| 1. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 2. |
- Mullins, N., et al.
(författare)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 3. |
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| 4. |
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| 5. |
- de Heus, R. A. A., et al.
(författare)
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Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension
- 2019
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Ingår i: Journal of the American Heart Association. - : Ovid Technologies (Wolters Kluwer Health). - 2047-9980. ; 8:10
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Tidskriftsartikel (refereegranskat)abstract
- Background-Hypertension is common among patients with Alzheimer disease. Because this group has been excluded from hypertension trials, evidence regarding safety of treatment is lacking. This secondary analysis of a randomized controlled trial assessed whether antihypertensive treatment increases the prevalence of orthostatic hypotension (OH) in patients with Alzheimer disease. Methods and Results-Four hundred seventy-seven patients with mild-to-moderate Alzheimer disease were randomized to the calcium-channel blocker nilvadipine 8 mg/day or placebo for 78 weeks. Presence of OH (blood pressure drop >= 20/>= 10 mm Hg after 1 minute of standing) and OH-related adverse events (dizziness, syncope, falls, and fractures) was determined at 7 follow-up visits. Mean age of the study population was 72.2 +/- 8.2 years and mean Mini-Mental State Examination score was 20.4 +/- 3.8. Baseline blood pressure was 137.8 +/- 14.0/77.0 +/- 8.6 mm Hg. Grade I hypertension was present in 53.4% (n=255). After 13 weeks, blood pressure had fallen by -7.8/-3.9 mm Hg for nilvadipine and by -0.4/-0.8 mm Hg for placebo (P<0.001). Across the 78-week intervention period, there was no difference between groups in the proportion of patients with OH at a study visit (odds ratio [95% CI] 1.1 [0.8-1.5], P 0.62), nor in the proportion of visits where a patient met criteria for OH, corrected for number of visits (7.7 +/- 13.8% versus 7.3 +/- 11.6%). OH-related adverse events were not more often reported in the intervention group compared with placebo. Results were similar for those with baseline hypertension. Conclusions-This study suggests that initiation of a low dose of antihypertensive treatment does not significantly increase the risk of OH in patients with mild-to-moderate Alzheimer disease.
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| 6. |
- Dyer, A. H., et al.
(författare)
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Cognitive Outcomes of Long-term Benzodiazepine and Related Drug (BDZR) Use in People Living With Mild to Moderate Alzheimer's Disease: Results From NILVAD
- 2020
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Ingår i: Journal of the American Medical Directors Association. - : Elsevier BV. - 1525-8610. ; 21:2, s. 194-200
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Benzodiazepines and related drugs (BDZRs) have been associated with an increased risk of Alzheimer's disease (AD) in later life. Despite this, it remains unclear whether ongoing BDZR use may further accelerate cognitive decline in those diagnosed with mild to moderate AD. Design: This study was embedded within NILVAD, a randomized controlled trial of nilvadipine in mild to moderate AD. Cognition was measured at baseline and 18 months using the Alzheimer Disease Assessment Scale, Cognitive Subsection (ADAS-Cog). We assessed predictors of long-term BDZR use and analyzed the effect of ongoing BDZR use on ADAS-Cog scores at 18 months. Additionally, the impact of BDZR use on adverse events, incident delirium, and falls over 18-month follow-up was assessed adjusting for relevant covariates. Setting and Participants: 448 participants with mild to moderate AD recruited from 23 academic centers in 9 European countries. Results: Overall, 14% (62/448) were prescribed an ongoing BDZR for the study duration. Increasing total number of (non-BDZR) medications was associated with a greater likelihood of BDZR prescription (odds ratio 1.16, 95% confidence interval 1.05-1.29). At 18 months, BDZR use was not associated with greater cognitive decline on the ADAS-Cog controlling for baseline ADAS-Cog scores, age, gender, study arm, and other clinical covariates (beta = 1.62, -1.34 to 4.56). However, ongoing BDZR use was associated with a greater likelihood of adverse events [incidence rate ratio (IRR) 1.19, 1.05-1.34], incident delirium (IRR 2.31, 1.45-3.68), and falls (IRR 1.66, 1.02-2.65) over 18 months that persisted after robust adjustment for covariates. Conclusions and Implications: This study found no effect of ongoing BDZR use on ADAS-Cog scores in those with mild to moderate AD over 18 months. However, ongoing use of these medications was associated with an increased risk of adverse events, delirium, and falls. Thus, BDZR use should be avoided where possible and deprescribing interventions should be encouraged in older adults with AD. (C) 2019 AMDA - The Society for Post-Acute and Long-Term Care Medicine.
