Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status.

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Michele D Binder

2016-03-01

Full Text Available Multiple Sclerosis (MS is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients.

A geometric framework for evaluating rare variant tests of association.

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Liu, Keli; Fast, Shannon; Zawistowski, Matthew; Tintle, Nathan L

2013-05-01

The wave of next-generation sequencing data has arrived. However, many questions still remain about how to best analyze sequence data, particularly the contribution of rare genetic variants to human disease. Numerous statistical methods have been proposed to aggregate association signals across multiple rare variant sites in an effort to increase statistical power; however, the precise relation between the tests is often not well understood. We present a geometric representation for rare variant data in which rare allele counts in case and control samples are treated as vectors in Euclidean space. The geometric framework facilitates a rigorous classification of existing rare variant tests into two broad categories: tests for a difference in the lengths of the case and control vectors, and joint tests for a difference in either the lengths or angles of the two vectors. We demonstrate that genetic architecture of a trait, including the number and frequency of risk alleles, directly relates to the behavior of the length and joint tests. Hence, the geometric framework allows prediction of which tests will perform best under different disease models. Furthermore, the structure of the geometric framework immediately suggests additional classes and types of rare variant tests. We consider two general classes of tests which show robustness to noncausal and protective variants. The geometric framework introduces a novel and unique method to assess current rare variant methodology and provides guidelines for both applied and theoretical researchers. © 2013 Wiley Periodicals, Inc.

The Advantage of Discordance

DEFF Research Database (Denmark)

Dalton, Leslie W.; Gerds, Thomas A.

2017-01-01

Discordance among multiple assessments has been a reason to criticize a biomarker. But, if different assessments are all relevant, the meaning of discordance requires explanation. As an example, for 1085 breast cancers, a low (score 1), intermediate (score 2) or high nuclear grade (NG) (score 3) ...

Operational interpretations of quantum discord

International Nuclear Information System (INIS)

Cavalcanti, D.; Modi, K.; Aolita, L.; Boixo, S.; Piani, M.; Winter, A.

2011-01-01

Quantum discord quantifies nonclassical correlations beyond the standard classification of quantum states into entangled and unentangled. Although it has received considerable attention, it still lacks any precise interpretation in terms of some protocol in which quantum features are relevant. Here we give quantum discord its first information-theoretic operational meaning in terms of entanglement consumption in an extended quantum-state-merging protocol. We further relate the asymmetry of quantum discord with the performance imbalance in quantum state merging and dense coding.

Poisson Approximation-Based Score Test for Detecting Association of Rare Variants.

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Fang, Hongyan; Zhang, Hong; Yang, Yaning

2016-07-01

Genome-wide association study (GWAS) has achieved great success in identifying genetic variants, but the nature of GWAS has determined its inherent limitations. Under the common disease rare variants (CDRV) hypothesis, the traditional association analysis methods commonly used in GWAS for common variants do not have enough power for detecting rare variants with a limited sample size. As a solution to this problem, pooling rare variants by their functions provides an efficient way for identifying susceptible genes. Rare variant typically have low frequencies of minor alleles, and the distribution of the total number of minor alleles of the rare variants can be approximated by a Poisson distribution. Based on this fact, we propose a new test method, the Poisson Approximation-based Score Test (PAST), for association analysis of rare variants. Two testing methods, namely, ePAST and mPAST, are proposed based on different strategies of pooling rare variants. Simulation results and application to the CRESCENDO cohort data show that our methods are more powerful than the existing methods. © 2016 John Wiley & Sons Ltd/University College London.

Epidemiology of discordance between symptoms and signs of dry eye.

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Ong, Erin S; Felix, Elizabeth R; Levitt, Roy C; Feuer, William J; Sarantopoulos, Constantine D; Galor, Anat

2018-05-01

The frequent lack of association between dry eye (DE) symptoms and signs leads to challenges in diagnosing and assessing the disease. Participants underwent ocular surface examinations to evaluate signs of disease and completed questionnaires to assess ocular symptoms, psychological status and medication use. To assess nociceptive system integrity, quantitative sensory testing (QST), including vibratory and thermal threshold measures and temporal summation of pain were obtained at the forearm and forehead. Correlations between DE discordance score (degree of discrepancy between symptom severity and DE signs) and patient characteristics were determined. Higher discordance scores indicated more symptoms than signs. 326 patients participated (mean age: 62 years; SD: 10 years; 92% men). Age was negatively correlated with DE discordance score (Pearson r=-0.30, p<0.0005), while mental health indices were positively correlated. Chronic pain elsewhere in the body (ie, non-ocular pain conditions) and intensity ratings of prolonged aftersensations of pain evoked by noxious hot and cold stimuli were also significantly correlated with DE discordance score. Multiple linear regression demonstrated that post-traumatic stress disorder and non-ocular pain intensity were important predictors of DE discordance score, Dry Eye Questionnaire-5 and Ocular Surface Disease Index and that DE discordance was also sensitive to QST as well. The present study provides evidence that the degree of discordance between DE symptom report and measurable signs of ocular surface disease is associated with comorbidities related to clinical pain and to hyperalgesia as demonstrated with QST. Understanding the epidemiology of DE discordance can aid in interpreting the DE exam and individualising treatment. © 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.

Rare variant testing across methods and thresholds using the multi-kernel sequence kernel association test (MK-SKAT).

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Urrutia, Eugene; Lee, Seunggeun; Maity, Arnab; Zhao, Ni; Shen, Judong; Li, Yun; Wu, Michael C

Analysis of rare genetic variants has focused on region-based analysis wherein a subset of the variants within a genomic region is tested for association with a complex trait. Two important practical challenges have emerged. First, it is difficult to choose which test to use. Second, it is unclear which group of variants within a region should be tested. Both depend on the unknown true state of nature. Therefore, we develop the Multi-Kernel SKAT (MK-SKAT) which tests across a range of rare variant tests and groupings. Specifically, we demonstrate that several popular rare variant tests are special cases of the sequence kernel association test which compares pair-wise similarity in trait value to similarity in the rare variant genotypes between subjects as measured through a kernel function. Choosing a particular test is equivalent to choosing a kernel. Similarly, choosing which group of variants to test also reduces to choosing a kernel. Thus, MK-SKAT uses perturbation to test across a range of kernels. Simulations and real data analyses show that our framework controls type I error while maintaining high power across settings: MK-SKAT loses power when compared to the kernel for a particular scenario but has much greater power than poor choices.

Fetoscopic laser coagulation of intertwin anastomoses reduces discordant placental autophagic activities in discordant twin growth

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Yao-Lung Chang

2015-10-01

Conclusion: The discordance of placenta autophagic activity in the monochorionic twin with sIUGR was reduced after laser coagulation of the intertwin anastomoses, which may result from the effect of correction of the discordant intertwin placenta perfusion.

Influence of Seasonality and Circulating Cytokines on Serial QuantiFERON Discordances

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Marsha L. Griffin

2018-01-01

Full Text Available Objectives. An 18-month prospective study serially tested healthcare workers (HCWs for tuberculosis infection (TBI and reported discordant QuantiFERON Gold In-Tube® (QFT results in some participants. The purpose of the current study was to investigate whether the interferon-gamma (IFN-γ measured by QFT in discordant individuals could be influenced by other circulating cytokines that vary seasonally at the time of phlebotomy. Methods. The CDC funded TBESC Task Order 18 (TO18 project to assess the use of Interferon Gamma Release Assays (IGRAs, T-SPOT.TB® and QFT, compared to the tuberculin skin test (TST for the serial testing of TBI in HCW at 4 US sites. Unstimulated plasma from 9 discordant TO18 participants at 4 different time points from the Houston site was multiplexed to determine the association between circulating cytokines and antigen stimulated IFN-γ levels. Results. IL-12, IL-1β, IL-3, GCSF, and IL-7 were associated with the amount of IFN-γ measured in response to antigen stimulation. In addition to these cytokines, a significant relationship was found between a positive QFT result and the spring season. Conclusions. Allergens during the spring season can result in the upregulation of IL-1β and IL-3, and this upregulation was observed with the amount of IFN-γ measured in discordant results.

Birth weight discordance and perinatal mortality among triplets

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Egić Amira

2005-01-01

growth abnormality and discordance, which increase foetal surveillance, through the use of biophysical profiles, non-stress tests, and Doppler velocimetry, thus assessing foetal well-being and the appropriate moment for obstetric intervention.

Computing quantum discord is NP-complete

International Nuclear Information System (INIS)

Huang, Yichen

2014-01-01

We study the computational complexity of quantum discord (a measure of quantum correlation beyond entanglement), and prove that computing quantum discord is NP-complete. Therefore, quantum discord is computationally intractable: the running time of any algorithm for computing quantum discord is believed to grow exponentially with the dimension of the Hilbert space so that computing quantum discord in a quantum system of moderate size is not possible in practice. As by-products, some entanglement measures (namely entanglement cost, entanglement of formation, relative entropy of entanglement, squashed entanglement, classical squashed entanglement, conditional entanglement of mutual information, and broadcast regularization of mutual information) and constrained Holevo capacity are NP-hard/NP-complete to compute. These complexity-theoretic results are directly applicable in common randomness distillation, quantum state merging, entanglement distillation, superdense coding, and quantum teleportation; they may offer significant insights into quantum information processing. Moreover, we prove the NP-completeness of two typical problems: linear optimization over classical states and detecting classical states in a convex set, providing evidence that working with classical states is generically computationally intractable. (paper)

Collapse–revival of quantum discord and entanglement

International Nuclear Information System (INIS)

Yan, Xue-Qun; Zhang, Bo-Ying

2014-01-01

In this paper the correlations dynamics of two atoms in the case of a micromaser-type system is investigated. Our results predict certain quasi-periodic collapse and revival phenomena for quantum discord and entanglement when the field is in Fock state and the two atoms are initially in maximally mixed state, which is a special separable state. Our calculations also show that the oscillations of the time evolution of both quantum discord and entanglement are almost in phase and they both have similar evolution behavior in some time range. The fact reveals the consistency of quantum discord and entanglement in some dynamical aspects. - Highlights: • The correlations dynamics of two atoms in the case of a micromaser-type system is investigated. • A quasi-periodic collapse and revival phenomenon for quantum discord and entanglement is reported. • A phenomenon of correlations revivals different from that of non-Markovian dynamics is revealed. • The oscillations of time evolution of both quantum discord and entanglement are almost in phase in our system. • Quantum discord and entanglement have similar evolution behavior in some time range

Revealing Tripartite Quantum Discord with Tripartite Information Diagram

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Wei-Ting Lee

2017-11-01

Full Text Available A new measure based on the tripartite information diagram is proposed for identifying quantum discord in tripartite systems. The proposed measure generalizes the mutual information underlying discord from bipartite to tripartite systems, and utilizes both one-particle and two-particle projective measurements to reveal the characteristics of the tripartite quantum discord. The feasibility of the proposed measure is demonstrated by evaluating the tripartite quantum discord for systems with states close to Greenberger–Horne–Zeilinger, W, and biseparable states. In addition, the connections between tripartite quantum discord and two other quantum correlations—namely genuine tripartite entanglement and genuine tripartite Einstein–Podolsky–Rosen steering—are briefly discussed. The present study considers the case of quantum discord in tripartite systems. However, the proposed framework can be readily extended to general N-partite systems.

Discordant results between biochemical and molecular transthyretin

Indian Academy of Sciences (India)

Discordant results between biochemical and molecular transthyretin assays: lessons learned from a unique testing algorithm at the Mayo Clinic. Honey V. Reddi Brittany C. Thomas Kurt S. Willkomm Matthew J. Ferber Kandelaria M. Rumilla Kimiyo M. Raymond John F. O'Brien W. Edward Highsmith. Research Note Volume ...

Global quantum discord and matrix product density operators

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Huang, Hai-Lin; Cheng, Hong-Guang; Guo, Xiao; Zhang, Duo; Wu, Yuyin; Xu, Jian; Sun, Zhao-Yu

2018-06-01

In a previous study, we have proposed a procedure to study global quantum discord in 1D chains whose ground states are described by matrix product states [Z.-Y. Sun et al., Ann. Phys. 359, 115 (2015)]. In this paper, we show that with a very simple generalization, the procedure can be used to investigate quantum mixed states described by matrix product density operators, such as quantum chains at finite temperatures and 1D subchains in high-dimensional lattices. As an example, we study the global discord in the ground state of a 2D transverse-field Ising lattice, and pay our attention to the scaling behavior of global discord in 1D sub-chains of the lattice. We find that, for any strength of the magnetic field, global discord always shows a linear scaling behavior as the increase of the length of the sub-chains. In addition, global discord and the so-called "discord density" can be used to indicate the quantum phase transition in the model. Furthermore, based upon our numerical results, we make some reliable predictions about the scaling of global discord defined on the n × n sub-squares in the lattice.

Discordant Dry Eye Disease (An American Ophthalmological Society Thesis)

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Shtein, Roni M.; Harper, Daniel E.; Pallazola, Vincent; Harte, Steven E.; Hussain, Munira; Sugar, Alan; Williams, David A.; Clauw, Daniel J.

2016-01-01

Purpose To improve understanding of dry eye disease and highlight a subgroup of patients who have a component of central sensitization and neuropathic pain contributing to their condition. Methods Prospective, cross-sectional, IRB-approved study comparing isolated dry eye disease (n=48) to fibromyalgia (positive control; n=23) and healthy (negative control; n=26) individuals with ocular surface examination, corneal confocal microscopy, quantitative sensory testing, and self-reported ocular symptoms and systemic associations. A subset of patients also underwent skin biopsy and/or brain neuroimaging. Dry eye patients were split into concordant (ie, those with dry eyes on examination) and discordant (ie, those with dry eye symptoms but normal examination) subgroups for further analysis. We hypothesized that on the systemic measures included, concordant patients would resemble healthy controls, whereas discordant patients would show evidence of centralized mechanisms similar to fibromyalgia. Results Schirmer test and Ocular Surface Disease Index (OSDI) scores indicated significant decreases in tear production (Schirmer: healthy, 18.5±8.2 mm; dry, 11.2±5.4 mm; fibromyalgia, 14.4±7.5; Pdry eye symptoms (OSDI: healthy, 1.9±3.0; dry, 20.3±17.7; fibromyalgia, 20.3±17.1; Pdry eye and fibromyalgia patients, compared to controls. The discordant subgroup had decreased corneal nerve density and decreased visual quality-of-life scores, similar to patients with fibromyalgia. Concordant patients were more similar to healthy controls on these measures. Conclusions Individuals with discordant dry eye may have a central pathophysiologic mechanism leading to their eye pain symptoms, which could be an important factor to consider in treatment of chronic idiopathic dry eye. PMID:28050051

Discordant Dry Eye Disease (An American Ophthalmological Society Thesis).

Science.gov (United States)

Shtein, Roni M; Harper, Daniel E; Pallazola, Vincent; Harte, Steven E; Hussain, Munira; Sugar, Alan; Williams, David A; Clauw, Daniel J

2016-08-01

To improve understanding of dry eye disease and highlight a subgroup of patients who have a component of central sensitization and neuropathic pain contributing to their condition. Prospective, cross-sectional, IRB-approved study comparing isolated dry eye disease (n=48) to fibromyalgia (positive control; n=23) and healthy (negative control; n=26) individuals with ocular surface examination, corneal confocal microscopy, quantitative sensory testing, and self-reported ocular symptoms and systemic associations. A subset of patients also underwent skin biopsy and/or brain neuroimaging. Dry eye patients were split into concordant (ie, those with dry eyes on examination) and discordant (ie, those with dry eye symptoms but normal examination) subgroups for further analysis. We hypothesized that on the systemic measures included, concordant patients would resemble healthy controls, whereas discordant patients would show evidence of centralized mechanisms similar to fibromyalgia. Schirmer test and Ocular Surface Disease Index (OSDI) scores indicated significant decreases in tear production (Schirmer: healthy, 18.5±8.2 mm; dry, 11.2±5.4 mm; fibromyalgia, 14.4±7.5; P dry eye symptoms (OSDI: healthy, 1.9±3.0; dry, 20.3±17.7; fibromyalgia, 20.3±17.1; P dry eye and fibromyalgia patients, compared to controls. The discordant subgroup had decreased corneal nerve density and decreased visual quality-of-life scores, similar to patients with fibromyalgia. Concordant patients were more similar to healthy controls on these measures. Individuals with discordant dry eye may have a central pathophysiologic mechanism leading to their eye pain symptoms, which could be an important factor to consider in treatment of chronic idiopathic dry eye.

Global quantum discord in multipartite systems

Energy Technology Data Exchange (ETDEWEB)

Rulli, C. C.; Sarandy, M. S. [Instituto de Fisica, Universidade Federal Fluminense, Av. Gal. Milton Tavares de Souza s/n, Gragoata, 24210-346 Niteroi, RJ (Brazil)

2011-10-15

We propose a global measure for quantum correlations in multipartite systems, which is obtained by suitably recasting the quantum discord in terms of relative entropy and local von Neumann measurements. The measure is symmetric with respect to subsystem exchange and is shown to be nonnegative for an arbitrary state. As an illustration, we consider tripartite correlations in the Werner-GHZ (Greenberger-Horne-Zeilinger) state and multipartite correlations at quantum criticality. In particular, in contrast with the pairwise quantum discord, we show that the global quantum discord is able to characterize the infinite-order quantum phase transition in the Ashkin-Teller spin chain.

Quantum discord for two-qubit X states

International Nuclear Information System (INIS)

Ali, Mazhar; Rau, A. R. P.; Alber, G.

2010-01-01

Quantum discord, a kind of quantum correlation, is defined as the difference between quantum mutual information and classical correlation in a bipartite system. In general, this correlation is different from entanglement, and quantum discord may be nonzero even for certain separable states. Even in the simple case of bipartite quantum systems, this different kind of quantum correlation has interesting and significant applications in quantum information processing. So far, quantum discord has been calculated explicitly only for a rather limited set of two-qubit quantum states and expressions for more general quantum states are not known. In this article, we derive explicit expressions for quantum discord for a larger class of two-qubit states, namely, a seven-parameter family of so called X states that have been of interest in a variety of contexts in the field. We also study the relation between quantum discord, classical correlation, and entanglement for a number of two-qubit states to demonstrate that they are independent measures of correlation with no simple relative ordering between them.

Variants of PLCXD3 are not associated with variant or sporadic Creutzfeldt-Jakob disease in a large international study.

Science.gov (United States)

Balendra, Rubika; Uphill, James; Collinson, Claire; Druyeh, Ronald; Adamson, Gary; Hummerich, Holger; Zerr, Inga; Gambetti, Pierluigi; Collinge, John; Mead, Simon

2016-04-07

Human prion diseases are relentlessly progressive neurodegenerative disorders which include sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD). Aside from variants of the prion protein gene (PRNP) replicated association at genome-wide levels of significance has proven elusive. A recent association study identified variants in or near to the PLCXD3 gene locus as strong disease risk factors in multiple human prion diseases. This study claimed the first non-PRNP locus to be highly significantly associated with prion disease in genomic studies. A sub-study of a genome-wide association study with imputation aiming to replicate the finding at PLCXD3 including 129 vCJD and 2500 sCJD samples. Whole exome sequencing to identify rare coding variants of PLCXD3. Imputation of relevant polymorphisms was accurate based on wet genotyping of a sample. We found no supportive evidence that PLCXD3 variants are associated with disease. The marked discordance in vCJD genotype frequencies between studies, despite extensive overlap in vCJD cases, and the finding of Hardy-Weinberg disequilibrium in the original study, suggests possible reasons for the discrepancies between studies.

Sexual Orientation Discordance and Young Adult Mental Health.

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Lourie, Michael A; Needham, Belinda L

2017-05-01

During the course of sexual development, many people experience dissonance between dimensions of sexual orientation, including attraction, behavior, and identity. This study assesses the relationship between sexual orientation discordance and mental health. Data were obtained from the National Longitudinal Study of Adolescent to Adult Health (n = 8,915; female = 54.62 %; non-Hispanic black = 18.83 %, Hispanic = 14.91 %, other race (non-white) = 10.79 %). Multivariable linear regression evaluated the correlation between sexual orientation discordance and perceived stress and depressive symptomatology. Models were stratified by sex and sexual identity. Among self-identified heterosexual females and mostly heterosexual males, sexual orientation discordance predicted significantly increased depressive symptomatology. No other subpopulation demonstrated a significant correlation between sexual orientation discordance and depressive symptomatology or perceived stress. The association between sexual orientation discordance and depressive symptomatology suggests a link between sexuality, self-concept, and mental health.

Revival and robustness of Bures distance discord under decoherence channels

International Nuclear Information System (INIS)

Shi, Jia-dong; Wang, Dong; Ma, Yang-cheng; Ye, Liu

2016-01-01

In this paper, we demonstrate the revival and robustness of Bures distance discord in comparison with entanglement under local decoherent evolutions. The results show that in depolarizing channel Bures distance discord revives after a dark point of time, while entanglement will damp into death without revival. In addition, in hybrid channel the declining initial condition can enable Bures distance discord to decay more smoothly within a limited time, but speed up the death of entanglement. In this sense, Bures distance discord is typically more robust against decoherence than entanglement. Furthermore, we also provide a geometric interpretation concerning these phenomena. - Highlights: • Bures distance discord is more robust against decoherence than entanglement. • Bures distance discord revives after a dark point of time, while entanglement damps to death. • The initial condition enables Bures distance discord to damp smoothly, but it speeds up the death of entanglement. • A geometric interpretation concerning these phenomena has been provided.

Refining discordant gene trees.

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Górecki, Pawel; Eulenstein, Oliver

2014-01-01

Evolutionary studies are complicated by discordance between gene trees and the species tree in which they evolved. Dealing with discordant trees often relies on comparison costs between gene and species trees, including the well-established Robinson-Foulds, gene duplication, and deep coalescence costs. While these costs have provided credible results for binary rooted gene trees, corresponding cost definitions for non-binary unrooted gene trees, which are frequently occurring in practice, are challenged by biological realism. We propose a natural extension of the well-established costs for comparing unrooted and non-binary gene trees with rooted binary species trees using a binary refinement model. For the duplication cost we describe an efficient algorithm that is based on a linear time reduction and also computes an optimal rooted binary refinement of the given gene tree. Finally, we show that similar reductions lead to solutions for computing the deep coalescence and the Robinson-Foulds costs. Our binary refinement of Robinson-Foulds, gene duplication, and deep coalescence costs for unrooted and non-binary gene trees together with the linear time reductions provided here for computing these costs significantly extends the range of trees that can be incorporated into approaches dealing with discordance.

Visual Bias Predicts Gait Adaptability in Novel Sensory Discordant Conditions

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Brady, Rachel A.; Batson, Crystal D.; Peters, Brian T.; Mulavara, Ajitkumar P.; Bloomberg, Jacob J.

2010-01-01

We designed a gait training study that presented combinations of visual flow and support-surface manipulations to investigate the response of healthy adults to novel discordant sensorimotor conditions. We aimed to determine whether a relationship existed between subjects visual dependence and their postural stability and cognitive performance in a new discordant environment presented at the conclusion of training (Transfer Test). Our training system comprised a treadmill placed on a motion base facing a virtual visual scene that provided a variety of sensory challenges. Ten healthy adults completed 3 training sessions during which they walked on a treadmill at 1.1 m/s while receiving discordant support-surface and visual manipulations. At the first visit, in an analysis of normalized torso translation measured in a scene-movement-only condition, 3 of 10 subjects were classified as visually dependent. During the Transfer Test, all participants received a 2-minute novel exposure. In a combined measure of stride frequency and reaction time, the non-visually dependent subjects showed improved adaptation on the Transfer Test compared to their visually dependent counterparts. This finding suggests that individual differences in the ability to adapt to new sensorimotor conditions may be explained by individuals innate sensory biases. An accurate preflight assessment of crewmembers biases for visual dependence could be used to predict their propensities to adapt to novel sensory conditions. It may also facilitate the development of customized training regimens that could expedite adaptation to alternate gravitational environments.

Detection of verbal discordances during sleep.

Science.gov (United States)

Perrin, Fabien; Bastuji, Hélène; Garcia-Larrea, Luis

2002-07-19

We used an electrophysiological marker of linguistic discordance, the N400 wave, to investigate how linguistic and pseudo-linguistic stimuli are categorised during sleep as compared to waking. During wakefulness, signs of discordance detection were, as expected, greater for pseudo-words than for real but semantically incongruous words, relative to congruous words. In sleep stage 2 all signs of hierarchic process of discordance disappeared. A new hierarchic process reappeared in paradoxical sleep, which differed from that of waking, responses to pseudo-words being similar to those to congruous words. Linguistic absurdity appears to be accepted in a different manner during paradoxical sleep than during waking, and this might explain why absurd contents are so naturally incorporated into otherwise plausible dream stories.

Cognitive function in unaffected twins discordant for affective disorder

DEFF Research Database (Denmark)

Christensen, Maj Vinberg; Kyvik, Kirsten Ohm; Kessing, Lars Vedel

2006-01-01

. Cognitive performance of 203 High-Risk and Low-Risk twins was compared. RESULTS: Healthy twins discordant for unipolar disorder showed lower performance on almost all measures of cognitive function: selective and sustained attention, executive function, language processing and working and declarative memory...... impairment found seemed to be related to genetic liability, as the MZ High-Risk twins showed significant impairment on selective and sustained attention, executive function, language processing and working and declarative memory, whereas the DZ High-Risk twins presented with significantly lower scores only......, and also after adjustment for demographic variables, subclinical symptoms and minor psychopathology. Healthy twins discordant for bipolar disorder showed lower performance on tests measuring episodic and working memory, also after adjustment for the above-mentioned covariables. The discrete cognitive...

Geometric picture of quantum discord for two-qubit quantum states

International Nuclear Information System (INIS)

Shi Mingjun; Jiang Fengjian; Sun Chunxiao; Du Jiangfeng

2011-01-01

Among various definitions of quantum correlations, quantum discord has attracted considerable attention. To find an analytical expression for quantum discord is an intractable task. Exact results are known only for very special states, namely two-qubit X-shaped states. We present in this paper a geometric viewpoint, from which two-qubit quantum discord can be described clearly. The known results on X state discord are restated in the directly perceivable geometric language. As a consequence, the dynamics of classical correlations and quantum discord for an X state in the presence of decoherence is endowed with geometric interpretation. More importantly, we extend the geometric method to the case of more general states, for which numerical as well as analytical results on quantum discord have not yet been obtained. Based on the support of numerical computations, some conjectures are proposed to help us establish the geometric picture. We find that the geometric picture for these states has an intimate relationship with that for X states. Thereby, in some cases, analytical expressions for classical correlations and quantum discord can be obtained.

Cough Aerosol Cultures of Mycobacterium tuberculosis: Insights on TST / IGRA Discordance and Transmission Dynamics.

Directory of Open Access Journals (Sweden)

Edward C Jones-López

Full Text Available The diagnosis of latent tuberculosis (TB infection (LTBI is complicated by the absence of a gold standard. Discordance between tuberculin skin tests (TST and interferon gamma release assays (IGRA occurs in 10-20% of individuals, but the underlying mechanisms are poorly understood.We analyzed data from a prospective household contact study that included cough aerosol culture results from index cases, environmental and contact factors. We assessed contacts for LTBI using TST and IGRA at baseline and six weeks. We examined TST/IGRA discordance in qualitative and quantitative analyses, and used multivariable logistic regression analysis with generalized estimating equations to analyze predictors of discordance.We included 96 TB patients and 384 contacts. Discordance decreased from 15% at baseline to 8% by six weeks. In adjusted analyses, discordance was related to less crowding (p = 0.004, non-cavitary disease (OR 1.41, 95% CI: 1.02-1.96; p = 0.03, and marginally with BCG vaccination in contacts (OR 1.40, 95% CI: 0.99-1.98, p = 0.06.We observed significant individual variability and temporal dynamism in TST and IGRA results in household contacts of pulmonary TB cases. Discordance was associated with a less intense infectious exposure, and marginally associated with a BCG-mediated delay in IGRA conversion. Cough aerosols provide an additional dimension to the assessment of infectiousness and risk of infection in contacts.

The characteristics of transferrin variants by carbohydrate-deficient transferrin tests using capillary zone electrophoresis.

Science.gov (United States)

Yoo, Gilsung; Kim, Juwon; Yoon, Kap Joon; Lee, Jong-Han

2018-04-17

Transferrin is the major plasma transport protein for iron. We aimed to investigate the characteristics of transferrin variant by carbohydrate-deficient transferrin (CDT) test using capillary zone electrophoresis. We retrospectively analyzed the CDT tests of 2449 patients from March 2009 to May 2017 at a tertiary hospital in Korea. CDT was quantified using a Capillarys 2 system (Sebia, Lisses, France) by capillary zone electrophoresis. The characteristics of variant transferrin patterns using electropherogram of CDT tests were analyzed. Seventy-seven (3.1%) patients were classified as variant transferrin. Mean age of these patients was 51.8 years, and the male-to-female ratio was 3.5:1. The most common variants were the BC variants (n = 37), followed by the CD variants (n = 27), unclear patterns (n = 7), BD variants (n = 3), CC variants (n = 2), misclassification (n = 1). In the variant Tf group, the most common disease was alcoholic liver cirrhosis (n = 22, 28.6%), followed by the toxic effects of substances (n = 17, 22.1%), and mental and behavioral disorders attributable to alcohol (n = 11, 14.3%). Nonvariant group showed a predominance of the toxic substance effects (n = 880, 37.1%), a personal history of suicide attempts (n = 634, 26.7%), and mental and behavioral disorders due to alcohol (n = 336, 14.2%). We analyzed the basic characteristics of variant transferrin by CDT tests using capillary zone electrophoresis. The prevalence of variant transferrin was 3.1% of the study subjects. Male patients, alcohol abusers, and liver cirrhosis patients predominated in the variant transferrin population. Further prospective studies are warranted to elucidate variant transferrin in clinical practice. © 2018 Wiley Periodicals, Inc.

Discordance

Science.gov (United States)

Villa, I. M.; Hanchar, J. M.

2013-12-01

Half a century ago, discordant U-Pb ages of metamorphic zircon were viewed as Pb loss by diffusion. Various diffusionist schools of thought debated vigorously whether diffusion was episodic or continuous [1], but nobody questioned the reality of diffusive Pb loss. Only imaging by cathodoluminescence (CL) [2] and back-scattered electrons (BSE) [3] brought a paradigm change in U-Pb geochronology. In situ dating shows routinely accretion of young zircon rims onto older cores that never display Pb diffusion gradients across the interface. Other minerals (monazite, xenotime, etc.) show the same pattern: irregular patches of uniform age separated by sharp age gradients coinciding with petrologic boundaries. As U-Pb discordance is caused by diachronous, heterochemical mineral generations, zircon and monazite closure temperatures, and strict diffusionism, are irrelevant [4]. Knowing what to pay attention to, analytical protocols for U-Pb dating include both of the following: (i) CL/BSE characterization of phase mixtures; (ii) mass spectrometric analysis including U/Th ratios (and ideally trace element fingerprinting on the same fraction [5]). It is clear that the petrologic context is just as essential as mass spectrometry for accurate geochronology. The K-Ar community rarely uses imaging, and the tight context between microstructures, mineral chemistry, petrology and geochronology is missed. Yet the data would be clear if one looked for it. CL and/or BSE imaging and X-ray mapping of K-feldspar and micas is finding ubiquitous evidence of discrete patches of juxtaposed mineral generations. The Ca/Cl/K ratios in 39Ar-40Ar dating fulfill the same role as U/Th ratios in U-Pb dating for fingerprinting successive heterochemical mineral generations. Any linear correlation in a common-denominator three-isotope correlation diagram is certain evidence of binary mixing between heterochemical end-members. A correlation in a Ca/K vs Ar/K diagram requires two minerals having different

Quantum discord dynamics of two qubits in single-mode cavities

International Nuclear Information System (INIS)

Wang Chen; Chen Qing-Hu

2013-01-01

The dynamics of quantum discord for two identical qubits in two independent single-mode cavities and a common single-mode cavity are discussed. For the initial Bell state with correlated spins, while the entanglement sudden death can occur, the quantum discord vanishes only at discrete moments in the independent cavities and never vanishes in the common cavity. Interestingly, quantum discord and entanglement show opposite behavior in the common cavity, unlike in the independent cavities. For the initial Bell state with anti-correlated spins, quantum discord and entanglement behave in the same way for both independent cavities and a common cavity. It is found that the detunings always stabilize the quantum discord. (general)

HIV discordant couples: What is new? | Kongnyuy | Clinics in Mother ...

African Journals Online (AJOL)

We reviewed the existing literature on the HIV discordant couples: determinants of seroconversion, reproductive options, ethical issues and future perspectives. About 10% to 20% of couples in Sub-Saharan Africa are HIV discordant. Factors influencing the risk of seroconversion in HIV discordant couples include the ...

Steady state quantum discord for circularly accelerated atoms

Energy Technology Data Exchange (ETDEWEB)

Hu, Jiawei, E-mail: hujiawei@nbu.edu.cn [Center for Nonlinear Science and Department of Physics, Ningbo University, Ningbo, Zhejiang 315211 (China); Yu, Hongwei, E-mail: hwyu@hunnu.edu.cn [Center for Nonlinear Science and Department of Physics, Ningbo University, Ningbo, Zhejiang 315211 (China); Synergetic Innovation Center for Quantum Effects and Applications, Hunan Normal University, Changsha, Hunan 410081 (China)

2015-12-15

We study, in the framework of open quantum systems, the dynamics of quantum entanglement and quantum discord of two mutually independent circularly accelerated two-level atoms in interaction with a bath of fluctuating massless scalar fields in the Minkowski vacuum. We assume that the two atoms rotate synchronically with their separation perpendicular to the rotating plane. The time evolution of the quantum entanglement and quantum discord of the two-atom system is investigated. For a maximally entangled initial state, the entanglement measured by concurrence diminishes to zero within a finite time, while the quantum discord can either decrease monotonically to an asymptotic value or diminish to zero at first and then followed by a revival depending on whether the initial state is antisymmetric or symmetric. When both of the two atoms are initially excited, the generation of quantum entanglement shows a delayed feature, while quantum discord is created immediately. Remarkably, the quantum discord for such a circularly accelerated two-atom system takes a nonvanishing value in the steady state, and this is distinct from what happens in both the linear acceleration case and the case of static atoms immersed in a thermal bath.

Relating quantum discord with the quantum dense coding capacity

Energy Technology Data Exchange (ETDEWEB)

Wang, Xin; Qiu, Liang, E-mail: lqiu@cumt.edu.cn; Li, Song; Zhang, Chi [China University of Mining and Technology, School of Sciences (China); Ye, Bin [China University of Mining and Technology, School of Information and Electrical Engineering (China)

2015-01-15

We establish the relations between quantum discord and the quantum dense coding capacity in (n + 1)-particle quantum states. A necessary condition for the vanishing discord monogamy score is given. We also find that the loss of quantum dense coding capacity due to decoherence is bounded below by the sum of quantum discord. When these results are restricted to three-particle quantum states, some complementarity relations are obtained.

Relating quantum discord with the quantum dense coding capacity

International Nuclear Information System (INIS)

Wang, Xin; Qiu, Liang; Li, Song; Zhang, Chi; Ye, Bin

2015-01-01

We establish the relations between quantum discord and the quantum dense coding capacity in (n + 1)-particle quantum states. A necessary condition for the vanishing discord monogamy score is given. We also find that the loss of quantum dense coding capacity due to decoherence is bounded below by the sum of quantum discord. When these results are restricted to three-particle quantum states, some complementarity relations are obtained

Incidental copy-number variants identified by routine genome testing in a clinical population

Science.gov (United States)

Boone, Philip M.; Soens, Zachry T.; Campbell, Ian M.; Stankiewicz, Pawel; Cheung, Sau Wai; Patel, Ankita; Beaudet, Arthur L.; Plon, Sharon E.; Shaw, Chad A.; McGuire, Amy L.; Lupski, James R.

2013-01-01

Purpose Mutational load of susceptibility variants has not been studied on a genomic scale in a clinical population, nor has the potential to identify these mutations as incidental findings during clinical testing been systematically ascertained. Methods Array comparative genomic hybridization, a method for genome-wide detection of DNA copy-number variants, was performed clinically on DNA from 9,005 individuals. Copy-number variants encompassing or disrupting single genes were identified and analyzed for their potential to confer predisposition to dominant, adult-onset disease. Multigene copy-number variants affecting dominant, adult-onset cancer syndrome genes were also assessed. Results In our cohort, 83 single-gene copy-number variants affected 40 unique genes associated with dominant, adult-onset disorders and unrelated to the patients’ referring diagnoses (i.e., incidental) were found. Fourteen of these copy-number variants are likely disease-predisposing, 25 are likely benign, and 44 are of unknown clinical consequence. When incidental copy-number variants spanning up to 20 genes were considered, 27 copy-number variants affected 17 unique genes associated with dominant, adult-onset cancer predisposition. Conclusion Copy-number variants potentially conferring susceptibility to adult-onset disease can be identified as incidental findings during routine genome-wide testing. Some of these mutations may be medically actionable, enabling disease surveillance or prevention; however, most incidentally observed single-gene copy-number variants are currently of unclear significance to the patient. PMID:22878507

Epigenetic signature of birth weight discordance in adult twins

DEFF Research Database (Denmark)

Tan, Qihua; Nielsen, Morten Frost Munk; Heijmans, Bastiaan T

2014-01-01

between birth weight and adult life health while controlling for not only genetics but also postnatal rearing environment. We performed an epigenome-wide profiling on blood samples from 150 pairs of adult monozygotic twins discordant for birth weight to look for molecular evidence of epigenetic signatures...... profiling did not reveal epigenetic signatures of birth weight discordance although some sites displayed age-dependent intra-pair differential methylation in the extremely discordant twin pairs....

Operational meaning of discord in terms of teleportation fidelity

Science.gov (United States)

Adhikari, Satyabrata; Banerjee, Subhashish

2012-12-01

Quantum discord is a prominent measure of quantum correlations, playing an important role in expanding its horizon beyond entanglement. Here we provide an operational meaning of (geometric) discord, which quantifies the amount of nonclassical correlations of an arbitrary quantum system based on its minimal distance from the set of classical states, in terms of teleportation fidelity for general two-qubit and (d⊗d)-dimensional isotropic and Werner states. A critical value of the discord is found beyond which the two-qubit state must violate Bell's inequality. This is illustrated by an open-system model of a dissipative two-qubit state. For the (d⊗d)-dimensional states the lower bound of discord is shown to be obtainable from an experimentally measurable witness operator.

Quantum Discord in Two-Qubit System Constructed from the Yang—Baxter Equation

International Nuclear Information System (INIS)

Gou Li-Dan; Wang Xiao-Qian; Sun Yuan-Yuan; Xu Yu-Mei

2014-01-01

Quantum correlations among parts of a composite quantum system are a fundamental resource for several applications in quantum information. In general, quantum discord can measure quantum correlations. In that way, we investigate the quantum discord of the two-qubit system constructed from the Yang—Baxter Equation. The density matrix of this system is generated through the unitary Yang—Baxter matrix R. The analytical expression and numerical result of quantum discord and geometric measure of quantum discord are obtained for the Yang—Baxter system. These results show that quantum discord and geometric measure of quantum discord are only connect with the parameter θ, which is the important spectral parameter in Yang—Baxter equation. (general)

HIV sero-discordance among Nigerian couples: challenges and ...

African Journals Online (AJOL)

History of extramarital affairs, alcoholism, viral subtype, age range and duration of marriage were seen as independent behavioral and sexual risk factors for HIV infection among spouses that were HIV-infected in sero-discordant relationship. The highest incidence of HIV sero-discordance occurred among couples < 5 years ...

Quantum discord of Bell cat states under amplitude damping

International Nuclear Information System (INIS)

Daoud, M; Laamara, R Ahl

2012-01-01

The evolution of pairwise quantum correlations of Bell cat states under amplitude damping is examined using the concept of quantum discord which goes beyond entanglement. A closed expression of the quantum discord is explicitly derived. We used the Koashi–Winter relation, a relation which facilitates the optimization process of the conditional entropy. We also discuss the temporal evolution of bipartite quantum correlations under a dephasing channel and compare the behaviors of quantum discord and entanglement whose properties are characterized through the concurrence. (paper)

Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia

Institute of Scientific and Technical Information of China (English)

Jinsong Tang; Fan He; Fengyu Zhang; Yin Yao Shugart; Chunyu Liu; Yanqing Tang; Raymond C.K.Chan; Chuan-Yue Wang; Yong-Gang Yao; Xiaogang Chen; Yu Fan; Hong Li; Qun Xiang; Deng-Feng Zhang; Zongchang Li; Ying He; Yanhui Liao; Ya Wang

2017-01-01

Schizophrenia is a common disorder with a high heritability,but its genetic architecture is still elusive.We implemented whole-genome sequencing (WGS) analysis of 8 families with monozygotic (MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations (DNMs) or inherited variants with susceptibility to schizophrenia.Eight non-synonymous DNMs (including one splicing site) were identified and shared by twins,which were either located in previously reported schizophrenia risk genes (p.V24689I mutation in TTN,p.S2506T mutation in GCN1L1,IVS3+1G ＞ T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis.By searching the inherited rare damaging or loss-of-function (LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes,we were able to distill genetic alterations in several schizophrenia risk genes,including GAD1,PLXNA2,RELN and FEZ1.Four inherited copy number variations (CNVs;including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families,respectively.Most of families carried both missense DNMs and inherited risk variants,which might suggest that DNMs,inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility.Our results support that schizophrenia is caused by a combination of multiple genetic factors,with each DNM/variant showing a relatively small effect size.

A social work study for the effects of different factors on compatible and discordant couples

Directory of Open Access Journals (Sweden)

Mehdi Esalat

2012-04-01

Full Text Available In this paper, we perform an empirical investigation to examine the impact different factors on compatible and discordant couples. The survey is performed in one of western regions of Iran near the city of Esfahan. In our study, we choose two groups of people from the population with no family dispute and from the people who have requested divorce. They are asked to fill in a questionnaire and the results are analyzed. We used Chi-square tests to verify any meaningful difference between compatible and discordant couples on different issues. The survey concludes that compatible and discordant couples were different in their motivation, marital satisfaction, continued incentive generation, finding better position among relatives and accomplishing their religious duties to get married.

Discord as a quantum resource for bi-partite communication

International Nuclear Information System (INIS)

Chrzanowski, Helen M.; Assad, Syed M.; Symul, Thomas; Lam, Ping Koy; Gu, Mile; Modi, Kavan; Vedral, Vlatko; Ralph, Timothy C.

2014-01-01

Coherent interactions that generate negligible entanglement can still exhibit unique quantum behaviour. This observation has motivated a search beyond entanglement for a complete description of all quantum correlations. Quantum discord is a promising candidate. Here, we experimentally demonstrate that under certain measurement constraints, discord between bipartite systems can be consumed to encode information that can only be accessed by coherent quantum interactions. The inability to access this information by any other means allows us to use discord to directly quantify this ‘quantum advantage’

Case report: Suspected clinical-radiological discord

Directory of Open Access Journals (Sweden)

Martin Tombe

2013-02-01

Full Text Available 17-year male student presented with vague constitutional symptoms and jaundice. His clinical chest findings initially suggested a discord with radiological findings. It turned out that the patient had a rare congenital disorder in addition to a seemingly common condition that brought him to the hospital. The purpose of this case presentation is to share some challenges of a clinical-radiological discord in a teaching hospital in Zimbabwe. It shows a flow of teamwork from House Officers to the Consultants as well as radiological back up.

Discordant CSF/plasma HIV-1 RNA in individuals on virologically suppressive antiretroviral therapy in Western India.

Science.gov (United States)

Dravid, Ameet N; Natrajan, Kartik; Kulkarni, Milind M; Saraf, Chinmay K; Mahajan, Uma S; Kore, Sachin D; Rathod, Niranjan M; Mahajan, Umakant S; Wadia, Rustom S

2018-02-01

Aim of this study was to estimate the prevalence of cerebrospinal fluid (CSF)/Plasma HIV-1 RNA discordance in virologically suppressed individuals presenting with incident neurologic symptoms.In this retrospective cohort study conducted between March 1, 2009, and March 1, 2017, HIV-1 infected adults exposed to atleast 12 months of antiretroviral therapy (ART) and having plasma viral load (VL) CSF/Plasma HIV-1 RNA discordance by measuring HIV-1 RNA in collected plasma and CSF samples. CSF/plasma HIV-1 RNA discordance was defined as either detectable CSF HIV-1 RNA (VL > 20 copies/mL) with an undetectable plasma RNA (complete viral suppression, VL ≤20 copies/mL) or CSF HIV-1 RNA ≥ 0.5 log10 higher than plasma RNA when plasma VL was between 20 and 1000 copies/mL (low-level viremia, LLV).Out of 1584 virologically suppressed patients, 71 (4.4%) presented with incident neurologic symptoms. Twenty out of 71 (28.2%) patients were diagnosed with CSF/Plasma HIV-1 discordance. Median plasma and CSF VL in patients with discordance was 120 [interquartile range (IQR): CSF HIV-1 genotypic resistance testing was done showed mutations that would compromise efficacy of prescribed ART regimen. Prevalence of CSF/plasma HIV-1 RNA discordance was higher among neurologically symptomatic patients with plasma LLV as compared with those with complete viral suppression (70% vs 11.8%, P CSF/plasma HIV-1 RNA discordance indicates replication of HIV-1 that has adapted to the CNS or has developed antiretroviral drug resistance. Larger studies should be performed to study incidence of discordance in India. This will help in managing patients presenting with neurologic symptoms on suppressive ART with appropriate neuroeffective therapy.

The sudden death and sudden birth of quantum discord.

Science.gov (United States)

Xia, Wei; Hou, Jin-Xing; Wang, Xiao-Hui; Liu, Si-Yuan

2018-03-28

The interaction of quantum system and its environment brings out abundant quantum phenomenons. The sudden death of quantum resources, including entanglement, quantum discord and coherence, have been studied from the perspective of quantum breaking channels (QBC). QBC of quantum resources reveal the common features of quantum resources. The definition of QBC implies the relationship between quantum resources. However, sudden death of quantum resources can also appear under some other quantum channels. We consider the dynamics of Bell-diagonal states under a stochastic dephasing noise along the z-direction, and the sudden death and sudden birth of quantum discord are investigated. Next we explain this phenomenon from the geometric structure of quantum discord. According to the above results, the states with sudden death and sudden birth can be filtered in three-parameter space. Then we provide two necessary conditions to judge which kind of noise channels can make Bell-diagonal states sudden death and sudden birth. Moreover, the relation between quantum discord and coherence indicates that the sudden death and sudden birth of quantum discord implies the sudden death and sudden birth of coherence in an optimal basis.

Longitudinal weight differences, gene expression, and blood biomarkers in BMI discordant identical twins

Science.gov (United States)

van Dongen, Jenny; Willemsen, Gonneke; Heijmans, Bastiaan T.; Neuteboom, Jacoline; Kluft, Cornelis; Jansen, Rick; Penninx, Brenda W.J.; Slagboom, P. Eline; de Geus, Eco J.C.; Boomsma, Dorret I.

2015-01-01

Background BMI discordant monozygotic (MZ) twins allows an examination of the causes and consequences of adiposity in a genetically controlled design. Few studies have examined longitudinal BMI discordance in MZ pairs. Objectives To study the development over time of BMI discordance in adolescent and adult MZ twin pairs, and to examine lifestyle, metabolic, inflammatory, and gene expression differences associated with concurrent and long-term BMI discordance in MZ pairs. Subjects/Methods BMI data from 2775 MZ twin pairs, collected in eight longitudinal surveys and a biobank project between 1991 and 2011, were analyzed to characterize longitudinal discordance. Lifestyle characteristics were compared within discordant pairs (ΔBMI ≥ 3 kg/m2) and biomarkers (lipids, glucose, insulin, CRP, fibrinogen, IL-6, TNF-α and sIL-6R and liver enzymes AST, ALT and GGT) and gene expression were compared in peripheral blood from discordant pairs who participated in the NTR biobank project. Results The prevalence of discordance ranged from 3.2% in 1991 (mean age=17, SD=2.4) to 17.4% (N=202 pairs) in 2009 (mean age=35, SD=15), and was 16.5% (N=174) among pairs participating in the biobank project (mean age=35, SD=12). Of 699 MZ with BMI data from 3-5 time points, 17 pairs (2.4%) were long-term discordant (at all available time points; mean follow-up range=6.4 years). Concurrently discordant pairs showed significant differences in self-ratings of which twin eats most (p=2.3×10−13), but not in leisure time exercise activity (p=0.28) and smoking (p>0.05). Ten out of 14 biomarkers showed significantly more unfavorable levels in the heavier of twin of the discordant pairs (p-values BMI discordance is uncommon in adolescent identical pairs but increases with higher pair-mean of BMI at older ages, although long-term BMI discordance is rare. In discordant pairs, the heavier twin had a more unfavorable blood biomarker profile than the genetically matched leaner twin, in support of

[Analysis for Discordance of Positive and Negative Blood Typing by Gel Card].

Science.gov (United States)

Li, Cui-Ying; Xu, Hong; Lei, Hui-Fen; Liu, Juan; Li, Xiao-Wei

2017-08-01

To explore the method of Gel card identifying ABO blood group, determine the inconsistent cause and the distribution of disease affecting factors, and put forward a method of its solutions. To collect 240 positive and negative typing-discordant blood speciments from patients examined by Gel card and send these speciments to blood type reference laboratory for examining with the classic tube method and serological test, such as salivary blood-group substance, in order to performe genotyping method when serologic test can not be determined. Among 240 positive and negative typing-discordant blood speciments from patients examined by Gel card, 107 blood speciments were positive and negative consistent examined by false agglutination test (44.58%), 133 blood specinents were discordent examined by false agglutination (55.42%), out of them, 35 cases (14.58%) with inconsistent cold agglutination test, 22 cases (9.17%) with weakened AB antigenicity, 16 cases (6.67%) with ABO subtyping, 12 cases (5.00%) with positive direct antiglobulin test, 11 cases (4.58%) with reduced or without antibodies, 11 cases (4.58%) with false aggregation caused by drugs or protein, 11 cases (4.58%) with salivary blood-type substances, 8 cases (3.33%) with non-ABO alloantibody, and 7 cases (2.92%) with allogeneic bone marrow transplantation. The distribution of disease were following: blood disease (16.83%), tumor (11.88%), and cardiopulmonary diseases (11.39%); chi-square test results indicated that the distribution significantly different. The analysis of ABO blood grouping shows a variety factors influencing positive and negative blood typing, and the Gel Card identification can produc more false positive blood types. Therefore, more attention should be paid on the high incidence diseases, such as blood disease, tumor, and cardiopulmonary disease.

The STS-constructivist reform: some discordant notes | Nworgu ...

African Journals Online (AJOL)

It would appear that as many more voices join in the advocacy for STS constructivist Reform in science teaching/learning, more discordant notes are emitted. The purpose of the paper therefore, was to spotlight some of these discordant notes emitted in the course of the on-going reform advocacy. Specifically, three of such ...

Risk factors for discordant immune response among HIV-infected ...

African Journals Online (AJOL)

Risk factors for discordant immune response among HIV-infected patients initiating antiretroviral therapy: A retrospective cohort study. ... Multivariate logistic regression models were used to estimate adjusted odds ratios (AORs) to determine associations between discordant immune response and clinical and demographic ...

Lipid discordance and carotid plaque in obese patients in primary prevention.

Science.gov (United States)

Masson, Walter; Siniawski, Daniel; Lobo, Martín; Molinero, Graciela

2018-01-01

Obese patients with lipid discordance (non-HDL cholesterol levels 30mg/dL above the LDL-c value) may have a greater prevalence of carotid atherosclerotic plaque (CAP). Our study objectives were: 1) To assess the prevalence of lipid discordance in a primary prevention population of obese patients; 2) To investigate the association between lipid discordance and presence of CAP. Obese subjects aged >18 years (BMI ≥30kg/m 2 ) with no cardiovascular disease, diabetes, or lipid-lowering treatment from six cardiology centers were included. Lipid discordance was defined when, regardless of the LDL-c level, the non-HDL cholesterol value exceeded the LDL-c value by 30mg/dL. Presence of CAP was identified by ultrasonography. Univariate and multivariate analyses were performed to explore the association between lipid discordance and presence of CAP. The study simple consisted of 325 obese patients (57.2% men; mean age, 52.3 years). Prevalence of lipid discordance was 57.9%. CAP was found in 38.6% of patients, but the proportion was higher in subjects with lipid discordance as compared to those without this lipid pattern (44.4% vs. 30.7%, P=.01). In both the univariate (OR: 1.80; 95% CI: 1.14-2.87; P=.01) and the multivariate analysis (OR: 2.07; 95% CI: 1.22-3.54; P=.007), presence of lipid discordance was associated to an increased probability of CAP. In these obese patients, lipid discordance was associated to greater prevalence of CAP. Evaluation of obese patients with this strategy could help identify subjects with higher residual cardiovascular risk. Copyright © 2017 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.

Improving power for rare-variant tests by integrating external controls.

Science.gov (United States)

Lee, Seunggeun; Kim, Sehee; Fuchsberger, Christian

2017-11-01

Due to the drop in sequencing cost, the number of sequenced genomes is increasing rapidly. To improve power of rare-variant tests, these sequenced samples could be used as external control samples in addition to control samples from the study itself. However, when using external controls, possible batch effects due to the use of different sequencing platforms or genotype calling pipelines can dramatically increase type I error rates. To address this, we propose novel summary statistics based single and gene- or region-based rare-variant tests that allow the integration of external controls while controlling for type I error. Our approach is based on the insight that batch effects on a given variant can be assessed by comparing odds ratio estimates using internal controls only vs. using combined control samples of internal and external controls. From simulation experiments and the analysis of data from age-related macular degeneration and type 2 diabetes studies, we demonstrate that our method can substantially improve power while controlling for type I error rate. © 2017 WILEY PERIODICALS, INC.

Definition of intertwin birth weight discordance.

Science.gov (United States)

Breathnach, Fionnuala M; McAuliffe, Fionnuala M; Geary, Michael; Daly, Sean; Higgins, John R; Dornan, James; Morrison, John J; Burke, Gerard; Higgins, Shane; Dicker, Patrick; Manning, Fiona; Mahony, Rhona; Malone, Fergal D

2011-07-01

To establish the level of birth weight discordance at which perinatal morbidity increases in monochorionic and dichorionic twin pregnancy. This prospective multicenter cohort study included 1,028 unselected twin pairs recruited over a 2-year period. Participants underwent two weekly ultrasonographic surveillance from 24 weeks of gestation with surveillance of monochorionic twins two-weekly from 16 weeks. Analysis using Cox proportional hazards compared a composite measure of perinatal morbidity (including any of the following: mortality, respiratory distress syndrome, hypoxic-ischemic encephalopathy, periventricular leukomalacia, necrotizing enterocolitis, or sepsis) at different degrees of birth weight discordance with adjustment for chorionicity, gestational age, twin-twin transfusion syndrome, birth order, gender, and growth restriction. Perinatal outcome data were recorded for 977 patients (100%) who continued the study with both fetuses alive beyond 24 weeks, including 14 cases of twin-twin transfusion syndrome. Adjusting for gestation at delivery, twin order, gender, and growth restriction, perinatal mortality, individual morbidity, and composite perinatal morbidity were all seen to increase with birth weight discordance exceeding 18% for dichorionic pairs (hazard ratio 2.2, 95% confidence interval [CI] 1.6-2.9, Pbirth weights were appropriate for gestational age. : The threshold for birth weight discordance established by this prospective study is 18% both for dichorionic twin pairs and for monochorionic twins without twin-twin transfusion syndrome. This threshold is considerably lower than that defined by many retrospective series as pathologic. We suggest that an anticipated difference of 18% in birth weight should prompt more intensive fetal monitoring.

Thermal quantum discord of spins in an inhomogeneous magnetic field

International Nuclear Information System (INIS)

Guo Jinliang; Mi Yingjuan; Zhang Jian; Song Heshan

2011-01-01

In contrast with the thermal entanglement, we study the quantum discord and classical correlation in a two-qubit Heisenberg XXZ model with an inhomogeneous magnetic field. It is shown that the effects of the external magnetic fields, including the uniform and inhomogeneous magnetic fields, on the thermal entanglement, quantum discord and classical correlation behave differently in various aspects, which depend on system temperature and model type. We can tune the inhomogeneous magnetic field to enhance the entanglement or classical correlation and meanwhile decrease the quantum discord. In addition, taking into account the inhomogeneous magnetic field, the sudden change in the behaviour of quantum discord still survives, which can detect the critical points of quantum phase transitions at finite temperature, but not for a uniform magnetic field.

Single-variant and multi-variant trend tests for genetic association with next-generation sequencing that are robust to sequencing error.

Science.gov (United States)

Kim, Wonkuk; Londono, Douglas; Zhou, Lisheng; Xing, Jinchuan; Nato, Alejandro Q; Musolf, Anthony; Matise, Tara C; Finch, Stephen J; Gordon, Derek

2012-01-01

As with any new technology, next-generation sequencing (NGS) has potential advantages and potential challenges. One advantage is the identification of multiple causal variants for disease that might otherwise be missed by SNP-chip technology. One potential challenge is misclassification error (as with any emerging technology) and the issue of power loss due to multiple testing. Here, we develop an extension of the linear trend test for association that incorporates differential misclassification error and may be applied to any number of SNPs. We call the statistic the linear trend test allowing for error, applied to NGS, or LTTae,NGS. This statistic allows for differential misclassification. The observed data are phenotypes for unrelated cases and controls, coverage, and the number of putative causal variants for every individual at all SNPs. We simulate data considering multiple factors (disease mode of inheritance, genotype relative risk, causal variant frequency, sequence error rate in cases, sequence error rate in controls, number of loci, and others) and evaluate type I error rate and power for each vector of factor settings. We compare our results with two recently published NGS statistics. Also, we create a fictitious disease model based on downloaded 1000 Genomes data for 5 SNPs and 388 individuals, and apply our statistic to those data. We find that the LTTae,NGS maintains the correct type I error rate in all simulations (differential and non-differential error), while the other statistics show large inflation in type I error for lower coverage. Power for all three methods is approximately the same for all three statistics in the presence of non-differential error. Application of our statistic to the 1000 Genomes data suggests that, for the data downloaded, there is a 1.5% sequence misclassification rate over all SNPs. Finally, application of the multi-variant form of LTTae,NGS shows high power for a number of simulation settings, although it can have

Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia.

Science.gov (United States)

Tang, Jinsong; Fan, Yu; Li, Hong; Xiang, Qun; Zhang, Deng-Feng; Li, Zongchang; He, Ying; Liao, Yanhui; Wang, Ya; He, Fan; Zhang, Fengyu; Shugart, Yin Yao; Liu, Chunyu; Tang, Yanqing; Chan, Raymond C K; Wang, Chuan-Yue; Yao, Yong-Gang; Chen, Xiaogang

2017-06-20

Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive. We implemented whole-genome sequencing (WGS) analysis of 8 families with monozygotic (MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations (DNMs) or inherited variants with susceptibility to schizophrenia. Eight non-synonymous DNMs (including one splicing site) were identified and shared by twins, which were either located in previously reported schizophrenia risk genes (p.V24689I mutation in TTN, p.S2506T mutation in GCN1L1, IVS3+1G > T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis. By searching the inherited rare damaging or loss-of-function (LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes, we were able to distill genetic alterations in several schizophrenia risk genes, including GAD1, PLXNA2, RELN and FEZ1. Four inherited copy number variations (CNVs; including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families, respectively. Most of families carried both missense DNMs and inherited risk variants, which might suggest that DNMs, inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility. Our results support that schizophrenia is caused by a combination of multiple genetic factors, with each DNM/variant showing a relatively small effect size. Copyright © 2017 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. All rights reserved.

Experimental verification of quantum discord in continuous-variable states

International Nuclear Information System (INIS)

Hosseini, S; Haw, J Y; Assad, S M; Chrzanowski, H M; Janousek, J; Symul, T; Lam, P K; Rahimi-Keshari, S; Ralph, T C

2014-01-01

We introduce a simple and efficient technique to verify quantum discord in unknown Gaussian states and a certain class of non-Gaussian states. We show that any separation in the peaks of the marginal distributions of one subsystem conditioned on two different outcomes of homodyne measurements performed on the other subsystem indicates correlation between the corresponding quadratures, and hence nonzero discord. We also apply this method to non-Gaussian states that are prepared by overlapping a statistical mixture of coherent and vacuum states on a beam splitter. We experimentally demonstrate this technique by verifying nonzero quantum discord in a bipartite Gaussian and certain non-Gaussian states. (paper)

Multiple linear combination (MLC) regression tests for common variants adapted to linkage disequilibrium structure.

Science.gov (United States)

Yoo, Yun Joo; Sun, Lei; Poirier, Julia G; Paterson, Andrew D; Bull, Shelley B

2017-02-01

By jointly analyzing multiple variants within a gene, instead of one at a time, gene-based multiple regression can improve power, robustness, and interpretation in genetic association analysis. We investigate multiple linear combination (MLC) test statistics for analysis of common variants under realistic trait models with linkage disequilibrium (LD) based on HapMap Asian haplotypes. MLC is a directional test that exploits LD structure in a gene to construct clusters of closely correlated variants recoded such that the majority of pairwise correlations are positive. It combines variant effects within the same cluster linearly, and aggregates cluster-specific effects in a quadratic sum of squares and cross-products, producing a test statistic with reduced degrees of freedom (df) equal to the number of clusters. By simulation studies of 1000 genes from across the genome, we demonstrate that MLC is a well-powered and robust choice among existing methods across a broad range of gene structures. Compared to minimum P-value, variance-component, and principal-component methods, the mean power of MLC is never much lower than that of other methods, and can be higher, particularly with multiple causal variants. Moreover, the variation in gene-specific MLC test size and power across 1000 genes is less than that of other methods, suggesting it is a complementary approach for discovery in genome-wide analysis. The cluster construction of the MLC test statistics helps reveal within-gene LD structure, allowing interpretation of clustered variants as haplotypic effects, while multiple regression helps to distinguish direct and indirect associations. © 2016 The Authors Genetic Epidemiology Published by Wiley Periodicals, Inc.

Stakeholders perception of HIV sero-discordant couples in western ...

African Journals Online (AJOL)

Stakeholders perception of HIV sero-discordant couples in western Kenya. E Were, K Wools-Kaloustian, J Baliddawa, PO Ayuo, J Sidle, K Fife. Abstract. Objective: To describe the perceptions of key stakeholders regarding the counselling needs of HI V sero-discordant couples as part of preparation for a clinical trial ...

How discordant morphological and molecular evolution among microorganisms can revise our notions of biodiversity on earth

Science.gov (United States)

Lahr, Daniel J. G.; Laughinghouse, H. Dail; Oliverio, Angela; Gao, Feng; Katz, Laura A.

2014-01-01

Microscopy has revealed a tremendous diversity of bacterial and eukaryotic forms. More recent molecular analyses show discordance in estimates of biodiversity based on morphological analyses. Moreover, phylogenetic analyses of the diversity of microbial forms have revealed evidence of convergence at scales as large as interdomain – i.e. convergent forms shared between bacteria and eukaryotes. Here, we highlight examples of such discordance, focusing on exemplary lineages such as testate amoebae, ciliates and cyanobacteria, which have long histories of morphological study. We discuss examples in two categories: 1) morphologically identical (or highly similar) individuals that are genetically distinct and 2) morphologically distinct individuals that are genetically distinct. We argue that hypotheses about discordance can be tested using the concept of neutral morphologies, or more broadly neutral phenotypes, as a null hypothesis. PMID:25156897

The feasibility of the interferon gamma release assay and predictors of discordance with the tuberculin skin test for the diagnosis of latent tuberculosis infection in a remote Aboriginal community.

