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- Thomas, HS, et al.
(author)
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- 2019
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- Weismuller, T. J., et al.
(author)
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Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis
- 2017
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In: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 152:8
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Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 4150 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P <.001 and HR, 0.90; P =.03, respectively) and malignancy (HR, 0.68; P =.008 and HR, 0.77; P =.004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P <.001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P =.002 and HR, 0.68; P <.001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P <.001 and adjusted HR for women, 0.48; P =.003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P <.001) or no IBD (HR, 1.15; P =.002). CONCLUSIONS: In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.
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- Maas, R. R., et al.
(author)
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Progressive deafness–dystonia due to SERAC1 mutations: A study of 67 cases
- 2017
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In: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 82:6, s. 1004-1015
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Journal article (peer-reviewed)abstract
- Objective: 3-Methylglutaconic aciduria, dystonia–deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. Methods: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. Results: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days–33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic “putaminal eye” was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. Interpretation: MEGDHEL syndrome is a progressive deafness–dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004–1015. © 2017 American Neurological Association
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- Ratajczak-Tretel, B, et al.
(author)
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Prediction of underlying atrial fibrillation in patients with a cryptogenic stroke : results from the NOR-FIB Study
- 2023
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In: Journal of Neurology. - 1432-1459. ; 270:8, s. 4049-4059
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Journal article (peer-reviewed)abstract
- BACKGROUND: Atrial fibrillation (AF) detection and treatment are key elements to reduce recurrence risk in cryptogenic stroke (CS) with underlying arrhythmia. The purpose of the present study was to assess the predictors of AF in CS and the utility of existing AF-predicting scores in The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study.METHOD: The NOR-FIB study was an international prospective observational multicenter study designed to detect and quantify AF in CS and cryptogenic transient ischaemic attack (TIA) patients monitored by the insertable cardiac monitor (ICM), and to identify AF-predicting biomarkers. The utility of the following AF-predicting scores was tested: AS5F, Brown ESUS-AF, CHA 2DS 2-VASc, CHASE-LESS, HATCH, HAVOC, STAF and SURF. RESULTS: In univariate analyses increasing age, hypertension, left ventricle hypertrophy, dyslipidaemia, antiarrhythmic drugs usage, valvular heart disease, and neuroimaging findings of stroke due to intracranial vessel occlusions and previous ischemic lesions were associated with a higher likelihood of detected AF. In multivariate analysis, age was the only independent predictor of AF. All the AF-predicting scores showed significantly higher score levels for AF than non-AF patients. The STAF and the SURF scores provided the highest sensitivity and negative predictive values, while the AS5F and SURF reached an area under the receiver operating curve (AUC) > 0.7.CONCLUSION: Clinical risk scores may guide a personalized evaluation approach in CS patients. Increasing awareness of the usage of available AF-predicting scores may optimize the arrhythmia detection pathway in stroke units.
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- Ratajczak-Tretel, B, et al.
(author)
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Underlying causes of cryptogenic stroke and TIA in the nordic atrial fibrillation and stroke (NOR-FIB) study : the importance of comprehensive clinical evaluation
- 2023
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In: BMC Neurology. - : Springer Science and Business Media LLC. - 1471-2377. ; 23:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Cryptogenic stroke is a heterogeneous condition, with a wide spectrum of possible underlying causes for which the optimal secondary prevention may differ substantially. Attempting a correct etiological diagnosis to reduce the stroke recurrence should be the fundamental goal of modern stroke management.METHODS: Prospective observational international multicenter study of cryptogenic stroke and cryptogenic transient ischemic attack (TIA) patients clinically monitored for 12 months to assign the underlying etiology. For atrial fibrillation (AF) detection continuous cardiac rhythm monitoring with insertable cardiac monitor (Reveal LINQ, Medtronic) was performed. The 12-month follow-up data for 250 of 259 initially included NOR-FIB patients were available for analysis.RESULTS: After 12 months follow-up probable stroke causes were revealed in 43% patients, while 57% still remained cryptogenic. AF and atrial flutter was most prevalent (29%). In 14% patients other possible causes were revealed (small vessel disease, large-artery atherosclerosis, hypercoagulable states, other cardioembolism). Patients remaining cryptogenic were younger (p < 0.001), had lower CHA 2DS 2-VASc score (p < 0.001) on admission, and lower NIHSS score (p = 0.031) and mRS (p = 0.016) at discharge. Smoking was more prevalent in patients that were still cryptogenic (p = 0.014), while dyslipidaemia was less prevalent (p = 0.044). Stroke recurrence rate was higher in the cryptogenic group compared to the group where the etiology was revealed, 7.7% vs. 2.8%, (p = 0.091). CONCLUSION: Cryptogenic stroke often indicates the inability to identify the cause in the acute phase and should be considered as a working diagnosis until efforts of diagnostic work up succeed in identifying a specific underlying etiology. Timeframe of 6-12-month follow-up may be considered as optimal.TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02937077, EudraCT 2018-002298-23.
