| 1. |
- Aad, G., et al.
(författare)
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Readiness of the ATLAS Tile Calorimeter for LHC collisions
- 2010
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Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 70:4, s. 1193-1236
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Tidskriftsartikel (refereegranskat)abstract
- The Tile hadronic calorimeter of the ATLAS detector has undergone extensive testing in the experimental hall since its installation in late 2005. The readout, control and calibration systems have been fully operational since 2007 and the detector has successfully collected data from the LHC single beams in 2008 and first collisions in 2009. This paper gives an overview of the Tile Calorimeter performance as measured using random triggers, calibration data, data from cosmic ray muons and single beam data. The detector operation status, noise characteristics and performance of the calibration systems are presented, as well as the validation of the timing and energy calibration carried out with minimum ionising cosmic ray muons data. The calibration systems' precision is well below the design value of 1%. The determination of the global energy scale was performed with an uncertainty of 4%.
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| 2. |
- Aad, G., et al.
(författare)
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Studies of the performance of the ATLAS detector using cosmic-ray muons
- 2011
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Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 71:3
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Tidskriftsartikel (refereegranskat)abstract
- Muons from cosmic-ray interactions in the atmosphere provide a high-statistics source of particles that can be used to study the performance and calibration of the ATLAS detector. Cosmic-ray muons can penetrate to the cavern and deposit energy in all detector subsystems. Such events have played an important role in the commissioning of the detector since the start of the installation phase in 2005 and were particularly important for understanding the detector performance in the time prior to the arrival of the first LHC beams. Global cosmic-ray runs were undertaken in both 2008 and 2009 and these data have been used through to the early phases of collision data-taking as a tool for calibration, alignment and detector monitoring. These large datasets have also been used for detector performance studies, including investigations that rely on the combined performance of different subsystems. This paper presents the results of performance studies related to combined tracking, lepton identification and the reconstruction of jets and missing transverse energy. Results are compared to expectations based on a cosmic-ray event generator and a full simulation of the detector response.
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| 3. |
- Aad, G., et al.
(författare)
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The ATLAS Inner Detector commissioning and calibration
- 2010
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Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 70:3, s. 787-821
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Tidskriftsartikel (refereegranskat)abstract
- The ATLAS Inner Detector is a composite tracking system consisting of silicon pixels, silicon strips and straw tubes in a 2 T magnetic field. Its installation was completed in August 2008 and the detector took part in data-taking with single LHC beams and cosmic rays. The initial detector operation, hardware commissioning and in-situ calibrations are described. Tracking performance has been measured with 7.6 million cosmic-ray events, collected using a tracking trigger and reconstructed with modular pattern-recognition and fitting software. The intrinsic hit efficiency and tracking trigger efficiencies are close to 100%. Lorentz angle measurements for both electrons and holes, specific energy-loss calibration and transition radiation turn-on measurements have been performed. Different alignment techniques have been used to reconstruct the detector geometry. After the initial alignment, a transverse impact parameter resolution of 22.1 +/- 0.9 mu m and a relative momentum resolution sigma (p) /p=(4.83 +/- 0.16)x10(-4) GeV(-1)xp (T) have been measured for high momentum tracks.
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| 4. |
- Aad, G., et al.
(författare)
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The ATLAS Simulation Infrastructure
- 2010
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Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 70:3, s. 823-874
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Tidskriftsartikel (refereegranskat)abstract
- The simulation software for the ATLAS Experiment at the Large Hadron Collider is being used for large-scale production of events on the LHC Computing Grid. This simulation requires many components, from the generators that simulate particle collisions, through packages simulating the response of the various detectors and triggers. All of these components come together under the ATLAS simulation infrastructure. In this paper, that infrastructure is discussed, including that supporting the detector description, interfacing the event generation, and combining the GEANT4 simulation of the response of the individual detectors. Also described are the tools allowing the software validation, performance testing, and the validation of the simulated output against known physics processes.
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| 5. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)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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| 6. |
- Aad, G., et al.
(författare)
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Commissioning of the ATLAS Muon Spectrometer with cosmic rays
- 2010
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Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 70:3, s. 875-916
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Tidskriftsartikel (refereegranskat)abstract
- The ATLAS detector at the Large Hadron Collider has collected several hundred million cosmic ray events during 2008 and 2009. These data were used to commission the Muon Spectrometer and to study the performance of the trigger and tracking chambers, their alignment, the detector control system, the data acquisition and the analysis programs. We present the performance in the relevant parameters that determine the quality of the muon measurement. We discuss the single element efficiency, resolution and noise rates, the calibration method of the detector response and of the alignment system, the track reconstruction efficiency and the momentum measurement. The results show that the detector is close to the design performance and that the Muon Spectrometer is ready to detect muons produced in high energy proton-proton collisions.
