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| 3. |
- Arking, D. E., et al.
(author)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Journal article (peer-reviewed)abstract
- The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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| 12. |
- Smiljanic, R., et al.
(author)
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The Gaia-ESO Survey: The analysis of high-resolution UVES spectra of FGK-type stars
- 2014
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In: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 570
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Journal article (peer-reviewed)abstract
- Context. The ongoing Gaia-ESO Public Spectroscopic Survey is using FLAMES at the VLT to obtain high-quality medium-resolution Giraffe spectra for about 10(5) stars and high-resolution UVES spectra for about 5000 stars. With UVES, the Survey has already observed 1447 FGK-type stars. Aims. These UVES spectra are analyzed in parallel by several state-of-the-art methodologies. Our aim is to present how these analyses were implemented, to discuss their results, and to describe how a final recommended parameter scale is defined. We also discuss the precision (method-to-method dispersion) and accuracy (biases with respect to the reference values) of the final parameters. These results are part of the Gaia-ESO second internal release and will be part of its first public release of advanced data products. Methods. The final parameter scale is tied to the scale defined by the Gaia benchmark stars, a set of stars with fundamental atmospheric parameters. In addition, a set of open and globular clusters is used to evaluate the physical soundness of the results. Each of the implemented methodologies is judged against the benchmark stars to define weights in three different regions of the parameter space. The final recommended results are the weighted medians of those from the individual methods. Results. The recommended results successfully reproduce the atmospheric parameters of the benchmark stars and the expected T-eff-log g relation of the calibrating clusters. Atmospheric parameters and abundances have been determined for 1301 FGK-type stars observed with UVES. The median of the method-to-method dispersion of the atmospheric parameters is 55K for T-eff, 0.13dex for log g and 0.07 dex for [Fe/H]. Systematic biases are estimated to be between 50-100 K for T-eff, 0.10-0.25 dex for log g and 0.05-0.10 dex for [Fe/H]. Abundances for 24 elements were derived: C, N, O, Na, Mg, Al, Si, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Mo, Ba, Nd, and Eu. The typical method-to-method dispersion of the abundances varies between 0.10 and 0.20 dex. Conclusions. The Gaia-ESO sample of high-resolution spectra of FGK-type stars will be among the largest of its kind analyzed in a homogeneous way. The extensive list of elemental abundances derived in these stars will enable significant advances in the areas of stellar evolution and Milky Way formation and evolution.
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| 14. |
- Vimaleswaran, K. S., et al.
(author)
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Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts
- 2013
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In: Plos Medicine. - : Public Library of Science (PLoS). - 1549-1676 .- 1549-1277. ; 10:2
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Journal article (peer-reviewed)abstract
- BACKGROUND: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. METHODS AND FINDINGS: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n=123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p=6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p=6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p=0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p=0.88; metabolism score, p=0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p=0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). CONCLUSIONS: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
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| 15. |
- Bergemann, M., et al.
(author)
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The Gaia-ESO Survey : radial metallicity gradients and age-metallicity relation of stars in the Milky Way disk
- 2014
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 565, s. A89-
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Journal article (peer-reviewed)abstract
- We study the relationship between age, metallicity, and alpha-enhancement of FGK stars in the Galactic disk. The results are based upon the analysis of high-resolution UVES spectra from the Gaia-ESO large stellar survey. We explore the limitations of the observed dataset, i.e. the accuracy of stellar parameters and the selection effects that are caused by the photometric target preselection. We find that the colour and magnitude cuts in the survey suppress old metal-rich stars and young metal-poor stars. This suppression may be as high as 97% in some regions of the age-metallicity relationship. The dataset consists of 144 stars with a wide range of ages from 0.5 Gyr to 13.5 Gyr, Galactocentric distances from 6 kpc to 9.5 kpc, and vertical distances from the plane 0 < vertical bar Z vertical bar < 1.5 kpc. On this basis, we find that i) the observed age-metallicity relation is nearly flat in the range of ages between 0 Gyr and 8 Gyr; ii) at ages older than 9 Gyr, we see a decrease in [Fe/H] and a clear absence of metal-rich stars; this cannot be explained by the survey selection functions; iii) there is a significant scatter of [Fe/H] at any age; and iv) [Mg/Fe] increases with age, but the dispersion of [Mg/Fe] at ages > 9 Gyr is not as small as advocated by some other studies. In agreement with earlier work, we find that radial abundance gradients change as a function of vertical distance from the plane. The [Mg/Fe] gradient steepens and becomes negative. In addition, we show that the inner disk is not only more alpha-rich compared to the outer disk, but also older, as traced independently by the ages and Mg abundances of stars.
