Cross-code comparison of the edge codes SOLPS-ITER, SOLEDGE2D and UEDGE in modelling a low-power scenario in the DTT

As reactor-level nuclear fusion experiments are approaching, a solution to the power exhaust issue in future fusion reactors is still missing. The maximum steady-state heat load that can be exhausted by the present technology is around 10 MW/m2. Different promising strategies aiming at successfully managing the power exhaust in reactor-relevant conditions such that the limit is not exceeded are under investigation, and will be tested in the Divertor Tokamak Test (DTT) experiment. Meanwhile, the design of tokamaks beyond the DTT, e.g. EU-DEMO/ARC, is progressing at a high pace. A strategy to work around the present lack of reactor-relevant data consists of exploiting modelling to reduce the uncertainty in the extrapolation in the design phase. Different simulation tools, with their own capabilities and limitations, can be employed for this purpose. In this work, we compare SOLPS-ITER, SOLEDGE2D and UEDGE, three state-of-the-art edge codes heavily used in power exhaust studies, in modelling the same DTT low-power, pure-deuterium, narrow heat-flux-width scenario. This simplified, although still reactor-relevant, testbed eases the cross-comparison and the interpretation of the code predictions, to identify areas where results differ and develop understanding of the underlying causes. Under the conditions investigated, the codes show encouraging agreement in terms of key parameters at both targets, including peak parallel heat flux (1-45%), ion temperature (2-19%), and inner target plasma density (1-23%) when run with similar input. However, strong disagreement is observed for the remaining quantities, from 30% at outer mid-plane up to a factor 4-5 at the targets. The results primarily reflect limitations of the codes: the SOLPS-ITER plasma mesh not reaching the first wall, SOLEDGE2D not including ion-neutral temperature equilibration, and UEDGE enforcing a common ion-neutral temperature. Potential improvements that could help enhance the accuracy of the code models for future applications are also discussed.

Changes in the Plasma Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1(APE1/Ref-1) Level during Cancer Surgery: An Observational Study

Background and Objectives: Propofol-based total intravenous anesthesia (TIVA) is presumed to have more favorable effects on the prognosis of patients with cancer compared with volatile inhaled anesthesia (VIA). We hypothesized that these anesthetics target plasma apurinic apyrimidinic endonuclease/redox effector factor-1 (APE1/Ref-1) as a possible mechanism of action. Materials and Methods: The plasma APE1/Ref-1 level was evaluated three times during surgery for cancer, i.e., before anesthesia, immediately after cancer resection, and finally, in the recovery room. Blood (3 cc) was drawn from the radial artery catheter, and plasma APE1/Ref-1 levels were compared according to measurement time and between the two groups. Spearman’s Rho correlation analysis was performed to determine relationships among body mass index, American Society of Anesthesiologists classification, age, sex, cancer type, and tumor-node-metastasis (TNM) stage. A total of 166 patients (VIA: 129; TIVA: 37) were enrolled. Results: Plasma APE1/Ref-1 level increased significantly (p = 0.028) after cancer resection compared with before surgery, but no significant difference was observed between anesthetics (p = 0.134). The post-resection plasma APE1/Ref-1 level showed a positive correlation with the NM stages, but not the T stage. Conclusions: The plasma APE1/Ref-1 level increased during surgery with more severe lymph node invasion, but there were no significant differences according to the anesthetics used.

External Evaluation of Population Pharmacokinetic Models and Bayes-Based Dosing of Infliximab

Despite the well-demonstrated efficacy of infliximab in inflammatory diseases, treatment failure remains frequent. Dose adjustment using Bayesian methods has shown in silico its interest in achieving target plasma concentrations. However, most of the published models have not been fully validated in accordance with the recommendations. This study aimed to submit these models to an external evaluation and verify their predictive capabilities. Eight models were selected for external evaluation, carried out on an independent database (409 concentrations from 157 patients). Each model was evaluated based on the following parameters: goodness-of-fit (comparison of predictions to observations), residual error model (population weighted residuals (PWRES), individual weighted residuals (IWRES), and normalized prediction distribution errors (NPDE)), and predictive performances (prediction-corrected visual predictive checks (pcVPC) and Bayesian simulations). The performances observed during this external evaluation varied greatly from one model to another. The eight evaluated models showed a significant bias in population predictions (from −7.19 to 7.38 mg/L). Individual predictions showed acceptable bias and precision for six of the eight models (mean error of −0.74 to −0.29 mg/L and mean percent error of −16.6 to −0.4%). Analysis of NPDE and pcVPC confirmed these results and revealed a problem with the inclusion of several covariates (weight, concomitant immunomodulatory treatment, presence of anti-drug antibodies). This external evaluation showed satisfactory results for some models, notably models A and B, and highlighted several prospects for improving the pharmacokinetic models of infliximab for clinical-biological application.

Degeneracy Effects of Energy loss Straggling of Homo and Hetero Di-Cluster Ions

The energy loss straggling is obtained from an exact quantum mechanical evaluation, which takes into account the degeneracy of the target plasma, and later it is compared with common classical and degeneracy approximation as a function of incident Homo (H-H, He-He) and Hetero (He-H) di-cluster energy in Kev with different kinds of plasma target. For homonuclear di-clusters (H-H) and (He-He) decreasing temperature, the exact calculation approaches the high degeneracy limit, but the differences are still significant. However, as the temperature rises, the exact result approaches the classical limit. Finally, the energy loss straggling increases with the increasing atomic number of the projectiles (He-He). Our research focuses on targets in the weakly coupled electron gas limit, where we can use the random phase approximation (RPA). This kind of plasma has not been widely researched, considering the fact that it is essential for inertial confinement fusion (ICF).

