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Therapeutic drug monitoring (TDM) may be beneficial for cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), such as palbociclib, ribociclib, and abemaciclib, due to established exposure–toxicity relationships and the potential for monitoring treatment adherence. Developing a method for quantifying CDK4/6is, abemaciclib metabolites (M2, M20), and letrozole in dried blood spots (DBS) could be useful to enhance the feasibility of TDM. Thus, an optimized LC-MS/MS method was developed using the HemaXis DB10 device for volumetric (10 µL) DBS collection. Chromatographic separation was achieved using a reversed-phase XBridge BEH C18 column. Detection was performed with a triple quadrupole mass spectrometer, utilizing ESI source switching between negative and positive ionization modes and multiple reaction monitoring acquisition. Analytical validation followed FDA, EMA, and IATDMCT guidelines, demonstrating high selectivity, adequate sensitivity (LLOQ S/N ≥ 30), and linearity (r ≥ 0.997). Accuracy and precision met acceptance criteria (between-run: accuracy 95–106%, CV ≤ 10.6%). Haematocrit independence was confirmed (22–55%),with high recovery rates (81–93%) and minimal matrix effects (ME 0.9–1.1%). The stability of analytes under home-sampling conditions was also verified. Clinical validation supports DBS-based TDM as feasible, with conversion models developed for estimating plasma concentrations (the reference for TDM target values) of letrozole, abemaciclib, and its metabolites. Preliminary data for palbociclib and ribociclib are also presented. [ABSTRACT FROM AUTHOR]

Recently, non-thermal technologies have emerged as a means to ensure the safety of agricultural products while also promoting plant growth and reducing pathogenic and chemical contamination of seeds. An experiment was conducted to investigate the effect of various treatments on the germination characteristics of alfalfa seeds. The experiment utilised a completely randomised design with five treatments and three replications, including cold plasma exposure, direct current (DC) electromagnetic field, magnetic field, and a combination of plasma exposure with magnetic and electromagnetic fields. The treated seeds were compared to the control seeds (without exposure) in terms of seedling length, germination rate index (GRI), vigor index, and seed germination. The results indicated that cold plasma treatment and a combination of plasma and magnetic field treatment significantly increased the germination rate compared to the control and other treatments. Furthermore, the combined treatment of plasma and electromagnetic fields, as well as the individual treatment with magnetic fields, resulted in a significant increase in root length and, consequently, the allometric coefficient. Non-thermal technologies are a promising approach to enhancing seed performance, particularly in terms of the rate of germination and seedling length.

Recently, non-thermal technologies have emerged as a means to ensure the safety of agricultural products while also promoting plant growth and reducing pathogenic and chemical contamination of seeds. An experiment was conducted to investigate the effect of various treatments on the germination characteristics of alfalfa seeds. The experiment utilised a completely randomised design with five treatments and three replications, including cold plasma exposure, direct current (DC) electromagnetic field, magnetic field, and a combination of plasma exposure with magnetic and electromagnetic fields. The treated seeds were compared to the control seeds (without exposure) in terms of seedling length, germination rate index (GRI), vigor index, and seed germination. The results indicated that cold plasma treatment and a combination of plasma and magnetic field treatment significantly increased the germination rate compared to the control and other treatments. Furthermore, the combined treatment of plasma and electromagnetic fields, as well as the individual treatment with magnetic fields, resulted in a significant increase in root length and, consequently, the allometric coefficient. Non-thermal technologies are a promising approach to enhancing seed performance, particularly in terms of the rate of germination and seedling length. [ABSTRACT FROM AUTHOR]

This work investigated tungsten samples that were pre-damaged at room (300 K) and high temperatures (573 and 873 K) using 3.5 MeV iron ions and then exposed to the high-flux deuterium plasma. The vacancy-type defects and the behavior of deuterium retention in the investigated tungsten were characterized and compared to study the effect of high-temperature pre-damage. Results of slow positron annihilation with Doppler broadening spectroscopy indicate the introduction of numerous defects by the room-temperature damage and the formation of larger-sized vacancy clusters by the high-temperature pre-damage. Surface observation demonstrates that the pre-damage at room temperature effectively suppressed the formation of intra-granular blisters, while the pre-damage at high temperature did not exhibit such a significant suppression effect on blister formation. Thermal desorption results show that pre-damage at room temperature significantly increases deuterium desorption. Pre-damage at high temperatures also strengthens deuterium desorption, not as significantly as room-temperature pre-damage, and meanwhile produces additional desorption at around 900 K. These results indicate differences between room-temperature and high-temperature pre-damage in the generation of defects and their impact on deuterium retention. Compared to room-temperature pre-damage, high-temperature pre-damage tends to generate defects with a larger average size, weakening the suppression effect on deuterium aggregation and blistering within the grains of tungsten, reducing the quantity of deuterium trapping sites and producing higher-energy deuterium traps.

The impact of helium plasma exposure on the tungsten surface damage structure development and erosion has been investigated by comparing the impact of hydrogen plasma exposure. Crystal orientation dependence of the undulating surface structure formation and erosion rate is observed on the plasma-exposed tungsten surface independently from the plasma species. The top surface of the plasma exposed tungsten has a tendency to {100} plane independently from the initial surface orientation. Although hydrogen and/or helium cause no erosion in tungsten under incident ion energy exposure conditions below the sputtering threshold, inevitable minute impurities, like oxygen, play an essential role in erosion, and significant erosion can be observed even at 30 eV.

