| 1. |
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| 2. |
- Roselli, Carolina, et al.
(författare)
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Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
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Tidskriftsartikel (refereegranskat)abstract
- Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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| 3. |
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| 4. |
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| 5. |
- Mulic, A., et al.
(författare)
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The frequency of enamel and dentin caries lesions among elderly Norwegians
- 2020
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Ingår i: Acta Odontologica Scandinavica. - : Informa UK Limited. - 0001-6357 .- 1502-3850. ; 78:1, s. 6-12
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To describe the distribution of enamel-, dentin-, root- and secondary caries within an elderly population in Northern-Norway. Material and methods: A study population (n = 1 173) was divided into age groups: 65-69 (seniors), 70-74 (young elderly), 75-79 (elderly) and 80-94 (old elderly). Seven examiners registered presence, location and severity of caries lesions on x-rays and intra-oral photos. Severity of approximal, occlusal, secondary and root caries was graded (D1-2: into enamel; D3-5: into dentin, root caries)(,) and decayed missing filled surfaces/teeth (DMFS/DMFT) were calculated. T-test, ANOVA and a Bonferroni correction were used. Results: The seniors had more primary caries (DS1-5) compared to the oldest age groups, while the old elderly had significantly more secondary caries than the other groups (p < .05). Of those >= 65 years 13.8% were affected with root caries, 21% among the oldest. About 48% of the old elderly had one or more surfaces with untreated caries lesions into dentin, while for the other groups the number was 35% (p < 0.05). Conclusion: Individuals seem to maintain good oral health up to at least 80 years of age. Those older than 80 years have more root caries needing more intensified caries-controlling measures and a higher prevalence of untreated dentin lesions often in need of operative treatment.
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| 8. |
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| 9. |
- Corino, Valentina D A, et al.
(författare)
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Circadian variation of variability and irregularity of heart rate in patients with permanent atrial fibrillation: Relation to symptoms and rate-control drugs.
- 2015
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Ingår i: American Journal of Physiology: Heart and Circulatory Physiology. - : American Physiological Society. - 1522-1539 .- 0363-6135. ; 309:12, s. 2152-2157
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study is to evaluate the diurnal variation of the variability and irregularity of the heart rate (HR) in patients with permanent atrial fibrillation (AF), with and without rate-control drugs. Thirty-eight patients with permanent AF were part of an investigator-blind cross-over study, comparing diltiazem, verapamil, metoprolol, and carvedilol. We analyzed five Holter recordings per patient: at baseline (no rate-control drug) and with each of the four drug regimens. HR, variability (standard deviation, pNN20, pNN50, pNN80, and rMSSD) and irregularity (approximate (APEn) and sample entropy) parameters were computed in 20-minute long non-overlapping segments. Circadian rhythmicity was evaluated using the cosinor analysis to each parameter series, that is characterized by the 24-h mean (MESOR) and the excursion over the mean (the amplitude). Arrhythmia-related symptoms were assessed by a questionnaire measuring symptoms severity (SS) and frequency (SF). HR and variability parameters showed a significant circadian variation in most patients, whereas only a small minority of the patients had circadian variation of irregularity parameters. The patients with circadian ApEn at baseline had more severe symptoms (SS = 9±4 vs. 6±5, p<0.05; circadian vs. non-circadian variation). All drugs decreased the MESOR of HR and increased the MESOR of variability parameters. Only carvedilol and metoprolol decreased the normalized amplitude over the 24-h of all parameters and HR. In conclusion, HR and RR variability parameters present a circadian variation in patients with permanent AF, whereas few patients demonstrated circadian fluctuations in irregularity parameters, suggesting different physiological mechanisms.
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| 10. |
- Corino, Valentina D.A., et al.