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| 23. |
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| 24. |
- Almquist, H, et al.
(författare)
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Performance of simultaneous emission-transmission systems for attenuation-corrected SPEct: a method for validation applied to two camera systems
- 2001
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Ingår i: Nuclear Medicine Communications. - 1473-5628. ; 22:7, s. 759-766
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Tidskriftsartikel (refereegranskat)abstract
- Several commercially available systems for attenuation correction in single photon emission computed tomography (SPECT) based on a transmission scan have been introduced that vary in performance. A test procedure for attenuation correction in SPECT is described and applied to two principally different gamma camera systems (the Siemens Multispect 3 triple-headed system [3HS] and the ADAC Genesys Vertex double-headed system [2HS]). The test procedure was based on geometrically well-defined phantoms. A torso phantom was used to illustrate the attenuation correction methods. The test procedure can be used without detailed knowledge of or access to the algorithms used for attenuation correction. The influence on the transmission measurement of radioactivity in a phantom was higher for the 2HS than for the 3HS. The 3HS produced satisfactory attenuation maps and corrected emission count rates to a constant value independent of phantom density and size. With the 2HS, there was a progressive decrease in the correction of emission count rates with increasing phantom density, and about 30% lower corrected count rates in the large compared with the small phantom. A decrease in measured attenuation coefficients in the vicinity of an emission source was demonstrated in large but not small phantoms. A likely explanation is erroneous correction of downscatter into the transmission energy window. This study demonstrates the need for independent evaluation of systems for attenuation correction in SPECT.
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| 25. |
- Almquist, Helén, et al.
(författare)
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Quantitative SPECT by attenuation correction of the projection set using transmission data: evaluation of a method
- 1990
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Ingår i: European Journal Of Nuclear Medicine. - 1432-105X. ; 16:8-10, s. 587-594
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Tidskriftsartikel (refereegranskat)abstract
- A method for measuring attenuation coefficients in single-photon emission tomography (SPECT) is described and evaluated, together with a method for attenuation correction using these measured attenuation coefficients. Build-up, caused by scattered photons, is corrected for by a simple substitution in the algorithms. Transmission studies are performed with a 99mTc- or 57Co flood source, and emission phantom studies with 99mTc line sources. The method is evaluated with variable but well-defined phantoms. The result is accurate attenuation coefficients for different densities, dimensions and geometries, and an accuracy of corrected emission activities of better than +/- 10% in most cases. The present limitations of the method for attenuation correction are discussed.
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| 26. |
- Alvarez-Madrazo, S., et al.
(författare)
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Common Polymorphisms in the CYP11B1 and CYP11B2 Genes: Evidence for a Digenic Influence on Hypertension
- 2013
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Ingår i: Hypertension. - : Ovid Technologies (Wolters Kluwer Health). - 0194-911X .- 1524-4563. ; 61:1, s. 232-239
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Tidskriftsartikel (refereegranskat)abstract
- The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case-control collections for discovery (n = 3340) and confirmation (n = 2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio = 1.16, P = 8.54x10(-5)). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio = 1.11; P = 7.4x10(-3)), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio = 0.88, P = 2.2x10(-3)). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis.
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| 27. |
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| 28. |
- Bajc, Marika, et al.
(författare)
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Lung ventilation/perfusion SPECT in the artificially embolized pig.
- 2002
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Ingår i: Journal of Nuclear Medicine. - 0161-5505. ; 43:5, s. 640-647
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Tidskriftsartikel (refereegranskat)abstract
- Planar lung scintigraphy is a standard method used for the diagnosis of lung embolism, but it is hampered by the high incidence of nondiagnostic tests. Ventilation/perfusion SPECT may possibly improve this situation. The objective of this study was to compare planar lung scintigraphy with ventilation/perfusion SPECT using pigs with artificially engendered lung emboli labeled with (201)Tl. METHODS: Sixteen anesthetized pigs were each injected with zero to 4 latex emboli. Cylindric emboli were used in the first 7 pigs and flat 3-tailed emboli were used in the remaining 9 pigs. The pigs spontaneously inhaled 30 MBq (99m)Tc-diethylenetriaminepentaacetic acid aerosol for ventilation scintigraphy. Planar scintigraphy and SPECT were performed using a double-head gamma camera in (99m)Tc and (201)Tl windows. Immediately thereafter, 100 MBq (99m)Tc-labeled macroaggregated albumin were injected intravenously followed by SPECT and, finally, planar scintigraphy. The ventilation background was subtracted from the perfusion tomograms for calculation of a normalized ventilation/perfusion (V/P) quotient image set. RESULTS: The cylindric emboli caused artifacts in the ventilation images; therefore, these were excluded from the final analysis. However, for the planar perfusion images of these pigs, sensitivity and specificity were 71% and 91%, respectively, whereas SPECT yielded 100% for both. For the 3-tailed emboli and ventilation/perfusion images, the sensitivity and specificity were 64% and 79%, respectively, for the planar modality, whereas SPECT yielded values of 91% and 87%, respectively. CONCLUSION: V/P SPECT may improve the diagnostic power of lung scintigraphy.
