| 1. |
|
|
| 2. |
|
|
| 3. |
- Krasilnikov, A., et al.
(författare)
-
Evidence of 9 Be + p nuclear reactions during 2ω CH and hydrogen minority ICRH in JET-ILW hydrogen and deuterium plasmas
- 2018
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 58:2
-
Tidskriftsartikel (refereegranskat)abstract
- The intensity of 9Be + p nuclear fusion reactions was experimentally studied during second harmonic (2ω CH) ion-cyclotron resonance heating (ICRH) and further analyzed during fundamental hydrogen minority ICRH of JET-ILW hydrogen and deuterium plasmas. In relatively low-density plasmas with a high ICRH power, a population of fast H+ ions was created and measured by neutral particle analyzers. Primary and secondary nuclear reaction products, due to 9Be + p interaction, were observed with fast ion loss detectors, γ-ray spectrometers and neutron flux monitors and spectrometers. The possibility of using 9Be(p, d)2α and 9Be(p, α)6Li nuclear reactions to create a population of fast alpha particles and study their behaviour in non-active stage of ITER operation is discussed in the paper.
|
|
| 4. |
|
|
| 5. |
-
- 2018
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 58:1
-
Forskningsöversikt (refereegranskat)
|
|
| 6. |
- Bombarda, F., et al.
(författare)
-
Runaway electron beam control
- 2019
-
Ingår i: Plasma Physics and Controlled Fusion. - : IOP Publishing. - 1361-6587 .- 0741-3335. ; 61:1
-
Tidskriftsartikel (refereegranskat)
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Joffrin, E., et al.
(författare)
-
Overview of the JET preparation for deuterium-tritium operation with the ITER like-wall
- 2019
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 59:11
-
Forskningsöversikt (refereegranskat)abstract
- For the past several years, the JET scientific programme (Pamela et al 2007 Fusion Eng. Des. 82 590) has been engaged in a multi-campaign effort, including experiments in D, H and T, leading up to 2020 and the first experiments with 50%/50% D-T mixtures since 1997 and the first ever D-T plasmas with the ITER mix of plasma-facing component materials. For this purpose, a concerted physics and technology programme was launched with a view to prepare the D-T campaign (DTE2). This paper addresses the key elements developed by the JET programme directly contributing to the D-T preparation. This intense preparation includes the review of the physics basis for the D-T operational scenarios, including the fusion power predictions through first principle and integrated modelling, and the impact of isotopes in the operation and physics of D-T plasmas (thermal and particle transport, high confinement mode (H-mode) access, Be and W erosion, fuel recovery, etc). This effort also requires improving several aspects of plasma operation for DTE2, such as real time control schemes, heat load control, disruption avoidance and a mitigation system (including the installation of a new shattered pellet injector), novel ion cyclotron resonance heating schemes (such as the three-ions scheme), new diagnostics (neutron camera and spectrometer, active Alfven eigenmode antennas, neutral gauges, radiation hard imaging systems...) and the calibration of the JET neutron diagnostics at 14 MeV for accurate fusion power measurement. The active preparation of JET for the 2020 D-T campaign provides an incomparable source of information and a basis for the future D-T operation of ITER, and it is also foreseen that a large number of key physics issues will be addressed in support of burning plasmas.
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
|
|
| 18. |
|
|
| 19. |
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
-
- 2018
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 58:9
-
Tidskriftsartikel (refereegranskat)
|
|
| 26. |
- Murari, A., et al.
(författare)
-
A control oriented strategy of disruption prediction to avoid the configuration collapse of tokamak reactors
- 2024
-
Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- The objective of thermonuclear fusion consists of producing electricity from the coalescence of light nuclei in high temperature plasmas. The most promising route to fusion envisages the confinement of such plasmas with magnetic fields, whose most studied configuration is the tokamak. Disruptions are catastrophic collapses affecting all tokamak devices and one of the main potential showstoppers on the route to a commercial reactor. In this work we report how, deploying innovative analysis methods on thousands of JET experiments covering the isotopic compositions from hydrogen to full tritium and including the major D-T campaign, the nature of the various forms of collapse is investigated in all phases of the discharges. An original approach to proximity detection has been developed, which allows determining both the probability of and the time interval remaining before an incoming disruption, with adaptive, from scratch, real time compatible techniques. The results indicate that physics based prediction and control tools can be developed, to deploy realistic strategies of disruption avoidance and prevention, meeting the requirements of the next generation of devices.
