| 1. |
- Smiljanic, R., et al.
(författare)
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The Gaia-ESO Survey: The analysis of high-resolution UVES spectra of FGK-type stars
- 2014
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Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 570
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Tidskriftsartikel (refereegranskat)abstract
- Context. The ongoing Gaia-ESO Public Spectroscopic Survey is using FLAMES at the VLT to obtain high-quality medium-resolution Giraffe spectra for about 10(5) stars and high-resolution UVES spectra for about 5000 stars. With UVES, the Survey has already observed 1447 FGK-type stars. Aims. These UVES spectra are analyzed in parallel by several state-of-the-art methodologies. Our aim is to present how these analyses were implemented, to discuss their results, and to describe how a final recommended parameter scale is defined. We also discuss the precision (method-to-method dispersion) and accuracy (biases with respect to the reference values) of the final parameters. These results are part of the Gaia-ESO second internal release and will be part of its first public release of advanced data products. Methods. The final parameter scale is tied to the scale defined by the Gaia benchmark stars, a set of stars with fundamental atmospheric parameters. In addition, a set of open and globular clusters is used to evaluate the physical soundness of the results. Each of the implemented methodologies is judged against the benchmark stars to define weights in three different regions of the parameter space. The final recommended results are the weighted medians of those from the individual methods. Results. The recommended results successfully reproduce the atmospheric parameters of the benchmark stars and the expected T-eff-log g relation of the calibrating clusters. Atmospheric parameters and abundances have been determined for 1301 FGK-type stars observed with UVES. The median of the method-to-method dispersion of the atmospheric parameters is 55K for T-eff, 0.13dex for log g and 0.07 dex for [Fe/H]. Systematic biases are estimated to be between 50-100 K for T-eff, 0.10-0.25 dex for log g and 0.05-0.10 dex for [Fe/H]. Abundances for 24 elements were derived: C, N, O, Na, Mg, Al, Si, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Mo, Ba, Nd, and Eu. The typical method-to-method dispersion of the abundances varies between 0.10 and 0.20 dex. Conclusions. The Gaia-ESO sample of high-resolution spectra of FGK-type stars will be among the largest of its kind analyzed in a homogeneous way. The extensive list of elemental abundances derived in these stars will enable significant advances in the areas of stellar evolution and Milky Way formation and evolution.
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| 2. |
- Holmgren, Christina M, et al.
(författare)
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Changes in Medication Preceding Out-of-hospital Cardiac Arrest Where Resuscitation Was Attempted
- 2014
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Ingår i: Journal of Cardiovascular Pharmacology. - : Lippincott Williams & Wilkins. - 0160-2446 .- 1533-4023. ; 63:6, s. 497-503
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To describe recent changes in medication preceding out-of-hospital cardiac arrest (OHCA) where resuscitation was attempted. Methods: OHCA victims were identified by the Swedish Cardiac Arrest Register and linked by means of their unique 10-digit personal identification numbers to the Prescribed Drug Register. We identified new claimed prescriptions during a 6-month period before the OHCA compared with those claimed in the period 12 to 18 months before. The 7-digit Anatomical Therapeutical Chemical codes of individual drugs were used. The study period was November 2007-January 2011. Results: OHCA victims with drugs were (1) older than those who did not claim any drugs in any period (70 +/- 16 years vs. 54 +/- 22 years, P < 0.001), (2) more often women (34% vs. 20%, P < 0.001), and (3) had more often a presumed cardiac etiology (67% vs. 54%, P < 0.001). The OHCA victims were less likely to have ventricular tachycardia/ventricular fibrillation as the first recorded ;rhythm (26% vs. 33%, P < 0.001) or to survive 1 month (9% vs. 17%, P < 0.0001). New prescriptions were claimed by 5122 (71%) of 7243 OHCA victims. The most frequently claimed new drugs were paracetamol (acetaminophen) 10.3%, furosemide 7.8%, and omeprazole 7.6%. Of drugs known or supposed to cause QT prolongation, ciprofloxacin was the most frequent (3.4%) altogether; 16% had a new claimed prescription of a drug included in the "qtdrugs.org" lists. Conclusions: Most OHCA victims had new drugs prescribed within 6 months before the event but most often intended for diseases other than cardiac. No claims can be made as to the causality.
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| 3. |
- Holst, Anders G., et al.
(författare)
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Inhibition of the KCa2 potassium channel in atrial fibrillation: a randomized phase 2 trial
- 2023
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Ingår i: Nature Medicine. - 1078-8956 .- 1546-170X.
