The effects of the levosimendan metabolites OR-1855 and OR-1896 on endothelial pro-inflammatory responses

The calcium sensitizer levosimendan is used for the treatment of acute decompensated heart failure. A small portion (4–7%) of levosimendan is metabolized to the pharmacologically active metabolite OR-1896 via the inactive intermediate OR-1855. In addition, levosimendan has been shown to exert positive effects on the endothelium in vitro antagonizing vascular dysfunction and inflammation. However, the function of the levosimendan metabolites within this context is still unknown. In this study, we thus investigated the impact of the metabolites OR-1896 and OR-1855 on endothelial inflammatory processes in vitro. We observed a reduction of IL-1β-dependent endothelial adhesion molecule ICAM-1 and VCAM-1 as well as interleukin (IL) -6 expression upon levosimendan treatment but not after treatment with OR-1855 or OR-1896, as assessed by western blotting, flow cytometry, and qRT-PCR. Instead, the metabolites impaired IL-1β-induced ROS formation via inactivation of the MAPK p38, ERK1/2, and JNK. Our results suggest that the levosimendan metabolites OR-1896 and OR-1855 have certain anti-inflammatory properties, partly other than levosimendan. Importantly, they additionally show that the intermediate metabolite OR-1855 does, in fact, have pharmacological effects in the endothelium. This is interesting, as the metabolites are responsible for the long-term therapeutic effects of levosimendan, and heart failure is associated with vascular dysfunction and inflammation

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Viscous Resuspension of a sediment caused by oscillating stratified flows

It is known that a sediment of settled particles can resuspend under the action of shear. In this paper, based on a mathematical model given by Leighton &amp; Acrivos [6], we study theoretically the viscous resuspension of a sediment in a Couette channel with harmonically oscillating walls. Numerical experiments reveal that the resuspension height and the particle volume concentration at the bottom of the channel depend on the frequency of the oscillation. While oscillation of the top wall has nearly no influence on the sediment, a moving bottom wall causes the settled particles to completely resuspend if the frequency is large enough. 1 Introduction A settled bed of negatively buoyant particles can resuspend when in comes in contact with a clear fluid, even if Brownian motion or turbulence at very small Reynolds numbers are absent. This phenomenon, called viscous resuspension, was first observed by Gadala -Maria [3] and Gadala-Maria &amp; Acrivos [4], and has been the subject of several exp..

CISM 1995 Course on the Flow of Particles in Suspensions

This book presents a broad overview of the issues related to the flow of particles in suspensions. Chapters cover the newest research in advanced theoretical approaches and recent experimental techniques. Topics include macroscopic transport properties, the mechanics of capsules and cells, hydrodynamic diffusion and phase separation

Das versteht man(n) nicht : der Einfluss von Genderaspekten beim Dolmetschen für Personen aus dem arabisch-islamischen Raum

Gegenstand dieser Diplomarbeit sind die Genderaspekte beim Dolmetschen im Kommunalbereich für Personen aus dem arabisch-islamischen Raum. Welche Rolle das Geschlecht der DolmetscherInnen in gedolmetschten Gesprächssituationen spielt, welche Chancen und Schwierigkeiten die unterschiedlichen Geschlechterkonstellationen beim Dolmetschen bergen und zu welchen Problemen es aufgrund von kulturellen Unterschieden und Tabus kommen kann, stellen die zentralen Fragestellungen dieser Arbeit dar. Dabei wurde von der Hypothese ausgegangen, dass das Geschlecht der AkteurInnen immer Einfluss auf die Dolmetschung ausübt. Ebenso wurde angenommen, dass das Geschlecht beim Kommunaldolmetschen einen anderen Stellenwert einnimmt als beim Konferenzdolmetschen sowie dass sich dessen Bedeutung auch von Setting zu Setting unterscheidet. Um die Auswirkungen von Gender in der Praxis zu untersuchen, wurden Leitfadeninterviews mit fünf weiblichen und zwei männlichen Arabisch-DolmetscherInnen durchgeführt. Diese Interviews wurden transkribiert, deren Transkripte in einzelne Kategorien unterteilt und qualitativ ausgewertet, wobei die aufgestellten Hypothesen weitgehend verifiziert werden konnten. Die Geschlechterrollen wirken sich laut den InterviewpartnerInnen immer auf die Dolmetschung aus, wobei der Einfluss von Gender beim Kommunaldolmetschen größer ist. Obwohl bis auf die Hypothese, dass der Großteil an Arabisch-DolmetscherInnen männlichen Geschlechts ist, alle Hypothesen durch die durchgeführten Interviews bestätigt werden konnten, gilt einschränkend zu beachten, dass beim Dolmetschen stets viele verschiedene Einflussfaktoren zusammenspielen. Diese Diplomarbeit konzentrierte sich im Besonderen auf den Stellenwert der Genderfragen beim Dolmetschen. Weitere Studien, die vor allem Faktoren wie Herkunft, Sozialisation und Ausbildung der DolmetscherInnen miteinbeziehen, wären eine sinnvolle und wünschenswerte Ergänzung der vorliegenden Arbeit.The subject of this thesis are the gender aspects in Community Interpreting for people from Arabic-Islamic countries. How significant the interpreter?s sex in interpreted communication is, which opportunities and difficulties lie in the different gender constellations during the interpretation process and which problems could arise because of cultural differences and taboos, are the key questions of this paper. The hypothesis is that the participants? sex always has an influence on the interpretation process. It can be furthermore assumed that in Community Interpreting the significance of the gender will be different from Conference Interpreting. Additionally, how important the gender aspect is, will also depend on the different settings. To find out more about the impacts of gender in practice, semi-structured interviews with five female and two male interpreters for Arabic have been undertaken. The interviews have been transcribed, divided in different categories and interpreted on the basis of a qualitative analysis. In doing so, it has been possible to verify nearly all the above hypotheses. According to the interview partners, the gender roles always have an influence on the interpretation process. However, the impact of gender is bigger in Community Interpreting. Although all hypotheses ? apart from the one expecting a majority of male interpreters for Arabic ? could be confirmed by the interviews, it is important to consider the fact that in an interpretation process there are always several influencing factors interacting at the same time. This thesis concentrates especially on the importance of gender aspects during the interpretation process. More studies, which take particularly factors like the origin, socialization and education of the interpreters into consideration, would be a considerably useful supplement to the present paper.vorgelegt von Eva SchaflingerAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersZsfassung in dt. und engl. SpracheGraz, Univ., Dipl.-Arb., 2013(VLID)23356