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
- Dorlo, Thomas P C, et al.
(författare)
-
Pharmacokinetics of miltefosine in Old World cutaneous leishmaniasis patients.
- 2008
-
Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 52:8, s. 2855-60
-
Tidskriftsartikel (refereegranskat)abstract
- The pharmacokinetics of miltefosine in leishmaniasis patients are, to a great extent, unknown. We examined and characterized the pharmacokinetics of miltefosine in a group of patients with Old World (Leishmania major) cutaneous leishmaniasis. Miltefosine plasma concentrations were determined in samples taken during and up to 5 months after the end of treatment from 31 Dutch military personnel who contracted cutaneous leishmaniasis in Afghanistan and were treated with 150 mg miltefosine/day for 28 days. Samples were analyzed with a validated liquid chromatography-tandem mass spectrometry assay with a lower limit of quantification (LLOQ) of 4 ng/ml. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling, using NONMEM. The pharmacokinetics of miltefosine could best be described by an open two-compartment disposition model, with a first elimination half-life of 7.05 days and a terminal elimination half-life of 30.9 days. The median concentration in the last week of treatment (days 22 to 28) was 30,800 ng/ml. The maximum duration of follow-up was 202 days after the start of treatment. All analyzed samples contained a concentration above the LLOQ. Miltefosine is eliminated from the body much slower than previously thought and is therefore still detectable in human plasma samples taken 5 to 6 months after the end of treatment. The presence of subtherapeutic miltefosine concentrations in the blood beyond 5 months after treatment might contribute to the selection of resistant parasites, and moreover, the measures for preventing the teratogenic risks of miltefosine treatment should be reconsidered.
|
|
| 30. |
- Fenstermacher, M.E., et al.
(författare)
-
DIII-D research advancing the physics basis for optimizing the tokamak approach to fusion energy
- 2022
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 62:4
-
Tidskriftsartikel (refereegranskat)abstract
- DIII-D physics research addresses critical challenges for the operation of ITER and the next generation of fusion energy devices. This is done through a focus on innovations to provide solutions for high performance long pulse operation, coupled with fundamental plasma physics understanding and model validation, to drive scenario development by integrating high performance core and boundary plasmas. Substantial increases in off-axis current drive efficiency from an innovative top launch system for EC power, and in pressure broadening for Alfven eigenmode control from a co-/counter-I p steerable off-axis neutral beam, all improve the prospects for optimization of future long pulse/steady state high performance tokamak operation. Fundamental studies into the modes that drive the evolution of the pedestal pressure profile and electron vs ion heat flux validate predictive models of pedestal recovery after ELMs. Understanding the physics mechanisms of ELM control and density pumpout by 3D magnetic perturbation fields leads to confident predictions for ITER and future devices. Validated modeling of high-Z shattered pellet injection for disruption mitigation, runaway electron dissipation, and techniques for disruption prediction and avoidance including machine learning, give confidence in handling disruptivity for future devices. For the non-nuclear phase of ITER, two actuators are identified to lower the L-H threshold power in hydrogen plasmas. With this physics understanding and suite of capabilities, a high poloidal beta optimized-core scenario with an internal transport barrier that projects nearly to Q = 10 in ITER at ∼8 MA was coupled to a detached divertor, and a near super H-mode optimized-pedestal scenario with co-I p beam injection was coupled to a radiative divertor. The hybrid core scenario was achieved directly, without the need for anomalous current diffusion, using off-axis current drive actuators. Also, a controller to assess proximity to stability limits and regulate β N in the ITER baseline scenario, based on plasma response to probing 3D fields, was demonstrated. Finally, innovative tokamak operation using a negative triangularity shape showed many attractive features for future pilot plant operation.
|
|
| 31. |
- López-Isac, Elena, et al.
