| 1. |
- Arking, D. E., et al.
(författare)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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| 2. |
- Bagge, Louise, et al.
(författare)
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Quality of life is not improved aftermitral valve surgery combined with epicardial left atrial cryoablation as compared with mitral valve surgery alone : a substudy of the double blind randomized SWEDish Multicentre Atrial Fibrillation study (SWEDMAF)
- 2018
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Ingår i: Europace. - : Oxford University Press. - 1099-5129 .- 1532-2092. ; 20, s. F343-F350
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Concomitant surgical ablation of atrial fibrillation (AF) in patients undergoing mitral valve surgery (MVS) has almost become routine despite lack of convincing information about improved quality-of-life (QOL) and clinical benefit. Quality-of-life was therefore assessed after MVS with or without epicardial left atrial cryoablation. Methods and results: Sixty-five patients with permanent AF randomized to MVS with or without left atrial cryoablation, in the doubleblinded multicentre SWEDMAF trial, replied to the Short Form 36 QOL survey at 6 and 12 months follow-up. The QOL scores at 12month follow-up did not differ significantly between patients undergoing MVS combined with cryoablation vs. those undergoing MVS alone regarding Physical Component Summary mean 42.8 (95% confidence interval 38.3-47.3) vs. mean 44.0 (40.1-47.7), P =0.700 or Mental Component Summary mean 53.1 (49.7-56.4) vs. mean 48.4 (44.6-52.2), P=0.075. All patients, irrespective of allocated procedure, reached the same QOL after surgery as an age-matched Swedish general population. The Physical Component Summary in patients with sinus rhythm did also not differ from those in AF at 12months; mean 45.4 (42.0-48.7) vs. mean 40.5 (35.5-45.6), P=0.096) nor was there a difference in Mental Component Summary; mean 51.0 (48.0-54.1) vs. mean 49.6 (44.6-54.5), P=0.581). Conclusion: Left atrial cryoablation added to MVS does not improve health-related QOL in patients with permanent AF, a finding that raises concerns regarding recommendations made for this combined procedure.
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| 3. |
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| 4. |
- Brander, Søren, et al.
(författare)
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Biochemical evidence of both copper chelation and oxygenase activity at the histidine brace
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Lytic polysaccharide monooxygenase (LPMO) and copper binding protein CopC share a similar mononuclear copper site. This site is defined by an N-terminal histidine and a second internal histidine side chain in a configuration called the histidine brace. To understand better the determinants of reactivity, the biochemical and structural properties of a well-described cellulose-specific LPMO from Thermoascus aurantiacus (TaAA9A) is compared with that of CopC from Pseudomonas fluorescens (PfCopC) and with the LPMO-like protein Bim1 from Cryptococcus neoformans. PfCopC is not reduced by ascorbate but is a very strong Cu(II) chelator due to residues that interacts with the N-terminus. This first biochemical characterization of Bim1 shows that it is not redox active, but very sensitive to H2O2, which accelerates the release of Cu ions from the protein. TaAA9A oxidizes ascorbate at a rate similar to free copper but through a mechanism that produce fewer reactive oxygen species. These three biologically relevant examples emphasize the diversity in how the proteinaceous environment control reactivity of Cu with O2.
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| 5. |
- Fuertes, Elaine, et al.
(författare)
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Residential air pollution does not modify the positive association between physical activity and lung function in current smokers in the ECRHS study
- 2018
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 120, s. 364-372
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Very few studies have examined whether a long-term beneficial effect of physical activity on lung function can be influenced by living in polluted urban areas.OBJECTIVE: We assessed whether annual average residential concentrations of nitrogen dioxide (NO2) and particulate matter with aerodynamic diameters < 2.5 μm (PM2.5) and <10 μm (PM10) modify the effect of physical activity on lung function among never- (N = 2801) and current (N = 1719) smokers in the multi-center European Community Respiratory Health Survey.METHODS: Associations between repeated assessments (at 27-57 and 39-67 years) of being physically active (physical activity: ≥2 times and ≥1 h per week) and forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were evaluated using adjusted mixed linear regression models. Models were conducted separately for never- and current smokers and stratified by residential long-term NO2, PM2.5 mass and PM10 mass concentrations (≤75th percentile (low/medium) versus >75th percentile (high)).RESULTS: Among current smokers, physical activity and lung function were positively associated regardless of air pollution levels. Among never-smokers, physical activity was associated with lung function in areas with low/medium NO2, PM2.5 mass and PM10 mass concentrations (e.g. mean difference in FVC between active and non-active subjects was 43.0 mL (13.6, 72.5), 49.5 mL (20.1, 78.8) and 49.7 mL (18.6, 80.7), respectively), but these associations were attenuated in high air pollution areas. Only the interaction term of physical activity and PM10 mass for FEV1 among never-smokers was significant (p-value = 0.03).CONCLUSIONS: Physical activity has beneficial effects on adult lung function in current smokers, irrespective of residential air pollution levels in Western Europe. Trends among never-smokers living in high air pollution areas are less clear.
