| 1. |
- Arking, D. E., et al.
(författare)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Tidskriftsartikel (refereegranskat)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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| 2. |
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| 3. |
- Di Angelantonio, E., et al.
(författare)
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Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease
- 2014
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Ingår i: Jama-Journal of the American Medical Association. - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 311:12, s. 1225-1233
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE The value of measuring levels of glycated hemoglobin (HbA(1c)) for the prediction of first cardiovascular events is uncertain. OBJECTIVE To determine whether adding information on HbA(1c) values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk. DESIGN, SETTING, AND PARTICIPANTS Analysis of individual-participant data available from 73 prospective studies involving 294 998 participants without a known history of diabetes mellitus or CVD at the baseline assessment. MAIN OUTCOMES AND MEASURES Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (>= 7.5%) risk. RESULTS During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20 840 incident fatal and nonfatal CVD outcomes (13 237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA(1c) values and CVD risk. The association between HbA(1c) values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA(1c) was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA(1c) assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels. CONCLUSIONS AND RELEVANCE In a study of individuals without known CVD or diabetes, additional assessment of HbA(1c) values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.
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| 4. |
- Hellgren, K., et al.
(författare)
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Ankylosing Spondylitis, Psoriatic Arthritis, and Risk of Malignant Lymphoma : A Cohort Study Based on Nationwide Prospectively Recorded Data From Sweden
- 2014
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 66:5, s. 1282-1290
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Data on lymphoma risk in ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are scarce. This study was undertaken to assess the risk of lymphoma in AS and PsA overall and in relation to therapies, including tumor necrosis factor inhibitor (TNFi), for which lymphoma risks are a concern. Methods. Through the Swedish National Patient Register we assembled nationwide prevalence cohorts of patients with AS (n = 8,707) and patients with PsA (n = 19,283) for whom data were obtained between 2001 and 2010. Each cohort member was matched to 5 population comparator subjects. Linkage with the nationwide Cancer Register identified all lymphomas recorded from 2001 to 2010. Through the Swedish Biologics Register (Anti-Rheumatic Therapy in Sweden [ARTIS]), we identified patients exposed to TNFi in the AS cohort (n = 1,908) and the PsA cohort (n = 2,605) before lymphoma diagnosis. Hazard ratios (HRs) for lymphoma were estimated by Cox regression. Crude incidences of lymphoma in TNFi-exposed and TNFi-naive patients were compared. Results. For AS patients, the HR of having lymphoma versus the general population was 0.9 (95% confidence interval [95% CI] 0.5-1.6) (14 lymphomas). For PsA patients, the corresponding HR was 1.2 (95% CI 0.9-1.7) (45 lymphomas). For PsA patients treated with methotrexate and/or sulfasalazine, the HR of having lymphoma was 1.7 (95% CI 1.0-3.1). The numbers and incidence of lymphoma were not materially different in TNFi-exposed versus TNFi-naive AS and PsA patients, although the numbers of lymphomas were small. Conclusion. In contrast to rheumatoid arthritis, the average risks of lymphoma in AS or PsA are not elevated, although increased risks in a subset of PsA patients cannot be excluded. Our findings indicate that TNFi does not affect the risk of lymphoma in AS or in PsA.
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| 5. |
- Ganna, Andrea, et al.
(författare)
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Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart Disease
- 2014
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 10:12, s. e1004801-
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.
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| 6. |
- Haldrup, K., et al.
(författare)
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Guest-Host Interactions Investigated by Time-Resolved X-ray Spectroscopies and Scattering at MHz Rates: Solvation Dynamics and Photoinduced Spin Transition in Aqueous Fe(bipy)(3)(2+)
- 2012
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Ingår i: The Journal of Physical Chemistry Part A: Molecules, Spectroscopy, Kinetics, Environment and General Theory. - : American Chemical Society (ACS). - 1520-5215. ; 116:40, s. 9878-9887
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Tidskriftsartikel (refereegranskat)abstract
- We have studied the photoinduced low spin (LS) to high spin (HS) conversion of [Fe(bipy)(3)](2+) in aqueous solution. In a laser pump/X-ray probe synchrotron setup permitting simultaneous, time-resolved X-ray diffuse scattering (XDS) and X-ray spectroscopic measurements at a 3.26 MHz repetition rate, we observed the interplay between intramolecular dynamics and the intermolecular caging solvent response with better than 100 ps time resolution. On this time scale, the initial ultrafast spin transition and the associated intramolecular geometric structure changes are long completed, as is the solvent heating due to the initial energy dissipation from the excited HS molecule. Combining information from X-ray emission spectroscopy and scattering, the excitation fraction as well as the temperature and density changes of the solvent can be closely followed on the subnanosecond time scale of the HS lifetime, allowing the detection of an ultrafast change in bulk solvent density. An analysis approach directly utilizing the spectroscopic data in the XDS analysis effectively reduces the number of free parameters, and both combined permit extraction of information about the ultrafast structural dynamics of the caging solvent, in particular, a decrease in the number of water molecules in the first solvation shell is inferred, as predicted by recent theoretical work.