(författare)
-
Brief Report : IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies
- 2016
-
Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 68:9, s. 2338-2344
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc–RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc–RA loci through an interdisease meta–genome-wide association (meta-GWAS) strategy. Methods: The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case–control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. Results: This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P < 5 × 10−6) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc–RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 × 10−12). Analysis of the biologic relevance of the known SSc–RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. Conclusion: This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.
|
|
| 32. |
|
|
| 33. |
|
|
| 34. |
- Hobirk, J., et al.
(författare)
-
Improved confinement in JET hybrid discharges
- 2009
-
Ingår i: 36th EPS Conference on Plasma Physics 2009, EPS 2009 - Europhysics Conference Abstracts. - 9781622763368 ; , s. 150-153
-
Konferensbidrag (refereegranskat)
|
|
| 35. |
- Hobirk, J., et al.
(författare)
-
Improved confinement in JET hybrid discharges
- 2012
-
Ingår i: Plasma Physics and Controlled Fusion. - : IOP Publishing. - 0741-3335 .- 1361-6587. ; 54:9, s. 095001-
-
Tidskriftsartikel (refereegranskat)abstract
- A new technique has been developed to produce plasmas with improved confinement relative to the H 98,y2 scaling law (ITER Physics Expert Groups on Confinement and Transport and Confinement Modelling and Database ITER Physics Basics Editors and ITER EDA 1999 Nucl. Fusion 39 2175) on the JET tokamak. In the mid-size tokamaks ASDEX upgrade and DIII-D heating during the current formation is used to produce a flat q-profile with a minimum close to 1. On JET this technique leads to q-profiles with similar minimum q but opposite to the other tokamaks not to an improved confinement state. By changing the method utilizing a faster current ramp with temporary higher current than in the flattop (current overshoot) plasmas with improved confinement (H 98,y2=1.35) and good stability (β N3) have been produced and extended to many confinement times only limited by technical constraints. The increase in H 98,y2-factor is stronger with more heating power as can be seen in a power scan. The q-profile development during the high power phase in JET is reproduced by current diffusion calculated by TRANSP and CRONOS. Therefore the modifications produced by the current overshoot disappear quickly from the edge but the confinement improvement lasts longer, in some cases up to the end of the heating phase.
|
|
| 36. |
- Kreeftmeijer-Vegter, A. R., et al.
(författare)
-
Population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome
- 2015
-
Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 80:2, s. 242-252
-
Tidskriftsartikel (refereegranskat)abstract
- AimThe aim was to investigate the population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome. MethodsNon-linear mixed effects modelling was performed on samples collected during a randomized controlled trial. Samples were collected from children who were receiving 2.5mg kg(-1) levamisole (or placebo) orally once every other day. One hundred and thirty-six plasma samples were collected from 38 children from India and Europe and included in the analysis. A one compartment model described the data well. ResultsThe apparent clearance rate (CL/F) and distribution volume (V/F) were 44l h(-1) 70kg(-1) and 236l 70kg(-1), respectively; estimated interindividual variability was 32-42%. In addition to allometric scaling of CL/F and V/F to body weight, we identified a significant proportional effect of age on CL/F (-10.1% per year). The pharmacokinetics parameters were not affected by gender, tablet strength or study centre. The median (interquartile range) maximum plasma concentration of levamisole was 438.3 (316.5-621.8) ng ml(-1), and the median area under the concentration-time curve was 2847 (2267-3761) ng ml(-1) h. Median t(max) and t(1/2) values were 1.65 (1.32-2.0) h and 2.60 (2.06-3.65) h, respectively. ConclusionsHere, we present the first pharmacokinetic data regarding levamisole in children with steroid-sensitive nephrotic syndrome. The pharmacokinetic profile of levamisole in children was similar to findings reported in adults, although the elimination rate was slightly higher in children.
|
|
| 37. |
- Litaudon, X., et al.
