High Plasma Exposure Research Articles

High Plasma Exposure of Statins Associated With Increased Risk of Contrast-Induced Acute Kidney Injury in Chinese Patients With Coronary Artery Disease.

The role of statins in reducing the incidence of contrast-induced acute kidney injury (CI-AKI) remains controversial. We sought to evaluate the association between CI-AKI and high plasma exposure of statins in coronary artery disease (CAD) patients undergoing coronary angiography (CAG). This association was first evaluated in 1,219 patients with CAD receiving atorvastatin (AT) therapy and validated in 635 patients receiving rosuvastatin (RST) therapy. The plasma concentrations of statins were quantified using validated UPLC-MS/MS methods and CI-AKI incidence was assessed during the first 48 h postoperatively. Among all participants (n = 1,854), AKI occurred in 57 of 1219 (4.7%) in the AT cohort and 30 of 635 (4.7%) in the RST cohort. High plasma AT-all exposure was associated with increased risk of CI-AKI (odds ratio [OR]: 2.265; 95% confidence interval [CI]: 1.609–3.187; p < 0.0001). Plasma AT-all concentration in the CI-AKI group (22.40 ± 24.63 ng/mL) was 2.6-fold higher than that in the control group (8.60 ± 9.65 ng/mL). High plasma RST exposure also significantly increased the risk of CI-AKI (OR: 2.281; 95% CI: 1.441–3.612; p = 0.0004). We further divided patients into two subgroups for each statin according to baseline renal function, and association between high plasma statin exposure and CI-AKI still remained highly significant in both subgroups. This study suggests for the first time that high plasma exposure of statins may significantly increase the risk of CI-AKI. Statins should be used with greater caution in CAD patients undergoing CAG to reduce the occurrence of CI-AKI.

Nanochannel structures in W enhance radiation tolerance

Developing high performance plasma facing materials (PFMs) is one of the greatest challenges for fusion reactors, because PFMs face unprecedented harsh environments including high flux plasma exposure, fast neutron irradiation and large transmutation gas. Tungsten (W) is considered as one of the most promising PFMs. Rapid accumulation of helium (He) atoms in such environments can lead to the He bubbles nucleation and even the formation of nano- to micro-scale “fuzz” on W surface, which greatly degrade the properties of W itself. The possible ejection of large W particulates into the core plasma can cause plasma instabilities. Here, we present a new strategy to address the root causes of bubble nucleation and “fuzz” formation by concurrently releasing He outside of W matrix through the nano-engineered channel structure (nanochannels). Comparing to ordinary bulk W, nanochannel W films with high surface-to-volume ratios are found to not only delay the growth of He bubbles, but also suppress the formation of “fuzz” (less than a half of the “fuzz” thickness formation in bulk W). Molecular dynamic (MD) simulation results elucidate that low vacancy formation energy and high He binding energy in the nanochannel surface effectively help He release and affect He clusters distribution in W during He ion irradiation.

Materials surface damage and modification under high power plasma exposures

Influence of powerful plasma impacts on several materials used for the construction of energy systems, i.e. different grades of steels as well as tungsten coatings, has been discussed. Irradiations of these materials with hydrogen and helium plasma streams have been performed in several high-current-pulse and quasi-stationary plasma accelerators which provided the variation of a power load upon the exposed surface as well as changes of the particle flux in wide ranges: the energy flux density in the range of 1-25 MJ/m2, particle flux - up to 1026-1029 ion/m2s, the plasma stream velocity - up to about 500 km/s, and the pulse duration in the range of 1-250 μs.A response of the investigated materials to extreme plasma loads, which are relevant to transient events in fusion reactors, is briefly discussed. It is demonstrated that a broad combination of mechanisms of powerful plasma interactions with various materials includes not only a surface damage caused by different erosion mechanisms, but under certain conditions it may also result in a significant improvement of material properties in the near-surface surface layer of several tens-μm in thickness. Some improvement of the structure and substructure of such a layer may be caused by the high-speed quenching, the shock wave formation and material alloying with plasma- and coating-species. The creation of unique surface structures and a considerable improvement of physical and mechanical properties of different materials can be achieved by the pulsed plasma alloying, i.e. pre-deposited coating modifications and mixing caused by the impacting plasma streams.

