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- 2019
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Tidskriftsartikel (refereegranskat)
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- Saevarsdottir, S., et al.
(författare)
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Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
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- Bonduelle, M, et al.
(författare)
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A multi-centre cohort study of the physical health of 5-year-old children conceived after intracytoplasmic sperm injection, in vitro fertilization and natural conception
- 2005
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Ingår i: Hum Reprod. ; 20:2, s. 413-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Over a million children have been born from assisted conception worldwide. Newer techniques being introduced appear less and less 'natural', such as intracytoplasmic sperm injection (ICSI), but there is little information on these children beyond the neonatal period. METHODS: 540 ICSI conceived 5-year-old children from five European countries were comprehensively assessed, along with 538 matched naturally conceived children and 437 children conceived with standard IVF. RESULTS: Of the 540 ICSI children examined, 63 (4.2%) had experienced a major congenital malformation. Compared with naturally conceived children, the odds of a major malformation were 2.77 (95% CI 1.41-5.46) for ICSI children and 1.80 (95% CI 0.85-3.81) for IVF children; these estimates were little affected by adjustment for socio-demographic factors. The higher rate observed in the ICSI group was due partially to an excess of malformations in the (boys') urogenital system. In addition, ICSI and IVF children were more likely than naturally conceived children to have had a significant childhood illness, to have had a surgical operation, to require medical therapy and to be admitted to hospital. A detailed physical examination revealed no further substantial differences between the groups, however. CONCLUSIONS: Singleton ICSI and IVF 5-year-olds are more likely to need health care resources than naturally conceived children. Assessment of singleton ICSI and IVF children at 5 years of age was generally reassuring, however, we found that ICSI children presented with more major congenital malformations and both ICSI and IVF children were more likely to need health care resources than naturally conceived children. Ongoing monitoring of these children is therefore required.
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- Kyro, C., et al.
(författare)
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ALKYLRESORCINOLS (BIOMARKERS OF WHOLE-GRAIN INTAKE) AND RISK OF COLORECTAL CANCER IN THE EUROPEAN PROSPECTIVE INVESTIGATION INTO CANCER AND NUTRITION
- 2013
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Ingår i: Annals of Nutrition and Metabolism. - : S. Karger. - 0250-6807 .- 1421-9697. ; 63:Supplement 1, s. 1207-1208
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and objectives: Few studies have investigatedthe association between whole-grain intake and colorectal cancer.Whole-grain products are one of the dietary items proneto measurement errors, making the use of objective measures,such as biomarkers, highly relevant. The objective of the studywas to investigate the association between biomarkers ofwhole-grain intake, alkylresorcinols, and colorectal cancer ina nested case-control study within the European ProspectiveInvestigation into Cancer and Nutrition (EPIC). Methods: We included 1372 first incident colorectal cancercases and 1372 individually matched controls and calculatedthe incidence rate ratios (IRR) for overall and sub-sites of colorectalcancer using conditional logistic regression adjusted forpotential confounders.Results: Plasma total alkylresorcinol concentrations werenot associated with risk of overall colorectal cancer, proximalcolon cancer or rectal cancer. However, high plasma total alkylresorcinolconcentrations were statistically significantly associatedwith lower incidence of cancer located in the distal (leftor descending) part of the colon. Adjusted IRR of distal coloncancer for highest versus lowest quartile of plasma alkylresorcinolwas 0.48 (95% confidence interval = 0.28 to 0.83). Furthermore,we observed an inverse association with colon cancerfor the Scandinavian part of the participants. Alkylresorcinolsmay be more appropriate as biomarkers in Middle Europe andScandinavia i.e. in areas where whole grains are regularly consumed.Conclusions: Whole-grain intake, assessed by alkylresorcinols,was associated with a lower incidence of distal coloncancer. Alkylresorcinols seem useful as objective biomarkersof whole-grain intake in populations where whole-grains are astaple part of the diet. Acknowledgements: This work was supportedby World Cancer Research Fund International (WCRF)and WCRF Netherlands (WCRF NL) (2011/436), and NordForsk(Centre of Excellence programme HELGA (070015)).
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- Michelsen, B., et al.