(författare)
-
Prospects for steady-state scenarios on JET
- 2007
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 47:9, s. 1285-1292
-
Tidskriftsartikel (refereegranskat)abstract
- In the 2006 experimental campaign, progress has been made on JET to operate non-inductive scenarios at higher applied powers (31 MW) and density (n(1) similar to 4 x 10(19) m(-3)), with ITER-relevant safety factor (q(95) similar to 5) and plasma shaping, taking advantage of the new divertor capabilities. The extrapolation of the performance using transport modelling benchmarked on the experimental database indicates that the foreseen power upgrade (similar to 45 MW) will allow the development of non-inductive scenarios where the bootstrap current is maximized together with the fusion yield and not, as in present-day experiments, at its expense. The tools for the long-term JET programme are the new ITER-like ICRH antenna (similar to 15 MW), an upgrade of the NB power (35 MW/20s or 17.5 MW/40s), a new ITER-like first wall, a new pellet injector for edge localized mode control together with improved diagnostic and control capability. Operation with the new wall will set new constraints on non-inductive scenarios that are already addressed experimentally and in the modelling. The fusion performance and driven current that could be reached at high density and power have been estimated using either 0D or 1-1/2D validated transport models. In the high power case (45 MW), the calculations indicate the potential for the operational space of the non-inductive regime to be extended in terms of current (similar to 2.5 MA) and density (n(1) > 5 x 10(19) m(-3)), with high beta(N) (beta(N) > 3.0) and a fraction of the bootstrap current within 60-70% at high toroidal field (similar to 3.5 T).
|
|
| 38. |
- Neu, R., et al.
(författare)
-
First operation with the JET International Thermonuclear Experimental Reactor-like wall
- 2013
-
Ingår i: Physics of Plasmas. - : AIP Publishing. - 1070-664X .- 1089-7674. ; 20:5, s. 056111-1-056111-13
-
Tidskriftsartikel (refereegranskat)abstract
- To consolidate International Thermonuclear Experimental Reactor (ITER) design choices and prepare for its operation, Joint European Torus (JET) has implemented ITER's plasma facing materials, namely, Be for the main wall and W in the divertor. In addition, protection systems, diagnostics, and the vertical stability control were upgraded and the heating capability of the neutral beams was increased to over 30 MW. First results confirm the expected benefits and the limitations of all metal plasma facing components (PFCs) but also yield understanding of operational issues directly relating to ITER. H-retention is lower by at least a factor of 10 in all operational scenarios compared to that with C PFCs. The lower C content (≈ factor 10) has led to much lower radiation during the plasma burn-through phase eliminating breakdown failures. Similarly, the intrinsic radiation observed during disruptions is very low, leading to high power loads and to a slow current quench. Massive gas injection using a D2/Ar mixture restores levels of radiation and vessel forces similar to those of mitigated disruptions with the C wall. Dedicated L-H transition experiments indicate a 30% power threshold reduction, a distinct minimum density, and a pronounced shape dependence. The L-mode density limit was found to be up to 30% higher than for C allowing stable detached divertor operation over a larger density range. Stable H-modes as well as the hybrid scenario could be re-established only when using gas puff levels of a few 1021 es-1. On average, the confinement is lower with the new PFCs, but nevertheless, H factors up to 1 (H-Mode) and 1.3 (at β N ≈ 3, hybrids) have been achieved with W concentrations well below the maximum acceptable level.
|
|
| 39. |
- Setälä, H., et al.
