| 421. |
- Sysojev, AO, et al.
(författare)
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A GENOME-WIDE INVESTIGATION OF PERSISTENCE TO TREATMENT WITH METHOTREXATE IN SWEDISH EARLY RHEUMATOID ARTHRITIS PATIENTS
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 178-178
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Despite being the anchor drug for treating rheumatoid arthritis (RA), methotrexate (MTX) provides a good response only in some of the treated patients [1]. If MTX treatment outcome has a substantial genetic component, genetic variants could provide useful predictors for identification of patients likely to respond and remain on treatment. So far, studies have focused mainly on primary response, and attempts to explain the inter-patient variability through genetic variants have been inconclusive or underpowered [2,3].ObjectivesWe aimed to investigate whether there are genetic variants associated with persistence to treatment with MTX (at one and three years) in early RA, and to estimate any underlying heritability.MethodsWe conducted a genome-wide association study (GWAS) on persistence to treatment with MTX in DMARD-monotherapy. We included participants from the Epidemiological Investigation of RA (EIRA) study and the Swedish Rheumatology Quality Register’s biobank, diagnosed with early RA and treated with MTX as their first ever DMARD. Persistence to MTX was defined as remaining on treatment at one and three years, respectively, with no additional DMARDs added during that period. Estimation of SNP-based heritability was done using restricted maximum likelihood. We performed the analyses for all RA, and two disease subsets: those positive for either ACPA or rheumatoid factor, and those negative for both.ResultsAfter quality control, 3403 of an initial 3609 early RA patients of European ancestry and above five million SNPs remained for the primary analysis. Among these, 65% were persistent at one year, and 44% were persistent at three years. In secondary analysis we excluded 218 patients due to missing sero-status. Of the remaining, 72% were seropositive. No SNP reached genome-wide significance, neither for persistence at one nor at three years. The SNP-based heritability was estimated to 0.35 (95%CI 0.04-0.65) for persistence at one year and 0.09 (95%CI 0.00-0.37) for persistence at three years. Analyses stratified by sero-status provided results comparable to the main analysis with similar proportions of persistent patients and no SNP reaching genome-wide significance for any of the subgroups. Point estimates of heritability for persistence in the seropositive group at one year (h2 = 0.08, 95%CI 0.00-0.51) was lower than for seropositive persistence at three years (h2 = 0.19, 95%CI 0.00-0.62) while point estimates for the seronegative heritability were zero for both persistence outcomes.ConclusionDespite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The low heritability observed along with the lack of strong independent associations, may indicate that genetic influence from common genetic variants on persistence to MTX is minor, and of a polygenic nature.References[1]Saevarsdottir, S., et al., Predictors of response to methotrexate in early DMARD naive rheumatoid arthritis: results from the initial open-label phase of the SWEFOT trial. Ann Rheum Dis, 2011. 70(3): p. 469-75.[2]Ling, S., J. Bluett, and A. Barton, Prediction of response to methotrexate in rheumatoid arthritis. Expert Rev Clin Immunol, 2018. 14(5): p. 419-429.[3]Szostak, B., et al., Using pharmacogenetics to predict methotrexate response in rheumatoid arthritis patients. Expert Opin Drug Metab Toxicol, 2020. 16(7): p. 617-626.AcknowledgementsThe authors would like to thank the participants of the EIRA study and the SRQ biobank as well as deCODE genetics for making this study possible.Disclosure of InterestsAnton Öberg Sysojev: None declared, Saedis Saevarsdottir Employee of: Part-time employee of deCODE genetics Inc., Lina M. Diaz-Gallo: None declared, Lars Alfredsson: None declared, Lars Klareskog: None declared, - SRQ Biobank Group: None declared, Thomas Frisell: None declared, Leonid Padyukov: None declared, Johan Askling Grant/research support from: Karolinska Institutet has entered into agreements with the following companies, with JA as PI: Abbvie, BMS, Eli Lilly, Galapagos, Janssen, Pfizer, Roche, Samsung Bioepis and Sanofi., Helga Westerlind: None declared
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| 423. |
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| 424. |
- Talamelli, A., et al.
