaus, Wilfried; Annesi-Maesano, Isabella; Sunyer, Jordi; Ghantous, Akram; Pershagen, Göran; Holland, Nina; Murphy, Susan K.; DeMeo, Dawn L.; Burchard, Esteban G.; Ladd-Acosta, Christine; Snieder, Harold; Nystad, Wenche; Koppelman, Gerard H.; Relton, Caroline L.; Jaddoe, Vincent W.V.; Wilcox, Allen; Melén, Erik; London, Stephanie J.

2016-01-01

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10−16). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure. PMID:27040690

Effectiveness of guideline dissemination and implementation strategies on health care professionals' behaviour and patient outcomes in the cancer care context: a systematic review protocol.

PubMed

Tomasone, Jennifer R; Chaudhary, Rushil; Brouwers, Melissa C

2015-08-25

Health care professionals (HCPs) are able to make effective decisions regarding patient care through the use of systematically developed clinical practice guidelines (CPGs). These recommendations are especially important in a cancer health care context as patients are exposed to a multitude of interdisciplinary HCPs offering high-quality care throughout diagnosis, treatment, survivorship and palliative care. Although a large number of CPGs targeted towards cancer are widely disseminated, it is unknown whether implementation strategies targeting the use of these guidelines are effective in effecting HCP behaviour and patient outcomes in the cancer care context. The purpose of this systematic review will be to determine the effectiveness of different CPG dissemination and implementation interventions on HCPs' behaviour and patient outcomes in the cancer health care context. Five electronic databases (CINAHL, the Cochrane Controlled Trials Register, MEDLINE via Ovid, EMBASE via Ovid and PsycINFO via Ovid) will be searched to include all studies examining the dissemination and/or implementation of CPGs in a cancer care setting targeting all HCPs. CPG implementation strategies will be included if the CPGs were systematically developed (e.g. literature review/evidence-informed, expert panel, evidence appraisal). The studies will be limited to randomized controlled trials, controlled clinical trials and quasi-experimental (interrupted time series, controlled before-and-after designs) studies. Two independent reviewers will assess articles for eligibility, data extraction and quality appraisal. The aim of this review is to inform cancer care health care professionals and policymakers about evidence-based implementation strategies that will allow for effective use of CPGs. PROSPERO CRD42015019331.

Clinical Practice Guideline Implementation Strategy Patterns in Veterans Affairs Primary Care Clinics

PubMed Central

Hysong, Sylvia J; Best, Richard G; Pugh, Jacqueline A

2007-01-01

Background The Department of Veterans Affairs (VA) mandated the system-wide implementation of clinical practice guidelines (CPGs) in the mid-1990s, arming all facilities with basic resources to facilitate implementation; despite this resource allocation, significant variability still exists across VA facilities in implementation success. Objective This study compares CPG implementation strategy patterns used by high and low performing primary care clinics in the VA. Research Design Descriptive, cross-sectional study of a purposeful sample of six Veterans Affairs Medical Centers (VAMCs) with high and low performance on six CPGs. Subjects One hundred and two employees (management, quality improvement, clinic personnel) involved with guideline implementation at each VAMC primary care clinic. Measures Participants reported specific strategies used by their facility to implement guidelines in 1-hour semi-structured interviews. Facilities were classified as high or low performers based on their guideline adherence scores calculated through independently conducted chart reviews. Findings High performing facilities (HPFs) (a) invested significantly in the implementation of the electronic medical record and locally adapting it to provider needs, (b) invested dedicated resources to guideline-related initiatives, and (c) exhibited a clear direction in their strategy choices. Low performing facilities exhibited (a) earlier stages of development for their electronic medical record, (b) reliance on preexisting resources for guideline implementation, with little local adaptation, and (c) no clear direction in their strategy choices. Conclusion A multifaceted, yet targeted, strategic approach to guideline implementation emphasizing dedicated resources and local adaptation may result in more successful implementation and higher guideline adherence than relying on standardized resources and taxing preexisting channels. PMID:17355583

An Algorithm Using Twelve Properties of Antibiotics to Find the Recommended Antibiotics, as in CPGs

PubMed Central

Tsopra, R.; Venot, A.; Duclos, C.

2014-01-01

Background Clinical Decision Support Systems (CDSS) incorporating justifications, updating and adjustable recommendations can considerably improve the quality of healthcare. We propose a new approach to the design of CDSS for empiric antibiotic prescription, based on implementation of the deeper medical reasoning used by experts in the development of clinical practice guidelines (CPGs), to deduce the recommended antibiotics. Methods We investigated two methods (“exclusion” versus “scoring”) for reproducing this reasoning based on antibiotic properties. Results The “exclusion” method reproduced expert reasoning the more accurately, retrieving the full list of recommended antibiotics for almost all clinical situations. Discussion This approach has several advantages: (i) it provides convincing explanations for physicians; (ii) updating could easily be incorporated into the CDSS; (iii) it can provide recommendations for clinical situations missing from CPGs. PMID:25954422

Knowledge Translation in Audiology

PubMed Central

Kothari, Anita; Bagatto, Marlene P.; Seewald, Richard; Miller, Linda T.; Scollie, Susan D.

2011-01-01

The impetus for evidence-based practice (EBP) has grown out of widespread concern with the quality, effectiveness (including cost-effectiveness), and efficiency of medical care received by the public. Although initially focused on medicine, EBP principles have been adopted by many of the health care professions and are often represented in practice through the development and use of clinical practice guidelines (CPGs). Audiology has been working on incorporating EBP principles into its mandate for professional practice since the mid-1990s. Despite widespread efforts to implement EBP and guidelines into audiology practice, gaps still exist between the best evidence based on research and what is being done in clinical practice. A collaborative dynamic and iterative integrated knowledge translation (KT) framework rather than a researcher-driven hierarchical approach to EBP and the development of CPGs has been shown to reduce the knowledge-to-clinical action gaps. This article provides a brief overview of EBP and CPGs, including a discussion of the barriers to implementing CPGs into clinical practice. It then offers a discussion of how an integrated KT process combined with a community of practice (CoP) might facilitate the development and dissemination of evidence for clinical audiology practice. Finally, a project that uses the knowledge-to-action (KTA) framework for the development of outcome measures in pediatric audiology is introduced. PMID:22194314

Epigenetic Variation in Monozygotic Twins: A Genome-Wide Analysis of DNA Methylation in Buccal Cells

PubMed Central

van Dongen, Jenny; Ehli, Erik A.; Slieker, Roderick C.; Bartels, Meike; Weber, Zachary M.; Davies, Gareth E.; Slagboom, P. Eline; Heijmans, Bastiaan T.; Boomsma, Dorret I.

2014-01-01

DNA methylation is one of the most extensively studied epigenetic marks in humans. Yet, it is largely unknown what causes variation in DNA methylation between individuals. The comparison of DNA methylation profiles of monozygotic (MZ) twins offers a unique experimental design to examine the extent to which such variation is related to individual-specific environmental influences and stochastic events or to familial factors (DNA sequence and shared environment). We measured genome-wide DNA methylation in buccal samples from ten MZ pairs (age 8–19) using the Illumina 450k array and examined twin correlations for methylation level at 420,921 CpGs after QC. After selecting CpGs showing the most variation in the methylation level between subjects, the mean genome-wide correlation (rho) was 0.54. The correlation was higher, on average, for CpGs within CpG islands (CGIs), compared to CGI shores, shelves and non-CGI regions, particularly at hypomethylated CpGs. This finding suggests that individual-specific environmental and stochastic influences account for more variation in DNA methylation in CpG-poor regions. Our findings also indicate that it is worthwhile to examine heritable and shared environmental influences on buccal DNA methylation in larger studies that also include dizygotic twins. PMID:24802513

Identification of Inhibitory Premotor Interneurons Activated at a Late Phase in a Motor Cycle during Drosophila Larval Locomotion

PubMed Central

Itakura, Yuki; Kohsaka, Hiroshi; Ohyama, Tomoko; Zlatic, Marta

2015-01-01

Rhythmic motor patterns underlying many types of locomotion are thought to be produced by central pattern generators (CPGs). Our knowledge of how CPG networks generate motor patterns in complex nervous systems remains incomplete, despite decades of work in a variety of model organisms. Substrate borne locomotion in Drosophila larvae is driven by waves of muscular contraction that propagate through multiple body segments. We use the motor circuitry underlying crawling in larval Drosophila as a model to try to understand how segmentally coordinated rhythmic motor patterns are generated. Whereas muscles, motoneurons and sensory neurons have been well investigated in this system, far less is known about the identities and function of interneurons. Our recent study identified a class of glutamatergic premotor interneurons, PMSIs (period-positive median segmental interneurons), that regulate the speed of locomotion. Here, we report on the identification of a distinct class of glutamatergic premotor interneurons called Glutamatergic Ventro-Lateral Interneurons (GVLIs). We used calcium imaging to search for interneurons that show rhythmic activity and identified GVLIs as interneurons showing wave-like activity during peristalsis. Paired GVLIs were present in each abdominal segment A1-A7 and locally extended an axon towards a dorsal neuropile region, where they formed GRASP-positive putative synaptic contacts with motoneurons. The interneurons expressed vesicular glutamate transporter (vGluT) and thus likely secrete glutamate, a neurotransmitter known to inhibit motoneurons. These anatomical results suggest that GVLIs are premotor interneurons that locally inhibit motoneurons in the same segment. Consistent with this, optogenetic activation of GVLIs with the red-shifted channelrhodopsin, CsChrimson ceased ongoing peristalsis in crawling larvae. Simultaneous calcium imaging of the activity of GVLIs and motoneurons showed that GVLIs’ wave-like activity lagged behind that of motoneurons by several segments. Thus, GVLIs are activated when the front of a forward motor wave reaches the second or third anterior segment. We propose that GVLIs are part of the feedback inhibition system that terminates motor activity once the front of the motor wave proceeds to anterior segments. PMID:26335437

Identification of Inhibitory Premotor Interneurons Activated at a Late Phase in a Motor Cycle during Drosophila Larval Locomotion.

PubMed

Itakura, Yuki; Kohsaka, Hiroshi; Ohyama, Tomoko; Zlatic, Marta; Pulver, Stefan R; Nose, Akinao

2015-01-01

Rhythmic motor patterns underlying many types of locomotion are thought to be produced by central pattern generators (CPGs). Our knowledge of how CPG networks generate motor patterns in complex nervous systems remains incomplete, despite decades of work in a variety of model organisms. Substrate borne locomotion in Drosophila larvae is driven by waves of muscular contraction that propagate through multiple body segments. We use the motor circuitry underlying crawling in larval Drosophila as a model to try to understand how segmentally coordinated rhythmic motor patterns are generated. Whereas muscles, motoneurons and sensory neurons have been well investigated in this system, far less is known about the identities and function of interneurons. Our recent study identified a class of glutamatergic premotor interneurons, PMSIs (period-positive median segmental interneurons), that regulate the speed of locomotion. Here, we report on the identification of a distinct class of glutamatergic premotor interneurons called Glutamatergic Ventro-Lateral Interneurons (GVLIs). We used calcium imaging to search for interneurons that show rhythmic activity and identified GVLIs as interneurons showing wave-like activity during peristalsis. Paired GVLIs were present in each abdominal segment A1-A7 and locally extended an axon towards a dorsal neuropile region, where they formed GRASP-positive putative synaptic contacts with motoneurons. The interneurons expressed vesicular glutamate transporter (vGluT) and thus likely secrete glutamate, a neurotransmitter known to inhibit motoneurons. These anatomical results suggest that GVLIs are premotor interneurons that locally inhibit motoneurons in the same segment. Consistent with this, optogenetic activation of GVLIs with the red-shifted channelrhodopsin, CsChrimson ceased ongoing peristalsis in crawling larvae. Simultaneous calcium imaging of the activity of GVLIs and motoneurons showed that GVLIs' wave-like activity lagged behind that of motoneurons by several segments. Thus, GVLIs are activated when the front of a forward motor wave reaches the second or third anterior segment. We propose that GVLIs are part of the feedback inhibition system that terminates motor activity once the front of the motor wave proceeds to anterior segments.

Real-time biomimetic Central Pattern Generators in an FPGA for hybrid experiments

PubMed Central

Ambroise, Matthieu; Levi, Timothée; Joucla, Sébastien; Yvert, Blaise; Saïghi, Sylvain

2013-01-01

This investigation of the leech heartbeat neural network system led to the development of a low resources, real-time, biomimetic digital hardware for use in hybrid experiments. The leech heartbeat neural network is one of the simplest central pattern generators (CPG). In biology, CPG provide the rhythmic bursts of spikes that form the basis for all muscle contraction orders (heartbeat) and locomotion (walking, running, etc.). The leech neural network system was previously investigated and this CPG formalized in the Hodgkin–Huxley neural model (HH), the most complex devised to date. However, the resources required for a neural model are proportional to its complexity. In response to this issue, this article describes a biomimetic implementation of a network of 240 CPGs in an FPGA (Field Programmable Gate Array), using a simple model (Izhikevich) and proposes a new synapse model: activity-dependent depression synapse. The network implementation architecture operates on a single computation core. This digital system works in real-time, requires few resources, and has the same bursting activity behavior as the complex model. The implementation of this CPG was initially validated by comparing it with a simulation of the complex model. Its activity was then matched with pharmacological data from the rat spinal cord activity. This digital system opens the way for future hybrid experiments and represents an important step toward hybridization of biological tissue and artificial neural networks. This CPG network is also likely to be useful for mimicking the locomotion activity of various animals and developing hybrid experiments for neuroprosthesis development. PMID:24319408

Coordination of Fictive Motor Activity in the Larval Zebrafish Is Generated by Non-Segmental Mechanisms

PubMed Central

Wiggin, Timothy D.; Peck, Jack H.; Masino, Mark A.

2014-01-01

The cellular and network basis for most vertebrate locomotor central pattern generators (CPGs) is incompletely characterized, but organizational models based on known CPG architectures have been proposed. Segmental models propose that each spinal segment contains a circuit that controls local coordination and sends longer projections to coordinate activity between segments. Unsegmented/continuous models propose that patterned motor output is driven by gradients of neurons and synapses that do not have segmental boundaries. We tested these ideas in the larval zebrafish, an animal that swims in discrete episodes, each of which is composed of coordinated motor bursts that progress rostrocaudally and alternate from side to side. We perturbed the spinal cord using spinal transections or strychnine application and measured the effect on fictive motor output. Spinal transections eliminated episode structure, and reduced both rostrocaudal and side-to-side coordination. Preparations with fewer intact segments were more severely affected, and preparations consisting of midbody and caudal segments were more severely affected than those consisting of rostral segments. In reduced preparations with the same number of intact spinal segments, side-to-side coordination was more severely disrupted than rostrocaudal coordination. Reducing glycine receptor signaling with strychnine reversibly disrupted both rostrocaudal and side-to-side coordination in spinalized larvae without disrupting episodic structure. Both spinal transection and strychnine decreased the stability of the motor rhythm, but this effect was not causal in reducing coordination. These results are inconsistent with a segmented model of the spinal cord and are better explained by a continuous model in which motor neuron coordination is controlled by segment-spanning microcircuits. PMID:25275377

Corruption of the intra-gene DNA methylation architecture is a hallmark of cancer.

PubMed

Bartlett, Thomas E; Zaikin, Alexey; Olhede, Sofia C; West, James; Teschendorff, Andrew E; Widschwendter, Martin

2013-01-01

Epigenetic processes--including DNA methylation--are increasingly seen as having a fundamental role in chronic diseases like cancer. It is well known that methylation levels at particular genes or loci differ between normal and diseased tissue. Here we investigate whether the intra-gene methylation architecture is corrupted in cancer and whether the variability of levels of methylation of individual CpGs within a defined gene is able to discriminate cancerous from normal tissue, and is associated with heterogeneous tumour phenotype, as defined by gene expression. We analysed 270985 CpGs annotated to 18272 genes, in 3284 cancerous and 681 normal samples, corresponding to 14 different cancer types. In doing so, we found novel differences in intra-gene methylation pattern across phenotypes, particularly in those genes which are crucial for stem cell biology; our measures of intra-gene methylation architecture are a better determinant of phenotype than measures based on mean methylation level alone (K-S test [Formula: see text] in all 14 diseases tested). These per-gene methylation measures also represent a considerable reduction in complexity, compared to conventional per-CpG beta-values. Our findings strongly support the view that intra-gene methylation architecture has great clinical potential for the development of DNA-based cancer biomarkers.

Reconciling pairs of concurrently used clinical practice guidelines using Constraint Logic Programming.

PubMed

Wilk, Szymon; Michalowski, Martin; Michalowski, Wojtek; Hing, Marisela Mainegra; Farion, Ken

2011-01-01

This paper describes a new methodological approach to reconciling adverse and contradictory activities (called points of contention) occurring when a patient is managed according to two or more concurrently used clinical practice guidelines (CPGs). The need to address these inconsistencies occurs when a patient with more than one disease, each of which is a comorbid condition, has to be managed according to different treatment regimens. We propose an automatic procedure that constructs a mathematical guideline model using the Constraint Logic Programming (CLP) methodology, uses this model to identify and mitigate encountered points of contention, and revises the considered CPGs accordingly. The proposed procedure is used as an alerting mechanism and coupled with a guideline execution engine warns the physician about potential problems with the concurrent application of two or more guidelines. We illustrate the operation of our procedure in a clinical scenario describing simultaneous use of CPGs for duodenal ulcer and transient ischemic attack.

Coordination Polymer Gels with Modular Nanomorphologies, Tunable Emissions, and Stimuli-Responsive Behavior Based on an Amphiphilic Tripodal Gelator.

PubMed

Sutar, Papri; Maji, Tapas Kumar

2017-08-21

The recent upsurge in research on coordination polymer gels (CPGs) stems from their synthetic modularity, nanoscale processability, and versatile functionalities. Here we report self-assembly of an amphiphilic, tripodal low-molecular weight gelator (L) that consists of 4,4',4-[1,3,5-phenyl-tri(methoxy)]-tris-benzene core and 2,2':6',2″-terpyridyl termini, with different metal ions toward the formation of CPGs that show controllable nanomorphologies, tunable emission, and stimuli-responsive behaviors. L can also act as a selective chemosensor for Zn II with very low limit of detection (0.18 ppm) in aqueous medium. Coordination-driven self-assembly of L with Zn II in H 2 O/MeOH solvent mixture results in a coordination polymer hydrogel (ZnL) that exhibits sheet like morphology and charge-transfer emission. On the other hand, coordination of L with Tb III and Eu III in CHCl 3 /tetrahydrofuran solvent mixture results in green- and red-emissive CPGs, respectively, with nanotubular morphology. Moreover, precise stoichiometric control of L/Eu III /Tb III ratio leads to the formation of bimetallic CPGs that show emissions over a broad spectral range, including white-light-emission. We also explore the multistimuli responsive properties of the white-light-emitting CPG by exploiting the dynamics of Ln III -tpy coordination.

How to adapt existing evidence-based clinical practice guidelines: a case example with smoking cessation guidelines in Canada

PubMed Central

Selby, Peter; Hunter, Katie; Rogers, Jess; Lang-Robertson, Kelly; Soklaridis, Sophie; Chow, Virginia; Tremblay, Michèle; Koubanioudakis, Denise; Dragonetti, Rosa; Hussain, Sarwar; Zawertailo, Laurie

2017-01-01

Objective To develop and encourage the adoption of clinical practice guidelines (CPGs) for smoking cessation in Canada by engaging stakeholders in the adaptation of existing high-quality CPGs using principles of the ADAPTE framework. Methods An independent expert body in guideline review conducted a review and identified six existing CPGs, which met a priori criteria for quality and potential applicability to the local context. Summary statements were extracted and assigned a grade of recommendation and level of evidence by a second expert panel. Regional knowledge exchange brokers recruited additional stakeholders to build a multidisciplinary network of over 800 clinicians, researchers and decision-makers from across Canada. This interprofessional network and other stakeholders were offered various opportunities to provide input on the guideline both online and in person. We actively encouraged end-user input into the development and adaptation of the guidelines to ensure applicability to various practice settings and to promote adoption. Results The final guideline contained 24 summary statements along with supporting clinical considerations, across six topic area sections. The guideline was adopted by various provincial/territorial and national government and non-governmental organisations. Conclusions This method can be applied in other jurisdictions to adapt existing high-quality smoking cessation CPGs to the local context and to facilitate subsequent adoption by various stakeholders. PMID:29102984

Evidence-based medicine, clinical practice guidelines, and common sense in the management of osteoporosis.

PubMed

Lewiecki, E Michael; Binkley, Neil

2009-01-01

To evaluate the benefits and limitations of randomized controlled trials (RCTs), clinical practice guidelines (CPGs), and clinical judgment in the management of osteoporosis. A review was conducted of the English-language literature on the origins and applications of RCTs, CPGs, evidence-based medicine, and clinical judgment in the management of osteoporosis. Evidence-based medicine is use of the currently available best evidence in making clinical decisions for individual patients. CPGs are recommendations for making clinical decisions based on research evidence, sometimes with consideration of expert opinion, health care policy, and costs of care. The highest levels of medical evidence are usually thought to be RCTs and meta-analyses of high-quality RCTs. Although it is desirable and appropriate for clinicians to consider research evidence from RCTs and recommendations presented in CPGs in making clinical decisions, other factors-such as patient preference, comorbidities, affordability, and availability of care-are important for the actual implementation of evidence-based medicine. Decisions about who to treat, which drug to use, how best to monitor, and how long to treat require clinical skills in addition to knowledge of medical research. The necessity of integrating common sense and clinical judgment is highlighted by the fact that many patients treated for osteoporosis in clinical practice would not qualify for participation in the pivotal clinical trials that demonstrated efficacy and safety of the drugs used to treat them.

Evidence-based Medicine in Pediatric Orthopaedics: Evidence-based Practice Committee Summary of Levels of Evidence, Clinical Practice Guidelines, Appropriate Use Criteria, and Best Practice Guidelines.

PubMed

Gandhi, Jigar S; Shea, Kevin G; Sponseller, Paul D; Brighton, Brian K; Ganley, Theodore J

2018-04-30

The concept of evidence-based medicine has evolved over the past 2 decades, and has become a cornerstone to clinical decision-making in virtually every aspect of medicine. With a commitment to providing its members with high-quality evidence-based guidelines, the American Academy of Orthopaedic Surgeons has instituted concerted efforts since 2006 to develop clinical practice guidelines (CPGs) and appropriate use criteria (AUCs) for certain orthopaedic conditions. Many of these CPGs and AUCs detail the management of pediatric orthopaedic conditions. By the same token, members of the Pediatric Orthopaedic Society of North America (POSNA) Evidence Based Practice Committee have been publishing succinct evaluations of randomized controlled trials in pediatric orthopaedic surgery to create an evidence-based repository for quick reference to available high-level evidence as well as resource to identify gaps in the current research and identify opportunities for future investigation. In instances where higher-level evidence needed to develop CPGs is not available to address a critically important clinical question, consensus recommendations from experts in the field have been obtained to develop best practice guidelines (BPGs). The purpose of this review is to provide readers with a deeper understanding of the key principles of evidence-based medicine and methodologies used for the development of CPGs, AUCs, and BPGs.

CNVs affecting cancer predisposing genes (CPGs) detected as incidental findings in routine germline diagnostic chromosomal microarray (CMA) testing.

PubMed

Innes, Josie; Reali, Lisa; Clayton-Smith, Jill; Hall, Georgina; Lim, Derek Hk; Burghel, George J; French, Kim; Khan, Unzela; Walker, Daniel; Lalloo, Fiona; Evans, D Gareth R; McMullan, Dominic; Maher, Eamonn R; Woodward, Emma R

2018-02-01

Identification of CNVs through chromosomal microarray (CMA) testing is the first-line investigation in individuals with learning difficulties/congenital abnormalities. Although recognised that CMA testing may identify CNVs encompassing a cancer predisposition gene (CPG), limited information is available on the frequency and nature of such results. We investigated CNV gains and losses affecting 39 CPGs in 3366 pilot index case individuals undergoing CMA testing, and then studied an extended cohort (n=10 454) for CNV losses at 105 CPGs and CNV gains at 9 proto-oncogenes implicated in inherited cancer susceptibility. In the pilot cohort, 31/3366 (0.92%) individuals had a CNV involving one or more of 16/39 CPGs. 30/31 CNVs involved a tumour suppressor gene (TSG), and 1/30 a proto-oncogene (gain of MET ). BMPR1A , TSC2 and TMEM127 were affected in multiple cases. In the second stage analysis, 49/10 454 (0.47%) individuals in the extended cohort had 50 CNVs involving 24/105 CPGs. 43/50 CNVs involved a TSG and 7/50 a proto-oncogene (4 gains, 3 deletions). The most frequently involved genes, FLCN (n=10) and SDHA (n=7), map to the Smith-Magenis and cri-du-chat regions, respectively. Incidental identification of a CNV involving a CPG is not rare and poses challenges for future cancer risk estimation. Prospective data collection from CPG-CNV cohorts ascertained incidentally and through syndromic presentations is required to determine the risks posed by specific CNVs. In particular, ascertainment and investigation of adults with CPG-CNVs and adults with learning disability and cancer, could provide important information to guide clinical management and surveillance. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Design and pilot evaluation of a system to develop computer-based site-specific practice guidelines from decision models.

PubMed

Sanders, G D; Nease, R F; Owens, D K

2000-01-01

Local tailoring of clinical practice guidelines (CPGs) requires experts in medicine and evidence synthesis unavailable in many practice settings. The authors' computer-based system enables developers and users to create, disseminate, and tailor CPGs, using normative decision models (DMs). ALCHEMIST, a web-based system, analyzes a DM, creates a CPG in the form of an annotated algorithm, and displays for the guideline user the optimal strategy. ALCHEMIST'S interface enables remote users to tailor the guideline by changing underlying input variables and observing the new annotated algorithm that is developed automatically. In a pilot evaluation of the system, a DM was used to evaluate strategies for staging non-small-cell lung cancer. Subjects (n = 15) compared the automatically created CPG with published guidelines for this staging and critiqued both using a previously developed instrument to rate the CPGs' usability, accountability, and accuracy on a scale of 0 (worst) to 2 (best), with higher scores reflecting higher quality. The mean overall score for the ALCHEMIST CPG was 1.502, compared with the published-CPG score of 0.987 (p = 0.002). The ALCHEMIST CPG scores for usability, accountability, and accuracy were 1.683, 1.393, and 1.430, respectively; the published CPG scores were 1.192, 0.941, and 0.830 (each comparison p < 0.05). On a scale of 1 (worst) to 5 (best), users' mean ratings of ALCHEMIST'S ease of use, usefulness of content, and presentation format were 4.76, 3.98, and 4.64, respectively. The results demonstrate the feasibility of a web-based system that automatically analyzes a DM and creates a CPG as an annotated algorithm, enabling remote users to develop site-specific CPGs. In the pilot evaluation, the ALCHEMIST guidelines met established criteria for quality and compared favorably with national CPGs. The high usability and usefulness ratings suggest that such systems can be a good tool for guideline development.

D-WISE: Diabetes Web-Centric Information and Support Environment: conceptual specification and proposed evaluation.

PubMed

Abidi, Samina; Vallis, Michael; Raza Abidi, Syed Sibte; Piccinini-Vallis, Helena; Imran, Syed Ali

2014-06-01

To develop and evaluate Diabetes Web-Centric Information and Support Environment (D-WISE) that offers 1) a computerized decision-support system to assist physicians to A) use the Canadian Diabetes Association clinical practice guidelines (CDA CPGs) to recommend evidence-informed interventions; B) offer a computerized readiness assessment strategy to help physicians administer behaviour-change strategies to help patients adhere to disease self-management programs; and 2) a patient-specific diabetes self-management application, accessible through smart mobile devices, that offers behaviour-change interventions to engage patients in self-management. The above-mentioned objectives were pursued through a knowledge management approach that involved 1) Translation of paper-based CDA CPGs and behaviour-change models as computerized decision-support tools that will assist physicians to offer evidence-informed and personalized diabetes management and behaviour-change strategies; 2) Engagement of patients in their diabetes care by generating a diabetes self-management program that takes into account their preferences, challenges and needs; 3) Empowering patients to self-manage their condition by providing them with personalized educational and motivational messages through a mobile self-management application. The theoretical foundation of our research is grounded in behaviour-change models and healthcare knowledge management. We used 1) knowledge modelling to computerize the paper-based CDA CPGs and behaviour-change models, in particular, the behaviour-change strategy elements of A) readiness-to-change assessments; B) motivation-enhancement interventions categorized along the lines of patients' being ready, ambivalent or not ready; and C) self-efficacy enhancement. The CDA CPGs and the behaviour-change models are modelled and computerized in terms of A) a diabetes management ontology that serves as the knowledge resource for all the services offered by D-WISE; B) decision support services that use logic-based reasoning algorithms to utilize the knowledge encoded within the diabetes management ontology to assist physicians by recommending patient-specific diabetes-management interventions and behaviour-change strategies; C) a mobile diabetes self-management application to engage and educate diabetes patients to self-manage their condition in a home-based setting while working in concert with their family physicians. We have been successful in creating and conducting a usability assessment of the physician decision support tool. These results will be published once the patient self- management application has been evaluated. D-WISE will be evaluated through pilot studies measuring 1) the usability of the e-Health interventions; and 2) the impact of the interventions on patients' behaviour changes and diabetes control. Copyright © 2014 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

SMYD2 promoter DNA methylation is associated with abdominal aortic aneurysm (AAA) and SMYD2 expression in vascular smooth muscle cells.

PubMed

Toghill, Bradley J; Saratzis, Athanasios; Freeman, Peter J; Sylvius, Nicolas; Bown, Matthew J

2018-01-01

Abdominal aortic aneurysm (AAA) is a deadly cardiovascular disease characterised by the gradual, irreversible dilation of the abdominal aorta. AAA is a complex genetic disease but little is known about the role of epigenetics. Our objective was to determine if global DNA methylation and CpG-specific methylation at known AAA risk loci is associated with AAA, and the functional effects of methylation changes. We assessed global methylation in peripheral blood mononuclear cell DNA from 92 individuals with AAA and 93 controls using enzyme-linked immunosorbent assays, identifying hyper-methylation in those with large AAA and a positive linear association with AAA diameter ( P  < 0.0001, R 2  = 0.3175).We then determined CpG methylation status of regulatory regions in genes located at AAA risk loci identified in genome-wide association studies, using bisulphite next-generation sequencing (NGS) in vascular smooth muscle cells (VSMCs) taken from aortic tissues of 44 individuals (24 AAAs and 20 controls). In IL6R , 2 CpGs were hyper-methylated ( P  = 0.0145); in ERG , 13 CpGs were hyper-methylated ( P  = 0.0005); in SERPINB9 , 6 CpGs were hypo-methylated ( P  = 0.0037) and 1 CpG was hyper-methylated ( P  = 0.0098); and in SMYD2 , 4 CpGs were hypo-methylated ( P  = 0.0012).RT-qPCR was performed for each differentially methylated gene on mRNA from the same VSMCs and compared with methylation. This analysis revealed downregulation of SMYD2 and SERPINB9 in AAA, and a direct linear relationship between SMYD2 promoter methylation and SMYD2 expression ( P  = 0.038). Furthermore, downregulation of SMYD2 at the site of aneurysm in the aortic wall was further corroborated in 6 of the same samples used for methylation and gene expression analysis with immunohistochemistry. This study is the first to assess DNA methylation in VSMCs from individuals with AAA using NGS, and provides further evidence there is an epigenetic basis to AAA. Our study shows that methylation status of the SMYD2 promoter may be linked with decreased SMYD2 expression in disease pathobiology. In support of our work, downregulated SMYD2 has previously been associated with adverse cardiovascular physiology and inflammation, which are both hallmarks of AAA. The identification of such adverse epigenetic modifications could potentially contribute towards the development of epigenetic treatment strategies in the future.

Reconciling Pairs of Concurrently Used Clinical Practice Guidelines Using Constraint Logic Programming

PubMed Central

Wilk, Szymon; Michalowski, Martin; Michalowski, Wojtek; Hing, Marisela Mainegra; Farion, Ken

2011-01-01

This paper describes a new methodological approach to reconciling adverse and contradictory activities (called points of contention) occurring when a patient is managed according to two or more concurrently used clinical practice guidelines (CPGs). The need to address these inconsistencies occurs when a patient with more than one disease, each of which is a comorbid condition, has to be managed according to different treatment regimens. We propose an automatic procedure that constructs a mathematical guideline model using the Constraint Logic Programming (CLP) methodology, uses this model to identify and mitigate encountered points of contention, and revises the considered CPGs accordingly. The proposed procedure is used as an alerting mechanism and coupled with a guideline execution engine warns the physician about potential problems with the concurrent application of two or more guidelines. We illustrate the operation of our procedure in a clinical scenario describing simultaneous use of CPGs for duodenal ulcer and transient ischemic attack. PMID:22195153

Interactions between Dorsal and Ventral Root Stimulation on the Generation of Locomotor-Like Activity in the Neonatal Mouse Spinal Cord

PubMed Central

2016-01-01

Abstract We investigated whether dorsal (DR) and ventral root (VR) stimulus trains engage common postsynaptic components to activate the central pattern generator (CPG) for locomotion in the neonatal mouse spinal cord. VR stimulation did not activate the first order interneurons mediating the activation of the locomotor CPG by sacrocaudal afferent stimulation. Simultaneous stimulation of adjacent dorsal or ventral root pairs, subthreshold for evoking locomotor-like activity, did not summate to activate the CPG. This suggests that locomotor-like activity is triggered when a critical class of efferent or afferent axons is stimulated and does not depend on the number of stimulated axons or activated postsynaptic neurons. DR- and VR-evoked episodes exhibited differences in the coupling between VR pairs. In DR-evoked episodes, the coupling between the ipsilateral and contralateral flexor/extensor roots was similar and stronger than the bilateral extensor roots. In VR-evoked episodes, ipsilateral flexor/extensor coupling was stronger than both the contralateral flexor/extensor and the bilateral extensor coupling. For both types of stimulation, the coupling was greatest between the bilateral L1/L2 flexor-dominated roots. This indicates that the recruitment and/or the firing pattern of motoneurons differed in DR and VR-evoked episodes. However, the DR and VR trains do not appear to activate distinct CPGs because trains of DR and VR stimuli at frequencies too low to evoke locomotor-like activity did so when they were interleaved. These results indicate that the excitatory actions of VR stimulation converge onto the CPG through an unknown pathway that is not captured by current models of the locomotor CPG. PMID:27419215

A DNA methylation fingerprint of 1628 human samples

PubMed Central

Fernandez, Agustin F.; Assenov, Yassen; Martin-Subero, Jose Ignacio; Balint, Balazs; Siebert, Reiner; Taniguchi, Hiroaki; Yamamoto, Hiroyuki; Hidalgo, Manuel; Tan, Aik-Choon; Galm, Oliver; Ferrer, Isidre; Sanchez-Cespedes, Montse; Villanueva, Alberto; Carmona, Javier; Sanchez-Mut, Jose V.; Berdasco, Maria; Moreno, Victor; Capella, Gabriel; Monk, David; Ballestar, Esteban; Ropero, Santiago; Martinez, Ramon; Sanchez-Carbayo, Marta; Prosper, Felipe; Agirre, Xabier; Fraga, Mario F.; Graña, Osvaldo; Perez-Jurado, Luis; Mora, Jaume; Puig, Susana; Prat, Jaime; Badimon, Lina; Puca, Annibale A.; Meltzer, Stephen J.; Lengauer, Thomas; Bridgewater, John; Bock, Christoph; Esteller, Manel

2012-01-01

Most of the studies characterizing DNA methylation patterns have been restricted to particular genomic loci in a limited number of human samples and pathological conditions. Herein, we present a compromise between an extremely comprehensive study of a human sample population with an intermediate level of resolution of CpGs at the genomic level. We obtained a DNA methylation fingerprint of 1628 human samples in which we interrogated 1505 CpG sites. The DNA methylation patterns revealed show this epigenetic mark to be critical in tissue-type definition and stemness, particularly around transcription start sites that are not within a CpG island. For disease, the generated DNA methylation fingerprints show that, during tumorigenesis, human cancer cells underwent a progressive gain of promoter CpG-island hypermethylation and a loss of CpG methylation in non-CpG-island promoters. Although transformed cells are those in which DNA methylation disruption is more obvious, we observed that other common human diseases, such as neurological and autoimmune disorders, had their own distinct DNA methylation profiles. Most importantly, we provide proof of principle that the DNA methylation fingerprints obtained might be useful for translational purposes by showing that we are able to identify the tumor type origin of cancers of unknown primary origin (CUPs). Thus, the DNA methylation patterns identified across the largest spectrum of samples, tissues, and diseases reported to date constitute a baseline for developing higher-resolution DNA methylation maps and provide important clues concerning the contribution of CpG methylation to tissue identity and its changes in the most prevalent human diseases. PMID:21613409

How do we know if a clinical practice guideline is good? A response to Djulbegovic and colleagues' use of fast-and-frugal decision trees to improve clinical care strategies.

PubMed

Mercuri, Mathew

2018-04-17

Clinical practice guidelines (CPGs) and clinical pathways have become important tools for improving the uptake of evidence-based care. Where CPGs are good, adherence to the recommendations within is thought to result in improved patient outcomes. However, the usefulness of such tools for improving patient important outcomes depends both on adherence to the guideline and whether or not the CPG in question is good. This begs the question of what it is that makes a CPG good? In this issue of the Journal, Djulbegovic and colleagues offer a theory to help guide the development of CPGs. The "fast-and-frugal tree" (FFT) heuristic theory is purported to provide the theoretical structure needed to quantitatively assess clinical guidelines in practice, something that the lack of theory to guide CPG development has precluded. In this paper, I examine the role of FFTs in providing an adequate theoretical framework for developing CPGs. In my view, positioning guideline development within the FFT framework may help with problems related to adherence. However, I believe that FTTs fall short in providing panel members with the theoretical basis needed to justify which factors should be considered when developing a CPG, how information on those factors derived from research studies should be interpreted, and how those factors should be integrated into the recommendation. © 2018 John Wiley & Sons, Ltd.

Transculturalization of a diabetes-specific nutrition algorithm: Asian application.

PubMed

Su, Hsiu-Yueh; Tsang, Man-Wo; Huang, Shih-Yi; Mechanick, Jeffrey I; Sheu, Wayne H-H; Marchetti, Albert

2012-04-01

The prevalence of type 2 diabetes (T2D) in Asia is growing at an alarming rate, posing significant clinical and economic risk to health care stakeholders. Commonly, Asian patients with T2D manifest a distinctive combination of characteristics that include earlier disease onset, distinct pathophysiology, syndrome of complications, and shorter life expectancy. Optimizing treatment outcomes for such patients requires a coordinated inclusive care plan and knowledgeable practitioners. Comprehensive management starts with medical nutrition therapy (MNT) in a broader lifestyle modification program. Implementing diabetes-specific MNT in Asia requires high-quality and transparent clinical practice guidelines (CPGs) that are regionally adapted for cultural, ethnic, and socioeconomic factors. Respected CPGs for nutrition and diabetes therapy are available from prestigious medical societies. For cost efficiency and effectiveness, health care authorities can select these CPGs for Asian implementation following abridgement and cultural adaptation that includes: defining nutrition therapy in meaningful ways, selecting lower cutoff values for healthy body mass indices and waist circumferences (WCs), identifying the dietary composition of MNT based on regional availability and preference, and expanding nutrition therapy for concomitant hypertension, dyslipidemia, overweight/obesity, and chronic kidney disease. An international task force of respected health care professionals has contributed to this process. To date, task force members have selected appropriate evidence-based CPGs and simplified them into an algorithm for diabetes-specific nutrition therapy. Following cultural adaptation, Asian and Asian-Indian versions of this algorithmic tool have emerged. The Asian version is presented in this report.

Customized Clinical Practice Guidelines for Management of Adult Cataract in Iran

PubMed Central

Rajavi, Zhaleh; Javadi, Mohammad Ali; Daftarian, Narsis; Safi, Sare; Nejat, Farhad; Shirvani, Armin; Ahmadieh, Hamid; Shahraz, Saeid; Ziaei, Hossein; Moein, Hamidreza; Motlagh, Behzad Fallahi; Feizi, Sepehr; Foroutan, Alireza; Hashemi, Hassan; Hashemian, Seyed Javad; Jabbarvand, Mahmoud; Jafarinasab, Mohammad Reza; Karimian, Farid; Mohammad-Rabei, Hossein; Mohammadpour, Mehrdad; Nassiri, Nader; Panahi-Bazaz, Mahmoodreza; Rohani, Mohammad Reza; Sedaghat, Mohammad Reza; Sheibani, Kourosh

2015-01-01

Purpose: To customize clinical practice guidelines (CPGs) for cataract management in the Iranian population. Methods: First, four CPGs (American Academy of Ophthalmology 2006 and 2011, Royal College of Ophthalmologists 2010, and Canadian Ophthalmological Society 2008) were selected from a number of available CPGs in the literature for cataract management. All recommendations of these guidelines, together with their references, were studied. Each recommendation was summarized in 4 tables. The first table showed the recommendation itself in clinical question components format along with its level of evidence. The second table contained structured abstracts of supporting articles related to the clinical question with their levels of evidence. The third table included the customized recommendation of the internal group respecting its clinical advantage, cost, and complications. In the fourth table, the internal group their recommendations from 1 to 9 based on the customizing capability of the recommendation (applicability, acceptability, external validity). Finally, customized recommendations were sent one month prior to a consensus session to faculty members of all universities across the country asking for their comments on recommendations. Results: The agreed recommendations were accepted as conclusive while those with no agreement were discussed at the consensus session. Finally, all customized recommendations were codified as 80 recommendations along with their sources and levels of evidence for the Iranian population. Conclusion: Customization of CPGs for management of adult cataract for the Iranian population seems to be useful for standardization of referral, diagnosis and treatment of patients. PMID:27051491

A critical review of recent clinical practice guidelines on the diagnosis and treatment of non-neurogenic male lower urinary tract symptoms

PubMed Central

Chua, Michael Erlano; Mendoza, Jonathan; See, Manuel; Esmena, Ednalyn; Aguila, Dean; Silangcruz, Jan Michael; Reyes, Buenaventura Jose; Luna, Saturnino; Morales, Marcelino

2015-01-01

Introduction: We provide an overview of the quality of recent clinical clinical practice guidelines (CPGs) for non-neurogenic male lower urinary tract symptoms (LUTS) and summarize the recommendations for their diagnosis, assessment, and treatment. Methods: We systematically searched recent (2008–2013) CPGs for non-neurogenic male LUTS. Eligible CPGs were assessed and appraised using Appraisal of Guidelines, Research and Evaluation II (AGREE II) tool by a CPG-appraisal group. The appraisal scores for each guideline were summarized according to each domain and in total. A recommendation summary was made across the guidelines for diagnostics, conservative management, medical, minimally invasive therapy, and surgical management. Results: A total of 8 guidelines were considered. According to AGREE II appraisal of guidelines, the National Institute for Health and Clinical Excellence (NICE), American Urological Association (AUA) and European Association of Urology (EAU) consistently scored high on the guideline domains assessed. Recommendations on diagnostics, conservative management, medical, and surgical management were consistent among the top 3 guidelines. However, we noted a discrepancy in recommending minimally invasive therapy as an alternative management of moderate to severe or bothersome non-neurogenic male LUTS secondary to benign prostatic enlargement (BPE); the NICE guideline, in particular, does not recommend using minimally invasive therapy. Conclusion: The quality of recent CPGs on non-neurogenic male LUTS was appraised and summarized. The guidelines from NICE, AUA and EAU were considered highly compliant to the AGREE II proposition for guideline formation and development. PMID:26279717

A critical review of recent clinical practice guidelines on the diagnosis and treatment of non-neurogenic male lower urinary tract symptoms.

PubMed

Chua, Michael Erlano; Mendoza, Jonathan; See, Manuel; Esmena, Ednalyn; Aguila, Dean; Silangcruz, Jan Michael; Reyes, Buenaventura Jose; Luna, Saturnino; Morales, Marcelino

2015-01-01

We provide an overview of the quality of recent clinical clinical practice guidelines (CPGs) for non-neurogenic male lower urinary tract symptoms (LUTS) and summarize the recommendations for their diagnosis, assessment, and treatment. We systematically searched recent (2008-2013) CPGs for non-neurogenic male LUTS. Eligible CPGs were assessed and appraised using Appraisal of Guidelines, Research and Evaluation II (AGREE II) tool by a CPG-appraisal group. The appraisal scores for each guideline were summarized according to each domain and in total. A recommendation summary was made across the guidelines for diagnostics, conservative management, medical, minimally invasive therapy, and surgical management. A total of 8 guidelines were considered. According to AGREE II appraisal of guidelines, the National Institute for Health and Clinical Excellence (NICE), American Urological Association (AUA) and European Association of Urology (EAU) consistently scored high on the guideline domains assessed. Recommendations on diagnostics, conservative management, medical, and surgical management were consistent among the top 3 guidelines. However, we noted a discrepancy in recommending minimally invasive therapy as an alternative management of moderate to severe or bothersome non-neurogenic male LUTS secondary to benign prostatic enlargement (BPE); the NICE guideline, in particular, does not recommend using minimally invasive therapy. The quality of recent CPGs on non-neurogenic male LUTS was appraised and summarized. The guidelines from NICE, AUA and EAU were considered highly compliant to the AGREE II proposition for guideline formation and development.

Prenatal Exposure to Maternal Cigarette Smoking and DNA Methylation: Epigenome-Wide Association in a Discovery Sample of Adolescents and Replication in an Independent Cohort at Birth through 17 Years of Age

PubMed Central

Lee, Ken W.K.; Richmond, Rebecca; Hu, Pingzhao; French, Leon; Shin, Jean; Bourdon, Celine; Reischl, Eva; Waldenberger, Melanie; Zeilinger, Sonja; Gaunt, Tom; McArdle, Wendy; Ring, Susan; Woodward, Geoff; Bouchard, Luigi; Gaudet, Daniel; Smith, George Davey; Relton, Caroline; Paus, Tomas

2014-01-01

Background: Prenatal exposure to maternal cigarette smoking (prenatal smoke exposure) had been associated with altered DNA methylation (DNAm) at birth. Objective: We examined whether such alterations are present from birth through adolescence. Methods: We used the Infinium HumanMethylation450K BeadChip to search across 473,395 CpGs for differential DNAm associated with prenatal smoke exposure during adolescence in a discovery cohort (n = 132) and at birth, during childhood, and during adolescence in a replication cohort (n = 447). Results: In the discovery cohort, we found five CpGs in MYO1G (top-ranking CpG: cg12803068, p = 3.3 × 10–11) and CNTNAP2 (cg25949550, p = 4.0 × 10–9) to be differentially methylated between exposed and nonexposed individuals during adolescence. The CpGs in MYO1G and CNTNAP2 were associated, respectively, with higher and lower DNAm in exposed versus nonexposed adolescents. The same CpGs were differentially methylated at birth, during childhood, and during adolescence in the replication cohort. In both cohorts and at all developmental time points, the differential DNAm was in the same direction and of a similar magnitude, and was not altered appreciably by adjustment for current smoking by the participants or their parents. In addition, four of the five EWAS (epigenome-wide association study)–significant CpGs in the adolescent discovery cohort were also among the top sites of differential methylation in a previous birth cohort, and differential methylation of CpGs in CYP1A1, AHRR, and GFI1 observed in that study was also evident in our discovery cohort. Conclusions: Our findings suggest that modifications of DNAm associated with prenatal maternal smoking may persist in exposed offspring for many years—at least until adolescence. Citation: Lee KW, Richmond R, Hu P, French L, Shin J, Bourdon C, Reischl E, Waldenberger M, Zeilinger S, Gaunt T, McArdle W, Ring S, Woodward G, Bouchard L, Gaudet D, Davey Smith G, Relton C, Paus T, Pausova Z. 2015. Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age. Environ Health Perspect 123:193–199; http://dx.doi.org/10.1289/ehp.1408614 PMID:25325234

Long-Range Correlations in Stride Intervals May Emerge from Non-Chaotic Walking Dynamics

PubMed Central

Ahn, Jooeun; Hogan, Neville

2013-01-01

Stride intervals of normal human walking exhibit long-range temporal correlations. Similar to the fractal-like behaviors observed in brain and heart activity, long-range correlations in walking have commonly been interpreted to result from chaotic dynamics and be a signature of health. Several mathematical models have reproduced this behavior by assuming a dominant role of neural central pattern generators (CPGs) and/or nonlinear biomechanics to evoke chaos. In this study, we show that a simple walking model without a CPG or biomechanics capable of chaos can reproduce long-range correlations. Stride intervals of the model revealed long-range correlations observed in human walking when the model had moderate orbital stability, which enabled the current stride to affect a future stride even after many steps. This provides a clear counterexample to the common hypothesis that a CPG and/or chaotic dynamics is required to explain the long-range correlations in healthy human walking. Instead, our results suggest that the long-range correlation may result from a combination of noise that is ubiquitous in biological systems and orbital stability that is essential in general rhythmic movements. PMID:24086274

Descending propriospinal neurons mediate restoration of locomotor function following spinal cord injury

PubMed Central

Benthall, Katelyn N.; Hough, Ryan A.

2016-01-01

Following spinal cord injury (SCI) in the lamprey, there is virtually complete recovery of locomotion within a few weeks, but interestingly, axonal regeneration of reticulospinal (RS) neurons is mostly limited to short distances caudal to the injury site. To explain this situation, we hypothesize that descending propriospinal (PS) neurons relay descending drive from RS neurons to indirectly activate spinal central pattern generators (CPGs). In the present study, the contributions of PS neurons to locomotor recovery were tested in the lamprey following SCI. First, long RS neuron projections were interrupted by staggered spinal hemitransections on the right side at 10% body length (BL; normalized from the tip of the oral hood) and on the left side at 30% BL. For acute recovery conditions (≤1 wk) and before axonal regeneration, swimming muscle burst activity was relatively normal, but with some deficits in coordination. Second, lampreys received two spaced complete spinal transections, one at 10% BL and one at 30% BL, to interrupt long-axon RS neuron projections. At short recovery times (3–5 wk), RS and PS neurons will have regenerated their axons for short distances and potentially established a polysynaptic descending command pathway. At these short recovery times, swimming muscle burst activity had only minor coordination deficits. A computer model that incorporated either of the two spinal lesions could mimic many aspects of the experimental data. In conclusion, descending PS neurons are a viable mechanism for indirect activation of spinal locomotor CPGs, although there can be coordination deficits of locomotor activity. NEW & NOTEWORTHY In the lamprey following spinal lesion-mediated interruption of long axonal projections of reticulospinal (RS) neurons, sensory stimulation still elicited relatively normal locomotor muscle burst activity, but with some coordination deficits. Computer models incorporating the spinal lesions could mimic many aspects of the experimental results. Thus, after disruption of long-axon projections from RS neurons in the lamprey, descending propriospinal (PS) neurons appear to be a viable compensatory mechanism for indirect activation of spinal locomotor networks. PMID:27760818

Descending propriospinal neurons mediate restoration of locomotor function following spinal cord injury.

PubMed

Benthall, Katelyn N; Hough, Ryan A; McClellan, Andrew D

2017-01-01

Following spinal cord injury (SCI) in the lamprey, there is virtually complete recovery of locomotion within a few weeks, but interestingly, axonal regeneration of reticulospinal (RS) neurons is mostly limited to short distances caudal to the injury site. To explain this situation, we hypothesize that descending propriospinal (PS) neurons relay descending drive from RS neurons to indirectly activate spinal central pattern generators (CPGs). In the present study, the contributions of PS neurons to locomotor recovery were tested in the lamprey following SCI. First, long RS neuron projections were interrupted by staggered spinal hemitransections on the right side at 10% body length (BL; normalized from the tip of the oral hood) and on the left side at 30% BL. For acute recovery conditions (≤1 wk) and before axonal regeneration, swimming muscle burst activity was relatively normal, but with some deficits in coordination. Second, lampreys received two spaced complete spinal transections, one at 10% BL and one at 30% BL, to interrupt long-axon RS neuron projections. At short recovery times (3-5 wk), RS and PS neurons will have regenerated their axons for short distances and potentially established a polysynaptic descending command pathway. At these short recovery times, swimming muscle burst activity had only minor coordination deficits. A computer model that incorporated either of the two spinal lesions could mimic many aspects of the experimental data. In conclusion, descending PS neurons are a viable mechanism for indirect activation of spinal locomotor CPGs, although there can be coordination deficits of locomotor activity. In the lamprey following spinal lesion-mediated interruption of long axonal projections of reticulospinal (RS) neurons, sensory stimulation still elicited relatively normal locomotor muscle burst activity, but with some coordination deficits. Computer models incorporating the spinal lesions could mimic many aspects of the experimental results. Thus, after disruption of long-axon projections from RS neurons in the lamprey, descending propriospinal (PS) neurons appear to be a viable compensatory mechanism for indirect activation of spinal locomotor networks. Copyright © 2017 the American Physiological Society.

CpG Sites Associated with Cigarette Smoking: Analysis of Epigenome-Wide Data from the Sister Study

PubMed Central

Harlid, Sophia; Xu, Zongli; Panduri, Vijayalakshmi; Sandler, Dale P.

2014-01-01

Background: Smoking increases the risk of many diseases, and it is also linked to blood DNA methylation changes that may be important in disease etiology. Objectives: We sought to identify novel CpG sites associated with cigarette smoking. Methods: We used two epigenome-wide data sets from the Sister Study to identify and confirm CpG sites associated with smoking. One included 908 women with methylation measurements at 27,578 CpG sites using the HumanMethylation27 BeadChip; the other included 200 women with methylation measurements for 473,844 CpG sites using the HumanMethylation450 BeadChip. Significant CpGs from the second data set that were not included in the 27K assay were validated by pyrosequencing in a subset of 476 samples from the first data set. Results: Our study successfully confirmed smoking associations for 9 previously established CpGs and identified 2 potentially novel CpGs: cg26764244 in GNG12 (p = 9.0 × 10–10) and cg22335340 in PTPN6 (p = 2.9 × 10–05). We also found strong evidence of an association between smoking status and cg02657160 in CPOX (p = 7.3 × 10–7), which has not been previously reported. All 12 CpGs were undermethylated in current smokers and showed an increasing percentage of methylation in former and never-smokers. Conclusions: We identified 2 potentially novel smoking related CpG sites, and provided independent replication of 10 previously reported CpGs sites related to smoking, one of which is situated in the gene CPOX. The corresponding enzyme is involved in heme biosynthesis, and smoking is known to increase heme production. Our study extends the evidence base for smoking-related changes in DNA methylation. Citation: Harlid S, Xu Z, Panduri V, Sandler DP, Taylor JA. 2014. CpG sites associated with cigarette smoking: analysis of epigenome-wide data from the Sister Study. Environ Health Perspect 122:673–678; http://dx.doi.org/10.1289/ehp.1307480 PMID:24704585

CpG Oligodeoxynucleotides Facilitate Delivery of Whole Inactivated H9N2 Influenza Virus via Transepithelial Dendrites of Dendritic Cells in Nasal Mucosa

PubMed Central

Qin, Tao; Yin, Yinyan; Yu, Qinghua; Huang, Lulu; Wang, Xiaoqing; Lin, Jian

2015-01-01

ABSTRACT The spread of the low-pathogenicity avian H9N2 influenza virus has seriously increased the risk of a new influenza pandemic. Although whole inactivated virus (WIV) vaccine via intranasal pathway is the effective method of blocking virus transmission, the mucosal barrier seems to be a major factor hampering its development. CpG oligodeoxynucleotides, a known adjuvant, can target downstream dendritic cells (DCs) and effectively enhance the mucosal and systemic immune responses. However, the ability of CpGs to assist H9N2 WIV in transepithelial transport remains unknown. Here, in vitro and in vivo, we showed that CpGs provided assistance for H9N2 WIV in recruiting DCs to the nasal epithelial cells (ECs) and forming transepithelial dendrites (TEDs) to capture luminal viruses. CD103+ DCs participated in this process. Chemokine CCL20 from nasal ECs played a key role in driving DC recruitment and TED formation. Virus-loaded DCs quickly migrated into the draining cervical lymph nodes (CLNs) for antigen presentation. In addition, the competence of CpGs was independent of direct epithelial transport via the transcellular or paracellular pathway. Taken together, our data demonstrated that CpGs enhanced the transport of H9N2 WIV via TEDs of nasal DCs, which might be a novel mechanism for optimal adaptive immune responses. IMPORTANCE This paper demonstrates by both an in vivo and an in vitro coculture model that CpG oligodeoxynucleotides, known as an adjuvant generally targeting downstream immune responses, also are crucial for the transport of H9N2 WIV across nasal epithelial cells (ECs) via the uptake of transepithelial dendrites (TEDs). Our results prove for the first time to our knowledge that the immune-potentiating mechanism of CpGs is based on strengthening the transepithelial uptake of H9N2 WIV in nasal mucosa. These findings provide a fresh perspective for further improvement of intranasal influenza vaccines, which are urgently needed in the face of the potential threat of H9N2 influenza. PMID:25810544

Comprehensive mitigation framework for concurrent application of multiple clinical practice guidelines.

PubMed

Wilk, Szymon; Michalowski, Martin; Michalowski, Wojtek; Rosu, Daniela; Carrier, Marc; Kezadri-Hamiaz, Mounira

2017-02-01

In this work we propose a comprehensive framework based on first-order logic (FOL) for mitigating (identifying and addressing) interactions between multiple clinical practice guidelines (CPGs) applied to a multi-morbid patient while also considering patient preferences related to the prescribed treatment. With this framework we respond to two fundamental challenges associated with clinical decision support: (1) concurrent application of multiple CPGs and (2) incorporation of patient preferences into the decision making process. We significantly expand our earlier research by (1) proposing a revised and improved mitigation-oriented representation of CPGs and secondary medical knowledge for addressing adverse interactions and incorporating patient preferences and (2) introducing a new mitigation algorithm. Specifically, actionable graphs representing CPGs allow for parallel and temporal activities (decisions and actions). Revision operators representing secondary medical knowledge support temporal interactions and complex revisions across multiple actionable graphs. The mitigation algorithm uses the actionable graphs, revision operators and available (and possibly incomplete) patient information represented in FOL. It relies on a depth-first search strategy to find a valid sequence of revisions and uses theorem proving and model finding techniques to identify applicable revision operators and to establish a management scenario for a given patient if one exists. The management scenario defines a safe (interaction-free) and preferred set of activities together with possible patient states. We illustrate the use of our framework with a clinical case study describing two patients who suffer from chronic kidney disease, hypertension, and atrial fibrillation, and who are managed according to CPGs for these diseases. While in this paper we are primarily concerned with the methodological aspects of mitigation, we also briefly discuss a high-level proof of concept implementation of the proposed framework in the form of a clinical decision support system (CDSS). The proposed mitigation CDSS "insulates" clinicians from the complexities of the FOL representations and provides semantically meaningful summaries of mitigation results. Ultimately we plan to implement the mitigation CDSS within our MET (Mobile Emergency Triage) decision support environment. Copyright © 2016 Elsevier Inc. All rights reserved.

Prioritising Responses Of Nurses To deteriorating patient Observations (PRONTO) protocol: testing the effectiveness of a facilitation intervention in a pragmatic, cluster-randomised trial with an embedded process evaluation and cost analysis.

