| 1. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 2. |
- Barrett, Jennifer H., et al.
(författare)
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Genome-wide association study identifies three new melanoma susceptibility loci
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1108-1113
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Tidskriftsartikel (refereegranskat)abstract
- We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 x 10(-9)), an SNP in MX2 (rs45430, P = 2.9 x 10-9) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 x 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 x 10(-7) under a fixed-effects model and P = 1.2 x 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.
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| 3. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 4. |
- Machiela, Mitchell J., et al.
(författare)
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Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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| 5. |
- Ställberg, Björn, et al.
(författare)
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A real-life cost-effectiveness evaluation of budesonide/formoterol maintenance and reliever therapy in asthma
- 2008
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 0954-6111 .- 1532-3064. ; 102:10, s. 1360-1370
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To evaluate direct asthma-related costs in Swedish primary care in a real-life setting. DESIGN: 12-month open-label study. SETTING Swedish primary care in a real-life setting. PARTICIPANTS 1776 patients with persistent asthma. INTERVENTIONS Patients with persistent asthma were randomised to one of three treatments: a free adjustable combination of budesonide (100-400 microg/inhalation) and formoterol (4.5 or 9 microg/inhalation) via separate inhalers plus terbutaline as needed; budesonide/formoterol (160/4.5 microg or 80/4.5 microg, two inhalations twice daily) plus terbutaline as needed; budesonide/formoterol (160/4.5 microg or 80/4.5 microg, one inhalation twice daily or two inhalations once daily), for maintenance plus additional inhalations as needed. Doses depended on previous inhaled corticosteroid dose. Patients attended the clinic at 0, 1.5, and 12 months. Telephone interviews were conducted at 4, 6, 8, and 10 months. MAIN OUTCOME MEASURES The primary endpoint was direct asthma-related healthcare costs. RESULTS Statistically significant reductions in annual direct costs per patient were observed with budesonide/formoterol maintenance and reliever therapy compared with the free adjustable combination of budesonide and formoterol (-13%, P<0.001) and fixed-dose budesonide/formoterol plus terbutaline (-20%, P<0.001). Time to first severe exacerbation did not differ significantly across treatment groups, with a mean reduction of 28% versus the free adjustable combination of budesonide and formoterol (P=0.076). Patients receiving budesonide/formoterol maintenance and reliever therapy used a significantly lower daily dose of budesonide compared with the conventional (P<0.001). CONCLUSIONS This study reports direct cost savings with budesonide/formoterol maintenance and reliever therapy compared with conventional treatment regimens with at least equivalent efficacy.
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| 6. |
- Torbert, R. B., et al.
(författare)
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The FIELDS Instrument Suite on MMS : Scientific Objectives, Measurements, and Data Products
- 2016
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Ingår i: Space Science Reviews. - : Springer Science+Business Media B.V.. - 0038-6308 .- 1572-9672. ; 199:1-4, s. 105-135
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Forskningsöversikt (refereegranskat)abstract
- The FIELDS instrumentation suite on the Magnetospheric Multiscale (MMS) mission provides comprehensive measurements of the full vector magnetic and electric fields in the reconnection regions investigated by MMS, including the dayside magnetopause and the night-side magnetotail acceleration regions out to 25 Re. Six sensors on each of the four MMS spacecraft provide overlapping measurements of these fields with sensitive cross-calibrations both before and after launch. The FIELDS magnetic sensors consist of redundant flux-gate magnetometers (AFG and DFG) over the frequency range from DC to 64 Hz, a search coil magnetometer (SCM) providing AC measurements over the full whistler mode spectrum expected to be seen on MMS, and an Electron Drift Instrument (EDI) that calibrates offsets for the magnetometers. The FIELDS three-axis electric field measurements are provided by two sets of biased double-probe sensors (SDP and ADP) operating in a highly symmetric spacecraft environment to reduce significantly electrostatic errors. These sensors are complemented with the EDI electric measurements that are free from all local spacecraft perturbations. Cross-calibrated vector electric field measurements are thus produced from DC to 100 kHz, well beyond the upper hybrid resonance whose frequency provides an accurate determination of the local electron density. Due to its very large geometric factor, EDI also provides very high time resolution (similar to 1 ms) ambient electron flux measurements at a few selected energies near 1 keV. This paper provides an overview of the FIELDS suite, its science objectives and measurement requirements, and its performance as verified in calibration and cross-calibration procedures that result in anticipated errors less than 0.1 nT in B and 0.5 mV/m in E. Summaries of data products that result from FIELDS are also described, as well as algorithms for cross-calibration. Details of the design and performance characteristics of AFG/DFG, SCM, ADP, SDP, and EDI are provided in five companion papers.
