The international fusion materials irradiation facility-DEMO-oriented neutron source (IFMIF-DONES) is a facility that is designed under the framework of the EU fusion roadmap. It is going to be an ...essential irradiation facility for testing and qualifying candidate materials under severe irradiation conditions of a neutron field having an energy spectrum like the one present in a fusion power reactor. The material specimens are irradiated in a containment structure named the test cell (TC), which is part of the test systems (TS). The TC also houses a part of the other major system (lithium system, LS), which provides the liquid lithium for the reaction through a piping system. At a point, the lithium piping needs to exit the TS, but the primary safety boundary must be continuous around these penetrations. Therefore, a special barrier, called the test systems–lithium systems interface cell (TLIC), has been developed around the piping system to provide a safety-approved and remotely maintainable vacuum boundary envelope. In this paper, the integrated design development of the TLIC is described, consisting of the design development according to the RCC-MRx code, the remote-handling (RH) needs, and the procedures and safety-related special needs of the design.
IFMIF-DONES is a facility under construction in Granada, whose main goal is the validation and characterization of materials under a fusion prototypic irradiation field. This field is created by the ...interaction of a high energy intense continuous deuteron beam and a flowing liquid lithium target. The requirements imposed on the beam at the interaction point are a complex trade-off among the scientific experimental needs for the materials irradiation defined at the top-level requirements (20 dpa in a volume of 0.3 dm3 and 50 dpa in 0.1 dm3), and the technical constraints of several systems such as the Accelerator Systems, the Lithium Systems, and the Test Systems. Recent simulations with the initial definition of beam-on-target requirements showed the necessity of redefining them in order to fulfill the irradiation needs. This contribution will address the main challenges to gather the inputs for the definition and reassessment of the beam-on-target requirements. A comparison detailing the main changes compared to the previous ones will be given, together with a short overview of the studies ongoing by different systems to analyze the impact of each beam-on-target requirements on the performance of the whole facility.
•Fusion materials irradiation.•Deuteron accelerator.•High current accelerator.•Beam delivery system.•Beam on-target.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•7Be has no radiological implications in the hydrogen trap room of future IFMIF-DONES during normal operation and maintenance operations.•In normal operation maximum ambient dose equivalent rates of ...15.1 mSv/h at contact with the hydrogen trap and 0.31 mSv/h at 1 m has been assessed.•In maintenance operation maximum dose rates of 1.42 mSv/h has been estimated.•A concrete wall 30 cm thick located at 1 m of the hydrogen trap would reduce the dose rate at allowed radiation dose limits levels for workers.
The radiological impact that 7Be and activated corrosion products (ACP) dissolved in Li could have in normal operation and maintenance in the surroundings of the hydrogen trap (HT) of future IFMIF-DONES facility has been assessed. Ambient dose equivalent rates were calculated with radiation transport program MCNP at half height of trap. Four different Y contents were considered in the trap: 1, 3, 5 and 8 kg. In normal operation dose rates in the range 13.7–15.1 mSv/h have been found in contact with the trap and 0.28–0.31 mSv/h at 1 m of the trap. 7Be has a very low contribution to dose (3–3.7 µSv/h). Dose simulations have shown that a concrete wall 30 cm thick can reduce dose rates to acceptable dose limits. In maintenance operation the trap is drained and Li film remains attached to Y pebbles. Three possible Li film thickness have been considered: 10, 50 and 100 µm. Estimated 7Be activity is below exemption limits during maintenance. Assessed dose rates are in the range 34–1420 µSv/h at contact with the trap and a maximum of 10.9 µSv/h at 1 m of the trap.