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- Howe, LJ, et al.
(author)
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Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects
- 2022
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:65, s. 581-
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Journal article (peer-reviewed)abstract
- Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.
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- Ratajczak-Tretel, B., et al.
(author)
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Atrial fibrillation in cryptogenic stroke and TIA patients in the nordic atrial fibrillation and stroke The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study : Main results
- 2023
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In: European Stroke Journal. - : SAGE Publications. - 2396-9873 .- 2396-9881. ; 8:1, s. 148-156
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Journal article (peer-reviewed)abstract
- Introduction: Secondary stroke prevention depends on proper identification of the underlying etiology and initiation of optimal treatment after the index event. The aim of the NOR-FIB study was to detect and quantify underlying atrial fibrillation (AF) in patients with cryptogenic stroke (CS) or transient ischaemic attack (TIA) using insertable cardiac monitor (ICM), to optimise secondary prevention, and to test the feasibility of ICM usage for stroke physicians. Patients and methods: Prospective observational international multicenter real-life study of CS and TIA patients monitored for 12 months with ICM (Reveal LINQ) for AF detection. Results: ICM insertion was performed in 91.5% by stroke physicians, within median 9 days after index event. Paroxysmal AF was diagnosed in 74 out of 259 patients (28.6%), detected early after ICM insertion (mean 48 ± 52 days) in 86.5% of patients. AF patients were older (72.6 vs 62.2; p < 0.001), had higher pre-stroke CHA₂DS₂-VASc score (median 3 vs 2; p < 0.001) and admission NIHSS (median 2 vs 1; p = 0.001); and more often hypertension (p = 0.045) and dyslipidaemia (p = 0.005) than non-AF patients. The arrhythmia was recurrent in 91.9% and asymptomatic in 93.2%. At 12-month follow-up anticoagulants usage was 97.3%. Discussion and conclusions: ICM was an effective tool for diagnosing underlying AF, capturing AF in 29% of the CS and TIA patients. AF was asymptomatic in most cases and would mainly have gone undiagnosed without ICM. The insertion and use of ICM was feasible for stroke physicians in stroke units.
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- Hikmat, O., et al.
(author)
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Expanding the phenotypic spectrum of BCS1L-related mitochondrial disease
- 2021
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In: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 8:11, s. 2155-2165
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Journal article (peer-reviewed)abstract
- Objective: To delineate the full phenotypic spectrum of BCS1L-related disease, provide better understanding of the genotype-phenotype correlations and identify reliable prognostic disease markers. Methods: We performed a retrospective multinational cohort study of previously unpublished patients followed in 15 centres from 10 countries. Patients with confirmed biallelic pathogenic BCS1L variants were considered eligible. Clinical, laboratory, neuroimaging and genetic data were analysed. Patients were stratified into different groups based on the age of disease onset, whether homozygous or compound heterozygous for the c.232A>G (p.Ser78Gly) variant, and those with other pathogenic BCS1L variants. Results: Thirty-three patients were included. We found that growth failure, lactic acidosis, tubulopathy, hepatopathy and early death were more frequent in those with disease onset within the first month of life. In those with onset after 1 month, neurological features including movement disorders and seizures were more frequent. Novel phenotypes, particularly involving movement disorder, were identified in this group. The presence of the c.232A>G (p.Ser78Gly) variant was associated with significantly worse survival and exclusively found in those with disease onset within the first month of life, whilst other pathogenic BCS1L variants were more frequent in those with later symptom onset. Interpretation: The phenotypic spectrum of BCS1L-related disease comprises a continuum of clinical features rather than a set of separate syndromic clinical identities. Age of onset defines BCS1L-related disease clinically and early presentation is associated with poor prognosis. Genotype correlates with phenotype in the presence of the c.232A>G (p.Ser78Gly) variant.
