| 1. |
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| 2. |
- Eriksson, Bengt I., 1946, et al.
(författare)
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Efficacy of delayed thromboprophylaxis with dabigatran: Pooled analysis.
- 2012
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Ingår i: Thrombosis research. - : Elsevier BV. - 1879-2472 .- 0049-3848. ; 130:6, s. 871-876
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Oral thromboprophylaxis with dabigatran etexilate should be initiated as a half dose 1 to 4h after major orthopaedic surgery. However, a delay in dosing could occur for clinical or logistical reasons. A post hoc analysis was carried out to determine if patients with delayed dosing received adequate anticoagulation. PATIENTS AND METHODS: The RE-MODEL™ and RE-NOVATE® trials compared 220mg and 150mg dabigatran etexilate with 40mg enoxaparin. Pooled data for major venous thromboembolism (VTE) and VTE-related mortality (efficacy outcome) and major bleeding events (MBE), MBE/clinically relevant bleeding events, and all bleeding events (safety outcomes) were analysed. Results in patients with dosing delayed more than 4h postsurgery were compared with those of patients without a delay. RESULTS: Onset of treatment was delayed in 724 (13.3%) of 5425 patients. Efficacy of 220mg dabigatran etexilate was similar in patients without delayed dosing, patients with a delay and patients with a delay until the day after surgery. Rates of efficacy outcome were higher in patients on 150mg dabigatran etexilate, but more than 80% of these patients were undertreated based on age or renal clearance status. Some differences in bleeding events were seen among patient groups by treatment arm. CONCLUSION: Dabigatran etexilate thromboprophylaxis should be initiated 1 to 4h postsurgery. Results from our post-hoc analysis indicate that no loss of efficacy appears to occur if initiation of dabigatran etexilate 220mg needs to be delayed.
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| 3. |
- 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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| 4. |
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| 5. |
- Schafmayer, Clemens, et al.
(författare)
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Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms
- 2019
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 68:5, s. 854-865
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Tidskriftsartikel (refereegranskat)abstract
- Objective Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. Design Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. Results We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p< 0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3x10-10 and 0.002 (OR allelic = 1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). Conclusion I n silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
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| 6. |
- Schosserer, Markus, et al.
(författare)
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Methylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Several pathways modulating longevity and stress resistance converge on translation by targeting ribosomal proteins or initiation factors, but whether this involves modifications of ribosomal RNA is unclear. Here, we show that reduced levels of the conserved RNA methyltransferase NSUN5 increase the lifespan and stress resistance in yeast, worms and flies. Rcm1, the yeast homologue of NSUN5, methylates C2278 within a conserved region of 25S rRNA. Loss of Rcm1 alters the structural conformation of the ribosome in close proximity to C2278, as well as translational fidelity, and favours recruitment of a distinct subset of oxidative stress-responsive mRNAs into polysomes. Thus, rather than merely being a static molecular machine executing translation, the ribosome exhibits functional diversity by modification of just a single rRNA nucleotide, resulting in an alteration of organismal physiological behaviour, and linking rRNA-mediated translational regulation to modulation of lifespan, and differential stress response.
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| 7. |
- Stief, Peter, et al.
(författare)
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Intracellular nitrate storage by diatoms can be an important nitrogen pool in freshwater and marine ecosystems
- 2022
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Ingår i: Communications Earth and Environment. - : Springer Science and Business Media LLC. - 2662-4435. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Identifying and quantifying nitrogen pools is essential for understanding the nitrogen cycle in aquatic ecosystems. The ubiquitous diatoms represent an overlooked nitrate pool as they can accumulate nitrate intracellularly and utilize it for nitrogen assimilation, dissipation of excess photosynthetic energy, and Dissimilatory Nitrate Reduction to Ammonium (DNRA). Here, we document the global co-occurrence of diatoms and intracellular nitrate in phototrophic microbial communities in freshwater (n = 69), coastal (n = 44), and open marine (n = 4) habitats. Diatom abundance and total intracellular nitrate contents in water columns, sediments, microbial mats, and epilithic biofilms were highly significantly correlated. In contrast, diatom community composition had only a marginal influence on total intracellular nitrate contents. Nitrate concentrations inside diatom cells exceeded ambient nitrate concentrations ∼100–4000-fold. The collective intracellular nitrate pool of the diatom community accounted for <1% of total nitrate in pelagic habitats and 65–95% in benthic habitats. Accordingly, nitrate-storing diatoms are emerging as significant contributors to benthic nitrogen cycling, in particular through Dissimilatory Nitrate Reduction to Ammonium activity under anoxic conditions.
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| 8. |
- Yin, Wenguang, et al.
(författare)
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An essential function for autocrine hedgehog signaling in epithelial proliferation and differentiation in the trachea
- 2022
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Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 149:3
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Tidskriftsartikel (refereegranskat)abstract
- The tracheal epithelium is a primary target for pulmonary diseases as it provides a conduit for air flow between the environment and the lung lobes. The cellular and molecular mechanisms underlying airway epithelial cell proliferation and differentiation remain poorly understood. Hedgehog (HH) signaling orchestrates communication between epithelial and mesenchymal cells in the lung, where it modulates stromal cell proliferation, differentiation and signaling back to the epithelium. Here, we reveal a previously unreported autocrine function of HH signaling in airway epithelial cells. Epithelial cell depletion of the ligand sonic hedgehog (SHH) or its effector smoothened (SMO) causes defects in both epithelial cell proliferation and differentiation. In cultured primary human airway epithelial cells, HH signaling inhibition also hampers cell proliferation and differentiation. Epithelial HH function is mediated, at least in part, through transcriptional activation, as HH signaling inhibition leads to downregulation of cell type-specific transcription factor genes in both the mouse trachea and human airway epithelial cells. These results provide new insights into the role of HH signaling in epithelial cell proliferation and differentiation during airway development.
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| 17. |
- Becher, Christoph, et al.
