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The radiolytic behaviors of aqueous ammonia solutions under γ-ray irradiation were investigated, focusing on several factors, including initial ammonia concentration, absorbed dose, and H3BO3 concentration. The main species including ammonia, H2O2, nitrogen oxides, and H2, were quantitatively analyzed. The results revealed the significant influence of the initial ammonia concentration on the radiolytic behavior of the aqueous ammonia solution. The existence of ammonia in the solution exhibited suppression of the concentrations of H2O2 and O2. Furthermore, the radiolysis of aerated aqueous ammonia solution led to the formation of nitrogen oxides (NO2− and NO3−). This process was driven by multiple oxidation reactions, in which O2 and ·OH played crucial roles. Interestingly, the addition of H3BO3 provided protection to ammonia during γ irradiation, while the concentration of H2O2 was increased. [ABSTRACT FROM AUTHOR]

A mathematical model of co-decontamination process (1A) containing U(VI), Pu(IV), Zr(IV), and Ru(III) was developed with a high-performance Iteration of Extraction Equilibrium (ITEE) algorithm. ITEE algorithm not only guarantees the positive solution set but also possesses better computational efficiency than L-BFGS-B and fsolve algorithms. This model was used to study the effects of the HNO3 concentration and the location of the feed stage on the extraction and decontamination efficiencies. The results show HNO3 is beneficial to the extraction of U, Pu, and Zr. More extraction stages boost the extraction of U and Pu into the organic phase. [ABSTRACT FROM AUTHOR]

For survival analysis applications we propose a novel procedure for identifying subgroups with large treatment effects, with focus on subgroups where treatment is potentially detrimental. The approach, termed forest search, is relatively simple and flexible. All‐possible subgroups are screened and selected based on hazard ratio thresholds indicative of harm with assessment according to the standard Cox model. By reversing the role of treatment one can seek to identify substantial benefit. We apply a splitting consistency criteria to identify a subgroup considered “maximally consistent with harm.” The type‐1 error and power for subgroup identification can be quickly approximated by numerical integration. To aid inference we describe a bootstrap bias‐corrected Cox model estimator with variance estimated by a Jacknife approximation. We provide a detailed evaluation of operating characteristics in simulations and compare to virtual twins and generalized random forests where we find the proposal to have favorable performance. In particular, in our simulation setting, we find the proposed approach favorably controls the type‐1 error for falsely identifying heterogeneity with higher power and classification accuracy for substantial heterogeneous effects. Two real data applications are provided for publicly available datasets from a clinical trial in oncology, and HIV. [ABSTRACT FROM AUTHOR]

Hollow polyethylene spheres were achieved from solution-based ɑ-diimine nickel catalyst system with morphological controllable one-step synthesis. • Homogenous ɑ- diimine nickel complexes often produce bulk viscous polyethylene. • Spherical hollow polyethylene produced by coordination dispersion polymerization. • Tri-nuclear nickel complex show high activity for ethylene polymerization. In this paper, ɑ-diimine nickel catalyst without immobilization was successfully used for one-step synthesis of spherical hollow polyethylene particles at mild condition (1.0 MPa, 25 °C) by conducting coordination dispersion polymerization. It was found 2-methyl-2-pentanol (MP) played a key role in the formation of the unusual hollow particular morphology. By varying the addition amount of MP, changing the bulky groups of alkyl aluminum, and adjusting the concentration of nickel catalyst, the particle size was finely tuned. A plausible mechanism was proposed to interpret the formation of these polyethylene hollow particles. [ABSTRACT FROM AUTHOR]