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- Liu, Jimmy Z, et al.
(author)
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Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.
- 2013
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:6, s. 670-5
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Journal article (peer-reviewed)abstract
- Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.
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- Schult, A. L., et al.
(author)
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Colonoscopy quality improvement after initial training: A cross-sectional study of intensive short-term training
- 2023
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In: Endoscopy International Open. - : Georg Thieme Verlag KG. - 2364-3722 .- 2196-9736. ; 11:01
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Journal article (peer-reviewed)abstract
- Background and study aims High-quality is crucial for the effectiveness of colonoscopy and can be achieved by high-quality training and verified with assessment of key performance indicators (KPIs) for colonoscopy such as cecum intubation rate (CIR), adenoma detection rate (ADR) and adequate polyp resection. Typically, trainees achieve adequate CIR after 275 procedures, but little is known about learning curves for KPIs after initial training.Methods This cross-sectional study includes work-up colonoscopies after a positive screening test with fecal occult blood testing (FIT) or sigmoidoscopy, performed by either trainees after 300 training colonoscopies or by consultants. Outcome measures were KPIs. We assessed inter-endoscopist variation in trainees and learning curves for trainees as a group. We also compared KPIs for trainees and consultants as a group.Results Data from 6,655 colonoscopies performed by 21 trainees and 921 colonoscopies performed by 17 consultants were included. Most trainees achieved target standards for main KPIs. With time, trainees shortened cecum intubation time and withdrawal time without decreasing their ADR, reduced the proportion of painful colonoscopies, and increased the adequate polyp resection rate (all P < 0.01). Compared to consultants, trainees had higher CIR (97.7 % vs. 96.3 %, P = 0.02), ADR after positive FIT (57.6 % vs. 50.3 %, P < 0.01), and proximal ADR after sigmoidoscopy screening (41.1 % vs. 29.8 %; P < 0.01), higher adequate polyp resection rate (94.9 % vs. 93.1 %, P = 0.01) and fewer serious adverse events (0.65 % vs. 1.41 %, P = 0.02).Conclusions Trainees performed high-quality colonoscopies and achieved international target standards. Several KPIs continuously improved after initial training. Trainees outperformed consultants on several KPIs.
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- Torkildsen, J. V., et al.
(author)
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App-Based Morphological Training Produces Lasting Effects on Word Knowledge in Primary School Children: A Randomized Controlled Trial
- 2022
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In: Journal of Educational Psychology. - : American Psychological Association (APA). - 0022-0663 .- 1939-2176. ; 114:4, s. 833-854
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Journal article (peer-reviewed)abstract
- Morphemes, the smallest meaning-bearing units of language, recur in many words. Therefore, morphological knowledge can facilitate the comprehension of novel words. This study tested the effectiveness of a morphological training program on children's learning and retention of exposed words and morphologically related unexposed words compared with an active control condition. Norwegian second graders (N = 717) unselected for ability were individually randomized to either a morphological (n = 366) or a mathematical training program (n = 351). Both programs lasted for 8 weeks and were delivered as self-contained apps in a classroom setting. The morphological training built on the principle that frequency of target elements together with variation of nontarget elements can support implicit learning. Treatment-blind examiners assessed participants' meaning-based knowledge (word comprehension and definitions) and code-based knowledge (word reading fluency and spelling) at pretraining, immediately post training, and at follow-up 6 months later. An intention-to-treat analysis showed lasting effects of the morphological training on meaning-based knowledge of exposed words (posttest: d = .37; follow-up: d = .31) and unexposed words containing trained morphemes (posttest: d = .27; follow-up: d = .27) and code-based knowledge of exposed words (posttest: d = .22; follow-up: d = .13). For code-based knowledge of unexposed words, there were significant training effects at the posttest (d = .12) but not follow-up (d = .05). There were no significant effects on a far-transfer measure of general vocabulary. These results demonstrate that a brief morphological training program can produce lasting and educationally meaningful gains in students' word knowledge. Educational Impact and Implications Statement Words can consist of several meaningful parts, or morphemes, such as -ist in guitarist and re- in reuse. Understanding common morphemes helps children infer the meanings of new words. In this study, we tested the effects of working with an educational application (app) focusing on morphemes. Children completed app exercises such as sorting words or pictures according to their meaning, combining morphemes to build words, or identifying the correct word or morpheme to fit a sentence or picture context. We found that the app was effective in improving Norwegian second graders' ability to explain, understand, read, and spell words, including words which were not shown in the app, but which contained trained morphemes. The brief low-cost training produced long-term effects with a minimal burden on teachers.