(författare)
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High degree of consensus amongst an expert panel regarding focal resurfacing of chondral and osteochondral lesions of the femur with mini-implants
- 2023
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Ingår i: Knee Surgery, Sports Traumatology, Arthroscopy. - : Springer Nature. - 0942-2056 .- 1433-7347. ; 31:9, s. 4027-4034
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The rationale for the use of mini-implants for partial resurfacing in the treatment of femoral chondral and osteochondral lesions is still under debate. The evidence supporting best practise guidelines is based on studies with low-level evidence. A consensus group of experts was convened to collaboratively advance towards consensus opinions regarding the best available evidence. The purpose of this article is to report the resulting consensus statements.Methods: Twenty-five experts participated in a process based on the Delphi method of achieving consensus. Questions and statements were drafted via an online survey of two rounds, for initial agreement and comments on the proposed statements. An in-person meeting between the panellists was organised during the 2022 ESSKA congress to further discuss and debate each of the statements. A final agreement was made via a final online survey a few days later. The strength of consensus was characterised as: consensus, 51–74% agreement; strong consensus, 75–99% agreement; unanimous, 100% agreement.Results: Statements were developed in the fields of patient assessment and indications, surgical considerations and postoperative care. Between the 25 statements that were discussed by this working group, 18 achieved unanimous, whilst 7 strong consensus.Conclusion: The consensus statements, derived from experts in the field, represent guidelines to assist clinicians in decision-making for the appropriate use of mini-implants for partial resurfacing in the treatment of femoral chondral and osteochondral lesions. Level of evidence: Level V.
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| 18. |
- Becher, Christoph, et al.
(författare)
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High degree of consensus amongst an expert panel regarding focal resurfacing of chondral and osteochondral lesions of the femur with mini-implants
- 2023
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Ingår i: Knee Surgery, Sports Traumatology, Arthroscopy. - : Springer Nature. - 0942-2056 .- 1433-7347. ; 31:9, s. 4027-4034
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: The rationale for the use of mini-implants for partial resurfacing in the treatment of femoral chondral and osteochondral lesions is still under debate. The evidence supporting best practise guidelines is based on studies with low-level evidence. A consensus group of experts was convened to collaboratively advance towards consensus opinions regarding the best available evidence. The purpose of this article is to report the resulting consensus statements. Methods: Twenty-five experts participated in a process based on the Delphi method of achieving consensus. Questions and statements were drafted via an online survey of two rounds, for initial agreement and comments on the proposed statements. An in-person meeting between the panellists was organised during the 2022 ESSKA congress to further discuss and debate each of the statements. A final agreement was made via a final online survey a few days later. The strength of consensus was characterised as: consensus, 51–74% agreement; strong consensus, 75–99% agreement; unanimous, 100% agreement. Results: Statements were developed in the fields of patient assessment and indications, surgical considerations and postoperative care. Between the 25 statements that were discussed by this working group, 18 achieved unanimous, whilst 7 strong consensus. Conclusion: The consensus statements, derived from experts in the field, represent guidelines to assist clinicians in decision-making for the appropriate use of mini-implants for partial resurfacing in the treatment of femoral chondral and osteochondral lesions. Level of evidence: Level V.
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| 19. |
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| 20. |
- Bozkurt, Murat Fani, et al.
(författare)
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Guideline for PET/CT imaging of neuroendocrine neoplasms with Ga-68-DOTA-conjugated somatostatin receptor targeting peptides and F-18-DOPA
- 2017
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : SPRINGER. - 1619-7070 .- 1619-7089. ; 44:9, s. 1588-1601
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Tidskriftsartikel (refereegranskat)abstract
- Purpose & Methods Neuroendocrine neoplasms are a heterogenous group of tumours, for which nuclear medicine plays an important role in the diagnostic work-up as well as in the targeted therapeutic options. This guideline is aimed to assist nuclear medicine physicians in recommending, performing, reporting and interpreting the results of somatostatin receptor (SSTR) PET/CT imaging using Ga-68-DOTA-conjugated peptides, as well as F-18-DOPA imaging for various neuroendocrine neoplasms. Results & Conclusion The previous procedural guideline by EANM regarding the use PET/CT tumour imaging with Ga-68-conjugated peptides has been revised and updated with the relevant and recent literature in the field with contribution of distinguished experts.
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| 21. |
- Brambatti, Michela, et al.
(författare)
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Comparison of dabigatran versus warfarin in diabetic patients with atrial fibrillation : Results from the RE-LY trial
- 2015
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 196, s. 127-131
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Diabetes mellitus (DM) is frequent among patients with atrial fibrillation (AF). The RE-LY trial permits evaluation of patient characteristics, outcomes and the effectiveness of dabigatran etexilate among diabetic individuals. Methods: Patient characteristics and outcomes were compared between diabetic and non-diabetic patients and the relative efficacy of each dose of dabigatran (150 mg bid and 110 mg bid) versus warfarin was evaluated. Results: Of 18,113 patients in RE-LY, 4221 patients (23.3%) had DM. Patients with DM were younger (70.9 vs. 71.7 years), more likely to have hypertension (86.6% vs. 76.5%), coronary artery disease (37.4% vs. 24.9%) and peripheral vascular disease (5.6% vs. 3.2%); (all p < 0.01). Time in therapeutic range for warfarin-treated patients was 65% for diabetic versus 68% for non-diabetic patients (p < 0.001). Regardless of assigned treatment, stroke or systemic embolism was more common among patients with DM (1.9% per year vs. 1.3% per year, p < 0.001). DM was also associated with an increased risk of death (5.1% per year vs. 3.5% per year, p < 0.001) and major bleeding (4.2% per year vs. 3.0% per year, p < 0.001). The absolute reduction in stroke or systemic embolism with dabigatran compared to warfarin was greater among patients with DM than those without DM (dabigatran 110 mg: 0.59% per year vs. 0.05% per year; dabigatran 150 mg: 0.89% per year vs. 0.51% per year). Conclusions: Compared to non-DM patients, AF patients with DM derive a greater absolute risk reduction in embolic events when treated with dabigatran. ClinicalTrials.gov Identifier: NCT00262600.
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| 22. |
- Carl, Johannes, et al.
