| 1. |
- Lodin, Karin, et al.
(författare)
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Patient global assessment and inflammatory markers in patients with idiopathic inflammatory myopathies : A longitudinal study
- 2024
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Ingår i: Seminars in Arthritis & Rheumatism. - : Elsevier. - 0049-0172 .- 1532-866X. ; 65
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Tidskriftsartikel (refereegranskat)abstract
- AimTo explore if patient global assessment (PGA) is associated with inflammation over time and if associations are explained by other measures of disease activity and function in patients with idiopathic inflammatory myopathies (IIM).MethodsPGA and systemic inflammatory markers prospectively collected over five years were retrieved from the International MyoNet registry for 1200 patients with IIM. Associations between PGA, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and creatine kinase (CK) were analyzed using mixed models. Mediation analysis was used to test if the association between PGA and inflammatory markers during the first year of observation could be explained by measures of disease activity and function.ResultsPGA improved, and inflammatory markers decreased during the first year of observation. In the mixed models, high levels of inflammatory markers were associated with worse PGA in both men and women across time points during five years of observation. In men, but not in women, the association between elevated ESR, CRP and poorer PGA was explained by measures of function and disease activity. With a few exceptions, the association between improved PGA and reduced inflammatory markers was partially mediated by improvements in all measures of function and disease activity.ConclusionIncreased levels of systemic inflammation are associated with poorer PGA in patients with IIM. In addition to known benefits of lowered inflammation, these findings emphasize the need to reduce systemic inflammation to improve subjective health in patients with IIM. Furthermore, the results demonstrate the importance of incorporating PGA as an outcome measure in clinical practice and clinical trials.
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| 2. |
- Leclair, Valerie, et al.
(författare)
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Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies
- 2023
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 96
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Tidskriftsartikel (refereegranskat)abstract
- Background In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM. Methods We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or-associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules. Findings We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl,-Mi2,-Jo1,-Jo1/Ro52,-TIF1 gamma or negative for all analysed autoantibodies. Associations with HLA-DRB1*11, HLA-DRB1*15, HLA-DQA1*03, and HLA-DQB1*03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1*03, HLA-DQA1*05, and HLA-DQB1*02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/ Ro52-dominated subgroups. HLA-DRB1*16, HLA-DRB1*07 alleles were most frequent in anti-Mi2 and HLA- DRB1*01 and HLA-DRB1*07 alleles in the anti-TIF1 gamma subgroup. The HLA-DRB1*13, HLA-DQA1*01 and HLA-DQB1*06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1 gamma, and the negative subgroup. Interpretation Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features. Funding See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript. Copyright (c) 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 3. |
- Bianchi, Matteo, et al.
(författare)
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Contribution of rare genetic variation to disease susceptibility in a large Scandinavian myositis cohort
- 2022
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Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 74:2, s. 342-352
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Tidskriftsartikel (refereegranskat)abstract
- Objective Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs.Methods Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune-related genes in a Scandinavian case–control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant– and gene-level enrichment analyses, was implemented to explore genotype–phenotype relations.Results Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle–specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants.Conclusion Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.
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| 4. |
- Lundtoft, Christian, et al.
(författare)
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Complement C4 copy number variation is linked to SSA/Ro and SSB/La autoantibodies in systemic inflammatory autoimmune diseases.
- 2022
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Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 74:8, s. 1440-1450
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Tidskriftsartikel (refereegranskat)abstract
- Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. We asked if C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) or myositis.Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterised Scandinavian patients with SLE, pSS or myositis, and 1,251 healthy controls.A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the three diseases. The strongest association was detected for patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (OR=18.0; CI95% : 10.2-33.3), whereas a weaker association was seen for patients without SSA/SSB autoantibodies (OR=3.1; CI95% : 1.7-5.5). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals' capacity to deposit C4b on immune complexes.We show that a low C4A copy number more strongly is associated with the autoantibody repertoire than with the clinically defined disease entities. These results may have implication for understanding the aetiopathogenetic mechanisms of systemic inflammatory autoimmune diseases, and for patient stratification when taking the genetic profile into account. This article is protected by copyright. All rights reserved.
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| 5. |
- Cubo, Rubén, et al.