S1P1 Modulator-Induced Gαi Signaling and β-Arrestin Recruitment Are Both Necessary to Induce Rapid and Efficient Reduction of Blood Lymphocyte Count In Vivo

S1P1 (sphingosine-1-phosphate receptor 1) agonists prevent lymphocyte egress from secondary lymphoid organs and cause a reduction in the number of circulating blood lymphocytes. We hypothesized that S1P1 receptor modulators with pathway-selective signaling properties could help to further elucidate the molecular mechanisms involved in lymphocyte trapping. A proprietary S1P1 receptor modulator library was screened for compounds with clear potency differences in β-arrestin recruitment and G protein alpha i subunit (G αi) protein-mediated signaling. We describe here the structure-activity relationships of highly potent S1P1 modulators with apparent pathway selectivity for β-arrestin recruitment. The most differentiated compound, D3-2, displayed a 180-fold higher potency in the β-arrestin recruitment assay (EC50 0.9 nM) compared with the G αi-activation assay (167 nM), whereas ponesimod, a S1P1 modulator that is currently in advanced clinical development in multiple sclerosis, was equipotent in both assays (EC50 1.5 and 1.1 nM, respectively). Using these novel compounds as pharmacological tools, we showed that although a high potency in β-arrestin recruitment is required to fully internalize S1P1 receptors, the potency in inducing G αi signaling determines the rate of receptor internalization in vitro. In contrast to ponesimod, the compound D3-2 did not reduce the number or circulating lymphocytes in rats despite high plasma exposures. Thus, for rapid and maximal S1P1 receptor internalization a high potency in both G αi signaling and β-arrestin recruitment is mandatory and this translates into efficient reduction of the number of circulating lymphocytes in vivo.

Microstructure and nano-hardness of single crystal tungsten exposed to high flux deuterium plasma

The impact of the high flux deuterium plasma (mimicking ITER conditions) exposure on the surface hardness and microstructure of single crystal tungsten is assessed. Transmission electron microscopy revealed that the plasma exposure resulted in the formation of a dense dislocation network with a density of dislocation lines reaching (1–5) × 1013 m−2, depending on the exposure temperature. A combined analysis of the already available data and obtained here results suggest that under the investigated plasma conditions a highly localized plastic deformation occurs irrespective of the initial dislocation density or availability of grains and sub-grains. On the one hand, the presence of the plastic deformation explains the high level of sub-surface D trapping measured by nuclear reaction analysis (up to 10−2 atomic fraction within the top layer), and on the other hand—it explains the extra hardness measured within the region of the plasma-induced plastic deformation. A dedicated experiment to validate the above hypothesis is proposed.

The electrochemistry of iron oxide thin films nanostructured by high ion flux plasma exposure

Photo-electrochemical (PEC) water splitting of hematite photoanodes suffers from low performance and efficiency. One way to increase the performance is to increase the electrochemically active surface area available for the oxygen evolution reaction. In this study, we use high ion flux, low energy helium plasma exposure to nanostructure sputtered iron thin films. Subsequent annealing in air at 645 °C leads to the formation of PEC active hematite (α-Fe2O3) phase in these films. The surface area, as derived from electrochemical impedance spectroscopy (EIS), was seen to increase 10–40 times with plasma exposure. The photocurrent density increased by 2–5 times for the plasma exposed films as compared to the unexposed films. However, the less nanostructured film showed a higher photocurrent density. These findings were explained by detailed chemical and structural characterization in combination with electrochemical characterization and attributed to the presence of secondary elements in the film as well as to the presence of secondary iron oxide phases apart from hematite. This work demonstrates the complex effect of plasma exposure on both film morphology and chemical composition of PEC thin films and provides further understanding on how this technique can be used for nanostructuring of other functional films.

