| 1. |
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| 2. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 3. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 4. |
- Romagnoni, A, et al.
(författare)
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Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10351-
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Tidskriftsartikel (refereegranskat)abstract
- Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
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| 5. |
- Craddock, Nick, et al.
(författare)
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Tidskriftsartikel (refereegranskat)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 6. |
- Culverhouse, R. C., et al.
(författare)
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Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression
- 2018
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 23:1, s. 133-142
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Tidskriftsartikel (refereegranskat)abstract
- The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.
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| 7. |
- Okada, Yukinori, et al.
(författare)
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Genetics of rheumatoid arthritis contributes to biology and drug discovery
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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| 15. |
- Snoeker, B. A.M., et al.
(författare)
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Is meniscal status in the anterior cruciate ligament injured knee associated with change in bone surface area? An exploratory analysis of the KANON trial
- 2021
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Ingår i: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 29:6, s. 841-848
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To study bone shape changes as a potential early feature of post-traumatic structural knee OA development, we estimated the association between meniscal status in the anterior cruciate ligament (ACL) injured knee and longitudinal condyle changes in bone surface area. Design: We used data from the KANON trial, including 121 young ACL-injured adults. We obtained baseline and 2-year follow-up knee MRIs. Our outcome was change in the bone surface areas (mean mm2, log-transformed) in 4 locations (femur, tibia, patella, and trochlea femur) in the medial and lateral compartment from baseline to 2 years. Meniscal pathology was defined as both present at baseline and newly developed (i.e., incident or progressed) using ACLOAS. We used multilevel linear regression adjusted for baseline bone area, age, sex, body mass index, treatment arm (i.e., early or optional delayed ACL reconstruction), and location. We analyzed medial and lateral compartment separately. We present results as percentage (%) bone area change difference with 95% confidence intervals (CI). Results: We analyzed 109 subjects (median 27 (18–36) years, 83% men) due to missing MRI information. The bone surface area increased on average by ∼2% over 2 years. The differences between knees with and without baseline meniscal pathology were 1.1% (95%CI 0.0–2.3%) and 1.4% (95%CI 0.6–2.2%) in the medial and lateral compartment, respectively, and 1.2% (95%CI 0.3–2.0%) and 1.3% (95%CI 0.6–2.0%) for medial and lateral newly developed pathology, respectively. Conclusion: Our finding of ∼1% increase bone area in compartment with meniscal pathology suggests a potentially important association between meniscal integrity and early bone surface area changes after ACL injury. Trial registration number ISRCTN 84752559.
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| 18. |
- Bowes, Heather M, et al.
(författare)
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Scaling the peak and steady-state aerobic power of running and walking humans.
- 2021
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Ingår i: European Journal of Applied Physiology. - : Springer Nature. - 1439-6319 .- 1439-6327. ; 121:10, s. 2925-2938
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The first aim of this experiment was to evaluate the appropriateness of linear and non-linear (allometric) models to scale peak aerobic power (oxygen consumption) against body mass. The possibilities that oxygen consumption would scale allometrically across the complete metabolic range, and that the scaling exponents would differ significantly between basal and maximal-exercise states, were then evaluated. It was further hypothesised that the scaling exponent would increase in a stepwise manner with elevations in exercise intensity. Finally, the utility of applying the scaling exponent derived for peak aerobic power to another population sample was evaluated.METHODS: Basal, steady-state walking and peak (treadmill) oxygen-consumption data were measured using 60 relatively homogeneous men (18-40 year; 56.0-117.1 kg), recruited across five mass classes. Linear and allometric regressions were applied, with the utility of each scaling method evaluated.RESULTS: Oxygen consumption scaled allometrically with body mass across the complete metabolic range, and was always superior to both ratiometric analysis and linear regression. The scaling exponent increased significantly from rest (mass0.57) to maximal exercise (mass0.75; P < 0.05), but not between steady-state walking (mass0.87) and maximal exercise (P > 0.05). When used with an historical database, the maximal-exercise exponent successfully removed the mass bias.CONCLUSION: It has been demonstrated that the oxygen consumption of healthy humans scales allometrically with body mass across the entire metabolic range. Moreover, only two scaling exponents (rest and exercise) were required to produce mass-independent outcomes from those data. Accordingly, ratiometric and linear regression analyses are not recommended as scaling methods.