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| 18. |
- Hansen, T. W., et al.
(author)
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Ambulatory blood pressure monitoring for risk stratification in obese and non-obese subjects from 10 populations
- 2014
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In: Journal of Human Hypertension. - : Springer Science and Business Media LLC. - 0950-9240 .- 1476-5527. ; 28:9, s. 535-542
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Journal article (peer-reviewed)abstract
- Overweight clusters with high blood pressure (BP), but the independent contribution of both risk factors remains insufficiently documented. In a prospective population study involving 8467 participants (mean age 54.6 years; 47.0% women) randomly recruited from 10 populations, we studied the contribution of body mass index (BMI) to risk over and beyond BP, taking advantage of the superiority of ambulatory over conventional BP. Over 10.6 years (median), 1271 participants (15.0%) died and 1092 (12.9%), 637 (7.5%) and 443 (5.2%) experienced a fatal or nonfatal cardiovascular, cardiac or cerebrovascular event. Adjusted for sex and age, low BMI (<20.7 kg m(-2)) predicted death (hazard ratio (HR) vs average risk, 1.52; P<0.0001) and high BMI (>= 30.9 kg m(-2)) predicted the cardiovascular end point (HR, 1.27; P = 0.006). With adjustments including 24-h systolic BP, these HRs were 1.50 (P <0.001) and 0.98 (P = 0.91), respectively. Across quartiles of the BMI distribution, 24-h and nighttime systolic BP predicted every end point (1.13 <= standardized HR <= 1.67; 0.046 <= P<0.0001). The interaction between systolic BP and BMI was nonsignificant (P >= 0.22). Excluding smokers removed the contribution of BMI categories to the prediction of mortality. In conclusion, BMI only adds to BP in risk stratification for mortality but not for cardiovascular outcomes. Smoking probably explains the association between increased mortality and low BMI.
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| 19. |
- Magrini, L., et al.
(author)
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The Gaia-ESO Survey: Abundance ratios in the inner-disk open clusters Trumpler 20, NGC 4815, NGC 6705
- 2014
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In: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 563
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Journal article (peer-reviewed)abstract
- Context. Open clusters are key tools to study the spatial distribution of abundances in the disk and their evolution with time. Aims. Using the first release of stellar parameters and abundances of the Gaia-ESO Survey, we analyse the chemical properties of stars in three old/intermediate-age open clusters, namely NGC 6705, NGC 4815, and Trumpler 20, which are all located in the inner part of the Galactic disk at Galactocentric radius R-GC similar to 7 kpc. We aim to prove their homogeneity and to compare them with the field population. Methods. We study the abundance ratios of elements belonging to two different nucleosynthetic channels: alpha-elements and iron-peak elements. For each element, we analyse the internal chemical homogeneity of cluster members, and we compare the cumulative distributions of cluster abundance ratios with those of solar neighbourhood turn-off stars and of inner-disk/bulge giants. We compare the abundance ratios of field and cluster stars with two chemical evolution models that predict different alpha-enhancement dependences on the Galactocentric distance due to different assumptions on the infall and star-formation rates. Results. The main results can be summarised as follows: i) cluster members are chemically homogeneous within 3 sigma in all analysed elements; ii) the three clusters have comparable [El/Fe] patterns within similar to 1 sigma, but they differ in their global metal content [El/H] with NGC 4815 having the lowest metallicity; their [El/Fe] ratios show differences and analogies with those of the field population, in both the solar neighbourhood and the bulge/inner disk; iii) comparing the abundance ratios with the results of two chemical evolution models and with field star abundance distributions, we find that the abundance ratios of Mg, Ni, and Ca in NGC 6705 might require an inner birthplace, implying a subsequent variation in its R-GC during its lifetime, which is consistent with previous orbit determination. Conclusions. Using the results of the first internal data release, we show the potential of the Gaia-ESO Survey through a homogeneous and detailed analysis of the cluster versus field populations to reveal the chemical structure of our Galaxy using a completely uniform analysis of different populations. We verify that the Gaia-ESO Survey data are able to identify the unique chemical properties of each cluster by pinpointing the composition of the interstellar medium at the epoch and place of formation. The full dataset of the Gaia-ESO Survey is a superlative tool to constrain the chemical evolution of our Galaxy by disentangling different formation and evolution scenarios.