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| 7. |
- Kalman, L. V., et al.
(författare)
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Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting
- 2016
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Ingår i: Clinical Pharmacology and Therapeutics. - : WILEY-BLACKWELL. - 0009-9236 .- 1532-6535. ; 99:2, s. 172-185
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Tidskriftsartikel (refereegranskat)abstract
- This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.
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| 8. |
- Scott, J., et al.
(författare)
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Prospective cohort study of early biosignatures of response to lithium in bipolar-I-disorders: overview of the H2020-funded R-LiNK initiative
- 2019
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Ingår i: International Journal of Bipolar Disorders. - : Springer Science and Business Media LLC. - 2194-7511. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Lithium is recommended as a first line treatment for bipolar disorders. However, only 30% of patients show an optimal outcome and variability in lithium response and tolerability is poorly understood. It remains difficult for clinicians to reliably predict which patients will benefit without recourse to a lengthy treatment trial. Greater precision in the early identification of individuals who are likely to respond to lithium is a significant unmet clinical need. Structure The H2020-funded Response to Lithium Network (R-LiNK; ) will undertake a prospective cohort study of over 300 individuals with bipolar-I-disorder who have agreed to commence a trial of lithium treatment following a recommendation by their treating clinician. The study aims to examine the early prediction of lithium response, non-response and tolerability by combining systematic clinical syndrome subtyping with examination of multi-modal biomarkers (or biosignatures), including omics, neuroimaging, and actigraphy, etc. Individuals will be followed up for 24 months and an independent panel will assess and classify each participants' response to lithium according to predefined criteria that consider evidence of relapse, recurrence, remission, changes in illness activity or treatment failure (e.g. stopping lithium; new prescriptions of other mood stabilizers) and exposure to lithium. Novel elements of this study include the recruitment of a large, multinational, clinically representative sample specifically for the purpose of studying candidate biomarkers and biosignatures; the application of lithium-7 magnetic resonance imaging to explore the distribution of lithium in the brain; development of a digital phenotype (using actigraphy and ecological momentary assessment) to monitor daily variability in symptoms; and economic modelling of the cost-effectiveness of introducing biomarker tests for the customisation of lithium treatment into clinical practice. Also, study participants with sub-optimal medication adherence will be offered brief interventions (which can be delivered via a clinician or smartphone app) to enhance treatment engagement and to minimize confounding of lithium non-response with non-adherence. Conclusions The paper outlines the rationale, design and methodology of the first study being undertaken by the newly established R-LiNK collaboration and describes how the project may help to refine the clinical response phenotype and could translate into the personalization of lithium treatment.
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| 9. |
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| 10. |
- Kalman, JL, et al.
(författare)
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Investigating the phenotypic and genetic associations between personality traits and suicidal behavior across major mental health diagnoses
- 2022
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Ingår i: European archives of psychiatry and clinical neuroscience. - : Springer Science and Business Media LLC. - 1433-8491 .- 0940-1334. ; 272:8, s. 1611-1620
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Tidskriftsartikel (refereegranskat)abstract
- Personality traits influence risk for suicidal behavior. We examined phenotype- and genotype-level associations between the Big Five personality traits and suicidal ideation and attempt in major depressive, bipolar and schizoaffective disorder, and schizophrenia patients (N = 3012) using fixed- and random-effects inverse variance-weighted meta-analyses. Suicidal ideations were more likely to be reported by patients with higher neuroticism and lower extraversion phenotypic scores, but showed no significant association with polygenic load for these personality traits. Our findings provide new insights into the association between personality and suicidal behavior across mental illnesses and suggest that the genetic component of personality traits is unlikely to have strong causal effects on suicidal behavior.