Treatment of individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) requires careful consideration of potential drug‐drug interactions. The pharmacokinetic interaction of the HCV fixed‐dose combination treatment of elbasvir/grazoprevir (EBR/GZR) when coadministered with the fixed‐dose combination HIV treatment of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (EVG/COB/TDF/FTC) was evaluated in 22 healthy adults. In period 1, oral doses of EVG/COB/TDF/FTC (150 mg/150 mg/300 mg/200 mg) were administered once daily for 7 days. In period 2, oral doses of EBR/GZR (50 mg/100 mg) were administered once daily for 10 days. In period 3, oral doses of EVG/COB/TDF/FTC were coadministered with EBR/GZR once daily for 10 days. The pharmacokinetics of EVG/COB/TDF/FTC were not clinically meaningfully altered by concomitant EBR/GZR administration. Geometric mean ratios (90%CIs) for area under the plasma concentration‐time curve from time 0 to 24 hours (AUC0‐24) in the presence/absence of EBR/GZR were 1.1 (1.0, 1.2) for elvitegravir; 1.1 (1.0, 1.1) for emtricitabine; 1.2 (1.1, 1.2) for tenofovir; and 1.5 (1.4, 1.6) for cobicistat. In comparison, the AUC0‐24 of elbasvir was ∼2 times higher and the AUC0‐24 of grazoprevir was ∼5 times higher following concomitant administration of EVG/COB/TDF/FTC and EBR/GZR. Geometric mean ratios (90%CI) for AUC0‐24 in the presence/absence of EVG/COB/TDF/FTC were 2.2 (2.0, 2.4) for elbasvir and 5.4 (4.5, 6.4) for grazoprevir. Coadministration of EVG/COB/TDF/FTC and EBR/GZR was generally well tolerated in healthy adults in this study. Nevertheless, because of the increased GZR exposure that occurs with coadministration of EVG/COB/TDF/FTC and EBR/GZR, coadministration of this combination is not recommended in those coinfected with HIV and HCV. [ABSTRACT FROM AUTHOR]

Treatment of individuals coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) requires careful consideration of potential drug‐drug interactions. We evaluated the pharmacokinetic interaction of the direct‐acting antiviral agents elbasvir and grazoprevir coadministered with the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF). Three open‐label, multidose studies in healthy adults were conducted. In the first study (N = 10), participants received TDF 300 mg once daily, elbasvir 50 mg once daily, and elbasvir coadministered with TDF. In the second study (N = 12), participants received TDF 300 mg once daily, grazoprevir 200 mg once daily, and grazoprevir coadministered with TDF. In the third study (N = 14), participants received TDF 300 mg once daily and TDF 300 mg coadministered with coformulated elbasvir/grazoprevir 50 mg/100 mg once daily. Pharmacokinetics and safety were evaluated. Following coadministration, the tenofovir area under the plasma concentration‐time curve to 24 hours and maximum plasma concentration geometric mean ratios (90% confidence intervals) for tenofovir and coadministered drug(s) versus tenofovir were 1.3 (1.2, 1.5) and 1.5 (1.3, 1.6), respectively, when coadministered with elbasvir; 1.2 (1.1, 1.3) and 1.1 (1.0, 1.2), respectively, when coadministered with grazoprevir; and 1.3 (1.2, 1.4) and 1.1 (1.0, 1.4), respectively, when coadministered with the elbasvir/grazoprevir coformulation. TDF had minimal effect on elbasvir and grazoprevir pharmacokinetics. Elbasvir and/or grazoprevir coadministered with TDF resulted in no clinically meaningful tenofovir exposure increases and was generally well tolerated, with no deaths, serious adverse events (AEs), discontinuations due to AEs, or laboratory AEs reported. No dose adjustments for elbasvir/grazoprevir or TDF are needed for coadministration in HCV/HIV‐coinfected people. [ABSTRACT FROM AUTHOR]