Surface damage and microscopic defect evolution of tungsten (W) armor under transient heat loads are key factors for fuel retention in fusion reactors. In this work, experiments were conducted to investigate the effects of cyclic thermal shocks on deuterium (D) retention and surface blistering in W. Thermal shock experiments were conducted on recrystallized W using an electron beam with a power density of 0.15 GW m ^−2 across 100–1500 cycles, followed by D plasma exposure with high-fluence (∼1 × 10 ^26 D m ^−2 ). The results demonstrate that samples subjected to 500 and 1500 cycles exhibit a significant presence of sub-grains within 90 μ m. Notably, the inhibition of blistering induced by thermal shock leads to a substantial reduction in D retention (5.45 × 10 ^19 D m ^−2 ) at lower cycle numbers (100 cycles) compared to the reference sample (2.35 × 10 ^20 D m ^−2 ) which was only exposed to D plasma. When cycle numbers increase to 500 and 1500, D retention reaches 1.98 × 10 ^20 D m ^−2 and 4.56 × 10 ^20 D m ^−2 , respectively. Based on the tritium migration analysis program, we propose that total D retention is a consequence of the competition between defects reduced by thermal shock-induced suppression of blistering and defects generated by plastic deformation induced by thermal stress. D retention initially decreases with the increase in cycle numbers, followed by a subsequent rise, with the inflection point slightly higher than 500 cycles. Additionally, due to the extensive scope of thermal stress, an escalated exposure period will result in substantial D captured by heat-induced defects, consequently intensifying the D retention. Whether there exists an upper limit to D retention induced by the increasing thermal shock cycles necessitates further experimental analysis. Nonetheless, it is evident that thermal shock significantly contributes to D retention within a profoundly deep bulk region under high cycles.

Ultra-high temperature ceramics (UHTCs) have shown aspiration to overcome challenges in the thermal protection system (TPS) by designing new materials referred to as multi-component UHTCs (MC-UHTCs) in the compositional space. MC-UHTCs have shown remarkable improvement in oxidation resistance due to the formation of the Hf 6 Ta 2 O 17 superstructure during plasma exposure. Herein, the Hf 6 Ta 2 O 17 superstructure is synthesized via a solid-state reaction between HfO 2 and Ta 2 O 5 powder mixtures during spark plasma sintering (SPS). The compositions chosen are 50 vol% of HfO 2 -50 vol% of Ta 2 O 5 (50HO-50TO) and 70 vol% of HfO 2 -30 vol% of Ta 2 O 5 (70HO-30TO). The phase quantification via Rietveld analysis showed Hf 6 Ta 2 O 17 as a principal phase with some residual Ta 2 O 5 phase in both the samples. The high-temperature thermal stability of the samples was evaluated using high-velocity plasma jet exposure for up to 3 min. 50HO-50TO was able to withstand the intense plasma condition, which is attributed to the higher content of the Hf 6 Ta 2 O 17 phase (∼84%) and lower strain in the Ta 2 O 5 phase. The augmentation in the Hf 6 Ta 2 O 17 phase to 94.7% (in 50HO-50TO) post plasma exposure has been attributed to the invariant transformation from a liquid state to Hf 6 Ta 2 O 17 at temperatures >2500 °C during testing. The mechanical integrity is elucidated from the insignificant change in the hardness ∼13.3 GPa before and 11.2 GPa after plasma exposure of the 50HO-50TO sample. As a result, the Hf 6 Ta 2 O 17 superstructure's thermo-mechanical stability suggests developing novel oxidation-resistant MC-UHTCs in compositional space for reusable space vehicle applications. [ABSTRACT FROM AUTHOR]

Background: About 32 million pregnant women are at the risk of malaria infection yearly in malaria-endemic sub-Saharan Africa. To mitigate the risks associated with malaria in pregnancy, the WHO recommends ≥3 doses of intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP), covering from the second trimester of pregnancy until delivery., Methods: This cross-sectional study assessed the uptake and extent of adherence with IPTp-SP among pregnant women in Osun State, Nigeria, from October 2020 to March 2021. Assessment of the uptake was done by extracting information from the validated case report forms. Venous blood samples were obtained to assess the levels of sulphadoxine in plasma through HPLC-UV., Results: In total, 49.24%, 38.17% and 12.58% of the study participants obtained 1, 2 and ≥3 doses of IPTp-SP, respectively. In assessing the extent of adherence, 46.67% obtained their last dose within 28 d before sample collection. Uptake of IPTp-SP is not associated with gravidity (p=0.603), but is weakly associated with the age of the study participants (p=0.04). The median (IQR) plasma sulphadoxine concentration was 10.6248 (2.8124-27.1242) ug/mL., Conclusions: Utilisation of the intervention is still very low and adherence appears to be inadequate among the study population, suggesting that more advocacy on the IPTp-SP strategy and the implementation of directly observed therapy is necessary., (© The Author(s) 2024. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Mucopolysaccharidosis IIIA (MPS IIIA) is an inherited lysosomal storage disorder caused by mutations in the N-sulfoglucosamine sulfohydrolase gene that result in deficient enzymatic degradation of heparan sulfate (HS), resulting in progressive neurodegeneration in early childhood and premature death. A chemically modified variant of recombinant human sulfamidase, SOBI003, has shown to cross the blood-brain barrier (BBB) in mice and achieve pharmacologically relevant levels in cerebrospinal fluid (CSF). We report on a phase 1/2, open-label, first-in-human (FIH) study (NCT03423186) and its extension study (NCT03811028) to evaluate the long-term safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD) and clinical efficacy of SOBI003 in patients with MPS IIIA for up to 104 weeks. Six patients aged 1–6 years with confirmed MPS IIIA with developmental age ≥ 12 months received weekly intravenous injections of SOBI003 at 3 mg/kg (Cohort 1, n = 3) or 10 mg/kg (Cohort 2, n = 3). During the extension study, the individual dose of SOBI003 could be adjusted up to 20 mg/kg at the discretion of the investigator. SOBI003 was generally well tolerated. Serum concentrations of SOBI003 increased in proportion to dose, and presence in CSF confirmed that SOBI003 crosses the BBB. Anti-drug antibodies (ADA) were detected in serum and CSF in all patients, with subsequent reductions in serum SOBI003 exposure at high ADA titers. SOBI003 exerted a clear PD effect: a mean reduction in HS levels in CSF of 79% was recorded at the last assessment, together with reductions in HS levels in serum and urine. Neurocognitive development age-equivalent scores showed a stabilization of cognition for all patients, whereas no clear overall clinical effect was observed on adaptive behavior, sleep pattern or quality of life. SOBI003 was well tolerated when administered as weekly intravenous infusions at doses of up to 20 mg/kg for up to 104 weeks. ADA development was common and likely affected both PK and PD parameters. SOBI003 crossed the BBB and showed pharmacological activity on HS in CSF. [ABSTRACT FROM AUTHOR]