PubMed

Bucknall, Tracey K; Harvey, Gill; Considine, Julie; Mitchell, Imogen; Rycroft-Malone, Jo; Graham, Ian D; Mohebbi, Mohammadreza; Watts, Jennifer; Hutchinson, Alison M

2017-07-11

Vital signs are the primary indicator of physiological status and for determining the need for urgent clinical treatment. Yet, if physiological signs of deterioration are missed, misinterpreted or mismanaged, then critical illness, unplanned intensive care admissions, cardiac arrest and death may ensue. Although evidence demonstrates the benefit of early recognition and management of deteriorating patients, failure to escalate care and manage deteriorating patients remains a relatively frequent occurrence in hospitals. A pragmatic cluster-randomised controlled trial design will be used to measure clinical effectiveness and cost of a facilitation intervention to improve nurses' vital sign measurement, interpretation, treatment and escalation of care for patients with abnormal vital signs. A cost consequence analysis will evaluate the intervention cost and effectiveness, and a process evaluation will determine how the implementation of the intervention contributes to outcomes. We will compare clinical outcomes and costs from standard implementation of clinical practice guidelines (CPGs) to facilitated implementation of CPGs. The primary outcome will be adherence to the CPGs by nurses, as measured by escalation of care as per organisational policy. The study will be conducted in four Australian major metropolitan teaching hospitals. In each hospital, eight to ten wards will be randomly allocated to intervention and control groups. Control wards will receive standard implementation of CPGs, while intervention wards will receive standard CPG implementation plus facilitation, using facilitation methods and processes tailored to the ward context. The intervention will be administered to all nursing staff at the ward level for 6 months. At each hospital, two types of facilitators will be provided: a hospital-level facilitator as the lead; and two ward-level facilitators for each ward. This study uses an innovative, networked approach to facilitation to enable uptake of CPGs. Findings will inform the intervention utility and knowledge translation measurement approaches. If successful, the study methodology and intervention has potential for translation to other health care standards. Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12616000544471p.

Genome-Wide Associations between Genetic and Epigenetic Variation Influence mRNA Expression and Insulin Secretion in Human Pancreatic Islets

PubMed Central

Olsson, Anders H.; Volkov, Petr; Bacos, Karl; Dayeh, Tasnim; Hall, Elin; Nilsson, Emma A.; Ladenvall, Claes; Rönn, Tina; Ling, Charlotte

2014-01-01

Genetic and epigenetic mechanisms may interact and together affect biological processes and disease development. However, most previous studies have investigated genetic and epigenetic mechanisms independently, and studies examining their interactions throughout the human genome are lacking. To identify genetic loci that interact with the epigenome, we performed the first genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human pancreatic islets. We related 574,553 single nucleotide polymorphisms (SNPs) with genome-wide DNA methylation data of 468,787 CpG sites targeting 99% of RefSeq genes in islets from 89 donors. We identified 67,438 SNP-CpG pairs in cis, corresponding to 36,783 SNPs (6.4% of tested SNPs) and 11,735 CpG sites (2.5% of tested CpGs), and 2,562 significant SNP-CpG pairs in trans, corresponding to 1,465 SNPs (0.3% of tested SNPs) and 383 CpG sites (0.08% of tested CpGs), showing significant associations after correction for multiple testing. These include reported diabetes loci, e.g. ADCY5, KCNJ11, HLA-DQA1, INS, PDX1 and GRB10. CpGs of significant cis-mQTLs were overrepresented in the gene body and outside of CpG islands. Follow-up analyses further identified mQTLs associated with gene expression and insulin secretion in human islets. Causal inference test (CIT) identified SNP-CpG pairs where DNA methylation in human islets is the potential mediator of the genetic association with gene expression or insulin secretion. Functional analyses further demonstrated that identified candidate genes (GPX7, GSTT1 and SNX19) directly affect key biological processes such as proliferation and apoptosis in pancreatic β-cells. Finally, we found direct correlations between DNA methylation of 22,773 (4.9%) CpGs with mRNA expression of 4,876 genes, where 90% of the correlations were negative when CpGs were located in the region surrounding transcription start site. Our study demonstrates for the first time how genome-wide genetic and epigenetic variation interacts to influence gene expression, islet function and potential diabetes risk in humans. PMID:25375650

Achieving 90% Adoption of Clinical Practice Guidelines Using the Delphi Consensus Method in a Large Orthopedic Group.

PubMed

Bini, Stefano A; Mahajan, John

2016-11-01

Little is known about the implementation rate of clinical practice guidelines (CPGs). Our purpose was to report on the adoption rate of CPGs created and implemented by a large orthopedic group using the Delphi consensus method. The draft CPGs were created before the group's annual meeting by 5 teams each assigned a subset of topics. The draft guidelines included a statement and a summary of the available evidence. Each guideline was debated in both small-group and plenary sessions. Voting was anonymous and a 75% supermajority was required for passage. A Likert scale was used to survey the patient's experience with the process at 1 week, and the Kirkpatrick evaluation model was used to gauge the efficacy of the process over a 6-month time frame. Eighty-five orthopedic surgeons attended the meeting. Fifteen guidelines grouped into 5 topics were created. All passed. Eighty-six percent of attendees found the process effective and 84% felt that participating in the process made it more likely that they would adopt the guidelines. At 1 week, an average of 62% of attendees stated they were practicing the guideline as written (range: 35%-72%), and at 6 months, 96% stated they were practicing them (range: 82%-100%). We have demonstrated that a modified Delphi method for reaching consensus can be very effective in both creating CPGs and leading to their adoption. Further we have shown that the process is well received by participants and that an inclusionary approach can be highly successful. Copyright © 2016 Elsevier Inc. All rights reserved.

Author financial conflicts of interest, industry funding, and clinical practice guidelines for anticancer drugs.

PubMed

Tibau, Ariadna; Bedard, Philippe L; Srikanthan, Amirrtha; Ethier, Josee-Lyne; Vera-Badillo, Francisco E; Templeton, Arnoud J; Ocaña, Alberto; Seruga, Bostjan; Barnadas, Agustí; Amir, Eitan

2015-01-01

Clinical practice guidelines (CPGs) and consensus statements (CSs) are used to apply evidence-based medicine or expert recommendations to clinical practice. Here we explore author financial conflicts of interest (FCOIs), sources of guideline funding, and their relationship with endorsement of specific drugs. An electronic search of MEDLINE was conducted to identify CPGs and CSs for common solid cancers published between January 2003 and October 2013. The search was restricted to articles evaluating systemic therapy. We extracted data on self-reported author FCOIs, funding sources, use of manuscript writers, and endorsement of specific drugs in the abstract of the article. Of 142 articles evaluated, 64% were CPGs, and 36% were CSs. The proportion of articles reporting FCOIs improved from 11% in 2003 to 93% in 2013 (P for trend < .001). Only 45% of articles explicitly reported funding sources. Of these, 65% disclosed partial or full industry sponsorship. Use of manuscript writers was declared in 13%, but many articles did not explicitly report the role of authors in the writing of the manuscript. Endorsement of specific drugs was significantly associated with author FCOIs (odds ratio [OR], 7.29; P = .001), but not with industry funding (OR, 0.95; P = .37). Reporting of FCOIs in CPGs and CSs has improved over time. Despite prevalent funding of guideline development by industry, such funding is not associated with endorsement of specific drugs. Author FCOIs are prevalent, and endorsement of a specific drug seems to be more common when authors have FCOIs with the pharmaceutical company marketing that drug. © 2014 by American Society of Clinical Oncology.

Emergency department management of gastro-enteritis in Australia and New Zealand.

PubMed

Schutz, Jacquie; Babl, Franz E; Sheriff, Nisa; Borland, Meredith

2008-10-01

Comparison of clinical practice guideline (CPG) recommendations and reported physician management of gastro-enteritis at Paediatric Research in Emergency Departments International Collaborative (PREDICT) network sites as a baseline for further randomised controlled trials. Two part survey comprising: (i) review of CPGs from PREDICT sites for gastro-enteritis; and (ii) survey of senior emergency department physicians regarding the management of gastro-enteritis. All 11 PREDICT sites participated. Nine CPGs were available with three sites using a common CPG. For moderate dehydration, eight CPGs advocated nasogastric (NG) rehydration in preference to intravenous (IV) rehydration. The IV route was reserved for severe dehydration or failed NG rehydration. In the second component of the survey, 78 of 83 (94%) physicians responded. In moderate dehydration, 82% of respondents used NG rehydration. In severe dehydration, 86% used IV fluids; 12% used NG and 3% an initial IV bolus followed by NG fluid. Serum electrolytes were measured universally with IV fluid use and by 22% using NG rehydration. The IV fluid bolus was with normal saline (86%). Fifty-four per cent used anti-emetics 'rarely' or 'sometimes'. The commonest agents were ondansetron (60%) and metoclopramide (29%). CPG recommendations and physician practice for the management of gastro-enteritis were similar across PREDICT sites with a focus on NG for moderate dehydration and IV for severe dehydration. A variety of fluids and administration rates were used. Anti-emetics were used infrequently. The efficacy and safety of newer anti-emetics should be explored in collaborative studies. Collaborative development of new CPGs should be considered to simplify fluid regimens.

Prediction of gestational age based on genome-wide differentially methylated regions.

PubMed

Bohlin, J; Håberg, S E; Magnus, P; Reese, S E; Gjessing, H K; Magnus, M C; Parr, C L; Page, C M; London, S J; Nystad, W

2016-10-07

We explored the association between gestational age and cord blood DNA methylation at birth and whether DNA methylation could be effective in predicting gestational age due to limitations with the presently used methods. We used data from the Norwegian Mother and Child Birth Cohort study (MoBa) with Illumina HumanMethylation450 data measured for 1753 newborns in two batches: MoBa 1, n = 1068; and MoBa 2, n = 685. Gestational age was computed using both ultrasound and the last menstrual period. We evaluated associations between DNA methylation and gestational age and developed a statistical model for predicting gestational age using MoBa 1 for training and MoBa 2 for predictions. The prediction model was additionally used to compare ultrasound and last menstrual period-based gestational age predictions. Furthermore, both CpGs and associated genes detected in the training models were compared to those detected in a published prediction model for chronological age. There were 5474 CpGs associated with ultrasound gestational age after adjustment for a set of covariates, including estimated cell type proportions, and Bonferroni-correction for multiple testing. Our model predicted ultrasound gestational age more accurately than it predicted last menstrual period gestational age. DNA methylation at birth appears to be a good predictor of gestational age. Ultrasound gestational age is more strongly associated with methylation than last menstrual period gestational age. The CpGs linked with our gestational age prediction model, and their associated genes, differed substantially from the corresponding CpGs and genes associated with a chronological age prediction model.

European Fissure Sealant Guidelines: assessment using AGREE II.

PubMed

San Martin-Galindo, L; Rodríguez-Lozano, F J; Abalos-Labruzzi, C; Niederman, R

2017-02-01

Pit and fissure sealants are effective in reducing the incidence of occlusal caries, and multiple clinical practice guidelines (CPGs) have been developed for recommending their proper use. The usefulness of CPGs depends on their quality and on the rigour of the guideline development process. A study was made to assess the quality of current European CPGs based on the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument, which uses 23 key items rated on a 7-point scale to assess practice guideline development and the quality of reporting. A search was conducted for fissure sealant guidelines for preventing caries in children and adults at high and low risk published in the last 10 years. Calibration was carried out before scoring to assess agreement between the appraisers using the AGREE II instrument. The searches identified 19 relevant guidelines, and following application of the inclusion/exclusion criteria, three guidelines were retained for evaluation. The proportion of observed agreement was calculated, expressed by the agreement separately for positive and negative ratings (PA = 0.89, NA = 0-91). The results of the guideline assessments revealed the highest score for the Irish guideline, a moderate score for the French guideline and the lowest score for the European guideline. Based on the AGREE II instrument, the results obtained show significant variation in the quality assessment of the three European Fissure Sealant Guidelines. Future studies should be carried out both to develop quality dental CPGs and to investigate effective ways of adopting them. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A national survey of Chinese medicine doctors and clinical practice guidelines in China.

PubMed

Liu, Mengyu; Zhang, Chi; Zha, Qinglin; Yang, Wei; Yuwen, Ya; Zhong, Linda; Bian, Zhaoxiang; Han, Xuejie; Lu, Aiping

2017-09-06

Clinical practice guidelines (CPGs) for Chinese medicine (CM) are being developed to assist doctors with appropriate decisions concerning CM care. To date, there has been little investigation on the perspectives of those to whom the guidelines are directed. A self-administered questionnaire was sent to 4503 doctors in 28 provinces of China in the latter half of 2012. Questions were organized around the topics of knowledge, application, practice changes, beliefs and outcomes of implementation. Basic classificatory data on specialties and years of qualification were also collected. Replies were received from 4495 CM doctors (99.82%). Of these, 85.56% of CM doctors reported being familiar with CPG recommendations, but the overall adherence rate was only 50.39%. The length of time practicing CM may influence the rate of adherence, since 709 doctors (51.90%) with less than 5 years of experience reported never having followed CPGs. Doctors in nine specialties showed a modest degree of homogeneity in their attitudes towards CM diagnosis and treatment, which were generally positive. Most doctors regarded CPG-recommended therapies as safe (92%), economic (84%), and effective (76%). Approximately four-fifths of those questioned selected 'acceptable' (60.84%) and 'acceptable after revision' (19.23%) regarding their comprehensive assessment of the CPGs. An encouraging result from this survey is that the majority of CM doctors support the concept of CPGs for the practice of CM. However, the results of this survey also suggest that improving the adherence of CM doctors to the guidelines remains a major challenge to improving the practice standards for CM.

How updating textual clinical practice guidelines impacts clinical decision support systems: a case study with bladder cancer management.

PubMed

Bouaud, Jacques; Séroussi, Brigitte; Brizon, Ambre; Culty, Thibault; Mentré, France; Ravery, Vincent

2007-01-01

Guideline-based clinical decision support systems (CDSSs) can be effective in increasing physician compliance with recommendations. However, the ever growing pace at which medical knowledge is produced requires that clinical practice guidelines (CPGs) be updated regularly. It is therefore mandatory that CDSSs be revised accordingly. The French Association for Urology publishes CPGs on bladder cancer management every 2 years. We studied the impact of the 2004 revision of these guidelines, with respect to the 2002 version with a CDSS, UroDoc. We proposed a typology of knowledge base modifications resulting from the update of CPGs making the difference between practice, clinical conditions and recommendations refinement as opposed to new practice and new recommendations. The number of formalized recommendations increased from 577 in 2002 to 1,081 in 2004. We evaluated the two versions of UroDoc on a randomized sample of patient records. A single new practice that modifies a decision taken in 49% of all recorded decisions leads to a fall from 67% to 46% of the compliance rate of decisions.

Academy of Osseointegration's Summit on Clinical Practice Guidelines for the Edentulous Maxilla: Overview, Process, and Outcomes-Changing the Face of Implant Dentistry.

PubMed

Stanford, Clark M

2016-01-01

Starting in 2012, the Academy of Osseointegration initiated the planning process for an AO Summit to develop clinical practice guidelines (CPGs) for management of the edentulous maxilla. A planning committee led by Professor Clark Stanford and Dr Ole Jensen created a work plan based on five domain areas to be addressed by the summit. The five domain areas were defined as: (1) role of grafting for ridge development for implant placement, (2) role of implant design and systems in management of the edentulous maxilla, (3) role of imaging to guide implant placement, (4) role of biologics to assist in ridge development, and (5) role of prosthetic management. The summit was held in August 2014, and the results are presented in this overview. All of the supporting systematic reviews and the detailed CPGs are presented in this special edition of JOMI. While the evidence was observed to be weak in regard to the literature for most of the systematic reviews, the summit strived to establish the current best evidence and practical CPGs that will assist clinicians in practice.

CpG location and methylation level are crucial factors for the early detection of oral squamous cell carcinoma in brushing samples using bisulfite sequencing of a 13-gene panel.

PubMed

Morandi, Luca; Gissi, Davide; Tarsitano, Achille; Asioli, Sofia; Gabusi, Andrea; Marchetti, Claudio; Montebugnoli, Lucio; Foschini, Maria Pia

2017-01-01

Oral squamous cell carcinoma (OSCC) is usually diagnosed at an advanced stage and is commonly preceded by oral premalignant lesions. The mortality rates have remained unchanged (50% within 5 years after diagnosis), and it is related to tobacco smoking and alcohol intake. Novel molecular markers for early diagnosis are urgently needed. The purpose of this study was to evaluate the diagnostic value of methylation level in a set of 18 genes by bisulfite next-generation sequencing. With minimally invasive oral brushing, 28 consecutive OSCC, one squamous cell carcinoma with sarcomatoid features, six high-grade squamous intraepithelial lesions (HGSIL), 30 normal contralateral mucosa from the same patients, and 65 healthy donors were evaluated for DNA methylation analyzing 18 target genes by quantitative bisulfite next-generation sequencing. We further evaluated an independent cohort (validation dataset) made of 20 normal donors, one oral fibroma, 14 oral lichen planus (OLP), three proliferative verrucous leukoplakia (PVL), and two OSCC. Comparing OSCC with normal healthy donors and contralateral mucosa in 355 CpGs, we identified the following epigenetically altered genes: ZAP70 , ITGA4 , KIF1A , PARP15 , EPHX3 , NTM , LRRTM1 , FLI1 , MIR193 , LINC00599 , PAX1 , and MIR137HG showing hypermethylation and MIR296 , TERT , and GP1BB showing hypomethylation . The behavior of ZAP70 , GP1BB , H19 , EPHX3 , and MIR193 fluctuated among different interrogated CpGs. The gap between normal and OSCC samples remained mostly the same (Kruskal-Wallis P values < 0.05), but the absolute values changed conspicuously. ROC curve analysis identified the most informative CpGs, and we correctly stratified OSCC and HGSIL from normal donors using a multiclass linear discriminant analysis in a 13-gene panel (AUC 0.981). Only the OSCC with sarcomatoid features was negative. Three contralateral mucosa were positive, a sign of a possible field cancerization. Among imprinted genes, only MIR296 showed loss of imprinting. DNMT1 , TERC , and H19 together with the global methylation of long interspersed element 1 were unchanged. In the validation dataset, values over the threshold were detected in 2/2 OSCC, in 3/3 PVL, and in 2/14 OLP. Our data highlight the importance of CpG location and correct estimation of DNA methylation level for highly accurate early diagnosis of OSCC.

Association of the CpG Methylation Pattern of the Proximal Insulin Gene Promoter with Type 1 Diabetes

PubMed Central

Fradin, Delphine; Le Fur, Sophie; Mille, Clémence; Naoui, Nadia; Groves, Chris; Zelenika, Diana; McCarthy, Mark I.; Lathrop, Mark; Bougnères, Pierre

2012-01-01

The insulin (INS) region is the second most important locus associated with Type 1 Diabetes (T1D). The study of the DNA methylation pattern of the 7 CpGs proximal to the TSS in the INS gene promoter revealed that T1D patients have a lower level of methylation of CpG -19, -135 and -234 (p = 2.10−16) and a higher methylation of CpG -180 than controls, while methylation was comparable for CpG -69, -102, -206. The magnitude of the hypomethylation relative to a control population was 8–15% of the corresponding levels in controls and was correlated in CpGs -19 and -135 (r = 0.77) and CpG -135 and -234 (r = 0.65). 70/485 (14%) of T1D patients had a simultaneous decrease in methylation of CpG -19, -135, -234 versus none in 317 controls. CpG methylation did not correlate with glycated hemoglobin or with T1D duration. The methylation of CpG -69, -102, -180, -206, but not CpG -19, -135, -234 was strongly influenced by the cis-genotype at rs689, a SNP known to show a strong association with T1D. We hypothesize that part of this genetic association could in fact be mediated at the statistical and functional level by the underlying changes in neighboring CpG methylation. Our observation of a CpG-specific, locus-specific methylation pattern, although it can provide an epigenetic biomarker of a multifactorial disease, does not indicate whether the reported epigenetic pattern preexists or follows the establishment of T1D. To explore the effect of chronic hyperglycemia on CpG methylation, we studied non obese patients with type 2 diabetes (T2D) who were found to have decreased CpG-19 methylation versus age-matched controls, similar to T1D (p = 2.10−6) but increased CpG-234 methylation (p = 5.10−8), the opposite of T1D. The causality and natural history of the different epigenetic changes associated with T1D or T2D remain to be determined. PMID:22567146

Audiometric Testing Guideline Adherence in Children Undergoing Tympanostomy Tubes: A Population-Based Study.

PubMed

Beyea, Jason A; Rosen, Emily; Stephens, Trina; Nguyen, Paul; Hall, Stephen F

2018-02-01

Objective Tympanostomy tube (TT) insertion is the most common ambulatory surgery performed on children. American Academy of Otolaryngology-Head and Neck Surgery Founda-tion (AAO-HNSF) Clinical Practice Guidelines (CPGs) recommend hearing testing for all pediatric TT candidates. The aim of this study was to assess audiometric testing in this population. Study Design Retrospective population-based cohort study. Setting All hospitals in the Canadian province of Ontario. Subjects and Methods All patients 12 years of age and younger who underwent at least 1 TT procedure between January 1993 and June 2016. The primary outcomes were the percentage of patients who underwent a hearing test within 1 year before and/or 1 year after surgery. Results A total of 316,599 bilateral TT procedures were performed during the study period (1993 to 2016). Presurgical hearing tests increased from 55.7% to 74.9%, and postsurgical hearing tests increased from 42.2% to 68.9%. Younger surgeons demonstrated a greater adherence to the CPGs (relative risk [RR], 1.22; 95% CI, 1.08-1.38; P = .001). Remarkably, there was not a spike in preoperative hearing tests following the introduction of the CPGs in 2013 (RR, 1.12; 95% CI, 0.85-1.47; P = .432). Presurgical hearing testing ranged from 26.1% to 83.5% across health regions. Conclusion In this cohort of children who underwent TT placement, the trends of preoperative and postoperative audiometric testing are increasing but are still lower than recommended by the CPGs, despite a tripling of practicing audiologists. This study describes the current state of testing in Ontario and highlights issues of access to audiology services, possible parent preferences, and the importance of ongoing continuing medical education for all health care practitioners.

DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood

PubMed Central

Tobi, Elmar W.; Slieker, Roderick C.; Luijk, René; Dekkers, Koen F.; Stein, Aryeh D.; Xu, Kate M.; Slagboom, P. Eline; van Zwet, Erik W.; Lumey, L. H.; Heijmans, Bastiaan T.

2018-01-01

Although it is assumed that epigenetic mechanisms, such as changes in DNA methylation (DNAm), underlie the relationship between adverse intrauterine conditions and adult metabolic health, evidence from human studies remains scarce. Therefore, we evaluated whether DNAm in whole blood mediated the association between prenatal famine exposure and metabolic health in 422 individuals exposed to famine in utero and 463 (sibling) controls. We implemented a two-step analysis, namely, a genome-wide exploration across 342,596 cytosine-phosphate-guanine dinucleotides (CpGs) for potential mediators of the association between prenatal famine exposure and adult body mass index (BMI), serum triglycerides (TG), or glucose concentrations, which was followed by formal mediation analysis. DNAm mediated the association of prenatal famine exposure with adult BMI and TG but not with glucose. DNAm at PIM3 (cg09349128), a gene involved in energy metabolism, mediated 13.4% [95% confidence interval (CI), 5 to 28%] of the association between famine exposure and BMI. DNAm at six CpGs, including TXNIP (cg19693031), influencing β cell function, and ABCG1 (cg07397296), affecting lipid metabolism, together mediated 80% (95% CI, 38.5 to 100%) of the association between famine exposure and TG. Analyses restricted to those exposed to famine during early gestation identified additional CpGs mediating the relationship with TG near PFKFB3 (glycolysis) and METTL8 (adipogenesis). DNAm at the CpGs involved was associated with gene expression in an external data set and correlated with DNAm levels in fat depots in additional postmortem data. Our data are consistent with the hypothesis that epigenetic mechanisms mediate the influence of transient adverse environmental factors in early life on long-term metabolic health. The specific mechanism awaits elucidation. PMID:29399631

Epigenomic profiling of DNA methylation in paired prostate cancer versus adjacent benign tissue

PubMed Central

Geybels, Milan S.; Zhao, Shanshan; Wong, Chao-Jen; Bibikova, Marina; Klotzle, Brandy; Wu, Michael; Ostrander, Elaine A.; Fan, Jian-Bing; Feng, Ziding; Stanford, Janet L.

2016-01-01

Background Aberrant DNA methylation may promote prostate carcinogenesis. We investigated epigenome-wide DNA methylation profiles in prostate cancer (PCa) compared to adjacent benign tissue to identify differentially methylated CpG sites. Methods The study included paired PCa and adjacent benign tissue samples from 20 radical prostatectomy patients. Epigenetic profiling was done using the Infinium HumanMethylation450 BeadChip. Linear models that accounted for the paired study design and False Discovery Rate Q-values were used to evaluate differential CpG methylation. mRNA expression levels of the genes with the most differentially methylated CpG sites were analyzed. Results In total, 2,040 differentially methylated CpG sites were identified in PCa versus adjacent benign tissue (Q-value <0.001), the majority of which were hypermethylated (n = 1,946; 95%). DNA methylation profiles accurately distinguished between PCa and benign tissue samples. Twenty-seven top-ranked hypermethylated CpGs had a mean methylation difference of at least 40% between tissue types, which included 25 CpGs in 17 genes. Furthermore, for ten genes over 50% of promoter region CpGs were hypermethylated in PCa versus benign tissue. The top-ranked differentially methylated genes included three genes that were associated with both promoter hypermethylation and reduced gene expression: SCGB3A1, HIF3A, and AOX1. Analysis of The Cancer Genome Atlas (TCGA) data provided confirmatory evidence for our findings. Conclusions This study of PCa versus adjacent benign tissue showed many differentially methylated CpGs and regions in and outside gene promoter regions, which may potentially be used for the development of future epigenetic-based diagnostic tests or as therapeutic targets. PMID:26383847

Epigenomic profiling of DNA methylation in paired prostate cancer versus adjacent benign tissue.

PubMed

Geybels, Milan S; Zhao, Shanshan; Wong, Chao-Jen; Bibikova, Marina; Klotzle, Brandy; Wu, Michael; Ostrander, Elaine A; Fan, Jian-Bing; Feng, Ziding; Stanford, Janet L

2015-12-01

Aberrant DNA methylation may promote prostate carcinogenesis. We investigated epigenome-wide DNA methylation profiles in prostate cancer (PCa) compared to adjacent benign tissue to identify differentially methylated CpG sites. The study included paired PCa and adjacent benign tissue samples from 20 radical prostatectomy patients. Epigenetic profiling was done using the Infinium HumanMethylation450 BeadChip. Linear models that accounted for the paired study design and False Discovery Rate Q-values were used to evaluate differential CpG methylation. mRNA expression levels of the genes with the most differentially methylated CpG sites were analyzed. In total, 2,040 differentially methylated CpG sites were identified in PCa versus adjacent benign tissue (Q-value < 0.001), the majority of which were hypermethylated (n = 1,946; 95%). DNA methylation profiles accurately distinguished between PCa and benign tissue samples. Twenty-seven top-ranked hypermethylated CpGs had a mean methylation difference of at least 40% between tissue types, which included 25 CpGs in 17 genes. Furthermore, for 10 genes over 50% of promoter region CpGs were hypermethylated in PCa versus benign tissue. The top-ranked differentially methylated genes included three genes that were associated with both promoter hypermethylation and reduced gene expression: SCGB3A1, HIF3A, and AOX1. Analysis of The Cancer Genome Atlas (TCGA) data provided confirmatory evidence for our findings. This study of PCa versus adjacent benign tissue showed many differentially methylated CpGs and regions in and outside gene promoter regions, which may potentially be used for the development of future epigenetic-based diagnostic tests or as therapeutic targets. © 2015 Wiley Periodicals, Inc.

An integrated -omics analysis of the epigenetic landscape of gene expression in human blood cells.

PubMed

Kennedy, Elizabeth M; Goehring, George N; Nichols, Michael H; Robins, Chloe; Mehta, Divya; Klengel, Torsten; Eskin, Eleazar; Smith, Alicia K; Conneely, Karen N

2018-06-19

Gene expression can be influenced by DNA methylation 1) distally, at regulatory elements such as enhancers, as well as 2) proximally, at promoters. Our current understanding of the influence of distal DNA methylation changes on gene expression patterns is incomplete. Here, we characterize genome-wide methylation and expression patterns for ~ 13 k genes to explore how DNA methylation interacts with gene expression, throughout the genome. We used a linear mixed model framework to assess the correlation of DNA methylation at ~ 400 k CpGs with gene expression changes at ~ 13 k transcripts in two independent datasets from human blood cells. Among CpGs at which methylation significantly associates with transcription (eCpGs), > 50% are distal (> 50 kb) or trans (different chromosome) to the correlated gene. Many eCpG-transcript pairs are consistent between studies and ~ 90% of neighboring eCpGs associate with the same gene, within studies. We find that enhancers (P < 5e-18) and microRNA genes (P = 9e-3) are overrepresented among trans eCpGs, and insulators and long intergenic non-coding RNAs are enriched among cis and distal eCpGs. Intragenic-eCpG-transcript correlations are negative in 60-70% of occurrences and are enriched for annotated gene promoters and enhancers (P < 0.002), highlighting the importance of intragenic regulation. Gene Ontology analysis indicates that trans eCpGs are enriched for transcription factor genes and chromatin modifiers, suggesting that some trans eCpGs represent the influence of gene networks and higher-order transcriptional control. This work sheds new light on the interplay between epigenetic changes and gene expression, and provides useful data for mining biologically-relevant results from epigenome-wide association studies.

[The German program for disease management guidelines--implementation with pathways and quality management].

PubMed

Ollenschläger, Günter; Lelgemann, Monika; Kopp, Ina

2007-07-15

In Germany, physicians enrolled in disease management programs are legally obliged to follow evidence-based clinical practice guidelines. That is why a Program for National Disease Management Guidelines (German DM-CPG Program) was established in 2002 aiming at implementation of best-practice evidence-based recommendations for nationwide as well as regional disease management programs. Against this background the article reviews programs, methods and tools for implementing DM-CPGs via clinical pathways as well as regional guidelines for outpatient care. Special reference is given to the institutionalized program of adapting DM-CPGs for regional use by primary-care physicians in the State of Hesse.

Realising the Promise of Cancer Predisposition Genes

PubMed Central

Rahman, Nazneen

2016-01-01

Genes in which germline mutations confer high or moderate increased risks of cancer are called cancer predisposition genes (CPG). Over 100 CPGs have been identified providing important scientific insights in many areas, particularly mechanisms of cancer causation. Moreover, clinical utilisation of CPGs has had substantial impact in diagnosis, optimised management and prevention of cancer. The recent transformative advances in DNA sequencing bring the promise of many more CPG discoveries and greater, broader clinical applications. However, there is also considerable potential for incorrect inferences and inappropriate clinical applications. Realising the promise of cancer predisposition genes for science and medicine will thus require careful navigation. PMID:24429628

Self-reported attitudes, skills and use of evidence-based practice among Canadian doctors of chiropractic: a national survey

PubMed Central

Bussières, André E.; Terhorst, Lauren; Leach, Matthew; Stuber, Kent; Evans, Roni; Schneider, Michael J.

2015-01-01

Objectives: To identify Canadian chiropractors’ attitudes, skills and use of evidence based practice (EBP), as well as their level of awareness of previously published chiropractic clinical practice guidelines (CPGs). Methods: 7,200 members of the Canadian Chiropractic Association were invited by e-mail to complete an online version of the Evidence Based practice Attitude & utilisation SurvEy (EBASE); a valid and reliable measure of participant attitudes, skills and use of EBP. Results: Questionnaires were completed by 554 respondents. Most respondents (>75%) held positive attitudes toward EBP. Over half indicated a high level of self-reported skills in EBP, and over 90% expressed an interest in improving these skills. A majority of respondents (65%) reported over half of their practice was based on evidence from clinical research, and only half (52%) agreed that chiropractic CPGs significantly impacted on their practice. Conclusions: While most Canadian chiropractors held positive attitudes towards EBP, believed EBP was useful, and were interested in improving their skills in EBP, many did not use research evidence or CPGs to guide clinical decision making. Our findings should be interpreted cautiously due to the low response rate. PMID:26816412

Dutch guidelines for physiotherapy in patients with stress urinary incontinence: an update.

PubMed

Bernards, Arnold T M; Berghmans, Bary C M; Slieker-Ten Hove, Marijke C Ph; Staal, J Bart; de Bie, Rob A; Hendriks, Erik J M

2014-02-01

Stress urinary incontinence (SUI) is the most common form of incontinence impacting on quality of life (QOL) and is associated with high financial, social, and emotional costs. The purpose of this study was to provide an update existing Dutch evidence-based clinical practice guidelines (CPGs) for physiotherapy management of patients with stress urinary incontinence (SUI) in order to support physiotherapists in decision making and improving efficacy and uniformity of care. A computerized literature search of relevant databases was performed to search for information regarding etiology, prognosis, and physiotherapy assessment and management in patients with SUI. Where no evidence was available, recommendations were based on consensus. Clinical application of CPGs and feasibility were reviewed. The diagnostic process consists of systematic history taking and physical examination supported by reliable and valid assessment tools to determine physiological potential for recovery. Therapy is related to different problem categories. SUI treatment is generally based on pelvic floor muscle exercises combined with patient education and counseling. An important strategy is to reduce prevalent SUI by reducing influencing risk factors. Scientific evidence supporting assessment and management of SUI is strong. The CPGs reflect the current state of knowledge of effective and tailor-made intervention in SUI patients.

Critical Points and Traveling Wave in Locomotion: Experimental Evidence and Some Theoretical Considerations.

PubMed

Saltiel, Philippe; d'Avella, Andrea; Tresch, Matthew C; Wyler, Kuno; Bizzi, Emilio

2017-01-01

The central pattern generator (CPG) architecture for rhythm generation remains partly elusive. We compare cat and frog locomotion results, where the component unrelated to pattern formation appears as a temporal grid, and traveling wave respectively. Frog spinal cord microstimulation with N-methyl-D-Aspartate (NMDA), a CPG activator, produced a limited set of force directions, sometimes tonic, but more often alternating between directions similar to the tonic forces. The tonic forces were topographically organized, and sites evoking rhythms with different force subsets were located close to the constituent tonic force regions. Thus CPGs consist of topographically organized modules. Modularity was also identified as a limited set of muscle synergies whose combinations reconstructed the EMGs. The cat CPG was investigated using proprioceptive inputs during fictive locomotion. Critical points identified both as abrupt transitions in the effect of phasic perturbations, and burst shape transitions, had biomechanical correlates in intact locomotion. During tonic proprioceptive perturbations, discrete shifts between these critical points explained the burst durations changes, and amplitude changes occurred at one of these points. Besides confirming CPG modularity, these results suggest a fixed temporal grid of anchoring points, to shift modules onsets and offsets. Frog locomotion, reconstructed with the NMDA synergies, showed a partially overlapping synergy activation sequence. Using the early synergy output evoked by NMDA at different spinal sites, revealed a rostrocaudal topographic organization, where each synergy is preferentially evoked from a few, albeit overlapping, cord regions. Comparing the locomotor synergy sequence with this topography suggests that a rostrocaudal traveling wave would activate the synergies in the proper sequence for locomotion. This output was reproduced in a two-layer model using this topography and a traveling wave. Together our results suggest two CPG components: modules, i.e., synergies; and temporal patterning, seen as a temporal grid in the cat, and a traveling wave in the frog. Animal and limb navigation have similarities. Research relating grid cells to the theta rhythm and on segmentation during navigation may relate to our temporal grid and traveling wave results. Winfree's mathematical work, combining critical phases and a traveling wave, also appears important. We conclude suggesting tracing, and imaging experiments to investigate our CPG model.

Asymmetric Operation of the Locomotor Central Pattern Generator in the Neonatal Mouse Spinal Cord

PubMed Central

Endo, Toshiaki; Kiehn, Ole

2008-01-01

The rhythmic voltage oscillations in motor neurons (MNs) during locomotor movements reflect the operation of the pre-MN central pattern generator (CPG) network. Recordings from MNs can thus be used as a method to deduct the organization of CPGs. Here, we use continuous conductance measurements and decomposition methods to quantitatively assess the weighting and phase tuning of synaptic inputs to different flexor and extensor MNs during locomotor-like activity in the isolated neonatal mice lumbar spinal cord preparation. Whole cell recordings were obtained from 22 flexor and 18 extensor MNs in rostral and caudal lumbar segments. In all flexor and the large majority of extensor MNs the extracted excitatory and inhibitory synaptic conductances alternate but with a predominance of inhibitory conductances, most pronounced in extensors. These conductance changes are consistent with a “push–pull” operation of locomotor CPG. The extracted excitatory and inhibitory synaptic conductances varied between 2 and 56% of the mean total conductance. Analysis of the phase tuning of the extracted synaptic conductances in flexor and extensor MNs in the rostral lumbar cord showed that the flexor-phase–related synaptic conductance changes have sharper locomotor-phase tuning than the extensor-phase–related conductances, suggesting a modular organization of premotor CPG networks consisting of reciprocally coupled, but differently composed, flexor and extensor CPG networks. There was a clear difference between phase tuning in rostral and caudal MNs, suggesting a distinct operation of CPG networks in different lumbar segments. The highly asymmetric features were preserved throughout all ranges of locomotor frequencies investigated and with different combinations of locomotor-inducing drugs. The asymmetric nature of CPG operation and phase tuning of the conductance profiles provide important clues to the organization of the rodent locomotor CPG and are compatible with a multilayered and distributed structure of the network. PMID:18829847

Transcultural diabetes nutrition therapy algorithm: the Asian Indian application.

PubMed

Joshi, Shashank R; Mohan, V; Joshi, S S; Mechanick, Jeffrey I; Marchetti, Albert

2012-04-01

India and other countries in Asia are experiencing rapidly escalating epidemics of type 2 diabetes (T2D) and cardiovascular disease. The dramatic rise in the prevalence of these illnesses has been attributed to rapid changes in demographic, socioeconomic, and nutritional factors. The rapid transition in dietary patterns in India-coupled with a sedentary lifestyle and specific socioeconomic pressures-has led to an increase in obesity and other diet-related noncommunicable diseases. Studies have shown that nutritional interventions significantly enhance metabolic control and weight loss. Current clinical practice guidelines (CPGs) are not portable to diverse cultures, constraining the applicability of this type of practical educational instrument. Therefore, a transcultural Diabetes Nutrition Algorithm (tDNA) was developed and then customized per regional variations in India. The resultant India-specific tDNA reflects differences in epidemiologic, physiologic, and nutritional aspects of disease, anthropometric cutoff points, and lifestyle interventions unique to this region of the world. Specific features of this transculturalization process for India include characteristics of a transitional economy with a persistently high poverty rate in a majority of people; higher percentage of body fat and lower muscle mass for a given body mass index; higher rate of sedentary lifestyle; elements of the thrifty phenotype; impact of festivals and holidays on adherence with clinic appointments; and the role of a systems or holistic approach to the problem that must involve politics, policy, and government. This Asian Indian tDNA promises to help guide physicians in the management of prediabetes and T2D in India in a more structured, systematic, and effective way compared with previous methods and currently available CPGs.

Enrichment of methylated molecules using enhanced-ice-co-amplification at lower denaturation temperature-PCR (E-ice-COLD-PCR) for the sensitive detection of disease-related hypermethylation.

PubMed

Mauger, Florence; Kernaleguen, Magali; Lallemand, Céline; Kristensen, Vessela N; Deleuze, Jean-François; Tost, Jörg

2018-05-01

The detection of specific DNA methylation patterns bears great promise as biomarker for personalized management of cancer patients. Co-amplification at lower denaturation temperature-PCR (COLD-PCR) assays are sensitive methods, but have previously only been able to analyze loss of DNA methylation. Enhanced (E)-ice-COLD-PCR reactions starting from 2 ng of bisulfite-converted DNA were developed to analyze methylation patterns in two promoters with locked nucleic acid (LNA) probes blocking amplification of unmethylated CpGs. The enrichment of methylated molecules was compared to quantitative (q)PCR and quantified using serial dilutions. E-ice-COLD-PCR allowed the multiplexed enrichment and quantification of methylated DNA. Assays were validated in primary breast cancer specimens and circulating cell-free DNA from cancer patients. E-ice-COLD-PCR could prove a useful tool in the context of DNA methylation analysis for personalized medicine.

Developmental procedures for the clinical practice guidelines for conscious sedation in dentistry for the Korean Academy of Dental Sciences.

PubMed

An, So-Youn; Seo, Kwang-Suk; Kim, Seungoh; Kim, Jongbin; Lee, Deok-Won; Hwang, Kyung-Gyun; Kim, Hyun Jeong

2016-12-01

Evidence-based clinical practice guidelines (CPGs) are defined as "statements that are scientifically reviewed about evidence and systematically developed to assist in the doctors' and patients' decision making in certain clinical situations." This recommendation aims to promote good clinical practice for the provision of safe and effective practices of conscious sedation in dentistry. The development of this clinical practice guideline was conducted by performing a systematic search of the literature for evidence-based CPGs. Existing guidelines, relevant systematic reviews, policy documents, legislation, or other recommendations were reviewed and appraised. To supplement this information, key questions were formulated by the Guideline Development Group and used as the basis for designing systematic literature search strategies to identify literature that may address these questions. Guideline documents were evaluated through a review of domestic and international databases for the development of a renewing of existing conscious sedation guidelines for dentistry. Clinical practice guidelines were critically appraised for their methodologies using Appraisal of guidelines for research and evaluation (AGREE) II. A total of 12 existing CPGs were included and 13 recommendations were made in a range of general, adult, and pediatric areas. The clinical practice guidelines for conscious sedation will be reviewed in 5 years' time for further updates to reflect significant changes in the field.

Not of one mind: mental models of clinical practice guidelines in the Veterans Health Administration.

PubMed

Hysong, Sylvia J; Best, Richard G; Pugh, Jacqueline A; Moore, Frank I

2005-06-01

The purpose of this paper is to present differences in mental models of clinical practice guidelines (CPGs) among 15 Veterans Health Administration (VHA) facilities throughout the United States. Two hundred and forty-four employees from 15 different VHA facilities across four service networks around the country were invited to participate. Participants were selected from different levels throughout each service setting from primary care personnel to facility leadership. This qualitative study used purposive sampling, a semistructured interview process for data collection, and grounded theory techniques for analysis. A semistructured interview was used to collect information on participants' mental models of CPGs, as well as implementation strategies and barriers in their facility. Analysis of these interviews using grounded theory techniques indicated that there was wide variability in employees' mental models of CPGs. Findings also indicated that high-performing facilities exhibited both (a) a clear, focused shared mental model of guidelines and (b) a tendency to use performance feedback as a learning opportunity, thus suggesting that a shared mental model is a necessary but not sufficient step toward successful guideline implementation. We conclude that a clear shared mental model of guidelines, in combination with a learning orientation toward feedback are important components for successful guideline implementation and improved quality of care.

Pharmacological guidelines for schizophrenia: a systematic review and comparison of recommendations for the first episode

PubMed Central

Keating, Dolores; McWilliams, Stephen; Schneider, Ian; Hynes, Caroline; Cousins, Gráinne; Strawbridge, Judith; Clarke, Mary

2017-01-01

Objectives Clinical practice guidelines (CPGs) support the translation of research evidence into clinical practice. Key health questions in CPGs ensure that recommendations will be applicable to the clinical context in which the guideline is used. The objectives of this study were to identify CPGs for the pharmacological treatment of first-episode schizophrenia; assess the quality of these guidelines using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument; and compare recommendations in relation to the key health questions that are relevant to the pharmacological treatment of first-episode schizophrenia. Methods A multidisciplinary group identified key health questions that are relevant to the pharmacological treatment of first-episode schizophrenia. The MEDLINE and EMBASE databases, websites of professional organisations and international guideline repositories, were searched for CPGs that met the inclusion criteria. The AGREE II instrument was applied by three raters and data were extracted from the guidelines in relation to the key health questions. Results In total, 3299 records were screened. 10 guidelines met the inclusion criteria. 3 guidelines scored well across all domains. Recommendations varied in specificity. Side effect concerns, rather than comparative efficacy benefits, were a key consideration in antipsychotic choice. Antipsychotic medication is recommended for maintenance of remission following a first episode of schizophrenia but there is a paucity of evidence to guide duration of treatment. Clozapine is universally regarded as the medication of choice for treatment resistance. There is less evidence to guide care for those who do not respond to clozapine. Conclusions An individual's experience of using antipsychotic medication for the initial treatment of first-episode schizophrenia may have implications for future engagement, adherence and outcome. While guidelines of good quality exist to assist in medicines optimisation, the evidence base required to answer key health questions relevant to the pharmacological treatment of first-episode schizophrenia is limited. PMID:28062471

DNA methylation analysis of Homeobox genes implicates HOXB7 hypomethylation as risk factor for neural tube defects

PubMed Central

Rochtus, Anne; Izzi, Benedetta; Vangeel, Elise; Louwette, Sophie; Wittevrongel, Christine; Lambrechts, Diether; Moreau, Yves; Winand, Raf; Verpoorten, Carla; Jansen, Katrien; Van Geet, Chris; Freson, Kathleen

2015-01-01

Neural tube defects (NTDs) are common birth defects of complex etiology. Though family- and population-based studies have confirmed a genetic component, the responsible genes for NTDs are still largely unknown. Based on the hypothesis that folic acid prevents NTDs by stimulating methylation reactions, epigenetic factors, such as DNA methylation, are predicted to be involved in NTDs. Homeobox (HOX) genes play a role in spinal cord development and are tightly regulated in a spatiotemporal and collinear manner, partly by epigenetic modifications. We have quantified DNA methylation for the different HOX genes by subtracting values from a genome-wide methylation analysis using leukocyte DNA from 10 myelomeningocele (MMC) patients and 6 healthy controls. From the 1575 CpGs profiled for the 4 HOX clusters, 26 CpGs were differentially methylated (P-value < 0.05; β-difference > 0.05) between MMC patients and controls. Seventy-seven percent of these CpGs were located in the HOXA and HOXB clusters, with the most profound difference for 3 CpGs within the HOXB7 gene body. A validation case-control study including 83 MMC patients and 30 unrelated healthy controls confirmed a significant association between MMC and HOXB7 hypomethylation (-14.4%; 95% CI: 11.9–16.9%; P-value < 0.0001) independent of the MTHFR 667C>T genotype. Significant HOXB7 hypomethylation was also present in 12 unaffected siblings, each related to a MMC patient, suggestive of an epigenetic change induced by the mother. The inclusion of a neural tube formation model using zebrafish showed that Hoxb7a overexpression but not depletion resulted in deformed body axes with dysmorphic neural tube formation. Our results implicate HOXB7 hypomethylation as risk factor for NTDs and highlight the importance for future genome-wide DNA methylation analyses without preselecting candidate pathways. PMID:25565354

Transforming clinical practice guidelines and clinical pathways into fast-and-frugal decision trees to improve clinical care strategies.

PubMed

Djulbegovic, Benjamin; Hozo, Iztok; Dale, William

2018-02-27

Contemporary delivery of health care is inappropriate in many ways, largely due to suboptimal Q5 decision-making. A typical approach to improve practitioners' decision-making is to develop evidence-based clinical practice guidelines (CPG) by guidelines panels, who are instructed to use their judgments to derive practice recommendations. However, mechanisms for the formulation of guideline judgments remains a "black-box" operation-a process with defined inputs and outputs but without sufficient knowledge of its internal workings. Increased explicitness and transparency in the process can be achieved by implementing CPG as clinical pathways (CPs) (also known as clinical algorithms or flow-charts). However, clinical recommendations thus derived are typically ad hoc and developed by experts in a theory-free environment. As any recommendation can be right (true positive or negative), or wrong (false positive or negative), the lack of theoretical structure precludes the quantitative assessment of the management strategies recommended by CPGs/CPs. To realize the full potential of CPGs/CPs, they need to be placed on more solid theoretical grounds. We believe this potential can be best realized by converting CPGs/CPs within the heuristic theory of decision-making, often implemented as fast-and-frugal (FFT) decision trees. This is possible because FFT heuristic strategy of decision-making can be linked to signal detection theory, evidence accumulation theory, and a threshold model of decision-making, which, in turn, allows quantitative analysis of the accuracy of clinical management strategies. Fast-and-frugal provides a simple and transparent, yet solid and robust, methodological framework connecting decision science to clinical care, a sorely needed missing link between CPGs/CPs and patient outcomes. We therefore advocate that all guidelines panels express their recommendations as CPs, which in turn should be converted into FFTs to guide clinical care. © 2018 John Wiley & Sons, Ltd.

To adopt, to adapt, or to contextualise? The big question in clinical practice guideline development.

PubMed

Dizon, Janine Margarita; Machingaidze, Shingai; Grimmer, Karen

2016-09-13

Developing new clinical practice guidelines (CPGs) can be time-consuming and expensive. A more efficient approach could be to adopt, adapt or contextualise recommendations from existing good quality CPGs so that the resultant guidance is tailored to the local context. The first steps are to search for international CPGs that have a similar purpose, end-users and patients to your situation. The second step is to critically appraise the methodological quality of the CPGs to ensure that your guidance is based on credible evidence. Then the decisions begin. Can you simply 'adopt' this (parent) clinical practice guidelines, and implement the recommendations in their entirety, without any changes, in your setting? If so, then no further work is required. However this situation is rare. What is more likely, is that even if recommendations from the parent clinical practice guidelines can be adopted, how they are implemented needs to address local issues. Thus you may need to 'contextualise' the guidance, by addressing implementation issues such as local workforce, training, health systems, equipment and/or access to services. Generally this means that additional information is required (Practice/Context Points) to support effective implementation of the clinical practice guidelines recommendations. In some cases, you may need to 'adapt' the guidance, where you will make changes to the recommendations so that care is relevant to your local environments. This may involve additional work to search for local research, or obtain local consensus, regarding how best to adapt recommendations. For example, adaptation might reflect substituting one drug for another (drugs have similar effects, but the alternative drug to the recommended one may be cheaper, more easily obtained or more culturally acceptable). There is lack of standardisation of clinical practice guidelines terminology, leading clinical practice guideline activities often being poorly conceptualised or reported. We provide an approach that would help improve efficiency and standardisation of clinical practice guidelines activities.

Evaluation of Industry Relationships Among Authors of Otolaryngology Clinical Practice Guidelines.

PubMed

Horn, Jarryd; Checketts, Jake Xavier; Jawhar, Omar; Vassar, Matt

2018-03-01

Financial relationships between physicians and industry have influence on patient care. Therefore, organizations producing clinical practice guidelines (CPGs) must have policies limiting financial conflicts during guideline development. To evaluate payments received by physician authors of otolaryngology CPGs, compare disclosure statements for accuracy, and investigate the extent to which the American Academy of Otolaryngology-Head and Neck Surgery complied with standards for guideline development from the Institute of Medicine (IOM). This cross-sectional analysis retrieved CPGs from the American Academy of Otolaryngology-Head and Neck Surgery Foundation that were published or revised from January 1, 2013, through December 31, 2015, by 49 authors. Data were retrieved from December 1 through 31, 2016. Industry payments received by authors were extracted using the Centers for Medicare & Medicaid Services Open Payments database. The values and types of these payments were then evaluated and used to determine whether self-reported disclosure statements were accurate and whether guidelines adhered to applicable IOM standards. The monetary amounts and types of payments received by physicians who author otolaryngology guidelines and the accuracy of disclosure statements. Of the 49 physicians in this sample, 39 (80%) received an industry payment. Twenty-one authors (43%) accepted more than $1000; 12 (24%), more than $10 000; 7 (14%), more than $50 000; and 2 (4%), more than $100 000. Mean (SD) financial payments amounted to $18 431 ($53 459) per physician. Total reimbursement for all authors was $995 282. Disclosure statements disagreed with the Open Payments database for 3 authors, amounting to approximately $20 000 among them. Of the 3 IOM standards assessed, only 1 was consistently enforced. Some CPG authors failed to fully disclose all financial conflicts of interest, and most guideline development panels and chairpersons had conflicts. In addition, adherence to IOM standards for guideline development was lacking. This study is relevant to CPG panels authoring recommendations, physicians implementing CPGs to guide patient care, and the organizations establishing policies for guideline development.

The updating of clinical practice guidelines: insights from an international survey

PubMed Central

2011-01-01

Background Clinical practice guidelines (CPGs) have become increasingly popular, and the methodology to develop guidelines has evolved enormously. However, little attention has been given to the updating process, in contrast to the appraisal of the available literature. We conducted an international survey to identify current practices in CPG updating and explored the need to standardize and improve the methods. Methods We developed a questionnaire (28 items) based on a review of the existing literature about guideline updating and expert comments. We carried out the survey between March and July 2009, and it was sent by email to 106 institutions: 69 members of the Guidelines International Network who declared that they developed CPGs; 30 institutions included in the U.S. National Guideline Clearinghouse database that published more than 20 CPGs; and 7 institutions selected by an expert committee. Results Forty-four institutions answered the questionnaire (42% response rate). In the final analysis, 39 completed questionnaires were included. Thirty-six institutions (92%) reported that they update their guidelines. Thirty-one institutions (86%) have a formal procedure for updating their guidelines, and 19 (53%) have a formal procedure for deciding when a guideline becomes out of date. Institutions describe the process as moderately rigorous (36%) or acknowledge that it could certainly be more rigorous (36%). Twenty-two institutions (61%) alert guideline users on their website when a guideline is older than three to five years or when there is a risk of being outdated. Twenty-five institutions (64%) support the concept of "living guidelines," which are continuously monitored and updated. Eighteen institutions (46%) have plans to design a protocol to improve their guideline-updating process, and 21 (54%) are willing to share resources with other organizations. Conclusions Our study is the first to describe the process of updating CPGs among prominent guideline institutions across the world, providing a comprehensive picture of guideline updating. There is an urgent need to develop rigorous international standards for this process and to minimize duplication of effort internationally. PMID:21914177

Epigenome-Wide Tumor DNA Methylation Profiling Identifies Novel Prognostic Biomarkers of Metastatic-Lethal Progression in Men Diagnosed with Clinically Localized Prostate Cancer.

PubMed

Zhao, Shanshan; Geybels, Milan S; Leonardson, Amy; Rubicz, Rohina; Kolb, Suzanne; Yan, Qingxiang; Klotzle, Brandy; Bibikova, Marina; Hurtado-Coll, Antonio; Troyer, Dean; Lance, Raymond; Lin, Daniel W; Wright, Jonathan L; Ostrander, Elaine A; Fan, Jian-Bing; Feng, Ziding; Stanford, Janet L

2017-01-01

Aside from Gleason sum, few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential. Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of prostate cancer patients followed prospectively for at least 5 years. Metastasis was confirmed by positive bone scan, MRI, CT, or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from nonrecurrent tumors, and which were complementary to Gleason sum. Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P < 0.05) AUC (range, 0.66-0.75) or pAUC (range, 0.007-0.009). The biomarkers that improved discrimination of patients with metastatic-lethal prostate cancer include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset, the AUC for Gleason sum alone (0.82) significantly increased with the addition of four individual CpGs (range, 0.86-0.89; all P <0.05). Eight differentially methylated CpGs that distinguish patients with metastatic-lethal from nonrecurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. Clin Cancer Res; 23(1); 311-9. ©2016 AACR. ©2016 American Association for Cancer Research.

Aberrant signature methylome by DNMT1 hot spot mutation in hereditary sensory and autonomic neuropathy 1E.

PubMed

Sun, Zhifu; Wu, Yanhong; Ordog, Tamas; Baheti, Saurabh; Nie, Jinfu; Duan, Xiaohui; Hojo, Kaori; Kocher, Jean-Pierre; Dyck, Peter J; Klein, Christopher J

2014-08-01

DNA methyltransferase 1 (DNMT1) is essential for DNA methylation, gene regulation and chromatin stability. We previously discovered DNMT1 mutations cause hereditary sensory and autonomic neuropathy type 1 with dementia and hearing loss (HSAN1E; OMIM 614116). HSAN1E is the first adult-onset neurodegenerative disorder caused by a defect in a methyltransferase gene. HSAN1E patients appear clinically normal until young adulthood, then begin developing the characteristic symptoms involving central and peripheral nervous systems. Some HSAN1E patients also develop narcolepsy and it has recently been suggested that HSAN1E is allelic to autosomal dominant cerebellar ataxia, deafness, with narcolepsy (ADCA-DN; OMIM 604121), which is also caused by mutations in DNMT1. A hotspot mutation Y495C within the targeting sequence domain of DNMT1 has been identified among HSAN1E patients. The mutant DNMT1 protein shows premature degradation and reduced DNA methyltransferase activity. Herein, we investigate genome-wide DNA methylation at single-base resolution through whole-genome bisulfite sequencing of germline DNA in 3 pairs of HSAN1E patients and their gender- and age-matched siblings. Over 1 billion 75-bp single-end reads were generated for each sample. In the 3 affected siblings, overall methylation loss was consistently found in all chromosomes with X and 18 being most affected. Paired sample analysis identified 564,218 differentially methylated CpG sites (DMCs; P<0.05), of which 300 134 were intergenic and 264 084 genic CpGs. Hypomethylation was predominant in both genic and intergenic regions, including promoters, exons, most CpG islands, L1, L2, Alu, and satellite repeats and simple repeat sequences. In some CpG islands, hypermethylated CpGs outnumbered hypomethylated CpGs. In 201 imprinted genes, there were more DMCs than in non-imprinted genes and most were hypomethylated. Differentially methylated region (DMR) analysis identified 5649 hypomethylated and 1872 hypermethylated regions. Importantly, pathway analysis revealed 1693 genes associated with the identified DMRs were highly associated in diverse neurological disorders and NAD+/NADH metabolism pathways is implicated in the pathogenesis. Our results provide novel insights into the epigenetic mechanism of neurodegeneration arising from a hotspot DNMT1 mutation and reveal pathways potentially important in a broad category of neurological and psychological disorders.