(författare)
-
Urban and agricultural soils : Conflicts and trade-offs in the optimization of ecosystem services
- 2014
-
Ingår i: Urban Ecosystems. - : Springer Science and Business Media LLC. - 1083-8155 .- 1573-1642. ; 17:1, s. 239-253
-
Tidskriftsartikel (refereegranskat)abstract
- On-going human population growth and changing patterns of resource consumption are increasing global demand for ecosystem services, many of which are provided by soils. Some of these ecosystem services are linearly related to the surface area of pervious soil, whereas others show non-linear relationships, making ecosystem service optimization a complex task. As limited land availability creates conflicting demands among various types of land use, a central challenge is how to weigh these conflicting interests and how to achieve the best solutions possible from a perspective of sustainable societal development. These conflicting interests become most apparent in soils that are the most heavily used by humans for specific purposes: urban soils used for green spaces, housing, and other infrastructure and agricultural soils for producing food, fibres and biofuels. We argue that, despite their seemingly divergent uses of land, agricultural and urban soils share common features with regards to interactions between ecosystem services, and that the trade-offs associated with decision-making, while scale- and context-dependent, can be surprisingly similar between the two systems. We propose that the trade-offs within land use types and their soil-related ecosystems services are often disproportional, and quantifying these will enable ecologists and soil scientists to help policy makers optimizing management decisions when confronted with demands for multiple services under limited land availability.
|
|
| 40. |
- Versloot, T W, et al.
(författare)
-
Comparison between dominant NB and dominant IC heated ELMy H-mode discharges in JET
- 2011
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 51:10, s. 103033-
-
Tidskriftsartikel (refereegranskat)abstract
- The experiment described in this paper is aimed at characterization of ELMy H-mode discharges with varying momentum input, rotation, power deposition profiles and ion to electron heating ratio obtained by varying the proportion between ion cyclotron (IC) and neutral beam (NB) heating. The motivation for the experiment was to verify if the basic confinement and transport properties of the baseline ITER H-mode are robust to these changes, and similar to those derived mostly from dominant NB heated H-modes. No significant difference in the density and temperature profiles or in the global confinement were found. Although ion temperature profiles were seen to be globally stiff, some variation of stiffness was obtained in the experiment by varying the deposition profiles, but not one that could significantly affect the profiles in terms of global confinement. This analysis shows the thermal plasma energy confinement enhancement factor to be independent of the heating mix, for the range of conditions explored. Moreover, the response of the global confinement to changes in density and power were also independent of heating mix, reflecting the changes in the pedestal, which is in agreement with globally stiff profiles. Consistently, the pedestal characteristics (pressure and width) and their dependences on global parameters such as density and power were the same during NB only or with predominant IC heating.
|
|
| 41. |
- Bhagwat, Pradyumna, 1986-
(författare)
-
SECURITY OF SUPPLY DURING THE ENERGY TRANSITION:THE ROLE OF CAPACITY MECHANISMS
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The push for clean energy has caused a rapid growth of renewables in the electricity supply mix of the EU. Although one would assume that the impact of these technologies is entirely positive, recent research and experience indicate that there is reason for concern namely regarding the security of supply. In this context, the concern is how renewable energy sources (RES) affect the business case of conventional power generation. In response to this concern, capacity mechanisms are being considered or have already been implemented by various member states of the EU. However, in a highly interconnected electricity system, such as the one in Europe, there appears to be a risk that the uncoordinated implementation of capacity mechanisms may cause unintended cross-border effects. This research explored the performance of various capacity mechanisms in an electricity system with a strong growth in the portfolio share of variable renewable energy sources (RES). The cross-border effects of implementing various capacity mechanisms in an interconnected power system were also analyzed. In this research, two capacity mechanisms, namely a strategic reserve and a capacity market, were modeled as extensions to the EMLab-Generation agent-based model. Furthermore, two variations of a capacity market were analyzed. The first was a yearly capacity market design and the second was a forward capacity market with long term contracts. A survey of experts on the US capacity markets supplemented the modeling work with practical insights.
|
|
| 42. |
- Byakika-Kibwika, Pauline, et al.
(författare)
-
Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults.