(författare)
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An experimental investigation of the response of hot-wire X-probes in shear flows
- 2000
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Ingår i: Experiments in Fluids. - : Springer Science and Business Media LLC. - 0723-4864 .- 1432-1114. ; 28:5, s. 425-435
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Tidskriftsartikel (refereegranskat)abstract
- The response of her-wire X-probes in regions of strong velocity gradients (such as in the near wall region of boundary layer flows) is investigated experimentally. Although the wall-normal velocity component should be close to zero near the wall, one usually encounters an increased absolute value of this component when the wall is approached. Moreover some physically inconsistent behaviour in other measured quantities, for instance the Reynolds stresses, may be found. These effects can be due to a physical displacement of the wires (e.g. a wall-normal displacement of the two wires so that they do not cross at their mid-points), but also due to the influence of the probe on the local flow field. The latter might be an effect of blockage or wall interference and can be treated as a virtual displacement. The response equations of an X-probe with different wall-normal displacement of the wires are derived and applied in order to correct the measured data. A systematic experimental investigation of the effect of varying the physical displacement of the wires is also made, and it is shown that both the first and second order correction terms of the probe response equations can be estimated from this experiment. A correction procedure for measurements close to the wall is proposed and used to correct Reynolds stress profiles in a flat plate boundary-layer. It is also shown that the present experimental set-up can be used to estimate some turbulence correlations which otherwise are unaccessible with standard measurement techniques.
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| 425. |
- Talamelli, A., et al.
(författare)
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Experimental investigation of streaky structures in a relaminarizing boundary layer
- 2002
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Ingår i: Journal of Turbulence. - 1468-5248. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- An experimental investigation of a boundary layer subjected to a relaminarization process is performed. The initially turbulent boundary layer develops on a plate mounted inside a two-dimensional convergent channel, and the results show that the mean velocity profiles of the boundary layer develop towards the self-similar laminar solution. Two-point correlation measurements, performed by means of two miniaturized single-wire hot-wire probes with variable relative spanwise separation, show the presence of elongated longitudinal structures. The absolute spanwise separation of these streaks decreases in the downstream direction. However, if the size is normalized with the displacement thickness of the boundary layer, the relative streak spacing shows a significant increase. Also, when scaled with the viscous length scale l* the streak spacing (defined as average distance between low- and high-speed streaks) increases from about 60l* in the turbulent boundary layer to 150-180l* in the relaminarizing region. To process only the laminar part of the velocity signals a filtering procedure based on a threshold value of the second derivative of the time signals has been applied showing a slight increase in the detected spanwise scales. Finally, measurements were carried out at an enhanced level of free stream turbulence. Although small differences can be observed, the results are qualitatively similar to the ones obtained at a low level of free stream turbulence.
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| 426. |
- Talamelli, A., et al.
(författare)
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The new high Reynolds number pipe flow facility at CICLoPE
- 2008
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Ingår i: 38th AIAA Fluid Dynamics Conference and Exhibit. - 9781563479427
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Konferensbidrag (refereegranskat)abstract
- A new facility to study wall bounded turbulent °ow has been designed and will be installed in the laboratory of Center for International Collaboration on Long Pipe Experiments "CICLoPE" in Predappio (Italy). The facility consists of a large pipe, allowing to reach high Reynolds numbers, where all turbulent scales can be resolved with standard measurement techniques. The pipe operates with air at ambient conditions and has a close loop circuit allowing to maintain stable conditions over long period of time. The pipe is located in a tunnel 60 m underground, thus ensuring very low level of external perturbations. Great care has been taken during the design phase to minimize all potential disturbances in order to ensure optimal measuring conditions along the whole pipe.
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| 427. |
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| 428. |
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| 429. |
- Theorell, Töres, et al.
(författare)
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Job strain and cardiovascular disease risk factors : Meta-analysis of individual-participant data from 47,000 men and women
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:6, s. e67323-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundJob strain is associated with an increased coronary heart disease risk, but few large-scale studies have examined the relationship of this psychosocial characteristic with the biological risk factors that potentially mediate the job strain – heart disease association.Methodology and Principal FindingsWe pooled cross-sectional, individual-level data from eight studies comprising 47,045 participants to investigate the association between job strain and the following cardiovascular disease risk factors: diabetes, blood pressure, pulse pressure, lipid fractions, smoking, alcohol consumption, physical inactivity, obesity, and overall cardiovascular disease risk as indexed by the Framingham Risk Score. In age-, sex-, and socioeconomic status-adjusted analyses, compared to those without job strain, people with job strain were more likely to have diabetes (odds ratio 1.29; 95% CI: 1.11–1.51), to smoke (1.14; 1.08–1.20), to be physically inactive (1.34; 1.26–1.41), and to be obese (1.12; 1.04–1.20). The association between job strain and elevated Framingham risk score (1.13; 1.03–1.25) was attributable to the higher prevalence of diabetes, smoking and physical inactivity among those reporting job strain.ConclusionsIn this meta-analysis of work-related stress and cardiovascular disease risk factors, job strain was linked to adverse lifestyle and diabetes. No association was observed between job strain, clinic blood pressure or blood lipids.
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