Aberrant signature methylome by DNMT1 hot spot mutation in hereditary sensory and autonomic neuropathy 1E

PubMed Central

Sun, Zhifu; Wu, Yanhong; Ordog, Tamas; Baheti, Saurabh; Nie, Jinfu; Duan, Xiaohui; Hojo, Kaori; Kocher, Jean-Pierre; Dyck, Peter J; Klein, Christopher J

2014-01-01

DNA methyltransferase 1 (DNMT1) is essential for DNA methylation, gene regulation and chromatin stability. We previously discovered DNMT1 mutations cause hereditary sensory and autonomic neuropathy type 1 with dementia and hearing loss (HSAN1E; OMIM 614116). HSAN1E is the first adult-onset neurodegenerative disorder caused by a defect in a methyltransferase gene. HSAN1E patients appear clinically normal until young adulthood, then begin developing the characteristic symptoms involving central and peripheral nervous systems. Some HSAN1E patients also develop narcolepsy and it has recently been suggested that HSAN1E is allelic to autosomal dominant cerebellar ataxia, deafness, with narcolepsy (ADCA-DN; OMIM 604121), which is also caused by mutations in DNMT1. A hotspot mutation Y495C within the targeting sequence domain of DNMT1 has been identified among HSAN1E patients. The mutant DNMT1 protein shows premature degradation and reduced DNA methyltransferase activity. Herein, we investigate genome-wide DNA methylation at single-base resolution through whole-genome bisulfite sequencing of germline DNA in 3 pairs of HSAN1E patients and their gender- and age-matched siblings. Over 1 billion 75-bp single-end reads were generated for each sample. In the 3 affected siblings, overall methylation loss was consistently found in all chromosomes with X and 18 being most affected. Paired sample analysis identified 564,218 differentially methylated CpG sites (DMCs; P < 0.05), of which 300 134 were intergenic and 264 084 genic CpGs. Hypomethylation was predominant in both genic and intergenic regions, including promoters, exons, most CpG islands, L1, L2, Alu, and satellite repeats and simple repeat sequences. In some CpG islands, hypermethylated CpGs outnumbered hypomethylated CpGs. In 201 imprinted genes, there were more DMCs than in non-imprinted genes and most were hypomethylated. Differentially methylated region (DMR) analysis identified 5649 hypomethylated and 1872 hypermethylated regions. Importantly, pathway analysis revealed 1693 genes associated with the identified DMRs were highly associated in diverse neurological disorders and NAD+/NADH metabolism pathways is implicated in the pathogenesis. Our results provide novel insights into the epigenetic mechanism of neurodegeneration arising from a hotspot DNMT1 mutation and reveal pathways potentially important in a broad category of neurological and psychological disorders. PMID:25033457

Stimulation of the basal and central amygdala in the mustached bat triggers echolocation and agonistic vocalizations within multimodal output

PubMed Central

Ma, Jie; Kanwal, Jagmeet S.

2014-01-01

The neural substrate for the perception of vocalizations is relatively well described, but how their timing and specificity are tightly coupled with accompanying physiological changes and context-appropriate behaviors remains unresolved. We hypothesized that temporally integrated vocal and emotive responses, especially the expression of fear, vigilance and aggression, originate within the amygdala. To test this hypothesis, we performed electrical microstimulation at 461 highly restricted loci within the basal and central amygdala in awake mustached bats. At a subset of these sites, high frequency stimulation with weak constant current pulses presented at near-threshold levels triggered vocalization of either echolocation pulses or social calls. At the vast majority of locations, microstimulation produced a constellation of changes in autonomic and somatomotor outputs. These changes included widespread co-activation of significant tachycardia and hyperventilation and/or rhythmic ear pinna movements (PMs). In a few locations, responses were constrained to vocalization and/or PMs despite increases in the intensity of stimulation. The probability of eliciting echolocation pulses vs. social calls decreased in a medial-posterior to anterolateral direction within the centrobasal amygdala. Microinjections of kainic acid (KA) at stimulation sites confirmed the contribution of cellular activity rather than fibers-of-passage in the control of multimodal outputs. The results suggest that localized clusters of neurons may simultaneously modulate the activity of multiple central pattern generators (CPGs) present within the brainstem. PMID:24624089

Stimulation of the basal and central amygdala in the mustached bat triggers echolocation and agonistic vocalizations within multimodal output.

PubMed

Ma, Jie; Kanwal, Jagmeet S

2014-01-01

The neural substrate for the perception of vocalizations is relatively well described, but how their timing and specificity are tightly coupled with accompanying physiological changes and context-appropriate behaviors remains unresolved. We hypothesized that temporally integrated vocal and emotive responses, especially the expression of fear, vigilance and aggression, originate within the amygdala. To test this hypothesis, we performed electrical microstimulation at 461 highly restricted loci within the basal and central amygdala in awake mustached bats. At a subset of these sites, high frequency stimulation with weak constant current pulses presented at near-threshold levels triggered vocalization of either echolocation pulses or social calls. At the vast majority of locations, microstimulation produced a constellation of changes in autonomic and somatomotor outputs. These changes included widespread co-activation of significant tachycardia and hyperventilation and/or rhythmic ear pinna movements (PMs). In a few locations, responses were constrained to vocalization and/or PMs despite increases in the intensity of stimulation. The probability of eliciting echolocation pulses vs. social calls decreased in a medial-posterior to anterolateral direction within the centrobasal amygdala. Microinjections of kainic acid (KA) at stimulation sites confirmed the contribution of cellular activity rather than fibers-of-passage in the control of multimodal outputs. The results suggest that localized clusters of neurons may simultaneously modulate the activity of multiple central pattern generators (CPGs) present within the brainstem.

Allele-Specific Methylation Occurs at Genetic Variants Associated with Complex Disease

PubMed Central

Hutchinson, John N.; Raj, Towfique; Fagerness, Jes; Stahl, Eli; Viloria, Fernando T.; Gimelbrant, Alexander; Seddon, Johanna; Daly, Mark; Chess, Andrew; Plenge, Robert

2014-01-01

We hypothesize that the phenomenon of allele-specific methylation (ASM) may underlie the phenotypic effects of multiple variants identified by Genome-Wide Association studies (GWAS). We evaluate ASM in a human population and document its genome-wide patterns in an initial screen at up to 380,678 sites within the genome, or up to 5% of the total genomic CpGs. We show that while substantial inter-individual variation exists, 5% of assessed sites show evidence of ASM in at least six samples; the majority of these events (81%) are under genetic influence. Many of these cis-regulated ASM variants are also eQTLs in peripheral blood mononuclear cells and monocytes and/or in high linkage-disequilibrium with variants linked to complex disease. Finally, focusing on autoimmune phenotypes, we extend this initial screen to confirm the association of cis-regulated ASM with multiple complex disease-associated variants in an independent population using next-generation bisulfite sequencing. These four variants are implicated in complex phenotypes such as ulcerative colitis and AIDS progression disease (rs10491434), Celiac disease (rs2762051), Crohn's disease, IgA nephropathy and early-onset inflammatory bowel disease (rs713875) and height (rs6569648). Our results suggest cis-regulated ASM may provide a mechanistic link between the non-coding genetic changes and phenotypic variation observed in these diseases and further suggests a route to integrating DNA methylation status with GWAS results. PMID:24911414

Vitamin D receptor gene methylation is associated with ethnicity, tuberculosis and TaqI polymorphism

PubMed Central

Andraos, Charlene; Koorsen, Gerrit; Knight, Julian C; Bornman, Liza

2014-01-01

The Vitamin D Receptor (VDR) gene encodes a transcription factor which, on activation by vitamin D, modulates diverse biological processes including calcium homeostasis and immune function. Genetic variation involving VDR shows striking differences in allele frequency between populations and has been associated with disease susceptibility including tuberculosis and autoimmunity, although results have often been conflicting. We hypothesized that methylation of VDR may be population specific and that the combination of differential methylation and genetic variation may characterise TB predisposition. We use bisulphite conversion and/or pyrosequencing to analyse the methylation status of 17 CpGs of VDR and to genotype 7 SNPs in the 3′ CpG Island (CGI 1060), including the commonly studied SNPs ApaI (rs7975232) and TaqI (rs731236). We show that for lymphoblastoid cell lines from two ethnically diverse populations (Yoruba from HapMap, n=30 and Caucasians, n=30) together with TB cases (n=32) and controls (n=29) from the Venda population of South Africa there are methylation variable positions (MVPs) in the 3′ end that significantly distinguish ethnicity (9/17 CpGs) and TB status (3/17 CpGs). Moreover methylation status shows complex association with TaqI genotype highlighting the need to consider both genetic and epigenetic variants in genetic studies of VDR association with disease. PMID:21168462

Format guidelines to make them vivid, intuitive, and visual: use simple formatting rules to optimize usability and accessibility of clinical practice guidelines.

PubMed

Versloot, Judith; Grudniewicz, Agnes; Chatterjee, Ananda; Hayden, Leigh; Kastner, Monika; Bhattacharyya, Onil

2015-06-01

We present simple formatting rules derived from an extensive literature review that can improve the format of clinical practice guidelines (CPGs), and potentially increase the likelihood of being used. We recently conducted a review of the literature from medicine, psychology, design, and human factors engineering on characteristics of guidelines that are associated with their use in practice, covering both the creation and communication of content. The formatting rules described in this article are derived from that review. The formatting rules are grouped into three categories that can be easily applied to CPGs: first, Vivid: make it stand out; second, Intuitive: match it to the audience's expectations, and third, Visual: use alternatives to text. We highlight rules supported by our broad literature review and provide specific 'how to' recommendations for individuals and groups developing evidence-based materials for clinicians. The way text documents are formatted influences their accessibility and usability. Optimizing the formatting of CPGs is a relatively inexpensive intervention and can be used to facilitate the dissemination of evidence in healthcare. Applying simple formatting principles to make documents more vivid, intuitive, and visual is a practical approach that has the potential to influence the usability of guidelines and to influence the extent to which guidelines are read, remembered, and used in practice.

Systematic review of clinical practice guidelines to identify recommendations for rehabilitation after stroke and other acquired brain injuries

PubMed Central

Lannin, Natasha A; Hoffmann, Tammy

2018-01-01

Objectives Rehabilitation clinical practice guidelines (CPGs) contain recommendation statements aimed at optimising care for adults with stroke and other brain injury. The aim of this study was to determine the quality, scope and consistency of CPG recommendations for rehabilitation covering the acquired brain injury populations. Design Systematic review. Interventions Included CPGs contained recommendations for inpatient rehabilitation or community rehabilitation for adults with an acquired brain injury diagnosis (stroke, traumatic or other non-progressive acquired brain impairments). Electronic databases (n=2), guideline organisations (n=4) and websites of professional societies (n=17) were searched up to November 2017. Two independent reviewers used the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, and textual syntheses were used to appraise and compare recommendations. Results From 427 papers screened, 20 guidelines met the inclusion criteria. Only three guidelines were rated high (>75%) across all domains of AGREE-II; highest rated domains were ‘scope and purpose’ (85.1, SD 18.3) and ‘clarity’ (76.2%, SD 20.5). Recommendations for assessment and for motor therapies were most commonly reported, however, varied in the level of detail across guidelines. Conclusion Rehabilitation CPGs were consistent in scope, suggesting little difference in rehabilitation approaches between vascular and traumatic brain injury. There was, however, variability in included studies and methodological quality. PROSPERO registration number CRD42016026936. PMID:29490958

Mediation analysis of alcohol consumption, DNA methylation, and epithelial ovarian cancer.

PubMed

Wu, Dongyan; Yang, Haitao; Winham, Stacey J; Natanzon, Yanina; Koestler, Devin C; Luo, Tiane; Fridley, Brooke L; Goode, Ellen L; Zhang, Yanbo; Cui, Yuehua

2018-03-01

Epigenetic factors and consumption of alcohol, which suppresses DNA methylation, may influence the development and progression of epithelial ovarian cancer (EOC). However, there is a lack of understanding whether these factors interact to affect the EOC risk. In this study, we aimed to gain insight into this relationship by identifying leukocyte-derived DNA methylation markers acting as potential mediators of alcohol-associated EOC. We implemented a causal inference test (CIT) and the VanderWeele and Vansteelandt multiple mediator model to examine CpG sites that mediate the association between alcohol consumption and EOC risk. We modified one step of the CIT by adopting a high-dimensional inference procedure. The data were based on 196 cases and 202 age-matched controls from the Mayo Clinic Ovarian Cancer Case-Control Study. Implementation of the CIT test revealed two CpG sites (cg09358725, cg11016563), which represent potential mediators of the relationship between alcohol consumption and EOC case-control status. Implementation of the VanderWeele and Vansteelandt multiple mediator model further revealed that these two CpGs were the key mediators. Decreased methylation at both CpGs was more common in cases who drank alcohol at the time of enrollment vs. those who did not. cg11016563 resides in TRPC6 which has been previously shown to be overexpressed in EOC. These findings suggest two CpGs may serve as novel biomarkers for EOC susceptibility.

Conflict of Interest Policies for Organizations Producing a Large Number of Clinical Practice Guidelines

PubMed Central

Norris, Susan L.; Holmer, Haley K.; Burda, Brittany U.; Ogden, Lauren A.; Fu, Rongwei

2012-01-01

Background Conflict of interest (COI) of clinical practice guideline (CPG) sponsors and authors is an important potential source of bias in CPG development. The objectives of this study were to describe the COI policies for organizations currently producing a significant number of CPGs, and to determine if these policies meet 2011 Institute of Medicine (IOM) standards. Methodology/Principal Findings We identified organizations with five or more guidelines listed in the National Guideline Clearinghouse between January 1, 2009 and November 5, 2010. We obtained the COI policy for each organization from publicly accessible sources, most often the organization's website, and compared those polices to IOM standards related to COI. 37 organizations fulfilled our inclusion criteria, of which 17 (46%) had a COI policy directly related to CPGs. These COI policies varied widely with respect to types of COI addressed, from whom disclosures were collected, monetary thresholds for disclosure, approaches to management, and updating requirements. Not one organization's policy adhered to all seven of the IOM standards that were examined, and nine organizations did not meet a single one of the standards. Conclusions/Significance COI policies among organizations producing a large number of CPGs currently do not measure up to IOM standards related to COI disclosure and management. CPG developers need to make significant improvements in these policies and their implementation in order to optimize the quality and credibility of their guidelines. PMID:22629391

Not of One Mind: Mental Models of Clinical Practice Guidelines in the Veterans Health Administration

PubMed Central

Hysong, Sylvia J; Best, Richard G; Pugh, Jacqueline A; Moore, Frank I

2005-01-01

Objective The purpose of this paper is to present differences in mental models of clinical practice guidelines (CPGs) among 15 Veterans Health Administration (VHA) facilities throughout the United States. Data Sources Two hundred and forty-four employees from 15 different VHA facilities across four service networks around the country were invited to participate. Participants were selected from different levels throughout each service setting from primary care personnel to facility leadership. Study Design This qualitative study used purposive sampling, a semistructured interview process for data collection, and grounded theory techniques for analysis. Data Collection A semistructured interview was used to collect information on participants' mental models of CPGs, as well as implementation strategies and barriers in their facility. Findings Analysis of these interviews using grounded theory techniques indicated that there was wide variability in employees' mental models of CPGs. Findings also indicated that high-performing facilities exhibited both (a) a clear, focused shared mental model of guidelines and (b) a tendency to use performance feedback as a learning opportunity, thus suggesting that a shared mental model is a necessary but not sufficient step toward successful guideline implementation. Conclusions We conclude that a clear shared mental model of guidelines, in combination with a learning orientation toward feedback are important components for successful guideline implementation and improved quality of care. PMID:15960693

From movement to pain: a tribute to professor James P. Lund.

PubMed

Westberg, Karl-Gunnar; McFarland, David; Kolta, Arlette; Stohler, Christian; Feine, Jocelyne; Woda, Alain

2008-01-01

This tribute article to Professor James P. Lund stems from 6 of the presentations delivered at the July 1, 2008, symposium that honored 3 "giants" in orofacial neuroscience: B. J. Sessle, A. G. Hannam, and J. P. Lund. It was noted that soon after his training as a dentist in Australia, Jim Lund became interested in research. At the time he decided to do a PhD, there was a lot of discussion about how rhythmic movements were programmed. The early belief, based on Sherrington's studies of motor systems, was that these movements were simply an alternating series of reflexes. In the late 1960s and early 1970s, some still shared this belief, whereas others favored Graham Brown's hypothesis that repetitive movements were centrally programmed and did not depend on reflexes triggered by sensory inputs. There was no strong evidence then for either scenario except for the rhythmic movements of respiration. Lund's pioneering work during his PhD proved the existence of a central pattern generator (CPG) for mastication in the brainstem. Since then he has been interested in understanding how CPGs function and how sensory feedback works to adjust the motor patterns that they produce. Sections in this tribute article to Lund are written by some of his close collaborators and reflect the evolution of his work throughout the years. The first 4 presentations in this article (by K.-G. Westberg, D. McFarland, A. Kolta, and C. Stohler) highlight various aspects of these interests, and the final 2 presentations (by J. Feine and A. Woda) focus especially on clinical aspects of Lund's interests. The last section of this article is a final commentary from Professor Lund.

Statistical method evaluation for differentially methylated CpGs in base resolution next-generation DNA sequencing data.

PubMed

Zhang, Yun; Baheti, Saurabh; Sun, Zhifu

2018-05-01

High-throughput bisulfite methylation sequencing such as reduced representation bisulfite sequencing (RRBS), Agilent SureSelect Human Methyl-Seq (Methyl-seq) or whole-genome bisulfite sequencing is commonly used for base resolution methylome research. These data are represented either by the ratio of methylated cytosine versus total coverage at a CpG site or numbers of methylated and unmethylated cytosines. Multiple statistical methods can be used to detect differentially methylated CpGs (DMCs) between conditions, and these methods are often the base for the next step of differentially methylated region identification. The ratio data have a flexibility of fitting to many linear models, but the raw count data take consideration of coverage information. There is an array of options in each datatype for DMC detection; however, it is not clear which is an optimal statistical method. In this study, we systematically evaluated four statistic methods on methylation ratio data and four methods on count-based data and compared their performances with regard to type I error control, sensitivity and specificity of DMC detection and computational resource demands using real RRBS data along with simulation. Our results show that the ratio-based tests are generally more conservative (less sensitive) than the count-based tests. However, some count-based methods have high false-positive rates and should be avoided. The beta-binomial model gives a good balance between sensitivity and specificity and is preferred method. Selection of methods in different settings, signal versus noise and sample size estimation are also discussed.

Tobacco exposure-related alterations in DNA methylation and gene expression in human monocytes: the Multi-Ethnic Study of Atherosclerosis (MESA)

PubMed Central

Reynolds, Lindsay M.; Lohman, Kurt; Pittman, Gary S.; Barr, R. Graham; Chi, Gloria C.; Kaufman, Joel; Wan, Ma; Bell, Douglas A.; Blaha, Michael J.; Rodriguez, Carlos J.; Liu, Yongmei

2017-01-01

ABSTRACT Alterations in DNA methylation and gene expression in blood leukocytes are potential biomarkers of harm and mediators of the deleterious effects of tobacco exposure. However, methodological issues, including the use of self-reported smoking status and mixed cell types have made previously identified alterations in DNA methylation and gene expression difficult to interpret. In this study, we examined associations of tobacco exposure with DNA methylation and gene expression, utilizing a biomarker of tobacco exposure (urine cotinine) and CD14+ purified monocyte samples from 934 participants of the community-based Multi-Ethnic Study of Atherosclerosis (MESA). Urine cotinine levels were measured using an immunoassay. DNA methylation and gene expression were measured with microarrays. Multivariate linear regression was used to test for associations adjusting for age, sex, race/ethnicity, education, and study site. Urine cotinine levels were associated with methylation of 176 CpGs [false discovery rate (FDR)<0.01]. Four CpGs not previously identified by studies of non-purified blood samples nominally replicated (P value<0.05) with plasma cotinine-associated methylation in 128 independent monocyte samples. Urine cotinine levels associated with expression of 12 genes (FDR<0.01), including increased expression of P2RY6 (Beta ± standard error = 0.078 ± 0.008, P = 1.99 × 10−22), a gene previously identified to be involved in the release of pro-inflammatory cytokines. No cotinine-associated (FDR<0.01) methylation profiles significantly (FDR<0.01) correlated with cotinine-associated (FDR<0.01) gene expression profiles. In conclusion, our findings i) identify potential monocyte-specific smoking-associated methylation patterns and ii) suggest that alterations in methylation may not be a main mechanism regulating gene expression in monocytes in response to cigarette smoking. PMID:29166816

An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray.

PubMed

Salas, Lucas A; Koestler, Devin C; Butler, Rondi A; Hansen, Helen M; Wiencke, John K; Kelsey, Karl T; Christensen, Brock C

2018-05-29

Genome-wide methylation arrays are powerful tools for assessing cell composition of complex mixtures. We compare three approaches to select reference libraries for deconvoluting neutrophil, monocyte, B-lymphocyte, natural killer, and CD4+ and CD8+ T-cell fractions based on blood-derived DNA methylation signatures assayed using the Illumina HumanMethylationEPIC array. The IDOL algorithm identifies a library of 450 CpGs, resulting in an average R 2  = 99.2 across cell types when applied to EPIC methylation data collected on artificial mixtures constructed from the above cell types. Of the 450 CpGs, 69% are unique to EPIC. This library has the potential to reduce unintended technical differences across array platforms.

Primary care clinical practice guidelines in South Africa: qualitative study exploring perspectives of national stakeholders.

PubMed

Kredo, Tamara; Abrams, Amber; Young, Taryn; Louw, Quinette; Volmink, Jimmy; Daniels, Karen

2017-08-29

Clinical practice guidelines (CPGs) are common tools in policy and clinical practice informing clinical decisions at the bedside, governance of health facilities, health insurer and government spending, and patient choices. South Africa's health sector is transitioning to a national health insurance system, aiming to build on other primary health care initiatives to transform the previously segregated, inequitable services. Within these plans CPGs are an integral tool for delivering standardised and cost effective care. Currently, there is no accepted standard approach to developing, adapting or implementing CPGs efficiently or effectively in South Africa. We explored the current players; drivers; and the context and processes of primary care CPG development from the perspective of stakeholders operating at national level. We used a qualitative approach. Sampling was initially purposeful, followed by snowballing and further sampling to reach representivity of primary care service providers. Individual in-depth interviews were recorded and transcribed verbatim. We used thematic content analysis to analyse the data. We conducted 37 in-depth interviews from June 2014-July 2015. We found CPG development and implementation were hampered by lack of human and funding resources for technical and methodological work; fragmentation between groups, and between national and provincial health sectors; and lack of agreed systems for CPG development and implementation. Some CPG contributors steadfastly work to improve processes aiming to enhance communication, use of evidence, and transparency to ensure credible guidance is produced. Many interviewed had shared values, and were driven to address inequity, however, resource gaps were perceived to create an enabling environment for commercial interests or personal agendas to drive the CPG development process. Our findings identified strengths and gaps in CPG development processes, and a need for national standards to guide CPG development and implementation. Based on our findings and suggestions from participants, a possible way forward would be for South Africa to have a centrally coordinated CPG unit to address these needs and aspects of fragmentation by devising processes that support collaboration, transparency and credibility across sectors and disciplines. Such an initiative will require adequate resourcing to build capacity and ensure support for the delivery of high quality CPGs for South African primary care.

An innovative peer assessment approach to enhance guideline adherence in physical therapy: single-masked, cluster-randomized controlled trial.

PubMed

Maas, Marjo J M; van der Wees, Philip J; Braam, Carla; Koetsenruijter, Jan; Heerkens, Yvonne F; van der Vleuten, Cees P M; Nijhuis-van der Sanden, Maria W G

2015-04-01

Clinical practice guidelines (CPGs) are not readily implemented in clinical practice. One of the impeding factors is that physical therapists do not hold realistic perceptions of their adherence to CPGs. Peer assessment (PA) is an implementation strategy that aims at improving guideline adherence by enhancing reflective practice, awareness of professional performance, and attainment of personal goals. The purpose of this study was to compare the effectiveness of PA with the usual case discussion (CD) strategy on adherence to CPGs for physical therapist management of upper extremity complaints. A single-masked, cluster-randomized controlled trial with pretest-posttest design was conducted. Twenty communities of practice (n=149 physical therapists) were randomly assigned to groups receiving PA or CD, with both interventions consisting of 4 sessions over 6 months. Both PA and CD groups worked on identical clinical cases relevant to the guidelines. Peer assessment focused on individual performance observed and evaluated by peers; CD focused on discussion. Guideline adherence was measured with clinical vignettes, reflective practice was measured with the Self-Reflection and Insight Scale (SRIS), awareness of performance was measured via the correlation between perceived and assessed improvement, and attainment of personal goals was measured with written commitments to change. The PA groups improved more on guideline adherence compared with the CD groups (effect=22.52; 95% confidence interval [95% CI]=2.38, 42.66; P=.03). The SRIS scores did not differ between PA and CD groups. Awareness of performance was greater for the PA groups (r=.36) than for the CD groups (r=.08) (effect=14.73; 95% CI=2.78, 26.68; P=.01). The PA strategy was more effective than the CD strategy in attaining personal goals (effect=0.50; 95% CI=0.04, 0.96; P=.03). Limited validity of clinical vignettes as a proxy measure of clinical practice was a limitation of the study. Peer assessment was more effective than CD in improving adherence to CPGs. Personal feedback may have contributed to its effectiveness. Future research should address the role of the group coach. © 2015 American Physical Therapy Association.

Factors influencing performance of health workers in the management of seriously sick children at a Kenyan tertiary hospital--participatory action research.

PubMed

Irimu, Grace W; Greene, Alexandra; Gathara, David; Kihara, Harrison; Maina, Christopher; Mbori-Ngacha, Dorothy; Zurovac, Dejan; Migiro, Santau; English, Mike

2014-02-07

Implementation of World Health Organization case management guidelines for serious childhood illnesses remains a challenge in hospitals in low-income countries. Facilitators of and barriers to implementation of locally adapted clinical practice guidelines (CPGs) have not been explored. This ethnographic study based on the theory of participatory action research (PAR) was conducted in Kenyatta National Hospital, Kenya's largest teaching hospital. The primary intervention consisted of dissemination of locally adapted CPGs. The PRECEDE-PROCEED health education model was used as the conceptual framework to guide and examine further reinforcement activities to improve the uptake of the CPGs. Activities focussed on introduction of routine clinical audits and tailored educational sessions. Data were collected by a participant observer who also facilitated the PAR over an eighteen-month period. Naturalistic inquiry was utilized to obtain information from all hospital staff encountered while theoretical sampling allowed in-depth exploration of emerging issues. Data were analysed using interpretive description. Relevance of the CPGs to routine work and emergence of a champion of change facilitated uptake of best-practices. Mobilization of basic resources was relatively easily undertaken while activities that required real intellectual and professional engagement of the senior staff were a challenge. Accomplishments of the PAR were largely with the passive rather than active involvement of the hospital management. Barriers to implementation of best-practices included i) mismatch between the hospital's vision and reality, ii) poor communication, iii) lack of objective mechanisms for monitoring and evaluating quality of clinical care, iv) limited capacity for planning strategic change, v) limited management skills to introduce and manage change, vi) hierarchical relationships, and vii) inadequate adaptation of the interventions to the local context. Educational interventions, often regarded as 'quick-fixes' to improve care in low-income countries, may be necessary but are unlikely to be sufficient to deliver improved services. We propose that an understanding of organizational issues that influence the behaviour of individual health professionals should guide and inform the implementation of best-practices.

TSA-induced DNMT1 down-regulation represses hTERT expression via recruiting CTCF into demethylated core promoter region of hTERT in HCT116.

PubMed

Choi, Jee-Hye; Min, Na Young; Park, Jina; Kim, Jin Hong; Park, Soo Hyun; Ko, Young Jong; Kang, Yoonsung; Moon, Young Joon; Rhee, Sangmyung; Ham, Seung Wook; Park, Ae Ja; Lee, Kwang-Ho

2010-01-01

Trichostatin A (TSA), an inhibitor of histone deacetylase, is a well-known antitumor agent that effectively and selectively induces tumor growth arrest and apoptosis. Recently, it was reported that hTERT is one of the primary targets for TSA-induced apoptosis in cancer cells but the mechanism of which has not yet been elucidated. In the present study, to better understand the epigenetic regulation mechanism responsible for the repression of hTERT by TSA, we examined expression of hTERT in the HCT116 colon cancer cell line after treatment with TSA and performed site-specific CpG methylation analysis of the hTERT promoter. We found that TSA-induced the demethylation of site-specific CpGs on the promoter of hTERT, which was caused by down-regulation of DNA methyltransferase 1 (DNMT1). Among the demethylated region, the 31st-33rd CpGs contained a binding site for CTCF, an inhibitor of hTERT transcription. ChIP analysis revealed that TSA-induced demethylation of the 31st-33rd CpGs promoted CTCF binding on hTERT promoter, leading to repression of hTERT. Taken together, down-regulation of DNMT1 by TSA caused demethylation of a CTCF binding site on the hTERT promoter, the result of which was repression of hTERT via recruitment of CTCF to the promoter. Copyright 2009 Elsevier Inc. All rights reserved.

Evidence-informed health policy 2 - survey of organizations that support the use of research evidence.

PubMed

Lavis, John N; Paulsen, Elizabeth J; Oxman, Andrew D; Moynihan, Ray

2008-12-17

Previous surveys of organizations that support the development of evidence-informed health policies have focused on organizations that produce clinical practice guidelines (CPGs) or undertake health technology assessments (HTAs). Only rarely have surveys focused at least in part on units that directly support the use of research evidence in developing health policy on an international, national, and state or provincial level (i.e., government support units, or GSUs) that are in some way successful or innovative or that support the use of research evidence in low- and middle-income countries (LMICs). We drew on many people and organizations around the world, including our project reference group, to generate a list of organizations to survey. We modified a questionnaire that had been developed originally by the Appraisal of Guidelines, Research and Evaluation in Europe (AGREE) collaboration and adapted one version of the questionnaire for organizations producing CPGs and HTAs, and another for GSUs. We sent the questionnaire by email to 176 organizations and followed up periodically with non-responders by email and telephone. We received completed questionnaires from 152 (86%) organizations. More than one-half of the organizations (and particularly HTA agencies) reported that examples from other countries were helpful in establishing their organization. A higher proportion of GSUs than CPG- or HTA-producing organizations involved target users in the selection of topics or the services undertaken. Most organizations have few (five or fewer) full-time equivalent (FTE) staff. More than four-fifths of organizations reported providing panels with or using systematic reviews. GSUs tended to use a wide variety of explicit valuation processes for the research evidence, but none with the frequency that organizations producing CPGs, HTAs, or both prioritized evidence by its quality. Between one-half and two-thirds of organizations do not collect data systematically about uptake, and roughly the same proportions do not systematically evaluate their usefulness or impact in other ways. The findings from our survey, the most broadly based of its kind, both extend or clarify the applicability of the messages arising from previous surveys and related documentary analyses, such as how the 'principles of evidence-based medicine dominate current guideline programs' and the importance of collaborating with other organizations. The survey also provides a description of the history, structure, processes, outputs, and perceived strengths and weaknesses of existing organizations from which those establishing or leading similar organizations can draw.

Conventional Prompt Global Strike and Long-Range Ballistic Missiles: Background and Issues

DTIC Science & Technology

2012-02-13

Ballistic Missiles Congressional Research Service Forward-Based Global Strike ( FBGS ...missiles in the CPGS program. Forward-Based Global Strike ( FBGS ) Analysts have also explored the option of deploying long-range land-based ballistic

Methylation changes and pathways affected in preterm birth: a role for SLC6A3 in neurodevelopment.

PubMed

Arpón, Ana; Milagro, Fermín I; Laja, Ana; Segura, Víctor; de Pipaón, Miguel Sáenz; Riezu-Boj, José-Ignacio; Alfredo Martínez, J

2018-01-01

To analyze whether preterm newborns show differences in methylation patterns in comparison to full-term newborns in white blood cells. Anthropometrical, biochemical features and methylation levels of preterm newborns (n = 24) and full-term newborns (n = 22) recruited in La Paz University Hospital (Spain) were assessed at 12 months of gestational age, whereas Bayley Scale of Infant Development was evaluated at 24/36 months. From all the statistically significant CpGs, methylation levels of cg00997378 (SLC6A3 gene) showed the highest differences (p < 0.0001), being associated with prematurity risk factors.  SLC6A3 methylation, previously related to attention-deficit/hyperactivity disorder, neuronal function and behavior, might be a potential epigenetic biomarker with value in the early diagnosis and management of neurodevelopmental diseases in newborns.

Maternal alcohol consumption and offspring DNA methylation: findings from six general population-based birth cohorts

PubMed Central

Sharp, Gemma C; Arathimos, Ryan; Reese, Sarah E; Page, Christian M; Felix, Janine; Küpers, Leanne K; Rifas-Shiman, Sheryl L; Liu, Chunyu; Burrows, Kimberley; Zhao, Shanshan; Magnus, Maria C; Duijts, Liesbeth; Corpeleijn, Eva; DeMeo, Dawn L; Litonjua, Augusto; Baccarelli, Andrea; Hivert, Marie-France; Oken, Emily; Snieder, Harold; Jaddoe, Vincent; Nystad, Wenche; London, Stephanie J; Relton, Caroline L; Zuccolo, Luisa

2018-01-01

Aim: Alcohol consumption during pregnancy is sometimes associated with adverse outcomes in offspring, potentially mediated by epigenetic modifications. We aimed to investigate genome-wide DNA methylation in cord blood of newborns exposed to alcohol in utero. Materials & methods: We meta-analyzed information from six population-based birth cohorts within the Pregnancy and Childhood Epigenetics consortium. Results: We found no strong evidence of association at either individual CpGs or across larger regions of the genome. Conclusion: Our findings suggest no association between maternal alcohol consumption and offspring cord blood DNA methylation. This is in stark contrast to the multiple strong associations previous studies have found for maternal smoking, which is similarly socially patterned. However, it is possible that a combination of a larger sample size, higher doses, different timings of exposure, exploration of a different tissue and a more global assessment of genomic DNA methylation might show evidence of association. PMID:29172695

Use of declarative statements in creating and maintaining computer-interpretable knowledge bases for guideline-based care.

PubMed

Tu, Samson W; Hrabak, Karen M; Campbell, James R; Glasgow, Julie; Nyman, Mark A; McClure, Robert; McClay, James; Abarbanel, Robert; Mansfield, James G; Martins, Susana M; Goldstein, Mary K; Musen, Mark A

2006-01-01

Developing computer-interpretable clinical practice guidelines (CPGs) to provide decision support for guideline-based care is an extremely labor-intensive task. In the EON/ATHENA and SAGE projects, we formulated substantial portions of CPGs as computable statements that express declarative relationships between patient conditions and possible interventions. We developed query and expression languages that allow a decision-support system (DSS) to evaluate these statements in specific patient situations. A DSS can use these guideline statements in multiple ways, including: (1) as inputs for determining preferred alternatives in decision-making, and (2) as a way to provide targeted commentaries in the clinical information system. The use of these declarative statements significantly reduces the modeling expertise and effort required to create and maintain computer-interpretable knowledge bases for decision-support purpose. We discuss possible implications for sharing of such knowledge bases.

Employment of hypersonic glide vehicles: Proposed criteria for use

DOE Office of Scientific and Technical Information (OSTI.GOV)

Olguin, Abel

Hypersonic Glide Vehicles (HGVs) are a type of reentry vehicle that couples the high speed of ballistic missiles with the maneuverability of aircraft. The HGV has been in development since the 1970s, and its technology falls under the category of Conventional Prompt Global Strike (CPGS) weapons. As noted by James M. Acton, a senior associate in the Nuclear Policy Program at the Carnegie Endowment, CPGS is a “missile in search of a mission.” With the introduction of any significant new military capability, a doctrine for use—including specifics regarding how, when and where it would be used, as well as tactics,more » training and procedures—must be clearly defined and understood by policy makers, military commanders, and planners. In this paper, benefits and limitations of the HGV are presented. Proposed criteria and four scenarios illustrate a possible method for assessing when to use an HGV.« less

Development of clinical practice guidelines for patients with comorbidity and multiple diseases.

PubMed

Bernabeu-Wittel, M; Alonso-Coello, P; Rico-Blázquez, M; Rotaeche Del Campo, R; Sánchez Gómez, S; Casariego Vales, E

2014-01-01

The management of patients with comorbidity and polypathology represents a challenge for all healthcare systems. Clinical practice guidelines (CPGs) have limitations when applied to this population. The aim of this study is to propose the terminology and methodology for optimally approach comorbidity and polypathology in the CPGs. Based on a literature review, we suggest a number of proposals for the approach in different phases of CPG preparation, with special attention to the inclusion of clusters of comorbidity in the initial questions the implementation of indirect evidence, the burden of disease management for patients and their environment, when establishing recommendations, as well as the strategies of dissemination and implementation. These proposals should be developed in greater depth with the implication of more agents in order to have valid and useful tools for this population. Copyright © 2014 Elsevier España, S.L. All rights reserved.

[Development of clinical practice guidelines for patients with comorbidity and multiple diseases].

PubMed

Bernabeu-Wittel, M; Alonso-Coello, P; Rico-Blázquez, M; Rotaeche del Campo, R; Sánchez Gómez, S; Casariego Vales, E

2014-01-01

The management of patients with comorbidity and polypathology represents a challenge for all healthcare systems. Clinical practice guidelines (CPGs) have limitations when applied to this population. The aim of this study is to propose the terminology and methodology for optimally approach comorbidity and polypathology in the CPGs. Based on a literature review, we suggest a number of proposals for the approach in different phases of CPG preparation, with special attention to the inclusion of clusters of comorbidity in the initial questions the implementation of indirect evidence, the burden of disease management for patients and their environment, when establishing recommendations, as well as the strategies of dissemination and implementation. These proposals should be developed in greater depth with the implication of more agents in order to have valid and useful tools for this population. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

Modeling uncertainty in computerized guidelines using fuzzy logic.

PubMed Central

Jaulent, M. C.; Joyaux, C.; Colombet, I.; Gillois, P.; Degoulet, P.; Chatellier, G.

2001-01-01

Computerized Clinical Practice Guidelines (CPGs) improve quality of care by assisting physicians in their decision making. A number of problems emerges since patients with close characteristics are given contradictory recommendations. In this article, we propose to use fuzzy logic to model uncertainty due to the use of thresholds in CPGs. A fuzzy classification procedure has been developed that provides for each message of the CPG, a strength of recommendation that rates the appropriateness of the recommendation for the patient under consideration. This work is done in the context of a CPG for the diagnosis and the management of hypertension, published in 1997 by the French agency ANAES. A population of 82 patients with mild to moderate hypertension was selected and the results of the classification system were compared to whose given by a classical decision tree. Observed agreement is 86.6% and the variability of recommendations for patients with close characteristics is reduced. PMID:11825196

An XML-based system for the flexible classification and retrieval of clinical practice guidelines.

PubMed Central

Ganslandt, T.; Mueller, M. L.; Krieglstein, C. F.; Senninger, N.; Prokosch, H. U.

2002-01-01

Beneficial effects of clinical practice guidelines (CPGs) have not yet reached expectations due to limited routine adoption. Electronic distribution and reminder systems have the potential to overcome implementation barriers. Existing electronic CPG repositories like the National Guideline Clearinghouse (NGC) provide individual access but lack standardized computer-readable interfaces necessary for automated guideline retrieval. The aim of this paper was to facilitate automated context-based selection and presentation of CPGs. Using attributes from the NGC classification scheme, an XML-based metadata repository was successfully implemented, providing document storage, classification and retrieval functionality. Semi-automated extraction of attributes was implemented for the import of XML guideline documents using XPath. A hospital information system interface was exemplarily implemented for diagnosis-based guideline invocation. Limitations of the implemented system are discussed and possible future work is outlined. Integration of standardized computer-readable search interfaces into existing CPG repositories is proposed. PMID:12463831

Venous thromboprophylaxis in general surgery ward admissions: strategies for improvement.

PubMed

Galante, Mariana; Languasco, Agustín; Gotta, Daniel; Bell, Soledad; Lancelotti, Tomás; Knaze, Viktoria; Saubidet, Cristián Lopez; Grand, Beatriz; Milberg, Matías

2012-12-01

To estimate the adherence to institutional venous thromboprophylaxis clinical practice guidelines (CPGs) in general surgery patients and to assess the effectiveness of a multi-strategy improvement intervention. A prospective before-after study. Two teaching hospitals located in the city of Buenos Aires, Argentina. Prescriptions belonging to patients admitted to the general surgery wards were evaluated. A multi-strategy intervention that included (i) simplification of institutional CPGs for venous thromboprophylaxis using a single drug at a single dose, based on the American College of Chest Physicians recommendations, (ii) distribution of pocket cards with an algorithm for the implementation of new recommendations to both, physicians and nurses, working in the general surgery units, (iii) educational talks, (iv) paper-based reminders and (v) audit and feedback. The adherence of the venous thromboprophylaxis prescription to the institutional recommendations. The prescriptions of 100 admitted patients before and 90 after the intervention were included in the analysis. The initial rate of adherence was 31%. After the intervention this rate rose to 71.1% (P< 0.001). The major improvement observed was the reduction in omitted prophylaxis in patients at risk of venous thromboembolism from 45 to 13.3% (P< 0.001). In the adjusted model, prescribing compliance with CPGs was five times more likely during the second stage than during the first stage (OR = 5.60, 95% CI = 2.92-10.74). Simple and economical interventions such as those described in this study can improve general surgeons compliance with the institutional and international guidelines, thus assuring patient safety and quality of health care.

Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling.

PubMed

Zannas, Anthony S; Arloth, Janine; Carrillo-Roa, Tania; Iurato, Stella; Röh, Simone; Ressler, Kerry J; Nemeroff, Charles B; Smith, Alicia K; Bradley, Bekh; Heim, Christine; Menke, Andreas; Lange, Jennifer F; Brückl, Tanja; Ising, Marcus; Wray, Naomi R; Erhardt, Angelika; Binder, Elisabeth B; Mehta, Divya

2015-12-17

Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear. We examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n = 392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n = 85) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n = 124) and gene expression data (n = 297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2 % (110/353) of these CpGs and transcription in 81.7 % (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias. Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk.

Concordance of DNA methylation profiles between breast core biopsy and surgical excision specimens containing ductal carcinoma in situ (DCIS).

PubMed

Chen, Youdinghuan; Marotti, Jonathan D; Jenson, Erik G; Onega, Tracy L; Johnson, Kevin C; Christensen, Brock C

2017-08-01

The utility and reliability of assessing molecular biomarkers for translational applications on pre-operative core biopsy specimens assume consistency of molecular profiles with larger surgical specimens. Whether DNA methylation in ductal carcinoma in situ (DCIS), measured in core biopsy and surgical specimens are similar, remains unclear. Here, we compared genome-scale DNA methylation measured in matched core biopsy and surgical specimens from DCIS, including specific DNA methylation biomarkers of subsequent invasive cancer. DNA was extracted from guided 2mm cores of formalin fixed paraffin embedded (FFPE) specimens, bisulfite-modified, and measured on the Illumina HumanMethylation450 BeadChip. DNA methylation profiles of core biopsies exhibited high concordance with matched surgical specimens. Within-subject variability in DNA methylation was significantly lower than between-subject variability (all P<2.20E-16). In 641 CpGs whose methylation was related with increased hazard of invasive breast cancer, lower within-subject than between-subject variability was observed in 92.3% of the study participants (P<0.05). Between patient-matched core biopsy and surgical specimens, <0.6% of CpGs measured had changes in median DNA methylation >15%, and a pathway analysis of these CpGs indicated enrichment for genes related with wound healing. Our results indicate that DNA methylation measured in core biopsies are representative of the matched surgical specimens and suggest that DCIS biomarkers measured in core biopsies can inform clinical decision-making. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Conventional Prompt Global Strike and Long-Range Ballistic Missiles: Background and Issues

DTIC Science & Technology

2013-01-10

and Long-Range Ballistic Missiles Congressional Research Service Forward-Based Global Strike ( FBGS ...they may address the nuclear ambiguity issues raised by long-range ballistic missiles in the CPGS program. Forward-Based Global Strike ( FBGS

Voluntary Movement Frequencies in Submaximal One- and Two-Legged Knee Extension Exercise and Pedaling

PubMed Central

Stang, Julie; Wiig, Håvard; Hermansen, Marte; Hansen, Ernst Albin

2016-01-01

Understanding of behavior and control of human voluntary rhythmic stereotyped leg movements is useful in work to improve performance, function, and rehabilitation of exercising, healthy, and injured humans. The present study aimed at adding to the existing understanding within this field. To pursue the aim, correlations between freely chosen movement frequencies in relatively simple, single-joint, one- and two-legged knee extension exercise were investigated. The same was done for more complex, multiple-joint, one- and two-legged pedaling. These particular activities were chosen because they could be considered related to some extent, as they shared a key aspect of knee extension, and because they at the same time were different. The activities were performed at submaximal intensities, by healthy individuals (n = 16, thereof eight women; 23.4 ± 2.7 years; 1.70 ± 0.11 m; 68.6 ± 11.2 kg). High and fair correlations (R-values of 0.99 and 0.75) occurred between frequencies generated with the dominant leg and the nondominant leg during knee extension exercise and pedaling, respectively. Fair to high correlations (R-values between 0.71 and 0.95) occurred between frequencies performed with each of the two legs in an activity, and the two-legged frequency performed in the same type of activity. In general, the correlations were higher for knee extension exercise than for pedaling. Correlations between knee extension and pedaling frequencies were of modest occurrence. The correlations between movement frequencies generated separately by each of the legs might be interpreted to support the following working hypothesis, which was based on existing literature. It is likely that involved central pattern generators (CPGs) of the two legs share a common frequency generator or that separate frequency generators of each leg are attuned via interneuronal connections. Further, activity type appeared to be relevant. Thus, the apparent common rhythmogenesis for the two legs appeared to be stronger for the relatively simple single-joint activity of knee extension exercise as compared to the more complex multi-joint activity of pedaling. Finally, it appeared that the shared aspect of knee extension in the related types of activities of knee extension exercise and pedaling was insufficient to cause obvious correlations between generated movement frequencies in the two types of activities. PMID:26973486

Methylation on the Circadian Gene BMAL1 Is Associated with the Effects of a Weight Loss Intervention on Serum Lipid Levels.

PubMed

Samblas, Mirian; Milagro, Fermin I; Gómez-Abellán, Purificación; Martínez, J Alfredo; Garaulet, Marta

2016-06-01

The circadian clock system has been linked to the onset and development of obesity and some accompanying comorbidities. Epigenetic mechanisms, such as DNA methylation, are putatively involved in the regulation of the circadian clock system. The aim of this study was to investigate the influence of a weight loss intervention based on an energy-controlled Mediterranean dietary pattern in the methylation levels of 3 clock genes, BMAL1, CLOCK, and NR1D1, and the association between the methylation levels and changes induced in the serum lipid profile with the weight loss treatment. The study sample enrolled 61 women (body mass index = 28.6 ± 3.4 kg/m(2); age: 42.2 ± 11.4 years), who followed a nutritional program based on a Mediterranean dietary pattern. DNA was isolated from whole blood obtained at the beginning and end point. Methylation levels at different CpG sites of BMAL1, CLOCK, and NR1D1 were analyzed by Sequenom's MassArray. The energy-restricted intervention modified the methylation levels of different CpG sites in BMAL1 (CpGs 5, 6, 7, 9, 11, and 18) and NR1D1 (CpGs 1, 10, 17, 18, 19, and 22). Changes in cytosine methylation in the CpG 5 to 9 region of BMAL1 with the intervention positively correlated with the eveningness profile (p = 0.019). The baseline methylation of the CpG 5 to 9 region in BMAL1 positively correlated with energy (p = 0.047) and carbohydrate (p = 0.017) intake and negatively correlated with the effect of the weight loss intervention on total cholesterol (p = 0.032) and low-density lipoprotein cholesterol (p = 0.005). Similar significant and positive correlations were found between changes in methylation levels in the CpG 5 to 9 region of BMAL1 due to the intervention and changes in serum lipids (p < 0.05). This research describes apparently for the first time an association between changes in the methylation of the BMAL1 gene with the intervention and the effects of a weight loss intervention on blood lipids levels. © 2016 The Author(s).

A 2013 survey of clinical practice patterns in the management of primary hypothyroidism.

PubMed

Burch, Henry B; Burman, Kenneth D; Cooper, David S; Hennessey, James V

2014-06-01

In 2012, comprehensive clinical practice guidelines (CPGs) were published regarding the management of hypothyroidism. We sought to document current practices in the management of primary hypothyroidism and compare these results with recommendations made in the 2012 American Thyroid Association (ATA)/American Association of Clinical Endocrinologists (AACE) hypothyroidism CPGs. In addition, we sought to examine differences in management among international members of U.S.-based endocrine societies and to compare survey results with those obtained from a survey of ATA members performed 12 years earlier. Clinical members of The Endocrine Society (TES), the ATA, and the AACE were asked to take a web-based survey consisting of 30 questions dealing with testing, treatment, and modulating factors in the management of primary hypothyroidism. In total, 880 respondents completed the survey, including 618 members of TES, 582 AACE members, and 208 ATA members. North American respondents accounted for 67.6%, Latin American 9.7%, European 9.2%, Asia and Oceania 8.1%, and Africa and Middle East 5.5%. Overt hypothyroidism would be treated using l-T4 alone by 99.2% of respondents; 0.8% would use combination l-T4 and liothyronine (l-T3) therapy. Generic l-T4 would be used by 49.3% and a brand name by 49.9%. The rate of replacement would be gradual (38.5%); an empiric dose, adjusted to achieve target (33.6%); or a calculated full replacement dose (27.8%). A target TSH of 1.0 to 1.9 mU/L was favored in the index case, but 3.0 to 3.9 mU/L was the most commonly selected TSH target for an octogenarian. Persistent hypothyroid symptoms despite achieving a target TSH would prompt testing for other causes by 84.3% of respondents, a referral to primary care by 11.3%, and a change to l-T4 plus l-T3 therapy by 3.6%. Evaluation of persistent symptoms would include measurement of T3 levels by 21.9% of respondents. Subclinical disease with a TSH 5.0 to 10.0 mU/L would be treated without further justification by 21.3% of respondents, or in the presence of positive thyroid peroxidase antibodies (62.3%), hypothyroid symptoms (60.9%), high low-density lipoprotein (52.9%), or goiter (46.6%). The TSH target for a newly pregnant patient was <2.5 mU/L for 96.1% of respondents, with 63.5% preferring a TSH target <1.5 mU/L. Thyroid hormone levels would be checked every 4 weeks during pregnancy by 67.7% and every 8 weeks by an additional 21.4%. A hypothyroid patient with TSH of 0.5 mU/L who becomes pregnant would receive an immediate l-T4 dose increase by only 36.9% of respondents. The current survey of clinical endocrinologists catalogs current practice patterns in the management of hypothyroidism and demonstrates 1) a nearly exclusive preference for l-T4 alone as initial therapy, 2) the widespread use of age-specific TSH targets for replacement therapy, 3) a low threshold for treating mild thyroid failure, 4) meticulous attention to TSH targets in the pregnant and prepregnant woman, and 5) a highly variable approach to both the rate and means of restoring euthyroidism for overt disease. Both alignment and focal divergence from recent CPGs are demonstrated.

Extensive sequence-influenced DNA methylation polymorphism in the human genome

PubMed Central

2010-01-01

Background Epigenetic polymorphisms are a potential source of human diversity, but their frequency and relationship to genetic polymorphisms are unclear. DNA methylation, an epigenetic mark that is a covalent modification of the DNA itself, plays an important role in the regulation of gene expression. Most studies of DNA methylation in mammalian cells have focused on CpG methylation present in CpG islands (areas of concentrated CpGs often found near promoters), but there are also interesting patterns of CpG methylation found outside of CpG islands. Results We compared DNA methylation patterns on both alleles between many pairs (and larger groups) of related and unrelated individuals. Direct observation and simulation experiments revealed that around 10% of common single nucleotide polymorphisms (SNPs) reside in regions with differences in the propensity for local DNA methylation between the two alleles. We further showed that for the most common form of SNP, a polymorphism at a CpG dinucleotide, the presence of the CpG at the SNP positively affected local DNA methylation in cis. Conclusions Taken together with the known effect of DNA methylation on mutation rate, our results suggest an interesting interdependence between genetics and epigenetics underlying diversity in the human genome. PMID:20497546

Self-reported smoking, serum cotinine, and blood DNA methylation.

PubMed

Zhang, Yan; Florath, Ines; Saum, Kai-Uwe; Brenner, Hermann

2016-04-01

Epigenome-wide profiling of DNA methylation pattern with respect to tobacco smoking has given rise to a new measure of smoking exposure. We investigated the relationships of methylation markers with both cotinine, an established marker of internal smoking exposure, and self-reported smoking. Blood DNA methylation levels across the genome and serum cotinine were measured in 1000 older adults aged 50-75 years. Epigenome-wide scans were performed to identify methylation markers associated with cotinine. The inter-dose-response relationships between the number of cigarettes smoked per day, cotinine concentration, and DNA methylation were modeled by restricted cubic spline regression. Of 61 CpGs that passed the genome-wide significance threshold (p<1.13×10(-7)), 40 CpGs in 25 chromosomal regions were successfully replicated, showing 0.2-3% demethylation per 10ng/ml increases in cotinine. The strongest associations were observed for several loci at AHRR, F2RL3, 2q37.1, 6p21.33, and GFI1 that were previously identified to be related to self-reported smoking. One locus at RAB34 was newly discovered. Both cotinine and methylation markers exhibited non-linear relationships with the number of cigarettes smoked per day, where the highest rates of increase in cotinine and decreases in methylation were observed at low smoking intensity (1-15 cigarettes/day) and plateaued at high smoking intensity (>15-20 cigarettes/day). A clear linear relationship was observed between cotinine concentration and methylation level. Both cotinine and methylation markers showed similar accuracy in distinguishing current from never smoker, but only methylation markers distinguished former from never smoker with high accuracy. Our study corroborates and expands the list of smoking-associated DNA methylation markers. Methylation levels were linearly related to cotinine concentration and provided accurate measures for both current and past smoking exposure. Copyright © 2016 Elsevier Inc. All rights reserved.

DNA methylation as a predictor of fetal alcohol spectrum disorder.

PubMed

Lussier, Alexandre A; Morin, Alexander M; MacIsaac, Julia L; Salmon, Jenny; Weinberg, Joanne; Reynolds, James N; Pavlidis, Paul; Chudley, Albert E; Kobor, Michael S

2018-01-01

Fetal alcohol spectrum disorder (FASD) is a developmental disorder that manifests through a range of cognitive, adaptive, physiological, and neurobiological deficits resulting from prenatal alcohol exposure. Although the North American prevalence is currently estimated at 2-5%, FASD has proven difficult to identify in the absence of the overt physical features characteristic of fetal alcohol syndrome. As interventions may have the greatest impact at an early age, accurate biomarkers are needed to identify children at risk for FASD. Building on our previous work identifying distinct DNA methylation patterns in children and adolescents with FASD, we have attempted to validate these associations in a different clinical cohort and to use our DNA methylation signature to develop a possible epigenetic predictor of FASD. Genome-wide DNA methylation patterns were analyzed using the Illumina HumanMethylation450 array in the buccal epithelial cells of a cohort of 48 individuals aged 3.5-18 (24 FASD cases, 24 controls). The DNA methylation predictor of FASD was built using a stochastic gradient boosting model on our previously published dataset FASD cases and controls (GSE80261). The predictor was tested on the current dataset and an independent dataset of 48 autism spectrum disorder cases and 48 controls (GSE50759). We validated findings from our previous study that identified a DNA methylation signature of FASD, replicating the altered DNA methylation levels of 161/648 CpGs in this independent cohort, which may represent a robust signature of FASD in the epigenome. We also generated a predictive model of FASD using machine learning in a subset of our previously published cohort of 179 samples (83 FASD cases, 96 controls), which was tested in this novel cohort of 48 samples and resulted in a moderately accurate predictor of FASD status. Upon testing the algorithm in an independent cohort of individuals with autism spectrum disorder, we did not detect any bias towards autism, sex, age, or ethnicity. These findings further support the association of FASD with distinct DNA methylation patterns, while providing a possible entry point towards the development of epigenetic biomarkers of FASD.

Epigenetic Contribution of the Myosin Light Chain Kinase Gene to the Risk for Acute Respiratory Distress Syndrome

PubMed Central

Szilágyi, Keely L.; Liu, Cong; Zhang, Xu; Wang, Ting; Fortman, Jeffrey D.; Zhang, Wei; Garcia, Joe G.N.

2016-01-01

Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome with a considerable case fatality rate (~30-40%). Health disparities exist with African descent subjects (ADs) exhibiting greater mortality than European descent individuals (EDs). Myosin light chain kinase (MLCK) is encoded by MYLK whose genetic variants are implicated in ARDS pathogenesis and may influence ARDS mortality. As baseline population-specific epigenetic changes, i.e. cytosine modifications, have been observed between AD and ED individuals, epigenetic variations in MYLK may provide insights into ARDS disparities. We compared methylation levels of MYLK CpGs between ARDS patients and ICU controls overall and by ethnicity in a nested case control study of 39 ARDS cases and 75 non-ARDS intensive care unit controls. Two MYLK CpG sites (cg03892735, cg23344121) were differentially modified between ARDS subjects and controls (p<0.05; q<0.25) in a logistic regression model, where no effect modification from ethnicity or age was found. One CpG site was associated with ARDS in patients less than 58 years old, cg19611163 (intron 19,20). Two CpG sites were associated with ARDS in EDs only, gene body CpG (cg01894985, intron 2,3) and CpG (cg16212219, intron 31,32), with higher modification levels exhibited in ARDS subjects than controls. Cis-acting mQTL (modified cytosine quantitative trait loci) were identified using linear regression between local genetic variants and modification levels for two ARDS-associated CpGs (cg23344121, cg16212219). In summary, these ARDS-associated MYLK CpGs with effect modification by ethnicity and local mQTL, suggest that MYLK epigenetic variation and local genetic background may contribute to health disparities observed in ARDS. PMID:27543902

Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach

PubMed Central

Joehanes, Roby; Liu, Chunyu; Aslibekyan, Stella; Demerath, Ellen W.; Guan, Weihua; Zhi, Degui; Willinger, Christine; Courchesne, Paul; Multhaup, Michael; Irvin, Marguerite R.; Schadt, Eric E.; Bressler, Jan; North, Kari; Sundström, Johan; Gustafsson, Stefan; Shah, Sonia; McRae, Allan F.; Harris, Sarah E.; Gibson, Jude; Redmond, Paul; Corley, Janie; Starr, John M.; Visscher, Peter M.; Wray, Naomi R.; Krauss, Ronald M.; Feinberg, Andrew; Fornage, Myriam; Pankow, James S.; Lind, Lars; Fox, Caroline; Ingelsson, Erik; Arnett, Donna K.; Boerwinkle, Eric; Liang, Liming; Levy, Daniel; Deary, Ian J.

2017-01-01

Background The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. Methods and Findings We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. Conclusions We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases. PMID:28095459

Evaluation of all African clinical practice guidelines for hypertension: Quality and opportunities for improvement.

PubMed

Okwen, Patrick Mbah; Maweu, Irene; Grimmer, Karen; Margarita Dizon, Janine

2018-06-14

Good-quality clinical practice guidelines (CPGs) provide recommendations based on current best-evidence summaries. Hypertension is a prevalent noncommunicable disease in Africa, with disastrous sequelae (stroke, heart, and kidney disease). Its effective management relies on good quality, current, locally relevant evidence. This paper reports on an all African review of the guidance documents currently informing hypertension management. Attempts were made to contact 62 African countries for formal guidance documents used nationally to inform diagnosis and management of hypertension. Their quality was assessed by using Appraisal of Guidelines for Research & Evaluation (AGREE) II, scored by 2 independent reviewers. Differences in domain scores were compared between documents written prior to 2011 and 2011 onward. Findings were compared with earlier African CPG reviews. Guidelines and protocols were provided by 26 countries. Six used country-specific stand-alone hypertension guidelines, and 10 used protocols embedded in Standard Treatment Guidelines for multiple conditions. Six used guidelines developed by the World Health Organization, and 4 indicated ad hoc use of international guidance (US, Portugal, and Brazil). Only 1 guidance document met CPG construction criteria, and none scored well on all AGREE domain scores. The lowest-scoring domain was rigour of development. There was no significant quality difference between pre-2011 and post-2011 guidance documents, and there were variable AGREE II scores for the same CPGs when comparing the African reviews. The quality of hypertension guidance used by African nations could be improved. The need for so many guidance documents is questioned. Adopting a common evidence base from international good-quality CPGs and layering it with local contexts offer 1 way to efficiently improve African hypertension CPG quality and implementation. © 2018 John Wiley & Sons, Ltd.