Directory of Open Access Journals (Sweden)

Gonzalo G Alvarez

Full Text Available The tuberculin skin test (TST is the standard test used to screen for latent TB infection (LTBI in the northern Canadian territory of Nunavut. Interferon gamma release assays (IGRA are T cell blood-based assays to diagnose LTBI. The Bacillus Calmette-Guerin (BCG vaccine is part of the routine immunization schedule in Nunavut. The objective of this study was to test the feasibility, and predictors of discordance between the Tuberculin Skin Test (TST and the IGRA assay in a medically under-serviced remote arctic Aboriginal population.Both the TST and QuantiFERON-TB Gold (Qiagen group IGRA tests were offered to people in their homes as part of a public health campaign aimed at high TB risk residential areas in Iqaluit, Nunavut, Canada. Feasibility was measured by the capacity of the staff to do the test successfully as measured by the proportion of results obtained.In this population of predominantly young Inuit who were mostly BCG vaccinated, the use of IGRA for the diagnosis of LTBI was feasible. IGRA testing resulted in more available test results reaching patients (95.6% vs 90.9% p = 0.02 but took longer (median 8 days (IGRA vs 2 days (TST, p value < 0.0001. 44/256 participants (17.2% had discordant results. Multivariable regression analysis suggested that discordant results were most likely to have received multiple BCG vaccinations (RR 20.03, 95% CI, 3.94-101.82, followed by BCG given post infancy (RR 8.13, 95% CI, 2.54-26.03 and then to a lesser degree when BCG was given in infancy (RR 6.43, 95% CI, 1.72-24.85.IGRA is feasible in Iqaluit, Nunavut, a remote Arctic community. IGRA testing results in more test results available to patients compared to TST. This test could result in fewer patients requiring latent TB treatment among those previously vaccinated with BCG in a region with limited public health human resources.

a reflection on the impact of HIV discordance on child HIV infection

African Journals Online (AJOL)

cqq1a

2010-05-09

May 9, 2010 ... discordant couples with an HIV positive man is almost the same as that of discordant couples with an HIV positive woman [1]. There is a need to better analyze the impact of HIV sero-discordance in the context of pregnancy and prevention of mother to child transmission (PMTCT). In general, PMTCT ...

Interpreting quantum discord through quantum state merging

International Nuclear Information System (INIS)

Madhok, Vaibhav; Datta, Animesh

2011-01-01

We present an operational interpretation of quantum discord based on the quantum state merging protocol. Quantum discord is the markup in the cost of quantum communication in the process of quantum state merging, if one discards relevant prior information. Our interpretation has an intuitive explanation based on the strong subadditivity of von Neumann entropy. We use our result to provide operational interpretations of other quantities like the local purity and quantum deficit. Finally, we discuss in brief some instances where our interpretation is valid in the single-copy scenario.

Intrapair birthweight discordance in twins

African Journals Online (AJOL)

2009-10-05

The prevalence of birthweight discordance was 28.8% when a 15% cut-off point was used but dropped to. 9.6% when a 25% cut-off point was applied. Grand multiparity was associated with a significantly increased risk.

Comparison of the attempts of quantum discord and quantum entanglement to capture quantum correlations

International Nuclear Information System (INIS)

Qasimi, Asma Al-; James, Daniel F. V.

2011-01-01

Measurements of quantum systems disturb their states. To quantify this nonclassical characteristic, Zurek and Ollivier [Phys. Rev. Lett. 88, 017901 (2001)] introduced the quantum discord, a quantum correlation that can be nonzero even when entanglement in the system is zero. Discord has aroused great interest as a resource that is more robust against the effects of decoherence and offers the exponential speed-up of certain computational algorithms. Here, we study general two-level bipartite systems and give general results on the relationship between discord, entanglement, and linear entropy. We also identify the states for which discord takes a maximal value for a given entropy or entanglement, thus placing strong bounds on entanglement-discord and entropy-discord relations. We find out that although discord and entanglement are identical for pure states, they differ when generalized to mixed states as a result of the difference in the method of generalization.

Prevalence of discordant microscopic changes with automated CBC analysis

Directory of Open Access Journals (Sweden)

Fabiano de Jesus Santos

2014-12-01

Full Text Available Introduction:The most common cause of diagnostic error is related to errors in laboratory tests as well as errors of results interpretation. In order to reduce them, the laboratory currently has modern equipment which provides accurate and reliable results. The development of automation has revolutionized the laboratory procedures in Brazil and worldwide.Objective:To determine the prevalence of microscopic changes present in blood slides concordant and discordant with results obtained using fully automated procedures.Materials and method:From January to July 2013, 1,000 hematological parameters slides were analyzed. Automated analysis was performed on last generation equipment, which methodology is based on electrical impedance, and is able to quantify all the figurative elements of the blood in a universe of 22 parameters. The microscopy was performed by two experts in microscopy simultaneously.Results:The data showed that only 42.70% were concordant, comparing with 57.30% discordant. The main findings among discordant were: Changes in red blood cells 43.70% (n = 250, white blood cells 38.46% (n = 220, and number of platelet 17.80% (n = 102.Discussion:The data show that some results are not consistent with clinical or physiological state of an individual, and cannot be explained because they have not been investigated, which may compromise the final diagnosis.Conclusion:It was observed that it is of fundamental importance that the microscopy qualitative analysis must be performed in parallel with automated analysis in order to obtain reliable results, causing a positive impact on the prevention, diagnosis, prognosis, and therapeutic follow-up.

Monozygotic twins discordant for attention-deficit/hyperactivity disorder: ascertainment and clinical characteristics.

Science.gov (United States)

Sharp, Wendy S; Gottesman, Rebecca F; Greenstein, Deanna K; Ebens, Christen L; Rapoport, Judith L; Castellanos, F Xavier

2003-01-01

Nongenetic factors and phenomenology of attention-deficit/hyperactivity disorder (ADHD) were examined in monozygotic (MZ) twin pairs discordant for ADHD. Recruitment included telephone screening (n = 297 pairs), behavioral ratings obtained from parents and teachers (n = 59 pairs), and, finally, in-person assessment (n = 25 pairs; structured classroom observation, diagnostic interview, psychoeducational evaluation, birth record review, establishment of monozygosity, and anatomic brain imaging). Affected twins were further contrasted with previously studied affected singletons. Of the 25 MZ twin pairs qualifying for in-person evaluation, only 10 proved discordant for ADHD. Affected twins were mostly comparable with affected singletons on clinical measures, although fathers' self-ratings of childhood ADHD status were significantly lower in twins than in singletons. Discordance for ADHD in MZ twins appears to be ascribable to greater environmental discordance and decreased familiality. Despite these differences, affected twins were phenotypically comparable with affected singletons. Thus MZ twins discordant for ADHD, while rare, can inform research on the etiology and pathophysiology of this disorder.

Illustrating, Quantifying, and Correcting for Bias in Post-hoc Analysis of Gene-Based Rare Variant Tests of Association

Directory of Open Access Journals (Sweden)

Kelsey E. Grinde

2017-09-01

Full Text Available To date, gene-based rare variant testing approaches have focused on aggregating information across sets of variants to maximize statistical power in identifying genes showing significant association with diseases. Beyond identifying genes that are associated with diseases, the identification of causal variant(s in those genes and estimation of their effect is crucial for planning replication studies and characterizing the genetic architecture of the locus. However, we illustrate that straightforward single-marker association statistics can suffer from substantial bias introduced by conditioning on gene-based test significance, due to the phenomenon often referred to as “winner's curse.” We illustrate the ramifications of this bias on variant effect size estimation and variant prioritization/ranking approaches, outline parameters of genetic architecture that affect this bias, and propose a bootstrap resampling method to correct for this bias. We find that our correction method significantly reduces the bias due to winner's curse (average two-fold decrease in bias, p < 2.2 × 10−6 and, consequently, substantially improves mean squared error and variant prioritization/ranking. The method is particularly helpful in adjustment for winner's curse effects when the initial gene-based test has low power and for relatively more common, non-causal variants. Adjustment for winner's curse is recommended for all post-hoc estimation and ranking of variants after a gene-based test. Further work is necessary to continue seeking ways to reduce bias and improve inference in post-hoc analysis of gene-based tests under a wide variety of genetic architectures.

Subjects with Discordant Airways Obstruction: Lost between Spirometric Definitions of COPD

Directory of Open Access Journals (Sweden)

Bernd Lamprecht

2011-01-01

Full Text Available Background. Since the FEV1/FVC ratio declines with age, using the fixed ratio of 0.70 leads to overdiagnosis of COPD in older populations and underdiagnosis among young adults. Objective. To evaluate whether discordant obstructive cases (FEV1/FVC < 0.70 but ≥LLN are a healthy population or have clinical features that would place them at increased risk. Methods. We used post-bronchodilator spirometry data from the population-based Austrian Burden of Obstructive Lung Disease (BOLD study. Those with post-bronchodilator FEV1/FVC ratio discordant obstructive cases. Results. Discordant obstructive cases were more likely to be older, male and never-smokers. Additionally they had less respiratory symptoms and less severe impairment of FEV1. However, discordant obstructive cases reported significantly more often a diagnosis of heart disease than subjects with normal lung function (27.2% vs 7.3%, P=.015. Conclusion. The clinical profile of discordant obstructive cases includes potentially important comorbid disease.

Do MZ twins have discordant experiences of friendship? A qualitative hypothesis-generating MZ twin differences study

Science.gov (United States)

Moran, Nicola; Plomin, Robert

2017-01-01

Using a qualitative monozygotic (MZ) twin differences design we explored whether adolescent MZ twins report discordant peer relationships and, if so, whether they perceive them as causes, consequences or correlates of discordant behaviour. We gathered free-response questionnaire data from 497 families and conducted in-depth telephone interviews with 97 of them. Within this dataset n = 112 families (23% of the sample) described discordant peer relationships. Six categories of discordance were identified (peer victimisation, peer rejection, fewer friends, different friends, different attitudes to friendship and dependence on co-twin). Participants described peer relationship discordance arising as a result of chance occurrences, enhanced vulnerability in one twin or discordant behaviour. Consequences of discordant peer relationships were seen as discordance in self-confidence, future plans, social isolation, mental health and interests. In all cases the twin with worse peer experiences was seen as having a worse outcome. Specific hypotheses are presented. PMID:28727730

Evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines.

Science.gov (United States)

Ghosh, Rajarshi; Oak, Ninad; Plon, Sharon E

2017-11-28

The American College of Medical Genetics and American College of Pathologists (ACMG/AMP) variant classification guidelines for clinical reporting are widely used in diagnostic laboratories for variant interpretation. The ACMG/AMP guidelines recommend complete concordance of predictions among all in silico algorithms used without specifying the number or types of algorithms. The subjective nature of this recommendation contributes to discordance of variant classification among clinical laboratories and prevents definitive classification of variants. Using 14,819 benign or pathogenic missense variants from the ClinVar database, we compared performance of 25 algorithms across datasets differing in distinct biological and technical variables. There was wide variability in concordance among different combinations of algorithms with particularly low concordance for benign variants. We also identify a previously unreported source of error in variant interpretation (false concordance) where concordant in silico predictions are opposite to the evidence provided by other sources. We identified recently developed algorithms with high predictive power and robust to variables such as disease mechanism, gene constraint, and mode of inheritance, although poorer performing algorithms are more frequently used based on review of the clinical genetics literature (2011-2017). Our analyses identify algorithms with high performance characteristics independent of underlying disease mechanisms. We describe combinations of algorithms with increased concordance that should improve in silico algorithm usage during assessment of clinically relevant variants using the ACMG/AMP guidelines.

Quantum discord and quantum phase transition in spin chains

OpenAIRE

Dillenschneider, Raoul

2008-01-01

Quantum phase transitions of the transverse Ising and antiferromagnetic XXZ spin S=1/2 chains are studied using quantum discord. Quantum discord allows the measure of quantum correlations present in many-body quantum systems. It is shown that the amount of quantum correlations increases close to the critical points. The observations are in agreement with the information provided by the concurrence which measures the entanglement of the many-body system.

Geometric measure of pairwise quantum discord for superpositions of multipartite generalized coherent states

International Nuclear Information System (INIS)

Daoud, M.; Ahl Laamara, R.

2012-01-01

We give the explicit expressions of the pairwise quantum correlations present in superpositions of multipartite coherent states. A special attention is devoted to the evaluation of the geometric quantum discord. The dynamics of quantum correlations under a dephasing channel is analyzed. A comparison of geometric measure of quantum discord with that of concurrence shows that quantum discord in multipartite coherent states is more resilient to dissipative environments than is quantum entanglement. To illustrate our results, we consider some special superpositions of Weyl–Heisenberg, SU(2) and SU(1,1) coherent states which interpolate between Werner and Greenberger–Horne–Zeilinger states. -- Highlights: ► Pairwise quantum correlations multipartite coherent states. ► Explicit expression of geometric quantum discord. ► Entanglement sudden death and quantum discord robustness. ► Generalized coherent states interpolating between Werner and Greenberger–Horne–Zeilinger states

Geometric measure of pairwise quantum discord for superpositions of multipartite generalized coherent states

Energy Technology Data Exchange (ETDEWEB)

Daoud, M., E-mail: m_daoud@hotmail.com [Department of Physics, Faculty of Sciences, University Ibnou Zohr, Agadir (Morocco); Ahl Laamara, R., E-mail: ahllaamara@gmail.com [LPHE-Modeling and Simulation, Faculty of Sciences, University Mohammed V, Rabat (Morocco); Centre of Physics and Mathematics, CPM, CNESTEN, Rabat (Morocco)

2012-07-16

We give the explicit expressions of the pairwise quantum correlations present in superpositions of multipartite coherent states. A special attention is devoted to the evaluation of the geometric quantum discord. The dynamics of quantum correlations under a dephasing channel is analyzed. A comparison of geometric measure of quantum discord with that of concurrence shows that quantum discord in multipartite coherent states is more resilient to dissipative environments than is quantum entanglement. To illustrate our results, we consider some special superpositions of Weyl–Heisenberg, SU(2) and SU(1,1) coherent states which interpolate between Werner and Greenberger–Horne–Zeilinger states. -- Highlights: ► Pairwise quantum correlations multipartite coherent states. ► Explicit expression of geometric quantum discord. ► Entanglement sudden death and quantum discord robustness. ► Generalized coherent states interpolating between Werner and Greenberger–Horne–Zeilinger states.

Time Series Discord Detection in Medical Data using a Parallel Relational Database

Energy Technology Data Exchange (ETDEWEB)

Woodbridge, Diane; Rintoul, Mark Daniel; Wilson, Andrew T.; Goldstein, Richard

2015-10-01

Recent advances in sensor technology have made continuous real-time health monitoring available in both hospital and non-hospital settings. Since data collected from high frequency medical sensors includes a huge amount of data, storing and processing continuous medical data is an emerging big data area. Especially detecting anomaly in real time is important for patients’ emergency detection and prevention. A time series discord indicates a subsequence that has the maximum difference to the rest of the time series subsequences, meaning that it has abnormal or unusual data trends. In this study, we implemented two versions of time series discord detection algorithms on a high performance parallel database management system (DBMS) and applied them to 240 Hz waveform data collected from 9,723 patients. The initial brute force version of the discord detection algorithm takes each possible subsequence and calculates a distance to the nearest non-self match to find the biggest discords in time series. For the heuristic version of the algorithm, a combination of an array and a trie structure was applied to order time series data for enhancing time efficiency. The study results showed efficient data loading, decoding and discord searches in a large amount of data, benefiting from the time series discord detection algorithm and the architectural characteristics of the parallel DBMS including data compression, data pipe-lining, and task scheduling.

Search for Genomic Alterations in Monozygotic Twins Discordant for Cleft Lip and/or Palate

DEFF Research Database (Denmark)

Kimani, Jane W; Yoshiura, Koh-Ichiro; Shi, Min

2009-01-01

consisting of 1,536 SNPs, to scan for genomic alterations in a sample of monozygotic twin pairs with discordant cleft lip and/or palate phenotypes. Paired analysis for deletions, amplifications and loss of heterozygosity, along with sequence verification of SNPs with discordant genotype calls did not reveal...... any genomic discordance between twin pairs in lymphocyte DNA samples. Our results demonstrate that postzygotic genomic alterations are not a common cause of monozygotic twin discordance for isolated cleft lip and/or palate. However, rare or balanced genomic alterations, tissue-specific events...

High discordance in blood and genital tract HIV-1 drug resistance in Indian women failing first-line therapy.

Science.gov (United States)

Saravanan, Shanmugam; Gomathi, Selvamurthi; Delong, Allison; Kausalya, Bagavathi; Sivamalar, Sathasivam; Poongulali, Selvamuthu; Brooks, Katherine; Kumarasamy, Nagalingeswaran; Balakrishnan, Pachamuthu; Solomon, Sunil S; Cu-Uvin, Susan; Kantor, Rami

2018-05-24

Examine HIV-1 plasma viral load (PVL) and genital tract (GT) viral load (GVL) and drug resistance in India. At the YRG Centre for AIDS Research and Education, Chennai, we tested: PVL in women on first-line ART for ≥6 months; GVL when PVL >2000 copies/mL; and plasma, genital and proviral reverse transcriptase drug resistance when GVL >2000 copies/mL. Wilcoxon rank-sum and Fisher's exact tests were used to identify failure and resistance associations. Pearson correlations were calculated to evaluate PVL-GVL associations. Inter-compartmental resistance discordance was evaluated using generalized estimating equations. Of 200 women, 37% had detectable (>400 copies/mL) PVL and 31% had PVL >1000 copies/mL. Of women with detectable PVL, 74% had PVL >2000 copies/mL, of which 74% had detectable GVL. Higher PVL was associated with higher GVL. Paired plasma and genital sequences were available for 21 women; mean age of 34 years, median ART duration of 33 months, median CD4 count of 217 cells/mm3, median PVL of 5.4 log10 copies/mL and median GVL of 4.6 log10 copies/mL. Drug resistance was detected in 81%-91% of samples and 67%-76% of samples had dual-class resistance. Complete three-compartment concordance was seen in only 10% of women. GT-proviral discordance was significantly larger than plasma-proviral discordance. GT or proviral mutations discordant from plasma led to clinically relevant resistance in 24% and 30%, respectively. We identified high resistance and high inter-compartmental resistance discordance in Indian women, which might lead to unrecognized resistance transmission and re-emergence compromising treatment outcomes, particularly relevant to countries like India, where sexual HIV transmission is predominant.

Sexual violence and associated factors among women in HIV discordant and concordant relationships in Uganda.

Science.gov (United States)

Shuaib, Faisal M B; Ehiri, John E; Jolly, Pauline; Zhang, Qionghui; Emusu, Donath; Ngu, Julius; Foushee, Herman; Katongole, Drake; Kirby, Russell; Wabwire-Mangen, Fred

2012-01-01

HIV serodiscordance is a sexual partnership in which one partner is infected with HIV while the other is not. Managing emotional and sexual intimacy in HIV serodiscordant unions can be difficult due to concerns about HIV transmission and the challenge of initiating and maintaining safe sex. In situations where couples are jointly aware of their HIV status, women in serodiscordant unions may face increased risk of partner violence. We conducted an investigation to assess risk factors for HIV serodiscordance and determine if HIV serodiscordance is associated with incident sexual violence among a cohort of women attending HIV post-test club services at three AIDS Information Centers (AICs) in Uganda. Using a prospective study of 250 women, we elicited information about sexual violence using structured face-to-face interviews. Sexual violence and risk factors were assessed and compared among HIV positive women in HIV discordant unions, HIV negative women in discordant unions, and HIV negative women in negative concordant unions. Multivariable logistic regression was used to assess the association between participants' serostatus and sexual violence. HIV negative women in serodiscordant relationships (36.1±11.1 years, range: 19-65 years) were significantly older than either HIV positive women in serodiscordant relationships (32.2±9.0 years, range: 18-56 years), or HIV negative women in concordant relationships (32.3±11.0 years, range: 18-62), (p=0.033). Early age at sexual debut was associated with a 2.4-fold increased risk of experiencing sexual violence (OR 2.4, 95% CI 1.27-4.65). Based on unadjusted analysis, HIV positive women in discordant relationship were at highest risk for sexual violence compared to HIV negative women in discordant unions, and HIV negative women in negative concordant unions. HIV negative women in discordant relationships and those in concordant negative relationships showed no increased risk for sexual violence. However, couples' HIV

Enhancing Quantum Discord in Cavity QED by Applying Classical Driving Field

International Nuclear Information System (INIS)

Qian Yi; Xu Jing-Bo

2012-01-01

We investigate the quantum discord dynamics in a cavity quantum electrodynamics system, which consists of two noninteracting two-level atoms driven by independent optical fields and classical fields, and find that the quantum discord vanishes only asymptotically although entanglement disappears suddenly during the time evolution in the absence of classical fields. It is shown that the amount of quantum discord can be increased by adjusting the classical driving fields because the increasing degree of the amount of quantum mutual information is greater than classical correlation by applying the classical driving fields. Finally, the influence of the classical driving field on the fidelity of the system is also examined. (general)

Entanglement and discord of the superposition of Greenberger-Horne-Zeilinger states

International Nuclear Information System (INIS)

Parashar, Preeti; Rana, Swapan

2011-01-01

We calculate the analytic expression for geometric measure of entanglement for arbitrary superposition of two N-qubit canonical orthonormal Greenberger-Horne-Zeilinger (GHZ) states and the same for two W states. In the course of characterizing all kinds of nonclassical correlations, an explicit formula for quantum discord (via relative entropy) for the former class of states has been presented. Contrary to the GHZ state, the closest separable state to the W state is not classical. Therefore, in this case, the discord is different from the relative entropy of entanglement. We conjecture that the discord for the N-qubit W state is log 2 N.

Illustrating, Quantifying, and Correcting for Bias in Post-hoc Analysis of Gene-Based Rare Variant Tests of Association

Science.gov (United States)

Grinde, Kelsey E.; Arbet, Jaron; Green, Alden; O'Connell, Michael; Valcarcel, Alessandra; Westra, Jason; Tintle, Nathan

2017-01-01

To date, gene-based rare variant testing approaches have focused on aggregating information across sets of variants to maximize statistical power in identifying genes showing significant association with diseases. Beyond identifying genes that are associated with diseases, the identification of causal variant(s) in those genes and estimation of their effect is crucial for planning replication studies and characterizing the genetic architecture of the locus. However, we illustrate that straightforward single-marker association statistics can suffer from substantial bias introduced by conditioning on gene-based test significance, due to the phenomenon often referred to as “winner's curse.” We illustrate the ramifications of this bias on variant effect size estimation and variant prioritization/ranking approaches, outline parameters of genetic architecture that affect this bias, and propose a bootstrap resampling method to correct for this bias. We find that our correction method significantly reduces the bias due to winner's curse (average two-fold decrease in bias, p bias and improve inference in post-hoc analysis of gene-based tests under a wide variety of genetic architectures. PMID:28959274

Fine-scale patterns of population stratification confound rare variant association tests.

Directory of Open Access Journals (Sweden)

Timothy D O'Connor

Full Text Available Advances in next-generation sequencing technology have enabled systematic exploration of the contribution of rare variation to Mendelian and complex diseases. Although it is well known that population stratification can generate spurious associations with common alleles, its impact on rare variant association methods remains poorly understood. Here, we performed exhaustive coalescent simulations with demographic parameters calibrated from exome sequence data to evaluate the performance of nine rare variant association methods in the presence of fine-scale population structure. We find that all methods have an inflated spurious association rate for parameter values that are consistent with levels of differentiation typical of European populations. For example, at a nominal significance level of 5%, some test statistics have a spurious association rate as high as 40%. Finally, we empirically assess the impact of population stratification in a large data set of 4,298 European American exomes. Our results have important implications for the design, analysis, and interpretation of rare variant genome-wide association studies.

Monozygotic twins discordant for ROHHAD phenotype.

Science.gov (United States)

Patwari, Pallavi P; Rand, Casey M; Berry-Kravis, Elizabeth M; Ize-Ludlow, Diego; Weese-Mayer, Debra E

2011-09-01

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) falls within a group of pediatric disorders with both respiratory control and autonomic nervous system dysregulation. Children with ROHHAD typically present after 1.5 years of age with rapid weight gain as the initial sign. Subsequently, they develop alveolar hypoventilation, autonomic nervous system dysregulation, and, if untreated, cardiorespiratory arrest. To our knowledge, this is the first report of discordant presentation of ROHHAD in monozygotic twins. Twin girls, born at term, had concordant growth and development until 8 years of age. From 8 to 12 years of age, the affected twin developed features characteristic of ROHHAD including obesity, alveolar hypoventilation, scoliosis, hypothalamic dysfunction (central diabetes insipidus, hypothyroidism, premature pubarche, and growth hormone deficiency), right paraspinal/thoracic ganglioneuroblastoma, seizures, and autonomic dysregulation including altered pain perception, large and sluggishly reactive pupils, hypothermia, and profound bradycardia that required a cardiac pacemaker. Results of genetic testing for PHOX2B (congenital central hypoventilation syndrome disease-defining gene) mutations were negative. With early recognition and conservative management, the affected twin had excellent neurocognitive outcome that matched that of the unaffected twin. The unaffected twin demonstrated rapid weight gain later in age but not development of signs/symptoms consistent with ROHHAD. This discordant twin pair demonstrates key features of ROHHAD including the importance of early recognition (especially hypoventilation), complexity of signs/symptoms and clinical course, and importance of initiating comprehensive, multispecialty care. These cases confound the hypothesis of a monogenic etiology for ROHHAD and indicate alternative etiologies including autoimmune or epigenetic phenomenon or a combination of genetic

Non-local correlation and quantum discord in two atoms in the non-degenerate model

International Nuclear Information System (INIS)

Mohamed, A.-B.A.

2012-01-01

By using geometric quantum discord (GQD) and measurement-induced nonlocality (MIN), quantum correlation is investigated for two atoms in the non-degenerate two-photon Tavis–Cummings model. It is shown that there is no asymptotic decay for MIN while asymptotic decay exists for GQD. Quantum correlations can be strengthened by introducing the dipole–dipole interaction. The evolvement period of quantum correlation gets shorter with the increase in the dipole–dipole parameter. It is found that there exists not only quantum nonlocality without entanglement but also quantum nonlocality without quantum discord. Also, the MIN and GQD are raised rather than entanglement, and also with weak initial entanglement, there are MIN and entanglement in a interval of death quantum discord. - Highlights: ► Geometric quantum discord (GQD) and measurement induced nonlocality (MIN) are used to investigate the correlations of two two-level atoms. ► There is no asymptotic decay for MIN while asymptotic decay exists for GQD. ► Quantum correlations can be strengthened by introducing the dipole–dipole interaction. ► There exists not only quantum nonlocality without entanglement but also without discord. ► Weak initial entanglement leads to MIN and entanglement in intervals of death discord.

Geometric measure of quantum discord and total quantum correlations in an N-partite quantum state

International Nuclear Information System (INIS)

Hassan, Ali Saif M; Joag, Pramod S

2012-01-01

Quantum discord, as introduced by Ollivier and Zurek (2001 Phys. Rev. Lett. 88 017901), is a measure of the discrepancy between quantum versions of two classically equivalent expressions for mutual information and is found to be useful in quantification and application of quantum correlations in mixed states. It is viewed as a key resource present in certain quantum communication tasks and quantum computational models without containing much entanglement. An early step toward the quantification of quantum discord in a quantum state was by Dakic et al (2010 Phys. Rev. Lett. 105 190502) who introduced a geometric measure of quantum discord and derived an explicit formula for any two-qubit state. Recently, Luo and Fu (2010 Phys. Rev. A 82 034302) introduced a generic form of the geometric measure of quantum discord for a bipartite quantum state. We extend these results and find generic forms of the geometric measure of quantum discord and total quantum correlations in a general N-partite quantum state. Further, we obtain computable exact formulas for the geometric measure of quantum discord and total quantum correlations in an N-qubit quantum state. The exact formulas for the N-qubit quantum state can be used to get experimental estimates of the quantum discord and the total quantum correlation. (paper)

Sociodemographic Correlates of HIV Discordant and Concordant ...

African Journals Online (AJOL)

AIDS is significant. An understanding of the characteristics of HIV- affected couples will help modify preventive strategies. The aim of this study was to compare the HIV discordant and concordant partnerships for sociodemographic ...

Accurate Breakpoint Mapping in Apparently Balanced Translocation Families with Discordant Phenotypes Using Whole Genome Mate-Pair Sequencing

DEFF Research Database (Denmark)

Aristidou, Constantia; Koufaris, Costas; Theodosiou, Athina

2017-01-01

Familial apparently balanced translocations (ABTs) segregating with discordant phenotypes are extremely challenging for interpretation and counseling due to the scarcity of publications and lack of routine techniques for quick investigation. Recently, next generation sequencing has emerged...... and non-affected members carrying the same translocations. PTCD1, ATP5J2-PTCD1, CADPS2, and STPG1 were disrupted by the translocations in three families, rendering them initially as possible disease candidate genes. However, subsequent mutation screening and structural variant analysis did not reveal any...... can also be used in routine clinical investigation of ABT cases. Unlike de novo translocations, no associations were determined here between familial two-way ABTs and the phenotype of the affected members, in which the presence of cryptic imbalances and complex chromosomal rearrangements has been...

Analytic Expression of Geometric Discord in Arbitrary Mixture of any Two Bi-qubit Product Pure States

International Nuclear Information System (INIS)

Xie Chuan-Mei; Xing Hang; Zhang Zhan-Jun; Liu Yi-Min

2015-01-01

Quantum correlations in a family of states comprising any mixture of a pair of arbitrary bi-qubit product pure states are studied by employing geometric discord [Phys. Rev. Lett. 105 (2010) 190502] as the quantifier. First, the inherent symmetry in the family of states about local unitary transformations is revealed. Then, the analytic expression of geometric discords in the states is worked out. Some concrete discussions and analyses on the captured geometric discords are made so that their distinct features are exposed. It is found that, the more averagely the two bi-qubit product states are mixed, the bigger geometric discord the mixed state owns. Moreover, the monotonic relationships of geometric discord with different parameters are revealed. (paper)

Exercise — Exploring Mutuality and Discordance(s Between Sport and Public Health

Directory of Open Access Journals (Sweden)

Eling D. de Bruin

2013-01-01

Full Text Available Sports is a peer-reviewed scientific journal that revolves around the interdisciplinary area of exercise sciences applied in sport and public health. The intention of Sports is to link several scientific disciplines in an integrated fashion in order to address critical issues related to exercise science, sports and public health. As the first Editor-in-Chief of Sports, I would like to share a few comments about this interdisciplinary field of research by discussing the mutuality and discordances between exercise as it is applied in sports and public health.

prenatal ultrasound diagnosis of discordant occipital encephalocele

African Journals Online (AJOL)

drclement

PRENATAL ULTRASOUND DIAGNOSIS OF DISCORDANT OCCIPITAL. ENCEPHALOCELE IN MULTIPLE PREGNANCY - A CASE REPORT. *O.U Ogbeide (MBBS, FMCR), *EJ IKUBOR (MBBS). *Department of Radiology University of Benin Teaching Hospital, Benin-City, Nigeria. Correspondence: Dr Ogbeide Osesogie ...

Maternal concern about child weight in a study of weight-discordant siblings.

Science.gov (United States)

Kral, Tanja V E; Moore, Reneé H; Compher, Charlene W

2015-01-01

This study examined concern about child weight in mothers of weight-discordant siblings and determined the accuracy of maternal self-report versus measured child height, weight, and corresponding body mass index (BMI; kg/m(2) ) z-score. Discordant sibling design. Forty-seven mothers of 5- to 12-year-old, weight-discordant siblings. Mothers self-reported their concern about child weight for each child separately and for a subset of children, self-reported their heights and weights. Siblings' height, weight, waist circumference, and adiposity were measured. The majority (83%) of mothers expressed concern about their overweight/obese child's weight and 20% of mothers expressed concern about their normal-weight child's weight (p concern about child weight were positively associated with difference scores in sibling BMI z-score (r = 0.42; p = .01) and percent body fat (r = 0.56; p concern for their overweight/obese child's weight was greater for sibling pairs who were more discordant in their weight. © 2014 Wiley Periodicals, Inc.

Time Series Discord Detection in Medical Data using a Parallel Relational Database [PowerPoint

Energy Technology Data Exchange (ETDEWEB)

Woodbridge, Diane; Wilson, Andrew T.; Rintoul, Mark Daniel; Goldstein, Richard H.

2015-11-01

Recent advances in sensor technology have made continuous real-time health monitoring available in both hospital and non-hospital settings. Since data collected from high frequency medical sensors includes a huge amount of data, storing and processing continuous medical data is an emerging big data area. Especially detecting anomaly in real time is important for patients’ emergency detection and prevention. A time series discord indicates a subsequence that has the maximum difference to the rest of the time series subsequences, meaning that it has abnormal or unusual data trends. In this study, we implemented two versions of time series discord detection algorithms on a high performance parallel database management system (DBMS) and applied them to 240 Hz waveform data collected from 9,723 patients. The initial brute force version of the discord detection algorithm takes each possible subsequence and calculates a distance to the nearest non-self match to find the biggest discords in time series. For the heuristic version of the algorithm, a combination of an array and a trie structure was applied to order time series data for enhancing time efficiency. The study results showed efficient data loading, decoding and discord searches in a large amount of data, benefiting from the time series discord detection algorithm and the architectural characteristics of the parallel DBMS including data compression, data pipe-lining, and task scheduling.

Quantum discord and classical correlation signatures of mobility edges in one-dimensional aperiodic single-electron systems

International Nuclear Information System (INIS)

Gong, Longyan; Zhu, Hao; Zhao, Shengmei; Cheng, Weiwen; Sheng, Yubo

2012-01-01

We investigate numerically the quantum discord and the classical correlation in a one-dimensional slowly varying potential model and a one-dimensional Soukoulis–Economou ones, respectively. There are well-defined mobility edges in the slowly varying potential model, while there are discrepancies on mobility edges in the Soukoulis–Economou ones. In the slowly varying potential model, we find that extended and localized states can be distinguished by both the quantum discord and the classical correlation. There are sharp transitions in the quantum discord and the classical correlation at mobility edges. Based on these, we study “mobility edges” in the Soukoulis–Economou model using the quantum discord and the classical correlation, which gives another perspectives for these “mobility edges”. All these provide us good quantities, i.e., the quantum discord and the classical correlation, to reflect mobility edges in these one-dimensional aperiodic single-electron systems. Moreover, our studies propose a consistent interpretation of the discrepancies between previous numerical results about the Soukoulis–Economou model. -- Highlights: ► Quantum discord and classical correlation can signal mobility edges in two models. ► An interpretation for mobility edges in the Soukoulis–Economou model is proposed. ► Quantum discord and classical correlation can reflect well localization properties.

An Efficient Stepwise Statistical Test to Identify Multiple Linked Human Genetic Variants Associated with Specific Phenotypic Traits.

Directory of Open Access Journals (Sweden)

Iksoo Huh

Full Text Available Recent advances in genotyping methodologies have allowed genome-wide association studies (GWAS to accurately identify genetic variants that associate with common or pathological complex traits. Although most GWAS have focused on associations with single genetic variants, joint identification of multiple genetic variants, and how they interact, is essential for understanding the genetic architecture of complex phenotypic traits. Here, we propose an efficient stepwise method based on the Cochran-Mantel-Haenszel test (for stratified categorical data to identify causal joint multiple genetic variants in GWAS. This method combines the CMH statistic with a stepwise procedure to detect multiple genetic variants associated with specific categorical traits, using a series of associated I × J contingency tables and a null hypothesis of no phenotype association. Through a new stratification scheme based on the sum of minor allele count criteria, we make the method more feasible for GWAS data having sample sizes of several thousands. We also examine the properties of the proposed stepwise method via simulation studies, and show that the stepwise CMH test performs better than other existing methods (e.g., logistic regression and detection of associations by Markov blanket for identifying multiple genetic variants. Finally, we apply the proposed approach to two genomic sequencing datasets to detect linked genetic variants associated with bipolar disorder and obesity, respectively.

Post-mortem testing; germline BRCA1/2 variant detection using archival FFPE non-tumor tissue

DEFF Research Database (Denmark)

Petersen, Annabeth Høgh; Jørgensen, Mads Malik Aagaard; Nielsen, Henriette Roed

2016-01-01

Accurate estimation of cancer risk in HBOC families often requires BRCA1/2 testing, but this may be impossible in deceased family members. Previous, testing archival formalin-fixed, paraffin-embedded (FFPE) tissue for germline BRCA1/2 variants was unsuccessful, except for the Jewish founder mutat...... samples from non-tumor tissue. Accurate genetic counseling is achievable in families where variant testing would otherwise be impossible.European Journal of Human Genetics advance online publication, 6 January 2016; doi:10.1038/ejhg.2015.268....

Discordance in the diagnosis of diabetes: Comparison between HbA1c and fasting plasma glucose.

Science.gov (United States)

Ho-Pham, Lan T; Nguyen, Uyen D T; Tran, Truong X; Nguyen, Tuan V

2017-01-01

HbA1c has been introduced as a complementary diagnostic test for diabetes, but its impact on disease prevalence is unknown. This study evaluated the concordance between HbA1c and fasting plasma glucose (FPG) in the diagnosis of diabetes in the general population. The study was designed as a population based investigation, with participants being sampled from the Ho Chi Minh City, Vietnam. Blood samples were collected after overnight fasting and analyzed within 4 hours after collection. HbA1c was measured with high pressure liquid chromatography (Arkray Adams, Japan). FPG was measured by the hexokinase method (Advia Autoanalyzer; Bayer Diagnostics, Germany). Diabetes was defined as HbA1c ≥ 6.5% or FPG ≥ 7.0 mmol/L. Prediabetes was classified as HbA1c between 5.7% and 6.4%. The study included 3523 individuals (2356 women) aged 30 years and above. Based on the HbA1c test, the prevalence of diabetes and prediabetes was 9.7% (95%CI, 8.7-10.7%; n = 342) and 34.6% (33.0-36.2; n = 1219), respectively. Based on the FPG test, the prevalence of diabetes and prediabetes was 6.3% (95%CI, 5.5-7.2%; n = 223) and 12.1% (11.1-13.2; n = 427). Among the 427 individuals identified by FPG as "pre-diabetes", 28.6% were classified as diabetes by HbA1c test. The weighted kappa statistic of concordance between HbA1c and FPG was 0.55, with most of the discordance being in the prediabetes group. These data indicate that there is a significant discordance in the diagnosis of diabetes between FPG and HbA1c measurements, and the discordance could have significant impact on clinical practice. FPG appears to underestimate the burden of undiagnosed diabetes.

Analyses of User Rationality and System Learnability: Performing Task Variants in User Tests

Science.gov (United States)

Law, Effie Lai-Chong; Blazic, Borka Jerman; Pipan, Matic

2007-01-01

No systematic empirical study on investigating the effects of performing task variants on user cognitive strategy and behaviour in usability tests and on learnability of the system being tested has been documented in the literature. The current use-inspired basic research work aims to identify the underlying cognitive mechanisms and the practical…

Mito-nuclear discord in six congeneric lineages of Holarctic ducks (genus Anas).

Science.gov (United States)

Peters, Jeffrey L; Winker, Kevin; Millam, Kendra C; Lavretsky, Philip; Kulikova, Irina; Wilson, Robert E; Zhuravlev, Yuri N; McCracken, Kevin G

2014-06-01

Many species have Holarctic distributions that extend across Europe, Asia and North America. Most genetics research on these species has examined only mitochondrial (mt) DNA, which has revealed wide variance in divergence between Old World (OW) and New World (NW) populations, ranging from shallow, unstructured genealogies to deeply divergent lineages. In this study, we sequenced 20 nuclear introns to test for concordant patterns of OW-NW differentiation between mtDNA and nuclear (nu) DNA for six lineages of Holarctic ducks (genus Anas). Genetic differentiation for both marker types varied widely among these lineages (idiosyncratic population histories), but mtDNA and nuDNA divergence within lineages was not significantly correlated. Moreover, compared with the association between mtDNA and nuDNA divergence observed among different species, OW-NW nuDNA differentiation was generally lower than mtDNA divergence, at least for lineages with deeply divergent mtDNA. Furthermore, coalescent estimates indicated significantly higher rates of gene flow for nuDNA than mtDNA for four of the six lineages. Thus, Holarctic ducks show prominent mito-nuclear discord between OW and NW populations, and we reject differences in sorting rates as the sole cause of the within-species discord. Male-mediated intercontinental gene flow is likely a leading contributor to this discord, although selection could also cause increased mtDNA divergence relative to weak nuDNA differentiation. The population genetics of these ducks contribute to growing evidence that mtDNA can be an unreliable indicator of stage of speciation and that more holistic approaches are needed for species delimitation. © 2014 John Wiley & Sons Ltd.

Incident HSV-2 Infections Are Common Among HIV-1-discordant Couples

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Muiru, Anthony N.; Guthrie, Brandon L.; Bosire, Rose; Merkel, Michele; Liu, Amy Y.; Choi, Robert Y.; Lohman-Payne, Barbara; Gatuguta, Ann; Mackelprang, Romel D.; Kiarie, James N.; Farquhar, Carey

2013-01-01

Background. The synergy between herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1) is well known, but lack of knowledge about the epidemiology of HSV-2 acquisition in HIV-1-discordant couples hampers development of HSV-2 prevention interventions that could reduce HIV-1 transmission. Methods. HIV-1-discordant couples were enrolled in Nairobi, Kenya, and followed for up to 2 years. HSV-2 status was determined using HerpeSelect HSV-2 ELISA. Correlates of prevalence and incidence were assessed. Results. Of 469 HIV-1-discordant couples, at baseline, 353 (75.3%) were affected by HSV-2, of which 189 (53.5%) were concordantly HSV-2 seropositive and 164 (46.5%) were HSV-2-discordant. Prevalence was lowest among HIV-1-uninfected men (39.9%) compared to HIV-1-infected women (64.8%), HIV-1-infected men (66.7%), and HIV-1-uninfected women (68.5%). During follow-up, HSV-2 seroincidence was 14.9 per 100 person-years. Incidence was 1.6-fold higher among females compared to males (95% confidence interval [CI], 1.00–2.48) and 2.5-fold higher in HIV-1-infected compared to uninfected women (95% CI, 1.12–5.74). At least 30% of incident HSV-2 infections originated from an outside partner. Conclusions. The high HSV-2 prevalence and incidence in HIV-1-discordant couples in sub-Saharan Africa suggest HSV-2 treatment and prevention could be an effective targeted strategy to reduce HSV-2 and HIV-1 transmission in this high-risk population. PMID:23840044

Quantum discord for a central two-qubit system coupled to an XY-spin-chain environment

International Nuclear Information System (INIS)

Liu Benqiong; Shao Bin; Zou Jian

2010-01-01

We investigate the dynamic behaviors of quantum discord for a central two-qubit system coupled to an XY-spin-chain environment. In the weak-coupling regime, we show that the quantum discord for the two central qubits can become minimized rapidly close to the critical point of a quantum phase transition. By considering the two qubits that are initially prepared in the Werner state, we study the evolution of the quantum discord and that of entanglement under the same conditions. Our results imply that entanglement can disappear completely after a finite time, while the quantum discord decreases and tends to be a stable value according to the initial-state parameter for a very-long-time interval. In this sense, the quantum discord is more robust than entanglement for the quantum system exposed to the environment. The relation between the quantum correlations and the classical correlation is also shown for two particular cases.

The double switch for atrioventricular discordance.

Science.gov (United States)

Brawn, William J

2005-01-01

Conventional surgery for atrioventricular discordance usually associated with ventricular arterial discordance leaves the morphologic right ventricle in the systemic circulation. Long-term follow-up results with this approach reveal a high incidence of right ventricular failure. The double switch procedure was introduced to restore the morphologic left ventricle to the systemic circulation. This operation is performed in two main ways: the atrial-arterial switch and the atrial switch plus Rastelli procedure. This double switch approach has been successful at least in the medium term in abolishing morphologic right ventricular failure and its associated tricuspid valve regurgitation. In the atrial-arterial switch group, there is an incidence of morphologic left ventricular dysfunction, sometimes associated with neoaortic valve regurgitation, and the minority of cases need aortic valve replacement. The long-term function of the morphologic left ventricle and the aortic valve need careful surveillance in the future. The atrial-Rastelli group of patients has not in the medium term shown evidence of ventricular dysfunction but will require change on a regular basis of their ventricular to pulmonary artery valved conduits.

A Qualitative Study of Anticipated Decision Making around Type 2 Diabetes Genetic Testing: the Role of Scientifically Concordant and Discordant Expectations.

Science.gov (United States)

Carmichael, Alicia G; Hulswit, Bailey B; Moe, Emily J; Jayaratne, Toby Epstein; Yashar, Beverly M

2017-06-01

Type 2 diabetes mellitus (T2DM) genetic testing is undergoing clinical trials to measure the efficacy of genetic counseling for behavior-based risk reduction. The expectations patients bring to the testing process may play an important role in individual outcomes. We conducted a qualitative exploration of anticipated decision-making and expectations around T2DM genetic testing. Semi-structured interviews were completed with Mexican Americans (n = 34), non-Hispanic Black Americans (n = 39), and non-Hispanic White Americans (n = 39) at risk for T2DM. Transcripts were analyzed for themes. Most participants would accept T2DM genetic testing in order to motivate risk-reducing behaviors or apprise family members of their risk. Participants who would decline testing wished to avoid emotional distress or believed the test would not reveal new risk information. Non-Hispanic Whites and those with college education declined genetic testing more often than other groups. Those without college education were more likely to have testing expectations that were discordant with current science, such as conflating genetic testing with common 'blood tests.' Understanding expectations and decision-making factors around T2DM genetic testing will better prepare healthcare professionals to counsel their patients. This may lead to a higher efficacy of T2DM genetic testing and counseling.

Metabolome and fecal microbiota in monozygotic twin pairs discordant for weight: a Big Mac challenge.

Science.gov (United States)

Bondia-Pons, Isabel; Maukonen, Johanna; Mattila, Ismo; Rissanen, Aila; Saarela, Maria; Kaprio, Jaakko; Hakkarainen, Antti; Lundbom, Jesper; Lundbom, Nina; Hyötyläinen, Tuulia; Pietiläinen, Kirsi H; Orešič, Matej

2014-09-01

Postprandial responses to food are complex, involving both genetic and environmental factors. We studied postprandial responses to a Big Mac meal challenge in monozygotic co-twins highly discordant for body weight. This unique design allows assessment of the contribution of obesity, independent of genetic liability. Comprehensive metabolic profiling using 3 analytical platforms was applied to fasting and postprandial serum samples from 16 healthy monozygotic twin pairs discordant for weight (body mass index difference >3 kg/m(2)). Nine concordant monozygotic pairs were examined as control pairs. Fecal samples were analyzed to assess diversity of the major bacterial groups by using 5 different validated bacterial group specific denaturing gradient gel electrophoresis methods. No differences in fecal bacterial diversity were detected when comparing co-twins discordant for weight (ANOVA, P<0.05). We found that within-pair similarity is a dominant factor in the metabolic postprandial response, independent of acquired obesity. Branched chain amino acids were increased in heavier as compared with leaner co-twins in the fasting state, but their levels converged postprandially (paired t tests, FDR q<0.05). We also found that specific bacterial groups were associated with postprandial changes of specific metabolites. Our findings underline important roles of genetic and early life factors in the regulation of postprandial metabolite levels. © FASEB.

Quantum Discord Determines the Interferometric Power of Quantum States

Science.gov (United States)

Girolami, Davide; Souza, Alexandre M.; Giovannetti, Vittorio; Tufarelli, Tommaso; Filgueiras, Jefferson G.; Sarthour, Roberto S.; Soares-Pinto, Diogo O.; Oliveira, Ivan S.; Adesso, Gerardo

2014-05-01

Quantum metrology exploits quantum mechanical laws to improve the precision in estimating technologically relevant parameters such as phase, frequency, or magnetic fields. Probe states are usually tailored to the particular dynamics whose parameters are being estimated. Here we consider a novel framework where quantum estimation is performed in an interferometric configuration, using bipartite probe states prepared when only the spectrum of the generating Hamiltonian is known. We introduce a figure of merit for the scheme, given by the worst-case precision over all suitable Hamiltonians, and prove that it amounts exactly to a computable measure of discord-type quantum correlations for the input probe. We complement our theoretical results with a metrology experiment, realized in a highly controllable room-temperature nuclear magnetic resonance setup, which provides a proof-of-concept demonstration for the usefulness of discord in sensing applications. Discordant probes are shown to guarantee a nonzero phase sensitivity for all the chosen generating Hamiltonians, while classically correlated probes are unable to accomplish the estimation in a worst-case setting. This work establishes a rigorous and direct operational interpretation for general quantum correlations, shedding light on their potential for quantum technology.

Discordance of conflict of interest self-disclosure and the Centers of Medicare and Medicaid Services.

Science.gov (United States)

Cherla, Deepa V; Olavarria, Oscar A; Holihan, Julie L; Viso, Cristina Perez; Hannon, Craig; Kao, Lillian S; Ko, Tien C; Liang, Mike K

2017-10-01

The Open Payments Database (OPD) discloses financial transactions between manufacturers and physicians. The concordance of OPD versus self-reported conflicts of interest (COI) is unknown. Our objectives were to compare (1) industry and self-disclosed COI in clinical literature, (2) payments within each disclosure level, and (3) industry- and self-disclosed COI and payments by specialty. This was an observational study. PubMed was searched for clinical studies accepted for publication from January 2014 to June 2016. Author and OPD-disclosed COIs were compared. Articles and authors were divided into full disclosure, incomplete industry disclosure, incomplete self-disclosure, and no COI. Primary outcome (differences in reported COI per article) was assessed using McNemar's test. Payment differences were compared using Kruskal-Wallis test. OPD- and self-disclosed COI differed (65.0% discordance rate by article, P disclosure category differed between specialties (P self-disclosure ($30,812). Significant discordance exists between self- and OPD-reported COI. Additional research is needed to determine reasons for these differences. Copyright © 2017 Elsevier Inc. All rights reserved.

Can the Catholic Church agree to condom use by HIV-discordant couples?

Science.gov (United States)

Bovens, L

2009-12-01

Does the position of the Roman Catholic Church on contraception also imply that the usage of condoms by HIV-discordant couples is illicit? A standard argument is to appeal to the doctrine of double effect to condone such usage, but this meets with the objection that there exists an alternative action that brings about the good effect-namely, abstinence. I argue against this objection, because an HIV-discordant couple does not bring about any bad outcome through condom usage-there is no disrespect displayed for the generative function of sex. One might retort that the badness of condom usage consists in thwarting the unitive function of sex. I argue that also this objection cannot be upheld. In conclusion, if there are no in-principle objections against condom usage for HIV-discordant couples, then policies that deny access to condoms to such couples are indefensible. HIV-discordant couples have a right to continue consummating their marriage in a manner that is minimally risky and this right cannot be trumped by utilitarian concerns that the distribution of condoms might increase promiscuity and along with it the HIV infection rate.

gsSKAT: Rapid gene set analysis and multiple testing correction for rare-variant association studies using weighted linear kernels.

Science.gov (United States)

Larson, Nicholas B; McDonnell, Shannon; Cannon Albright, Lisa; Teerlink, Craig; Stanford, Janet; Ostrander, Elaine A; Isaacs, William B; Xu, Jianfeng; Cooney, Kathleen A; Lange, Ethan; Schleutker, Johanna; Carpten, John D; Powell, Isaac; Bailey-Wilson, Joan E; Cussenot, Olivier; Cancel-Tassin, Geraldine; Giles, Graham G; MacInnis, Robert J; Maier, Christiane; Whittemore, Alice S; Hsieh, Chih-Lin; Wiklund, Fredrik; Catalona, William J; Foulkes, William; Mandal, Diptasri; Eeles, Rosalind; Kote-Jarai, Zsofia; Ackerman, Michael J; Olson, Timothy M; Klein, Christopher J; Thibodeau, Stephen N; Schaid, Daniel J

2017-05-01

Next-generation sequencing technologies have afforded unprecedented characterization of low-frequency and rare genetic variation. Due to low power for single-variant testing, aggregative methods are commonly used to combine observed rare variation within a single gene. Causal variation may also aggregate across multiple genes within relevant biomolecular pathways. Kernel-machine regression and adaptive testing methods for aggregative rare-variant association testing have been demonstrated to be powerful approaches for pathway-level analysis, although these methods tend to be computationally intensive at high-variant dimensionality and require access to complete data. An additional analytical issue in scans of large pathway definition sets is multiple testing correction. Gene set definitions may exhibit substantial genic overlap, and the impact of the resultant correlation in test statistics on Type I error rate control for large agnostic gene set scans has not been fully explored. Herein, we first outline a statistical strategy for aggregative rare-variant analysis using component gene-level linear kernel score test summary statistics as well as derive simple estimators of the effective number of tests for family-wise error rate control. We then conduct extensive simulation studies to characterize the behavior of our approach relative to direct application of kernel and adaptive methods under a variety of conditions. We also apply our method to two case-control studies, respectively, evaluating rare variation in hereditary prostate cancer and schizophrenia. Finally, we provide open-source R code for public use to facilitate easy application of our methods to existing rare-variant analysis results. © 2017 WILEY PERIODICALS, INC.

HIV Status Discordance: Associated Factors Among HIV Positive ...

African Journals Online (AJOL)

AJRH Managing Editor

HIV status Discordance among Pregnant Women in Lagos. African Journal ... Social marketing aimed at reducing concurrency should focus on both male and females, if we must .... This strategy is insufficient as available evidence shows that ...

Description of Discordance Between LDL Cholesterol, Non-HDL Cholesterol, and LDL Particle Number Among Patients of a Lipid Clinic

Directory of Open Access Journals (Sweden)

Joshua W Gaborcik

2017-09-01

Full Text Available Background: While LDL cholesterol measures the cholesterol content within an LDL particle (LDL-P, it may not reflect LDL-P concentrations. If discordance exists, LDL-P may better predict cardiovascular events compared to LDL-C and non-HDL cholesterol (non-HDL-C. In primary prevention patients, discordance has been associated with diabetes, ethnicity, gender, metabolic syndrome, and smoking history. Objective: To describe discordance in patients of a lipid clinic by exploring associations between patient characteristics and discordance among LDL-C, non-HDL-C, or LDL-P. Secondarily to compare proportion of patients with baseline concordance versus discordance who have ASCVD events, diagnoses of new onset diabetes or death. Methods: A retrospective, single-center cohort study at a large academic medical center was conducted. Patients establishing care from January 2009 through December 2012 with complete initial labs were included. Logistic regression models were used to explore associations between discordance and patient characteristics. Results: Of 603 patients screened, the final cohort included 166 patients with 104 (62.7% discordant. LDL-P was the most common discordant value. Discordance was associated with gender, smoking status, use of lipid lowering medications, and achieving patient specific LDL-C goals. In terms of any event observed after initial measurements, no significant differences were detected between discordant and concordant groups. Conclusion: Within a lipid clinic population, discordance was associated with male gender, smoking status, lipid-lowering therapy, and being at patient specific LDL-C goal. While associations were found in our population, clinicians should consider measuring LDL-P to fully assess presence or extent of discordance. Conflict of Interest We declare no conflicts of interest or financial interests that the authors or members of their immediate families have in any product or service discussed in the

Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits.

Science.gov (United States)

Wong, C C Y; Meaburn, E L; Ronald, A; Price, T S; Jeffries, A R; Schalkwyk, L C; Plomin, R; Mill, J

2014-04-01

Autism spectrum disorder (ASD) defines a group of common, complex neurodevelopmental disorders. Although the aetiology of ASD has a strong genetic component, there is considerable monozygotic (MZ) twin discordance indicating a role for non-genetic factors. Because MZ twins share an identical DNA sequence, disease-discordant MZ twin pairs provide an ideal model for examining the contribution of environmentally driven epigenetic factors in disease. We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort. This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism.

Comparison of Ion Personal Genome Machine Platforms for the Detection of Variants in BRCA1 and BRCA2.

Science.gov (United States)

Hwang, Sang Mee; Lee, Ki Chan; Lee, Min Seob; Park, Kyoung Un

2018-01-01

Transition to next generation sequencing (NGS) for BRCA1 / BRCA2 analysis in clinical laboratories is ongoing but different platforms and/or data analysis pipelines give different results resulting in difficulties in implementation. We have evaluated the Ion Personal Genome Machine (PGM) Platforms (Ion PGM, Ion PGM Dx, Thermo Fisher Scientific) for the analysis of BRCA1 /2. The results of Ion PGM with OTG-snpcaller, a pipeline based on Torrent mapping alignment program and Genome Analysis Toolkit, from 75 clinical samples and 14 reference DNA samples were compared with Sanger sequencing for BRCA1 / BRCA2 . Ten clinical samples and 14 reference DNA samples were additionally sequenced by Ion PGM Dx with Torrent Suite. Fifty types of variants including 18 pathogenic or variants of unknown significance were identified from 75 clinical samples and known variants of the reference samples were confirmed by Sanger sequencing and/or NGS. One false-negative results were present for Ion PGM/OTG-snpcaller for an indel variant misidentified as a single nucleotide variant. However, eight discordant results were present for Ion PGM Dx/Torrent Suite with both false-positive and -negative results. A 40-bp deletion, a 4-bp deletion and a 1-bp deletion variant was not called and a false-positive deletion was identified. Four other variants were misidentified as another variant. Ion PGM/OTG-snpcaller showed acceptable performance with good concordance with Sanger sequencing. However, Ion PGM Dx/Torrent Suite showed many discrepant results not suitable for use in a clinical laboratory, requiring further optimization of the data analysis for calling variants.

Adult glucose metabolism in extremely birthweight-discordant monozygotic twins

DEFF Research Database (Denmark)

Frost, M; Petersen, I; Brixen, K

2012-01-01

Low birthweight (BW) is associated with increased risk of type 2 diabetes. We compared glucose metabolism in adult BW-discordant monozygotic (MZ) twins, thereby controlling for genetic factors and rearing environment....

Detecting rare variants in case-parents association studies.

Directory of Open Access Journals (Sweden)

Kuang-Fu Cheng

Full Text Available Despite the success of genome-wide association studies (GWASs in detecting common variants (minor allele frequency ≥0.05 many suggested that rare variants also contribute to the genetic architecture of diseases. Recently, researchers demonstrated that rare variants can show a strong stratification which may not be corrected by using existing methods. In this paper, we focus on a case-parents study and consider methods for testing group-wise association between multiple rare (and common variants in a gene region and a disease. All tests depend on the numbers of transmitted mutant alleles from parents to their diseased children across variants and hence they are robust to the effect of population stratification. We use extensive simulation studies to compare the performance of four competing tests: the largest single-variant transmission disequilibrium test (TDT, multivariable test, combined TDT, and a likelihood ratio test based on a random-effects model. We find that the likelihood ratio test is most powerful in a wide range of settings and there is no negative impact to its power performance when common variants are also included in the analysis. If deleterious and protective variants are simultaneously analyzed, the likelihood ratio test was generally insensitive to the effect directionality, unless the effects are extremely inconsistent in one direction.

Placental pathology, birthweight discordance, and growth restriction in twin pregnancy: results of the ESPRiT Study.

Science.gov (United States)

Kent, Etaoin M; Breathnach, Fionnuala M; Gillan, John E; McAuliffe, Fionnuala M; Geary, Michael P; Daly, Sean; Higgins, John R; Hunter, Alyson; Morrison, John J; Burke, Gerard; Higgins, Shane; Carroll, Stephen; Dicker, Patrick; Manning, Fiona; Tully, Elizabeth; Malone, Fergal D

2012-09-01

We sought to evaluate the association between placental histological abnormalities and birthweight discordance and growth restriction in twin pregnancies. We performed a multicenter, prospective study of twin pregnancies. Placentas were examined for evidence of infarction, retroplacental hemorrhage, chorangioma, subchorial fibrin, or abnormal villus maturation. Association of placental lesions with chorionicity, birthweight discordance, and growth restriction were assessed. In all, 668 twin pairs were studied, 21.1% monochorionic and 78.9% dichorionic. Histological abnormalities were more frequent in placentas of smaller twins of birthweight discordant pairs (P = .02) and in placentas of small for gestational age infants (P = .0001) when compared to controls. The association of placental abnormalities with both birthweight discordance and small for gestational age was significant for dichorionic twins (P = .01 and .0001, respectively). No such association was seen in monochorionic twins. In a large, prospective, multicenter study, we observed a strong relationship between abnormalities of placental histology and birthweight discordance and growth restriction in dichorionic, but not monochorionic, twin pregnancies. Copyright © 2012 Mosby, Inc. All rights reserved.

Hybrid modelling of bed-discordant river confluences

Science.gov (United States)

Franca, M. J.; Guillén-Ludeña, S.; Cheng, Z.; Cardoso, A. H.; Constantinescu, G.

2016-12-01

In fluvial networks, tributaries are the main providers of sediment and water to the main rivers. Furthermore, confluences are environmental hotspots since they provide ecological connectivity and flow and morphology diversity. Mountain confluences, in particular, are characterized by narrow and steep tributaries that provide important sediment load to the confluence, whereas the main channel supplies the dominant flow discharge. This results in a marked bed discordance between the tributary and main channel. This discordance has been observed to be a key feature that alters the dynamics of the confluence, when compared to concordant confluences. The processes of initiation and maintenance of the morphology of confluences is still unknown, and research linking morphodynamics and hydrodynamics of river confluences is required to understand this. Here, a hybrid approach combining laboratory experiments made in a live-bed model of a river confluence, with 3D numerical simulations using advanced turbulence models is presented. We use the laboratory experiments performed by Guillén-Ludeña et al. (2016) for a 70o channel confluence, which focused on sediment transport and morphology changes rather than on the structure of the flow. Highly eddy resolving simulations were performed for two extreme bathymetric conditions, at the start of the experiment and at equilibrium scour conditions. The first allows to understand the initiation mechanisms which will condition later the equilibrium morphology. The second allows to understand the hydrodynamics actions which keep the equilibrium morphology. The patterns of the mean flow, turbulence and dynamics of the large-scale coherent structures, show how the main sediment-entrainment mechanisms evolve during the scour process. The present results contribute to a better understanding of the interaction between bed morphology and flow dynamics at discordant mountain river confluences.

Risky sexual behaviours among HIV Sero-discordant individuals ...

African Journals Online (AJOL)

Backgound: HIV/AIDS pandemic is a great public health concern hence the need to identify interventions to prevent new infections among risk groups. Objective: To determine risky sexual behaviours among HIV sero-discordant individuals attending Defence Forces Memorial Hospital (DFMH). Design: A descriptive ...

Development of AACAP practice parameters for gender nonconformity and gender discordance in children and adolescents.

Science.gov (United States)

Adelson, Stewart L

2011-10-01

The American Academy of Child and Adolescent Psychiatry (AACAP) is preparing a publication, Practice Parameter on Gay, Lesbian or Bisexual Sexual Orientation, Gender-Nonconformity, and Gender Discordance in Children and Adolescents. This article discusses the development of the part of the parameter related to gender nonconformity and gender discordance and describes the practice parameter preparation process,rationale, key scientific evidence, and methodology. Also discussed are terminology considerations, related clinical issues and practice skills, and overall organization of information including influences on gender development, gender role behavior, gender nonconformity and gender discordance, and their relationship to the development of sexual orientation.

Fitness of isogenic colony morphology variants of Pseudomonas aeruginosa in murine airway infection.

Directory of Open Access Journals (Sweden)

Elza Rakhimova

Full Text Available Chronic lung infections with Pseudomonas aeruginosa are associated with the diversification of the persisting clone into niche specialists and morphotypes, a phenomenon called 'dissociative behaviour'. To explore the potential of P. aeruginosa to change its morphotype by single step loss-of-function mutagenesis, a signature-tagged mini-Tn5 plasposon library of the cystic fibrosis airway isolate TBCF10839 was screened for colony morphology variants under nine different conditions in vitro. Transposon insertion into 1% of the genome changed colony morphology into eight discernable morphotypes. Half of the 55 targets encode features of primary or secondary metabolism whereby quinolone production was frequently affected. In the other half the transposon had inserted into genes of the functional categories transport, regulation or motility/chemotaxis. To mimic dissociative behaviour of isogenic strains in lungs, pools of 25 colony morphology variants were tested for competitive fitness in an acute murine airway infection model. Six of the 55 mutants either grew better or worse in vivo than in vitro, respectively. Metabolic proficiency of the colony morphology variant was a key determinant for survival in murine airways. The most common morphotype of self-destructive autolysis did unexpectedly not impair fitness. Transposon insertions into homologous genes of strain PAO1 did not reproduce the TBCF10839 mutant morphotypes for 16 of 19 examined loci pointing to an important role of the genetic background on colony morphology. Depending on the chosen P. aeruginosa strain, functional genome scans will explore other areas of the evolutionary landscape. Based on our discordant findings of mutant phenotypes in P. aeruginosa strains PAO1, PA14 and TBCF10839, we conclude that the current focus on few reference strains may miss modes of niche adaptation and dissociative behaviour that are relevant for the microevolution of complex traits in the wild.

Discordance Between Appropriate Use Criteria for Nuclear Myocardial Perfusion Imaging From Different Specialty Societies: A Potential Concern for Health Policy.

