| 1. |
- Lahrouchi, Najim, et al.
(författare)
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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
- 2020
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 142:4, s. 324-338
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-3)). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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| 2. |
- Sikkema, Lisa, et al.
(författare)
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An integrated cell atlas of the lung in health and disease
- 2023
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Ingår i: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 29:6, s. 1563-1577
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Tidskriftsartikel (refereegranskat)abstract
- Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1 + profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.
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| 3. |
- Arthur Hvidtfeldt, Ulla, et al.
(författare)
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Long-term exposure to fine particle elemental components and lung cancer incidence in the ELAPSE pooled cohort
- 2021
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Ingår i: Environmental Research. - : Elsevier BV. - 0013-9351 .- 1096-0953. ; 193
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Tidskriftsartikel (refereegranskat)abstract
- Background: An association between long-term exposure to fine particulate matter (PM2.5) and lung cancer has been established in previous studies. PM2.5 is a complex mixture of chemical components from various sources and little is known about whether certain components contribute specifically to the associated lung cancer risk. The present study builds on recent findings from the Effects of Low-level Air Pollution: A Study in Europe (ELAPSE) collaboration and addresses the potential association between specific elemental components of PM2.5 and lung cancer incidence.Methods: We pooled seven cohorts from across Europe and assigned exposure estimates for eight components of PM2.5 representing non-tail pipe emissions (copper (Cu), iron (Fe), and zinc (Zn)), long-range transport (sulfur (S)), oil burning/industry emissions (nickel (Ni), vanadium (V)), crustal material (silicon (Si)), and biomass burning (potassium (K)) to cohort participants' baseline residential address based on 100 m by 100 m grids from newly developed hybrid models combining air pollution monitoring, land use data, satellite observations, and dispersion model estimates. We applied stratified Cox proportional hazards models, adjusting for potential confounders (age, sex, calendar year, marital status, smoking, body mass index, employment status, and neighborhood-level socio-economic status).Results: The pooled study population comprised 306,550 individuals with 3916 incident lung cancer events during 5,541,672 person-years of follow-up. We observed a positive association between exposure to all eight components and lung cancer incidence, with adjusted HRs of 1.10 (95% CI 1.05, 1.16) per 50 ng/m(3) PM2.5 K, 1.09 (95% CI 1.02, 1.15) per 1 ng/m3 PM2.5 Ni, 1.22 (95% CI 1.11, 1.35) per 200 ng/m(3) PM2.5 S, and 1.07 (95% CI 1.02, 1.12) per 200 ng/m(3) PM2.5 V. Effect estimates were largely unaffected by adjustment for nitrogen dioxide (NO2). After adjustment for PM2.5 mass, effect estimates of K, Ni, S, and V were slightly attenuated, whereas effect estimates of Cu, Si, Fe, and Zn became null or negative.Conclusions: Our results point towards an increased risk of lung cancer in connection with sources of combustion particles from oil and biomass burning and secondary inorganic aerosols rather than non-exhaust traffic emissions. Specific limit values or guidelines targeting these specific PM2.5 components may prove helpful in future lung cancer prevention strategies.
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| 4. |
- Dreja, Julia, et al.