- 2012
-
Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 67:5, s. 1217-23
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Treatment of HIV/malaria-coinfected patients with antiretroviral therapy (ART) and artemisinin-based combination therapy has potential for drug interactions. We investigated the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine after administration of a single dose of 80/480 mg of artemether/lumefantrine to HIV-infected adults, taken with and without lopinavir/ritonavir.METHODS: A two-arm parallel study of 13 HIV-infected ART-naive adults and 16 HIV-infected adults stable on 400/100 mg of lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (ClinicalTrials.gov, NCT 00619944). Each participant received a single dose of 80/480 mg of artemether/lumefantrine under continuous cardiac function monitoring. Plasma concentrations of artemether, dihydroartemisinin and lumefantrine were measured.RESULTS: Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly reduced artemether maximum concentration (C(max)) and area under the concentration-time curve (AUC) [median (range): 112 (20-362) versus 56 (17-236) ng/mL, P = 0.03; and 264 (92-1129) versus 151 (38-606) ng · h/mL, P < 0.01]. Dihydroartemisinin C(max) and AUC were not affected [66 (10-111) versus 73 (31-224) ng/mL, P = 0.55; and 213 (68-343) versus 175 (118-262) ng · h/mL P = 0.27]. Lumefantrine C(max) and AUC increased during co-administration [2532 (1071-5957) versus 7097 (2396-9462) ng/mL, P < 0.01; and 41,119 (12,850-125,200) versus 199,678 (71,205-251,015) ng · h/mL, P < 0.01].CONCLUSIONS: Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly increases lumefantrine exposure, but decreases artemether exposure. Population pharmacokinetic and pharmacodynamic trials will be highly valuable in evaluating the clinical significance of this interaction and determining whether dosage modifications are indicated.
|
|
| 43. |
- Crombag, Marie-Rose B S, et al.
(författare)
-
Impact of Older Age on the Exposure of Paclitaxel : a Population Pharmacokinetic Study.
- 2019
-
Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 36:2, s. 33-
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Limited available data suggest that older patients are more prone to develop paclitaxel-induced toxicity than their younger peers. It remains unclear whether this is related to age-dependent pharmacokinetics (PK) of paclitaxel. Primary objective of this study was to determine the influence of older age on the PK of paclitaxel.METHODS: PK data of patients aged ≥70 years who received paclitaxel intravenously at the Netherlands Cancer Institute (NKI) and the Radboud University Medical Center between September 2012 and May 2017 were collected. These prospectively collected data were pooled with previously published databases from multiple clinical trials conducted at the NKI and Erasmus MC Cancer Institute. A previously developed 3-compartment population PK model with saturable distribution and elimination was used to describe paclitaxel plasma concentration-time data. Hereafter, influence of age on paclitaxel PK was assessed in a previously established full covariate model.RESULTS: In total, paclitaxel PK data from 684 patients were available, consisting of 166 patients ≥70 years (24%). Median age of the cohort was 61 years (range 18 to 84 years). The impact of age, either treated as a continuous or dichotomous covariate (<70 versus ≥70 years), on the elimination of paclitaxel was only marginal but statistically significant (both p < 0.001 with no clinically relevant decrease in interindividual variability). For a typical patient, maximal elimination capacity decreased by only 5% for a 10-year increment of age.CONCLUSION: In this extensive multi-center dataset, which included a considerable number of older patients, older age had no clinically relevant impact on paclitaxel PK.
|
|
| 44. |
|
|
| 45. |
- de Vries, P. C., et al.