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| 6. |
- Fuks, Kateryna B., et al.
(författare)
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Arterial blood pressure and long-term exposure to traffic-related air pollution : an analysis in the European Study of Cohorts for Air Pollution Effects (ESCAPE)
- 2014
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Ingår i: Journal of Environmental Health Perspectives. - : National Institute of Environmental Health Sciences (NIEHS). - 0091-6765 .- 1552-9924. ; 122:9, s. 896-905
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND: Long-term exposure to air pollution is hypothesized to elevate arterial blood pressure (BP). The existing evidence is scarce and country-specific. OBJECTIVES: We investigated the cross-sectional association of long-term traffic-related air pollution with BP and prevalent hypertension in European populations. METHODS: Fifteen population-based cohorts, participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE), were analysed. Residential exposure to particulate matter and nitrogen oxides was modelled with land use regression using a uniform protocol. Traffic exposure was assessed with traffic indicator variables. We analysed systolic and diastolic BP in participants medicated and non-medicated with BP lowering medication (BPLM) separately, adjusting for personal and area-level risk factors and environmental noise. Prevalent hypertension was defined as ≥ 140 mmHg systolic, or ≥ 90 mmHg diastolic BP, or intake of BPLM. We combined cohort-specific results using random-effects meta-analysis. RESULTS: In the main meta-analysis of 113,926 participants, traffic load on major roads within 100 m of the residence was associated with increased systolic and diastolic BP in non-medicated participants (0.35 mmHg [95% CI: 0.02-0.68] and 0.22 mmHg [95% CI: 0.04-0.40] per 4,000,000 vehicles × m/day, respectively). The estimated odds ratio for prevalent hypertension was 1.05 [95% CI: 0.99-1.11] per 4,000,000 vehicles × m/day. Modelled air pollutants and BP were not clearly associated. CONCLUSIONS: In this first comprehensive meta-analysis of European population-based cohorts we observed a weak positive association of high residential traffic exposure with BP in non-medicated participants, and an elevated OR for prevalent hypertension. The relationship of modelled air pollutants with BP was inconsistent.
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| 7. |
- Johnsson, Kerstin, et al.