The cytomegalovirus (CMV) viral terminase inhibitor letermovir is indicated for prevention of CMV infection in CMV‐seropositive allogeneic hematopoietic stem cell transplant recipients. In this analysis, functional variants in solute carrier organic anion transporter family member 1B1 (SLCO1B1), uridine diphosphate‐glucuronosyltransferase 1A1 (UGT1A1), and breast cancer resistance protein (BCRP) were assessed for effects on letermovir pharmacokinetics (PK) using pooled genetic information from 296 participants in 12 phase 1 studies. Letermovir area under the plasma concentration‐time curve (AUC) was increased in carriers of the SLCO1B1 variant rs4149056 C allele relative to noncarriers with a geometric mean ratio (GMR) of 1.18 (95% confidence interval [CI], 1.06–1.30) for carriers of 1 copy and 1.42 (1.10–1.84) for carriers of 2 copies of the risk allele C compared with noncarriers. The SLCO1B1 variant rs4149032 T allele was associated with a decrease in letermovir AUC with GMR (95%CI) of 0.93 (0.85–1.02) and 0.82 (0.73–0.92) for carriers of 1 and 2 copies of the risk allele T, respectively, compared with noncarriers. The UGT1A1*6 variant rs4148323 A allele was present predominantly in Asian participants and was associated with an increase in letermovir AUC compared with noncarriers (GMR, 1.36; 95%CI, 1. 1.07–1.74). SLCO1B1 variant rs2306283, UGT1A1*28 TA promoter repeat, and BCRP variant rs2231142 had no effect on letermovir PK. Together, these data suggest that variants of enzymes and transporters that are involved in the disposition of letermovir in vitro may account for some variability in letermovir PK, but do not affect exposure to a clinically relevant extent. [ABSTRACT FROM AUTHOR]

Background: Elbasvir/grazoprevir is a once-daily fixed-dose combination therapy for the treatment of chronic HCV infection, including HCV/HIV coinfection.Objectives: To evaluate the pharmacokinetic interaction of elbasvir and grazoprevir with raltegravir or dolutegravir.Methods: Three open-label trials in healthy adult participants were conducted. In the raltegravir trials, participants received a single dose of raltegravir 400 mg, a single dose of elbasvir 50 mg or grazoprevir 200 mg, and raltegravir with either elbasvir or grazoprevir. In the dolutegravir trial, participants received a single dose of dolutegravir 50 mg alone or co-administered with once-daily elbasvir 50 mg and grazoprevir 200 mg.Results: The raltegravir AUC0-∞ geometric mean ratio (GMR) (90% CI) was 1.02 (0.81-1.27) with elbasvir and 1.43 (0.89-2.30) with grazoprevir. Dolutegravir AUC0-∞ GMR (90% CI) was 1.16 (1.00-1.34) with elbasvir and grazoprevir. The elbasvir AUC0-∞ GMR (90% CI) was 0.81 (0.57-1.17) with raltegravir and 0.98 (0.93-1.04) with dolutegravir. The grazoprevir AUC0-24 GMR (90% CI) was 0.89 (0.72-1.09) with raltegravir and 0.81 (0.67-0.97) with dolutegravir.Conclusions: Elbasvir or grazoprevir co-administered with raltegravir or dolutegravir resulted in no clinically meaningful drug-drug interactions and was generally well tolerated. These results support the assertion that no dose adjustments for elbasvir, grazoprevir, raltegravir or dolutegravir are needed for co-administration in HCV/HIV-coinfected people. [ABSTRACT FROM AUTHOR]

The aims of these phase I trials were to evaluate the pharmacokinetic interaction between elbasvir (EBR) or grazoprevir (GZR) and buprenorphine/naloxone (BUP/NAL). Trial 1 was a single‐dose trial in healthy participants. Trial 2 was a multiple‐dose trial in participants on BUP/NAL maintenance therapy. Coadministration of EBR or GZR with BUP/NAL had minimal effect on the pharmacokinetics of BUP/NAL, EBR, and GZR. The geometric mean ratios (GMRs (90% CI)) for BUP, norbuprenorphine, and NAL AUC0‐∞ were 0.98 (0.89–1.08), 0.97 (0.86–1.09), and 0.88 (0.78–1.00) in the presence/absence of EBR; 0.98 (0.81–1.19), 1.13 (0.97–1.32), and 1.10 (0.82–1.47) in the presence/absence of GZR. The GMRs (90% CI) for EBR and GZR AUC0‐∞ in the absence/presence of BUP/NAL were 1.22 (0.98–1.52) and 0.86 (0.63–1.18). In conclusion, no dose adjustment for BUP/NAL, EBR, or GZR is required for patients with HCV infection receiving EBR/GZR and BUP/NAL maintenance therapy. [ABSTRACT FROM AUTHOR]