Present work showed that Ti 3 SiC 2 ceramic has good ablation resistance at 1600 °C. The mass ablation rate and linear ablation rate after exposure to plasma flame for 120 s are −0.23 mg/s and 5.58 μm/s, respectively. After ablation for 120 s, the micro-morphologies of cross section of the ablation fringe show that the ablation layer was divided into four-layers: an oxide outer layer, a porous layer, a decomposition layer, and the matrix layer. The formation of porous layer is mainly related to the Ti vacancies caused by the outward diffusion of Ti ions, and outward diffusion of gaseous SiO and CO. The dense and large grain-sized TiO 2 oxide layer is dismembered by the generated SiO 2 to form a fine-structured TiO 2 and SiO 2 mixture. The solid-liquid mixed oxide layer is quickly blown away under the shearing force of plasma flow, resulting in a significant increase of linear ablation rate. [ABSTRACT FROM AUTHOR]

The development of a new class of multicomponent ultra‐high temperature ceramics (MC‐UHTCs), often referred to as high‐entropy UHTCs, has gained increased interest due to the possibility of improved thermomechanical and oxidation properties. In this study, a systematic approach by gradual addition in the UHTC components ranging from a binary to a dense quaternary (Ta,Nb,Hf,Ti)C is synthesized using spark plasma sintering (SPS). The solid solutioning was the critical factor in homogenizing the composition in the multicomponent system. The segregation of NbC and HfC was seen in binary and ternary UHTC systems, while a single‐phase homogeneity was observed in the quaternary UHTC improving its hardness up to 34.8 GPa. The presence of closely spaced slip lines in the MC‐UHTCs enhances resistance to indentation damage up to 72% at an applied load of 200 N. The formation of complex mixed oxide phase of Hf6Ta2O17 ensued in the lower to negligible oxidation even up to 3 min of plasma exposure with temperature exceeding 2800°C. In sum, though the entropy remains medium (0.96R) for the selected system, the quaternary UHTC system undoubtedly has significantly better thermomechanical performance when compared to established baseline UHTCs. This raises the debate on the justification for calling a multicomponent system a "high entropy" to be seen in a new light. The developed MC‐UHTCs elicits the paradigm of this new class of UHTCs expanding their potential in thermal protection systems for hypersonic applications. [ABSTRACT FROM AUTHOR]

In nuclear fusion, hydrogen isotopes transportation in tungsten has been identified as a crucial process which could affect various key processes in the operation of a fusion device, such as tritium self-sustaining and operational safety. To enhance the understanding of deuterium diffusion and trapping in millimeter-thick tungsten under high-flux plasma conditions, we carried out a systematic simulation investigation on the deuterium plasma exposure and subsequent thermal desorption using the TMAP7 code based on experimental results. The simulation reveals that the defect concentration with a low de-trapping energy , as estimated solely from simulating thermal desorption, is lower than its actual density due to the temperature history of plasma exposure and subsequent cooling processes. Moreover, the growth rate of deuterium mobile concentration exhibits nonmonotonic behavior over time during plasma exposure, which strongly depends on the ratio of defect concentration with a high de-trapping energy to that with a low de-trapping energy. Additionally, we observed that the maximum deuterium diffusion depth does not follow a proportional relationship with the square root of exposure time, which is attributed to the growing number of plasma-induced defects and the reducing injection coefficient with increasing fluences. This work provides valuable insights into the understanding of deuterium transportation in tungsten during high-flux plasma exposure which could contribute to understanding and modelling of hydrogen isotopes recycling in future fusion devices.