(författare)
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Volumetric analysis of small bowel motility in an unselected cohort of patients with Crohn’s disease
- 2020
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 32:10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Quantified terminal ileal motility during magnetic resonance enterography (MRE) has been suggested to be used as a biomarker of Crohn's disease (CD). The aim of the present study was to evaluate this method in clinical practice. Methods: Healthy volunteers and all consecutive patients referred to MRE during a 2-year period were asked to participate and complete the Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS) to assess gastrointestinal symptoms. Medical records were scrutinized, and motility indices (MIs) were calculated from MR images. Key Results: Twenty-two healthy controls and 134 examinations with CD were included (inclusion rate: 76.3%). Patients with CD had increased mural thickness of the terminal ileum, increased fecal calprotectin, and more symptoms than controls. Patients with active CD had increased mural thickness of ileum and terminal ileum, higher MR activity indices, and signs of inflammation in laboratory analyses, but similar symptoms, compared with inactive disease. After exclusion of sole colon disease (n = 13), MI inversely correlated with mural thickness in terminal ileum, and MI was lower in active disease versus controls in ileum (P =.019) and terminal ileum (P =.005), and versus inactive disease in terminal ileum (P =.044). The area under the curve of MI in terminal ileum was 0.736 for active CD against healthy controls (P =.002) and 0.682 for active against inactive CD (P =.001). MIs were similar in controls and inactive CD. Conclusions and Interferences: MI reflects inflammatory activity in the intestine. Alterations in MI did not explain symptomatology in inactive CD, without measurable inflammatory parameters in morphology or laboratory analyses.
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| 5. |
- Hvidtfeldt, Ulla Arthur, et al.
(författare)
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Long-term low-level ambient air pollution exposure and risk of lung cancer - A pooled analysis of 7 European cohorts
- 2021
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 146
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Tidskriftsartikel (refereegranskat)abstract
- Background/aim: Ambient air pollution has been associated with lung cancer, but the shape of the exposure-response function - especially at low exposure levels - is not well described. The aim of this study was to address the relationship between long-term low-level air pollution exposure and lung cancer incidence.Methods: The Effects of Low-level Air Pollution: a Study in Europe (ELAPSE) collaboration pools seven cohorts from across Europe. We developed hybrid models combining air pollution monitoring, land use data, satellite observations, and dispersion model estimates for nitrogen dioxide (NO2), fine particulate matter (PM2.5), black carbon (BC), and ozone (O-3) to assign exposure to cohort participants' residential addresses in 100 m by 100 m grids. We applied stratified Cox proportional hazards models, adjusting for potential confounders (age, sex, calendar year, marital status, smoking, body mass index, employment status, and neighborhood-level socioeconomic status). We fitted linear models, linear models in subsets, Shape-Constrained Health Impact Functions (SCHIF), and natural cubic spline models to assess the shape of the association between air pollution and lung cancer at concentrations below existing standards and guidelines.Results: The analyses included 307,550 cohort participants. During a mean follow-up of 18.1 years, 3956 incident lung cancer cases occurred. Median (Q1, Q3) annual (2010) exposure levels of NO2, PM2.5, BC and O-3 (warm season) were 24.2 mu g/m(3) (19.5, 29.7), 15.4 mu g/m(3) (12.8, 17.3), 1.6 10(-5)m(-1) (1.3, 1.8), and 86.6 mu g/m(3) (78.5, 92.9), respectively. We observed a higher risk for lung cancer with higher exposure to PM2.5 (HR: 1.13, 95% CI: 1.05, 1.23 per 5 mu g/m(3)). This association was robust to adjustment for other pollutants. The SCHIF, spline and subset analyses suggested a linear or supra-linear association with no evidence of a threshold. In subset analyses, risk estimates were clearly elevated for the subset of subjects with exposure below the EU limit value of 25 mu g/m(3). We did not observe associations between NO2, BC or O-3 and lung cancer incidence.Conclusions: Long-term ambient PM2.5 exposure is associated with lung cancer incidence even at concentrations below current EU limit values and possibly WHO Air Quality Guidelines.
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| 6. |
- Hörberg, Lisa, et al.