Science.gov (United States)

Winchester, David E; Wolinsky, David; Beyth, Rebecca J; Shaw, Leslee J

2016-05-01

Appropriate use criteria (AUC) assist health care professionals in making decisions about procedures and diagnostic testing. In some cases, multiple AUC exist for a single procedure or test. To date, the extent of agreement between multiple AUC has not been evaluated. To measure discordance between the American College of Cardiology Foundation (ACCF) AUC and the American College of Radiology (ACR) Appropriateness Criteria for gauging the appropriateness of nuclear myocardial perfusion imaging. Retrospective cohort study at an academically affiliated Veterans Affairs medical center. Participants were Veteran patients who underwent nuclear myocardial perfusion imaging between December 2010 and July 2011 with rating of appropriateness by the ACCF and ACR criteria. Analysis was performed in March 2015. The primary outcome was the agreement of appropriateness category as measured by κ statistic. The secondary outcome was a comparison of nuclear myocardial perfusion imaging results and frequency of ischemia across appropriateness categories for the 2 rating methods. Of 67 indications in the ACCF AUC, 35 (52.2%) could not be matched to an ACR rating, 18 (26.9%) had the same appropriateness category, and 14 (20.9%) disagreed on appropriateness. The study cohort comprised 592 individuals. Their mean (SD) age was 62.6 (9.4) years, and 570 of 592 (96.2%) were male. When applied to the patient cohort, 111 patients (18.8%) could not be matched to an ACR rating, 349 patients (59.0%) had the same appropriateness category for the ACR and ACCF methods, and 132 patients (22.3%) were discordant. Overall, the agreement of appropriateness between the 2 methods was poor (κ = 0.34, P < .001). Ischemia was rare among patients rated as "inappropriate" by the ACCF AUC (1 of 39 patients [2.6%]), while ischemia was more common among patients rated as "usually not appropriate" by the ACR Appropriateness Criteria (14 of 80 patients [17.5%]). Substantial discordance may exist between

Discordance Rate between Thyroid Fine Needle Aspiration Cytology ...

African Journals Online (AJOL)

Discordance Rate between Thyroid Fine Needle Aspiration Cytology and Histopathologic Diagnosis. Wondwossen Ergete, Daniel Abebe. Abstract. Fine Needle Aspiration (FNA) of the thyroid is a low cost procedure, which can give an accurate diagnosis promptly. The objective of this study was to assess the diagnostic ...

BRCA1 and BRCA2 genetic testing-pitfalls and recommendations for managing variants of uncertain clinical significance.

Science.gov (United States)

Eccles, D M; Mitchell, G; Monteiro, A N A; Schmutzler, R; Couch, F J; Spurdle, A B; Gómez-García, E B

2015-10-01

Increasing use of BRCA1/2 testing for tailoring cancer treatment and extension of testing to tumour tissue for somatic mutation is moving BRCA1/2 mutation screening from a primarily prevention arena delivered by specialist genetic services into mainstream oncology practice. A considerable number of gene tests will identify rare variants where clinical significance cannot be inferred from sequence information alone. The proportion of variants of uncertain clinical significance (VUS) is likely to grow with lower thresholds for testing and laboratory providers with less experience of BRCA. Most VUS will not be associated with a high risk of cancer but a misinterpreted VUS has the potential to lead to mismanagement of both the patient and their relatives. Members of the Clinical Working Group of ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) global consortium (www.enigmaconsortium.org) observed wide variation in practices in reporting, disclosure and clinical management of patients with a VUS. Examples from current clinical practice are presented and discussed to illustrate potential pitfalls, explore factors contributing to misinterpretation, and propose approaches to improving clarity. Clinicians, patients and their relatives would all benefit from an improved level of genetic literacy. Genetic laboratories working with clinical geneticists need to agree on a clinically clear and uniform format for reporting BRCA test results to non-geneticists. An international consortium of experts, collecting and integrating all available lines of evidence and classifying variants according to an internationally recognized system, will facilitate reclassification of variants for clinical use. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Developmental profile of speech-language and communicative functions in an individual with the preserved speech variant of Rett syndrome.

Science.gov (United States)

Marschik, Peter B; Vollmann, Ralf; Bartl-Pokorny, Katrin D; Green, Vanessa A; van der Meer, Larah; Wolin, Thomas; Einspieler, Christa

2014-08-01

We assessed various aspects of speech-language and communicative functions of an individual with the preserved speech variant of Rett syndrome (RTT) to describe her developmental profile over a period of 11 years. For this study, we incorporated the following data resources and methods to assess speech-language and communicative functions during pre-, peri- and post-regressional development: retrospective video analyses, medical history data, parental checklists and diaries, standardized tests on vocabulary and grammar, spontaneous speech samples and picture stories to elicit narrative competences. Despite achieving speech-language milestones, atypical behaviours were present at all times. We observed a unique developmental speech-language trajectory (including the RTT typical regression) affecting all linguistic and socio-communicative sub-domains in the receptive as well as the expressive modality. Future research should take into consideration a potentially considerable discordance between formal and functional language use by interpreting communicative acts on a more cautionary note.

Discordance Between Preoperative and Postoperative Bladder Cancer Location: Implications for Partial-Bladder Radiation

Energy Technology Data Exchange (ETDEWEB)

Goldsmith, Benjamin; Tucker, Kai; Conway, Robert Greg; He, Jiwei [Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania (United States); Guzzo, Thomas [Department of Urology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania (United States); Bekelman, Justin; Deville, Curtiland; Vapiwala, Neha [Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania (United States); Malkowicz, S. Bruce [Department of Urology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania (United States); Christodouleas, John, E-mail: christojo@uphs.upenn.edu [Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania (United States)

2013-03-01

Purpose: There is strong interest in partial-bladder radiation whether as a boost or definitive therapy to limit long-term toxicity. It is unclear that a standard preoperative examination can accurately identify all sites of disease within the bladder. The purpose of this study was to determine the correlation between preoperative localization of bladder tumors with postoperative findings to facilitate partial-bladder radiation techniques when appropriate. Methods and Materials: We examined patients with clinically staged T1-T4 invasive transitional cell carcinoma (TCC) or TCC with variant histology with no history of radiation or partial cystectomy undergoing radical cystectomy. Patients were scored as “under-detected” if a bladder site was involved with invasive disease (≥T1) at the time of cystectomy, but not identified preoperatively. Patients were additionally scored as “widely under-detected” if they had postoperative lesions that were not identified preoperatively in a given site, nor in any adjacent site. Rates of under-detected and widely under-detected lesions, as well as univariate and multivariate association between clinical variables and under-detection, were evaluated using logistic regression. Results: Among 222 patients, 96% (213/222) had at least 1 area of discordance. Fifty-eight percent of patients were under-detected in at least 1 location, whereas 12% were widely under-detected. Among 24 patients with a single site of disease on preoperative evaluation, 21/24 (88%) had at least 1 under-detected lesion and 14/24 (58%) were widely under-detected. On multivariate analysis, only solitary site of preoperative disease was associated with increased levels of under-detection of invasive disease (OR = 4.161, 95% CI, 1.368-12.657). Conclusion: Our study shows a stark discordance between preoperative and postoperative localization of bladder tumors. From a clinical perspective, incomplete localization of all sites of disease within the bladder

DNA Methylation Changes in the IGF1R Gene in Birth Weight Discordant Adult Monozygotic Twins

DEFF Research Database (Denmark)

Tsai, Pei-Chien; Van Dongen, Jenny; Tan, Qihua

2015-01-01

persists into adulthood. To investigate this further, we performed epigenome-wide association analyses of blood DNA methylation using Infinium HumanMethylation450 BeadChip profiles in 71 adult monozygotic (MZ) twin pairs who were extremely discordant for birth weight. A signal mapping to the IGF1R gene (cg...... were not significant. However, a meta-analysis across the four independent samples, in total 216 birth-weight discordant MZ twin pairs, showed a significant positive association between birth weight and DNA methylation differences at IGF1R (random-effects meta-analysis p = .04), and the effect...... was particularly pronounced in older twins (random-effects meta-analysis p = .008, 98 older birth-weight discordant MZ twin pairs). The results suggest that severe intra-uterine growth differences (birth weight discordance >20%) are associated with methylation changes in the IGF1R gene in adulthood, independent...

The association between weight gain during pregnancy and intertwin delivery weight discordance using 2011-2015 birth registration data from the USA.

Science.gov (United States)

Xiao, Yanni; Shen, Minxue; Ma, Shujuan; Tao, Xuan; Wen, Shi Wu; Tan, Hongzhuan

2018-06-01

To assess the effect of weight gain during pregnancy on intertwin delivery weight discordance. In the present retrospective cohort study using twin delivery records, data were extracted from the 2011-2015 USA birth registration dataset created by the Centers for Disease Control and Prevention. The outcome variable was delivery weight discordance. The nonlinear association of weight gain during pregnancy with delivery weight discordance was examined using a generalized additive model, adjusting for potential confounders. A total of 255 627 twin pairs were included in this analysis. Weight gain during pregnancy showed an inverse, yet nonlinear, association with intertwin delivery weight discordance. Women with weight gain of approximately 25 kg exhibited the lowest level of discordance. When stratified by pre-pregnancy body mass index, the association of weight gain with discordance became insignificant among obese women. When categorizing weight gain according to recommendations from the Institute of Medicine, inadequate weight gain was associated with increased risk of discordance among women of any pre-pregnancy body mass index. Twin pregnancies with maternal weight gain of approximately 25 kg demonstrated the lowest risk of developing intertwin delivery weight discordance, while inadequate weight gain was a risk factor for delivery weight discordance in all pre-pregnancy body mass index categories. © 2018 International Federation of Gynecology and Obstetrics.

Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium.

Science.gov (United States)

Amendola, Laura M; Jarvik, Gail P; Leo, Michael C; McLaughlin, Heather M; Akkari, Yassmine; Amaral, Michelle D; Berg, Jonathan S; Biswas, Sawona; Bowling, Kevin M; Conlin, Laura K; Cooper, Greg M; Dorschner, Michael O; Dulik, Matthew C; Ghazani, Arezou A; Ghosh, Rajarshi; Green, Robert C; Hart, Ragan; Horton, Carrie; Johnston, Jennifer J; Lebo, Matthew S; Milosavljevic, Aleksandar; Ou, Jeffrey; Pak, Christine M; Patel, Ronak Y; Punj, Sumit; Richards, Carolyn Sue; Salama, Joseph; Strande, Natasha T; Yang, Yaping; Plon, Sharon E; Biesecker, Leslie G; Rehm, Heidi L

2016-06-02

Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG-AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data

DEFF Research Database (Denmark)

2017-01-01

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox-Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients...... with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient-parent trios that were generally...... not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population....

Management of language discordance in clinical nursing practice--A critical review.

Science.gov (United States)

Probst, Sebastian; Imhof, Lorenz

2016-05-01

Language plays an essential role in the provision of nursing care, since successful communication is a vital prerequisite to being able to provide appropriate nursing care efficiently and effectively. It is not known what kinds of interventions are effective in overcoming language discordance in nursing practice. This critical review aimed to examine the interventions that are most successfully used to overcome language discordance in nursing. A critical review of the literature was performed and 24 relevant research papers were included. A search was carried out between January 2004 and September 2014 in MEDLINE, Cochrane Database of Systematic Reviews, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Psychinfo, Germanistic online, Pragmatis and Linguistic & Language Behaviour Abstracts (LLBA). Both authors independently screened the titles (n=299), abstracts and full texts to decide which articles should be chosen. The inclusion criteria were: (1) articles examine the problem of language discordance in various health care settings and (2) articles published in English, German, French or Italian. Articles were included irrespective of their design. Data were analysed using the Critical Appraisal Skills Program Tool (CASP). In total, 24 publications met the inclusion criteria. Most of the studies (n=20) were focused on the nursing intervention of using an interpreter and three were describing the nursing assessment. The study designs of the included studies were mainly non-experimental studies, qualitative studies or reviews. The only suggested intervention described in the articles is the use of ad-hoc or professional interpreters for communicating with patients who do not speak the local language. Health care institutions should provide more strategies for clinical practice to overcome language discordance. Copyright © 2015 Elsevier Inc. All rights reserved.

Examining the Relationship between Communication Patterns of Source Family and Self-Consciousness with Defensive Styles of Discordant Couples

OpenAIRE

Ma’asoomeh Kheirkhah; Ebrahim Namani

2016-01-01

Research has shown the relationship between communication patterns of source family with defensive styles of discordant couples. For this reason, the present research has examined the relationship between communication patterns of source family and self-consciousness with defensive styles of discordant couples. This study is a descriptive-correlation type. Its population consisted of all discordant couples referred to counseling centers of Mashhad in 2015. Among the referred 140 disc...

A matter of phylogenetic scale: Distinguishing incomplete lineage sorting from lateral gene transfer as the cause of gene tree discord in recent versus deep diversification histories.

Science.gov (United States)

Knowles, L Lacey; Huang, Huateng; Sukumaran, Jeet; Smith, Stephen A

2018-03-01

Discordant gene trees are commonly encountered when sequences from thousands of loci are applied to estimate phylogenetic relationships. Several processes contribute to this discord. Yet, we have no methods that jointly model different sources of conflict when estimating phylogenies. An alternative to analyzing entire genomes or all the sequenced loci is to identify a subset of loci for phylogenetic analysis. If we can identify data partitions that are most likely to reflect descent from a common ancestor (i.e., discordant loci that indeed reflect incomplete lineage sorting [ILS], as opposed to some other process, such as lateral gene transfer [LGT]), we can analyze this subset using powerful coalescent-based species-tree approaches. Test data sets were simulated where discord among loci could arise from ILS and LGT. Data sets where analyzed using the newly developed program CLASSIPHY (Huang et al., ) to assess whether our ability to distinguish the cause of discord among loci varied when ILS and LGT occurred in the recent versus deep past and whether the accuracy of these inferences were affected by the mutational process. We show that accuracy of probabilistic classification of individual loci by the cause of discord differed when ILS and LGT events occurred more recently compared with the distant past and that the signal-to-noise ratio arising from the mutational process contributes to difficulties in inferring LGT data partitions. We discuss our findings in terms of the promise and limitations of identifying subsets of loci for species-tree inference that will not violate the underlying coalescent model (i.e., data partitions in which ILS, and not LGT, contributes to discord). We also discuss the empirical implications of our work given the many recalcitrant nodes in the tree of life (e.g., origins of angiosperms, amniotes, or Neoaves), and recent arguments for concatenating loci. © 2018 Botanical Society of America.

Entanglement and discord for qubits and higher spin systems

Indian Academy of Sciences (India)

In this paper, after §2 that sets out definitions and notation, §3 will consider an entangled pair of ... Section 4 presents a correlation called discord between two subsystems [7] .... Its 'triplet' counterpart, with a plus sign in place of the minus,.

Decoherence, discord, and the quantum master equation for cosmological perturbations

Science.gov (United States)

Hollowood, Timothy J.; McDonald, Jamie I.

2017-05-01

We examine environmental decoherence of cosmological perturbations in order to study the quantum-to-classical transition and the impact of noise on entanglement during inflation. Given an explicit interaction between the system and environment, we derive a quantum master equation for the reduced density matrix of perturbations, drawing parallels with quantum Brownian motion, where we see the emergence of fluctuation and dissipation terms. Although the master equation is not in Lindblad form, we see how typical solutions exhibit positivity on super-horizon scales, leading to a physically meaningful density matrix. This allows us to write down a Langevin equation with stochastic noise for the classical trajectories which emerge from the quantum system on super-horizon scales. In particular, we find that environmental decoherence increases in strength as modes exit the horizon, with the growth driven essentially by white noise coming from local contributions to environmental correlations. Finally, we use our master equation to quantify the strength of quantum correlations as captured by discord. We show that environmental interactions have a tendency to decrease the size of the discord and that these effects are determined by the relative strength of the expansion rate and interaction rate of the environment. We interpret this in terms of the competing effects of particle creation versus environmental fluctuations, which tend to increase and decrease the discord respectively.

Patient-physician discordance in global assessment in early spondyloarthritis and its change over time: the DESIR cohort.

Science.gov (United States)

Desthieux, Carole; Molto, Anna; Granger, Benjamin; Saraux, Alain; Fautrel, Bruno; Gossec, Laure

2016-09-01

To assess patient-physician discordance in global assessment of disease activity in early axial spondyloarthritis (axSpA) over time and determinants of discordance. DESIR (Devenir des Spondyloarthropathies Indifférenciées Récentes) is a French, multicentre, longitudinal cohort of patients with early inflammatory back pain suggestive of axSpA. Patient global assessment (PGA) and physician global assessment (PhGA) were rated with a 0-10 numerical rating scale, every 6 months during 2 years then at 3 years. Discordance was defined by the absolute difference |PGA-PhGA|≥3 (range 0-10) and was analysed at each visit. Determinants of (PGA-PhGA) were assessed at the visit level by a generalised linear mixed model. A total of 702 patients were analysed at baseline (401 with complete data over 3 years): mean age 33.8±8.6 years, 379 (54.0%) female, mean symptom duration 18.1±10.5 months. Mean PGA values were always higher than mean PhGA values with a mean absolute difference of 1.8 points. At baseline, 202 (28.8%) patients had discordance mainly by PGA>PhGA; over 3 years the frequency of discordance was stable (range 25.5-28.8%). Discordance was not stable at the patient level, 118 (29.4%) patients were discordant once and 88 (22.0%) twice, and only 92 (22.9%) more than twice. Determinants of (PGA-PhGA) were spine pain (β=0.24, ppatient characteristic. 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/

Placental cord insertion and birthweight discordance in twin pregnancies: results of the national prospective ESPRiT Study.

Science.gov (United States)

Kent, Etaoin M; Breathnach, Fionnuala M; Gillan, John E; McAuliffe, Fionnuala M; Geary, Michael P; Daly, Sean; Higgins, John R; Dornan, James; Morrison, John J; Burke, Gerard; Higgins, Shane; Carroll, Stephen; Dicker, Patrick; Manning, Fiona; Malone, Fergal D

2011-10-01

The purpose of this study was to evaluate the impact of noncentral placental cord insertion on birthweight discordance in twins. We performed a multicenter, prospective trial of twin pregnancies. Placental cord insertion was documented as central, marginal, or velamentous according to a defined protocol. Association of the placental cord insertion site with chorionicity, birthweight discordance, and growth restriction were assessed. Eight hundred sixteen twin pairs were evaluated; 165 pairs were monochorionic, and 651 pairs were dichorionic. Monochorionic twins had higher rates of marginal (P = .0068) and velamentous (P < .0001) placental cord insertion. Noncentral placental cord insertion was more frequent in smaller twins of discordant pairs than control pairs (29.8% vs 19.1%; P = .004). Velamentous placental cord insertion in monochorionic twins was associated significantly with birthweight discordance (odds ratio, 3.5; 95% confidence interval, 1.3-9.4) and growth restriction (odds ratio, 4; 95% confidence interval, 1.1-14.3). Noncentral placental cord insertion contributes to birthweight discordance in monochorionic twin pregnancies. Sonographic delineation of placental cord insertion may be of value in antenatal assessment of twin pregnancies. Copyright © 2011 Mosby, Inc. All rights reserved.

svclassify: a method to establish benchmark structural variant calls.

Science.gov (United States)

Parikh, Hemang; Mohiyuddin, Marghoob; Lam, Hugo Y K; Iyer, Hariharan; Chen, Desu; Pratt, Mark; Bartha, Gabor; Spies, Noah; Losert, Wolfgang; Zook, Justin M; Salit, Marc

2016-01-16

The human genome contains variants ranging in size from small single nucleotide polymorphisms (SNPs) to large structural variants (SVs). High-quality benchmark small variant calls for the pilot National Institute of Standards and Technology (NIST) Reference Material (NA12878) have been developed by the Genome in a Bottle Consortium, but no similar high-quality benchmark SV calls exist for this genome. Since SV callers output highly discordant results, we developed methods to combine multiple forms of evidence from multiple sequencing technologies to classify candidate SVs into likely true or false positives. Our method (svclassify) calculates annotations from one or more aligned bam files from many high-throughput sequencing technologies, and then builds a one-class model using these annotations to classify candidate SVs as likely true or false positives. We first used pedigree analysis to develop a set of high-confidence breakpoint-resolved large deletions. We then used svclassify to cluster and classify these deletions as well as a set of high-confidence deletions from the 1000 Genomes Project and a set of breakpoint-resolved complex insertions from Spiral Genetics. We find that likely SVs cluster separately from likely non-SVs based on our annotations, and that the SVs cluster into different types of deletions. We then developed a supervised one-class classification method that uses a training set of random non-SV regions to determine whether candidate SVs have abnormal annotations different from most of the genome. To test this classification method, we use our pedigree-based breakpoint-resolved SVs, SVs validated by the 1000 Genomes Project, and assembly-based breakpoint-resolved insertions, along with semi-automated visualization using svviz. We find that candidate SVs with high scores from multiple technologies have high concordance with PCR validation and an orthogonal consensus method MetaSV (99.7 % concordant), and candidate SVs with low scores are

Bayesian detection of causal rare variants under posterior consistency.

KAUST Repository

Liang, Faming

2013-07-26

Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD), to tackle this problem. The new method simultaneously addresses two issues: (i) (Global association test) Are there any of the variants associated with the disease, and (ii) (Causal variant detection) Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI) Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

Bayesian detection of causal rare variants under posterior consistency.

Directory of Open Access Journals (Sweden)

Faming Liang

Full Text Available Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD, to tackle this problem. The new method simultaneously addresses two issues: (i (Global association test Are there any of the variants associated with the disease, and (ii (Causal variant detection Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

Bayesian detection of causal rare variants under posterior consistency.

KAUST Repository

Liang, Faming; Xiong, Momiao

2013-01-01

Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD), to tackle this problem. The new method simultaneously addresses two issues: (i) (Global association test) Are there any of the variants associated with the disease, and (ii) (Causal variant detection) Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI) Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

'We keep her status to ourselves': experiences of stigma and discrimination among HIV-discordant couples in South Africa, Tanzania and Ukraine.

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Rispel, Laetitia C; Cloete, Allanise; Metcalf, Carol A

2015-01-01

In HIV-discordant relationships, the HIV-negative partner also carries the burden of a stigmatised disease. For this reason, couples often hide their HIV-discordant status from family, friends and community members. This perpetuates the silence around HIV-discordant relationships and impacts on targeted HIV prevention, treatment and counselling efforts. This article reports on experiences of stigma and discrimination among HIV-discordant couples in South Africa, Tanzania and Ukraine. During 2008, HIV-discordant couples who had been in a relationship for at least one year were recruited purposively through health-care providers and civil society organisations in the three countries. Participants completed a brief self-administered questionnaire, while semi-structured interviews were conducted with each partner separately and with both partners together. Interviews were analysed using thematic content analysis. Fifty-one couples were recruited: 26 from South Africa, 10 from Tanzania, and 15 from Ukraine. Although most participants had disclosed their HIV status to someone other than their partner, few were living openly with HIV discordance. Experiences of stigma were common and included being subjected to gossip, rumours and name-calling, and HIV-negative partners being labelled as HIV-positive. Perpetrators of discrimination included family members and health workers. Stigma and discrimination present unique and complex challenges to couples in HIV sero-discordant relationships in these three diverse countries. Addressing stigmatisation of HIV-discordant couples requires a holistic human rights approach and specific programme efforts to address discrimination in the health system.

Quantum discord length is enhanced while entanglement length is not by introducing disorder in a spin chain.

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Sadhukhan, Debasis; Roy, Sudipto Singha; Rakshit, Debraj; Prabhu, R; Sen De, Aditi; Sen, Ujjwal

2016-01-01

Classical correlation functions of ground states typically decay exponentially and polynomially, respectively, for gapped and gapless short-range quantum spin systems. In such systems, entanglement decays exponentially even at the quantum critical points. However, quantum discord, an information-theoretic quantum correlation measure, survives long lattice distances. We investigate the effects of quenched disorder on quantum correlation lengths of quenched averaged entanglement and quantum discord, in the anisotropic XY and XYZ spin glass and random field chains. We find that there is virtually neither reduction nor enhancement in entanglement length while quantum discord length increases significantly with the introduction of the quenched disorder.

QUANTUM DISCORD AND QUANTUM COMPUTING - AN APPRAISAL

OpenAIRE

Datta, Animesh; Shaji, Anil

2011-01-01

We discuss models of computing that are beyond classical. The primary motivation is to unearth the cause of nonclassical advantages in computation. Completeness results from computational complexity theory lead to the identification of very disparate problems, and offer a kaleidoscopic view into the realm of quantum enhancements in computation. Emphasis is placed on the `power of one qubit' model, and the boundary between quantum and classical correlations as delineated by quantum discord. A ...

Differences in knowledge, attitudes and behaviors of Israeli HIV-uninfected gay men in HIV-discordant vs. concordant steady relationships.

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Tairy, Daniel; Levy, Itzchak; Turner, Dan; Livnat, Yuval; Mor, Zohar

2018-06-01

HIV-discordant gay male couples may play an important role in HIV-transmissions. This cross-sectional study compared the knowledge, attitudes and sexual behaviors of HIV-uninfected gay men, between those in HIV-discordant and those in HIV-concordant steady relationships. Anonymous questionnaires were distributed electronically in designated gay-related internet sites and in AIDS-clinics in 2015. The dependent variable was defined as a steady relationship of an HIV-uninfected man with an HIV-infected partner. Risky sexual behavior was defined as unprotected anal intercourse (UAI) with a sex partner whose HIV-status was either positive or unknown. Of 2,319 responders, 460 (20%) were HIV-uninfected gay men in steady relationships, of whom 72 were in HIV-discordant relationships and 388 were in HIV-concordant relationships. Those in HIV-discordant relationships presented better established knowledge regarding HIV-transmission, more lenient attitudes regarding UAI, and reported being involved in riskier sexual behavior, both within and outside their steady relationship compared to men in HIV-concordant relationships. UAI was performed by 48% of the HIV-discordant couples and was associated with the use of sero-positioning strategy and with achieving undetectable viral-load. These findings reflect the complexity of constant use of condoms during long-term sero-discordant relationships. Targeted interventions for HIV-prevention in HIV-discordant couples should be employed for balancing the partners' desire for intimacy and sexual pleasure in the relationship, while reducing the risk for acquiring HIV. ART: Antiretroviral therapy; PEP: Post exposure prophylaxis; PrEP: Pre exposure prophylaxis; STI: Sexually transmitted infections; UAI: Unprotected anal intercourse.

Short- and long-term perinatal outcome in twin pregnancies affected by weight discordance

DEFF Research Database (Denmark)

Vedel, Cathrine; Oldenburg, Anna; Worda, Katharina

2017-01-01

INTRODUCTION: The objective was to investigate the association between chorionicity-specific intertwin birthweight discordance and adverse outcomes including long-term follow up at 6, 18, and 48-60 months after term via Ages and Stages Questionnaire. MATERIAL AND METHODS: In this secondary analysis...... outcomes. Ages and Stages Questionnair scores were compared using the method of generalized estimating equation to account for the correlation within twins. RESULTS: The 75th and 90th percentiles for birthweight discordance were 14.8 and 21.4% for monochorionic and 16.0 and 23.8% for dichorionic twins...

Scales of Time Where the Quantum Discord Allows an Efficient Execution of the DQC1 Algorithm

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M. Ávila

2014-01-01

Full Text Available The power of one qubit deterministic quantum processor (DQC1 (Knill and Laflamme (1998 generates a nonclassical correlation known as quantum discord. The DQC1 algorithm executes in an efficient way with a characteristic time given by τ=Tr[Un]/2n, where Un is an n qubit unitary gate. For pure states, quantum discord means entanglement while for mixed states such a quantity is more than entanglement. Quantum discord can be thought of as the mutual information between two systems. Within the quantum discord approach the role of time in an efficient evaluation of τ is discussed. It is found that the smaller the value of t/T is, where t is the time of execution of the DQC1 algorithm and T is the scale of time where the nonclassical correlations prevail, the more efficient the calculation of τ is. A Mösbauer nucleus might be a good processor of the DQC1 algorithm while a nuclear spin chain would not be efficient for the calculation of τ.

Nanogeochronology of discordant zircon measured by atom probe microscopy of Pb-enriched dislocation loops

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Peterman, Emily M.; Reddy, Steven M.; Saxey, David W.; Snoeyenbos, David R.; Rickard, William D. A.; Fougerouse, Denis; Kylander-Clark, Andrew R. C.

2016-01-01

Isotopic discordance is a common feature in zircon that can lead to an erroneous age determination, and it is attributed to the mobilization and escape of radiogenic Pb during its post-crystallization geological evolution. The degree of isotopic discordance measured at analytical scales of ~10 μm often differs among adjacent analysis locations, indicating heterogeneous distributions of Pb at shorter length scales. We use atom probe microscopy to establish the nature of these sites and the mechanisms by which they form. We show that the nanoscale distribution of Pb in a ~2.1 billion year old discordant zircon that was metamorphosed c. 150 million years ago is defined by two distinct Pb reservoirs. Despite overall Pb loss during peak metamorphic conditions, the atom probe data indicate that a component of radiogenic Pb was trapped in 10-nm dislocation loops that formed during the annealing of radiation damage associated with the metamorphic event. A second Pb component, found outside the dislocation loops, represents homogeneous accumulation of radiogenic Pb in the zircon matrix after metamorphism. The 207Pb/206Pb ratios measured from eight dislocation loops are equivalent within uncertainty and yield an age consistent with the original crystallization age of the zircon, as determined by laser ablation spot analysis. Our results provide a specific mechanism for the trapping and retention of radiogenic Pb during metamorphism and confirm that isotopic discordance in this zircon is characterized by discrete nanoscale reservoirs of Pb that record different isotopic compositions and yield age data consistent with distinct geological events. These data may provide a framework for interpreting discordance in zircon as the heterogeneous distribution of discrete radiogenic Pb populations, each yielding geologically meaningful ages. PMID:27617295

Sleep-EEG in dizygotic twins discordant for Williams syndrome.

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Bódizs, Róbert; Gombos, Ferenc; Szocs, Katalin; Réthelyi, János M; Gerván, Patrícia; Kovács, Ilona

2014-01-30

Reports on twin pairs concordant and discordant for Williams syndrome were published before, but no study unravelled sleep physiology in these cases yet. We aim to fill this gap by analyzing sleep records of a twin pair discordant for Williams syndrome extending our focus on presleep wakefulness and sleep spindling. We performed multiplex ligation-dependent probe amplification of the 7q11.23 region of a 17 years old dizygotic opposite-sex twin pair discordant for Williams syndrome. Polysomnography of laboratory sleep at this age was analyzed and followed-up after 1.5 years by ambulatory polysomnography. Sleep stages scoring, EEG power spectra and sleep spindle analyses were carried out. The twin brother showed reduced levels of amplification for all of the probes in the 7q11.23 region indicating a typical deletion spanning at least 1.038 Mb between FKBP6 and CLIP2. The results of the twin sister showed normal copy numbers in the investigated region. Lower sleep times and efficiencies, as well as higher slow wave sleep percents of the twin brother were evident during both recordings. Roughly equal NREM, Stage 2 and REM sleep percents were found. EEG analyses revealed state and derivation-independent decreases in alpha power, lack of an alpha spectral peak in presleep wakefulness, as well as higher NREM sleep sigma peak frequency in the twin brother. Faster sleep spindles with lower amplitude and shorter duration characterized the records of the twin brother. Spectra show a striking reliability and correspondence between the two situations (laboratory vs. home records). Alterations in sleep and specific neural oscillations including the alpha/sigma waves are inherent aspects of Williams syndrome.

Specificity of the Association between Marital Discord and Longitudinal Changes in Symptoms of Depression and Generalized Anxiety Disorder in the Irish Longitudinal Study on Ageing.

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Whisman, Mark A; Robustelli, Briana L; Labrecque, Lindsay T

2018-03-25

This longitudinal study was conducted to evaluate actor and partner effects of marital discord on changes in symptoms of depression and generalized anxiety disorder (GAD) in a large population sample of Irish adults (N = 1,445 couples), adjusting for the potential confounds of quality of other social relationships and other psychopathology symptoms. The Actor-Partner Interdependence Model was used to examine actor and partner effects of marital discord on changes in symptoms of depression and GAD at a 2-year follow-up. Additional models examined these associations adjusting for family and friend discord and symptoms of the other type of psychopathology (depressive or GAD symptoms). Actor effects of marital discord on depressive and anxiety symptoms were greater for men than for women. There were significant, positive actor effects of marital discord on depressive symptoms for husbands and wives, which remained significant when adjusting for family and friend discord and GAD symptoms. There were significant, positive actor effects of marital discord on GAD symptoms for husbands, which remained significant when adjusting for family and friend discord and depressive symptoms. Results demonstrate that longitudinal associations between marital discord and depressive symptoms (for wives and husbands) and GAD symptoms (for husbands) are incremental to other rival explanations (family and friend discord and the other set of symptoms). Findings provide evidence for a potential causal association leading from marital discord to symptoms of depression and GAD. © 2018 Family Process Institute.

Computing Coherence Vectors and Correlation Matrices with Application to Quantum Discord Quantification

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Jonas Maziero

2016-01-01

Full Text Available Coherence vectors and correlation matrices are important functions frequently used in physics. The numerical calculation of these functions directly from their definitions, which involves Kronecker products and matrix multiplications, may seem to be a reasonable option. Notwithstanding, as we demonstrate in this paper, some algebraic manipulations before programming can reduce considerably their computational complexity. Besides, we provide Fortran code to generate generalized Gell-Mann matrices and to compute the optimized and unoptimized versions of associated Bloch’s vectors and correlation matrix in the case of bipartite quantum systems. As a code test and application example, we consider the calculation of Hilbert-Schmidt quantum discords.

DISCORDANCE BETWEEN BLUE-LIGHT AUTOFLUORESCENCE AND NEAR-INFRARED AUTOFLUORESCENCE IN AGE-RELATED MACULAR DEGENERATION.

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Heiferman, Michael J; Fawzi, Amani A

2016-12-01

To identify the origin and significance of discordance between blue-light autofluorescence (BL-AF; 488 nm) and near-infrared autofluorescence (NI-AF; 787 nm) in patients with age-related macular degeneration (AMD). A total of 86 eyes of 59 patients with a diagnosis of AMD were included in this cross-sectional study conducted between March 9, 2015 and May 1, 2015. A masked observer examined the BL-AF, NI-AF, and spectral-domain optical coherence tomography images. Areas with discordance of autofluorescence patterns between NI-AF and BL-AF images were correlated with structural findings at the corresponding location in optical coherence tomography scans. Seventy-nine eyes had discordance between BL-AF and NI-AF. The most common optical coherence tomography finding accounting for these discrepancies was pigment migration accounting for 35 lesions in 21 eyes. The most clinically relevant finding was geographic atrophy missed on BL-AF in 7 eyes. Our findings indicate that variations in the distribution of lipofuscin, melanin and melanolipofuscin account for the majority of discordance between BL-AF and NI-AF. Given our finding of missed geographic atrophy lesions on BL-AF in 24% of eyes with geographic atrophy (7/29 eyes), clinicians should consider multimodal imaging, including NI-AF and optical coherence tomography, especially in clinical trials of geographic atrophy.

Equivalence of qubit-environment entanglement and discord generation via pure dephasing interactions and the resulting consequences

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Roszak, Katarzyna; Cywiński, Łukasz

2018-01-01

We find that when a qubit initialized in a pure state experiences pure dephasing due to interaction with an environment, separable qubit-environment states generated during the evolution also have zero quantum discord with respect to the environment. What follows is that the set of separable states which can be reached during the evolution has zero volume, and hence, such effects as sudden death of qubit-environment entanglement are very unlikely. In the case of the discord with respect to the qubit, a vast majority of qubit-environment separable states is discordant, but in specific situations zero-discord states are possible. This is conceptually important since there is a connection between the discordance with respect to a given subsystem and the possibility of describing the evolution of this subsystem using completely positive maps. Finally, we use the formalism to find an exemplary evolution of an entangled state of two qubits that is completely positive, and occurs solely due to interaction of only one of the qubits with its environment (so one could guess that it corresponds to a local operation, since it is local in a physical sense), but which nevertheless causes the enhancement of entanglement between the qubits. While this simply means that the considered evolution is completely positive, but does not belong to local operations and classical communication, it shows how much caution has to be exercised when identifying evolution channels that belong to that class.

Metabolome and fecal microbiota in monozygotic twin pairs discordant for weight: a Big Mac challenge

OpenAIRE

Bondia-Pons, Isabel; Maukonen, Johanna; Mattila, Ismo; Rissanen, Aila; Saarela, Maria; Kaprio, Jaakko; Hakkarainen, Antti; Lundbom, Jesper; Lundbom, Nina; Hy?tyl?inen, Tuulia; Pietil?inen, Kirsi H.; Ore?i?, Matej

2014-01-01

Postprandial responses to food are complex, involving both genetic and environmental factors. We studied postprandial responses to a Big Mac meal challenge in monozygotic co-twins highly discordant for body weight. This unique design allows assessment of the contribution of obesity, independent of genetic liability. Comprehensive metabolic profiling using 3 analytical platforms was applied to fasting and postprandial serum samples from 16 healthy monozygotic twin pairs discordant for weight (...

Robust detection of discordant sites in regional frequency analysis

NARCIS (Netherlands)

Neykov, N.M.; Neytchev, P.N.; Van Gelder, P.H.A.J.M.; Todorov, V.K.

2007-01-01

The discordancy measure in terms of the sample L?moment ratios (L?CV, L?skewness, L?kurtosis) of the at?site data is widely recommended in the screening process of atypical sites in the regional frequency analysis (RFA). The sample mean and the covariance matrix of the L?moments ratios, on which the

The role of variants from the innate immune system genes in tuberculosis and skin test response in a Native American population.

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Lindenau, Juliana D; Salzano, Francisco M; Hurtado, Ana M; Hill, Kim R; Hutz, Mara H

2016-10-01

Native American populations show higher tuberculosis (TB) mortality and infectivity rates than non-Native populations. Variants in the innate immune system seem to have an important role on TB susceptibility. The role of some innate immune system variants in TB susceptibility and/or skin test response (PPD) were investigated in the Aché, a Native American population. Complement receptor 1 and toll like receptor 9 variants were associated with anergy to PPD and protection to TB, respectively. These findings demonstrate an important role of the innate immune system variants in TB susceptibility. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Barriers to Antiretroviral Initiation in HIV-1-Discordant Couples

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Guthrie, Brandon L.; Choi, Robert Y.; Liu, Amy Y.; Mackelprang, Romel D.; Rositch, Anne F.; Bosire, Rose; Manyara, Lucy; Gatuguta, Anne; Kiarie, James N.; Farquhar, Carey

2011-01-01

BACKGROUND In Kenya and much of sub-Saharan Africa, nearly half of all couples affected by HIV are discordant. Antiretroviral therapy (ART) slows disease progression in HIV-1-infected individuals, and reduces transmission to uninfected partners. We examined time to ART initiation and factors associated with delayed initiation in HIV-1-discordant couples in Nairobi. METHODS HIV-1-discordant couples were enrolled and followed quarterly for up to 2 years. Clinical staff administered questionnaires and conducted viral loads and CD4 counts. Participants with a CD4 count meeting ART criteria were referred to a nearby PEPFAR-funded treatment center. Barriers to ART initiation among participants with a CD4 count eligible for ART were assessed by Cox regression. RESULTS Of 439 HIV-1-infected participants (63.6% females and 36.4% males) 146 met CD4 count criteria for ART during follow-up. Median time from meeting CD4 criteria until ART initiation was 8.9 months, with 42.0% of eligible participants on ART by 6 months and 63.4% on ART by 1 year. The CD4 count at the time of eligibility was inversely associated with time to ART initiation (HR=0.49, p< 0.001). Compared to homeowners, those paying higher rents started ART 48% more slowly (p=0.062) and those paying lower rents started 71% more slowly (p=0.002). CONCLUSIONS Despite access to regular health care, referrals to treatment centers, and free access to ART, over a third of participants with an eligible CD4 count had not started ART within 1 year. Factors of lower socioeconomic status may slow ART initiation and targeted approaches are needed to avoid delays in treatment initiation. PMID:21826010

"Getting tested is almost like going to the Salem witch trials": discordant discourses between Western public health messages and sociocultural expectations surrounding HIV testing among East African immigrant women.

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De Jesus, Maria; Carrete, Claudia; Maine, Cathleen; Nalls, Patricia

2015-01-01

Washington, DC, has the highest AIDS diagnosis rate in the USA, and Black women are disproportionately affected. Although HIV testing is the first entryway into vital treatment services, evidence reveals that foreign-born blacks have a lower rate of recent HIV testing than US-born blacks. To date, however, there are no studies that examine the culture-specific perceptions of HIV testing among East African immigrant women (who comprise a large share of Black Africans in DC) to better understand their potential barriers to testing. Adopting the PEN-3 cultural model as our theoretical framework, the main objective of this study was to examine East African women's HIV testing perceptions and partner communication norms. Between October 2012 and March 2013, trained interviewers conducted a total of 25 interviews with East African women in the Washington, DC, metropolitan area. For triangulation purposes, data collection consisted of both in-depth, semi-structured interviews and cognitive interviews, in which participants were administered a quantitative survey and assessed on how they interpreted items. Qualitative thematic analysis revealed a systematic pattern of discordant responses across participants. While they were aware of messages related to Western public health discourse surrounding HIV testing (e.g., Everyone should get tested for HIV; One should talk to one's spouse about HIV testing), divergent sociocultural expectations rooted in cultural and religious beliefs prevailed (e.g., Getting an HIV test brings shame to the person who got tested and to one's family; it implies one is engaging in immoral behavior; One should not talk with one's spouse about HIV testing; doing so breaks cultural norms). Implications of using a culture-centered model to examine the role of sociocultural expectations in HIV prevention research and to develop culturally responsive prevention strategies are discussed.

What can we learn from the dynamics of entanglement and quantum discord in the Tavis-Cummings model?

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Restrepo, Juliana; Rodriguez, Boris A.

We revisit the problem of the dynamics of quantum correlations in the exact Tavis-Cummings model. We show that many of the dynamical features of quantum discord attributed to dissipation are already present in the exact framework and are due to the well known non-linearities in the model and to the choice of initial conditions. Through a comprehensive analysis, supported by explicit analytical calculations, we find that the dynamics of entanglement and quantum discord are far from being trivial or intuitive. In this context, we find states that are indistinguishable from the point of view of entanglement and distinguishable from the point of view of quantum discord, states where the two quantifiers give opposite information and states where they give roughly the same information about correlations at a certain time. Depending on the initial conditions, this model exhibits a fascinating range of phenomena that can be used for experimental purposes such as: Robust states against change of manifold or dissipation, tunable entanglement states and states with a counterintuitive sudden birth as the number of photons increase. We furthermore propose an experiment called quantum discord gates where discord is zero or non-zero depending on the number of photons. This work was supported by the Vicerrectoria de Investigacion of the Universidad Antonio Narino, Colombia under Project Number 20141031 and by the Departamento Administrativo de Ciencia, Tecnologia e Innovacion (COLCIENCIAS) of Colombia under Grant Number.

Risk factors for discordant immune response among HIV-infected patients initiating antiretroviral therapy: A retrospective cohort study

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B P Muzah

2012-10-01

Full Text Available Background. The therapeutic goal of antiretroviral therapy (ART is sustained immune recovery and viral suppression. However, some patients experience poor CD4 cell count responses despite achieving viral suppression. Such discordant immune responses have been associated with poor clinical outcomes. Objective. We aimed to determine the prevalence of discordant immune response and explore associated factors in a retrospective cohort of patients attending 2 large public sector clinics, during the 6 months following ART initiation. Methods. Data were analysed from 810 HIV-infected adults initiated on first-line ART at 2 clinics in Johannesburg, between 1 November 2008 and 31 December 2009. Multivariate logistic regression models were used to estimate adjusted odds ratios (AORs to determine associations between discordant immune response and clinical and demographic factors. Results. At ART initiation, 65% (n=592 of participants were female, with a mean age of 38.5 years. Median baseline CD4 cell count was 155 cells/mm3, 70% (n=645 of patients had a haemoglobin level >11 g/dl and 88% (n=803 were initiated on stavudine-lamivudine-efavirenz/nevirapine (D4T-3TC-EFV/NVP. Six months after ART initiation, 24% (n=220 of patients had a discordant immune response and 7% (n=67 a discordant virological response. On multivariate analysis, baseline CD cell count ≥200 cells/mm3 (AOR 3.02; 95% confidence interval (CI 2.08 - 4.38; p

Discordance between location of positive cores in biopsy and location of positive surgical margin following radical prostatectomy.

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Kim, Ji Won; Park, Hyoung Keun; Kim, Hyeong Gon; Ham, Dong Yeub; Paick, Sung Hyun; Lho, Yong Soo; Choi, Woo Suk

2015-10-01

We compared location of positive cores in biopsy and location of positive surgical margin (PSM) following radical prostatectomy. This retrospective analysis included patients who were diagnosed as prostate cancer by standard 12-core transrectal ultrasonography guided prostate biopsy, and who have PSM after radical prostatectomy. After exclusion of number of biopsy cores location data, 46 patients with PSM were identified. Locations of PSM in pathologic specimen were reported as 6 difference sites (apex, base and lateral in both sides). Discordance of biopsy result and PSM was defined when no positive cores in biopsy was identified at the location of PSM. Most common location of PSM were right apex (n=21) and left apex (n=15). Multiple PSM was reported in 21 specimens (45.7%). In 32 specimens (69.6%) with PSM, one or more concordant positive biopsy cores were identified, but 14 specimens (28%) had no concordant biopsy cores at PSM location. When discordant rate was separated by locations of PSM, right apex PSM had highest rate of discordant (38%). The discordant group had significantly lower prostate volume and lower number of positive cores in biopsy than concordant group. This study showed that one fourth of PSM occurred at location where tumor was not detected at biopsy and that apex PSM had highest rate of discordant. Careful dissection to avoid PSM should be performed in every location, including where tumor was not identified in biopsy.

Increased expression and altered methylation of HERVWE1 in the human placentas of smaller fetuses from monozygotic, dichorionic, discordant twins.

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Yu Gao

Full Text Available BACKGROUND: The human endogenous retroviral family W, Env(C7, member 1 gene (HERVWE1 is thought to participate in trophoblast cell fusion, and its expression is diminished in the placentas of singleton intrauterine growth-retarded pregnancies. However, there is limited information about the role of HERVWE1 in discordant fetal growth in twins. This study was to compare HERVWE1 gene expression between the placentas of discordant monozygotic twins and to identify its regulation by methylation. METHODOLOGY/PRINCIPAL FINDINGS: Fetuses from twenty-one pairs of monozygotic, dichorionic, discordant twins were marked as "smaller" or "larger" according to birth weight. Placental HERVWE1 mRNA and protein expression profiles were analyzed using quantitative RT-PCR and immunohistochemistry (IHC staining. Methylation profiles of the HERVWE1 promoter region were analyzed using a pyrosequencing assay. DNA methyltransferase (DNMT transcript levels were analyzed by RT-PCR. 5-methyl cytosine (5-MC was stained using an immunohistochemical assay. There was a significant negative correlation between HERVWE1 mRNA levels and birth weight in twins (P0.05. The DNMT3b3 mRNA levels in the smaller group were significantly downregulated compared with the larger group in discordant twins(P<0.05, whereas the DNMT3b7 mRNA levels in the smaller group were significantly upregulated compared with the larger group in discordant twins(P<0.05. CONCLUSIONS/SIGNIFICANCE: In discordant, monozygotic, dichorionic twins, HERVWE1 expression was higher in smaller fetuses and lower in larger fetuses. Methylation of the HERVWE1 gene promoter region may participate in the regulation of HERVWE1 gene expression in discordant twin pregnancies.

Increased Expression and Altered Methylation of HERVWE1 in the Human Placentas of Smaller Fetuses from Monozygotic, Dichorionic, Discordant Twins

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Wang, Zilian; Luo, Yanmin; Sun, Hongyu; Zhou, Yi; Huang, Linhuan; Li, Manchao; Fang, Qun; Jiang, Shiwen

2012-01-01

Background The human endogenous retroviral family W, Env(C7), member 1 gene (HERVWE1) is thought to participate in trophoblast cell fusion, and its expression is diminished in the placentas of singleton intrauterine growth-retarded pregnancies. However, there is limited information about the role of HERVWE1 in discordant fetal growth in twins. This study was to compare HERVWE1 gene expression between the placentas of discordant monozygotic twins and to identify its regulation by methylation. Methodology/Principal Findings Fetuses from twenty-one pairs of monozygotic, dichorionic, discordant twins were marked as “smaller” or “larger” according to birth weight. Placental HERVWE1 mRNA and protein expression profiles were analyzed using quantitative RT-PCR and immunohistochemistry (IHC) staining. Methylation profiles of the HERVWE1 promoter region were analyzed using a pyrosequencing assay. DNA methyltransferase (DNMT) transcript levels were analyzed by RT-PCR. 5-methyl cytosine (5-MC) was stained using an immunohistochemical assay. There was a significant negative correlation between HERVWE1 mRNA levels and birth weight in twins (P0.05). The DNMT3b3 mRNA levels in the smaller group were significantly downregulated compared with the larger group in discordant twins(P<0.05), whereas the DNMT3b7 mRNA levels in the smaller group were significantly upregulated compared with the larger group in discordant twins(P<0.05). Conclusions/Significance In discordant, monozygotic, dichorionic twins, HERVWE1 expression was higher in smaller fetuses and lower in larger fetuses. Methylation of the HERVWE1 gene promoter region may participate in the regulation of HERVWE1 gene expression in discordant twin pregnancies. PMID:22457770

Morphometric analysis of craniofacial features in mono- and dizygotic twins discordant for unilateral cleft lip and palate.

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Tessler, Alexis Y; Franchi, Lorenzo; McNamara, James A; Baccetti, Tiziano

2011-09-01

To compare craniofacial differences between twins discordant for surgically repaired unilateral cleft lip and palate (CLP) during the developmental ages and to test the effect of zygosity on the shape and size of the craniofacial skeleton of the same twins by means of thin plate spline (TPS) analysis. Lateral and posteroanterior (PA) cephalometric films from 19 sets of monozygotic (MZ) twins (15 male and 4 female) and 10 dizygotic (DZ) twins (7 male and 3 female) were analyzed. TPS analysis evaluated statistically significant differences in the craniofacial shape and size between affected and unaffected twins within MZ and DZ twin couples. No statistically significant differences in craniofacial shape or size between CLP and non-CLP MZ or DZ twins were observed. The level of morphological similarity in CLP vs non-CLP MZ twins was statistically greater than in DZ twins. Morphometric analysis showed that surgically repaired CLP does not produce significant shape or size differences in the craniofacial features of MZ or DZ twins discordant for unilateral CLP.

Comparison of statistical tests for association between rare variants and binary traits.

OpenAIRE

Bacanu, SA; Nelson, MR; Whittaker, JC

2012-01-01

: Genome-wide association studies have found thousands of common genetic variants associated with a wide variety of diseases and other complex traits. However, a large portion of the predicted genetic contribution to many traits remains unknown. One plausible explanation is that some of the missing variation is due to the effects of rare variants. Nonetheless, the statistical analysis of rare variants is challenging. A commonly used method is to contrast, within the same region (gene), the fr...

Turbulent flow structure at a discordant river confluence: Asymmetric jet dynamics with implications for channel morphology

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Sukhodolov, Alexander N.; Krick, Julian; Sukhodolova, Tatiana A.; Cheng, Zhengyang; Rhoads, Bruce L.; Constantinescu, George S.

2017-06-01

Only a handful of field studies have examined turbulent flow structure at discordant confluences; the dynamics of flow at such confluences have mainly been examined in the laboratory. This paper reports results of a field-based investigation of turbulent flow structure at a discordant river confluence. These results support the hypothesis that flow at a discordant alluvial confluence with a velocity ratio greater than 2 exhibits jet-like characteristics. Scaling analysis shows that the dynamics of the jet core are quite similar to those of free jets but that the complex structure of flow at the confluence imposes strong effects that can locally suppress or enhance the spreading rate of the jet. This jet-like behavior of the flow has important implications for morphodynamic processes at these types of confluences. The highly energetic core of the jet at this discordant confluence is displaced away from the riverbed, thereby inhibiting scour; however, helical motion develops adjacent to the jet, particularly at high flows, which may promote scour. Numerical experiments demonstrate that the presence or absence of a depositional wedge at the mouth of the tributary can strongly influence detachment of the jet from the bed and the angle of the jet within the confluence.

Discordant tasks and motor adjustments affect interactions between adaptations to altered kinematics and dynamics

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Fritzie Arce

2010-01-01

Full Text Available Motor control and adaptation are multi-determinate processes with complex interactions. This is reflected for example in the ambiguous nature of interactions during sequential adaptation of reaching under kinematics and dynamics perturbations. It has been suggested that perturbations based on the same kinematic parameter interfere. Others posited that opposing motor adjustments underlie interference. Here, we examined the influence of discordances in task and in motor adjustments on sequential adaptations to visuomotor rotation and viscous force field perturbations. These two factors – perturbation direction and task discordance – have been examined separately by previous studies, thus the inherent difficulty to identify the roots of interference. Forty-eight human subjects adapted sequentially to one or two types of perturbations, of matched or conflicting directions. We found a gradient of interaction effects based on perturbation direction and task discordance. Perturbations of matched directions showed facilitation while perturbations of opposite directions, which required opposing motor adjustments, interfered with each other. Further, interaction effects increased with greater task discordance. We also found that force field and visuomotor rotation had mutual anterograde and retrograde effects. However, we found independence between anterograde and retrograde interferences between similar tasks. The results suggest that the newly acquired internal models of kinematic and dynamic perturbations are not independent but they share common neuronal resources and interact between them. Such overlap does not necessarily imply competition of resources. Rather, our results point to an additional principle of sensorimotor adaptation allowing the system to tap or harness common features across diverse sensory inputs and task contexts whenever available.

Genetics Home Reference: GM2-gangliosidosis, AB variant

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... Resources Genetic Testing (1 link) Genetic Testing Registry: Tay-Sachs disease, variant AB General Information from MedlinePlus (5 links) ... AB variant Activator Deficiency/GM2 Gangliosidosis Activator-deficient Tay-Sachs disease GM2 Activator Deficiency Disease GM2 gangliosidosis, type AB ...

‘Getting tested is almost like going to the Salem witch trials’: Discordant discourses between western public health messages and sociocultural expectations surrounding HIV testing among East African immigrant women

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DE JESUS, Maria; CARRETE, Claudia; MAINE, Cathleen; NALLS, Patricia

2015-01-01

Washington, DC has the highest AIDS diagnosis rate in the United States and Black women are disproportionately affected. Although HIV testing is the first entryway into vital treatment services, evidence reveals that foreign-born blacks have a lower rate of recent HIV testing than U.S.-born blacks. To date, however, there are no studies that examine the culture-specific perceptions of HIV testing among East African immigrant women (who comprise a large share of Black Africans in DC) to better understand their potential barriers to testing. Adopting the PEN-3 cultural model as our theoretical framework, the main objective of this study was to examine East African women’s HIV testing perceptions and partner communication norms. Between October 2012 and March 2013, trained interviewers conducted a total of 25 interviews with East African women in the Washington DC Metropolitan area. For triangulation purposes, data collection consisted of both in-depth, semi-structured interviews and cognitive interviews, in which participants were administered a quantitative survey and assessed on how they interpreted items. Qualitative thematic analysis revealed a systematic pattern of discordant responses across participants. While they were aware of messages related to western public health discourse surrounding HIV testing (e.g., Everyone should get tested for HIV; One should talk to one’s spouse about HIV testing), divergent sociocultural expectations rooted in cultural and religious beliefs prevailed (e.g., Getting an HIV test brings shame to the person who got tested and to one’s family; it implies one is engaging in immoral behavior; One should not talk with one’s spouse about HIV testing; doing so breaks cultural norms). Implications of using a culture-centered model to examine the role of sociocultural expectations in HIV prevention research and to develop culturally responsive prevention strategies are discussed. PMID:25616443

FDG PET and CT in locally advanced adenocarcinomas of the distal oesophagus. Clinical relevance of a discordant PET finding

International Nuclear Information System (INIS)

Stahl, A.; Wieder, H.; Schwaiger, M.; Weber, W.A.; Stollfuss, J.; Ott, K.; Fink, U.

2005-01-01

Aim: the incidence of adenocarcinomas of the distal oesophagus (ADE) has dramatically increased in Western countries. The clinical importance of a FDG PET finding discordant with CT was determined in patients with locally advanced ADE. In addition, tumour standardized uptake values (SUV) were correlated with patient survival. Patients, methods: 40 consecutive patients were analyzed retrospectively. All patients underwent an attenuation corrected FDG PET scan (neck, chest, abdomen) and contrast enhanced helical CT of the chest and abdomen. PET and CT scans were reviewed independently and concomitantly with respect to metastases in predefined lymph node sites and organs. Any discordance between PET and CT was assessed for clinical relevance. Clinical relevance was defined as a change in the overall therapeutic concept (curative vs. palliative). Follow-up imaging and histological evaluation served as the gold standard. Mean tumour SUVs were determined by 1.5 cm regions of interest placed over the tumour's maximum. Results: when read independently from the CT scan FDG PET indicated a clinically relevant change in tumour stage in 9/40 patients (23%) and a non-relevant change in 11/40 patients (28%). PET was correct in 5/9 patients (56%) with clinically relevant discordances. In 4/9 patients PET was incorrect (3 false positive due to suspicion of MI-lymph nodes or lung metastases, 1 false negative in disseminated liver metastases). With concomitant reading, PET indicated a clinically relevant change in tumour stage in 6/40 patients (15%) and a non-relevant change in 5/40 patients (13%). PET was correct in 5/6 patients (83%) with clinically relevant discordances. The patient with disseminated liver disease remained the single false negative. Overall, the benefit from PET was based on its higher diagnostic accuracy at organ sites. Tumour SUV did not correlate with patient survival. Conclusion: about half of discordances between FDG PET and CT are clinically relevant

Analytical detection of influenza A(H3N2)v and other A variant viruses from the USA by rapid influenza diagnostic tests.

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Balish, Amanda; Garten, Rebecca; Klimov, Alexander; Villanueva, Julie

2013-07-01

The performance of rapid influenza diagnostic tests (RIDTs) that detect influenza viral nucleoprotein (NP) antigen has been reported to be variable. Recent human infections with variant influenza A viruses that are circulating in pigs prompted the investigation of the analytical reactivity of RIDTs with these variant viruses. To determine analytical reactivity of seven FDA-cleared RIDTs with influenza A variant viruses in comparison with the reactivity with recently circulating seasonal influenza A viruses. Tenfold serial dilutions of cell culture-grown seasonal and variant influenza A viruses were prepared and tested in duplicate with seven RIDTs. All RIDTs evaluated in this study detected the seasonal influenza A(H3N2) virus, although detection limits varied among assays. All but one examined RIDT identified the influenza A(H1N1)pdm09 virus. However, only four of seven RIDTs detected all influenza A(H3N2)v, A(H1N2)v, and A(H1N1)v viruses. Reduced sensitivity of RIDTs to variant influenza viruses may be due to amino acid differences between the NP proteins of seasonal viruses and the NP proteins from viruses circulating in pigs. Clinicians should be aware of the limitations of RIDTs to detect influenza A variant viruses. Specimens from patients with influenza-like illness in whom H3N2v is suspected should be sent to public health laboratories for additional diagnostic testing. Published 2012. This article is a US Government work and is in the public domain in the USA.

Relationship between Discordance in Parental Monitoring and Behavioral Problems among Chilean Adolescents

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Han, Yoonsun; Grogan-Kaylor, Andrew; Bares, Cristina; Ma, Julie; Castillo, Marcela; Delva, Jorge

2012-01-01

This study investigated the role of discrepancies between parent and youth reports of perceived parental monitoring in adolescent problem behaviors with a Chilean sample (N= 850). Higher levels of discordance concerning parental monitoring predicted greater levels of maladaptive youth behaviors. A positive association between parent-youth discordance and externalizing problems indicated that large adult-youth disagreement in parental monitoring may impose a great risk, despite protective efforts of parental monitoring. Although the direct relationship between parental monitoring and youth internalizing behaviors was not significant, parent-youth incongruence in monitoring was associated with greater levels of internalizing behaviors. Therefore, differing assessments of parental behaviors, as an indicator of less optimal family functioning, may provide important information about youth maladjustment and may potentially provide a beginning point for family-focused intervention. PMID:23097593

Psychiatric outcomes of bullying victimization: a study of discordant monozygotic twins.

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Silberg, J L; Copeland, W; Linker, J; Moore, A A; Roberson-Nay, R; York, T P

2016-07-01

Bullying victimization in childhood is associated with a broad array of serious mental health disturbances, including anxiety, depression, and suicidal ideation and behavior. The key goal of this study was to evaluate whether bullying victimization is a true environmental risk factor for psychiatric disturbance using data from 145 bully-discordant monozygotic (MZ) juvenile twin pairs from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) and their follow-up into young adulthood. Since MZ twins share an identical genotype and familial environment, a higher rate of psychiatric disturbance in a bullied MZ twin compared to their non-bullied MZ co-twin would be evidence of an environmental impact of bullying victimization. Environmental correlations between being bullied and the different psychiatric traits were estimated by fitting structural equation models to the full sample of MZ and DZ twins (N = 2824). Environmental associations were further explored using the longitudinal data on the bullying-discordant MZ twins. Being bullied was associated with a wide range of psychiatric disorders in both children and young adults. The analysis of data on the MZ-discordant twins supports a genuine environmental impact of bullying victimization on childhood social anxiety [odds ratio (OR) 1.7], separation anxiety (OR 1.9), and young adult suicidal ideation (OR 1.3). There was a shared genetic influence on social anxiety and bullying victimization, consistent with social anxiety being both an antecedent and consequence of being bullied. Bullying victimization in childhood is a significant environmental trauma and should be included in any mental health assessment of children and young adults.

F-15 inlet/engine test techniques and distortion methodologies studies. Volume 2: Time variant data quality analysis plots

Science.gov (United States)

Stevens, C. H.; Spong, E. D.; Hammock, M. S.

1978-01-01

Time variant data quality analysis plots were used to determine if peak distortion data taken from a subscale inlet model can be used to predict peak distortion levels for a full scale flight test vehicle.

Associations of FTO and MC4R Variants with Obesity Traits in Indians and the Role of Rural/Urban Environment as a Possible Effect Modifier.

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Taylor, A E; Sandeep, M N; Janipalli, C S; Giambartolomei, C; Evans, D M; Kranthi Kumar, M V; Vinay, D G; Smitha, P; Gupta, V; Aruna, M; Kinra, S; Sullivan, R M; Bowen, L; Timpson, N J; Davey Smith, G; Dudbridge, F; Prabhakaran, D; Ben-Shlomo, Y; Reddy, K S; Ebrahim, S; Chandak, G R

2011-01-01

Few studies have investigated the association between genetic variation and obesity traits in Indian populations or the role of environmental factors as modifiers of these relationships. In the context of rapid urbanisation, resulting in significant lifestyle changes, understanding the aetiology of obesity is important. We investigated associations of FTO and MC4R variants with obesity traits in 3390 sibling pairs from four Indian cities, most of whom were discordant for current dwelling (rural or urban). The FTO variant rs9939609 predicted increased weight (0.09 Z-scores, 95% CI: 0.03, 0.15) and BMI (0.08 Z-scores, 95% CI: 0.02, 0.14). The MC4R variant rs17782313 was weakly associated with weight and hip circumference (P < .05). There was some indication that the association between FTO and weight was stronger in urban than that in rural dwellers (P for interaction = .03), but no evidence for effect modification by diet or physical activity. Further studies are needed to investigate ways in which urban environment may modify genetic risk of obesity.

Associations of FTO and MC4R Variants with Obesity Traits in Indians and the Role of Rural/Urban Environment as a Possible Effect Modifier

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A. E. Taylor

2011-01-01

Full Text Available Few studies have investigated the association between genetic variation and obesity traits in Indian populations or the role of environmental factors as modifiers of these relationships. In the context of rapid urbanisation, resulting in significant lifestyle changes, understanding the aetiology of obesity is important. We investigated associations of FTO and MC4R variants with obesity traits in 3390 sibling pairs from four Indian cities, most of whom were discordant for current dwelling (rural or urban. The FTO variant rs9939609 predicted increased weight (0.09 Z-scores, 95% CI: 0.03, 0.15 and BMI (0.08 Z-scores, 95% CI: 0.02, 0.14. The MC4R variant rs17782313 was weakly associated with weight and hip circumference (P<.05. There was some indication that the association between FTO and weight was stronger in urban than that in rural dwellers (P for interaction = .03, but no evidence for effect modification by diet or physical activity. Further studies are needed to investigate ways in which urban environment may modify genetic risk of obesity.

Assessment of spatial discordance of primary and effective seed dispersal of European beech (Fagus sylvatica L.) by ecological and genetic methods.