Impact of plastic deformation on plasma induced damage and deuterium retention in tungsten

ABSTRACTRecent theoretical and subsequent experimental studies suggest that the uptake and release of deuterium (D) in tungsten (W) under high flux ITER-relevant plasma exposure is controlled by dislocation microstructure. Thanks to numerical calculations, a comprehensive mechanism for the nucleation and growth of D bubbles on dislocation network was proposed. The process of bubble nucleation can be described as D atom trapping at a dislocation line, its in-core migration, the coalescence of several D atoms into a multiple cluster eventually transforming into a nano-bubble. This view implies that the initial microstructure might be crucial for D uptake and degradation of the sub-surface layer under prolonged plasma exposure. In this work, we apply several experimental techniques to investigate the microstructure and mechanical properties of surface and sub-surface layer of W in recrystallized and plastically-deformed condition exposed to the high flux plasma. We use transmission and scanning electron microscopy, thermal desorption spectroscopy as well as nano-indentation measurements.

Deuterium retention in RAFM steels after high fluence plasma exposure

Deuterium retention and detrapping behavior in the ferritic-martensitic steels EUROFER’97 and P92 after exposure to plasma at high fluences ≥ 1026D/m2 was studied using thermal desorption spectroscopy (TDS), supported by nuclear reaction analysis. Low-temperature irradiation at 450K and fluences ≥ 1026D/m2 with low impact energy D+ / D++He+ ions of 40eV at PSI-2 resulted in a deuterium inventory of 7–18 ×1019D/m2 predominantly at depths ≥8.6µm. Helium admixture led to a reduction of total D retention in both steels, irrespective of surface erosion and composition. The deuterium spectra of both steels displayed one D2 desorption peak at ∼ 540–570K and HD maxima at 540–590, 700–730 and 900–930K. It is suggested that deuterium is mostly retained in the bulk of steel material on interfaces of carbide precipitates and on grain boundaries.

Microstructure and deuterium retention of beryllium co-deposition layer formed under high density plasma exposure

A systematic study of the temperature effect on the microstructure and the deuterium retention property in beryllium co-deposition layers has been carried out using W samples exposed to D+Be and D+Be+He mixture plasmas in the linear divertor plasma simulator PISCES-B. A deposition layer consisting of small grains of ∼10nm with original hexagonal close-packed structure of beryllium was formed on a sample exposed to D+Be mixture plasmas at low temperature of 373K. He seeding to the mixture plasmas was found to cause amorphization of the layer. In contrast, columnar structure consisting of Be2C due to crystal growth appeared at high temperature exposure cases of > 773K both with and without He seeding. The formation of these deposition layers brought about a significant D retention. Assuming all retained D atoms uniformly distribute within the deposition layers, the D/Be ratios are estimated to be about 0.05 for the low temperature exposure case of 573K, and to be about 0.01 even for the high temperature at 773K. In addition, post-irradiation of 3keV-D2+ for Be deposited sample demonstrated that the hydrogen isotope retention behavior can be modified drastically, once the Be deposition layer is formed.

An integrated strategy using UPLC–QTOF-MSE and UPLC–QTOF-MRM (enhanced target) for pharmacokinetics study of wine processed Schisandra Chinensis fructus in rats

Currently the pharmacokinetic (PK) research of herbal medicines is still limited and facing critical technical challenges on quantitative analysis of multi-components from biological matrices which often accompanied by lacking of authentic standards and low concentration. This present work contributes to the development of an integrated strategy for extensive pharmacokinetics assessments, and a selective and sensitive method independent of authentic standards for multi-components analysis based on the use of ultra-performance liquid chromatography/quadrupole-time-of-flight/MSE (UPLC-TOF-MSE) and UPLC-TOF-MRM (rnhanced target). Initially, phytochemicals were identified by UPLC-TOF-MSE analysis, subsequently the identified components were matched with authentic standards and pre-classified, and UPLC–QTOF-MRM method optimized and developed. To guarantee reliable results, three rules are necessary: (1) detection with a mass error of less than 5ppm; (2) same class chemical compositions with structural high similarity between analytes with and without authentic reference substance; (3) a matching retention time between TOF-MRM mode and TOF-MSE within 0.2min. The developed and validated method was applied for the simultaneous determination of 12 lignans in rat plasma after administered with wine processed Schisandra Chinensis fructus (WPSCF) extract. Such an approach was found capable of providing extensive pharmacokinetic profiles of multi-components absorbed into blood after oral administrated with WPSCF extract. The results also indicated that significant difference in pharmacokinetics parameters of dibenzocyclooctadiene lignans was observed between schizandrin and gomisin compounds. For lignans, the absorption via gastrointestinal tract were all rapid and maintained relatively long retention time, especially for schisantherin A and schisantherin B with higher plasma exposure.