In this work, MoAlB samples for plasma exposure test were condensed by spark plasma sintering at 1200 °C for 10 min. Ablation resistance of MoAlB ceramic was investigated in a plasma torch facility for about 30 s at high temperature range of ∼1670−2550 °C, which provided a quasi-real hypersonic service environment. The results showed that the linear ablation rate was increased from 0 μm/s at ∼1670 °C to 86.4 μm/s at ∼2550 °C. At ∼1670 °C, the ablated surface of MoAlB ceramic was covered by Al 2 O 3 layer, presenting excellent ablation resistance. At ∼2220 °C, the macroscopic cracks were induced by thermal stress, which opened up channels for the inward diffusion of oxygen and deteriorated the ablation resistance of the substrate. Above ∼2400 °C, the volatile MoO 3 and B 2 O 3 and the erosion of viscous oxides by the high shearing force of plasma stream were the main ablation mechanisms. [ABSTRACT FROM AUTHOR]

The W (tungsten) samples were placed at Top, Equator and Bottom plasma facing walls of QUEST (Q-shu University Experiment with Steady-State-Spherical Tokamak) device and exposed to 754 shots of hydrogen plasma during 2017A/W (Autumn/Winter) campaign. Thereafter, their surface morphologies and chemical states were evaluated by TEM (Transmission Electron Microscope) and XPS (X-ray photoelectron spectroscopy). The XPS results showed that a thick carbon layer about 3–18 nm has formed throughout the wall surface. Among them, the Bottom wall had the deposition layer with the thickness of 2 nm, which was thinner than the top wall, namely erosion-dominated. On the other hand, a thick C layer about 18 nm was deposited on the Equator wall. The additional 1 keV D2+ was implanted into these samples and the D (deuterium) retention enhancement was estimated. The D2 TDS (Thermal Desorption Spectroscopy) spectra for all the samples had two major desorption stages at 400 K and 650 K, namely the desorption of D trapped by irradiation damages and deposition layer. The erosion/deposition profile would be caused by wall position and plasma condition, like a current start-up experiment. The desorption temperature of H2 (hydrogen) was shifted toward higher temperature side compared to that exposed to previous plasma campaign (2016 A/W), suggesting that H was mainly accumulated in the deposition layer with forming C–H bonds.

Major depressive disorder (MDD) is the leading cause of disability worldwide. The majority of antidepressant drugs require several weeks or months of treatment to demonstrate efficacy and a subset of patients are resistant to such interventions. Ketamine demonstrates rapid and long-lasting antidepressant effects in treatment resistant patients; however, side effects may limit its widespread clinical utility. The pharmaceutical industry is engaged in developing novel rapid-acting antidepressant drugs and the establishment of clinically relevant assays are needed to advance this process. Wistar Kyoto (WKY) rats are a valuable model of many of the characteristics of MDD and their resistance to selective serotonin reuptake inhibitors (SSRIs) in several behavioral paradigms emulates treatment resistance in clinical populations. Here, we confirmed the depressive-like phenotype of WKY rats in comparison to Sprague Dawley rats, characterized by increased immobility in the forced swim test, decreased locomotor activity and entries to the centre in the open field test, anhedonia in the female urine sniffing test and working memory deficits in the delayed non-match to position task. Single subcutaneous administration of 5 mg/kg ketamine in WKY rats mirrored the plasma exposure produced by the antidepressant dose in the clinic and rescued depressive-like behaviors. The same dose induced transient side effects, including decreased locomotor activity and reduced positive affect-associated vocalizations. Furthermore, ketamine acutely impaired working memory but induced pro-cognitive effects at a later time point. These data confirm the WKY rat as a preclinical model of depression. Ketamine's efficacy in recovering this depressive-like phenotype while inducing transient dissociative-like effects supports this as a translational model suitable for investigating novel antidepressant drugs.

Major depressive disorder (MDD) is the leading cause of disability worldwide. The majority of antidepressant drugs require several weeks or months of treatment to demonstrate efficacy and a subset of patients are resistant to such interventions. Ketamine demonstrates rapid and long-lasting antidepressant effects in treatment resistant patients; however, side effects may limit its widespread clinical utility. The pharmaceutical industry is engaged in developing novel rapid-acting antidepressant drugs and the establishment of clinically relevant assays are needed to advance this process. Wistar Kyoto (WKY) rats are a valuable model of many of the characteristics of MDD and their resistance to selective serotonin reuptake inhibitors (SSRIs) in several behavioral paradigms emulates treatment resistance in clinical populations. Here, we confirmed the depressive-like phenotype of WKY rats in comparison to Sprague Dawley rats, characterized by increased immobility in the forced swim test, decreased locomotor activity and entries to the centre in the open field test, anhedonia in the female urine sniffing test and working memory deficits in the delayed non-match to position task. Single subcutaneous administration of 5 mg/kg ketamine in WKY rats mirrored the plasma exposure produced by the antidepressant dose in the clinic and rescued depressive-like behaviors. The same dose induced transient side effects, including decreased locomotor activity and reduced positive affect-associated vocalizations. Furthermore, ketamine acutely impaired working memory but induced pro-cognitive effects at a later time point. These data confirm the WKY rat as a preclinical model of depression. Ketamine's efficacy in recovering this depressive-like phenotype while inducing transient dissociative-like effects supports this as a translational model suitable for investigating novel antidepressant drugs. [ABSTRACT FROM AUTHOR]

