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| 2. |
- van Rheenen, W, et al.
(författare)
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Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
- 2021
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 53:12, s. 1636-
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
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- Buunen, M, et al.
(författare)
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COLOR II. A randomized clinical trial comparing laparoscopic and open surgery for rectal cancer.
- 2009
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Ingår i: Danish medical bulletin. - 1603-9629 .- 0907-8916. ; 56:2, s. 89-91
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Laparoscopic resection of rectal cancer has been proven efficacious but morbidity and oncological outcome need to be investigated in a randomized clinical trial. Trial design: Non-inferiority randomized clinical trial. METHODS: The COLOR II trial is an ongoing international randomized clinical trial. Currently 27 hospitals from Europe, South Korea and Canada are including patients. The primary endpoint is loco-regional recurrence rate three years post-operatively. Secondary endpoints cover quality of life, overall and disease free survival, post-operative morbidity and health economy analysis. RESULTS: By July 2008, 27 hospitals from the Netherlands, Belgium, Germany, Sweden, Spain, Denmark, South Korea and Canada had included 739 patients. The intra-operative conversion rate in the laparoscopic group was 17%. Distribution of age, location of the tumor and radiotherapy were equal in both treatment groups. Most tumors are located in the mid-rectum (41%). CONCLUSION: Laparoscopic surgery in the treatment of rectal cancer is feasible. The results and safety of laparoscopic surgery in the treatment of rectal cancer remain unknown, but are subject of interim analysis within the COLOR II trial. Completion of inclusion is expected by the end of 2009. Trial registration: Clinicaltrials.gov, identifier: NCT00297791 (www.clinicaltrials.gov).
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| 4. |
- Hop, Paul J., et al.
(författare)
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Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
- 2022
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 14:633
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
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| 5. |
- de Jong, P. A., et al.
(författare)
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Progression of lung disease on computed tomography and pulmonary function tests in children and adults with cystic fibrosis
- 2006
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Ingår i: Thorax. - 0040-6376. ; 61:1, s. 80-5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A study was undertaken to compare the ability of computed tomographic (CT) scores and pulmonary function tests to detect changes in lung disease in children and adults with cystic fibrosis (CF). METHODS: CT scans and pulmonary function tests were retrospectively studied in a cohort of patients with CF aged 5-52 years for whom two or three CT scans at 3 year intervals were available, together with pulmonary function test results. All CT scans were scored by two observers. Pulmonary function results were expressed as percentage predicted and Z scores. RESULTS: Of 119 patients studied, two CT scans were available in 92 patients and three in 24. CT (composite and component) scores and lung function both deteriorated significantly (p<0.02). Peripheral bronchiectasis worsened by 1.7% per year in children (p<0.0001) and by 1.5% per year in adults (p<0.0001). Bronchiectasis worsened in 68 of 92 patients while forced expiratory volume in 1 second (FEV1) worsened in 54 of 92 patients; bronchiectasis also deteriorated in 27 patients with stable or improving FEV1. The CT score (and its components) and pulmonary function tests showed similar rates of deterioration in adults and children (p>0.09). CONCLUSION: The peripheral bronchiectasis CT score deteriorates faster and more frequently than lung function parameters in children and adults with CF, which indicates that pulmonary function tests and CT scans measure different aspects of CF lung disease. Our data support previous findings that the peripheral bronchiectasis CT score has an added value to pulmonary function tests in monitoring CF lung disease.
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| 9. |
- Kuhry, E., et al.
(författare)
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Impact of hospital case volume on short-term outcome after laparoscopic operation for colonic cancer
- 2005
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Ingår i: Surgical endoscopy. - 1432-2218. ; 19:5, s. 687-92
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: High hospital case volume has been associated with improved outcome after open operation for colorectal malignancies. METHODS: To assess the impact of hospital case volume on short-term outcome after laparoscopic operation for colon cancer, we conducted an analysis of patients who underwent laparoscopic colon resection within the COlon Cancer Laparoscopic or Open Resection (COLOR) trial. RESULTS: A total of 536 patients with adenocarcinoma of the colon were included in the analysis. Median operating time was 240, 210 and 188 min in centers with low, medium, and high case volumes, respectively (p < 0.001). A significant difference in conversion rate was observed among low, medium, and high case volume hospitals (24% vs 24% vs 9%; p < 0.001). A higher number of lymph nodes were harvested at high case volume hospitals (p < 0.001). After operation, fewer complications (p = 0.006) and a shorter hospital stay (p < 0.001) were observed in patients treated at hospitals with high caseloads. CONCLUSIONS: Laparoscopic operation for colon cancer at hospitals with high caseloads appears to be associated with improved short-term results.
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