| 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. |
- Amare, Azmeraw T, et al.
(författare)
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Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study.
- 2018
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 65-74
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Tidskriftsartikel (refereegranskat)abstract
- Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ).To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association.A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017.Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained.Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P<5×10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.
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| 4. |
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| 5. |
- Coombes, Brandon J, et al.
(författare)
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Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study.
- 2021
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Ingår i: Complex psychiatry. - : S. Karger AG. - 2673-3005 .- 2673-298X. ; 7:3-4, s. 80-89
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Tidskriftsartikel (refereegranskat)abstract
- Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (β = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.
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| 6. |
- De Brouwer, Sara, et al.
(författare)
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Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification.
- 2010
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 16:17, s. 4353-62
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Tidskriftsartikel (refereegranskat)abstract
- Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic significance of ALK copy number and expression.
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| 7. |
- Herrera-Rivero, Marisol, et al.
(författare)
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Exploring the genetics of lithium response in bipolar disorders.
- 2023
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Ingår i: Research square.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II.We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism.Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.
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| 8. |
- Herrera-Rivero, Marisol, et al.
(författare)
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Exploring the genetics of lithium response in bipolar disorders
- 2024
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Ingår i: International Journal of Bipolar Disorders. - 2194-7511. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.
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| 9. |
- Herrera-Rivero, Marisol, et al.
(författare)
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Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder.
- 2023
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Ingår i: Research square.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1×10- 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP's age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.
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| 10. |
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| 11. |
- Hou, Liping, et al.
(författare)
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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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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:15, s. 3383-94
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Tidskriftsartikel (refereegranskat)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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| 12. |
- 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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| 13. |
- Kelsoe, John, et al.
(författare)
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Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study.
- 2023
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Ingår i: Research square.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.
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| 14. |
- Lidbeck, Cecilia, et al.
(författare)
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Motor Development in Children with Cerebral Palsy in Sweden : A Population-Based Longitudinal Register Study
- 2023
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Ingår i: Children. - : MDPI. - 2227-9067. ; 10:12
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to explore longitudinal motor development in children with cerebral palsy (CP) in Sweden with respect to the Gross Motor Function Classification System (GMFCS). In this national CP registry-based study, 2138 children aged 0.5-19 years participated (42% girls). The distribution with respect to GMFCS was I: 49%, II: 16%, III: 10%, IV: 14%, and V: 11%. In total, 5538 assessments (mean 2.7, min-max: 1-9) with the Gross Motor Function Measure-66 were included. Data were analysed using non-linear mixed-effects regression models, and the Stable Limit Model was selected to fit data. Five distinct curves of predicted gross motor development with respect to GMFCS levels were obtained. The achieved motor development was maintained over time. The estimated average GMFM-66 limit and the average age when 90% of the expected limits were reached were at GMFCS I: 88 at age 4.5; GMFCS II: 71 at age 4.2; GMFCS III: 54 at age 3.1; GMFCS IV: 38 at age 2.6, and at GMFCS V: 18 at age 0.9. In conclusion, this is the first national population-based study following motor development in CP. Five distinct curves reported in previous controlled research studies were confirmed. Our study adds knowledge about motor development captured in children's everyday context.
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| 15. |
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| 16. |
- Martinsson, Caroline, et al.
(författare)
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Preference-based patient participation for most, if not all: A cross-sectional study of patient participation amongst persons with end-stage kidney disease
- 2021
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Ingår i: Health Expectations. - : Wiley. - 1369-6513 .- 1369-7625. ; 24:5, s. 1833-1841
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Tidskriftsartikel (refereegranskat)abstract
- Background Patient participation is considered central for good healthcare. Yet, the concept is not fully understood when it comes to patients experiences of participation in conjunction with their preferences, particularly in long-term healthcare. The aim of this study was to investigate the extent and variation of preference-based patient participation in patients with end-stage kidney disease (ESKD). Methods A cross-sectional study was conducted with 346 patients in renal care. The main variables were patients preferences for and experiences of patient participation, determined using the Patient Preferences for Patient Participation tool, the 4Ps. Analyses identified the degree of match between preferences and experiences, that is, the preference-based patient participation measure. Results Overall, 57%-84% of the patients reached a sufficient level of preference-based patient participation on the items, while 2%-12% reached an insufficient level. A mismatch indicated either less or more participation than preferred; for example, 40% had less experience than preferred for taking part in planning, and 40% had more than preferred for managing treatment. Conclusion This study shows that, although many patients reach a sufficient level of preference-based patient participation, this is not the case for all patients and/or attributes. Further opportunities for a mutual understanding of patients preferences are needed for healthcare professionals to support person-centred patient participation. Patient or Public Contribution The 4Ps is manufactured in collaboration with people with experience of the patient role, and persons living with ESKD were engaged in identifying their preferences and experiences of participation in renal care.