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| 7. |
- Albert, F, et al.
(författare)
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Laser produced X-ray source in the 10-60 keV range at 1 kHz. Modified irradiation schemes in order to reach medical imaging quality
- 2001
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Ingår i: Journal de Physique IV. - : EDP Sciences. - 1155-4339. ; 11:PR2, s. 429-432
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Tidskriftsartikel (refereegranskat)abstract
- By tightly focusing ultra-short pulses from a Ti:sapphire terawatt laser onto a high-Z metallic target, hard x-ray pulses of short duration are produced. In most of our previous work concerning x-rays, a 150 mJ laser pulse with a 110 A duration has been used. Using mostly tin and tantalum targets, hard x-rays in the 10-60 keV range have been produced and used in differential absorption imaging around the K-alpha absorption edge of a contrast agent and also in imaging employing gated viewing for suppression of scattered radiation. In order to increase the x-ray yield (shortening the acquisition time) an increase in the laser repetition rate is desirable while still staying in the K-alpha energy regime. We have used a I kHz repetition-rate laser delivering 35 fs pulses in order to work towards these goals. We have clear evidence of hard x-ray generation above 30 keV, even for low laser pulse energies. We also studied the effect of a fs prepulse. The medical imaging capability of the source was explored. The use of a prepulse has been optimized in order to improve the image quality as well as the overall x-ray generation yield.
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| 8. |
- Arriaga, I., et al.
(författare)
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SMILE - A miniaturized fluxgate magnetometer
- 2007
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Ingår i: 18TH ESA SYMPOSIUM ON EUROPEAN ROCKET AND BALLOON PROGRAMMES AND RELATED RESEARCH. ; , s. 569-572
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Konferensbidrag (refereegranskat)abstract
- The SMILE (Small Magnetometer in Low-mass Experiment) instrument is a miniaturized digital fluxgate magnetometer that combines a miniature triaxial sensor with volume compensation with digital data processing implemented in a single FPGA. This report presents first results of numerical simulations of the sensor. We also discuss the digital solutions used in SMILE.
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| 9. |
- Ergun, R. E., et al.
(författare)
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The Axial Double Probe and Fields Signal Processing for the MMS Mission
- 2016
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Ingår i: Space Science Reviews. - : Springer Netherlands. - 0038-6308 .- 1572-9672. ; 199:1-4, s. 167-188
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Forskningsöversikt (refereegranskat)abstract
- The Axial Double Probe (ADP) instrument measures the DC to similar to 100 kHz electric field along the spin axis of the Magnetospheric Multiscale (MMS) spacecraft (Burch et al., Space Sci. Rev., 2014, this issue), completing the vector electric field when combined with the spin plane double probes (SDP) (Torbert et al., Space Sci. Rev., 2014, this issue, Lindqvist et al., Space Sci. Rev., 2014, this issue). Two cylindrical sensors are separated by over 30 m tip-to-tip, the longest baseline on an axial DC electric field ever attempted in space. The ADP on each of the spacecraft consists of two identical, 12.67 m graphite coilable booms with second, smaller 2.25 m booms mounted on their ends. A significant effort was carried out to assure that the potential field of the MMS spacecraft acts equally on the two sensors and that photo- and secondary electron currents do not vary over the spacecraft spin. The ADP on MMS is expected to measure DC electric field with a precision of similar to 1 mV/m, a resolution of similar to 25 mu V/m, and a range of similar to 1 V/m in most of the plasma environments MMS will encounter. The Digital Signal Processing (DSP) units on the MMS spacecraft are designed to perform analog conditioning, analog-to-digital (A/D) conversion, and digital processing on the ADP, SDP, and search coil magnetometer (SCM) (Le Contel et al., Space Sci. Rev., 2014, this issue) signals. The DSP units include digital filters, spectral processing, a high-speed burst memory, a solitary structure detector, and data compression. The DSP uses precision analog processing with, in most cases, > 100 dB in dynamic range, better that -80 dB common mode rejection in electric field (E) signal processing, and better that -80 dB cross talk between the E and SCM (B) signals. The A/D conversion is at 16 bits with similar to 1/4 LSB accuracy and similar to 1 LSB noise. The digital signal processing is powerful and highly flexible allowing for maximum scientific return under a limited telemetry volume. The ADP and DSP are described in this article.
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| 10. |
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