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| 20. |
- Palmer, Nicholette D, et al.
(author)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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In: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Journal article (peer-reviewed)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 21. |
- Sacco, G. G., et al.
(author)
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The Gaia-ESO Survey: processing FLAMES-UVES spectra
- 2014
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In: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 565
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Journal article (peer-reviewed)abstract
- The Gaia-ESO Survey is a large public spectroscopic survey that aims to derive radial velocities and fundamental parameters of about 10(5) Milky Way stars in the field and in clusters. Observations are carried out with the multi-object optical spectrograph FLAMES, using simultaneously the medium-resolution (R similar to 20 000) GIRAFFE spectrograph and the high-resolution (R similar to 47 000) UVES spectrograph. In this paper we describe the methods and the software used for the data reduction, the derivation of the radial velocities, and the quality control of the FLAMES-UVES spectra. Data reduction has been performed using a workflow specifically developed for this project. This workflow runs the ESO public pipeline optimizing the data reduction for the Gaia-ESO Survey, automatically performs sky subtraction, barycentric correction and normalisation, and calculates radial velocities and a first guess of the rotational velocities. The quality control is performed using the output parameters from the ESO pipeline, by a visual inspection of the spectra and by the analysis of the signal-to-noise ratio of the spectra. Using the observations of the first 18 months, specifically targets observed multiple times at different epochs, stars observed with both GIRAFFE and UVES, and observations of radial velocity standards, we estimated the precision and the accuracy of the radial velocities. The statistical error on the radial velocities is sigma similar to 0.4 km s(-1) and is mainly due to uncertainties in the zero point of the wavelength calibration. However, we found a systematic bias with respect to the GIRAFFE spectra (similar to 0.9 km s(-1)) and to the radial velocities of the standard stars (similar to 0.5 km s(-1)) retrieved from the literature. This bias will be corrected in the future data releases, when a common zero point for all the set-ups and instruments used for the survey is be established.
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| 28. |
- Friel, E. D., et al.
(author)
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Gaia-ESO Survey : Properties of the intermediate age open cluster NGC 4815
- 2014
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 563, s. A117-
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Journal article (peer-reviewed)abstract
- Context. NGC 4815 is a populous similar to 500 Myr open cluster at R-gc similar to 7 kpc observed in the first six months of the Gaia-ESO Survey. Located in the inner Galactic disk, NGC 4815 is an important potential tracer of the abundance gradient, where relatively few intermediate age open clusters are found. Aims. The Gaia-ESO Survey data can provide an improved characterization of the cluster properties, such as age, distance, reddening, and abundance profile. Methods. We use the survey derived radial velocities, stellar atmospheric parameters, metallicity, and elemental abundances for stars targeted as potential members of this cluster to carry out an analysis of cluster properties. The radial velocity distribution of stars in the cluster field is used to define the cluster systemic velocity and derive likely cluster membership for stars observed by the Gaia-ESO Survey. We investigate the distributions of Fe and Fe-peak elements, alpha-elements, and the light elements Na and Al and characterize the cluster's internal chemical homogeneity comparing it to the properties of radial velocity non-member stars. Utilizing these cluster properties, the cluster color-magnitude diagram is analyzed and theoretical isochrones are fit to derive cluster reddening, distance, and age. Results. NGC 4815 is found to have a mean metallicity of [Fe/H] = +0.03 +/- 0.05 dex (s.d.). Elemental abundances of cluster members show typically very small internal variation, with internal dispersions of similar to 0.05 dex. The alpha-elements [Ca/Fe] and [Si/Fe] show solar ratios, but [Mg/Fe] is moderately enhanced, while [Ti/Fe] appears slightly deficient. As with many open clusters, the light elements [Na/Fe] and [Al/Fe] are enhanced, [Na/Fe] significantly so, although the role of internal mixing and the assumption of local thermodynamical equilibrium in the analysis remain to be investigated. From isochrone fits to color-magnitude diagrams, we find a cluster age of 0.5 to 0.63 Gyr, a reddening of E(B-V) = 0.59 to 0.65, and a distance modulus (m -M)(0) = 11.95 to 12.20, depending on the choice of theoretical models, leading to a Galactocentric distance of 6.9 kpc.
