| 1. |
- Amare, Azmeraw, et al.
(författare)
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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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Ingår i: Research square. - : Research Square Platform LLC.
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Amare, Azmeraw T, et al.
(författare)
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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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Ingår i: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261
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Tidskriftsartikel (refereegranskat)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder 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=2367) 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<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
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| 3. |
- Kalman, Janos L, et al.
(författare)
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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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Ingår i: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 21:1, s. 68-75
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Northcott, Paul A, et al.
(författare)
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Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 511:7510, s. 428-428
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Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
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| 5. |
- Stegmayr, Bernd, 1949-, et al.
(författare)
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Using the World Apheresis Association Registry Helps to Improve the Treatment Quality of Therapeutic Apheresis
- 2021
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Ingår i: Transfusion Medicine and Hemotherapy. - : S. Karger. - 1660-3796 .- 1660-3818. ; 48:4, s. 234-239
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Forskningsöversikt (refereegranskat)abstract
- Therapeutic apheresis (TA) is prescribed to patients that suffer from a severe progressive disease that is not sufficiently treated by conventional medications. A way to gain more knowledge about this treatment is usually by the local analysis of data. However, the use of large quality assessment registries enables analyses of even rare findings. Here, we report some of the recent data from the World Apheresis Association (WAA) registry. Data from >104,000 procedures were documented, and TA was performed on >15,000 patients. The main indication for TA was the collection of autologous stem cells (45% of patients) as part of therapy for therapy. Collection of stem cells from donors for allogeneic transplantation was performed in 11% of patients. Patients with indications such as neurological diseases underwent plasma exchange (28%). Extracorporeal photochemotherapy, lipid apheresis, and antibody removal were other indications. Side effects recorded in the registry have decreased significantly over the years, with approximately only 10/10,000 procedures being interrupted for medical reasons. Conclusion: Collection of data from TA procedures within a multinational and multicenter concept facilitates the improvement of treatment by enabling the analysis of and feedback on indications, procedures, effects, and side effects. (c) 2021 S. Karger AG, Basel
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| 6. |
- Toss, Fredrik, 1984-, et al.
(författare)
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Does prophylactic calcium in apheresis cause more harm than good? : Centre heterogeneity within the World Apheresis Association Register prevents firm conclusions
- 2018
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Ingår i: Vox Sanguinis. - : John Wiley & Sons. - 0042-9007 .- 1423-0410. ; 113:7, s. 632-638
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Tidskriftsartikel (refereegranskat)abstract
- Background and objectives: Symptomatic hypocalcaemia is common during apheresis procedures based on citrate‐based anticoagulants. As a consequence, patients often receive prophylactic calcium treatment. However, a recent publication based on the World Apheresis Association (WAA) register suggested harmful effects of such prophylactic calcium use. Recognizing possible limitations in the previous WAA register analyses, we critically re‐evaluate the data, to test whether a change in prophylactic calcium usage may be warranted.Materials and methods: Using the WAA register, we reanalysed previous data by means of centre and treatment type stratification, to explore the role of prophylactic calcium as a risk factor for adverse events.Results: There was large variability in adverse event rates dependent on the centre performing the apheresis procedure and dependent on the type of procedure. When this variability was accounted for, there was no clear effect of calcium administration on risk of adverse effects.Conclusion: Shortcomings in the previous WAA register analyses may have failed to account for important confounding factors resulting in a substantial overestimation of the risk attributable to calcium usage. Overall our findings do not support a negative effect of prophylactic calcium administration in the apheresis setting.
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| 7. |
- Vrielink, Hans, et al.
(författare)
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The world apheresis association registry, 2023 update
- 2023
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Ingår i: Transfusion and apheresis science. - : Elsevier. - 1473-0502 .- 1878-1683. ; 62:6
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Forskningsöversikt (refereegranskat)abstract
- The WAA apheresis registry contains data on more than 140,000 apheresis procedures conducted in 12 different countries. The aim is to give an update of indications, type and number of procedures and adverse events (AEs).Material and Methods: The WAA-registry is used for registration of apheresis procedures and is free of charge. The responsible person for a center can apply at the site www.waa-registry.orgResults: Data includes reported AEs from 2012 and various procedures and diagnoses during the years 2018–2022; the latter in total from 27 centers registered a total of 9500 patients (41% women) that began therapeutic apheresis (TA) during the period. A total of 58,355 apheresis procedures were performed. The mean age was 50 years (range 0–94). The most common apheresis procedure was stem cell collection for which multiple myeloma was the most frequent diagnosis (51%). Donor cell collection was done in 14% and plasma exchange (PEX) in 28% of patients; In relation to all performed procedures PEX, using a centrifuge (35%) and LDL-apheresis (20%) were the most common. The main indication for PEX was TTP (17%). Peripheral veins were used in 56% as the vascular access. The preferred anticoagulant was ACD. AEs occurred in 2.7% of all procedures and were mostly mild (1%) and moderate 1.5% (needed supportive medication) and, only rarely, severe (0.15%).Conclusion: The data showed a wide range of indications and variability in apheresis procedures with low AE frequency.