Laser-driven proton acceleration from ultrathin foils with nanoholes

Structured solid targets are widely investigated to increase the energy absorption of high-power laser pulses so as to achieve efficient ion acceleration. Here we report the first experimental study of the maximum energy of proton beams accelerated from sub-micrometric foils perforated with holes of nanometric size. By showing the lack of energy enhancement in comparison to standard flat foils, our results suggest that the high contrast routinely achieved with a double plasma mirror does not prevent damaging of the nanostructures prior to the main interaction. Particle-in-cell simulations support that even a short scale length plasma, formed in the last hundreds of femtoseconds before the peak of an ultrashort laser pulse, fills the holes and hinders enhanced electron heating. Our findings reinforce the need for improved laser contrast, as well as for accurate control and diagnostics of on-target plasma formation.

Raman microscopy-based quantification of the physical properties of intracellular lipids

ABSTRACTThe physical properties of lipids, such as viscosity, are homeostatically maintained in cells, and are intimately involved in physiological roles. Measurement of the physical properties of plasma membranes has been achieved primarily through chemical or genetically encoded fluorescent probes, however, the effect of the probes themselves on these physical properties hampered accurate measurements. In addition, as most probes target plasma membranes, physical properties of lipids in intracellular organelles, including lipid droplets (LDs) are yet to be analyzed. Here, we present a novel Raman microscopy-based approach for quantifying the intracellular physical properties of lipids under deuterium-labeled fatty acid treatment conditions. Focusing on the fact that Raman spectra of carbon-deuterium vibration are altered depending on the surrounding lipid species, we quantitatively represented the physical properties of lipids as the gauche/trans conformational ratio of the introduced labeled fatty acids, which can be used as an indicator of viscosity. Intracellular Raman imaging revealed that the gauche/trans ratio of cytosolic regions was robustly preserved against stimuli attempting to alter the lipid composition. This was likely due to LDs functioning as a buffer against excess gauche/trans ratio. The novel approach, that is, using the target lipid itself as a probe, overcomes the issues presented by conventional probes, making it useful for the quantitative evaluation of biological functions and regulatory mechanisms associated with the physical state of intracellular lipid environments.

Prolonged versus intermittent β-lactam antibiotics intravenous infusion strategy in sepsis or septic shock patients: a systematic review with meta-analysis and trial sequential analysis of randomized trials

Background The prolonged β-lactam infusion strategy has emerged as the standard treatment for sepsis or septic shock despite its unknown efficacy. This study aimed to assess the efficacy of prolonged versus intermittent β-lactam antibiotics infusion on outcomes in sepsis or septic shock patients by conducting a systematic review and meta-analysis. Methods A thorough search was conducted on MEDLINE, the Cochrane Central Register of Controlled Trials, and the Igaku Chuo Zasshi databases. Randomized controlled trials (RCTs) comparing mortality between prolonged and intermittent infusion in adult patients with sepsis or septic shock were included. The primary outcome was hospital mortality. The secondary outcomes were the attainment of the target plasma concentration, clinical cure, adverse events, and occurrence of antibiotic-resistant bacteria. We performed a subgroup analysis stratified according to the year of publication before or after 2015 and a trial sequential analysis (TSA). The Der Simonian–Laird random-effects models were subsequently used to report the pooled risk ratios (RR) with confidence intervals (CI). Results We identified 2869 studies from the 3 databases, and 13 studies were included in the meta-analysis. Hospital mortality did not decrease (RR 0.69 [95%CI 0.47–1.02]) in the prolonged infusion group. The attainment of the target plasma concentration and clinical cure significantly improved (RR 0.40 [95%CI 0.21–0.75] and RR 0.84 [95%CI 0.73–0.97], respectively) in the prolonged infusion group. There were, however, no significant differences in the adverse events and the occurrence of antibiotic-resistant bacteria between the groups (RR 1.01 (95%CI 0.95–1.06) and RR 0.53 [95%CI 0.10–2.83], respectively). For the subgroup analysis, a significant improvement in hospital mortality or clinical cure was reported in studies published in or after 2015 (RR 0.66 [95%CI 0.44–0.98] and RR 0.67 [95%CI 0.50–0.90], respectively). The results of the TSA indicated an insufficient number of studies for a definitive analysis. Conclusions The prolonged infusion of β-lactam antibiotics significantly improved upon attaining the target plasma concentration and clinical cure without increasing the adverse event or the occurrence of antibiotic-resistant bacteria. Prolonged infusion could not improve hospital mortality although an improvement was shown for studies published in or after 2015. Further studies are warranted as suggested by our TSA results.

First experiments on ICRF discharge generation by a W7-X-like antenna in the Uragan-2M stellarator

In support of the ICRF experiments planned on the Wendelstein 7-X (W7-X) stellarator, i.e. fast ion generation, wall conditioning, target plasma production and heating, a first experimental study on plasma production has been made in the Uragan-2M (U-2M) stellarator using W7-X-like two-strap antenna. In all the experiments, antenna monopole phasing was used. The W7-X-like antenna operation with launched radiofrequency power of ~100 kW have been performed in helium (p = (4–14) × 10−2 Pa) with the vacuum vessel walls pre-loaded with hydrogen. Production of plasma with a density higher than 1012 cm−3 was observed near the first harmonic of the hydrogen cyclotron frequency. Operation at first hydrogen harmonic is feasible in W7-X future ICRF experiments.

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of the putative agents tested demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1- and 1.5-fold in lung, respectively. The antiviral activity data reported to date have been acquired under different laboratory conditions across multiple groups, applying variable levels of stringency. However, this analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds which are unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.