Science.gov (United States)

Millerón, M; López de Heredia, U; Lorenzo, Z; Alonso, J; Dounavi, A; Gil, L; Nanos, N

2013-03-01

Spatial discordance between primary and effective dispersal in plant populations indicates that postdispersal processes erase the seed rain signal in recruitment patterns. Five different models were used to test the spatial concordance of the primary and effective dispersal patterns in a European beech (Fagus sylvatica) population from central Spain. An ecological method was based on classical inverse modelling (SSS), using the number of seed/seedlings as input data. Genetic models were based on direct kernel fitting of mother-to-offspring distances estimated by a parentage analysis or were spatially explicit models based on the genotype frequencies of offspring (competing sources model and Moran-Clark's Model). A fully integrated mixed model was based on inverse modelling, but used the number of genotypes as input data (gene shadow model). The potential sources of error and limitations of each seed dispersal estimation method are discussed. The mean dispersal distances for seeds and saplings estimated with these five methods were higher than those obtained by previous estimations for European beech forests. All the methods show strong discordance between primary and effective dispersal kernel parameters, and for dispersal directionality. While seed rain was released mostly under the canopy, saplings were established far from mother trees. This discordant pattern may be the result of the action of secondary dispersal by animals or density-dependent effects; that is, the Janzen-Connell effect. © 2013 Blackwell Publishing Ltd.

'Testing Together Challenges the Relationship': Consequences of HIV Testing as a Couple in a High HIV Prevalence Setting in Rural South Africa.

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Hanani Tabana

Full Text Available We conducted qualitative individual and combined interviews with couples to explore their experiences since the time of taking an HIV test and receiving the test result together, as part of a home-based HIV counselling and testing intervention.This study was conducted in October 2011 in rural KwaZulu-Natal, South Africa, about 2 years after couples tested and received results together. Fourteen couples were purposively sampled: discordant, concordant negative and concordant positive couples.Learning about each other's status together challenged relationships of the couples in different ways depending on HIV status and gender. The mutual information confirmed suspected infidelity that had not been discussed before. Negative women in discordant partnerships remained with their positive partner due to social pressure and struggled to maintain their HIV negative status. Most of the couple relationships were characterized by silence and mistrust. Knowledge of sero-status also led to loss of sexual intimacy in some couples especially the discordant. For most men in concordant negative couples, knowledge of status was an awakening of the importance of fidelity and an opportunity for behaviour change, while for concordant positive and discordant couples, it was seen as proof of infidelity. Although positive HIV status was perceived as confirmation of infidelity, couples continued their relationship and offered some support for each other, living and managing life together. Sexual life in these couples was characterized by conflict and sometimes violence. In the concordant negative couples, trust was enhanced and behaviour change was promised.Findings suggest that testing together as couples challenged relationships in both negative and positive ways. Further, knowledge of HIV status indicated potential to influence behaviour change especially among concordant negatives. In the discordant and concordant positive couples, traditional gender roles exposed

Efficacy of Stochastic Vestibular Stimulation to Improve Locomotor Performance in a Discordant Sensory Environment

Science.gov (United States)

Temple, D. R.; De Dios, Y. E.; Layne, C. S.; Bloomberg, J. J.; Mulavara, A. P.

2016-01-01

Astronauts exposed to microgravity face sensorimotor challenges incurred when readapting to a gravitational environment. Sensorimotor Adaptability (SA) training has been proposed as a countermeasure to improve locomotor performance during re-adaptation, and it is suggested that the benefits of SA training may be further enhanced by improving detection of weak sensory signals via mechanisms such as stochastic resonance when a non-zero level of stochastic white noise based electrical stimulation is applied to the vestibular system (stochastic vestibular stimulation, SVS). The purpose of this study was to test the efficacy of using SVS to improve short-term adaptation in a sensory discordant environment during performance of a locomotor task.

Quantum discord as a resource for quantum cryptography.

Science.gov (United States)

Pirandola, Stefano

2014-11-07

Quantum discord is the minimal bipartite resource which is needed for a secure quantum key distribution, being a cryptographic primitive equivalent to non-orthogonality. Its role becomes crucial in device-dependent quantum cryptography, where the presence of preparation and detection noise (inaccessible to all parties) may be so strong to prevent the distribution and distillation of entanglement. The necessity of entanglement is re-affirmed in the stronger scenario of device-independent quantum cryptography, where all sources of noise are ascribed to the eavesdropper.

Discordance between liver biopsy and Fibroscan® in assessing liver fibrosis in chronic hepatitis b: risk factors and influence of necroinflammation.

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Seung Up Kim

Full Text Available BACKGROUND: Few studies have investigated predictors of discordance between liver biopsy (LB and liver stiffness measurement (LSM using FibroScan®. We assessed predictors of discordance between LB and LSM in chronic hepatitis B (CHB and investigated the effects of necroinflammatory activity. METHODS: In total, 150 patients (107 men, 43 women were prospectively enrolled. Only LSM with ≥ 10 valid measurements was considered reliable. Liver fibrosis was evaluated using the Laennec system. LB specimens <15 mm in length were considered ineligible. Reference cutoff LSM values to determine discordance were calculated from our cohort (6.0 kPa for ≥ F2, 7.5 kPa for ≥ F3, and 9.4 kPa for F4. RESULTS: A discordance, defined as a discordance of at least two stages between LB and LSM, was identified in 21 (14.0% patients. In multivariate analyses, fibrosis stages F3-4 and F4 showed independent negative associations with discordance (P = 0.002; hazard ratio [HR], 0.073; 95% confidence interval [CI], 0.014-0.390 for F3-4 and P = 0.014; HR, 0.067; 95% CI, 0.008-0.574 for F4. LSM values were not significantly different between maximal activity grades 1-2 and 3-4 in F1 and F2 fibrosis stages, whereas LSM values were significantly higher in maximal activity grade 3-4 than 1-2 in F3 and F4 fibrosis stage (median 8.6 vs. 11.3 kPa in F3, P = 0.049; median 11.9 vs. 19.2 kPa in F4, P = 0.009. CONCLUSION: Advanced fibrosis stage (F3-4 or cirrhosis (F4 showed a negative correlation with discordance between LB and LSM in patients with CHB, and maximal activity grade 3-4 significantly influenced LSM values in F3 and F4.

Characterizing the dynamics of quantum discord under phase damping with POVM measurements

International Nuclear Information System (INIS)

Jiang Feng-Jian; Jian-Feng Ye; Yan Xin-Hu; Lü Hai-Jiang

2015-01-01

In the analysis of quantum discord, the minimization of average entropy traditionally involved over orthogonal projective measurements may be attained at more optimal decompositions by using the positive-operator-valued measure (POVM) measurements. Taking advantage of the quantum steering ellipsoid in combination with three-element POVM optimization, we show that, for a family of two-qubit X states locally interacting with Markovian non-dissipative environments, the decay rates of quantum discord show smooth dynamical evolutions without any sudden change. This is in contrast to two-element orthogonal projective measurements, in which case the sudden change of the decay rates of quantum and classical decoherences may be a common phenomenon. Notwithstanding this, we find that a subset of X states (including the Bell diagonal states) involving POVM optimization can still preserve the sudden change character as usual. (paper)

A case study of discordant overlapping meta-analyses: vitamin d supplements and fracture.

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Mark J Bolland

Full Text Available BACKGROUND: Overlapping meta-analyses on the same topic are now very common, and discordant results often occur. To explore why discordant results arise, we examined a common topic for overlapping meta-analyses- vitamin D supplements and fracture. METHODS AND FINDINGS: We identified 24 meta-analyses of vitamin D (with or without calcium and fracture in a PubMed search in October 2013, and analysed a sample of 7 meta-analyses in the highest ranking general medicine journals. We used the AMSTAR tool to assess the quality of the meta-analyses, and compared their methodologies, analytic techniques and results. Applying the AMSTAR tool suggested the meta-analyses were generally of high quality. Despite this, there were important differences in trial selection, data extraction, and analytical methods that were only apparent after detailed assessment. 25 trials were included in at least one meta-analysis. Four meta-analyses included all eligible trials according to the stated inclusion and exclusion criteria, but the other 3 meta-analyses "missed" between 3 and 8 trials, and 2 meta-analyses included apparently ineligible trials. The relative risks used for individual trials differed between meta-analyses for total fracture in 10 of 15 trials, and for hip fracture in 6 of 12 trials, because of different outcome definitions and analytic approaches. The majority of differences (11/16 led to more favourable estimates of vitamin D efficacy compared to estimates derived from unadjusted intention-to-treat analyses using all randomised participants. The conclusions of the meta-analyses were discordant, ranging from strong statements that vitamin D prevents fractures to equally strong statements that vitamin D without calcium does not prevent fractures. CONCLUSIONS: Substantial differences in trial selection, outcome definition and analytic methods between overlapping meta-analyses led to discordant estimates of the efficacy of vitamin D for fracture prevention

The Discordance Between HER-2/NEU Expression Assessed by Immunohistochemistry (IHC and Fluorescence in Situ Hybridization (FISH: Is It Important to Detect?

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Berna Bozkurt Duman

2014-02-01

Conclusion: The clinical implication of this discordance rate and it\\'s affect on the choice of appropriate therapy are of critical importance. As such, it would be beneficial for each hospital to determine its own discordance rate.

What predicts intention-behavior discordance? A review of the action control framework

NARCIS (Netherlands)

Rhodes, R.E.; de Bruijn, G.J.

2013-01-01

The physical activity intention-behavior gap is a focus of considerable research. The purpose of this article is to overview contemporary evidence for predictors of this intention-behavior discordance using the action control framework developed in our laboratories. We propose the hypothesis that

Positivity in Marriage: The Role of Discord and Physical Aggression against Wives.

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Langhinrichsen-Rohling, Jennifer; And Others

1994-01-01

Considered perceptions of relationship quality (positive communication, caring gestures, recollections of happiest times) in 81 discordant clinic and 51 nondiscordant community couples. Spouses in nondistressed community marriages reported more frequent and higher quality positive communication and longer lasting and more recent happiest memories…

Detection of ATM germline variants by the p53 mitotic centrosomal localization test in BRCA1/2-negative patients with early-onset breast cancer.

Science.gov (United States)

Prodosmo, Andrea; Buffone, Amelia; Mattioni, Manlio; Barnabei, Agnese; Persichetti, Agnese; De Leo, Aurora; Appetecchia, Marialuisa; Nicolussi, Arianna; Coppa, Anna; Sciacchitano, Salvatore; Giordano, Carolina; Pinnarò, Paola; Sanguineti, Giuseppe; Strigari, Lidia; Alessandrini, Gabriele; Facciolo, Francesco; Cosimelli, Maurizio; Grazi, Gian Luca; Corrado, Giacomo; Vizza, Enrico; Giannini, Giuseppe; Soddu, Silvia

2016-09-06

Variant ATM heterozygotes have an increased risk of developing cancer, cardiovascular diseases, and diabetes. Costs and time of sequencing and ATM variant complexity make large-scale, general population screenings not cost-effective yet. Recently, we developed a straightforward, rapid, and inexpensive test based on p53 mitotic centrosomal localization (p53-MCL) in peripheral blood mononuclear cells (PBMCs) that diagnoses mutant ATM zygosity and recognizes tumor-associated ATM polymorphisms. Fresh PBMCs from 496 cancer patients were analyzed by p53-MCL: 90 cases with familial BRCA1/2-positive and -negative breast and/or ovarian cancer, 337 with sporadic cancers (ovarian, lung, colon, and post-menopausal breast cancers), and 69 with breast/thyroid cancer. Variants were confirmed by ATM sequencing. A total of seven individuals with ATM variants were identified, 5/65 (7.7 %) in breast cancer cases of familial breast and/or ovarian cancer and 2/69 (2.9 %) in breast/thyroid cancer. No variant ATM carriers were found among the other cancer cases. Excluding a single case in which both BRCA1 and ATM were mutated, no p53-MCL alterations were observed in BRCA1/2-positive cases. These data validate p53-MCL as reliable and specific test for germline ATM variants, confirm ATM as breast cancer susceptibility gene, and highlight a possible association with breast/thyroid cancers.

Antiretroviral Therapy Reduces HIV Transmission in Discordant Couples in Rural Yunnan, China

Science.gov (United States)

He, Na; Duan, Song; Ding, Yingying; Rou, Keming; McGoogan, Jennifer M.; Jia, Manhong; Yang, Yuecheng; Wang, Jibao; Montaner, Julio S. G.; Wu, Zunyou

2013-01-01

Background Although HIV treatment as prevention (TasP) via early antiretroviral therapy (ART) has proven to reduce transmissions among HIV-serodiscordant couples, its full implementation in developing countries remains a challenge. In this study, we determine whether China's current HIV treatment program prevents new HIV infections among discordant couples in rural China. Methods A prospective, longitudinal cohort study was conducted from June 2009 to March 2011, in rural Yunnan. A total of 1,618 HIV-discordant couples were eligible, 1,101 were enrolled, and 813 were followed for an average of 1.4 person-years (PY). Routine ART was prescribed to HIV-positive spouses according to eligibility (CD4HIV incidence. Results A total of 17 seroconversions were documented within 1,127 PY of follow-up, for an overall incidence of 1.5 per 100 PY. Epidemiological and genetic evidence confirmed that all 17 seroconverters were infected via marital secondary sexual transmission. Having an ART-experienced HIV-positive partner was associated with a lower rate of seroconvertion compared with having an ART-naïve HIV-positive partner (0.8 per 100 PY vs. 2.4 per 100 PY, HR = 0.34, 95%CI = 0.12–0.97, p = 0.0436). While we found that ART successfully suppressed plasma viral load to HIV incidence among discordant couples in our sample, demonstrating the effectiveness of China's HIV treatment program at preventing new infections, and providing support for earlier ART initiation and TasP implementation in this region. PMID:24236010

Cardio-Metabolic Features of Type 2 Diabetes Subjects Discordant in the Diagnosis of Metabolic Syndrome

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Sa Rah Lee

2012-10-01

Full Text Available BackgroundThe aim of this study is to investigate the cardio-metabolic parameters and surrogate markers of insulin resistance in a discordant group of type 2 diabetes (T2DM subjects who satisfy the Adults Treatment Panel (ATP III criteria, but not the International Diabetes Federation (IDF criteria, for metabolic syndrome (MetS.MethodsWe assessed the prevalence of MetS in T2DM subjects (n=167 who were selected from subjects registered at the diabetes center of Dong-A University Medical Center. We used the ATP III criteria and the IDF criteria for the diagnosis of MetS and sorted the subjects into 2 MetS groups: one group diagnosed per ATP III criteria (MetSa and one diagnosed per IDF criteria (MetSi. We then compared the clinical characteristics, metabolic parameters (homeostasis model assessment of insulin resistance, aspartate aminotransferase, alanine aminotransferase, and uric acid values and co-morbidities (prevalence of microalbuminuria, fatty liver, and cardiovascular disease between the MetSa, MetSi, and discordant MetS groups.ResultsThe prevalence of MetS in the MetSa group (73.6% was higher than in the MetSi group (62.2%. The MetS prevalence in the discordant group was 11.4%. The discordant group showed no significant differences in clinical characteristics (except waist circumference and body mass index, metabolic parameters, or prevalence of co-morbidities, as compared with subjects with MetS by both criteria.ConclusionIn this study, cardio-metabolic features of the subjects diagnosed with MetS using ATP III criteria, but not IDF criteria, are not significantly different from those of subjects diagnosed with MetS using both criteria.

Monozygotic twin discordant for Down syndrome: mos 47,XX,+21/46,XX and 46,XX.

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Choi, Sun Ah; Ko, Jung Min; Shin, Choong Ho; Yang, Sei Won; Choi, Jin Sun; Oh, Sun Kyung

2013-08-01

Monozygotic twins, developed from a single zygote, are almost identical in clinical phenotype and concordant karyotypes. Monozygotic twins with discordant karyotypes are thought to be quite rare. Here, we report monochorionic-diamniotic twins discordant for Down syndrome. On findings of prenatal ultrasonography, nuchal translucency thickness was different between twins, and suggested that one of the twins was at high risk for having chromosomal abnormalities including Down syndrome. The twins were monochorionic-diamniotic; therefore, chorionic villi sampling of the common placenta was performed. The karyotype of the chorionic villi cells was 46,XX, and pregnancy was maintained. After delivery, dysmorphic clinical features suggesting Down syndrome were found in one of the twins, while the other twin showed a morphologically normal appearance. Karyotypes of peripheral blood leukocytes were repeatedly normal in the dysmorphic twin; however, the karyotype of skin fibroblasts from the dysmorphic twin indicated Down syndrome mosaicism; 47,XX,+21[99]/46,XX[2]. The karyotype of skin fibroblasts from the morphologically normal twin was 46,XX. Monozygosity of the twins was confirmed by a short tandem repeat analysis using 16 polymorphic markers. A mitotic nondisjunction followed by the twinning would explain the discordant karyotypes between monozygotic twins.

Movement Discordance between Healthy and Non-Healthy US Adults.

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Ann M Swartz

Full Text Available Physical activity is known to significantly impact cardiometabolic health. Accelerometer data, as a measure of physical activity, can be used to objectively identify a disparity in movement (movement discordance between healthy and unhealthy adults. The purpose of this study was to examine the Movement Discordance between healthy and unhealthy adults in a large US population sample.Demographic, health and accelerometer data from the National Health and Nutrition Examination Study (NHANES 2003-2004 and 2005-2006 cohorts were used for this study. Participants were classified as either having a "normal" or "abnormal" value for each cardiometabolic health parameter examined, based on published criteria. Linear regression analyses were performed to determine significance of each abnormal health parameter (risk factor in its unique effect on the accelerometer counts, controlling for age and gender. Average accelerometer counts per minute (cpm by gender and age categories were estimated separately for the groups of normal and abnormal cardiometabolic risk.Average cpm for those with healthy levels of each individual cardiometabolic health parameter range from 296 cpm (for C reactive protein to 337 cpm (for waist circumference, while average cpm for those with abnormal levels of each individual cardiometabolic health parameter range from 216 cpm (for insulin to 291 cpm (for LDL-cholesterol. After controlling for age and gender, waist circumference, HbA1c, Insulin, Homocysteine, and HDL-Cholesterol were the cardiometabolic health parameters that showed significant, unique and independent effects on cpm. Overall, individuals who have abnormal values for all significant cardiometabolic health parameters ("unhealthy" averaged 267 cpm (SE = 15 cpm, while the healthy sample of this study averaged 428 cpm (SE = 10 cpm. The difference in cpm between the unhealthy and healthy groups is similar between males and females. Further, for both males and females, the

Longitudinal Associations among Discordant Sexual Orientation Dimensions and Hazardous Drinking in a Cohort of Sexual Minority Women

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Talley, Amelia E.; Aranda, Frances; Hughes, Tonda L.; Everett, Bethany; Johnson, Timothy P.

2015-01-01

We examined differences between sexual minority women’s (SMW’s) sexual identity and sexual behavior or sexual attraction as potential contributors to hazardous drinking across a 10-year period. Data are from a longitudinal study examining drinking and drinking-related problems in a diverse, community-based sample of self-identified SMW (Wave 1: n = 447; Wave 2: n = 384; Wave 3: n = 354). Longitudinal cross-lagged models showed that SMW who report higher levels of identity-behavior or identity-attraction discordance may be at greater risk of concurrent and subsequent hazardous drinking. Results of multigroup models suggest that sexual orientation discordance is a more potent risk factor for risky drinking outcomes among SMW in older adulthood than in younger adulthood. Findings support that discordance between sexual orientation dimensions may contribute to hazardous drinking among SMW and provide evidence that cognitive-behavioral consistency is important for individuals expressing diverse and fluid sexual identities, attraction, and behavior. PMID:25911224

Laboratory testing of hemolytic properties of materials that come in contact with blood: Comparative application testing method’s two variants according to the standard ASTM F756 in accordance with ISO 10993-4

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Pavlović Katarina B.

2010-01-01

Full Text Available The presence of hemolytic material in contact with blood may produce increased levels of blood cell lysis and increased levels of plasma hemoglobin. This may induce toxic effects or other effects which may stress the kidneys or other organs. In this paper two variants of in vitro method and obtained results’ comparison were presented for testing of hemolytic properties of six raw materials (Polipropylene Moplen EP 540 P, Policarbonate colorless 164 R-112, Policarbonate brown 164 R-51918, Polietylene NG 3026 K, Polietylene NG - Purell GB 7250, Polietylene VG - Hiplex 5502 for medical device manufacturing and one raw material (Polietylen NG granulate used for infusion solutions’s plastic bottles manufacturing. One of method’s variants relies on raw material direct contact with swine blood and the other on extract of the material contact with swine blood. Both method’s variants imply reading of the absorbance of the supernatant after tubes were incubated and centrifuged. According to values obtained and using the standard curve free hemoglobin concentration is determined and based on this percentage hemolysis of raw material. Positive and negative controls were used in both variants where water for injection (WFI was used as positive control in which partial or complete hemolysis of erythrocytes occurs due to osmotic shock and phosphate buffer saline was used as negative control with no hemolytic property. In this paper comparison of results obtained by both method’s variants for testing of seven raw materials was presented, while these conclusions can not be used neither for all materials, nor for all applications without preliminary testing using both variants and then choosing more sensitive and more reliable one. It was shown and stated in the paper as well that incubation time being 3, 15 or 24 h, had no impact on the variant’s with direct contact sensitivity. This comparative approach was used for drawing conclusions in terms of

Asymmetry and discordance for congenital anomalies in conjoined twins: a report of six cases.

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Ornoy, A; Navot, D; Menashi, M; Laufer, N; Chemke, J

1980-10-01

Six pairs of conjoined twins have been studied. The first case was a pair of 13-week-old omphalopagus fetuses. One was a holoacradius amorphus and the other had rachischisis and anencephaly. The second case was a pair of omphalopagus twins. One of the twins was macerated and corresponded to a developmental age of 13-14 weeks, while the other was developed to 28-30 weeks of gestation and exhibited urogenital and gastrointestinal defects not found in the smaller twin. In the third case, that of a thoracoomphalopagus, one had cleft lip and palate, pulmonic stenosis, and atresia of the ileocecal valve, while the other did not show these anomalies. In the fourth cae, also omphalopagus twins, one had a lumbosacral meningomyelocele and severe gastrointestinal and urogenital anomalies not found in the second twin. The fifth case was a pair of thoracoomphalopagus twins, sharing a common heart with asymmetrical anomalies. The sixth case was a diprosopus anencephalic conjoined twin. The first pairs of conjoined twins were discordant for several abnormalities in nonshared organs, in addition to having abnormalities of the conjoined organs. It seems that discordance in conjoined twins is not a rare finding. The factors that play a role in discordance of anomalies in conjoined twins are probably similar to the factors in monozygotic twins--i.e., environmental, genetic, and abnormal placental and/or fetal circulation.

Genetic determinants of LDL, lipoprotein(a), triglyceride-rich lipoproteins and HDL: concordance and discordance with cardiovascular disease risk

DEFF Research Database (Denmark)

Nordestgaard, Børge G; Tybjærg-Hansen, Anne

2011-01-01

To evaluate whether new and known genetic determinants of plasma levels of LDL cholesterol, lipoprotein(a), triglyceride-rich lipoproteins, and HDL cholesterol associate with the risk of cardiovascular disease expected from the effect on lipoprotein levels. Concordance or discordance of such gene......To evaluate whether new and known genetic determinants of plasma levels of LDL cholesterol, lipoprotein(a), triglyceride-rich lipoproteins, and HDL cholesterol associate with the risk of cardiovascular disease expected from the effect on lipoprotein levels. Concordance or discordance...

Indeterminate human immunodeficiency virus western blot results in Iranian patients with discordant screening assay results

International Nuclear Information System (INIS)

Ravanshad, M.; Sabahi, F.; Mahboudi, F.; Sabahi, F.

2006-01-01

The Western blot (WB) assay is the most widely accepted confirmatory assay for the detection and confirmation of antibodies to human immunodeficiency virus type 1 (HIV-1) and 2 (HIV-2). However, indeterminate WB reactivity to HIV-1 and HIV-2 proteins may occur in individuals who do not appear to be infected with HIV. In this study, we describe the results of indeterminate WB reactivity in Iranian patients with discordant screening assays. The samples were obtained from Iranian Blood Transfusion Center, Tehran, Iran and evaluated in the Biotechnology Process Development Center, Pasteur Institute of Iran, Tehran, Iran between 2003 and 2004. A total of 4707 were tested for the presence of HIV-1 antibodies. Six hundred and four (12.8%) patients tested for HIV were positive for HIV-1 antibody. Nine (1.49%) have discordant results among screening assays and indeterminate WB results as interpreted by Centers for Disease Control and Prevention (CDC) criteria. Most (66.7%) of these indeterminate WB results were due to p24 reactivity. However, 2(22.2%) display reactivity to both gp41 and gp120 proteins [Positive by World Health Organization (WHO) criteria]. Of 9 WB assays initially indeterminate by the CDC criteria and with follow-up samples 8(88.8%) became negative when retested subsequently while one (11.1%) remained indeterminate for more than a year and were thus considered negative. In addition all the indeterminate samples were negative when assessed by polymerase chain reaction assay. In general, there were was an 88.8% concordance between the CDC and WHO criteria for an indeterminate WB result. The CDC II criteria for an indeterminate WB result. The CDC II criteria best met the specified objectives for diagnosis in our setting. (author)

Personal, family and social functioning among older couples concordant and discordant for high-risk alcohol consumption.

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Moos, Rudolf H; Schutte, Kathleen K; Brennan, Penny L; Moos, Bernice S

2011-02-01

This study compares the personal, family and social functioning of older husbands and wives concordant or discordant for high-risk alcohol consumption and identifies predictors of changes in concordance and high-risk consumption. Three groups of couples were identified at baseline and followed 10 years later: (i) concordant couples in which husbands and wives engaged in low-risk alcohol consumption (n = 54); (ii) concordant couples in which husbands and wives engaged in high-risk alcohol consumption (n = 38); and (iii) discordant couples in which one partner engaged in high-risk alcohol consumption and the other partner did not (n = 75). At each follow-up, husbands and wives completed an inventory that assessed their personal, family and social functioning. Compared to the low-risk concordant group, husbands and wives in the high-risk concordant group were more likely to rely on tension-reduction coping, reported more friend approval of drinking, and were less involved in religious activities; however, they did not differ in the quality of the spousal relationship. The frequency of alcohol consumption declined among husbands in discordant couples, but not among husbands in concordant couples. Predictors of high-risk drinking included tension-reduction coping, friend approval of drinking and, for husbands, their wives' level of drinking. High-risk and discordant alcohol consumption do not seem to be linked to decrements in family functioning among older couples in long-term stable marriages. The predictors of heavy alcohol consumption among older husbands and wives identify points of intervention that may help to reduce their high-risk drinking. © 2010 Society for the Study of Addiction. No claim to US government works.

Clinical Utility of Short Social Cognitive Tests in Early Differentiation of Behavioral Variant Frontotemporal Dementia from Alzheimer’s Disease

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Buhl, Christian; Stokholm, Jette; Gade, Anders

2013-01-01

Traditional cognitive tests used in clinical practice may not be sensitive enough for the early differentiation of behavioral variant frontotemporal dementia (bvFTD) from Alzheimer's disease (AD). A growing body of literature has shown that deficits in various aspects of social cognition can be f...

Heritability of cortical thickness changes over time in twin pairs discordant for schizophrenia.

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Hedman, Anna M; van Haren, Neeltje E M; van Baal, G Caroline M; Brouwer, Rachel M; Brans, Rachel G H; Schnack, Hugo G; Kahn, René S; Hulshoff Pol, Hilleke E

2016-06-01

Cortical thickness and surface area changes have repeatedly been found in schizophrenia. Whether progressive loss in cortical thickness and surface area are mediated by genetic or disease related factors is unknown. Here we investigate to what extent genetic and/or environmental factors contribute to the association between change in cortical thickness and surface area and liability to develop schizophrenia. Longitudinal magnetic resonance imaging study over a 5-year interval. Monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia were compared with healthy control twin pairs using repeated measures analysis of variance (RM-ANOVA) and structural equation modeling (SEM). Twins discordant for schizophrenia and healthy control twins were recruited from the twin cohort at the University Medical Centre Utrecht, The Netherlands. A total of 90 individuals from 46 same sex twin pairs were included: 9 MZ and 10 DZ discordant for schizophrenia and 14 MZ and 13 (11 complete and 2 incomplete) DZ healthy twin-pairs. Age varied between 19 and 57years. Higher genetic liability for schizophrenia was associated with progressive global thinning of the cortex, particularly of the left superior temporal cortex. Higher environmental liability for schizophrenia was associated with global attenuated thinning of the cortex, and including of the left superior temporal cortex. Cortical surface area change was heritable, but not significantly associated with higher genetic or environmental liability for schizophrenia. Excessive cortical thinning, particularly of the left superior temporal cortex, may represent a genetic risk marker for schizophrenia. Copyright © 2015 Elsevier B.V. All rights reserved.

A systematic approach to assessing the clinical significance of genetic variants.

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Duzkale, H; Shen, J; McLaughlin, H; Alfares, A; Kelly, M A; Pugh, T J; Funke, B H; Rehm, H L; Lebo, M S

2013-11-01

Molecular genetic testing informs diagnosis, prognosis, and risk assessment for patients and their family members. Recent advances in low-cost, high-throughput DNA sequencing and computing technologies have enabled the rapid expansion of genetic test content, resulting in dramatically increased numbers of DNA variants identified per test. To address this challenge, our laboratory has developed a systematic approach to thorough and efficient assessments of variants for pathogenicity determination. We first search for existing data in publications and databases including internal, collaborative and public resources. We then perform full evidence-based assessments through statistical analyses of observations in the general population and disease cohorts, evaluation of experimental data from in vivo or in vitro studies, and computational predictions of potential impacts of each variant. Finally, we weigh all evidence to reach an overall conclusion on the potential for each variant to be disease causing. In this report, we highlight the principles of variant assessment, address the caveats and pitfalls, and provide examples to illustrate the process. By sharing our experience and providing a framework for variant assessment, including access to a freely available customizable tool, we hope to help move towards standardized and consistent approaches to variant assessment. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Imaging-histologic discordance at sonographically guided percutaneous biopsy of breast lesions

International Nuclear Information System (INIS)

Kim, Min Jung; Kim, Eun-Kyung; Park, Sun Young; Jung, Hae Kyoung; Park, Byeong-Woo; Kim, Haeryung; Oh, Ki Keun

2008-01-01

Objective: To determine the frequency of imaging-histologic discordance at percutaneous breast biopsy and to evaluate differences in clinical and radiologic findings between pathologically upgraded lesions and non-upgraded lesions. Materials and methods: From February 2000 to June 2005, we reviewed 386 cases that had suspicious imaging findings but yielded benign histology at US-core needle biopsy and that underwent subsequent excisional biopsy. In 74 of 386 cases, the benign histology at core needle biopsy could not provide a satisfactory explanation for the radiologically suspicious lesions. The clinical, radiologic and histologic findings were reviewed for those 74 cases that were classified as the upgrade group and the non-upgrade group after excisional biopsy. Results: The upgrade rate was 17.6% (95% confidence interval, 10.6-27.8%, 13 of 74 cases) revealed upgraded pathology at the subsequent excisional biopsy. Besides the size of masses, there were no statistically significant differences in imaging findings between the upgrade and non-upgrade groups at excisional biopsy. Conclusion: This upgrade rate of 17.6% suggests that excisional biopsy or re-biopsy is warranted in those cases presenting imaging-histologic discordance at US-guided core biopsy

Genome-wide analysis of DNA methylation differences in muscle and fat from monozygotic twins discordant for type 2 diabetes

DEFF Research Database (Denmark)

Ribel-Madsen, Rasmus; Fraga, Mario F; Jacobsen, Stine

2012-01-01

Monozygotic twins discordant for type 2 diabetes constitute an ideal model to study environmental contributions to type 2 diabetic traits. We aimed to examine whether global DNA methylation differences exist in major glucose metabolic tissues from these twins.......Monozygotic twins discordant for type 2 diabetes constitute an ideal model to study environmental contributions to type 2 diabetic traits. We aimed to examine whether global DNA methylation differences exist in major glucose metabolic tissues from these twins....

The importance of functional tests to assess the effect of a new CFTR variant when genotype-phenotype correlation is not possible.

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Hinzpeter, Alexandre; Reboul, Marie-Pierre; Callebaut, Isabelle; Zordan, Cécile; Costes, Bruno; Guichoux, Julie; Iron, Albert; Lacombe, Didier; Martin, Natacha; Arveiler, Benoit; Fanen, Pascale; Fergelot, Patricia; Girodon, Emmanuelle

2017-05-01

In vitro functional tests aimed to investigate CFTR dysfunction appear critical to help elucidate the functional impact of new variants of uncertain clinical significance and solve inconclusive cases, especially in early deceased newborns.

Quantum discord is Bohr’s notion of non-mechanical disturbance introduced to counter the Einstein–Podolsky–Rosen argument

International Nuclear Information System (INIS)

Wiseman, Howard M.

2013-01-01

By rigorously formalizing the Einstein–Podolsky–Rosen (EPR) argument, and Bohr’s reply, one can appreciate that both arguments were technically correct. Their opposed conclusions about the completeness of quantum mechanics hinged upon an explicit difference in their criteria for when a measurement on Alice’s system can be regarded as not disturbing Bob’s system. The EPR criteria allow their conclusion–incompleteness–to be reached by establishing the physical reality of just a single observable q (not of both q and its conjugate observable p), but I show that Bohr’s definition of disturbance prevents the EPR chain of reasoning from establishing even this. Moreover, I show that Bohr’s definition is intimately related to the asymmetric concept of quantum discord from quantum information theory: if and only if the joint state has no Alice-discord, she can measure any observable without disturbing (in Bohr’s sense) Bob’s system. Discord can be present even when systems are unentangled, and this has implications for our understanding of the historical development of notions of quantum nonlocality. -- Highlights: •Both the EPR argument, and Bohr’s reply, were technically correct. •Their opposed conclusions came from different criteria for disturbance. •Bohr’s criterion works against even the simplified (one-variable) EPR argument. •Bohr’s criterion for disturbance is intimately related to quantum discord. •This illuminates the historical development of notions of quantum nonlocality

Discordant tooth agenesis and peg-shaped in a pair of monozygotic twins: Clinical and molecular study

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Lívia Azeredo Alves Antunes

2013-01-01

Full Text Available The present report aimed to study an uncommon case of a pair of twins that presented a discordant dental phenotype. Family investigation, clinical, radiographic examination and molecular analysis were performed in both girls. Molecular analysis confirmed the monozygosity by deoxyribonucleic acid chip technology. One twin presented tooth agenesis in left upper lateral incisor and peg-shaped on the contra lateral side while the other twin had no dental alterations. The dental casts study employed digital caliper to compare morphological dimensions and showed alteration only in peg-shaped tooth. In conclusion, this study provide support that one or more mutated gene could cause discordances in dental phenotype in these monozygotic twins.

Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

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Mengmeng Du

Full Text Available Genome-wide association studies (GWAS have identified many common single nucleotide polymorphisms (SNPs associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs. We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33. We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s.

Discordance in investigator-reported and adjudicated sudden death in TIOSPIR

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Robert A. Wise

2017-03-01

Full Text Available Accurate and consistent determination of cause of death is challenging in chronic obstructive pulmonary disease (COPD patients. TIOSPIR (N=17 135 compared the safety and efficacy of tiotropium Respimat 5/2.5 µg with HandiHaler 18 µg in COPD patients. All-cause mortality was a primary end-point. A mortality adjudication committee (MAC assessed all deaths. We aimed to investigate causes of discordance in investigator-reported and MAC-adjudicated causes of death and their impact on results, especially cardiac and sudden death. The MAC provided independent, blinded assessment of investigator-reported deaths (n=1302 and assigned underlying cause of death. Discordance between causes of death was assessed descriptively (shift tables. There was agreement between investigator-reported and MAC-adjudicated deaths in 69.4% of cases at the system organ class level. Differences were mainly observed for cardiac deaths (16.4% investigator, 5.1% MAC and deaths assigned to general disorders including sudden death (17.4% investigator, 24.6% MAC. Reasons for discrepancies included investigator attribution to the immediate (e.g. myocardial infarction (MI over the underlying cause of death (e.g. COPD and insufficient information for a definitive cause. Cause-specific mortality varies in COPD, depending on the method of assignment. Sudden death, witnessed and unwitnessed, is common in COPD and often attributed to MI without supporting evidence.

Genetic moderation of the association between adolescent romantic involvement and depression: Contributions of serotonin transporter gene polymorphism, chronic stress, and family discord.

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Starr, Lisa R; Hammen, Constance

2016-05-01

Studies support a link between adolescent romantic involvement and depression. Adolescent romantic relationships may increase depression risk by introducing chronic stress, and genetic vulnerability to stress reactivity/emotion dysregulation may moderate these associations. We tested genetic moderation of longitudinal associations between adolescent romantic involvement and later depressive symptoms by a polymorphism in the serotonin transporter linked polymorphic region gene (5-HTTLPR) and examined contributory roles of chronic stress and family discord. Three hundred eighty-one youth participated at ages 15 and 20. The results indicated that 5-HTTLPR moderated the association between age 15 romantic involvement and age 20 depressive symptoms, with strongest effects for short homozygotes. Conditional process analysis revealed that chronic stress functioned as a moderated mediator of this association, fully accounting for the romantic involvement-depression link among short/short genotypes. Also, romantic involvement predicted later depressive symptoms most strongly among short-allele carriers with high family discord. The results have important implications for understanding the romantic involvement-depression link and the behavioral and emotional correlates of the 5-HTTLPR genotype.

Accurate genotyping across variant classes and lengths using variant graphs

DEFF Research Database (Denmark)

Sibbesen, Jonas Andreas; Maretty, Lasse; Jensen, Jacob Malte

2018-01-01

of read k-mers to a graph representation of the reference and variants to efficiently perform unbiased, probabilistic genotyping across the variation spectrum. We demonstrate that BayesTyper generally provides superior variant sensitivity and genotyping accuracy relative to existing methods when used...... collecting a set of candidate variants across discovery methods, individuals and databases, and then realigning the reads to the variants and reference simultaneously. However, this realignment problem has proved computationally difficult. Here, we present a new method (BayesTyper) that uses exact alignment...... to integrate variants across discovery approaches and individuals. Finally, we demonstrate that including a ‘variation-prior’ database containing already known variants significantly improves sensitivity....

Pairwise correlations via quantum discord and its geometric measure in a four-qubit spin chain

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Abdel-Baset A. Mohamed

2013-04-01

Full Text Available The dynamic of pairwise correlations, including quantum entanglement (QE and discord (QD with geometric measure of quantum discord (GMQD, are shown in the four-qubit Heisenberg XX spin chain. The results show that the effect of the entanglement degree of the initial state on the pairwise correlations is stronger for alternate qubits than it is for nearest-neighbor qubits. This parameter results in sudden death for QE, but it cannot do so for QD and GMQD. With different values for this entanglement parameter of the initial state, QD and GMQD differ and are sensitive for any change in this parameter. It is found that GMQD is more robust than both QD and QE to describe correlations with nonzero values, which offers a valuable resource for quantum computation.

Annotating DNA variants is the next major goal for human genetics.

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Cutting, Garry R

2014-01-02

Clinical genetic testing has undergone a dramatic transformation in the past two decades. Diagnostic laboratories that previously tested for well-established disease-causing DNA variants in a handful of genes have evolved into sequencing factories identifying thousands of variants of known and unknown medical consequence. Sorting out what does and does not cause disease in our genomes is the next great challenge in making genetics a central feature of healthcare. I propose that closing the gap in our ability to interpret variation responsible for Mendelian disorders provides a grand and unprecedented opportunity for geneticists. Human geneticists are well placed to coordinate a systematic evaluation of variants in collaboration with basic scientists and clinicians. Sharing of knowledge, data, methods, and tools will aid both researchers and healthcare workers in achieving their common goal of defining the pathogenic potential of variants. Generation of variant annotations will inform genetic testing and will deepen our understanding of gene and protein function, thereby aiding the search for molecular targeted therapies. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Discordance of Mutation Statuses of Epidermal Growth Factor Receptor and K-ras between Primary Adenocarcinoma of Lung and Brain Metastasis

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Kun-Ming Rau

2016-04-01

Full Text Available Mutations on epidermal growth factor receptor (EGFR of adenocarcinomas of lung have been found to be associated with increased sensitivity to EGFR tyrosine kinase inhibitors and K-ras mutations may correlate with primary resistance. We aimed to explore the discordant mutation statuses of EGFR and K-ras between primary tumors and matched brain metastases in adenocarcinomas of lung. We used a sensitive Scorpion ARMS method to analyze EGFR mutation, and Sanger sequencing followed by allele-specific real-time polymerase chain reaction to analyze K-ras mutation. Forty-nine paired tissues with both primary adenocarcinoma of lung and matched brain metastasis were collected. Thirteen patients (26.5% were discordant for the status of EGFR between primary and metastatic sites. K-ras gene could be checked in paired specimens from 33 patients, thirteen patients (39.6% were discordant for the status of K-ras. In primary lung adenocarcinoma, there were 14 patients of mutant EGFR had mutant K-ras synchronously. This study revealed that the status of EGFR mutation in lung adenocarcinomas is relatively consistent between primary and metastatic sites compared to K-ras mutation. However, there are still a few cases of adenocarcinoma of lung showing discordance for the status of EGFR mutation. Repeated analysis of EGFR mutation is highly recommended if tissue from metastatic or recurrent site is available for the evaluation of target therapy.

Influence of cytochrome 2C19 allelic variants on on-treatment platelet reactivity evaluated by five different platelet function tests.

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Gremmel, Thomas; Kopp, Christoph W; Moertl, Deddo; Seidinger, Daniela; Koppensteiner, Renate; Panzer, Simon; Mannhalter, Christine; Steiner, Sabine

2012-05-01

The antiplatelet effect of clopidogrel has been linked to cytochrome P450 2C19 (CYP2C19) carrier status. The presence of loss of function and gain of function variants were found to have a gene-dose effect on clopidogrel metabolism. However, genotyping is only one aspect of predicting response to clopidogrel and several platelet function tests are available to measure platelet response. Patients and methods We studied the influence of CYP2C19 allelic variants on on-treatment platelet reactivity as assessed by light transmission aggregometry (LTA), the VerifyNow P2Y12 assay, the VASP assay, multiple electrode aggregometry (MEA), and the Impact-R in 288 patients after stenting for cardiovascular disease. Allelic variants of CYP2C19 were determined with the Infiniti® CYP450 2C19+ assay and categorized into four metabolizer states (ultrarapid, extensive, intermediate, poor). Platelet reactivity increased linearly from ultrarapid to poor metabolizers using the VerifyNow P2Y12 assay (P = 0.04), the VASP assay (P = 0.02) and the Impact-R (P = 0.04). The proportion of patients with high on-treatment residual platelet reactivity (HRPR) identified by LTA, the VerifyNow P2Y12 assay and the VASP assay increased when the metabolizer status decreased, while no such relationship could be identified for results of MEA and Impact-R. The presence of loss of function variants (*2/*2, *2-8*/wt, *2/*17) was an independent predictor of HRPR in LTA and the VASP assay while it did not reach statistical significance in the VerifyNow P2Y12 assay, MEA, and the Impact-R. Depending on the type of platelet function test differences in the association of on-treatment platelet reactivity with CYP2C19 carrier status are observed. Copyright © 2011 Elsevier Ltd. All rights reserved.

Cellulase variants

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Blazej, Robert; Toriello, Nicholas; Emrich, Charles; Cohen, Richard N.; Koppel, Nitzan

2015-07-14

This invention provides novel variant cellulolytic enzymes having improved activity and/or stability. In certain embodiments the variant cellulotyic enzymes comprise a glycoside hydrolase with or comprising a substitution at one or more positions corresponding to one or more of residues F64, A226, and/or E246 in Thermobifida fusca Cel9A enzyme. In certain embodiments the glycoside hydrolase is a variant of a family 9 glycoside hydrolase. In certain embodiments the glycoside hydrolase is a variant of a theme B family 9 glycoside hydrolase.

Graphic and algebraic solutions of the discordant lead-uranium age problem

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Stieff, L.R.; Stern, T.W.

1961-01-01

Uranium-bearing minerals that give lead-uranium and lead-lead ages that are essentially in agreement, i.e. concordant, generally are considered to have had a relatively simple geologic history and to have been unaltered since their deposition. The concordant ages obtained on such materials are, therefore, assumed to approach closely the actual age of the minerals. Many uranium-bearing samples, particularly uranium ores, give the following discordant age sequences; Pb206 U238 generation of radiogenic lead. The evaluation of discordant lead isotope age data may be separated into two operations. The first operation, with which this paper is concerned, is mechanical in nature and involves the calculation of the different possible concordant ages corresponding to the various processes assumed to have produced the discordant ages. The second operation is more difficult to define and requires, in part, some personal judgement. It includes a synthesis of the possible concordant age solutions with other independent geologic and isotopic evidence. The concordant age ultimately chosen as most acceptable should be consistent not only with the known events in the geologic history of the area, the age relations of the enclosing rocks, and the mineralogic and paragenetic evidence, but also with other independent age measurements and the isotopic data obtained on the lead in related or associated non-radioactive minerals. The calculation of the possible concordant ages from discordant age data has been greatly simplified by Wetherill's graphical method of plotting the mole ratios of radiogenic Pb206 U238 ( N206 N238) vs. radiogenic Pb207 U235 ( N207 N235) after correcting for the contaminating common Pb206 and Pb207. The linear relationships noted in this graphical procedure have been extended to plots of the mole ratios of total Pb206 U238 ( tN206 N238) vs. total Pb207 U235 ( tN207 N235). This modification permits the calculation of concordant ages for unaltered samples using

Models accounting for intention-behavior discordance in the physical activity domain: a user's guide, content overview, and review of current evidence.

Science.gov (United States)

Rhodes, Ryan E; Yao, Christopher A

2015-02-07

There is a growing concern among researchers with the limited effectiveness and yet subsequent stagnation of theories applied to physical activity (PA). One of the most highlighted areas of concern is the established gap between intention and PA, yet the considerable use of models that assume intention is the proximal antecedent of PA. The objective of this review was to: 1) provide a guide and thematic analysis of the available models that include constructs that address intention-behavior discordance and 2) highlight the evidence for these structures in the PA domain. A literature search was conducted among 13 major databases to locate relevant models and PA studies published before August 2014. Sixteen models were identified and nine overall themes for post-intentional constructs were created. Of the 16 models, eight were applied to 36 PA studies. Early evidence supported maintenance self-efficacy, behavioral regulation strategies, affective judgments, perceived control/opportunity, habit, and extraversion as reliable predictors of post-intention PA. Several intention-behavior discordance models exist within the literature, but are not used frequently. Further efforts are needed to test these models, preferably with experimental designs.

Hormonal contraception does not increase women's HIV acquisition risk in Zambian discordant couples, 1994-2012.

Science.gov (United States)

Wall, Kristin M; Kilembe, William; Vwalika, Bellington; Htee Khu, Naw; Brill, Ilene; Chomba, Elwyn; Johnson, Brent A; Haddad, Lisa; Tichacek, Amanda; Allen, Susan

2015-06-01

To determine the impact of hormonal contraceptive methods on risk of HIV acquisition among HIV-negative women cohabiting with HIV-positive male partners. From 1994-2012, HIV discordant couples recruited from a couples' voluntary HIV counseling and testing center in Lusaka, Zambia were followed longitudinally. HIV-negative partners were tested quarterly. This analysis is restricted to couples in which the man was HIV-positive and the woman was HIV-negative at enrollment and the man was not on antiretroviral treatment. Multivariate Cox models evaluated associations between time-varying contraceptive methods and HIV acquisition among women. Sensitivity analyses explored exposure misclassification and time-varying confounder mediation. Among 1393 couples, 252 incident infections occurred in women over 2842 couple-years (8.9 infections per 100 couple-years; 95% CI, 7.8-10.0). Multivariate Cox models indicated that neither injectable [adjusted hazard ratio (aHR)=1.2; 95% CI, 0.8-1.7], oral contraceptive pill (OCP, aHR=1.3; 95% CI, 0.9-1.8), or implant (aHR=1.1; 95% CI, 0.5-2.2) use was significantly associated with HIV acquisition relative to non-hormonal contraception controlling for woman's age, literacy and time-varying measures of genital ulceration/inflammation. This remained true when only looking at the subset of infections acquired from the spouse (82% of infections) and additionally controlling for baseline HIV viral load of the male partner, pregnancy status, and time-varying measures of sperm on a vaginal swab wet prep and self-reported unprotected sex. OCP and injectable users reported more unprotected sex (pcontraception and HIV acquisition risk in women. Condom use and reinforced condom counseling should always be recommended for HIV discordant couples. HIV testing of sex partners together is critical to establish HIV risk, ascertain couple fertility intentions and counsel appropriately. These findings add to a controversial literature and uniquely address

TREM2 Variants in Alzheimer's Disease

Science.gov (United States)

Guerreiro, Rita; Wojtas, Aleksandra; Bras, Jose; Carrasquillo, Minerva; Rogaeva, Ekaterina; Majounie, Elisa; Cruchaga, Carlos; Sassi, Celeste; Kauwe, John S.K.; Younkin, Steven; Hazrati, Lilinaz; Collinge, John; Pocock, Jennifer; Lashley, Tammaryn; Williams, Julie; Lambert, Jean-Charles; Amouyel, Philippe; Goate, Alison; Rademakers, Rosa; Morgan, Kevin; Powell, John; St. George-Hyslop, Peter; Singleton, Andrew; Hardy, John

2013-01-01

BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.) PMID:23150934

TESTING TREE-CLASSIFIER VARIANTS AND ALTERNATE MODELING METHODOLOGIES IN THE EAST GREAT BASIN MAPPING UNIT OF THE SOUTHWEST REGIONAL GAP ANALYSIS PROJECT (SW REGAP)

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We tested two methods for dataset generation and model construction, and three tree-classifier variants to identify the most parsimonious and thematically accurate mapping methodology for the SW ReGAP project. Competing methodologies were tested in the East Great Basin mapping un...

Exercise testing in patients with variant angina: results, correlation with clinical and angiographic features and prognostic significance

International Nuclear Information System (INIS)

Waters, D.D.; Szlachcic, J.; Bourassa, M.G.; Scholl, J.-M.; Theroux, P.

1982-01-01

Eighty-two patients with variant angina underwent a treadmill exercise test using 14 ECG leads, and 67 also underwent exercise thallium-201 scans. The test induced ST elevation in 25 patients (30%), ST depression in 21 (26%) and no ST-segment abnormality in 36 (44%). ST elevation during exercise occurred in the same ECG leads as during spontaneous attacks at rest, and was always associated with a large perfusion defect on the exercise thallium scan. In contrast, exercise-induced ST depression often did not occur in the leads that exhibited ST elevation during episodes at rest. The ST-segment response to exercise did not accurately predict coronary anatomy: Coronary stenoses greater than or equal to 70% were present in 14 of 25 patients (56%) with ST elevation, in 13 of 21 (62%) with ST depression and in 14 of 36 (39%) with no ST-segment abnormality (NS). However, the degree of disease activity did correlate with the result of the exercise test: ST elevation occurred during exercise in 11 of 14 patients who had an average of more than two spontaneous attacks per day, in 12 of 24 who had between two attacks per day and two per week, and in only two of 31 who had fewer than two attacks per week (p<0.005). ST elevation during exercise was reproducible in five of five patients retested during an active phase of their disease, but not in three of three patients who had been angina-free for a least 1 month before the repeat test. We conclude that in variant angina patients, the results of an exercise test correlate well with the degree of disease activity but not with coronary anatomy, and do not define a high-risk subgroup

Bipartite non-classical correlations for a lossy two connected qubit-cavity systems: trace distance discord and Bell's non-locality

Science.gov (United States)

Mohamed, Abdel-Baset A.

2018-04-01

In this paper, some non-classical correlations are investigated for bipartite partitions of two qubits trapped in two spatially separated cavities connected by an optical fiber. The results show that the trace distance discord and Bell's non-locality introduce other quantum correlations beyond the entanglement. Moreover, the correlation functions of the trace distance discord and the Bell's non-locality are very sensitive to the initial correlations, the coupling strengths, and the dissipation rates of the cavities. The fluctuations of the correlation functions between their initial values and gained (loss) values appear due to the unitary evolution of the system. These fluctuations depend on the chosen initial correlations between the two subsystems. The maximal violations of Bell's inequality occur when the logarithmic negativity and the trace distance discord reach certain values. It is shown that the robustness of the non-classical correlations, against the dissipation rates of the cavities, depends on the bipartite partitions reduced density matrices of the system, and is also greatly enhanced by choosing appropriate coupling strengths.

Case series of fertility treatment in HIV-discordant couples (male positive, female negative: the Ontario experience.

Directory of Open Access Journals (Sweden)

Trent Newmeyer

Full Text Available The success of combination antiretroviral therapies for the treatment of human immunodeficiency virus (HIV has resulted in prolonged life expectancy (over 40 years from diagnosis and an improved quality of life for people living with HIV. The risk of vertical HIV transmission during pregnancy has been reduced to less than 1%. As a result of these breakthroughs and as many of these individuals are of reproductive age, fertility issues are becoming increasingly important for this population. One population in which conception planning and reduction of horizontal HIV transmission warrants further research is HIV-discordant couples where the male partner is HIV-positive and the female partner is HIV-negative. Sperm washing is a technique carried out in a fertility clinic that separates HIV from the seminal fluid. Although sperm washing followed by intrauterine insemination significantly reduces the risk of horizontal HIV transmission, there has been limited access to the procedure in North America. Furthermore, little is known about the conception decision-making experiences of HIV-discordant couples who might benefit from sperm washing. Chart reviews and semi-structured interviews were completed with 12 HIV-discordant couples in Ontario, Canada. Couples were recruited through HIV clinics and one fertility clinic that offered sperm washing. Participants identified a number of factors that affected their decision-making around pregnancy planning. Access to sperm washing and other fertility services was an issue (cost, travel and few clinics. Participants identified a lack of information on the procedure (availability, safety. Sources of support (social networks, healthcare providers were unevenly distributed, especially among those who did not disclose their HIV status to friends and family. Finally, the stigmatisation of HIV continues to have a negative affect on HIV-discordant couples and their intentions to conceive. Access to sperm washing and

Maternal inheritance and mitochondrial DNA variants in familial Parkinson's disease

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Pfeiffer Ronald F

2010-04-01

Full Text Available Abstract Background Mitochondrial function is impaired in Parkinson's disease (PD and may contribute to the pathogenesis of PD, but the causes of mitochondrial impairment in PD are unknown. Mitochondrial dysfunction is recapitulated in cell lines expressing mitochondrial DNA (mtDNA from PD patients, implicating mtDNA variants or mutations, though the role of mtDNA variants or mutations in PD risk remains unclear. We investigated the potential contribution of mtDNA variants or mutations to the risk of PD. Methods We examined the possibility of a maternal inheritance bias as well as the association between mitochondrial haplogroups and maternal inheritance and disease risk in a case-control study of 168 multiplex PD families in which the proband and one parent were diagnosed with PD. 2-tailed Fisher Exact Tests and McNemar's tests were used to compare allele frequencies, and a t-test to compare ages of onset. Results The frequency of affected mothers of the proband with PD (83/167, 49.4% was not significantly different from the frequency of affected females of the proband generation (115/259, 44.4% (Odds Ratio 1.22; 95%CI 0.83 - 1.81. After correcting for multiple tests, there were no significant differences in the frequencies of mitochondrial haplogroups or of the 10398G complex I gene polymorphism in PD patients compared to controls, and no significant associations with age of onset of PD. Mitochondrial haplogroup and 10398G polymorphism frequencies were similar in probands having an affected father as compared to probands having an affected mother. Conclusions These data fail to demonstrate a bias towards maternal inheritance in familial PD. Consistent with this, we find no association of common haplogroup-defining mtDNA variants or for the 10398G variant with the risk of PD. However, these data do not exclude a role for mtDNA variants in other populations, and it remains possible that other inherited mitochondrial DNA variants, or somatic m

Gray and white matter volume abnormalities in monozygotic and same-gender dizygotic twins discordant for schizophrenia

DEFF Research Database (Denmark)

Hilshoff, Hilleke E.; Brans, Rachel G. H.; van Haren, Neeltje E. M.

2004-01-01

BACKGROUND: Whole brain tissue volume decreases in schizophrenia have been related to both genetic risk factors and disease-related (possibly nongenetic) factors; however, whether genetic and environmental risk factors in the brains of patients with schizophrenia are differentially reflected...... in gray or white matter volume change is not known. METHODS: Magnetic resonance imaging (1.5 T) brain scans of 11 monozygotic and 11 same-gender dizygotic twin pairs discordant for schizophrenia were acquired and compared with 11 monozygotic and 11 same-gender dizygotic healthy control twin pairs. RESULTS......: Repeated-measures volume analysis of covariance revealed decreased whole brain volume in the patients with schizophrenia as compared with their co-twins and with healthy twin pairs. Decreased white matter volume was found in discordant twin pairs compared with healthy twin pairs, particularly...

Somatic cancer variant curation and harmonization through consensus minimum variant level data

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Deborah I. Ritter

2016-11-01

Full Text Available Abstract Background To truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG of the Clinical Genome Resource (ClinGen, in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD. MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVLD standards, and in a working partnership with ClinVar, we aim to streamline the somatic variant curation efforts in the community and reduce redundancy and time burden for the interpretation of cancer variants in clinical practice. Methods We developed MVLD through a consensus approach by i reviewing clinical actionability interpretations from institutions participating in the WG, ii conducting extensive literature search of clinical somatic interpretation schemas, and iii survey of cancer variant web portals. A forthcoming guideline on cancer variant interpretation, from the Association of Molecular Pathology (AMP, can be incorporated into MVLD. Results Along with harmonizing standardized terminology for allele interpretive and descriptive fields that are collected by many databases, the MVLD includes unique fields for cancer variants such as Biomarker Class, Therapeutic Context and Effect. In addition, MVLD includes recommendations for controlled semantics and ontologies. The Somatic WG is collaborating with ClinVar to evaluate MVLD use for somatic variant submissions. ClinVar is an open and centralized repository where sequencing laboratories can report summary-level variant data with clinical significance, and ClinVar accepts cancer variant data. Conclusions We expect the use of the MVLD to streamline clinical interpretation of cancer variants, enhance interoperability among multiple redundant curation efforts, and increase submission of

CDKL5 variants

Science.gov (United States)

Kalscheuer, Vera M.; Hennig, Friederike; Leonard, Helen; Downs, Jenny; Clarke, Angus; Benke, Tim A.; Armstrong, Judith; Pineda, Mercedes; Bailey, Mark E.S.; Cobb, Stuart R.

2017-01-01

Objective: To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene. Methods: We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity. Results: The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants, we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also describe benign splicing and nonsense variants within these exons, suggesting that isoform hCDKL5_5 is likely to have little or no neurologic significance. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency. Conclusions: These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency. Together, these analyses support the view that the predominant brain isoform in humans (hCDKL5_1) is crucial for normal neurodevelopment and that the catalytic domain is the primary functional domain. PMID:29264392

Discordant inflammatory changes in the apophyseal and sacroiliac joints: serial observations in enthesitis-related arthritis

Science.gov (United States)

Amies, Thomas; Vendhan, Kanimozhi; Humphries, Paul; Sen, Debajit; Ioannou, Yiannis; Hall-Craggs, Margaret A

2016-01-01

Objective: To determine the extent to which inflammation of the sacroiliac joints (SIJs) and apophyseal joints (AJs) changes concordantly after treatment in enthesitis-related arthritis (ERA). Methods: A retrospective study was performed with institutional review board approval. 31 young patients with ERA who had been scanned between March 2009 and November 2014 were included. All patients had post-contrast imaging of the SIJs and lumbar spine and short tau inversion-recovery (STIR) images of the SIJs. The severity of sacroiliitis was scored using a modification of an established technique, and inflammation of the AJs was evaluated using a recently described grading system. The changes in SIJ and AJ scores after treatment were classified as either concordant or discordant, and the proportion of scan pairs in these groups was recorded. In addition, the correlation between change in SIJ STIR score (Δnfla) and change in AJ score (ΔAJ) was assessed using Spearman's correlation coefficient. Results: Of a total of 43 scan pairs, the changes in inflammation were concordant in 16 scan pairs and discordant in 27 scan pairs. There was no significant correlation between Δnfla and ΔAJ (R = 0.14, p = 0.37). Conclusion: Inflammatory changes in the SIJs and AJs are often discordant. This may be a reason why patients experience ongoing back pain despite apparent improvement in one or the other site. Advances in knowledge: Inflammation may behave differently at different anatomical sites. The SIJs and AJs should both be imaged in patients with ERA with back pain. PMID:27376529

Exploration of quantum phases transition in the XXZ model with Dzyaloshinskii-Moriya interaction using trance distance discord

Science.gov (United States)

Zhang, Ren-jie; Xu, Shuai; Shi, Jia-dong; Ma, Wen-chao; Ye, Liu

2015-11-01

In the paper, we researched the quantum phase transition (QPT) in the anisotropic spin XXZ model by exploiting the quantum renormalization group (QRG) method. The innovation point is that we adopt a new approach called trace distance discord to indicate the quantum correlation of the system. QPT after several iterations of renormalization in current system has been observed. Consequently, it opened the possibility of investigation of QPR in the geometric discord territory. While the anisotropy suppresses the correlation due to favoring of the alignment of spins, the DM interaction restores the spoiled correlation via creation of the quantum fluctuations. We also apply quantum renormalization group method to probe the thermodynamic limit of the model and emerging of nonanalytic behavior of the correlation.

Impact of a visual aid on discordance between physicians and family members about prognosis of critically ill patients.

Science.gov (United States)

Burelli, Gabrielle; Berthelier, Chloé; Vanacker, Hélène; Descaillot, Léonard; Philippon-Jouve, Bénédicte; Fabre, Xavier; Kaaki, Mahmoud; Chakarian, Jean-Charles; Domine, Alexandre; Beuret, Pascal

2018-06-01

This study aimed to evaluate the impact of a visual aid on the discordance about prognosis between physicians and family members. The study was performed in a general intensive care department with two 6-bed units. In the unit A, family members could consult a visual aid depicting day by day the evolution of global, hemodynamic, respiratory, renal and neurological conditions of the patient on a 10-point scale. In the unit B, they only received oral medical information. On day 7 of the ICU stay, the physician and family members estimated the prognosis of the patient among four proposals (life threatened; steady state but may worsen; steady state, should heal; will heal). Then we compared the rate of discordance about prognosis between physicians and family members in the two units. Seventy-nine consecutive patients admitted in the intensive care department and still present at day 7, their family members and physicians, were enrolled. Patients in the two units were comparable in age, sex ratio, reason for admission, SAPS II at admission and SOFA score at day 7. In the unit A, physician-family members discordance about prognosis occurred for 12 out of 39 patients (31%) vs. 22 out of 40 patients (55%) in the unit B (P=0.04). In our study, adding a visual aid depicting the evolution of the condition of critically ill patients day by day to classic oral information allowed the family to have an estimate of the prognosis less discordant with the estimate of the physician. Copyright © 2018 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.

Association analysis identifies ZNF750 regulatory variants in psoriasis

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Birnbaum Ramon Y

2011-12-01

Full Text Available Abstract Background Mutations in the ZNF750 promoter and coding regions have been previously associated with Mendelian forms of psoriasis and psoriasiform dermatitis. ZNF750 encodes a putative zinc finger transcription factor that is highly expressed in keratinocytes and represents a candidate psoriasis gene. Methods We examined whether ZNF750 variants were associated with psoriasis in a large case-control population. We sequenced the promoter and exon regions of ZNF750 in 716 Caucasian psoriasis cases and 397 Caucasian controls. Results We identified a total of 47 variants, including 38 rare variants of which 35 were novel. Association testing identified two ZNF750 haplotypes associated with psoriasis (p ZNF750 promoter and 5' UTR variants displayed a 35-55% reduction of ZNF750 promoter activity, consistent with the promoter activity reduction seen in a Mendelian psoriasis family with a ZNF750 promoter variant. However, the rare promoter and 5' UTR variants identified in this study did not strictly segregate with the psoriasis phenotype within families. Conclusions Two haplotypes of ZNF750 and rare 5' regulatory variants of ZNF750 were found to be associated with psoriasis. These rare 5' regulatory variants, though not causal, might serve as a genetic modifier of psoriasis.

Genetics in psychiatry: common variant association studies

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Buxbaum Joseph D

2010-03-01

Full Text Available Abstract Many psychiatric conditions and traits are associated with significant heritability. Genetic risk for psychiatric conditions encompass rare variants, identified due to major effect, as well as common variants, the latter analyzed by association analyses. We review guidelines for common variant association analyses, undertaking after assessing evidence of heritability. We highlight the importance of: suitably large sample sizes; an experimental design that controls for ancestry; careful data cleaning; correction for multiple testing; small P values for positive findings; assessment of effect size for positive findings; and, inclusion of an independent replication sample. We also note the importance of a critical discussion of any prior findings, biological follow-up where possible, and a means of accessing the raw data.