We conducted two phase I trials to evaluate the pharmacokinetic interactions between elbasvir (EBR), grazoprevir (GZR), and methadone (MK‐8742‐P010 and MK‐5172‐P030) in non‐hepatitis C virus (HCV)‐infected participants on methadone maintenance therapy. Coadministration of EBR or GZR with methadone had no clinically meaningful effect on EBR, GZR, or methadone pharmacokinetics. The geometric mean ratios (GMRs) for R‐ and S‐methadone AUC0‐24 were 1.03 (90% confidence interval (CI), 0.92–1.15) and 1.09 (90% CI, 0.94–1.26) in the presence/absence of EBR; and 1.09 (90% CI, 1.02–1.17) and 1.23 (90% CI, 1.12–1.35) in the presence/absence of GZR. The GMRs for EBR and GZR AUC0‐24 in participants receiving methadone relative to a healthy historical cohort not receiving methadone were 1.20 (90% CI, 0.94–1.53) and 1.03 (90% CI, 0.76–1.41), respectively. These results indicate that no dose adjustment is required for individuals with HCV infection receiving stable methadone therapy and the EBR/GZR fixed‐dose regimen. [ABSTRACT FROM AUTHOR]

Abstract: A broadband circularly polarized antenna based on the crossed‐dipole structure is designed. The antenna consists of a pair of dual‐side printed crossed dipoles, a loop phase delay line, and a parasitic patch. By modifying the configuration of the dipoles and introducing a parasitic patch, a wide axial ratio (AR) bandwidth is obtained. A defected ground plane is designed, which has a significant improvement in extending the 3‐dB AR bandwidth and enhances the gain. The proposed prototype is manufactured and measured for validation. Measured results show that the antenna achieves both −10 dB impedance bandwidth and 3‐dB AR bandwidth of 68.6% (2.3–4.7 GHz). Moreover, the average gain of the antenna is about 8 dBi within the operating band, with a floating less than 2 dB. [ABSTRACT FROM AUTHOR]

The family of sufficient dimension reduction (SDR) methods that produce informative combinations of predictors, or indices, are particularly useful for high-dimensional regression analysis. In many such analyses, it becomes increasingly common that there is available a priori subject knowledge of the predictors; for example, they belong to different groups. While many recent SDR proposals have greatly expanded the scope of the methods’ applicability, how to effectively incorporate the prior predictor structure information remains a challenge. In this article, we aim at dimension reduction that recovers full regression information while preserving the predictor group structure. Built upon a new concept of the direct sum envelope, we introduce a systematic way to incorporate the group information in most existing SDR estimators. As a result, the reduction outcomes are much easier to interpret. Moreover, the envelope method provides a principled way to build a variety of prior structures into dimension reduction analysis. Both simulations and real data analysis demonstrate the competent numerical performance of the new method. [ABSTRACT FROM AUTHOR]

Stratification in randomization and analysis are widely employed to balance treatment groups in clinical trials. However, the potential power loss due to under-stratification or over-stratification has not been thoroughly evaluated in the typical setting of confirmatory clinical trials. In cases where there are too many strata and some have small sample sizes or a small number of events, it is common practice to combine these small strata during analysis. However, there is a lack of guidance on how those small strata should be combined. This paper presents extensive simulation studies to evaluate the impact of under-stratification or over-stratification on the power of survival analysis and the estimate of hazard ratio using stratified log-rank test and Cox PH model, respectively. The difference in power between stratified and unstratified log-rank tests is also investigated under different scenarios. Our results suggest that failing to consider prognostic stratification factors with strong effects, and/or accounting for non-prognostic factors such as noise and predictive factors, may reduce the power of the stratified log-rank test. Additionally, methods of combining small strata are explored and compared. [ABSTRACT FROM AUTHOR]