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| 17. |
- Martinsson, Svante, 1985, et al.
(författare)
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Barcoding gap, but no support for cryptic speciation in the earthworm Aporrectodea longa (Clitellata: Lumbricidae)
- 2017
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Ingår i: Mitochondrial DNA. - : Informa UK Limited. - 1940-1736 .- 1940-1744. ; 28:2, s. 147-155
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Tidskriftsartikel (refereegranskat)abstract
- DNA-barcoding, using the mitochondrial marker COI, has been found successful for the identification of specimens in many animal groups, but may not be suited for species discovery and delimitation if used alone. In this study, we investigate whether two observed COI haplogroups in the earthworm Aporrectodea longa correspond to two cryptic species or if the variation is intraspecific. This is done by complementing COI with two nuclear markers, ITS2 and Histone 3. The variation is studied using distance methods, parsimony networks and Bayesian coalescent trees, and the statistical distinctness of the groups is tested on gene trees using the genealogical sorting index, Rosenberg’s PAB and Rodrigo et al.’s P(RD). We also applied multilocus species delimitation based on the multispecies coalescence model. The two haplogroups were found in COI, and all tests except P(RD) found them to be significantly distinct. However, in ITS2, the same groups were not recovered in any analyses or tests. H3 was invariable in A. longa, and was, therefore, included only in the multilocus analysis, which preferred a model treating A. longa as one species over a model splitting it into two. We also compared two measurements of size, body length, and no. of segments between the groups. No difference in body length was found, and although a significant difference in no. of segments was noted the haplogroup with the lower mean showed both the highest and the lowest value. When combined, these results led us to the conclusion that there is no support for the separation of A. longa into two cryptic species. This study again highlights the importance of complementing mitochondrial barcodes with more data when establishing species boundaries.
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| 18. |
- Mondal, Tanmoy, 1981, et al.
(författare)
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Sense-antisense lncRNA pair encoded by locus 6p22.3 determines neuroblastoma susceptibility via the USP36-CHD7-SOX9 regulatory axis
- 2018
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Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 33:3
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Tidskriftsartikel (refereegranskat)abstract
- Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.
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| 19. |
- Ou, Anna H., et al.
(författare)
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Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study
- 2024
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Ingår i: TRANSLATIONAL PSYCHIATRY. - 2158-3188. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.
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| 20. |
- Pettersson, Anna, et al.
(författare)
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Experiences of a One-hour Algorithm in Chest Pain Patients With a Nonelevated Troponin T at Presentation.
- 2018
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Ingår i: Critical Pathways in Cardiology. - 1535-282X .- 1535-2811. ; 17:1, s. 6-12
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to evaluate the use of a 1-hour measurement of high-sensitivity cardiac troponin T (hs-cTnT) in an emergency department (ED) population of chest pain patients with a nonelevated baseline hs-cTnT and to examine the prevalence of early dynamic changes in hs-cTnT and the association with admission rate, diagnosis, and outcome.Methods: All patients with a chief complaint of chest pain presenting to the ED of Karolinska University Hospital, Solna, Sweden, from December 2014 to September 2015 who had a baseline hs-cTnT of ≤14 ng/L and a second value obtained within >30 to ≤90 minutes were followed for 30 days regarding admission, readmission, myocardial infarction (MI), and death.Results: A total of 1091 patients were included. Dynamic 1-hour changes in hs-cTnT defined as an increase or decrease of ≥3 ng/L occurred in 23 patients (2.1%). Fifteen patients (65.2%) in the dynamic group were admitted, compared with 148 patients (13.9%) in the nondynamic group (P < 0.001). Four of the admitted patients (26.7%) in the dynamic and 1 (0.7%) in the nondynamic group were diagnosed with an MI (P < 0.001). No death or MI occurred within 30 days among those discharged from the ED.Conclusions: Dynamic 1-hour changes in hs-cTnT were uncommon but associated with a higher rate of admission and of MI in an unselected population of chest pain patients with a nonelevated hs-cTnT at presentation. Lack of dynamic changes makes MI highly unlikely, and a 1-hour measurement may facilitate an early rule out of MI but should be used together with clinical assessment.