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| 11. |
- Lawlor, B., et al.
(författare)
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Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial
- 2018
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Ingår i: Plos Medicine. - : Public Library of Science (PLoS). - 1549-1676. ; 15:9
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Tidskriftsartikel (refereegranskat)abstract
- Background This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated antiinflammatory and anti-tau activity in preclinical studies, properties that could have diseasemodifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged > 50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of >= 12 and < 27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease +/- specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADASCog 12 on placebo was 0.79 (95% CI, -0.07 +/- 1.64) at 13 weeks, 6.41 (5.33 +/- 7.49) at 52 weeks, and 9.63 (8.33 +/- 10.93) at 78 weeks and on nilvadipine was 0.88 (0.02 +/- 1.74) at 13 weeks, 5.75 (4.66 +/- 6.85) at 52 weeks, and 9.41 (8.09 +/- 10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease.
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| 12. |
- Leebens-Mack, James H., et al.
(författare)
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One thousand plant transcriptomes and the phylogenomics of green plants
- 2019
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 574:7780, s. 679-
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Tidskriftsartikel (refereegranskat)abstract
- Green plants (Viridiplantae) include around 450,000-500,000 species(1,2) of great diversity and have important roles in terrestrial and aquatic ecosystems. Here, as part of the One Thousand Plant Transcriptomes Initiative, we sequenced the vegetative transcriptomes of 1,124 species that span the diversity of plants in a broad sense (Archaeplastida), including green plants (Viridiplantae), glaucophytes (Glaucophyta) and red algae (Rhodophyta). Our analysis provides a robust phylogenomic framework for examining the evolution of green plants. Most inferred species relationships are well supported across multiple species tree and supermatrix analyses, but discordance among plastid and nuclear gene trees at a few important nodes highlights the complexity of plant genome evolution, including polyploidy, periods of rapid speciation, and extinction. Incomplete sorting of ancestral variation, polyploidization and massive expansions of gene families punctuate the evolutionary history of green plants. Notably, we find that large expansions of gene families preceded the origins of green plants, land plants and vascular plants, whereas whole-genome duplications are inferred to have occurred repeatedly throughout the evolution of flowering plants and ferns. The increasing availability of high-quality plant genome sequences and advances in functional genomics are enabling research on genome evolution across the green tree of life.
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| 13. |
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| 14. |
- 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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| 15. |
- 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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| 16. |
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| 17. |
- Bolckmans, Roel, et al.
(författare)
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Does Smoking Cessation Reduce Surgical Recurrence After Primary Ileocolic Resection for Crohns Disease?