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| 29. |
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| 30. |
- Bajc, Marika, et al.
(författare)
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Ventilation/Perfusion SPECT for diagnostics of pulmonary embolism in clinical practice.
- 2008
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 264:4, s. 379-387
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The aim of this retrospective study is to illustrate clinical utility and impact of pulmonary embolism (PE) diagnostics of up to date Ventilation/Perfusion SPECT (V/P (SPECT)) applying holistic interpretation criteria. MATERIAL AND METHODS: During a 2-year period 2328 consecutive patients referred to V/P(SPECT) for clinically suspected PE were examined. Final diagnosis was established by physicians clinically responsible for patient care. To establish the performance of V/P(SPECT) negative for PE, patients were followed up by medical records for 6 months. RESULTS: Ventilation/Perfusion SPECT was feasible in 99% of the patients. Data for follow-up were available in 1785 patients (77%). PE was reported in 607 patients (34%). Normal pattern was described in 420 patients (25%). Pathology other than PE such as a pneumonia, left heart failure, obstructive lung disease, tumour was described in 724 patients (41%). Report was nondiagnostic in 19 patients (1%). Six cases were classified as falsely negative because PE was diagnosed at follow-up and was fatal in one case. Six cases were classified as falsely positive because the clinician decided not to treat. In 608 patients with final PE diagnosis, 601 patients had positive V/P(SPECT) (99%). In 1177 patients without final PE diagnosis 1153 patients had negative V/P(SPECT) (98%). CONCLUSIONS: Holistic interpretation of V/P(SPECT,) yields high negative and positive predictive values and only 1% of nondiagnostic findings and was feasible in 99% of patients. It is a responsibility and a challenge of nuclear medicine to provide optimal care of patients with suspected PE by making V/P(SPECT) available.
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| 31. |
- Beaumont, Robin N, et al.
(författare)
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Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.
- 2023
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Ingår i: Nature genetics. - 1546-1718 .- 1061-4036. ; 55:11, s. 1807-19
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Tidskriftsartikel (refereegranskat)abstract
- A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n=65,405), maternal (n=61,228) and paternal (n=52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.
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| 32. |
- Buntgen, U., et al.
(författare)
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Tree rings reveal globally coherent signature of cosmogenic radiocarbon events in 774 and 993 CE
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Though tree-ring chronologies are annually resolved, their dating has never been independently validated at the global scale. Moreover, it is unknown if atmospheric radiocarbon enrichment events of cosmogenic origin leave spatiotemporally consistent fingerprints. Here we measure the 14C content in 484 individual tree rings formed in the periods 770–780 and 990–1000 CE. Distinct 14C excursions starting in the boreal summer of 774 and the boreal spring of 993 ensure the precise dating of 44 tree-ring records from five continents. We also identify a meridional decline of 11-year mean atmospheric radiocarbon concentrations across both hemispheres. Corroborated by historical eye-witness accounts of red auroras, our results suggest a global exposure to strong solar proton radiation. To improve understanding of the return frequency and intensity of past cosmic events, which is particularly important for assessing the potential threat of space weather on our society, further annually resolved 14C measurements are needed.