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Tidskriftsartikel (refereegranskat)abstract
- Existing antiarrhythmic drugs to treat atrial fibrillation (AF) have incomplete efficacy, contraindications and adverse effects, including proarrhythmia. AP30663, an inhibitor of the KCa2 channel, has demonstrated AF efficacy in animals; however, its efficacy in humans with AF is unknown. Here we conducted a phase 2 trial in which patients with a current episode of AF lasting for 7 days or less were randomized to receive an intravenous infusion of 3 or 5 mg kg−1 AP30663 or placebo. The trial was prematurely discontinued because of slow enrollment during the coronavirus disease 2019 pandemic. The primary endpoint of the trial was cardioversion from AF to sinus rhythm within 90 min from the start of the infusion, analyzed with Bayesian statistics. Among 59 patients randomized and included in the efficacy analyses, the primary endpoint occurred in 42% (5 of 12), 55% (12 of 22) and 0% (0 of 25) of patients treated with 3 mg kg−1 AP30663, 5 mg kg−1 AP30663 or placebo, respectively. Both doses demonstrated more than 99.9% probability of superiority over placebo, surpassing the prespecified 95% threshold. The mean time to cardioversion, a secondary endpoint, was 47 (s.d. = 23) and 41 (s.d. = 24) minutes for 3 mg kg−1 and 5 mg kg−1 AP30663, respectively. AP30663 caused a transient increase in the QTcF interval, with a maximum mean effect of 37.7 ms for the 5 mg kg−1 dose. For both dose groups, no ventricular arrhythmias occurred and adverse event rates were comparable to the placebo group. AP30663 demonstrated AF cardioversion efficacy in patients with recent-onset AF episodes. KCa2 channel inhibition may be an attractive mechanism for rhythm control of AF that should be studied further in randomized trials. ClinicalTrials.gov registration: NCT04571385 .
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| 4. |
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| 5. |
- Bentzen, B. H., et al.
(författare)
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Mechanisms of Action of the KCa2-Negative Modulator AP30663, a Novel Compound in Development for Treatment of Atrial Fibrillation in Man
- 2020
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Aims Small conductance Ca2+-activated K+ channels (SK channels, K(Ca)2) are a new target for treatment of atrial fibrillation (AF). AP30663 is a small molecule inhibitor of K(Ca)2 channels that is currently in clinical development for treatment of AF. The aim of this study is to present the electrophysiological profile and mechanism of action of AP30663 and its efficacy in prolonging atrial refractoriness in rodents, and by bioinformatic analysis investigate if genetic variants in KCNN2 or KCNN3 influence the expression level of these in human heart tissue. Methods and Results Whole-cell and inside-out patch-clamp recordings of heterologously expressed K(Ca)2 channels revealed that AP30663 inhibits K(Ca)2 channels with minor effects on other relevant cardiac ion channels. AP30663 modulates the K(Ca)2.3 channel by right-shifting the Ca2+-activation curve. In isolated guinea pig hearts AP30663 significantly prolonged the atrial effective refractory period (AERP) with minor effects on the QT-interval corrected for heart rate. Similarly, in anaesthetized rats 5 and 10 mg/kg of AP30663 changed the AERP to 130.7 +/- 5.4% and 189.9 +/- 18.6 of baseline values. The expression quantitative trait loci analyses revealed that the genome wide association studies for AF SNP rs13376333 in KCNN3 is associated with increased mRNA expression of KCNN3 in human atrial appendage tissue. Conclusions AP30663 is a novel negative allosteric modulator of K(Ca)2 channels that concentration-dependently prolonged rodent atrial refractoriness with minor effects on the QT-interval. Moreover, AF associated SNPs in KCNN3 influence KCNN3 mRNA expression in human atrial tissue. These properties support continued development of AP30663 for treatment of AF in man.
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| 6. |
- Björkenheim, Anna, 1980-, et al.