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The IFMIF-DONES (International Fusion Materials Irradiation Facility-Demo Oriented NEutron Source) test cell (TC) biological shielding is responsible of providing sufficient protection for the ...surrounding rooms and cells from intensive neutron irradiation and gamma radiation from inside of the TC. The TC biological shielding is composed of surrounding shielding walls, two top shielding plugs, six piping and cabling plugs (PCPs), TC floor, and removable shielding materials below the TC floor. Based on the previous TC configuration, the design of the lower shielding plug has been further developed by defining the specifications of embedded helium active cooling systems with the support of neutronic simulations, CFD analysis, and remote handling requirements. The PCP design is updated to provide sufficient space for pipe and cable connections. A preliminary piping of the water cooling system inside the heavy concrete shielding walls has been performed to qualify the capability of removing volumetric nuclear heating during irradiation experiments. The geometry of TC surrounding shielding walls are adjusted according to the latest design of PCPs and LSP as well as the requirements of the active cooling pipes which are embedded in the TC surrounding walls.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Introduction The strengthening effect of prophylactic internal fixation (PIF) with a bone plate at the radial osteocutaneous flap donor site has previously been demonstrated using the sheep ...tibia model of the human radius. This study investigated whether a finite element (FE) model could accurately represent this biomechanical model and whether stress or strain based failure criteria are most appropriate. Methods An FE model of an osteotomised sheep tibia bone was strengthened using 4 types of plates with unilocking or bicortical screw fixation. Torsion and 4-point bending simulations were performed. The maximum von Mises stresses and strain failure criteria were studied. Results The strengthening effects when applying stress failure criteria factor 1.76–4.57 bending and 1.33–1.80 torsion were comparable to the sheep biomechanical model factor 1.73–2.43 bending and 1.54–2.63 torsion. The strongest construct was the straight 3.5 mm stainless steel unilocking plate. Applying strain criteria the strongest construct was the straight 3.5 mm stainless DCP plate with bicortical screw fixation. Conclusions The FE model was validated by comparison with the sheep tibia model. The complex biomechanics at the bone-screw interface require further investigation. This FE modelling technique may be applied to a model of the human radius and other sites.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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Alignment strategy for IFMIF-DONES facility Arranz, Fernando; Becerril, Santiago; Bernardi, Davide ...
Fusion engineering and design,
March 2024, 2024-03-00, Volume:
200
Journal Article
Peer reviewed
Open access
This article addresses the challenges associated with the alignment of the equipment within the IFMIF DONES installation and presents the strategy devised to achieve acceptable levels of uncertainty. ...The primary obstacles stem from the need to align equipment located in different rooms, some of which are inaccessible for manual operations. Additionally, the elevated radiation levels in certain areas impose restrictions on the fiducials that can be employed.
The article details the outcomes of implementing the proposed alignment procedure, including the specific equipment used and the achieved levels of uncertainty.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Polyethylene glycol (PEG)-coated nanopharmaceuticals can cause mild to severe hypersensitivity reactions (HSRs), which can occasionally be life threatening or even lethal. The phenomenon represents ...an unsolved immune barrier to the use of these drugs, yet its mechanism is poorly understood. This study showed that a single i.v. injection in pigs of a low dose of PEGylated liposomes (Doxebo) induced a massive rise of anti-PEG IgM in blood, peaking at days 7–9 and declining over 6 weeks. Bolus injections of PEG-liposomes during seroconversion resulted in anaphylactoid shock (pseudo-anaphylaxis) within 2–3 min, although similar treatments of naı̈ve animals led to only mild hemodynamic disturbance. Parallel measurement of pulmonary arterial pressure (PAP) and sC5b-9 in blood, taken as measures of HSR and complement activation, respectively, showed a concordant rise of the two variables within 3 min and a decline within 15 min, suggesting a causal relationship between complement activation and pulmonary hypertension. We also observed a rapid decline of anti-PEG IgM in the blood within minutes, increased binding of PEGylated liposomes to IgM + B cells in the spleen of immunized animals compared to control, and increased C3 conversion by PEGylated liposomes in the serum of immunized pigs. These observations taken together suggest rapid binding of anti-PEG IgM to PEGylated liposomes, leading to complement activation via the classical pathway, entailing anaphylactoid shock and accelerated blood clearance of liposome–IgM complexes. These data suggest that complement activation plays a causal role in severe HSRs to PEGylated nanomedicines and that pigs can be used as a hazard identification model to assess the risk of HSRs in preclinical safety studies.