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| 33. |
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| 34. |
- Engvall, Sara, 1984-
(författare)
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Opening the black box of mathematics teachers’ professional growth : a study of the process of teacher learning
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There is a lot of research done on professional development programs for teachers, especially with a focus on different characteristics of the program and whether it makes teachers change their teaching practice to such an extent that it enhances student achievement. However, there is not much research done on the learning process. As long as we do not open the black box of teacher learning it is difficult to say anything about what characteristics in a professional development program actually are important for teachers to learn, develop and grow as professionals.The aim of the thesis is to better understand the process of teacher learning while participating in aprofessional development program. The focus is on different aspects of the process of teacher professional growth, as well as on external factors that have an impact on the process of learning. The participants are secondary school teachers that participated in a professional development program in formative assessment. The data have been collected during and after the professional development program took place. Different types of data have been used in this thesis; teacher interviews, classroom observations and questionnaires, and have been collected over a time period of two and a half years. In two of the included papers the studies focus on four mathematics teachers, and the learning process is explored from two different perspectives: how the professional growth can develop, and how their testing of formative assessment activities relates to their understanding of formative assessment. In one of the papers all secondary school teachers are included and a comparison in expectancy of being able to use high quality formative assessment after the professional development program between the mathematics teachers and the other teachers were conducted. In the fourth paper focus is on all mathematics teachers in the study and their motivation are investigated over a time period of two years.The four papers take different perspectives to explore the professional growth for teachers while participating in a professional development program in formative assessment. The results show the complexity of teacher learning and indicate that large-scale implementations risk being inefficient and not reach the intended goals.
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| 35. |
- Gustafsson, Björn, 1948, et al.
(författare)
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The welfare of Sweden's old-age pensioners in times of bust and boom from 1990
- 2009
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Ingår i: Ageing & Society. - 0144-686X .- 1469-1779. ; 29:4, s. 539-561
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Tidskriftsartikel (refereegranskat)abstract
- This study analyses the development of the economic wellbeing of Swedes aged 65 years and older from 1990. This period was characterised by Sweden's deepest and most prolonged recession since the Great Depression, but was then followed by buoyant growth. In a series of interventions from 1991 through to 1998, pensions were cut and their full price indexation abandoned. In spite of these dramatic measures, this study shows that pensioners fared better than the working-age population, but also that poverty among older Swedes increased in absolute terms. During the following years of rapid economic growth, in contrast, the growth in pensioners' income fell behind that of workers and their relative poverty increased. The analysis shows that the limited resources of many older Swedes put them close to a Social poverty line. The study also shows that income inequality among older Swedes has grown with the increasing importance of capital income for the better off We conclude that the increasing gap between better-off and worse-off older people raises issues about the future provision of expenditures on public services for them. The paper concludes that, overall, poverty among older people in Sweden remains low by international standards and that the Swedish welfare state has maintained its resilience.
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| 36. |
- Holzgraefe, Bernhard, et al.
(författare)
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Does permissive hypoxaemia during extracorporeal membrane oxygenation cause long-term neurological impairment? : A study in patients with H1N1-induced severe respiratory failure
- 2017
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Ingår i: European Journal of Anaesthesiology. - 0265-0215 .- 1365-2346. ; 34:2, s. 98-103
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Extracorporeal Life Support Organisation accepts permissive hypoxaemia in adult patients during extracorporeal membrane oxygenation (ECMO). The neurological long-term outcome of this approach has not yet been studied.OBJECTIVES: We investigated the prevalence of brain lesions and cognitive dysfunction in survivors from the Influenza A/H1N1 2009 pandemic treated with permissive hypoxaemia during ECMO for severe acute respiratory distress syndrome (ARDS). Our hypothesis was that this method is reasonable if tissue hypoxia is avoided.DESIGN: Long-term follow-up study after ECMO.SETTING: Karolinska University Hospital, Sweden, from October 2012 to July 2013.PATIENTS: Seven patients treated with ECMO for severe influenza A/H1N1-induced ARDS were studied 3.2 years after treatment. Blood lactate concentrations were used as a surrogate for tissue oxygenation.INTERVENTIONS: Neurocognitive outcome was studied with standardised cognitive tests and MRI of the brain.MAIN OUTCOME MEASURES: Cognitive functioning and hypoxic brain lesions after permissive hypoxaemia during ECMO. The observation period was the first 10 days of ECMO or the entire treatment period if shorter than 10 days.RESULTS: Eleven of 13 patients were still alive 3 years after ECMO. We were able to contact seven of these patients (mean age 31 years), who all agreed to participate in this study. Mean +/- SD peripherally measured arterial saturation during the observation period was 79 +/- 10%. Full-scale Intelligence Quotient was within one standard deviation or above from the mean of a healthy population in five patients, and was 1.5 SD below the mean in one patient. In one other patient, it could not be determined because of a lack of formal education. Memory functioning was normal in all patients. MRI showed no changes related to cerebral hypoxia.CONCLUSIONS: Permissive hypoxaemia during ECMO might not negatively affect long-term cognitive outcome if adequate organ perfusion is maintained.
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| 37. |
- Jögi, Jonas, et al.
(författare)
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Heart failure diagnostics based on ventilation/perfusion single photon emission computed tomography pattern and quantitative perfusion gradients.
