| 1. |
- Granger, CB, et al.
(författare)
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Clinical events after transitioning from apixaban versus warfarin to warfarin at the end of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial
- 2015
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 169:1, s. 25-30
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Tidskriftsartikel (refereegranskat)abstract
- Background We sought to assess the occurrence of events after blinded study drug discontinuation and transition to open-label vitamin K antagonist (VKA) in ARISTOTLE.Methods At the end of ARISTOTLE, blinded study drug was stopped, and open-label VKA was recommended. For patients completing the trial on blinded study drug, a 2-day bridging period with apixaban or apixaban placebo was recommended (while beginning open-label VKA). Outcomes were assessed during the 30 days after stopping blinded study drug.Results Of the 6,809 patients in the apixaban group and 6,588 in the warfarin group who completed the trial on study drug, there were 21 strokes or systemic emboli (4.02%/year) and 26 major bleeding (4.97%/year) events in the apixaban group (transitioning to VKA) and 5 strokes or systemic emboli (0.99%/year) and 10 major bleeding (1.97%/year) events in the warfarin group (continuing on VKA), with most of the imbalance between groups being after the first week. Similar results were seen in the first 30 days of the trial where warfarin-naive patients starting warfarin had a higher rate of stroke or systemic emboli (5.41%/year) than warfarin-experienced patients (1.42%/year), a pattern not seen when starting apixaban. No similar increase in events with apixaban versus warfarin was seen during temporary or permanent study drug discontinuation during the trial.Conclusions The excess in thrombotic and bleeding events in the apixaban group after study drug discontinuation appears to be related to an increased risk associated with the initiation of a VKA rather than a direct effect of apixaban. Whether >= 2 days of apixaban bridging improves outcomes during VKA transition is unknown and deserves further evaluation.
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| 2. |
- Alexander, John H., et al.
(författare)
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Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome
- 2011
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 365:8, s. 699-708
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Tidskriftsartikel (refereegranskat)abstract
- Background: Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome.Methods: We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events.Results: The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P = 0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P = 0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo.Conclusions: The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events.
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| 3. |
- Alexander, John H., et al.
(författare)
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Documentation of study medication dispensing in a prospective large randomized clinical trial : Experiences from the ARISTOTLE Trial
- 2013
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 166:3, s. 559-
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Tidskriftsartikel (refereegranskat)abstract
- Background In ARISTOTLE, apixaban resulted in a 21% reduction in stroke, a 31% reduction in major bleeding, and an 11% reduction in death. However, approval of apixaban was delayed to investigate a statement in the clinical study report that "7.3% of subjects in the apixaban group and 1.2% of subjects in the warfarin group received, at some point during the study, a container of the wrong type." Methods Rates of study medication dispensing error were characterized through reviews of study medication container tear-off labels in 6,520 participants from randomly selected study sites. The potential effect of dispensing errors on study outcomes was statistically simulated in sensitivity analyses in the overall population. Results The rate of medication dispensing error resulting in treatment error was 0.04%. Rates of participants receiving at least 1 incorrect container were 1.04% (34/3,273) in the apixaban group and 0.77% (25/3,247) in the warfarin group. Most of the originally reported errors were data entry errors in which the correct medication container was dispensed but the wrong container number was entered into the case report form. Sensitivity simulations in the overall trial population showed no meaningful effect of medication dispensing error on the main efficacy and safety outcomes. Conclusions Rates of medication dispensing error were low and balanced between treatment groups. The initially reported dispensing error rate was the result of data recording and data management errors and not true medication dispensing errors. These analyses confirm the previously reported results of ARISTOTLE.
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| 4. |
- Beal, Jacob, et al.
(författare)
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Robust estimation of bacterial cell count from optical density
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 5. |
- Chu, Audrey Y, et al.
(författare)
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Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:1, s. 125-130
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Tidskriftsartikel (refereegranskat)abstract
- Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10(-8); false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
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| 6. |
- Darwich, Adam S., et al.
(författare)
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Model-Informed Precision Dosing: Background, Requirements, Validation, Implementation, and Forward Trajectory of Individualizing Drug Therapy
- 2021
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Ingår i: Annual Review of Pharmacology and Toxicology. - : Annual Reviews Inc.. - 0362-1642 .- 1545-4304. ; 61:36, s. 1-21
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Tidskriftsartikel (refereegranskat)abstract
- Model-informed precision dosing (MIPD) has become synonymous with modern approaches forindividualizing drug therapy, in which the characteristics of each patient are considered as opposedto applying a one-size-fits-all alternative. This review provides a brief account of the currentknowledge, practices, and opinions on MIPD while defining an achievable vision for MIPDin clinical care based on available evidence.We begin with a historical perspective on variabilityin dose requirements and then discuss technical aspects of MIPD, including the need for clinicaldecision support tools, practical validation, and implementation of MIPD in health care.Wealso discuss novel ways to characterize patient variability beyond the common perceptions of geneticcontrol. Finally, we address current debates on MIPD from the perspectives of the new drugdevelopment, health-care economics, and drug regulations.
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| 7. |
- Ding, Li, et al.
(författare)
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Somatic mutations affect key pathways in lung adenocarcinoma
- 2008
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 455:7216, s. 1069-1075
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Tidskriftsartikel (refereegranskat)abstract
- Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
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| 8. |
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| 9. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 10. |
- McKeever, Ed, et al.
(författare)
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Emplaced Partnerships and the Ethics of Care, Recognition and Resilience
- 2023
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Ingår i: Journal of Business Ethics. - : Springer Nature. - 1573-0697 .- 0167-4544. ; 184:4, s. 757-772
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the SI is to bring to the fore the places in which cross-sector partnerships (CSPs) are formed; how place shapes the dynamics of CSPs, and how CSPs shape the specific settings in which they develop. The papers demonstrate that partnerships and place are intrinsically reciprocal: the morality and materiality inherent in places repeatedly reset the reference points for partners, trigger epiphanies, shift identities, and redistribute capacities to act. Place thus becomes generative of partnerships in the most profound sense: by developing an awareness of their emplacement, CSPs commit to place, and through their place-based commitments produce three intertwined modalities of place-specific ethics that bind CSPs and place: ethic of recognition, an ethic of care, and an ethic of resilience. Our authors have found vivid examples of how emplaced CSPs embody these ethics, signaling hope for the sustainability of our (always hyper-local) life-worlds.
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