| 1. |
- Le Clerc, S., et al.
(author)
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HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
- 2021
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Journal article (peer-reviewed)abstract
- Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 x 10(-3); FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
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| 2. |
- Cearns, M., et al.
(author)
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Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach
- 2022
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In: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 220:4, s. 219-228
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Journal article (peer-reviewed)abstract
- Background Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment. Aims To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder. Method This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi(+)Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework. Results The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data. Conclusions Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
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| 3. |
- Olvegård, Maja, et al.
(author)
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High intensity profile monitor for time resolved spectrometry at the CLIC Test Facility 3
- 2012
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In: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 683, s. 29-39
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Journal article (peer-reviewed)abstract
- The power source of the Compact Linear Collider (CLIC) relies on the generation and deceleration of a high-intensity electron drive beam. In order to provide the best radio-frequency (RF) to beam-energy transfer efficiency, the electron beam is accelerated using fully loaded RF cavities, which leads to strong beam loading effects resulting in a high-energy transient. The stability of the RF power produced by the drive beam depends on the stability of the drive beam energy and energy spread along the pulse. The control and the monitoring of the time evolution of the beam energy distribution are therefore crucial for the accelerator performance. For this purpose segmented beam dumps, which are simple and robust devices, have been designed and installed at the CLIC Test Facility 3 (CTF3). These devices are located at the end of spectrometer lines and provide horizontal beam profiles with a time resolution better than 10 ns. The segmented dumps are composed of parallel, vertical, metallic plates, and are based on the same principle as a Faraday cup: the impinging beam current is read by a fast acquisition channel. Both FLUKA and Geant4 simulations were performed to define the optimum detector geometry for beam energies ranging from 5 MeV to 150 MeV. This paper presents a detailed description of the different steps of the design: the optimization of the detector spatial resolution, the minimization of the thermal load and the long-term damage resulting from high radiation doses. Four segmented dumps are currently used in the CTF3 complex. Their measured performance and limitations are presented in this paper. Typical beam spectra as measured in the CTF3 linac are also presented along with a description of the RF manipulations needed for tuning the beam energy spectrum.
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| 4. |
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| 5. |
- Reinbold, C. S., et al.
(author)
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Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder
- 2018
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In: Frontiers in Psychiatry. - : Frontiers Media SA. - 1664-0640. ; 9
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Journal article (peer-reviewed)abstract
- Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen) Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD associated miRNAs However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.
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| 6. |
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| 7. |
- Kalman, Janos L, et al.
(author)
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Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.
- 2019
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In: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 21:1, s. 68-75
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Journal article (peer-reviewed)abstract
- Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18years] vs adulthood [>18years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.
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| 11. |
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| 13. |
- Adli, E., et al.
(author)
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X-band rf power production and deceleration in the two-beam test stand of the Compact Linear Collider test facility
- 2011
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In: Physical Review Special Topics - Accelerators and Beams. - 1098-4402. ; 14:8, s. 081001-
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Journal article (peer-reviewed)abstract
- We discuss X-band rf power production and deceleration in the two-beam test stand of the CLIC test facility at CERN. The rf power is extracted from an electron drive beam by a specially designed power extraction structure. In order to test the structures at high-power levels, part of the generated power is recirculated to an input port, thus allowing for increased deceleration and power levels within the structure. The degree of recirculation is controlled by a splitter and phase shifter. We present a model that describes the system and validate it with measurements over a wide range of parameters. Moreover, by correlating rf power measurements with the energy lost by the electron beam, as measured in a spectrometer placed after the power extraction structure, we are able to identify system parameters, including the form factor of the electron beam. The quality of the agreement between model and reality gives us confidence to extrapolate the results found in the present test facility towards the parameter regime of CLIC.
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| 14. |
- Amare, Azmeraw, et al.
(author)
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Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.
- 2023
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In: Research square. - : Research Square Platform LLC.
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Journal article (peer-reviewed)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.
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| 15. |
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| 16. |
- Hou, Liping, et al.
(author)
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Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.
- 2016
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In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:15, s. 3383-94
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Journal article (peer-reviewed)abstract
- Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p=5.87×10(-9); odds ratio=1.12) and markers within ERBB2 (rs2517959, p=4.53×10(-9); odds ratio=1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
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| 17. |
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| 18. |
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| 19. |
- Olvegård, Maja, et al.
(author)
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Beam profile monitoring at the test beam line at the Compact Linear Collider test facility
- 2013
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In: Physical Review Special Topics - Accelerators and Beams. - 1098-4402. ; 16:8, s. 082802-
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Journal article (peer-reviewed)abstract
- The Compact Linear Collider, CLIC is a study for a future linear electron-positron collider based on a two-beam acceleration scheme in which a high intensity drive beam is decelerated in order to provide the power to accelerate the main beam for collision in the TeV range. The power extracted from the drive beam deteriorates the beam quality and increases the energy spread significantly. Monitoring of the beam properties is therefore challenging but essential. These challenges are being addressed experimentally at the CLIC Test Facility where up to 55% of the power is extracted from the beam in the test beam line, TBL, a small-scale version of the CLIC drive beam decelerator, leaving the beam with a very wide energy profile. For monitoring of the transverse beam profile and Twiss parameters we use Optical Transition Radiation screens and quadrupole scans. The intra-pulse train energy spectrum before and after deceleration is measured with segmented beam dumps. In this report we discuss the performance of these diagnostic devices with a particular emphasis on the large energy spread and its effect on the beam imaging techniques, and with a final outlook to the CLIC drive beam diagnostics.
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| 20. |
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| 21. |
- Shea, T. J., et al.
(author)
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Overview and status of diagnostics for the ESS project
- 2018
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In: Proceedings of the 6th International Beam Instrumentation Conference, IBIC 2017. - 9783954501922 ; , s. 8-15
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Conference paper (peer-reviewed)abstract
- The European Spallation Source, now under construction in Lund, Sweden, aims to be the world's most powerful pulsed neutron scattering facility. Driving the neutron source is a 5 MW superconducting proton linear accelerator operating at 4 percent beam duty factor and 14 Hz repetition rate. Nineteen partner institutions from across Europe are working with the Accelerator Division in Lund to design and construct the accelerator. The suite of accelerator instrumentation consists of over 20 unique system types developed by over 20 partners and collaborators. Although the organizational complexity presents challenges, it also provides the vast capabilities required to achieve the technical goals. At this time, the beam instrumentation team is in transition, completing the design phase while scaling up to the deployment phase. Commissioning of the ion source has commenced in Catania, preparations for installation on the Lund site are ramping up, and basic R&D on target instrumentation continues. Beam commissioning results from the systems immediately following the ion source will be presented, along with technical highlights and status of the many remaining instrumentation systems.
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| 22. |
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