Transmembrane drug transporters can be important determinants of the pharmacokinetics, efficacy, and safety profiles of drugs. To investigate the potential cooperative and/or counteracting interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in physiology and pharmacology, we generated a new mouse model (Bab12), deficient for Slco1a/1b, Slco2b1, Abcb1a/1b and Abcg2. Bab12 mice were viable and fertile. We compared wild-type, Slco1a/1b/2b1 -/- , Abcb1a/1b;Abcg2 -/- and Bab12 strains. Endogenous plasma conjugated bilirubin levels ranked as follows: wild-type = Abcb1a/1b;Abcg2 -/- << Slco1a/1b/2b1 -/- < Bab12 mice. Plasma levels of rosuvastatin and fexofenadine were elevated in Slco1a/1b/2b1 -/- and Abcb1a/1b;Abcg2 -/- mice compared to wild-type, and dramatically increased in Bab12 mice. Although systemic exposure of larotrectinib and repotrectinib was substantially increased in the separate multidrug transporter knockout strains, no additive effects were observed in the combination Bab12 mice. Significantly higher plasma exposure of fluvastatin and pravastatin was only found in Slco1a/1b/2b1-deficient mice. However, noticeable transport by Slco1a/1b/2b1 and Abcb1a/1b and Abcg2 across the BBB was observed for fluvastatin and pravastatin, respectively, by comparing Bab12 mice with Abcb1a/1b;Abcg2 -/- or Slco1a/1b/2b1 -/- mice. Quite varying behavior in plasma exposure of erlotinib and its metabolites was observed among these strains. Bab12 mice revealed that Abcb1a/1b and/or Abcg2 can contribute to conjugated bilirubin elimination when Slco1a/1b/2b1 are absent. Our results suggest that the interplay of Slco1a/1b/2b1, Abcb1a/1b, and Abcg2 could markedly affect the pharmacokinetics of some, but not all drugs and metabolites. The Bab12 mouse model will represent a useful tool for optimizing drug development and clinical application, including efficacy and safety., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Wenlong Li reports financial support was provided by China Scholarship Council and National Natural Science Foundation of China. Yaogeng Wang reports financial support was provided by China Scholarship Council. Margarida Martins reports financial support was provided by DiacetylM BV. Alfred Schinkel reports a relationship with Taconic Biosciences Inc that includes: funding grants., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Deuterium (D) retention behavior in tungsten (W) exposed to D plasma and D2 gas was studied by means of thermal desorption spectroscopy (TDS): D plasma exposure in which W was exposed to D plasma with 35 eV/D+ at 393 K for 0.5 h to the fluence of 3.8 × 1024 D/m2; D2 gas charging in which W was exposed to D2 gas of 500 kPa at 773 K for 4 h. TDS shows that the total D retention in plasma exposure W is ~1022 D/m2, two orders of magnitude higher than that of gas charging W; however, the D2 desorption peak of gas charging W is 952 K, much higher than 691 K of plasma exposure W at the heating rate of 20 K/min. The detrapping energies of deuterium were determined experimentally from the measured peak temperatures at different heating rates and were found to be 2.17 eV for the gas charging W and 1.04 eV for the plasma exposure W, respectively.

The selection of optimum statin intensity is inconclusive, and the association of plasma exposure of statins and metabolites with major adverse cardiovascular events (MACEs) is unclear. This study sought to compare the effect of low (quartile 1), intermediate (quartiles 2 and 3), and high (quartile 4) plasma exposure of statins and metabolites on MACE, re-ischemia events and death in patients with coronary artery disease (CAD) at 5 years. A total of 1,644 patients in atorvastatin (AT) cohort and 804 patients in rosuvastatin (RST) cohort were included, and their plasma concentration of statins and metabolites was categorized as low-, mid-, or high-group. The association between the plasma levels of statins and metabolites and the incidence of primary endpoint in patients was assessed by Cox proportional hazard models. Intensive AT exposure (Q4 > 5.32 ng/ml) was significantly associated with increased risk of death compared with low (hazard ratio [HR]: 1.522; 95% confidence interval [CI]: 1.035–1.061; P = 0.0022) or moderate exposure (HR: 2.054; 95% CI: 1.348–3.130; P = 0.0008). This association was also found in AT’s five metabolites (all P < 0.01). In patients with RST treatment, moderate RST concentration (0.53–4.29 ng/ml) versus low concentration had a significantly lower risk of MACE and re-ischemia events. (HR: 0.532, 95% CI: 0.347–0.815, P = 0.0061 and HR: 0.505, 95% CI: 0.310–0.823, P = 0.0061, respectively). A higher plasma exposure of AT and metabolites has a significantly higher risk of death, and moderate RST exposure has a significantly lower risk of MACE and re-ischemia events in Chinese patients with CAD. The harms of high plasma exposure should be considered when prescribing statins to patients because it may be a risk factor for having poor prognosis in patients with CAD.

Amphetamine (AMP), methylphenidate (MPH), and atomoxetine (ATX) are approved treatments for ADHD, and together with nicotine (NIC), represent pharmacological agents widely studied on cognitive domains including attention and impulsive action in humans. These agents thus represent opportunities for clinical observation to be reinvestigated in the preclinical setting, i.e., reverse translation. The present study investigated each drug in male, Long Evans rats trained to perform either (1) the five-choice serial reaction time task (5-CSRTT), (2) Go/NoGo task, or (3) a progressive ratio (PR) task, for the purpose of studying each drug on attention, impulsive action and motivation. Specific challenges were adopted in the 5-CSRTT designed to tax attention and impulsivity, i.e., high frequency of stimulus presentation (sITI), variable reduction in stimulus duration (sSD), and extended delay to stimulus presentation (10-s ITI). Initially, performance of a large (> 80) cohort of rats in each task variant was conducted to examine performance stability over repeated challenge sessions, and to identify subgroups of “high” and “low” attentive rats (sITI and sSD schedules), and “high” and “low” impulsives (10-s ITI). Using an adaptive sequential study design, the effects of AMP, MPH, ATX, and NIC were examined and contrasting profiles noted across the tests. Both AMP (0.03–0.3 mg/kg) and MPH (1–6 mg/kg) improved attentional performance in the sITI but not sSD or 10-s ITI condition, NIC (0.05–0.2 mg/kg) improved accuracy across all conditions. ATX (0.1–1 mg/kg) detrimentally affected performance in the sITI and sSD condition, notably in “high” performers. In tests of impulsive action, ATX reduced premature responses notably in the 10-s ITI condition, and also reduced false alarms in Go/NoGo. Both AMP and NIC increased premature responses in all task variants, although AMP reduced false alarms highlighting differences between these two measures of impulsive action. The effect of MPH was mixed and appeared baseline dependent. ATX reduced break point for food reinforcement suggesting a detrimental effect on motivation for primary reward. Taken together these studies highlight differences between AMP, MPH, and ATX which may translate to their clinical profiles. NIC had the most reliable effect on attentional accuracy, whereas ATX was reliably effective against all tests of impulsive action.