- 2008
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Ingår i: Nuclear Medicine Communications. - 1473-5628. ; 29:8, s. 666-673
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Left heart failure (LHF) is a common and frequently overlooked condition owing to insufficient diagnostic methods. This can potentially delay onset of treatment. Our clinical experience with ventilation/perfusion single photon emission computed tomography (V/P SPECT) indicates that perfusion shows an antigravitational distribution pattern in LHF. The aim of the study was to test the hypothesis that LHF diagnosis can be made on the basis of V/P SPECT, and to develop and perform a first evaluation of objective parameters for LHF diagnostics in terms of perfusion gradients. METHODS: This retrospective study included 247 consecutive patients with clinical suspicion of pulmonary embolism (PE), who were examined with V/P SPECT. Perfusion gradients were developed and quantified in dorso-ventral and cranio-caudal directions. Quantitative results were compared with visual interpretation of patients with normal and heart failure patterns. Patients with LHF pattern were retrospectively followed up by review of medical records to confirm or discard heart failure diagnosis at the time of V/P SPECT examination. RESULTS: LHF pattern on V/P SPECT was identified in 36 patients (15%), normal ventilation/perfusion pattern was found in 67 patients (27%), and PE in 62 patients (25%). The follow-up confirmed heart failure diagnosis in 32 of the 36 cases with LHF pattern, leading to a positive predictive value of 88% for LHF diagnosis based on V/P SPECT. Dorso-ventral perfusion gradients discriminated normal from LHF patients. CONCLUSION: In patients with suspected PE, LHF is common. Appropriate V/P SPECT pattern recognition, supported by objectively determined dorso-ventral perfusion gradients, allows the diagnosis of LHF. A positive perfusion gradient in the dorso-ventral direction should lead to consideration of heart failure as a possible explanation for the symptoms in these patients.
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| 38. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 39. |
- Karlson, Björn W., 1953, et al.
(författare)
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A VOYAGER Meta-Analysis of the Impact of Statin Therapy on Low-Density Lipoprotein Cholesterol and Triglyceride Levels in Patients With Hypertriglyceridemia
- 2016
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Ingår i: American Journal of Cardiology. - : Elsevier BV. - 0002-9149 .- 1879-1913. ; 117:9, s. 1444-1448
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Tidskriftsartikel (refereegranskat)abstract
- Elevated triglyceride (TG) levels are associated with increased cardiovascular disease risk. In patients with mild-to-moderate hypertriglyceridemia, defined by the European Atherosclerosis Society Consensus Panel as a TG level of 177 to 885 mg/dl (2.0 to 10.0 mmol/L), low-density lipoprotein cholesterol (LDL-C) reduction remains the primary treatment goal. Using data from the indiVidual patient meta-analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin and simvastatin (VOYAGER) meta-analysis, we analyzed LDL-C and TG reductions in patients with baseline TG 2177 mg/dl (>= 2.0 mmol/L). Least squares mean percentage change from baseline in LDL-C and TG was compared using 15,800 patient exposures to rosuvastatin 5 to 40 mg, atorvastatin 10 to 80 mg, and simvastatin 10 to 80 mg in patients with baseline TG >= 177 mg/dl (>= 2.0 mmol/L). Comparisons were made using mixed-effects models with data only from studies directly comparing treatments by randomized design. Mean LDL-C reductions ranged from -26.9% to -55.5%. Rosuvastatin 10 to 40 mg resulted in significantly greater LDL-C reductions than equal or double doses of atorvastatin and simvastatin (p <0.05). Mean TG reductions ranged from -15.1% to -31.3%. Rosuvastatin 10 mg resulted in significantly greater TG reductions than atorvastatin 10 mg (p <0.05). Rosuvastatin 20 and 40 mg resulted in TG reductions similar to those with equal doses of atorvastatin. Rosuvastatin 10 to 40 mg resulted in significantly greater TG reductions than equal or double doses of simvastatin (p <0.05). In conclusion, in patients with hypertriglyceridemia, LDL-C reduction was substantial and dependent on the choice and dose of statin. TG reduction was numerically less than for LDL-C, and additional TG-lowering therapy may be considered to further reduce residual cardiovascular risk. (C) 2016 Elsevier Inc. All rights reserved.
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| 40. |
- Karlson, Björn W., 1953, et al.