Management of Falls in Community-Dwelling Older Adults: Clinical Guidance Statement From the Academy of Geriatric Physical Therapy of the American Physical Therapy Association

PubMed Central

Avin, Keith G.; Hanke, Timothy A.; Kirk-Sanchez, Neva; McDonough, Christine M.; Shubert, Tiffany E.; Hartley, Greg

2015-01-01

Background Falls in older adults are a major public health concern due to high prevalence, impact on health outcomes and quality of life, and treatment costs. Physical therapists can play a major role in reducing fall risk for older adults; however, existing clinical practice guidelines (CPGs) related to fall prevention and management are not targeted to physical therapists. Objective The purpose of this clinical guidance statement (CGS) is to provide recommendations to physical therapists to help improve outcomes in the identification and management of fall risk in community-dwelling older adults. Design and Methods The Subcommittee on Evidence-Based Documents of the Practice Committee of the Academy of Geriatric Physical Therapy developed this CGS. Existing CPGs were identified by systematic search and critically appraised using the Appraisal of Guidelines, Research, and Evaluation in Europe II (AGREE II) tool. Through this process, 3 CPGs were recommended for inclusion in the CGS and were synthesized and summarized. Results Screening recommendations include asking all older adults in contact with a health care provider whether they have fallen in the previous year or have concerns about balance or walking. Follow-up should include screening for balance and mobility impairments. Older adults who screen positive should have a targeted multifactorial assessment and targeted intervention. The components of this assessment and intervention are reviewed in this CGS, and barriers and issues related to implementation are discussed. Limitations A gap analysis supports the need for the development of a physical therapy–specific CPG to provide more precise recommendations for screening and assessment measures, exercise parameters, and delivery models. Conclusion This CGS provides recommendations to assist physical therapists in the identification and management of fall risk in older community-dwelling adults. PMID:25573760

Management of falls in community-dwelling older adults: clinical guidance statement from the Academy of Geriatric Physical Therapy of the American Physical Therapy Association.

PubMed

Avin, Keith G; Hanke, Timothy A; Kirk-Sanchez, Neva; McDonough, Christine M; Shubert, Tiffany E; Hardage, Jason; Hartley, Greg

2015-06-01

Falls in older adults are a major public health concern due to high prevalence, impact on health outcomes and quality of life, and treatment costs. Physical therapists can play a major role in reducing fall risk for older adults; however, existing clinical practice guidelines (CPGs) related to fall prevention and management are not targeted to physical therapists. The purpose of this clinical guidance statement (CGS) is to provide recommendations to physical therapists to help improve outcomes in the identification and management of fall risk in community-dwelling older adults. The Subcommittee on Evidence-Based Documents of the Practice Committee of the Academy of Geriatric Physical Therapy developed this CGS. Existing CPGs were identified by systematic search and critically appraised using the Appraisal of Guidelines, Research, and Evaluation in Europe II (AGREE II) tool. Through this process, 3 CPGs were recommended for inclusion in the CGS and were synthesized and summarized. Screening recommendations include asking all older adults in contact with a health care provider whether they have fallen in the previous year or have concerns about balance or walking. Follow-up should include screening for balance and mobility impairments. Older adults who screen positive should have a targeted multifactorial assessment and targeted intervention. The components of this assessment and intervention are reviewed in this CGS, and barriers and issues related to implementation are discussed. A gap analysis supports the need for the development of a physical therapy-specific CPG to provide more precise recommendations for screening and assessment measures, exercise parameters, and delivery models. This CGS provides recommendations to assist physical therapists in the identification and management of fall risk in older community-dwelling adults. © 2015 American Physical Therapy Association.

Choice of surrogate tissue influences neonatal EWAS findings.

PubMed

Lin, Xinyi; Teh, Ai Ling; Chen, Li; Lim, Ives Yubin; Tan, Pei Fang; MacIsaac, Julia L; Morin, Alexander M; Yap, Fabian; Tan, Kok Hian; Saw, Seang Mei; Lee, Yung Seng; Holbrook, Joanna D; Godfrey, Keith M; Meaney, Michael J; Kobor, Michael S; Chong, Yap Seng; Gluckman, Peter D; Karnani, Neerja

2017-12-05

Epigenomes are tissue specific and thus the choice of surrogate tissue can play a critical role in interpreting neonatal epigenome-wide association studies (EWAS) and in their extrapolation to target tissue. To develop a better understanding of the link between tissue specificity and neonatal EWAS, and the contributions of genotype and prenatal factors, we compared genome-wide DNA methylation of cord tissue and cord blood, two of the most accessible surrogate tissues at birth. In 295 neonates, DNA methylation was profiled using Infinium HumanMethylation450 beadchip arrays. Sites of inter-individual variability in DNA methylation were mapped and compared across the two surrogate tissues at birth, i.e., cord tissue and cord blood. To ascertain the similarity to target tissues, DNA methylation profiles of surrogate tissues were compared to 25 primary tissues/cell types mapped under the Epigenome Roadmap project. Tissue-specific influences of genotype on the variable CpGs were also analyzed. Finally, to interrogate the impact of the in utero environment, EWAS on 45 prenatal factors were performed and compared across the surrogate tissues. Neonatal EWAS results were tissue specific. In comparison to cord blood, cord tissue showed higher inter-individual variability in the epigenome, with a lower proportion of CpGs influenced by genotype. Both neonatal tissues were good surrogates for target tissues of mesodermal origin. They also showed distinct phenotypic associations, with effect sizes of the overlapping CpGs being in the same order of magnitude. The inter-relationship between genetics, prenatal factors and epigenetics is tissue specific, and requires careful consideration in designing and interpreting future neonatal EWAS. This birth cohort is a prospective observational study, designed to study the developmental origins of health and disease, and was retrospectively registered on 1 July 2010 under the identifier NCT01174875 .

Teleconferenced Educational Detailing: Diabetes Education for Primary Care Physicians

ERIC Educational Resources Information Center

Harris, Stewart B.; Leiter, Lawrence A.; Webster-Bogaert, Susan; Van, Daphne M.; O'Neill, Colleen

2005-01-01

Introduction: Formal didactic continuing medical education (CME) is relatively ineffective for changing physician behavior. Diabetes mellitus is an increasingly prevalent disease, and interventions to improve adherence to clinical practice guidelines (CPGs) are needed. Methods: A stratified, cluster-randomized, controlled trial design was used to…

Expanding a First-Order Logic Mitigation Framework to Handle Multimorbid Patient Preferences

PubMed Central

Michalowski, Martin; Wilk, Szymon; Rosu, Daniela; Kezadri, Mounira; Michalowski, Wojtek; Carrier, Marc

2015-01-01

The increasing prevalence of multimorbidity is a challenge for physicians who have to manage a constantly growing number of patients with simultaneous diseases. Adding to this challenge is the need to incorporate patient preferences as key components of the care process, thanks in part to the emergence of personalized and participatory medicine. In our previous work we proposed a framework employing first order logic to represent clinical practice guidelines (CPGs) and to mitigate possible adverse interactions when concurrently applying multiple CPGs to a multimorbid patient. In this paper, we describe extensions to our methodological framework that (1) broaden our definition of revision operators to support required and desired types of revisions defined in secondary knowledge sources, and (2) expand the mitigation algorithm to apply revisions based on their type. We illustrate the capabilities of the expanded framework using a clinical case study of a multimorbid patient with stable cardiac artery disease who suffers a sudden onset of deep vein thrombosis. PMID:26958226

Strehl ratio: a tool for optimizing optical nulls and singularities.

PubMed

Hénault, François

2015-07-01

In this paper a set of radial and azimuthal phase functions are reviewed that have a null Strehl ratio, which is equivalent to generating a central extinction in the image plane of an optical system. The study is conducted in the framework of Fraunhofer scalar diffraction, and is oriented toward practical cases where optical nulls or singularities are produced by deformable mirrors or phase plates. The identified solutions reveal unexpected links with the zeros of type-J Bessel functions of integer order. They include linear azimuthal phase ramps giving birth to an optical vortex, azimuthally modulated phase functions, and circular phase gratings (CPGs). It is found in particular that the CPG radiometric efficiency could be significantly improved by the null Strehl ratio condition. Simple design rules for rescaling and combining the different phase functions are also defined. Finally, the described analytical solutions could also serve as starting points for an automated searching software tool.

Base resolution methylome profiling: considerations in platform selection, data preprocessing and analysis

PubMed Central

Sun, Zhifu; Cunningham, Julie; Slager, Susan; Kocher, Jean-Pierre

2015-01-01

Bisulfite treatment-based methylation microarray (mainly Illumina 450K Infinium array) and next-generation sequencing (reduced representation bisulfite sequencing, Agilent SureSelect Human Methyl-Seq, NimbleGen SeqCap Epi CpGiant or whole-genome bisulfite sequencing) are commonly used for base resolution DNA methylome research. Although multiple tools and methods have been developed and used for the data preprocessing and analysis, confusions remains for these platforms including how and whether the 450k array should be normalized; which platform should be used to better fit researchers’ needs; and which statistical models would be more appropriate for differential methylation analysis. This review presents the commonly used platforms and compares the pros and cons of each in methylome profiling. We then discuss approaches to study design, data normalization, bias correction and model selection for differentially methylated individual CpGs and regions. PMID:26366945

Sex differences in DNA methylation and expression in zebrafish brain: a test of an extended 'male sex drive' hypothesis.

PubMed

Chatterjee, Aniruddha; Lagisz, Malgorzata; Rodger, Euan J; Zhen, Li; Stockwell, Peter A; Duncan, Elizabeth J; Horsfield, Julia A; Jeyakani, Justin; Mathavan, Sinnakaruppan; Ozaki, Yuichi; Nakagawa, Shinichi

2016-09-30

The sex drive hypothesis predicts that stronger selection on male traits has resulted in masculinization of the genome. Here we test whether such masculinizing effects can be detected at the level of the transcriptome and methylome in the adult zebrafish brain. Although methylation is globally similar, we identified 914 specific differentially methylated CpGs (DMCs) between males and females (435 were hypermethylated and 479 were hypomethylated in males compared to females). These DMCs were prevalent in gene body, intergenic regions and CpG island shores. We also discovered 15 distinct CpG clusters with striking sex-specific DNA methylation differences. In contrast, at transcriptome level, more female-biased genes than male-biased genes were expressed, giving little support for the male sex drive hypothesis. Our study provides genome-wide methylome and transcriptome assessment and sheds light on sex-specific epigenetic patterns and in zebrafish for the first time. Copyright © 2016 Elsevier B.V. All rights reserved.

Network architectures and circuit function: testing alternative hypotheses in multifunctional networks.

PubMed

Leonard, J L

2000-05-01

Understanding how species-typical movement patterns are organized in the nervous system is a central question in neurobiology. The current explanations involve 'alphabet' models in which an individual neuron may participate in the circuit for several behaviors but each behavior is specified by a specific neural circuit. However, not all of the well-studied model systems fit the 'alphabet' model. The 'equation' model provides an alternative possibility, whereby a system of parallel motor neurons, each with a unique (but overlapping) field of innervation, can account for the production of stereotyped behavior patterns by variable circuits. That is, it is possible for such patterns to arise as emergent properties of a generalized neural network in the absence of feedback, a simple version of a 'self-organizing' behavioral system. Comparison of systems of identified neurons suggest that the 'alphabet' model may account for most observations where CPGs act to organize motor patterns. Other well-known model systems, involving architectures corresponding to feed-forward neural networks with a hidden layer, may organize patterned behavior in a manner consistent with the 'equation' model. Such architectures are found in the Mauthner and reticulospinal circuits, 'escape' locomotion in cockroaches, CNS control of Aplysia gill, and may also be important in the coordination of sensory information and motor systems in insect mushroom bodies and the vertebrate hippocampus. The hidden layer of such networks may serve as an 'internal representation' of the behavioral state and/or body position of the animal, allowing the animal to fine-tune oriented, or particularly context-sensitive, movements to the prevalent conditions. Experiments designed to distinguish between the two models in cases where they make mutually exclusive predictions provide an opportunity to elucidate the neural mechanisms by which behavior is organized in vivo and in vitro. Copyright 2000 S. Karger AG, Basel

The left end of rat L1 (L1Rn, long interspersed repeated) DNA which is a CpG island can function as a promoter.

PubMed Central

Nur, I; Pascale, E; Furano, A V

1988-01-01

Here we report that the 600 bp promoter-like region at the left end of a newly isolated and characterized rat L1 DNA element can activate the prokaryotic chloramphenicol acyltransferase gene in a rat cell line. Activation only occurs when the promoter region is oriented to the transferase gene as it is to the L1 protein encoding sequences and is 75% inhibited by methylation of just 5 of the 22 CpGs present in the promoter. The G + C rich promoter contains enough CpGs to qualify it as a CpG island, but in contrast to other CpG islands, genomic L1 promoters are fully methylated in both somatic cell and sperm DNA as judged by restriction enzyme analysis. Partial demethylation of the genomic promoters by treatment with 5-azacytidine failed to produce discrete L1 transcripts. The relationship of methylation to the evolutionary history and fate of the rat L1 promoter is discussed. Images PMID:2459662

Traumatic brain injury in modern war

NASA Astrophysics Data System (ADS)

Ling, Geoffrey S. F.; Hawley, Jason; Grimes, Jamie; Macedonia, Christian; Hancock, James; Jaffee, Michael; Dombroski, Todd; Ecklund, James M.

2013-05-01

Traumatic brain injury (TBI) is common and especially with military service. In Iraq and Afghanistan, explosive blast related TBI has become prominent and is mainly from improvised explosive devices (IED). Civilian standard of care clinical practice guidelines (CPG) were appropriate has been applied to the combat setting. When such CPGs do not exist or are not applicable, new practice standards for the military are created, as for TBI. Thus, CPGs for prehospital care of combat TBI CPG [1] and mild TBI/concussion [2] were introduced as was a DoD system-wide clinical care program, the first large scale system wide effort to address all severities of TBI in a comprehensive organized way. As TBI remains incompletely understood, substantial research is underway. For the DoD, leading this effort are The Defense and Veterans Brain Injury Center, National Intrepid Center of Excellence and the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury. This program is a beginning, a work in progress ready to leverage advances made scientifically and always with the intent of providing the best care to its military beneficiaries.

Epigenetic contribution of the myosin light chain kinase gene to the risk for acute respiratory distress syndrome.

PubMed

Szilágyi, Keely L; Liu, Cong; Zhang, Xu; Wang, Ting; Fortman, Jeffrey D; Zhang, Wei; Garcia, Joe G N

2017-02-01

Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome with a considerable case fatality rate (∼30%-40%). Health disparities exist with African descent (AD) subjects exhibiting greater mortality than European descent (ED) individuals. Myosin light chain kinase is encoded by MYLK, whose genetic variants are implicated in ARDS pathogenesis and may influence ARDS mortality. As baseline population-specific epigenetic changes, that is, cytosine modifications, have been observed between AD and ED individuals, epigenetic variations in MYLK may provide insights into ARDS disparities. We compared methylation levels of MYLK cytosine-guanine dinucleotides (CpGs) between ARDS patients and intensive care unit (ICU) controls overall and by ethnicity in a nested case-control study of 39 ARDS cases and 75 non-ARDS ICU controls. Two MYLK CpG sites (cg03892735 and cg23344121) were differentially modified between ARDS subjects and controls (P < 0.05; q < 0.25) in a logistic regression model, where no effect modification by ethnicity or age was found. One CpG site was associated with ARDS in patients aged <58 years, cg19611163 (intron 19, 20). Two CpG sites were associated with ARDS in EDs only, gene body CpG (cg01894985, intron 2, 3) and CpG (cg16212219, intron 31, 32), with higher modification levels exhibited in ARDS subjects than controls. Cis-acting modified cytosine quantitative trait loci (mQTL) were identified using linear regression between local genetic variants and modification levels for 2 ARDS-associated CpGs (cg23344121 and cg16212219). In summary, these ARDS-associated MYLK CpGs with effect modification by ethnicity and local mQTL suggest that MYLK epigenetic variation and local genetic background may contribute to health disparities observed in ARDS. Copyright © 2016 Elsevier Inc. All rights reserved.

Management of acute agitation in Hong Kong and comparisons with Australasia.

PubMed

Chan, Esther Wai Yin; Tang, Cedric; Lao, Kim Shi Jian; Ling Pong, Leung; Tsui, Matthew Sik Hon; Ho, Hiu Fai; Wong, Gordon Chi Keung; Kong, David Chee Ming; McD Taylor, David; Knott, Jonathan C; Wong, Ian Chi Kei

2015-12-01

Little is known about the use of sedation drugs for the management of acute agitation in Hong Kong's Accident and Emergency Departments (AEDs) and how it compares with Australasian practice. The aim of this study was to determine drug preferences, clinicians' perceived confidence in management, barriers/gaps in training and perceived usefulness of existing clinical practice guidelines (CPGs) in Hong Kong. A validated questionnaire was used, with case vignettes typical of patients presenting to AEDs with acute agitation. The questionnaire was distributed by hand to all trainees and fellows of the Hong Kong College of Emergency Medicine (HKCEM). Two reminders were sent. Of 483 HKCEM members, 280 (58.0% [95% CI 53.5-62.3]) responded. For monotherapy, 46.8% (95% CI 41.0-52.6) of respondents chose haloperidol to manage the undifferentiated patient, followed by midazolam (33.9%, 95% CI 28.6-39.7) and diazepam (13.9%, 95% CI 10.4-18.5). Most respondents (83.6%, 95% CI 78.8-87.5) would not administer combination therapy. Respondents were confident in managing agitation overall. The lack of local/institutional CPGs (55.7%, 95% CI 49.9-61.4) was perceived as an important barrier. Institutional guidelines were considered the most useful CPGs (66.4%, 95% CI 60.7-71.7). Most respondents (72.9%, 95% CI 67.4-77.7) perceived a HKCEM endorsed CPG would be useful. Haloperidol and benzodiazepines are frequently used as monotherapy for the management of acute agitation in Hong Kong's AEDs. Management in Hong Kong differs from Australasian practice in that combination therapy is less common and clinicians' choice of sedation drugs are less variable overall. Results suggest that future work on CPG development and training regarding the safe use of combination therapy would be well received. © 2015 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.

Meta-analysis of epigenome-wide association studies of cognitive abilities.

PubMed

Marioni, Riccardo E; McRae, Allan F; Bressler, Jan; Colicino, Elena; Hannon, Eilis; Li, Shuo; Prada, Diddier; Smith, Jennifer A; Trevisi, Letizia; Tsai, Pei-Chien; Vojinovic, Dina; Simino, Jeannette; Levy, Daniel; Liu, Chunyu; Mendelson, Michael; Satizabal, Claudia L; Yang, Qiong; Jhun, Min A; Kardia, Sharon L R; Zhao, Wei; Bandinelli, Stefania; Ferrucci, Luigi; Hernandez, Dena G; Singleton, Andrew B; Harris, Sarah E; Starr, John M; Kiel, Douglas P; McLean, Robert R; Just, Allan C; Schwartz, Joel; Spiro, Avron; Vokonas, Pantel; Amin, Najaf; Ikram, M Arfan; Uitterlinden, Andre G; van Meurs, Joyce B J; Spector, Tim D; Steves, Claire; Baccarelli, Andrea A; Bell, Jordana T; van Duijn, Cornelia M; Fornage, Myriam; Hsu, Yi-Hsiang; Mill, Jonathan; Mosley, Thomas H; Seshadri, Sudha; Deary, Ian J

2018-01-08

Cognitive functions are important correlates of health outcomes across the life-course. Individual differences in cognitive functions are partly heritable. Epigenetic modifications, such as DNA methylation, are susceptible to both genetic and environmental factors and may provide insights into individual differences in cognitive functions. Epigenome-wide meta-analyses for blood-based DNA methylation levels at ~420,000 CpG sites were performed for seven measures of cognitive functioning using data from 11 cohorts. CpGs that passed a Bonferroni correction, adjusting for the number of CpGs and cognitive tests, were assessed for: longitudinal change; being under genetic control (methylation QTLs); and associations with brain health (structural MRI), brain methylation and Alzheimer's disease pathology. Across the seven measures of cognitive functioning (meta-analysis n range: 2557-6809), there were epigenome-wide significant (P < 1.7 × 10 -8 ) associations for global cognitive function (cg21450381, P = 1.6 × 10 -8 ), and phonemic verbal fluency (cg12507869, P = 2.5 × 10 -9 ). The CpGs are located in an intergenic region on chromosome 12 and the INPP5A gene on chromosome 10, respectively. Both probes have moderate correlations (~0.4) with brain methylation in Brodmann area 20 (ventral temporal cortex). Neither probe showed evidence of longitudinal change in late-life or associations with white matter brain MRI measures in one cohort with these data. A methylation QTL analysis suggested that rs113565688 was a cis methylation QTL for cg12507869 (P = 5 × 10 -5 and 4 × 10 -13 in two lookup cohorts). We demonstrate a link between blood-based DNA methylation and measures of phonemic verbal fluency and global cognitive ability. Further research is warranted to understand the mechanisms linking genomic regulatory changes with cognitive function to health and disease.

Factors affecting the persistence of drug-induced reprogramming of the cancer methylome

PubMed Central

Bell, Joshua S. K.; Kagey, Jacob D.; Barwick, Benjamin G.; Dwivedi, Bhakti; McCabe, Michael T.; Kowalski, Jeanne; Vertino, Paula M.

2016-01-01

ABSTRACT Aberrant DNA methylation is a critical feature of cancer. Epigenetic therapy seeks to reverse these changes to restore normal gene expression. DNA demethylating agents, including 5-aza-2′-deoxycytidine (DAC), are currently used to treat certain leukemias, and can sensitize solid tumors to chemotherapy and immunotherapy. However, it has been difficult to pin the clinical efficacy of these agents to specific demethylation events, and the factors that contribute to the durability of response remain largely unknown. Here we examined the genome-wide kinetics of DAC-induced DNA demethylation and subsequent remethylation after drug withdrawal in breast cancer cells. We find that CpGs differ in both their susceptibility to demethylation and propensity for remethylation after drug removal. DAC-induced demethylation was most apparent at CpGs with higher initial methylation levels and further from CpG islands. Once demethylated, such sites exhibited varied remethylation potentials. The most rapidly remethylating CpGs regained >75% of their starting methylation within a month of drug withdrawal. These sites had higher pretreatment methylation levels, were enriched in gene bodies, marked by H3K36me3, and tended to be methylated in normal breast cells. In contrast, a more resistant class of CpG sites failed to regain even 20% of their initial methylation after 3 months. These sites had lower pretreatment methylation levels, were within or near CpG islands, marked by H3K79me2 or H3K4me2/3, and were overrepresented in sites that become aberrantly hypermethylated in breast cancers. Thus, whereas DAC-induced demethylation affects both endogenous and aberrantly methylated sites, tumor-specific hypermethylation is more slowly regained, even as normal methylation promptly recovers. Taken together, these data suggest that the durability of DAC response is linked to its selective ability to stably reset at least a portion of the cancer methylome. PMID:27082926

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

PubMed

Whitworth, James; Smith, Philip S; Martin, Jose-Ezequiel; West, Hannah; Luchetti, Andrea; Rodger, Faye; Clark, Graeme; Carss, Keren; Stephens, Jonathan; Stirrups, Kathleen; Penkett, Chris; Mapeta, Rutendo; Ashford, Sofie; Megy, Karyn; Shakeel, Hassan; Ahmed, Munaza; Adlard, Julian; Barwell, Julian; Brewer, Carole; Casey, Ruth T; Armstrong, Ruth; Cole, Trevor; Evans, Dafydd Gareth; Fostira, Florentia; Greenhalgh, Lynn; Hanson, Helen; Henderson, Alex; Hoffman, Jonathan; Izatt, Louise; Kumar, Ajith; Kwong, Ava; Lalloo, Fiona; Ong, Kai Ren; Paterson, Joan; Park, Soo-Mi; Chen-Shtoyerman, Rakefet; Searle, Claire; Side, Lucy; Skytte, Anne-Bine; Snape, Katie; Woodward, Emma R; Tischkowitz, Marc D; Maher, Eamonn R

2018-06-12

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ 2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Performance of health workers in the management of seriously sick children at a Kenyan tertiary hospital: before and after a training intervention.

PubMed

Irimu, Grace W; Gathara, David; Zurovac, Dejan; Kihara, Harrison; Maina, Christopher; Mwangi, Julius; Mbori-Ngacha, Dorothy; Todd, Jim; Greene, Alexandra; English, Mike

2012-01-01

Implementation of WHO case management guidelines for serious common childhood illnesses remains a challenge in hospitals in low-income countries. The impact of locally adapted clinical practice guidelines (CPGs) on the quality-of-care of patients in tertiary hospitals has rarely been evaluated. We conducted, in Kenyatta National Hospital, an uncontrolled before and after study with an attempt to explore intervention dose-effect relationships, as CPGs were disseminated and training was progressively implemented. The emergency triage, assessment and treatment plus admission care (ETAT+) training and locally adapted CPGs targeted common, serious childhood illnesses. We compared performance in the pre-intervention (2005) and post-intervention periods (2009) using quality indicators for three diseases: pneumonia, dehydration and severe malnutrition. The indicators spanned four domains in the continuum of care namely assessment, classification, treatment, and follow-up care in the initial 48 hours of admission. In the pre-intervention period patients' care was largely inconsistent with the guidelines, with nine of the 15 key indicators having performance of below 10%. The intervention produced a marked improvement in guideline adherence with an absolute effect size of over 20% observed in seven of the 15 key indicators; three of which had an effect size of over 50%. However, for all the five indicators that required sustained team effort performance continued to be poor, at less than 10%, in the post-intervention period. Data from the five-year period (2005-09) suggest some dose dependency though the adoption rate of the best-practices varied across diseases and over time. Active dissemination of locally adapted clinical guidelines for common serious childhood illnesses can achieve a significant impact on documented clinical practices, particularly for tasks that rely on competence of individual clinicians. However, more attention must be given to broader implementation strategies that also target institutional and organisational aspects of service delivery to further enhance quality-of-care.

The parental non-equivalence of imprinting control regions during mammalian development and evolution.

PubMed

Schulz, Reiner; Proudhon, Charlotte; Bestor, Timothy H; Woodfine, Kathryn; Lin, Chyuan-Sheng; Lin, Shau-Ping; Prissette, Marine; Oakey, Rebecca J; Bourc'his, Déborah

2010-11-18

In mammals, imprinted gene expression results from the sex-specific methylation of imprinted control regions (ICRs) in the parental germlines. Imprinting is linked to therian reproduction, that is, the placenta and imprinting emerged at roughly the same time and potentially co-evolved. We assessed the transcriptome-wide and ontology effect of maternally versus paternally methylated ICRs at the developmental stage of setting of the chorioallantoic placenta in the mouse (8.5dpc), using two models of imprinting deficiency including completely imprint-free embryos. Paternal and maternal imprints have a similar quantitative impact on the embryonic transcriptome. However, transcriptional effects of maternal ICRs are qualitatively focused on the fetal-maternal interface, while paternal ICRs weakly affect non-convergent biological processes, with little consequence for viability at 8.5dpc. Moreover, genes regulated by maternal ICRs indirectly influence genes regulated by paternal ICRs, while the reverse is not observed. The functional dominance of maternal imprints over early embryonic development is potentially linked to selection pressures favoring methylation-dependent control of maternal over paternal ICRs. We previously hypothesized that the different methylation histories of ICRs in the maternal versus the paternal germlines may have put paternal ICRs under higher mutational pressure to lose CpGs by deamination. Using comparative genomics of 17 extant mammalian species, we show here that, while ICRs in general have been constrained to maintain more CpGs than non-imprinted sequences, the rate of CpG loss at paternal ICRs has indeed been higher than at maternal ICRs during evolution. In fact, maternal ICRs, which have the characteristics of CpG-rich promoters, have gained CpGs compared to non-imprinted CpG-rich promoters. Thus, the numerical and, during early embryonic development, functional dominance of maternal ICRs can be explained as the consequence of two orthogonal evolutionary forces: pressure to tightly regulate genes affecting the fetal-maternal interface and pressure to avoid the mutagenic environment of the paternal germline.

The Parental Non-Equivalence of Imprinting Control Regions during Mammalian Development and Evolution

PubMed Central

Bestor, Timothy H.; Woodfine, Kathryn; Lin, Chyuan-Sheng; Lin, Shau-Ping; Prissette, Marine; Oakey, Rebecca J.; Bourc'his, Déborah

2010-01-01

In mammals, imprinted gene expression results from the sex-specific methylation of imprinted control regions (ICRs) in the parental germlines. Imprinting is linked to therian reproduction, that is, the placenta and imprinting emerged at roughly the same time and potentially co-evolved. We assessed the transcriptome-wide and ontology effect of maternally versus paternally methylated ICRs at the developmental stage of setting of the chorioallantoic placenta in the mouse (8.5dpc), using two models of imprinting deficiency including completely imprint-free embryos. Paternal and maternal imprints have a similar quantitative impact on the embryonic transcriptome. However, transcriptional effects of maternal ICRs are qualitatively focused on the fetal-maternal interface, while paternal ICRs weakly affect non-convergent biological processes, with little consequence for viability at 8.5dpc. Moreover, genes regulated by maternal ICRs indirectly influence genes regulated by paternal ICRs, while the reverse is not observed. The functional dominance of maternal imprints over early embryonic development is potentially linked to selection pressures favoring methylation-dependent control of maternal over paternal ICRs. We previously hypothesized that the different methylation histories of ICRs in the maternal versus the paternal germlines may have put paternal ICRs under higher mutational pressure to lose CpGs by deamination. Using comparative genomics of 17 extant mammalian species, we show here that, while ICRs in general have been constrained to maintain more CpGs than non-imprinted sequences, the rate of CpG loss at paternal ICRs has indeed been higher than at maternal ICRs during evolution. In fact, maternal ICRs, which have the characteristics of CpG-rich promoters, have gained CpGs compared to non-imprinted CpG-rich promoters. Thus, the numerical and, during early embryonic development, functional dominance of maternal ICRs can be explained as the consequence of two orthogonal evolutionary forces: pressure to tightly regulate genes affecting the fetal-maternal interface and pressure to avoid the mutagenic environment of the paternal germline. PMID:21124941

Lack of chart reminder effectiveness on family medicine resident JNC-VI and NCEP III guideline knowledge and attitudes.

PubMed

Echlin, Paul S; Upshur, Ross E G; Markova, Tsveti P

2004-07-05

The literature demonstrates that medical residents and practicing physicians have an attitudinal-behavioral discordance concerning their positive attitudes towards clinical practice guidelines (CPG), and the implementation of these guidelines into clinical practice patterns. A pilot study was performed to determine if change in a previously identified CPG compliance factor (accessibility) would produce a significant increase in family medicine resident knowledge and attitude toward the guidelines. The primary study intervention involved placing a summary of the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) and the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP III) CPGs in all patient (>18 yr.) charts for a period of three months. The JNC VI and NCEP III CPGs were also distributed to each Wayne State family medicine resident, and a copy of each CPG was placed in the preceptor's area of the involved clinics. Identical pre- and post- intervention questionnaires were administered to all residents concerning CPG knowledge and attitude. Post-intervention analysis failed to demonstrate a significant difference in CPG knowledge. A statistically significant post-intervention difference was found in only on attitude question. The barriers to CPG compliance were identified as 1) lack of CPG instruction; 2) lack of critical appraisal ability; 3) insufficient time; 4) lack of CPG accessibility; and 5) lack of faculty modeling. This study demonstrated no significant post intervention changes in CPG knowledge, and only one question that reflected attitude change. Wider resident access to dedicated clinic time, increased faculty modeling, and the implementation of an electronic record/reminder system that uses a team-based approach are compliance factors that should be considered for further investigation. The interpretation of CPG non-compliance will benefit from a causal matrix focused on physician knowledge, attitudes, and behavior. Recent findings in resident knowledge-behavior discordance may direct the future investigation of physician CPG non-compliance away from generalized barrier research, and toward the development of information that maximizes the sense of individual practitioner urgency and certainty.

Pediatric Audiology in North America: Current Clinical Practice and How It Relates to the American Academy of Audiology Pediatric Amplification Guideline.

PubMed

Moodie, Sheila; Rall, Eileen; Eiten, Leisha; Lindley, George; Gordey, Dave; Davidson, Lisa; Bagatto, Marlene; Scollie, Susan

2016-03-01

There is broad consensus that screening and diagnosis of permanent hearing loss in children must be embedded within a comprehensive, evidence-based, family-centered intervention program. Clinical practice guidelines (CPGs) for pediatric hearing assessment and hearing aid verification aim to reduce variability in practice and increase the use of effective evidence-based diagnostic and treatment options so that optimal outcomes may be achieved. To be of value, guidelines must be translated and implemented into practice and ongoing monitoring of their use in practice should occur. This paper provides the results of two studies that aim to examine current pediatric audiology and amplification practice in North America. A concurrent embedded mixed methods design was used. An electronic survey was distributed to North American audiologists who delivered pediatric audiology services with 350 audiologists participating in study 1 and 63 audiologists participating in study 2. A quantitative approach was the predominant method of data collection. Respondents were prompted to provide additional qualitative text and detail regarding their quantitative response choice. This qualitative text was used during the analysis phase and combined with quantitative results to assist understanding of respondents' knowledge, skills, and barriers/facilitators to implement best practice in pediatric amplification. Approximately 70% of audiologists reported using best-practice protocols for pediatric hearing aid fitting. Despite widespread knowledge and increased use of CPGs over the last 18 yrs, results of these studies show that variation in practice patterns continue to exist. Several examples of implementation challenges are discussed with recommendations provided. In order for audiologists working with children who are deaf or hard of hearing and their families to achieve the principles of family-centered early intervention, practice guidelines must continue to be developed, disseminated, and translated as they have a positive impact on the services provided. Researchers and clinical audiologists who deliver services must continue to collaborate to understand the "how" and "why" of implementing guidelines into practice and to identify the barriers/facilitators encountered in trying to do so. American Academy of Audiology.

Mecp2 deficiency leads to altered Htr2c pre-mRNA editing and HTR2C isoform distribution in mouse hippocampus and cerebellum

USDA-ARS?s Scientific Manuscript database

Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, a methyl-CpG binding protein and transcriptional repressor. CpG methylation plays an important role in genomic imprinting since imprinted genes are regulated by regions of differentially methylated CpGs (or ICs). A ...

Nurses’ Role in the Joint Theater Trauma System

DTIC Science & Technology

2008-12-01

elevation, etc) and input for ventilator-associated pneumonia and infection control CPGs. In addition, a methicillin - resistant Staphylococcus aureus and...Standard Form 298 (Rev. 8-98) Prescribed by ANSI-Std Z39-18 REPORT DOCUMENTATION PAGE Form Approved OMB No. 0704-0188 Public reporting burden...MONITORING AGENCY REPORT NUMBER 12. DISTRIBUTION AVAILABILITY STATEMENT Distribution A: Approved for public release; distribution is

People Getting a Grip on Arthritis: A Knowledge Transfer Strategy to Empower Patients with Rheumatoid Arthritis and Osteoarthritis

ERIC Educational Resources Information Center

Brosseau, Lucie; Lineker, Sydney; Bell, Mary; Wells, George; Casimiro, Lynn; Egan, Mary; Cranney, Ann; Tugwell, Peter; Wilson, Keith G.; De Angelis, Gino; Loew, Laurianne

2012-01-01

Objective: The purpose of this study was twofold. First, to help people with arthritis become aware of and utilize Rheumatoid Arthritis (RA) and Osteoarthritis (OA) Clinical Practice Guidelines (CPGs) as they relate to self-management strategies. Second, to evaluate the impact of specific Knowledge Translation (KT) activities on CPG uptake. More…

Integrating Clinical Practice Guidelines into Daily Practice: Impact of an Interactive Workshop on Drafting of a Written Action Plan for Asthma Patients

ERIC Educational Resources Information Center

Labelle, Martin; Beaulieu, Michele; Renzi, Paolo; Rahme, Elham; Thivierge, Robert L.

2004-01-01

Introduction: Written action plans (WAPs) are instructions that enable asthmatics to manage their condition appropriately and are recommended by current asthma clinical practice guidelines (CPGs). However, general practitioners (GPs) rarely draft WAPs for their patients. An interactive, case-based workshop for asthma, combined with an objective…

[Development of quality of care indicators to support chronic disease management].

PubMed

Beaulieu, Marie-dominique; Pomey, Marie-pascale; Del Grande, Claudio; Côté, Brigitte; Tremblay, Éric; Ghorbel, Monia; Hua, Phuong

2015-01-01

This article presents the results of a project conducted by the Institut national d'excellence en santé et en services sociaux of Québec to develop quality of care indicators for the management of six chronic illnesses. Indicators were identified through literature searches and analysis of clinical practice guidelines (CPGs). Interdisciplinary expert panels assessed their validity and the strength of the evidence on which they were based. Representatives of patients (N = 19) and professionals (N = 29) were consulted on their relevance and acceptability. Indicators were categorized according to the Chronic Care Model (CCM). A total of 164 indicators were developed, 126 specific to the illnesses under study and 38 on processes and outcomes generic to the CCM. There was convergence between patients and professionals on the relevance of a majority of indicators. Professionals expressed concerns on the indicators measured by means of patient surveys that they considered to be too subjective. The importance given to CPGs as the main source of indicators resulted in a great number of indicators of the technical quality ofcare. Using the CCM contributed to a broader perspective of quality. The consultation process identified some of the concerns of professionals about indicator measurement, thusguidingfuture implementation initiatives.

Coordination polymer gels with important environmental and biological applications.

PubMed

Jung, Jong Hwa; Lee, Ji Ha; Silverman, Julian R; John, George

2013-02-07

Coordination Polymer Gels (CPGs) constitute a subset of solid-like metal ion and bridging organic ligand structures (similar to metal-organic frameworks) that form multi-dimensional networks through a trapped solvent as a result of non-covalent interactions. While physical properties of these gels are similar to conventional high molecular weight organic polymer gels, coordination polymer gel systems are often fully reversible and can be assembled and disassembled in the presence of additional energy (heat, sonication, shaking) to give a solution of solvated gelators. Compared to gels resulting from purely organic self-assembled low molecular weight gelators, metal ions incorporated into the fibrilar networks spanning the bulk solvent can impart CPGs with added functionalities. The solid/liquid nature of the gels allows for species to migrate through the gel system and interact with metals, ligands, and the solvent. Chemosensing, catalysis, fluorescence, and drug-delivery applications are some of the many potential uses for these dynamic systems, taking advantage of the metal ion's coordination, the organic polydentate ligand's orientation and functionality, or a combination of these properties. By fine tuning these systems through metal ion and ligand selection and by directing self-assembly with external stimuli the rational synthesis of practical systems can be envisaged.

A significant association between BDNF promoter methylation and the risk of drug addiction.

PubMed

Xu, Xuting; Ji, Huihui; Liu, Guili; Wang, Qinwen; Liu, Huifen; Shen, Wenwen; Li, Longhui; Xie, Xiaohu; Zhou, Wenhua; Duan, Shiwei

2016-06-10

As a member of the neurotrophic factor family, brain derived neurotrophic factor (BDNF) plays an important role in the survival and differentiation of neurons. The aim of our work was to evaluate the role of BDNF promoter methylation in drug addiction. A total of 60 drug abusers (30 heroin and 30 methylamphetamine addicts) and 52 healthy age- and gender-matched controls were recruited for the current case control study. Bisulfite pyrosequencing technology was used to determine the methylation levels of five CpGs (CpG1-5) on the BDNF promoter. Among the five CpGs, CpG5 methylation was significantly lower in drug abusers than controls. Moreover, significant associations were found between CpG5 methylation and addictive phenotypes including tension-anxiety, anger-hostility, fatigue-inertia, and depression-dejection. In addition, luciferase assay showed that the DNA fragment of BDNF promoter played a key role in the regulation of gene expression. Our results suggest that BDNF promoter methylation is associated with drug addiction, although further studies are needed to understand the mechanisms by which BDNF promoter methylation contributes to the pathophysiology of drug addiction. Copyright © 2016. Published by Elsevier B.V.

CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors

PubMed Central

Negrotto, Soledad; Ng, Kwok Peng; Jankowska, Ania M.; Bodo, Juraj; Gopalan, Banu; Guinta, Kathryn; Mulloy, James C.; Hsi, Eric; Maciejewski, Jaroslaw; Saunthararajah, Yogen

2011-01-01

The DNA hypomethylating drug decitabine maintains normal hematopoietic stem cell (HSC) self-renewal but induces terminal differentiation in acute myeloid leukemia (AML) cells. The basis for these contrasting cell-fates, and for selective CpG hypomethylation by decitabine, is poorly understood. Promoter CpGs, with methylation measured by microarray, were classified by the direction of methylation change with normal myeloid maturation. In AML cells, the methylation pattern at maturation-responsive CpG suggested at least partial maturation. Consistent with partial maturation, in gene expression analyses, AML cells expressed high levels of the key lineage-specifying factor CEBPA, but relatively low levels of the key late-differentiation driver CEBPE. In methylation analysis by mass-spectrometry, CEBPE promoter CpG that are usually hypomethylated during granulocyte maturation were significantly hypermethylated in AML cells. Decitabine treatment induced cellular differentiation of AML cells, and the largest methylation decreases were at CpG that are hypomethylated with myeloid maturation, including CEBPE promoter CpG. In contrast, decitabine-treated normal HSC retained immature morphology, and methylation significantly decreased at CpG that are less methylated in immature cells. High expression of lineage-specifying factor and aberrant epigenetic repression of some key late-differentiation genes distinguishes AML cells from normal HSC and could explain the contrasting differentiation and methylation responses to decitabine. PMID:21836612

Epigenetic differences between monozygotic twins discordant for amyotrophic lateral sclerosis (ALS) provide clues to disease pathogenesis.

PubMed

Young, Paul E; Kum Jew, Stephen; Buckland, Michael E; Pamphlett, Roger; Suter, Catherine M

2017-01-01

Amyotrophic lateral sclerosis (ALS) is a devastating late-onset neurodegenerative disorder in which only a small proportion of patients carry an identifiable causative genetic lesion. Despite high heritability estimates, a genetic etiology for most sporadic ALS remains elusive. Here we report the epigenetic profiling of five monozygotic twin pairs discordant for ALS, four with classic ALS and one with the progressive muscular atrophy ALS variant, in whom previous whole genome sequencing failed to uncover a genetic basis for their disease discordance. By studying cytosine methylation patterns in peripheral blood DNA we identified thousands of large between-twin differences at individual CpGs. While the specific sites of differences were mostly idiosyncratic to a twin pair, a proportion involving GABA signalling were common to all ALS individuals. For both idiosyncratic and common sites the differences occurred within genes and pathways related to neurobiological functions or dysfunctions, some of particular relevance to ALS such as glutamate metabolism and the Golgi apparatus. All four classic ALS patients were epigenetically older than their unaffected co-twins, suggesting accelerated aging in multiple tissues in this disease. In conclusion, widespread changes in methylation patterns were found in ALS-affected co-twins, consistent with an epigenetic contribution to disease. These DNA methylation findings could be used to develop blood-based ALS biomarkers, gain insights into disease pathogenesis, and provide a reference for future large-scale ALS epigenetic studies.

DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors.

PubMed

Amatruda, James F; Ross, Julie A; Christensen, Brock; Fustino, Nicholas J; Chen, Kenneth S; Hooten, Anthony J; Nelson, Heather; Kuriger, Jacquelyn K; Rakheja, Dinesh; Frazier, A Lindsay; Poynter, Jenny N

2013-06-27

Aberrant DNA methylation is a prominent feature of many cancers, and may be especially relevant in germ cell tumors (GCTs) due to the extensive epigenetic reprogramming that occurs in the germ line during normal development. We used the Illumina GoldenGate Cancer Methylation Panel to compare DNA methylation in the three main histologic subtypes of pediatric GCTs (germinoma, teratoma and yolk sac tumor (YST); N = 51) and used recursively partitioned mixture models (RPMM) to test associations between methylation pattern and tumor and demographic characteristics. We identified genes and pathways that were differentially methylated using generalized linear models and Ingenuity Pathway Analysis. We also measured global DNA methylation at LINE1 elements and evaluated methylation at selected imprinted loci using pyrosequencing. Methylation patterns differed by tumor histology, with 18/19 YSTs forming a distinct methylation class. Four pathways showed significant enrichment for YSTs, including a human embryonic stem cell pluripotency pathway. We identified 190 CpG loci with significant methylation differences in mature and immature teratomas (q < 0.05), including a number of CpGs in stem cell and pluripotency-related pathways. Both YST and germinoma showed significantly lower methylation at LINE1 elements compared with normal adjacent tissue while there was no difference between teratoma (mature and immature) and normal tissue. DNA methylation at imprinted loci differed significantly by tumor histology and location. Understanding methylation patterns may identify the developmental stage at which the GCT arose and the at-risk period when environmental exposures could be most harmful. Further, identification of relevant genetic pathways could lead to the development of new targets for therapy.

Breast tumor DNA methylation patterns associated with smoking in the Carolina Breast Cancer Study.

PubMed

Conway, Kathleen; Edmiston, Sharon N; Parrish, Eloise; Bryant, Christopher; Tse, Chiu-Kit; Swift-Scanlan, Theresa; McCullough, Lauren E; Kuan, Pei Fen

2017-06-01

Tobacco smoking is a risk factor in several cancers, yet its roles as a putative etiologic exposure or poor prognostic factor in breast cancer are less clear. Altered DNA methylation contributes to breast cancer development and may provide a mechanistic link between smoking and gene expression changes leading to cancer development or progression. Using a cancer-focused array, we examined methylation at 933 CpGs in 517 invasive breast tumors in the Carolina Breast Cancer Study to determine whether methylation patterns differ by exposure to tobacco smoke. Multivariable generalized linear regression models were used to compare tumor methylation profiles between smokers and never smokers, overall, or stratified on hormone receptor (HR) status. Modest differences in CpG methylation were detected at p < 0.05 in breast tumors from current or ever smokers compared with never smokers. In stratified analyses, HR- tumors from smokers exhibited primarily hypomethylation compared with tumors from never smokers; hypomethylation was similarly detected within the more homogeneous basal-like subtype. Most current smoking-associated CpG loci exhibited methylation levels in former smokers that were intermediate between those in current and never smokers and exhibited progressive changes in methylation with increasing duration of smoking. Among former smokers, restoration of methylation toward baseline (never smoking) levels was observed with increasing time since quitting. Moreover, smoking-related hypermethylation was stronger in HR+ breast tumors from blacks than in whites. Our results suggest that breast tumor methylation patterns differ with tobacco smoke exposure; however, additional studies are needed to confirm these findings.

Aberrant DNA methylation patterns of spermatozoa in men with unexplained infertility.

PubMed

Urdinguio, Rocío G; Bayón, Gustavo F; Dmitrijeva, Marija; Toraño, Estela G; Bravo, Cristina; Fraga, Mario F; Bassas, Lluís; Larriba, Sara; Fernández, Agustín F

2015-05-01

Are there DNA methylation alterations in sperm that could explain the reduced biological fertility of male partners from couples with unexplained infertility? DNA methylation patterns, not only at specific loci but also at Alu Yb8 repetitive sequences, are altered in infertile individuals compared with fertile controls. Aberrant DNA methylation of sperm has been associated with human male infertility in patients demonstrating either deficiencies in the process of spermatogenesis or low semen quality. Case and control prospective study. This study compares 46 sperm samples obtained from 17 normospermic fertile men and 29 normospermic infertile patients. Illumina Infinium HD Human Methylation 450K arrays were used to identify genomic regions showing differences in sperm DNA methylation patterns between five fertile and seven infertile individuals. Additionally, global DNA methylation of sperm was measured using the Methylamp Global DNA Methylation Quantification Ultra kit (Epigentek) in 14 samples, and DNA methylation at several repetitive sequences (LINE-1, Alu Yb8, NBL2, D4Z4) measured by bisulfite pyrosequencing in 44 sperm samples. A sperm-specific DNA methylation pattern was obtained by comparing the sperm methylomes with the DNA methylomes of differentiated somatic cells using data obtained from methylation arrays (Illumina 450 K) of blood, neural and glial cells deposited in public databases. In this study we conduct, for the first time, a genome-wide study to identify alterations of sperm DNA methylation in individuals with unexplained infertility that may account for the differences in their biological fertility compared with fertile individuals. We have identified 2752 CpGs showing aberrant DNA methylation patterns, and more importantly, these differentially methylated CpGs were significantly associated with CpG sites which are specifically methylated in sperm when compared with somatic cells. We also found statistically significant (P < 0.001) associations between DNA hypomethylation and regions corresponding to those which, in somatic cells, are enriched in the repressive histone mark H3K9me3, and between DNA hypermethylation and regions enriched in H3K4me1 and CTCF, suggesting that the relationship between chromatin context and aberrant DNA methylation of sperm in infertile men could be locus-dependent. Finally, we also show that DNA methylation patterns, not only at specific loci but also at several repetitive sequences (LINE-1, Alu Yb8, NBL2, D4Z4), were lower in sperm than in somatic cells. Interestingly, sperm samples at Alu Yb8 repetitive sequences of infertile patients showed significantly lower DNA methylation levels than controls. Our results are descriptive and further studies would be needed to elucidate the functional effects of aberrant DNA methylation on male fertility. Overall, our data suggest that aberrant sperm DNA methylation might contribute to fertility impairment in couples with unexplained infertility and they provide a promising basis for future research. This work has been financially supported by Fundación Cientifica de la AECC (to R.G.U.); IUOPA (to G.F.B.); FICYT (to E.G.T.); the Spanish National Research Council (CSIC; 200820I172 to M.F.F.); Fundación Ramón Areces (to M.F.F); the Plan Nacional de I+D+I 2008-2011/2013-2016/FEDER (PI11/01728 to AF.F., PI12/01080 to M.F.F. and PI12/00361 to S.L.); the PN de I+D+I 2008-20011 and the Generalitat de Catalunya (2009SGR01490). A.F.F. is sponsored by ISCIII-Subdirección General de Evaluación y Fomento de la Investigación (CP11/00131). S.L. is sponsored by the Researchers Stabilization Program from the Spanish National Health System (CES09/020). The IUOPA is supported by the Obra Social Cajastur, Spain. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Conventional Prompt Global Strike and Long Range Ballistic Missiles: Background and Issues

DTIC Science & Technology

2017-02-03

Conventional Prompt Global Strike and Long-Range Ballistic Missiles: Background and Issues Amy F. Woolf Specialist in Nuclear Weapons Policy...February 3, 2017 Congressional Research Service 7-5700 www.crs.gov R41464 Conventional Prompt Global Strike and Long-Range Ballistic Missiles...Congressional Research Service Summary Conventional prompt global strike (CPGS) weapons would allow the United States to strike targets anywhere

Donor age and C1orf132/MIR29B2C determine age-related methylation signature of blood after allogeneic hematopoietic stem cell transplantation.

PubMed

Spólnicka, Magdalena; Piekarska, Renata Zbieć; Jaskuła, Emilia; Basak, Grzegorz W; Jacewicz, Renata; Pięta, Agnieszka; Makowska, Żanetta; Jedrzejczyk, Maciej; Wierzbowska, Agnieszka; Pluta, Agnieszka; Robak, Tadeusz; Berent, Jarosław; Branicki, Wojciech; Jędrzejczak, Wiesław; Lange, Andrzej; Płoski, Rafał

2016-01-01

Our recent study demonstrated that DNA methylation status in a set of CpGs located in ELOVL2, C1orf132, TRIM59, KLF14, and FHL2 can accurately predict calendar age in blood. In the present work, we used these markers to evaluate the effect of allogeneic hematopoietic stem cell transplantation (HSCT) on the age-related methylation signature of human blood. DNA methylation in 32 CpGs was investigated in 16 donor-recipient pairs using pyrosequencing. DNA was isolated from the whole blood collected from recipients 27-360 days (mean 126) after HSCT and from the donors shortly before the HSCT. It was found that in the recipients, the predicted age did not correlate with their calendar age but was correlated with the calendar age (r = 0.94, p = 4 × 10(-8)) and predicted age (r = 0.97, p = 5 × 10(-10)) of a respective donor. Despite this strong correlation, the predicted age of a recipient was consistently lower than the predicted age of a donor by 3.7 years (p = 7.8 × 10(-4)). This shift was caused by hypermethylation of the C1orf132 CpGs, for C1orf132 CpG_1. Intriguingly, the recipient-donor methylation difference correlated with calendar age of the donor (r = 0.76, p = 6 × 10(-4)). This finding could not trivially be explained by shifts of the major cellular factions of blood. We confirm the single previous report that after HSCT, the age of the donor is the major determinant of age-specific methylation signature in recipient's blood. A novel finding is the unique methylation dynamics of C1orf132 which encodes MIR29B2C implicated in the self-renewing of hematopoietic stem cells. This observation suggests that C1orf132 could influence graft function after HSCT.

DNA methylation in the APOE genomic region is associated with cognitive function in African Americans.

PubMed

Liu, Jiaxuan; Zhao, Wei; Ware, Erin B; Turner, Stephen T; Mosley, Thomas H; Smith, Jennifer A

2018-05-08

Genetic variations in apolipoprotein E (APOE) and proximal genes (PVRL2, TOMM40, and APOC1) are associated with cognitive function and dementia, particularly Alzheimer's disease. Epigenetic mechanisms such as DNA methylation play a central role in the regulation of gene expression. Recent studies have found evidence that DNA methylation may contribute to the pathogenesis of dementia, but its association with cognitive function in populations without dementia remains unclear. We assessed DNA methylation levels of 48 CpG sites in the APOE genomic region in peripheral blood leukocytes collected from 289 African Americans (mean age = 67 years) from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Using linear regression, we examined the relationship between methylation in the APOE genomic region and multiple cognitive measures including learning, memory, processing speed, concentration, language and global cognitive function. We identified eight CpG sites in three genes (PVRL2, TOMM40, and APOE) that showed an inverse association between methylation level and delayed recall, a measure of memory, after adjusting for age and sex (False Discovery Rate q-value < 0.1). All eight CpGs are located in either CpG islands (CGIs) or CGI shelves, and six of them are in promoter regions. Education and APOE ε4 carrier status significantly modified the effect of methylation in cg08583001 (PVRL2) and cg22024783 (TOMM40), respectively. Together, methylation of the eight CpGs explained an additional 8.7% of the variance in delayed recall, after adjustment for age, sex, education, and APOE ε4 carrier status. Methylation was not significantly associated with any other cognitive measures. Our results suggest that methylation levels at multiple CpGs in the APOE genomic region are inversely associated with delayed recall during normal cognitive aging, even after accounting for known genetic predictors for cognition. Our findings highlight the important role of epigenetic mechanisms in influencing cognitive performance, and suggest that changes in blood methylation may be an early indicator of individuals at risk for dementia as well as potential targets for intervention in asymptomatic populations.

Epigenetic Gene Promoter Methylation at Birth Is Associated With Child’s Later Adiposity

PubMed Central

Godfrey, Keith M.; Sheppard, Allan; Gluckman, Peter D.; Lillycrop, Karen A.; Burdge, Graham C.; McLean, Cameron; Rodford, Joanne; Slater-Jefferies, Joanne L.; Garratt, Emma; Crozier, Sarah R.; Emerald, B. Starling; Gale, Catharine R.; Inskip, Hazel M.; Cooper, Cyrus; Hanson, Mark A.

2011-01-01

OBJECTIVE Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans. RESEARCH DESIGN AND METHODS Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5′ from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ≥5% and a 5–95% range ≥10%, we related methylation status to maternal pregnancy diet and to child’s adiposity at age 9 years. Replication was sought in a second independent cohort. RESULTS In cohort 1, retinoid X receptor-α (RXRA) chr9:136355885+ and endothelial nitric oxide synthase (eNOS) chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient [β] 17% per SD change in methylation [95% CI 4–31], P = 0.009, n = 64, and β = 20% [9–32], P < 0.001, n = 66, respectively) and %fat mass (β = 10% [1–19], P = 0.023, n = 64 and β =12% [4–20], P = 0.002, n = 66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (β = 6% [2–10] and β = 4% [1–7], respectively, both P = 0.002, n = 239). CONCLUSIONS Our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease. PMID:21471513

Patients' Experiences With Vehicle Collision to Inform the Development of Clinical Practice Guidelines: A Narrative Inquiry.

PubMed

Lindsay, Gail M; Mior, Silvano A; Côté, Pierre; Carroll, Linda J; Shearer, Heather M

2016-01-01

The purpose of this narrative inquiry was to explore the experiences of persons who were injured in traffic collisions and seek their recommendations for the development of clinical practice guideline (CPG) for the management of minor traffic injuries. Patients receiving care for traffic injuries were recruited from 4 clinics in Ontario, Canada resulting in 11 adult participants (5 men, 6 women). Eight were injured while driving cars, 1 was injured on a motorcycle, 2 were pedestrians, and none caused the collision. Using narrative inquiry methodology, initial interviews were audiotaped, and follow-up interviews were held within 2 weeks to extend the story of experience created from the first interview. Narrative plotlines across the 11 stories were identified, and a composite story inclusive of all recommendations was developed by the authors. The research findings and composite narrative were used to inform the CPG Expert Panel in the development of new CPGs. Four recommended directions were identified from the narrative inquiry process and applied. First, terminology that caused stigma was a concern. This resulted in modified language ("injured persons") being adopted by the Expert Panel, and a new nomenclature categorizing layers of injury was identified. Second, participants valued being engaged as partners with health care practitioners. This resulted in inclusion of shared decision-making as a foundational recommendation connecting CPGs and care planning. Third, emotional distress was recognized as a factor in recovery. Therefore, the importance of early detection and the ongoing evaluation of risk factors for delayed recovery were included in all CPGs. Fourth, participants shared that they were unfamiliar with the health care system and insurance industry before their accident. Thus, repeatedly orienting injured persons to the system was advised. A narrative inquiry of 11 patients' experiences with traffic collision and their recommendations for clinical guidelines informed the Ontario Protocol for Traffic Injury Management Collaboration in the development of new Minor Injury Guidelines. The values and findings of the qualitative inquiry were interwoven into each clinical pathway and embedded within the final guideline report submitted to government. Copyright © 2016 National University of Health Sciences. Published by Elsevier Inc. All rights reserved.

Associations Between MAOA-uVNTR Genotype, Maltreatment, MAOA Methylation, and Alcohol Consumption in Young Adult Males.