The selection of optimum statin intensity is inconclusive, and the association of plasma exposure of statins and metabolites with major adverse cardiovascular events (MACEs) is unclear. This study sought to compare the effect of low (quartile 1), intermediate (quartiles 2 and 3), and high (quartile 4) plasma exposure of statins and metabolites on MACE, re-ischemia events and death in patients with coronary artery disease (CAD) at 5 years. A total of 1,644 patients in atorvastatin (AT) cohort and 804 patients in rosuvastatin (RST) cohort were included, and their plasma concentration of statins and metabolites was categorized as low-, mid-, or high-group. The association between the plasma levels of statins and metabolites and the incidence of primary endpoint in patients was assessed by Cox proportional hazard models. Intensive AT exposure (Q4 > 5.32 ng/ml) was significantly associated with increased risk of death compared with low (hazard ratio [HR]: 1.522; 95% confidence interval [CI]: 1.035–1.061; P = 0.0022) or moderate exposure (HR: 2.054; 95% CI: 1.348–3.130; P = 0.0008). This association was also found in AT's five metabolites (all P < 0.01). In patients with RST treatment, moderate RST concentration (0.53–4.29 ng/ml) versus low concentration had a significantly lower risk of MACE and re-ischemia events. (HR: 0.532, 95% CI: 0.347–0.815, P = 0.0061 and HR: 0.505, 95% CI: 0.310–0.823, P = 0.0061, respectively). A higher plasma exposure of AT and metabolites has a significantly higher risk of death, and moderate RST exposure has a significantly lower risk of MACE and re-ischemia events in Chinese patients with CAD. The harms of high plasma exposure should be considered when prescribing statins to patients because it may be a risk factor for having poor prognosis in patients with CAD. [ABSTRACT FROM AUTHOR]

Amphetamine (AMP), methylphenidate (MPH), and atomoxetine (ATX) are approved treatments for ADHD, and together with nicotine (NIC), represent pharmacological agents widely studied on cognitive domains including attention and impulsive action in humans. These agents thus represent opportunities for clinical observation to be reinvestigated in the preclinical setting, i.e., reverse translation. The present study investigated each drug in male, Long Evans rats trained to perform either (1) the five-choice serial reaction time task (5-CSRTT), (2) Go/NoGo task, or (3) a progressive ratio (PR) task, for the purpose of studying each drug on attention, impulsive action and motivation. Specific challenges were adopted in the 5-CSRTT designed to tax attention and impulsivity, i.e., high frequency of stimulus presentation (sITI), variable reduction in stimulus duration (sSD), and extended delay to stimulus presentation (10-s ITI). Initially, performance of a large (> 80) cohort of rats in each task variant was conducted to examine performance stability over repeated challenge sessions, and to identify subgroups of "high" and "low" attentive rats (sITI and sSD schedules), and "high" and "low" impulsives (10-s ITI). Using an adaptive sequential study design, the effects of AMP, MPH, ATX, and NIC were examined and contrasting profiles noted across the tests. Both AMP (0.03–0.3 mg/kg) and MPH (1–6 mg/kg) improved attentional performance in the sITI but not sSD or 10-s ITI condition, NIC (0.05–0.2 mg/kg) improved accuracy across all conditions. ATX (0.1–1 mg/kg) detrimentally affected performance in the sITI and sSD condition, notably in "high" performers. In tests of impulsive action, ATX reduced premature responses notably in the 10-s ITI condition, and also reduced false alarms in Go/NoGo. Both AMP and NIC increased premature responses in all task variants, although AMP reduced false alarms highlighting differences between these two measures of impulsive action. The effect of MPH was mixed and appeared baseline dependent. ATX reduced break point for food reinforcement suggesting a detrimental effect on motivation for primary reward. Taken together these studies highlight differences between AMP, MPH, and ATX which may translate to their clinical profiles. NIC had the most reliable effect on attentional accuracy, whereas ATX was reliably effective against all tests of impulsive action. [ABSTRACT FROM AUTHOR]

• We used two different types of proteins including whey and gluten for creation of edible films. • Low pressure glow plasma created from Ar and air at 50 W for 5, 10 and 15 min was applied for both types of edible films. • The mechanical properties of whey protein films improved at 10 min while the plasma improved the gluten films properties at 5 min. • The surface roughness of whey protein films increased significantly, however, a decrease was observed in gluten films after plasma treatment. • Solubility and WVP of films did not changed considerably as the effect of plasma can be observed at the Nano metric scale of films surface. In this research, the influence of different cold plasma treatments was investigated as a novel method for modification of protein film properties. The films were prepared from whey and gluten proteins using solvent casting method and then treated with vacuum low-pressure glow plasma using air and argon gases at 50 KW for 5, 10, and 15 min and further analyzed mechanically and physicochemically. The images of atomic force microscopy (AFM) revealed a significant increase in roughness of whey protein films after plasma treatment, while the roughness of treated gluten films diminished dramatically. Furthermore, the tensile strength of films improved significantly after 10 min of process, from 6.902 to 10.772 MPa and from 1.854 to 2.571 MPa for whey protein and gluten films, respectively. Introduction of functional groups such as C O and O C bonds plus cross link creation was observed by FTIR which could lead to changes in different film features. Although gas permeability of both edible polymers decreased significantly, other parameters including solubility and water vapor permeability of control and plasma treated (PT) films did not show dramatic differences. Therefore, the optimum condition and time of low-pressure glow plasma has the potential for modifying protein films. [ABSTRACT FROM AUTHOR]