(författare)
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Achievement of 2011 European low-density lipoprotein cholesterol (LDL-C) goals of either < 70 mg/dl or >= 50% reduction in high-risk patients: Results from VOYAGER
- 2013
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 228:1, s. 265-269
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Tidskriftsartikel (refereegranskat)abstract
- Objective Guidelines published in 2011 by the European Atherosclerosis Society and the European Society of Cardiology recommend a goal of either low-density lipoprotein cholesterol (LDL-C) <70 mg/dl (∼1.8 mmol/l) or ≥50% reduction in LDL-C for patients at very high cardiovascular risk. The aim of this study was to determine the percentage of high-risk patients from the VOYAGER individual patient data meta-analysis treated with rosuvastatin 10–40 mg, atorvastatin 10–80 mg or simvastatin 10–80 mg who achieved this goal. Methods We analysed 25,075 patient exposures from high-risk patients. Paired comparisons were made between each rosuvastatin dose and an equal or higher dose of either atorvastatin or simvastatin, with a series of meta-analyses that included only randomised studies that directly compared rosuvastatin and its comparator treatments. Results As statin dose increased, higher percentages of patients achieved LDL-C <70 mg/dl or ≥50% LDL-C reduction. A greater percentage achieved this goal with rosuvastatin 10–40 mg (43.8–79.0%) than with equal or double milligram doses of atorvastatin (16.1–65.2%) or simvastatin (0–39.7%). Paired comparisons showed statistically significant differences for: rosuvastatin 10 mg vs. atorvastatin 10–20 mg and simvastatin 10–20 mg; rosuvastatin 20 mg vs. atorvastatin 20–40 mg and simvastatin 20–80 mg; and rosuvastatin 40 mg vs. atorvastatin 40–80 mg and simvastatin 40–80 mg (all p < 0.001). Conclusion These data from VOYAGER highlight the importance of an effective statin at an appropriate dose to achieve treatment goals for LDL-C in patients with very high cardiovascular risk.
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| 41. |
- Karlson, Björn W., 1953, et al.
(författare)
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Achievement of combined goals of low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol with three different statins: Results from VOYAGER
- 2014
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Ingår i: IJC Metabolic and Endocrine. - : Elsevier Ireland Ltd. - 2214-7624. ; 5, s. 61-66
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Tidskriftsartikel (refereegranskat)abstract
- Background: Guidelines suggest that the combination of low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) is the most clinically relevant goal for lipid-lowering treatments. Methods: Data from VOYAGER, an individual patient data meta-analysis including 32,258 patients from 37 clinical trials, was used to determine the percentage of patients reaching combined goals of LDL-C and non-HDL-C following treatment with simvastatin, atorvastatin, or rosuvastatin. Paired comparisons were made between each dose of rosuvastatin and the same or higher doses of simvastatin and atorvastatin. Results: Each dose of rosuvastatin brought significantly more patients to the combined goal of LDL-C <. 100. mg/dL and non-HDL-C <. 130. mg/dL than the same or double dose of atorvastatin; atorvastatin 80. mg was significantly superior to rosuvastatin 10. mg (all p. <. 0.001). Each dose of rosuvastatin helped significantly more patients reach the combined goal than any dose of simvastatin (all p. <. 0.001), except for rosuvastatin 10. mg versus simvastatin 80. mg (non-significant). Also, each dose of rosuvastatin helped significantly more patients to reach the combined goal of LDL-C <. 70. mg/dL and non-HDL-C <. 100. mg/dL than the same or double dose of atorvastatin (all p. <. 0.001). Every dose of rosuvastatin was significantly superior to all doses of simvastatin (all p. ≤. 0.020), except for rosuvastatin 10. mg versus simvastatin 40. mg and 80. mg (non-significant). Conclusions: Physicians' choice of statin and dose is important in helping patients achieve the combined LDL-C and non-HDL-C goals recommended in established guidelines.
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| 42. |
- Karlson, Björn W., 1953, et al.
(författare)
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Comparison of the effects of different statins and doses on lipid levels in patients with diabetes: Results from VOYAGER
- 2012
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Ingår i: Nutrition Metabolism and Cardiovascular Diseases. - : Elsevier BV. - 0939-4753 .- 1590-3729. ; 22:9, s. 697-703
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Diabetes mellitus is a well-known risk factor for cardiovascular disease, and brings an increased risk of vascular events and a higher mortality rate. Treatment guidelines recommend statins in patients with diabetes, with low-density lipoprotein cholesterol (LDL-C) targets of 100 mg dl(-1) (similar to 2.5 mmol l(-1)), and 80 (similar to 2.0 mmol l(-1)) or 70 mg dl(-1) (similar to 1.8 mmol l(-1)) in especially high-risk patients. The current study used the VOYAGER (an indiVidual patient data-meta-analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin, and simvastatin) database to characterise effects of rosuvastatin, atorvastatin and simvastatin in different doses on lipid levels in diabetes patients. Methods and results: The VOYAGER database included individual patient data from 37 studies involving comparisons of rosuvastatin with either atorvastatin or simvastatin. Of the 32 258 patients included, 8859 (27.5%) had diabetes. Rosuvastatin appeared to be the most efficacious of the three statins, both for lowering LDL-C and for reaching a target level of <70 mg dl(-1) for LDL-C. It was also more effective than atorvastatin at raising high-density lipoprotein cholesterol in the diabetes population. These results are consistent with the overall VOYAGER results. Conclusions: This meta-analysis of 8859 patients with diabetes mellitus shows favourable effects on lipids with the three statins studied, in line with results for the overall VOYAGER population. The importance of using an effective statin at an effective dose to reach treatment goals for such high-risk patients is evident. (c) 2012 Elsevier B.V. All rights reserved.