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| 19. |
- Bowes, Heather M., et al.
(författare)
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The scaling of human basal and resting metabolic rates
- 2021
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Ingår i: European Journal of Applied Physiology. - : Springer Science and Business Media LLC. - 1439-6319 .- 1439-6327. ; 121:1
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: In tachymetabolic species, metabolic rate increases disproportionately with body mass, and that inter-specific relationship is typically modelled allometrically. However, intra-specific analyses are less common, particularly for healthy humans, so the possibility that human metabolism would also scale allometrically was investigated.METHODS: Basal metabolic rate was determined (respirometry) for 68 males (18-40 years; 56.0-117.1 kg), recruited across five body-mass classes. Data were collected during supine, normothermic rest from well-rested, well-hydrated and post-absorptive participants. Linear and allometric regressions were applied, and three scaling methods were assessed. Data from an historical database were also analysed (2.7-108.9 kg, 4811 males; 2.0-96.4 kg, 2364 females).RESULTS: Both linear and allometric functions satisfied the statistical requirements, but not the biological pre-requisite of an origin intercept. Mass-independent basal metabolic data beyond the experimental mass range were not achieved using linear regression, which yielded biologically impossible predictions as body mass approached zero. Conversely, allometric regression provided a biologically valid, powerful and statistically significant model: metabolic rate = 0.739 * body mass0.547 (P < 0.05). Allometric analysis of the historical male data yielded an equivalent, and similarly powerful model: metabolic rate = 0.873 * body mass0.497 (P < 0.05).CONCLUSION: It was established that basal and resting metabolic rates scale allometrically with body mass in humans from 10-117 kg, with an exponent of 0.50-0.55. It was also demonstrated that ratiometric scaling yielded invalid metabolic predictions, even within the relatively narrow experimental mass range. Those outcomes have significant physiological implications, with applications to exercising states, modelling, nutrition and metabolism-dependent pharmacological prescriptions.
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| 20. |
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| 21. |
- Hinks, A, et al.
(författare)
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Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases
- 2017
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 76:4, s. 765-772
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Tidskriftsartikel (refereegranskat)abstract
- Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides.MethodsDense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed.ResultsWe identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA.ConclusionsThe findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.
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| 22. |
- Ishigaki, Kazuyoshi, et al.
(författare)
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Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:11, s. 1640-1651
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.
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| 23. |
- Kia, Richard, et al.
(författare)
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MicroRNA-122 : a novel hepatocyte-enriched in vitro marker of drug-induced cellular toxicity
- 2015
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Ingår i: Toxicological Sciences. - : Oxford University Press. - 1096-6080 .- 1096-0929. ; 144:1, s. 173-185
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Tidskriftsartikel (refereegranskat)abstract
- Emerging hepatic models for the study of drug-induced toxicity include pluripotent stem cell-derived hepatocyte-like cells (HLCs) and complex hepatocyte-non-parenchymal cellular coculture to mimic the complex multicellular interactions that recapitulate the niche environment in the human liver. However, a specific marker of hepatocyte perturbation, required to discriminate hepatocyte damage from non-specific cellular toxicity contributed by non-hepatocyte cell types or immature differentiated cells is currently lacking, as the cytotoxicity assays routinely used in in vitro toxicology research depend on intracellular molecules which are ubiquitously present in all eukaryotic cell types. In this study, we demonstrate that microRNA-122 (miR-122) detection in cell culture media can be used as a hepatocyte-enriched in vitro marker of drug-induced toxicity in homogeneous cultures of hepatic cells, and a cell-specific marker of toxicity of hepatic cells in heterogeneous cultures such as HLCs generated from various differentiation protocols and pluripotent stem cell lines, where conventional cytotoxicity assays using generic cellular markers may not be appropriate. We show that the sensitivity of the miR-122 cytotoxicity assay is similar to conventional assays that measure lactate dehydrogenase activity and intracellular adenosine triphosphate when applied in hepatic models with high levels of intracellular miR-122, and can be multiplexed with other assays. MiR-122 as a biomarker also has the potential to bridge results in in vitro experiments to in vivo animal models and human samples using the same assay, and to link findings from clinical studies in determining the relevance of in vitro models being developed for the study of drug-induced liver injury.