- 2020
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Ingår i: Diseases of the Colon & Rectum. - : Lippincott Williams & Wilkins. - 0012-3706 .- 1530-0358. ; 63:2, s. 200-206
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Tobacco smoking is a known risk factor for recurrence of Crohns disease after surgical resection. OBJECTIVE: This study assessed the effect of smoking cessation on long-term surgical recurrence after primary ileocolic resection for Crohns disease. DESIGN: A retrospective review of a prospectively maintained database was conducted. SETTINGS: Patient demographic data and medical and surgical details were combined from 2 specialist centers. After ethical approval, patients were contacted in case of missing data regarding smoking habit. PATIENTS: All patients undergoing ileocolic resection between 2000 and 2012 for histologically confirmed Crohns disease were included. Those with previous intestinal resection, strictureplasty for Crohns disease, leak after ileocolic resection, or who were never reversed were excluded. MAIN OUTCOME MEASURES: The primary end point was surgical recurrence measured by Kaplan-Meier survival analysis and secondary medical therapy at time of follow-up. RESULTS: Over a 12-year period, 290 patients underwent ileocolic resection. Full smoking data were available for 242 (83%) of 290 patients. There were 169 nonsmokers (70%; group 1), 42 active smokers at the time of ileocolic resection who continued smoking up to last follow-up (17%; group 2), and 31 (13%) who quit smoking after ileocolic resection (group 3). The median time of smoking exposure after ileocolic resection for group 3 was 3 years (interquartile range, 0-6 y), and median follow-up time for the whole group was 112 months (9 mo; interquartile range, 84-148 mo). Kaplan-Meier survival analysis showed a significantly higher surgical recurrence rate for group 2 compared with group 3 (16/42 (38%) vs 3/31 (10%); p = 0.02; risk ratio = 3.9 (95% CI, 1-12)). In addition, significantly more patients in group 2 without surgical recurrence received immunomodulatory maintenance therapy compared with group 3 (12/26 (46%) vs 4/28 (14%); p = 0.01; risk ratio = 3.2 (95% CI, 1-9)). LIMITATIONS: The study was limited by its retrospective design and small number of patients. CONCLUSIONS: Smoking cessation after primary ileocolic resection for Crohns disease may significantly reduce long-term risk of surgical recurrence and is associated with less use of maintenance therapy. See Video Abstract at http://links.lww.com/DCR/B86.
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| 18. |
- Bolckmans, R., et al.
(författare)
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Temporary faecal diversion in ileocolic resection for Crohns disease: is there an impact on long-term surgical recurrence?
- 2020
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Ingår i: Colorectal Disease. - : WILEY. - 1462-8910 .- 1463-1318. ; 22:4, s. 430-438
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Tidskriftsartikel (refereegranskat)abstract
- Aim Temporary faecal diversion after ileocolic resection (ICR) for Crohns disease reduces postoperative anastomotic complications in high-risk patients. The aim of this study was to assess if this approach also reduces long-term surgical recurrence. Method This was a multicentre retrospective review of prospectively maintained databases. Patient demographics, medical and surgical details were collected by three specialist centres. All patients had undergone an ICR between 2000 and 2012. The primary end-point was surgical recurrence. Results Three hundred and twelve patients (80%) underwent an ICR without covering ileostomy (one stage). Seventy-seven (20%) had undergone an ICR with end ileostomy/double-barrel ileostomy/enterocolostomy followed by closure (two stage). The median follow-up was 105 months [interquartile range (IQR) 76-136 months]. The median time to ileostomy closure was 9 months (IQR 5-12 months). There was no significant difference in surgical recurrence between the one- and two-stage groups (18% vs 16%, P = 0.94). We noted that smokers (20% vs 34%, P = 0.01) and patients with penetrating disease (28% vs 52%, P amp;lt; 0.01) were more likely to be defunctioned. A reduced recurrence rate was observed in the small high-risk group of patients who were smokers with penetrating disease behaviour treated with a two-stage strategy (0/10 vs 4/7, P = 0.12). Conclusion Despite having higher baseline risk factors, the results in terms of rate of surgical recurrence over 9 years are similar for patients having a two-stage compared with a one-stage procedure.
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| 19. |
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| 20. |
- Kalman, Björn, 1961-, et al.
(författare)
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Estimation of durability of new surface courses using accelerated load test and expert's opinions
- 2022
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Ingår i: Proceedings of the 11th International Conference on the Bearing Capacity of Roads, Railways and Airfields. - London : CRC Press. - 9781003222910 ; , s. 502-510
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Konferensbidrag (refereegranskat)abstract
- There is an increasing interest among road authorities in studying sustain ability assessment of road infrastructure. The durability of the surface course is a critical factor in these calculations and must be carefully considered in the analysis. New types of asphalt mixes with the potential to improve the results in the sustainability assessment have no proven track record and are thus more likely not to be used until solid perform ance data is available. To bridge the gap and diminish the uncertainty about the durability of Green asphalt mixes for surface courses, a combination of laboratory tests and tests in a circular road simulator were performed. Eight mixes were tested in total, four stone mastic asphalt mixes and four porous asphalt mixes. Each group contained a reference mix with well-established performance. The mixes were characterized with dynamic IDT, com plex shear modulus and water sensitivity using MiST (moisture induced stress test). Part of the loose mixes was oven aged at 85 °C simulate long term ageing. Plates of aged and virgin mixes were then tested in a circular road simulator in a program set up to check their sensitivity towards rutting, raveling, freeze-thaw cycles, polishing and fatigue. A combination of expert’s opinion from academia and national road administrations together with the data from the tests were used to estimate the performance of the new Green mixes.