(författare)
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Reproducibility of measurements with a semi-automatic software package for the evaluation of rectal cancer
- 2020
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Ingår i: Acta Radiologica. - : SAGE Publications. - 0284-1851 .- 1600-0455. ; 61:5, s. 586-594
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Tidskriftsartikel (refereegranskat)abstract
- Background: Staging of rectal cancer with MRI has major impact on treatment choice and may be of importance in new cancer management strategies such as “wait-and-see” policy. Purpose: To assess the reproducibility of a software package recently developed at our department to measure volumes, apparent diffusion coefficient, and the skewness of apparent diffusion coefficient in lymph nodes and tumors in rectal cancer patients before and after chemoradiation treatment. Material and Methods: This study included 20 consecutive patients with biopsy-verified rectal cancer, in whom MRI staging had been performed both before and after chemoradiation treatment. The diffusion-weighted images were transferred to the software. The volume, apparent diffusion coefficient, and skewness were determined for 93 lymph nodes and 40 tumors. The volumes were compared with manual measurements of the volume of the same lymph nodes and tumors. Results: The agreement in semi-automatic measurements of lymph nodes was very good (ICC = 0.99), and in tumors good (ICC = 0.88). The agreement in manual measurements of lymph nodes was very good (ICC = 0.95) when all lymph nodes were included, but low (ICC = 0.52) if three outliers were excluded. Bland–Altman plots showed clear agreement between manual and semi-automatic measurements in the lymph nodes, but not in measurements of tumors. The values of apparent diffusion coefficient and skewness in tumors differed before and after treatment but did not differ in lymph nodes as a group. Conclusion: The software package showed a high degree of reproducibility in measurements on lymph nodes but requires further development to improve the reproducibility of tumor measurements.
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| 7. |
- Kriit, Hedi Katre, et al.
(författare)
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Using Distributed Lag Non-Linear Models to Estimate Exposure Lag-Response Associations between Long-Term Air Pollution Exposure and Incidence of Cardiovascular Disease
- 2022
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI AG. - 1661-7827 .- 1660-4601. ; 19:5
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Tidskriftsartikel (refereegranskat)abstract
- Long-term air pollution exposure increases the risk for cardiovascular disease, but little is known about the temporal relationships between exposure and health outcomes. This study aims to estimate the exposure-lag response between air pollution exposure and risk for ischemic heart disease (IHD) and stroke incidence by applying distributed lag non-linear models (DLNMs). Annual mean concentrations of particles with aerodynamic diameter less than 2.5 µm (PM2.5 ) and black carbon (BC) were estimated for participants in five Swedish cohorts using dispersion models. Simultaneous estimates of exposure lags 1–10 years using DLNMs were compared with separate year specific (single lag) estimates and estimates for lag 1–5-and 6–10-years using moving average exposure. The DLNM estimated no exposure lag-response between PM2.5 total, BC, and IHD. However, for PM2.5 from local sources, a 20% risk increase per 1 µg/m3 for 1-year lag was estimated. A risk increase for stroke was suggested in relation to lags 2–4-year PM2.5 and BC, and also lags 8–9-years BC. No associations were shown in single lag models. Increased risk estimates for stroke in relation to lag 1–5-and 6–10-years BC moving averages were observed. Estimates generally supported a greater contribution to increased risk from exposure windows closer in time to incident IHD and incident stroke. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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| 8. |
- Leander, John, 1976-, et al.
(författare)
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Dataset for damage detection retrieved from a monitored bridge pre and post verified damage
- 2023
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Ingår i: Data in Brief. - : Elsevier BV. - 2352-3409. ; 51
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Tidskriftsartikel (refereegranskat)abstract
- The Vänersborg Bridge in southwest Sweden is a single-leaf bascule bridge carrying railway traffic over a canal. The load consists of passing commuter trains, occasional freight trains and leaf openings to allow ships to pass on the canal. The bridge constructed from 1914 to 1916 was built by riveted truss members in steel. Over the years, several assessments and maintenance actions have been performed to keep the bridge in service. During autumn 2021, a long-term monitoring campaign was initiated with the installation of sensors to register the load effect and possible changes in the behaviour. In March 2023, the cloud-based service employed detected an abrupt change of behaviour. An emergency inspection revealed a large crack in one of the truss members in the counter-weight part. The published dataset contains sensor data from 64 registered bridge openings, comprising accelerations, strains, inclinations, and weather conditions. Data from before the fracture, during, and after are provided. During the bridge opening events, the data was recorded continuously with a sampling rate of 200 Hz. The evidence of damage in a real case scenario makes the dataset valuable for testing and evaluation of data-driven routines for infrastructure surveillance.