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| 30. |
- Ho, J. E., et al.
(author)
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Clinical and genetic correlates of growth differentiation factor 15 in the community
- 2012
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In: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 58:11, s. 1582-1591
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Journal article (peer-reviewed)abstract
- BACKGROUND: Growth differentiation factor 15(GDF15), a stress-responsive cytokine produced in cardiovascular cells under conditions of inflammation and oxidative stress, is emerging as an important prognostic marker in individuals with and without existing cardiovascular disease (CVD). We therefore examined the clinical and genetic correlates of circulating GDF15 concentrations, which have not been investigated collectively. METHODS: Plasma GDF15 concentrations were measured in 2991 participants in the Framingham Offspring Study who were free of clinically overt CVD (mean age, 59 years; 56% women). Clinical correlates of GDF15 were examined in multivariable analyses. We then conducted a genomewide association study of the GDF15 concentration that included participants in the Framingham Offspring Study and participants in the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study. RESULTS: GDF15 was positively associated with age, smoking, antihypertensive treatment, diabetes, worse kidney function, and use of nonsteroidal antiinflammatory drugs (NSAIDs), but it was negatively associated with total cholesterol and HDL cholesterol. Clinical correlates accounted for 38% of interindividual variation in the circulating GDF15 concentration, whereas genetic factors accounted for up to 38% of the residual variability (h 2 = 0.38; P = 2.5 X 10 -11). We identified 1 locus of genomewide significance. This locus, which is on chromosome 19p13.11 and includes the GDF15 gene, is associated with GDF15 concentration (smallest P = 2.74 X 10 -32 for rs888663). Conditional analyses revealed 2 independent association signals at this locus (rs888663 and rs1054564), which were associated with altered cis gene expression in blood cell lines. CONCLUSIONS: In ambulatory individuals, both cardiometabolic risk factors and genetic factors play important roles in determining circulating GDF15 concentrations and contribute similarly to the overall variation.
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| 31. |
- Howes, Louise, et al.
(author)
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The Gaia-ESO Survey: the most metal-poor stars in the Galactic bulge
- 2014
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In: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 1365-2966 .- 0035-8711. ; 445:4, s. 4241-4246
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Journal article (peer-reviewed)abstract
- We present the first results of the EMBLA survey (Extremely Metal-poor BuLge stars with AAOmega), aimed at finding metal-poor stars in the Milky Way bulge, where the oldest stars should now preferentially reside. EMBLA utilizes SkyMapper photometry to pre-select metal-poor candidates, which are subsequently confirmed using AAOmega spectroscopy. We describe the discovery and analysis of four bulge giants with -2.72 <= [Fe/H] <= -2.48, the lowest metallicity bulge stars studied with high-resolution spectroscopy to date. Using FLAMES/UVES spectra through the Gaia-ESO Survey we have derived abundances of twelve elements. Given the uncertainties, we find a chemical similarity between these bulge stars and halo stars of the same metallicity, although the abundance scatter may be larger, with some of the stars showing unusual [alpha/Fe] ratios.
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| 32. |
- Jofre, P., et al.