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| 24. |
- Kim, Kwangwoo, et al.
(författare)
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High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci
- 2015
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 74:3
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Tidskriftsartikel (refereegranskat)abstract
- Objective A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. Methods We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45 790 European case-control samples. Results We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5x10(-8)), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. Conclusions This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.
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| 25. |
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| 26. |
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| 27. |
- Rothwell, S, et al.
(författare)
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Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups
- 2019
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:7, s. 996-1002
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Tidskriftsartikel (refereegranskat)abstract
- Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies.MethodsWe collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups.ResultsWe report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10–5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10–53 and HLA-DRB1*03:01, p=3.25×10–9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10–26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10–11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10–13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10–6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10–64) and position 9 of HLA-B (p=7.03×10–11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies.ConclusionsThese findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.
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| 30. |
- Bowes, John, et al.
(författare)
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PTPN22 is associated with susceptibility to psoriatic arthritis but not psoriasis : evidence for a further PsA-specific risk locus
- 2015
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 74:10, s. 1882-1885
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis; it has a higher estimated genetic component than psoriasis alone, however most genetic susceptibility loci identified for PsA to date are also shared with psoriasis. Here we attempt to validate novel single nucleotide polymorphisms selected from our recent PsA Immunochip study and determine specificity to PsA. Methods A total of 15 single nucleotide polymorphisms were selected (P-Immunochip <1x10(-4)) for validation genotyping in 1177 cases and 2155 controls using TaqMan. Meta-analysis of Immunochip and validation data sets consisted of 3139 PsA cases and 11 078 controls. Novel PsA susceptibility loci were compared with data from two large psoriasis studies (WTCCC2 and Immunochip) to determine PsA specificity. Results We found genome-wide significant association to rs2476601, mapping to PTPN22 (p=1.49x10(-9), OR=1.32), but no evidence for association in the psoriasis cohort (p=0.34) and the effect estimates were significantly different between PsA and psoriasis (p=3.2x10(-4)). Additionally, we found genome-wide significant association to the previously reported psoriasis risk loci; NOS2 (rs4795067, p=5.27x10(-9)). Conclusions For the first time, we report genome-wide significant association of PTPN22 (rs2476601) to PsA susceptibility, but no evidence for association to psoriasis.
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| 31. |
- Bowes, M. A., et al.
(författare)
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Marked and rapid change of bone shape in acutely ACL injured knees – an exploratory analysis of the Kanon trial
- 2019
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Ingår i: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 27:4, s. 638-645
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Tidskriftsartikel (refereegranskat)abstract
- Background: To investigate changes in knee 3D bone shape over the first 5 years after acute anterior cruciate ligament (ACL) injury in participants of the randomized controlled KANON-trial. Methods: Serial MR images over 5 years from 121 young (32 women, mean age 26.1 years) adults with an acute ACL tear in a previously un-injured knee were analyzed using statistical shape models for bone. A matched reference cohort of 176 individuals was selected from the Osteoarthritis Initiative (OAI). Primary endpoint was change in bone area of the medial femoral condyle; exploratory analyses compared results by treatment and examined other knee regions. Comparisons were made using repeated measures mixed model ANOVA with adjustment for age, sex and body mass index (BMI). Results: Mean medial femur bone area increased 3.2% (78.0 [95% CI 70.2 to 86.4] mm2) over 5 years after ACL injury and most prominently in knees treated with ACL reconstruction (ACLR). A higher rate of increase occurred over the first 2 years compared to the latter 3-years (66.2 [59.3 to 73.2] vs 17.6 [12.2 to 23.0] mm2) and was 6.7 times faster than in the reference cohort. The pattern and location of shape change in the extrapolated KANON data was very similar to that observed in another knee-osteoarthritis cohort. Conclusion: 3D shape modelling after acute ACL injury revealed rapid bone shape changes, already evident at 3 months. The bone-change pattern after ACL injury demonstrated flattening and bone growth on the outer margins of the condyles similar to that reported in established knee osteoarthritis.