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| 21. |
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| 22. |
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| 23. |
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| 24. |
- 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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| 25. |
- Kalman, Thordis Disa, 1959-
(författare)
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Surgery and stomas in Crohn's disease
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This study investigates the evolution of abdominal surgery in treatment of Crohn´s disease (CD) in the era of immunomodulatory drugs and biologicals. It concerns risk of abdominal surgery overall and sub-categories of abdominal surgery, risk of repeat surgery and factors that affect this risk, and risk of getting a stoma. Surgical recurrence is a major clinical problem as repeat procedures are more complex and expose the patients to a higher medical risk both in conjunction with surgery and afterwards. Updated information on abdominal surgery for CD will be of use when making decisions about medical vs surgical interventions.In a nationwide cohort of 21 273 patients with CD during the years 1990-2014, the cumulative incidence of abdominal surgery within five years of diagnosis decreased continuously down to 17.3% for patients diagnosed with CD during the last calendar period of study, 2009–2014. Ileocecal resection was the most common primary procedure. The incidence of colectomy was low in all calendar periods and continuously decreased. The incidence of proctectomy was very low even after decades with the disease, 3.0% for patients diagnosed 1990-1995 with a median follow-up of 21 years. Incidence of repeat abdominal surgery within five years of primary procedure decreased in the 90s down 16.0% in the 1996– 2000 period with a risk of ileocolic reresection of 4.4%. After 2000, despite introduction of biologicals in 1998, no further significant decrease in repeat surgery was observed.In a retrospective review of prospectively maintained databases at three university hospitals, the rate of surgical recurrence for 389 patients with CD who had been treated with a primary ileocecal resection between 2000-2012 was investigated. The patients were operated receiving either a temporary stoma (20%) or a primary anastomosis (80%) with a median follow-up time of 105 months. Patients selected to temporary stoma had a higher prevalence of baseline risk factors usually associated with an increased risk of recurrence such as penetrating disease behaviour. Despite this, there was no difference in long-term surgical recurrence between the one- and two-stage groups; 18% vs 16%.In a retrospective review of prospectively maintained databases at two university hospitals, the effect of smoking cessation on rate of surgical recurrence was assessed. 242 patients were included with a median follow-up of 112 months. Surgical recurrence rate for smokers vs quitters was 16/42 (38%) vs 3/31 (10%); p = 0.02; risk ratio = 3.9 despite a median time for smoking exposure after the primary procedure of three years. Among the non-smokers 28/169 (17%) had a surgical recurrence at last follow-up. 8 out of 11 smoking patients who needed a second resection went on to need a third resection. Of the patients who were free of surgical recurrence at follow-up, those who had quit smoking were significantly less likely to have been put on medical therapy compared with smokers with a risk ratio of 3.2.In an observational study of a nationwide cohort of 19 146 patients with incident CD 2002- 2013 and followed through 2017, the incidence and prevalence of stoma was investigated. The cumulative incidence of stoma formation within five years was 2.4% and remained constant from 2002 and onwards although cumulative ever-use of biologicals increased and time to start with treatment with biologicals decreased. 48% of all stomas were reversed. Ileostomies encompassed about two-thirds of all stomas and risk of stoma was higher among patients with elderly-onset CD and among patients with perianal manifestations of the disease. 28% of the patients who underwent surgery with formation of a stoma had perianal disease. 0.6% of all incident patients had a permanent stoma five years after diagnosis.