(författare)
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Calculating Deep Brain Stimulation Amplitudes and Power Consumption by Constrained Optimization
- 2019
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Ingår i: Journal of Neural Engineering. - : IOP Publishing. - 1741-2560 .- 1741-2552. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Deep brain stimulation (DBS) consists of delivering electrical stimuli to a brain target via an implanted lead to treat neurological and psychiatric conditions. Individualized stimulation is vital to ensure therapeutic results, since DBS may otherwise become ineffective or cause undesirable side effects. Since the DBS pulse generator is battery-driven, power consumption incurred by the stimulation is important. In this study, target coverage and power consumption are compared over a patient population for clinical and model-based patient-specific settings calculated by constrained optimization.Approach: Brain models for five patients undergoing bilateral DBS were built. Mathematical optimization of activated tissue volume was utilized to calculate stimuli amplitudes, with and without specifying the volumes, where stimulation was not allowed to avoid side effects. Power consumption was estimated using measured impedance values and battery life under both clinical and optimized settings.Results: It was observed that clinical settings were generally less aggressive than the ones suggested by unconstrained model-based optimization, especially under asymmetrical stimulation. The DBS settings satisfying the constraints were close to the clinical values.Significance: The use of mathematical models to suggest optimal patient-specific DBS settings that observe technological and safety constraints can save time in clinical practice. It appears though that the considered safety constraints based on brain anatomy depend on the patient and further research into it is needed. This work highlights the need of specifying the brain volumes to be avoided by stimulation while optimizing the DBS amplitude, in contrast to minimizing general stimuli overspill, and applies the technique to a cohort of patients. It also stresses the importance of considering power consumption in DBS optimization, since it increases with the square of the stimuli amplitude and also critically affects battery life through pulse frequency and duty cycle.
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| 6. |
- Medvedev, Alexander, 1958-, et al.
(författare)
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Control-Engineering Perspective on Deep Brain Stimulation : Revisited
- 2019
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Ingår i: 2019 American Control Conference (ACC). - 9781538679265 - 9781538679272 - 9781538679289 - 9781538679012 ; , s. 860-865
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Konferensbidrag (refereegranskat)abstract
- Deep brain stimulation (DBS) is a an established therapy in neurological and mental disorders making use of electrical pulses chronically delivered to a certain disease-specific neural target through surgically implanted electrodes. The therapeutical effect of DBS is highly individual and depends on the target coverage by the stimuli and the amount of spill beyond it. This can be suitably formulated as an optimization problem. Since the biological mechanism underlying the DBS therapy is mainly unknown, and due to high inter-patient and intra-patient variability of the DBS effect, a pragmatic approach to the DBS programming is to consider the process as tuning of a control system for the symptoms. Such a technology assumes that the symptoms are accurately quantified. The paper summarizes the progress in the individualized DBS and presents the results of a limited clinical study making use of the proposed DBS programming approach.
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| 7. |
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| 8. |
- Cubo, Rubén, et al.
(författare)
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Deep Brain Stimulation therapies : a control-engineering perspective
- 2017
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Ingår i: Proc. American Control Conference. - : IEEE. - 9781509059928 - 9781509045839 - 9781509059942 ; , s. 104-109
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Konferensbidrag (refereegranskat)abstract
- Deep Brain Stimulation (DBS) is an established therapy for treating e.g. Parkinson's disease, essential tremor, as well as epilepsy. In DBS, chronic pulsatile electrical stimulation is administered to a certain target area of the brain through a surgically implanted lead. The stimuli parameters have to be properly tuned in order to achieve therapeutical effect that in most cases is alleviation of motor symptoms. Tuning of DBS currently is a tedious task since it is performed manually by medical personnel in a trial-and-error manner. It can be dramatically improved and expedited by means of recently developed mathematical models together with control and estimation technology. This paper presents a control engineering perspective on DBS, viewing it as a control system for minimizing the severity of the symptoms through coordinated manipulation of the stimuli parameters. The DBS model structure comprises a stimuli model, an activation model, and a symptoms model. Each of those is individualized from patient data obtained through medical imaging, electrical measurements, and objective symptom quantification. The proposed approach is illustrated by simulation and clinical data from an individualized DBS model being developed by the authors.
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| 9. |
- Cubo, Rubén, et al.
(författare)
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Semi-Individualized electrical models in deep brain stimulation : A variability analysis
- 2017
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Ingår i: 2017 IEEE Conference on Control Technology and Applications (CCTA). - : IEEE. - 9781509021833 - 9781509021826 - 9781509021819 ; , s. 517-522
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Konferensbidrag (refereegranskat)abstract
- Deep Brain Stimulation (DBS) is a well-established treatment in neurodegenerative diseases, e.g. Parkinson's Disease. It consists of delivering electrical stimuli to a target in the brain via a chronically implanted lead. To expedite the tuning of DBS stimuli to best therapeutical effect, mathematical models have been developed during recent years. The electric field produced by the stimuli in the brain for a given lead position is evaluated by numerically solving a Partial Differential Equation with the medium conductivity as a parameter. The latter is patient- and target-specific but difficult to measure in vivo. Estimating brain tissue conductivity through medical imaging is feasible but time consuming due to registration, segmentation and post-processing. On the other hand, brain atlases are readily available and processed. This study analyzes how alternations in the conductivity due to inter-patient variability or lead position uncertainties affect both the stimulation shape and the activation of a given target. Results suggest that stimulation shapes are similar, with a Dice's Coefficient between 93.2 and 98.8%, with a higher similarity at lower depths. On the other hand, activation shows a significant variation of 17 percentage points, with most of it being at deeper positions as well. It is concluded that, as long as the lead is not too deep, atlases can be used for conductivity maps with acceptable accuracy instead of fully individualized though medical imaging models.
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| 10. |
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