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| 21. |
- Pixberg, Caroline, et al.
(författare)
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Acute Toxicity Grade 3 and 4 After Irradiation in Children and Adolescents : Results From the IPPARCA Collaboration
- 2016
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier BV. - 0360-3016 .- 1879-355X. ; 94:4, s. 792-799
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: In the context of oncologic therapy for children, radiation therapy is frequently indicated. This study identified the frequency of and reasons for the development of high-grade acute toxicity and possible sequelae.Materials and Methods: Irradiated children have been prospectively documented since 2001 in the Registry for the Evaluation of Side Effects After Radiation in Childhood and Adolescence (RiSK) database in Germany and since 2008 in the registry for radiation therapy toxicity (RADTOX) in Sweden. Data were collected using standardized, published forms. Toxicity classification was based on Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria.Results: As of June 2013, 1500 children have been recruited into the RiSK database and 485 into the RADTOX registry leading to an analysis population of 1359 patients (age range 0-18). A total of 18.9% (n=257) of all investigated patients developed high-grade acute toxicity (grades 3/4). High-grade toxicity of the bone marrow was documented for 63.8% (n=201) of those patients, oral mucositis for 7.6% (n=24), and dermatitis for 7.6% (n=24). Patients with high-grade acute toxicity received concomitant chemotherapy more frequently (56%) than patients with no or lower acute toxicity (31.5%). In multivariate analyses, concomitant chemotherapy, diagnosis of Ewing sarcoma, and total radiation dose showed a statistically noticeable effect (P <=.05) on acute toxicity, whereas age, concomitant chemotherapy, Hodgkin lymphoma, Ewing sarcoma, total radiation dose, and acute toxicity influenced the time until maximal late toxicity.Conclusions: Generally, high-grade acute toxicity after irradiation in children and adolescence occurs in a moderate proportion of patients (18.9%). As anticipated, the probability of acute toxicity appeared to depend on the prescribed dose as well as concomitant chemotherapy. The occurrence of chronic toxicity correlates with the prior acute toxicity grade. Age seems to influence the time until maximal late toxicity but not the development of acute toxicity.
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| 22. |
- Svanbergsson, Alexander, et al.
(författare)
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FRET-Based Screening Identifies p38 MAPK and PKC Inhibition as Targets for Prevention of Seeded α-Synuclein Aggregation
- 2021
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Ingår i: Neurotherapeutics. - : Springer Science and Business Media LLC. - 1878-7479 .- 1933-7213. ; 18:3, s. 1692-1709
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Tidskriftsartikel (refereegranskat)abstract
- Aggregation of α-synuclein is associated with neurodegeneration and a hallmark pathology in synucleinopathies. These aggregates are thought to function as prion-like particles where the conformation of misfolded α-synuclein determines the traits of the induced pathology, similar to prion diseases. Still, little is known about the molecular targets facilitating the conformation-specific biological effects, but their identification could form the basis for new therapeutic interventions. High-throughput screening of annotated compound libraries could facilitate mechanistic investigation by identifying targets with impact on α-synuclein aggregation. To this end, we developed a FRET-based cellular reporter in HEK293T cells, with sensitivity down to 6.5 nM α-synuclein seeds. Using this model system, we identified GF109203X, SB202190, and SB203580 as inhibitors capable of preventing induction of α-synuclein aggregation via inhibition of p38 MAPK and PKC, respectively. We further investigated the mechanisms underlying the protective effects and found alterations in the endo-lysosomal system to be likely candidates of the protection. We found the changes did not stem from a reduction in uptake but rather alteration of lysosomal abundance and degradative capacity. Our findings highlight the value high-throughput screening brings to the mechanistic investigation of α-synuclein aggregation while simultaneously identifying novel therapeutic compounds.