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- Zuo, H., et al.
(author)
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Vitamin B6 catabolism and lung cancer risk : Results from the Lung Cancer Cohort Consortium (LC3)
- 2019
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In: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 30:3, s. 478-485
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Journal article (peer-reviewed)abstract
- Background Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known. Materials and methods For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models. Results PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19-1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36-2.10), men (OR: 1.60, 95% CI: 1.28-2.00), and for cancers diagnosed within 3 years of blood draw (OR: 1.73, 95% CI: 1.34-2.23). Conclusion Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor.
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- Beiske, A G, et al.
(author)
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Health-related quality of life in secondary progressive multiple sclerosis.
- 2007
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 13:3, s. 386-92
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Journal article (peer-reviewed)abstract
- Common disability scales in multiple sclerosis (MS) are often weighted towards physical disability. Non-motor symptoms such as depression, fatigue and pain substantially influence wellbeing in MS. Health-related quality of life (HRQoL) measures the broader impact of MS and might indicate less obvious disease burdens. We analysed HRQoL, using the Nottingham Health Profile Part I (NHP-I), among 345 secondary progressive MS (SPMS) patients participating in a randomized trial of interferon-beta1a (IFN-beta1a), 22 mug subcutaneously weekly, or matching placebo. The results did not reveal any beneficial effect of IFN-beta1a in any outcome measure. NHP-I sub- and sum scores were compared for 217 population controls and correlated with demographic and clinical disease variables. SPMS patients had lower NHP-I sum and all subscores than the controls. Patients experiencing disease progression reported worse NHP-I sum scores. Increased fatigue, Expanded Disability Status Scale (EDSS) and Arm Index scores were independently associated with reduction in several NHP-I subscores. SPMS patients had significantly lower HRQoL than controls and physical disability (EDSS and Arm Index), disease progression and fatigue strongly influenced this. MS.
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- Beiske, A. G., et al.
(author)
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Health-related quality of life in secondary progressive multiple sclerosis
- 2007
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In: Multiple Sclerosis Journal. - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 13:3, s. 386-392
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Journal article (peer-reviewed)abstract
- Common disability scales in multiple sclerosis (MS) are often weighted towards physical disability. Non-motor symptoms such as depression, fatigue and pain substantially influence wellbeing in MS. Health-related quality of life (HRQoL) measures the broader impact of MS and might indicate less obvious disease burdens. We analysed HRQoL, using the Nottingham Health Profile Part I (NHP-I), among 345 secondary progressive MS (SPMS) patients participating in a randomized trial of interferon-beta 1a (IFN-beta 1a), 22 mu g subcutaneously weekly, or matching placebo. The results did not reveal any beneficial effect of IFN-beta 1a in any outcome measure. NHP-I sub- and sum scores were compared for 217 population controls and correlated with demographic and clinical disease variables. SPMS patients had lower NHP-I sum and all subscores than the controls. Patients experiencing disease progression reported worse NHP-I sum scores. Increased fatigue, Expanded Disability Status Scale (EDSS) and Arm Index scores were independently associated with reduction in several NHP-I subscores. SPMS patients had significantly lower HRQoL than controls and physical disability (EDSS and Arm Index), disease progression and fatigue strongly influenced this. MS influenced subdimensions such as pain, sleep and emotional reactions. Increased focus on optimizing symptomatic treatment and psychosocial patient care could improve patients' HRQoL.
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