(författare)
-
Effect of toroidal field ripple on plasma rotation in JET
- 2008
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 48:3
-
Tidskriftsartikel (refereegranskat)abstract
- Dedicated experiments on TF ripple effects on the performance of tokamak plasmas have been carried out at JET. The TF ripple was found to have a profound effect on the plasma rotation. The central Mach number, M, defined as the ratio of the rotation velocity and the thermal velocity, was found to drop as a function of TF ripple amplitude (3) from an average value of M = 0.40-0.55 for operations at the standard JET ripple of 6 = 0.08% to M = 0.25-0.40 for 6 = 0.5% and M = 0.1-0.3 for delta = 1%. TF ripple effects should be considered when estimating the plasma rotation in ITER. With standard co-current injection of neutral beam injection (NBI), plasmas were found to rotate in the co-current direction. However, for higher TF ripple amplitudes (delta similar to 1%) an area of counter rotation developed at the edge of the plasma, while the core kept its co-rotation. The edge counter rotation was found to depend, besides on the TF ripple amplitude, on the edge temperature. The observed reduction of toroidal plasma rotation with increasing TF ripple could partly be explained by TF ripple induced losses of energetic ions, injected by NBI. However, the calculated torque due to these losses was insufficient to explain the observed counter rotation and its scaling with edge parameters. It is suggested that additional TF ripple induced losses of thermal ions contribute to this effect.
|
|
| 46. |
- de Vries, P. C., et al.
(författare)
-
Effect of toroidal field ripple on the formation of internal transport barriers
- 2008
-
Ingår i: Plasma Physics and Controlled Fusion. - : IOP Publishing. - 0741-3335 .- 1361-6587. ; 50:6
-
Tidskriftsartikel (refereegranskat)abstract
- The effect of a toroidal field (TF) ripple on the formation and performance of internal transport barriers (ITBs) has been studied in JET. It was found that the TF ripple had a profound effect on the toroidal plasma rotation. An increased TF ripple up to delta = 1% led to a lower rotation and reduced the rotational shear in the region where the ITBs were formed. ITB triggering events were observed in all cases and it is thought that the rotational shear may be less important for this process than, for example, the q-profile. However, the increase in the pressure gradient following the ITB trigger was reduced in discharges with a larger TF ripple and consequently a lower rotational shear. This suggests that toroidal rotation and its shear play a role in the growth of the ITB once it has been triggered.
|
|
| 47. |
- de Vries, P. C., et al.
(författare)
-
Multi-machine analysis of termination scenarios with comparison to simulations of controlled shutdown of ITER discharges
- 2018
-
Ingår i: Nuclear Fusion. - : IOP PUBLISHING LTD. - 0029-5515 .- 1741-4326. ; 58:2
-
Tidskriftsartikel (refereegranskat)abstract
- To improve our understanding of the dynamics and control of ITER terminations, a study has been carried out on data from existing tokamaks. The aim of this joint analysis is to compare the assumptions for ITER terminations with the present experience basis. The study examined the parameter ranges in which present day devices operated during their terminations, as well as the dynamics of these parameters. The analysis of a database, built using a selected set of experimental termination cases, showed that, the H-mode density decays slower than the plasma current ramp-down. The consequential increase in f(GW) limits the duration of the H-mode phase or result in disruptions. The lower temperatures after the drop out of H-mode will allow the plasma internal inductance to increase. But vertical stability control remains manageable in ITER at high internal inductance when accompanied by a strong elongation reduction. This will result in ITER terminations remaining longer at low q (q(95) similar to 3) than most present-day devices during the current ramp-down. A fast power ramp-down leads to a larger change in beta(P) at the H-L transition, but the experimental data showed that these are manageable for the ITER radial position control. The analysis of JET data shows that radiation and impurity levels significantly alter the H-L transition dynamics. Self-consistent calculations of the impurity content and resulting radiation should be taken into account when modelling ITFR termination scenarios. The results from this analysis can be used to better prescribe the inputs for the detailed modelling and preparation of ITER termination scenarios.
|
|
| 48. |
- de Vries, P. C., et al.