(author)
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Gaia FGK benchmark stars : Metallicity
- 2014
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 564, s. A133-
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Journal article (peer-reviewed)abstract
- Context. To calibrate automatic pipelines that determine atmospheric parameters of stars, one needs a sample of stars, or "benchmark stars", with well-defined parameters to be used as a reference. Aims. We provide detailed documentation of the iron abundance determination of the 34 FGK-type benchmark stars that are selected to be the pillars for calibration of the one billion Gaia stars. They cover a wide range of temperatures, surface gravities, and metallicities. Methods. Up to seven different methods were used to analyze an observed spectral library of high resolutions and high signal-to-noise ratios. The metallicity was determined by assuming a value of effective temperature and surface gravity obtained from fundamental relations; that is, these parameters were known a priori and independently from the spectra. Results. We present a set of metallicity values obtained in a homogeneous way for our sample of benchmark stars. In addition to this value, we provide detailed documentation of the associated uncertainties.Finally, we report a value of the metallicity of the cool giant psi Phe for the first time.
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| 36. |
- Tang, Wenbo, et al.
(author)
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Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function
- 2014
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:7, s. e100776-
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Journal article (peer-reviewed)abstract
- Background: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. Methods: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. Results: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 x 10(-7)). In addition, meta-analysis using the five cohorts with >= 3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 x 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. Conclusions: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
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| 37. |
- Warden, Diane, et al.
(author)
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Anticipated Benefits of Care (ABC) : psychometrics and predictive value in psychiatric disorders
- 2010
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In: Psychological Medicine. - 0033-2917 .- 1469-8978. ; 40:6, s. 955-965
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Journal article (peer-reviewed)abstract
- BACKGROUND: Attitudes and expectations about treatment have been associated with symptomatic outcomes, adherence and utilization in patients with psychiatric disorders. No measure of patients' anticipated benefits of treatment on domains of everyday functioning has previously been available.MethodThe Anticipated Benefits of Care (ABC) is a new, 10-item questionnaire used to measure patient expectations about the impact of treatment on domains of everyday functioning. The ABC was collected at baseline in adult out-patients with major depressive disorder (MDD) (n=528), bipolar disorder (n=395) and schizophrenia (n=447) in the Texas Medication Algorithm Project (TMAP). Psychometric properties of the ABC were assessed, and the association of ABC scores with treatment response at 3 months was evaluated. RESULTS: Evaluation of the ABC's internal consistency yielded Cronbach's alpha of 0.90-0.92 for patients across disorders. Factor analysis showed that the ABC was unidimensional for all patients and for patients with each disorder. For patients with MDD, lower anticipated benefits of treatment was associated with less symptom improvement and lower odds of treatment response [odds ratio (OR) 0.72, 95% confidence interval (CI) 0.57-0.87, p=0.0011]. There was no association between ABC and symptom improvement or treatment response for patients with bipolar disorder or schizophrenia, possibly because these patients had modest benefits with treatment. CONCLUSIONS: The ABC is the first self-report that measures patient expectations about the benefits of treatment on everyday functioning, filling an important gap in available assessments of attitudes and expectations about treatment. The ABC is simple, easy to use, and has acceptable psychometric properties for use in research or clinical settings.
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| 40. |
- Berndt, Sonja I., et al.
(author)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Journal article (peer-reviewed)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 41. |
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| 42. |
- Damiani, F., et al.