Although studies show an annual trend for immunosuppressive drugs, particularly during different seasons, no data are available for antiretroviral drugs exposures in different periods of the year. For this reason, the aim of this study was to investigate an association between seasonality and antiretroviral drugs plasma concentrations. Antiretroviral drugs exposures were measured with liquid chromatography validated methods. A total of 4148 human samples were analysed. Lopinavir, etravirine and maraviroc levels showed seasonal fluctuation. In detail, maraviroc and etravirine concentrations decreased further in summer than in winter. In contrast, lopinavir concentrations had an opposite trend, increasing more in summer than in winter. The etravirine efficacy cut-off value of 300 ng/mL seems to be affected by seasonality: 77.1% and 22.9% of samples achieved this therapeutic target, respectively, in winter and summer, whereas 30% in winter and 70% in summer did not reach this value. Finally, age over 50 years and summer remained in the final multivariate regression model as predictors of the etravirine efficacy cut-off. This study highlights the seasonal variation in antiretroviral drugs plasma concentrations during the year, leading to a better understanding of inter-individual variability in drug exposures. Studies are required in order to confirm these data, clarifying which aspects may be involved.

• D was introduced into the CLF-1 steel using D ion irradiation, D plasma exposure in PREFACE and EAST separately. • D retention and release behavior of the CLF-1 steel was examined using TDS. • Different D retention and release behavior of the CLF-1 steel irradiated in three conditions were showed. Deuterium (D) retention behavior in a reduced activation ferritic/martensitic (RAFM) steel (CLF-1) is measured by thermal desorption spectrometry (TDS) after irradiation by D ion in an ion beam facility, exposure to D plasma in a linear ECR plasma generator, and exposure to D plasmas in the EAST tokamak separately. The D release behavior of the CLF-1 steel under the three-different D implantation condition is compared. Results indicate that D release behavior in the CLF-1 steel after the tokamak exposure experiments differs significantly from those after laboratory D ion implantation experiments or D plasma exposure experiments in a linear ECR plasma generator. This demonstrates that using low temperature plasmas in laboratory facilities alone is not sufficient in the study of hydrogen isotope retention behavior in a realistic tokamak environment. In order to simulate the plasma and material interaction in tokamak more felicitously, more work need to do to improve the linear plasma generator at present. Possible explanations have been proposed to explain the different D release behavior in the CLF-1 steel after D implantation in three different environment. [ABSTRACT FROM AUTHOR]

Silver (Ag) is one of the most suitable metals for electrodes in high-performance organic optoelectronic devices due to its high conductivity and reflectivity, and low parasitic absorption loss at visible wavelengths. However, the electronic work function of Ag is not ideal for use as either the cathode or anode in many organic optoelectronic devices. In this report, we investigate the formation of an ultrathin surface oxide layer on a Ag electrode and its impact on hole injection into an organic conjugated polymer semiconductor. The surface oxide is formed by exposing the Ag electrode to a low-power O 2 /Ar plasma and which changes the electrical properties of the pure Ag electrode. We study the morphology and the chemical composition of the Ag surfaces after different plasma treatment times through X-ray photoelectron spectroscopy, scanning electron microscopy and dark-field optical microscopy. After plasma exposure the surface oxide is composed of both AgO x and Ag 2 CO 3. As plasma exposure time increases from 1 s to 7 s, the fraction of AgO x increases while Ag 2 CO 3 decreases gradually. Both the turn-on voltages and barrier heights of poly(9,9-dioctylfluorene-alt-benzothiadiazole) (F8BT) hole-only devices decrease with plasma treated Ag surfaces indicating that the work function of the Ag surface is increased by the surface oxide. F8BT hole-only devices with a thin MoO 3 layer and a thicker AgO x layer on the electrode are found to be stable compared to thinner surface oxides and un-treated Ag surfaces. Ultrathin AgO x films are fabricated on Ag back electrodes by exposing Ag to an O 2 /Ar plasma for different durations. This approach can increase the surface work function, reduce the barrier to hole injection into conjugated polymer films and increase electrode stability. Image 1 • Inverted organic semiconducting polymer hole-only devices were fabricated directly on Ag back electrodes. • Native silver oxide hole transport layers were intentionally formed on the Ag electrodes. • The electrical properties and stability of organic hole-only devices were improved with partially-oxidized Ag electrodes. [ABSTRACT FROM AUTHOR]

In this work, the nano-indentation of plasma-exposed tungsten is simulated at room temperature and elevated temperature (300–700 K) by the recently developed crystal plasticity finite element model. A nonlinear function is applied to characterize the depth profile of plasma-induced dislocation density in the sub-surface region. The model parameters are calibrated by comparing the simulated results with corresponding experimental data at 300 K for both the force-depth and hardness-depth relationships. Furthermore, the mechanical responses of plasma-exposed tungsten are predicted at 500 K and 700 K in order to characterize the plasma effect at the fusion-relevant operational temperature. The dominant results and conclusions are that: (1) The heterogeneously distributed dislocations in the sub-surface region induced by the plasma exposure are responsible for the increase of hardness at 300 K. (2) The plasma-induced microstructural modification does not yield to considerable increase of hardness at operational temperature. (3) The expansion of the plastic zone in the sub-surface region is, to some extent, limited by the presence of plasma-induced dislocations. Whereas, the increase of temperature can effectively reduce this limitation. • Nano-indentation of plasma-exposed tungsten is simulated by CPFEM. • Numerical results can match well with corresponding experimental data. • Increase of hardness at 300 K comes from heterogeneously distributed dislocations. • Expansion of the plastic zone is limited by the plasma-induced dislocations [ABSTRACT FROM AUTHOR]

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.