Cerebral metabolism, anatomy, and cognition in monozygotic twins discordant for dementia of the Alzheimer type.

Science.gov (United States)

Luxenberg, J S; May, C; Haxby, J V; Grady, C; Moore, A; Berg, G; White, B J; Robinette, D; Rapoport, S I

1987-03-01

One pair of monozygotic twins discordant for dementia of the Alzheimer type (DAT) was studied using neuropsychological testing, quantitative x-ray computed tomography (QCT) and magnetic resonance imaging (MRI) of the brain. Cerebral glucose metabolism was measured using positron emission tomography (PET) and 2-[18-F]fluoro-2-deoxy-D-glucose (FDG). The affected twin had a seven year history of progressive cognitive impairment and was severely demented. Neuropsychological testing of the affected twin demonstrated marked deficits in all areas of cognitive function. The asymptomatic twin showed some impairment on tests of perceptual organisation and delayed recall. The affected twin had loss of gray matter and ventricular enlargement on QCT and MRI compared with healthy controls (p less than 0.05). He also had frontal and parietal lobe hypometabolism and increased asymmetry of metabolism on PET compared to both his twin and healthy age-matched controls (p less than 0.05). PET, QCT, and MRI distinguished changes in the twin with DAT compared with his brother and healthy controls. Although the subtle neuropsychological abnormalities of the asymptomatic twin may be signs of early DAT, they were not accompanied by any changes in regional cerebral metabolism or brain structure.

Cannabis Involvement and Nonsuicidal Self-Injury: A Discordant Twin Approach.

Science.gov (United States)

Few, Lauren R; Grant, Julia D; Nelson, Elliot C; Trull, Timothy J; Grucza, Richard A; Bucholz, Kathleen K; Verweij, Karin J H; Martin, Nicholas G; Statham, Dixie J; Madden, Pamela A F; Heath, Andrew C; Lynskey, Michael T; Agrawal, Arpana

2016-11-01

Cannabis use, particularly at an early age, has been linked to suicidal thoughts and behavior, but minimal work has examined the association between cannabis use and lifetime nonsuicidal self-injury (NSSI). The current study aims to characterize the overlap between lifetime and early cannabis use and NSSI and to examine genetic and environmental mechanisms of this association. Adult male and female twins from the Australian Twin Registry (N = 9,583) were used to examine the odds of NSSI associated with lifetime cannabis use and early cannabis use (i.e., accounting for the age at onset of cannabis use and NSSI. Lifetime cannabis use (odds ratio [OR] = 2.84, 95% CI [2.23, 3.61]) and early cannabis use were associated with increased odds of NSSI (OR = 2.15, 95% CI [1.75, 2.65]), and this association remained when accounting for covariates. The association was only significant, however, in MZ twin pairs discordant for early cannabis use (OR = 3.20, 95% CI [1.17, 8.73]). Replication analyses accounting for the temporal ordering of cannabis use and NSSI yielded similar findings of nominal significance. Results suggest that NSSI is associated with cannabis involvement via differing mechanisms. For lifetime cannabis use, the lack of association in discordant pairs suggests the role of shared genes and family environment. However, in addition to such shared familial influences, person-specific and putatively causal factors contribute to the relationship between early cannabis use and NSSI. Therefore, delaying the onset of cannabis use may reduce exposure to influences that exacerbate vulnerabilities to NSSI.

Hormonal contraception does not increase women's HIV acquisition risk in Zambian discordant couples, 1994–2012

Science.gov (United States)

Wall, Kristin M.; Kilembe, William; Vwalika, Bellington; Khu, Naw Htee; Brill, Ilene; Chomba, Elwyn; Johnson, Brent A.; Haddad, Lisa; Tichacek, Amanda; Allen, Susan

2015-01-01

Objective To determine the impact of hormonal contraceptive methods on risk of HIV acquisition among HIV-negative women cohabiting with HIV-positive male partners. Study design From 1994–2012, HIV discordant couples recruited from a couples’ voluntary HIV counseling and testing center in Lusaka, Zambia were followed longitudinally. HIV-negative partners were tested quarterly. This analysis is restricted to couples in which the man was HIV-positive and the woman was HIV-negative at enrollment and the man was not on antiretroviral treatment. Multivariate Cox models evaluated associations between time-varying contraceptive methods and HIV acquisition among women. Sensitivity analyses explored exposure misclassification and time-varying confounder mediation. Results Among 1393 couples, 252 incident infections occurred in women over 2842 couple-years (8.9 infections per 100 couple-years; 95% CI, 7.8–10.0). Multivariate Cox models indicated that neither injectable [adjusted hazard ratio (aHR)=1.2; 95% CI, 0.8–1.7], oral contraceptive pill (OCP, aHR=1.3; 95% CI, 0.9–1.8), or implant (aHR=1.1; 95% CI, 0.5–2.2) use was significantly associated with HIV acquisition relative to non-hormonal contraception controlling for woman's age, literacy and time-varying measures of genital ulceration/inflammation. This remained true when only looking at the subset of infections acquired from the spouse (82% of infections) and additionally controlling for baseline HIV viral load of the male partner, pregnancy status, and time-varying measures of sperm on a vaginal swab wet prep and self-reported unprotected sex. OCP and injectable users reported more unprotected sex (pcontraception and HIV acquisition risk in women. Condom use and reinforced condom counseling should always be recommended for HIV discordant couples. HIV testing of sex partners together is critical to establish HIV risk, ascertain couple fertility intentions and counsel appropriately. Implications These findings

Neuroanatomic alterations and social and communication deficits in monozygotic twins discordant for autism disorder.

Science.gov (United States)

Mitchell, Shanti R; Reiss, Allan L; Tatusko, Danielle H; Ikuta, Ichiro; Kazmerski, Dana B; Botti, Jo-Anna C; Burnette, Courtney P; Kates, Wendy R

2009-08-01

Investigating neuroanatomic differences in monozygotic twins who are discordant for autism can help unravel the relative contributions of genetics and environment to this pervasive developmental disorder. The authors used magnetic resonance imaging (MRI) to investigate several brain regions of interest in monozygotic twins who varied in degree of phenotypic discordance for narrowly defined autism. The subjects were 14 pairs of monozygotic twins between the ages of 5 and 14 years old and 14 singleton age- and gender-matched typically developing comparison subjects. The monozygotic twin group was a cohort of children with narrowly defined autistic deficits and their co-twins who presented with varying levels of autistic deficits. High-resolution MRIs were acquired and volumetric/area measurements obtained for the frontal lobe, amygdala, and hippocampus and subregions of the prefrontal cortex, corpus callosum, and cerebellar vermis. No neurovolumetric/area differences were found between twin pairs. Relative to typically developing comparison subjects, dorsolateral prefrontal cortex volumes and anterior areas of the corpus callosum were significantly altered in autistic twins, and volumes of the posterior vermis were altered in both autistic twins and co-twins. Intraclass correlation analysis of brain volumes between children with autism and their co-twins indicated that the degree of within-pair neuroanatomic concordance varied with brain region. In the group of subjects with narrowly defined autism only, dorsolateral prefrontal cortex, amygdala, and posterior vermis volumes were significantly associated with the severity of autism based on scores from the Autism Diagnostic Observation Schedule-Generic. These findings support previous research demonstrating alterations in the prefrontal cortex, corpus callosum, and posterior vermis in children with autism and further suggest that alterations are associated with the severity of the autism phenotype. Continued research

Twin birth order, birthweight and birthweight discordance: any relationship

Directory of Open Access Journals (Sweden)

Onyiriuka A.N.

2010-12-01

Full Text Available Background: It is widely believed that in twin pairs, at birth, the first-born weigh more than the second-born but this concept has been challenged. Objective: To assess the truthfulness of this common concept that first-born twins are usually heavier than their second-born siblings at birth. Methods: In a series of 104 sets of live-born twins, the birth weights of first-born twins were compared with those of their second-born siblings, after controlling for gender. Their intra-pair birthweight differences were determined and twin pairs whose birthweight difference was 15% or more were designated as discordant. Results: Twin I was heavier than Twin II in 61.5% of cases while Twin II was heavier than Twin I in 28.9% of cases. Twins I and II had equal birthweights in 9.6% of cases. Comparing the mean birthweight of the first-born-male twin with that of second-born- male twin, it was 2515+427g (95% Confidence Interval, CI=2402-2628 versus 2432 +435g (95% CI=2321-2543 p>0.05. The mean birthweight of first-born-female twin was 2326+445g (95% CI=2214-2439 while that of the second-born-female twin was 2325+501g (95% CI=2197-2453 p>0.05. When the birthweight difference exceeded 750g, the probability that Twin I will be heavier than Twin II was 83.3% (5 of 6. Conclusion: Although the first-born twin was more often heavier than their second-born siblings, either could weigh more or less at birth. The larger the birthweight difference between growth-discordant twin pair, the greater the probability that the heavier twin would be delivered first

One-norm geometric quantum discord and critical point estimation in the XY spin chain

Energy Technology Data Exchange (ETDEWEB)

Cheng, Chang-Cheng; Wang, Yao; Guo, Jin-Liang, E-mail: guojinliang80@163.com

2016-11-15

In contrast with entanglement and quantum discord (QD), we investigate the thermal quantum correlation in terms of Schatten one-norm geometric quantum discord (GQD) in the XY spin chain, and analyze their capabilities in detecting the critical point of quantum phase transition. We show that the one-norm GQD can reveal more properties about quantum correlation between two spins, especially for the long-range quantum correlation at finite temperature. Under the influences of site distance, anisotropy and temperature, one-norm GQD and its first derivative make it possible to detect the critical point efficiently for a general XY spin chain. - Highlights: • Comparing with entanglement and QD, one-norm GQD is more robust versus the temperature. • One-norm GQD is more efficient in characterization of long-range quantum correlation between two distant qubits. • One-norm GQD performs well in highlighting the critical point of QPT at zero or low finite temperature. • One-norm GQD has a number of advantages over QD in detecting the critical point of the spin chain.

Comparison of the BioRad Variant and Primus Ultra2 high-pressure liquid chromatography (HPLC) instruments for the detection of variant hemoglobins.

Science.gov (United States)

Gosselin, R C; Carlin, A C; Dwyre, D M

2011-04-01

Hemoglobin variants are a result of genetic changes resulting in abnormal or dys-synchronous hemoglobin chain production (thalassemia) or the generation of hemoglobin chain variants such as hemoglobin S. Automated high-pressure liquid chromatography (HPLC) systems have become the method of choice for the evaluation of patients suspected with hemoglobinopathies. In this study, we evaluated the performance of two HPLC methods used in the detection of common hemoglobin variants: Variant and Ultra2. There were 377 samples tested, 26% (99/377) with HbS, 8.5% (32/377) with HbC, 20.7% (78/377) with other hemoglobin variant or thalassemia, and 2.9% with increased hemoglobin A(1) c. The interpretations of each chromatograph were compared. There were no differences noted for hemoglobins A(0), S, or C. There were significant differences between HPLC methods for hemoglobins F, A(2), and A(1) c. However, there was good concordance between normal and abnormal interpretations (97.9% and 96.2%, respectively). Both Variant and Ultra2 HPLC methods were able to detect most common hemoglobin variants. There was better discrimination for fast hemoglobins, between hemoglobins E and A(2), and between hemoglobins S and F using the Ultra2 HPLC method. © 2010 Blackwell Publishing Ltd.

Cough-variant asthma: a diagnostic dilemma in the occupational setting.

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Lipińska-Ojrzanowska, A; Wiszniewska, M; Walusiak-Skorupa, J

2015-03-01

Cough-variant asthma (Corrao's syndrome) is defined as the presence of chronic non-productive cough in patients with bronchial hyperresponsiveness (BHR) and response to bronchodilator therapy. This variant of asthma may present a diagnostic problem in occupational medicine. To describe additional evaluation of cough-variant asthma in a cyanoacrylate-exposed worker in whom standard diagnostic testing was negative. A female beautician was evaluated for suspected occupational allergic rhinitis and asthma. A specific inhalation challenge test (SICT) was performed with cyanoacrylate glues used for applying artificial eyelashes and nails. Spirometry and peak expiratory flow (PEF) measurements were recorded hourly for 24h; methacholine challenge testing was performed and nasal lavage (NL) samples were analysed for eosinophilia. After SICT, the patient developed sneezing, nasal airflow obstruction and cough. Declines in forced expiratory volume in 1 s and PEF were not observed. Eosinophil proportions in NL fluid increased markedly at 4 and 24h after SICT. A significant increase in BHR also occurred 24h after SICT. Clinical symptoms, post-challenge BHR and increased NL eosinophil counts confirmed a positive response to SICT and validated the diagnosis of cough-variant occupational asthma. SICT may be useful in cases where history and clinical data suggest cough-variant asthma and spirometric indices are negative. © The Author 2014. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A guide for functional analysis of BRCA1 variants of uncertain significance

DEFF Research Database (Denmark)

Millot, Gaël A; Carvalho, Marcelo A; Caputo, Sandrine M

2012-01-01

of these variants, the effect on protein function is unknown making it difficult to infer the consequences on risks of breast and ovarian cancers. Thus, many individuals undergoing genetic testing for BRCA1 mutations receive test results reporting a variant of uncertain clinical significance (VUS), leading...... to issues in risk assessment, counseling, and preventive care. Here, we describe functional assays for BRCA1 to directly or indirectly assess the impact of a variant on protein conformation or function and how these results can be used to complement genetic data to classify a VUS as to its clinical...

Probing quantum entanglement, quantum discord, classical correlation, and the quantum state without disturbing them

International Nuclear Information System (INIS)

Li Zhenni; Jin Jiasen; Yu Changshui

2011-01-01

We present schemes for a type of one-parameter bipartite quantum state to probe quantum entanglement, quantum discord, the classical correlation, and the quantum state based on cavity QED. It is shown that our detection does not influence all these measured quantities. We also discuss how the spontaneous emission introduced by our probe atom influences our detection.

Novel epigenetic changes unveiled by monozygotic twins discordant for smoking habits.

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Allione, Alessandra; Marcon, Francesca; Fiorito, Giovanni; Guarrera, Simonetta; Siniscalchi, Ester; Zijno, Andrea; Crebelli, Riccardo; Matullo, Giuseppe

2015-01-01

Exposure to cigarette smoking affects the epigenome and could increase the risk of developing diseases such as cancer and cardiovascular disorders. Changes in DNA methylation associated with smoking may help to identify molecular pathways that contribute to disease etiology. Previous studies are not completely concordant in the identification of differentially methylated regions in the DNA of smokers. We performed an epigenome-wide DNA methylation study in a group of monozygotic (MZ) twins discordant for smoking habits to determine the effect of smoking on DNA methylation. As MZ twins are considered genetically identical, this model allowed us to identify smoking-related DNA methylation changes independent from genetic components. We investigated the whole blood genome-wide DNA methylation profiles in 20 MZ twin pairs discordant for smoking habits by using the Illumina HumanMethylation450 BeadChip. We identified 22 CpG sites that were differentially methylated between smoker and non-smoker MZ twins by intra-pair analysis. We confirmed eight loci already described by other groups, located in AHRR, F2RL3, MYOG1 genes, at 2q37.1 and 6p21.33 regions, and also identified several new loci. Moreover, pathway analysis showed an enrichment of genes involved in GTPase regulatory activity. Our study confirmed the evidence of smoking-related DNA methylation changes, emphasizing that well-designed MZ twin models can aid the discovery of novel DNA methylation signals, even in a limited sample population.

Identifying genetic variants that affect viability in large cohorts.

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Hakhamanesh Mostafavi

2017-09-01

Full Text Available A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10-6 for fathers and P~2.0 × 10-3 for mothers, consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10-3. Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD, body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans.

Evaluating how variants of floristic quality assessment indicate wetland condition.

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Kutcher, Thomas E; Forrester, Graham E

2018-03-28

Biological indicators are useful tools for the assessment of ecosystem condition. Multi-metric and multi-taxa indicators may respond to a broader range of disturbances than simpler indicators, but their complexity can make them difficult to interpret, which is critical to indicator utility for ecosystem management. Floristic Quality Assessment (FQA) is an example of a biological assessment approach that has been widely tested for indicating freshwater wetland condition, but less attention has been given to clarifying the factors controlling its response. FQA quantifies the aggregate of vascular plant species tolerance to habitat degradation (conservatism), and model variants have incorporated species richness, abundance, and indigenity (native or non-native). To assess bias, we tested FQA variants in open-canopy freshwater wetlands against three independent reference measures, using practical vegetation sampling methods. FQA variants incorporating species richness did not correlate with our reference measures and were influenced by wetland size and hydrogeomorphic class. In contrast, FQA variants lacking measures of species richness responded linearly to reference measures quantifying individual and aggregate stresses, suggesting a broad response to cumulative degradation. FQA variants incorporating non-native species, and a variant additionally incorporating relative species abundance, improved performance over using only native species. We relate our empirical findings to ecological theory to clarify the functional properties and implications of the FQA variants. Our analysis indicates that (1) aggregate conservatism reliably declines with increased disturbance; (2) species richness has varying relationships with disturbance and increases with site area, confounding FQA response; and (3) non-native species signal human disturbance. We propose that incorporating species abundance can improve FQA site-level relevance with little extra sampling effort. Using our

Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

DEFF Research Database (Denmark)

Winham, Stacey J; Pirie, Ailith; Chen, Yian Ann

2016-01-01

). Results: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta=1.1E-6,HRSet1......=1.17,HRSet2= 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01). Conclusions: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival...

Glucose 6-phosphate dehydrogenase variants in Japan.

Science.gov (United States)

Miwa, S

1980-01-01

Fifty-four cases of glucose 6-phosphate dehydrogenase (G6PD) deficiency have so far been reported in Japan. Among them, 21 G6PD variants have been characterized. Nineteen out of the 21 variants were characterized in our laboratory and G6PD Heian and "Kyoto" by others. G6PD Tokyo, Tokushima, Ogikubo, Kurume, Fukushima, Yokohama, Yamaguchi, Wakayama, Akita, Heian and "Kyoto" were classified as Class 1, because all these cases showed chronic hemolytic anemia and severe enzyme deficiency. All these variants showed thermal instability. G6PD Mediterranean-like, Ogori, Gifu and Fukuoka were classified as Class 2, whereas G6PD Hofu, B(-) Chinese, Ube, Konan, Kamiube and Kiwa belonged to Class 3. All the 6 Class 3 variants were found as the results of the screening tests. The incidence of the deficiency in Japanese seems to be 0.1-0.5% but that of the cases which may slow drug-induced hemolysis would be much less. G6PD Ube and Konan appear to be relatively common in Japan.

IgG western blot for confirmatory diagnosis of equivocal cases of toxoplasmosis by EIA-IgG and fluorescent antibody test.

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Khammari, Imen; Saghrouni, Fatma; Yaacoub, Alia; Gaied Meksi, Sondoss; Ach, Hinda; Garma, Lamia; Fathallah, Akila; Ben Saïd, Moncef

2013-08-01

The performance values of available techniques used in serodiagnosis of toxoplasmosis are satisfactory but they raise problems of equivocal and discordant results for very low IgG titers. Recently marketed, LDBio-Toxo II IgG Western blot (IB) showed an excellent correlation with the dye test. We estimated the proportion of equivocal and discordant results between the enzyme immunoassay Platelia Toxo IgG (EIA-IgG) and fluorescent antibody test (FAT) and assessed the usefulness of the IB as a confirmatory test. Out of 2,136 sera collected from pregnant women, 1,644 (77.0%) tested unequivocally positive and 407 (19.0%) were negative in both EIA-IgG and FAT. The remaining 85 (4%) sera showed equivocal or discordant results. Among them, 73 (85.9%) were positive and 12 (14.1%) were negative in IB. Forty-one (89.1%) equivocal sera in EIA-IgG and 46 (86.8%) equivocal sera in FAT were positive in IB. Reducing the cut-off values of both screening techniques improved significantly their sensitivity in detecting very low IgG titers at the expense of their specificity. In conclusion, equivocal results in routine-used techniques and their discordance in determination of the immune status in pregnancy women were not uncommon. IB test appeard to be highly useful in these situations as a confirmatory technique.

Software Application Profile: RVPedigree: a suite of family-based rare variant association tests for normally and non-normally distributed quantitative traits.

Science.gov (United States)

Oualkacha, Karim; Lakhal-Chaieb, Lajmi; Greenwood, Celia Mt

2016-04-01

RVPedigree (Rare Variant association tests in Pedigrees) implements a suite of programs facilitating genome-wide analysis of association between a quantitative trait and autosomal region-based genetic variation. The main features here are the ability to appropriately test for association of rare variants with non-normally distributed quantitative traits, and also to appropriately adjust for related individuals, either from families or from population structure and cryptic relatedness. RVPedigree is available as an R package. The package includes calculation of kinship matrices, various options for coping with non-normality, three different ways of estimating statistical significance incorporating triaging to enable efficient use of the most computationally-intensive calculations, and a parallelization option for genome-wide analysis. The software is available from the Comprehensive R Archive Network [CRAN.R-project.org] under the name 'RVPedigree' and at [https://github.com/GreenwoodLab]. It has been published under General Public License (GPL) version 3 or newer. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Mitochondrial DNA Copy Number in Sleep Duration Discordant Monozygotic Twins.

Science.gov (United States)

Wrede, Joanna E; Mengel-From, Jonas; Buchwald, Dedra; Vitiello, Michael V; Bamshad, Michael; Noonan, Carolyn; Christiansen, Lene; Christensen, Kaare; Watson, Nathaniel F

2015-10-01

Mitochondrial DNA (mtDNA) copy number is an important component of mitochondrial function and varies with age, disease, and environmental factors. We aimed to determine whether mtDNA copy number varies with habitual differences in sleep duration within pairs of monozygotic twins. Academic clinical research center. 15 sleep duration discordant monozygotic twin pairs (30 twins, 80% female; mean age 42.1 years [SD 15.0]). Sleep duration was phenotyped with wrist actigraphy. Each twin pair included a "normal" (7-9 h/24) and "short" (sleeping twin. Fasting peripheral blood leukocyte DNA was assessed for mtDNA copy number via the n-fold difference between qPCR measured mtDNA and nuclear DNA creating an mtDNA measure without absolute units. We used generalized estimating equation linear regression models accounting for the correlated data structure to assess within-pair effects of sleep duration on mtDNA copy number. Mean within-pair sleep duration difference per 24 hours was 94.3 minutes (SD 62.6 min). We found reduced sleep duration (β = 0.06; 95% CI 0.004, 0.12; P sleep efficiency (β = 0.51; 95% CI 0.06, 0.95; P sleep duration was associated with a decrease in mtDNA copy number of 0.06. Likewise, a 1% decrease in actigraphy-defined sleep efficiency was associated with a decrease in mtDNA copy number of 0.51. Reduced sleep duration and sleep efficiency were associated with reduced mitochondrial DNA copy number in sleep duration discordant monozygotic twins offering a potential mechanism whereby short sleep impairs health and longevity through mitochondrial stress. © 2015 Associated Professional Sleep Societies, LLC.

DNA damage response in monozygotic twins discordant for smoking habits.

Science.gov (United States)

Marcon, Francesca; Carotti, Daniela; Andreoli, Cristina; Siniscalchi, Ester; Leopardi, Paola; Caiola, Stefania; Biffoni, Mauro; Zijno, Andrea; Medda, Emanuela; Nisticò, Lorenza; Rossi, Sabrina; Crebelli, Riccardo

2013-03-01

Previous studies in twins indicate that non-shared environment, beyond genetic factors, contributes substantially to individual variation in mutagen sensitivity; however, the role of specific causative factors (e.g. tobacco smoke, diet) was not elucidated. In this investigation, a population of 22 couples of monozygotic twins with discordant smoking habits was selected with the aim of evaluating the influence of tobacco smoke on individual response to DNA damage. The study design virtually eliminated the contribution of genetic heterogeneity to the intra-pair variation in DNA damage response, and thus any difference in the end-points investigated could directly be attributed to the non-shared environment experienced by co-twins, which included as main factor cigarette smoke exposure. Peripheral lymphocytes of study subjects were challenged ex vivo with γ-rays, and the induction, processing, fixation of DNA damage evaluated through multiple approaches. Folate status of study subjects was considered significant covariate since it is affected by smoking habits and can influence radiosensitivity. Similar responses were elicited by γ-rays in co-twins for all the end-points analysed, despite their discordant smoking habits. Folate status did not modify DNA damage response, even though a combined effect of smoking habits, low-plasma folic acid level, and ionising radiation was observed on apoptosis. A possible modulation of DNA damage response by duration and intensity of tobacco smoke exposure was suggested by Comet assay and micronucleus data, but the effect was quantitatively limited. Overall, the results obtained indicate that differences in smoking habits do not contribute to a large extent to inter-individual variability in the response to radiation-induced DNA damage observed in healthy human populations.

Radioimmunological activity of 22K variant of human growth hormone

International Nuclear Information System (INIS)

Camillo, M.A.P.; Ribela, M.T.C.P.; Rogero, J.R.

1986-01-01

From a preparation of human growth hormone its integral variant (hGH-22K) was isolated by isoelectric focusing, having a pI of 5,20 and relative mobility (Rm) of 0,621 in the polyacrylamide gel electrophoresis. Several experiments for the characterization of the isolated variant were carried out. The immunological properties was tested by radioimmunoassay (RIE), in which the activity of the isolated variant and the activity of the total preparation were compared. The dose response-curves obtained by RIE were found to be considered parallels (p [pt

HABP2 G534E Variant in Papillary Thyroid Carcinoma.

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Jerneja Tomsic

Full Text Available The main nonmedullary form of thyroid cancer is papillary thyroid carcinoma (PTC that accounts for 80-90% of all thyroid malignancies. Only 3-10% of PTC patients have a positive family history of PTC yet the familiality is one of the highest of all cancers as measured by case control studies. A handful of genes have been implicated accounting for a small fraction of this genetic predisposition. It was therefore of considerable interest that a mutation in the HABP2 gene was recently implicated in familial PTC. The present work was undertaken to examine the extent of HABP2 variant involvement in PTC. The HABP2 G534E variant (rs7080536 was genotyped in blood DNA from 179 PTC families (one affected individual per family, 1160 sporadic PTC cases and 1395 controls. RNA expression of HABP2 was tested by qPCR in RNA extracted from tumor and normal thyroid tissue from individuals that are homozygous wild-type or heterozygous for the variant. The variant was found to be present in 6.1% familial cases, 8.0% sporadic cases (2 individuals were homozygous for the variant and 8.7% controls. The variant did not segregate with PTC in one large and 6 smaller families in which it occurred. In keeping with data from the literature and databases the expression of HABP2 was highest in the liver, much lower in 3 other tested tissues (breast, kidney, brain but not found in thyroid. Given these results showing lack of any involvement we suggest that the putative role of variant HABP2 in PTC should be carefully scrutinized.

“One Should Have Two Homelands”: Discord and Hope in Soma Morgenstern’s Sparks in the Abyss

Directory of Open Access Journals (Sweden)

Kata Gellen

2017-02-01

Full Text Available Soma Morgenstern’s three-part novel Sparks in the Abyss, written between 1930 and 1943, exudes a spirit of serenity and optimism at the same time that its narrative is structured by repeated scenes of conflict and violence. This paper seeks to account for the place of discord in the trilogy. Morgenstern uses the interwar Galician homeland as a site to articulate the possibility of traditional Jewish life in modern Europe. By inhabiting two homes—East and West, Galicia and Vienna, secularism and piety—Jews will be able to negotiate the inevitable discord and occasional brutality that they face in the world. The lessons learned by a Western secular Jew in pluralist Galicia create hope for the negotiation of difference, if not for the complete overcoming of violence, on the eve of World War II.

Non-random X chromosome inactivation in an affected twin in a monozygotic twin pair discordant for Wiedemann-Beckwith syndrome

Energy Technology Data Exchange (ETDEWEB)

Oestavik, R.E.; Eiklid, K.; Oerstavik, K.H. [Ulleval Univ. Hospital, Oslo (Norway)] [and others

1995-03-27

Wiedemann-Beckwith syndrome (WBS) is a syndrome including exomphalos, macroglossia, and generalized overgrowth. The locus has been assigned to 11p15, and genomic imprinting may play a part in the expression of one or more genes involved. Most cases are sporadic. An excess of female monozygotic twins discordant for WBS have been reported, and it has been proposed that this excess could be related to the process of X chromosome inactivation. We have therefore studied X chromosome inactivation in 13-year-old monozygotic twin girls who were discordant for WBS. In addition, both twins had Tourette syndrome. The twins were monochorionic and therefore the result of a late twinning process. This has also been the case in previously reported discordant twin pairs with information on placentation. X chromosome inactivation was determined in DNA from peripheral blood cells by PCR analysis at the androgen receptor locus. The affected twin had a completely skewed X inactivation, where the paternal allele was on the active X chromosome in all cells. The unaffected twin had a moderately skewed X inactivation in the same direction, whereas the mother had a random pattern. Further studies are necessary to establish a possible association between the expression of WBS and X chromosome inactivation. 18 refs., 2 figs., 1 tab.

A Modified Reading the Mind in the Eyes Test Predicts Behavioral Variant Frontotemporal Dementia Better Than Executive Function Tests

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Matthias L. Schroeter

2018-01-01

Full Text Available Behavioral variant frontotemporal dementia (bvFTD is characterized by deep alterations in behavior and personality. Although revised diagnostic criteria agree for executive dysfunction as most characteristic, impairments in social cognition are also suggested. The study aimed at identifying those neuropsychological and behavioral parameters best discriminating between bvFTD and healthy controls. Eighty six patients were diagnosed with possible or probable bvFTD according to Rascovsky et al. (2011 and compared with 43 healthy age-matched controls. Neuropsychological performance was assessed with a modified Reading the Mind in the Eyes Test (RMET, Stroop task, Trail Making Test (TMT, Hamasch-Five-Point Test (H5PT, and semantic and phonemic verbal fluency tasks. Behavior was assessed with the Apathy Evaluation Scale, Frontal Systems Behavioral Scale, and Bayer Activities of Daily Living Scale. Each test’s discriminatory power was investigated by Receiver Operating Characteristic curves calculating the area under the curve (AUC. bvFTD patients performed significantly worse than healthy controls in all neuropsychological tests. Discriminatory power (AUC was highest in behavioral questionnaires, high in verbal fluency tasks and the RMET, and lower in executive function tests such as the Stroop task, TMT and H5PT. As fluency tasks depend on several cognitive functions, not only executive functions, results suggest that the RMET discriminated better between bvFTD and control subjects than other executive tests. Social cognition should be incorporated into diagnostic criteria for bvFTD in the future, such as in the International Classification of Diseases (ICD-11, as already suggested in the Diagnostic and Statistical Manual for Mental Disorders (DSM-5.

Regularized rare variant enrichment analysis for case-control exome sequencing data.

Science.gov (United States)

Larson, Nicholas B; Schaid, Daniel J

2014-02-01

Rare variants have recently garnered an immense amount of attention in genetic association analysis. However, unlike methods traditionally used for single marker analysis in GWAS, rare variant analysis often requires some method of aggregation, since single marker approaches are poorly powered for typical sequencing study sample sizes. Advancements in sequencing technologies have rendered next-generation sequencing platforms a realistic alternative to traditional genotyping arrays. Exome sequencing in particular not only provides base-level resolution of genetic coding regions, but also a natural paradigm for aggregation via genes and exons. Here, we propose the use of penalized regression in combination with variant aggregation measures to identify rare variant enrichment in exome sequencing data. In contrast to marginal gene-level testing, we simultaneously evaluate the effects of rare variants in multiple genes, focusing on gene-based least absolute shrinkage and selection operator (LASSO) and exon-based sparse group LASSO models. By using gene membership as a grouping variable, the sparse group LASSO can be used as a gene-centric analysis of rare variants while also providing a penalized approach toward identifying specific regions of interest. We apply extensive simulations to evaluate the performance of these approaches with respect to specificity and sensitivity, comparing these results to multiple competing marginal testing methods. Finally, we discuss our findings and outline future research. © 2013 WILEY PERIODICALS, INC.

Risk Factors Associated with Discordant Ki-67 Levels between Preoperative Biopsy and Postoperative Surgical Specimens in Breast Cancers.

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Hyung Sun Kim

Full Text Available The Ki-67 labelling index is significant for the management of breast cancer. However, the concordance of Ki-67 expression between preoperative biopsy and postoperative surgical specimens has not been well evaluated. This study aimed to find the correlation in Ki-67 expression between biopsy and surgical specimens and to determine the clinicopathological risk factors associated with discordant values.Ki-67 levels were immunohistochemically measured using paired biopsy and surgical specimens in 310 breast cancer patients between 2008 and 2013. ΔKi-67 was calculated by postoperative Ki-67 minus preoperative levels. The outliers of ΔKi-67 were defined as [lower quartile of ΔKi-67-1.5 × interquartile range (IQR] or (upper quartile + 1.5 × IQR and were evaluated according to clinicopathological parameters by logistic regression analysis.The median preoperative and postoperative Ki-67 levels were 10 (IQR, 15 and 10 (IQR, 25, respectively. Correlation of Ki-67 levels between the two specimens indicated a moderately positive relationship (coefficient = 0.676. Of 310 patients, 44 (14.2% showed outliers of ΔKi-67 (range, ≤-20 or ≥28. A significant association with poor prognostic factors was found among these patients. Multivariate analysis determined that significant risk factors for outliers of ΔKi-67 were tumor size >1 cm, negative progesterone receptor (PR expression, grade III cancer, and age ≤35 years. Among 171 patients with luminal human epidermal growth factor receptor 2-negative tumors, breast cancer subtype according to preoperative or postoperative Ki-67 levels discordantly changed in 46 (26.9% patients and a significant proportion of patients with discordant cases had ≥1 risk factor.Ki-67 expression showed a substantial concordance between biopsy and surgical specimens. Extremely discordant Ki-67 levels may be associated with aggressive tumor biology. In patients with luminal subtype disease, clinical application of Ki-67

Same Genes, Different Brains: Neuroanatomical Differences Between Monozygotic Twins Discordant for Musical Training.

Science.gov (United States)

de Manzano, Örjan; Ullén, Fredrik

2018-01-01

Numerous cross-sectional and observational longitudinal studies show associations between expertise and regional brain anatomy. However, since these designs confound training with genetic predisposition, the causal role of training remains unclear. Here, we use a discordant monozygotic (identical) twin design to study expertise-dependent effects on neuroanatomy using musical training as model behavior, while essentially controlling for genetic factors and shared environment of upbringing. From a larger cohort of monozygotic twins, we were able to recruit 18 individuals (9 pairs) that were highly discordant for piano practice. We used structural and diffusion magnetic resonance imaging to analyze the auditory-motor network and within-pair differences in cortical thickness, cerebellar regional volumes and white-matter microstructure/fractional anisotropy. The analyses revealed that the musically active twins had greater cortical thickness in the auditory-motor network of the left hemisphere and more developed white matter microstructure in relevant tracts in both hemispheres and the corpus callosum. Furthermore, the volume of gray matter in the left cerebellar region of interest comprising lobules I-IV + V, was greater in the playing group. These findings provide the first clear support for that a significant portion of the differences in brain anatomy between experts and nonexperts depend on causal effects of training. © The Author 2017. Published by Oxford University Press.

Glycolysis-induced discordance between glucose metabolic rates measured with radiolabeled fluorodeoxyglucose and glucose

International Nuclear Information System (INIS)

Ackermann, R.F.; Lear, J.L.

1989-01-01

We have developed an autoradiographic method for estimating the oxidative and glycolytic components of local CMRglc (LCMRglc), using sequentially administered [ 18 F]fluorodeoxyglucose (FDG) and [ 14 C]-6-glucose (GLC). FDG-6-phosphate accumulation is proportional to the rate of glucose phosphorylation, which occurs before the divergence of glycolytic (GMg) and oxidative (GMo) glucose metabolism and is therefore related to total cerebral glucose metabolism GMt: GMg + GMo = GMt. With oxidative metabolism, the 14 C label of GLC is temporarily retained in Krebs cycle-related substrate pools. We hypothesize that with glycolytic metabolism, however, a significant fraction of the 14 C label is lost from the brain via lactate production and efflux from the brain. Thus, cerebral GLC metabolite concentration may be more closely related to GMo than to GMt. If true, the glycolytic metabolic rate will be related to the difference between FDG- and GLC-derived LCMRglc. Thus far, we have studied normal awake rats, rats with limbic activation induced by kainic acid (KA), and rats visually stimulated with 16-Hz flashes. In KA-treated rats, significant discordance between FDG and GLC accumulation, which we attribute to glycolysis, occurred only in activated limbic structures. In visually stimulated rats, significant discordance occurred only in the optic tectum

Attention problems and Attention-Deficit/Hyperactivity Disorder in discordant and concordant monozygotic twins: Evidence of environmental mediators.

NARCIS (Netherlands)

Lehn, H.; Derks, E.M.; Hudziak, J.; Heutink, P.; van Beijsterveldt, C.E.M.; Boomsma, D.I.

2007-01-01

OBJECTIVE: To study familial and nonfamilial environmental influences on attention problems and attention-deficit/hyperactivity disorder (ADHD) in monozygotic twins discordant and concordant-high and low for these traits. METHOD: Ninety-five twin pairs from The Netherlands Twin Register were

The power of gene-based rare variant methods to detect disease-associated variation and test hypotheses about complex disease.

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Loukas Moutsianas

2015-04-01

Full Text Available Genome and exome sequencing in large cohorts enables characterization of the role of rare variation in complex diseases. Success in this endeavor, however, requires investigators to test a diverse array of genetic hypotheses which differ in the number, frequency and effect sizes of underlying causal variants. In this study, we evaluated the power of gene-based association methods to interrogate such hypotheses, and examined the implications for study design. We developed a flexible simulation approach, using 1000 Genomes data, to (a generate sequence variation at human genes in up to 10K case-control samples, and (b quantify the statistical power of a panel of widely used gene-based association tests under a variety of allelic architectures, locus effect sizes, and significance thresholds. For loci explaining ~1% of phenotypic variance underlying a common dichotomous trait, we find that all methods have low absolute power to achieve exome-wide significance (~5-20% power at α = 2.5 × 10(-6 in 3K individuals; even in 10K samples, power is modest (~60%. The combined application of multiple methods increases sensitivity, but does so at the expense of a higher false positive rate. MiST, SKAT-O, and KBAC have the highest individual mean power across simulated datasets, but we observe wide architecture-dependent variability in the individual loci detected by each test, suggesting that inferences about disease architecture from analysis of sequencing studies can differ depending on which methods are used. Our results imply that tens of thousands of individuals, extensive functional annotation, or highly targeted hypothesis testing will be required to confidently detect or exclude rare variant signals at complex disease loci.

Irradiation defects in clayey minerals in association with discordance-type uranium deposit; Les Defauts d'Irradiation dans les Mineraux argileux associes aux gisements d'Uranium de type Discordance

Energy Technology Data Exchange (ETDEWEB)

Morichon, E.; Beaufort, D. [Universite de Poitiers, Laboratoire HydrASA, CNRS-FRE 3114, 86 - Poitiers (France); Morichon, E.; Allard, Th. [IMPMC, UMR 7590, 75 - Paris (France)

2009-07-01

Radioactivity generates defects in minerals and these defects are the witnesses of the presence of radio-elements, and therefore represent an interesting potential for uranium prospecting. Investigations made in the Athabasca basin in Canada reveal irradiation defects in very old clays (kaolinite, illite and sudoite) in the alteration halo of discordance-type uranium deposits. The authors comment the defect concentration variation among the different drillings. These differences show that hexavalent uranium circulated in the whole geological system

Ovarian response and cumulative live birth rate of women undergoing in-vitro fertilisation who had discordant anti-Mullerian hormone and antral follicle count measurements: a retrospective study.

Directory of Open Access Journals (Sweden)

Hang Wun Raymond Li

Full Text Available OBJECTIVE: To evaluate ovarian response and cumulative live birth rate of women undergoing in-vitro fertilization (IVF treatment who had discordant baseline serum anti-Mullerian hormone (AMH level and antral follicle count (AFC. METHODS: This is a retrospective cohort study on 1,046 women undergoing the first IVF cycle in Queen Mary Hospital, Hong Kong. Subjects receiving standard IVF treatment with the GnRH agonist long protocol were classified according to their quartiles of baseline AMH and AFC measurements after GnRH agonist down-regulation and before commencing ovarian stimulation. The number of retrieved oocytes, ovarian sensitivity index (OSI and cumulative live-birth rate for each classification category were compared. RESULTS: Among our studied subjects, 32.2% were discordant in their AMH and AFC quartiles. Among them, those having higher AMH within the same AFC quartile had higher number of retrieved oocytes and cumulative live-birth rate. Subjects discordant in AMH and AFC had intermediate OSI which differed significantly compared to those concordant in AMH and AFC on either end. OSI of those discordant in AMH and AFC did not differ significantly whether either AMH or AFC quartile was higher than the other. CONCLUSIONS: When AMH and AFC are discordant, the ovarian responsiveness is intermediate between that when both are concordant on either end. Women having higher AMH within the same AFC quartile had higher number of retrieved oocytes and cumulative live-birth rate.

Identification of POMC exonic variants associated with substance dependence and body mass index.

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Fan Wang

Full Text Available Risk of substance dependence (SD and obesity has been linked to the function of melanocortin peptides encoded by the proopiomelanocortin gene (POMC.POMC exons were Sanger sequenced in 280 African Americans (AAs and 308 European Americans (EAs. Among them, 311 (167 AAs and 114 EAs were affected with substance (alcohol, cocaine, opioid and/or marijuana dependence and 277 (113 AAs and164 EAs were screened controls. We identified 23 variants, including two common polymorphisms (rs10654394 and rs1042571 and 21 rare variants; 12 of which were novel. We used logistic regression to analyze the association between the two common variants and SD or body mass index (BMI, with sex, age, and ancestry proportion as covariates. The common variant rs1042571 in the 3'UTR was significantly associated with BMI in EAs (Overweight: P(adj = 0.005; Obese: P(adj = 0.018; Overweight+Obese: P(adj = 0.002 but not in AAs. The common variant, rs10654394, was not associated with BMI and neither common variant was associated with SD in either population. To evaluate the association between the rare variants and SD or BMI, we collapsed rare variants and tested their prevalence using Fisher's exact test. In AAs, rare variants were nominally associated with SD overall and with specific SD traits (SD: P(FET,1df = 0.026; alcohol dependence: P(FET,1df = 0.027; cocaine dependence: P(FET,1df = 0.007; marijuana dependence: P(FET,1df = 0.050 (the P-value from cocaine dependence analysis survived Bonferroni correction. There was no such effect in EAs. Although the frequency of the rare variants did not differ significantly between the normal-weight group and the overweight or obese group in either population, certain rare exonic variants occurred only in overweight or obese subjects without SD.These findings suggest that POMC exonic variants may influence risk for both SD and elevated BMI, in a population-specific manner. However, common and rare variants in this gene may exert

The UK10K project identifies rare variants in health and disease

DEFF Research Database (Denmark)

Walter, Klaudia; Min, Josine L.; Huang, Jie

2015-01-01

-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive...

Listeners' processing of a given reduced word pronunciation variant directly reflects their exposure to this variant: Evidence from native listeners and learners of French.

Science.gov (United States)

Brand, Sophie; Ernestus, Mirjam

2018-05-01

In casual conversations, words often lack segments. This study investigates whether listeners rely on their experience with reduced word pronunciation variants during the processing of single segment reduction. We tested three groups of listeners in a lexical decision experiment with French words produced either with or without word-medial schwa (e.g., /ʀvy/ and /ʀvy/ for revue). Participants also rated the relative frequencies of the two pronunciation variants of the words. If the recognition accuracy and reaction times (RTs) for a given listener group correlate best with the frequencies of occurrence holding for that given listener group, recognition is influenced by listeners' exposure to these variants. Native listeners' relative frequency ratings correlated well with their accuracy scores and RTs. Dutch advanced learners' accuracy scores and RTs were best predicted by their own ratings. In contrast, the accuracy and RTs from Dutch beginner learners of French could not be predicted by any relative frequency rating; the rating task was probably too difficult for them. The participant groups showed behaviour reflecting their difference in experience with the pronunciation variants. Our results strongly suggest that listeners store the frequencies of occurrence of pronunciation variants, and consequently the variants themselves.

Prevalence of pathogenic germline variants detected by multigene sequencing in unselected Japanese patients with ovarian cancer.

Science.gov (United States)

Hirasawa, Akira; Imoto, Issei; Naruto, Takuya; Akahane, Tomoko; Yamagami, Wataru; Nomura, Hiroyuki; Masuda, Kiyoshi; Susumu, Nobuyuki; Tsuda, Hitoshi; Aoki, Daisuke

2017-12-22

Pathogenic germline BRCA1 , BRCA2 ( BRCA1/2 ), and several other gene variants predispose women to primary ovarian, fallopian tube, and peritoneal carcinoma (OC), although variant frequency and relevance information is scarce in Japanese women with OC. Using targeted panel sequencing, we screened 230 unselected Japanese women with OC from our hospital-based cohort for pathogenic germline variants in 75 or 79 OC-associated genes. Pathogenic variants of 11 genes were identified in 41 (17.8%) women: 19 (8.3%; BRCA1 ), 8 (3.5%; BRCA2 ), 6 (2.6%; mismatch repair genes), 3 (1.3%; RAD51D ), 2 (0.9%; ATM ), 1 (0.4%; MRE11A ), 1 ( FANCC ), and 1 ( GABRA6 ). Carriers of BRCA1/2 or any other tested gene pathogenic variants were more likely to be diagnosed younger, have first or second-degree relatives with OC, and have OC classified as high-grade serous carcinoma (HGSC). After adjustment for these variables, all 3 features were independent predictive factors for pathogenic variants in any tested genes whereas only the latter two remained for variants in BRCA1/2 . Our data indicate similar variant prevalence in Japanese patients with OC and other ethnic groups and suggest that HGSC and OC family history may facilitate genetic predisposition prediction in Japanese patients with OC and referring high-risk patients for genetic counseling and testing.

Postoperative Surgical Site Infections: Understanding the Discordance Between Surveillance Systems.

Science.gov (United States)

Ali-Mucheru, Mariam N; Seville, Maria T; Miller, Vickie; Sampathkumar, Priya; Etzioni, David A

2018-04-18

To characterize agreement in the ascertainment of surgical site infections (SSIs) between the National Surgical Quality Improvement Program (NSQIP), National Healthcare Safety Network (NHSN), and administrative data. The NSQIP, NHSN, and administrative data are the primary systems used to monitor and report SSIs for the purpose of quality control and benchmarking of hospitals and surgeons. These systems have different methods for identifying SSIs. We queried the NHSN, NSQIP, and administrative data systems for patients who had an operation at 1 of 4 hospitals within a single health system between January 2013 and September 2015. The detection of an SSI during a postoperative hospitalization was the outcome of analysis. Any SSI detected by one (or more) of these systems was analyzed by 2 reviewers to determine the presence of discrete elements of documentation constituting evidence of SSI. Concordance between the 3 systems (NHSN, NSQIP, and administrative data) was analyzed using Cohen's kappa. After application of appropriate exclusion criteria, a cohort of 9447 inpatient operations was analyzed. In total, 130 SSIs were detected by 1 or more of the 3 systems, with reported SSI rates of 0.5% (NHSN), 0.7% (administrative data), and 1.0% (NSQIP). Of these 130 SSIs, only 17 SSIs were reported by all 3 systems. The concordance between these 3 systems was moderate (kappa values NSQIP-NHSN = 0.50 [0.40-0.60], administrative-NHSN = 0.36 [0.24-0.47], and administrative-NSQIP = 0.47 [0.38-0.57]). Chart review found that reasons for discordance were related to issues of different criteria as well as inaccuracies. There is significant discordance in the determination of SSIs reported by the NHSN, NSQIP, and administrative data. The differences and limitations of each of these systems have to be recognized, especially when using these data for quality reports and pay for performance.

Non-invasive fetal RHD genotyping for RhD negative women stratified into RHD gene deletion or variant groups: comparative accuracy using two blood collection tube types.

Science.gov (United States)

Hyland, Catherine A; Millard, Glenda M; O'Brien, Helen; Schoeman, Elizna M; Lopez, Genghis H; McGowan, Eunike C; Tremellen, Anne; Puddephatt, Rachel; Gaerty, Kirsten; Flower, Robert L; Hyett, Jonathan A; Gardener, Glenn J

2017-12-01

Non-invasive fetal RHD genotyping in Australia to reduce anti-D usage will need to accommodate both prolonged sample transport times and a diverse population demographic harbouring a range of RHD blood group gene variants. We compared RHD genotyping accuracy using two blood sample collection tube types for RhD negative women stratified into deleted RHD gene haplotype and RHD gene variant cohorts. Maternal blood samples were collected into EDTA and cell-free (cf)DNA stabilising (BCT) tubes from two sites, one interstate. Automated DNA extraction and polymerase chain reaction (PCR) were used to amplify RHD exons 5 and 10 and CCR5. Automated analysis flagged maternal RHD variants, which were classified by genotyping. Time between sample collection and processing ranged from 2.9 to 187.5 hours. cfDNA levels increased with time for EDTA (range 0.03-138 ng/μL) but not BCT samples (0.01-3.24 ng/μL). For the 'deleted' cohort (n=647) all fetal RHD genotyping outcomes were concordant, excepting for one unexplained false negative EDTA sample. Matched against cord RhD serology, negative predictive values using BCT and EDTA tubes were 100% and 99.6%, respectively. Positive predictive values were 99.7% for both types. Overall 37.2% of subjects carried an RhD negative baby. The 'variant' cohort (n=15) included one novel RHD and eight hybrid or African pseudogene variants. Review for fetal RHD specific signals, based on one exon, showed three EDTA samples discordant to BCT, attributed to high maternal cfDNA levels arising from prolonged transport times. For the deleted haplotype cohort, fetal RHD genotyping accuracy was comparable for samples collected in EDTA and BCT tubes despite higher cfDNA levels in the EDTA tubes. Capacity to predict fetal RHD genotype for maternal carriers of hybrid or pseudogene RHD variants requires stringent control of cfDNA levels. We conclude that fetal RHD genotyping is feasible in the Australian environment to avoid unnecessary anti

Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease

Directory of Open Access Journals (Sweden)

Laura Ibanez

2018-04-01

Full Text Available Background: The prevalence of dementia in Parkinson disease (PD increases dramatically with advancing age, approaching 80% in patients who survive 20 years with the disease. Increasing evidence suggests clinical, pathological and genetic overlap between Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia with PD. However, the contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established.Objective: To assess the contribution of coding variants in Mendelian dementia-causing genes on the risk of developing PD and the effect on cognitive performance of PD patients.Methods: We analyzed the coding regions of the amyloid-beta precursor protein (APP, Presenilin 1 and 2 (PSEN1, PSEN2, and Granulin (GRN genes from 1,374 PD cases and 973 controls using pooled-DNA targeted sequence, human exome-chip and whole-exome sequencing (WES data by single variant and gene base (SKAT-O and burden tests analyses. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE or the Montreal Cognitive Assessment (MoCA. The effect of coding variants in dementia-causing genes on cognitive performance was tested by multiple regression analysis adjusting for gender, disease duration, age at dementia assessment, study site and APOE carrier status.Results: Known AD pathogenic mutations in the PSEN1 (p.A79V and PSEN2 (p.V148I genes were found in 0.3% of all PD patients. There was a significant burden of rare, likely damaging variants in the GRN and PSEN1 genes in PD patients when compared with frequencies in the European population from the ExAC database. Multiple regression analysis revealed that PD patients carrying rare variants in the APP, PSEN1, PSEN2, and GRN genes exhibit lower cognitive tests scores than non-carrier PD patients (p = 2.0 × 10−4, independent of age at PD diagnosis, age at evaluation, APOE status or recruitment site.Conclusions: Pathogenic mutations in

Qualitative analysis of an educational intervention with HIV-discordant heterosexual Latino couples.

Science.gov (United States)

Pérez-Jiménez, David; Orengo-Aguayo, Rosaura E

2011-12-01

This qualitative analysis elucidates the potential elements of the intervention that may be effective in terms of a) increasing knowledge about HIV/ AIDS in the members of this population; b) increasing the use of male condoms and the practice of mutual masturbation; and c) changing opinions toward male condom use and mutual masturbation. Five heterosexual HIV-discordant couples participated in the adapted intervention, which consisted of four three-hour-long sessions. One month after the intervention, we conducted a qualitative semi-structured interview with every participant to evaluate issues related to the process and content of the activities comprising the intervention, the impact of the intervention, logistics, and recruitment and retention as well as to make a more general evaluation. The information was submitted to qualitative content analysis. After the intervention, participants reported having better attitudes regarding safer sex, particularly in terms of condom use. A reason given by the participants to feel more positive toward condom use and mutual masturbation was that these practices could prevent the infection of the HIV-negative partner. This study provides important evidence of an intervention that promises to be efficacious in preventing some high-risk sexual behaviors among Latino HIV-discordant heterosexual couples. The evidence presented seems to suggest that an intervention that includes basic relevant information about HIV/AIDS, that explains the benefits of condom use and other safer sex options, and that provides effective negotiation and communication strategies could significantly reduce HIV transmission among these couples.

Targeted Resequencing and Functional Testing Identifies Low-Frequency Missense Variants in the Gene Encoding GARP as Significant Contributors to Atopic Dermatitis Risk.

Science.gov (United States)

Manz, Judith; Rodríguez, Elke; ElSharawy, Abdou; Oesau, Eva-Maria; Petersen, Britt-Sabina; Baurecht, Hansjörg; Mayr, Gabriele; Weber, Susanne; Harder, Jürgen; Reischl, Eva; Schwarz, Agatha; Novak, Natalija; Franke, Andre; Weidinger, Stephan

2016-12-01

Gene-mapping studies have consistently identified a susceptibility locus for atopic dermatitis and other inflammatory diseases on chromosome band 11q13.5, with the strongest association observed for a common variant located in an intergenic region between the two annotated genes C11orf30 and LRRC32. Using a targeted resequencing approach we identified low-frequency and rare missense mutations within the LRRC32 gene encoding the protein GARP, a receptor on activated regulatory T cells that binds latent transforming growth factor-β. Subsequent association testing in more than 2,000 atopic dermatitis patients and 2,000 control subjects showed a significant excess of these LRRC32 variants in individuals with atopic dermatitis. Structural protein modeling and bioinformatic analysis predicted a disruption of protein transport upon these variants, and overexpression assays in CD4 + CD25 - T cells showed a significant reduction in surface expression of the mutated protein. Consistently, flow cytometric (FACS) analyses of different T-cell subtypes obtained from atopic dermatitis patients showed a significantly reduced surface expression of GARP and a reduced conversion of CD4 + CD25 - T cells into regulatory T cells, along with lower expression of latency-associated protein upon stimulation in carriers of the LRRC32 A407T variant. These results link inherited disturbances of transforming growth factor-β signaling with atopic dermatitis risk. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

MYO7A and USH2A gene sequence variants in Italian patients with Usher syndrome.

Science.gov (United States)

Sodi, Andrea; Mariottini, Alessandro; Passerini, Ilaria; Murro, Vittoria; Tachyla, Iryna; Bianchi, Benedetta; Menchini, Ugo; Torricelli, Francesca

2014-01-01

To analyze the spectrum of sequence variants in the MYO7A and USH2A genes in a group of Italian patients affected by Usher syndrome (USH). Thirty-six Italian patients with a diagnosis of USH were recruited. They received a standard ophthalmologic examination, visual field testing, optical coherence tomography (OCT) scan, and electrophysiological tests. Fluorescein angiography and fundus autofluorescence imaging were performed in selected cases. All the patients underwent an audiologic examination for the 0.25-8,000 Hz frequencies. Vestibular function was evaluated with specific tests. DNA samples were analyzed for sequence variants of the MYO7A gene (for USH1) and the USH2A gene (for USH2) with direct sequencing techniques. A few patients were analyzed for both genes. In the MYO7A gene, ten missense variants were found; three patients were compound heterozygous, and two were homozygous. Thirty-four USH2A gene variants were detected, including eight missense variants, nine nonsense variants, six splicing variants, and 11 duplications/deletions; 19 patients were compound heterozygous, and three were homozygous. Four MYO7A and 17 USH2A variants have already been described in the literature. Among the novel mutations there are four USH2A large deletions, detected with multiplex ligation dependent probe amplification (MLPA) technology. Two potentially pathogenic variants were found in 27 patients (75%). Affected patients showed variable clinical pictures without a clear genotype-phenotype correlation. Ten variants in the MYO7A gene and 34 variants in the USH2A gene were detected in Italian patients with USH at a high detection rate. A selective analysis of these genes may be valuable for molecular analysis, combining diagnostic efficiency with little time wastage and less resource consumption.

Two novel haemoglobin variants that affect haemoglobin A1c measurement by ion-exchange chromatography

NARCIS (Netherlands)

Bots, Michael; Stroobants, An K.; Delzenne, Barend; Soeters, Maarten R.; de Vries, Johan E.; Weykamp, Cas W.; Norg, Roelf J. C.; Veldthuis, Martijn; van Zwieten, Rob

2015-01-01

Haemoglobin (Hb) variants are well-known factors interfering with accurate HbA1c testing. This report describes two novel Hb variants leading to inappropriate quantification of HbA1c by ion-exchange chromatography. Glycated forms of novel Hb variants were recognised in the blood of two patients with

Oliver Sacks: Our Correspondence About Twins/Twin Research: Vanishing Twins Syndrome; Discordant Sex in MZ Twins; Pregnancy Outcomes in IVF and ICSI Conceived Twins/Print and Media: Superfetated Twins; Twins Discordant for Smoking; Twins in Fashion; Yale University Twin Hockey Players; Conjoined Twin-Visiting Professor.

Science.gov (United States)

Segal, Nancy L

2017-08-01

The late neurologist and author, Oliver Sacks, published an insightful 1986 review of Marjorie Wallace's book, The Silent Twins, in the New York Times. Taking exception to his assertion about Sir Francis Galton, I wrote a letter to the Times' editor. The letter was unpublished, but it brought a wonderful response from Sacks himself that is reproduced and examined. Next, brief reviews of twin research concerning the vanishing twin syndrome (VTS), discordant sex in a monozygotic (MZ) twin pair, and multiple pregnancy outcomes from assisted reproductive technology (ART) are presented. This section is followed by popular coverage of superfetated twins, smoking-discordant co-twins, twins in fashion, Yale University twin hockey players, and a visiting professor who was a conjoined twin.

Genetic evidence and integration of various data sources for classifying uncertain variants into a single model.

NARCIS (Netherlands)

Goldgar, D.E.; Easton, D.F.; Byrnes, G.B.; Spurdle, A.B.; Iversen, E.S.; Greenblatt, M.S.; Boffetta, P.; Couch, F.J.; Wind, N. de; Eccles, D.; Foulkes, W.D.; Genuardi, M.; Hofstra, R.M.; Hogervorst, F.; Hoogerbrugge-van der Linden, N.; Plon, S.E.; Radice, P.; Rasmussen, L.; Sinilnikova, O.M.; Tavtigian, S.V.

2008-01-01

Genetic testing often results in the finding of a variant whose clinical significance is unknown. A number of different approaches have been employed in the attempt to classify such variants. For some variants, case-control, segregation, family history, or other statistical studies can provide

Skepticism, truth as coherence, and constructivist epistemology: grounds for resolving the discord between science and religion?

Science.gov (United States)

Staver, John R.

2010-03-01

Science and religion exhibit multiple relationships as ways of knowing. These connections have been characterized as cousinly, mutually respectful, non-overlapping, competitive, proximate-ultimate, dominant-subordinate, and opposing-conflicting. Some of these ties create stress, and tension between science and religion represents a significant chapter in humans' cultural heritage before and since the Enlightenment. Truth, knowledge, and their relation are central to science and religion as ways of knowing, as social institutions, and to their interaction. In religion, truth is revealed through God's word. In science, truth is sought after via empirical methods. Discord can be viewed as a competition for social legitimization between two social institutions whose goals are explaining the world and how it works. Under this view, the root of the discord is truth as correspondence. In this concept of truth, knowledge corresponds to the facts of reality, and conflict is inevitable for many because humans want to ask which one—science or religion—gets the facts correct. But, the root paradox, also known as the problem of the criterion, suggests that seeking to know nature as it is represents a fruitless endeavor. The discord can be set on new ground and resolved by taking a moderately skeptical line of thought, one which employs truth as coherence and a moderate form of constructivist epistemology. Quantum mechanics and evolution as scientific theories and scientific research on human consciousness and vision provide support for this line of argument. Within a constructivist perspective, scientists would relinquish only the pursuit of knowing reality as it is. Scientists would retain everything else. Believers who hold that religion explains reality would come to understand that God never revealed His truth of nature; rather, He revealed His truth in how we are to conduct our lives.

A machine learning model to determine the accuracy of variant calls in capture-based next generation sequencing.

Science.gov (United States)

van den Akker, Jeroen; Mishne, Gilad; Zimmer, Anjali D; Zhou, Alicia Y

2018-04-17

Next generation sequencing (NGS) has become a common technology for clinical genetic tests. The quality of NGS calls varies widely and is influenced by features like reference sequence characteristics, read depth, and mapping accuracy. With recent advances in NGS technology and software tools, the majority of variants called using NGS alone are in fact accurate and reliable. However, a small subset of difficult-to-call variants that still do require orthogonal confirmation exist. For this reason, many clinical laboratories confirm NGS results using orthogonal technologies such as Sanger sequencing. Here, we report the development of a deterministic machine-learning-based model to differentiate between these two types of variant calls: those that do not require confirmation using an orthogonal technology (high confidence), and those that require additional quality testing (low confidence). This approach allows reliable NGS-based calling in a clinical setting by identifying the few important variant calls that require orthogonal confirmation. We developed and tested the model using a set of 7179 variants identified by a targeted NGS panel and re-tested by Sanger sequencing. The model incorporated several signals of sequence characteristics and call quality to determine if a variant was identified at high or low confidence. The model was tuned to eliminate false positives, defined as variants that were called by NGS but not confirmed by Sanger sequencing. The model achieved very high accuracy: 99.4% (95% confidence interval: +/- 0.03%). It categorized 92.2% (6622/7179) of the variants as high confidence, and 100% of these were confirmed to be present by Sanger sequencing. Among the variants that were categorized as low confidence, defined as NGS calls of low quality that are likely to be artifacts, 92.1% (513/557) were found to be not present by Sanger sequencing. This work shows that NGS data contains sufficient characteristics for a machine-learning-based model to

Quantitative Missense Variant Effect Prediction Using Large-Scale Mutagenesis Data.

Science.gov (United States)

Gray, Vanessa E; Hause, Ronald J; Luebeck, Jens; Shendure, Jay; Fowler, Douglas M

2018-01-24

Large datasets describing the quantitative effects of mutations on protein function are becoming increasingly available. Here, we leverage these datasets to develop Envision, which predicts the magnitude of a missense variant's molecular effect. Envision combines 21,026 variant effect measurements from nine large-scale experimental mutagenesis datasets, a hitherto untapped training resource, with a supervised, stochastic gradient boosting learning algorithm. Envision outperforms other missense variant effect predictors both on large-scale mutagenesis data and on an independent test dataset comprising 2,312 TP53 variants whose effects were measured using a low-throughput approach. This dataset was never used for hyperparameter tuning or model training and thus serves as an independent validation set. Envision prediction accuracy is also more consistent across amino acids than other predictors. Finally, we demonstrate that Envision's performance improves as more large-scale mutagenesis data are incorporated. We precompute Envision predictions for every possible single amino acid variant in human, mouse, frog, zebrafish, fruit fly, worm, and yeast proteomes (https://envision.gs.washington.edu/). Copyright © 2017 Elsevier Inc. All rights reserved.

Geometric quantum discord and Berry phase between two charge qubits coupled by a quantum transmission line

International Nuclear Information System (INIS)

Zhu Han-Jie; Zhang Guo-Feng

2014-01-01

Geometric quantum discord (GQD) and Berry phase between two charge qubits coupled by a quantum transmission line are investigated. We show how GQDs evolve and investigate their dependencies on the parameters of the system. We also calculate the energy and the Berry phase and compare them with GQD, finding that there are close connections between them. (general)

Dynamics of quantum discord in a quantum critical environment

International Nuclear Information System (INIS)

Xi Zhengjun; Li Yongming; Lu Xiaoming; Sun Zhe

2011-01-01

We study the dynamics of quantum discord (QD) of two qubits independently coupled to an Ising spin chain in a transverse field, which exhibits a quantum phase transition. For this model, we drive the corresponding Kraus operators, obtain the analytic results of QD and compare the dynamics of QD with the dynamics of relative entropy of entanglement nearby the critical point. It is shown that the impact of the quantum criticality environment on QD can be concentrated in a very narrow region nearby the critical point, so it supplies an efficient way to detect the critical points. In the vicinity of the critical point, the evolution of QD is shown to be more complicated than that of entanglement. Furthermore, we find that separable states can also be used to reflect the quantum criticality of the environment.