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| 43. |
- Karlson, Björn W., 1953, et al.
(författare)
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Doses of rosuvastatin, atorvastatin and simvastatin that induce equal reductions in LDL-C and non-HDL-C: Results from the VOYAGER meta-analysis
- 2016
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Ingår i: European Journal of Preventive Cardiology. - : Oxford University Press (OUP). - 2047-4873 .- 2047-4881. ; 23:7, s. 744-747
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Tidskriftsartikel (refereegranskat)abstract
- Background Achieving the greatest reduction in atherogenic lipoproteins requires the optimum dose and potency of statin. Using data from the VOYAGER meta-analysis, we determined doses of rosuvastatin, atorvastatin and simvastatin that induce equal reductions in low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). Methods Least squares mean percentage change in LDL-C and non-HDL-C was calculated using 38,052 patient exposures to rosuvastatin 5-40mg, atorvastatin 10-80mg and simvastatin 10-80mg. Equipotent doses were estimated by linear interpolation between actual adjacent doses. Results Rosuvastatin 5mg reduced LDL-C by 39% and non-HDL-C by 35%. Equivalent reductions in LDL-C required atorvastatin 15mg or simvastatin 39mg. Equivalent reductions in non-HDL-C required atorvastatin 14 mg or simvastatin 42mg. Rosuvastatin 10mg reduced LDL-C by 44% and non-HDL-C by 40%. Equivalent reductions in LDL-C required atorvastatin 29 mg or simvastatin 72mg. Equivalent reductions in non-HDL-C required atorvastatin 27 mg or simvastatin 77mg. Rosuvastatin 20mg reduced LDL-C by 50% and non-HDL-C by 45%. Equivalent reductions in LDL-C and non-HDL-C required atorvastatin 70 mg and atorvastatin 62mg, respectively, and were not achieved with the maximum 80mg dose of simvastatin. Rosuvastatin 40mg reduced LDL-C by 55% and non-HDL-C by 50%. Comparable reductions were not achieved with the maximum 80mg doses of atorvastatin or simvastatin. Conclusions Regarding reductions in LDL-C and non-HDL-C, each rosuvastatin dose is equivalent to doses 3-3.5 times higher for atorvastatin and 7-8 times higher for simvastatin.
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| 44. |
- Karlson, Björn W., 1953, et al.
(författare)
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Effects of age, gender and statin dose on lipid levels: Results from the VOYAGER meta-analysis database
- 2017
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 265, s. 54-59
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims The effectiveness of statins in the treatment of dyslipidaemia and reduction of cardiovascular risk is well established. However, the association of statin-mediated lipid effects with age and gender is unclear. This study aimed to determine whether age and gender are associated with statin-mediated changes in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and non-HDL-C. Methods Individual patient data (n = 32,258) were obtained from VOYAGER. Least-squares mean percentage change from baseline in LDL-C, non-HDL-C and HDL-C with atorvastatin 10–80 mg, rosuvastatin 5–40 mg or simvastatin 10–80 mg was estimated in women aged <70 years, women aged ≥70 years, men aged <70 years and men aged ≥70 years. Results All statins and doses gave significant dose-dependent reductions in LDL-C and non-HDL-C, and increases in HDL-C, in all four patient groups. A 2.1% greater reduction in LDL-C was observed in women, compared with men (p < 0.0001). Patients aged ≥70 years experienced a 2.7% greater reduction in LDL-C compared with younger patients (p < 0.0001). Similar results were also observed for statin-mediated changes in non-HDL-C. Men experienced a significantly greater increase in HDL-C than women, and patients aged ≥70 years achieved a significantly greater increase than younger patients (both p = 0.001). Conclusions While statins improve the lipid profile in all gender and age groups analysed, the improvements are greater in women than in men and in those aged ≥70 years compared with those aged <70 years. © 2017 Elsevier B.V.