PubMed

Bendre, Megha; Comasco, Erika; Checknita, Dave; Tiihonen, Jari; Hodgins, Sheilagh; Nilsson, Kent W

2018-03-01

Epigenetic mechanisms are candidate moderators of the effect of maltreatment on brain and behavior. Interactions between maltreatment and the monoamine oxidase A upstream variable number tandem repeat genotype (MAOA-uVNTR) are associated with alcohol-related problems. However, presently it is not known whether DNA methylation moderates this association. The study focused on 53 young adult males and aimed to determine whether MAOA methylation moderated the association of alcohol-related problems with the interaction of MAOA-uVNTR and maltreatment, and whether alcohol consumption moderated the association of MAOA methylation with the interaction of MAOA-uVNTR and maltreatment. MAOA-uVNTR genotypes with ≤ 3 and > 3 repeats were categorized as short (S) and long (L), respectively. Data on maltreatment were obtained retrospectively, using self-reported questionnaires. DNA methylation of 16 candidate CpGs within part of the MAOA first exon and intron was assessed and grouped based on principal component analyses. Alcohol-related problems were assessed using the Alcohol Use Disorders Identification Test (AUDIT). Alcohol consumption was measured using AUDIT-C. Moderation effects were assessed and probed using the moderated moderation model and Johnson-Neyman's method, respectively. Carriers of the S allele, who experienced maltreatment and displayed lower Component 1 (mean of CpGs 13-16 in the first intron) MAOA methylation levels, reported higher AUDIT score in contrast to L-allele carriers. Carriers of the S allele, who reported higher AUDIT-C score and experienced maltreatment, displayed lower Component 3 (mean of CpGs 2-6 in the first exon) MAOA methylation levels than L-allele carriers. Intronic methylation moderated the association of alcohol-related problems with the interaction of MAOA-uVNTR and maltreatment. Alcohol consumption moderated the association of exonic methylation with the interaction of MAOA-uVNTR and maltreatment. These results suggest that epigenetic factors as well as genotype and maltreatment play a role in the development of alcohol misuse among young adult males. Copyright © 2017 by the Research Society on Alcoholism.

Strategies to assess the validity of recommendations: a study protocol

PubMed Central

2013-01-01

Background Clinical practice guidelines (CPGs) become quickly outdated and require a periodic reassessment of evidence research to maintain their validity. However, there is little research about this topic. Our project will provide evidence for some of the most pressing questions in this field: 1) what is the average time for recommendations to become out of date?; 2) what is the comparative performance of two restricted search strategies to evaluate the need to update recommendations?; and 3) what is the feasibility of a more regular monitoring and updating strategy compared to usual practice?. In this protocol we will focus on questions one and two. Methods The CPG Development Programme of the Spanish Ministry of Health developed 14 CPGs between 2008 and 2009. We will stratify guidelines by topic and by publication year, and include one CPG by strata. We will develop a strategy to assess the validity of CPG recommendations, which includes a baseline survey of clinical experts, an update of the original exhaustive literature searches, the identification of key references (reference that trigger a potential recommendation update), and the assessment of the potential changes in each recommendation. We will run two alternative search strategies to efficiently identify important new evidence: 1) PLUS search based in McMaster Premium LiteratUre Service (PLUS) database; and 2) a Restrictive Search (ReSe) based on the least number of MeSH terms and free text words needed to locate all the references of each original recommendation. We will perform a survival analysis of recommendations using the Kaplan-Meier method and we will use the log-rank test to analyse differences between survival curves according to the topic, the purpose, the strength of recommendations and the turnover. We will retrieve key references from the exhaustive search and evaluate their presence in the PLUS and ReSe search results. Discussion Our project, using a highly structured and transparent methodology, will provide guidance of when recommendations are likely to be at risk of being out of date. We will also assess two novel restrictive search strategies which could reduce the workload without compromising rigour when CPGs developers check for the need of updating. PMID:23967896

DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk.

PubMed

Baglietto, Laura; Ponzi, Erica; Haycock, Philip; Hodge, Allison; Bianca Assumma, Manuela; Jung, Chol-Hee; Chung, Jessica; Fasanelli, Francesca; Guida, Florence; Campanella, Gianluca; Chadeau-Hyam, Marc; Grankvist, Kjell; Johansson, Mikael; Ala, Ugo; Provero, Paolo; Wong, Ee Ming; Joo, Jihoon; English, Dallas R; Kazmi, Nabila; Lund, Eiliv; Faltus, Christian; Kaaks, Rudolf; Risch, Angela; Barrdahl, Myrto; Sandanger, Torkjel M; Southey, Melissa C; Giles, Graham G; Johansson, Mattias; Vineis, Paolo; Polidoro, Silvia; Relton, Caroline L; Severi, Gianluca

2017-01-01

DNA methylation changes are associated with cigarette smoking. We used the Illumina Infinium HumanMethylation450 array to determine whether methylation in DNA from pre-diagnostic, peripheral blood samples is associated with lung cancer risk. We used a case-control study nested within the EPIC-Italy cohort and a study within the MCCS cohort as discovery sets (a total of 552 case-control pairs). We validated the top signals in 429 case-control pairs from another 3 studies. We identified six CpGs for which hypomethylation was associated with lung cancer risk: cg05575921 in the AHRR gene (p-value pooled  = 4 × 10 -17 ), cg03636183 in the F2RL3 gene (p-value pooled  = 2 × 10 - 13 ), cg21566642 and cg05951221 in 2q37.1 (p-value pooled  = 7 × 10 -16 and 1 × 10 -11 respectively), cg06126421 in 6p21.33 (p-value pooled  = 2 × 10 -15 ) and cg23387569 in 12q14.1 (p-value pooled  = 5 × 10 -7 ). For cg05951221 and cg23387569 the strength of association was virtually identical in never and current smokers. For all these CpGs except for cg23387569, the methylation levels were different across smoking categories in controls (p-values heterogeneity  ≤ 1.8 x10 - 7 ), were lowest for current smokers and increased with time since quitting for former smokers. We observed a gain in discrimination between cases and controls measured by the area under the ROC curve of at least 8% (p-values ≥ 0.003) in former smokers by adding methylation at the 6 CpGs into risk prediction models including smoking status and number of pack-years. Our findings provide convincing evidence that smoking and possibly other factors lead to DNA methylation changes measurable in peripheral blood that may improve prediction of lung cancer risk. © 2016 UICC.

South African Guidelines Excellence (SAGE): Adopt, adapt, or contextualise?

PubMed

Dizon, J M; Grimmer, K; Louw, Q; Kredo, T; Young, T; Machingaidze, S

2016-12-01

Clinical practice guideline (CPG) activities must be planned carefully for efficient use of available resources and evidence-based implementation. De novo development of CPGs may sometimes 'recreate the wheel' and delay implementation. Three innovative alternatives to de novo CPG development (adopt, contextualise or adapt) are outlined, which have greater potential than de novo development to best use the limited available resources, personnel and time in settings such as South Africa.

Evaluation of Different Oligonucleotide Base Substitutions at CpG Binding sites in Multiplex Bisulfite-PCR sequencing.

PubMed

Lu, Jennifer; Ru, Kelin; Candiloro, Ida; Dobrovic, Alexander; Korbie, Darren; Trau, Matt

2017-03-22

Multiplex bisulfite-PCR sequencing is a convenient and scalable method for the quantitative determination of the methylation state of target DNA regions. A challenge of this application is the presence of CpGs in the same region where primers are being placed. A common solution to the presence of CpGs within a primer-binding region is to substitute a base degeneracy at the cytosine position. However, the efficacy of different substitutions and the extent to which bias towards methylated or unmethylated templates may occur has never been evaluated in bisulfite multiplex sequencing applications. In response, we examined the performance of four different primer substitutions at the cytosine position of CpG's contained within the PCR primers. In this study, deoxyinosine-, 5-nitroindole-, mixed-base primers and primers with an abasic site were evaluated across a series of methylated controls. Primers that contained mixed- or deoxyinosine- base modifications performed most robustly. Mixed-base primers were further selected to determine the conditions that induce bias towards methylated templates. This identified an optimized set of conditions where the methylated state of bisulfite DNA templates can be accurately assessed using mixed-base primers, and expands the scope of bisulfite resequencing assays when working with challenging templates.

Twenty-years of splenic preservation at a level 1 pediatric trauma center.

PubMed

Bairdain, Sigrid; Litman, Heather J; Troy, Michael; McMahon, Maria; Almodovar, Heidi; Zurakowski, David; Mooney, David P

2015-05-01

Splenic preservation is the standard of care for hemodynamically stable children with splenic injuries. We report a 20-year single-institutional series of children with splenic injuries managed without a splenectomy. Children evaluated and treated for blunt splenic injury at Boston Children's Hospital from 1994 to 2014 were extracted from the trauma registry. Demographics, clinical characteristics, complications, and outcomes were reviewed. Three time-periods were evaluated based upon the development and modification of splenic injury clinical pathway guidelines (CPGs). Survival was defined as being discharged from the hospital alive. 502 suffered isolated splenic injuries. The median AAST grade of splenic injury increased across the three CPG time periods (p<0.001). No splenic-injury related mortalities occurred. Hospital length of stay decreased significantly secondary to splenic injury CPGs (p<0.001). 99% of the patients were discharged home. In children managed over the last 20years for isolated splenic injury, no patient died or underwent splenectomy. Hospital length of stay decreased across time, despite an increase in the severity of splenic injuries encountered. Splenectomy has become so unusual in the management of hemodynamically stable children with a splenic injury that it may no longer be a legitimate outcome marker. Copyright © 2015 Elsevier Inc. All rights reserved.

Clinical algorithms to aid osteoarthritis guideline dissemination.

PubMed

Meneses, S R F; Goode, A P; Nelson, A E; Lin, J; Jordan, J M; Allen, K D; Bennell, K L; Lohmander, L S; Fernandes, L; Hochberg, M C; Underwood, M; Conaghan, P G; Liu, S; McAlindon, T E; Golightly, Y M; Hunter, D J

2016-09-01

Numerous scientific organisations have developed evidence-based recommendations aiming to optimise the management of osteoarthritis (OA). Uptake, however, has been suboptimal. The purpose of this exercise was to harmonize the recent recommendations and develop a user-friendly treatment algorithm to facilitate translation of evidence into practice. We updated a previous systematic review on clinical practice guidelines (CPGs) for OA management. The guidelines were assessed using the Appraisal of Guidelines for Research and Evaluation for quality and the standards for developing trustworthy CPGs as established by the National Academy of Medicine (NAM). Four case scenarios and algorithms were developed by consensus of a multidisciplinary panel. Sixteen guidelines were included in the systematic review. Most recommendations were directed toward physicians and allied health professionals, and most had multi-disciplinary input. Analysis for trustworthiness suggests that many guidelines still present a lack of transparency. A treatment algorithm was developed for each case scenario advised by recommendations from guidelines and based on panel consensus. Strategies to facilitate the implementation of guidelines in clinical practice are necessary. The algorithms proposed are examples of how to apply recommendations in the clinical context, helping the clinician to visualise the patient flow and timing of different treatment modalities. Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

The process of collecting and evaluating evidences for the development of Guidelines for the management of rheumatoid arthritis, Japan College of Rheumatology 2014: Utilization of GRADE approach.

PubMed

Kojima, Masayo; Nakayama, Takeo; Kawahito, Yutaka; Kaneko, Yuko; Kishimoto, Mitsumasa; Hirata, Shintaro; Seto, Yohei; Endo, Hirahito; Ito, Hiromu; Kojima, Toshihisa; Nishida, Keiichiro; Matsushita, Isao; Tsutani, Kiichiro; Igarashi, Ataru; Kamatani, Naoyuki; Hasegawa, Mieko; Miyasaka, Nobuyuki; Yamanaka, Hisashi

2016-01-01

To describe the process of collecting and evaluating evidence for treating rheumatoid arthritis (RA) for developing clinical practice guidelines (CPGs) for rheumatologists in Japan. The task force comprised rheumatologists, epidemiologists, health economists, and patients. First, the critical outcomes were determined according to a three-round Delphi method, and eight topics with 88 clinical questions (CQs) were formulated. A systematic review of CQs was conducted using the Cochran Database of Systematic Reviews, MEDLINE, and Japana Centra Revvo Medicina (2003-2012). A questionnaire survey and focus group interview were performed to capture the patients' values and preferences. Data from the National Health Insurance drug price list and product information provided by pharmaceutical companies were collected to evaluate drug cost and safety. The GRADE approach was used to describe the evidence quality and determine the strength of recommendations. Recommendations were developed using a modified Delphi method by a multidisciplinary panel including patients. Eight meetings and frequent e-mail communications were conducted to draft a quality assessment of evidence and recommendations. For 88 CQs, recommendation statements were determined. Using the GRADE approach, new CPGs successfully addressed important clinical issues for treating RA patients. Timely updating of recommendations should be routinely considered.

Epigenome-Wide Association Study Identifies Cardiac Gene Patterning and a Novel Class of Biomarkers for Heart Failure.

PubMed

Meder, Benjamin; Haas, Jan; Sedaghat-Hamedani, Farbod; Kayvanpour, Elham; Frese, Karen; Lai, Alan; Nietsch, Rouven; Scheiner, Christina; Mester, Stefan; Bordalo, Diana Martins; Amr, Ali; Dietrich, Carsten; Pils, Dietmar; Siede, Dominik; Hund, Hauke; Bauer, Andrea; Holzer, Daniel Benjamin; Ruhparwar, Arjang; Mueller-Hennessen, Matthias; Weichenhan, Dieter; Plass, Christoph; Weis, Tanja; Backs, Johannes; Wuerstle, Maximilian; Keller, Andreas; Katus, Hugo A; Posch, Andreas E

2017-10-17

Biochemical DNA modification resembles a crucial regulatory layer among genetic information, environmental factors, and the transcriptome. To identify epigenetic susceptibility regions and novel biomarkers linked to myocardial dysfunction and heart failure, we performed the first multi-omics study in myocardial tissue and blood of patients with dilated cardiomyopathy and controls. Infinium human methylation 450 was used for high-density epigenome-wide mapping of DNA methylation in left-ventricular biopsies and whole peripheral blood of living probands. RNA deep sequencing was performed on the same samples in parallel. Whole-genome sequencing of all patients allowed exclusion of promiscuous genotype-induced methylation calls. In the screening stage, we detected 59 epigenetic loci that are significantly associated with dilated cardiomyopathy (false discovery corrected P ≤0.05), with 3 of them reaching epigenome-wide significance at P ≤5×10 -8 . Twenty-seven (46%) of these loci could be replicated in independent cohorts, underlining the role of epigenetic regulation of key cardiac transcription regulators. Using a staged multi-omics study design, we link a subset of 517 epigenetic loci with dilated cardiomyopathy and cardiac gene expression. Furthermore, we identified distinct epigenetic methylation patterns that are conserved across tissues, rendering these CpGs novel epigenetic biomarkers for heart failure. The present study provides to our knowledge the first epigenome-wide association study in living patients with heart failure using a multi-omics approach. © 2017 American Heart Association, Inc.

Epigenetic differences between monozygotic twins discordant for amyotrophic lateral sclerosis (ALS) provide clues to disease pathogenesis

PubMed Central

Young, Paul E.; Kum Jew, Stephen; Buckland, Michael E.; Pamphlett, Roger

2017-01-01

Amyotrophic lateral sclerosis (ALS) is a devastating late-onset neurodegenerative disorder in which only a small proportion of patients carry an identifiable causative genetic lesion. Despite high heritability estimates, a genetic etiology for most sporadic ALS remains elusive. Here we report the epigenetic profiling of five monozygotic twin pairs discordant for ALS, four with classic ALS and one with the progressive muscular atrophy ALS variant, in whom previous whole genome sequencing failed to uncover a genetic basis for their disease discordance. By studying cytosine methylation patterns in peripheral blood DNA we identified thousands of large between-twin differences at individual CpGs. While the specific sites of differences were mostly idiosyncratic to a twin pair, a proportion involving GABA signalling were common to all ALS individuals. For both idiosyncratic and common sites the differences occurred within genes and pathways related to neurobiological functions or dysfunctions, some of particular relevance to ALS such as glutamate metabolism and the Golgi apparatus. All four classic ALS patients were epigenetically older than their unaffected co-twins, suggesting accelerated aging in multiple tissues in this disease. In conclusion, widespread changes in methylation patterns were found in ALS-affected co-twins, consistent with an epigenetic contribution to disease. These DNA methylation findings could be used to develop blood-based ALS biomarkers, gain insights into disease pathogenesis, and provide a reference for future large-scale ALS epigenetic studies. PMID:28797086

Conventional Prompt Global Strike: Capabilities Today While Planning for Tomorrow

DTIC Science & Technology

2012-03-19

sound. Scramjet powered vehicles are envisioned to operate at speeds up to at least Mach 15.”18 It is beyond the scope of this paper to recommend...launch, the WaveRider “completed the longest supersonic combustion scramjet - powered flight in history, flying at approximately Mach 5 for 143...seconds. This technology is setting the foundation for hypersonic application”17 and could power a hypersonic CPGS delivery vehicle . NASA describes a

Deterrence with China: Avoiding Nuclear Miscalculation

DTIC Science & Technology

2014-01-01

When each nation can manage these three elements in the correct way, the cost -benefit calculations of each side should favor deterrence of a...under pressure to justify the cost of its plans to replace its SSBN fleet. After a recent 2-year delay in the planned SSBN replacement program, any...of CPGS may prove advantageous in some scenarios,31 but those advantages do not come with- out a cost to nuclear deterrence stability with China—a

Conventional Prompt Global Strike and Long-Range Ballistic Missiles: Background and Issues

DTIC Science & Technology

2013-04-26

developing scramjet — supersonic combustion ramjet—technologies that may contribute to the long-range strike mission in the future. In this type of vehicle ... vehicle that could deploy on a modified Peacekeeper land- based ballistic missile—a system known as the Conventional Strike Missile (CSM). In FY2008...into the Air Force CSM and two possible hypersonic glide vehicles . Congress appropriated $174.8 million for CPGS capability development in FY2012. DOD

The PTSD Practitioner Registry: An Innovative Tracking, Dissemination, and Support Tool for Providers in Military and Nonmilitary Settings

DTIC Science & Technology

2016-10-01

are being conducted with 60 providers to assess practitioner needs and interests in the registry as well as pre-test the proposed registry survey . In...15. SUBJECT TERMS PTSD, qualitative interviews, survey development, best practices, CPGs 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF...being; and to identify factors enabling the implementation of clinical best practices in the treatment of PTSD. This clinician-informed online survey and

Quality of clinical practice guidelines of lower extremity venous ulcers.

PubMed

Rumbo-Prieto, José María; Arantón-Areosa, Luis; Palomar-Llatas, Federico; Romero-Martín, Manuel

The clinical variability and professional uncertainty in the prevention and treatment of lower extremity venous ulcers (VU) has as a main consequence, the fact that patients can be subjected to diagnostic and therapeutic tests, sometimes of dubious utility, these may even be harmful to the health of the patient and that, at other times, certain procedures or processes that may be appropriate to the patient's situation and needs may be omitted. It is for this reason that a series of specific documents called clinical practice guidelines for the approach of VU (CPG-VU) have been created, with the aim of improving the effectiveness and quality of care, reducing unjustified variability and establishing homogeneous criteria for its handling. Nevertheless, the literature shows that not all CPGs have the same methodological and evidence-drawing criteria. Many of them are of poor scientific quality and editorial rigor. This implies that CPGs should be periodically reviewed and updated based on the most current evidence and their quality contrasted with validated instruments such as AGREE-II. After an analysis of the quality of six CPG-VU available today, it has been possible to identify what guidelines are recommended for its implementation in the practice of care, which should be modified to improve their applicability and development of the evidence. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Barriers Against Implementing Blunt Abdominal Trauma Guidelines in a Hospital: A Qualitative Study.

PubMed

Zaboli, Rouhollah; Tofighi, Shahram; Aghighi, Ali; Shokouh, Seyyed Javad Hosaini; Naraghi, Nader; Goodarzi, Hassan

2016-08-01

Clinical practice guidelines are structured recommendations that help physicians and patients to make proper decisions when dealing with a specific clinical condition. Because blunt abdominal trauma causes a various range of mild, single-system, and multisystem injuries, early detection will help to reduce mortality and resulting disability. Emergency treatment should be initiated based on CPGs. This study aimed to determine the variables affecting implementing blunt abdominal trauma CPGs in an Iranian hospital. This study was conducted as a qualitative and phenomenology study in the Family Hospital in Tehran (Iran) in 2015. The research population included eight experts and key people in the area of blunt abdominal trauma clinical practice guidelines. Sampling was based on purposive and nonrandom methods. A semistructured interview was done for the data collection. A framework method was applied for the data analysis by using Atlas.ti software. After framework analyzing and various reviewing and deleting and combining the codes from 251 codes obtained, 15 families and five super families were extracted, including technical knowledge barriers, economical barriers, barriers related to deployment and monitoring, political will barriers, and managing barriers. Structural reform is needed for eliminating the defects available in the healthcare system. As with most of the codes, subconcepts and concepts are classified into the field of human resources; it seems that the education and knowledge will be more important than other resources such as capital and equipment.

BECon: a tool for interpreting DNA methylation findings from blood in the context of brain.

PubMed

Edgar, R D; Jones, M J; Meaney, M J; Turecki, G; Kobor, M S

2017-08-01

Tissue differences are one of the largest contributors to variability in the human DNA methylome. Despite the tissue-specific nature of DNA methylation, the inaccessibility of human brain samples necessitates the frequent use of surrogate tissues such as blood, in studies of associations between DNA methylation and brain function and health. Results from studies of surrogate tissues in humans are difficult to interpret in this context, as the connection between blood-brain DNA methylation is tenuous and not well-documented. Here, we aimed to provide a resource to the community to aid interpretation of blood-based DNA methylation results in the context of brain tissue. We used paired samples from 16 individuals from three brain regions and whole blood, run on the Illumina 450 K Human Methylation Array to quantify the concordance of DNA methylation between tissues. From these data, we have made available metrics on: the variability of cytosine-phosphate-guanine dinucleotides (CpGs) in our blood and brain samples, the concordance of CpGs between blood and brain, and estimations of how strongly a CpG is affected by cell composition in both blood and brain through the web application BECon (Blood-Brain Epigenetic Concordance; https://redgar598.shinyapps.io/BECon/). We anticipate that BECon will enable biological interpretation of blood-based human DNA methylation results, in the context of brain.

[After seven years of National Disease Management Guidelines: quo vadis?].

PubMed

Weinbrenner, Susanne; Conrad, Susann; Weikert, Beate; Kopp, Ina

2010-01-01

After seven years the National Disease Management Guidelines Programme (German DM-CPG Programme) that was established under the auspices of the German Medical Association, the National Association of Statutory Health Insurance Physicians and the Association of the Scientific Medical Societies in Germany has been widely accepted by both health care professionals and patients. DM-CPGs are available as tools for knowledge and quality management for widespread chronic diseases showing need for improvement in treatment pathways and coordination between health care providers. The main objective of the German DM-CPG Programme is to establish consensus among the medical professions on evidence-based key recommendations covering all sectors of health care provision and facilitating the coordination of care for the individual patient over time and across interfaces. German DM-CPGs provide a conceptual basis for disease management and integrative care aiming at the implementation of best practice recommendations for prevention, acute care, rehabilitation, chronic care and management aspects for high priority health care topics. Thus, representatives of all disciplines, professions and patients concerned with the topic of an individual German DM-CPG are involved in the development process. The methodology of guideline development is in accordance with international standards. However, the improvement of strategies for effective implementation and continuous update remain challenging. Future work will also focus on content-related aspects such as co-morbidity, gender and migration background. Copyright © 2010. Published by Elsevier GmbH.

International lessons in new methods for grading and integrating cost effectiveness evidence into clinical practice guidelines.

PubMed

Antioch, Kathryn M; Drummond, Michael F; Niessen, Louis W; Vondeling, Hindrik

2017-01-01

Economic evidence is influential in health technology assessment world-wide. Clinical Practice Guidelines (CPG) can enable economists to include economic information on health care provision. Application of economic evidence in CPGs, and its integration into clinical practice and national decision making is hampered by objections from professions, paucity of economic evidence or lack of policy commitment. The use of state-of-art economic methodologies will improve this. Economic evidence can be graded by 'checklists' to establish the best evidence for decision making given methodological rigor. New economic evaluation checklists, Multi-Criteria Decision Analyses (MCDA) and other decision criteria enable health economists to impact on decision making world-wide. We analyse the methodologies for integrating economic evidence into CPG agencies globally, including the Agency of Health Research and Quality (AHRQ) in the USA, National Health and Medical Research Council (NHMRC) and Australian political reforms. The Guidelines and Economists Network International (GENI) Board members from Australia, UK, Canada and Denmark presented the findings at the conference of the International Health Economists Association (IHEA) and we report conclusions and developments since. The Consolidated Guidelines for the Reporting of Economic Evaluations (CHEERS) 24 item check list can be used by AHRQ, NHMRC, other CPG and health organisations, in conjunction with the Drummond ten-point check list and a questionnaire that scores that checklist for grading studies, when assessing economic evidence. Cost-effectiveness Analysis (CEA) thresholds, opportunity cost and willingness-to-pay (WTP) are crucial issues for decision rules in CEA generally, including end-of-life therapies. Limitations of inter-rater reliability in checklists can be addressed by including more than one assessor to reach a consensus, especially when impacting on treatment decisions. We identify priority areas to generate economic evidence for CPGs by NHMRC, AHRQ, and other agencies. The evidence may cover demand for care issues such as involved time, logistics, innovation price, price sensitivity, substitutes and complements, WTP, absenteeism and presentism. Supply issues may include economies of scale, efficiency changes, and return on investment. Involved equity and efficiency measures may include cost-of-illness, disease burden, quality-of-life, budget impact, cost-effective ratios, net benefits and disparities in access and outcomes. Priority setting remains essential and trade-off decisions between policy criteria can be based on MCDA, both in evidence based clinical medicine and in health planning.

Neuroinspired control strategies with applications to flapping flight

NASA Astrophysics Data System (ADS)

Dorothy, Michael Ray

This dissertation is centered on a theoretical, simulation, and experimental study of control strategies which are inspired by biological systems. Biological systems, along with sufficiently complicated engineered systems, often have many interacting degrees of freedom and need to excite large-displacement oscillations in order to locomote. Combining these factors can make high-level control design difficult. This thesis revolves around three different levels of abstraction, providing tools for analysis and design. First, we consider central pattern generators (CPGs) to control flapping-flight dynamics. The key idea here is dimensional reduction - we want to convert complicated interactions of many degrees of freedom into a handful of parameters which have intuitive connections to the overall system behavior, leaving the control designer unconcerned with the details of particular motions. A rigorous mathematical and control theoretic framework to design complex three-dimensional wing motions is presented based on phase synchronization of nonlinear oscillators. In particular, we show that flapping-flying dynamics without a tail or traditional aerodynamic control surfaces can be effectively controlled by a reduced set of central pattern generator parameters that generate phase-synchronized or symmetry-breaking oscillatory motions of two main wings. Furthermore, by using a Hopf bifurcation, we show that tailless aircraft (inspired by bats) alternating between flapping and gliding can be effectively stabilized by smooth wing motions driven by the central pattern generator network. Results of numerical simulation with a full six-degree-of-freedom flight dynamic model validate the effectiveness of the proposed neurobiologically inspired control approach. Further, we present experimental micro aerial vehicle (MAV) research with low-frequency flapping and articulated wing gliding. The importance of phase difference control via an abstract mathematical model of central pattern generators is confirmed with a robotic bat on a 3-DOF pendulum platform. An aerodynamic model for the robotic bat based on the complex wing kinematics is presented. Closed loop experiments show that control dimension reduction is achievable - unstable longitudinal modes are stabilized and controlled using only two control parameters. A transition of flight modes, from flapping to gliding and vice-versa, is demonstrated within the CPG control scheme. The second major thrust is inspired by this idea that mode switching is useful. Many bats and birds adopt a mixed strategy of flapping and gliding to provide agility when necessary and to increase overall efficiency. This work explores dwell time constraints on switched systems with multiple, possibly disparate invariant limit sets. We show that, under suitable conditions, trajectories globally converge to a superset of the limit sets and then remain in a second, larger superset. We show the effectiveness of the dwell-time conditions by using examples of nonlinear switching limit cycles from our work on flapping flight. This level of abstraction has been found to be useful in many ways, but it also produces its own challenges. For example, we discuss death of oscillation which can occur for many limit-cycle controllers and the difficulty in incorporating fast, high-displacement reflex feedback. This leads us to our third major thrust - considering biologically realistic neuron circuits instead of a limit cycle abstraction. Biological neuron circuits are incredibly diverse in practice, giving us a convincing rationale that they can aid us in our quest for flexibility. Nevertheless, that flexibility provides its own challenges. It is not currently known how most biological neuron circuits work, and little work exists that connects the principles of a neuron circuit to the principles of control theory. We begin the process of trying to bridge this gap by considering the simplest of classical controllers, PD control. We propose a simple two-neuron, two-synapse circuit based on the concept that synapses provide attenuation and a delay. We present a simulation-based method of analysis, including a smoothing algorithm, a steady-state response curve, and a system identification procedure for capturing differentiation. There will never be One True Control Method that will solve all problems. Nature's solution to a diversity of systems and situations is equally diverse. This will inspire many strategies and require a multitude of analysis tools. This thesis is my contribution of a few.

An epigenetic biomarker of aging for lifespan and healthspan

PubMed Central

Levine, Morgan E.; Lu, Ake T.; Quach, Austin; Chen, Brian H.; Assimes, Themistocles L.; Bandinelli, Stefania; Hou, Lifang; Baccarelli, Andrea A.; Stewart, James D.; Li, Yun; Whitsel, Eric A.; Wilson, James G; Reiner, Alex P; Aviv, Abraham; Lohman, Kurt; Liu, Yongmei; Ferrucci, Luigi

2018-01-01

Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using an innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer's disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated with increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging. PMID:29676998

Exercise training alters DNA methylation patterns in genes related to muscle growth and differentiation in mice.

PubMed

Kanzleiter, Timo; Jähnert, Markus; Schulze, Gunnar; Selbig, Joachim; Hallahan, Nicole; Schwenk, Robert Wolfgang; Schürmann, Annette

2015-05-15

The adaptive response of skeletal muscle to exercise training is tightly controlled and therefore requires transcriptional regulation. DNA methylation is an epigenetic mechanism known to modulate gene expression, but its contribution to exercise-induced adaptations in skeletal muscle is not well studied. Here, we describe a genome-wide analysis of DNA methylation in muscle of trained mice (n = 3). Compared with sedentary controls, 2,762 genes exhibited differentially methylated CpGs (P < 0.05, meth diff >5%, coverage >10) in their putative promoter regions. Alignment with gene expression data (n = 6) revealed 200 genes with a negative correlation between methylation and expression changes in response to exercise training. The majority of these genes were related to muscle growth and differentiation, and a minor fraction involved in metabolic regulation. Among the candidates were genes that regulate the expression of myogenic regulatory factors (Plexin A2) as well as genes that participate in muscle hypertrophy (Igfbp4) and motor neuron innervation (Dok7). Interestingly, a transcription factor binding site enrichment study discovered significantly enriched occurrence of CpG methylation in the binding sites of the myogenic regulatory factors MyoD and myogenin. These findings suggest that DNA methylation is involved in the regulation of muscle adaptation to regular exercise training. Copyright © 2015 the American Physiological Society.

Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer.

PubMed

Teschendorff, Andrew E; Menon, Usha; Gentry-Maharaj, Aleksandra; Ramus, Susan J; Weisenberger, Daniel J; Shen, Hui; Campan, Mihaela; Noushmehr, Houtan; Bell, Christopher G; Maxwell, A Peter; Savage, David A; Mueller-Holzner, Elisabeth; Marth, Christian; Kocjan, Gabrijela; Gayther, Simon A; Jones, Allison; Beck, Stephan; Wagner, Wolfgang; Laird, Peter W; Jacobs, Ian J; Widschwendter, Martin

2010-04-01

Polycomb group proteins (PCGs) are involved in repression of genes that are required for stem cell differentiation. Recently, it was shown that promoters of PCG target genes (PCGTs) are 12-fold more likely to be methylated in cancer than non-PCGTs. Age is the most important demographic risk factor for cancer, and we hypothesized that its carcinogenic potential may be referred by irreversibly stabilizing stem cell features. To test this, we analyzed the methylation status of over 27,000 CpGs mapping to promoters of approximately 14,000 genes in whole blood samples from 261 postmenopausal women. We demonstrate that stem cell PCGTs are far more likely to become methylated with age than non-targets (odds ratio = 5.3 [3.8-7.4], P < 10(-10)), independently of sex, tissue type, disease state, and methylation platform. We identified a specific subset of 69 PCGT CpGs that undergo hypermethylation with age and validated this methylation signature in seven independent data sets encompassing over 900 samples, including normal and cancer solid tissues and a population of bone marrow mesenchymal stem/stromal cells (P < 10(-5)). We find that the age-PCGT methylation signature is present in preneoplastic conditions and may drive gene expression changes associated with carcinogenesis. These findings shed substantial novel insights into the epigenetic effects of aging and support the view that age may predispose to malignant transformation by irreversibly stabilizing stem cell features.

Implementation strategies for guidelines at ICUs: a systematic review.

PubMed

Jordan, Portia; Mpasa, Ferestas; Ten Ham-Baloyi, Wilma; Bowers, Candice

2017-05-08

Purpose The purpose of this paper is to critically analyze empirical studies related to the implementation strategies for clinical practice guidelines (CPGs) in intensive care units (ICUs). Design/methodology/approach A systematic review with a narrative synthesis adapted from Popay et al.'s method for a narrative synthesis was conducted. A search using CINAHL, Google Scholar, Academic search complete, Cochrane Register for Randomized Controlled Trials, MEDLINE via PUBMED and grey literature was conducted in 2014 and updated in 2016 (August). After reading the abstracts, titles and full-text articles, 11 ( n=11) research studies met the inclusion criteria. Findings After critical appraisal, using the Joanna Briggs Critical Appraisal Tools, eight randomized controlled trials conducted in adult and neonatal ICUs using implementation strategies remained. Popay et al.'s method for narrative synthesis was adapted and used to analyze and synthesize the data and formulate concluding statements. Included studies found that multi-faceted strategies appear to be more effective than single strategies. Strategies mostly used were printed educational materials, information/ sessions, audit, feedback, use of champion leaders, educational outreach visits, and computer or internet usage. Practical training, monitoring visits and grand rounds were less used. Practical implications Findings can be used by clinicians to implement the best combination of multi-faceted implementation strategies in the ICUs in order to enhance the optimal use of CPGs. Originality/value No systematic review was previously done on the implementation strategies that should be used best for optimal CPG implementation in the ICU.

The US Public Health Service “treating tobacco use and dependence clinical practice guidelines” as a legal standard of care

PubMed Central

Torrijos, Randy M; Glantz, Stanton A

2006-01-01

Background The important factors in evaluating the role of clinical practice guidelines (CPGs) in medical malpractice litigation have been discussed for several years, but have focused on broad policy implications rather than on a concrete example of how an actual guideline might be evaluated. There are four items that need to be considered in negligence torts: legal duty, a breach of that duty, causal relationship between breach and injury, and damages. Objective To identify the arguments related to legal duty. Results The Treating Tobacco Use and Dependence (revised 2000) CPG, sponsored by the US Public Health Service, recommends effective and inexpensive treatments for nicotine addiction, the largest preventable cause of death in the US, and can be used as an example to focus on important considerations about the appropriateness of CPGs in the judicial system. Furthermore, the failure of many doctors and hospitals to deal with tobacco use and dependence raises the question of whether this failure could be considered malpractice, given the Public Health Service guideline's straightforward recommendations, their efficacy in preventing serious disease and cost‐effectiveness. Conclusion Although each case of medical malpractice depends on a multitude of factors unique to individual cases, a court could have sufficient basis to find that the failure to adequately treat the main cause of preventable disease and death in the US qualifies as a violation of the legal duty that doctors and hospitals owe to patients habituated to tobacco use and dependence. PMID:17130373

Recombinant domains III of Tick-Borne Encephalitis Virus envelope protein in combination with dextran and CpGs induce immune response and partial protectiveness against TBE virus infection in mice.

PubMed

Ershova, Anna S; Gra, Olga A; Lyaschuk, Alexander M; Grunina, Tatyana M; Tkachuk, Artem P; Bartov, Mikhail S; Savina, Darya M; Sergienko, Olga V; Galushkina, Zoya M; Gudov, Vladimir P; Kozlovskaya, Liubov I; Kholodilov, Ivan S; Gmyl, Larissa V; Karganova, Galina G; Lunin, Vladimir G; Karyagina, Anna S; Gintsburg, Alexander L

2016-10-07

E protein of tick-borne encephalitis virus (TBEV) and other flaviviruses is located on the surface of the viral particle. Domain III of this protein seems to be a promising component of subunit vaccines for prophylaxis of TBE and kits for diagnostics of TBEV. Three variants of recombinant TBEV E protein domain III of European, Siberian and Far Eastern subtypes fused with dextran-binding domain of Leuconostoc citreum KM20 were expressed in E. coli and purified. The native structure of domain III was confirmed by ELISA antibody kit and sera of patients with tick-borne encephalitis. Immunogenic and protective properties of the preparation comprising these recombinant proteins immobilized on a dextran carrier with CpG oligonucleotides as an adjuvant were investigated on the mice model. All 3 variants of recombinant proteins immobilized on dextran demonstrate specific interaction with antibodies from the sera of TBE patients. Thus, constructed recombinant proteins seem to be promising for TBE diagnostics. The formulation comprising the 3 variants of recombinant antigens immobilized on dextran and CpG oligonucleotides, induces the production of neutralizing antibodies against TBEV of different subtypes and demonstrates partial protectivity against TBEV infection. Studied proteins interact with the sera of TBE patients, and, in combination with dextran and CPGs, demonstrate immunogenicity and limited protectivity on mice compared with reference "Tick-E-Vac" vaccine.

Day case hernia repair: weak evidence or practice gap?

PubMed

Scarfe, Anje; Duncan, Joanna; Ma, Ning; Cameron, Alun; Rankin, David; Karatassas, Alex; Fletcher, David; Watters, David; Maddern, Guy

2018-06-01

Analysis of a private insurer's administrative data set revealed significant variation in the length of hospital stay following hernia surgery. This review examined factors influencing the performance of day surgery for inguinal, femoral and umbilical hernia repair in adults. A systematic literature search was conducted in the PubMed, Embase and Cochrane Library databases to identify studies and clinical practice guidelines (CPGs) comparing same day hernia surgery to surgery followed by an overnight stay. Screening of studies by abstract and full text was completed by a single researcher and checked by a second. Studies were selected for inclusion based on a step-wise approach across three phases. Limited evidence from one systematic review, and three case series studies including 3213 patients found that same day hernia surgery was as safe and effective as an overnight stay. All identified CPGs recommended a same day procedure for most patients. Two case series studies reported that 3-8% of patients were ineligible for day procedures due to medical reasons; however, the characteristics of patients, in general, which are not suitable, have not been adequately investigated. Day surgery for groin hernia repair is safe and effective for most patients. However, evidence-based support is only one of many factors that may contribute to the uptake of day surgery in Australia. There is an opportunity for key stakeholders across the private healthcare system to deliver an equally effective but more sustainable and affordable hernia care by increasing the day surgery rates. © 2018 Royal Australasian College of Surgeons.

Barriers Against Implementing Blunt Abdominal Trauma Guidelines in a Hospital: A Qualitative Study

PubMed Central

Zaboli, Rouhollah; Tofighi, Shahram; Aghighi, Ali; Shokouh, Seyyed Javad Hosaini; Naraghi, Nader; Goodarzi, Hassan

2016-01-01

Introduction Clinical practice guidelines are structured recommendations that help physicians and patients to make proper decisions when dealing with a specific clinical condition. Because blunt abdominal trauma causes a various range of mild, single-system, and multisystem injuries, early detection will help to reduce mortality and resulting disability. Emergency treatment should be initiated based on CPGs. This study aimed to determine the variables affecting implementing blunt abdominal trauma CPGs in an Iranian hospital. Methods This study was conducted as a qualitative and phenomenology study in the Family Hospital in Tehran (Iran) in 2015. The research population included eight experts and key people in the area of blunt abdominal trauma clinical practice guidelines. Sampling was based on purposive and nonrandom methods. A semistructured interview was done for the data collection. A framework method was applied for the data analysis by using Atlas.ti software. Results After framework analyzing and various reviewing and deleting and combining the codes from 251 codes obtained, 15 families and five super families were extracted, including technical knowledge barriers, economical barriers, barriers related to deployment and monitoring, political will barriers, and managing barriers. Conclusion Structural reform is needed for eliminating the defects available in the healthcare system. As with most of the codes, subconcepts and concepts are classified into the field of human resources; it seems that the education and knowledge will be more important than other resources such as capital and equipment. PMID:27757191

Adult monozygotic twins discordant for intra-uterine growth have indistinguishable genome-wide DNA methylation profiles.

PubMed

Souren, Nicole Y P; Lutsik, Pavlo; Gasparoni, Gilles; Tierling, Sascha; Gries, Jasmin; Riemenschneider, Matthias; Fryns, Jean-Pierre; Derom, Catherine; Zeegers, Maurice P; Walter, Jörn

2013-05-26

Low birth weight is associated with an increased adult metabolic disease risk. It is widely discussed that poor intra-uterine conditions could induce long-lasting epigenetic modifications, leading to systemic changes in regulation of metabolic genes. To address this, we acquire genome-wide DNA methylation profiles from saliva DNA in a unique cohort of 17 monozygotic monochorionic female twins very discordant for birth weight. We examine if adverse prenatal growth conditions experienced by the smaller co-twins lead to long-lasting DNA methylation changes. Overall, co-twins show very similar genome-wide DNA methylation profiles. Since observed differences are almost exclusively caused by variable cellular composition, an original marker-based adjustment strategy was developed to eliminate such variation at affected CpGs. Among adjusted and unchanged CpGs 3,153 are differentially methylated between the heavy and light co-twins at nominal significance, of which 45 show sensible absolute mean β-value differences. Deep bisulfite sequencing of eight such loci reveals that differences remain in the range of technical variation, arguing against a reproducible biological effect. Analysis of methylation in repetitive elements using methylation-dependent primer extension assays also indicates no significant intra-pair differences. Severe intra-uterine growth differences observed within these monozygotic twins are not associated with long-lasting DNA methylation differences in cells composing saliva, detectable with up-to-date technologies. Additionally, our results indicate that uneven cell type composition can lead to spurious results and should be addressed in epigenomic studies.

Development of a novel, multilayered presentation format for clinical practice guidelines.

PubMed

Kristiansen, Annette; Brandt, Linn; Alonso-Coello, Pablo; Agoritsas, Thomas; Akl, Elie A; Conboy, Tara; Elbarbary, Mahmoud; Ferwana, Mazen; Medani, Wedad; Murad, Mohammad Hassan; Rigau, David; Rosenbaum, Sarah; Spencer, Frederick A; Treweek, Shaun; Guyatt, Gordon; Vandvik, Per Olav

2015-03-01

Bridging the gap between clinical research and everyday health-care practice requires effective communication strategies. To address current shortcomings in conveying practice recommendations and supporting evidence, we are creating and testing presentation formats for clinical practice guidelines (CPGs). We carried out multiple cycles of brainstorming and sketching, developing a prototype. Physicians participating in the user testing viewed CPG formats linked to clinical scenarios and engaged in semistructured interviews applying a think-aloud method for exploring important aspects of user experience. We developed a multilayered presentation format that allows clinicians to successively view more in-depth information. Starting with the recommendations, clinicians can, on demand, access a rationale and a key information section containing statements on quality of the evidence, balance between desirable and undesirable consequences, values and preferences, and resource considerations. We collected feedback from 27 stakeholders and performed user testing with 47 practicing physicians from six countries. Advisory group feedback and user testing of the first version revealed problems with conceptual understanding of underlying CPG methodology, as well as difficulties with the complexity of the layout and content. Extensive revisions made before the second round of user testing resulted in most participants expressing overall satisfaction with the final presentation format. We have developed an electronic, multilayered, CPG format that enhances the usability of CPGs for frontline clinicians. We have implemented the format in electronic guideline tools that guideline organizations can now use when authoring and publishing their guidelines.

The US Public Health Service "treating tobacco use and dependence clinical practice guidelines" as a legal standard of care.

PubMed

Torrijos, Randy M; Glantz, Stanton A

2006-12-01

The important factors in evaluating the role of clinical practice guidelines (CPGs) in medical malpractice litigation have been discussed for several years, but have focused on broad policy implications rather than on a concrete example of how an actual guideline might be evaluated. There are four items that need to be considered in negligence torts: legal duty, a breach of that duty, causal relationship between breach and injury, and damages. To identify the arguments related to legal duty. The Treating Tobacco Use and Dependence (revised 2000) CPG, sponsored by the US Public Health Service, recommends effective and inexpensive treatments for nicotine addiction, the largest preventable cause of death in the US, and can be used as an example to focus on important considerations about the appropriateness of CPGs in the judicial system. Furthermore, the failure of many doctors and hospitals to deal with tobacco use and dependence raises the question of whether this failure could be considered malpractice, given the Public Health Service guideline's straightforward recommendations, their efficacy in preventing serious disease and cost-effectiveness. Although each case of medical malpractice depends on a multitude of factors unique to individual cases, a court could have sufficient basis to find that the failure to adequately treat the main cause of preventable disease and death in the US qualifies as a violation of the legal duty that doctors and hospitals owe to patients habituated to tobacco use and dependence.

Association of interleukin-6 methylation in leukocyte DNA with serum level and the risk of ischemic heart disease.

PubMed

Yang, Qinghui; Zhao, Yushi; Zhang, Zhijie; Chen, Jianxin

2016-07-01

Background Interleukin-6 (IL-6), a multifunctional cytokine, plays an important role in the development of ischemic heart disease (IHD), and DNA hypomethylation of 2 CpGs, located downstream in the proximity of the IL-6 gene promoter, has been associated with risk factor for IHD. This study was to examine the association of blood leukocyte DNA methylation of the 2 CpGs in IL-6 with the risk of IHD and the serum IL-6 level. Methods IL-6 methylation levels of 582 cases and 673 controls were measured using the bisulfite pyrosequencing technology. Serum level of IL-6 was measured using enzyme-linked immunosorbent assay. Results The IL-6 methylation was significantly lower in IHD cases than in the controls, irrespective of CpG site. After multivariate adjustment, lower (< median) average IL-6 methylation was associated with an increased risk of IHD (OR 1.57, 95% CI 1.22-2.02, p < 0.001). Average IL-6 methylation level was inversely associated with serum IL-6 level (β = -1.02 pg/mL per increase in IL-6 methylation, p = 0.002) among IHD cases. This significant relationship was not observed among controls. Conclusions DNA hypomethylation of IL-6 gene measured in blood leukocytes was associated with increased risk of IHD. IL-6 demethylation may upregulate its expression, whereby exerting its risk effect on the development of IHD.

Evaluation of Role 2 (R2) Medical Resources in the Afghanistan Combat Theater: Past, Present and Future

DTIC Science & Technology

2017-10-01

casualty care using descriptive statistical analysis and modeling techniques. Aim 2: Identify the ideal provider training and competency assessment... Methodologies , Course  Type,  Course  Availability,  Assessment  Criteria,  Requirements,  Funding,  Alignment  with Clinical  Practice  Guidelines  (CPGs...Aim 1:  Descriptive study of all available information for combat casualties in Afghanistan.  Specific Tasks:  1) who – patients treated; clinician mix

Early palliative care and its translation into oncology practice in Canada: barriers and challenges.

PubMed

Fassbender, Konrad; Watanabe, Sharon M

2015-07-01

This article reviews the progress Canada has made integrating palliative care into oncologic practice. Key clinical practice guidelines (CPGs) have influenced and have been translated into Canadian oncology policy and operations. Comprehensive accreditation standards exist to guide oncology practice in institutional and ambulatory care settings. Common barriers and challenges are discussed: education and attitudes, compassion fatigue, terminology, paucity of research, aggressive cancer care, and organization and operational considerations. As a result, eight made-in-Canada innovations emerged and are described. Lessons learned and recommendations describe a plan for action.

PTSD and DNA Methylation in Select Immune Function Gene Promoter Regions: A Repeated Measures Case-control Study of U.S. Military Service Members

DTIC Science & Technology

2013-06-24

barrier induced by status epilepticus within the rat piriform cortex in interferon-gamma inde- pendent pathway. Brain Res. 1447, 126–134. doi:10.1016...hippocampus following status epilepticus . Neuroscience 170, 711–721. doi:10.1016/j.neuroscience. 2010.07.048 Sananbenesi, F., and Fischer, A. (2009). The...methylation status of each CpG locus was analyzed individually as a T/C SNP using QCpG software (Qiagen Pyrosequencing). The loci of specific CpGs measured

Epigenetic Characterization of Ovarian Cancer

DTIC Science & Technology

2008-12-01

Gusberg, A. H., Whitaker, R. S., Gray , J. W., Fujii, S., Berchuck, A. and S. K. Murphy. YY1/E2F3 modulates antimicrotubule drug response in epithelial... GTG GGT TTT TGG TGT TGG GTA TT-3’; and a shared reverse primer that does not anneal to CpGs, 5’-AAC CCC ACT CCC ACC CTA CTC C-3’. PCR was performed...Superscript II RNase H- reverse transcriptase (Invitrogen). Forward primer: 5’-GCG ACA TCG GTG ACT TCA T-3’ and reverse primer 5’-ATA CAT GTC CGC CAG CTT

Comparative whole genome DNA methylation profiling of cattle sperm and somatic tissues reveals striking hypomethylated patterns in sperm

PubMed Central

Zhou, Yang; Connor, Erin E; Bickhart, Derek M; Li, Congjun; Baldwin, Ransom L; Schroeder, Steven G; Rosen, Benjamin D; Yang, Liguo; Van Tassell, Curtis P

2018-01-01

Abstract Background Although sperm DNA methylation has been studied in humans and other species, its status in cattle is largely unknown. Results Using whole-genome bisulfite sequencing (WGBS), we profiled the DNA methylome of cattle sperm through comparison with three somatic tissues (mammary gland, brain, and blood). Large differences between cattle sperm and somatic cells were observed in the methylation patterns of global CpGs, pericentromeric satellites, partially methylated domains (PMDs), hypomethylated regions (HMRs), and common repeats. As expected, we observed low methylation in the promoter regions and high methylation in the bodies of active genes. We detected selective hypomethylation of megabase domains of centromeric satellite clusters, which may be related to chromosome segregation during meiosis and their rapid transcriptional activation upon fertilization. We found more PMDs in sperm cells than in somatic cells and identified meiosis-related genes such asKIF2B and REPIN1, which are hypomethylated in sperm but hypermethylated in somatic cells. In addition to the common HMRs around gene promoters, which showed substantial differences between sperm and somatic cells, the sperm-specific HMRs also targeted to distinct spermatogenesis-related genes, including BOLL, MAEL, ASZ1, SYCP3, CTCFL, MND1, SPATA22, PLD6, DDX4, RBBP8, FKBP6, and SYCE1. Although common repeats were heavily methylated in both sperm and somatic cells, some young Bov-A2 repeats, which belong to the SINE family, were hypomethylated in sperm and could affect the promoter structures by introducing new regulatory elements. Conclusions Our study provides a comprehensive resource for bovine sperm epigenomic research and enables new discoveries about DNA methylation and its role in male fertility. PMID:29635292

Comparative whole genome DNA methylation profiling of cattle sperm and somatic tissues reveals striking hypomethylated patterns in sperm.

PubMed

Zhou, Yang; Connor, Erin E; Bickhart, Derek M; Li, Congjun; Baldwin, Ransom L; Schroeder, Steven G; Rosen, Benjamin D; Yang, Liguo; Van Tassell, Curtis P; Liu, George E

2018-05-01

Although sperm DNA methylation has been studied in humans and other species, its status in cattle is largely unknown. Using whole-genome bisulfite sequencing (WGBS), we profiled the DNA methylome of cattle sperm through comparison with three somatic tissues (mammary gland, brain, and blood). Large differences between cattle sperm and somatic cells were observed in the methylation patterns of global CpGs, pericentromeric satellites, partially methylated domains (PMDs), hypomethylated regions (HMRs), and common repeats. As expected, we observed low methylation in the promoter regions and high methylation in the bodies of active genes. We detected selective hypomethylation of megabase domains of centromeric satellite clusters, which may be related to chromosome segregation during meiosis and their rapid transcriptional activation upon fertilization. We found more PMDs in sperm cells than in somatic cells and identified meiosis-related genes such asKIF2B and REPIN1, which are hypomethylated in sperm but hypermethylated in somatic cells. In addition to the common HMRs around gene promoters, which showed substantial differences between sperm and somatic cells, the sperm-specific HMRs also targeted to distinct spermatogenesis-related genes, including BOLL, MAEL, ASZ1, SYCP3, CTCFL, MND1, SPATA22, PLD6, DDX4, RBBP8, FKBP6, and SYCE1. Although common repeats were heavily methylated in both sperm and somatic cells, some young Bov-A2 repeats, which belong to the SINE family, were hypomethylated in sperm and could affect the promoter structures by introducing new regulatory elements. Our study provides a comprehensive resource for bovine sperm epigenomic research and enables new discoveries about DNA methylation and its role in male fertility.

Bayesian inference supports a location and neighbour-dependent model of DNA methylation propagation at the MGMT gene promoter in lung tumours.

PubMed

Bonello, Nicolas; Sampson, James; Burn, John; Wilson, Ian J; McGrown, Gail; Margison, Geoff P; Thorncroft, Mary; Crossbie, Philip; Povey, Andrew C; Santibanez-Koref, Mauro; Walters, Kevin

2013-11-07

We exploit model-based Bayesian inference methodologies to analyse lung tumour-derived methylation data from a CpG island in the O6-methylguanine-DNA methyltransferase (MGMT) promoter. Interest is in modelling the changes in methylation patterns in a CpG island in the first exon of the promoter during lung tumour development. We propose four competils of methylation state propagation based on two mechanisms. The first is the location-dependence mechanism in which the probability of a gain or loss of methylation at a CpG within the promoter depends upon its location in the CpG sequence. The second mechanism is that of neighbour-dependence in which gain or loss of methylation at a CpG depends upon the methylation status of the immediately preceding CpG. Our data comprises the methylation status at 12 CpGs near the 5' end of the CpG island in two lung tumour samples for both alleles of a nearby polymorphism. We use approximate Bayesian computation, a computationally intensive rejection-sampling algorithm to infer model parameters and compare models without the need to evaluate the likelihood function. We compare the four proposed models using two criteria: the approximate Bayes factors and the distribution of the Euclidean distance between the summary statistics of the observed and simulated datasets. Our model-based analysis demonstrates compelling evidence for both location and neighbour dependence in the process of aberrant DNA methylation of this MGMT promoter CpG island in lung tumours. We find equivocal evidence to support the hypothesis that the methylation patterns of the two alleles evolve independently. © 2013 Published by Elsevier Ltd. All rights reserved.

GRASP/Ada 95: Reverse Engineering Tools for Ada

NASA Technical Reports Server (NTRS)

Cross, James H., II

1996-01-01

The GRASP/Ada project (Graphical Representations of Algorithms, Structures, and Processes for Ada) has successfully created and prototyped an algorithmic level graphical representation for Ada software, the Control Structure Diagram (CSD), and a new visualization for a fine-grained complexity metric called the Complexity Profile Graph (CPG). By synchronizing the CSD and the CPG, the CSD view of control structure, nesting, and source code is directly linked to the corresponding visualization of statement level complexity in the CPG. GRASP has been integrated with GNAT, the GNU Ada 95 Translator to provide a comprehensive graphical user interface and development environment for Ada 95. The user may view, edit, print, and compile source code as a CSD with no discernible addition to storage or computational overhead. The primary impetus for creation of the CSD was to improve the comprehension efficiency of Ada software and, as a result, improve reliability and reduce costs. The emphasis has been on the automatic generation of the CSD from Ada 95 source code to support reverse engineering and maintenance. The CSD has the potential to replace traditional prettyprinted Ada source code. The current update has focused on the design and implementation of a new Motif compliant user interface, and a new CSD generator consisting of a tagger and renderer. The Complexity Profile Graph (CPG) is based on a set of functions that describes the context, content, and the scaling for complexity on a statement by statement basis. When combined graphicafly, the result is a composite profile of complexity for the program unit. Ongoing research includes the development and refinement of the associated functions, and the development of the CPG generator prototype. The current Version 5.0 prototype provides the capability for the user to generate CSDs and CPGs from Ada 95 source code in a reverse engineering as well as forward engineering mode with a level of flexibility suitable for practical application. This report provides an overview of the GRASP/Ada project with an emphasis on the current update.

DNA methylation of miRNA coding sequences putatively associated with childhood obesity.

PubMed

Mansego, M L; Garcia-Lacarte, M; Milagro, F I; Marti, A; Martinez, J A

2017-02-01

Epigenetic mechanisms may be involved in obesity onset and its consequences. The aim of the present study was to evaluate whether DNA methylation status in microRNA (miRNA) coding regions is associated with childhood obesity. DNA isolated from white blood cells of 24 children (identification sample: 12 obese and 12 non-obese) from the Grupo Navarro de Obesidad Infantil study was hybridized in a 450 K methylation microarray. Several CpGs whose DNA methylation levels were statistically different between obese and non-obese were validated by MassArray® in 95 children (validation sample) from the same study. Microarray analysis identified 16 differentially methylated CpGs between both groups (6 hypermethylated and 10 hypomethylated). DNA methylation levels in miR-1203, miR-412 and miR-216A coding regions significantly correlated with body mass index standard deviation score (BMI-SDS) and explained up to 40% of the variation of BMI-SDS. The network analysis identified 19 well-defined obesity-relevant biological pathways from the KEGG database. MassArray® validation identified three regions located in or near miR-1203, miR-412 and miR-216A coding regions differentially methylated between obese and non-obese children. The current work identified three CpG sites located in coding regions of three miRNAs (miR-1203, miR-412 and miR-216A) that were differentially methylated between obese and non-obese children, suggesting a role of miRNA epigenetic regulation in childhood obesity. © 2016 World Obesity Federation.

Impact of Consuming Extra-Virgin Olive Oil or Nuts within a Mediterranean Diet on DNA Methylation in Peripheral White Blood Cells within the PREDIMED-Navarra Randomized Controlled Trial: A Role for Dietary Lipids.

PubMed

Arpón, Ana; Milagro, Fermín I; Razquin, Cristina; Corella, Dolores; Estruch, Ramón; Fitó, Montserrat; Marti, Amelia; Martínez-González, Miguel A; Ros, Emilio; Salas-Salvadó, Jordi; Riezu-Boj, José-Ignacio; Martínez, J Alfredo

2017-12-23

DNA methylation could be reversible and mouldable by environmental factors, such as dietary exposures. The objective was to analyse whether an intervention with two Mediterranean diets, one rich in extra-virgin olive oil (MedDiet + EVOO) and the other one in nuts (MedDiet + nuts), was influencing the methylation status of peripheral white blood cells (PWBCs) genes. A subset of 36 representative individuals were selected within the PREvención con DIeta MEDiterránea (PREDIMED-Navarra) trial, with three intervention groups in high cardiovascular risk volunteers: MedDiet + EVOO, MedDiet + nuts, and a low-fat control group. Methylation was assessed at baseline and at five-year follow-up. Ingenuity pathway analysis showed routes with differentially methylated CpG sites (CpGs) related to intermediate metabolism, diabetes, inflammation, and signal transduction. Two CpGs were specifically selected: cg01081346- CPT1B / CHKB-CPT1B and cg17071192- GNAS/GNASAS , being associated with intermediate metabolism. Furthermore, cg01081346 was associated with PUFAs intake, showing a role for specific fatty acids on epigenetic modulation. Specific components of MedDiet, particularly nuts and EVOO, were able to induce methylation changes in several PWBCs genes. These changes may have potential benefits in health; especially those changes in genes related to intermediate metabolism, diabetes, inflammation and signal transduction, which may contribute to explain the role of MedDiet and fat quality on health outcomes.