Differences in the Load-Velocity Profile Between 4 Bench-Press Variants.

Science.gov (United States)

García-Ramos, Amador; Pestaña-Melero, Francisco Luis; Pérez-Castilla, Alejandro; Rojas, Francisco Javier; Haff, Guy Gregory

2018-03-01

To compare the load-velocity relationship between 4 variants of the bench-press (BP) exercise. The full load-velocity relationship of 30 men was evaluated by means of an incremental loading test starting at 17 kg and progressing to the individual 1-repetition maximum (1RM) in 4 BP variants: concentric-only BP, concentric-only BP throw (BPT), eccentric-concentric BP, and eccentric-concentric BPT. A strong and fairly linear relationship between mean velocity (MV) and %1RM was observed for the 4 BP variants (r 2  > .96 for pooled data and r 2  > .98 for individual data). The MV associated with each %1RM was significantly higher in the eccentric-concentric technique than in the concentric-only technique. The only significant difference between the BP and BPT variants was the higher MV with the light to moderate loads (20-70%1RM) in the BPT using the concentric-only technique. MV was significantly and positively correlated between the 4 BP variants (r = .44-.76), which suggests that the subjects with higher velocities for each %1RM in 1 BP variant also tend to have higher velocities for each %1RM in the 3 other BP variants. These results highlight the need for obtaining specific equations for each BP variant and the existence of individual load-velocity profiles.

Product Variant Master as a Means to Handle Variant Design

DEFF Research Database (Denmark)

Hildre, Hans Petter; Mortensen, Niels Henrik; Andreasen, Mogens Myrup

1996-01-01

be implemented in the CAD system I-DEAS. A precondition for high degree of computer support is identification of a product variant master from which new variants can be derived. This class platform defines how a product build up fit certain production methods and rules governing determination of modules...

Association testing of copy number variants in schizophrenia and autism spectrum disorders

Directory of Open Access Journals (Sweden)

Crespi Bernard J

2012-05-01

Full Text Available Abstract Background Autism spectrum disorders and schizophrenia have been associated with an overlapping set of copy number variant loci, but the nature and degree of overlap in copy number variants (deletions compared to duplications between these two disorders remains unclear. Methods We systematically evaluated three lines of evidence: (1 the statistical bases for associations of autism spectrum disorders and schizophrenia with a set of the primary CNVs thus far investigated, from previous studies; (2 data from case series studies on the occurrence of these CNVs in autism spectrum disorders, especially among children, and (3 data on the extent to which the CNVs were associated with intellectual disability and developmental, speech, or language delays. We also conducted new analyses of existing data on these CNVs in autism by pooling data from seven case control studies. Results Four of the CNVs considered, dup 1q21.1, dup 15q11-q13, del 16p11.2, and dup 22q11.21, showed clear statistical evidence as autism risk factors, whereas eight CNVs, del 1q21.1, del 3q29, del 15q11.2, del 15q13.3, dup 16p11.2, dup 16p13.1, del 17p12, and del 22q11.21, were strongly statistically supported as risk factors for schizophrenia. Three of the CNVs, dup 1q21.1, dup 16p11.2, and dup 16p13.1, exhibited statistical support as risk factors for both autism and schizophrenia, although for each of these CNVs statistical significance was nominal for tests involving one of the two disorders. For the CNVs that were statistically associated with schizophrenia but were not statistically associated with autism, a notable number of children with the CNVs have been diagnosed with autism or ASD; children with these CNVs also demonstrate a high incidence of intellectual disability and developmental, speech, or language delays. Conclusions These findings suggest that although CNV loci notably overlap between autism and schizophrenia, the degree of strongly statistically

Comparison and optimization of in silico algorithms for predicting the pathogenicity of sodium channel variants in epilepsy.

Science.gov (United States)

Holland, Katherine D; Bouley, Thomas M; Horn, Paul S

2017-07-01

Variants in neuronal voltage-gated sodium channel α-subunits genes SCN1A, SCN2A, and SCN8A are common in early onset epileptic encephalopathies and other autosomal dominant childhood epilepsy syndromes. However, in clinical practice, missense variants are often classified as variants of uncertain significance when missense variants are identified but heritability cannot be determined. Genetic testing reports often include results of computational tests to estimate pathogenicity and the frequency of that variant in population-based databases. The objective of this work was to enhance clinicians' understanding of results by (1) determining how effectively computational algorithms predict epileptogenicity of sodium channel (SCN) missense variants; (2) optimizing their predictive capabilities; and (3) determining if epilepsy-associated SCN variants are present in population-based databases. This will help clinicians better understand the results of indeterminate SCN test results in people with epilepsy. Pathogenic, likely pathogenic, and benign variants in SCNs were identified using databases of sodium channel variants. Benign variants were also identified from population-based databases. Eight algorithms commonly used to predict pathogenicity were compared. In addition, logistic regression was used to determine if a combination of algorithms could better predict pathogenicity. Based on American College of Medical Genetic Criteria, 440 variants were classified as pathogenic or likely pathogenic and 84 were classified as benign or likely benign. Twenty-eight variants previously associated with epilepsy were present in population-based gene databases. The output provided by most computational algorithms had a high sensitivity but low specificity with an accuracy of 0.52-0.77. Accuracy could be improved by adjusting the threshold for pathogenicity. Using this adjustment, the Mendelian Clinically Applicable Pathogenicity (M-CAP) algorithm had an accuracy of 0.90 and a

Qualitative Analysis of an Educational Intervention with HIV-Discordant Heterosexual Latino Couples

Science.gov (United States)

Pérez-Jiménez, David; Orengo-Aguayo, Rosaura E.

2012-01-01

Objective This qualitative analysis elucidates the potential elements of the intervention that may be effective in terms of a) increasing knowledge about HIV/AIDS in the members of this population; b) increasing the use of male condoms and the practice of mutual masturbation; and c) changing opinions toward male condom use and mutual masturbation. Methods Five heterosexual HIV-discordant couples participated in the adapted intervention, which consisted of four three-hour-long sessions. One month after the intervention, we conducted a qualitative semi-structured interview with every participant to evaluate issues related to the process and content of the activities comprising the intervention, the impact of the intervention, logistics, and recruitment and retention as well as to make a more general evaluation. The information was submitted to qualitative content analysis. Results After the intervention, participants reported having better attitudes regarding safer sex, particularly in terms of condom use. A reason given by the participants to feel more positive toward condom use and mutual masturbation was that these practices could prevent the infection of the HIV-negative partner. Conclusion This study provides important evidence of an intervention that promises to be efficacious in preventing some high-risk sexual behaviors among Latino HIV-discordant heterosexual couples. The evidence presented seems to suggest that an intervention that includes basic relevant information about HIV/AIDS, that explains the benefits of condom use and other safer sex options, and that provides effective negotiation and communication strategies could significantly reduce HIV transmission among these couples. PMID:22263299

Genome-wide placental DNA methylation analysis of severely growth-discordant monochorionic twins reveals novel epigenetic targets for intrauterine growth restriction.

Science.gov (United States)

Roifman, Maian; Choufani, Sanaa; Turinsky, Andrei L; Drewlo, Sascha; Keating, Sarah; Brudno, Michael; Kingdom, John; Weksberg, Rosanna

2016-01-01

Intrauterine growth restriction (IUGR), which refers to reduced fetal growth in the context of placental insufficiency, is etiologically heterogeneous. IUGR is associated not only with perinatal morbidity and mortality but also with adult-onset disorders, such as cardiovascular disease and diabetes, posing a major health burden. Placental epigenetic dysregulation has been proposed as one mechanism that causes IUGR; however, the spectrum of epigenetic pathophysiological mechanisms leading to IUGR remains to be elucidated. Monozygotic monochorionic twins are particularly affected by IUGR, in the setting of severe discordant growth. Because monozygotic twins have the same genotype at conception and a shared maternal environment, they provide an ideal model system for studying epigenetic dysregulation of the placenta. We compared genome-wide placental DNA methylation patterns of severely growth-discordant twins to identify novel candidate genes for IUGR. Snap-frozen placental samples for eight severely growth-discordant monozygotic monochorionic twin pairs were obtained at delivery from each twin. A high-resolution DNA methylation array platform was used to identify methylation differences between IUGR and normal twins. Our analysis revealed differentially methylated regions in the promoters of eight genes: DECR1, ZNF300, DNAJA4, CCL28, LEPR, HSPA1A/L, GSTO1, and GNE. The largest methylation differences between the two groups were in the promoters of DECR1 and ZNF300. The significance of these group differences was independently validated by bisulfite pyrosequencing, implicating aberrations in fatty acid beta oxidation and transcriptional regulation, respectively. Further analysis of the array data identified methylation changes most prominently affecting the Wnt and cadherin pathways in the IUGR cohort. Our results suggest that IUGR in monozygotic twins is associated with impairments in lipid metabolism and transcriptional regulation as well as cadherin and Wnt

Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data

NARCIS (Netherlands)

Allen, Andrew S.; Berkovic, Samuel F.; Bridgers, Joshua; Cossette, Patrick; Dlugos, Dennis; Epstein, Michael P.; Glauser, Tracy; Goldstein, David B.; Heinzen, Erin L.; Jiang, Yu; Johnson, Michael R.; Kuzniecky, Ruben; Lowenstein, Daniel H.; Marson, Anthony G.; Mefford, Heather C.; O'Brien, Terence J.; Ottman, Ruth; Petrou, Steven; Petrovski, Slavé; Poduri, Annapurna; Ren, Zhong; Scheffer, Ingrid E.; Sherr, Elliott; Wang, Quanli; Balling, Rudi; Barisic, Nina; Baulac, Stéphanie; Caglayan, Hande; Craiu, Dana; De Jonghe, Peter; Depienne, Christel; Guerrini, Renzo; Helbig, Ingo; Hjalgrim, Helle; Hoffman-Zacharska, Dorota; Jähn, Johanna A.; Klein, Karl Martin; Koeleman, Bobby; Komarek, Vladimir; Krause, Roland; Leguern, Eric; Lehesjoki, Anna-Elina; Lemke, Johannes R.; Lerche, Holger; Linnankivi, Tarja; Marini, Carla; May, Patrick; Møller, Rikke S.; Muhle, Hiltrud; Pal, Deb; Palotie, Aarno; Rosenow, Felix; Selmer, Kaja; Serratosa, Jose M.; Sisodiya, Sanjay M.; Stephani, Ulrich; Sterbova, Katalin; Striano, Pasquale; Suls, Arvid; Talvik, Tiina; von Spiczak, Sarah; Weber, Yvonne G.; Weckhuysen, Sarah; Zara, Federico; Abou-Khalil, Bassel; Alldredge, Brian K.; Amrom, Dina; Andermann, Eva; Andermann, Frederick; Bautista, Jocelyn F.; Bluvstein, Judith; Cascino, Gregory D.; Consalvo, Damian; Crumrine, Patricia; Devinsky, Orrin; Fiol, Miguel E.; Fountain, Nathan B.; French, Jacqueline; Friedman, Daniel; Haas, Kevin; Haut, Sheryl R.; Hayward, Jean; Joshi, Sucheta; Kanner, Andres; Kirsch, Heidi E.; Kossoff, Eric H.; Kuperman, Rachel; McGuire, Shannon M.; Motika, Paul V.; Novotny, Edward J.; Paolicchi, Juliann M.; Parent, Jack; Park, Kristen; Shellhaas, Renée A; Sirven, Joseph; Smith, Michael C.; Sullivan, Joseph; Thio, Liu Lin; Venkat, Anu; Vining, Eileen P. G.; Von Allmen, Gretchen K.; Weisenberg, Judith L.; Widdess-Walsh, Peter; Winawer, Melodie R.

2017-01-01

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox-Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Science.gov (United States)

Karbassi, Izabela; Maston, Glenn A; Love, Angela; DiVincenzo, Christina; Braastad, Corey D; Elzinga, Christopher D; Bright, Alison R; Previte, Domenic; Zhang, Ke; Rowland, Charles M; McCarthy, Michele; Lapierre, Jennifer L; Dubois, Felicita; Medeiros, Katelyn A; Batish, Sat Dev; Jones, Jeffrey; Liaquat, Khalida; Hoffman, Carol A; Jaremko, Malgorzata; Wang, Zhenyuan; Sun, Weimin; Buller-Burckle, Arlene; Strom, Charles M; Keiles, Steven B; Higgins, Joseph J

2016-01-01

We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies collected from internal and external sources. Scores were calculated by trained scientists using a quantitative framework that assigned differential weighting to these five types of data. We performed descriptive and comparative statistics on the dataset and tested interobserver concordance among the trained scientists. Private variants defined as variants found within single families (n = 5,182), were either VUS (80.5%; n = 4,169) or likely pathogenic (19.5%; n = 1,013). The remaining variants (n = 6,712) were VUS (38.4%; n = 2,577) or likely benign/benign (34.7%; n = 2,327) or likely pathogenic/pathogenic (26.9%, n = 1,808). Exact agreement between the trained scientists on the final variant score was 98.5% [95% confidence interval (CI) (98.0, 98.9)] with an interobserver consistency of 97% [95% CI (91.5, 99.4)]. Variant scores were stable and showed increasing odds of being in agreement with new data when re-evaluated periodically. This carefully curated, standardized variant pathogenicity scoring system provides reliable pathogenicity scores for DNA variants encountered in a clinical laboratory setting. © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

Efficient utilization of rare variants for detection of disease-related genomic regions.

Directory of Open Access Journals (Sweden)

Lei Zhang

2010-12-01

Full Text Available When testing association between rare variants and diseases, an efficient analytical approach involves considering a set of variants in a genomic region as the unit of analysis. One factor complicating this approach is that the vast majority of rare variants in practical applications are believed to represent background neutral variation. As a result, analyzing a single set with all variants may not represent a powerful approach. Here, we propose two alternative strategies. In the first, we analyze the subsets of rare variants exhaustively. In the second, we categorize variants selectively into two subsets: one in which variants are overrepresented in cases, and the other in which variants are overrepresented in controls. When the proportion of neutral variants is moderate to large we show, by simulations, that the both proposed strategies improve the statistical power over methods analyzing a single set with total variants. When applied to a real sequencing association study, the proposed methods consistently produce smaller p-values than their competitors. When applied to another real sequencing dataset to study the difference of rare allele distributions between ethnic populations, the proposed methods detect the overrepresentation of variants between the CHB (Chinese Han in Beijing and YRI (Yoruba people of Ibadan populations with small p-values. Additional analyses suggest that there is no difference between the CHB and CHD (Chinese Han in Denver datasets, as expected. Finally, when applied to the CHB and JPT (Japanese people in Tokyo populations, existing methods fail to detect any difference, while it is detected by the proposed methods in several regions.

Breast lesions with imaging-histologic discordance during US-guided 14G automated core biopsy: can the directional vacuum-assisted removal replace the surgical excision? Initial findings

International Nuclear Information System (INIS)

Kim, Min Jung; Kim, Eun-Kyung; Lee, Ji Young; Youk, Ji Hyun; Oh, Ki Keun; Park, Byeong-Woo; Kim, Seung-Il; Kim, Haeryoung

2007-01-01

The purpose of this study was to determine the frequency of carcinoma at percutaneous directional vacuum-assisted removal (DVAR) in women with imaging-histologic discordance during ultrasound (US)-guided automated core needle biopsy, and to determine the role of DVAR in breast lesions with imaging-histologic discordance. A US-guided 14-gauge automated core needle biopsy was performed on 837 consecutive lesions. Imaging-histologic discordance was prospectively considered in 33 of 634 benign biopsies. DVAR was recommended in those lesions. Among the 33 lesions, 26 lesions that underwent subsequent DVAR or surgical excision made up our study population. Medical records, imaging studies, and histologic findings were reviewed. Among the 26 lesions, 18 lesions underwent subsequent US-guided DVAR, with 8-gauge probes for 15 of the lesions, and 11-gauge for three of the lesions. Two lesions were diagnosed as having carcinoma (2/18, 11.1% of upgrade rate; 3.1-32.8% CI). The remaining eight lesions underwent subsequent surgical excision, and carcinoma was diagnosed in one case (12.5% of upgrade rate; 2.2-47.1% CI). A US-guided DVAR of the breast mass with imaging-histologic discordance during US-guided 14-gauge automated core needle biopsy is a valuable alternative to surgery as a means of obtaining a definitive histological diagnosis. (orig.)

Genome-wide association study in discordant sibships identifies multiple inherited susceptibility alleles linked to lung cancer.

Science.gov (United States)

Galvan, Antonella; Falvella, Felicia S; Frullanti, Elisa; Spinola, Monica; Incarbone, Matteo; Nosotti, Mario; Santambrogio, Luigi; Conti, Barbara; Pastorino, Ugo; Gonzalez-Neira, Anna; Dragani, Tommaso A

2010-03-01

We analyzed a series of young (median age = 52 years) non-smoker lung cancer patients and their unaffected siblings as controls, using a genome-wide 620 901 single-nucleotide polymorphism (SNP) array analysis and a case-control DNA pooling approach. We identified 82 putatively associated SNPs that were retested by individual genotyping followed by use of the sib transmission disequilibrium test, pointing to 36 SNPs associated with lung cancer risk in the discordant sibs series. Analysis of these 36 SNPs in a polygenic model characterized by additive and interchangeable effects of rare alleles revealed a highly statistically significant dosage-dependent association between risk allele carrier status and proportion of cancer cases. Replication of the same 36 SNPs in a population-based series confirmed the association with lung cancer for three SNPs, suggesting that phenocopies and genetic heterogeneity can play a major role in the complex genetics of lung cancer risk in the general population.

Hairy cell leukemia-variant

International Nuclear Information System (INIS)

Quadri, Mohammad I.; Al-Sheikh, Iman H.

2001-01-01

Hairy cell leukaemia variant is a very rare chronic lymphoproliferative disorder and is closely related to hairy cell leukemia. We hereby describe a case of hairy cell leukaemia variant for the first time in Saudi Arabia. An elderly Saudi man presented with pallor, massive splenomegaly, and moderate hepatomegaly. Hemoglobin was 7.7 g/dl, Platelets were 134 x109/l and white blood count was 140x10 9/l with 97% being abnormal lymphoid cells with cytoplasmic projections. The morphology, cytochemistry, and immunophenotype of the lymphoid cells were classical of hairy cell leukaemia variant. The bone marrow was easily aspirated and findings were consistent with hairy cell leukaemia variant. (author)

Exceptions to the rule: case studies in the prediction of pathogenicity for genetic variants in hereditary cancer genes.

Science.gov (United States)

Rosenthal, E T; Bowles, K R; Pruss, D; van Kan, A; Vail, P J; McElroy, H; Wenstrup, R J

2015-12-01

Based on current consensus guidelines and standard practice, many genetic variants detected in clinical testing are classified as disease causing based on their predicted impact on the normal expression or function of the gene in the absence of additional data. However, our laboratory has identified a subset of such variants in hereditary cancer genes for which compelling contradictory evidence emerged after the initial evaluation following the first observation of the variant. Three representative examples of variants in BRCA1, BRCA2 and MSH2 that are predicted to disrupt splicing, prematurely truncate the protein, or remove the start codon were evaluated for pathogenicity by analyzing clinical data with multiple classification algorithms. Available clinical data for all three variants contradicts the expected pathogenic classification. These variants illustrate potential pitfalls associated with standard approaches to variant classification as well as the challenges associated with monitoring data, updating classifications, and reporting potentially contradictory interpretations to the clinicians responsible for translating test outcomes to appropriate clinical action. It is important to address these challenges now as the model for clinical testing moves toward the use of large multi-gene panels and whole exome/genome analysis, which will dramatically increase the number of genetic variants identified. © 2015 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Gender Differences in Depressive Symptoms Among HIV-Positive Concordant and Discordant Heterosexual Couples in China

OpenAIRE

Li, Li; Liang, Li-Jung; Lin, Chunqing; Ji, Guoping; Xiao, Yongkang

2016-01-01

HIV seropositive individuals and their heterosexual partners/spouses, either seropositive or seronegative, are facing several mental health challenges. The objective of this study was to examine gender differences in depressive symptoms among HIV-positive concordant and HIV-discordant couples. We identified heterosexual couples from participants of a randomized controlled trial conducted in Anhui province, China. A total of 265 couples, comprising 129 HIV+ male/HIV− female couples, 98 HIV− ma...

Genomic constitution of an H-2:Tla variant leukemia.

Science.gov (United States)

Shen, F W; Chaganti, R S; Doucette, L A; Litman, G W; Steinmetz, M; Hood, L; Boyse, E A

1984-10-01

A TL+ leukemia of a (B6 X A)F1 hybrid mouse (H-2b/H-2a) was previously subjected to immunoselection against H-2a by passage in (B6 X A.SW)F1 mice (H-2b/H-2s). A variant leukemia line was obtained that serologically lacked not only the H-2a phenotype but also the TL phenotype determined by the linked cis Tlaa allele of strain A. The H-2b phenotype and the TL phenotype of the Tlab allele of the B6 strain, which is expressed only by leukemia cells, were retained by the variant. Southern blotting with an H-2 cDNA probe that identifies restriction fragment polymorphisms distinguishing alleles of the H-2 and Tla regions of the B6 and A strains indicates that both the H-2a and Tlaa alleles are missing from the genome of this H-2a:Tlaa negative variant. Since the variant has two apparently unaltered chromosomes 17, where the H-2:Tla complex is situated, and since the intensity of bands in Southern blotting is suggestive of H-2b homozygosity, it is considered that loss of the H-2a:Tlaa haplotype by the variant was accompanied by duplication of the H-2b:Tlab haplotype. The implied change from heterozygosity to homozygosity that the variant has undergone with respect to H-2:Tla was not paralleled by a similar change at the three other loci tested, since the variant retained heterozygosity for Pep-3 (chromosome 1), Gpi-1 (chromosome 7), and Es-1 (chromosome 8).

Association studies of low-frequency coding variants in nonsyndromic cleft lip with or without cleft palate.

Science.gov (United States)

Leslie, Elizabeth J; Carlson, Jenna C; Shaffer, John R; Buxó, Carmen J; Castilla, Eduardo E; Christensen, Kaare; Deleyiannis, Frederic W B; Field, Leigh L; Hecht, Jacqueline T; Moreno, Lina; Orioli, Ieda M; Padilla, Carmencita; Vieira, Alexandre R; Wehby, George L; Feingold, Eleanor; Weinberg, Seth M; Murray, Jeffrey C; Marazita, Mary L

2017-06-01

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a group of common human birth defects with complex etiology. Although genome-wide association studies have successfully identified a number of risk loci, these loci only account for about 20% of the heritability of orofacial clefts. The "missing" heritability may be found in rare variants, copy number variants, or interactions. In this study, we investigated the role of low-frequency variants genotyped in 1995 cases and 1626 controls on the Illumina HumanCore + Exome chip. We performed two statistical tests, Sequence Kernel Association Test (SKAT) and Combined Multivariate and Collapsing (CMC) method using two minor allele frequency cutoffs (1% and 5%). We found that a burden of low-frequency coding variants in N4BP2, CDSN, PRTG, and AHRR were associated with increased risk of NSCL/P. Low-frequency variants in other genes were associated with decreased risk of NSCL/P. These results demonstrate that low-frequency variants contribute to the genetic etiology of NSCL/P. © 2017 Wiley Periodicals, Inc.

Evaluation of type 2 diabetes genetic risk variants in Chinese adults

DEFF Research Database (Denmark)

Gan, Wei; Walters, Robin G; Holmes, Michael V

2016-01-01

: Association signals were directionally consistent between CKB and the original discovery GWAS: of 56 variants passing quality control, 48 showed the same direction of effect (binomial test, p = 2.3 × 10(-8)). We observed a consistent overall trend towards lower risk variant effect sizes in CKB than in case......-control samples of GWAS meta-analyses (mean 19-22% decrease in log odds, p ≤ 0.0048), likely to reflect correction of both 'winner's curse' and spectrum bias effects. The association with risk of diabetes of a genetic risk score, based on lead variants at 25 loci considered to act through beta cell function...

Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic

DEFF Research Database (Denmark)

Ahlborn, Lise B; Dandanell, Mette; Steffensen, Ane Y

2015-01-01

by functional analysis at the protein level. Results from a validated mini-gene splicing assay indicated that nine BRCA1 variants resulted in splicing aberrations leading to truncated transcripts and thus can be considered pathogenic (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5072C>T/p.Thr1691Ile, c......Pathogenic germline mutations in the BRCA1 gene predispose carriers to early onset breast and ovarian cancer. Clinical genetic screening of BRCA1 often reveals variants with uncertain clinical significance, complicating patient and family management. Therefore, functional examinations are urgently...... needed to classify whether these uncertain variants are pathogenic or benign. In this study, we investigated 14 BRCA1 variants by in silico splicing analysis and mini-gene splicing assay. All 14 alterations were missense variants located within the BRCT domain of BRCA1 and had previously been examined...

Frequencies and implications of discordant findings of interictal SPECT and itcal SPECT in patients with intractable epilepsy

International Nuclear Information System (INIS)

Lee, D. S.; Lee, S. K.; Jeong, J. K.; Lee, M. C.; Ko, C. S.

1997-01-01

Interictal SPECT could be used at best as a reference image to ictal SPECT, and cause sometimes confusion if it had given unexplained discordant findings from ictal SPECT. We investigated implications of discordant findings which occurred in 26 among 268 which found their epileptogenic zones using ictal EEG and/or operative outcome. Sensitivity of interictal SPECT was only 36%. Among these 268, 69 patients had no structural lesions on MR, 14 of whom had decreased perfusion on interictal SPECT (8 trues and 6 falses (adjacent or contralateral)). Structural lesion were found in 199 on MR, 103 of whom had decreased perfusion (89 trues and 14 falses). Among 26 having discordant cases, 10 interictal SPECT were proved wrong after operation and/or invasive EEG and the other 16 were on speculation using PET and ictal EEG. Ictal hyperperfusion was observed in 14 patients in these interictal SPECT. Six ictal studies were found postictal accompanied by contralateral propagation or not. Two patients had dual pathology, and the remaining 2 unknown. Interictal SPECT was done on the 2nd day after ictal study(24), the 3rd day (18), the 4th day(16), the 5th day (23). Four among 24 interictal studies (17%) of the 2nd day and the other 4 among 57 of 3rd to 5th day revealed ictal hyperperfusion on interictal SPECT. Six interictal studies (2.7% among 221) acquired on the indifferent day showed also ictal hyperperfusion. We could suggest that the next day is not desirable for interictal SPECT after ictal study, as ictal hyperperfusion on interictal study confounded more than postictal findings of ictal SPECT in the discrete localization than reassuring ictal study

Frequencies and implications of discordant findings of interictal SPECT and itcal SPECT in patients with intractable epilepsy

Energy Technology Data Exchange (ETDEWEB)

Lee, D S; Lee, S K; Jeong, J K; Lee, M C; Ko, C S [College of Medicine, Seoul National Univ., Seoul (Korea, Republic of)

1997-07-01

Interictal SPECT could be used at best as a reference image to ictal SPECT, and cause sometimes confusion if it had given unexplained discordant findings from ictal SPECT. We investigated implications of discordant findings which occurred in 26 among 268 which found their epileptogenic zones using ictal EEG and/or operative outcome. Sensitivity of interictal SPECT was only 36%. Among these 268, 69 patients had no structural lesions on MR, 14 of whom had decreased perfusion on interictal SPECT (8 trues and 6 falses (adjacent or contralateral)). Structural lesion were found in 199 on MR, 103 of whom had decreased perfusion (89 trues and 14 falses). Among 26 having discordant cases, 10 interictal SPECT were proved wrong after operation and/or invasive EEG and the other 16 were on speculation using PET and ictal EEG. Ictal hyperperfusion was observed in 14 patients in these interictal SPECT. Six ictal studies were found postictal accompanied by contralateral propagation or not. Two patients had dual pathology, and the remaining 2 unknown. Interictal SPECT was done on the 2nd day after ictal study(24), the 3rd day (18), the 4th day(16), the 5th day (23). Four among 24 interictal studies (17%) of the 2nd day and the other 4 among 57 of 3rd to 5th day revealed ictal hyperperfusion on interictal SPECT. Six interictal studies (2.7% among 221) acquired on the indifferent day showed also ictal hyperperfusion. We could suggest that the next day is not desirable for interictal SPECT after ictal study, as ictal hyperperfusion on interictal study confounded more than postictal findings of ictal SPECT in the discrete localization than reassuring ictal study.

Birth weight and gestational age on retinopathy of prematurity in discordant twins in China

Directory of Open Access Journals (Sweden)

Zong-Hua Wang

2014-08-01

Full Text Available AIM:To assess the relative effect of birth weight and gestational age on retinopathy of prematurity (ROP using preterm twin pairs discordant for birth weigh in a tertiary neonatal intensive care unit in China.METHODS: Fifty-six discordant twin pairs of 112 preterm infants were retrospectively analyzed. The twin pairs were divided into two subgroups based on birth weight in each pair. The occurrence of ROP and severe ROP requiring treatment were compared between the lower birth weight infants and their co-twins with the higher birth weight. Some neonatal morbidities related to prematurity and neonatal characteristics were also compared between the twin pairs.RESULTS: Based on the univariate analysis, gestational age and birth weight were significantly associated with the occurrence and progression of ROP. But no significant differences in ROP between larger and smaller infants were observed in the twin-paired analysis. The incidence of neonatal morbidities regarding respiratory distress syndrome (RDS, patent ductus arteriosus (PDA, intraventricular hemorrhage (IVH, sepsis and neonatal characteristics regarding gender distribution, one- and five-minute Apgar score, postnatal steroid treatment, blood transfusion, supplemental oxygen therapy, and mechanical ventilation were not different between the twins. However, gestational age of ≤28wk was significantly associated with significantly higher rates of ROP and severe ROP.CONCLUSION: Gestational age is a better predictor of ROP than birth weight in the twin-paired study.

Identifying pathogenicity of human variants via paralog-based yeast complementation.

Directory of Open Access Journals (Sweden)

Fan Yang

2017-05-01

Full Text Available To better understand the health implications of personal genomes, we now face a largely unmet challenge to identify functional variants within disease-associated genes. Functional variants can be identified by trans-species complementation, e.g., by failure to rescue a yeast strain bearing a mutation in an orthologous human gene. Although orthologous complementation assays are powerful predictors of pathogenic variation, they are available for only a few percent of human disease genes. Here we systematically examine the question of whether complementation assays based on paralogy relationships can expand the number of human disease genes with functional variant detection assays. We tested over 1,000 paralogous human-yeast gene pairs for complementation, yielding 34 complementation relationships, of which 33 (97% were novel. We found that paralog-based assays identified disease variants with success on par with that of orthology-based assays. Combining all homology-based assay results, we found that complementation can often identify pathogenic variants outside the homologous sequence region, presumably because of global effects on protein folding or stability. Within our search space, paralogy-based complementation more than doubled the number of human disease genes with a yeast-based complementation assay for disease variation.

Practice Parameter on Gay, Lesbian, or Bisexual Sexual Orientation, Gender Nonconformity, and Gender Discordance in Children and Adolescents

Science.gov (United States)

Medicus, Jennifer

2012-01-01

Children and adolescents who are growing up gay, lesbian, bisexual, gender nonconforming, or gender discordant experience unique developmental challenges. They are at risk for certain mental health problems, many of which are significantly correlated with stigma and prejudice. Mental health professionals have an important role to play in fostering…

Osteopontin splice variants are differential predictors of breast cancer treatment responses.

Science.gov (United States)

Zduniak, Krzysztof; Agrawal, Anil; Agrawal, Siddarth; Hossain, Md Monir; Ziolkowski, Piotr; Weber, Georg F

2016-07-11

Osteopontin is a marker for breast cancer progression, which in previous studies has also been associated with resistance to certain anti-cancer therapies. It is not known which splice variants may mediate treatment resistance. Here we analyze the association of osteopontin variant expression before treatment, differentiated according to immunohistochemistry with antibodies to exon 4 and to the osteopontin-c splice junction respectively, with the ensuing therapy responses in 119 Polish breast cancer patients who presented between 1995 and 2008. We found from Cox hazard models, logrank test and Wilcoxon test that osteopontin exon 4 was associated with a favorable response to tamoxifen, but a poor response to chemotherapy with CMF (cyclophosphamide, methotrexate, fluorouracil). Osteopontin-c is prognostic, but falls short of being a significant predictor for sensitivity to treatment. The addition of osteopontin splice variant immunohistochemistry to standard pathology work-ups has the potential to aid decision making in breast cancer treatment.

Osteopontin splice variants are differential predictors of breast cancer treatment responses

International Nuclear Information System (INIS)

Zduniak, Krzysztof; Agrawal, Anil; Agrawal, Siddarth; Hossain, Md Monir; Ziolkowski, Piotr; Weber, Georg F.

2016-01-01

Osteopontin is a marker for breast cancer progression, which in previous studies has also been associated with resistance to certain anti-cancer therapies. It is not known which splice variants may mediate treatment resistance. Here we analyze the association of osteopontin variant expression before treatment, differentiated according to immunohistochemistry with antibodies to exon 4 and to the osteopontin-c splice junction respectively, with the ensuing therapy responses in 119 Polish breast cancer patients who presented between 1995 and 2008. We found from Cox hazard models, logrank test and Wilcoxon test that osteopontin exon 4 was associated with a favorable response to tamoxifen, but a poor response to chemotherapy with CMF (cyclophosphamide, methotrexate, fluorouracil). Osteopontin-c is prognostic, but falls short of being a significant predictor for sensitivity to treatment. The addition of osteopontin splice variant immunohistochemistry to standard pathology work-ups has the potential to aid decision making in breast cancer treatment

Canine parvovirus (CPV-2) variants circulating in Nigerian dogs

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Apaa, T. T.; Daly, J. M.; Tarlinton, R. E.

2016-01-01

Canine parvovirus type 2 (CPV-2) is a highly contagious viral disease with three variants (CPV-2a, CPV-2b and CPV-2c) currently circulating in dogs worldwide. The main aim of this study was to determine the prevalent CPV-2 variant in faecal samples from 53 dogs presenting with acute gastroenteritis suspected to be and consistent with CPV-2 to Nigerian Veterinary Clinics in 2013–2014. Seventy-five per cent of these dogs tested positive for CPV-2 in a commercial antigen test and/or by PCR. Partial sequencing of the VP2 gene of six of these demonstrated them to be CPV-2a. Most of the dogs (60 per cent) were vaccinated, with 74 per cent of them puppies less than six months old. PMID:27933190

Discordance between olfactory psychophysical measurements and olfactory event related potentials in five patients with olfactory dysfunction following upper respiratory infection.

Science.gov (United States)

Guan, Jing; Ni, Dao-feng; Wang, Jian; Gao, Zhi-qiang

2009-07-05

Subjective olfactory tests are easy to perform and popularly applied in the clinic, but using only these, it is difficult to diagnose all disorders of the olfactory system. The olfactory event related potentials technique offers further insight into the olfactory system and is an ideal objective test. This analysis was of subjective and objective data on the olfactory function of twelve patients with loss of smell associated with an upper respiratory infection (URI). We tested the twelve patients with URI induced olfactory loss by medical history, physical examination of the head and neck, olfactory tests and medical imaging. Olfactory function was assessed by Toyota and Takagi olfactometry including olfactory detection and recognition thresholds and olfactory event-related potentials (OERPs) recorded with OEP-98C Olfactometer. An unusual phenomenon was observed in five patients in whom the subjective detection and recognition thresholds were normal, while the expected OERPs were not detectable. We suggest that the discordance between olfactory psychophysical measurements and OERPs might be the results of abnormal electrophysiology related with olfactory neuropathy caused by viral URI. In addition, the measurement of OERPs might play a significant role in evaluating olfactory dysfunction.

Discordance between olfactory psychophysical measurements and olfactory event related potentials in five patients with olfactory dysfunction following upper respiratory infection

Institute of Scientific and Technical Information of China (English)

GUAN Jing; NI Dao-feng; WANG Jian; GAO Zhi-qiang

2009-01-01

Background Subjective olfactory tests are easy to perform and popularly applied in the clinic, but using only these, it is difficult to diagnose all disorders of the olfactory system. The olfactory event related potentials technique offers further insight into the olfactory system and is an ideal objective test. This analysis was of subjective and objective data on the olfactory function of twelve patients with loss of smell associated with an upper respiratory infection (URI). Methods We tested the twelve patients with URI induced olfactory loss by medical history, physical examination of the head and neck, olfactory tests and medical imaging. Olfactory function was assessed by Toyota and Takagi olfactometry including olfactory detection and recognition thresholds and olfactory event-related potentials (OERPs) recorded with OEP-98C Olfactometer. Results An unusual phenomenon was observed in five patients in whom the subjective detection and recognition thresholds were normal, while the expected OERPs were not detectable. Conclusions We suggest that the discordance between olfactory psychophysical measurements and OERPs might be the results of abnormal electrephysiology related with olfactory neuropathy caused by viral URI. In addition, the measurement of OERPs might play a significant role in evaluating olfactory dysfunction.

HbA1c levels in individuals heterozygous for hemoglobin variants.

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Tavares, Ricardo Silva; Souza, Fábio Oliveira de; Francescantonio, Isabel Cristina Carvalho Medeiros; Soares, Weslley Carvalho; Mesquita, Mauro Meira

2017-04-01

To evaluate the levels of glycated hemoglobin (HbA1c) in patients heterozygous for hemoglobin variants and compare the results of this test with those of a control group. This was an experimental study based on the comparison of HbA1c tests in two different populations, with a test group represented by individuals heterozygous for hemoglobin variants (AS and AC) and a control group consisting of people with electrophoretic profile AA. The two populations were required to meet the following inclusion criteria: Normal levels of fasting glucose, hemoglobin, urea and triglycerides, bilirubin > 20 mg/dL and non-use of acetylsalicylic acid. 50 heterozygous subjects and 50 controls were evaluated between August 2013 and May 2014. The comparison of HbA1c levels between heterozygous individuals and control subjects was performed based on standard deviation, mean and G-Test. The study assessed a test group and a control group, both with 39 adults and 11 children. The mean among heterozygous adults for HbA1c was 5.0%, while the control group showed a rate of 5.74%. Heterozygous children presented mean HbA1c at 5.11%, while the controls were at 5.78%. G-Test yielded p=0.93 for children and p=0.89 for adults. Our study evaluated HbA1c using ion exchange chromatography resins, and the patients heterozygous for hemoglobin variants showed no significant difference from the control group.

Increased frequency of micronuclei in adults with a history of childhood sexual abuse: a discordant monozygotic twin study.

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Timothy P York

Full Text Available Childhood sexual abuse (CSA is a traumatic life event associated with an increased lifetime risk for psychopathology/morbidity. The long-term biological consequences of CSA-elicited stress on chromosomal stability in adults are unknown. The primary aim of this study was to determine if the rate of acquired chromosomal changes, measured using the cytokinesis-block micronucleus assay on stimulated peripheral blood lymphocytes, differs in adult female monozygotic twins discordant for CSA.Monozygotic twin pairs discordant for CSA were identified from a larger population-based sample of female adult twins for whom the experience of CSA was assessed by self-report (51 individuals including a reference sample. Micronuclei (MN contain chromatin from structurally normal or abnormal chromosomes that are excluded from the daughter nuclei during cell division and serve as a biomarker to assess acquired chromosomal instability.Female twins exposed to CSA exhibited a 1.63-fold average increase in their frequency of MN compared to their nonexposed genetically identical cotwins (Paired t-test, t₁₆ = 2.65, P = 0.017. No additional effects of familial factors were detected after controlling for the effect of CSA exposure. A significant interaction between CSA history and age was observed, suggesting that the biological effects of CSA on MN formation may be cumulative.These data support a direct link between CSA exposure and MN formation measured in adults that is not attributable to genetic or environmental factors shared by siblings. Further research is warranted to understand the biological basis for the observed increase in acquired chromosomal findings in people exposed to CSA and to determine if acquired somatic chromosomal abnormalities/somatic clonal mosaicism might mediate the adult pathology associated with CSA.

Discordance of HIV and HSV-2 biomarkers and self-reported sexual behaviour among orphan adolescents in Western Kenya.

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Cho, Hyunsan; Luseno, Winnie; Halpern, Carolyn; Zhang, Lei; Mbai, Isabella; Milimo, Benson; Hallfors, Denise Dion

2015-06-01

This paper examines the discordance between biological data of HIV and herpes simplex virus type 2 (HSV-2) infections and self-reported questionnaire responses among orphan adolescents in Western Kenya. In 2011, 837 orphan adolescents from 26 primary schools were enrolled in an HIV prevention trial. At baseline, blood samples were drawn for HIV and HSV-2 infection biomarker testing, and participants completed an audio computer-assisted self-interviewing survey. Comparing biological data with self-reported responses indicated that 70% of HIV-positive (7 out of 10) and 64% of HSV-2-positive (18 out of 28 positive) participants reported never having had sex. Among ever-married adolescents, 65% (57 out of 88) reported never having had sex. Overall, 10% of study participants appeared to have inconsistently reported their sexual behaviour. Logistic regression analyses indicated that lower educational level and exam scores were significant predictors of inconsistent reporting. Our study demonstrates the discordance between infections measured by biomarkers and self-reports of having had sex among orphan adolescents in Kenya. In order to detect programme effects accurately in prevention research, it is necessary to collect both baseline and endline biological data. Furthermore, it is recommended to triangulate multiple data sources about adolescent participants' self-reported information about marriage and pregnancies from school records and parent/guardians to verify the information. Researchers should recognise potential threats to validity in data and design surveys to consider cognitive factors and/or cultural context to obtain more accurate and reliable information from adolescents regarding HIV/sexually transmitted infection risk behaviours. NCT01501864. 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.

IL10 low-frequency variants in Behçet's disease patients.

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Matos, Mafalda; Xavier, Joana M; Abrantes, Patrícia; Sousa, Inês; Rei, Nádia; Davatchi, Fereydoun; Shahram, Farhad; Jesus, Gorete; Barcelos, Filipe; Vedes, Joana; Salgado, Manuel; Abdollahi, Bahar Sadeghi; Nadji, Abdolhadi; Moraes-Fontes, Maria Francisca; Shafiee, Niloofar Mojarad; Ghaderibarmi, Fahmida; Vaz Patto, José; Crespo, Jorge; Oliveira, Sofia A

2017-05-01

To explain the missing heritability after the genome-wide association studies era, sequencing studies allow the identification of low-frequency variants with a stronger effect on disease risk. Common variants in the interleukin 10 gene (IL10) have been consistently associated with Behçet's disease (BD) and the goal of this study is to investigate the role of low-frequency IL10 variants in BD susceptibility. To identify IL10 low-frequency variants, a discovery group of 50 Portuguese BD patients were Sanger-sequenced in a 7.7 kb genomic region encompassing the complete IL10 gene, 0.9 kb upstream and 2 kb downstream, and two conserved regions in the putative promoter. To assess if the novel variants are BD- and/or Portuguese-specific, they were assayed in an additional group of BD patients (26 Portuguese and 964 Iranian) and controls (104 Portuguese and 823 Iranian). Rare IL10 coding variants were not detected in BD patients, but we identified 28 known single nucleotide polymorphisms with minor allele frequencies ranging from 0.010 to 0.390, and five novel non-coding variants in five heterozygous cases. ss836185595, located in the IL10 3' untranslated region, was also detected in one Iranian control individual and therefore is not specific to BD. The remaining novel IL10 variants (ss836185596 and ss836185602 in intron 3, ss836185598 and ss836185604 in the putative promoter region) were not found in the replication dataset. This study highlights the importance of screening the whole gene and regulatory regions when searching for novel variants associated with complex diseases, and the need to develop bioinformatics tools to predict the functional impact of non-coding variants and statistical tests which incorporate these predictions. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Discordance in histopathologic evaluation of melanoma sentinel lymph node biopsy with clinical follow-up: results from a prospectively collected database.

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Dandekar, Monisha; Lowe, Lori; Fullen, Douglas R; Johnson, Timothy M; Sabel, Michael S; Wong, Sandra L; Patel, Rajiv M

2014-10-01

Sentinel lymph node (SLN) status currently represents the single most important prognostic factor in clinically localized melanoma and is widely used in patients with melanoma at significant risk for nodal micrometastasis. Although several studies have looked at the rates and implications of inaccuracies in the histopathologic diagnosis of melanocytic lesions, accuracy in the histologic interpretation of the SLN in melanoma has not been addressed. The goal of this study was to determine the rates of discordance in the histopathologic evaluation of the SLN and the potential clinical impact on patients referred to a comprehensive melanoma center. A prospectively collected database was queried for melanoma patients who had SLN biopsies performed at outside institutions before referral to the University of Michigan Multidisciplinary Melanoma Program between 2006 and 2009. These cases were reviewed and clinical follow-up obtained. After internal review of the SLN material, 13 (8 %) of 167 cases had major discrepancies in diagnosis that impacted patient management and prognosis. The disease of five patients was subsequently downstaged and the disease of eight patients was upstaged after internal review of the SLNs and reversal in diagnoses. There appears to be a small yet significant rate of discordance in diagnosis of the SLN for melanoma after expert histopathologic review. The implications of this discordance and revision of diagnosis is substantial. Expert histopathologic review of the SLN warrants consideration to provide the most accurate prognostic information and optimal patient care.

Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis

DEFF Research Database (Denmark)

Hinrichsen, Inga; Brieger, Angela; Trojan, Jörg

2013-01-01

Lynch syndrome is caused by a germline mutation in a mismatch repair gene, most commonly the MLH1 gene. However, one third of the identified alterations are missense variants with unclear clinical significance. The functionality of these variants can be tested in the laboratory, but the results...

Cultured gut microbiota from twins discordant for obesity modulate adiposity and metabolic phenotypes in mice

OpenAIRE

Ridaura, Vanessa K.; Faith, Jeremiah J.; Rey, Federico E.; Cheng, Jiye; Duncan, Alexis E.; Kau, Andrew L.; Griffin, Nicholas W.; Lombard, Vincent; Henrissat, Bernard; Bain, James R.; Muehlbauer, Michael J.; Ilkayeva, Olga; Semenkovich, Clay F.; Funai, Katsuhiko; Hayashi, David K.

2013-01-01

The role of specific gut microbes in shaping body composition remains unclear. We transplanted fecal microbiota from adult female twin pairs discordant for obesity into germ-free mice fed low-fat mouse chow, as well as diets representing different levels of saturated fat and fruit and vegetable consumption typical of the USA. Increased total body and fat mass, as well as obesity-associated metabolic phenotypes were transmissible with uncultured fecal communities, and with their corresponding ...

Gray and white matter density changes in monozygotic and same-sex dizygotic twins discordant for schizophrenia using voxel-based morphometry

DEFF Research Database (Denmark)

Hulshoff Pol, HE; Schnack, HG; Mandl, RC

2006-01-01

Global gray matter brain tissue volume decreases in schizophrenia have been associated to disease-related (possibly nongenetic) factors. Global white matter brain tissue volume decreases were related to genetic risk factors for the disease. However, which focal gray and white matter brain regions...... best reflect the genetic and environmental risk factors in the brains of patients with schizophrenia remains unresolved. 1.5-T MRI brain scans of 11 monozygotic and 11 same-sex dizygotic twin-pairs discordant for schizophrenia were compared to 11 monozygotic and 11 same-sex dizygotic healthy control...... twin-pairs using voxel-based morphometry. Linear regression analysis was done in each voxel for the average and difference in gray and white matter density separately, in each twin-pair, with group (discordant, healthy) and zygosity (monozygotic, dizygotic) as between subject variables, and age, sex...

Exome Sequencing Identifies Potential Risk Variants for Mendelian Disorders at High Prevalence in Qatar

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Rodriguez-Flores, Juan L.; Fakhro, Khalid; Hackett, Neil R.; Salit, Jacqueline; Fuller, Jennifer; Agosto-Perez, Francisco; Gharbiah, Maey; Malek, Joel A.; Zirie, Mahmoud; Jayyousi, Amin; Badii, Ramin; Al-Marri, Ajayeb Al-Nabet; Chouchane, Lotfi; Stadler, Dora J.; Hunter-Zinck, Haley; Mezey, Jason G.; Crystal, Ronald G.

2013-01-01

Exome sequencing of families of related individuals has been highly successful in identifying genetic polymorphisms responsible for Mendelian disorders. Here, we demonstrate the value of the reverse approach, where we use exome sequencing of a sample of unrelated individuals to analyze allele frequencies of known causal mutations for Mendelian diseases. We sequenced the exomes of 100 individuals representing the three major genetic subgroups of the Qatari population (Q1 Bedouin, Q2 Persian-South Asian, Q3 African) and identified 37 variants in 33 genes with effects on 36 clinically significant Mendelian diseases. These include variants not present in 1000 Genomes and variants at high frequency when compared to 1000 Genomes populations. Several of these Mendelian variants were only segregating in one Qatari subpopulation, where the observed subpopulation specificity trends were confirmed in an independent population of 386 Qataris. Pre-marital genetic screening in Qatar tests for only 4 out of the 37, such that this study provides a set of Mendelian disease variants with potential impact on the epidemiological profile of the population that could be incorporated into the testing program if further experimental and clinical characterization confirms high penetrance. PMID:24123366

Modelling Product Families for Product Configuration Systems with Product Variant Master

DEFF Research Database (Denmark)

Mortensen, Niels Henrik; Hvam, Lars; Haug, Anders

2010-01-01

This article presents an evaluation of applying a suggested method for modelling product families for product configuration based on theory for modelling mechanical products,systems theory and object-oriented modelling. The modelling technique includes a so-called product variant master and CRC-cards...... the three views. Modelling of characteristics of the product variants in a product family Modelling of constraints between parts in the product family Visualisation of the entire product family on a poster e.g. 1x2 meters The product variant master and CRC-cards are means to bridge the gap between domain...... experts and IT-developers, thus making it possible for the domain experts (e.g. engineers from product development) to express their knowledge in a form that is understandable both for the domain experts and the IT-developers. The product variant master and CRC-cards have currently been tested and further...

Low multiple electrode aggregometry platelet responses are not associated with non-synonymous variants in G-protein coupled receptor genes.

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Norman, Jane E; Lee, Kurtis R; Walker, Mary E; Murden, Sherina L; Harris, Jessica; Mundell, Stuart; J Murphy, Gavin; Mumford, Andrew D

2015-10-01

Multiple electrode aggregometry (MEA) improves prediction of thrombosis and bleeding in cardiac patients. However, the causes of inter-individual variation in MEA results are incompletely understood. We explore whether low MEA results are associated with platelet G-protein coupled receptor (GPCR) gene variants. The effects of P2Y12 receptor (P2Y12), thromboxane A2 receptor (TPα) and protease-activated receptor 1 (PAR1) dysfunction on the MEA ADP-test, ASPI-test and TRAP-test were determined using receptor antagonists. Cardiac surgery patients with pre-operative MEA results suggesting GPCR dysfunction were selected for P2Y12 (P2RY12), TPα (TBXA2R) and PAR1 (F2R) sequencing. In control blood samples, P2Y12, TPα or PAR1 antagonists markedly reduced ADP-test, ASPI-test and TRAP-test results respectively. In the 636 patients from a cohort of 2388 cardiac surgery patients who were not receiving aspirin or a P2Y12 blocker, the median ADP-test result was 75.1 U (range 4.8-153.2), ASPI-test 83.7 U (1.4-157.3) and TRAP-test 117.7 U (2.4-194.1), indicating a broad range of results unexplained by anti-platelet drugs. In 238 consenting patients with unexplained low MEA results, three P2RY12 variants occurred in 70/107 (65%) with suspected P2Y12 dysfunction and four TBXA2R variants occurred in 19/22 (86%) with suspected TPα dysfunction although the later group was too small to draw meaningful conclusions about variant frequency. All the variants were synonymous and unlikely to cause GPCR dysfunction. There were no F2R variants in the 109 cases with suspected PAR1 dysfunction. MEA results suggesting isolated platelet GPCR dysfunction were common in cardiac surgery patients, but were not associated with non-synonymous variants in P2RY12 or F2R. Copyright © 2015 Elsevier Ltd. All rights reserved.

A rabies virus vampire bat variant shows increased neuroinvasiveness in mice when compared to a carnivore variant.

Science.gov (United States)

Mesquita, Leonardo Pereira; Gamon, Thais Helena Martins; Cuevas, Silvia Elena Campusano; Asano, Karen Miyuki; Fahl, Willian de Oliveira; Iamamoto, Keila; Scheffer, Karin Correa; Achkar, Samira Maria; Zanatto, Dennis Albert; Mori, Cláudia Madalena Cabrera; Maiorka, Paulo César; Mori, Enio

2017-12-01

Rabies is one of the most important zoonotic diseases and is caused by several rabies virus (RABV) variants. These variants can exhibit differences in neurovirulence, and few studies have attempted to evaluate the neuroinvasiveness of variants derived from vampire bats and wild carnivores. The aim of this study was to evaluate the neuropathogenesis of infection with two Brazilian RABV street variants (variant 3 and crab-eating fox) in mice. BALB/c mice were inoculated with RABV through the footpad, with the 50% mouse lethal dose (LD 50 ) determined by intracranial inoculation. The morbidity of rabies in mice infected with variant 3 and the crab-eating fox strain was 100% and 50%, respectively, with an incubation period of 7 and 6 days post-inoculation (dpi), respectively. The clinical disease in mice was similar with both strains, and it was characterized initially by weight loss, ruffled fur, hunched posture, and hind limb paralysis progressing to quadriplegia and recumbency at 9 to 12 dpi. Histological lesions within the central nervous system (CNS) characterized by nonsuppurative encephalomyelitis with neuronal degeneration and necrosis were observed in mice infected with variant 3 and those infected with the crab-eating fox variant. However, lesions and the presence of RABV antigen, were more widespread within the CNS of variant-3-infected mice, whereas in crab-eating fox-variant-infected mice, RABV antigens were more restricted to caudal areas of the CNS, such as the spinal cord and brainstem. In conclusion, the results shown here demonstrate that the RABV vampire bat strain (variant 3) has a higher potential for neuroinvasiveness than the carnivore variant.

Lack of Association of CD55 Receptor Genetic Variants and Severe Malaria in Ghanaian Children

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Kathrin Schuldt

2017-03-01

Full Text Available In a recent report, the cellular receptor CD55 was identified as a molecule essential for the invasion of human erythrocytes by Plasmodium falciparum, the causal agent of the most severe form of malaria. As this invasion process represents a critical step during infection with the parasite, it was hypothesized that genetic variants in the gene could affect severe malaria (SM susceptibility. We performed high-resolution variant discovery of rare and common genetic variants in the human CD55 gene. Association testing of these variants in over 1700 SM cases and unaffected control individuals from the malaria-endemic Ashanti Region in Ghana, West Africa, were performed on the basis of single variants, combined rare variant analyses, and reconstructed haplotypes. A total of 26 genetic variants were detected in coding and regulatory regions of CD55. Five variants were previously unknown. None of the single variants, rare variants, or haplotypes showed evidence for association with SM or P. falciparum density. Here, we present the first comprehensive analysis of variation in the CD55 gene in the context of SM and show that genetic variants present in a Ghanaian study group appear not to influence susceptibility to the disease.

Association analysis of KIT, MITF, and PAX3 variants with white markings in Spanish horses.

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Negro, S; Imsland, F; Valera, M; Molina, A; Solé, M; Andersson, L

2017-06-01

Several variants in the KIT, PAX3 and MITF genes have previously been associated with white markings in horses. In this study, we examined eight variants of these genes in 70 Menorca Purebred horses (PRMe, only black solid-coloured horses) and 70 Spanish Purebred horses (PRE, different coat colour patterns) that were scored for the extent of white markings. A maximum-likelihood chi-square test, logistic regression model and ridge regression analyses showed that a missense mutation (p.Arg682His) in KIT was associated with white facial markings (P horses. The relative contribution of this variant to white markings in PRMe horses was estimated at 47.6% (head) and 43.4% (total score). In PRE horses, this variant was also associated with hindlimb scores (P T intronic variant located 29.9 kb downstream from the transcription start site of the MITF gene was associated with less white markings on forelimbs (P horses, with a relative contribution of 63.9%, whereas in PRE horses this variant was associated with white facial markings (P horses, providing breeders with an opportunity to use genetic testing to aid in breeding for their desired level of white markings. © 2017 Stichting International Foundation for Animal Genetics.

Screening and Invasive Testing in Twins

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Giovanni Monni

2014-07-01

Full Text Available Prenatal screening and testing for trisomy 21 in twin pregnancies poses a number of challenges: the exact estimate of the a priori risk of trisomy 21, the choice of prenatal screening test and/or invasive techniques to employ for the diagnosis and the impact of the result on the options of treatment in case of discordant results within a twin pair or among multiples. These different aspects are discussed below while recognizing that many issues remain unresolved.

Immuno-Virological Discordance and the Risk of NonAIDS and AIDS Events in a Large Observational Cohort of HIV-Patients in Europe

DEFF Research Database (Denmark)

Zoufaly, Alexander; Cozzi-Lepri, Alessandro; Reekie, Joanne

2014-01-01

The impact of immunosuppression despite virological suppression (immuno-virological discordance, ID) on the risk of developing fatal and non-fatal AIDS/non-AIDS events is unclear and remains to be elucidated....

Cerivastatin, Genetic Variants, and the Risk of Rhabdomyolysis

Science.gov (United States)

Marciante, Kristin D.; Durda, Jon P.; Heckbert, Susan R.; Lumley, Thomas; Rice, Ken; McKnight, Barbara; Totah, Rheem A.; Tamraz, Bani; Kroetz, Deanna L.; Fukushima, Hisayo; Kaspera, Rüdiger; Bis, Joshua C.; Glazer, Nicole L.; Li, Guo; Austin, Thomas R.; Taylor, Kent D.; Rotter, Jerome I.; Jaquish, Cashell E.; Kwok, Pui-Yan; Tracy, Russell P.; Psaty, Bruce M.

2011-01-01

Objective The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response--rhabdomyolysis in a small proportion of users-- points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis. Methods The study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association (GWA) study to identify risk factors in other regions of the genome. 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies. Results Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (p = 0.002), but not variants in CYP2C8 (p = 0.073) or the UGTs (p = 0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (OR: 1.89, 95% CI: 1.40 to 2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (p rhabdomyolysis (OR: 0.48; 95% CI: 0.36 to 0.63). Conclusion We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin. PMID:21386754

Conservation law for distributed entanglement of formation and quantum discord

International Nuclear Information System (INIS)

Fanchini, Felipe F.; Cornelio, Marcio F.; Oliveira, Marcos C. de; Caldeira, Amir O.

2011-01-01

We present a direct relation, based upon a monogamic principle, between entanglement of formation (EOF) and quantum discord (QD), showing how they are distributed in an arbitrary tripartite pure system. By extending it to a paradigmatic situation of a bipartite system coupled to an environment, we demonstrate that the EOF and the QD obey conservation relation. By means of this relation we show that in the deterministic quantum computer with one pure qubit the protocol has the ability to rearrange the EOF and the QD, which implies that quantum computation can be understood on a different basis as a coherent dynamics where quantum correlations are distributed between the qubits of the computer. Furthermore, for a tripartite mixed state we show that the balance between distributed EOF and QD results in a stronger version of the strong subadditivity of entropy.

Genotyping Fanconi anemia patients from Serbia reveals three novel FANCD2 variants

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Filipović-Tričković Jelena

2017-01-01

Full Text Available Fanconi anemia is rare inherited disease characterized by wide spectrum of congenital anomalies, progressive pancytopenia, and predisposition to hematological malignancies and solid tumors. Molecular genetic analysis of mutations in FANC genes is of a great importance for diagnosis confirmation, prenatal and carrier testing, as well as for prediction of chemotherapy outcome and disease complications. In this study we performed screening of frequently affected regions of FANCD2 gene for sequence variants in six unrelated FA-D2 patients in Serbia. This is the first molecular analysis of FANCD2 gene in Serbian FA-D2 patients. A total of 10 sequence variants were detected, one in homozygous, and nine in heterozygous state. Two variants were found within exons, and eight within introns, in deep intronic regions. In-silico analysis showed that among all detected variants one exon variant and three intron variants might have impact on splicing mechanism. Heterozygous variants found in intron 3, c.206-246delG; exon 26, c.2396 C>A and intron 28, c.2715+573 C>T were not previously reported. In-silico analysis revealed that among them, two (intron 3, c.206-246 delG and exon 26, c.2396 C>A could be novel disease-causing mutations. Many variants were found in more than one patient, including those unreported, indicating their possible ethnic association. Great number of variants in some patients suggests their non-random emergence in Fanconi anemia pathway. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 173046

Targeted deep resequencing identifies coding variants in the PEAR1 gene that play a role in platelet aggregation.

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Yoonhee Kim

Full Text Available Platelet aggregation is heritable, and genome-wide association studies have detected strong associations with a common intronic variant of the platelet endothelial aggregation receptor1 (PEAR1 gene both in African American and European American individuals. In this study, we used a sequencing approach to identify additional exonic variants in PEAR1 that may also determine variability in platelet aggregation in the GeneSTAR Study. A 0.3 Mb targeted region on chromosome 1q23.1 including the entire PEAR1 gene was Sanger sequenced in 104 subjects (45% male, 49% African American, age = 52±13 selected on the basis of hyper- and hypo- aggregation across three different agonists (collagen, epinephrine, and adenosine diphosphate. Single-variant and multi-variant burden tests for association were performed. Of the 235 variants identified through sequencing, 61 were novel, and three of these were missense variants. More rare variants (MAF<5% were noted in African Americans compared to European Americans (108 vs. 45. The common intronic GWAS-identified variant (rs12041331 demonstrated the most significant association signal in African Americans (p = 4.020×10(-4; no association was seen for additional exonic variants in this group. In contrast, multi-variant burden tests indicated that exonic variants play a more significant role in European Americans (p = 0.0099 for the collective coding variants compared to p = 0.0565 for intronic variant rs12041331. Imputation of the individual exonic variants in the rest of the GeneSTAR European American cohort (N = 1,965 supports the results noted in the sequenced discovery sample: p = 3.56×10(-4, 2.27×10(-7, 5.20×10(-5 for coding synonymous variant rs56260937 and collagen, epinephrine and adenosine diphosphate induced platelet aggregation, respectively. Sequencing approaches confirm that a common intronic variant has the strongest association with platelet aggregation in African Americans

Subsets of microsatellite-unstable colorectal cancers exhibit discordance between the CpG island methylator phenotype and MLH1 methylation status.

Science.gov (United States)

Kim, Jung H; Rhee, Ye-Y; Bae, Jeong-M; Kwon, Hyeong-J; Cho, Nam-Y; Kim, Mi J; Kang, Gyeong H

2013-07-01

Although the presence of MLH1 methylation in microsatellite-unstable colorectal cancer generally indicates involvement of the CpG island methylator phenotype (CIMP) in the development of the tumor, these two conditions do not always correlate. A minority of microsatellite-unstable colorectal cancers exhibit discordance between CIMP and MLH1 methylation statuses. However, the clinicopathological features of such microsatellite-unstable colorectal cancers with discrepant MLH1 methylation and CIMP statuses remain poorly studied. Microsatellite-unstable colorectal cancers (n=220) were analyzed for CIMP and MLH1 methylation statuses using the MethyLight assay. Based on the combinatorial CIMP and MLH1 methylation statuses, the microsatellite-unstable colorectal cancers were grouped into four subtypes (CIMP-high (CIMP-H) MLH1 methylation-positive (MLH1m+), CIMP-H MLH1 methylation-negative, CIMP-low/0 (CIMP-L/0) MLH1m+, and CIMP-L/0 MLH1 methylation-negative), which were compared in terms of their associations with clinicopathological and molecular features. The CIMP-L/0 MLH1 methylation-negative and CIMP-H MLH1m+ subtypes were predominant, comprising 63.6 and 24.1% of total microsatellite-unstable colorectal cancers, respectively. The discordant subtypes, CIMP-H MLH1 methylation-negative and CIMP-L/0 MLH1m+, were found in 5 and 7% of microsatellite-unstable colorectal cancers, respectively. The CIMP-H MLH1 methylation-negative subtype exhibited elevated incidence rates in male patients and was associated with larger tumor size, more frequent loss of MSH2 expression, increased frequency of KRAS mutation, and advanced cancer stage. The CIMP-L/0 MLH1m+ subtype was associated with onset at an earlier age, a predominance of MLH1 loss, and earlier cancer stage. None of the CIMP-L/0 MLH1m+ subtype patients succumbed to death during the follow-up. Our findings suggest that the discordant subtypes of colorectal cancers exhibit distinct clinicopathological and molecular features

Optimizing Prevention of HIV and Unplanned Pregnancy in Discordant African Couples.