The influence of plasma exposure on structural, morphological and optical properties of copper (II) acetylacetonate thin films deposited by thermal evaporation technique was investigated. Copper (II) acetylacetonate as-grown thin films were exposed to the atmospheric plasma for different times. The exposure of as-grown cu(acac) 2 thin film to atmospheric plasma for 5 min modified its structural, morphological and optical properties. The effect of plasma exposure on structure and roughness of cu(acac) 2 thin films was evaluated by XRD and AFM techniques, respectively. The XRD results showed an increment in crystallinity due to exposure for 5 min, but, when the exposure time reaches 10 min, the film was transformed to an amorphous state. The AFM results revealed a strong modification of films roughness when the average roughness decreased from 63.35 nm to ~1 nm as a result of interaction with plasma. The optical properties of as-grown and plasma exposured cu(acac) 2 thin films were studied using spectrophotometric method. The exposure of cu(acac) 2 thin films to plasma produced the indirect energy gap decrease from 3.20 eV to 2.67 eV for 10 min exposure time. The dispersion parameters were evaluated in terms of single oscillator model for as-grown and plasma exposured thin films. The influence of plasma exposure on third order optical susceptibility was studied. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Salicylic acid (SA) has a long history of safe use as ingredient in topical cosmetic products. In 2016, the Committee for Risk Assessment of the European Chemicals Agency proposed to classify SA as a Category 2 reproductive toxicant based on adverse developmental effects in animal toxicity studies. This hazard-based classification (based on mg/kg doses) requires a reassessment of the safety of the current SA concentrations in cosmetic consumer products. Herein, a safety reassessment was performed in which margins of safety were calculated based on literature data on the NOAEL plasma exposure levels from animal reproductive toxicity studies with ASA (rapidly converts to SA in plasma), human SA plasma levels from oral exposure to ASA and human dermal exposure to SA-containing cosmetic products. In addition, a literature review was performed, which shows that there are no adverse developmental effects despite extensive human clinical oral use of ASA up to the maximum recommended therapeutic doses. The plasma exposure-based safety assessment for SA combined with an absence of any clinical health risk with oral ASA use in the literature supports that there is an acceptable margin of safety for the consumer exposure to SA as authorized in the current EU cosmetic regulation. [ABSTRACT FROM AUTHOR]

Silver nanoparticles (Ag NPs) tarnish easily upon exposure to ambient air, and eventually lose their ability as a plasmonic sensor via weakened localized surface plasmon resonance (LSPR). We have demonstrated the enhancement in plasmonic sensitivity of tarnished Ag NP aggregates to vapors of volatile organic compounds (VOCs) such as ethanol and butanol by Ar plasma exposure. The response of Ag NP aggregates to the VOC vapors was examined by measuring the change in optical extinction spectra before and after exposure to the vapors. The sensitivity of Ag NP aggregates decreased gradually when stored in ambient air. The performance of tarnished Ag NPs for ethanol sensing was recovered by exposure to argon (Ar) plasma for 15 s. The reduction from oxidized Ag to metallic one was recognized, while morphological change was hardly noticeable after the plasma exposure. We conclude, therefore, that a compositional change rather than a morphological change occurred on Ag NP surfaces enhances the sensing ability of tarnished Ag NP aggregates to the VOC vapors. [ABSTRACT FROM AUTHOR]

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-Fe 2 O 3 ) 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. [ABSTRACT FROM AUTHOR]

Optimization of benzamide PPARδ modulator 1 led to ( E )-6-(2-((4-(furan-2-yl)- N -methylbenzamido)methyl)phenoxy)-4-methylhex-4-enoic acid ( 18 ), a potent selective PPARδ modulator with significantly improved exposure in multiple species following oral administration. [ABSTRACT FROM AUTHOR]

While polymers are widely utilized materials in the biomedical industry, they are rarely used in an unmodified state. Some kind of a surface treatment is often necessary to achieve properties suitable for specific applications. There are multiple methods of surface treatment, each with their own pros and cons, such as plasma and laser treatment, UV lamp modification, etching, grafting, metallization, ion sputtering and others. An appropriate treatment can change the physico-chemical properties of the surface of a polymer in a way that makes it attractive for a variety of biological compounds, or, on the contrary, makes the polymer exhibit antibacterial or cytotoxic properties, thus making the polymer usable in a variety of biomedical applications. This review examines four popular methods of polymer surface modification: laser treatment, ion implantation, plasma treatment and nanoparticle grafting. Surface treatment-induced changes of the physico-chemical properties, morphology, chemical composition and biocompatibility of a variety of polymer substrates are studied. Relevant biological methods are used to determine the influence of various surface treatments and grafting processes on the biocompatibility of the new surfaces--mammalian cell adhesion and proliferation is studied as well as other potential applications of the surface-treated polymer substrates in the biomedical industry. [ABSTRACT FROM AUTHOR]