(författare)
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Patient-reported Outcomes In Relation To Continuously Monitored Rhythm Before And During Two Years After Atrial Fibrillation Ablation Using A Disease-specific And A Generic Instrument
- 2018
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Konferensbidrag (refereegranskat)abstract
- Background: Patients with AF have a lower health-related quality of life (HRQoL) than the general population.Objective: To assess the effect of AF ablation on AF-specific and generic patient-reported outcomes (PRO), compare it to a Swedish age- and sex-matched population and evaluate any association with the AF burden.Methods: Patients scheduled for AF ablation completed the generic SF-36 and the AF-specific PRO questionnaires before and six, 12 and 24 months after AF ablation. All patients underwent continuous ECG monitoring via an implantable loop recorder.Results: 54 patients completed the follow-up. After ablation, the generic SF-36 improved and both summary scores reached normative levels at 24 months, while physical functioning, role-physical and vitality remained lower than norms. Responders with an AF burden ≤0.5% at each visit after ablation reached the norms in all domains, while non-responders reached norms in only social functioning and MCS. All AF6 items and the sum score showed moderate to large improvement in both responders and non-responders. Higher AF burden was independently associated with poorer PCS and AF6 sum score. The AF sum score correlated with all SF-36 domains, but all AF6 items did not correlate with the SF-36 summary scores.Conclusion: The AF-specific AF6 questionnaire was more sensitive to changes in PRO related to AF burden than was the generic SF-36. Higher AF burden after ablation was associated with poorer AF-specific PRO and poorer generic physical but not mental health. Focusing on AF-specific symptoms and their impact on quality of life as an outcome after AF ablation is reasonable, as improving PROs is the main goal of AF ablation.
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| 7. |
- Diness, J. G., et al.
(författare)
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Inhibition of K(Ca)2 Channels Decreased the Risk of Ventricular Arrhythmia in the Guinea Pig Heart During Induced Hypokalemia
- 2020
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background Hypokalemia reduces the cardiac repolarization reserve. This prolongs the QT-interval and increases the risk of ventricular arrhythmia; a risk that is exacerbated by administration of classical class 3 anti-arrhythmic agents. Small conductance Ca2+-activated K+-channels (K(Ca)2) are a promising new atrial selective target for treatment of atrial fibrillation. Under physiological conditions K(Ca)2 plays a minor role in ventricular repolarization. However, this might change under hypokalemia because of concomitant increases in ventriculay -60r intracellur Ca2+. Purpose To study the effects of pharmacological K(Ca)2 channel inhibition by the compounds AP14145, ICA, or AP30663 under hypokalemic conditions as compared to dofetilide and hypokalemia alone time-matched controls (TMC). Methods The current at +10 mV was compared in HEK293 cells stably expressing K(Ca)2.3 perfused first with normo- and then hypokalemic solutions (4 mM K+ and 2.5 mM K+, respectively). Guinea pig hearts were isolated and perfused with normokalemic (4 mM K+) Krebs-Henseleit solution, followed by perfusion with drug or vehicle control. The perfusion was then changed to hypokalemic solution (2.5 mM K+) in presence of drug. 30 animals were randomly assigned to 5 groups: ICA, AP14145, AP30663, dofetilide, or TMC. QT-interval, the interval from the peak to the end of the T wave (Tp-Te), ventricular effective refractory period (VERP), arrhythmia score, and ventricular fibrillation (VF) incidence were recorded. Results Hypokalemia slightly increased K(Ca)2.3 current compared to normokalemia. Application of K(Ca)2 channel inhibitors and dofetilide prolonged the QT interval corrected for heart rate. Dofetilide, but none of the K(Ca)2 channel inhibitors increased Tp-Te during hypokalemia. During hypokalemia 4/6 hearts in the TMC group developed VF (two spontaneously, two by S1S2 stimulation) whereas 5/6 hearts developed VF in the dofetilide group (two spontaneously, three by S1S2 stimulation). In comparison, 0/6, 1/6, and 1/6 hearts developed VF when treated with the K(Ca)2 channel inhibitors AP30663, ICA, or AP14145, respectively. Conclusion Hypokalemia was associated with an increased incidence of VF, an effect that also seen in the presence of dofetilide. In comparison, the structurally and functionally different K(Ca)2 channel inhibitors, ICA, AP14145, and AP30663 protected the heart from hypokalemia induced VF. These results support that K(Ca)2 inhibition may be associated with a better safety and tolerability profile than dofetilide.
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| 8. |
- Diness, J. G., et al.