Science.gov (United States)

Wall, Kristin M; Kilembe, William; Vwalika, Bellington; Haddad, Lisa B; Khu, Naw Htee; Brill, Ilene; Onwubiko, Udodirim; Chomba, Elwyn; Tichacek, Amanda; Allen, Susan

2017-08-01

Dual method use, which combines condoms with a more effective modern contraceptive to optimize prevention of HIV and unplanned pregnancy, is underutilized in high-risk heterosexual couples. Heterosexual HIV-discordant Zambian couples were enrolled from couples' voluntary HIV counseling and testing services into an open cohort with 3-monthly follow-up (1994-2012). Relative to dual method use, defined as consistent condom use plus modern contraception, we examine predictors of (1) condom-only use (suboptimal pregnancy prevention) or (2) modern contraceptive use with inconsistent condom use (effective pregnancy prevention and suboptimal HIV prevention). Among 3,049 couples, dual method use occurred in 28% of intervals in M+F- and 23% in M-F+, p HIV+ (adjusted hazard ratio, aHR = 1.15); baseline oral contraceptive pill (aHR = 0.76), injectable (aHR = 0.48), or implant (aHR = 0.60) use; woman's age (aHR = 1.04 per 5 years) and lifetime number of sex partners (aHR = 1.01); postpartum periods (aHR = 1.25); and HIV stage of the index partner III/IV versus I (aHR = 1.10). Predictors (p HIV+ male circumcision (aHR = 1.51), while time-varying implant use was associated with more consistent condom use (aHR = 0.80). Three-quarters of follow-up intervals did not include dual method use. This highlights the need for counseling to reduce unintended pregnancy and HIV transmission and enable safer conception.

Variants of cellobiohydrolases

Energy Technology Data Exchange (ETDEWEB)

Bott, Richard R.; Foukaraki, Maria; Hommes, Ronaldus Wilhelmus; Kaper, Thijs; Kelemen, Bradley R.; Kralj, Slavko; Nikolaev, Igor; Sandgren, Mats; Van Lieshout, Johannes Franciscus Thomas; Van Stigt Thans, Sander

2018-04-10

Disclosed are a number of homologs and variants of Hypocrea jecorina Ce17A (formerly Trichoderma reesei cellobiohydrolase I or CBH1), nucleic acids encoding the same and methods for producing the same. The homologs and variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted and/or deleted.

Estimating phylogenetic relationships despite discordant gene trees across loci: the species tree of a diverse species group of feather mites (Acari: Proctophyllodidae).

Science.gov (United States)

Knowles, Lacey L; Klimov, Pavel B

2011-11-01

With the increased availability of multilocus sequence data, the lack of concordance of gene trees estimated for independent loci has focused attention on both the biological processes producing the discord and the methodologies used to estimate phylogenetic relationships. What has emerged is a suite of new analytical tools for phylogenetic inference--species tree approaches. In contrast to traditional phylogenetic methods that are stymied by the idiosyncrasies of gene trees, approaches for estimating species trees explicitly take into account the cause of discord among loci and, in the process, provides a direct estimate of phylogenetic history (i.e. the history of species divergence, not divergence of specific loci). We illustrate the utility of species tree estimates with an analysis of a diverse group of feather mites, the pinnatus species group (genus Proctophyllodes). Discord among four sequenced nuclear loci is consistent with theoretical expectations, given the short time separating speciation events (as evident by short internodes relative to terminal branch lengths in the trees). Nevertheless, many of the relationships are well resolved in a Bayesian estimate of the species tree; the analysis also highlights ambiguous aspects of the phylogeny that require additional loci. The broad utility of species tree approaches is discussed, and specifically, their application to groups with high speciation rates--a history of diversification with particular prevalence in host/parasite systems where species interactions can drive rapid diversification.

Variation of properties of clayey minerals and associated phases about uranium deposits related to proterozoic discordances; Variation des proprietes des mineraux argileux et des phases associees autour des gisements d'uranium lies aux discordances Proterozoiques

Energy Technology Data Exchange (ETDEWEB)

Beaufort, D.; Patrier, P.; Laverret, E.; Gaboreau, St.; Billault, V. [HYDRASA, Universite de Poitiers-CNRS, 86 - Poitiers (France); Quirt, D. [AREVA Resources Canada AREVA Resources Canada Inc., Saskatoon, SK (Canada)

2009-07-01

The authors propose explanations for the clayey alteration which surrounds uranium deposits related to proterozoic discordances as it is noticed in Canada (Athabasca) and Australia (Kombolgie). The observed mineral sequences are interpreted as the product of an increasing interaction between infiltrated diagenetic acid and oxidising solutions on the one hand, and platform rocks on the other hand, at temperatures between 150 and 200 C. These interpretations are based on crystallographic and crystallochemical investigations

A new detection method for the K variant of butyrylcholinesterase based on PCR primer introduced restriction analysis (PCR-PIRA).

Science.gov (United States)

Shibuta, K; Abe, M; Suzuki, T

1994-01-01

The K variant of human butyrylcholinesterase is caused by a G/A transition in the butyrylcholinesterase gene, which neither creates nor destroys any restriction site. In an attempt to detect the K variant both simply and rapidly, we developed a two step method of "PCR primer introduced restriction analysis" (PCR-PIRA). The first step was used to introduce a new Fun4HI site into the normal allele for a screening test, while the second step was performed to create a new MaeIII site on the variant allele for a specific test. This method thus enabled us to distinguish clearly the K variant from the normal allele, and also showed that the frequency of the K variant allele is 0.164 in the Japanese population. Images PMID:7966197

Simple and complex dysembryoplastic neuroepithelial tumors (DNT) variants: clinical profile, MRI, and histopathology

Energy Technology Data Exchange (ETDEWEB)

Campos, Alexandre R.; Clusmann, Hans; Lehe, Marec von; Schramm, Johannes [University of Bonn Medical Center, Department of Neurosurgery, Bonn (Germany); Niehusmann, Pitt; Becker, Albert J. [University of Bonn Medical Center, Department of Neuropathology, Bonn (Germany); Urbach, Horst [University of Bonn Medical Center, Department of Radiology, Bonn (Germany)

2009-07-15

Dysembryoplastic neuroepithelial tumors (DNTs) are long-term epilepsy associated tumors subdivided into simple and complex variants. The purpose of this study was to relate different DNT components identified on magnetic resonance imaging (MRI) to histopathological features and to test the hypothesis that glial nodules as a histopathological feature of complex variants induce an occasional glioma misdiagnosis. Clinical, MRI, and histopathologic features of DNTs operated between 1988 and 2008 were reviewed. From a total of 61 DNTs, 48 simple and 13 complex variants were identified. Multiple or single pseudocysts in a cortical/subcortical location with small cysts sometimes separated from the tumor represented the glioneuronal element and were found in all DNTs. FLAIR hyperintense tissue was found between pseudocysts but - in neocortical DNTs - also circumscript in deeper tumor parts. Calcification and hemorrhages in this location occurred in four of 13 complex variants, and one of these patients was also the only one with tumor growth. Patients with complex variants had earlier seizure onset, and complex variants were more often located outside the temporal lobe. Although complex variants represented a higher diagnostic challenge, misdiagnoses also occurred in simple variants. One of five of DNTs showed contrast enhancement, which varied on follow-up studies with enhancing parts becoming nonenhancing and vice versa. The glioneuronal element is readily identifiable on MRI and should be considered to support the DNT diagnosis. Complex DNT variants have a different clinical profile and a more variable histopathological and MRI appearance; however, misdiagnoses occasionally also occur in simple variants. (orig.)

Frequent discordance between morphology and mitochondrial DNA in a species group of European water beetles (Coleoptera: Dytiscidae

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David T. Bilton

2017-03-01

Full Text Available The Hydroporus memnonius species group includes both widespread and range restricted diving beetle taxa in the western Palaearctic, some of which have been divided into a number of geographical subspecies. Of these, Hydroporus necopinatus is distributed in the far west of Europe, from central Spain to southern Britain, and has been split into three subspecies, occurring in Iberia (necopinatus sst., France (robertorum and England (roni respectively—the last of these being a rare example of an insect taxon apparently endemic to northern Europe. Here we explore inter-relationships between populations and subspecies of H. necopinatus and related members of the Hydroporus melanarius subgroup, using mitochondrial COI sequence data. We reveal widespread discordance between mitochondrial DNA sequence variation and morphology in areas where H. necopinatus and H. melanarius come into contact, consistent with historical introgressive hybridization between these taxa. In light of this discordance, the lack of clear genetic divergence between H. necopinatus subspecies, and the fact that both robertorum and roni are morphologically intermediate between H. necopinatus sstr. and H. melanarius, we suggest that these taxa may be of hybridogenic origin, rather than representing discrete evolutionary lineages.

BRCA1 and BRCA2 genetic testing—pitfalls and recommendations for managing variants of uncertain clinical significance

OpenAIRE

Eccles, D. M.; Mitchell, G.; Monteiro, A. N. A.; Schmutzler, R.; Couch, F. J.; Spurdle, A. B.; Gómez-García, E. B.

2015-01-01

BackgroundIncreasing use of BRCA1/2 testing for tailoring cancer treatment and extension of testing to tumour tissue for somatic mutation is moving BRCA1/2 mutation screening from a primarily prevention arena delivered by specialist genetic services into mainstream oncology practice. A considerable number of gene tests will identify rare variants where clinical significance cannot be inferred from sequence information alone. The proportion of Variants of Uncertain clinical Significance (VUS) ...

Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects.

Science.gov (United States)

Seo, Heewon; Kwon, Eun Jin; You, Young-Ah; Park, Yoomi; Min, Byung Joo; Yoo, Kyunghun; Hwang, Han-Sung; Kim, Ju Han; Kim, Young Ju

2018-01-24

Ritodrine is a commonly used tocolytic to prevent preterm labour. However, it can cause unexpected serious adverse reactions, such as pulmonary oedema, pulmonary congestion, and tachycardia. It is unknown whether such adverse reactions are associated with pharmacogenomic variants in patients. Whole-exome sequencing of 13 subjects with serious ritodrine-induced cardiac and pulmonary side-effects was performed to identify causal genes and variants. The deleterious impact of nonsynonymous substitutions for all genes was computed and compared between cases (n = 13) and controls (n = 30). The significant genes were annotated with Gene Ontology (GO), and the associated disease terms were categorised into four functional classes for functional enrichment tests. To assess the impact of distributed rare variants in cases with side effects, we carried out rare variant association tests with a minor allele frequency ≤ 1% using the burden test, the sequence Kernel association test (SKAT), and optimised SKAT. We identified 28 genes that showed significantly lower gene-wise deleteriousness scores in cases than in controls. Three of the identified genes-CYP1A1, CYP8B1, and SERPINA7-are pharmacokinetic genes. The significantly identified genes were categorized into four functional classes: ion binding, ATP binding, Ca 2+ -related, and ciliopathies-related. These four classes were significantly enriched with ciliary genes according to SYSCILIA Gold Standard genes (P side effects may be associated with deleterious genetic variants in ciliary and pharmacokinetic genes.

Genotype-Phenotype Characterization of Novel Variants in Six Italian Patients with Familial Exudative Vitreoretinopathy.

Science.gov (United States)

Iarossi, Giancarlo; Bertelli, Matteo; Maltese, Paolo Enrico; Gusson, Elena; Marchini, Giorgio; Bruson, Alice; Benedetti, Sabrina; Volpetti, Sabrina; Catena, Gino; Buzzonetti, Luca; Ziccardi, Lucia

2017-01-01

Familial exudative vitreoretinopathy (FEVR) is a complex disorder characterized by incomplete development of the retinal vasculature. Here, we report the results obtained on the spectrum of genetic variations and correlated phenotypes found in a cohort of Italian FEVR patients. Eight probands (age range 7-19 years) were assessed by genetic analysis and comprehensive age-appropriate ophthalmic examination. Genetic testing investigated the genes most widely associated in literature with FEVR: FZD4 , LRP5 , TSPAN12 , and NDP . Clinical and genetic evaluations were extended to relatives of probands positive to genetic testing. Six out of eight probands (75%) showed a genetic variation probably related to the phenotype. We identified four novel genetic variants, one variant already described in association with Norrie disease and one previously described linked to autosomal dominant FEVR. Pedigree analysis of patients led to the classification of four autosomal dominant cases of FEVR (caused by FZD4 and TSPAN12 variants) and two X-linked FEVR probands ( NDP variants). None of the patients showed variants in the LRP5 gene. This study represents the largest cohort study in Italian FEVR patients. Our findings are in agreement with the previous literature confirming that FEVR is a clinically and genetically heterogeneous retinal disorder, even when it manifests in the same family.

Genotype-Phenotype Characterization of Novel Variants in Six Italian Patients with Familial Exudative Vitreoretinopathy

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Giancarlo Iarossi

2017-01-01

Full Text Available Familial exudative vitreoretinopathy (FEVR is a complex disorder characterized by incomplete development of the retinal vasculature. Here, we report the results obtained on the spectrum of genetic variations and correlated phenotypes found in a cohort of Italian FEVR patients. Eight probands (age range 7–19 years were assessed by genetic analysis and comprehensive age-appropriate ophthalmic examination. Genetic testing investigated the genes most widely associated in literature with FEVR: FZD4, LRP5, TSPAN12, and NDP. Clinical and genetic evaluations were extended to relatives of probands positive to genetic testing. Six out of eight probands (75% showed a genetic variation probably related to the phenotype. We identified four novel genetic variants, one variant already described in association with Norrie disease and one previously described linked to autosomal dominant FEVR. Pedigree analysis of patients led to the classification of four autosomal dominant cases of FEVR (caused by FZD4 and TSPAN12 variants and two X-linked FEVR probands (NDP variants. None of the patients showed variants in the LRP5 gene. This study represents the largest cohort study in Italian FEVR patients. Our findings are in agreement with the previous literature confirming that FEVR is a clinically and genetically heterogeneous retinal disorder, even when it manifests in the same family.

Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with kiaa2022 pathogenic variants and review of the literature.

Science.gov (United States)

Lorenzo, Melissa; Stolte-Dijkstra, Irene; van Rheenen, Patrick; Smith, Ronald Garth; Scheers, Tom; Walia, Jagdeep S

2018-04-25

KIAA2022 is an X-linked intellectual disability (XLID) syndrome affecting males more severely than females. Few males with KIAA2022 variants and XLID have been reported. We present a clinical report of two unrelated males, with two nonsense KIAA2022 pathogenic variants, with profound intellectual disabilities, limited language development, strikingly similar autistic behavior, delay in motor milestones, and postnatal growth restriction. Patient 1, 19-years-old, has long ears, deeply set eyes with keratoconus, strabismus, a narrow forehead, anteverted nares, café-au-lait spots, macroglossia, thick vermilion of the upper and lower lips, and prognathism. He has gastroesophageal reflux, constipation with delayed rectosigmoid colonic transit time, difficulty regulating temperature, several musculoskeletal issues, and a history of one grand mal seizure. Patient 2, 10-years-old, has mild dysmorphic features, therapy resistant vomiting with diminished motility of the stomach, mild constipation, cortical visual impairment with intermittent strabismus, axial hypotonia, difficulty regulating temperature, and cutaneous mastocytosis. Genetic testing identified KIAA2022 variant c.652C > T(p.Arg218*) in Patient 1, and a novel nonsense de novo variant c.2707G > T(p.Glu903*) in Patient 2. We also summarized features of all reported males with KIAA2022 variants to date. This report not only adds knowledge of a novel pathogenic variant to the KIAA2022 variant database, but also likely extends the spectrum by describing novel dysmorphic features and medical conditions including macroglossia, café-au-lait spots, keratoconus, severe cutaneous mastocytosis, and motility problems of the GI tract, which may help physicians involved in the care of patients with this syndrome. Lastly, we describe the power of social media in bringing families with rare medical conditions together. © 2018 Wiley Periodicals, Inc.

Integrating functional data to prioritize causal variants in statistical fine-mapping studies.

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Gleb Kichaev

2014-10-01

Full Text Available Standard statistical approaches for prioritization of variants for functional testing in fine-mapping studies either use marginal association statistics or estimate posterior probabilities for variants to be causal under simplifying assumptions. Here, we present a probabilistic framework that integrates association strength with functional genomic annotation data to improve accuracy in selecting plausible causal variants for functional validation. A key feature of our approach is that it empirically estimates the contribution of each functional annotation to the trait of interest directly from summary association statistics while allowing for multiple causal variants at any risk locus. We devise efficient algorithms that estimate the parameters of our model across all risk loci to further increase performance. Using simulations starting from the 1000 Genomes data, we find that our framework consistently outperforms the current state-of-the-art fine-mapping methods, reducing the number of variants that need to be selected to capture 90% of the causal variants from an average of 13.3 to 10.4 SNPs per locus (as compared to the next-best performing strategy. Furthermore, we introduce a cost-to-benefit optimization framework for determining the number of variants to be followed up in functional assays and assess its performance using real and simulation data. We validate our findings using a large scale meta-analysis of four blood lipids traits and find that the relative probability for causality is increased for variants in exons and transcription start sites and decreased in repressed genomic regions at the risk loci of these traits. Using these highly predictive, trait-specific functional annotations, we estimate causality probabilities across all traits and variants, reducing the size of the 90% confidence set from an average of 17.5 to 13.5 variants per locus in this data.

Discordancia de peso al nacer: consecuencias y su perdurabilidad en el desarrollo psicológico del gemelo de menor peso intrapar (Intertwin birth weight discordance: its effects and their persistence in the psychological development of the lightest intrapair twin

Directory of Open Access Journals (Sweden)

Elena Escolano-Pérez

2015-08-01

Full Text Available More twins are being born with intrapair birth weight discordances. Discordance in birth weight is a risk factor that can affect the development of twins, especially that of the lightest twin. However, few studies have analysed the possible consequences of birth weight discordance on the lightest twin beyond possible neonatal obstetric problems. Thus,little is known about the consequences of birth weight discordance on the psychological development of such babies.This article reviews the literature and summarizes the effects of birth weight discordance on the psychological development of the lightest intrapair twins compared with their heavier twin siblings and the persistence of these effects during their lifetime. The literature shows that the lightest intrapair twins obtain lower scores than their siblings in cognitive, verbal, and psychomotor skills. They are also more likely to have traits associated with the development of hyperactivity. These differences persist from childhood to youth. There is no information about adulthood. In conclusion, birth weight discordance has marked effects on the psychological development of intrapair lower weight twins, both in relation to the affected dimensions and the persistence of these effects over time. Further research is needed on designing early preventative interventions that would optimize the development of these children. This proposal is of relevance, given that the optimal development of all children is the basis of a society in continuous progress.

Differentially Methylated DNA Regions in Monozygotic Twin Pairs Discordant for Rheumatoid Arthritis

DEFF Research Database (Denmark)

Svendsen, Anders J; Gervin, Kristina; Lyle, Robert

2016-01-01

: Smoking was significantly associated with hypomethylation of a DMR overlapping the promoter region of the RNF5 and the AGPAT1, which are implicated in inflammation and autoimmunity, whereas DMARD treatment induced hypermethylation of the same region. Additionally, the promotor region of both S100A6......OBJECTIVES: In an explorative epigenome-wide association study (EWAS) to search for gene independent, differentially methylated DNA positions and regions (DMRs) associated with rheumatoid arthritis (RA) by studying monozygotic (MZ) twin pairs discordant for RA. METHODS: Genomic DNA was isolated......: We identified several differentially methylated regions associated with RA, which may represent environmental effects or consequences of the disease and plausible biological pathways pertinent to the pathogenesis of RA....

Protein variants in Hiroshima and Nagasaki: tales of two cities.

Science.gov (United States)

Neel, J V; Satoh, C; Smouse, P; Asakawa, J; Takahashi, N; Goriki, K; Fujita, M; Kageoka, T; Hazama, R

1988-12-01

/drift/equilibrium theory. We suggest that this finding is primarily due to the relatively recent (in genetic time) agglomeration of previously separated tribal populations; efforts to test for agreement with the expectations of this theory by using data from modern cosmopolitan populations are exercises in futility. (10) All of these findings should characterize DNA variants in exons as more data become available, since the finding are the protein expression of such variants.

Rapid screening for targeted genetic variants via high-resolution melting curve analysis.

Science.gov (United States)

Chambliss, Allison B; Resnick, Molly; Petrides, Athena K; Clarke, William A; Marzinke, Mark A

2017-03-01

Current methods for the detection of single nucleotide polymorphisms (SNPs) associated with aberrant drug-metabolizing enzyme function are hindered by long turnaround times and specialized techniques and instrumentation. In this study, we describe the development and validation of a high-resolution melting (HRM) curve assay for the rapid screening of variant genotypes for targeted genetic polymorphisms in the cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A5. Sequence-specific primers were custom-designed to flank nine SNPs within the genetic regions of aforementioned drug metabolizing enzymes. PCR amplification was performed followed by amplicon denaturation by precise temperature ramping in order to distinguish genotypes by melting temperature (Tm). A standardized software algorithm was used to assign amplicons as 'reference' or 'variant' as compared to duplicate reference sequence DNA controls for each SNP. Intra-assay (n=5) precision of Tms for all SNPs was ≤0.19%, while inter-assay (n=20) precision ranged from 0.04% to 0.21%. When compared to a reference method of Sanger sequencing, the HRM assay produced no false negative results, and overcall frequency ranged from 0% to 26%, depending on the SNP. Furthermore, HRM genotyping displayed accuracy over input DNA concentrations ranging from 10 to 200 ng/μL. The presented assay provides a rapid method for the screening for genetic variants in targeted CYP450 regions with a result of 'reference' or 'variant' available within 2 h from receipt of extracted DNA. The method can serve as a screening approach to rapidly identify individuals with variant sequences who should be further investigated by reflexed confirmatory testing for aberrant cytochrome P450 enzymatic activity. Rapid knowledge of variant status may aid in the avoidance of adverse clinical events by allowing for dosing of normal metabolizer patients immediately while identifying the need to wait for confirmatory testing in those patients who are

Influence of HFE variants and cellular iron on monocyte chemoattractant protein-1

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Simmons Zachary

2009-02-01

Full Text Available Abstract Background Polymorphisms in the MHC class 1-like gene known as HFE have been proposed as genetic modifiers of neurodegenerative diseases that include neuroinflammation as part of the disease process. Variants of HFE are relatively common in the general population and are most commonly associated with iron overload, but can promote subclinical cellular iron loading even in the absence of clinically identified disease. The effects of the variants as well as the resulting cellular iron dyshomeostasis potentially impact a number of disease-associated pathways. We tested the hypothesis that the two most common HFE variants, H63D and C282Y, would affect cellular secretion of cytokines and trophic factors. Methods We screened a panel of cytokines and trophic factors using a multiplexed immunoassay in human neuroblastoma SH-SY5Y cells expressing different variants of HFE. The influence of cellular iron secretion on the potent chemokine monocyte chemoattractant protein-1 (MCP-1 was assessed using ferric ammonium citrate and the iron chelator, desferroxamine. Additionally, an antioxidant, Trolox, and an anti-inflammatory, minocycline, were tested for their effects on MCP-1 secretion in the presence of HFE variants. Results Expression of the HFE variants altered the labile iron pool in SH-SY5Y cells. Of the panel of cytokines and trophic factors analyzed, only the release of MCP-1 was affected by the HFE variants. We further examined the relationship between iron and MCP-1 and found MCP-1 secretion tightly associated with intracellular iron status. A potential direct effect of HFE is considered because, despite having similar levels of intracellular iron, the association between HFE genotype and MCP-1 expression was different for the H63D and C282Y HFE variants. Moreover, HFE genotype was a factor in the effect of minocycline, a multifaceted antibiotic used in treating a number of neurologic conditions associated with inflammation, on MCP-1

Weighting sequence variants based on their annotation increases power of whole-genome association studies

DEFF Research Database (Denmark)

Sveinbjornsson, Gardar; Albrechtsen, Anders; Zink, Florian

2016-01-01

The consensus approach to genome-wide association studies (GWAS) has been to assign equal prior probability of association to all sequence variants tested. However, some sequence variants, such as loss-of-function and missense variants, are more likely than others to affect protein function...... for the family-wise error rate (FWER), using as weights the enrichment of sequence annotations among association signals. We show that this weighted adjustment increases the power to detect association over the standard Bonferroni correction. We use the enrichment of associations by sequence annotation we have...

Variants of Moreau's sweeping process

International Nuclear Information System (INIS)

Siddiqi, A.H.; Manchanda, P.

2001-07-01

In this paper we prove the existence and uniqueness of two variants of Moreau's sweeping process -u'(t) is an element of Nc (t) (u(t)), where in one variant we replace u(t) by u'(t) in the right-hand side of the inclusion and in the second variant u'(t) and u(t) are respectively replaced by u''(t) and u'(t). (author)

Characterization of form variants of Xenorhabdus luminescens.

Science.gov (United States)

Gerritsen, L J; de Raay, G; Smits, P H

1992-01-01

From Xenorhabdus luminescens XE-87.3 four variants were isolated. One, which produced a red pigment and antibiotics, was luminescent, and could take up dye from culture media, was considered the primary form (XE-red). A pink-pigmented variant (XE-pink) differed from the primary form only in pigmentation and uptake of dye. Of the two other variants, one produced a yellow pigment and fewer antibiotics (XE-yellow), while the other did not produce a pigment or antibiotics (XE-white). Both were less luminescent, did not take up dye, and had small cell and colony sizes. These two variants were very unstable and shifted to the primary form after 3 to 5 days. It was not possible to separate the primary form and the white variant completely; subcultures of one colony always contained a few colonies of the other variant. The white variant was also found in several other X. luminescens strains. DNA fingerprints showed that all four variants are genetically identical and are therefore derivatives of the same parent. Protein patterns revealed a few differences among the four variants. None of the variants could be considered the secondary form. The pathogenicity of the variants decreased in the following order: XE-red, XE-pink, XE-yellow, and XE-white. The mechanism and function of this variability are discussed. Images PMID:1622273

Physiological responses of somaclonal variants of triploid bermudagrass (Cynodon transvaalensis x Cynodon dactylon) to drought stress.

Science.gov (United States)

Lu, Shaoyun; Chen, Chuanhao; Wang, Zhongcheng; Guo, Zhenfei; Li, Haihang

2009-03-01

Eight somaclonal variants with enhanced drought tolerance were isolated from regenerated plants of triploid bermudagrass (Cynodon dactylon x Cynodon transvaalensis cv., TifEagle). Three of them (10-17, 89-02, 117-08) with strong drought tolerance were selected for investigations of physiological responses to drought stress. Compared to the parent control, TifEagle, the somaclonal variants had higher relative water contents and relative growth, and lower ion leakages in the greenhouse tests, while no difference in evapotranspirational water losses and soil water contents was observed between the variants and TifEagle. The variants also had less leaf firing in the field tests under drought stress. Superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX) activities decreased gradually in responses to drought stress in all plants and exhibited negative correlations with ion leakage, indicating that the declined activities of these antioxidant enzymes were associated with drought injury in the triploid bermudagrass. However, CAT activities were significantly higher in all three variants than in TifEagle during drought stress. Two variants, 10-17 and 89-02, also had significantly higher APX activities than TifEagle before and during the first 4 days of drought treatments. These two lines also showed higher SOD activities after prolonged drought stress. Proline, total soluble sugars and sucrose were accumulated under drought stress in all plants and exhibited positive correlations with ion leakage. More proline and sugars were accumulated in TifEagle than in the variants. The results indicated that higher activities of the antioxidant enzymes in the variants during drought stress are associated with their increased drought tolerance.

Frequency of a FAS ligand gene variant associated with inherited feline autoimmune lymphoproliferative syndrome in British shorthair cats in New Zealand.

Science.gov (United States)

Aberdein, D; Munday, J S; Dittmer, K E; Heathcott, R W; Lyons, L A

2017-11-01

AIMS To determine the frequency of the FAS-ligand gene (FASLG) variant associated with feline autoimmune lymphoproliferative syndrome (FALPS) and the proportion of carriers of the variant in three British shorthair (BSH) breeding catteries in New Zealand. METHODS Buccal swabs were collected from all cats in two BSH breeding catteries from the South Island and one from the North Island of New Zealand. DNA was extracted and was tested for the presence of the FASLG variant using PCR. Cats with the FASLG variant were identified and the frequency of the FASLG variant allele calculated. Pedigree analysis was performed and inbreeding coefficients were calculated for cats with the FASLG variant. RESULTS Of 32 BSH cats successfully tested for the presence of the FASLG variant, one kitten (3%) was homozygous (FALPS-affected), and seven (22%) cats were heterozygous (carriers) for the FASLG variant allele, and 24 (75%) cats were homozygous for the wild type allele. The overall frequency of the FASLG variant allele in these 32 cats was 0.14. Cats carrying the FASLG variant were from all three breeding catteries sampled, including two catteries that had not previously reported cases of FALPS. Pedigree analysis revealed common ancestry of FALPS-affected and carrier cats within six generations, as well as frequent inbreeding, with inbreeding coefficients >0.12 for five cats with the FASLG variant. CONCLUSIONS AND CLINICAL RELEVANCE There was a high frequency of the FASLG variant allele (0.14) in this small sample of BSH cats, with 22% of healthy cats identified as carriers of the FASLG variant. For an inherited disease, lethal at a young age, in a small population in which inbreeding is common, these results are significant. To prevent future cases of disease and stop further spread of the FASLG variant allele within the BSH population in New Zealand, it is recommended that all BSH and BSH-cross cats be tested for the presence of the FASLG variant before mating. Cats identified as

Friends and social contexts as unshared environments: A discordant sibling analysis of obesity- and health-related behaviors in young adolescents

Science.gov (United States)

Objective. This study uses a weight-discordant sibling design to examine the relationships between best friend’s body mass index z-score (zBMI) and siblings’ zBMI and obesity-related health behaviors (energy intake, consumption of sugar-sweetened beverages [SSB], physical activity and sedentary time...

Preferência por discordância em casos de auto-depreciação: analisando conversas de pessoas com afasia

Directory of Open Access Journals (Sweden)

Lívia Miranda de Oliveira

2011-02-01

Full Text Available O objetivo deste trabalho é verificar se a organização da preferência nas conversas, focalizando a preferência por discordância em casos de auto-depreciação, apresentaria-se conforme a descrição de Pomerantz publicada em 1984 sob o título “Concordando e discordando de avaliações: algumas características dos formatos de turno preferidos/despreferidos”. Com tal intuito, foram analisadas conversas gravadas em audio e video, envolvendo pessoas com afasia, segundo a perspectiva da Análise da Conversa Etnometodológica. As análises realizadas neste estudo corroboram a tese de Pomerantz sobre a preferência por discordância em casos de auto-depreciação, chamando a atenção para o fato de que a proposta de organização da preferência da autora também procede em conversas que envolvem pessoas com afasia.

Random Plant Viral Variants Attain Temporal Advantages During Systemic Infections and in Turn Resist other Variants of the Same Virus.

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Zhang, Xiao-Feng; Guo, Jiangbo; Zhang, Xiuchun; Meulia, Tea; Paul, Pierce; Madden, Laurence V; Li, Dawei; Qu, Feng

2015-10-20

Infection of plants with viruses containing multiple variants frequently leads to dominance by a few random variants in the systemically infected leaves (SLs), for which a plausible explanation is lacking. We show here that SL dominance by a given viral variant is adequately explained by its fortuitous lead in systemic spread, coupled with its resistance to superinfection by other variants. We analyzed the fate of a multi-variant turnip crinkle virus (TCV) population in Arabidopsis and N. benthamiana plants. Both wild-type and RNA silencing-defective plants displayed a similar pattern of random dominance by a few variant genotypes, thus discounting a prominent role for RNA silencing. When introduced to plants sequentially as two subpopulations, a twelve-hour head-start was sufficient for the first set to dominate. Finally, SLs of TCV-infected plants became highly resistant to secondary invasions of another TCV variant. We propose that random distribution of variant foci on inoculated leaves allows different variants to lead systemic movement in different plants. The leading variants then colonize large areas of SLs, and resist the superinfection of lagging variants in the same areas. In conclusion, superinfection resistance is the primary driver of random enrichment of viral variants in systemically infected plants.

Novel Parvovirus and Related Variant in Human Plasma

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Fryer, Jacqueline F.; Kapoor, Amit; Minor, Philip D.; Delwart, Eric

2006-01-01

We report a novel parvovirus (PARV4) and related variants in pooled human plasma used in the manufacture of plasma-derived medical products. Viral DNA was detected by using highly selective polymerase chain reaction assays; 5% of pools tested positive, and amounts of DNA ranged from 106 copies/mL plasma. PMID:16494735

Semantic prioritization of novel causative genomic variants

KAUST Repository

Boudellioua, Imene

2017-04-17

Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

Semantic prioritization of novel causative genomic variants

KAUST Repository

Boudellioua, Imene; Mohamad Razali, Rozaimi; Kulmanov, Maxat; Hashish, Yasmeen; Bajic, Vladimir B.; Goncalves-Serra, Eva; Schoenmakers, Nadia; Gkoutos, Georgios V.; Schofield, Paul N.; Hoehndorf, Robert

2017-01-01

Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

Electrocardiogram voltage discordance: Interpretation of low QRS voltage only in the precordial leads.

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Kim, Diana H; Verdino, Ralph J

To define clinical correlates of low voltage isolated to precordial leads on the surface electrocardiogram (ECG). Low voltage (V) on the ECG is defined as QRS Vvoltage isolated to the precordial leads with normal limb lead voltages is unclear. Twelve-lead ECGs with QRS V>5mm in one or more limb leads and voltage was found in 256 of 150,000 ECGs (~0.2%). 50.4% of patients had discordant ECGs that correlated with classic etiologies, with a higher incidence of LV dilation in those with classic etiologies than those without. Low precordial voltage is associated with classic etiologies and LV dilation. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic determinants of LDL, lipoprotein(a), triglyceride-rich lipoproteins and HDL: concordance and discordance with cardiovascular disease risk

DEFF Research Database (Denmark)

Nordestgaard, Børge G; Tybjærg-Hansen, Anne

2011-01-01

To evaluate whether new and known genetic determinants of plasma levels of LDL cholesterol, lipoprotein(a), triglyceride-rich lipoproteins, and HDL cholesterol associate with the risk of cardiovascular disease expected from the effect on lipoprotein levels. Concordance or discordance...... of such genetic determinants with cardiovascular disease risk will either favor or disfavor that these lipoproteins are causally related to cardiovascular disease....

Functional non-synonymous variants of ABCG2 and gout risk.

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Stiburkova, Blanka; Pavelcova, Katerina; Zavada, Jakub; Petru, Lenka; Simek, Pavel; Cepek, Pavel; Pavlikova, Marketa; Matsuo, Hirotaka; Merriman, Tony R; Pavelka, Karel

2017-11-01

Common dysfunctional variants of ATP binding cassette subfamily G member 2 (Junior blood group) (ABCG2), a high-capacity urate transporter gene, that result in decreased urate excretion are major causes of hyperuricemia and gout. In the present study, our objective was to determine the frequency and effect on gout of common and rare non-synonymous and other functional allelic variants in the ABCG2 gene. The main cohort recruited from the Czech Republic consisted of 145 gout patients; 115 normouricaemic controls were used for comparison. We amplified, directly sequenced and analysed 15 ABCG2 exons. The associations between genetic variants and clinical phenotype were analysed using the t-test, Fisher's exact test and a logistic and linear regression approach. Data from a New Zealand Polynesian sample set and the UK Biobank were included for the p.V12M analysis. In the ABCG2 gene, 18 intronic (one dysfunctional splicing) and 11 exonic variants were detected: 9 were non-synonymous (2 common, 7 rare including 1 novel), namely p.V12M, p.Q141K, p.R147W, p.T153M, p.F373C, p.T434M, p.S476P, p.D620N and p.K360del. The p.Q141K (rs2231142) variant had a significantly higher minor allele frequency (0.23) in the gout patients compared with the European-origin population (0.09) and was significantly more common among gout patients than among normouricaemic controls (odds ratio = 3.26, P gout (42 vs 48 years, P = 0.0143) and a greater likelihood of a familial history of gout (41% vs 27%, odds ratio = 1.96, P = 0.053). In a meta-analysis p.V12M exerted a protective effect from gout (P gout. Non-synonymous allelic variants of ABCG2 had a significant effect on earlier onset of gout and the presence of a familial gout history. ABCG2 should thus be considered a common and significant risk factor for gout. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Construction of Nef-positive doxycycline-dependent HIV-1 variants using bicistronic expression elements

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Velden, Yme U. van der; Kleibeuker, Wendy; Harwig, Alex; Klaver, Bep; Siteur-van Rijnstra, Esther; Frankin, Esmay; Berkhout, Ben; Das, Atze T., E-mail: a.t.das@amc.uva.nl

2016-01-15

Conditionally replicating HIV-1 variants that can be switched on and off at will are attractive tools for HIV research. We previously developed a genetically modified HIV-1 variant that replicates exclusively when doxycycline (dox) is administered. The nef gene in this HIV-rtTA variant was replaced with the gene encoding the dox-dependent rtTA transcriptional activator. Because loss of Nef expression compromises virus replication in primary cells and precludes studies on Nef function, we tested different approaches to restore Nef production in HIV-rtTA. Strategies that involved translation via an EMCV or synthetic internal ribosome entry site (IRES) failed because these elements were incompatible with efficient virus replication. Fusion protein approaches with the FMDV 2A peptide and human ubiquitin were successful and resulted in genetically-stable Nef-expressing HIV-rtTA strains that replicate more efficiently in primary T-cells and human immune system (HIS) mice than Nef-deficient variants, thus confirming the positive effect of Nef on in vivo virus replication. - Highlights: • Different approaches to encode additional proteins in the HIV-1 genome were tested. • IRES translation elements are incompatible with efficient HIV-1 replication. • Ubiquitin and 2A fusion protein approaches allow efficient HIV-1 replication. • Doxycycline-controlled HIV-1 variants that encode all viral proteins were developed. • Nef stimulates HIV-rtTA replication in primary cells and human immune system mice.

Influence of population diversity on neurovirulence potential of plaque purified L-Zagreb variants.

Science.gov (United States)

Ivancic-Jelecki, Jelena; Forcic, Dubravko; Jagusic, Maja; Kosutic-Gulija, Tanja; Mazuran, Renata; Balija, Maja Lang; Isakov, Ofer; Shomron, Noam

2016-04-29

Despite continuing research efforts, determinants of mumps virus virulence are still largely unknown. One of consequences of this is difficulty in striking a balance between efficacy and safety of live attenuated mumps vaccines. Among mumps vaccine strains associated with occurrence of postvaccinal aseptic meningitis is L-Zagreb, developed by further attenuation of vaccine strain L-3. Starting from an archived L-Zagreb sample with suboptimal neuroattenuation score, we isolated different viral variants and compared their genetic and phenotypic properties, in investigation of neurovirulence markers. Six different L-Zagreb variants were isolated by plaque purification. Their neurovirulent status was determined by rat-based neurovirulence test; population structure was determined by deep sequencing. We isolated one well neuroattenuated viral variant, two marginally neuroattenuated, and three insufficiently neuroattenuated. No genetic markers of neurovirulence could be identified. None of variants had detectable amounts of defective interfering particles. Two characteristics set insufficiently neuroattenuated variants apart from less-neurovirulent ones: elevated variability level in regions 1293-3314, 5363-7773 and 9382-11657, and/or elevated number of mutations present in frequencies ≥ 1%. The most neurovirulent variants possessed both of these features. Distinctive heterogeneity profiles were obtained for insufficiently neuroattenuated L-Zagreb variants. No markers that would discriminate between marginally and well neuroattenuated variants were identified. The findings of this study may serve as a guideline during development of an improved L3/L-Zagreb vaccine strain. Copyright © 2016 Elsevier Ltd. All rights reserved.

Novel genetic variants in miR-191 gene and familial ovarian cancer

International Nuclear Information System (INIS)

Shen, Jie; DiCioccio, Richard; Odunsi, Kunle; Lele, Shashikant B; Zhao, Hua

2010-01-01

Half of the familial aggregation of ovarian cancer can't be explained by any known risk genes, suggesting the existence of other genetic risk factors. Some of these unknown factors may not be traditional protein encoding genes. MicroRNA (miRNA) plays a critical role in tumorigenesis, but it is still unknown if variants in miRNA genes lead to predisposition to cancer. Considering the fact that miRNA regulates a number of tumor suppressor genes (TSGs) and oncogenes, genetic variations in miRNA genes could affect the levels of expression of TSGs or oncogenes and, thereby, cancer risk. To test this hypothesis in familial ovarian cancer, we screened for genetic variants in thirty selected miRNA genes, which are predicted to regulate key ovarian cancer genes and are reported to be misexpressed in ovarian tumor tissues, in eighty-three patients with familial ovarian cancer. All of the patients are non-carriers of any known BRCA1/2 or mismatch repair (MMR) gene mutations. Seven novel genetic variants were observed in four primary or precursor miRNA genes. Among them, three rare variants were found in the precursor or primary precursor of the miR-191 gene. In functional assays, the one variant located in the precursor of miR-191 resulted in conformational changes in the predicted secondary structures, and consequently altered the expression of mature miR-191. In further analysis, we found that this particular variant exists in five family members who had ovarian cancer. Our findings suggest that there are novel genetic variants in miRNA genes, and those certain genetic variants in miRNA genes can affect the expression of mature miRNAs and, consequently, might alter the regulation of TSGs or oncogenes. Additionally, the variant might be potentially associated with the development of familial ovarian cancer

[The phonological variant of primary progressive aphasia, a single case study].

Science.gov (United States)

Diesfeldt, H F A

2011-04-01

Primary progressive aphasia (PPA) is a neurodegenerative syndrome characterized by an insidious onset and gradual progression of deficits that can involve any aspect of language, including word finding, object naming, fluency, syntax, phonology and word comprehension. The initial symptoms occur in the absence of major deficits in other cognitive domains, including episodic memory, visuospatial abilities and visuoconstruction. According to recent diagnostic guidelines, PPA is typically divided into three variants: nonfluent variant PPA (also termed progressive nonfluent aphasia), semantic variant PPA (also termed semantic dementia) and logopenic/phonological variant PPA (also termed logopenic progressive aphasia). The paper describes a 79-yr old man, who presented with normal motor speech and production rate, impaired single word retrieval and phonemic errors in spontaneous speech and confrontational naming. Confrontation naming was strongly affected by lexical frequency. He was impaired on repetition of sentences and phrases. Reading was intact for regularly spelled words but not for irregular words (surface dyslexia). Comprehension was spared at the single word level, but impaired for complex sentences. He performed within the normal range on the Dutch equivalent of the Pyramids and Palm Trees (PPT) Pictures Test, indicating that semantic processing was preserved. There was, however, a slight deficiency on the PPT Words Test, which appeals to semantic knowledge of verbal associations. His core deficit was interpreted as an inability to retrieve stored lexical-phonological information for spoken word production in spontaneous speech, confrontation naming, repetition and reading aloud.

Swine Influenza/Variant Influenza Viruses

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... Address What's this? Submit What's this? Submit Button Influenza Types Seasonal Avian Swine Variant Pandemic Other Information on Swine Influenza/Variant Influenza Virus Language: English (US) Español Recommend ...

Northern Bobwhite (Colinus virginianus Mitochondrial Population Genomics Reveals Structure, Divergence, and Evidence for Heteroplasmy.

Directory of Open Access Journals (Sweden)

Yvette A Halley

Full Text Available Herein, we evaluated the concordance of population inferences and conclusions resulting from the analysis of short mitochondrial fragments (i.e., partial or complete D-Loop nucleotide sequences versus complete mitogenome sequences for 53 bobwhites representing six ecoregions across TX and OK (USA. Median joining (MJ haplotype networks demonstrated that analyses performed using small mitochondrial fragments were insufficient for estimating the true (i.e., complete mitogenome haplotype structure, corresponding levels of divergence, and maternal population history of our samples. Notably, discordant demographic inferences were observed when mismatch distributions of partial (i.e., partial D-Loop versus complete mitogenome sequences were compared, with the reduction in mitochondrial genomic information content observed to encourage spurious inferences in our samples. A probabilistic approach to variant prediction for the complete bobwhite mitogenomes revealed 344 segregating sites corresponding to 347 total mutations, including 49 putative nonsynonymous single nucleotide variants (SNVs distributed across 12 protein coding genes. Evidence of gross heteroplasmy was observed for 13 bobwhites, with 10 of the 13 heteroplasmies involving one moderate to high frequency SNV. Haplotype network and phylogenetic analyses for the complete bobwhite mitogenome sequences revealed two divergent maternal lineages (dXY = 0.00731; FST = 0.849; P < 0.05, thereby supporting the potential for two putative subspecies. However, the diverged lineage (n = 103 variants almost exclusively involved bobwhites geographically classified as Colinus virginianus texanus, which is discordant with the expectations of previous geographic subspecies designations. Tests of adaptive evolution for functional divergence (MKT, frequency distribution tests (D, FS and phylogenetic analyses (RAxML provide no evidence for positive selection or hybridization with the sympatric scaled quail

Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder.

Science.gov (United States)

Kasahara, Takaoki; Ishiwata, Mizuho; Kakiuchi, Chihiro; Fuke, Satoshi; Iwata, Nakao; Ozaki, Norio; Kunugi, Hiroshi; Minabe, Yoshio; Nakamura, Kazuhiko; Iwata, Yasuhide; Fujii, Kumiko; Kanba, Shigenobu; Ujike, Hiroshi; Kusumi, Ichiro; Kataoka, Muneko; Matoba, Nana; Takata, Atsushi; Iwamoto, Kazuya; Yoshikawa, Takeo; Kato, Tadafumi

2017-08-01

Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease. © 2016 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.

Maternal feeding practices and fussy eating in toddlerhood: a discordant twin analysis.

Science.gov (United States)

Harris, Holly A; Fildes, Alison; Mallan, Kimberley M; Llewellyn, Clare H

2016-07-13

Parental feeding practices are thought to play a causal role in shaping a child's fussiness; however, a child-responsive model suggests that feeding practices may develop in response to a child's emerging appetitive characteristics. We used a novel twin study design to test the hypothesis that mothers vary their feeding practices for twin children who differ in their 'food fussiness', in support of a child-responsive model. Participants were mothers and their 16 month old twin children (n = 2026) from Gemini, a British twin birth cohort of children born in 2007. Standardized psychometric measures of maternal 'pressure to eat', 'restriction' and 'instrumental feeding', as well as child 'food fussiness', were completed by mothers. Within-family analyses examined if twin-pair differences in 'food fussiness' were associated with differences in feeding practices using linear regression models. In a subset of twins (n = 247 pairs) who were the most discordant (highest quartile) on 'food fussiness' (difference score ≥ .50), Paired Samples T-test were used to explore the magnitude of differences in feeding practices between twins. Between-family analyses used Complex Samples General Linear Models to examine associations between feeding practices and 'food fussiness'. Within-pair differences in 'food fussiness' were associated with differential 'pressure to eat' and 'instrumental feeding' (ps feeding' were positively associated with 'food fussiness', while 'restriction' was negatively associated with 'food fussiness' (ps feeding practices according to their perceptions of their toddler's emerging fussy eating behavior. Specifically, the fussier toddler is pressured more than their less fussy co-twin, and is more likely to be offered food rewards. Guiding parents on how to respond to fussy eating may be an important aspect of promoting feeding practices that encourage food acceptance.

Beta-glucosidase variants and polynucleotides encoding same

Science.gov (United States)

Wogulis, Mark; Harris, Paul; Osborn, David

2017-06-27

The present invention relates to beta-glucosidase variants, e.g. beta-glucosidase variants of a parent Family GH3A beta-glucosidase from Aspergillus fumigatus. The present invention also relates to polynucleotides encoding the beta-glucosidase variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the beta-glucosidase variants.

Matrix metalloproteinase-2 gene variants and abdominal aortic aneurysm.

Science.gov (United States)

Smallwood, L; Warrington, N; Allcock, R; van Bockxmeer, F; Palmer, L J; Iacopetta, B; Golledge, J; Norman, P E

2009-08-01

To investigate associations between two polymorphisms of the matrix metalloproteinase-2 gene (MMP2) and the incidence and progression of abdominal aortic aneurysm (AAA). Cases and controls were recruited from a trial of screening for AAAs. The association between two variants of MMP2 (-1360C>T, and +649C>T) in men with AAA (n=678) and in controls (n=659) was examined using multivariate analyses. The association with AAA expansion (n=638) was also assessed. In multivariate analyses with adjustments for multiple testing, no association between either SNP and AAA presence or expansion was detected. MMP2 -1360C>T and +649C>T variants are not risk factors for AAA.

Mesotrypsin Signature Mutation in a Chymotrypsin C (CTRC) Variant Associated with Chronic Pancreatitis.

Science.gov (United States)

Szabó, András; Ludwig, Maren; Hegyi, Eszter; Szépeová, Renata; Witt, Heiko; Sahin-Tóth, Miklós

2015-07-10

Human chymotrypsin C (CTRC) protects against pancreatitis by degrading trypsinogen and thereby curtailing harmful intra-pancreatic trypsinogen activation. Loss-of-function mutations in CTRC increase the risk for chronic pancreatitis. Here we describe functional analysis of eight previously uncharacterized natural CTRC variants tested for potential defects in secretion, proteolytic stability, and catalytic activity. We found that all variants were secreted from transfected cells normally, and none suffered proteolytic degradation by trypsin. Five variants had normal enzymatic activity, whereas variant p.R29Q was catalytically inactive due to loss of activation by trypsin and variant p.S239C exhibited impaired activity possibly caused by disulfide mispairing. Surprisingly, variant p.G214R had increased activity on a small chromogenic peptide substrate but was markedly defective in cleaving bovine β-casein or the natural CTRC substrates human cationic trypsinogen and procarboxypeptidase A1. Mutation p.G214R is analogous to the evolutionary mutation in human mesotrypsin, which rendered this trypsin isoform resistant to proteinaceous inhibitors and conferred its ability to cleave these inhibitors. Similarly to the mesotrypsin phenotype, CTRC variant p.G214R was inhibited poorly by eglin C, ecotin, or a CTRC-specific variant of SGPI-2, and it readily cleaved the reactive-site peptide bonds in eglin C and ecotin. We conclude that CTRC variants p.R29Q, p.G214R, and p.S239C are risk factors for chronic pancreatitis. Furthermore, the mesotrypsin-like CTRC variant highlights how the same natural mutation in homologous pancreatic serine proteases can evolve a new physiological role or lead to pathology, determined by the biological context of protease function. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Two variants of the C-reactive protein gene are associated with risk of pre-eclampsia in an American Indian population.

Directory of Open Access Journals (Sweden)

Lyle G Best

Full Text Available The etiology of pre-eclampsia (PE is unknown; but it is accepted that normal pregnancy represents a distinctive challenge to the maternal immune system. C-reactive protein is a prominent component of the innate immune system; and we previously reported an association between PE and the CRP polymorphism, rs1205. Our aim was to explore the effects of additional CRP variants. The IBC (Cardiochip genotyping microarray focuses on candidate genes and pathways related to the pathophysiology of cardiovascular disease.This study recruited 140 cases of PE and 270 matched controls, of which 95 cases met criteria as severe PE, from an American Indian community. IBC array genotypes from 10 suitable CRP SNPs were analyzed. A replication sample of 178 cases and 427 controls of European ancestry was also genotyped.A nominally significant difference (p value <0.05 was seen in the distribution of discordant matched pairs for rs3093068; and Bonferroni corrected differences (P<0.005 were seen for rs876538, rs2794521, and rs3091244. Univariate conditional logistic regression odds ratios (OR were nominally significant for rs3093068 and rs876538 models only. Multivariate logistic models with adjustment for mother's age, nulliparity and BMI attenuated the effect (OR 1.58, P = 0.066, 95% CI 0.97-2.58 for rs876538 and (OR 2.59, P = 0.050, 95% CI 1.00-6.68 for rs3093068. An additive risk score of the above two risk genotypes shows a multivariate adjusted OR of 2.04 (P = 0.013, 95% CI 1.16-3.56. The replication sample also demonstrated significant association between PE and the rs876538 allele (OR = 1.55, P = 0.01, 95% CI 2.16-1.10. We also show putative functionality for the rs876538 and rs3093068 CRP variants.The CRP variants, rs876538 and rs3093068, previously associated with other cardiovascular disease phenotypes, show suggestive association with PE in this American Indian population, further supporting a possible role for CRP in PE.

Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

Directory of Open Access Journals (Sweden)

Douglas R Smith

Full Text Available Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1, were found to be significantly associated with pain sensitivity (especially migraine, sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls without such CNR1 variants. Similarly, heterozygous rare variants in DAGLA, which encodes diacylglycerol lipase alpha, were found to be significantly associated with seizures and neurodevelopmental disorders, including autism and abnormalities of brain morphology, compared to controls. Rare variants in MGLL, FAAH and CNR2 were not associated with any neurological phenotypes in the patients tested. Diacylglycerol lipase alpha synthesizes the endocannabinoid 2-AG in the brain, which interacts with CB1 receptors. The phenotypes associated with rare CNR1 variants are reminiscent of those implicated in the theory of clinical endocannabinoid deficiency syndrome. The severe phenotypes associated with rare DAGLA variants underscore the critical role of rapid 2-AG synthesis and the endocannabinoid system in regulating neurological function and development. Mapping of the variants to the 3D structure of the type 1 cannabinoid receptor, or primary structure of diacylglycerol lipase alpha, reveals clustering of variants in certain structural regions and is consistent with impacts to function.

DaMold: A data-mining platform for variant annotation and visualization in molecular diagnostics research.

Science.gov (United States)

Pandey, Ram Vinay; Pabinger, Stephan; Kriegner, Albert; Weinhäusel, Andreas

2017-07-01

Next-generation sequencing (NGS) has become a powerful and efficient tool for routine mutation screening in clinical research. As each NGS test yields hundreds of variants, the current challenge is to meaningfully interpret the data and select potential candidates. Analyzing each variant while manually investigating several relevant databases to collect specific information is a cumbersome and time-consuming process, and it requires expertise and familiarity with these databases. Thus, a tool that can seamlessly annotate variants with clinically relevant databases under one common interface would be of great help for variant annotation, cross-referencing, and visualization. This tool would allow variants to be processed in an automated and high-throughput manner and facilitate the investigation of variants in several genome browsers. Several analysis tools are available for raw sequencing-read processing and variant identification, but an automated variant filtering, annotation, cross-referencing, and visualization tool is still lacking. To fulfill these requirements, we developed DaMold, a Web-based, user-friendly tool that can filter and annotate variants and can access and compile information from 37 resources. It is easy to use, provides flexible input options, and accepts variants from NGS and Sanger sequencing as well as hotspots in VCF and BED formats. DaMold is available as an online application at http://damold.platomics.com/index.html, and as a Docker container and virtual machine at https://sourceforge.net/projects/damold/. © 2017 Wiley Periodicals, Inc.

Congenital anomalies and normal skeletal variants

International Nuclear Information System (INIS)

Guebert, G.M.; Yochum, T.R.; Rowe, L.J.

1987-01-01

Congenital anomalies and normal skeletal variants are a common occurrence in clinical practice. In this chapter a large number of skeletal anomalies of the spine and pelvis are reviewed. Some of the more common skeletal anomalies of the extremities are also presented. The second section of this chapter deals with normal skeletal variants. Some of these variants may simulate certain disease processes. In some instances there are no clear-cut distinctions between skeletal variants and anomalies; therefore, there may be some overlap of material. The congenital anomalies are presented initially with accompanying text, photos, and references, beginning with the skull and proceeding caudally through the spine to then include the pelvis and extremities. The normal skeletal variants section is presented in an anatomical atlas format without text or references

Discordancy or template-based recognition? Dissecting the cognitive basis of the rejection of foreign eggs in hosts of avian brood parasites

NARCIS (Netherlands)

Moskat, Csaba; Ban, Miklos; Szekely, Tamas; Komdeur, Jan; Lucassen, Rim W. G.; van Boheemen, Lotte A.; Hauber, Mark E.

2010-01-01

Many avian hosts have evolved antiparasite defence mechanisms, including egg rejection, to reduce the costs of brood parasitism. The two main alternative cognitive mechanisms of egg discrimination are thought to be based on the perceived discordancy of eggs in a clutch or the use of recognition

Minority stressors, rumination, and psychological distress in monozygotic twins discordant for sexual minority status.

Science.gov (United States)

Timmins, Liam; Rimes, Katharine A; Rahman, Qazi

2017-11-07

Lesbian, gay, and bisexual (LGB) individuals report higher levels of depression and anxiety than heterosexual people. Genetic factors may be a 'common cause' of sexual minority status and psychological distress. Alternatively, these may be correlated because of non-genetic environmental factors (e.g. minority stressors). This study investigated minority stressors and distress in monozygotic twins discordant for sexual minority status. This design provides a test of the role of non-shared environmental factors while minimizing differences due to genetics. Thirty-eight twin pairs in which one was heterosexual and the other was LGB completed a survey. Differences between twin pairs in minority stressors, rumination, psychological distress, and gender non-conformity were examined. Associations between these variables were also tested. Although there were no significant group differences for distress, LGB twins had higher rumination, a vulnerability factor for distress, than heterosexual co-twins. LGB twins also had higher scores than heterosexual co-twins on expectations of rejection, active concealment, self-stigma, prejudice events, childhood gender non-conformity, and lower scores on sexual orientation disclosure. Differences between twin pairs in rumination were positively associated with differences in acceptance concerns and self-stigma. Finally, self-stigma was positively associated with rumination in the full sample of heterosexual co-twins and microaggressions were positively associated with rumination when looking at exclusively heterosexual co-twins. These results support environmental factors as a causal explanation for disparities in rumination between LGB and heterosexual individuals. These factors likely include minority stressors. Rumination may also be associated with minority stressors in heterosexual MZ co-twins of LGB individuals.

Couple-level Motivations to Test for HIV for Gay Men in Relationships

Science.gov (United States)

Beougher, Sean C.; Bircher, Anja E.; Chakravarty, Deepalika; Darbes, Lynae A.; Gómez Mandic, Carmen; Neilands, Torsten B.; Garcia, Carla C.; Hoff, Colleen C.

2015-01-01

Previous studies of HIV testing among gay men describe the motivations, facilitators and barriers, behaviors, and demographic characteristics of individuals who test. What little research focuses on HIV testing among gay men in relationships shows that they do not test regularly or, in some cases, at all – their motivations to test have not been investigated. With so little data on HIV testing for this population, and the continued privileging of individually-focused approaches, gay men in relationships fall into a blind spot of research and prevention efforts. This study examined motivations to test for HIV using qualitative data from both partners in 20 gay male couples. Analysis revealed that the partners’ motivations were either event-related (e.g., participants testing the beginning of their relationship or HIV-negative participants in an HIV-discordant relationship testing after risky episode with their discordant primary partner) or partner-related (e.g., participants testing in response to a request or suggestion to test from their primary partner or participants testing out of concern for their primary partner’s health and wellbeing). These data provide insight into relationship-oriented motivations to test for HIV for gay men in relationships and, in doing so, demonstrates their commitment to their primary partner and relationship. These motivations can be leveraged to increase HIV testing among gay men in relationships, a population that tests less often than single gay men, yet, until recently, has been underserved by prevention efforts. PMID:25550145

Discordant introgression in a rapidly expanding hybrid swarm

Science.gov (United States)

Ward, Jessica L.; Blum, Mike J.; Walters, David M.; Porter, Brady A.; Burkhead, Noel; Freeman, Byron

2012-01-01

The erosion of species boundaries can involve rapid evolutionary change. Consequently, many aspects of the process remain poorly understood, including the formation, expansion, and evolution of hybrid swarms. Biological invasions involving hybridization present exceptional opportunities to study the erosion of species boundaries because timelines of interactions and outcomes are frequently well known. Here, we examined clinal variation across codominant and maternally inherited genetic markers as well as phenotypic traits to characterize the expansion and evolution of a hybrid swarm between native Cyprinella venusta and invasive Cyprinella lutrensis minnows. Discordant introgression of phenotype, microsatellite multilocus genotype, and mtDNA haplotype indicates that the observable expansion of the C. venusta x C. lutrensis hybrid swarm is a false invasion front. Both parental and hybrid individuals closely resembling C. lutrensis are numerically dominant in the expansion wake, indicating that the non-native parental phenotype may be selectively favored. These findings show that cryptic introgression can extend beyond the phenotypic boundaries of hybrid swarms and that hybrid swarms likely expand more rapidly than can be documented from phenotypic variation alone. Similarly, dominance of a single parental phenotype following an introduction event may lead to instances of species erosion being mistaken for species displacement without hybridization.

Advantage of using allele-specific copy numbers when testing for association in regions with common copy number variants.

Directory of Open Access Journals (Sweden)

Gaëlle Marenne

Full Text Available Copy number variants (CNV can be called from SNP-arrays; however, few studies have attempted to combine both CNV and SNP calls to test for association with complex diseases. Even when SNPs are located within CNVs, two separate association analyses are necessary, to compare the distribution of bi-allelic genotypes in cases and controls (referred to as SNP-only strategy and the number of copies of a region (referred to as CNV-only strategy. However, when disease susceptibility is actually associated with allele specific copy-number states, the two strategies may not yield comparable results, raising a series of questions about the optimal analytical approach. We performed simulations of the performance of association testing under different scenarios that varied genotype frequencies and inheritance models. We show that the SNP-only strategy lacks power under most scenarios when the SNP is located within a CNV; frequently it is excluded from analysis as it does not pass quality control metrics either because of an increased rate of missing calls or a departure from fitness for Hardy-Weinberg proportion. The CNV-only strategy also lacks power because the association testing depends on the allele which copy number varies. The combined strategy performs well in most of the scenarios. Hence, we advocate the use of this combined strategy when testing for association with SNPs located within CNVs.

Annotating pathogenic non-coding variants in genic regions.

Science.gov (United States)

Gelfman, Sahar; Wang, Quanli; McSweeney, K Melodi; Ren, Zhong; La Carpia, Francesca; Halvorsen, Matt; Schoch, Kelly; Ratzon, Fanni; Heinzen, Erin L; Boland, Michael J; Petrovski, Slavé; Goldstein, David B

2017-08-09

Identifying the underlying causes of disease requires accurate interpretation of genetic variants. Current methods ineffectively capture pathogenic non-coding variants in genic regions, resulting in overlooking synonymous and intronic variants when searching for disease risk. Here we present the Transcript-inferred Pathogenicity (TraP) score, which uses sequence context alterations to reliably identify non-coding variation that causes disease. High TraP scores single out extremely rare variants with lower minor allele frequencies than missense variants. TraP accurately distinguishes known pathogenic and benign variants in synonymous (AUC = 0.88) and intronic (AUC = 0.83) public datasets, dismissing benign variants with exceptionally high specificity. TraP analysis of 843 exomes from epilepsy family trios identifies synonymous variants in known epilepsy genes, thus pinpointing risk factors of disease from non-coding sequence data. TraP outperforms leading methods in identifying non-coding variants that are pathogenic and is therefore a valuable tool for use in gene discovery and the interpretation of personal genomes.While non-coding synonymous and intronic variants are often not under strong selective constraint, they can be pathogenic through affecting splicing or transcription. Here, the authors develop a score that uses sequence context alterations to predict pathogenicity of synonymous and non-coding genetic variants, and provide a web server of pre-computed scores.

Behavioral versus genetic correlates of lipoproteins and adiposity in identical twins discordant for exercise.

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Williams, Paul T; Blanche, Patricia J; Krauss, Ronald M

2005-07-19

Lipoprotein and weight differences between vigorously active and sedentary monozygotic (MZ) twins were used to (1) estimate the effects of training while controlling for genotype and (2) estimate genetic concordance (ie, similarity) in the presence of divergent lifestyles. Thirty-five pairs of MZ twins (25 male, 10 female) were recruited nationally who were discordant for vigorous exercise (running distances differed by > or =40 km in male and > or =32 km in female twins). The active twins ran an average (mean+/-SD) of 63.0+/-20.4 km/wk, whereas the mostly sedentary twins averaged 7.0+/-13.5 km/wk. The active twins had significantly lower body mass index (difference+/-SE, -2.12+/-0.57 kg/m2, P=0.0007) and significantly higher HDL cholesterol (0.14+/-0.04 mmol/L, P=0.004), HDL2 (2.71+/-1.04 U, P=0.01), and apolipoprotein (apo) A-I (0.10+/-0.03 g/L, P=0.004). Despite the difference in lifestyle, when adjusted for sex, the correlations between the discordant MZ twin pairs were significant (PHDL cholesterol (r=0.69), apoA-I (r=0.58), and HDL2 (r=0.67). There was no significant MZ twin correlation for body mass index (r=0.17). None of the active twins having an overweight twin were themselves overweight. Behavior (vigorous exercise) may reduce genetic influences on body mass index. In contrast, genetics (or shared environment) substantially influences HDL cholesterol and HDL subclasses, even in the presence of extreme behavioral differences. There may be greater individual control over moderate degrees of obesity, whereas low HDL cholesterol may be largely predetermined and less effectively treated by vigorous exercise.