(författare)
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Drug retention, inactive disease and response rates in 1860 patients with axial spondyloarthritis initiating secukinumab treatment: routine care data from 13 registries in the EuroSpA collaboration
- 2020
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Ingår i: RMD open. - : BMJ. - 2056-5933. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To explore 6-month and 12-month secukinumab effectiveness in patients with axial spondyloarthritis (axSpA) overall, as well as across (1) number of previous biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), (2) time since diagnosis and (3) different European registries. METHODS: Real-life data from 13 European registries participating in the European Spondyloarthritis Research Collaboration Network were pooled. Kaplan-Meier with log-rank test, Cox regression, χ² and logistic regression analyses were performed to assess 6-month and 12-month secukinumab retention, inactive disease/low-disease-activity states (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) <2/<4, Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3/<2.1) and response rates (BASDAI50, Assessment of Spondyloarthritis International Society (ASAS) 20/40, ASDAS clinically important improvement (ASDAS-CII) and ASDAS major improvement (ASDAS-MI)). RESULTS: We included 1860 patients initiating secukinumab as part of routine care. Overall 6-month/12-month secukinumab retention rates were 82%/72%, with significant (p<0.001) differences between the registries (6-month: 70-93%, 12-month: 53-86%) and across number of previous b/tsDMARDs (b/tsDMARD-naïve: 90%/73%, 1 prior b/tsDMARD: 83%/73%, ≥2 prior b/tsDMARDs: 78%/66%). Overall 6-month/12-month BASDAI<4 were observed in 51%/51%, ASDAS<1.3 in 9%/11%, BASDAI50 in 53%/47%, ASAS40 in 28%/22%, ASDAS-CII in 49%/46% and ASDAS-MI in 25%/26% of the patients. All rates differed significantly across number of previous b/tsDMARDs, were numerically higher for b/tsDMARD-naïve patients and varied significantly across registries. Overall, time since diagnosis was not associated with secukinumab effectiveness. CONCLUSIONS: In this study of 1860 patients from 13 European countries, we present the first comprehensive real-life data on effectiveness of secukinumab in patients with axSpA. Overall, secukinumab retention rates after 6 and 12months of treatment were high. Secukinumab effectiveness was consistently better for bionaïve patients, independent of time since diagnosis and differed across the European countries. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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| 10. |
- Nissen, M., et al.
(författare)
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The impact of a csDMARD in combination with a TNF inhibitor on drug retention and clinical remission in axial spondylarthritis
- 2022
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Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 61:12, s. 4741-4751
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Many axial spondylarthritis (axSpA) patients receive a conventional synthetic DMARD (csDMARD) in combination with a TNF inhibitor (TNFi). However, the value of this co-therapy remains unclear. The objectives were to describe the characteristics of axSpA patients initiating a first TNFi as monotherapy compared with co-therapy with csDMARD, to compare one-year TNFi retention and remission rates, and to explore the impact of peripheral arthritis. Methods Data was collected from 13 European registries. One-year outcomes included TNFi retention and hazard ratios (HR) for discontinuation with 95% CIs. Logistic regression was performed with adjusted odds ratios (OR) of achieving remission (Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP < 1.3 and/or BASDAI < 2) and stratified by treatment. Inter-registry heterogeneity was assessed using random-effect meta-analyses, combined results were presented when heterogeneity was not significant. Peripheral arthritis was defined as >= 1 swollen joint at baseline (=TNFi start). Results Amongst 24 171 axSpA patients, 32% received csDMARD co-therapy (range across countries: 13.5% to 71.2%). The co-therapy group had more baseline peripheral arthritis and higher CRP than the monotherapy group. One-year TNFi-retention rates (95% CI): 79% (78, 79%) for TNFi monotherapy vs 82% (81, 83%) with co-therapy (P < 0.001). Remission was obtained in 20% on monotherapy and 22% on co-therapy (P < 0.001); adjusted OR of 1.16 (1.07, 1.25). Remission rates at 12 months were similar in patients with/without peripheral arthritis. Conclusion This large European study of axial SpA patients showed similar one-year treatment outcomes for TNFi monotherapy and csDMARD co-therapy, although considerable heterogeneity across countries limited the identification of certain subgroups (e.g. peripheral arthritis) that may benefit from co-therapy.
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