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| 45. |
- Karlson, Björn W., 1953, et al.
(författare)
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Modeling Statin-Induced Reductions of Cardiovascular Events in Primary Prevention: A VOYAGER Meta-Analysis
- 2018
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Ingår i: Cardiology. - : S. Karger AG. - 0008-6312 .- 1421-9751. ; 140:1, s. 30-34
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We used individual patient data from the VOYAGER database to estimate cardiovascular (CV) risk reduction with commonly used high-intensity statins. Methods: In patients with known atherosclerotic CV disease (ASCVD) treated with high-intensity statin therapy (n = 6,735), the predicted risk reduction was estimated using the Cholesterol Treatment Trialists' Collaboration meta-analysis, which determined risk reduction per 38.7 mg/dL statin-mediated reduction in low-density lipoprotein cholesterol. Results: The greatest reductions in risk were seen in major vascular events (estimated rate ratios ranged from 0.55 with rosuvastatin [RSV] 40 mg to 0.60 with atorvastatin [ATV] 40 mg) and coronary heart disease death (estimated rate ratios ranged from 0.58 with RSV 40 mg to 0.64 with ATV 40 mg). Conclusions: Our results show that, in individuals without clinical ASCVD, statin therapy has the potential to reduce the frequency of CV events. (C) 2018 S. Karger AG, Basel
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| 46. |
- Karlson, Björn W., 1953, et al.
(författare)
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To what extent do high-intensity statins reduce low-density lipoprotein cholesterol in each of the four statin benefit groups identified by the 2013 American College of Cardiology/American Heart Association guidelines? A VOYAGER meta-analysis
- 2015
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 241:2, s. 450-454
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Tidskriftsartikel (refereegranskat)abstract
- Background: The 2013 American College of Cardiology and American Heart Association (ACC/AHA) guidelines identify four patient groups who benefit from moderate-or high-intensity statin treatment; those with: 1) atherosclerotic cardiovascular disease (ASCVD); 2) low-density lipoprotein cholesterol (LDL-C) >= 190 mg/dl; 3) diabetes; or 4) a 10-year ASCVD risk >= 7.5%. High-intensity statins, anticipated to reduce LDL-C by >= 50%, were identified as rosuvastatin 20-40 mg and atorvastatin 40-80 mg. Methods and Results: Individual patient data (32,258) from the VOYAGER database of 37 studies were used to calculate least-squares mean (LSM) percentage change in LDL-C during 8496 patient exposures to rosuvastatin 20-40 mg, and atorvastatin 40-80 mg in the four patient benefit groups. LSM percentage reductions in LDL-C with rosuvastatin 20 and 40 mg were greater than with atorvastatin 40 mg, overall and in each statin benefit group, and with rosuvastatin 40 mg were greater than with atorvastatin 80 mg overall and in three of the four benefit groups (all p < 0.05). For example, in the ASCVD group, 40%, 59%, 57% and 71% of patients treated with atorvastatin 40 mg, atorvastatin 80 mg, rosuvastatin 20 mg and rosuvastatin 40 mg, respectively, had a >= 50% reduction in LDL-C. Conclusions: The choice and dose of statin have an impact both on the percentage LDL-C reduction and achievement of >= 50% reduction in LDL-C, overall and within each of the four statin benefit groups outlined by the 2013 ACC/AHA guidelines. This may be of importance for clinicians in their choice of treatment for individual patients. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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| 47. |
- Karlson, Björn W., 1953, et al.
(författare)
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Variability of low-density lipoprotein cholesterol response with different doses of atorvastatin, rosuvastatin, and simvastatin: results from VOYAGER.
- 2016
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Ingår i: European heart journal. Cardiovascular pharmacotherapy. - : Oxford University Press (OUP). - 2055-6845 .- 2055-6837. ; 2:4, s. 212-7
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Tidskriftsartikel (refereegranskat)abstract
- Patient response to statin treatment is individual and varied. As a consequence, when using a specific-dose approach, as recommended in the 2013 American College of Cardiology/American Heart Association guideline, there will be a range of reductions in the concentration of low-density lipoprotein cholesterol (LDL-C). The aim of this study was to use individual patient data from the VOYAGER meta-analysis to determine the extent of the variability in LDL-C reduction in response to treatment across the recommended doses of different statins.
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| 48. |
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| 49. |
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| 50. |
- Ludvigsson, Johnny, et al.
(författare)
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GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus
- 2012
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 366:5, s. 433-442
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes.METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels.RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences.CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period.
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