(author)
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Gaia-ESO Survey: Empirical classification of VLT/Giraffe stellar spectra in the wavelength range 6440-6810 angstrom in the gamma Velorum cluster, and calibration of spectral indices
- 2014
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In: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 566
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Journal article (peer-reviewed)abstract
- We present a study of spectral diagnostics available from optical spectra with R = 17 000 obtained with the VLT/Giraffe HR15n setup, using observations from the Gaia-ESO Survey, on the gamma Vel young cluster, with the purpose of classifying these stars and finding their fundamental parameters. We define several spectroscopic indices, sampling the amplitude of TiO bands, the H alpha line core and wings, and temperature- and gravity-sensitive sets of lines, each useful as a T-eff or log g indicator over a limited range of stellar spectral types. H alpha line indices are also useful as chromospheric activity or accretion indicators. Furthermore, we use all indices to define additional global T-eff - and logg-sensitive indices tau and gamma, valid for the entire range of types in the observed sample. We find a clear difference between gravity indices of main-sequence and pre-main-sequence stars, as well as a much larger difference between these and giant stars. The potentially great usefulness of the (gamma, t) diagram as a distance-independent age measurement tool for young clusters is discussed. We discuss the effect on the defined indices of classical T Tauri star veiling, which is however detected in only a few stars in the present sample. Then, we present tests and calibrations of these indices, on the basis of both photometry and literature reference spectra, from the UVES Paranal Observatory Project and the ELODIE 3.1 Library. The known properties of these stars, spanning a wide range of stellar parameters, enable us to obtain a good understanding of the performances of our new spectral indices. For non-peculiar stars with known temperature, gravity, and metallicity, we are able to calibrate quantitatively our indices, and derive stellar parameters for a wide range of stellar types. To this aim, a new composite index is defined, providing a good metallicity indicator. The ability of our indices to select peculiar, or otherwise rare classes of stars is also established. For pre-main-sequence stars outside the parameter range of the ELODIE dataset, index calibration relies on model isochrones. We check our calibrations against current Gaia-ESO UVES results, plus a number of Survey benchmark stars, and also against Gaia-ESO observations of young clusters, which contribute to establishing the good performance of our method across a wide range of stellar parameters. Our gravity determination for late-type PMS stars is found to be accurate enough to let us obtain gravity-based age estimates for PMS clusters. Finally, our gravity determinations support the existence of an older pre-main-sequence population in the gamma Vel sky region, in agreement with evidence obtained from the lithium depletion pattern of the same stars.
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| 45. |
- Evangelou, Evangelos, et al.
(author)
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A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip
- 2014
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In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 73:12, s. 2130-2136
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Journal article (peer-reviewed)abstract
- Objectives Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. Methods We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. Results We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9x10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p= 5.6x10(-8)) and follow-up studies (p=7.3x10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9x10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2x10(-6), OR=1.27 in male specific analysis). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.
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| 48. |
- Gifstad, T, et al.
(author)
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Lower risk of revision with patellar tendon autografts compared with hamstring autografts: a registry study based on 45,998 primary ACL reconstructions in Scandinavia
- 2014
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In: The American journal of sports medicine. - : SAGE Publications. - 1552-3365 .- 0363-5465. ; 42:10, s. 2319-2328
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Journal article (peer-reviewed)abstract
- A number of studies have found comparable results after anterior cruciate ligament (ACL) reconstruction with patellar tendon autografts and hamstring autografts; however, few studies have been large enough to reveal differences in risk of revision with regard to clinical and demographic factors. Purpose: To present the distribution of grafts for ACL reconstruction based on data in the Scandinavian ACL registries and to compare the risk of revision between patellar tendon autografts and hamstring autografts. Potential associations with other clinical and demographic factors were also explored. Study design: Cohort study; Level of evidence, 2. Methods: A total of 45,998 primary ACL reconstructions, including 6736 patellar tendon autografts and 38,666 hamstring autografts, were identified in the Scandinavian ACL registries. The overall median follow-up time was 3 years (range, 0-8 years). To compare the risk of revision between groups of patients, univariate Kaplan-Meier analysis (with log-rank test) and the Cox proportional hazard regression model were applied. The hazard rate ratio with 95% CI was reported as a measure of effect. Results: Patellar tendon and hamstring autografts were used in 14.6% and 84.1% of the patients, respectively. The remaining patients received allografts, direct sutures, or other graft types (1.3%). The primary ACL injury occurred during soccer, team handball, or alpine activities in 67.5% of the patients in the patellar tendon group and 66.2% in the hamstring group. A total of 156 patients in the patellar tendon group and 1042 patients in the hamstring group underwent revision. The overall risk of revision was significantly lower in the patellar tendon group versus the hamstring group (hazard rate ratio = 0.63; 95% CI, 0.53-0.74), and it decreased with increasing age at surgery, although not strictly linearly. The lower risk of revision in the patellar tendon group was consistently observed across subgroups of patient sex, age, and concomitant cartilage injury ( P > .05, test for interaction) but seemed to be slightly more pronounced for patients injured during certain pivoting activities (soccer, team handball, and alpine activities) compared with other activities (hazard rate ratio = 0.57 vs 0.81; P = .058, test for interaction). Conclusion: The majority of primary ACL reconstructions in Scandinavia are performed with hamstring autografts. Results from the present large prospective study show that patients receiving patellar tendon autografts have a statistically significantly lower risk of revision compared with patients receiving hamstring autografts.