(författare)
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Physical Literacy in Europe: The Current State of Implementation in Research, Practice, and Policy
- 2023
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Ingår i: Journal of Exercise Science and Fitness. - : Elsevier BV. - 1728-869X .- 2226-5104. ; 21:1, s. 165-176
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Tidskriftsartikel (refereegranskat)abstract
- The holistic concept of physical literacy (PL) embraces different person-centered qualities (physical, cognitive, affective/psychological) necessary to lead physically active lifestyles. PL has recently gained increasing attention globally and Europe is no exception. However, scientific endeavors summarizing the current state of PL in Europe are lacking. Therefore, the goal of this study was to comprehensively assess and compare the implementation of PL in research, policy, and practice across the continent. We assembled a panel of experts representing 25 European countries. Employing a complementary mixed-methods design, the experts first prepared reviews about the current state of PL in their countries (categories: research, practice/policy). The reviews underwent comparative document analysis ensuring a transnational foureyes principle. For re-validation purposes, the representatives completed a quantitative survey with questions reflecting the inductive themes from the document analysis. The document analysis resulted in ten disjunct themes (related to “concept”, “research”, “practice/policy”, “future/prospect”) and yielded a heterogenous PL situation in Europe. The implementation state was strongly linked to conceptual discussions (e.g., existence of competing approaches), linguistic issues (e.g., translations), and country-specific traditions. Despite growing scholarly attention, PL hesitantly permeates practice and policy in most countries. Nevertheless, the experts largely anticipate increasing popularity of PL for the future. Despite the heterogeneous situation across Europe, the analysis has uncovered similarities among the countries, such as the presence of established yet not identical concept. Research should intensify academic activities (conceptuallinguistic elaborations, empirical work) before PL may gain further access into practical and political spheres in the long term.
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| 23. |
- Clayton, Aled, et al.
(författare)
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Summary of the ISEV workshop on extracellular vesicles as disease biomarkers, held in Birmingham, UK, during December 2017
- 2018
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Ingår i: Journal of Extracellular Vesicles. - : Wiley. - 2001-3078. ; 7
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of The International Society for Extracellular Vesicles. This report summarises the presentations and activities of the ISEV Workshop on extracellular vesicle biomarkers held in Birmingham, UK during December 2017. Among the key messages was broad agreement about the importance of biospecimen science. Much greater attention needs to be paid towards the provenance of collected samples. The workshop also highlighted clear gaps in our knowledge about pre-analytical factors that alter extracellular vesicles (EVs). The future utility of certified standards for credentialing of instruments and software, to analyse EV and for tracking the influence of isolation steps on the structure and content of EVs were also discussed. Several example studies were presented, demonstrating the potential utility for EVs in disease diagnosis, prognosis, longitudinal serial testing and stratification of patients. The conclusion of the workshop was that more effort focused on pre-analytical issues and benchmarking of isolation methods is needed to strengthen collaborations and advance more effective biomarkers.
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| 24. |
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| 25. |
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| 26. |
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| 27. |
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| 28. |
- Ezekowitz, Michael D., et al.
(författare)
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Comparison of Dabigatran and Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulant Therapy)
- 2016
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 134:8, s. 589-598
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included. METHODS: This is a post hoc analysis of the RE-LY trial. RESULTS: There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16-1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88-1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56-0.95 with VHD; HR, 0.84; 95% CI, 0.71-0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64-1.06) or without VHD (HR, 0.98; 95% CI, 0.83-1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37-0.93) and those without VHD (HR, 0.67; 95% CI, 0.52-0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65-1.45; and HR, 0.88; 95% CI, 0.70-1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD. CONCLUSIONS: The presence of any VHD did not influence the comparison of dabigatran with warfarin.
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| 29. |
- Ezekowitz, Michael D., et al.
(författare)
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Long-term evaluation of dabigatran 150 vs. 110 mg twice a day in patients with non-valvular atrial fibrillation
- 2016
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Ingår i: Europace. - : Oxford University Press (OUP). - 1099-5129 .- 1532-2092. ; 18:7, s. 973-978
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Tidskriftsartikel (refereegranskat)abstract
- Aims The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial allowed patients who completed the trial receiving their assigned dabigatran 150 mg (D150) or 110 mg (D110) twice a day to continue into the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial. This permitted assessment of outcomes over a median of 4.6 and a maximum of 6.7 years, respectively. Methods and results The analysed population included only those patients who completed RE-LY on dabigatran and continued into RELYABLE without interruption of assigned dabigatran. Cumulative risk was expressed as Kaplan-Meier plots. Outcomes were compared using Cox proportional hazard modelling. Stroke or systemic embolization rates were 1.25 and 1.54% per year (D150 and D110, respectively); hazard ratio (HR) 0.81 [95% confidence interval (CI): 0.68-0.96] (P = 0.02). Ischaemic stroke was 1.03 (D150) and 1.29%/year (D110); HR 0.79 (95% CI: 0.66-0.95) (P = 0.01). Haemorrhagic stroke rates were 0.11 (D150) and 0.13%/year (D110); HR 0.91 (95% CI: 0.51-1.62) (P = 0.75). Rates of major haemorrhage were 3.34 (D150) and 2.76%/year (D110); HR 1.22 (95% CI: 1.08-1.37) (P = 0.0008). Intracranial haemorrhage rates were 0.32 (D150) and 0.23%/year (D110); HR 1.37 (95% CI: 0.93-2.01) (P = 0.11). Mortality was 3.43 (D150) and 3.55%/year (D110); HR 0.97 (95% CI: 0.87-1.08) (P = 0.54). Conclusion Annualized rates of all outcomes were constant with better efficacy of D150, less major bleeding with D110, and low intracerebral haemorrhage rates for both doses. There were no additional safety concerns. This is the longest continuous randomized experience of a novel anticoagulant.
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| 30. |
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| 31. |
- Grüning, Björn, et al.