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IJS, KILJ, NUK, PNG, UL, UM
A small fraction of people vaccinated with mRNA-lipid nanoparticle (mRNA-LNP)-based COVID-19 vaccines display acute or subacute inflammatory symptoms whose mechanism has not been clarified to date. ...To better understand the molecular mechanism of these adverse events (AEs), here, we analyzed in vitro the vaccine-induced induction and interrelations of the following two major inflammatory processes: complement (C) activation and release of proinflammatory cytokines. Incubation of Pfizer-BioNTech's Comirnaty and Moderna's Spikevax with 75% human serum led to significant increases in C5a, sC5b-9, and Bb but not C4d, indicating C activation mainly via the alternative pathway. Control PEGylated liposomes (Doxebo) also induced C activation, but, on a weight basis, it was ~5 times less effective than that of Comirnaty. Viral or synthetic naked mRNAs had no C-activating effects. In peripheral blood mononuclear cell (PBMC) cultures supplemented with 20% autologous serum, besides C activation, Comirnaty induced the secretion of proinflammatory cytokines in the following order: IL-1α < IFN-γ < IL-1β < TNF-α < IL-6 < IL-8. Heat-inactivation of C in serum prevented a rise in IL-1α, IL-1β, and TNF-α, suggesting C-dependence of these cytokines' induction, although the C5 blocker Soliris and C1 inhibitor Berinert, which effectively inhibited C activation in both systems, did not suppress the release of any cytokines. These findings suggest that the inflammatory AEs of mRNA-LNP vaccines are due, at least in part, to stimulation of both arms of the innate immune system, whereupon C activation may be causally involved in the induction of some, but not all, inflammatory cytokines. Thus, the pharmacological attenuation of inflammatory AEs may not be achieved via monotherapy with the tested C inhibitors; efficacy may require combination therapy with different C inhibitors and/or other anti-inflammatory agents.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Complement (C) activation can underlie the infusion reactions to liposomes and other nanoparticle-based medicines, a hypersensitivity syndrome that can be partially reproduced in animal models. ...However, the sensitivities and manifestations substantially differ in different species, and C activation may not be the only cause of pathophysiological changes. In order to map the species variation of C-dependent and -independent pseudoallergy (CARPA/CIPA), here we used known C activators and C activator liposomes to compare their acute hemodynamic, hematological, and biochemical effects in rats. These C activators were cobra venom factor (CVF), zymosan, AmBisome (at 2 doses), its amphotericin B-free vehicle (AmBisombo), and a PEGylated cholesterol-containing liposome (PEG-2000-chol), all having different powers to activate C in rat blood. The pathophysiological endpoints measured were blood pressure, leukocyte and platelet counts, and plasma thromboxane B2, while C activation was assessed by C3 consumption using the Pan-Specific C3 assay. The results showed strong linear correlation between C activation and systemic hypotension, pointing to a causal role of C activation in the hemodynamic changes. The observed thrombocytopenia and leukopenia followed by leukocytosis also correlated with C3 conversion in case of C activators, but not necessarily with C activation by liposomes. These findings are consistent with the double hit hypothesis of hypersensitivity reactions (HSRs), inasmuch as strong C activation can fully account for all symptoms of HSRs, but in case of no-, or weak C activators, the pathophysiological response, if any, is likely to involve other activation pathways.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A tiny fraction of people immunized with lipid nanoparticle (LNP)-enclosed mRNA (LNP-mRNA) vaccines develop allergic symptoms following their first or subsequent vaccinations, including anaphylaxis. ...These reactions resemble complement (C) activation-related pseudoallergy (CARPA) to i.v. administered liposomes, for which pigs provide a naturally oversensitive model. Using this model, we injected i.v. the human vaccination dose (HVD) of BNT162b2 (Comirnaty, CMT) or its 2-fold (2x) or 5-fold (5x) amounts and measured the hemodynamic changes and other parameters of CARPA. We observed in 6 of 14 pigs transient pulmonary hypertension along with thromboxane A2 release into the blood and other hemodynamic and blood cell changes, including hypertension, granulocytosis, lymphopenia, and thrombocytopenia. One pig injected with 5x CMT developed an anaphylactic shock requiring resuscitation, while a repeat dose failed to induce the reaction, implying tachyphylaxis. These typical CARPA symptoms could not be linked to animal age, sex, prior immune stimulation with zymosan, immunization of animals with Comirnaty i.v., or i.m. 2 weeks before the vaccine challenge, and anti-PEG IgM levels in Comirnaty-immunized pigs. Nevertheless, IgM binding to the whole vaccine, used as antigen in an ELISA, was significantly higher in reactive animals compared to non-reactive ones. Incubation of Comirnaty with pig serum in vitro showed significant elevations of C3a anaphylatoxin and sC5b-9, the C-terminal complex. These data raise the possibility that C activation plays a causal or contributing role in the rare HSRs to Comirnaty and other vaccines with similar side effects. Further studies are needed to uncover the factors controlling these vaccine reactions in pigs and to understand their translational value to humans.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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