Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.

ITER monoblock performance under lifetime loading conditions in Magnum-PSI

The ITER divertor will be exposed to extremely high plasma fluences over its lifetime, and it is known that plasma exposure can lead to a variety of particle-induced surface-morphology and microstructure changes in tungsten. However, no data exists at fluences comparable to those expected over extended ITER operations (10 30−31 m−2) and so it is uncertain how these changes will evolve and affect the divertor performance over such long timescales. Six monoblocks were exposed to high flux plasma comparable to partially-detached plasma conditions in the ITER divertor in Magnum-PSI. Different exposures used different plasma species (H, He, D or D + He) and aimed to replicate conditions similar to those during different phases of the ITER staged approach. The highest fluence achieved was 10 30 D m−2, comparable to around one year of ITER Fusion Power Operation. Post-mortem analysis by Nuclear Reaction Analysis revealed very low deuterium retention throughout the blocks, while surface analysis showed no cracking or damage, but did observe helium fuzz growth at low ion energies of 8–18 eV, below typically assumed ion energy requirements for such growth to occur. Metallographic sectioning revealed recrystallization up to 2.2 mm below the surface of monoblocks exposed at peak surface temperatures of up to 1580 °C for different durations up to ~20 h. Finite Element Method analysis coupled to metallographic and Vickers Hardness identification of the boundary of the recrystallized region identified a faster recrystallization process compared to literature expectations, reinforcing that recrystallization dynamics is an important criterion for tungsten grade selection for the ITER divertor. Overall, no major damage or failure was identified, indicating that the design is capable of fulfilling its steady-state performance requirements under high flux, high fluence plasma loading conditions in the ITER divertor

ITER monoblock performance under lifetime loading conditions in Magnum-PSI

The ITER divertor will be exposed to extremely high plasma fluences over its lifetime, and it is known that plasma exposure can lead to a variety of particle-induced surface-morphology and microstructure changes in tungsten. However, no data exists at fluences comparable to those expected over extended ITER operations (10 30−31 m−2) and so it is uncertain how these changes will evolve and affect the divertor performance over such long timescales. Six monoblocks were exposed to high flux plasma comparable to partially-detached plasma conditions in the ITER divertor in Magnum-PSI. Different exposures used different plasma species (H, He, D or D + He) and aimed to replicate conditions similar to those during different phases of the ITER staged approach. The highest fluence achieved was 10 30 D m−2, comparable to around one year of ITER Fusion Power Operation. Post-mortem analysis by Nuclear Reaction Analysis revealed very low deuterium retention throughout the blocks, while surface analysis showed no cracking or damage, but did observe helium fuzz growth at low ion energies of 8–18 eV, below typically assumed ion energy requirements for such growth to occur. Metallographic sectioning revealed recrystallization up to 2.2 mm below the surface of monoblocks exposed at peak surface temperatures of up to 1580 °C for different durations up to ~20 h. Finite Element Method analysis coupled to metallographic and Vickers Hardness identification of the boundary of the recrystallized region identified a faster recrystallization process compared to literature expectations, reinforcing that recrystallization dynamics is an important criterion for tungsten grade selection for the ITER divertor. Overall, no major damage or failure was identified, indicating that the design is capable of fulfilling its steady-state performance requirements under high flux, high fluence plasma loading conditions in the ITER divertor

Mitigated blistering and deuterium retention in tungsten exposed to high-flux deuterium–neon mixed plasmas

Surface morphology and deuterium retention in tungsten exposed at surface temperature of &amp;nbsp;550 K to mixed deuterium–neon plasmas of different neon concentrations are investigated. It is found that the addition of neon up to 20% mitigates blistering on the surface. Cross-section view of the surface shows the formation of pores near the surface in the depth less than 100 nm. Deuterium depth profile is featured by an enhanced deuterium concentration within a depth of 16 nm but a mitigated penetration in depth larger than 1 µ m. Deuterium retention is reduced by up to a factor of four. It is suggested the open pores formed in the surface serves as an escaping channel, mitigates deuterium penetration towards bulk and retention in the bulk

Latest results of EUROfusion Plasma-Facing Components research in the areas of power loading, material erosion and fuel retention

The interaction between the edge-plasma in a fusion reactor and the surrounding first-wall components is one of the main issues for the realisation of fusion energy power plants. The EUROfusion Work Package on Plasma-Facing Components addresses the key areas of plasma-surface interaction in view of ITER and DEMO operation, which are mostly related to material erosion, surface damage and fuel retention. These aspects are both investigated experimentally (in tokamaks, linear plasma devices and lab experiments) and by modelling. Here, selective results regarding the main research topics are presented: In the area of tungsten (W) surface modifications, the interplay between W fuzz formation and W fuzz erosion depends strongly on the local plasma and surface conditions, as demonstrated by tokamak experiments. Complementary, experimental findings on the dependence of erosion on the surface structure in lab-scale experiments have led to the successful implementation of surface structure effects in numerical modelling. The qualification of ITER-like monoblocks at high fluences of up to 1031 D/m² in linear plasma facilities has shown no visible damages at cold plasma conditions. However, experiments with simultaneous plasma and pulsed heat loading (edge-localized modes simulations) show that synergistic effects can lower the W damage thresholds. Additionally, fuel retention studies show that nitrogen as a plasma impurity increases the fuel retention in W, and that deuterium implanted in the surface of W is capable of stabilizing displacement damages caused by neutron damage. Finally, the implications of these results on ITER and DEMO operation are discussed and an outlook on follow-up experiments is given: The results indicate that there are possible impacts on the ITER divertor lifetime and tritium removal. Other areas like the divertor shaping and the erosion need additional investigations in the future to quantify the impact on ITER and DEMO operation

Latest results of EUROfusion Plasma-Facing Components research in the areas of power loading, material erosion and fuel retention

The interaction between the edge-plasma in a fusion reactor and the surrounding first-wall components is one of the main issues for the realisation of fusion energy power plants. The EUROfusion Work Package on Plasma-Facing Components addresses the key areas of plasma-surface interaction in view of ITER and DEMO operation, which are mostly related to material erosion, surface damage and fuel retention. These aspects are both investigated experimentally (in tokamaks, linear plasma devices and lab experiments) and by modelling. Here, selective results regarding the main research topics are presented: In the area of tungsten (W) surface modifications, the interplay between W fuzz formation and W fuzz erosion depends strongly on the local plasma and surface conditions, as demonstrated by tokamak experiments. Complementary, experimental findings on the dependence of erosion on the surface structure in lab-scale experiments have led to the successful implementation of surface structure effects in numerical modelling. The qualification of ITER-like monoblocks at high fluences of up to 1031 D/m² in linear plasma facilities has shown no visible damages at cold plasma conditions. However, experiments with simultaneous plasma and pulsed heat loading (edge-localized modes simulations) show that synergistic effects can lower the W damage thresholds. Additionally, fuel retention studies show that nitrogen as a plasma impurity increases the fuel retention in W, and that deuterium implanted in the surface of W is capable of stabilizing displacement damages caused by neutron damage. Finally, the implications of these results on ITER and DEMO operation are discussed and an outlook on follow-up experiments is given: The results indicate that there are possible impacts on the ITER divertor lifetime and tritium removal. Other areas like the divertor shaping and the erosion need additional investigations in the future to quantify the impact on ITER and DEMO operation