(författare)
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Bioconda: A sustainable and comprehensive software distribution for the life sciences
- 2017
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We present Bioconda (https://bioconda.github.io), a distribution of bioinformatics software for the lightweight, multi-platform and language-agnostic package manager Conda. Currently, Bioconda offers a collection of over 3000 software packages, which is continuously maintained, updated, and extended by a growing global community of more than 200 contributors. Bioconda improves analysis reproducibility by allowing users to define isolated environments with defined software versions, all of which are easily installed and managed without administrative privileges.
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| 32. |
- Kagho, Mervic D., et al.
(författare)
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Total Synthesis via Biomimetic Late-Stage Heterocyclization: Assignment of the Relative Configuration and Biological Evaluation of the Nitraria Alkaloid (±)-Nitrabirine
- 2021
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 86, s. 14903-14914
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Tidskriftsartikel (refereegranskat)abstract
- The racemic total synthesis of nitrabirine (5) together with its previously undescribed epimer 2-epi nitrabirine (5′) is accomplished via a six-step route based on a biomimetic late-stage heterocyclization. This allowed the assignment of the relative configuration of nitrabirine by the lanthanide-induced shifts (LIS) experiment, which was later on confirmed by X-ray diffraction of obtained single crystals. Furthermore, oxidation studies demonstrated that the direct N-oxidation of nitrabirine does not yield nitrabirine N-oxide as reported earlier. In contrast, the reaction of hydrogen peroxide with nitrabirine (5) yields the salt 24′, whereas 2-epi nitrabirine (5′) surprisingly leads to a previously uncharacterized product 22 under the same conditions. Finally, a Fischer indole reaction gave access to novel tetracyclic nitrabirine derivatives 26a-d. A comprehensive biological evaluation of nitrabirine (5), 2-epi nitrabirine (5′), and all derivatives synthesized in this study revealed general biofilm dispersal effects against Candida albicans. Moreover, specific compounds showed moderate antibacterial activities as well as potent cytotoxic activities.
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| 33. |
- Kaminski, Clemens, et al.
(författare)
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Development of high speed spectroscopic imaging techniques for the time resolved study of spark ignition phenomena
- 2000
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Ingår i: SAE Technical Papers. - 400 Commonwealth Drive, Warrendale, PA, United States : SAE International. - 0148-7191.
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Tidskriftsartikel (refereegranskat)abstract
- This paper reports on the development of novel time resolved spectroscopic imaging techniques for the study of spark ignition phenomena in combustion cells and an SI-engine. The techniques are based on planar laser induced fluorescence imaging (PLIF) of OH radicals, on fuel tracer PLIF, and on chemiluminescence. The techniques could be achieved at repetition rates reaching several hundreds of kilo-Hz and were cycle resolved. These techniques offer a new path along which engine related diagnostics can be undertaken, providing a wealth of information on turbulent spark ignition.
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| 34. |
- Kim, Min Seo, et al.
(författare)
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Comparative safety of mRNA COVID-19 vaccines to influenza vaccines: A pharmacovigilance analysis using WHO international database
- 2022
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Ingår i: Journal of Medical Virology. - : WILEY. - 0146-6615 .- 1096-9071. ; 94:3, s. 1085-1095
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Tidskriftsartikel (refereegranskat)abstract
- Two messenger RNA (mRNA) vaccines developed by Pfizer-BioNTech and Moderna are being rolled out. Despite the high volume of emerging evidence regarding adverse events (AEs) associated with the COVID-19 mRNA vaccines, previous studies have thus far been largely based on the comparison between vaccinated and unvaccinated control, possibly highlighting the AE risks with COVID-19 mRNA vaccination. Comparing the safety profile of mRNA vaccinated individuals with otherwise vaccinated individuals would enable a more relevant assessment for the safety of mRNA vaccination. We designed a comparative safety study between 18 755 and 27 895 individuals who reported to VigiBase for adverse events following immunization (AEFI) with mRNA COVID-19 and influenza vaccines, respectively, from January 1, 2020, to January 17, 2021. We employed disproportionality analysis to rapidly detect relevant safety signals and compared comparative risks of a diverse span of AEFIs for the vaccines. The safety profile of novel mRNA vaccines was divergent from that of influenza vaccines. The overall pattern suggested that systematic reactions like chill, myalgia, fatigue were more noticeable with the mRNA COVID-19 vaccine, while injection site reactogenicity events were more prevalent with the influenza vaccine. Compared to the influenza vaccine, mRNA COVID-19 vaccines demonstrated a significantly higher risk for a few manageable cardiovascular complications, such as hypertensive crisis (adjusted reporting odds ratio [ROR], 12.72; 95% confidence interval [CI], 2.47-65.54), and supraventricular tachycardia (adjusted ROR, 7.94; 95% CI, 2.62-24.00), but lower risk of neurological complications such as syncope, neuralgia, loss of consciousness, Guillain-Barre syndrome, gait disturbance, visual impairment, and dyskinesia. This study has not identified significant safety concerns regarding mRNA vaccination in real-world settings. The overall safety profile patterned a lower risk of serious AEFI following mRNA vaccines compared to influenza vaccines.
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| 35. |
- Kirchhof, Paulus, et al.
(författare)
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Personalized management of atrial fibrillation : Proceedings from the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association consensus conference
- 2013
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Ingår i: Europace. - : Oxford University Press (OUP). - 1099-5129 .- 1532-2092. ; 15:11, s. 1540-1556
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Tidskriftsartikel (refereegranskat)abstract
- The management of atrial fibrillation (AF) has seen marked changes in past years, with the introduction of new oral anticoagulants, new antiarrhythmic drugs, and the emergence of catheter ablation as a common intervention for rhythm control. Furthermore, new technologies enhance our ability to detect AF. Most clinical management decisions in AF patients can be based on validated parameters that encompass type of presentation, clinical factors, electrocardiogram analysis, and cardiac imaging. Despite these advances, patients with AF are still at increased risk for death, stroke, heart failure, and hospitalizations. During the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association (AFNET/EHRA) consensus conference, we identified the following opportunities to personalize management of AF in a better manner with a view to improve outcomes by integrating atrial morphology and damage, brain imaging, information on genetic predisposition, systemic or local inflammation, and markers for cardiac strain. Each of these promising avenues requires validation in the context of existing risk factors in patients. More importantly, a new taxonomy of AF may be needed based on the pathophysiological type of AF to allow personalized management of AF to come to full fruition. Continued translational research efforts are needed to personalize management of this prevalent disease in a better manner. All the efforts are expected to improve the management of patients with AF based on personalized therapy.