(författare)
-
Scaling of the MHD perturbation amplitude required to trigger a disruption and predictions for ITER
- 2016
-
Ingår i: Nuclear Fusion. - : IOP PUBLISHING LTD. - 0029-5515 .- 1741-4326. ; 56:2
-
Tidskriftsartikel (refereegranskat)abstract
- The amplitude of locked instabilities, likely magnetic islands, seen as precursors to disruptions has been studied using data from the JET, ASDEX Upgrade and COMPASS tokamaks. It was found that the thermal quench, that often initiates the disruption, is triggered when the amplitude has reached a distinct level. This information can be used to determine thresholds for simple disruption prediction schemes. The measured amplitude in part depends on the distance of the perturbation to the measurement coils. Hence the threshold for the measured amplitude depends on the mode location (i.e. the rational q-surface) and thus indirectly on parameters such as the edge safety factor, q(95), and the internal inductance, li(3), that determine the shape of the q-profile. These dependencies can be used to set the disruption thresholds more precisely. For the ITER baseline scenario, with typically q(95) = 3.2, li(3) = 0.9 and taking into account the position of the measurement coils on ITER, the maximum allowable measured locked mode amplitude normalized to engineering parameters was estimated to be a.B-ML(r
|
|
| 49. |
- de Vries Schultink, Aurelia H M, et al.
(författare)
-
Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens.
- 2018
-
Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 45:3, s. 431-442
-
Tidskriftsartikel (refereegranskat)abstract
- Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure-response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab. Repeated measurements of LVEF, troponin T and NT-proBNP and dosing records of anthracyclines and trastuzumab were available from a previously published clinical trial. This trial included 206 evaluable patients with early breast cancer. Exposure to anthracycline and trastuzumab was simulated based on available dosing records and by using a kinetic-pharmacodynamic (K-PD) and a fixed pharmacokinetic (PK) model from literature, respectively. The change from baseline troponin T was described with a direct effect model, affected by simulated anthracycline concentrations, representing myocyte damage. The relationship between trastuzumab and LVEF was described by an indirect effect compartment model. The EC50 for LVEF decline was significantly affected by the maximum troponin T concentration after anthracycline treatment, explaining 15.1% of inter-individual variability. In this cohort, NT-proBNP changes could not be demonstrated to be related to anthracycline or trastuzumab treatment. Pharmacodynamic models for troponin T and LVEF were successfully developed, identifying maximum troponin T concentration after anthracycline treatment as a significant determinant for trastuzumab-induced LVEF decline. These models can help identify patients at risk of drug-induced cardiotoxicity and optimize cardiac monitoring strategies.
|
|
| 50. |
- de Vries Schultink, Aurelia H M, et al.
(författare)
-
Population Pharmacokinetics of MCLA-128, a HER2/HER3 Bispecific Monoclonal Antibody, in Patients with Solid Tumors.
- 2020
-
Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 59:7, s. 875-884
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors and is in development to overcome HER3-mediated resistance to anti-HER2 therapies. The aims of this analysis were to characterize the population pharmacokinetics of MCLA-128 in patients with various solid tumors, to evaluate patient-related factors that affect the disposition of MCLA-128, and to assess whether flat dosing is appropriate.METHODS: MCLA-128 concentration data following intravenous administration were collected in a phase I/II clinical trial. Pharmacokinetic data were analyzed using non-linear mixed-effects modeling. Different compartmental models were evaluated. Various body size parameters including body weight, body surface area, and fat-free mass were evaluated as covariates in addition to age, sex, HER2 status, and tumor burden.RESULTS: In total, 1115 serum concentration measurements were available from 116 patients. The pharmacokinetics of MCLA-128 was best described by a two-compartment model with linear and non-linear (Michaelis-Menten) clearance. Fat-free mass significantly affected the linear clearance and volume of distribution of the central compartment of MCLA-128, explaining 8.4% and 5.6% of inter-individual variability, respectively. Tumor burden significantly affected the non-linear clearance capacity. Simulations demonstrated that dosing based on body size parameters resulted in similar area under the plasma concentration-time curve for a dosing interval (AUC0-τ), maximum and trough concentrations of MCLA-128, compared to flat dosing.CONCLUSIONS: This analysis demonstrated that the pharmacokinetics of MCLA-128 exhibits similar disposition characteristics to other therapeutic monoclonal antibodies and that a flat dose of MCLA-128 in patients with various solid tumors is appropriate.
|
|