(författare)
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Non-invasive evaluation of the effect of metoprolol on the atrioventricular node during permanent atrial fibrillation
- 2014. - January
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Ingår i: Computing in Cardiology 2014. - : Oxford University Press (OUP). - 2325-8861. - 9781479943463 - 9781479943470 ; 41, s. 889-892
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Konferensbidrag (refereegranskat)abstract
- The aim of this study was to evaluate changes in AV nodal properties during administration of metoprolol, using a novel ECG-based method for parameter estimation. The AV nodal parameters account for the probability of an impulse not passing through the fast pathway, the absolute refractory periods of the slow and fast pathways (aRPs and aRPf), representing the functional refractory period, and related prolongation in the respective refractory periods. Twenty patients (age 71±8 years, 14 men) with permanent AF from the RATe control in Atrial Fibrillation (RATAF) database were included in this study. Recordings during baseline and metoprolol administration were analyzed. Furthermore, simulated RR series were generated mimicking metoprolol administration. During metoprolol administration, aRP was significantly prolonged in both pathways (aRPs: 342±39 vs. 408±81 ms, p<0.001; aRPf: 432±74 vs. 527±83 ms, p<0.001). Similar results were found for the simulated RR series: both aRPs and aRPf were significantly prolonged with metoprolol. The AV nodal parameters reflect expected changes after metoprolol administration, i.e., a prolongation in functional refractory period. The simulations suggest that aRP may serve as an estimate of the functional refractory period.
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| 11. |
- Corino, Valentina D. A., et al.
(författare)
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Rate-Control Drugs Affect Variability and Irregularity Measures of RR Intervals in Patients with Permanent Atrial Fibrillation
- 2015
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Ingår i: Journal of Cardiovascular Electrophysiology. - : Wiley. - 1540-8167 .- 1045-3873. ; 26:2, s. 137-141
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Tidskriftsartikel (refereegranskat)abstract
- Heart Rate Variability and Irregularity During AF IntroductionIrregularity measures have been suggested as risk indicators in patients with atrial fibrillation (AF); however, it is not known to what extent they are affected by commonly used rate-control drugs. We aimed at evaluating the effect of metoprolol, carvedilol, diltiazem, and verapamil on the variability and irregularity of the ventricular response in patients with permanent AF. Methods and ResultsSixty patients with permanent AF were part of an investigator-blind cross-over study, comparing 4 rate-control drugs (diltiazem, verapamil, metoprolol, and carvedilol). We analyzed five 20-minute segments per patient: baseline and the 4 drug regimens. On every segment, heart rate (HR) variability and irregularity of RR series were computed. The variability was assessed as standard deviation, pNN20, pNN50, pNN80, and rMSSD. The irregularity was assessed by regularity index, approximate (ApEn), and sample entropy. A significantly lower HR was obtained with all drugs, the HR was lowest using the calcium channel blockers. All drugs increased the variability of ventricular response in respect to baseline (as an example, rMSSD: baseline 171 47 milliseconds, carvedilol 229 +/- 58 milliseconds; P < 0.05 vs. baseline, metoprolol 226 +/- 66 milliseconds; P < 0.05 vs. baseline, verapamil 228 +/- 84; P < 0.05 vs. baseline, diltiazem 256 +/- 87 milliseconds; P < 0.05 vs. baseline and all other drugs). Only -blockers significantly increased the irregularity of the RR series (as an example, ApEn: baseline 1.86 +/- 0.13, carvedilol 1.92 +/- 0.09; P < 0.05 vs. baseline, metoprolol 1.93 +/- 0.08; P < 0.05 vs. baseline, verapamil 1.86 +/- 0.22 ns, diltiazem 1.88 +/- 0.16 ns). ConclusionModification of AV node conduction by rate-control drugs increase RR variability, while only -blockers affect irregularity.
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| 12. |
- Freedman, Ben, et al.
(författare)
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Screening for Atrial Fibrillation A Report of the AF-SCREEN International Collaboration
- 2017
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Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 135:19, s. 1851-
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 10% of ischemic strokes are associated with atrial fibrillation (AF) first diagnosed at the time of stroke. Detecting asymptomatic AF would provide an opportunity to prevent these strokes by instituting appropriate anticoagulation. The AF-SCREEN international collaboration was formed in September 2015 to promote discussion and research about AF screening as a strategy to reduce stroke and death and to provide advocacy for implementation of country-specific AF screening programs. During 2016, 60 expert members of AF-SCREEN, including physicians, nurses, allied health professionals, health economists, and patient advocates, were invited to prepare sections of a draft document. In August 2016, 51 members met in Rome to discuss the draft document and consider the key points arising from it using a Delphi process. These key points emphasize that screen-detected AF found at a single timepoint or by intermittent ECG recordings over 2 weeks is not a benign condition and, with additional stroke factors, carries sufficient risk of stroke to justify consideration of anticoagulation. With regard to the methods of mass screening, handheld ECG devices have the advantage of providing a verifiable ECG trace that guidelines require for AF diagnosis and would therefore be preferred as screening tools. Certain patient groups, such as those with recent embolic stroke of uncertain source (ESUS), require more intensive monitoring for AF. Settings for screening include various venues in both the community and the clinic, but they must be linked to a pathway for appropriate diagnosis and management for screening to be effective. It is recognized that health resources vary widely between countries and health systems, so the setting for AF screening should be both country-and health system-specific. Based on current knowledge, this white paper provides a strong case for AF screening now while recognizing that large randomized outcomes studies would be helpful to strengthen the evidence base.