The direct copolymerization of ethylene with polar monomers to produce functional polyolefins continues to be highly appealing due to its simple operation process and controllable product microstructure. Low-cost nickel catalysts have been extensively utilized in academia for the synthesis of polar polyethylenes. However, the development of high-temperature copolymerization catalysts suitable for industrial production conditions remains a significant challenge. Classified by the resultant copolymers, this review provides a comprehensive summary of the research progress in nickel complex catalyzed ethylene-polar monomer copolymerization at elevated temperatures in the past five years. The polymerization results of ethylene–methyl acrylate copolymers, ethylene-tert–butyl acrylate copolymers, ethylene–other fundamental polar monomer copolymers, and ethylene–special polar monomer copolymers are thoroughly summarized. The involved nickel catalysts include the phosphine-phenolate type, bisphosphine-monoxide type, phosphine-carbonyl type, phosphine-benzenamine type, and the phosphine-enolate type. The effective modulation of catalytic activity, molecular weight, molecular weight distribution, melting point, and polar monomer incorporation ratio by these catalysts is concluded and discussed. It reveals that the optimization of the catalyst system is mainly achieved through the methods of catalyst structure rational design, extra additive introduction, and single-site catalyst heterogenization. As a result, some outstanding catalysts are capable of producing polar polyethylenes that closely resemble commercial products. To achieve industrialization, it is essential to further emphasize the fundamental science of high-temperature copolymerization systems and the application performance of resultant polar polyethylenes. [ABSTRACT FROM AUTHOR]

Background In KEYNOTE-355 (NCT02819518), the addition of pembrolizumab to chemotherapy led to statistically significant improvements in progression-free survival and overall survival in patients with advanced triple-negative breast cancer with tumor programmed cell death ligand 1 (PD-L1) combined positive score of at least 10. We report patient-reported outcomes from KEYNOTE-355. Methods Patients were randomly assigned 2:1 to pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus investigator's choice chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30), Breast Cancer–Specific Quality of Life Questionnaire, and EuroQol 5-Dimension questionnaire visual analog scale were prespecified. Patient-reported outcomes were analyzed for patients who received at least 1 dose of study treatment and completed at least 1 patient-reported outcome assessment. Changes in patient-reported outcome scores from baseline were assessed at week 15 (latest time point at which completion and compliance rates were at least 60% and at least 80%, respectively). Time to deterioration in patient-reported outcomes was defined as time to first onset of at least a 10-point worsening in score from baseline. Results Patient-reported outcome analyses included 317 patients with tumor PD-L1 combined positive score of at least 10 (pembrolizumab plus chemotherapy: n = 217; placebo plus chemotherapy: n = 100). There were no between-group differences in change from baseline to week 15 in QLQ-C30 global health status/quality of life (QOL; least-squares mean difference = −1.81, 95% confidence interval [CI] = −6.92 to 3.30), emotional functioning (least-squares mean difference = −1.43, 95% CI = −7.03 to 4.16), physical functioning (least-squares mean difference = −1.05, 95% CI = −6.59 to 4.50), or EuroQol 5-Dimension questionnaire visual analog scale (least-squares mean difference = 0.18, 95% CI = −5.04 to 5.39) and no between-group difference in time to deterioration in QLQ-C30 global health status/QOL, emotional functioning, or physical functioning. Conclusions Together with the efficacy and safety findings, patient-reported outcome results from KEYNOTE-355 support pembrolizumab plus chemotherapy as a standard of care for patients with advanced triple-negative breast cancer with tumor PD-L1 expression (combined positive score ≥10). [ABSTRACT FROM AUTHOR]

In this work, the effects of the tungsten (W) converter and molybdenum target thickness on the 99Mo yield in the production of 99Mo via 100Mo(γ, n)99Mo photonuclear reaction were studied. The FLUKA program was applied to simulate the optimal size of the targets for the production of 99Mo under 50 MeV electron conditions, where the thicknesses of the W and Mo targets were 0.3 and 1.4 cm, respectively. The relative error between the calculation and the experimental results was less than 8%. The process of irradiating natural (natMo) and enriched (100Mo) molybdenum targets using electrons with a 1 mA average beam current was further simulated. The specific activity of enriched 100Mo is nearly ten times higher than that of natMo. The use of 100Mo targets also produces fewer radioactive impurities. This study provides a guidance on the size of W conversion and molybdenum targets, as well as the selection of molybdenum species, when producing 99Mo via photonuclear reaction. [ABSTRACT FROM AUTHOR]