(författare)
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The KCa2 Channel Inhibitor AP30663 Selectively Increases Atrial Refractoriness, Converts Vernakalant-Resistant Atrial Fibrillation and Prevents Its Reinduction in Conscious Pigs
- 2020
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To describe the effects of the KCa2 channel inhibitor AP30663 in pigs regarding tolerability, cardiac electrophysiology, pharmacokinetics, atrial functional selectivity, effectiveness in cardioversion of tachy-pacing induced vernakalant-resistant atrial fibrillation (AF), and prevention of reinduction of AF. Methods and Results: Six healthy pigs with implanted pacemakers and equipped with a Holter monitor were used to compare the effects of increasing doses (0, 5, 10, 15, 20, and 25 mg/kg) of AP30663 on the right atrial effective refractory period (AERP) and on various ECG parameters, including the QT interval. Ten pigs with implanted neurostimulators were long-term atrially tachypaced (A-TP) until sustained vernakalant-resistant AF was present. 20 mg/kg AP30663 was tested to discover if it could successfully convert vernakalant-resistant AF to sinus rhythm (SR) and protect against reinduction of AF. Seven anesthetized pigs were used for pharmacokinetic experiments. Two pigs received an infusion of 20 mg/kg AP30663 over 60 min while five pigs received 5 mg/kg AP30663 over 30 min. Blood samples were collected before, during, and after infusion on AP30663. AP30663 was well-tolerated and prominently increased the AERP in pigs with little effect on ventricular repolarization. Furthermore, it converted A-TP induced AF that had become unresponsive to vernakalant, and it prevented reinduction of AF in pigs. Both a >30 ms increase of the AERP and conversion of AF occurred in different pigs at a free plasma concentration level of around 1.0–1.4 µM of AP30663, which was achieved at a dose level of 5 mg/kg. Conclusion: AP30663 has shown properties in animals that would be of clinical interest in man. © Copyright © 2020 Diness, Kirchhoff, Speerschneider, Abildgaard, Edvardsson, Sørensen, Grunnet and Bentzen.
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| 9. |
- Dota, Corina-Dana, et al.
(författare)
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PC-Based ECG waveform recognition-validation of novel software against a reference ECG database
- 2009
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Ingår i: Ann Noninvasive Electrocardiol. - 1542-474X. ; 14 Suppl 1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: PC-based ECG measurements must cope with normal as well as pathological ECGs in a reliable manner. EClysis, a software for ECG measurements was tested against reference values from the Common Standards for Quantitative Electrocardiography (CSE) database. METHODS: Digital ECGs (12 leads, 500 Hz) were recorded by the CSE project. Data Set 3 contains reference values for 125 ECGs (33 normal and 92 pathological). Median values of measurements by 11 computer programs and by five cardiologists, respectively, refer to the earliest P and QRS onsets and to the latest P, QRS, and T offsets in any lead of a selected (index) beat. EClysis automatically measured all ECGs, without user interference. RESULTS: The PQRST points were correctly detected but in two ECGs with AV block II-III. The software was not designed to detect atrial activity in atrial fibrillation (n = 9) and flutter (n = 1). In one case of atrial fibrillation, atrial activity interfered with positioning of QRS and T offsets. Regression coefficients between EClysis and CSE (software-generated and human) were above 0.95 (P < 0.0001). The confidence intervals were 95% for the slope and the intercept of the regression lines. CONCLUSIONS: The PC-based detection and analysis of PQRST points showed a high level of agreement with the CSE database reference values.
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| 10. |
- Edvardsson, Berit, et al.
(författare)
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The medical and social prognosis of Sick Building Syndrome : a follow-up study focusing on female patients
- 2005
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Ingår i: Indoor air 2005. - Beijing : Tsinghua university press. ; , s. 3706-3710
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Konferensbidrag (refereegranskat)abstract
- A follow-up questionnaire focusing medical and social status, actions taken and personality traits was sent to 239 patients with Sick Building Syndrome (SBS) registered at the University Hospital in Umea, Sweden. The response rate was 79 percent. As females constituted 92 percent of the respondents all statistical analyses were restricted to women. Almost half of the respondents had been exposed to environments with visible water damages. Fatigue, irritated eyes and facial erythema were the most common symptoms. Nearly half of the patients claimed that the symptoms were more or less unchanged after 7 years or more. Twenty-five percent of the patients were on the sick-list and twenty percent drew disability pension due to SBS-symptoms at follow-up. Symptoms were often aggravated in different situations in everyday life. No important deviations concerning personality factors were found. The results support that early and comprehensive measures for rehabilitation are essential for these patients.
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| 11. |
- Gal, P., et al.