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| 28. |
- Meulenbroek, O., et al.
(författare)
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European multicentre double-blind placebo-controlled trial of Nilvadipine in mild-to-moderate Alzheimer's disease - The substudy protocols: NILVAD frailty; NILVAD blood and genetic biomarkers; NILVAD cerebrospinal fluid biomarkers; NILVAD cerebral blood flow
- 2016
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: In conjunction with the NILVAD trial, a European Multicentre Double-Blind Placebo Controlled trial of Nilvadipine in Mild-to-Moderate Alzheimer's disease (AD), there are four NILVAD substudies in which eligible NILVAD patients are also invited to participate. The main NILVAD protocol was previously published in BMJ Open (2014). The objectives of the NILVAD substudies are to determine whether frailty, cerebrospinal fluid (CSF), blood biomarker profile and Apolipoprotein E (APOE) status predict response to Nilvadipine, and to investigate the effect of Nilvadipine on cerebral blood flow and blood biomarkers. Methods and analysis: All participants who fulfil criteria for the main NILVAD study are eligible for participation in the NILVAD substudies. Participation is subject to informed consent and whether the substudy is available at a particular NILVAD study site. Each substudy entails extra measurements during the course of the main NILVAD study. For example, in the blood and genetic biomarkers substudy, extra blood (30 mL) will be collected at week 0, week 13, week 52 and week 78, while in the cerebral blood flow substudy, participants will receive an MRI and transcranial Doppler measurements at week 0, week 26 and week 78. In the CSF substudy, 10 mL CSF is collected at week 0 and week 78. Ethics and dissemination: All NILVAD substudies and all subsequent amendments have received ethical approval within each participating country, according to national regulations. Each participant provides written consent to participate. All participants remain anonymised throughout and the results of each substudy will be published in an international peer reviewed journal. © 2016 Published by the BMJ Publishing Group Limited.
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| 29. |
- Quaglia, Federica, et al.
(författare)
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DisProt in 2022 : improved quality and accessibility of protein intrinsic disorder annotation
- 2022
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 50:D1, s. D480-D487
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Tidskriftsartikel (refereegranskat)abstract
- The Database of Intrinsically Disordered Proteins (DisProt, URL: https://disprot.org) is the major repository of manually curated annotations of intrinsically disordered proteins and regions from the literature. We report here recent updates of DisProt version 9, including a restyled web interface, refactored Intrinsically Disordered Proteins Ontology (IDPO), improvements in the curation process and significant content growth of around 30%. Higher quality and consistency of annotations is provided by a newly implemented reviewing process and training of curators. The increased curation capacity is fostered by the integration of DisProt with APICURON, a dedicated resource for the proper attribution and recognition of biocuration efforts. Better interoperability is provided through the adoption of the Minimum Information About Disorder (MIADE) standard, an active collaboration with the Gene Ontology (GO) and Evidence and Conclusion Ontology (ECO) consortia and the support of the ELIXIR infrastructure.
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| 30. |
- Winter, M., et al.
(författare)
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Validation of national empirical pavement design approaches for cold recycled asphalt bases
- 2021
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Ingår i: Eleventh International Conference on the Bearing Capacity of Roads, Railways and Airfields. - London : CRC Press. - 9781003222880 ; , s. 87-95
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- The applied pavement design procedures differ from country to country within Europe. Especially the use of cold recycling materials which is handled similar to hot-mix asphalt (HMA) in the most available guidelines isn’t sufficient researched. To verify developed procedures, practical trial sections are indispensable. Within this study cold recycled asphalt base layers (CRAB) were assessed according to the German procedure for monitoring and evaluation of road surface conditions. It can be concluded, that the general applied empirical design approach, in which the CRAB layer thickness is increased by 50 % compared to a HMA base will result in a feasible pavement structure. In general, the re-designing of the sections according to various national empirical pavement design approaches partly results in high differences for same layer types.
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