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| 49. |
- Hemdan, Tammer, et al.
(author)
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The prognostic value and therapeutic target role of stathmin-1 in urinary bladder cancer
- 2014
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 111:6, s. 1180-1187
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Journal article (peer-reviewed)abstract
- Background:The oncoprotein-18/stathmin 1 (STMN1), involved in cell progression and migration, is associated with clinical outcome in breast cancer. Here we aim to investigate its clinical significance in urinary bladder cancer and its possibilities as a therapeutic target.Methods:Immunohistochemical analyses of STMN1 protein expression were performed in three patient cohorts: cohort I (n=115 Ta, n=115 T1, n=112 T2-4 stages), cohort II, based on randomised controlled trials (n=239 T1-T4), and cohort III of primary tumour/matched metastasis (n=90 T1-T4). The effects of STMN1 on cell proliferation and migration were evaluated in the urinary bladder cancer cell line, T24, by inhibiting STMN1-cellular expression using siRNA.Results:In cohort I, high STMN1 expression correlated to shorter disease-specific survival hazard ratio (HR)=2.04 (95% confidence interval (CI) 1.13-3.68; P=0.02), elevated p53- (P<0.001) and Ki67-protein levels (P<0.001). The survival result was validated in cohort II: HR=1.76 (95% CI 1.04-2.99; P=0.03). In the metastatic bladder cancer material, 70% of the patients were STMN1-positive in both the primary tumour and matched metastases. In vitro, the growth and migration of the T24 cells were significantly reduced (P<0.01, P<0.0001, respectively), when transfecting the cells with STMN1-siRNA.Conclusions:STMN1 protein expression has prognostic significance but is primarily a potential treatment target in urinary bladder cancer.
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| 50. |
- Herlin, Maria, et al.
(author)
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Quantitative characterization of changes in bone geometry, mineral density and biomechanical properties in two rat strains with different Ah-receptor structures after long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin
- 2010
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In: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 273:1-3, s. 1-11
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Journal article (peer-reviewed)abstract
- BACKGROUND: Both industrial chemicals and environmental pollutants can interfere with bone modeling and remodeling. Recently, detailed toxicological bone studies have been performed following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which exerts most of its toxic effects through the aryl hydrocarbon receptor (AhR). OBJECTIVES: The aims of the present study were to quantitatively evaluate changes in bone geometry, mineral density and biomechanical properties following long-term exposure to TCDD, and to further investigate the role of AhR in TCDD-induced bone alterations. To this end, tissue material used in the study was derived from TCDD-exposed Long-Evans (L-E) and Han/Wistar (H/W) rats, which differ markedly in sensitivity to TCDD-induced toxicity due to a strain difference in AhR structure. METHODS: Ten weeks old female L-E and H/W rats were administered TCDD s.c. once per week for 20 weeks, at doses corresponding to calculated daily doses of 0, 1, 10, 100 and 1000ngTCDD/kgbw (H/W only). Femur, tibia and vertebra from the L-E and H/W rats were analyzed by peripheral quantitative computed tomography (pQCT) and biomechanical testing at multiple sites. Dose-response modeling was performed to establish benchmark doses for the analyzed bone parameters, and to quantify strain sensitivity differences for those parameters, which were affected by TCDD exposure in both rat strains. RESULTS: Bone geometry and bone biomechanical parameters were affected by TCDD exposure, while bone mineral density parameters were less affected. The trabecular area at proximal tibia and the endocortical circumference at tibial diaphysis were the parameters that showed the highest maximal responses. Significant strain differences in response to TCDD treatment were observed, with the L-E rat being the most sensitive strain. For the parameters that were affected in both strains, the differences in sensitivity were quantified, showing the most pronounced (about 49-fold) strain difference for cross-sectional area of proximal tibia. CONCLUSION: The study provides novel information about TCDD-induced bone alterations at doses, which are of relevance from a health risk assessment point of view. In addition, the obtained results provide further support for a distinct role of the AhR in TCDD-induced bone alterations, and suggest that the benchmark dose modeling approach is appropriate for quantitative evaluation of bone toxicity parameters.
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