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| 13. |
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| 14. |
- Glimelius, Bengt, et al.
(författare)
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Adjuvant chemotherapy in colorectal cancer: a joint analysis of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group
- 2005
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Ingår i: Acta Oncol. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 44:8, s. 904-12
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Tidskriftsartikel (refereegranskat)abstract
- Due to uncertainties regarding clinically meaningful gains from adjuvant chemotherapy after colorectal cancer surgery, several Nordic Groups in the early 1990s initiated randomised trials to prove or reject such gains. This report gives the joint analyses after a minimum 5-year follow-up. Between October 1991 and December 1997, 2 224 patients under 76 years of age with colorectal cancer stages II and III were randomised to surgery alone (n = 1 121) or adjuvant chemotherapy (n = 1 103) which varied between trials (5FU/levamisole for 12 months, n = 444; 5FU/leucovorin for 4-5 months according to either a modified Mayo Clinic schedule (n = 262) or the Nordic schedule (n = 397). Some centres also randomised patients treated with 5FU/leucovorin to+/-levamisole). A total of 812 patients had colon cancer stage II, 708 colon cancer stage III, 323 rectal cancer stage II and 368 rectal cancer stage III. All analyses were according to intention-to-treat. No statistically significant difference in overall survival, stratified for country or region, could be found in any group of patients according to stage or site. In colon cancer stage III, an absolute difference of 7% (p = 0.15), favouring chemotherapy, was seen. The present analyses corroborate a small but clinically meaningful survival gain from adjuvant chemotherapy in colon cancer stage III, but not in the other presentations.
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| 15. |
- Holme, Oyvind, et al.
(författare)
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Effect of Flexible Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality A Randomized Clinical Trial
- 2014
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association. - 0098-7484 .- 1538-3598. ; 312:6, s. 606-615
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCEColorectal cancer is a major health burden. Screening is recommended in many countries. OBJECTIVE To estimate the effectiveness of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality in a population-based trial. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 100 210 individuals aged 50 to 64 years, identified from the population of Oslo city and Telemark County, Norway. Screening was performed in 1999-2000 (55-64-year age group) and in 2001 (50-54-year age group), with follow-up ending December 31, 2011. Of those selected, 1415 were excluded due to prior colorectal cancer, emigration, or death, and 3 could not be traced in the population registry.INTERVENTIONSParticipants randomized to the screening group were invited to undergo screening. Within the screening group, participants were randomized 1: 1 to receive once-only flexible sigmoidoscopy or combination of once-only flexible sigmoidoscopy and fecal occult blood testing (FOBT). Participants with positive screening test results (cancer, adenoma, polyp >= 10 mm, or positive FOBT) were offered colonoscopy. The control group received no intervention.MAIN OUTCOMES AND MEASURESColorectal cancer incidence and mortality.RESULTSA total of 98 792 participants were included in the intention-to-screen analyses, of whom 78 220 comprised the control group and 20 572 comprised the screening group (10 283 randomized to receive a flexible sigmoidoscopy and 10 289 to receive flexible sigmoidoscopy and FOBT). Adherence with screening was 63%. After a median of 10.9 years, 71 participants died of colorectal cancer in the screening group vs 330 in the control group (31.4 vs 43.1 deaths per 100 000 person-years; absolute rate difference, 11.7 [95% CI, 3.0-20.4]; hazard ratio [HR], 0.73 [95% CI, 0.56-0.94]). Colorectal cancer was diagnosed in 253 participants in the screening group vs 1086 in the control group (112.6 vs 141.0 cases per 100 000 person-years; absolute rate difference, 28.4 [95% CI, 12.1-44.7]; HR, 0.80 [95% CI, 0.70-0.92]). Colorectal cancer incidence was reduced in both the 50-to 54-year age group (HR, 0.68; 95% CI, 0.49-0.94) and the 55-to 64-year age group (HR, 0.83; 95% CI, 0.71-0.96). There was no difference between the flexible sigmoidoscopy only vs the flexible sigmoidoscopy and FOBT screening groups.CONCLUSIONS AND RELEVANCEIn Norway, once-only flexible sigmoidoscopy screening or flexible sigmoidoscopy and FOBT reduced colorectal cancer incidence and mortality on a population level compared with no screening. Screening was effective both in the 50-to 54-year and the 55-to 64-year age groups.