(författare)
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First Clinical Study with AP30663-a K(Ca)2 Channel Inhibitor in Development for Conversion of Atrial Fibrillation
- 2020
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Ingår i: Cts-Clinical and Translational Science. - : Wiley. - 1752-8054 .- 1752-8062. ; 13:6, s. 1336-1344
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Tidskriftsartikel (refereegranskat)abstract
- Pharmacological cardioversion of atrial fibrillation (AF) is frequently inefficacious. AP30663, a small conductance Ca(2+)activated K+(K(Ca)2) channel blocker, prolonged the atrial effective refractory period in preclinical studies and subsequently converted AF into normal sinus rhythm. This first-in-human study evaluated the safety and tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects were explored. Forty-seven healthy male volunteers (23.7 +/- 3.0 years) received AP30663 intravenously in ascending doses. Due to infusion site reactions, changes to the formulation and administration were implemented in the latter 24 volunteers. Extractions from a 24-hour continuous electrocardiogram were used to evaluate the PD effect of AP30663. Data were analyzed with a repeated measure analysis of covariance, noncompartmental analysis, and concentration-effect analysis. In total, 33 of 34 adverse events considered related to AP30663 exposure were related to the infusion site, mild in severity, and temporary in nature, although full recovery took up to 110 days. After formulation and administration changes, the local infusion site reaction remained, but the median duration was shorter despite higher dose levels. AP30663 displayed a less than dose proportional increase in peak plasma concentration (C-max) and a terminal half-life of around 5 hours. In healthy volunteers, no effect of AP30663 was observed on electrocardiographic parameters, other than a concentration-dependent effect on the corrected QT Fridericia's formula interval (+18.8 +/- 4.3 ms for the highest dose level compared with time matched placebo). In conclusion, administration of AP30663, a novel K(Ca)2 channel inhibitor, was safe and well-tolerated systemically in humans, supporting further development in patients with AF undergoing cardioversion.
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| 12. |
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| 13. |
- Kirchhof, Paulus, et al.
(författare)
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Comprehensive risk reduction in patients with atrial fibrillation : emerging diagnostic and therapeutic options - a report from the 3rd Atrial Fibrillation Competence NETwork/European Heart Rhythm Association consensus conference
- 2012
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Ingår i: Europace. - : Oxford University Press (OUP). - 1099-5129 .- 1532-2092. ; 14:1, s. 8-27
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Forskningsöversikt (refereegranskat)abstract
- While management of atrial fibrillation (AF) patients is improved by guideline-conform application of anticoagulant therapy, rate control, rhythm control, and therapy of accompanying heart disease, the morbidity and mortality associated with AF remain unacceptably high. This paper describes the proceedings of the 3rd Atrial Fibrillation NETwork (AFNET)/European Heart Rhythm Association (EHRA) consensus conference that convened over 60 scientists and representatives from industry to jointly discuss emerging therapeutic and diagnostic improvements to achieve better management of AF patients. The paper covers four chapters: (i) risk factors and risk markers for AF; (ii) pathophysiological classification of AF; (iii) relevance of monitored AF duration for AF-related outcomes; and (iv) perspectives and needs for implementing better antithrombotic therapy. Relevant published literature for each section is covered, and suggestions for the improvement of management in each area are put forward. Combined, the propositions formulate a perspective to implement comprehensive management in AF.
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| 14. |
- Lind, Karin, et al.
(författare)
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The Gaia-ESO Survey : A globular cluster escapee in the Galactic halo
- 2015
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 575
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Tidskriftsartikel (refereegranskat)abstract
- A small fraction of the halo field is made up of stars that share the light element (Z <= 13) anomalies characteristic of second generation globular cluster (GC) stars. The ejected stars shed light on the formation of the Galactic halo by tracing the dynamical history of the clusters, which are believed to have once been more massive. Some of these ejected stars are expected to show strong Al enhancement at the expense of shortage of Mg, but until now no such star has been found. We search for outliers in the Mg and Al abundances of the few hundreds of halo field stars observed in the first eighteen months of the Gaia-ESO public spectroscopic survey. One halo star at the base of the red giant branch, here referred to as 22593757-4648029 is found to have [Mg/Fe] = -0.36 +/- 0.04 and [Al/Fe] = 0.99 +/- 0.08, which is compatible with the most extreme ratios detected in GCs so far. We compare the orbit of 22593757-4648029 to GCs of similar metallicity and find it unlikely that this star has been tidally stripped with low ejection velocity from any of the clusters. However, both chemical and kinematic arguments render it plausible that the star has been ejected at high velocity from the anomalous GC omega Centauri within the last few billion years. We cannot rule out other progenitor GCs, because some may have disrupted fully, and the abundance and orbital data are inadequate for many of those that are still intact.
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| 15. |
- Linker, N. J., et al.