Impact of Consuming Extra-Virgin Olive Oil or Nuts within a Mediterranean Diet on DNA Methylation in Peripheral White Blood Cells within the PREDIMED-Navarra Randomized Controlled Trial: A Role for Dietary Lipids

PubMed Central

Razquin, Cristina; Estruch, Ramón; Fitó, Montserrat; Martínez-González, Miguel A.; Ros, Emilio

2017-01-01

DNA methylation could be reversible and mouldable by environmental factors, such as dietary exposures. The objective was to analyse whether an intervention with two Mediterranean diets, one rich in extra-virgin olive oil (MedDiet + EVOO) and the other one in nuts (MedDiet + nuts), was influencing the methylation status of peripheral white blood cells (PWBCs) genes. A subset of 36 representative individuals were selected within the PREvención con DIeta MEDiterránea (PREDIMED-Navarra) trial, with three intervention groups in high cardiovascular risk volunteers: MedDiet + EVOO, MedDiet + nuts, and a low-fat control group. Methylation was assessed at baseline and at five-year follow-up. Ingenuity pathway analysis showed routes with differentially methylated CpG sites (CpGs) related to intermediate metabolism, diabetes, inflammation, and signal transduction. Two CpGs were specifically selected: cg01081346–CPT1B/CHKB-CPT1B and cg17071192–GNAS/GNASAS, being associated with intermediate metabolism. Furthermore, cg01081346 was associated with PUFAs intake, showing a role for specific fatty acids on epigenetic modulation. Specific components of MedDiet, particularly nuts and EVOO, were able to induce methylation changes in several PWBCs genes. These changes may have potential benefits in health; especially those changes in genes related to intermediate metabolism, diabetes, inflammation and signal transduction, which may contribute to explain the role of MedDiet and fat quality on health outcomes. PMID:29295516

Adult monozygotic twins discordant for intra-uterine growth have indistinguishable genome-wide DNA methylation profiles

PubMed Central

2013-01-01

Background Low birth weight is associated with an increased adult metabolic disease risk. It is widely discussed that poor intra-uterine conditions could induce long-lasting epigenetic modifications, leading to systemic changes in regulation of metabolic genes. To address this, we acquire genome-wide DNA methylation profiles from saliva DNA in a unique cohort of 17 monozygotic monochorionic female twins very discordant for birth weight. We examine if adverse prenatal growth conditions experienced by the smaller co-twins lead to long-lasting DNA methylation changes. Results Overall, co-twins show very similar genome-wide DNA methylation profiles. Since observed differences are almost exclusively caused by variable cellular composition, an original marker-based adjustment strategy was developed to eliminate such variation at affected CpGs. Among adjusted and unchanged CpGs 3,153 are differentially methylated between the heavy and light co-twins at nominal significance, of which 45 show sensible absolute mean β-value differences. Deep bisulfite sequencing of eight such loci reveals that differences remain in the range of technical variation, arguing against a reproducible biological effect. Analysis of methylation in repetitive elements using methylation-dependent primer extension assays also indicates no significant intra-pair differences. Conclusions Severe intra-uterine growth differences observed within these monozygotic twins are not associated with long-lasting DNA methylation differences in cells composing saliva, detectable with up-to-date technologies. Additionally, our results indicate that uneven cell type composition can lead to spurious results and should be addressed in epigenomic studies. PMID:23706164

Augmentation of point of injury care: Reducing battlefield mortality-The IDF experience.

PubMed

Benov Avi; Elon, Glassberg; Baruch, Erez Nissim; Avi, Shina; Gilad, Twig; Moran, Levi; Itay, Zoarets; Ram, Sagi; Tarif, Bader; David, Dagan; Avraham, Yitzhak; Yitshak, Kreiss

2016-05-01

In 2012, the Israel Defense Forces Medical Corps (IDF-MC) set a goal of reducing mortality and eliminating preventable death on the battlefield. A force buildup plan entitled "My Brother's Keeper" was launched addressing: trauma medicine, training, change of Clinical Practice Guidelines (CPGs), injury prevention, data collection, global collaboration and more. The aim of this article is to examine how military medical care has evolved due "My Brother's Keeper" between Second Lebanon War (SLW, 2006) to Operation Protective Edge (OPE, 2014). Records of all casualties during OPE and SLW were extracted and analyzed from the I.D.F Trauma Registry. Noncombat injuries and civilian injuries from missile attacks were excluded from this analysis. The plans main impacts were; incorporation of a physician or paramedic as an integral part of each fighting company, implementation of new CPGs, introduction of new approaches for extremity haemorrhage control and Remote Damage Control Resuscitation at point of injury (POI) using single donor reconstituted freeze dried plasma (25 casualties) and transexamic acid (98 casualties). During OPE, 704 soldiers sustained injuries compared with 833 casualties during SLW. Fatalities were 65 and 119, respectively, cumulating to Case Fatality Rate of 9.2% and 14.3%, respectively. Significant changes in the way the IDF-MC provides combat casualty care have been made in recent years. It is the transformation from concept to doctrine and integration into a structured and Goal-Oriented Casualty Care System, especially POI care that led to the unprecedented survival rates in IDF as shown in this conflict. Copyright © 2015 Elsevier Ltd. All rights reserved.

The influence of aging on the methylation status of brain-derived neurotrophic factor gene in blood.

PubMed

Ihara, Kazushige; Fuchikami, Manabu; Hashizume, Masahiro; Okada, Satoshi; Kawai, Hisashi; Obuchi, Shuichi; Hirano, Hirohiko; Fujiwara, Yoshinori; Hachisu, Mitsugu; Hongyong, Kim; Morinobu, Shigeru

2018-06-28

Brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of psychiatric disorders in adults and elderly individuals, and as a result, the DNA methylation (DNAm) of the BDNF gene in peripheral tissues including blood has been extensively examined to develop a useful biomarker for psychiatric disorders. However, studies to date have not previously investigated the effect of age on DNAm of the BDNF gene in blood. In this context, we measured DNAm of 39 CpG units in the CpG island at the promoter of exon I of the BDNF gene. We analyzed genomic DNA from peripheral blood of 105 health Japanese women 20 to 80 years of age to identify aging-associated change in DNAm of the BDNF gene. In addition, we examined the relationship between total MMSE scores, numbers of stressful life events, and serum BDNF levels on DNAm of the BDNF gene. The DNAm rate at each CpG unit was measured using a MassArray ® system (Agena Bioscience), and serum BDNF levels were measured by ELISA. There was a significant correlation between DNAm and age in 13 CpGs. However, there was no significant correlation between DNAm and total MMSE scores, numbers of life events, or serum BDNF levels. Despite the small number of subjects and the inclusion of only female subjects, our results suggest that DNAm of 13 CpGs of the BDNF gene may be an appropriate biomarker for aging and useful for predicting increased susceptibility to age-related psychiatric disorders. © 2018 John Wiley & Sons, Ltd.

Epigenome-wide analysis of DNA methylation in lung tissue shows concordance with blood studies and identifies tobacco smoke-inducible enhancers.

PubMed

Stueve, Theresa Ryan; Li, Wen-Qing; Shi, Jianxin; Marconett, Crystal N; Zhang, Tongwu; Yang, Chenchen; Mullen, Daniel; Yan, Chunli; Wheeler, William; Hua, Xing; Zhou, Beiyun; Borok, Zea; Caporaso, Neil E; Pesatori, Angela C; Duan, Jubao; Laird-Offringa, Ite A; Landi, Maria Teresa

2017-08-01

Smoking-associated DNA hypomethylation has been observed in blood cells and linked to lung cancer risk. However, its cause and mechanistic relationship to lung cancer remain unclear. We studied the association between tobacco smoking and epigenome-wide methylation in non-tumor lung (NTL) tissue from 237 lung cancer cases in the Environment And Genetics in Lung cancer Etiology study, using the Infinium HumanMethylation450 BeadChip. We identified seven smoking-associated hypomethylated CpGs (P < 1.0 × 10-7), which were replicated in NTL data from The Cancer Genome Atlas. Five of these loci were previously reported as hypomethylated in smokers' blood, suggesting that blood-based biomarkers can reflect changes in the target tissue for these loci. Four CpGs border sequences carrying aryl hydrocarbon receptor binding sites and enhancer-specific histone modifications in primary alveolar epithelium and A549 lung adenocarcinoma cells. A549 cell exposure to cigarette smoke condensate increased these enhancer marks significantly and stimulated expression of predicted target xenobiotic response-related genes AHRR (P = 1.13 × 10-62) and CYP1B1 (P < 2.49 × 10-61). Expression of both genes was linked to smoking-related transversion mutations in lung tumors. Thus, smoking-associated hypomethylation may be a consequence of enhancer activation, revealing environmentally-induced regulatory elements implicated in lung carcinogenesis. Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US.

Aging effects on DNA methylation modules in human brain and blood tissue

PubMed Central

2012-01-01

Background Several recent studies reported aging effects on DNA methylation levels of individual CpG dinucleotides. But it is not yet known whether aging-related consensus modules, in the form of clusters of correlated CpG markers, can be found that are present in multiple human tissues. Such a module could facilitate the understanding of aging effects on multiple tissues. Results We therefore employed weighted correlation network analysis of 2,442 Illumina DNA methylation arrays from brain and blood tissues, which enabled the identification of an age-related co-methylation module. Module preservation analysis confirmed that this module can also be found in diverse independent data sets. Biological evaluation showed that module membership is associated with Polycomb group target occupancy counts, CpG island status and autosomal chromosome location. Functional enrichment analysis revealed that the aging-related consensus module comprises genes that are involved in nervous system development, neuron differentiation and neurogenesis, and that it contains promoter CpGs of genes known to be down-regulated in early Alzheimer's disease. A comparison with a standard, non-module based meta-analysis revealed that selecting CpGs based on module membership leads to significantly increased gene ontology enrichment, thus demonstrating that studying aging effects via consensus network analysis enhances the biological insights gained. Conclusions Overall, our analysis revealed a robustly defined age-related co-methylation module that is present in multiple human tissues, including blood and brain. We conclude that blood is a promising surrogate for brain tissue when studying the effects of age on DNA methylation profiles. PMID:23034122

Proper management of rheumatoid arthritis in Latin America. What the guidelines say?

PubMed

Brenol, Claiton V; Nava, Jorge Ivan Gamez; Soriano, Enrique R

2015-03-01

To analyze characteristics of clinical practice guidelines (CPGs) for the management of rheumatoid arthritis (RA) developed in Latin American (LA) countries and to describe the knowledge, use, and barriers for their implementation perceived among LA rheumatologists, a comprehensive literature search including Medline, PubMed, Cochrane Library, LILACS and Scielo was performed. The Appraisal of Guidelines for Research and Evaluation (AGREE) instrument was applied for evaluation. A survey was sent to PANLAR members containing questions related to knowledge about guidelines, application of the recommendations, and difficulties in implementing CPGs. Eight guidelines were identified. Most guidelines were evidence based (62 %), but in only 37 % a systematic literature search was done. None of the guidelines included patients' views and preferences, and only few of them stated an updating procedure. Funding body independence and disclosure of conflicts of interest were rarely reported. The survey was answered by 214 rheumatologists from all Latin American countries. Most rheumatologist reported knowledge and use of clinical guidelines, mainly international ones. In general, rheumatologist felt that guidelines apply to only a minority of patients seen in daily clinical practice. Limited access expensive drugs, suggested by the guidelines, was the most frequent barrier to guidelines implementation that was reported. A good number of guidelines on the treatment of rheumatoid arthritis have been developed in Latin America. Most of them are lacking some of the components recognized for high-quality clinical guidelines development. In spite that most rheumatologist know and apply guidelines, access to drugs is still a very important barrier to their implementation in Latin America.

CpG methylation of HPV 16 LCR at E2 binding site proximal to P97 is associated with cervical cancer in presence of intact E2.

PubMed

Bhattacharjee, Bornali; Sengupta, Sharmila

2006-10-25

Human papillomavirus type 16 (HPV-16) E2 protein negatively regulates transcription of the E6 and E7 genes. This study was done to test the hypothesis that methylation of the HPV 16 long control region (LCR) is overrepresented among cervical cancer (CaCx) cases compared to cytologically normal controls harboring intact E2 gene. Methylation of the E2 binding site (E2BS-I), proximal to the P97 promoter, was assessed by HpaII/ MspI restriction digestion while McrBC digestion was used to assess LCR-E6 (7289-540) for 57 CaCx samples and 15 normal controls. E2BS-I methylation was found to be significantly higher (56.14%) in cases compared to (20%) controls [OR(age-adjusted) (95% CI): 4.53 (1.05-19.43) p=0.042]. The difference between cases (54.39%) and controls (40%) with respect to LCR-E6 methylation status [OR(age-adjusted) (95% CI): 1.77(0.5-6.3); p=0.38] was not significant. Sequencing of a randomly selected set of 13 methylated malignant samples revealed absence or rare presence, of methylation at CpGs 7579, 7535, 7683 and 7862 respectively. Methylation was found to be more at CpGs within E2 binding sites proximal to the P97 promoter. These results indicate the involvement of E2 binding site methylation in presence of intact E2, leading to loss of E2 repressor activity in CaCx.

Pre-Service Mathematics Teachers' Pattern Conversion Ability: Generating Figural Patterns Based on Number Patterns

ERIC Educational Resources Information Center

Kiliç, Çigdem

2017-01-01

In that current study, pattern conversion ability of 25 pre-service mathematics teachers (producing figural patterns following number patterns) was investigated. During the study participants were asked to generate figural patterns based on those number patterns. The results of the study indicate that many participants could generate different…

Genome-wide base-resolution mapping of DNA methylation in single cells using single-cell bisulfite sequencing (scBS-seq).

PubMed

Clark, Stephen J; Smallwood, Sébastien A; Lee, Heather J; Krueger, Felix; Reik, Wolf; Kelsey, Gavin

2017-03-01

DNA methylation (DNAme) is an important epigenetic mark in diverse species. Our current understanding of DNAme is based on measurements from bulk cell samples, which obscures intercellular differences and prevents analyses of rare cell types. Thus, the ability to measure DNAme in single cells has the potential to make important contributions to the understanding of several key biological processes, such as embryonic development, disease progression and aging. We have recently reported a method for generating genome-wide DNAme maps from single cells, using single-cell bisulfite sequencing (scBS-seq), allowing the quantitative measurement of DNAme at up to 50% of CpG dinucleotides throughout the mouse genome. Here we present a detailed protocol for scBS-seq that includes our most recent developments to optimize recovery of CpGs, mapping efficiency and success rate; reduce hands-on time; and increase sample throughput with the option of using an automated liquid handler. We provide step-by-step instructions for each stage of the method, comprising cell lysis and bisulfite (BS) conversion, preamplification and adaptor tagging, library amplification, sequencing and, lastly, alignment and methylation calling. An individual with relevant molecular biology expertise can complete library preparation within 3 d. Subsequent computational steps require 1-3 d for someone with bioinformatics expertise.

A modular network for legged locomotion

NASA Astrophysics Data System (ADS)

Golubitsky, Martin; Stewart, Ian; Buono, Pietro-Luciano; Collins, J. J.

1998-04-01

In this paper we use symmetry methods to study networks of coupled cells, which are models for central pattern generators (CPGs). In these models the cells obey identical systems of differential equations and the network specifies how cells are coupled. Previously, Collins and Stewart showed that the phase relations of many of the standard gaits of quadrupeds and hexapods can be obtained naturally via Hopf bifurcation in small networks. For example, the networks they used to study quadrupeds all had four cells, with the understanding that each cell determined the phase of the motion of one leg. However, in their work it seemed necessary to employ several different four-oscillator networks to obtain all of the standard quadrupedal gaits. We show that this difficulty with four-oscillator networks is unavoidable, but that the problems can be overcome by using a larger network. Specifically, we show that the standard gaits of a quadruped, including walk, trot and pace, cannot all be realized by a single four-cell network without introducing unwanted conjugacies between trot and pace - conjugacies that imply a dynamic equivalence between these gaits that seems inconsistent with observations. In this sense a single network with four cells cannot model the CPG of a quadruped. We also introduce a single eight-cell network that can model all of the primary gaits of quadrupeds without these unwanted conjugacies. Moreover, this network is modular in that it naturally generalizes to provide models of gaits in hexapods, centipedes, and millipedes. The analysis of models for many-legged animals shows that wave-like motions, similar to those obtained by Kopell and Ermentrout, can be expected. However, our network leads to a prediction that the wavelength of the wave motion will divide twice the length of the animal. Indeed, we reproduce illustrations of wave-like motions in centipedes where the animal is approximately one-and-a-half wavelength long - motions that are consistent with this prediction. We discuss the implications of these results for the development of modular control networks for adaptive legged robots.

An open-access CMIP5 pattern library for temperature and precipitation: description and methodology

NASA Astrophysics Data System (ADS)

Lynch, Cary; Hartin, Corinne; Bond-Lamberty, Ben; Kravitz, Ben

2017-05-01

Pattern scaling is used to efficiently emulate general circulation models and explore uncertainty in climate projections under multiple forcing scenarios. Pattern scaling methods assume that local climate changes scale with a global mean temperature increase, allowing for spatial patterns to be generated for multiple models for any future emission scenario. For uncertainty quantification and probabilistic statistical analysis, a library of patterns with descriptive statistics for each file would be beneficial, but such a library does not presently exist. Of the possible techniques used to generate patterns, the two most prominent are the delta and least squares regression methods. We explore the differences and statistical significance between patterns generated by each method and assess performance of the generated patterns across methods and scenarios. Differences in patterns across seasons between methods and epochs were largest in high latitudes (60-90° N/S). Bias and mean errors between modeled and pattern-predicted output from the linear regression method were smaller than patterns generated by the delta method. Across scenarios, differences in the linear regression method patterns were more statistically significant, especially at high latitudes. We found that pattern generation methodologies were able to approximate the forced signal of change to within ≤ 0.5 °C, but the choice of pattern generation methodology for pattern scaling purposes should be informed by user goals and criteria. This paper describes our library of least squares regression patterns from all CMIP5 models for temperature and precipitation on an annual and sub-annual basis, along with the code used to generate these patterns. The dataset and netCDF data generation code are available at doi:10.5281/zenodo.495632.

Idiopathic granulomatous lobular mastitis - report of 43 cases from iran; introducing a preliminary clinical practice guideline.

PubMed

Omranipour, Ramesh; Mohammadi, S-Farzad; Samimi, Parisa

2013-12-01

We aimed to report a large series of idiopathic granulomatous lobular mastitis (IGLM) from Iran and sketch preliminary clinical practice guidelines (CPG) for approaching an inflammatory breast mass. In a retrospective records review, 43 consecutive IGLM cases were studied. Data on baseline, clinical, imaging, and pathologic characteristics were collected. The mean age of the women was 33.5 years. All but 1 were married and had given birth. 16% had a cancer-like presentation. Inflammatory signs, architectural distortion, and a nodular pattern were the most common findings clinically, mammographically and ultrasonographically, respectively. 29.5% of the pathological reports indicated necrosis which was more common in younger subjects (p = 0.016); microabscesses were associated with a shorter lactation course (p = 0.006). Corticosteroids had been used as the initial treatment modality in 51%, immunosuppressive agents had not been administered, and a 16% relapse rate was recorded. We recognized the need for a multidisciplinary approach covering radiology, oncology, and surgery to best handle diagnostic and therapeutic issues and manage relevant infections as well as the major differential diagnosis, i.e. malignancy. We hypothesized that a shorter lactation period may cause more milk stasis and extravasation and be contributory to IGLM. CPGs are needed to incorporate the needed multidisciplinary approach and to standardize IGLM care. We present one such guideline.

Idiopathic Granulomatous Lobular Mastitis – Report of 43 Cases from Iran; Introducing a Preliminary Clinical Practice Guideline

PubMed Central

Omranipour, Ramesh; Mohammadi, S-Farzad; Samimi, Parisa

2013-01-01

Summary Background We aimed to report a large series of idiopathic granulomatous lobular mastitis (IGLM) from Iran and sketch preliminary clinical practice guidelines (CPG) for approaching an inflammatory breast mass. Patients and Methods In a retrospective records review, 43 consecutive IGLM cases were studied. Data on baseline, clinical, imaging, and pathologic characteristics were collected. Results The mean age of the women was 33.5 years. All but 1 were married and had given birth. 16% had a cancer-like presentation. Inflammatory signs, architectural distortion, and a nodular pattern were the most common findings clinically, mammographically and ultrasonographically, respectively. 29.5% of the pathological reports indicated necrosis which was more common in younger subjects (p = 0.016); microabscesses were associated with a shorter lactation course (p = 0.006). Corticosteroids had been used as the initial treatment modality in 51%, immunosuppressive agents had not been administered, and a 16% relapse rate was recorded. We recognized the need for a multidisciplinary approach covering radiology, oncology, and surgery to best handle diagnostic and therapeutic issues and manage relevant infections as well as the major differential diagnosis, i.e. malignancy. Conclusion We hypothesized that a shorter lactation period may cause more milk stasis and extravasation and be contributory to IGLM. CPGs are needed to incorporate the needed multidisciplinary approach and to standardize IGLM care. We present one such guideline. PMID:24550752

Epigenetic effects of methoxychlor and vinclozolin on male gametes.

PubMed

Paoloni-Giacobino, Ariane

2014-01-01

Imprinting is an epigenetic form of gene regulation that mediates a parent-of-origin-dependent expression of the alleles of a number of genes. Imprinting, which occurs at specific sites within or surrounding the gene, called differentially methylated domains, consists in a methylation of CpGs. The appropriate transmission of genomics imprints is essential for the control of embryonic development and fetal growth. A number of endocrine disruptors (EDs) affect male reproductive tract development and spermatogenesis. It was postulated that the genetic effects of EDs might be induced by alterations in gene imprinting. We tested two EDs: methoxychlor and vinclozolin. Their administration during gestation induced in the offspring a decrease in sperm counts and significant modifications in the methylation pattern of a selection of paternally and maternally expressed canonical imprinted genes. The observation that imprinting was largely untouched in somatic cells suggests that EDs exert their damaging effects via the process of reprogramming that is unique to gamete development. Interestingly, the effects were transgenerational, although disappearing gradually from F1 to F3. A systematic analysis showed a heterogeneity in the CpG sensitivity to EDs. We propose that the deleterious effects of EDs on the male reproductive system are mediated by imprinting defects in the sperm. The reported effects of EDs on human male spermatogenesis might be mediated by analogous imprinting alterations. © 2014 Elsevier Inc. All rights reserved.

Knee Pain and Mobility Impairments: Meniscal and Articular Cartilage Lesions Revision 2018: Using the Evidence to Guide Physical Therapist Practice.

PubMed

2018-02-01

Meniscus and articular cartilage lesions are common knee injuries. The resulting knee pain and mobility impairments can be improved by physical therapists during nonoperative and operative management. Recommendations from clinical practice guidelines (CPGs) such as this revision, titled "Knee Pain and Mobility Impairments: Meniscal and Articular Cartilage Lesions," published in the February 2018 issue of JOSPT, can help physical therapists engage in evidence-informed practice and reduce unnecessary clinical variation. J Orthop Sports Phys Ther 2018;48(2):123-124. doi:10.2519/jospt.2018.0503.

An open-access CMIP5 pattern library for temperature and precipitation: Description and methodology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lynch, Cary D.; Hartin, Corinne A.; Bond-Lamberty, Benjamin

Pattern scaling is used to efficiently emulate general circulation models and explore uncertainty in climate projections under multiple forcing scenarios. Pattern scaling methods assume that local climate changes scale with a global mean temperature increase, allowing for spatial patterns to be generated for multiple models for any future emission scenario. For uncertainty quantification and probabilistic statistical analysis, a library of patterns with descriptive statistics for each file would be beneficial, but such a library does not presently exist. Of the possible techniques used to generate patterns, the two most prominent are the delta and least squared regression methods. We exploremore » the differences and statistical significance between patterns generated by each method and assess performance of the generated patterns across methods and scenarios. Differences in patterns across seasons between methods and epochs were largest in high latitudes (60-90°N/S). Bias and mean errors between modeled and pattern predicted output from the linear regression method were smaller than patterns generated by the delta method. Across scenarios, differences in the linear regression method patterns were more statistically significant, especially at high latitudes. We found that pattern generation methodologies were able to approximate the forced signal of change to within ≤ 0.5°C, but choice of pattern generation methodology for pattern scaling purposes should be informed by user goals and criteria. As a result, this paper describes our library of least squared regression patterns from all CMIP5 models for temperature and precipitation on an annual and sub-annual basis, along with the code used to generate these patterns.« less

An open-access CMIP5 pattern library for temperature and precipitation: Description and methodology

DOE PAGES

Lynch, Cary D.; Hartin, Corinne A.; Bond-Lamberty, Benjamin; ...

2017-05-15

Pattern scaling is used to efficiently emulate general circulation models and explore uncertainty in climate projections under multiple forcing scenarios. Pattern scaling methods assume that local climate changes scale with a global mean temperature increase, allowing for spatial patterns to be generated for multiple models for any future emission scenario. For uncertainty quantification and probabilistic statistical analysis, a library of patterns with descriptive statistics for each file would be beneficial, but such a library does not presently exist. Of the possible techniques used to generate patterns, the two most prominent are the delta and least squared regression methods. We exploremore » the differences and statistical significance between patterns generated by each method and assess performance of the generated patterns across methods and scenarios. Differences in patterns across seasons between methods and epochs were largest in high latitudes (60-90°N/S). Bias and mean errors between modeled and pattern predicted output from the linear regression method were smaller than patterns generated by the delta method. Across scenarios, differences in the linear regression method patterns were more statistically significant, especially at high latitudes. We found that pattern generation methodologies were able to approximate the forced signal of change to within ≤ 0.5°C, but choice of pattern generation methodology for pattern scaling purposes should be informed by user goals and criteria. As a result, this paper describes our library of least squared regression patterns from all CMIP5 models for temperature and precipitation on an annual and sub-annual basis, along with the code used to generate these patterns.« less

DNA methylation profiling of asbestos-treated MeT5A cell line reveals novel pathways implicated in asbestos response.

PubMed

Casalone, E; Allione, A; Viberti, C; Pardini, B; Guarrera, S; Betti, M; Dianzani, I; Aldieri, E; Matullo, G

2018-05-01

Occupational and environmental asbestos exposure is the main determinant of malignant pleural mesothelioma (MPM), however, the mechanisms by which its fibres contribute to cell toxicity and transformation are not completely clear. Aberrant DNA methylation is a common event in cancer but epigenetic modifications involved specifically in MPM carcinogenesis need to be better clarified. To investigate asbestos-induced DNA methylation and gene expression changes, we treated Met5A mesothelial cells with different concentrations of crocidolite and chrysotile asbestos (0.5 ÷ 5.0 µg/cm 2 , 72 h incubation). Overall, we observed 243 and 302 differentially methylated CpGs (≥ 10%) between the asbestos dose at 5 µg/cm 2 and untreated control, in chrysotile and crocidolite treatment, respectively. To examine the dose-response effect, Spearman's correlation test was performed and significant CpGs located in genes involved in migration/cell adhesion processes were identified in both treatments. Moreover, we found that both crocidolite and chrysotile exposure induced a significant up-regulation of CA9 and SRGN (log2 fold change > 1.5), previously reported as associated with a more aggressive MPM phenotype. However, we found no correlation between methylation and gene expression changes, except for a moderate significant inverse correlation at the promoter region of DKK1 (Spearman rho = - 1, P value = 0.02) after chrysotile exposure. These results describe for the first time the relationship between DNA methylation modifications and asbestos exposure. Our findings provide a basis to further explore and validate asbestos-induced DNA methylation changes, that could influence MPM carcinogenesis and possibly identifying new chemopreventive target.

Russian guidelines for the management of COPD: algorithm of pharmacologic treatment

PubMed Central

Aisanov, Zaurbek; Avdeev, Sergey; Arkhipov, Vladimir; Belevskiy, Andrey; Chuchalin, Alexander; Leshchenko, Igor; Ovcharenko, Svetlana; Shmelev, Evgeny; Miravitlles, Marc

2018-01-01

The high prevalence of COPD together with its high level of misdiagnosis and late diagnosis dictate the necessity for the development and implementation of clinical practice guidelines (CPGs) in order to improve the management of this disease. High-quality, evidence-based international CPGs need to be adapted to the particular situation of each country or region. A new version of the Russian Respiratory Society guidelines released at the end of 2016 was based on the proposal by Global Initiative for Obstructive Lung Disease but adapted to the characteristics of the Russian health system and included an algorithm of pharmacologic treatment of COPD. The proposed algorithm had to comply with the requirements of the Russian Ministry of Health to be included into the unified electronic rubricator, which required a balance between the level of information and the simplicity of the graphic design. This was achieved by: exclusion of the initial diagnostic process, grouping together the common pharmacologic and nonpharmacologic measures for all patients, and the decision not to use the letters A–D for simplicity and clarity. At all stages of the treatment algorithm, efficacy and safety have to be carefully assessed. Escalation and de-escalation is possible in the case of lack of or insufficient efficacy or safety issues. Bronchodilators should not be discontinued except in the case of significant side effects. At the same time, inhaled corticosteroid (ICS) withdrawal is not represented in the algorithm, because it was agreed that there is insufficient evidence to establish clear criteria for ICSs discontinuation. Finally, based on the Global Initiative for Obstructive Lung Disease statement, the proposed algorithm reflects and summarizes different approaches to the pharmacological treatment of COPD taking into account the reality of health care in the Russian Federation. PMID:29386887

Epigenetic regulation of the glucocorticoid receptor promoter 1(7) in adult rats.

PubMed

Witzmann, Simone R; Turner, Jonathan D; Mériaux, Sophie B; Meijer, Onno C; Muller, Claude P

2012-11-01

Regulation of glucocorticoid receptor (GR) levels is an important stress adaptation mechanism. Transcription factor Nfgi-a and environmentally induced Gr promoter 1 7 methylation have been implicated in fine-tuning the expression of Gr 1 7 transcripts. Here, we investigated Gr promoter 1 7 methylation and Gr 1 7 expression in adult rats exposed to either acute or chronic stress paradigms. A strong negative correlation was observed between the sum of promoter-wide methylation levels and Gr 1 7 transcript levels, independent of the stressor. Methylation of individual sites did not, however, correlate with transcript levels. This suggested that promoter 1 7 was directly regulated by promoter-wide DNA methylation. Although acute stress increased Ngfi-a expression in the hypothalamic paraventricular nucleus (PVN), Gr 1 7 transcript levels remained unaffected despite low methylation levels. Acute stress had little effect on these low methylation levels, except at four hippocampal CpGs. Chronic stress altered the corticosterone response to an acute stressor. In the adrenal and pituitary glands, but not in the brain, this was accompanied by an increase in methylation levels in orchestrated clusters rather than individual CpGs. PVN methylation levels, unaffected by acute or chronic stress, were significantly more variable within- than between-groups, suggesting that they were instated probably during the perinatal period and represent a pre-established trait. Thus, in addition to the known perinatal programming, the Gr 1 7 promoter is epigenetically regulated by chronic stress in adulthood, and retains promoter-wide tissue-specific plasticity. Differences in methylation susceptibility between the PVN in the perinatal period and the peripheral HPA axis tissues in adulthood may represent an important "trait" vs. "state" regulation of the Gr gene.

System-Wide Associations between DNA-Methylation, Gene Expression, and Humoral Immune Response to Influenza Vaccination.

PubMed

Zimmermann, Michael T; Oberg, Ann L; Grill, Diane E; Ovsyannikova, Inna G; Haralambieva, Iana H; Kennedy, Richard B; Poland, Gregory A

2016-01-01

Failure to achieve a protected state after influenza vaccination is poorly understood but occurs commonly among aged populations experiencing greater immunosenescence. In order to better understand immune response in the elderly, we studied epigenetic and transcriptomic profiles and humoral immune response outcomes in 50-74 year old healthy participants. Associations between DNA methylation and gene expression reveal a system-wide regulation of immune-relevant functions, likely playing a role in regulating a participant's propensity to respond to vaccination. Our findings show that sites of methylation regulation associated with humoral response to vaccination impact known cellular differentiation signaling and antigen presentation pathways. We performed our analysis using per-site and regionally average methylation levels, in addition to continuous or dichotomized outcome measures. The genes and molecular functions implicated by each analysis were compared, highlighting different aspects of the biologic mechanisms of immune response affected by differential methylation. Both cis-acting (within the gene or promoter) and trans-acting (enhancers and transcription factor binding sites) sites show significant associations with measures of humoral immunity. Specifically, we identified a group of CpGs that, when coordinately hypo-methylated, are associated with lower humoral immune response, and methylated with higher response. Additionally, CpGs that individually predict humoral immune responses are enriched for polycomb-group and FOXP2 transcription factor binding sites. The most robust associations implicate differential methylation affecting gene expression levels of genes with known roles in immunity (e.g. HLA-B and HLA-DQB2) and immunosenescence. We believe our data and analysis strategy highlight new and interesting epigenetic trends affecting humoral response to vaccination against influenza; one of the most common and impactful viral pathogens.

Quality Measures in Orthopaedic Sports Medicine: A Systematic Review.

PubMed

Abrams, Geoffrey D; Greenberg, Daniel R; Dragoo, Jason L; Safran, Marc R; Kamal, Robin N

2017-10-01

To report the current quality measures that are applicable to orthopaedic sports medicine physicians. Six databases were searched with a customized search term to identify quality measures relevant to orthopaedic sports medicine surgeons: MEDLINE/PubMed, EMBASE, the National Quality Forum (NQF) Quality Positioning System (QPS), the Agency for Healthcare Research and Quality (AHRQ) National Quality Measures Clearinghouse (NQMC), the Physician Quality Reporting System (PQRS) database, and the American Academy of Orthopaedic Surgeons (AAOS) website. Results were screened by 2 Board-certified orthopaedic surgeons with fellowship training in sports medicine and dichotomized based on sports medicine-specific or general orthopaedic (nonarthroplasty) categories. Hip and knee arthroplasty measures were excluded. Included quality measures were further categorized based on Donabedian's domains and the Center for Medicare and Medicaid (CMS) National Quality Strategy priorities. A total of 1,292 quality measures were screened and 66 unique quality measures were included. A total of 47 were sports medicine-specific and 19 related to the general practice of orthopaedics for a fellowship-trained sports medicine specialist. Nineteen (29%) quality measures were collected within PQRS, with 5 of them relating to sports medicine and 14 relating to general orthopaedics. AAOS Clinical Practice Guidelines (CPGs) comprised 40 (60%) of the included measures and were all within sports medicine. Five (8%) additional measures were collected within AHRQ and 2 (3%) within NQF. Most quality measures consist of process rather than outcome or structural measures. No measures addressing concussions were identified. There are many existing quality measures relating to the practice of orthopaedic sports medicine. Most quality measures are process measures described within PQRS or AAOS CPGs. Knowledge of quality measures are important as they may be used to improve care, are increasingly being used to determine physician reimbursement, and can inform future quality measure development efforts. Published by Elsevier Inc.

Asbestos-associated genome-wide DNA methylation changes in lung cancer.

PubMed

Kettunen, Eeva; Hernandez-Vargas, Hector; Cros, Marie-Pierre; Durand, Geoffroy; Le Calvez-Kelm, Florence; Stuopelyte, Kristina; Jarmalaite, Sonata; Salmenkivi, Kaisa; Anttila, Sisko; Wolff, Henrik; Herceg, Zdenko; Husgafvel-Pursiainen, Kirsti

2017-11-15

Previous studies have revealed a robust association between exposure to asbestos and human lung cancer. Accumulating evidence has highlighted the role of epigenome deregulation in the mechanism of carcinogen-induced malignancies. We examined the impact of asbestos on DNA methylation. Our genome-wide studies (using Illumina HumanMethylation450K BeadChip) of lung cancer tissue and paired normal lung from 28 asbestos-exposed or non-exposed patients, mostly smokers, revealed distinctive DNA methylation changes. We identified a number of differentially methylated regions (DMR) and differentially variable, differentially methylated CpGs (DVMC), with individual CpGs further validated by pyrosequencing in an independent series of 91 non-small cell lung cancer and paired normal lung. We discovered and validated BEND4, ZSCAN31 and GPR135 as significantly hypermethylated in lung cancer. DMRs in genes such as RARB (FDR 1.1 × 10 -19 , mean change in beta [Δ] -0.09), GPR135 (FDR 1.87 × 10 -8 , mean Δ -0.09) and TPO (FDR 8.58 × 10 -5 , mean Δ -0.11), and DVMCs in NPTN, NRG2, GLT25D2 and TRPC3 (all with p <0.05, t-test) were significantly associated with asbestos exposure status in exposed versus non-exposed lung tumors. Hypomethylation was characteristic to DVMCs in lung cancer tissue from asbestos-exposed subjects. When DVMCs related to asbestos or smoking were analyzed, 96% of the elements were unique to either of the exposures, consistent with the concept that the methylation changes in tumors may be specific for risk factors. In conclusion, we identified novel DNA methylation changes associated with lung tumors and asbestos exposure, suggesting that changes may be present in causal pathway from asbestos exposure to lung cancer. © 2017 UICC.

Alignment of practice guidelines with targeted-therapy drug funding policies in Ontario.

PubMed

Ramjeesingh, R; Meyer, R M; Brouwers, M; Chen, B E; Booth, C M

2013-02-01

We evaluated clinical practice guideline (cpg) recommendations from Cancer Care Ontario's Program in Evidence-Based Care (pebc) for molecularly targeted systemic treatments (tts) and subsequent funding decisions from the Ontario Ministry of Health and Long-Term Care. We identified pebc cpgs on tt published before June 1, 2010, and extracted information regarding the key evidence cited in support of cpg recommendations and the effect size associated with each tt. Those variables were compared with mohltc funding decisions as of June 2011. From 23 guidelines related to 17 tts, we identified 43 recommendations, among which 38 (88%) endorsed tt use. Among all the recommendations, 38 (88%) were based on published key evidence, with 82% (31 of 38) being supported by meta-analyses or phase iii trials. For the 38 recommendations endorsing tts, funding was approved in 28 (74%; odds ratio related to cpg recommendation: 29.9; p = 0.003). We were unable to demonstrate that recommendations associated with statistically significant improvements in overall survival [os: 14 of 16 (88%) vs. 8 of 14 (57%); p = 0.10] or disease- (dfs) or progression-free survival [pfs: 16 of 21 (76%) vs. 3 of 5 (60%); p = 0.59] were more likely to be funded than those with no significant difference. Moreover, we did not observe significant associations between funding approvals and absolute improvements of 3 months or more in os [6 of 6 (100%) vs. 3 of 6 (50%), p = 0.18] or pfs [6 of 8 (75%) vs. 10 of 12 (83%), p = 1.00]. For use of tts, most recommendations in pebc cpgs are based on meta-analyses or phase iii data, and funding decisions were strongly associated with those recommendations. Our data suggest a trend toward increased rates of funding for therapies with statistically significant improvements in os.

Evaluation of methylation status of the eNOS promoter at birth in relation to childhood bone mineral content

PubMed Central

Harvey, Nicholas C.; Lillycrop, Karen A.; Garratt, Emma; Sheppard, Allan; McLean, Cameron; Burdge, Graham; Slater-Jefferies, Jo; Rodford, Joanne; Crozier, Sarah; Inskip, Hazel; Emerald, Bright Starling; Gale, Catharine R; Hanson, Mark; Gluckman, Peter; Godfrey, Keith; Cooper, Cyrus

2013-01-01

Aim Our previous work has shown associations between childhood adiposity and perinatal methylation status of several genes in umbilical cord tissue, including endothelial nitric oxide synthase (eNOS). There is increasing evidence that eNOS is important in bone metabolism; we therefore related the methylation status of the eNOS gene promoter in stored umbilical cord to childhood bone size and density in a group of 9-year old children. Methods We used Sequenom MassARRAY to assess the methylation status of 2 CpGs in the eNOS promoter, identified from our previous study, in stored umbilical cords of 66 children who formed part of a Southampton birth cohort and who had measurements of bone size and density at age 9 years (Lunar DPXL DXA instrument). Results Percentage methylation varied greatly between subjects. For one of the two CpGs, eNOS chr7:150315553+, after taking account of age and sex there was a strong positive association between methylation status and the child’s whole body bone area (r=0.28,p=0.02), bone mineral content (r=0.34,p=0.005) and areal bone mineral density (r=0.34,p=0.005) at age 9 years. These associations were independent of previously documented maternal determinants of offspring bone mass. Conclusions Our findings suggest an association between methylation status at birth of a specific CpG within the eNOS promoter and bone mineral content in childhood. This supports a role for eNOS in bone growth and metabolism and implies that its contribution may at least in part occur during early skeletal development. PMID:22159788

The AAHKS Clinical Research Award: What Are the Costs of Knee Osteoarthritis in the Year Prior to Total Knee Arthroplasty?

PubMed

Bedard, Nicholas A; Dowdle, Spencer B; Anthony, Christopher A; DeMik, David E; McHugh, Michael A; Bozic, Kevin J; Callaghan, John J

2017-09-01

Despite American Academy of Orthopaedic Surgeons Clinical Practice Guidelines (CPGs) related to the non-arthroplasty management of osteoarthritis (OA) of the knee, non-recommended treatments remain in common use. We sought to determine the costs associated with non-arthroplasty management of knee OA in the year prior to total knee arthroplasty (TKA) and stratify them by CPG recommendation status. The Humana database was reviewed from 2007 to 2015 for primary TKA patients. Costs for hyaluronic acid (HA) and corticosteroid injections, physical therapy, braces, wedge insoles, opioids, non-steroidal anti-inflammatories, and tramadol in the year prior to TKA were calculated. Cost was defined as reimbursement paid by the insurance provider. Costs were analyzed relative to the overall non-inpatient costs for knee OA and categorized based on CPG recommendations. In total 86,081 primary TKA patients were analyzed and 65.8% had at least one treatment in the year prior to TKA. Treatments analyzed made up 57.6% of the total non-inpatient cost of knee OA in the year prior to TKA. Only 3 of the 8 treatments studied have a strong recommendation for their use (physical therapy, non-steroidal anti-inflammatories, tramadol) and costs for these interventions represented 12.2% of non-inpatient knee OA cost. In contrast, 29.3% of the costs are due to HA injections alone, which are not supported by CPGs. In the year prior to TKA, over half of the non-inpatient costs associated with knee OA are from injections, therapy, prosthetics, and prescriptions. Approximately 30% of this is due to HA injections alone. If only interventions recommend by the CPG are utilized then costs associated with knee OA could be decreased by 45%. Copyright © 2017 Elsevier Inc. All rights reserved.

Methylated site display (MSD)-AFLP, a sensitive and affordable method for analysis of CpG methylation profiles.

PubMed

Aiba, Toshiki; Saito, Toshiyuki; Hayashi, Akiko; Sato, Shinji; Yunokawa, Harunobu; Maruyama, Toru; Fujibuchi, Wataru; Kurita, Hisaka; Tohyama, Chiharu; Ohsako, Seiichiroh

2017-03-09

It has been pointed out that environmental factors or chemicals can cause diseases that are developmental in origin. To detect abnormal epigenetic alterations in DNA methylation, convenient and cost-effective methods are required for such research, in which multiple samples are processed simultaneously. We here present methylated site display (MSD), a unique technique for the preparation of DNA libraries. By combining it with amplified fragment length polymorphism (AFLP) analysis, we developed a new method, MSD-AFLP. Methylated site display libraries consist of only DNAs derived from DNA fragments that are CpG methylated at the 5' end in the original genomic DNA sample. To test the effectiveness of this method, CpG methylation levels in liver, kidney, and hippocampal tissues of mice were compared to examine if MSD-AFLP can detect subtle differences in the levels of tissue-specific differentially methylated CpGs. As a result, many CpG sites suspected to be tissue-specific differentially methylated were detected. Nucleotide sequences adjacent to these methyl-CpG sites were identified and we determined the methylation level by methylation-sensitive restriction endonuclease (MSRE)-PCR analysis to confirm the accuracy of AFLP analysis. The differences of the methylation level among tissues were almost identical among these methods. By MSD-AFLP analysis, we detected many CpGs showing less than 5% statistically significant tissue-specific difference and less than 10% degree of variability. Additionally, MSD-AFLP analysis could be used to identify CpG methylation sites in other organisms including humans. MSD-AFLP analysis can potentially be used to measure slight changes in CpG methylation level. Regarding the remarkable precision, sensitivity, and throughput of MSD-AFLP analysis studies, this method will be advantageous in a variety of epigenetics-based research.

Reparación Endovascular para Aneurisma de Aorta: Revisión Panorámica sobre su evidencia en el mundo y su aplicación en Latinoamérica.

PubMed

Calderón, María; Brito, Viviana; Alcaraz, Andrea; Rey-Ares, Lucila; Augustovski, Federico; García-Martí, Sebastián; Bardach, Ariel; Ciapponi, Agustín; López, Analía; Pichón-Riviere, Andrés

2018-05-10

Aortic aneurysm (AA) is a pathology with high morbidity and mortality. The management can be expectant, surgical, or through endovascular repair (EVAR). In Latin America the incidence of AA has increased and the analysis of therapeutic options, especially if they are expensive, is fundamental. To analyze available evidence on the effectiveness, safety and coverage policies of the EVAR. Panoramic review in the main bibliographical bases (MEDLINE, LILACS, EMBASE, Cochrane Library, DARE) and generic internet searchers, main health technology assessment (HTA) agencies and health insurance companies. Systematic reviews (SR), clinical practice guidelines (CPG), HTA and coverage policies, followed by the identification of primary studies published after the SR search date were included. A search of studies published until November 2015 in English and Spanish was carried out. 311 references were recovered, from which seven SRs were selected, one clinical study and 15 CPGs, consensus or coverage policies and ETS. For abdominal AA, high quality evidence showed no differences inlong-term survival with the use of EVAR compared to conventional surgery, but lower early mortality was observed (OR = 0.33, 95% CI 0.20 -0.55). EVAR was associated with a greater need for re-intervention. In the case of other types of AA, further evidence is still required to establish the benefit of EVAR. The CPGs, consensus, HTAs and coverage policies identified, mostly consider open surgery as the treatment of choice, reserving the EVAR for patients with high surgical risk for conventional surgery in the presence of favorable anatomy. Copyright © 2018. Published by Elsevier Inc.

Validation study of genes with hypermethylated promoter regions associated with prostate cancer recurrence

PubMed Central

Stott-Miller, Marni; Zhao, Shanshan; Wright, Jonathan L.; Kolb, Suzanne; Bibikova, Marina; Klotzle, Brandy; Ostrander, Elaine A.; Fan, Jian-Bing; Feng, Ziding; Stanford, Janet L.

2014-01-01

Background One challenge in prostate cancer (PCa) is distinguishing indolent from aggressive disease at diagnosis. DNA promoter hypermethylation is a frequent epigenetic event in PCa, but few studies of DNA methylation in relation to features of more aggressive tumors or PCa recurrence have been completed. Methods We used the Infinium® HumanMethylation450 BeadChip to assess DNA methylation in tumor tissue from 407 patients with clinically localized PCa who underwent radical prostatectomy. Recurrence status was determined by follow-up patient surveys, medical record review, and linkage with the SEER registry. The methylation status of 14 genes for which promoter hypermethylation was previously correlated with advanced disease or biochemical recurrence was evaluated. Average methylation level for promoter region CpGs in patients who recurred compared to those with no evidence of recurrence was analyzed. For two genes with differential methylation, time to recurrence was examined. Results During an average follow-up of 11.7 years, 104 (26%) patients recurred. Significant promoter hypermethylation in at least 50% of CpG sites in two genes, ABHD9 and HOXD3, was found in tumors from patients who recurred compared to those without recurrence. Evidence was strongest for HOXD3 (lowest P = 9.46x10−6), with higher average methylation across promoter region CpGs associated with reduced recurrence-free survival (P = 2×10−4). DNA methylation profiles did not differ by recurrence status for the other genes. Conclusions These results validate the association between promoter hypermethylation of ADHB9 and HOXD3 and PCa recurrence. Impact Tumor DNA methylation profiling may help distinguish PCa patients at higher risk for disease recurrence. PMID:24718283

Russian guidelines for the management of COPD: algorithm of pharmacologic treatment.

PubMed

Aisanov, Zaurbek; Avdeev, Sergey; Arkhipov, Vladimir; Belevskiy, Andrey; Chuchalin, Alexander; Leshchenko, Igor; Ovcharenko, Svetlana; Shmelev, Evgeny; Miravitlles, Marc

2018-01-01

The high prevalence of COPD together with its high level of misdiagnosis and late diagnosis dictate the necessity for the development and implementation of clinical practice guidelines (CPGs) in order to improve the management of this disease. High-quality, evidence-based international CPGs need to be adapted to the particular situation of each country or region. A new version of the Russian Respiratory Society guidelines released at the end of 2016 was based on the proposal by Global Initiative for Obstructive Lung Disease but adapted to the characteristics of the Russian health system and included an algorithm of pharmacologic treatment of COPD. The proposed algorithm had to comply with the requirements of the Russian Ministry of Health to be included into the unified electronic rubricator, which required a balance between the level of information and the simplicity of the graphic design. This was achieved by: exclusion of the initial diagnostic process, grouping together the common pharmacologic and nonpharmacologic measures for all patients, and the decision not to use the letters A-D for simplicity and clarity. At all stages of the treatment algorithm, efficacy and safety have to be carefully assessed. Escalation and de-escalation is possible in the case of lack of or insufficient efficacy or safety issues. Bronchodilators should not be discontinued except in the case of significant side effects. At the same time, inhaled corticosteroid (ICS) withdrawal is not represented in the algorithm, because it was agreed that there is insufficient evidence to establish clear criteria for ICSs discontinuation. Finally, based on the Global Initiative for Obstructive Lung Disease statement, the proposed algorithm reflects and summarizes different approaches to the pharmacological treatment of COPD taking into account the reality of health care in the Russian Federation.

Provider Adherence to Implementation of Clinical Practice Guidelines for Neurogenic Bowel in Adults With Spinal Cord Injury

PubMed Central

Goetz, Lance L; Nelson, Audrey L; Guihan, Marylou; Bosshart, Helen T; Harrow, Jeffrey J; Gerhart, Kevin D; Krasnicka, Barbara; Burns, Stephen P

2005-01-01

Background/Objectives: Clinical Practice Guidelines (CPGs) have been published on a number of topics in spinal cord injury (SCI) medicine. Research in the general medical literature shows that the distribution of CPGs has a minimal effect on physician practice without targeted implementation strategies. The purpose of this study was to determine (a) whether dissemination of an SCI CPG improved the likelihood that patients would receive CPG recommended care and (b) whether adherence to CPG recommendations could be improved through a targeted implementation strategy. Specifically, this study addressed the “Neurogenic Bowel Management in Adults with Spinal Cord Injury” Clinical Practice Guideline published in March 1998 by the Consortium for Spinal Cord Medicine Methods: CPG adherence was determined from medical record review at 6 Veterans Affairs SCI centers for 3 time periods: before guideline publication (T1), after guideline publication but before CPG implementation (T2), and after targeted CPG implementation (T3). Specific implementation strategies to enhance guideline adherence were chosen to address the barriers identified by SCI providers in focus groups before the intervention. Results: Overall adherence to recommendations related to neurogenic bowel did not change between T1 and T2 (P = not significant) but increased significantly between T2 and T3 (P < 0.001) for 3 of 6 guideline recommendations. For the other 3 guideline recommendations, adherence rates were noted to be high at T1. Conclusions: While publication of the CPG alone did not alter rates of provider adherence, the use of a targeted implementation plan resulted in increases in adherence rates with some (3 of 6) CPG recommendations for neurogenic bowel management. PMID:16869086

A novel method for repeatedly generating speckle patterns used in digital image correlation

NASA Astrophysics Data System (ADS)

Zhang, Juan; Sweedy, Ahmed; Gitzhofer, François; Baroud, Gamal

2018-01-01

Speckle patterns play a key role in Digital Image Correlation (DIC) measurement, and generating an optimal speckle pattern has been the goal for decades now. The usual method of generating a speckle pattern is by manually spraying the paint on the specimen. However, this makes it difficult to reproduce the optimal pattern for maintaining identical testing conditions and achieving consistent DIC results. This study proposed and evaluated a novel method using an atomization system to repeatedly generate speckle patterns. To verify the repeatability of the speckle patterns generated by this system, simulation and experimental studies were systematically performed. The results from both studies showed that the speckle patterns and, accordingly, the DIC measurements become highly accurate and repeatable using the proposed atomization system.

Pattern-set generation algorithm for the one-dimensional multiple stock sizes cutting stock problem

NASA Astrophysics Data System (ADS)

Cui, Yaodong; Cui, Yi-Ping; Zhao, Zhigang

2015-09-01

A pattern-set generation algorithm (PSG) for the one-dimensional multiple stock sizes cutting stock problem (1DMSSCSP) is presented. The solution process contains two stages. In the first stage, the PSG solves the residual problems repeatedly to generate the patterns in the pattern set, where each residual problem is solved by the column-generation approach, and each pattern is generated by solving a single large object placement problem. In the second stage, the integer linear programming model of the 1DMSSCSP is solved using a commercial solver, where only the patterns in the pattern set are considered. The computational results of benchmark instances indicate that the PSG outperforms existing heuristic algorithms and rivals the exact algorithm in solution quality.

Early stage hot spot analysis through standard cell base random pattern generation

NASA Astrophysics Data System (ADS)

Jeon, Joong-Won; Song, Jaewan; Kim, Jeong-Lim; Park, Seongyul; Yang, Seung-Hune; Lee, Sooryong; Kang, Hokyu; Madkour, Kareem; ElManhawy, Wael; Lee, SeungJo; Kwan, Joe

2017-04-01

Due to limited availability of DRC clean patterns during the process and RET recipe development, OPC recipes are not tested with high pattern coverage. Various kinds of pattern can help OPC engineer to detect sensitive patterns to lithographic effects. Random pattern generation is needed to secure robust OPC recipe. However, simple random patterns without considering real product layout style can't cover patterning hotspot in production levels. It is not effective to use them for OPC optimization thus it is important to generate random patterns similar to real product patterns. This paper presents a strategy for generating random patterns based on design architecture information and preventing hotspot in early process development stage through a tool called Layout Schema Generator (LSG). Using LSG, we generate standard cell based on random patterns reflecting real design cell structure - fin pitch, gate pitch and cell height. The output standard cells from LSG are applied to an analysis methodology to assess their hotspot severity by assigning a score according to their optical image parameters - NILS, MEEF, %PV band and thus potential hotspots can be defined by determining their ranking. This flow is demonstrated on Samsung 7nm technology optimizing OPC recipe and early enough in the process avoiding using problematic patterns.

Redundancy analysis allows improved detection of methylation changes in large genomic regions.

PubMed

Ruiz-Arenas, Carlos; González, Juan R

2017-12-14

DNA methylation is an epigenetic process that regulates gene expression. Methylation can be modified by environmental exposures and changes in the methylation patterns have been associated with diseases. Methylation microarrays measure methylation levels at more than 450,000 CpGs in a single experiment, and the most common analysis strategy is to perform a single probe analysis to find methylation probes associated with the outcome of interest. However, methylation changes usually occur at the regional level: for example, genomic structural variants can affect methylation patterns in regions up to several megabases in length. Existing DMR methods provide lists of Differentially Methylated Regions (DMRs) of up to only few kilobases in length, and cannot check if a target region is differentially methylated. Therefore, these methods are not suitable to evaluate methylation changes in large regions. To address these limitations, we developed a new DMR approach based on redundancy analysis (RDA) that assesses whether a target region is differentially methylated. Using simulated and real datasets, we compared our approach to three common DMR detection methods (Bumphunter, blockFinder, and DMRcate). We found that Bumphunter underestimated methylation changes and blockFinder showed poor performance. DMRcate showed poor power in the simulated datasets and low specificity in the real data analysis. Our method showed very high performance in all simulation settings, even with small sample sizes and subtle methylation changes, while controlling type I error. Other advantages of our method are: 1) it estimates the degree of association between the DMR and the outcome; 2) it can analyze a targeted or region of interest; and 3) it can evaluate the simultaneous effects of different variables. The proposed methodology is implemented in MEAL, a Bioconductor package designed to facilitate the analysis of methylation data. We propose a multivariate approach to decipher whether an outcome of interest alters the methylation pattern of a region of interest. The method is designed to analyze large target genomic regions and outperforms the three most popular methods for detecting DMRs. Our method can evaluate factors with more than two levels or the simultaneous effect of more than one continuous variable, which is not possible with the state-of-the-art methods.

Treatment preferences amongst physical therapists and chiropractors for the management of neck pain: results of an international survey.

PubMed

Carlesso, Lisa C; Macdermid, Joy C; Gross, Anita R; Walton, David M; Santaguida, P Lina

2014-03-24

Clinical practice guidelines on the management of neck pain make recommendations to help practitioners optimize patient care. By examining the practice patterns of practitioners, adherence to CPGs or lack thereof, is demonstrated. Understanding utilization of various treatments by practitioners and comparing these patterns to that of recommended guidelines is important to identify gaps for knowledge translation and improve treatment regimens. To describe the utilization of interventions in patients with neck pain by clinicians. A cross-sectional international survey was conducted from February 2012 to March 2013 to determine physical medicine, complementary and alternative medicine utilization amongst 360 clinicians treating patients with neck pain. The survey was international (19 countries) with Canada having the largest response (38%). Results were analyzed by usage amongst physical therapists (38%) and chiropractors (31%) as they were the predominant respondents. Within these professions, respondents were male (41-66%) working in private practice (69-95%). Exercise and manual therapies were consistently (98-99%) used by both professions but tests of subgroup differences determined that physical therapists used exercise, orthoses and 'other' interventions more, while chiropractors used phototherapeutics more. However, phototherapeutics (65%), Orthoses/supportive devices (57%), mechanical traction (55%) and sonic therapies (54%) were not used by the majority of respondents. Thermal applications (73%) and acupuncture (46%) were the modalities used most commonly. Analysis of differences across the subtypes of neck pain indicated that respondents utilize treatments more often for chronic neck pain and whiplash conditions, followed by radiculopathy, acute neck pain and whiplash conditions, and facet joint dysfunction by diagnostic block. The higher rates of usage of some interventions were consistent with supporting evidence (e.g. manual therapy). However, there was moderate usage of a number of interventions that have limited support or conflicting evidence (e.g. ergonomics). This survey indicates that exercise and manual therapy are core treatments provided by chiropractors and physical therapists. Future research should address gaps in evidence associated with variable practice patterns and knowledge translation to reduce usage of some interventions that have been shown to be ineffective.