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| 36. |
- Klein, Andreas, et al.
(författare)
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The Fermi energy as common parameter to describe charge compensation mechanisms: A path to Fermi level engineering of oxide electroceramics
- 2023
-
Ingår i: Journal of Electroceramics. - 1573-8663 .- 1385-3449. ; 51
-
Tidskriftsartikel (refereegranskat)abstract
- Chemical substitution, which can be iso- or heterovalent, is the primary strategy to tailor material properties. There are various ways how a material can react to substitution. Isovalent substitution changes the density of states while heterovalent substitution, i.e. doping, can induce electronic compensation, ionic compensation, valence changes of cations or anions, or result in the segregation or neutralization of the dopant. While all these can, in principle, occur simultaneously, it is often desirable to select a certain mechanism in order to determine material properties. Being able to predict and control the individual compensation mechanism should therefore be a key target of materials science. This contribution outlines the perspective that this could be achieved by taking the Fermi energy as a common descriptor for the different compensation mechanisms. This generalization becomes possible since the formation enthalpies of the defects involved in the various compensation mechanisms do all depend on the Fermi energy. In order to control material properties, it is then necessary to adjust the formation enthalpies and charge transition levels of the involved defects. Understanding how these depend on material composition will open up a new path for the design of materials by Fermi level engineering.
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| 37. |
- Klymenko, Oleksiy, et al.
(författare)
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Regulation and role of the ER stress transcription factor CHOP in alveolar epithelial type-II cells
- 2019
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Ingår i: Journal of Molecular Medicine. - : Springer Science and Business Media LLC. - 0946-2716 .- 1432-1440. ; 97:7, s. 973-990
-
Tidskriftsartikel (refereegranskat)abstract
- Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by type-II alveolar epithelial cell (AECII) injury and fibroblast hyperproliferation. Severe AECII endoplasmic reticulum (ER) stress is thought to underlie IPF, but is yet incompletely understood. We studied the regulation of C/EBP homologous protein (CHOP), a proapoptotic ER-stress-related transcription factor (TF) in AECII-like cells. Interestingly, single or combined overexpression of the active ER stress transducers activating transcription factor-4 (Atf4) and activating transcription factor-6 (p50Atf6) or spliced x-box-binding protein-1 (sXbp1) in MLE12 cells did not result in a substantial Chop induction, as compared to the ER stress inducer thapsigargin. Employing reporter gene assays of distinct CHOP promoter fragments, we could identify that, next to the conventional amino acid (AARE) and ER stress response elements (ERSE) within the CHOP promoter, activator protein-1 (AP-1) and c-Ets-1 TF binding sites are necessary for CHOP induction. Serial deletion and mutation analyses revealed that both AP-1 and c-Ets-1 motifs act in concert to induce CHOP expression. In agreement, CHOP promoter activity was greatly enhanced upon combined versus single overexpression of AP-1 and c-Ets-1. Moreover, combined overexpression of AP-1 and c-Ets-1 in MLE12 cells alone in the absence of any other ER stress inducer was sufficient to induce Chop protein expression. Further, AP-1 and c-Ets-1 were upregulated in AECII under ER stress conditions and in human IPF. Finally, Chop overexpression in vitro resulted in AECII apoptosis, lung fibroblast proliferation, and collagen-I production. We propose that CHOP activation by AP-1 and c-Ets-1 plays a key role in AECII maladaptive ER stress responses and consecutive fibrosis, offering new therapeutic prospects in IPF.Key messagesOverexpression of active ER stress sensors Atf4, Atf6, and Xbp1 does not induce Chop.AP-1 and c-Ets-1 TFs are necessary for induction of the ER stress factor Chop.AP-1 and c-Ets-1 alone induce Chop expression in the absence of any ER stress inducers.AP-1 and c-Ets-1 are induced in AECII under ER stress conditions and in human IPF.Chop expression alone triggers AECII apoptosis and consecutive profibrotic responses.
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| 38. |
- Kreutz, Clemens, et al.
(författare)
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Likelihood based observability analysis and confidence intervals for predictions of dynamic models
- 2012
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Ingår i: BMC Systems Biology. - : BioMed Central. - 1752-0509. ; 6:120
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Tidskriftsartikel (refereegranskat)abstract
- Background: Predicting a systems behavior based on a mathematical model is a primary task in Systems Biology. If the model parameters are estimated from experimental data, the parameter uncertainty has to be translated into confidence intervals for model predictions. For dynamic models of biochemical networks, the nonlinearity in combination with the large number of parameters hampers the calculation of prediction confidence intervals and renders classical approaches as hardly feasible. less thanbrgreater than less thanbrgreater thanResults: In this article reliable confidence intervals are calculated based on the prediction profile likelihood. Such prediction confidence intervals of the dynamic states can be utilized for a data-based observability analysis. The method is also applicable if there are non-identifiable parameters yielding to some insufficiently specified model predictions that can be interpreted as non-observability. Moreover, a validation profile likelihood is introduced that should be applied when noisy validation experiments are to be interpreted. less thanbrgreater than less thanbrgreater thanConclusions: The presented methodology allows the propagation of uncertainty from experimental to model predictions. Although presented in the context of ordinary differential equations, the concept is general and also applicable to other types of models. Matlab code which can be used as a template to implement the method is provided at http://www.fdmold.uni-freiburg.de/(similar to)ckreutz/PPL.
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| 39. |
- Mandenius, Carl-Fredrik, et al.
(författare)
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Quality-by-design for biotechnology-related pharmaceuticals.