Abstract The groundwater is an important route of human exposure to kinds of contaminants. This study was carried out to investigate the occurrence and spatial distribution of groundwater arsenic in the Jinghui irrigation district in Shaanxi Province, China. The water contamination was assessed for drinking purposes by comparing it to national guidelines, and the impacts of arsenic on human health were quantified using the health risk assessment model recommended by the USEPA. The results show that the concentration of groundwater arsenic ranges from 0.0012 to 0.0190 mg/L (average 0.0054 mg/L), and 2.58% of groundwater exceed the national guidelines of 0.01 mg/L for drinking. The carcinogenic risk of arsenic affecting adults has reached 3.50 × 10−4, significantly exceeding the national guideline (1.00 × 10−4.) The health risks resulting from oral exposure are higher than those of dermal exposure. The carcinogenic risk for adults is higher than that for children, while the non-carcinogenic risk for children is higher than that for adults. The area ratio of the carcinogenic risk is 42.82%, and the area of the non-carcinogenic risk is 69.19%. Groundwater arsenic mainly originates from the discharge of industrial wastewater and the slowly release of natural sediments. The results of this study can help to set up suitable management strategies to guarantee water supply and health safety for local residents. Highlights • The concentration of groundwater arsenic exceeds the national guideline. • The carcinogenic risk for adults is higher than that for children. • Risks resulting from oral exposure are higher than those of dermal exposure. • The area of the non-carcinogenic risk is greater than that of carcinogenic risk. • Arsenic mainly originates from the industrial wastewater and the natural sediments. [ABSTRACT FROM AUTHOR]

Polymers of higher olefin, obtained by Ziegler-type polymerization, have been used in some critical fields, e.g., as the membrane for extracorporeal membrane oxygenation (ECMO), which plays an important role in the treatment of patients with severe COVID-19. The polymer obtained by a single-site catalyst, e.g., metallocene catalysts, demonstrated a higher performance. The homo- and co-polymerization of allyltrimethylisilane (ATMS) and 4-methyl-1-pentene (4M1P) were conducted using syndiospecific (cat 1) and isospecific (cat 2) metallocene catalysts. Cat 1 showed low conversions and provided a polymer with a higher molecular weight, while cat 2 behaved oppositely. 13C-NMR spectra certified the stereotacticity of the resultant polymer, and the resonance of the carbon atom of CH2 (αα') between the two tertiary carbon atoms of the ATMS and 4M1P units were observed. This could be the evidence of the formation of a true copolymer. The crystallization of the polymer was explored using a differential scanning calorimeter (DSC) and wide angle X-ray diffraction (WAXD). All homopolymers and some of the copolymers showed high melting temperatures and low melting enthalpies. The WAXD patterns of the syndiotactic polymer and isotactic homopolymer or the ATMS-rich copolymer were consistent with the reported literature, but the isotactic 4M1P-rich copolymer provided the crystal form I, which is unusual for a 4M1P polymer without any pretreatment. [ABSTRACT FROM AUTHOR]

In our recent work, it was first demonstrated that aluminum (Al) ions generated in the process of H2O2 plasma sterilization can penetrate the sterilization package and contaminate the surgical instrument inside. In this paper, it is first reported that Al ions can be adsorbed in plasma by sterilization package with surface modification, significantly reducing the contamination, up to 92%. The surface modification is carried out by introducing a functional layer on the surface of the sterilization package. The special chemical groups in the functional layer can combine with Al ions in two ways, ion exchange and chelation, preventing them from contaminating the surgical instrument in the sterilization package. Through the research on the diffusion coefficient of Al in Si sterilized using the modified sterilization packages, it is found that surface modification of sterilization packages has a great influence on the physical mechanism of Al contamination. [ABSTRACT FROM AUTHOR]