Strong sub-surface plastic deformation induced by high flux plasma in tungsten

We present experimental data obtained by post-examination of polycrystalline and single crystal tungsten exposed to high flux deuterium plasma (1024D/m2/s). The exposures were performed in the temperature range 450–600K and followed by nuclear reaction analysis (NRA), transmission electron microscopy (TEM) and nano-indentation measurements. Direct TEM observation of the high dislocation density in the sub-surface of the plasma-exposed samples implies the occurrence of strong (and fast) local plastic deformation apparently enhanced by the availability of deuterium penetrating in the material. The sharp NRA profile, as usually measured after high flux low temperature plasma exposure, correlates well with the dislocation density evolution and hardness increase within 10–15μm of the material subsurface. Importantly, the heavy plastic deformation was induced in similar amounts in both commercial pure polycrystalline and single crystal tungsten grades.

Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439).

Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.

Subsurface deuterium bubble formation in W due to low-energy high flux deuterium plasma exposure

The deuterium (D) bubbles formed in W exposed to high flux D plasma were researched by scanning electron microscopy and transmission electron microscopy. After D plasma exposure at 500 K and 1000 K, a layer of nano-sized bubbles were homogenously distributed in W subsurface region. The D bubbles were homogenously nucleated due to the high D concentration, and the nucleation process is not related to the vacancy defects. At low temperature (500 K), D bubbles can grow by surface blistering, which caused different nano scale morphologies on different surfaces. At high temperature (1000 K), D bubbles mainly grow by vacancy clustering, which caused pinholes on the surface.

Pharmacokinetics, Safety, and Target Attainment of Single and Multiple Doses of CD101 IV

Introduction: CD101 is a novel, long-acting echinocandin with activity against Candida and Aspergillus spp. in development for prevention and treatment of serious fungal infections. CD101 has shown robust efficacy in neutropenic mouse infection models of disseminated candidiasis as well as aspergillosis and an excellent nonclinical safety/toxicology profile. Two randomized, double-blind, placebo-controlled, phase 1, dose-escalation trials were conducted to establish the safety and pharmacokinetics (PK) of single and multiple weekly dosing of CD101 administered intravenously. PK-pharmacodynamic (PD) analyses of these data were conducted to evaluate the probability of achieving therapeutic targets against Candida.Methods: Sequential cohorts of 8 healthy subjects (n=6, CD101; n=2, placebo) received a single dose of CD101 (50, 100, 200, 400 mg) or multiple weekly doses (100 mg x2, 200 mg x2, 400 mg x3) infused intravenously over 1 hour. PK was assessed using plasma and urine samples collected over 21 days. Safety and tolerability were assessed by adverse events (AEs), vital signs, physical exams, electrocardiograms, and safety laboratory values up to 21 days after dosing. Data from these clinical trials were used to develop a population PK model and perform Monte Carlo simulation (n=2000) evaluating a single dose of 400 mg and multiple weekly doses (400 mg x3 or 400 mg x1 followed by 200 mg x2) chosen for an upcoming Phase 2, dose-ranging trial in candidemia. For each dosing regimen, percent probabilities of PK-PD target attainment against Candida albicans (R303, human blood isolate) were calculated.Results: CD101 and placebo groups had similar incidences of AEs. The majority were mild, and all resolved completely. Slightly higher incidences of AEs and mild transient infusion reactions were seen in the group that received CD101 400 mg x 3 weekly doses. There were no clinically significant safety issues in observed or laboratory assessments, and no deaths, serious AEs, severe AEs, or withdrawals due to an AE. CD101 IV demonstrated dose-proportional plasma exposures, low apparent clearance (<0.3 L/h), long half-life (t1/2 >80 h), minimal urinary excretion (<1%), and minor accumulation (30% to 55%, multiple-dose study). The percent probability of therapeutic target attainment against C. albicans was 100% for both weekly dosing regimens of CD101 (Figure) and >99% for the single dose of CD101 400 mg.Conclusion: CD101 IV was safe and well tolerated as single and multiple doses up to 400 mg once weekly for up to 3 weeks. Target attainment analyses support the dosing regimens evaluated and suggest these regimens will effectively cover the vast majority of Candida likely to be encountered clinically. The high plasma exposures achieved with CD101 IV may improve treatment outcomes compared to other echinocandins, and its long t1/2 enables weekly dosing. These findings support the continued development of CD101 IV dosed once-weekly as treatment or prophylaxis for invasive fungal infections, delivering PK-PD optimized drug exposures while reducing the resources required for therapeutic drug monitoring. [Display omitted] DisclosuresSandison:Cidara Therapeutics, Inc.: Employment, Equity Ownership. Ong:Cidara Therapeutics, Inc.: Employment. Thye:Cidara Therapeutics, Inc.: Employment, Equity Ownership.