- 2009
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Ingår i: Biotechnology journal. - : Wiley. - 1860-7314 .- 1860-6768. ; 4:5, s. 600-9
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Tidskriftsartikel (refereegranskat)abstract
- The following article is a report from a workshop on Quality-by-Design (QbD) held at the 7th European Symposium on Biochemical Engineering Science (7 September 2008, Faro, Portugal).The aim of the workshop was to provide an update on the present status of using QbD in biotechnology-related applications in the pharmaceutical industry. The report summarizes the essential parts of the presentations and covers the industrial, academic, and regulatory aspects of QbD. It concludes with recommendations for further work and development.
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| 40. |
- Mansouri, Larry, et al.
(författare)
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Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
- 2016
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 128:23, s. 2666-2670
-
Tidskriftsartikel (refereegranskat)abstract
- We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBϵ, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence we screened a large patient cohort (n=1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal-zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary CNS lymphoma (3-4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases, 22.7%) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases, 27.3%). NFKBIE-deleted PMBL patients were more often therapy-refractory (P=.022) and displayed inferior outcome compared to wildtype patients (5-year survival: 59% vs. 78%; P=.034); however they appeared to benefit from radiotherapy (P=.022) and rituximab-containing regimens (P=.074). NFKBIEaberrations remained an independent factor in multivariate analysis (P=.003), also when restricting to immunochemotherapy-treated patients (P=.008). Whole-exome sequencing and gene expression-profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.
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| 41. |
- Mathey, Carina M, et al.
(författare)
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Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes
- 2022
-
Ingår i: Frontiers in Genetics. - : Frontiers Media S.A.. - 1664-8021. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Angioedema is a relatively rare but potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). As with hereditary forms of angioedema (HAE), this adverse reaction is mediated by bradykinin. Research suggests that ACEi/ARB-induced angioedema has a multifactorial etiology. In addition, recent case reports suggest that some ACEi/ARB-induced angioedema patients may carry pathogenic HAE variants. The aim of the present study was to investigate the possible association between ACEi/ARB-induced angioedema and HAE genes via systematic molecular genetic screening in a large cohort of ACEi/ARB-induced angioedema cases. Targeted re-sequencing of five HAE-associated genes (SERPING1, F12, PLG, ANGPT1, and KNG1) was performed in 212 ACEi/ARB-induced angioedema patients recruited in Germany/Austria, Sweden, and Denmark, and in 352 controls from a German cohort. Among patients, none of the identified variants represented a known pathogenic variant for HAE. Moreover, no significant association with ACEi/ARB-induced angioedema was found for any of the identified common [minor allele frequency (MAF) >5%] or rare (MAF < 5%) variants. However, several non-significant trends suggestive of possible protective effects were observed. The lowest p-value for an individual variant was found in PLG (rs4252129, p.R523W, p = 0.057, p.adjust > 0.999, Fisher's exact test). Variant p.R523W was found exclusively in controls and has previously been associated with decreased levels of plasminogen, a precursor of plasmin which is part of a pathway directly involved in bradykinin production. In addition, rare, potentially functional variants (MAF < 5%, Phred-scaled combined annotation dependent depletion score >10) showed a nominally significant enrichment in controls both: 1) across all five genes; and 2) in the F12 gene alone. However, these results did not withstand correction for multiple testing. In conclusion, our results suggest that HAE-associated mutations are, at best, a rare cause of ACEi/ARB-induced angioedema. Furthermore, we were unable to identify a significant association between ACEi/ARB-induced angioedema and other variants in the investigated genes. Further studies with larger sample sizes are warranted to draw more definite conclusions concerning variants with limited effect sizes, including protective variants.
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| 42. |
- Mork-Jansson, Astrid Elisabeth, et al.
(författare)
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Lil3 dimerization and chlorophyll binding in Arabidopsis thaliana
- 2015
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Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 589:20, s. 3064-3070
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Tidskriftsartikel (refereegranskat)abstract
- The two-helix light harvesting like (Lil) protein Lil3 belongs to the family of chlorophyll binding light harvesting proteins of photosynthetic membranes. A function in tetrapyrrol synthesis and stabilization of geranylgeraniol reductase has been shown. Lil proteins contain the chlorophyll a/b-binding motif; however, binding of chlorophyll has not been demonstrated. We find that Lil3.2 from Arabidopsis thaliana forms heterodimers with Lil3.1 and binds chlorophyll. Lil3.2 heterodimerization (25 +/- 7.8 nM) is favored relative to homodimerization (431 +/- 59 nM). Interaction of Lil3.2 with chlorophyll a (231 +/- 49 nM) suggests that heterodimerization precedes binding of chlorophyll in Arabidopsis thatiana.
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| 43. |
- Motel-Klingebiel, Andreas, 1964-, et al.
(författare)
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Altern im Wandel : Befunde des Deutschen Alterssurveys (DEAS)
- 2010
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Bok (refereegranskat)abstract
- Wie Menschen älter werden, wie lange sie leben und wie sich ihr Leben im Alter gestaltet, wird durch soziale und gesellschaftliche Bedingungen beeinflusst. Diese Bedingungen ändern sich über die Zeit und bilden den Hintergrund für einen Wandel der späteren Lebensphasen. Zu den Entwicklungen der letzten Jahrzehnte zählen eine gestiegene Lebenserwartung, Veränderungen in der Erwerbswelt, neue Lebenslaufmuster und Familienformen sowie ein Wandel in den gesellschaftlichen Werten und Normen und den Versorgungs- und Sicherungssystemen. Dieses Buch beschäftigt sich mit der Lebensphase Alter und zeigt auf der Grundlage des Deutschen Alterssurveys (DEAS), welcher Wandel sich vollzieht. Dadurch werden Chancen, Risiken und Gestaltungsoptionen für eine Gesellschaft des langen Lebens deutlich. Der DEAS wird durch das Bundesministerium für Familie, Senioren, Frauen und Jugend (BMFSFJ) gefördert.
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| 44. |
- Motel-Klingebiel, Andreas, 1964-, et al.