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| 8. |
- Witt, Volker, et al.
(författare)
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The WAA-registry
- 2024
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Ingår i: Transfusion and apheresis science. - : Elsevier. - 1473-0502 .- 1878-1683.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 9. |
- Witt, Volker, et al.
(författare)
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World apheresis registry data from 2003 to 2007, the pediatric and adolescent side of the registry
- 2008
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Ingår i: Transfusion and apheresis science. - : Elsevier BV. - 1473-0502 .- 1878-1683. ; 39:3, s. 255-260
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Paediatric patients are a special group in apheresis. It is general accepted to use adult indications in paediatric patients, but data in this age group are rare. In order to provide more information of apheresis practise in children and young adults (<21a) we will report of knowledge learnt by data from the registry from 2003 until 2007. Methods: This is a web-based registry. A link is available from the WAA homepage (www.worldapheresis.org). So far data from 12,448 procedures have been included. Six hundred and twelve procedures were performed in 135 children and young adults (308 procedures < 16a, 237 from 17 to 20a, and 67 with 21a) representing 5% of the total population. The median age was 14 years (range 1-21 years), 74 male and 61 female. These data were entered by 15 centres with a frequency of in median 18 aphereses in young patients per centre (range 1-287) from 2003 to 2007. Results: Main indications: haematological diseases and also nephrological, and neurological. The type of aphereses was mainly Leukapheresis (196, 33%), plasma exchange (149, 25%), photopheresis (127, 21%), and lipid aphereses (79, 13%). Blood access: peripheral vessels in 305 procedures (50 K, compared to 73% in adults), central venous catheter in 239 (38%), and AV-fistula in 2% and 0.3%, and in 8 (1.31%) procedures an arterial line was used. Anticoagulation was mostly by ACD (71%), heparin (18% or the combination of both (3%). 39 adverse events (AE) were registered in 22 (=3.59%) of the procedures. mostly graded as mild. Treatment was interrupted in 14 procedures (2.29%. AE's were abdominal pain, anaphylactic shock, flush, hyper- and hypotension, nausea, vertigo, cephalea and need for sedation and technical problems with the device and problems with the venous access. The rate of AE's was similar for stem cell harvesting and for plasma exchange (4%, and 4.7%). respectively). Conclusion: The paediatric data compared to the whole registry data set are showing that aphereses are performed as safe in paediatrics as in adults. Centres are mostly handling only a few cases younger than 21. Therefore more exchange of information and experience in paediatric apheresis is warranted.
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| 10. |
- Yuan, Bo, et al.
(författare)
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Temporal Trends of C-8-C-36 Chlorinated Paraffins in Swedish Coastal Sediment Cores over the Past 80 Years
- 2017
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 51:24, s. 14199-14208
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Tidskriftsartikel (refereegranskat)abstract
- Temporal trends of chlorinated paraffins (CPs) were analyzed in three sediment cores collected near different potential CP sources along the Swedish Baltic Sea coast. C-8-C-36 CPs were found in sediment dating back to the 1930s. The maximum CP concentrations found in proximity to a metropolitan sewage treatment plant, a wood related industrial area, and a steel factory were 48; 160, and 1400 ng/g d.w., respectively, in sediment sections dated from the early 1990s or the 2000s. The temporal trends agree with statistics on CP importation in Sweden or local industrial activities. MCCPs (C-14-C-17 CPs) and LCCPs (C->= 18 CPs) predominated, in most sediments with average percentage compositions of 47 +/- 20% and 37 +/- 20%, respectively. Concentrations of SCCPs in the three cores showed a decreasing trend in recent years. The temporal trends of MCCPs indicated that these are currently the predominant CPs in use. This study showed for the first time that LCCPs from C-18 to C-36, as well as C-8-C-17 CPs, are persistent in sediments over the last 30-80 years, indicating that CPs are persistent chemicals regaidless of alkane-chain lengths.
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