Treatment preferences amongst physical therapists and chiropractors for the management of neck pain: results of an international survey

PubMed Central

2014-01-01

Background Clinical practice guidelines on the management of neck pain make recommendations to help practitioners optimize patient care. By examining the practice patterns of practitioners, adherence to CPGs or lack thereof, is demonstrated. Understanding utilization of various treatments by practitioners and comparing these patterns to that of recommended guidelines is important to identify gaps for knowledge translation and improve treatment regimens. Aim To describe the utilization of interventions in patients with neck pain by clinicians. Methods A cross-sectional international survey was conducted from February 2012 to March 2013 to determine physical medicine, complementary and alternative medicine utilization amongst 360 clinicians treating patients with neck pain. Results The survey was international (19 countries) with Canada having the largest response (38%). Results were analyzed by usage amongst physical therapists (38%) and chiropractors (31%) as they were the predominant respondents. Within these professions, respondents were male (41-66%) working in private practice (69-95%). Exercise and manual therapies were consistently (98-99%) used by both professions but tests of subgroup differences determined that physical therapists used exercise, orthoses and ‘other’ interventions more, while chiropractors used phototherapeutics more. However, phototherapeutics (65%), Orthoses/supportive devices (57%), mechanical traction (55%) and sonic therapies (54%) were not used by the majority of respondents. Thermal applications (73%) and acupuncture (46%) were the modalities used most commonly. Analysis of differences across the subtypes of neck pain indicated that respondents utilize treatments more often for chronic neck pain and whiplash conditions, followed by radiculopathy, acute neck pain and whiplash conditions, and facet joint dysfunction by diagnostic block. The higher rates of usage of some interventions were consistent with supporting evidence (e.g. manual therapy). However, there was moderate usage of a number of interventions that have limited support or conflicting evidence (e.g. ergonomics). Conclusions This survey indicates that exercise and manual therapy are core treatments provided by chiropractors and physical therapists. Future research should address gaps in evidence associated with variable practice patterns and knowledge translation to reduce usage of some interventions that have been shown to be ineffective. PMID:24661461

High quality methylome-wide investigations through next-generation sequencing of DNA from a single archived dry blood spot

PubMed Central

Aberg, Karolina A.; Xie, Lin Y.; Nerella, Srilaxmi; Copeland, William E.; Costello, E. Jane; van den Oord, Edwin J.C.G.

2013-01-01

The potential importance of DNA methylation in the etiology of complex diseases has led to interest in the development of methylome-wide association studies (MWAS) aimed at interrogating all methylation sites in the human genome. When using blood as biomaterial for a MWAS the DNA is typically extracted directly from fresh or frozen whole blood that was collected via venous puncture. However, DNA extracted from dry blood spots may also be an alternative starting material. In the present study, we apply a methyl-CpG binding domain (MBD) protein enrichment-based technique in combination with next generation sequencing (MBD-seq) to assess the methylation status of the ~27 million CpGs in the human autosomal reference genome. We investigate eight methylomes using DNA from blood spots. This data are compared with 1,500 methylomes previously assayed with the same MBD-seq approach using DNA from whole blood. When investigating the sequence quality and the enrichment profile across biological features, we find that DNA extracted from blood spots gives comparable results with DNA extracted from whole blood. Only if the amount of starting material is ≤ 0.5µg DNA we observe a slight decrease in the assay performance. In conclusion, we show that high quality methylome-wide investigations using MBD-seq can be conducted in DNA extracted from archived dry blood spots without sacrificing quality and without bias in enrichment profile as long as the amount of starting material is sufficient. In general, the amount of DNA extracted from a single blood spot is sufficient for methylome-wide investigations with the MBD-seq approach. PMID:23644822

High quality methylome-wide investigations through next-generation sequencing of DNA from a single archived dry blood spot.

PubMed

Aberg, Karolina A; Xie, Lin Y; Nerella, Srilaxmi; Copeland, William E; Costello, E Jane; van den Oord, Edwin J C G

2013-05-01

The potential importance of DNA methylation in the etiology of complex diseases has led to interest in the development of methylome-wide association studies (MWAS) aimed at interrogating all methylation sites in the human genome. When using blood as biomaterial for a MWAS the DNA is typically extracted directly from fresh or frozen whole blood that was collected via venous puncture. However, DNA extracted from dry blood spots may also be an alternative starting material. In the present study, we apply a methyl-CpG binding domain (MBD) protein enrichment-based technique in combination with next generation sequencing (MBD-seq) to assess the methylation status of the ~27 million CpGs in the human autosomal reference genome. We investigate eight methylomes using DNA from blood spots. This data are compared with 1,500 methylomes previously assayed with the same MBD-seq approach using DNA from whole blood. When investigating the sequence quality and the enrichment profile across biological features, we find that DNA extracted from blood spots gives comparable results with DNA extracted from whole blood. Only if the amount of starting material is ≤ 0.5µg DNA we observe a slight decrease in the assay performance. In conclusion, we show that high quality methylome-wide investigations using MBD-seq can be conducted in DNA extracted from archived dry blood spots without sacrificing quality and without bias in enrichment profile as long as the amount of starting material is sufficient. In general, the amount of DNA extracted from a single blood spot is sufficient for methylome-wide investigations with the MBD-seq approach.

Parenting Styles and Youth Well-Being across Immigrant Generations

ERIC Educational Resources Information Center

Driscoll, Anne K.; Russell, Stephen T.; Crockett, Lisa J.

2008-01-01

This study examines generational patterns of parenting styles, the relationships between parenting styles and adolescent well-being among youth of Mexican origin, and the role of generational parenting style patterns in explaining generational patterns in youth behavior (delinquency and alcohol problems) and psychological well-being (depression…

Inferring a District-Based Hierarchical Structure of Social Contacts from Census Data

PubMed Central

Yu, Zhiwen; Liu, Jiming; Zhu, Xianjun

2015-01-01

Researchers have recently paid attention to social contact patterns among individuals due to their useful applications in such areas as epidemic evaluation and control, public health decisions, chronic disease research and social network research. Although some studies have estimated social contact patterns from social networks and surveys, few have considered how to infer the hierarchical structure of social contacts directly from census data. In this paper, we focus on inferring an individual’s social contact patterns from detailed census data, and generate various types of social contact patterns such as hierarchical-district-structure-based, cross-district and age-district-based patterns. We evaluate newly generated contact patterns derived from detailed 2011 Hong Kong census data by incorporating them into a model and simulation of the 2009 Hong Kong H1N1 epidemic. We then compare the newly generated social contact patterns with the mixing patterns that are often used in the literature, and draw the following conclusions. First, the generation of social contact patterns based on a hierarchical district structure allows for simulations at different district levels. Second, the newly generated social contact patterns reflect individuals social contacts. Third, the newly generated social contact patterns improve the accuracy of the SEIR-based epidemic model. PMID:25679787

An improved neutral landscape model for recreating real landscapes and generating landscape series for spatial ecological simulations.

PubMed

van Strien, Maarten J; Slager, Cornelis T J; de Vries, Bauke; Grêt-Regamey, Adrienne

2016-06-01

Many studies have assessed the effect of landscape patterns on spatial ecological processes by simulating these processes in computer-generated landscapes with varying composition and configuration. To generate such landscapes, various neutral landscape models have been developed. However, the limited set of landscape-level pattern variables included in these models is often inadequate to generate landscapes that reflect real landscapes. In order to achieve more flexibility and variability in the generated landscapes patterns, a more complete set of class- and patch-level pattern variables should be implemented in these models. These enhancements have been implemented in Landscape Generator (LG), which is a software that uses optimization algorithms to generate landscapes that match user-defined target values. Developed for participatory spatial planning at small scale, we enhanced the usability of LG and demonstrated how it can be used for larger scale ecological studies. First, we used LG to recreate landscape patterns from a real landscape (i.e., a mountainous region in Switzerland). Second, we generated landscape series with incrementally changing pattern variables, which could be used in ecological simulation studies. We found that LG was able to recreate landscape patterns that approximate those of real landscapes. Furthermore, we successfully generated landscape series that would not have been possible with traditional neutral landscape models. LG is a promising novel approach for generating neutral landscapes and enables testing of new hypotheses regarding the influence of landscape patterns on ecological processes. LG is freely available online.

Effectiveness of a strategy that uses educational games to implement clinical practice guidelines among Spanish residents of family and community medicine (e-EDUCAGUIA project): a clinical trial by clusters.

PubMed

Del Cura-González, Isabel; López-Rodríguez, Juan A; Sanz-Cuesta, Teresa; Rodríguez-Barrientos, Ricardo; Martín-Fernández, Jesús; Ariza-Cardiel, Gloria; Polentinos-Castro, Elena; Román-Crespo, Begoña; Escortell-Mayor, Esperanza; Rico-Blázquez, Milagros; Hernández-Santiago, Virginia; Azcoaga-Lorenzo, Amaya; Ojeda-Ruiz, Elena; González-González, Ana I; Ávila-Tomas, José F; Barrio-Cortés, Jaime; Molero-García, José M; Ferrer-Peña, Raul; Tello-Bernabé, María Eugenia; Trujillo-Martín, Mar

2016-05-17

Clinical practice guidelines (CPGs) have been developed with the aim of helping health professionals, patients, and caregivers make decisions about their health care, using the best available evidence. In many cases, incorporation of these recommendations into clinical practice also implies a need for changes in routine clinical practice. Using educational games as a strategy for implementing recommendations among health professionals has been demonstrated to be effective in some studies; however, evidence is still scarce. The primary objective of this study is to assess the effectiveness of a teaching strategy for the implementation of CPGs using educational games (e-learning EDUCAGUIA) to improve knowledge and skills related to clinical decision-making by residents in family medicine. The primary objective will be evaluated at 1 and 6 months after the intervention. The secondary objectives are to identify barriers and facilitators for the use of guidelines by residents of family medicine and to describe the educational strategies used by Spanish teaching units of family and community medicine to encourage implementation of CPGs. We propose a multicenter clinical trial with randomized allocation by clusters of family and community medicine teaching units in Spain. The sample size will be 394 residents (197 in each group), with the teaching units as the randomization unit and the residents comprising the analysis unit. For the intervention, both groups will receive an initial 1-h session on clinical practice guideline use and the usual dissemination strategy by e-mail. The intervention group (e-learning EDUCAGUIA) strategy will consist of educational games with hypothetical clinical scenarios in a virtual environment. The primary outcome will be the score obtained by the residents on evaluation questionnaires for each clinical practice guideline. Other included variables will be the sociodemographic and training variables of the residents and the teaching unit characteristics. The statistical analysis will consist of a descriptive analysis of variables and a baseline comparison of both groups. For the primary outcome analysis, an average score comparison of hypothetical scenario questionnaires between the EDUCAGUIA intervention group and the control group will be performed at 1 and 6 months post-intervention, using 95 % confidence intervals. A linear multilevel regression will be used to adjust the model. The identification of effective teaching strategies will facilitate the incorporation of available knowledge into clinical practice that could eventually improve patient outcomes. The inclusion of information technologies as teaching tools permits greater learning autonomy and allows deeper instructor participation in the monitoring and supervision of residents. The long-term impact of this strategy is unknown; however, because it is aimed at professionals undergoing training and it addresses prevalent health problems, a small effect can be of great relevance. ClinicalTrials.gov: NCT02210442 .

The Common Patterns of Nature

PubMed Central

Frank, Steven A.

2010-01-01

We typically observe large-scale outcomes that arise from the interactions of many hidden, small-scale processes. Examples include age of disease onset, rates of amino acid substitutions, and composition of ecological communities. The macroscopic patterns in each problem often vary around a characteristic shape that can be generated by neutral processes. A neutral generative model assumes that each microscopic process follows unbiased or random stochastic fluctuations: random connections of network nodes; amino acid substitutions with no effect on fitness; species that arise or disappear from communities randomly. These neutral generative models often match common patterns of nature. In this paper, I present the theoretical background by which we can understand why these neutral generative models are so successful. I show where the classic patterns come from, such as the Poisson pattern, the normal or Gaussian pattern, and many others. Each classic pattern was often discovered by a simple neutral generative model. The neutral patterns share a special characteristic: they describe the patterns of nature that follow from simple constraints on information. For example, any aggregation of processes that preserves information only about the mean and variance attracts to the Gaussian pattern; any aggregation that preserves information only about the mean attracts to the exponential pattern; any aggregation that preserves information only about the geometric mean attracts to the power law pattern. I present a simple and consistent informational framework of the common patterns of nature based on the method of maximum entropy. This framework shows that each neutral generative model is a special case that helps to discover a particular set of informational constraints; those informational constraints define a much wider domain of non-neutral generative processes that attract to the same neutral pattern. PMID:19538344

ampliMethProfiler: a pipeline for the analysis of CpG methylation profiles of targeted deep bisulfite sequenced amplicons.

PubMed

Scala, Giovanni; Affinito, Ornella; Palumbo, Domenico; Florio, Ermanno; Monticelli, Antonella; Miele, Gennaro; Chiariotti, Lorenzo; Cocozza, Sergio

2016-11-25

CpG sites in an individual molecule may exist in a binary state (methylated or unmethylated) and each individual DNA molecule, containing a certain number of CpGs, is a combination of these states defining an epihaplotype. Classic quantification based approaches to study DNA methylation are intrinsically unable to fully represent the complexity of the underlying methylation substrate. Epihaplotype based approaches, on the other hand, allow methylation profiles of cell populations to be studied at the single molecule level. For such investigations, next-generation sequencing techniques can be used, both for quantitative and for epihaplotype analysis. Currently available tools for methylation analysis lack output formats that explicitly report CpG methylation profiles at the single molecule level and that have suited statistical tools for their interpretation. Here we present ampliMethProfiler, a python-based pipeline for the extraction and statistical epihaplotype analysis of amplicons from targeted deep bisulfite sequencing of multiple DNA regions. ampliMethProfiler tool provides an easy and user friendly way to extract and analyze the epihaplotype composition of reads from targeted bisulfite sequencing experiments. ampliMethProfiler is written in python language and requires a local installation of BLAST and (optionally) QIIME tools. It can be run on Linux and OS X platforms. The software is open source and freely available at http://amplimethprofiler.sourceforge.net .

Study on the generation technology of Li brocade pattern mutant genes based on the AI and Java technology

NASA Astrophysics Data System (ADS)

Zhou, Yuping; Zhang, Qi

2018-04-01

In the information environment, digital and information processing to Li brocade patterns reveals an important means of Li ethnic style and inheriting the national culture. Adobe Illustrator CS3 and Java language were used in the paper to make "variation" processing to Li brocade patterns, and generate "Li brocade pattern mutant genes". The generation of pattern mutant genes includes color mutation, shape mutation, adding and missing transform, and twisted transform, etc. Research shows that Li brocade pattern mutant genes can be generated by using the Adobe Illustrator CS3 and the image processing tools of Java language edit, etc.

Replication of the Chicken β-Globin Locus: Early-Firing Origins at the 5′ HS4 Insulator and the ρ- and βA-Globin Genes Show Opposite Epigenetic Modifications

PubMed Central

Prioleau, Marie-Noëlle; Gendron, Marie-Claude; Hyrien, Olivier

2003-01-01

Chromatin structure is believed to exert a strong effect on replication origin function. We have studied the replication of the chicken β-globin locus, whose chromatin structure has been extensively characterized. This locus is delimited by hypersensitive sites (HSs) that mark the position of insulator elements. A stretch of condensed chromatin and another HS separate the β-globin domain from an adjacent folate receptor (FR) gene. We demonstrate here that in erythroid cells that express the FR but not the globin genes, replication initiates at four sites within the β-globin domain, one at the 5′ HS4 insulator and the other three near the ρ- and βA-globin genes. Three origins consist of G+C-rich sequences enriched in CpG dinucleotides. The fourth origin is A+T rich. Together with previous work, these data reveal that the insulator origin has unmethylated CpGs, hyperacetylated histones H3 and H4, and lysine 4-methylated histone H3. In contrast, opposite modifications are observed at the other G+C-rich origins. We also show that the whole region, including the stretch of condensed chromatin, replicates early in S phase in these cells. Therefore, different early-firing origins within the same locus may have opposite patterns of epigenetic modifications. The role of insulator elements in DNA replication is discussed. PMID:12724412

Computationally expanding infinium HumanMethylation450 BeadChip array data to reveal distinct DNA methylation patterns of rheumatoid arthritis

PubMed Central

Li, Chengzhe; Ai, Rizi; Wang, Mengchi; Firestein, Gary S.; Wang, Wei

2016-01-01

Motivation: DNA methylation signatures in rheumatoid arthritis (RA) have been identified in fibroblast-like synoviocytes (FLS) with Illumina HumanMethylation450 array. Since <2% of CpG sites are covered by the Illumina 450K array and whole genome bisulfite sequencing is still too expensive for many samples, computationally predicting DNA methylation levels based on 450K data would be valuable to discover more RA-related genes. Results: We developed a computational model that is trained on 14 tissues with both whole genome bisulfite sequencing and 450K array data. This model integrates information derived from the similarity of local methylation pattern between tissues, the methylation information of flanking CpG sites and the methylation tendency of flanking DNA sequences. The predicted and measured methylation values were highly correlated with a Pearson correlation coefficient of 0.9 in leave-one-tissue-out cross-validations. Importantly, the majority (76%) of the top 10% differentially methylated loci among the 14 tissues was correctly detected using the predicted methylation values. Applying this model to 450K data of RA, osteoarthritis and normal FLS, we successfully expanded the coverage of CpG sites 18.5-fold and accounts for about 30% of all the CpGs in the human genome. By integrative omics study, we identified genes and pathways tightly related to RA pathogenesis, among which 12 genes were supported by triple evidences, including 6 genes already known to perform specific roles in RA and 6 genes as new potential therapeutic targets. Availability and implementation: The source code, required data for prediction, and demo data for test are freely available at: http://wanglab.ucsd.edu/star/LR450K/. Contact: wei-wang@ucsd.edu or gfirestein@ucsd.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26883487

Circadian gene methylation profiles are associated with obesity, metabolic disturbances and carbohydrate intake.

PubMed

Ramos-Lopez, Omar; Samblas, Mirian; Milagro, Fermin I; Riezu-Boj, Jose I; Crujeiras, A B; Martinez, J Alfredo; Project, Mena

2018-03-26

The circadian clock regulates the daily rhythms of several physiological and behavioral processes. Disruptions in clock genes have been associated with obesity and related comorbidities. This study aimed to analyze the association of DNA methylation signatures at circadian rhythm pathway genes with body mass index (BMI), metabolic profiles and dietary intakes. DNA methylation profiling was determined by microarray in white blood cells from 474 adults from the Methyl Epigenome Network Association (MENA) project. Kyoto Encyclopedia of Genes and Genomes database was used to identify the genes integrating the circadian rhythm pathway. Network enrichment analyses were performed with the PathDIP platform. Associations between circadian methylation patterns with anthropometric measurements, the metabolic profile, clinical data and dietary intakes were analyzed. DNA methylation patterns of nine CpG sites at six circadian rhythm pathway genes were strongly correlated with BMI (false discovery rates <0.0001). These CpGs encompassed cg09578018 (RORA), cg20406576 (PRKAG2), cg10059324 (PER3), cg01180628 (BHLHE40), cg23871860 (FBXL3), cg16964728 (RORA), cg14129040 (CREB1), cg07012178 (PRKAG2) and cg24061580 (PRKAG2). Interestingly, network enrichment analyses revealed that the six BMI-associated genes statistically contributed to the regulation of the circadian rhythm pathway (p = 1.9E-10). In addition, methylation signatures at cg09578018 (RORA), cg24061580 (PRKAG2), cg01180628 (BHLHE40) and cg10059324 (PER3) also correlated with insulin resistance (p < 0.0001) and mean arterial blood pressure (p < 0.0001). Furthermore, relevant correlations (p < 0.05) between methylation at cg09578018 (RORA) and cg01180628 (BHLHE40) with total energy and carbohydrate intakes were found. This investigation revealed potential associations of DNA methylation profiles at circadian genes with obesity, metabolic disturbances and carbohydrate intake, with potential impact on weight homeostasis.

Generation 1.5 Written Error Patterns: A Comparative Study

ERIC Educational Resources Information Center

Doolan, Stephen M.; Miller, Donald

2012-01-01

In an attempt to contribute to existing research on Generation 1.5 students, the current study uses quantitative and qualitative methods to compare error patterns in a corpus of Generation 1.5, L1, and L2 community college student writing. This error analysis provides one important way to determine if error patterns in Generation 1.5 student…

Pattern self-repetition of fingerprints, lip prints, and palatal rugae among three generations of family: A forensic approach to identify family hierarchy.

PubMed

Mala, Sankeerti; Rathod, Vanita; Pundir, Siddharth; Dixit, Sudhanshu

2017-01-01

The unique pattern and structural diversity of fingerprints, lip prints, palatal rugae, and their occurrence in different patterns among individuals make it questionable whether they are completely unique even in a family hierarchy? Do they have any repetition of the patterns among the generations? Or is this a mere chaos theory? The present study aims to assess the pattern self-repetition of fingerprints, lip prints, and palatal rugae among three generations of ten different families. The present study was conducted at Rungta College of Dental Science and Research, Bhilai, India. Participants birth by origin of Chhattisgarh were only included in the study. Thirty participants from three consecutive generations of ten different families were briefed about the purpose of the study, and their fingerprints, lip prints, and palatal rugae impression were recorded and analyzed for the pattern of self-repetition. Multiple comparisons among the generations and one-way analysis of variance test were performed using SPSS 20 trial version. Among the pattern of primary palatal rugae, 10% showed repetition in all the three generations. Thirty percent showed repetition of the pattern of thumb fingerprints in all the three generation. The pattern of lip prints in the middle 1/3 rd of lower lip, 20% showed repetition in alternative generations. The evaluations of fingerprints, lip prints, and palatal rugae showed fractal dimensions, occurring variations in dimensions according to the complexity of each structure. Even though a minute self-repetition in the patterns of lip, thumb, and palate among the three consequent generations in a family was observed considering the sample size, these results need to be confirmed in a larger sample, either to establish the role of chaos theory in forensic science or identifying a particular pattern of the individual in his family hierarchy.

Caregiving Practice Patterns of Asian, Hispanic, and Non-Hispanic White American Family Caregivers of Older Adults Across Generations.

PubMed

Miyawaki, Christina E

2016-03-01

This study is a cross-sectional investigation of caregiving practice patterns among Asian, Hispanic and non-Hispanic White American family caregivers of older adults across three immigrant generations. The 2009 California Health Interview Survey (CHIS) dataset was used, and 591 Asian, 989 Hispanic and 6537 non-Hispanic White American caregivers of older adults were selected. First, descriptive analyses of caregivers' characteristics, caregiving situations and practice patterns were examined by racial/ethnic groups and immigrant generations. Practice patterns measured were respite care use, hours and length of caregiving. Three hypotheses on caregiving patterns based on assimilation theory were tested and analyzed using logistic regression and generalized linear models by racial/ethnic groups and generations. Caregiving patterns of non-Hispanic White caregivers supported all three hypotheses regarding respite care use, caregiving hours and caregiving duration, showing less caregiving involvement in later generations. However, Asian and Hispanic counterparts showed mixed results. Third generation Asian and Hispanic caregivers used respite care the least and spent the most caregiving hours per week and had the longest caregiving duration compared to earlier generations. These caregiving patterns revealed underlying cultural values related to filial responsibility, even among later generations of caregivers of color. Findings suggest the importance of considering the cultural values of each racial/ethnic group regardless of generation when working with racially and ethnically diverse populations of family caregivers of older adults.

Value of XML in the implementation of clinical practice guidelines--the issue of content retrieval and presentation.

PubMed

Hoelzer, S; Schweiger, R K; Boettcher, H A; Tafazzoli, A G; Dudeck, J

2001-01-01

The purpose of guidelines in clinical practice is to improve the effectiveness and efficiency of clinical care. It is known that nationally or internationally produced guidelines which, in particular, do not involve medical processes at the time of consultation, do not take local factors into account, and have no consistent implementation strategy, have limited impact in changing either the behaviour of physicians, or patterns of care. The literature provides evidence for the effectiveness of computerization of CPGs for increasing compliance and improving patient outcomes. Probably the most effective concepts are knowledge-based functions for decision support or monitoring that are integrated in clinical information systems. This approach is mostly restricted by the effort required for development and maintenance of the information systems and the limited number of implemented medical rules. Most of the guidelines are text-based, and are primarily published in medical journals and posted on the internet. However, internet-published guidelines have little impact on the behaviour of physicians. It can be difficult and time-consuming to browse the internet to find (a) the correct guidelines to an existing diagnosis and (b) and adequate recommendation for a specific clinical problem. Our objective is to provide a web-based guideline service that takes as input clinical data on a particular patient and returns as output a customizable set of recommendations regarding diagnosis and treatment. Information in healthcare is to a very large extent transmitted and stored as unstructured or slightly structured text such as discharge letters, reports, forms, etc. The same applies for facilities containing medical information resources for clinical purposes and research such as text books, articles, guidelines, etc. Physicians are used to obtaining information from text-based sources. Since most guidelines are text-based, it would be practical to use a document-based solution that preserves the original cohesiveness. The lack of structure limits the automatic identification and extraction of the information contained in these resources. For this reason, we have chosen a document-based approach using eXtensible Markup Language (XML) with its schema definition and related technologies. XML empowers the applications for in-context searching. In addition it allows the same content to be represented in different ways. Our XML reference clinical data model for guidelines has been realized with the XML schema definition. The schema is used for structuring new text-based guidelines and updating existing documents. It is also used to establish search strategies on the document base. We hypothesize that enabling the physicians to query the available CPGs easily, and to get access to selected and specific information at the point of care will foster increased use. Based on current evidence we are confident that it will have substantial impact on the care provided, and will improve health outcomes.

Immunostimulatory Properties of Lipid Modified CpG Oligonucleotides.

PubMed

Yu, Chunsong; An, Myunggi; Li, Meng; Liu, Haipeng

2017-08-07

Innate immune responses recognizing pathogen associated molecular patterns play important roles in adaptive immunity. As such, ligands which mimic the conserved products of microbial and activate innate immunity are widely used as adjuvants for vaccines. Synthetic single strand oligodeoxynucleotides (ODNs) containing unmethylated cytosine-guanine (CpG) motifs which bind Toll-like receptor 9 (TLR9) are powerful molecular adjuvants, potentiating both humoral and cellular responses. However, CpG ODN's in vitro potency has not been translated to in vivo settings primarily due to issues associated with delivery and toxicity. A major challenge in clinical application of CpG ODN is the efficient delivery to lymph nodes, the anatomic sites where all the immune responses are initiated. Targeting CpG to the key antigen presenting cells (APC) is essential for its application as a vaccine adjuvant, as it not only enhances CpG's efficacy, but also greatly reduces the systemic toxicity. We recently discovered an "albumin-hitchhiking" approach by which CpG ODNs were conjugated to a lipophilic lipid tail and follow subcutaneous injection, accumulated in lymph nodes by binding and transporting with endogenous albumin. This molecular approach targets CpG to antigen presenting cells in the draining lymph nodes via an endogenous albumin-mediated mechanism and simultaneously improves both the efficacy and safety of CpG as a vaccine adjuvant. Since CpG ODNs can be divided into structurally distinct classes, and each class of CpG ODN activates different types of immune cells and triggers different types of immunostimulatory activities, it is important to thoroughly evaluate the efficacy of this "albumin-hitchhiking" strategy in each class of CpG. Here we compare the immunostimulatory activities of three classes of lipid conjugated CpG ODNs in vitro and in vivo. Three representative sequences of lipid modified CpG ODNs were synthesized and their stimulatory effects as a vaccine adjuvant were evaluated. Our results showed that in vitro, lipid modified class A CpG exhibited enhanced stimulatory activities toward TLR transfected reporter cells or bone-marrow derived dendritic cells, whereas lipid-modification of class B or C CpG reduces the activation of TLR9 by 2-3 fold, as compared with unmodified class B and class C CpG, respectively. However, in vivo coadministration of ovalbumin (OVA) protein antigen mixed with lipid-conjugated class B or C CpG ODNs, but not class A CpGs induced dramatically increased OVA-specific humoral and cytotoxic CD8 + T cells responses compared with OVA mixed with unmodified CpGs. Further, lipid-modification greatly reduces the toxicity associated with CpG by minimizing the systemic dissemination. Taken together, these results demonstrated that amphiphilic modification of three classes of CpG motifs differentially affected and modulated the immunostimulatory activities in vitro and in vivo. Our study highlights the importance of in vivo lymph node targeting of CpG ODNs in fulfilling their use as vaccine adjuvants, providing implications for the rational design of molecular adjuvant for subunit vaccines.

Simple Process-Based Simulators for Generating Spatial Patterns of Habitat Loss and Fragmentation: A Review and Introduction to the G-RaFFe Model

PubMed Central

Pe'er, Guy; Zurita, Gustavo A.; Schober, Lucia; Bellocq, Maria I.; Strer, Maximilian; Müller, Michael; Pütz, Sandro

2013-01-01

Landscape simulators are widely applied in landscape ecology for generating landscape patterns. These models can be divided into two categories: pattern-based models that generate spatial patterns irrespective of the processes that shape them, and process-based models that attempt to generate patterns based on the processes that shape them. The latter often tend toward complexity in an attempt to obtain high predictive precision, but are rarely used for generic or theoretical purposes. Here we show that a simple process-based simulator can generate a variety of spatial patterns including realistic ones, typifying landscapes fragmented by anthropogenic activities. The model “G-RaFFe” generates roads and fields to reproduce the processes in which forests are converted into arable lands. For a selected level of habitat cover, three factors dominate its outcomes: the number of roads (accessibility), maximum field size (accounting for land ownership patterns), and maximum field disconnection (which enables field to be detached from roads). We compared the performance of G-RaFFe to three other models: Simmap (neutral model), Qrule (fractal-based) and Dinamica EGO (with 4 model versions differing in complexity). A PCA-based analysis indicated G-RaFFe and Dinamica version 4 (most complex) to perform best in matching realistic spatial patterns, but an alternative analysis which considers model variability identified G-RaFFe and Qrule as performing best. We also found model performance to be affected by habitat cover and the actual land-uses, the latter reflecting on land ownership patterns. We suggest that simple process-based generators such as G-RaFFe can be used to generate spatial patterns as templates for theoretical analyses, as well as for gaining better understanding of the relation between spatial processes and patterns. We suggest caution in applying neutral or fractal-based approaches, since spatial patterns that typify anthropogenic landscapes are often non-fractal in nature. PMID:23724108

Simple process-based simulators for generating spatial patterns of habitat loss and fragmentation: a review and introduction to the G-RaFFe model.

PubMed

Pe'er, Guy; Zurita, Gustavo A; Schober, Lucia; Bellocq, Maria I; Strer, Maximilian; Müller, Michael; Pütz, Sandro

2013-01-01

Landscape simulators are widely applied in landscape ecology for generating landscape patterns. These models can be divided into two categories: pattern-based models that generate spatial patterns irrespective of the processes that shape them, and process-based models that attempt to generate patterns based on the processes that shape them. The latter often tend toward complexity in an attempt to obtain high predictive precision, but are rarely used for generic or theoretical purposes. Here we show that a simple process-based simulator can generate a variety of spatial patterns including realistic ones, typifying landscapes fragmented by anthropogenic activities. The model "G-RaFFe" generates roads and fields to reproduce the processes in which forests are converted into arable lands. For a selected level of habitat cover, three factors dominate its outcomes: the number of roads (accessibility), maximum field size (accounting for land ownership patterns), and maximum field disconnection (which enables field to be detached from roads). We compared the performance of G-RaFFe to three other models: Simmap (neutral model), Qrule (fractal-based) and Dinamica EGO (with 4 model versions differing in complexity). A PCA-based analysis indicated G-RaFFe and Dinamica version 4 (most complex) to perform best in matching realistic spatial patterns, but an alternative analysis which considers model variability identified G-RaFFe and Qrule as performing best. We also found model performance to be affected by habitat cover and the actual land-uses, the latter reflecting on land ownership patterns. We suggest that simple process-based generators such as G-RaFFe can be used to generate spatial patterns as templates for theoretical analyses, as well as for gaining better understanding of the relation between spatial processes and patterns. We suggest caution in applying neutral or fractal-based approaches, since spatial patterns that typify anthropogenic landscapes are often non-fractal in nature.

Maskless micro-ion-beam reduction lithography system

DOEpatents

Leung, Ka-Ngo; Barletta, William A.; Patterson, David O.; Gough, Richard A.

2005-05-03

A maskless micro-ion-beam reduction lithography system is a system for projecting patterns onto a resist layer on a wafer with feature size down to below 100 nm. The MMRL system operates without a stencil mask. The patterns are generated by switching beamlets on and off from a two electrode blanking system or pattern generator. The pattern generator controllably extracts the beamlet pattern from an ion source and is followed by a beam reduction and acceleration column.

Comparing Drug-Disease Associations in Clinical Practice Guideline Recommendations and Drug Product Label Indications.

PubMed

Leung, Tiffany I; Dumontier, Michel

2015-01-01

Clinical practice guidelines (CPGs) and structured product labels (SPLs) are both intended to promote evidence-based medical practices and guide clinicians' prescribing decisions. However, it is unclear how well CPG recommendations about pharmacologic therapies for certain diseases match SPL indications for recommended drugs. In this study, we use publicly available data and text mining methods to examine drug-disease associations in CPG recommendations and SPL treatment indications for 15 common chronic conditions. Preliminary results suggest that there is a mismatch between guideline-recommended pharmacologic therapies and SPL indications. Conflicting or inconsistent recommendations and indications may complicate clinical decision making and implementation or measurement of best practices.

Design space exploration for early identification of yield limiting patterns

NASA Astrophysics Data System (ADS)

Li, Helen; Zou, Elain; Lee, Robben; Hong, Sid; Liu, Square; Wang, JinYan; Du, Chunshan; Zhang, Recco; Madkour, Kareem; Ali, Hussein; Hsu, Danny; Kabeel, Aliaa; ElManhawy, Wael; Kwan, Joe

2016-03-01

In order to resolve the causality dilemma of which comes first, accurate design rules or real designs, this paper presents a flow for exploration of the layout design space to early identify problematic patterns that will negatively affect the yield. A new random layout generating method called Layout Schema Generator (LSG) is reported in this paper, this method generates realistic design-like layouts without any design rule violation. Lithography simulation is then used on the generated layout to discover the potentially problematic patterns (hotspots). These hotspot patterns are further explored by randomly inducing feature and context variations to these identified hotspots through a flow called Hotspot variation Flow (HSV). Simulation is then performed on these expanded set of layout clips to further identify more problematic patterns. These patterns are then classified into design forbidden patterns that should be included in the design rule checker and legal patterns that need better handling in the RET recipes and processes.

Automatic Generation of English-Japanese Translation Pattern Utilizing Genetic Programming Technique

NASA Astrophysics Data System (ADS)

Matsumura, Koki; Tamekuni, Yuji; Kimura, Shuhei

There are a lot of constructional differences in an English-Japanese phrase template, and that often makes the act of translation difficult. Moreover, there exist various and tremendous phrase templates and sentence to be refered to. It is not easy to prepare the corpus that covers the all. Therefore, it is very significant to generate the translation pattern of the sentence pattern automatically from a viewpoint of the translation success rate and the capacity of the pattern dictionary. Then, for the purpose of realizing the automatic generation of the translation pattern, this paper proposed the new method for the generation of the translation pattern by using the genetic programming technique (GP). The technique tries to generate the translation pattern of various sentences which are not registered in the phrase template dictionary automatically by giving the genetic operation to the parsing tree of a basic pattern. The tree consists of the pair of the English-Japanese sentence generated as the first stage population. The analysis tree data base with 50,100,150,200 pairs was prepared as the first stage population. And this system was applied and executed for an English input of 1,555 sentences. As a result, the analysis tree increases from 200 to 517, and the accuracy rate of the translation pattern has improved from 42.57% to 70.10%. And, 86.71% of the generated translations was successfully done, whose meanings are enough acceptable and understandable. It seemed that this proposal technique became a clue to raise the translation success rate, and to find the possibility of the reduction of the analysis tree data base.

On the role of the reticular formation in vocal pattern generation.

PubMed

Jürgens, Uwe; Hage, Steffen R

2007-09-04

This review is an attempt to localize the brain region responsible for pattern generation of species-specific vocalizations. A catalogue is set up, listing the criteria considered to be essential for a vocal pattern generator. According to this catalogue, a vocal pattern generator should show vocalization-correlated activity, starting before vocal onset and reflecting specific acoustic features of the vocalization. Artificial activation by electrical or glutamatergic stimulation should produce artificially sounding vocalization. Lesioning is expected to have an inhibitory or deteriorating effect on vocalization. Anatomically, a vocal pattern generator can be assumed to have direct or, at least, oligosynaptic connections with all the motoneuron pools involved in phonation. A survey of the literature reveals that the only area meeting all these criteria is a region, reaching from the parvocellular pontine reticular formation just above the superior olive through the lateral reticular formation around the facial nucleus and nucleus ambiguus down to the caudalmost medulla, including the dorsal and ventral reticular nuclei and nucleus retroambiguus. It is proposed that vocal pattern generation takes place within this whole region.

NOVEL EPIGENETIC CHANGES IN CDKN2A ARE ASSOCIATED WITH PROGRESSION OF CERVICAL INTRAEPITHELIAL NEOPLASIA

PubMed Central

Wijetunga, N. Ari; Belbin, Thomas J.; Burk, Robert D.; Whitney, Kathleen; Abadi, Maria; Greally, John M.; Einstein, Mark H.; Schlecht, Nicolas F.

2016-01-01

Objective To conduct a comprehensive mapping of the genomic DNA methylation in CDKN2A, which codes for the p16INK4A and p14ARF proteins, and 14 of the most promising DNA methylation marker candidates previously reported to be associated with progression of low-grade cervical intraepithelial neoplasia (CIN1) to cervical cancer. Methods We analyzed DNA methylation in 68 HIV-seropositive and negative women with incident CIN1, CIN2, CIN3 and invasive cervical cancer, assaying 120 CpG dinucleotide sites spanning APC, CDH1, CDH13, CDKN2A, CDKN2B, DAPK1, FHIT, GSTP1, HIC1, MGMT, MLH1, RARB, RASSF1, TERT and TIMP3 using the Illumina Infinium array. Validation was performed using high resolution mapping of the target genes with HELP-tagging for 286 CpGs, followed by fine mapping of candidate genes with targeted bisulfite sequencing. We assessed for statistical differences in DNA methylation levels for each CpG loci assayed using univariate and multivariate methods correcting for multiple comparisons. Results In our discovery sample set, we identified dose dependent differences in DNA methylation with grade of disease in CDKN2A, APC, MGMT, MLH1 and HIC1, whereas single CpG locus differences between CIN2/3 and cancer groups were seen for CDH13, DAPK1 and TERT. Only those CpGs in the gene body of CDKN2A showed a monotonic increase in methylation between persistent CIN1, CIN2, CIN3 and cancers. Conclusion Our data suggests a novel link between early cervical disease progression and DNA methylation in a region downstream of the CDKN2A transcription start site that may lead to increased p16INK4A/p14ARF expression prior to development of malignant disease. PMID:27401842

PSYCHOTHERAPY VERSUS PHARMACOTHERAPY FOR POSTTRAUMATIC STRESS DISORDER: SYSTEMIC REVIEW AND META-ANALYSES TO DETERMINE FIRST-LINE TREATMENTS.

PubMed

Lee, Daniel J; Schnitzlein, Carla W; Wolf, Jonathan P; Vythilingam, Meena; Rasmusson, Ann M; Hoge, Charles W

2016-09-01

Current clinical practice guidelines (CPGs) for posttraumatic stress disorder (PTSD) offer contradictory recommendations regarding use of medications or psychotherapy as first-line treatment. Direct head-to-head comparisons are lacking. Systemic review of Medline, EMBASE, PILOTS, Cochrane Central Register of Controlled Trials, PsycINFO, and Global Health Library was conducted without language restrictions. Randomized clinical trials ≥8 weeks in duration using structured clinical interview-based outcome measures, active-control conditions (e.g. supportive psychotherapy), and intent-to-treat analysis were selected for analyses. Independent review, data abstraction, and bias assessment were performed using standardized processes. Study outcomes were grouped around conventional follow-up time periods (3, 6, and 9 months). Combined effect sizes were computed using meta-analyses for medication versus control, medication pre-/posttreatment, psychotherapy versus control, and psychotherapy pre-/posttreatment. Effect sizes for trauma-focused psychotherapies (TFPs) versus active control conditions were greater than medications versus placebo and other psychotherapies versus active controls. TFPs resulted in greater sustained benefit over time than medications. Sertraline, venlafaxine, and nefazodone outperformed other medications, although potential for methodological biases were high. Improvement following paroxetine and fluoxetine treatment was small. Venlafaxine and stress inoculation training (SIT) demonstrated large initial effects that decreased over time. Bupropion, citalopram, divalproex, mirtazapine, tiagabine, and topiramate failed to differentiate from placebo. Aripiprazole, divalproex, guanfacine, and olanzapine failed to differentiate from placebo when combined with an antidepressant. Study findings support use of TFPs over nontrauma-focused psychotherapy or medication as first-line interventions. Second-line interventions include SIT, and potentially sertraline or venlafaxine, rather than entire classes of medication, such as SSRIs. Future revisions of CPGs should prioritize studies that utilize active controls over waitlist or treatment-as-usual conditions. Direct head-to-head trials of TFPs versus sertraline or venlafaxine are needed. © 2016 Wiley Periodicals, Inc.

Transparency ethics in practice: Revisiting financial conflicts of interest disclosure forms in clinical practice guidelines

PubMed Central

Sharara, Nour; Kaltenbach, Tonya; Laine, Loren; McQuaid, Kenneth; Soetikno, Roy; Subramanian, Venkataraman

2017-01-01

Background Authors of clinical practice guidelines (CPGs) disclose financial conflicts of interest (FCOIs) to promote transparency ethics. Typically, they do so on standard declaration forms containing generic open-ended questions on FCOIs. Yet, the literature is scant on the format and effect of alternative disclosure forms. Does supplementing a standard form with subsequent detailed disclosure forms tailored to the context of the CPG improve the yield or accuracy of FCOIs declarations? Methods For an international CPG in gastroenterology on the endoscopic surveillance for colorectal neoplasia in inflammatory bowel disease, we compared the use of a standard FCOIs disclosure form with a contextual FCOIs disclosure form that detailed commercial relations related to the CPG topic. This included manufacturers of endoscopes, endoscopy equipment and accessories. Participants completed the generic form early, and the supplementary contextual form six months later. We then compared the FCOI disclosures obtained. Findings 26 participants provided FCOIs disclosures using both disclosure forms. We found discrepancies regarding (1) the disclosure of FCOIs (presence/absence), and (2) the listing of financial entities. While the number of participants who disclosed a FCOI remained the same (30.8%) using the two forms, disclosures were not from the same individuals: two additional participants disclosed a FCOI, whereas two participants withdrew previous disclosures. Among those who reported a FCOI in either form, we noted inconsistencies in disclosures for 70% of the participants. This included changes in FCOIs disclosure status or modifications of "their commercial relations". Discussion Accurate reporting of FCOIs advances the transparency and ethical integrity of CPGs. Our experience suggests that a contextual FCOIs disclosure form tailored to content of the CPG with narrow, detailed questions provides supplementary, more complete FCOIs declarations than generic forms alone. The finding raises challenges on how forms are best written and formatted, optimally timed, and more effectively processed with sensitivity to professional behaviour, so as to heighten transparency. PMID:28841650

Clinical practice guidelines (CPGs) reduce costs in the management of isolated splenic injuries at pediatric trauma centers.

PubMed

Gutierrez, Ivan M; Zurakowski, David; Chen, Qiaoli; Mooney, David P

2013-02-01

The American Pediatric Surgical Association Trauma Committee proposed the use of a clinical practice guideline (CPG) for the non-operative management of isolated splenic injuries in 1998. An analysis was conducted to determine the financial impact of CPGs on the management of these injuries. The Pediatric Health Information System database, which contains data from 44 children's hospitals, was used to identify children who sustained a graded isolated splenic injury between June 2005 and June 2010. Demographics, length of stay (LOS), readmission rates, and laboratory, imaging, procedural, and total cost data were determined for all hospitals verified as a pediatric trauma center by the American College of Surgeons and/or designated by their local authority. Comparisons were made between facilities self-identifying as having a splenic injury management CPG and those without a CPG. Children (1,154) with isolated splenic injuries (grades 1-4) were cared for in 26 pediatric trauma centers: 20 with a CPG and 6 without (non-CPG). Median costs were significantly lower at CPG than non-CPG centers for imaging (US $163 vs. US $641, P < .001), laboratory (US $629 vs. US $1,044, P < .001), and total hospital stay (US $9,868 vs. US $10,830, P < .001). The median LOS for CPG and non-CPG centers were similar (3 vs. 2 days, P = .38), as were readmission rates within 90 days (3.1 vs. 5.1 %, P = .21). Multiple linear regression indicated that LOS (P < .001) and utilization of a CPG (P = .007) are significant independent predictors of total cost. Utilization of a CPG to manage children with isolated splenic injuries at a pediatric trauma center results in significantly reduced imaging, laboratory, and total hospital costs independent of patient age, gender, grade, and LOS.

MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status.

PubMed

Bady, Pierre; Sciuscio, Davide; Diserens, Annie-Claire; Bloch, Jocelyne; van den Bent, Martin J; Marosi, Christine; Dietrich, Pierre-Yves; Weller, Michael; Mariani, Luigi; Heppner, Frank L; Mcdonald, David R; Lacombe, Denis; Stupp, Roger; Delorenzi, Mauro; Hegi, Monika E

2012-10-01

The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic glioma suggest a prognostic value for MGMT methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate MGMT classification to assess high throughput molecular databases. Promoter methylation-mediated gene silencing is strongly dependent on the location of the methylated CpGs, complicating classification. Using the HumanMethylation450 (HM-450K) BeadChip interrogating 176 CpGs annotated for the MGMT gene, with 14 located in the promoter, two distinct regions in the CpG island of the promoter were identified with high importance for gene silencing and outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg12434587 [corrected] and cg12981137 provided good classification properties and prognostic value (kappa = 0.85; log-rank p < 0.001) using a training-set of 63 glioblastomas from homogenously treated patients, for whom MGMT methylation was previously shown to be predictive for outcome based on classification by methylation-specific PCR. MGMT-STP27 was successfully validated in an independent cohort of chemo-radiotherapy-treated glioblastoma patients (n = 50; kappa = 0.88; outcome, log-rank p < 0.001). Lower prevalence of MGMT methylation among CpG island methylator phenotype (CIMP) positive tumors was found in glioblastomas from The Cancer Genome Atlas than in low grade and anaplastic glioma cohorts, while in CIMP-negative gliomas MGMT was classified as methylated in approximately 50 % regardless of tumor grade. The proposed MGMT-STP27 prediction model allows mining of datasets derived on the HM-450K or HM-27K BeadChip to explore effects of distinct epigenetic context of MGMT methylation suspected to modulate treatment resistance in different tumor types.

Novel epigenetic changes in CDKN2A are associated with progression of cervical intraepithelial neoplasia.

PubMed

Wijetunga, N Ari; Belbin, Thomas J; Burk, Robert D; Whitney, Kathleen; Abadi, Maria; Greally, John M; Einstein, Mark H; Schlecht, Nicolas F

2016-09-01

To conduct a comprehensive mapping of the genomic DNA methylation in CDKN2A, which codes for the p16(INK4A) and p14(ARF) proteins, and 14 of the most promising DNA methylation marker candidates previously reported to be associated with progression of low-grade cervical intraepithelial neoplasia (CIN1) to cervical cancer. We analyzed DNA methylation in 68 HIV-seropositive and negative women with incident CIN1, CIN2, CIN3 and invasive cervical cancer, assaying 120 CpG dinucleotide sites spanning APC, CDH1, CDH13, CDKN2A, CDKN2B, DAPK1, FHIT, GSTP1, HIC1, MGMT, MLH1, RARB, RASSF1, TERT and TIMP3 using the Illumina Infinium array. Validation was performed using high resolution mapping of the target genes with HELP-tagging for 286 CpGs, followed by fine mapping of candidate genes with targeted bisulfite sequencing. We assessed for statistical differences in DNA methylation levels for each CpG loci assayed using univariate and multivariate methods correcting for multiple comparisons. In our discovery sample set, we identified dose dependent differences in DNA methylation with grade of disease in CDKN2A, APC, MGMT, MLH1 and HIC1, whereas single CpG locus differences between CIN2/3 and cancer groups were seen for CDH13, DAPK1 and TERT. Only those CpGs in the gene body of CDKN2A showed a monotonic increase in methylation between persistent CIN1, CIN2, CIN3 and cancers. Our data suggests a novel link between early cervical disease progression and DNA methylation in a region downstream of the CDKN2A transcription start site that may lead to increased p16(INK4A)/p14(ARF) expression prior to development of malignant disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Identification and validation of seven new loci showing differential DNA methylation related to serum lipid profile: an epigenome-wide approach. The REGICOR study.

PubMed

Sayols-Baixeras, S; Subirana, I; Lluis-Ganella, C; Civeira, F; Roquer, J; Do, A N; Absher, D; Cenarro, A; Muñoz, D; Soriano-Tárraga, C; Jiménez-Conde, J; Ordovas, J M; Senti, M; Aslibekyan, S; Marrugat, J; Arnett, D K; Elosua, R

2016-10-15

Lipid traits (total, low-density and high-density lipoprotein cholesterol, and triglycerides) are risk factors for cardiovascular disease. DNA methylation is not only an inherited but also modifiable epigenetic mark that has been related to cardiovascular risk factors. Our aim was to identify loci showing differential DNA methylation related to serum lipid levels. Blood DNA methylation was assessed using the Illumina Human Methylation 450 BeadChip. A two-stage epigenome-wide association study was performed, with a discovery sample in the REGICOR study (n = 645) and validation in the Framingham Offspring Study (n = 2,542). Fourteen CpG sites located in nine genes (SREBF1, SREBF2, PHOSPHO1, SYNGAP1, ABCG1, CPT1A, MYLIP, TXNIP and SLC7A11) and 2 intergenic regions showed differential methylation in association with lipid traits. Six of these genes and 1 intergenic region were new discoveries showing differential methylation related to total cholesterol (SREBF2), HDL-cholesterol (PHOSPHO1, SYNGAP1 and an intergenic region in chromosome 2) and triglycerides (MYLIP, TXNIP and SLC7A11). These CpGs explained 0.7%, 9.5% and 18.9% of the variability of total cholesterol, HDL cholesterol and triglycerides in the Framingham Offspring Study, respectively. The expression of the genes SREBF2 and SREBF1 was inversely associated with methylation of their corresponding CpGs (P-value = 0.0042 and 0.0045, respectively) in participants of the GOLDN study (n = 98). In turn, SREBF1 expression was directly associated with HDL cholesterol (P-value = 0.0429). Genetic variants in SREBF1, PHOSPHO1, ABCG1 and CPT1A were also associated with lipid profile. Further research is warranted to functionally validate these new loci and assess the causality of new and established associations between these differentially methylated loci and lipid metabolism.

Guidelines for the symptomatic management of fever in children: systematic review of the literature and quality appraisal with AGREE II.

PubMed

Chiappini, Elena; Bortone, Barbara; Galli, Luisa; de Martino, Maurizio

2017-07-31

Several societies have produced and disseminated clinical practice guidelines (CPGs) for the symptomatic management of fever in children. However, to date, the quality of such guidelines has not been appraised. To identify and evaluate guidelines for the symptomatic management of fever in children. The research was conducted using PubMed, guideline websites, and Google (January 2010 to July 2016). The quality of the CPGs was independently assessed by two assessors using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) instrument, and specific recommendations in guidelines were summarised and evaluated. Domain scores were considered of sufficient quality when >60% and of good quality when >80%. Seven guidelines were retrieved. The median score for the scope and purpose domain was 85.3% (range 66.6-100%). The median score for the stakeholder involvement domain was 57.5% (range 33.3-83.3%) and four guidelines scored >60%. The median score for the rigour of development domain was 52.0% (range 14.6-98.9%), and only three guidelines scored >60%. The median score for the clarity of presentation domain was 80.9% (range 50.0-94.4%). The median score for the applicability domain was 39.3% (8.3-100%). Only one guideline scored >60%. The median score for the editorial independence domain was 48.84% (0-91.6%); only three guidelines scored >60%. Most guidelines were recommended for use even if with modification, especially in the methodology, the applicability and the editorial independence domains. Our results could help improve reporting of future guidelines, and affect the selection and use of guidelines in clinical practice. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Microbiota and epigenetic regulation of inflammatory mediators in type 2 diabetes and obesity.

PubMed

Remely, M; Aumueller, E; Jahn, D; Hippe, B; Brath, H; Haslberger, A G

2014-03-01

Metabolic syndrome is associated with alterations in the structure of the gut microbiota leading to low-grade inflammatory responses. An increased penetration of the impaired gut membrane by bacterial components is believed to induce this inflammation, possibly involving epigenetic alteration of inflammatory molecules such as Toll-like receptors (TLRs). We evaluated changes of the gut microbiota and epigenetic DNA methylation of TLR2 and TLR4 in three groups of subjects: type 2 diabetics under glucagon-like peptide-1 agonist therapy, obese individuals without established insulin resistance, and a lean control group. Clostridium cluster IV, Clostridium cluster XIVa, lactic acid bacteria, Faecalibacterium prausnitzii and Bacteroidetes abundances were analysed by PCR and 454 high-throughput sequencing. The epigenetic methylation in the regulatory region of TLR4 and TLR2 was analysed using bisulfite conversion and pyrosequencing. We observed a significantly higher ratio of Firmicutes/ Bacteroidetes in type 2 diabetics compared to lean controls and obese. Major differences were shown in lactic acid bacteria, with the highest abundance in type 2 diabetics, followed by obese and lean participants. In comparison, F. prausnitzii was least abundant in type 2 diabetics, and most abundant in lean controls. Methylation analysis of four CpGs in the first exon of TLR4 showed significantly lower methylation in obese individuals, but no significant difference between type 2 diabetics and lean controls. Methylation of seven CpGs in the promoter region of TLR2 was significantly lower in type 2 diabetics compared to obese subjects and lean controls. The methylation levels of both TLRs were significantly correlated with body mass index. Our data suggest that changes in gut microbiota and thus cell wall components are involved in the epigenetic regulation of inflammatory reactions. An improved diet targeted to induce gut microbial balance and in the following even epigenetic changes of pro-inflammatory genes may be effective in the prevention of metabolic syndrome.

Genome-wide DNA methylation study in human placenta identifies novel loci associated with maternal smoking during pregnancy.

PubMed

Morales, Eva; Vilahur, Nadia; Salas, Lucas A; Motta, Valeria; Fernandez, Mariana F; Murcia, Mario; Llop, Sabrina; Tardon, Adonina; Fernandez-Tardon, Guillermo; Santa-Marina, Loreto; Gallastegui, Mara; Bollati, Valentina; Estivill, Xavier; Olea, Nicolas; Sunyer, Jordi; Bustamante, Mariona

2016-10-01

We conducted an epigenome-wide association study (EWAS) of DNA methylation in placenta in relation to maternal tobacco smoking during pregnancy and examined whether smoking-induced changes lead to low birthweight. DNA methylation in placenta was measured using the Illumina HumanMethylation450 BeadChip in 179 participants from the INfancia y Medio Ambiente (INMA) birth cohort. Methylation levels across 431 311 CpGs were tested for differential methylation between smokers and non-smokers in pregnancy. We took forward three top-ranking loci for further validation and replication by bisulfite pyrosequencing using data of 248 additional participants of the INMA cohort. We examined the association of methylation at smoking-associated loci with birthweight by applying a mediation analysis and a two-sample Mendelian randomization approach. Fifty CpGs were differentially methylated in placenta between smokers and non-smokers during pregnancy [false discovery rate (FDR) < 0.05]. We validated and replicated differential methylation at three top-ranking loci: cg27402634 located between LINC00086 and LEKR1, a gene previously related to birthweight in genome-wide association studies; cg20340720 (WBP1L); and cg25585967 and cg12294026 (TRIO). Dose-response relationships with maternal urine cotinine concentration during pregnancy were confirmed. Differential methylation at cg27402634 explained up to 36% of the lower birthweight in the offspring of smokers (Sobel P-value < 0.05). A two-sample Mendelian randomization analysis provided evidence that decreases in methylation levels at cg27402634 lead to decreases in birthweight. We identified novel loci differentially methylated in placenta in relation to maternal smoking during pregnancy. Adverse effects of maternal smoking on birthweight of the offspring may be mediated by alterations in the placental methylome. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Generation of Customizable Micro-wavy Pattern through Grayscale Direct Image Lithography

PubMed Central

He, Ran; Wang, Shunqiang; Andrews, Geoffrey; Shi, Wentao; Liu, Yaling

2016-01-01

With the increasing amount of research work in surface studies, a more effective method of producing patterned microstructures is highly desired due to the geometric limitations and complex fabricating process of current techniques. This paper presents an efficient and cost-effective method to generate customizable micro-wavy pattern using direct image lithography. This method utilizes a grayscale Gaussian distribution effect to model inaccuracies inherent in the polymerization process, which are normally regarded as trivial matters or errors. The measured surface profiles and the mathematical prediction show a good agreement, demonstrating the ability of this method to generate wavy patterns with precisely controlled features. An accurate pattern can be generated with customizable parameters (wavelength, amplitude, wave shape, pattern profile, and overall dimension). This mask-free photolithography approach provides a rapid fabrication method that is capable of generating complex and non-uniform 3D wavy patterns with the wavelength ranging from 12 μm to 2100 μm and an amplitude-to-wavelength ratio as large as 300%. Microfluidic devices with pure wavy and wavy-herringbone patterns suitable for capture of circulating tumor cells are made as a demonstrative application. A completely customized microfluidic device with wavy patterns can be created within a few hours without access to clean room or commercial photolithography equipment. PMID:26902520

Identification of nuclear weapons

DOEpatents

Mihalczo, J.T.; King, W.T.

1987-04-10

A method and apparatus for non-invasively indentifying different types of nuclear weapons is disclosed. A neutron generator is placed against the weapon to generate a stream of neutrons causing fissioning within the weapon. A first detects the generation of the neutrons and produces a signal indicative thereof. A second particle detector located on the opposite side of the weapon detects the fission particles and produces signals indicative thereof. The signals are converted into a detected pattern and a computer compares the detected pattern with known patterns of weapons and indicates which known weapon has a substantially similar pattern. Either a time distribution pattern or noise analysis pattern, or both, is used. Gamma-neutron discrimination and a third particle detector for fission particles adjacent the second particle detector are preferably used. The neutrons are generated by either a decay neutron source or a pulled neutron particle accelerator.

Generation of shape complexity through tissue conflict resolution

PubMed Central

Rebocho, Alexandra B; Southam, Paul; Kennaway, J Richard; Coen, Enrico

2017-01-01

Out-of-plane tissue deformations are key morphogenetic events during plant and animal development that generate 3D shapes, such as flowers or limbs. However, the mechanisms by which spatiotemporal patterns of gene expression modify cellular behaviours to generate such deformations remain to be established. We use the Snapdragon flower as a model system to address this problem. Combining cellular analysis with tissue-level modelling, we show that an orthogonal pattern of growth orientations plays a key role in generating out-of-plane deformations. This growth pattern is most likely oriented by a polarity field, highlighted by PIN1 protein localisation, and is modulated by dorsoventral gene activity. The orthogonal growth pattern interacts with other patterns of differential growth to create tissue conflicts that shape the flower. Similar shape changes can be generated by contraction as well as growth, suggesting tissue conflict resolution provides a flexible morphogenetic mechanism for generating shape diversity in plants and animals. DOI: http://dx.doi.org/10.7554/eLife.20156.001 PMID:28166865

A pooling-based approach to mapping genetic variants associated with DNA methylation

PubMed Central

Kaplow, Irene M.; MacIsaac, Julia L.; Mah, Sarah M.; McEwen, Lisa M.; Kobor, Michael S.; Fraser, Hunter B.