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| 34. |
- Garcia-Martin, E. Elena, et al.
(författare)
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Sources, Composition, and Export of Particulate Organic Matter Across British Estuaries
- 2023
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Ingår i: Journal of Geophysical Research - Biogeosciences. - : American Geophysical Union (AGU). - 2169-8953 .- 2169-8961. ; 128:4
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Tidskriftsartikel (refereegranskat)abstract
- Estuaries receive and process a large amount of particulate organic carbon (POC) prior to its export into coastal waters. Studying the origin of this POC is key to understanding the fate of POC and the role of estuaries in the global carbon cycle. Here, we evaluated the concentrations of POC, as well as particulate organic nitrogen (PON), and used stable carbon and nitrogen isotopes to assess their sources across 13 contrasting British estuaries during five different sampling campaigns over 1 year. We found a high variability in POC and PON concentrations across the salinity gradient, reflecting inputs, and losses of organic material within the estuaries. Catchment land cover appeared to influence the contribution of POC to the total organic carbon flux from the estuary to coastal waters, with POC contributions >36% in estuaries draining catchments with a high percentage of urban/suburban land, and <11% in estuaries draining catchments with a high peatland cover. There was no seasonal pattern in the isotopic composition of POC and PON, suggesting similar sources for each estuary over time. Carbon isotopic ratios were depleted (-26.7 +/- 0.42 parts per thousand, average +/- sd) at the lowest salinity waters, indicating mainly terrigenous POC (TPOC). Applying a two-source mixing model, we observed high variability in the contribution of TPOC at the highest salinity waters between estuaries, with a median value of 57%. Our results indicate a large transport of terrigenous organic carbon into coastal waters, where it may be buried, remineralized, or transported offshore. Plain Language Summary Estuaries transport and process a large amount terrigenous particulate organic matter (i.e., carbon and nitrogen) prior to its export to coastal waters. In order to understand the fate of organic carbon and the role of estuaries in the global carbon cycle it is essential to improve our knowledge on its composition, origin, and amount of carbon transported. We quantified the elemental concentrations and stable isotopes composition of carbon and nitrogen to quantify the amount of terrigenous particulate organic matter transported by 13 British estuaries, which drain catchments of diverse land cover under different hydrological conditions. We found a great variability in particulate organic carbon (POC) and particulate organic nitrogen concentrations across the salinity gradient, implying inputs, and losses of material within the estuaries. Each estuary had similar sources of particulate material throughout the year. In most of the estuaries, the POC had a terrigenous origin at the lowest salinity waters. The terrigenous organic carbon contribution decreased toward coastal waters with an average contribution of 57% at the highest salinity waters, indicating a large transport of terrigenous organic carbon into coastal waters.
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| 36. |
- Han, Buhm, et al.
(författare)
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Fine Mapping Seronegative and Seropositive Rheumatoid Arthritis to Shared and Distinct HLA Alleles by Adjusting for the Effects of Heterogeneity
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 94:4, s. 522-532
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Tidskriftsartikel (refereegranskat)abstract
- Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA RA and observed independent associations for serine and leucine at position 11 in HLA-DR beta 1 (p = 1.4 x 10 (13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 x 10(-12), OR = 1.39) within the peptide binding grooves. These amino acid positions induced associations at HLA-DRB1*03 (encoding serine at 11) and HLA-B*08 (encoding aspartate at 9). We validated these findings in an independent set of 427 ACPA(-) case subjects, carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control subjects (HLA-DR beta 1 Ser11+Leu11: p = 5.8 x 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 x 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DR beta 1 position 11 were distinct (p < 2.9 x 10(-107)). We also identified an association with ACPA(+) RA at HLA-A position 77 (p = 2.7 x 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 15,870 control subjects. These results contribute to mounting evidence that ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate autoantigens contributing to pathogenesis. We expect that our approach might have broad applications in analyzing clinical conditions with heterogeneity at both major histocompatibility complex (MHC) and non-MHC regions.