(författare)
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Familie im Wohlfahrtsstaat – zwischen Verdrängung und gemischter Verantwortung
- 2007
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Ingår i: Zeitschrift für Familienforschung. - 1437-2940 .- 2196-2154. ; 17:3, s. 290-314
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Tidskriftsartikel (refereegranskat)abstract
- Dieser Beitrag diskutiert aus einer international vergleichenden Perspektive die Ausgestaltung informeller und formeller Hilfe- und Unterstützungsleistungen für ältere Menschen. Dabei bezieht er sich insbesondere auf das Spannungsverhältnis zwischen inter- und intragenerationaler familialer Hilfe und wohlfahrtsstaatlich organisierten Unterstützungen. Während die ‚Substitutionshypothese‘ in einer großzügigen wohlfahrtsstaatlichen Versorgung älterer Menschen ein Potential zur Verdrängung der Familie als Unterstützungssystem sieht („crowding out“), geht die ‚Hypothese der Verstärkung‘ von einer Stimulation familialer Hilfen durch wohlfahrtsstaatliche Interventionen aus („crowding in“). Die ‚Hypothese der gemischten Verantwortung‘ prognostiziert derweil, dass eine verbesserte Serviceinfrastruktur vor allem die intensivierte Mischung informeller und formellen Hilfe- und Unterstützungsleistungen nach sich zieht. Die ‚Hypothese der funktionalen Differenzierung‘ schließlich nimmt darüber hinaus an, dass diese Mischung nicht unspezifisch erfolgt, sondern sich charakteristische Zuständigkeiten herausbilden.Der Beitrag berichtet empirische Ergebnisse des Forschungsprojekts OASIS – Old Age and Autonomy: The Role of Service Sys-tems and Intergenerational Family Solidarity. Grundlage ist eine nach Alter geschichtete urbane Stichprobe von 6.106 Personen im Alter von mehr als 25 Jahren aus Norwegen, England, Deutschland, Spanien und Israel. Die Analyse zeigt, dass die Gesamtheit der von älteren Menschen empfangenen Hilfe in jenen Wohlfahrtsstaaten deutlich größer ist, die eine ausgeprägte Infrastruktur von formellen Dienstleistungen aufweisen. Unter Kontrolle von Sozialstrukturindikatoren, gesellschaftlichen Normen und individuellen Präferenzen, gesundheitlichen Einschränkungen sowie familialen Opportunitätsstrukturen lassen sich dabei keine Hinweise auf eine substantielle ‚Verdrängung‘ familialer Hilfen finden. Die Ergebnisse unterstützen stattdessen die Hypothesen einer ‚gemischten Verantwortung‘ und ‚funktionalen Differenzierung‘. Sie deuten darauf hin, dass in Gesellschaften mit gut entwickelten Dienstleitungsinfrastrukturen die Hilfe aus familialen und wohlfahrtsstaatlichen Leistungen häufig kumulativ vorzufinden sind und so auf die Lebensqualität im Alter wirken, während solche Mischungen in familial orientierten Wohlfahrtsregimes bei zugleich insgesamt geringerer Verbreitung von Hilfen nur selten vorkommen.
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| 45. |
- Motel-Klingebiel, Andreas, 1964-, et al.
(författare)
-
Social inequality in the later life: Cross-national comparison of quality of life
- 2004
-
Ingår i: European Journal of Ageing. - : Springer Science and Business Media LLC. - 1613-9372 .- 1613-9380. ; 1:1, s. 6-14
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Tidskriftsartikel (refereegranskat)abstract
- This paper analyses quality of life and inequality in old age in an international comparative and a life course perspective. Quality of life is seen as an outcome of unequal chances in life. We distinguish between overall and domain specific expressions of quality of life which allows us to analyse the determinants of overall quality of life and their development over the life course. The data presented come from the research project “OASIS - Old Age and Autonomy: The Role of Service Systems and Intergenerational Family Solidarity”. This data set is based on an age stratified random sample of the urban population (25–102 years) in Norway, England, Germany, Spain, and Israel (n=6,106). With advancing age, there are decreasing mean levels and increasing variation of quality of life. With age, the impact of physical health on overall quality of life increases, while the predictive power of other domains decreases. The results support the hypothesis of differentiation as well as the age-dependency hypothesis. For both these both aspects, international comparisons show similar results in different societies. These uniform age tendencies in modern European societies point to a limited importance of societal embeddedness and support the interpretation of age group differences as being life course effects.
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| 46. |
- Motel-Klingebiel, Andreas, 1964-, et al.
(författare)
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Welfare states do not crowd out the family: Evidence for mixed responsibility from comparative analyses
- 2005
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Ingår i: Ageing & Society. - : Cambridge University Press. - 0144-686X .- 1469-1779. ; 25:6, s. 863-882
-
Tidskriftsartikel (refereegranskat)abstract
- This paper discusses the informal and formal provision of help and support to older people from a comparative welfare state perspective, with particular reference to the relationships between inter-generational family help and welfare state support. While the ‘substitution’ hypothesis states that the generous provision of welfare state services in support of older people ‘crowds out’ family help, the ‘encouragement’ hypothesis predicts a stimulation of family help, and the ‘mixed responsibility’ hypothesis predicts a combination of family and formal help and support. The paper reports findings from the Old Age and Autonomy: The Role of Service Systems and Inter-generational Family Solidarity (OASIS) research project. This created a unique age-stratified sample of 6,106 people aged 25–102 years from the urban populations of Norway, England, Germany, Spain and Israel. The analyses show that the total quantity of help received by older people is greater in welfare states with a strong infrastructure of formal services. Moreover, when measures of the social structure, support preferences and familial opportunity structures were controlled, no evidence of a substantial ‘crowding out’ of family help was found. The results support the hypothesis of ‘mixed responsibility’, and suggest that in societies with well-developed service infrastructures, help from families and welfare state services act accumulatively, but that in familistic welfare regimes, similar combinations do not occur.
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| 47. |
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| 48. |
- Nagarakanti, Rangadham, et al.