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| 23. |
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Tron är mitt lokalbatteri : religion och religiositet i August Strindbergs liv och verk
- 2012
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Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- Tron är mitt lokalbatteri skriver August Strindberg i boken Ensam - ett av de sista verken. Tron tar sig många uttryck och strömkällan ger kraft till en mängd olika texter. Citatet ger en ingång till flera av dessa berättelser, och till berättelsen om Strindberg som sökare, mystiker, ateist och kristen. Bilden är mångskiftande.Till Damaskus, En Blå bok, Påsk, Mäster Olof, Giftasnovellerna, Sagospelen och Kammarspelen är några av de texter som betraktas ur detta perspektiv, men även hans tid i Frankrike, hans relation till den katolska kyrkan och till andra författare såsom Emanuel Swedenborg och Carl von Linne.Ett flertal författare och forskare som under lång tid arbetat med Strindbergs verk och liv medverkar. Avslutar gör biskop em Caroline Krook med en personlig betraktelse över det religiösa sökande som ses i August Strindbergs verk.
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| 24. |
- Årestedt, Liselott, et al.
(författare)
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Context Factors Facilitating and Hindering Patient Participation in Dialysis Care : A Focus Group Study With Patients and Staff
- 2020
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Ingår i: Worldviews on Evidence-Based Nursing. - : John Wiley & Sons. - 1545-102X .- 1741-6787. ; 17:6, s. 457-464
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSafe health care of good quality depends on structured and unceasing efforts to progress, promoting strategies tailored to the context, including elements such as patients' preferences. Although patient participation is a common concept in health care, there is yet limited understanding of the factors that facilitate and hinder it in a healthcare context.AimsThis paper identifies what patients and health professionals depict in terms of enablers and barriers for patient participation in dialysis care.MethodsAn explorative qualitative design was applied with seven focus group discussions with patients, staff, and managers across different types of hospitals, with the texts analyzed with content analysis.ResultsThe dialysis context represents three key elements-people, resources, and interactions-that can both enable and hinder patient participation. Both barriers and facilitators for patient participation were found to reside at individual, team, and organizational levels, with a greater number of enabling factors implied by both patients and staff.Linking Evidence to ActionWhile the dialysis context comprises opportunities for progress in favor of patient participation, a shared understanding of the concept is needed, along with how contextual factors can facilitate conditions for participation by patient preferences. In addition, the most favorable strategy for implementing person-centered care is not yet known, but to facilitate patient participation from a patient perspective, creating opportunities to enable staff and patients to share a common understanding is needed, along with tools to facilitate a dialogue on patient participation.
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| 25. |
- Årestedt, Liselott, et al.
(författare)
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Patient participation in dialysis care : a qualitative study of patients’ and health professionals’ perspectives
- 2019
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Ingår i: Health Expectations. - : John Wiley & Sons. - 1369-6513 .- 1369-7625. ; 22:6, s. 1285-1293
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background and objective End-stage renal disease (ESRD) affects a multitude of aspects in the patient's daily life, often entailing their own involvement in various aspects of the treatment. Although patient participation is a core health-care value, what the concept signifies is not yet fully known. The purpose of this paper is to conceptualize patient participation in dialysis care, depicting patients? and health-care professionals? perspectives. Design This explorative study employed qualitative interviews and content analysis. Setting and participants Seven focus group discussions engaging 42 key informants were performed, including patients, staff and managers with experience of dialysis care. Results In dialysis care, patient participation connotes a sharing of information and knowledge, the learning of and planning of care, including partaking in shared decisions with regards to treatment and management, and being involved in the management of one's own health-care treatment and/or self-care activities. Although these attributes were illustrated by all stakeholders, their significance varied: patients suggested that their preferences regarding primary aspects of participation vary, while staff considered patients? performance of dialysis to be the ultimate form of participation. Further, while patients considered multiple ways to execute participation, staff suggested that aspects such as sharing information were a route to, rather than actual, involvement. Conclusions Without a common understanding to denote the idea of patient participation, staff and patients are exposed to a potential deficit in terms of facilitating patient participation in everyday encounters of dialysis treatment. Further studies and means to serve a mutual understanding are needed.
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