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| 38. |
- Singer, Andrew C., et al.
(författare)
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Intra- and inter-pandemic variations of antiviral, antibiotics and decongestants in wastewater treatment plants and receiving rivers
- 2014
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Ingår i: PLOS ONE. - : Public library of science. - 1932-6203. ; 9:9
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Tidskriftsartikel (refereegranskat)abstract
- The concentration of eleven antibiotics (trimethoprim, oxytetracycline, ciprofloxacin, azithromycin, cefotaxime, doxycycline, sulfamethoxazole, erythromycin, clarithromycin, ofloxacin, norfloxacin), three decongestants (naphazoline, oxymetazoline, xylometazoline) and the antiviral drug oseltamivir's active metabolite, oseltamivir carboxylate (OC), were measured weekly at 21 locations within the River Thames catchment in England during the month of November 2009, the autumnal peak of the influenza A[H1N1]pdm09 pandemic. The aim was to quantify the pharmaceutical response to the pandemic and compare this to drug use during the late pandemic (March 2010) and the inter-pandemic periods (May 2011). A large and small wastewater treatment plant (WWTP) were sampled in November 2009 to understand the differential fate of the analytes in the two WWTPs prior to their entry in the receiving river and to estimate drug users using a wastewater epidemiology approach. Mean hourly OC concentrations in the small and large WWTP's influent were 208 and 350 ng/L (max, 2070 and 550 ng/L, respectively). Erythromycin was the most concentrated antibiotic measured in Benson and Oxford WWTPs influent (max = 6,870 and 2,930 ng/L, respectively). Napthazoline and oxymetazoline were the most frequently detected and concentrated decongestant in the Benson WWTP influent (1650 and 67 ng/L) and effluent (696 and 307 ng/L), respectively, but were below detection in the Oxford WWTP. OC was found in 73% of November 2009's weekly river samples (max = 193 ng/L), but only in 5% and 0% of the late-and inter-pandemic river samples, respectively. The mean river concentration of each antibiotic during the pandemic largely fell between 17-74 ng/L, with clarithromycin (max = 292 ng/L) and erythromycin (max = 448 ng/L) yielding the highest single measure. In general, the concentration and frequency of detecting antibiotics in the river increased during the pandemic. OC was uniquely well-suited for the wastewater epidemiology approach owing to its nature as a prodrug, recalcitrance and temporally-and spatially-resolved prescription statistics.
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| 39. |
- Singer, Andrew C., et al.
(författare)
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Intra- and inter-pandemic variations of antiviral, antibiotics and decongestants in wastewater treatment plants and receiving rivers
- 2015. - 1
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Ingår i: Water treatment in developed and developing nations. - Oakville, ON : Apple Academic Press. - 9781771882453 - 9781771882415 - 9780429154713 ; , s. 155-186
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Bokkapitel (refereegranskat)abstract
- Pandemics are unique public health emergencies that can result in a large sudden increase in the use of a restricted set of pharmaceuticals within a short time period. In the case of an influenza pandemic, antiviral use will greatly exceed inter-pandemic use in most countries by several orders of magnitude, as few countries maintain significant inter-pandemic usage-Japan being a notable exception [1]. Depending on the severity of the pandemic, antibiotics have the potential to significantly exceed inter-pandemic usage for the treatment of secondary bacterial respiratory infections [2]. Decongestant usage is also predicted to increase with an increase in upper-and lower-respiratory tract infections [3].
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