Pattern of brain activation during social cognitive tasks is related to social competence in siblings discordant for schizophrenia.

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Villarreal, Mirta F; Drucaroff, Lucas J; Goldschmidt, Micaela G; de Achával, Delfina; Costanzo, Elsa Y; Castro, Mariana N; Ladrón-de-Guevara, M Soledad; Busatto Filho, Geraldo; Nemeroff, Charles B; Guinjoan, Salvador M

2014-09-01

Measures of social competence are closely related to actual community functioning in patients with schizophrenia. However, the neurobiological mechanisms underlying competence in schizophrenia are not fully understood. We hypothesized that social deficits in schizophrenia are explained, at least in part, by abnormally lateralized patterns of brain activation in response to tasks engaging social cognition, as compared to healthy individuals. We predicted such patterns would be partly heritable, and therefore affected in patients' nonpsychotic siblings as well. We used a functional magnetic resonance image paradigm to characterize brain activation induced by theory of mind tasks, and two tests of social competence, the Test of Adaptive Behavior in Schizophrenia (TABS), and the Social Skills Performance Assessment (SSPA) in siblings discordant for schizophrenia and comparable healthy controls (n = 14 per group). Healthy individuals showed the strongest correlation between social competence and activation of right hemisphere structures involved in social cognitive processing, whereas in patients, the correlation pattern was lateralized to left hemisphere areas. Unaffected siblings of patients exhibited a pattern intermediate between the other groups. These results support the hypothesis that schizophrenia may be characterized by an abnormal functioning of nondominant hemisphere structures involved in the processing of socially salient information. Copyright © 2014 Elsevier Ltd. All rights reserved.

Histone variants and lipid metabolism

NARCIS (Netherlands)

Borghesan, Michela; Mazzoccoli, Gianluigi; Sheedfar, Fareeba; Oben, Jude; Pazienza, Valerio; Vinciguerra, Manlio

2014-01-01

Within nucleosomes, canonical histones package the genome, but they can be opportunely replaced with histone variants. The incorporation of histone variants into the nucleosome is a chief cellular strategy to regulate transcription and cellular metabolism. In pathological terms, cellular steatosis

Discordance Between Apolipoprotein B and LDL-Cholesterol in Young Adults Predicts Coronary Artery Calcification: The CARDIA Study.

Science.gov (United States)

Wilkins, John T; Li, Ron C; Sniderman, Allan; Chan, Cheeling; Lloyd-Jones, Donald M

2016-01-19

High levels of apolipoprotein B (apoB) have been shown to predict atherosclerotic cardiovascular disease (CVD) in adults even in the context of low levels of low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C). This study aimed to quantify the associations between apoB and the discordance between apoB and LDL-C or non-HDL-C in young adults and measured coronary artery calcium (CAC) in midlife. Data were derived from a multicenter cohort study of young adults recruited at ages 18 to 30 years. All participants with complete baseline CVD risk factor data, including apoB and year 25 (Y25) CAC score, were entered into this study. Presence of CAC was defined as having a positive, nonzero Agatston score as determined by computed tomography. Baseline apoB values were divided into tertiles of 4 mutually exclusive concordant/discordant groups, based on median apoB and LDL-C or non-HDL-C. Analysis included 2,794 participants (mean age: 25 ± 3.6 years; body mass index: 24.5 ± 5 kg/m(2); and 44.4% male). Mean lipid values were as follows: total cholesterol: 177.3 ± 33.1 mg/dl; LDL-C: 109.9 ± 31.1 mg/dl; non-HDL-C: 124.0 ± 33.5 mg/dl; HDL-C: 53 ± 12.8 mg/dl; and apoB: 90.7 ± 24 mg/dl; median triglycerides were 61 mg/dl. Compared with the lowest apoB tertile, higher odds of developing Y25 CAC were seen in the middle (odds ratio [OR]: 1.53) and high (OR: 2.28) tertiles based on traditional risk factor-adjusted models. High apoB and low LDL-C or non-HDL-C discordance was also associated with Y25 CAC in adjusted models (OR: 1.55 and OR: 1.45, respectively). These data suggest a dose-response association between apoB in young adults and the presence of midlife CAC independent of baseline traditional CVD risk factors. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

CLEVER: Clique-Enumerating Variant Finder

NARCIS (Netherlands)

Marschall, T.; Costa, I.; Canzar, S.; bauer, m; Klau, G.W.; Schliep, A.; Schönhuth, A.

2012-01-01

Motivation: Next-generation sequencing techniques have facilitated a large-scale analysis of human genetic variation. Despite the advances in sequencing speed, the computational discovery of structural variants is not yet standard. It is likely that many variants have remained undiscovered in most

Testing viability of cross subsidy using time-variant price elasticities of industrial demand for electricity: Indian experience

International Nuclear Information System (INIS)

Chattopadhyay, Pradip

2007-01-01

Indian electric tariffs are characterized by very high rates for industrial and commercial classes to permit subsidized electric consumption by residential and agricultural customers. We investigate the viability of this policy using monthly data for 1997-2003 on electric consumption by a few large industrial customers under the aegis of a small distribution company in the state of Uttar Pradesh. For a given price/cost ratio, it can be shown that if the cross-subsidizing class' electricity demand is sufficiently elastic, increasing the class' rates fail to recover incremental cross-subsidy necessary to support additional revenues for subsidized classes. This suboptimality is tested by individually estimating time-variant price-elasticities of demand for these industrial customers using Box-Cox and linear regressions. We find that at least for some of these customers, cross-subsidy was suboptimal prior to as late as October 2001, when rates were changed following reforms

Testing viability of cross subsidy using time-variant price elasticities of industrial demand for electricity: Indian experience

Energy Technology Data Exchange (ETDEWEB)

Chattopadhyay, Pradip [New Hampshire Public Utilities Commission, 21 South Fruit Street, Suite 10, Concord NH 03301 (United States)]. E-mail: pradip.chattopadhyay@puc.nh.gov

2007-01-15

Indian electric tariffs are characterized by very high rates for industrial and commercial classes to permit subsidized electric consumption by residential and agricultural customers. We investigate the viability of this policy using monthly data for 1997-2003 on electric consumption by a few large industrial customers under the aegis of a small distribution company in the state of Uttar Pradesh. For a given price/cost ratio, it can be shown that if the cross-subsidizing class' electricity demand is sufficiently elastic, increasing the class' rates fail to recover incremental cross-subsidy necessary to support additional revenues for subsidized classes. This suboptimality is tested by individually estimating time-variant price-elasticities of demand for these industrial customers using Box-Cox and linear regressions. We find that at least for some of these customers, cross-subsidy was suboptimal prior to as late as October 2001, when rates were changed following reforms.

The curation of genetic variants: difficulties and possible solutions.

Science.gov (United States)

Pandey, Kapil Raj; Maden, Narendra; Poudel, Barsha; Pradhananga, Sailendra; Sharma, Amit Kumar

2012-12-01

The curation of genetic variants from biomedical articles is required for various clinical and research purposes. Nowadays, establishment of variant databases that include overall information about variants is becoming quite popular. These databases have immense utility, serving as a user-friendly information storehouse of variants for information seekers. While manual curation is the gold standard method for curation of variants, it can turn out to be time-consuming on a large scale thus necessitating the need for automation. Curation of variants described in biomedical literature may not be straightforward mainly due to various nomenclature and expression issues. Though current trends in paper writing on variants is inclined to the standard nomenclature such that variants can easily be retrieved, we have a massive store of variants in the literature that are present as non-standard names and the online search engines that are predominantly used may not be capable of finding them. For effective curation of variants, knowledge about the overall process of curation, nature and types of difficulties in curation, and ways to tackle the difficulties during the task are crucial. Only by effective curation, can variants be correctly interpreted. This paper presents the process and difficulties of curation of genetic variants with possible solutions and suggestions from our work experience in the field including literature support. The paper also highlights aspects of interpretation of genetic variants and the importance of writing papers on variants following standard and retrievable methods. Copyright © 2012. Published by Elsevier Ltd.

Word Variant Identification in Old French

Directory of Open Access Journals (Sweden)

Peter Willett

1997-01-01

Full Text Available Increasing numbers of historical texts are available in machine-readable form, which retain the original spelling, which can be very different from the modern-day equivalents due to the natural evolution of a language, and because the concept of standardisation in spelling is comparatively modern. Among medieval vernacular writers, the same word could be spelled in different ways and the same author (or scribe might even use several alternative spellings in the same passage. Thus, we do not know,a priori, how many variant forms of a particular word there are in such texts, let alone what these variants might be. Searching on the modern equivalent, or even the commonest historical variant, of a particular word may thus fail to retrieve an appreciable number of occurrences unless the searcher already has an extensive knowledge of the language of the documents. Moreover, even specialist scholars may be unaware of some idiosyncratic variants. Here, we consider the use of computer methods to retrieve variant historical spellings.

Role of Androgen Receptor Variants in Prostate Cancer: Report from the 2017 Mission Androgen Receptor Variants Meeting.

Science.gov (United States)

Luo, Jun; Attard, Gerhardt; Balk, Steven P; Bevan, Charlotte; Burnstein, Kerry; Cato, Laura; Cherkasov, Artem; De Bono, Johann S; Dong, Yan; Gao, Allen C; Gleave, Martin; Heemers, Hannelore; Kanayama, Mayuko; Kittler, Ralf; Lang, Joshua M; Lee, Richard J; Logothetis, Christopher J; Matusik, Robert; Plymate, Stephen; Sawyers, Charles L; Selth, Luke A; Soule, Howard; Tilley, Wayne; Weigel, Nancy L; Zoubeidi, Amina; Dehm, Scott M; Raj, Ganesh V

2018-05-01

Although a number of studies have demonstrated the importance of constitutively active androgen receptor variants (AR-Vs) in prostate cancer, questions still remain about the precise role of AR-Vs in the progression of castration-resistant prostate cancer (CRPC). Key stakeholders and opinion leaders in prostate cancer convened on May 11, 2017 in Boston to establish the current state of the field of AR-Vs. The meeting "Mission Androgen Receptor Variants" was the second of its kind sponsored by the Prostate Cancer Foundation (PCF). This invitation-only event was attended by international leaders in the field and representatives from sponsoring organizations (PCF and industry sponsors). Eighteen faculty members gave short presentations, which were followed by in-depth discussions. Discussions focused on three thematic topics: (1) potential of AR-Vs as biomarkers of therapeutic resistance; (2) role of AR-Vs as functionally active CRPC progression drivers; and (3) utility of AR-Vs as therapeutic targets in CRPC. The three meeting organizers synthesized this meeting report, which is intended to summarize major data discussed at the meeting and identify key questions as well as strategies for addressing these questions. There was a critical consensus that further study of the AR-Vs is an important research focus in CRPC. Contrasting views and emphasis, each supported by data, were presented at the meeting, discussed among the participants, and synthesized in this report. This article highlights the state of knowledge and outlines the most pressing questions that need to be addressed to advance the AR-V field. Although further investigation is needed to delineate the role of androgen receptor (AR) variants in metastatic castration-resistant prostate cancer, advances in measurement science have enabled development of blood-based tests for treatment selection. Detection of AR variants (eg, AR-V7) identified a patient population with poor outcomes to existing AR

Pharmacogenetic testing through the direct-to-consumer genetic testing company 23andMe.

Science.gov (United States)

Lu, Mengfei; Lewis, Cathryn M; Traylor, Matthew

2017-06-19

Rapid advances in scientific research have led to an increase in public awareness of genetic testing and pharmacogenetics. Direct-to-consumer (DTC) genetic testing companies, such as 23andMe, allow consumers to access their genetic information directly through an online service without the involvement of healthcare professionals. Here, we evaluate the clinical relevance of pharmacogenetic tests reported by 23andMe in their UK tests. The research papers listed under each 23andMe report were evaluated, extracting information on effect size, sample size and ethnicity. A wider literature search was performed to provide a fuller assessment of the pharmacogenetic test and variants were matched to FDA recommendations. Additional evidence from CPIC guidelines, PharmGKB, and Dutch Pharmacogenetics Working Group was reviewed to determine current clinical practice. The value of the tests across ethnic groups was determined, including information on linkage disequilibrium between the tested SNP and causal pharmacogenetic variant, where relevant. 23andMe offers 12 pharmacogenetic tests to their UK customers, some of which are in standard clinical practice, and others which are less widely applied. The clinical validity and clinical utility varies extensively between tests. The variants tested are likely to have different degrees of sensitivity due to different risk allele frequencies and linkage disequilibrium patterns across populations. The clinical relevance depends on the ethnicity of the individual and variability of pharmacogenetic markers. Further research is required to determine causal variants and provide more complete assessment of drug response and side effects. 23andMe reports provide some useful pharmacogenetics information, mirroring clinical tests that are in standard use. Other tests are unspecific, providing limited guidance and may not be useful for patients without professional interpretation. Nevertheless, DTC companies like 23andMe act as a powerful

Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels

Science.gov (United States)

van Leeuwen, Elisabeth M.; Karssen, Lennart C.; Deelen, Joris; Isaacs, Aaron; Medina-Gomez, Carolina; Mbarek, Hamdi; Kanterakis, Alexandros; Trompet, Stella; Postmus, Iris; Verweij, Niek; van Enckevort, David J.; Huffman, Jennifer E.; White, Charles C.; Feitosa, Mary F.; Bartz, Traci M.; Manichaikul, Ani; Joshi, Peter K.; Peloso, Gina M.; Deelen, Patrick; van Dijk, Freerk; Willemsen, Gonneke; de Geus, Eco J.; Milaneschi, Yuri; Penninx, Brenda W.J.H.; Francioli, Laurent C.; Menelaou, Androniki; Pulit, Sara L.; Rivadeneira, Fernando; Hofman, Albert; Oostra, Ben A.; Franco, Oscar H.; Leach, Irene Mateo; Beekman, Marian; de Craen, Anton J.M.; Uh, Hae-Won; Trochet, Holly; Hocking, Lynne J.; Porteous, David J.; Sattar, Naveed; Packard, Chris J.; Buckley, Brendan M.; Brody, Jennifer A.; Bis, Joshua C.; Rotter, Jerome I.; Mychaleckyj, Josyf C.; Campbell, Harry; Duan, Qing; Lange, Leslie A.; Wilson, James F.; Hayward, Caroline; Polasek, Ozren; Vitart, Veronique; Rudan, Igor; Wright, Alan F.; Rich, Stephen S.; Psaty, Bruce M.; Borecki, Ingrid B.; Kearney, Patricia M.; Stott, David J.; Adrienne Cupples, L.; Neerincx, Pieter B.T.; Elbers, Clara C.; Francesco Palamara, Pier; Pe'er, Itsik; Abdellaoui, Abdel; Kloosterman, Wigard P.; van Oven, Mannis; Vermaat, Martijn; Li, Mingkun; Laros, Jeroen F.J.; Stoneking, Mark; de Knijff, Peter; Kayser, Manfred; Veldink, Jan H.; van den Berg, Leonard H.; Byelas, Heorhiy; den Dunnen, Johan T.; Dijkstra, Martijn; Amin, Najaf; Joeri van der Velde, K.; van Setten, Jessica; Kattenberg, Mathijs; van Schaik, Barbera D.C.; Bot, Jan; Nijman, Isaäc J.; Mei, Hailiang; Koval, Vyacheslav; Ye, Kai; Lameijer, Eric-Wubbo; Moed, Matthijs H.; Hehir-Kwa, Jayne Y.; Handsaker, Robert E.; Sunyaev, Shamil R.; Sohail, Mashaal; Hormozdiari, Fereydoun; Marschall, Tobias; Schönhuth, Alexander; Guryev, Victor; Suchiman, H. Eka D.; Wolffenbuttel, Bruce H.; Platteel, Mathieu; Pitts, Steven J.; Potluri, Shobha; Cox, David R.; Li, Qibin; Li, Yingrui; Du, Yuanping; Chen, Ruoyan; Cao, Hongzhi; Li, Ning; Cao, Sujie; Wang, Jun; Bovenberg, Jasper A.; Jukema, J. Wouter; van der Harst, Pim; Sijbrands, Eric J.; Hottenga, Jouke-Jan; Uitterlinden, Andre G.; Swertz, Morris A.; van Ommen, Gert-Jan B.; de Bakker, Paul I.W.; Eline Slagboom, P.; Boomsma, Dorret I.; Wijmenga, Cisca; van Duijn, Cornelia M.

2015-01-01

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of the Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10−4), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR. PMID:25751400

Gait Training Improves Performance in Healthy Adults Exposed to Novel Discordant Conditions

Science.gov (United States)

Batson, Crystal D.; Brady, Rachel A.; Peters, Brian T.; Mulavara, Ajitkumar P.; Bloomberg, Jacob J.

2010-01-01

After they return to Earth, astronauts experience sensorimotor disturbances that disrupt their ability to walk. We have previously shown that training with a variety of sensorimotor adaptive challenges enhances the capability of adapting to novel sensorimotor conditions. We are currently developing a sensorimotor adaptability (SA) training program designed to facilitate recovery of function after gravitational transitions. The purpose of this study was to determine whether trained subjects could transfer learned skills from one discordant visuo-proprioceptive environment to another. During three sessions, subjects walked at 2.5 km/h on a treadmill mounted on a motion base platform. Ten subjects trained with a combination of lateral treadmill translation and superimposed sinusoidal lateral optic flow that was presented on a large screen positioned in front of them. Ten controls completed the same training schedule while viewing only the forward optic flow with no visual or physical oscillation. Twenty minutes after the final training session, all subjects completed a 2-minute trial with a novel combination of visual and treadmill roll perturbations not previously experienced during the training (Transfer Test). Compared to the untrained group, participants who received SA training showed faster reaction times and, based on a composite score derived from stride frequency, heart rate, and reaction time, an overall enhanced performance. Our results showed that an SA training program can improve overall walking performance when subjects are exposed to novel incongruent sensory environments. This training has application for both enhancing adaptive responses in astronauts and reducing fall and injury risk in the elderly.

Effectiveness of semen washing to prevent HIV transmission and assist pregnancy in HIV-discordant couples: a systematic review and meta-analysis

Science.gov (United States)

Zafer, Maryam; Horvath, Hacsi; Mmeje, Okeoma; van der Poel, Sheryl; Semprini, Augusto; Rutherford, George; Brown, Joelle

2015-01-01

Objective To evaluate the effectiveness of semen washing in HIV-discordant couples in which the male partner is infected Design Systematic review and meta-analysis Setting All countries Patient(s) Forty single-arm, open label studies among HIV-discordant couples that underwent intrauterine insemination (IUI) or in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI) using washed semen Intervention(s) Semen washing followed by IUI, IVF, or IVF/ICSI Main outcome measure(s) Primary outcome: HIV transmission to HIV-uninfected women; secondary outcomes: HIV transmission to newborns and proportion of couples achieving a clinical pregnancy Result(s) No HIV transmission occurred in 11,585 cycles of assisted reproduction using washed semen among 3,994 women (95% confidence interval [CI] = 0–0.0001). Among the subset of HIV-infected men without plasma viral suppression at the time of semen washing, no HIV seroconversions occurred among 1,023 women following 2,863 cycles of assisted reproduction using washed semen (95%CI= 0–0.0006). Studies that measured HIV transmission to infants reported no cases of vertical transmission (0/1,026, 95% CI= 0–0.0029). Overall, 56.3% (2,357/4,184, 95%CI=54.8%–57.8%) of couples achieved a clinical pregnancy using washed semen. Conclusion(s) Semen washing appears to significantly reduce the risk of transmission in HIV-discordant couples desiring children, regardless of viral suppression in the male partner. There are no randomized, controlled studies or studies from low-income countries, especially those with a large burden of HIV. Continued development of lower-cost semen washing and assisted reproduction technologies is needed. Integration of semen washing into HIV prevention interventions could help further reduce the spread of HIV. PMID:26688556

An Event-Level Analysis of Condomless Anal Intercourse with a HIV-Discordant or HIV Status-Unknown Partner Among Black Men Who Have Sex with Men from a Multi-site Study.

Science.gov (United States)

Yang, Cui; Latkin, Carl; Tobin, Karin; Seal, David; Koblin, Beryl; Chander, Geetanjali; Siconolfi, Daniel; Flores, Stephen; Spikes, Pilgrim

2018-05-19

Despite the high HIV incidence and prevalence among black men who have sex with men (BMSM), little research has examined partner characteristics, partner seeking venue, sexual position, substance use, and sexual risk behavior at the sex event-level among BMSM. Using the baseline data from a multi-site study of 807 BMSM stratified by their HIV status, the goal of this study was to conduct a detailed event-level analysis of 1577 male anal sex events to assess the factors associated with condomless anal intercourse (CLAI) with a HIV-discordant or HIV status-unknown partner. We found CLAI with an HIV-discordant or unknown HIV status partner among HIV-negative BMSM was negatively associated with having sex with a main partner, and was positively associated with taking both receptive and insertive sexual positions during sex. As compared to a sex partner met at bar, night club or dance club, HIV-positive BMSM were less likely to engage in CLAI with HIV-discordant and unknown HIV status partner met at party or friend's house or at community organizations. HIV-positive BMSM had lower odds of engaging in CLAI with HIV-discordant and unknown HIV status partner if they had insertive sexual position or both receptive and insertive sexual positions. These results underscore the importance of delineating unique sex event-level factors associated with sexual risk behavior depending on individuals' HIV status. Our findings suggest event-level partner characteristics, sexual position, and partner seeking venues may contribute to disparities in HIV incidence.

Evolution of simeprevir-resistant variants over time by ultra-deep sequencing in HCV genotype 1b.

Science.gov (United States)

Akuta, Norio; Suzuki, Fumitaka; Sezaki, Hitomi; Suzuki, Yoshiyuki; Hosaka, Tetsuya; Kobayashi, Masahiro; Kobayashi, Mariko; Saitoh, Satoshi; Ikeda, Kenji; Kumada, Hiromitsu

2014-08-01

Using ultra-deep sequencing technology, the present study was designed to investigate the evolution of simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time. In Toranomon Hospital, 18 Japanese patients infected with HCV genotype 1b, received triple therapy of simeprevir/PEG-IFN/ribavirin (DRAGON or CONCERT study). Sustained virological response rate was 67%, and that was significantly higher in patients with IL28B rs8099917 TT than in those with non-TT. Six patients, who did not achieve sustained virological response, were tested for resistant variants by ultra-deep sequencing, at the baseline, at the time of re-elevation of viral loads, and at 96 weeks after the completion of treatment. Twelve of 18 resistant variants, detected at re-elevation of viral load, were de novo resistant variants. Ten of 12 de novo resistant variants become undetectable over time, and that five of seven resistant variants, detected at baseline, persisted over time. In one patient, variants of Q80R at baseline (0.3%) increased at 96-week after the cessation of treatment (10.2%), and de novo resistant variants of D168E (0.3%) also increased at 96-week after the cessation of treatment (9.7%). In conclusion, the present study indicates that the emergence of simeprevir-resistant variants after the start of treatment could not be predicted at baseline, and the majority of de novo resistant variants become undetectable over time. Further large-scale prospective studies should be performed to investigate the clinical utility in detecting simeprevir-resistant variants. © 2014 Wiley Periodicals, Inc.

An Evaluation of Factors Associated With Pathogenic PRSS1, SPINK1, CTFR, and/or CTRC Genetic Variants in Patients With Idiopathic Pancreatitis.

Science.gov (United States)

Jalaly, Niloofar Y; Moran, Robert A; Fargahi, Farshid; Khashab, Mouen A; Kamal, Ayesha; Lennon, Anne Marie; Walsh, Christi; Makary, Martin A; Whitcomb, David C; Yadav, Dhiraj; Cebotaru, Liudmila; Singh, Vikesh K

2017-08-01

We evaluated factors associated with pathogenic genetic variants in patients with idiopathic pancreatitis. Genetic testing (PRSS1, CFTR, SPINK1, and CTRC) was performed in all eligible patients with idiopathic pancreatitis between 2010 to 2015. Patients were classified into the following groups based on a review of medical records: (1) acute recurrent idiopathic pancreatitis (ARIP) with or without underlying chronic pancreatitis; (2) idiopathic chronic pancreatitis (ICP) without a history of ARP; (3) an unexplained first episode of acute pancreatitis (AP)pancreatitis. Logistic regression analysis was used to determine the factors associated with pathogenic genetic variants. Among 197 ARIP and/or ICP patients evaluated from 2010 to 2015, 134 underwent genetic testing. A total of 88 pathogenic genetic variants were found in 64 (47.8%) patients. Pathogenic genetic variants were identified in 58, 63, and 27% of patients with ARIP, an unexplained first episode of AP <35 years of age, and ICP without ARP, respectively. ARIP (OR: 18.12; 95% CI: 2.16-151.87; P=0.008) and an unexplained first episode of AP<35 years of age (OR: 2.46; 95% CI: 1.18-5.15; P=0.017), but not ICP, were independently associated with pathogenic genetic variants in the adjusted analysis. Pathogenic genetic variants are most likely to be identified in patients with ARIP and an unexplained first episode of AP<35 years of age. Genetic testing in these patient populations may delineate an etiology and prevent unnecessary diagnostic testing and procedures.

a potential source of spurious associations in genome-wide ...

Indian Academy of Sciences (India)

2010-04-01

Apr 1, 2010 ... Genome-wide association studies (GWAS) examine the entire human genome with the goal of identifying genetic variants. (usually single nucleotide polymorphisms (SNPs)) that are associated with phenotypic traits such as disease status and drug response. The discordance of significantly associated ...

Journal of Genetics | Indian Academy of Sciences

Indian Academy of Sciences (India)

Genome-wide association studies (GWAS) examine the entire human genome with the goal of identifying genetic variants (usually single nucleotide polymorphisms (SNPs)) that are associated with phenotypic traits such as disease status and drug response. The discordance of significantly associated SNPs for the same ...

Polycystic ovary syndrome is not associated with genetic variants that mark risk of type 2 diabetes.

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Saxena, R; Welt, C K

2013-06-01

Polycystic ovary syndrome (PCOS) is a disorder of irregular menses, hyperandrogenism and/or polycystic ovary morphology. A large proportion of women with PCOS also exhibit insulin resistance, β-cell dysfunction, impaired glucose tolerance and/or type 2 diabetes (T2D). We therefore hypothesized that genetic variants that predispose to risk of T2D also result in risk of PCOS. Variants robustly associated with T2D in candidate gene or genome-wide association studies (GWAS; n = 56 SNPs from 33 loci) were genotyped in women of European ancestry with PCOS (n = 525) and controls (n = 472), aged 18-45 years. Metabolic, reproductive and anthropomorphic data were examined as a function of the T2D variants. All genetic association analyses were adjusted for age, BMI and ancestry and were reported after correction for multiple testing. There was a nominal association between variants in KCNJ11 and risk of PCOS. However, a risk score of 33 independent T2D-associated variants from GWAS was not significantly associated with PCOS. T2D variants were associated with PCOS phenotype parameters including those in THADA and WFS1 with testosterone levels, ENPP/PC1 with triglyceride levels, FTO with glucose levels and KCNJ11 with FSH levels. Diabetes risk variants are not important risk variants for PCOS.

VaRank: a simple and powerful tool for ranking genetic variants

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Véronique Geoffroy

2015-03-01

Full Text Available Background. Most genetic disorders are caused by single nucleotide variations (SNVs or small insertion/deletions (indels. High throughput sequencing has broadened the catalogue of human variation, including common polymorphisms, rare variations or disease causing mutations. However, identifying one variation among hundreds or thousands of others is still a complex task for biologists, geneticists and clinicians.Results. We have developed VaRank, a command-line tool for the ranking of genetic variants detected by high-throughput sequencing. VaRank scores and prioritizes variants annotated either by Alamut Batch or SnpEff. A barcode allows users to quickly view the presence/absence of variants (with homozygote/heterozygote status in analyzed samples. VaRank supports the commonly used VCF input format for variants analysis thus allowing it to be easily integrated into NGS bioinformatics analysis pipelines. VaRank has been successfully applied to disease-gene identification as well as to molecular diagnostics setup for several hundred patients.Conclusions. VaRank is implemented in Tcl/Tk, a scripting language which is platform-independent but has been tested only on Unix environment. The source code is available under the GNU GPL, and together with sample data and detailed documentation can be downloaded from http://www.lbgi.fr/VaRank/.

BRCA1 and BRCA2 genetic testing—pitfalls and recommendations for managing variants of uncertain clinical significance

Science.gov (United States)

Eccles, D. M.; Mitchell, G.; Monteiro, A. N. A.; Schmutzler, R.; Couch, F. J.; Spurdle, A. B.; Gómez-García, E. B.

2015-01-01

Background Increasing use of BRCA1/2 testing for tailoring cancer treatment and extension of testing to tumour tissue for somatic mutation is moving BRCA1/2 mutation screening from a primarily prevention arena delivered by specialist genetic services into mainstream oncology practice. A considerable number of gene tests will identify rare variants where clinical significance cannot be inferred from sequence information alone. The proportion of variants of uncertain clinical significance (VUS) is likely to grow with lower thresholds for testing and laboratory providers with less experience of BRCA. Most VUS will not be associated with a high risk of cancer but a misinterpreted VUS has the potential to lead to mismanagement of both the patient and their relatives. Design Members of the Clinical Working Group of ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) global consortium (www.enigmaconsortium.org) observed wide variation in practices in reporting, disclosure and clinical management of patients with a VUS. Examples from current clinical practice are presented and discussed to illustrate potential pitfalls, explore factors contributing to misinterpretation, and propose approaches to improving clarity. Results and conclusion Clinicians, patients and their relatives would all benefit from an improved level of genetic literacy. Genetic laboratories working with clinical geneticists need to agree on a clinically clear and uniform format for reporting BRCA test results to non-geneticists. An international consortium of experts, collecting and integrating all available lines of evidence and classifying variants according to an internationally recognized system, will facilitate reclassification of variants for clinical use. PMID:26153499

Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

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Quartier, Angélique; Poquet, Hélène; Gilbert-Dussardier, Brigitte; Rossi, Massimiliano; Casteleyn, Anne-Sophie; Portes, Vincent des; Feger, Claire; Nourisson, Elsa; Kuentz, Paul; Redin, Claire; Thevenon, Julien; Mosca-Boidron, Anne-Laure; Callier, Patrick; Muller, Jean; Lesca, Gaetan; Huet, Frédéric; Geoffroy, Véronique; El Chehadeh, Salima; Jung, Matthieu; Trojak, Benoit; Le Gras, Stéphanie; Lehalle, Daphné; Jost, Bernard; Maury, Stéphanie; Masurel, Alice; Edery, Patrick; Thauvin-Robinet, Christel; Gérard, Bénédicte; Mandel, Jean-Louis; Faivre, Laurence; Piton, Amélie

2017-01-01

Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5′-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G>A (family 2) and a maternally inherited c.420-8A>G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up. PMID:28176767

Combined analyses of 20 common obesity susceptibility variants

DEFF Research Database (Denmark)

Sandholt, Camilla Helene; Sparsø, Thomas; Grarup, Niels

2010-01-01

Genome-wide association studies and linkage studies have identified 20 validated genetic variants associated with obesity and/or related phenotypes. The variants are common, and they individually exhibit small-to-modest effect sizes.......Genome-wide association studies and linkage studies have identified 20 validated genetic variants associated with obesity and/or related phenotypes. The variants are common, and they individually exhibit small-to-modest effect sizes....

Late-onset Alzheimer's risk variants in memory decline, incident mild cognitive impairment, and Alzheimer's disease.

Science.gov (United States)

Carrasquillo, Minerva M; Crook, Julia E; Pedraza, Otto; Thomas, Colleen S; Pankratz, V Shane; Allen, Mariet; Nguyen, Thuy; Malphrus, Kimberly G; Ma, Li; Bisceglio, Gina D; Roberts, Rosebud O; Lucas, John A; Smith, Glenn E; Ivnik, Robert J; Machulda, Mary M; Graff-Radford, Neill R; Petersen, Ronald C; Younkin, Steven G; Ertekin-Taner, Nilüfer

2015-01-01

We tested association of nine late-onset Alzheimer's disease (LOAD) risk variants from genome-wide association studies (GWAS) with memory and progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD) in older Caucasians, cognitively normal at baseline and longitudinally evaluated at Mayo Clinic Rochester and Jacksonville (n>2000). Each variant was tested both individually and collectively using a weighted risk score. APOE-e4 associated with worse baseline memory and increased decline with highly significant overall effect on memory. CLU-rs11136000-G associated with worse baseline memory and incident MCI/LOAD. MS4A6A-rs610932-C associated with increased incident MCI/LOAD and suggestively with lower baseline memory. ABCA7-rs3764650-C and EPHA1-rs11767557-A associated with increased rates of memory decline in subjects with a final diagnosis of MCI/LOAD. PICALM-rs3851179-G had an unexpected protective effect on incident MCI/LOAD. Only APOE-inclusive risk scores associated with worse memory and incident MCI/LOAD. The collective influence of the nine top LOAD GWAS variants on memory decline and progression to MCI/LOAD appears limited. Discovery of biologically functional variants at these loci may uncover stronger effects on memory and incident disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype

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Johnathan Cooper-Knock

2017-11-01

Full Text Available Amyotrophic lateral sclerosis (ALS is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs. We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18. Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033. We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025. Our data are

Variant Review with the Integrative Genomics Viewer.

Science.gov (United States)

Robinson, James T; Thorvaldsdóttir, Helga; Wenger, Aaron M; Zehir, Ahmet; Mesirov, Jill P

2017-11-01

Manual review of aligned reads for confirmation and interpretation of variant calls is an important step in many variant calling pipelines for next-generation sequencing (NGS) data. Visual inspection can greatly increase the confidence in calls, reduce the risk of false positives, and help characterize complex events. The Integrative Genomics Viewer (IGV) was one of the first tools to provide NGS data visualization, and it currently provides a rich set of tools for inspection, validation, and interpretation of NGS datasets, as well as other types of genomic data. Here, we present a short overview of IGV's variant review features for both single-nucleotide variants and structural variants, with examples from both cancer and germline datasets. IGV is freely available at https://www.igv.org Cancer Res; 77(21); e31-34. ©2017 AACR . ©2017 American Association for Cancer Research.

A Burkholderia pseudomallei colony variant necessary for gastric colonization.

Science.gov (United States)

Austin, C R; Goodyear, A W; Bartek, I L; Stewart, A; Sutherland, M D; Silva, E B; Zweifel, A; Vitko, N P; Tuanyok, A; Highnam, G; Mittelman, D; Keim, P; Schweizer, H P; Vázquez-Torres, A; Dow, S W C; Voskuil, M I

2015-02-03

Diverse colony morphologies are a hallmark of Burkholderia pseudomallei recovered from infected patients. We observed that stresses that inhibit aerobic respiration shifted populations of B. pseudomallei from the canonical white colony morphotype toward two distinct, reversible, yet relatively stable yellow colony variants (YA and YB). As accumulating evidence supports the importance of B. pseudomallei enteric infection and gastric colonization, we tested the response of yellow variants to hypoxia, acidity, and stomach colonization. Yellow variants exhibited a competitive advantage under hypoxic and acidic conditions and alkalized culture media. The YB variant, although highly attenuated in acute virulence, was the only form capable of colonization and persistence in the murine stomach. The accumulation of extracellular DNA (eDNA) was a characteristic of YB as observed by 4',6-diamidino-2-phenylindole (DAPI) staining of gastric tissues, as well as in an in vitro stomach model where large amounts of eDNA were produced without cell lysis. Transposon mutagenesis identified a transcriptional regulator (BPSL1887, designated YelR) that when overexpressed produced the yellow phenotype. Deletion of yelR blocked a shift from white to the yellow forms. These data demonstrate that YB is a unique B. pseudomallei pathovariant controlled by YelR that is specifically adapted to the harsh gastric environment and necessary for persistent stomach colonization. Seemingly uniform populations of bacteria often contain subpopulations that are genetically identical but display unique characteristics which offer advantages when the population is faced with infrequent but predictable stresses. The pathogen Burkholderia pseudomallei is capable of forming several reversible colony types, and it interconverted between one white type and two yellow types under certain environmental stresses. The two yellow forms exhibited distinct advantages in low-oxygen and acidic environments. One yellow

Whole-Exome Sequencing Reveals Clinically Relevant Variants in Family Affected with Autism Spectrum Disorder

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Jiaxiu Zhou

2016-10-01

Full Text Available Chromosomal microarray (CMA has been suggested as a first tier clinical diagnostic test for ASD. High-throughput sequencing (HTS has associated hundreds of genes associated with ASD. Whole Exome Sequencing (WES was used in combination with CMA to identify clinically-relevant ASD variants. In prior work, a trio-based (father, mother, and proband WGS (Whole Genome Sequencing was used to reveal clinically-relevant de novo, or inherited, rare variants in half (16 / 32 of the ASD families in which all probands had normal, or VOUS (Variant of Uncertain Clinical Significance, CMA results. In this study, after CMA screening chromosome structural abnormalities of a proband affected with ASD, a WES was performed on the patient and parents. Some rare de novo, and inherited, variants were detected using trio-based bioinformatics analysis. ASD variants were ranked by SFARI Gene score, HPO (human phenotype ontology, protein function damage, and manual searching PubMed. Sanger sequencing was used to validated some candidate variants in family members. A de novo homozygous mutation in SPG11 (p.C209F, two inherited, compound-heterozygote mutations in SCN9A (p.Q10R and p.R1893H and BEST1 (p.A135V and p.A297V were confirmed. Heterozygous mutations in TSC1 (p.S487C and SHANK2 (p.Arg569His inherited from mother were also confirmed.

Pharmacogenetic characterization of naturally occurring germline NT5C1A variants to chemotherapeutic nucleoside analogs

Science.gov (United States)

Saliba, Jason; Zabriskie, Ryan; Ghosh, Rajarshi; Powell, Bradford C; Hicks, Stephanie; Kimmel, Marek; Meng, Qingchang; Ritter, Deborah I; Wheeler, David A; Gibbs, Richard A; Tsai, Francis T F; Plon, Sharon E

2016-01-01

Background Mutations or alteration in expression of the 5’ nucleotidase gene family can confer altered responses to treatment with nucleoside analogs. While investigating leukemia susceptibility genes, we discovered a very rare p.L254P NT5C1A missense variant in the substrate recognition motif. Given the paucity of cellular drug response data from NT5C1A germline variation, we characterized p.L254P and eight rare variants of NT5C1A from genomic databases. Methods Through lentiviral infection, we created HEK293 cell lines that stably overexpress wildtype NT5C1A, p.L254P, or eight NT5C1A variants reported in the NHLBI Exome Variant server (one truncating and seven missense). IC50 values were determined by cytotoxicity assays after exposure to chemotherapeutic nucleoside analogs (Cladribine, Gemcitabine, 5-Fluorouracil). In addition, we used structure-based homology modeling to generate a 3D model for the C-terminal region of NT5C1A. Results The p.R180X (truncating), p.A214T, and p.L254P missense changes were the only variants that significantly impaired protein function across all nucleotide analogs tested (>5-fold difference versus WT; p<.05). Several of the remaining variants individually displayed differential effects (both more and less resistant) across the analogs tested. The homology model provided a structural framework to understand the impact of NT5C1A mutants on catalysis and drug processing. The model predicted active site residues within NT5C1A motif III and we experimentally confirmed that p.K314 (not p.K320) is required for NT5C1A activity. Conclusion We characterized germline variation and predicted protein structures of NT5C1A. Individual missense changes showed substantial variation in response to the different nucleoside analogs tested, which may impact patients’ responses to treatment. PMID:26906009

eCD4-Ig variants that more potently neutralize HIV-1.

Science.gov (United States)

Fetzer, Ina; Gardner, Matthew R; Davis-Gardner, Meredith E; Prasad, Neha R; Alfant, Barnett; Weber, Jesse A; Farzan, Michael

2018-03-28

The HIV-1 entry inhibitor eCD4-Ig is a fusion of CD4-Ig and a coreceptor-mimetic peptide. eCD4-Ig is markedly more potent than CD4-Ig, with neutralization efficiencies approaching those of HIV-1 broadly neutralizing antibodies (bNAbs). However, unlike bNAbs, eCD4-Ig neutralizes all HIV-1, HIV-2 and SIV isolates that it has been tested against, suggesting that it may be useful in clinical settings where antibody escape is a concern. Here we characterize three new eCD4-Ig variants, each with different architectures and each utilizing D1.22, a stabilized form of CD4 domain 1. These variants were 10- to 20-fold more potent than our original eCD4-Ig variant, with a construct bearing four D1.22 domains (eD1.22-HL-Ig) exhibiting the greatest potency. However, this variant mediated less efficient antibody-dependent cell-mediated cytotoxicity (ADCC) activity than eCD4-Ig itself or several other eCD4-Ig variants, including the smallest variant (eD1.22-Ig). A variant with the same architecture as original eCD4-Ig (eD1.22-D2-Ig) showed modestly higher thermal stability and best prevented promotion of infection of CCR5-positive, CD4-negative cells. All three variants, and eCD4-Ig itself, mediated more efficient shedding of the HIV-1 envelope glycoprotein gp120 than did CD4-Ig. Finally, we show that only three D1.22 mutations contributed to the potency of eD1.22-D2-Ig, and that introduction of these changes into eCD4-Ig resulted in a variant 9-fold more potent than eCD4-Ig and 2-fold more potent than eD1.22-D2-Ig. These studies will assist in developing eCD4-Ig variants with properties optimized for prophylaxis, therapy, and cure applications. IMPORTANCE HIV-1 bNAbs have properties different from antiretroviral compounds. Specifically, antibodies can enlist immune effector cells to eliminate infected cells, whereas antiretroviral compounds simply interfere with various steps in the viral lifecycle. Unfortunately, HIV-1 is adept at evading antibody recognition, limiting the

Germline Variants of Prostate Cancer in Japanese Families.

Directory of Open Access Journals (Sweden)

Takahide Hayano

Full Text Available Prostate cancer (PC is the second most common cancer in men. Family history is the major risk factor for PC. Only two susceptibility genes were identified in PC, BRCA2 and HOXB13. A comprehensive search of germline variants for patients with PC has not been reported in Japanese families. In this study, we conducted exome sequencing followed by Sanger sequencing to explore responsible germline variants in 140 Japanese patients with PC from 66 families. In addition to known susceptibility genes, BRCA2 and HOXB13, we identified TRRAP variants in a mutually exclusive manner in seven large PC families (three or four patients per family. We also found shared variants of BRCA2, HOXB13, and TRRAP from 59 additional small PC families (two patients per family. We identified two deleterious HOXB13 variants (F127C and G132E. Further exploration of the shared variants in rest of the families revealed deleterious variants of the so-called cancer genes (ATP1A1, BRIP1, FANCA, FGFR3, FLT3, HOXD11, MUTYH, PDGFRA, SMARCA4, and TCF3. The germline variant profile provides a new insight to clarify the genetic etiology and heterogeneity of PC among Japanese men.

An evaluation of inflammatory gene polymorphisms in sibships discordant for premature coronary artery disease: the GRACE-IMMUNE study

Directory of Open Access Journals (Sweden)

Samani Nilesh J

2010-01-01

Full Text Available Abstract Background Inflammatory cytokines play a crucial role in coronary artery disease (CAD. We investigated the association between 48 coding and three non-coding single nucleotide polymorphisms (SNPs from 35 inflammatory genes and the development of CAD, using a large discordant sibship collection (2699 individuals in 891 families. Methods Family-based association tests (FBAT and conditional logistic regression (CLR were applied to single SNPs and haplotypes and, in CLR, traditional risk factors of CAD were adjusted for. Results An association was observed between CAD and a common three-locus haplotype in the interleukin one (IL-1 cluster with P = 0.006 in all CAD cases, P = 0.01 in myocardial infarction (MI cases and P = 0.0002 in young onset CAD cases (P = 0.05 in young onset CAD cases, more so (P = 0.002 when hypercholesterolaemia was excluded. As many as 82% of individuals affected by CAD had hypercholesterolaemia compared to only 29% of those unaffected, making the two phenotypes difficult to separate. Conclusion Despite the multiple hypotheses tested, the robustness of family design to population confoundings and the consistency with previous findings increase the likelihood of true association. Further investigation using larger data sets is needed in order for this to be confirmed. See the related commentary by Keavney: http://www.biomedcentral.com/1741-7015/8/6

A clinically driven variant prioritization framework outperforms purely computational approaches for the diagnostic analysis of singleton WES data.

Science.gov (United States)

Stark, Zornitza; Dashnow, Harriet; Lunke, Sebastian; Tan, Tiong Y; Yeung, Alison; Sadedin, Simon; Thorne, Natalie; Macciocca, Ivan; Gaff, Clara; Oshlack, Alicia; White, Susan M; James, Paul A

2017-11-01

Rapid identification of clinically significant variants is key to the successful application of next generation sequencing technologies in clinical practice. The Melbourne Genomics Health Alliance (MGHA) variant prioritization framework employs a gene prioritization index based on clinician-generated a priori gene lists, and a variant prioritization index (VPI) based on rarity, conservation and protein effect. We used data from 80 patients who underwent singleton whole exome sequencing (WES) to test the ability of the framework to rank causative variants highly, and compared it against the performance of other gene and variant prioritization tools. Causative variants were identified in 59 of the patients. Using the MGHA prioritization framework the average rank of the causative variant was 2.24, with 76% ranked as the top priority variant, and 90% ranked within the top five. Using clinician-generated gene lists resulted in ranking causative variants an average of 8.2 positions higher than prioritization based on variant properties alone. This clinically driven prioritization approach significantly outperformed purely computational tools, placing a greater proportion of causative variants top or in the top 5 (permutation P-value=0.001). Clinicians included 40 of the 49 WES diagnoses in their a priori list of differential diagnoses (81%). The lists generated by PhenoTips and Phenomizer contained 14 (29%) and 18 (37%) of these diagnoses respectively. These results highlight the benefits of clinically led variant prioritization in increasing the efficiency of singleton WES data analysis and have important implications for developing models for the funding and delivery of genomic services.

Evaluating municipal websites: A methodological comparison of three think-aloud variants

NARCIS (Netherlands)

van den Haak, M.J.; de Jong, M.D.T.; Schellens, P.J.

2009-01-01

Usability methods have received relatively little methodological attention within the field of E-Government. This paper aims to address this gap by reporting on a usability test of the municipal website of Deventer (the Netherlands), carried out by means of three variants of the think-aloud method

Molecular Background of Colorectal Tumors From Patients with Lynch Syndrome Associated With Germline Variants in PMS2.

Science.gov (United States)

Ten Broeke, S W; van Bavel, T C; Jansen, A M L; Gómez-García, E; Hes, F J; van Hest, L P; Letteboer, T G W; Olderode-Berends, M J W; Ruano, D; Spruijt, L; Suerink, M; Tops, C M; van Eijk, R; Morreau, H; van Wezel, T; Nielsen, M

2018-05-11

Germline variants in the mismatch repair genes MLH1, MSH2 (EPCAM), MSH6, or PMS2 cause Lynch syndrome. Patients with these variants have an increased risk of developing colorectal cancers (CRCs) that differ from sporadic CRCs in genetic and histologic features. It has been a challenge to study CRCs associated with PMS2 variants (PMS2-associated CRCs) because these develop less frequently and in patients of older ages than colorectal tumors with variants in the other mismatch repair genes. We analyzed 20 CRCs associated with germline variants in PMS2, 22 sporadic CRCs, 18 CRCs with germline variants in MSH2, and 24 CRCs from patients with germline variants in MLH1. Tumor tissue blocks were collected from Dutch pathology departments in 2017. After extraction of tumor DNA, we used a platform designed to detect approximately 3000 somatic hotspot variants in 55 genes (including KRAS, APC, CTNNB1, and TP53). Somatic variant frequencies were compared using the Fisher's exact test. None of the PMS2-associated CRCs contained any somatic variants in the catenin beta 1 gene (CTNNB1), which encodes β-catenin, whereas 14/24 MLH1-associated CRCs (58%) contained variants in CTNNB1. Half of PMS2-associated CRCs contained KRAS variants, but only 20% of these were in hotspots that encoded G12D or G13D. These hotspot variants occurred more frequently in CRCs associated with variants in MLH1 (37.5%, P=.44) and MSH2 (and 71.4%, P=.035) than with variants in PMS2. In a genetic analysis of 84 colorectal tumors, we found tumors from patients with PMS2-associated Lynch syndrome to be distinct from colorectal tumors associated with defects in other mismatch repair genes. This might account for differences in development and less frequent occurrence. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Venous variants and anomalies on routine abdominal multi-detector row CT

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Koc, Zafer; Ulusan, Serife; Oguzkurt, Levent; Tokmak, Naime

2007-01-01

Objective: This study aims to determine the types and prevalence rates of anatomic variations of the hepatic veins, portal vein, inferior vena cava and renal veins, and to establish statistical correlations between various anomalies and frequency differences between male and female using multi-detector row computed tomography (CT). Materials and methods: One thousand one hundred and twenty patients (588 men, 532 women) were evaluated with routine abdominal CT. Frequencies of different variants were noted and compared, and correlations between three categories of variation were tested. Results: In total, 1261 abdominal vein variants and anomalies were identified in 756 (67.5%) of 1120 patients. Six hundred and forty-two hepatic vein variants were detected in 468 (41.8%) patients. One or more inferior right hepatic veins were identified in 356 (31.8%) individuals, and tributary hepatic veins were detected in 147 (13.1%) patients. Portal vein variations and anomalies were observed in 307 (27.4%) cases. The most frequent of these was trifurcation (139 patients, 12.4%). A total of 311 inferior vena cava and renal vein variants were identified in 258 (23%) cases. Six patients (0.5%) exhibited inferior vena cava anomalies, 62 (5.5%) had circumaortic renal veins, 53 (4.7%) had retroaortic renal veins, and 210 (18.8%) had multiple renal veins. Conclusion: The prevalence of abdominal vein variations is high, and routine abdominal CT demonstrates these abnormalities very well. The data suggest that hepatic vein variants and multiple right renal veins are more frequent in women than in men, and that hepatic vein variation is correlated with portal vein variation

Venous variants and anomalies on routine abdominal multi-detector row CT

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Koc, Zafer [Baskent University, School of Medicine, Department of Radiology, Adana (Turkey)]. E-mail: koczafer@gmail.com; Ulusan, Serife [Baskent University, School of Medicine, Department of Radiology, Adana (Turkey); Oguzkurt, Levent [Baskent University, School of Medicine, Department of Radiology, Adana (Turkey); Tokmak, Naime [Baskent University, School of Medicine, Department of Radiology, Adana (Turkey)

2007-02-15

Objective: This study aims to determine the types and prevalence rates of anatomic variations of the hepatic veins, portal vein, inferior vena cava and renal veins, and to establish statistical correlations between various anomalies and frequency differences between male and female using multi-detector row computed tomography (CT). Materials and methods: One thousand one hundred and twenty patients (588 men, 532 women) were evaluated with routine abdominal CT. Frequencies of different variants were noted and compared, and correlations between three categories of variation were tested. Results: In total, 1261 abdominal vein variants and anomalies were identified in 756 (67.5%) of 1120 patients. Six hundred and forty-two hepatic vein variants were detected in 468 (41.8%) patients. One or more inferior right hepatic veins were identified in 356 (31.8%) individuals, and tributary hepatic veins were detected in 147 (13.1%) patients. Portal vein variations and anomalies were observed in 307 (27.4%) cases. The most frequent of these was trifurcation (139 patients, 12.4%). A total of 311 inferior vena cava and renal vein variants were identified in 258 (23%) cases. Six patients (0.5%) exhibited inferior vena cava anomalies, 62 (5.5%) had circumaortic renal veins, 53 (4.7%) had retroaortic renal veins, and 210 (18.8%) had multiple renal veins. Conclusion: The prevalence of abdominal vein variations is high, and routine abdominal CT demonstrates these abnormalities very well. The data suggest that hepatic vein variants and multiple right renal veins are more frequent in women than in men, and that hepatic vein variation is correlated with portal vein variation.

Variants of glycoside hydrolases

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Teter, Sarah [Davis, CA; Ward, Connie [Hamilton, MT; Cherry, Joel [Davis, CA; Jones, Aubrey [Davis, CA; Harris, Paul [Carnation, WA; Yi, Jung [Sacramento, CA

2011-04-26

The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

HE4 Transcription- and Splice Variants-Specific Expression in Endometrial Cancer and Correlation with Patient Survival

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Shi-Wen Jiang

2013-11-01

Full Text Available We investigated the HE4 variant-specific expression patterns in various normal tissues as well as in normal and malignant endometrial tissues. The relationships between mRNA variants and age, body weight, or survival are analyzed. ICAT-labeled normal and endometrial cancer (EC tissues were analyzed with multidimensional liquid chromatography followed by tandem mass spectrometry. Levels of HE4 mRNA variants were measured by real-time PCR. Mean mRNA levels were compared among 16 normal endometrial samples, 14 grade 1 and 14 grade 3 endometrioid EC, 15 papillary serous EC, and 14 normal human tissue samples. The relationship between levels of HE4 variants and EC patient characteristics was analyzed with the use of Pearson correlation test. We found that, although all five HE4 mRNA variants are detectable in normal tissue samples, their expression is highly tissue-specific, with epididymis, trachea, breast and endometrium containing the highest levels. HE4-V0, -V1, and -V3 are the most abundant variants in both normal and malignant tissues. All variants are significantly increased in both endometrioid and papillary serous EC, with higher levels observed in grade 3 endometrioid EC. In the EC group, HE4-V1, -V3, and -V4 levels inversely correlate with EC patient survival, whereas HE4-V0 levels positively correlate with age. HE4 variants exhibit tissue-specific expression, suggesting that each variant may exert distinct functions in normal and malignant cells. HE4 levels appear to correlate with EC patient survival in a variant-specific manner. When using HE4 as a biomarker for EC management, the effects of age should be considered.

The discordance between subjectively and objectively measured physical function in women with fibromyalgia: association with catastrophizing and self-efficacy cognitions : The al-Ándalus project

NARCIS (Netherlands)

Estévez-López, F.|info:eu-repo/dai/nl/412501031; Álvarez-Gallardo, I.C.; Segura-Jiménez, V.; Soriano-Maldonado, A.; Borges-Cosic, M; Pulido-Martos, M.; Aparicio, V.A.; Carbonell-Baeza, A.; Delgado-Fernández, M.; Geenen, R.|info:eu-repo/dai/nl/087017571

2018-01-01

Purpose: People with fibromyalgia experience a disagreement between patient-reported (i.e., subjective) and performance-based (i.e., objective) status. This study aimed to (i) corroborate the discordance between subjectively and objectively measured physical function and (ii) examine whether

Joint Identification of Genetic Variants for Physical Activity in Korean Population

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Jayoun Kim

2014-07-01

Full Text Available There has been limited research on genome-wide association with physical activity (PA. This study ascertained genetic associations between PA and 344,893 single nucleotide polymorphism (SNP markers in 8842 Korean samples. PA data were obtained from a validated questionnaire that included information on PA intensity and duration. Metabolic equivalent of tasks were calculated to estimate the total daily PA level for each individual. In addition to single- and multiple-SNP association tests, a pathway enrichment analysis was performed to identify the biological significance of SNP markers. Although no significant SNP was found at genome-wide significance level via single-SNP association tests, 59 genetic variants mapped to 76 genes were identified via a multiple SNP approach using a bootstrap selection stability measure. Pathway analysis for these 59 variants showed that maturity onset diabetes of the young (MODY was enriched. Joint identification of SNPs could enable the identification of multiple SNPs with good predictive power for PA and a pathway enriched for PA.

Local binary patterns new variants and applications

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Jain, Lakhmi; Nanni, Loris; Lumini, Alessandra

2014-01-01

This book introduces Local Binary Patterns (LBP), arguably one of the most powerful texture descriptors, and LBP variants. This volume provides the latest reviews of the literature and a presentation of some of the best LBP variants by researchers at the forefront of textual analysis research and research on LBP descriptors and variants. The value of LBP variants is illustrated with reported experiments using many databases representing a diversity of computer vision applications in medicine, biometrics, and other areas. There is also a chapter that provides an excellent theoretical foundation for texture analysis and LBP in particular. A special section focuses on LBP and LBP variants in the area of face recognition, including thermal face recognition. This book will be of value to anyone already in the field as well as to those interested in learning more about this powerful family of texture descriptors.

Variants of β-lactamase KPC-2 that are resistant to inhibition by avibactam.

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Papp-Wallace, Krisztina M; Winkler, Marisa L; Taracila, Magdalena A; Bonomo, Robert A

2015-07-01

KPC-2 is the most prevalent class A carbapenemase in the world. Previously, KPC-2 was shown to hydrolyze the β-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam. In addition, substitutions at amino acid position R220 in the KPC-2 β-lactamase increased resistance to clavulanic acid. A novel bridged diazabicyclooctane (DBO) non-β-lactam β-lactamase inhibitor, avibactam, was shown to inactivate the KPC-2 β-lactamase. To better understand the mechanistic basis for inhibition of KPC-2 by avibactam, we tested the potency of ampicillin-avibactam and ceftazidime-avibactam against engineered variants of the KPC-2 β-lactamase that possessed single amino acid substitutions at important sites (i.e., Ambler positions 69, 130, 234, 220, and 276) that were previously shown to confer inhibitor resistance in TEM and SHV β-lactamases. To this end, we performed susceptibility testing, biochemical assays, and molecular modeling. Escherichia coli DH10B carrying KPC-2 β-lactamase variants with the substitutions S130G, K234R, and R220M demonstrated elevated MICs for only the ampicillin-avibactam combinations (e.g., 512, 64, and 32 mg/liter, respectively, versus the MICs for wild-type KPC-2 at 2 to 8 mg/liter). Steady-state kinetics revealed that the S130G variant of KPC-2 resisted inactivation by avibactam; the k2/K ratio was significantly lowered 4 logs for the S130G variant from the ratio for the wild-type enzyme (21,580 M(-1) s(-1) to 1.2 M(-1) s(-1)). Molecular modeling and molecular dynamics simulations suggested that the mobility of K73 and its ability to activate S70 (i.e., function as a general base) may be impaired in the S130G variant of KPC-2, thereby explaining the slowed acylation. Moreover, we also advance the idea that the protonation of the sulfate nitrogen of avibactam may be slowed in the S130G variant, as S130 is the likely proton donor and another residue, possibly K234, must compensate. Our findings show that residues S130 as well as K234 and R

Variant Creutzfeldt-Jakob Disease (vCJD)

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... Form Controls Cancel Submit Search the CDC Variant Creutzfeldt-Jakob Disease (vCJD) Note: Javascript is disabled or is not ... gov . Recommend on Facebook Tweet Share Compartir Variant Creutzfeldt-Jakob disease (vCJD) is a prion disease that was first ...

Joint association of nicotinic acetylcholine receptor variants with abdominal obesity in American Indians: the Strong Heart Family Study.

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Zhu, Yun; Yang, Jingyun; Yeh, Fawn; Cole, Shelley A; Haack, Karin; Lee, Elisa T; Howard, Barbara V; Zhao, Jinying

2014-01-01

Cigarette smoke is a strong risk factor for obesity and cardiovascular disease. The effect of genetic variants involved in nicotine metabolism on obesity or body composition has not been well studied. Though many genetic variants have previously been associated with adiposity or body fat distribution, a single variant usually confers a minimal individual risk. The goal of this study is to evaluate the joint association of multiple variants involved in cigarette smoke or nicotine dependence with obesity-related phenotypes in American Indians. To achieve this goal, we genotyped 61 tagSNPs in seven genes encoding nicotine acetylcholine receptors (nAChRs) in 3,665 American Indians participating in the Strong Heart Family Study. Single SNP association with obesity-related traits was tested using family-based association, adjusting for traditional risk factors including smoking. Joint association of all SNPs in the seven nAChRs genes were examined by gene-family analysis based on weighted truncated product method (TPM). Multiple testing was controlled by false discovery rate (FDR). Results demonstrate that multiple SNPs showed weak individual association with one or more measures of obesity, but none survived correction for multiple testing. However, gene-family analysis revealed significant associations with waist circumference (p = 0.0001) and waist-to-hip ratio (p = 0.0001), but not body mass index (p = 0.20) and percent body fat (p = 0.29), indicating that genetic variants are jointly associated with abdominal, but not general, obesity among American Indians. The observed combined genetic effect is independent of cigarette smoking per se. In conclusion, multiple variants in the nAChR gene family are jointly associated with abdominal obesity in American Indians, independent of general obesity and cigarette smoking per se.

Population structure analysis using rare and common functional variants

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Ding Lili

2011-11-01

Full Text Available Abstract Next-generation sequencing technologies now make it possible to genotype and measure hundreds of thousands of rare genetic variations in individuals across the genome. Characterization of high-density genetic variation facilitates control of population genetic structure on a finer scale before large-scale genotyping in disease genetics studies. Population structure is a well-known, prevalent, and important factor in common variant genetic studies, but its relevance in rare variants is unclear. We perform an extensive population structure analysis using common and rare functional variants from the Genetic Analysis Workshop 17 mini-exome sequence. The analysis based on common functional variants required 388 principal components to account for 90% of the variation in population structure. However, an analysis based on rare variants required 532 significant principal components to account for similar levels of variation. Using rare variants, we detected fine-scale substructure beyond the population structure identified using common functional variants. Our results show that the level of population structure embedded in rare variant data is different from the level embedded in common variant data and that correcting for population structure is only as good as the level one wishes to correct.

Ethical Dilemma and Management of Infertility in HIV Seropositive Discordant Couples: A Case Study in Nigeria.

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Umeora, Ouj; Chukwuneke, Fn

2013-01-01

The traditional African society places an invaluable premium on procreation and, in some communities, a woman's place in her matrimony is only confirmed on positive reproductive outcome. Infertility is rife in Nigeria, and HIV/acquired immunodeficiency syndrome (AIDS) infection is a global pandemic, which has led to a drop in life expectancy across the world. In Nigeria, a number of cultural norms relating to gender roles and power dynamics constitute a serious barrier to issues of sexuality and infertility. Couples are concerned about their infertility diagnostic test being disclosed to each other, especially before marriage. This concern is understandable, especially in an environment that lacks the modern concepts and attitude toward sexual matters. This is complicated by the advent of HIV/AIDS infection and the societal mind-set that look at seropostive individuals as transgressors. At present, sexual and reproductive health rights are currently not in place because ethical issues are not given prominence by many physicians in Nigeria. A case of an infertile and seropostive discordant couple, which raised a lot of medical and ethical concerns, is presented here to awaken the consciousness of Nigerian physicians and stimulate discussions on the ethical matters such as this in clinical practice.

Frequency of the ATM IVS10-6T→G variant in Australian multiple-case breast cancer families

International Nuclear Information System (INIS)

Lindeman, Geoffrey J; Suthers, Graeme; Kirk, Judy; Hiew, Melody; Visvader, Jane E; Leary, Jennifer; Field, Michael; Gaff, Clara L; Gardner, RJ McKinlay; Trainor, Kevin; Cheetham, Glenice

2004-01-01

Germline mutations in the genes BRCA1 and BRCA2 account for only a proportion of hereditary breast cancer, suggesting that additional genes contribute to hereditary breast cancer. Recently a heterozygous variant in the ataxia–telangiectasia mutated (ATM) gene, IVS10-6T→G, was reported by an Australian multiple-case breast cancer family cohort study (the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer) to confer a substantial breast cancer risk. Although this variant can result in a truncated ATM product, its clinical significance as a high-penetrance breast cancer allele or its role as a low-penetrance risk-modifier is controversial. We determined the frequency of ATM IVS10-6T→G variants in a cohort of individuals affected by breast and/or ovarian cancer who underwent BRCA1 and BRCA2 genetic testing at four major Australian familial cancer clinics. Seven of 495 patients (1.4%) were heterozygous for the IVS10-6T→G variant; the carrier rate in unselected Australian women with no family history of breast cancer is reported to be 6 of 725 (0.83%) (P = 0.4). Two of the seven probands also harboured a pathogenic BRCA1 mutation and one patient had a BRCA1 unclassified variant of uncertain significance. These findings indicate that the ATM IVS10-6T→G variant does not seem to occur at a significantly higher frequency in affected individuals from high-risk families than in the general population. A role for this variant as a low-penetrance allele or as a modifying gene in association with other genes (such as BRCA1) remains possible. Routine testing for ATM IVS10-6T→G is not warranted in mutation screening of affected individuals from high-risk families