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| 16. |
- Holme, Oyvind, et al.
(författare)
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Long-Term Effectiveness of Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality in Women and Men A Randomized Trial
- 2018
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Ingår i: Annals of Internal Medicine. - : American College of Physicians. - 0003-4819 .- 1539-3704. ; 168:11, s. 775-782
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Tidskriftsartikel (refereegranskat)abstract
- Background: The long-term effects of sigmoidoscopy screening on colorectal cancer (CRC) incidence and mortality in women and men are unclear.Objective: To determine the effectiveness of flexible sigmoidoscopy screening after 15 years of follow-up in women and men.Design: Randomized controlled trial. (ClinicalTrials.gov: NCT00119912)Setting: Oslo and Telemark County, Norway. Participants: Adults aged 50 to 64 years at baseline without prior CRC.Intervention: Screening (between 1999 and 2001) with flexible sigmoidoscopy with and without additional fecal blood testing versus no screening. Participants with positive screening results were offered colonoscopy.Measurements: Age-adjusted CRC incidence and mortality stratified by sex.Results: Of 98 678 persons, 20 552 were randomly assigned to screening and 78 126 to no screening. Adherence rates were 64.7% in women and 61.4% in men. Median follow-up was 14.8 years. The absolute risks for CRC in women were 1.86% in the screening group and 2.05% in the control group (risk difference, -0.19 percentage point [95% CI, -0.49 to 0.11 percentage point]; HR, 0.92 [CI, 0.79 to 1.07]). In men, the corresponding risks were 1.72% and 2.50%, respectively (risk difference, -0.78 percentage point [CI, -1.08 to -0.48 percentage points]; hazard ratio [HR], 0.66 [CI, 0.57 to 0.78]) (P for heterogeneity = 0.004). The absolute risks for death from CRC in women were 0.60% in the screening group and 0.59% in the control group (risk difference, 0.01 percentage point [CI, -0.16 to 0.18 percentage point]; HR, 1.01 [CI, 0.77 to 1.33]). The corresponding risks for death from CRC in men were 0.49% and 0.81%, respectively (risk difference, -0.33 percentage point [CI, -0.49 to -0.16 percentage point]; HR, 0.63 [CI, 0.47 to 0.83]) (P for heterogeneity = 0.014).Limitation: Follow-up through national registries.Conclusion: Offering sigmoidoscopy screening in Norway reduced CRC incidence and mortality in men but had little or no effect in women.
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| 17. |
- Ihle-Hansen, H, et al.
(författare)
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Montreal Cognitive Assessment in a 63- to 65-year-old Norwegian Cohort from the General Population: Data from the Akershus Cardiac Examination 1950 Study
- 2017
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Ingår i: Dementia and geriatric cognitive disorders extra. - : S. Karger AG. - 1664-5464. ; 7:3, s. 318-327
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Aims:</i></b> To investigate Montreal Cognitive Assessment (MoCA) test scores in a cohort aged 63–65 years from a general population in relation to the proposed cut-off score of 26 for mild cognitive impairment (MCI) and to explore the impact of education. <b><i>Methods:</i></b> MoCA scores were assessed in the Akershus Cardiac Examination 1950 Study, a cross-sectional cohort study of all men and women born in 1950 living in Akershus County, Norway. The participants were aged 63–65 at the time of data collection. <b><i>Results:</i></b> MoCA scores were available in 3,413 participants, of which 47% had higher education (>12 years). The mean MoCA score was 25.3 (95% confidence interval [CI] 25.2–25.4), and 49% had a score below the suggested cut-off of 26 points. Those with higher education had significantly higher scores (mean 26.2, 95% CI 26.1–26.3 vs. 24.4, 95% CI 24.3–24.6, p < 0.001). <b><i>Conclusions:</i></b> Approximately 50% scored below the cut-off score of 26 points, suggesting that the cut-off score may have been set too high to distinguish normal cognitive function from MCI. Educational level had a significant impact on MoCA scores.