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| 9. |
- Leander, Peter, et al.
(författare)
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A novel food-based foam as oral contrast agent with negative Hounsfield units for demarcation of small bowel loops on abdominal CT : tolerability and bowel distension in 25 volunteers
- 2021
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Ingår i: Acta Radiologica. - : SAGE Publications. - 0284-1851 .- 1600-0455. ; 62:12, s. 1559-1566
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Tidskriftsartikel (refereegranskat)abstract
- Background: Diseases of the bowel are not always displayed on conventional abdominal computed tomography (CT). The studied oral contrast agent aims to improve this. Purpose: To investigate whether the use of a novel oral contrast for abdominal CT enables the same diagnostic advantages as seen in magnetic resonance imaging (MRI). Material and Methods: Twenty-five consented volunteers drank up to 1400 mL of a stable, drinkable foam. Comments on acceptance and side effects were noted immediately and 24 h later. Foam palatability was documented through interviews, and distribution in the small bowel by Hounsfield units from the CT software. The CT results were compared with age- and sex-matched controls, pretreated according to routine. A non-enhanced abdominal CT protocol of lowest possible radiation dose was used. External referees evaluated all data obtained. Results: Foam was considered odd to swallow, and fullness was reported by all volunteers after 950 mL. Five had difficulties in drinking the last 320 mL and two abstained from it. All adverse symptoms were mild. The distribution in the small bowel was on par with standard agents. Foam density revealed stability with intraluminal values of around –550 HU from stomach to terminal ileum, satisfying the requirement of a great bowel lumen-to-wall contrast. External reviewers re-evaluated all our data, and one predicted the foam to offer a potential for improved diagnostics. Conclusion: A CT true-negative bowel filling agent was formulated, with high acceptance, few side effects, and a potential to mimic T1-weighted MRI images.
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| 10. |
- Leander, Peter, et al.
(författare)
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A novel food-based negative oral contrast agent compared with two conventional oral contrast agents in abdominal CT : a three-arm parallel blinded randomised controlled single-centre trial
- 2022
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Ingår i: European Radiology Experimental. - : Springer Science and Business Media LLC. - 2509-9280. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: A negative oral contrast agent (OCA) has been long sought for, to better delineate the bowel and visualise surrounding structures. Lumentin® 44 (L44) is a new OCA formulated to fill the entire small bowel. The aim of this study was to compare L44 with positive and neutral conventional OCA in abdominal computed tomography (CT). Methods: Forty-five oncologic patients were randomised to receive either L44 or one of the two comparators (MoviPrep® or diluted Omnipaque®). Abdominal CT examinations with intravenous contrast agent were acquired according to standard protocols. The studies were read independently by two senior radiologists. Results: The mean intraluminal Hounsfield units (HU)-values of regions-of-interest (ROIs) for each subsegment of small bowel and treatment group were -404.0 HU for L44, 166.1 HU for Omnipaque®, and 16.7 HU for MoviPrep® (L44 versus Omnipaque, p < 0.001: L44 versus MoviPrep p < 0.001; Omnipaque versus MoviPrep, p = 0.003). Adverse events, only mild, using L44 were numerically fewer than for using conventional oral contrast agents. Visualisation of abdominal structures beyond the small bowel was similar to the comparators. Conclusions: L44 is a negative OCA with luminal radiodensity at approximately -400 HU creating a unique small bowel appearance on CT scans. The high bowel wall-to-lumen contrast may enable improved visualisation in a range of pathologic conditions. L44 showed a good safety profile and was well accepted by patients studied. Trial registration: EudraCT (2017-002368-42) and in ClinicalTrials.gov (NCT03326518).
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