2015-01-01

DNA methylation is an epigenetic modification that plays a key role in gene regulation. Previous studies have investigated its genetic basis by mapping genetic variants that are associated with DNA methylation at specific sites, but these have been limited to microarrays that cover <2% of the genome and cannot account for allele-specific methylation (ASM). Other studies have performed whole-genome bisulfite sequencing on a few individuals, but these lack statistical power to identify variants associated with DNA methylation. We present a novel approach in which bisulfite-treated DNA from many individuals is sequenced together in a single pool, resulting in a truly genome-wide map of DNA methylation. Compared to methods that do not account for ASM, our approach increases statistical power to detect associations while sharply reducing cost, effort, and experimental variability. As a proof of concept, we generated deep sequencing data from a pool of 60 human cell lines; we evaluated almost twice as many CpGs as the largest microarray studies and identified more than 2000 genetic variants associated with DNA methylation. We found that these variants are highly enriched for associations with chromatin accessibility and CTCF binding but are less likely to be associated with traits indirectly linked to DNA, such as gene expression and disease phenotypes. In summary, our approach allows genome-wide mapping of genetic variants associated with DNA methylation in any tissue of any species, without the need for individual-level genotype or methylation data. PMID:25910490

A pooling-based approach to mapping genetic variants associated with DNA methylation

DOE PAGES

Kaplow, Irene M.; MacIsaac, Julia L.; Mah, Sarah M.; ...

2015-04-24

DNA methylation is an epigenetic modification that plays a key role in gene regulation. Previous studies have investigated its genetic basis by mapping genetic variants that are associated with DNA methylation at specific sites, but these have been limited to microarrays that cover <2% of the genome and cannot account for allele-specific methylation (ASM). Other studies have performed whole-genome bisulfite sequencing on a few individuals, but these lack statistical power to identify variants associated with DNA methylation. We present a novel approach in which bisulfite-treated DNA from many individuals is sequenced together in a single pool, resulting in a trulymore » genome-wide map of DNA methylation. Compared to methods that do not account for ASM, our approach increases statistical power to detect associations while sharply reducing cost, effort, and experimental variability. As a proof of concept, we generated deep sequencing data from a pool of 60 human cell lines; we evaluated almost twice as many CpGs as the largest microarray studies and identified more than 2000 genetic variants associated with DNA methylation. Here we found that these variants are highly enriched for associations with chromatin accessibility and CTCF binding but are less likely to be associated with traits indirectly linked to DNA, such as gene expression and disease phenotypes. In summary, our approach allows genome-wide mapping of genetic variants associated with DNA methylation in any tissue of any species, without the need for individual-level genotype or methylation data.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaplow, Irene M.; MacIsaac, Julia L.; Mah, Sarah M.

DNA methylation is an epigenetic modification that plays a key role in gene regulation. Previous studies have investigated its genetic basis by mapping genetic variants that are associated with DNA methylation at specific sites, but these have been limited to microarrays that cover <2% of the genome and cannot account for allele-specific methylation (ASM). Other studies have performed whole-genome bisulfite sequencing on a few individuals, but these lack statistical power to identify variants associated with DNA methylation. We present a novel approach in which bisulfite-treated DNA from many individuals is sequenced together in a single pool, resulting in a trulymore » genome-wide map of DNA methylation. Compared to methods that do not account for ASM, our approach increases statistical power to detect associations while sharply reducing cost, effort, and experimental variability. As a proof of concept, we generated deep sequencing data from a pool of 60 human cell lines; we evaluated almost twice as many CpGs as the largest microarray studies and identified more than 2000 genetic variants associated with DNA methylation. Here we found that these variants are highly enriched for associations with chromatin accessibility and CTCF binding but are less likely to be associated with traits indirectly linked to DNA, such as gene expression and disease phenotypes. In summary, our approach allows genome-wide mapping of genetic variants associated with DNA methylation in any tissue of any species, without the need for individual-level genotype or methylation data.« less

Decision support systems in clinical practice: The case of venous thromboembolism prevention.

PubMed

Nazarenko, G I; Kleymenova, E B; Payushik, S A; Otdelenov, V A; Sychev, D A; Yashina, L P

2015-01-01

Today medicine is facing a "knowledge crisis" in that explosively expanding medical knowledge encounters limited abilities to disseminate new practices [1]. Clinical practice guidelines (CPGs) are intended to promote high standards of care in specific areas of medicine by summarizing best clinical practice based on careful reviews of current research. However, doctors are often short of time to study these documents and check their updates, have little motivation for strict adherence to them. A systematic review of 11 studies reporting on 29 recommendations has found that median adherence to all recommendations was 34%, suggesting that potential benefits for patients from health research may be lost [2].Clinical decision support systems (CDSS) can serve as a knowledge translation tool, mediator between clinical guidelines and physicians by providing the right information to the right person at the right time. To evaluate the effectiveness of implementation of international and national CPGs for venous thromboembolism (VTE) prevention with the help of CDSS in a general hospital. A multifunctional CDSS based on national and international guidelines on the VTE prevention was developed and implemented in the Medical Center of the Bank of Russia (MC). The system has the following functionalities: 1) it supports the decision on the VTE prevention based on individual risk assessment of thrombosis (scales of Caprini, Rogers and Khorana, Padua Prediction Score, additional risk factors) and bleeding (IMPROVE scale for non-surgical patients, major bleeding scale for surgical patients and major orthopedic surgeries, hemorrhagic complications risk in cancer patients); 2) generates the summary containing the grade of recommendations and the level of evidence, personalized recommendations on regimen and duration of preventive antithrombotic therapy, dose correction according to creatinine clearance; 3) provides an audit form for and statistical analysis of VTE cases; 3) automatically generates a quality register for VTE prevention.CDSS was implemented in June 2014. We analyzed VTE cases identified by triggers (deep vein thrombosis diagnosed by Doppler ultrasound and pulmonary embolism at the chest CT) that occurred in 2014 before and after CDSS implementation, as well as in the first half of 2015. Patients with VTE diagnosed during the first 48 hours of hospitalization or receiving anticoagulants in therapeutic doses were excluded from the analysis. Chi-square test for linear trend and non-parametric methods of descriptive statistics were used for data analysis. CDSS utilization was regulated by a special hospital-wide policy; lectures were organized to educate doctors how to use the system. Although international recommendations require VTE risk assessment for all hospitalized patients (except those receiving anticoagulant in therapeutic doses), the doctors filled forms for only 306 patients during the first 6 months of CDSS functioning (14.1% of discharges with length of stay >48 hours during this period). In the first half of 2015 the coverage of VTE risk assessment with CDSS was 19% (n = 506). Correctness of filling out the forms was 78.4%, in the rest of cases doctors made mistakes in choosing patient's profile or when filling in risk scales.Doctors adhere to given recommendations in 85.4% of cases. Most often (47.5%) pharmacotherapy with low molecular weight heparin (LMWH), preventive doses, was recommended by the system, and in this category the adherence to recommended practice was the lowest (74.6%). Among patients who underwent pharmacoprophylaxis, in 21.1% cases the use of anticoagulants was inconsistent with clinical guidelines or drug package insert (typically inappropriate choice of LMWH prophylactic doses, delaying or reducing the duration of prophylaxis).The rate of hospital-acquired VTE significantly decreased after CDSS implementation and was 11.71, 8.28 and 4.84 per 1,000 hospitalizations in the first and second half of 2014 and in the first half of 2015, respectively (χ2 = 7.325, df = 1, p = 0.0068). The rate of postoperative VTE for the same period amounted to 8.76, 3.39 and 4.17 per 1,000 operations, respectively (χ2 = 7.266, df = 1, p = 0.007), reaching a level of the correspondent AHRQ safety indicator (4.99 per 1,000 operations) [3]. Deviations from clinical guidelines or anticoagulant package inserts were revealed in 74% of VTE cases; and more than 1/3 of deviations affected treatment outcomes. Coverage of hospitalized patients with documented VTE risk assessment gradually increased after the CDSS implementation, but remained at a low level (19% of eligible patients). Partly it may be attributed to the lack of CDSS integration in electronic health record or computerized physician order entry systems that would facilitate routine documentation of VTE and bleeding risks. However, the introduction of CDSS has allowed reducing significantly the rate of hospital-acquired VTE. This can be explained by drawing doctor's attention to the VTE problem and by training effect of CDSS. After receiving appropriate recommendations doctors adhere to them, on average, in 85.4% of cases, although for LMWH pharmacoprophylaxis this level was lower (74.6%). Development of hospital-acquired VTE in most cases (74%) was accompanied by non-compliance with CPGs recommendations, emphasizing the importance of additional measures for better adherence to evidence-based clinical practices.

Maternal blood contamination of collected cord blood can be identified using DNA methylation at three CpGs.

PubMed

Morin, Alexander M; Gatev, Evan; McEwen, Lisa M; MacIsaac, Julia L; Lin, David T S; Koen, Nastassja; Czamara, Darina; Räikkönen, Katri; Zar, Heather J; Koenen, Karestan; Stein, Dan J; Kobor, Michael S; Jones, Meaghan J

2017-01-01

Cord blood is a commonly used tissue in environmental, genetic, and epigenetic population studies due to its ready availability and potential to inform on a sensitive period of human development. However, the introduction of maternal blood during labor or cross-contamination during sample collection may complicate downstream analyses. After discovering maternal contamination of cord blood in a cohort study of 150 neonates using Illumina 450K DNA methylation (DNAm) data, we used a combination of linear regression and random forest machine learning to create a DNAm-based screening method. We identified a panel of DNAm sites that could discriminate between contaminated and non-contaminated samples, then designed pyrosequencing assays to pre-screen DNA prior to being assayed on an array. Maternal contamination of cord blood was initially identified by unusual X chromosome DNA methylation patterns in 17 males. We utilized our DNAm panel to detect contaminated male samples and a proportional amount of female samples in the same cohort. We validated our DNAm screening method on an additional 189 sample cohort using both pyrosequencing and DNAm arrays, as well as 9 publically available cord blood 450K data sets. The rate of contamination varied from 0 to 10% within these studies, likely related to collection specific methods. Maternal blood can contaminate cord blood during sample collection at appreciable levels across multiple studies. We have identified a panel of markers that can be used to identify this contamination, either post hoc after DNAm arrays have been completed, or in advance using a targeted technique like pyrosequencing.

Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis.

PubMed

Laffaire, Julien; Everhard, Sibille; Idbaih, Ahmed; Crinière, Emmanuelle; Marie, Yannick; de Reyniès, Aurelien; Schiappa, Renaud; Mokhtari, Karima; Hoang-Xuan, Khê; Sanson, Marc; Delattre, Jean-Yves; Thillet, Joëlle; Ducray, François

2011-01-01

Extensive genomic and gene expression studies have been performed in gliomas, but the epigenetic alterations that characterize different subtypes of gliomas remain largely unknown. Here, we analyzed the methylation patterns of 807 genes (1536 CpGs) in a series of 33 low-grade gliomas (LGGs), 36 glioblastomas (GBMs), 8 paired initial and recurrent gliomas, and 9 controls. This analysis was performed with Illumina's Golden Gate Bead methylation arrays and was correlated with clinical, histological, genomic, gene expression, and genotyping data, including IDH1 mutations. Unsupervised hierarchical clustering resulted in 2 groups of gliomas: a group corresponding to de novo GBMs and a group consisting of LGGs, recurrent anaplastic gliomas, and secondary GBMs. When compared with de novo GBMs and controls, this latter group was characterized by a very high frequency of IDH1 mutations and by a hypermethylated profile similar to the recently described glioma CpG island methylator phenotype. MGMT methylation was more frequent in this group. Among the LGG cluster, 1p19q codeleted LGG displayed a distinct methylation profile. A study of paired initial and recurrent gliomas demonstrated that methylation profiles were remarkably stable across glioma evolution, even during anaplastic transformation, suggesting that epigenetic alterations occur early during gliomagenesis. Using the Cancer Genome Atlas data set, we demonstrated that GBM samples that had an LGG-like hypermethylated profile had a high rate of IDH1 mutations and a better outcome. Finally, we identified several hypermethylated and downregulated genes that may be associated with LGG and GBM oncogenesis, LGG oncogenesis, 1p19q codeleted LGG oncogenesis, and GBM oncogenesis.

Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis

PubMed Central

Laffaire, Julien; Everhard, Sibille; Idbaih, Ahmed; Crinière, Emmanuelle; Marie, Yannick; de Reyniès, Aurelien; Schiappa, Renaud; Mokhtari, Karima; Hoang-Xuan, Khê; Sanson, Marc; Delattre, Jean-Yves; Thillet, Joëlle; Ducray, François

2011-01-01

Extensive genomic and gene expression studies have been performed in gliomas, but the epigenetic alterations that characterize different subtypes of gliomas remain largely unknown. Here, we analyzed the methylation patterns of 807 genes (1536 CpGs) in a series of 33 low-grade gliomas (LGGs), 36 glioblastomas (GBMs), 8 paired initial and recurrent gliomas, and 9 controls. This analysis was performed with Illumina's Golden Gate Bead methylation arrays and was correlated with clinical, histological, genomic, gene expression, and genotyping data, including IDH1 mutations. Unsupervised hierarchical clustering resulted in 2 groups of gliomas: a group corresponding to de novo GBMs and a group consisting of LGGs, recurrent anaplastic gliomas, and secondary GBMs. When compared with de novo GBMs and controls, this latter group was characterized by a very high frequency of IDH1 mutations and by a hypermethylated profile similar to the recently described glioma CpG island methylator phenotype. MGMT methylation was more frequent in this group. Among the LGG cluster, 1p19q codeleted LGG displayed a distinct methylation profile. A study of paired initial and recurrent gliomas demonstrated that methylation profiles were remarkably stable across glioma evolution, even during anaplastic transformation, suggesting that epigenetic alterations occur early during gliomagenesis. Using the Cancer Genome Atlas data set, we demonstrated that GBM samples that had an LGG-like hypermethylated profile had a high rate of IDH1 mutations and a better outcome. Finally, we identified several hypermethylated and downregulated genes that may be associated with LGG and GBM oncogenesis, LGG oncogenesis, 1p19q codeleted LGG oncogenesis, and GBM oncogenesis. PMID:20926426

The New England travel market: generational travel patterns, 1979 to 1996

Treesearch

Rod Warnick

2002-01-01

Generations of travelers who select New England as a primary destination are examined over time from the years of 1979 through 1996 and the analysis serves to update an earlier review of generational travel patterns of the region (Warnick, 1994). Changes in travel patterns are noted by overall adjusted annual change rates by demographic and geographic regions of...

Expedient generation of patterned surface aldehydes by microfluidic oxidation for chemoselective immobilization of ligands and cells.

PubMed

Westcott, Nathan P; Pulsipher, Abigail; Lamb, Brian M; Yousaf, Muhammad N

2008-09-02

An expedient and inexpensive method to generate patterned aldehydes on self-assembled monolayers (SAMs) of alkanethiolates on gold with control of density for subsequent chemoselective immobilization from commercially available starting materials has been developed. Utilizing microfluidic cassettes, primary alcohol oxidation of tetra(ethylene glycol) undecane thiol and 11-mercapto-1-undecanol SAMs was performed directly on the surface generating patterned aldehyde groups with pyridinium chlorochromate. The precise density of surface aldehydes generated can be controlled and characterized by electrochemistry. For biological applications, fibroblast cells were seeded on patterned surfaces presenting biospecifc cell adhesive (Arg-Glyc-Asp) RGD peptides.

Automated branching pattern report generation for laparoscopic surgery assistance

NASA Astrophysics Data System (ADS)

Oda, Masahiro; Matsuzaki, Tetsuro; Hayashi, Yuichiro; Kitasaka, Takayuki; Misawa, Kazunari; Mori, Kensaku

2015-05-01

This paper presents a method for generating branching pattern reports of abdominal blood vessels for laparoscopic gastrectomy. In gastrectomy, it is very important to understand branching structure of abdominal arteries and veins, which feed and drain specific abdominal organs including the stomach, the liver and the pancreas. In the real clinical stage, a surgeon creates a diagnostic report of the patient anatomy. This report summarizes the branching patterns of the blood vessels related to the stomach. The surgeon decides actual operative procedure. This paper shows an automated method to generate a branching pattern report for abdominal blood vessels based on automated anatomical labeling. The report contains 3D rendering showing important blood vessels and descriptions of branching patterns of each vessel. We have applied this method for fifty cases of 3D abdominal CT scans and confirmed the proposed method can automatically generate branching pattern reports of abdominal arteries.

Laser induced Erasable Patterns in a N* Liquid Crystal on an Iron Doped Lithium Niobate (Postprint)

DTIC Science & Technology

2017-10-12

be applied selectively to erase these patterns. Thus, a promising method is reported to generate reconfigurable patterns, photonic motives , and...erase these patterns. Thus, a promising method is reported to generate reconfigurable patterns, photonic motives , and touch sensitive devices in a...release (PA): distribution unlimited. loss of the patterns inscribed. Possible motives are not limited to graphics. It should be also possible to write

Patterning roadmap: 2017 prospects

NASA Astrophysics Data System (ADS)

Neisser, Mark

2017-06-01

Road mapping of semiconductor chips has been underway for over 20 years, first with the International Technology Roadmap for Semiconductors (ITRS) roadmap and now with the International Roadmap for Devices and Systems (IRDS) roadmap. The original roadmap was mostly driven bottom up and was developed to ensure that the large numbers of semiconductor producers and suppliers had good information to base their research and development on. The current roadmap is generated more top-down, where the customers of semiconductor chips anticipate what will be needed in the future and the roadmap projects what will be needed to fulfill that demand. The More Moore section of the roadmap projects that advanced logic will drive higher-resolution patterning, rather than memory chips. Potential solutions for patterning future logic nodes can be derived as extensions of `next-generation' patterning technologies currently under development. Advanced patterning has made great progress, and two `next-generation' patterning technologies, EUV and nanoimprint lithography, have potential to be in production as early as 2018. The potential adoption of two different next-generation patterning technologies suggests that patterning technology is becoming more specialized. This is good for the industry in that it lowers overall costs, but may lead to slower progress in extending any one patterning technology in the future.

Direct generation of abruptly focusing vortex beams using a 3/2 radial phase-only pattern.

PubMed

Davis, Jeffrey A; Cottrell, Don M; Zinn, Jonathan M

2013-03-20

Abruptly focusing Airy beams have previously been generated using a radial cubic phase pattern that represents the Fourier transform of the Airy beam. The Fourier transform of this pattern is formed using a system length of 2f, where f is the focal length of the Fourier transform lens. In this work, we directly generate these abruptly focusing Airy beams using a 3/2 radial phase pattern encoded onto a liquid crystal display. The resulting optical system is much shorter. In addition, we can easily produce vortex patterns at the focal point of these beams. Experimental results match theoretical predictions.

Test pattern generation for ILA sequential circuits

NASA Technical Reports Server (NTRS)

Feng, YU; Frenzel, James F.; Maki, Gary K.

1993-01-01

An efficient method of generating test patterns for sequential machines implemented using one-dimensional, unilateral, iterative logic arrays (ILA's) of BTS pass transistor networks is presented. Based on a transistor level fault model, the method affords a unique opportunity for real-time fault detection with improved fault coverage. The resulting test sets are shown to be equivalent to those obtained using conventional gate level models, thus eliminating the need for additional test patterns. The proposed method advances the simplicity and ease of the test pattern generation for a special class of sequential circuitry.

Self-Assembly of Human Serum Albumin: A Simplex Phenomenon

PubMed Central

Thakur, Garima; Prashanthi, Kovur; Jiang, Keren; Thundat, Thomas

2017-01-01

Spontaneous self-assemblies of biomolecules can generate geometrical patterns. Our findings provide an insight into the mechanism of self-assembled ring pattern generation by human serum albumin (HSA). The self-assembly is a process guided by kinetic and thermodynamic parameters. The generated protein ring patterns display a behavior which is geometrically related to a n-simplex model and is explained through thermodynamics and chemical kinetics. PMID:28930179

The heparanome--the enigma of encoding and decoding heparan sulfate sulfation.

PubMed

Lamanna, William C; Kalus, Ina; Padva, Michael; Baldwin, Rebecca J; Merry, Catherine L R; Dierks, Thomas

2007-04-30

Heparan sulfate (HS) is a cell surface carbohydrate polymer modified with sulfate moieties whose highly ordered composition is central to directing specific cell signaling events. The ability of the cell to generate these information rich glycans with such specificity has opened up a new field of "heparanomics" which seeks to understand the systems involved in generating these cell type and developmental stage specific HS sulfation patterns. Unlike other instances where biological information is encrypted as linear sequences in molecules such as DNA, HS sulfation patterns are generated through a non-template driven process. Thus, deciphering the sulfation code and the dynamic nature of its generation has posed a new challenge to system biologists. The recent discovery of two sulfatases, Sulf1 and Sulf2, with the unique ability to edit sulfation patterns at the cell surface, has opened up a new dimension as to how we understand the regulation of HS sulfation patterning and pattern-dependent cell signaling events. This review will focus on the functional relationship between HS sulfation patterning and biological processes. Special attention will be given to Sulf1 and Sulf2 and how these key editing enzymes might act in concert with the HS biosynthetic enzymes to generate and regulate specific HS sulfation patterns in vivo. We will further explore the use of knock out mice as biological models for understanding the dynamic systems involved in generating HS sulfation patterns and their biological relevance. A brief overview of new technologies and innovations summarizes advances in the systems biology field for understanding non-template molecular networks and their influence on the "heparanome".

The New England travel market: changes in generational travel patterns

Treesearch

Rodney B. Warnick

1995-01-01

The purpose of this study was to examine and explore the New England domestic travel market trends, from 1979 through 1991 within the context of generations. The existing travel markets, who travel to New England, are changing by age cohorts and specifically within different generations. The New England changes in generational travel patterns do not reflect national...

Generation of 3D templates of active sites of proteins with rigid prosthetic groups.

PubMed

Nebel, Jean-Christophe

2006-05-15

With the increasing availability of protein structures, the generation of biologically meaningful 3D patterns from the simultaneous alignment of several protein structures is an exciting prospect: active sites could be better understood, protein functions and protein 3D structures could be predicted more accurately. Although patterns can already be generated at the fold and topological levels, no system produces high-resolution 3D patterns including atom and cavity positions. To address this challenge, our research focuses on generating patterns from proteins with rigid prosthetic groups. Since these groups are key elements of protein active sites, the generated 3D patterns are expected to be biologically meaningful. In this paper, we present a new approach which allows the generation of 3D patterns from proteins with rigid prosthetic groups. Using 237 protein chains representing proteins containing porphyrin rings, our method was validated by comparing 3D templates generated from homologues with the 3D structure of the proteins they model. Atom positions were predicted reliably: 93% of them had an accuracy of 1.00 A or less. Moreover, similar results were obtained regarding chemical group and cavity positions. Results also suggested our system could contribute to the validation of 3D protein models. Finally, a 3D template was generated for the active site of human cytochrome P450 CYP17, the 3D structure of which is unknown. Its analysis showed that it is biologically meaningful: our method detected the main patterns of the cytochrome P450 superfamily and the motifs linked to catalytic reactions. The 3D template also suggested the position of a residue, which could be involved in a hydrogen bond with CYP17 substrates and the shape and location of a cavity. Comparisons with independently generated 3D models comforted these hypotheses. Alignment software (Nestor3D) is available at http://www.kingston.ac.uk/~ku33185/Nestor3D.html

Effects of traffic generation patterns on the robustness of complex networks

NASA Astrophysics Data System (ADS)

Wu, Jiajing; Zeng, Junwen; Chen, Zhenhao; Tse, Chi K.; Chen, Bokui

2018-02-01

Cascading failures in communication networks with heterogeneous node functions are studied in this paper. In such networks, the traffic dynamics are highly dependent on the traffic generation patterns which are in turn determined by the locations of the hosts. The data-packet traffic model is applied to Barabási-Albert scale-free networks to study the cascading failures in such networks and to explore the effects of traffic generation patterns on network robustness. It is found that placing the hosts at high-degree nodes in a network can make the network more robust against both intentional attacks and random failures. It is also shown that the traffic generation pattern plays an important role in network design.

Human spinal locomotor control is based on flexibly organized burst generators.

PubMed

Danner, Simon M; Hofstoetter, Ursula S; Freundl, Brigitta; Binder, Heinrich; Mayr, Winfried; Rattay, Frank; Minassian, Karen

2015-03-01

Constant drive provided to the human lumbar spinal cord by epidural electrical stimulation can cause local neural circuits to generate rhythmic motor outputs to lower limb muscles in people paralysed by spinal cord injury. Epidural spinal cord stimulation thus allows the study of spinal rhythm and pattern generating circuits without their configuration by volitional motor tasks or task-specific peripheral feedback. To reveal spinal locomotor control principles, we studied the repertoire of rhythmic patterns that can be generated by the functionally isolated human lumbar spinal cord, detected as electromyographic activity from the legs, and investigated basic temporal components shared across these patterns. Ten subjects with chronic, motor-complete spinal cord injury were studied. Surface electromyographic responses to lumbar spinal cord stimulation were collected from quadriceps, hamstrings, tibialis anterior, and triceps surae in the supine position. From these data, 10-s segments of rhythmic activity present in the four muscle groups of one limb were extracted. Such samples were found in seven subjects. Physiologically adequate cycle durations and relative extension- and flexion-phase durations similar to those needed for locomotion were generated. The multi-muscle activation patterns exhibited a variety of coactivation, mixed-synergy and locomotor-like configurations. Statistical decomposition of the electromyographic data across subjects, muscles and samples of rhythmic patterns identified three common temporal components, i.e. basic or shared activation patterns. Two of these basic patterns controlled muscles to contract either synchronously or alternatingly during extension- and flexion-like phases. The third basic pattern contributed to the observed muscle activities independently from these extensor- and flexor-related basic patterns. Each bifunctional muscle group was able to express both extensor- and flexor-patterns, with variable ratios across the samples of rhythmic patterns. The basic activation patterns can be interpreted as central drives implemented by spinal burst generators that impose specific spatiotemporally organized activation on the lumbosacral motor neuron pools. Our data thus imply that the human lumbar spinal cord circuits can form burst-generating elements that flexibly combine to obtain a wide range of locomotor outputs from a constant, repetitive input. It may be possible to use this flexibility to incorporate specific adaptations to gait and stance to improve locomotor control, even after severe central nervous system damage. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Human spinal locomotor control is based on flexibly organized burst generators

PubMed Central

Danner, Simon M.; Hofstoetter, Ursula S.; Freundl, Brigitta; Binder, Heinrich; Mayr, Winfried; Rattay, Frank

2015-01-01

Constant drive provided to the human lumbar spinal cord by epidural electrical stimulation can cause local neural circuits to generate rhythmic motor outputs to lower limb muscles in people paralysed by spinal cord injury. Epidural spinal cord stimulation thus allows the study of spinal rhythm and pattern generating circuits without their configuration by volitional motor tasks or task-specific peripheral feedback. To reveal spinal locomotor control principles, we studied the repertoire of rhythmic patterns that can be generated by the functionally isolated human lumbar spinal cord, detected as electromyographic activity from the legs, and investigated basic temporal components shared across these patterns. Ten subjects with chronic, motor-complete spinal cord injury were studied. Surface electromyographic responses to lumbar spinal cord stimulation were collected from quadriceps, hamstrings, tibialis anterior, and triceps surae in the supine position. From these data, 10-s segments of rhythmic activity present in the four muscle groups of one limb were extracted. Such samples were found in seven subjects. Physiologically adequate cycle durations and relative extension- and flexion-phase durations similar to those needed for locomotion were generated. The multi-muscle activation patterns exhibited a variety of coactivation, mixed-synergy and locomotor-like configurations. Statistical decomposition of the electromyographic data across subjects, muscles and samples of rhythmic patterns identified three common temporal components, i.e. basic or shared activation patterns. Two of these basic patterns controlled muscles to contract either synchronously or alternatingly during extension- and flexion-like phases. The third basic pattern contributed to the observed muscle activities independently from these extensor- and flexor-related basic patterns. Each bifunctional muscle group was able to express both extensor- and flexor-patterns, with variable ratios across the samples of rhythmic patterns. The basic activation patterns can be interpreted as central drives implemented by spinal burst generators that impose specific spatiotemporally organized activation on the lumbosacral motor neuron pools. Our data thus imply that the human lumbar spinal cord circuits can form burst-generating elements that flexibly combine to obtain a wide range of locomotor outputs from a constant, repetitive input. It may be possible to use this flexibility to incorporate specific adaptations to gait and stance to improve locomotor control, even after severe central nervous system damage. PMID:25582580

Initial benchmarking of a new electron-beam raster pattern generator for 130-100 nm maskmaking

NASA Astrophysics Data System (ADS)

Sauer, Charles A.; Abboud, Frank E.; Babin, Sergey V.; Chakarian, Varoujan; Ghanbari, Abe; Innes, Robert; Trost, David; Raymond, Frederick, III

2000-07-01

The decision by the Semiconductor Industry Association (SIA) to accelerate the continuing evolution to smaller linewidths is consistent with the commitment by Etec Systems, Inc. to rapidly develop new technologies for pattern generation systems with improved resolution, critical dimension (CD) uniformity, positional accuracy, and throughput. Current pattern generation designs are inadequate to meet the more advanced requirements for masks, particularly at or below the 100 nm node. Major changes to all pattern generation tools will be essential to meet future market requirements. An electron-beam (e-beam) system that is designed to meet the challenges for 130 - 100 nm device generation with extendibility to the 70-nm range will be discussed. This system has an architecture that includes a graybeam writing strategy, a new state system, and improved thermal management. Detailed changes include a pulse width modulated blanking system, per-pixel deflection, retrograde scanning multipass writing, and a column with a 50 kV accelerating voltage that supports a dose of up to 45 (mu) C/cm2 with minimal amounts of resist heating. This paper examines current issues, our approach to meeting International Technology Roadmap for Semiconductors (ITRS) requirements, and some preliminary results from a new pattern generator.

Geographic migration of black and white families over four generations.

PubMed

Sharkey, Patrick

2015-02-01

This article analyzes patterns of geographic migration of black and white American families over four consecutive generations. The analysis is based on a unique set of questions in the Panel Study of Income Dynamics (PSID) asking respondents about the counties and states in which their parents and grandparents were raised. Using this information along with the extensive geographic information available in the PSID survey, the article tracks the geographic locations of four generations of family members and considers the ways in which families and places are linked together over the course of a family's history. The patterns documented in the article are consistent with much of the demographic literature on the Great Migration of black Americans out of the South, but they reveal new insights into patterns of black migration after the Great Migration. In the most recent generation, black Americans have remained in place to a degree that is unique relative to the previous generation and relative to whites of the same generation. This new geographic immobility is the most pronounced change in black Americans' migration patterns after the Great Migration, and it is a pattern that has implications for the demography of black migration as well as the literature on racial inequality.

Automatic two- and three-dimensional mesh generation based on fuzzy knowledge processing

NASA Astrophysics Data System (ADS)

Yagawa, G.; Yoshimura, S.; Soneda, N.; Nakao, K.

1992-09-01

This paper describes the development of a novel automatic FEM mesh generation algorithm based on the fuzzy knowledge processing technique. A number of local nodal patterns are stored in a nodal pattern database of the mesh generation system. These nodal patterns are determined a priori based on certain theories or past experience of experts of FEM analyses. For example, such human experts can determine certain nodal patterns suitable for stress concentration analyses of cracks, corners, holes and so on. Each nodal pattern possesses a membership function and a procedure of node placement according to this function. In the cases of the nodal patterns for stress concentration regions, the membership function which is utilized in the fuzzy knowledge processing has two meanings, i.e. the “closeness” of nodal location to each stress concentration field as well as “nodal density”. This is attributed to the fact that a denser nodal pattern is required near a stress concentration field. What a user has to do in a practical mesh generation process are to choose several local nodal patterns properly and to designate the maximum nodal density of each pattern. After those simple operations by the user, the system places the chosen nodal patterns automatically in an analysis domain and on its boundary, and connects them smoothly by the fuzzy knowledge processing technique. Then triangular or tetrahedral elements are generated by means of the advancing front method. The key issue of the present algorithm is an easy control of complex two- or three-dimensional nodal density distribution by means of the fuzzy knowledge processing technique. To demonstrate fundamental performances of the present algorithm, a prototype system was constructed with one of object-oriented languages, Smalltalk-80 on a 32-bit microcomputer, Macintosh II. The mesh generation of several two- and three-dimensional domains with cracks, holes and junctions was presented as examples.

ROLE OF NMDA, NICOTINIC, AND GABA RECEPTORS IN THE STEADY STATE VISUAL EVOKED POTENTIAL IN RATS.

EPA Science Inventory

This manuscript characterizes the receptor pathways involved in pattern-evoked potential generation in rats

" NMDA and nicotinic acetylcholine receptors appear to be involved in the generation of the steady-state pattern evoked response in vivo.

" The pattern evok...

Breathing simulator of workers for respirator performance test.

PubMed

Yuasa, Hisashi; Kumita, Mikio; Honda, Takeshi; Kimura, Kazushi; Nozaki, Kosuke; Emi, Hitoshi; Otani, Yoshio

2015-01-01

Breathing machines are widely used to evaluate respirator performance but they are capable of generating only limited air flow patterns, such as, sine, triangular and square waves. In order to evaluate the respirator performance in practical use, it is desirable to test the respirator using the actual breathing patterns of wearers. However, it has been a difficult task for a breathing machine to generate such complicated flow patterns, since the human respiratory volume changes depending on the human activities and workload. In this study, we have developed an electromechanical breathing simulator and a respiration sampling device to record and reproduce worker's respiration. It is capable of generating various flow patterns by inputting breathing pattern signals recorded by a computer, as well as the fixed air flow patterns. The device is equipped with a self-control program to compensate the difference in inhalation and exhalation volume and the measurement errors on the breathing flow rate. The system was successfully applied to record the breathing patterns of workers engaging in welding and reproduced the breathing patterns.

Model-based guiding pattern synthesis for robust assembly of contact layers using directed self-assembly

NASA Astrophysics Data System (ADS)

Mitra, Joydeep; Torres, Andres; Ma, Yuansheng; Pan, David Z.

2018-01-01

Directed self-assembly (DSA) has emerged as one of the most compelling next-generation patterning techniques for sub 7 nm via or contact layers. A key issue in enabling DSA as a mainstream patterning technique is the generation of grapho-epitaxy-based guiding pattern (GP) shapes to assemble the contact patterns on target with high fidelity and resolution. Current GP generation is mostly empirical, and limited to a very small number of via configurations. We propose the first model-based GP synthesis algorithm and methodology for on-target and robust DSA, on general via pattern configurations. The final postoptical proximity correction-printed GPs derived from our original synthesized GPs are resilient to process variations and continue to maintain the same DSA fidelity in terms of placement error and target shape.

Controlling flows in microchannels with patterned surface charge and topography.

PubMed

Stroock, Abraham D; Whitesides, George M

2003-08-01

This Account reviews two procedures for controlling the flow of fluids in microchannels. The first procedure involves patterning the density of charge on the inner surfaces of a channel. These patterns generate recirculating electroosmotic flows in the presence of a steady electric field. The second procedure involves patterning topography on an inner surface of a channel. These patterns generate recirculation in the cross-section of steady, pressure-driven flows. This Account summarizes applications of these flow to mixing and to controlling dispersion (band broadening).

Assessment of CLIGEN precipitation and storm pattern generation under four precipitation depth categories in China

USDA-ARS?s Scientific Manuscript database

CLIGEN (CLImate GENerator) is a widely used stochastic weather generator to simulate continuous daily precipitation and storm pattern information for hydrological and soil erosion models. Although CLIGEN has been tested in several regions in the world, thoroughly assessment before applying it to Chi...

Sex-biased phoretic mite load on two seaweed flies: Coelopa frigida and Coelopa pilipes.

PubMed

Gilburn, Andre S; Stewart, Katie M; Edward, Dominic A

2009-12-01

Two hypotheses explain male-biased parasitism. Physiological costs of male sexually selected characteristics can reduce immunocompetence. Alternatively, ecological differences could generate male-biased parasitism. One method of comparing the importance of the two theories is to investigate patterns of phoresy, which are only likely to be generated by ecological rather than immunological differences between the sexes. Here we studied the pattern of phoresy of the mite, Thinoseius fucicola, on two species of seaweed fly hosts, Coelopa frigida and Coelopa pilipes. We found a highly male-biased pattern of phoresy of T. fucicola on both species. These are the first reported instances of sex-biased phoresy in a solely phoretic parasite. We also show the first two cases of size-biased phoresy. We suggest that ecological factors, particularly, male mate searching, generated male biased patterns of phoresy. We highlight the potential importance of studies of phoresy in determining the relative roles of the immunocompetence and ecological theories in generating male-biased parasitism. We suggest that more studies of patterns of phoresy are carried out to allow detailed comparisons with patterns of parasitism.

Efficient generation of holographic news ticker in holographic 3DTV

NASA Astrophysics Data System (ADS)

Kim, Seung-Cheol; Kim, Eun-Soo

2009-08-01

News ticker is used to show breaking news or news headlines in conventional 2-D broadcasting system. For the case of the breaking news, the fast creation is need, because the information should be sent quickly. In addition, if holographic 3- D broadcasting system is started in the future, news ticker will remain. On the other hands, some approaches for generation of CGH patterns have been suggested like the ray-tracing method and look-up table (LUT) method. However, these methods have some drawbacks that needs much time or needs huge memory size for look-up table. Recently, a novel LUT (N-LUT) method for fast generation of CGH patterns of 3-D objects with a dramatically reduced LUT without the loss of computational speed was proposed. Therefore, we proposed the method to efficiently generate the holographic news ticker in holographic 3DTV or 3-D movies using N-LUT method. The proposed method is largely consisted of five steps: construction of the LUT for each character, extraction of characters in news ticker, generation and shift of the CGH pattern for news ticker using the LUT for each character, composition of hologram pattern for 3-D video and hologram pattern for news ticker and reconstruct the holographic 3D video with news ticker. To confirm the proposed method, moving car in front of the castle is used as a 3D video and the words 'HOLOGRAM CAPTION GENERATOR' is used as a news ticker. From this simulation results confirmed the feasibility of the proposed method in fast generation of CGH patterns for holographic captions.

Computer Generated Holography with Intensity-Graded Patterns

PubMed Central

Conti, Rossella; Assayag, Osnath; de Sars, Vincent; Guillon, Marc; Emiliani, Valentina

2016-01-01

Computer Generated Holography achieves patterned illumination at the sample plane through phase modulation of the laser beam at the objective back aperture. This is obtained by using liquid crystal-based spatial light modulators (LC-SLMs), which modulate the spatial phase of the incident laser beam. A variety of algorithms is employed to calculate the phase modulation masks addressed to the LC-SLM. These algorithms range from simple gratings-and-lenses to generate multiple diffraction-limited spots, to iterative Fourier-transform algorithms capable of generating arbitrary illumination shapes perfectly tailored on the base of the target contour. Applications for holographic light patterning include multi-trap optical tweezers, patterned voltage imaging and optical control of neuronal excitation using uncaging or optogenetics. These past implementations of computer generated holography used binary input profile to generate binary light distribution at the sample plane. Here we demonstrate that using graded input sources, enables generating intensity graded light patterns and extend the range of application of holographic light illumination. At first, we use intensity-graded holograms to compensate for LC-SLM position dependent diffraction efficiency or sample fluorescence inhomogeneity. Finally we show that intensity-graded holography can be used to equalize photo evoked currents from cells expressing different levels of chanelrhodopsin2 (ChR2), one of the most commonly used optogenetics light gated channels, taking into account the non-linear dependence of channel opening on incident light. PMID:27799896

Disease relevant modifications of the methylome and transcriptome by particulate matter (PM2.5) from biomass combustion.

PubMed

Heßelbach, Katharina; Kim, Gwang-Jin; Flemming, Stephan; Häupl, Thomas; Bonin, Marc; Dornhof, Regina; Günther, Stefan; Merfort, Irmgard; Humar, Matjaz

2017-09-01

Exposure to particulate matter (PM) is recognized as a major health hazard, but molecular responses are still insufficiently described. We analyzed the epigenetic impact of ambient PM 2.5 from biomass combustion on the methylome of primary human bronchial epithelial BEAS-2B cells using the Illumina HumanMethylation450 BeadChip. The transcriptome was determined by the Affymetrix HG-U133 Plus 2.0 Array. PM 2.5 induced genome wide alterations of the DNA methylation pattern, including differentially methylated CpGs in the promoter region associated with CpG islands. Gene ontology analysis revealed that differentially methylated genes were significantly clustered in pathways associated with the extracellular matrix, cellular adhesion, function of GTPases, and responses to extracellular stimuli, or were involved in ion binding and shuttling. Differential methylations also affected tandem repeats. Additionally, 45 different miRNA CpG loci showed differential DNA methylation, most of them proximal to their promoter. These miRNAs are functionally relevant for lung cancer, inflammation, asthma, and other PM-associated diseases. Correlation of the methylome and transcriptome demonstrated a clear bias toward transcriptional activation by hypomethylation. Genes that exhibited both differential methylation and expression were functionally linked to cytokine and immune responses, cellular motility, angiogenesis, inflammation, wound healing, cell growth, differentiation and development, or responses to exogenous matter. Disease ontology of differentially methylated and expressed genes indicated their prominent role in lung cancer and their participation in dominant cancer related signaling pathways. Thus, in lung epithelial cells, PM 2.5 alters the methylome of genes and noncoding transcripts or elements that might be relevant for PM- and lung-associated diseases.

Disease relevant modifications of the methylome and transcriptome by particulate matter (PM2.5) from biomass combustion

PubMed Central

Heßelbach, Katharina; Kim, Gwang-Jin; Flemming, Stephan; Häupl, Thomas; Bonin, Marc; Dornhof, Regina; Günther, Stefan; Merfort, Irmgard; Humar, Matjaz

2017-01-01

ABSTRACT Exposure to particulate matter (PM) is recognized as a major health hazard, but molecular responses are still insufficiently described. We analyzed the epigenetic impact of ambient PM2.5 from biomass combustion on the methylome of primary human bronchial epithelial BEAS-2B cells using the Illumina HumanMethylation450 BeadChip. The transcriptome was determined by the Affymetrix HG-U133 Plus 2.0 Array. PM2.5 induced genome wide alterations of the DNA methylation pattern, including differentially methylated CpGs in the promoter region associated with CpG islands. Gene ontology analysis revealed that differentially methylated genes were significantly clustered in pathways associated with the extracellular matrix, cellular adhesion, function of GTPases, and responses to extracellular stimuli, or were involved in ion binding and shuttling. Differential methylations also affected tandem repeats. Additionally, 45 different miRNA CpG loci showed differential DNA methylation, most of them proximal to their promoter. These miRNAs are functionally relevant for lung cancer, inflammation, asthma, and other PM-associated diseases. Correlation of the methylome and transcriptome demonstrated a clear bias toward transcriptional activation by hypomethylation. Genes that exhibited both differential methylation and expression were functionally linked to cytokine and immune responses, cellular motility, angiogenesis, inflammation, wound healing, cell growth, differentiation and development, or responses to exogenous matter. Disease ontology of differentially methylated and expressed genes indicated their prominent role in lung cancer and their participation in dominant cancer related signaling pathways. Thus, in lung epithelial cells, PM2.5 alters the methylome of genes and noncoding transcripts or elements that might be relevant for PM- and lung-associated diseases. PMID:28742980

Molecular cloning, expression pattern, and 3D structural prediction of the cold inducible RNA-binding protein (CIRP) in Japanese flounder ( Paralichthys olivaceus)

NASA Astrophysics Data System (ADS)

Yang, Xiao; Gao, Jinning; Ma, Liman; Li, Zan; Wang, Wenji; Wang, Zhongkai; Yu, Haiyang; Qi, Jie; Wang, Xubo; Wang, Zhigang; Zhang, Quanqi

2015-02-01

Cold-inducible RNA-binding protein (CIRP) is a kind of RNA binding proteins that plays important roles in many physiological processes. The CIRP has been widely studied in mammals and amphibians since it was first cloned from mammals. On the contrary, there are little reports in teleosts. In this study, the Po CIRP gene of the Japanese flounder was cloned and sequenced. The genomic sequence consists of seven exons and six introns. The putative PoCIRP protein of flounder was 198 amino acid residues long containing the RNA recognition motif (RRM). Phylogenetic analysis showed that the flounder PoCIRP is highly conserved with other teleost CIRPs. The 5' flanking sequence was cloned by genome walking and many transcription factor binding sites were identified. There is a CpGs region located in promoter and exon I region and the methylation state is low. Quantitative real-time PCR analysis uncovered that Po CIRP gene was widely expressed in adult tissues with the highest expression level in the ovary. The mRNA of the Po CIRP was maternally deposited and the expression level of the gene was regulated up during the gastrula and neurula stages. In order to gain the information how the protein interacts with mRNA, we performed the modeling of the 3D structure of the flounder PoCIRP. The results showed a cleft existing the surface of the molecular. Taken together, the results indicate that the CIRP is a multifunctional molecular in teleosts and the findings about the structure provide valuable information for understanding the basis of this protein's function.

The effects of dietary betaine supplementation on fatty liver performance, serum parameters, histological changes, methylation status and the mRNA expression level of Spot14alpha in Landes goose fatty liver.

PubMed

Su, S Y; Dodson, M V; Li, X B; Li, Q F; Wang, H W; Xie, Z

2009-11-01

We evaluated the effects of betaine supplementation on liver weight, liver/body weight, serum parameters and morphological changes. Compared with the control and overfed groups, the geese that were fed the betaine diet showed increased liver weight and decreased abdominal adipose tissue weight compared with the overfeeding groups. Betaine treatment also significantly increased ChE, HDL, LDH and ALT levels (P<0.01 or P<0.05). Decreased macrovesicular steatosis and increased microvesicular steatosis were observed in the betaine-treated group, and the lipid was well-distributed in the betaine supplement group. The expression of S14alpha mRNA in the livers of the betaine-treated geese was higher than that in the control or the overfed geese. We performed sodium bisulfite sequencing of the individual alleles of this region (between +374 and -8 base pairs relative to the transcription start site), containing 33 CpG dinucleotides. In the overfed group expressing higher S14alpha transcripts, the average methylation at the 33 CpGs sites was 87.9%. This contrasted with 69.6% in the control group that showed lower expression of the S14alpha gene (P<0.01). However, no significant change in methylation in the transcription start site was found between the betaine-treated geese (82.6%) and the overfed geese (87.9%). These results indicate that the DNA methylation pattern in the S14alpha gene transcription start site may not be related to the expression of S14alpha transcript in response to betaine supplementation.

Broad DNA methylation changes of spermatogenesis, inflammation and immune response-related genes in a subgroup of sperm samples for assisted reproduction.

PubMed

Schütte, B; El Hajj, N; Kuhtz, J; Nanda, I; Gromoll, J; Hahn, T; Dittrich, M; Schorsch, M; Müller, T; Haaf, T

2013-11-01

Aberrant sperm DNA methylation patterns, mainly in imprinted genes, have been associated with male subfertility and oligospermia. Here, we performed a genome-wide methylation analysis in sperm samples representing a wide range of semen parameters. Sperm DNA samples of 38 males attending a fertility centre were analysed with Illumina HumanMethylation27 BeadChips, which quantify methylation of >27 000 CpG sites in cis-regulatory regions of almost 15 000 genes. In an unsupervised analysis of methylation of all analysed sites, the patient samples clustered into a major and a minor group. The major group clustered with samples from normozoospermic healthy volunteers and, thus, may more closely resemble the normal situation. When correlating the clusters with semen and clinical parameters, the sperm counts were significantly different between groups with the minor group exhibiting sperm counts in the low normal range. A linear model identified almost 3000 CpGs with significant methylation differences between groups. Functional analysis revealed a broad gain of methylation in spermatogenesis-related genes and a loss of methylation in inflammation- and immune response-related genes. Quantitative bisulfite pyrosequencing validated differential methylation in three of five significant candidate genes on the array. Collectively, we identified a subgroup of sperm samples for assisted reproduction with sperm counts in the low normal range and broad methylation changes (affecting approximately 10% of analysed CpG sites) in specific pathways, most importantly spermatogenesis-related genes. We propose that epigenetic analysis can supplement traditional semen parameters and has the potential to provide new insights into the aetiology of male subfertility. © 2013 American Society of Andrology and European Academy of Andrology.

Appropriateness of tumor marker request: a case of study

PubMed Central

Trevisiol, Chiara; Fabricio, Aline S. C.

2017-01-01

Appropriateness is crucial to provide efficient and high-quality health services at affordable costs. Laboratory medicine is a sector of special interest for the investigation of inappropriateness, due to the high rate of technological innovation and its pivotal role in many diseases and clinical settings. Some subjective aspects related to either the patient or physician seem to have a major role on inappropriateness rates. Given the psychological impact of cancer on both patients and physicians, tumor markers represent a case of study for appropriateness. The assessment of inappropriateness of laboratory tests has been focused mainly on ordering patterns. Appropriateness can barely be appraised by matching the requested test with the clinical problem because clinical information on the test requisition form is usually inadequate. Monitoring inappropriateness through individual clinical information may be feasible in inpatient (clinical data are available), while an indirect approach should be used for outpatients. To estimate inappropriateness in outpatients our group developed innovative models based on comparison between the actually ordered and expected requests of tumor marker, calculated according to recommendations of clinical practice guidelines (CPGs) applied to figures of cancer prevalence. The implementation of the model at national scale in Italy led to recognize a very high rate of overordering of tumor markers. The model was further focused by a dedicated algorithm to be adapted to different clinical conditions or organizational settings by applying performance indicators to cohort-wide structured information in electronic health records (EHRs). With this novel approach, we showed that inappropriateness is multifaceted even within the specific category of tumour markers. The model was effective in identifying both over- and underordering. Implementation of evidence based information and monitoring their impact on the clinical practice are parts of the same, multistage, process aimed at the progressive improvement of health care. PMID:28758100

Inferring chronological age from DNA methylation patterns of human teeth.

PubMed

Giuliani, Cristina; Cilli, Elisabetta; Bacalini, Maria Giulia; Pirazzini, Chiara; Sazzini, Marco; Gruppioni, Giorgio; Franceschi, Claudio; Garagnani, Paolo; Luiselli, Donata

2016-04-01

Current methods to determine chronological age from modern and ancient remains rely on both morphological and molecular approaches. However, low accuracy and the lack of standardized protocols make the development of alternative methods for the estimation of individual's age even more urgent for several research fields, such as biological anthropology, biodemography, forensics, evolutionary genetics, and ancient DNA studies. Therefore, the aim of this study is to identify genomic regions whose DNA methylation level correlates with age in modern teeth. We used MALDI-TOF mass spectrometry to analyze DNA methylation levels of specific CpGs located in the ELOVL2, FHL2, and PENK genes. We considered methylation data from cementum, dentin and pulp of 21 modern teeth (from 17 to 77 years old) to construct a mathematical model able to exploit DNA methylation values to predict age of the individuals. The median difference between the real age and that estimated using DNA methylation values is 1.20 years (SD = 1.9) if DNA is recovered from both cementum and pulp of the same modern teeth, 2.25 years (SD = 2.5) if DNA is recovered from dental pulp, 2.45 years (SD = 3.3) if DNA is extracted from cementum and 7.07 years (SD = 7.0) when DNA is recovered from dentin only. We propose for the first time the evaluation of DNA methylation at ELOVL2, FHL2, and PENK genes as a powerful tool to predict age in modern teeth for anthropological applications. Future studies are needed to apply this method also to historical and relatively ancient human teeth. © 2015 Wiley Periodicals, Inc.

Implementation of clinical practice guidelines on lifestyle interventions in Swedish primary healthcare - a two-year follow up.

PubMed

Kardakis, Therese; Jerdén, Lars; Nyström, Monica E; Weinehall, Lars; Johansson, Helene

2018-04-02

Implementation of interventions concerning prevention and health promotion in health care has faced particular challenges resulting in a low frequency and quality of these services. In November 2011, the Swedish National Board of Health and Welfare released national clinical practice guidelines to counteract patients' unhealthy lifestyle habits. Drawing on the results of a previous study as a point of departure, the aim of this two-year follow up was to assess the progress of work with lifestyle interventions in primary healthcare as well as the uptake and usage of the new guidelines on lifestyle interventions in clinical practice. Longitudinal study among health professionals with survey at baseline and 2 years later. Development over time and differences between professional groups were calculated with Pearson chi-square test. Eighteen percent of the physicians reported to use the clinical practice guidelines, compared to 58% of the nurses. Nurses were also more likely to consider them as a support in their work than physicians did. Over time, health professionals usage of methods to change patients' tobacco habits and hazardous use of alcohol had increased, and the nurses worked to a higher extent than before with all four lifestyles. Knowledge on methods for lifestyle change was generally high; however, there was room for improvement concerning methods on alcohol, unhealthy eating and counselling. Forty-one percent reported to possess thorough knowledge of counselling skills. Even if the uptake and usage of the CPGs on lifestyle interventions so far is low, the participants reported more frequent counselling on patients' lifestyle changes concerning use of tobacco and hazardous use of alcohol. However, these findings should be evaluated acknowledging the possibility of selection bias in favour of health promotion and lifestyle guidance, and the loss of one study site in the follow up. Furthermore, this study indicates important differences in physicians and nurses' attitudes to and use of the guidelines, where the nurses reported working to a higher extent with all four lifestyles compared to the first study. These findings suggest further investigations on the implementation process in clinical practice, and the physicians' uptake and use of the CPGs.

Effectiveness of implementation strategies in improving physician adherence to guideline recommendations in heart failure: a systematic review protocol.

PubMed

Van Spall, Harriette G C; Shanbhag, Deepti; Gabizon, Itzhak; Ibrahim, Quazi; Graham, Ian D; Harlos, Karen; Haynes, R Brian; Connolly, Stuart J

2016-03-31

The uptake of Clinical Practice Guideline (CPG) recommendations that improve outcomes in heart failure (HF) remains suboptimal. We will conduct a systematic review to identify implementation strategies that improve physician adherence to class I recommendations, those with clear evidence that benefits outweigh the risks. We will use American, Canadian and European HF guidelines as our reference. We will conduct a literature search in the databases of MEDLINE, EMBASE, HEALTHSTAR, CINAHL, Cochrane Library, Campbell Collaboration, Joanna Briggs Institute Evidence Based Practice, Centre for Reviews and Dissemination and Evidence Based Practice Centres. We will include prospective studies evaluating implementation interventions aimed at improving uptake of class I CPG recommendations in HF. We will extract data in duplicate. We will classify interventions according to their level of application (ie, provider, organisation, systems level) and common underlying characteristics (eg, education, decision-support, financial incentives) using the Cochrane Effective Practice and Organisation of Care Taxonomy. We will assess the impact of the intervention on adherence to the CPGs. Outcomes will include proportion of eligible patients who were: prescribed a CPG-recommended pharmacological treatment; referred for device consideration; provided self-care education at discharge; and provided left ventricular function assessment. We will include clinical outcomes such as hospitalisations, readmissions and mortality, if data is available. We will identify the common elements of successful and failing interventions, and examine the context in which they were applied, using the Process Redesign contextual framework. We will synthesise the results narratively and, if appropriate, will pool results for meta-analysis. In this review, we will assess the impact of implementation strategies and contextual factors on physician adherence to HF CPGs. We will explore why some interventions may succeed in one setting and fail in another. We will disseminate our findings through briefing reports, publications and presentations. CRD42015017155. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Trends in racial/ethnic and income disparities in foods and beverages consumed and purchased from stores among US households with children, 2000-2013.

PubMed

Ng, Shu Wen; Poti, Jennifer M; Popkin, Barry M

2016-09-01

It is unclear whether racial/ethnic and income differences in foods and beverages obtained from stores contribute to disparities in caloric intake over time. We sought to determine whether there are disparities in calories obtained from store-bought consumer packaged goods (CPGs), whether brands (name brands compared with private labels) matter, and if disparities have changed over time. We used NHANES individual dietary intake data among households with children along with the Nielsen Homescan data on CPG purchases among households with children. With NHANES, we compared survey-weighted energy intakes for 2003-2006 and 2009-2012 from store and nonstore sources by race/ethnicity [non-Hispanic whites (NHWs), non-Hispanic blacks (NHBs), and Hispanic Mexican-Americans) and income [≤185% federal poverty line (FPL), 186-400% FPL, and >400% FPL]. With the Nielsen data, we compared 2000-2013 trends in calories purchased from CPGs (obtained from stores) across brands by race/ethnicity (NHW, NHB, and Hispanic) and income. We conducted random-effect models to derive adjusted trends and differences in calories purchased (708,175 observations from 64,709 unique households) and tested whether trends were heterogeneous by race/ethnicity or income. Store-bought foods and beverages represented the largest component of dietary intake, with greater decreases in energy intakes in nonstore sources for foods and in store sources for beverages. Beverages from stores consistently decreased in all subpopulations. However, in adjusted models, reductions in CPG calories purchased in 2009-2012 were slower for NHB and low-income households than for NHW and high-income households, respectively. The decline in calories from name-brand food purchases was slower among NHB, Hispanic, and lowest-income households. NHW and high-income households had the highest absolute calories purchased in 2000. Across 2 large data sources, we found decreases in intake and purchases of beverages from stores across racial/ethnic and income groups. However, potentially beneficial reductions in calories purchased were more pronounced in some subgroups over others. © 2016 American Society for Nutrition.

Trends in racial/ethnic and income disparities in foods and beverages consumed and purchased from stores among US households with children, 2000–201312

PubMed Central

Poti, Jennifer M; Popkin, Barry M

2016-01-01

Background: It is unclear whether racial/ethnic and income differences in foods and beverages obtained from stores contribute to disparities in caloric intake over time. Objective: We sought to determine whether there are disparities in calories obtained from store-bought consumer packaged goods (CPGs), whether brands (name brands compared with private labels) matter, and if disparities have changed over time. Design: We used NHANES individual dietary intake data among households with children along with the Nielsen Homescan data on CPG purchases among households with children. With NHANES, we compared survey-weighted energy intakes for 2003–2006 and 2009–2012 from store and nonstore sources by race/ethnicity [non-Hispanic whites (NHWs), non-Hispanic blacks (NHBs), and Hispanic Mexican-Americans) and income [≤185% federal poverty line (FPL), 186–400% FPL, and >400% FPL]. With the Nielsen data, we compared 2000–2013 trends in calories purchased from CPGs (obtained from stores) across brands by race/ethnicity (NHW, NHB, and Hispanic) and income. We conducted random-effect models to derive adjusted trends and differences in calories purchased (708,175 observations from 64,709 unique households) and tested whether trends were heterogeneous by race/ethnicity or income. Results: Store-bought foods and beverages represented the largest component of dietary intake, with greater decreases in energy intakes in nonstore sources for foods and in store sources for beverages. Beverages from stores consistently decreased in all subpopulations. However, in adjusted models, reductions in CPG calories purchased in 2009–2012 were slower for NHB and low-income households than for NHW and high-income households, respectively. The decline in calories from name-brand food purchases was slower among NHB, Hispanic, and lowest-income households. NHW and high-income households had the highest absolute calories purchased in 2000. Conclusions: Across 2 large data sources, we found decreases in intake and purchases of beverages from stores across racial/ethnic and income groups. However, potentially beneficial reductions in calories purchased were more pronounced in some subgroups over others. PMID:27488233