(författare)
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Analytical performance of aPROMISE : automated anatomic contextualization, detection, and quantification of [18F]DCFPyL (PSMA) imaging for standardized reporting
- 2022
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 49:3, s. 1041-1051
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The application of automated image analyses could improve and facilitate standardization and consistency of quantification in [18F]DCFPyL (PSMA) PET/CT scans. In the current study, we analytically validated aPROMISE, a software as a medical device that segments organs in low-dose CT images with deep learning, and subsequently detects and quantifies potential pathological lesions in PSMA PET/CT. Methods: To evaluate the deep learning algorithm, the automated segmentations of the low-dose CT component of PSMA PET/CT scans from 20 patients were compared to manual segmentations. Dice scores were used to quantify the similarities between the automated and manual segmentations. Next, the automated quantification of tracer uptake in the reference organs and detection and pre-segmentation of potential lesions were evaluated in 339 patients with prostate cancer, who were all enrolled in the phase II/III OSPREY study. Three nuclear medicine physicians performed the retrospective independent reads of OSPREY images with aPROMISE. Quantitative consistency was assessed by the pairwise Pearson correlations and standard deviation between the readers and aPROMISE. The sensitivity of detection and pre-segmentation of potential lesions was evaluated by determining the percent of manually selected abnormal lesions that were automatically detected by aPROMISE. Results: The Dice scores for bone segmentations ranged from 0.88 to 0.95. The Dice scores of the PSMA PET/CT reference organs, thoracic aorta and liver, were 0.89 and 0.97, respectively. Dice scores of other visceral organs, including prostate, were observed to be above 0.79. The Pearson correlation for blood pool reference was higher between any manual reader and aPROMISE, than between any pair of manual readers. The standard deviations of reference organ uptake across all patients as determined by aPROMISE (SD = 0.21 blood pool and SD = 1.16 liver) were lower compared to those of the manual readers. Finally, the sensitivity of aPROMISE detection and pre-segmentation was 91.5% for regional lymph nodes, 90.6% for all lymph nodes, and 86.7% for bone in metastatic patients. Conclusion: In this analytical study, we demonstrated the segmentation accuracy of the deep learning algorithm, the consistency in quantitative assessment across multiple readers, and the high sensitivity in detecting potential lesions. The study provides a foundational framework for clinical evaluation of aPROMISE in standardized reporting of PSMA PET/CT.
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| 8. |
- 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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| 9. |
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| 10. |
- Probst, Johan, 1969-
(författare)
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Epicardial ablation - a study evaluating thoracoscopic and surgical ablation procedures for patients with intractable atrial fibrillation
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atrial fibrillation (AF) is a common condition, increasing in prevalence with age. Symptoms can be severe and quality of life is affected in patients suffering from AF. Treatment regimes aim to alleviate symptoms through rate or rhythm control. Rhythm control can be achieved effectively in early stages of AF with catheter ablation aiming for pulmonary vein isolation (PVI) however, in more advanced stages of the disease a surgical ablation is warranted if rhythm control is the goal.The aim of this thesis was to evaluate the thoracoscopic epicardial left atrial surgical procedure for AF (TELA-AF) in patients suffering from highly symptomatic, mainly longstanding persistent AF (LPAF). The hypothesis was that TELA-AF would be effective in treating LPAF and that quality of life (QoL) would increase accordingly.This thesis second hypothesis was that restoration of sinus rhythm would improve QoL in patients with permanent AF undergoing concomitant mitral valve surgery (MVS) and left atrial cryoablation compared to MVS alone.The TELA-AF surgical technique included pulmonary vein isolation, left atrial "box-lesion" and partial vagal denervation. Patients were followed with clinical evaluation, seven-day Holter electrocardiogram, symptom severity questionnaire (SSQ)and a short form QoL questionnaire (SF-36), six and 12 months after surgery and again after ten years.The concomitant MVS study was a sub-study of the randomized double-blinded SWEDMAF trial. Patients in permanent AF, accepted for MVS were randomized to MVS or MVS and cryo-ablation of the left atria. Patients self-reported QoL before and one year after surgery in the SF-36 questionnaire.Twelve months after the TELA-AF procedure freedom from AF was 83 % although 12 % suffered from an iatrogenic atrial tachycardia post-surgery. The SSQ scores improved significantly from baseline. The SF-36 scores were similar to patients suffering from severe chronic disease at baseline but were not significantly different from an age-matched normal population at follow-up.Ten years after surgery freedom from AF was 22 %, a significant reduction. Quality of life scores were however significantly better than baseline.Patients randomized to concomitant surgery experienced a significant increase in QoL one year after surgery, but there was no difference in QoL scores compared to the MVS-alone group.In conclusion, severe symptoms in AF patients translate to QoL scores as low as those observed in patients with severe chronic diseases. The TELA-AF procedure can alleviate AF related symptoms and improve QoL to the same level as a normal population in the short term. In the long term QoL can be maintained at a high level although displaying AF recurrence according to guidelines, challenging the concept of 30 seconds arrhythmia as a valid endpoint.We could not show any benefit in a concomitant surgery for patients in permanent AF accepted for MVS. It is therefore important to balance the benefits and side effects in both short- and long-term perspective in order to justify the addition of a surgical AF ablation during MVS.
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