An ultra-wideband dual-polarized tightly coupled dipole array (TCDA) with 10:1 bandwidth is presented. Aimed at solving the ultra-wideband impedance matching problem between the antenna and free space, a novel meta-material wide-angle impedance matching (WAIM) layer is presented. The meta-WAIM utilized a structure of planar double layers with the elliptical split ring on top and the concentric split ring on the bottom, which improves the beam scanning ability over the high-frequency band. The dual-polarized dipoles are arranged as "egg-create" and fed by the integrated double-Y balun. A resistive frequency selective surface (FSS) is loaded between the dipole and ground plane to improve the active VSWR and lower the overall profile, simultaneously. The proposed antenna array can operate over a 10:1 bandwidth (0.2–2 GHz) with an active VSWR < {2.1, 2.7, 4} and average radiation efficiency > {71.6 %, 68.9 %, 60.3 %} for the scan up to {broadside, 45°, 60°}, respectively. The overall antenna profile is 95 mm, which is only 0.063λ L evaluated at the lowest operating frequency. A prototype of a 6 × 10 array is simulated, fabricated, and measured. Good agreement is achieved between the simulated and measured results. [ABSTRACT FROM AUTHOR]

• BCN was surface modified with two silane coupling agents. • Composites exhibited excellent properties before and after gamma irradiation. • The performance of composites can be improved by improving the interfacial compatibility. • Modified BCN could weaken oxidative degradation of EP under γ irradiation. Polymer matrix composites reinforced with boron nitride (BN) have attracted much attention in the nuclear industry due to their attractive properties. Nevertheless, the performance of such composites largely depends on matrix–filler interactions. Herein, carbon-doped boron nitride (BCN), modified by two silane coupling agents, was used to fabricate epoxy composites, and the effect of gamma irradiation on the properties of epoxy resin composites was investigated. The research showed that the modified BCN/epoxy composites prepared herein exhibited excellent mechanical and thermal properties before and after gamma irradiation. The tensile strength of the composites increased up to 63.1 MPa at 0.5 wt % loadings compared to neat epoxy (54.7 MPa). After irradiation at 900 kGy, the tensile strength of the composites was 32.5% higher than that of neat EP. This improvement was ascribed to the excellent compatibility of the modified BCN and epoxy. Moreover, the char yield and the glass transition temperature significantly increased with incorporation of modified BCN before and after irradiation. The mechanism for the enhanced performance was that the barrier consisting of BN protected the matrix from further oxidative degradation. This study suggested that functionalized BN more effectively enhanced epoxy properties before and after irradiation. [ABSTRACT FROM AUTHOR]

In this paper, it is first demonstrated that Aluminum (Al) contamination is present; H2O2 plasma sterilization is widely used for sterilization of surgical instruments. The contamination amount of Al can reach as high as 7.9 × 1012 atoms/cm2. Aluminum is well known as a harmful element to human health, which may damage bones and the brain. During the use of the surgical instruments after H2O2 plasma sterilization in surgery, the contaminated Al may enter and reside in the human body and threaten the health and even life safety. Therefore, it is necessary to study the Al contamination present in H2O2 plasma sterilization to arouse public attention and take countermeasures. The physical mechanism of the Al contamination presented in H2O2 plasma sterilization is diffusion. In our previous study, we developed two physical models for calculating the diffusion coefficient. In this study, both models are used to calculate the diffusion coefficient of the contaminated Al in sterilized Si samples. From the calculation results, it is inferred that the contamination mechanism of Al presented in H2O2 plasma sterilization is closer to the model, where the diffusion coefficient value is a function of the plasma treatment time. [ABSTRACT FROM AUTHOR]