(författare)
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Early versus delayed implantation of a loop recorder in patients with unexplained syncope - Effects on care pathway and diagnostic yield
- 2013
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273. ; 170:2, s. 146-151
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Tidskriftsartikel (refereegranskat)abstract
- Background: This study looked to assess the care pathway and diagnostic yield in patients who received an implantable loop recorder (ILR) after an "initial phase of the diagnostic work-up" (initial work-up) or after a "full evaluation" of unexplained syncope. Methods and results: Physicians classified the timing of an ILR implant in 514 patients as either following an "initial work-up" (n = 128; 25%) or "full evaluation" (n = 386; 75%). Patients with an "initial work-up" underwent a median (IQ range) of 8 (6-14) tests prior to ILR implant compared to 14 (10-21) tests after "full evaluation" (p<0.0001). Hospitalization and injury before implant were less common in patients with an "initial work-up": 53 vs. 75%, p<0001, and 23% vs. 39%, p<0.001, as were visits to specialists, e. g. neurologist, 32% vs. 50%, p<0.001. At one year after implant, the syncope recurrence rate was 32% in the initial work-up group and 36% in the full evaluation group, and the incidence of recurrences with an ILR-guided diagnosis was 52% and 75% respectively. Diagnoses were cardiac in 90% after "initial work-up" vs. 79% after "full evaluation". Conclusions: Patients who only underwent an "initial work-up" had fewer investigations and a lower incidence of injury or hospitalization. The diagnostic yield from the ILR was high in both groups. Patients in both groups underwent more investigations than suggested in the ESC guidelines and could have benefitted from limiting the initial evaluation before an ILR is implanted. (c) 2013 Elsevier Ireland Ltd. All rights reserved.
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| 16. |
- Poci, Dritan, 1969-, et al.
(författare)
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Do Some Patients Younger Than 65 Years Old And With Incident Atrial Fibrillation Need Anticoagulation Treatment? : Conclusions From A Swedish Nationwide Registry Study
- 2018
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Konferensbidrag (refereegranskat)abstract
- Background: It is still under debate whether patients with atrial fibrillation (AF) and a low risk of cerebral infarction would benefit from anticoagulation.Objective: We aimed to assess whether younger patients with AF and lower CHA2DS2-VASc score would benefit from anticoagulation treatment.Methods: In a retrospective, nationwide cohort study, using the Swedish national registries, 59981 hospitalized patients were identified with incident AF. After exclusion of 11548 patients because of warfarin use before the AF diagnosis, or death, emigration or stroke within 30 days of AF diagnosis, the remaining 48 433 patients, among whom 27166 patients had no warfarin treatment, were, after adjustment for age, sex and year of AF diagnosis, divided according to age, sex and CHA2DS2-VASc score 0, 1, 2 and ≥3 and included in a time-varying analysis of warfarin treatment versus no treatment. Patients were followed up to 48 months after the inclusion.Results: In men <65 years and with a CHA2DS2-VASc score 2 or ≥3, the relative risk of having a stroke or cerebral infarction was lower when they received warfarin treatment, HR 0.35 (95% CI 0.18-0.69) and HR 0.37 (95% CI 0.23-0.59) respectively, as compared to HR 1.11 (95% CI 0.56-2.23) when the score was 1. Women younger than 65 years had a low relative risk when CHA2DS2-VASc score was ≥3 points, HR 0.31 (95% CI 0.16-0.59), as compared to HR 1.84 (95% CI 0.86-3.94) and HR 2.13 (95% CI 0.94-4.84) when the score was 2 and 1 respectively. The risk of intracranial bleeding was low and similar in all subgroups on anticoagulation except in the youngest men without risk factors.Conclusion: Women and men <65 years had a beneficial effect of warfarin if they had two risk factors other than age and sex, without an increased risk of bleeding. Our results support prophylactic anticoagulation treatment in patients under 65 years and a CHA2DS2-VASc score ≥2, other than age and sex.
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| 17. |
- Yfanti, Christina, et al.
(författare)
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A phase 1 trial of AP30663, a KCa2 channel inhibitor in development for conversion of atrial fibrillation
- 2024
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Ingår i: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY. - 0306-5251 .- 1365-2125.
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Tidskriftsartikel (refereegranskat)abstract
- Aims: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca2+ activated K+ (K(Ca)2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first-in-human trial.Methods: Sixteen healthy male volunteers were randomized into 2 cohorts: 6- and 8-mg/kg intravenous single-dose administration of AP30663 vs. placebo. Safety, pharmacokinetic and pharmacodynamic data were collected.Results: AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5-58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7-64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half-life of around 3 h.Conclusion: AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off-target inhibition of the I-Kr channel.
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