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| 7. |
- Ismail, K. M. K., et al.
(författare)
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Clinical subtypes of core premenstrual disorders: a Delphi survey
- 2013
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Ingår i: Archives of Womens Mental Health. - : Springer Science and Business Media LLC. - 1434-1816 .- 1435-1102. ; 16:3, s. 197-201
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to classify the clinical subtypes of core premenstrual disorders during
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| 8. |
- Johansson, K., et al.
(författare)
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Long-term changes in blood pressure following orlistat and sibutramine treatment : a meta-analysis
- 2010
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Ingår i: Obesity Reviews. - 1467-7881 .- 1467-789X. ; 11:11, s. 777-791
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Tidskriftsartikel (refereegranskat)abstract
- Previous meta-analyses investigating blood pressure effects of anti-obesity drugs have included studies using non-licensed doses, but not data from head-to-head studies. Furthermore, although diabetes is an important comorbidity in obesity, variation in blood pressure effects across diabetes status has not been investigated. The objective of this study was to estimate the effects on systolic (SBP) and diastolic blood pressure (DBP) of orlistat and sibutramine. Medline, EMBASE, the Cochrane controlled trials register and reference lists of identified articles from 1990 to February 2009 were searched. All placebo-controlled randomized controlled trials of 12-month duration or randomized head-to-head studies of any duration on adults using standard doses were included. Studies/study arms were excluded if they only evaluated weight maintenance after weight loss. Randomized controlled trials were identified, subjected to inclusion and exclusion criteria, and reviewed. Random effects models were used for assessment of weighted mean differences. Eighteen placebo-controlled (12 orlistat, 5540 patients; 6 sibutramine, 1495 patients) and four head-to-head trials (348 patients) met the inclusion criteria. Three orlistat and three sibutramine studies examined overweight subjects with type 2 diabetes (T2DM), as did two head-to-head trials. Mean baseline SBP ranged from 119 to 153 mmHg, and mean DBP from 69 to 98 mmHg. Overall, the placebo-controlled SBP change was -1.9 (95% CI; -2.7, -1.1) mmHg for orlistat, and 0.5 (-1.1, 2.1) mmHg for sibutramine. The corresponding values for DBP were -1.5 (-2.2, -0.8) and 1.7 (0.7, 2.6). Compared with patients without diabetes, diabetic patients treated with orlistat experienced smaller and non-significant reductions of SBP (-0.9; -2.6, 0.7 vs. -2.2; -3.0, -1.3) and DBP (-1.0; -2.4, 0.3 vs. -1.6; -2.4, -0.8). For sibutramine, higher on-treatment elevations in SBP (1.6; -1.3, 4.5 vs. 0.1; -1.8, 2.0) and DBP (2.4; 0.6, 4.1 vs. 1.4; 0.3, 2.5) were seen in patients with vs. without diabetes. In head-to-head trials, the overall differences between sibutramine and orlistat were small and non-significant for both SBP (1.0; -2.3, 4.3) and DBP (-0.2; -2.9, 2.5). In conclusion, in the studies using approved sibutramine doses, the drug caused significant elevations in DBP, while the overall SBP effect was near null. Moreover, absence of a blood pressure-lowering effect of orlistat ad a higher DBP elevation by sibutramine were observed for persons with diabetes. Head-to-head studies indicated that an indirect comparison of placebo-adjusted blood pressure effects may overestimate the adverse effects associated with sibutramine, but these studies were small, of shorter duration and of lower quality.
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| 9. |
- Uhlig, Jens, et al.
(författare)
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Table-Top Ultrafast X-Ray Microcalorimeter Spectrometry for Molecular Structure
- 2013
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Ingår i: Physical Review Letters. - 1079-7114. ; 110:13
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Tidskriftsartikel (refereegranskat)abstract
- This work presents an x-ray absorption measurement by use of ionizing radiation generated by a femtosecond pulsed laser source. The spectrometer was a microcalorimetric array whose pixels are capable of accurately measuring energies of individual radiation quanta. An isotropic continuum x-ray spectrum in the few-keV range was generated from a laser plasma source with a water-jet target. X rays were transmitted through a ferrocene powder sample to the detector, whose pixels have average photon energy resolution Delta E = 3.14 eV full-width-at-half-maximum at 5.9 keV. The bond distance of ferrocene was retrieved from this first hard-x-ray absorption fine-structure spectrum collected with an energy-dispersive detector. This technique will be broadly enabling for time-resolved observations of structural dynamics in photoactive systems. DOI: 10.1103/PhysRevLett.110.138302
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| 10. |
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