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| 18. |
- Olsson, Bertil, et al.
(författare)
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Safety and tolerability of an immediate-release formulation of theoral direct thrombin inhibitor AZD0837 in the prevention of stroke and systemic embolism in patients with atrial fibrillation.
- 2010
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 103:Jan 13, s. 604-612
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Tidskriftsartikel (refereegranskat)abstract
- AZD0837 is an investigational oral anticoagulant which is converted to the active form, ARH067637, a selective direct thrombin inhibitor. The present study, a multicentre, randomised, parallel-group, dose-guiding study, assessed the safety and tolerability of an immediate-release formulation of AZD0837 compared with dose-adjusted warfarin in the prevention of stroke and systemic embolic events in atrial fibrillation (AF) patients. Two hundred fifty AF patients with at least one additional risk factor for stroke were randomised to receive either immediate-release AZD0837 (150mg twice daily [bid] or 350mg bid, blinded treatment) or dose-adjusted warfarin (international normalised ratio 2.0-3.0, open treatment) for three months. The safety and tolerability of 150mg bid AZD0837 appeared to be as good as that of warfarin. Total bleeding events were six with 150mg bid AZD0837, 15 with 350mg bid AZD0837, and eight with warfarin. Alanine aminotransferase elevations (>3xupper limit of normal) were infrequent, without apparent differences between treatment groups. A numerically higher incidence of serious adverse events was observed with 350mg bid AZD0837 compared with 150mg bid, with six of 13 being cardiac related, all with different diagnoses. An increase in mean serum creatinine of approximately 10% was observed in both AZD0837 groups, which returned to baseline after completion of therapy. There were no strokes, transient ischaemic attacks or cerebral haemorrhages with any of the treatments. In conclusion, the safety and tolerability of 150mg bid immediate-release AZD0837 appeared to be as good as that of dose-adjusted warfarin. However, larger studies will be needed to define the safety profile of AZD0837.
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| 19. |
- Pilemalm, Sofie, 1973-, et al.
(författare)
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Turning Common Operational Picture Data into Double-loop Learning from Crises – can Vision Meet Reality?
- 2021
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Ingår i: Proceedings of the 18th ISCRAM Conference. - : Virginia Tech. - 9781949373615 ; , s. 417-430
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Konferensbidrag (refereegranskat)abstract
- This study proposes a framework for double-loop learning from crises, using common operational pictures (COP).In most crises, a COP is of outmost importance to gain a common understanding among inter-organizationalresponse. A COP is sometimes expressed through a map visualization. While the technologies to support COPprogress rapidly, the corresponding practice of evaluating the COP and situational awareness is not yet established. Tools that enable responders to learn after the crisis, look back in time on the COP development and detect the barriers that prevent the COP establishment, still seem absent. Double-loop learning is an organizational practice to learn from previous actions widely adopted in the safety domain, and lately used in crisis management. This paper addresses the perceived gap by presenting the technical, organizational and structural requirementsderived from document analysis, observation, and a workshop with multiple crisis management stakeholders, and integrating them to an initial framework.
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| 20. |
- Sandberg, Frida, et al.
(författare)
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Drug effect evaluation during permanent atrial fibrillation using an AV-node model
- 2013
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Ingår i: Computing in Cardiology 2013, CinC 2013. - 9781479908844 ; 40, s. 1243-1246
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Konferensbidrag (refereegranskat)abstract
- The purpose of the present study is to evaluate the effect of rate control drugs on the AV node characteristics during atrial fibrillation (AF) using a model-based approach. A statistical model of the AV nodal function is employed, defined by parameters which characterize the arrival rate of atrial impulses, the refractoriness of the fast and the slow AV-nodal pathway and the probability of atrial impulse to pass through either of the two pathways. The RATAF (RATe control in Atrial Fibrillation) study database consists of recordings from 60 patients with permanent AF at baseline and on treatment with metoprolol, verapamil, diltiazem and carvedilol, respectively. The resulting model parameter estimates indicate that the refractory period of the slow pathway as well as that of the fast pathway increased significantly during treatment with all four drugs. The results suggest that the proposed AV-node model can be used for non-invasive evaluation of the effect of rate control drugs.