Effect of high flux plasma exposure on the micro-structural and -mechanical properties of ITER specification tungsten

We have performed a combined study using transmission electron microscopy (TEM), nuclear reaction analysis (NRA) and nano-indentation (NI) techniques to reveal the impact of high flux plasma exposure on the properties of a sub-surface region of the commercially available pure tungsten fabricated following the ITER specification. TEM examination revealed the formation of a dense dislocation network and dislocation tangles, resulting in a strong increase in the dislocation density by at least one order of magnitude as compared to the bulk density. The plasma-induced dislocation microstructure vanishes within a depth of about 10–15μm from the top of the exposed surface. Surface hardness after the plasma exposure was characterized by NI and was found to increase significantly in the sub-surface region of 1.5–3μm. That was attributed to the resistance of the plasma-induced dislocation networks and deuterium-induced defects, whose presence within a depth of ∼1μm was unambiguously detected by the NRA measurements as well.

Sub-surface microstructure of single and polycrystalline tungsten after high flux plasma exposure studied by TEM

We have performed high flux plasma exposure of tungsten and subsequent microstructural characterization using transmission electron microscopy (TEM) techniques. The aim was to reveal the nanometric features in the sub-surface region as well as to compare the microstructural evolution in tungsten single crystal and ITER-relevant specification. In both types of samples, TEM examination revealed the formation of a dense dislocation network and dislocation tangles. The estimated dislocation density in the sub-surface region was of the order of 1014m−2 and it gradually decreased with a depth position of the examined sample. Besides individual dislocation lines, networks and tangles, the interstitial dislocation loops have been observed in all examined samples only after the exposure. Contrary to that, examination of the pristine single crystal W and backside of the plasma-exposed samples did not reveal the presence of dislocation loops and tangles. This clearly proves that high flux plasma exposure induces severe plastic deformation in the sub-surface region irrespective of the presence of initial dislocations and sub-grains, and the formation of dislocation tangles, networks and interstitial loops is a co-product of thermal stress and intensive plasma particles uptake.

Stereoselective pharmacokinetic study of rhynchophylline and isorhynchophylline epimers in rat plasma by liquid chromatography–tandem mass spectrometry

1. In this study, the stereoselective pharmacokinetics of rhynchophylline (RIN) and isorhynchophylline (IRN) in rat plasma were investigated using liquid chromatography–tandem mass spectrometry (LC–MS/MS).2. A rapid, robust and sensitive LC–MS/MS method for simultaneous quantification of RIN and IRN in rat plasma was established and validated. Chromatographic separation was performed on a Poroshell 120 EC-C18 column under a gradient elution with methanol and water containing 0.01% ammonia as mobile phase. Calibration curve was linear over a concentration range of 1–2000 ng/mL for both epimers.3. After intravenous administration, there was no apparent difference in pharmacokinetic parameters between two epimers. However, after oral administration, RIN showed remarkable higher plasma exposure than IRN. The bioavailability, Cmax and AUC0–t of RIN were about 9.2-fold, 6.4-fold and 9.1-fold higher than those of IRN at 10 mg/kg, and 7.8-fold, 4.3-fold and 7.7-fold at 20 mg/kg, respectively. Additionally, with dosage enhanced from 10 mg/kg to 20 mg/kg, the plasma concentrations of RIN or IRN increased significantly and the bioavailability enhanced about three times.4. In conclusion, the results of this work demonstrated for the first time that the pharmacokinetics of RIN and IRN have stereoselectivity.