(författare)
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Comparison of Characteristics and Outcomes of Dabigatran Versus Warfarin in Hypertensive Patients With Atrial Fibrillation (from the RE-LY Trial)
- 2015
-
Ingår i: American Journal of Cardiology. - : Elsevier BV. - 0002-9149 .- 1879-1913. ; 116:8, s. 1204-1209
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Tidskriftsartikel (refereegranskat)abstract
- Hypertension is frequent in patients with atrial fibrillation (AF) and is an independent risk factor for stroke. The Randomized Evaluation of Long Term Anticoagulant TherapY (RE-LY) trial found dabigatran 110 mg (D110) and 150 mg twice daily (D150) noninferior or superior to warfarin for stroke reduction in patients with AF, with either a reduction (D110) or similar rates (D150) of major bleeding. Baseline characteristics and outcomes were compared in patients with and without hypertension. The quality of blood pressure control was also assessed. In RE-LY, 14,283 patients (78.9%) had hypertension. The mean blood pressure at baseline was 132.6 +/- 17.6/77.7 +/- 10.6 and 124.8 +/- 16.7/74.6 +/- 10.0 mm Hg for patients with and without hypertension, respectively. More patients with hypertension were diabetic (25.6% vs 14.8%, p <0.001), women (38.6% vs 28.3%, p <0.001), and had greater CHADS(2) (2.3 vs 1.4, p <0.001) and CHA(2)DS(2)-VASc scores (3.8 vs 2.8, p <0.001). Mean blood pressure in all treatment arms in hypertensive patients was similar (130 +/- 18/76 +/- 11 mm Hg) during the trial. The efficacy and safety of D110 and D150 compared to warfarin were similar (p = nonsignificant) in hypertensive (stroke/systemic embolism rate of 1.47%, 1.20%, and 1.81% and major bleed rate of 2.89%, 3.70%, and 3.69% in the D110, D150, and W, respectively) and normotensive patients (stroke/systemic embolism rate of 1.79%, 0.78%, and 1.36% and major bleed rate of 2.84%, 2.37%, and 3.03% per year in the D110, D150, and W, respectively). Hypertensive patients had more major bleeds (3.39% vs. 2.76%; p = 0.007). Intracranial bleeds were similar (0.47% vs 0.31%; p = 0.12). In conclusion, patients with hypertension in RE-LY were more likely female, diabetic, with a greater CHADS(2) and CHA(2)DS(2)-VASc scores. Blood pressure control in RE-LY was excellent. The benefits of dabigatran over warfarin, including a substantial reduction of intracranial hemorrhage, were similar in both hypertensive and non-hypertensive patients.
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| 49. |
- Raue, Andreas, et al.
(författare)
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Joining forces of Bayesian and frequentist methodology: a study for inference in the presence of non-identifiability
- 2013
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Ingår i: Philosophical Transactions. Series A. - : Royal Society, The. - 1364-503X .- 1471-2962. ; 371:1984
-
Tidskriftsartikel (refereegranskat)abstract
- Increasingly complex applications involve large datasets in combination with nonlinear and high-dimensional mathematical models. In this context, statistical inference is a challenging issue that calls for pragmatic approaches that take advantage of both Bayesian and frequentist methods. The elegance of Bayesian methodology is founded in the propagation of information content provided by experimental data and prior assumptions to the posterior probability distribution of model predictions. However, for complex applications, experimental data and prior assumptions potentially constrain the posterior probability distribution insufficiently. In these situations, Bayesian Markov chain Monte Carlo sampling can be infeasible. From a frequentist point of view, insufficient experimental data and prior assumptions can be interpreted as non-identifiability. The profile-likelihood approach offers to detect and to resolve non-identifiability by experimental design iteratively. Therefore, it allows one to better constrain the posterior probability distribution until Markov chain Monte Carlo sampling can be used securely. Using an application from cell biology, we compare both methods and show that a successive application of the two methods facilitates a realistic assessment of uncertainty in model predictions.
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| 50. |
- Rosencher, Nadia, et al.
(författare)
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Type of anaesthesia and the safety and efficacy of thromboprophylaxis with enoxaparin or dabigatran etexilate in major orthopaedic surgery: pooled analysis of three randomized controlled trials.
- 2012
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Ingår i: Thrombosis journal. - : Springer Science and Business Media LLC. - 1477-9560. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: Background: There has been a shift towards greater use of neuraxial over general anaesthesia for patients undergoing total hip or knee arthroplasty. Furthermore, suggestions that peripheral nerve block may reduce adverse effects have recently been put forward. Although older studies showed a reduction in venous thromboembolism (VTE) with neuraxial compared with general anaesthesia, this difference has not been confirmed in studies using effective current thromboprophylaxis. We used a large data set to investigate the pattern of anaesthesia usage, and whether anaesthesia type affects efficacy and bleeding outcomes of thromboprophylaxis overall, within each treatment group, or for the novel oral anticoagulant dabigatran etexilate versus enoxaparin. Methods: Three previously reported trials compared 220 mg and 150 mg dabigatran etexilate once daily with enoxaparin after knee or hip arthroplasty. A pooled analysis was performed in patients receiving general or neuraxial anaesthesia, or the combination of either with peripheral nerve block (n = 8062). Outcome measures were major VTE plus VTE-related mortality, major bleeding and major plus clinically relevant bleeding events. Results: General, neuraxial and combination anaesthesia were used in 29%, 52% and 19% of patients, respectively. Differences in efficacy and safety between anaesthesia subgroups were small and not significant, except for a slightly higher rate of major VTE and VTE-related mortality with general versus neuraxial anaesthesia (odds ratio: 1.40; 95% confidence interval: 1.03–1.90; p = 0.035) in the overall population. There were no significant effects of anaesthesia type on efficacy or safety of dabigatran etexilate versus enoxaparin. Conclusions: Anaesthesia type did not greatly affect efficacy and safety outcomes in the pooled population of all three treatment groups. The efficacy and safety of dabigatran etexilate was comparable with enoxaparin, regardless of type of anaesthesia. Trial registration: ClinicalTrials.gov identifiers: NCT00168805, NCT00168818, NCT00152971.
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