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| 22. |
- Tarpgaard, Line S., et al.
(författare)
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Intact and cleaved plasma soluble urokinase receptor in patients with metastatic colorectal cancer treated with oxaliplatin with or without cetuximab
- 2015
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 137:10, s. 2470-2477
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Tidskriftsartikel (refereegranskat)abstract
- Circulating forms of the urokinase plasminogen activator receptor (uPAR) are associated with prognosis in patients with colorectal cancer. Preclinical studies have shown that uPAR can influence the state of phosphorylation and signalling activity of the epidermal growth factor receptor (EGFR) in a ligand-independent manner. The purpose of the study was to evaluate whether plasma soluble intact and cleaved uPAR(I-III) + (II-III) levels could identify a subpopulation of patients with metastatic colorectal cancer (mCRC) where treatment with cetuximab would have a beneficial effect. Plasma samples were available from 453 patients treated in the NORDIC VII study. Patients were randomized between FLOX and FLOX + cetuximab. The levels of uPAR(I-III) 1(II-III) were determined by time-resolved fluorescence immunoassay. We demonstrated that higher baseline plasma uPAR(I-III) 1(II-III) levels were significantly associated with shorter progression-free survival (PFS) (HR51.30, 1.14-1.48, p=0.0001) and overall survival (OS) (HR51.75, 1.52-2.02, p < 0.0001). Multivariate Cox analysis showed that plasma uPAR(I-III) 1(II-III) was an independent biomarker of short OS (HR51.45, 1.20-1.75, p=0.0001). There were no significant interactions between plasma uPAR(I-III) 1(II-III) levels, KRAS mutational status and treatment either PFS (p=0.43) or OS (p=0.095). However, further explorative analyses indicated that patients with low levels of circulating suPAR and a KRAS wild-type tumor have improved effect from treatment with FLOX+cetuximab as compared to patients with KRAS wild-type and high levels of suPAR. These results thus support the preclinical findings and should be further tested in an independent clinical data set.
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| 23. |
- Tarpgaard, Line S., et al.
(författare)
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TIMP-1 is under regulation of the EGF signaling axis and promotes an aggressive phenotype in KRAS-mutated colorectal cancer cells : A potential novel approach to the treatment of metastatic colorectal cancer
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:37, s. 59441-59457
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Tidskriftsartikel (refereegranskat)abstract
- It is now widely accepted that therapeutic antibodies targeting epidermal growth factor receptor (EGFR) can have efficacy in KRAS wild-type advanced colorectal cancer (CRC) patients. What remains to be ascertained is whether a subgroup of KRAS-mutated CRC patients might not also derive benefit from EGFR inhibitors. Metalloproteinase inhibitor 1 (TIMP-1) is a pleiotropic factor predictive of survival outcome of CRC patients. Levels of TIMP-1 were measured in pre-treatment plasma samples (n = 426) of metastatic CRC patients randomized to Nordic FLOX (5-fluorouracil and oxaliplatin) +/- cetuximab (NORDIC VII study). Multivariate analysis demonstrated a significant interaction between plasma TIMP-1 protein levels, KRAS status and treatment with patients bearing KRAS mutated tumors and high TIMP-1 plasma level (> 3rd quartile) showing a significantly longer overall survival if treated with cetuximab (HR, 0.48; 95% CI, 0.25 to 0.93). To gain mechanistic insights into this association we analyzed a set of five different CRC cell lines. We show here that EGFR signaling induces TIMP-1 expression in CRC cells, and that TIMP-1 promotes a more aggressive behavior, specifically in KRAS mutated cells. The two sets of data, clinical and in vitro, are complementary and support each other, lending strength to our contention that TIMP-1 plasma levels can identify a subset of patients with KRAS-mutated metastatic CRC that will have benefit from EGFR-inhibition therapy.
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| 24. |
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