Antibacterial activity of the novel semisynthetic lantibiotic NVB333 in vitro and in experimental infection models.

NVB333 is a novel semisynthetic lantibiotic derived from the amide coupling of 3,5-dichlorobenzylamine to the C-terminal of deoxyactagardine B. The in vitro activity of NVB333 includes efficacy against clinically relevant pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. NVB333 shows no cross-resistance with other antibiotics tested and a very low propensity for resistance development. After intravenous dosing NVB333 has high exposure in mouse plasma and shows generally improved in vivo activity compared with vancomycin in mouse infection models despite modest MIC values. In thigh infection models, promising efficacy was demonstrated against several strains of S. aureus including methicillin-resistant S. aureus (MRSA) and vancomycin-intermediate S. aureus (VISA) strains, and against Enterococcus faecalis UNT126-3. Area under the concentration curve (AUC)/MIC was shown to be the best predictor of efficacy against S. aureus UNT103-3 with an AUC/MIC of 138 (uncorrected for protein binding) achieving a static effect. NVB333 was also effective in a disseminated infection model where it conferred complete survival from the MRSA strain ATCC 33591. NVB333 showed rather modest lung penetration after intravenous dosing (AUC in lung 2-3% of plasma AUC), but because of very high plasma exposure, therapeutic levels of compound were achieved in the lung. Efficacy at least equal to vancomycin was demonstrated against an MRSA strain (UNT084-3) in a bronchoalveolar infection model. The impressive in vivo efficacy of NVB333 and strong resistance prognosis makes this compound an interesting candidate for development for treating systemic Gram-positive infections.

Deuterium retention in tungsten under combined high cycle ELM-like heat loads and steady-state plasma exposure

To investigate the synergistic effects of fuel retention in tungsten, experiments were performed in the linear plasma device PSI-2 where the transient heat loads were applied by a high energy laser during the steady-state plasma operation. The impact on the deuterium (D) retention of simultaneous and sequential exposures to laser and plasma has been investigated. A significant increase of D retention, more than a factor of 12, has been observed during the simultaneous transient heat loads and plasma exposure. Successive exposures to transient heat loads and deuterium plasma also show the increased content of D-atoms by more than a factor of 3.6 in comparison to the pure plasma loading. In both cases the increase is most likely due to enhanced hydrogen clustering by the thermal shock exposures, due to an increased mobility of D atoms along the shock-induced cracks as well as to increased diffusion of D atoms into the W material caused by strong temperature gradients during the laser pulse exposure.Comparison of the NRA and TDS measurements shows that only 34% of the retained deuterium in the tungsten specimen is located inside the near-surface layer (d<4µm) after simultaneous as well as sequential exposures of W to heat load.Enhanced blister formation has been observed under combined loading conditions at power densities close to the threshold for damaging. It is shown that blisters are not mainly responsible for the pronounced increase of the D retention.

Retention in tungsten resulting from extremely high fluence plasma exposure

PISCES-B was used for a series of high-fluence plasma exposures to investigate the deuterium fuel retention properties of tungsten, when exposed to continuous plasma irradiation. The goal was to determine whether the fuel retention in the tungsten saturates at sufficiently high fluence, or continues to increase as a function of the plasma fluence. During pure deuterium plasma exposure, up to a maximum deuterium fluence of 2×1028m−2, retention results indicate that saturation is not reached and that retention scales as the square root of time, indicative of diffusion dominating the fuel uptake of the tungsten. However, measurements performed while sculpting the PISCES plasma to replicate a burning plasma, by adding a small amount (5%) of helium ions to the incident deuterium plasma, indicate the deuterium uptake in the target is severely inhibited.