Background: Many people infected with hepatitis C virus have comorbidities, including hypercholesterolemia, that are treated with statins. In this study, we evaluated the drug–drug interaction potential of the hepatitis C virus inhibitors elbasvir (EBR) and grazoprevir (GZR) with statins. Pitavastatin, rosuvastatin, pravastatin, and atorvastatin are substrates of organic anion-transporting polypeptide 1B, whereas rosuvastatin and atorvastatin are also breast cancer resistance protein substrates. Methods: Three open-label, phase I clinical trials in healthy adults were conducted with multiple daily doses of oral GZR or EBR/GZR and single oral doses of statins. Trial 1: GZR 200 mg plus pitavastatin 10 mg. Trial 2: Part 1, GZR 200 mg plus rosuvastatin 10 mg, then EBR 50 mg/GZR 200 mg plus rosuvastatin 10 mg; Part 2, EBR 50 mg/GZR 200 mg plus pravastatin 40 mg. Trial 3: EBR 50 mg/GZR 200 mg plus atorvastatin 10 mg. Results: Neither GZR nor EBR pharmacokinetics were meaningfully affected by statins. Coadministration of EBR/GZR did not result in clinically relevant changes in the exposure of pitavastatin or pravastatin. However, EBR/GZR increased exposure to rosuvastatin (126%) and atorvastatin (94%). Coadministration of statins plus GZR or EBR/GZR was generally well tolerated. Conclusions: Although statins do not appreciably affect EBR or GZR pharmacokinetics, EBR/GZR can impact the pharmacokinetics of certain statins, likely via inhibition of breast cancer resistance protein but not organic anion-transporting polypeptide 1B. Coadministration of EBR/GZR with pitavastatin or pravastatin does not require adjustment of either dose of statin, whereas the dose of rosuvastatin and atorvastatin should be decreased when coadministered with EBR/GZR. [ABSTRACT FROM AUTHOR]

[Display omitted] • Newly developing copolymerization of cycloolefin with propylene/higher olefins (COC) • Recent progress of transition metal complex catalysts. • Continuously improving performances of COC materials. • Various COC materials and their potential application. • From academic researches to industrial processes. Demanding synthetic polymers with properties of the optical, electrical, hydrophobic, thermo- and chemical stability, cyclic olefin copolymers (COCs) have been quickly developed for the usage of optical materials, high-frequency and high-speed electronic devices, pharmaceutical packaging and so on. Recently the newly developing copolymers of cyclic olefins with propylene or higher olefins have been intensively investigated with more attention for not only new copolymers but also advanced properties providing new extensive applications for the expanding markets. The progress of new copolymers has been centralized on development of suitable transition metal complex catalysts, being finely tuning complex catalysts in order to improve polymerization activities and tailor copolymers with their microstructures controlled. To providing the whole view of transition metal complex catalysts in copolymerizing cyclic olefins with propylene or higher olefins with both academic and industrial points, the review classifies different types of complex catalysts to correlate their structural features with catalytic performances as well as the microstructures of resultant copolymers; it would potentially enhance industrial investments and commercialization of new processes for advanced COCs through using efficient complex catalysts. [ABSTRACT FROM AUTHOR]

Background: Pembrolizumab monotherapy showed durable antitumour activity and manageable safety in patients with metastatic triple-negative breast cancer. We aimed to examine whether the addition of pembrolizumab would enhance the antitumour activity of chemotherapy in patients with metastatic triple-negative breast cancer.Methods: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 209 sites in 29 countries, we randomly assigned patients 2:1 with untreated locally recurrent inoperable or metastatic triple-negative breast cancer using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy. Randomisation was stratified by type of on-study chemotherapy (taxane or gemcitabine-carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ≥1 or <1), and previous treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes or no). Eligibility criteria included age at least 18 years, centrally confirmed triple-negative breast cancer; at least one measurable lesion; provision of a newly obtained tumour sample for determination of triple-negative breast cancer status and PD-L1 status by immunohistochemistry at a central laboratory; an Eastern Cooperative Oncology Group performance status score 0 or 1; and adequate organ function. The sponsor, investigators, other study site staff (except for the unmasked pharmacist), and patients were masked to pembrolizumab versus saline placebo administration. In addition, the sponsor, the investigators, other study site staff, and patients were masked to patient-level tumour PD-L1 biomarker results. Dual primary efficacy endpoints were progression-free survival and overall survival assessed in the PD-L1 CPS of 10 or more, CPS of 1 or more, and intention-to-treat populations. The definitive assessment of progression-free survival was done at this interim analysis; follow-up to assess overall survival is continuing. For progression-free survival, a hierarchical testing strategy was used, such that testing was done first in patients with CPS of 10 or more (prespecified statistical criterion was α=0·00411 at this interim analysis), then in patients with CPS of 1 or more (α=0·00111 at this interim analysis, with partial alpha from progression-free survival in patients with CPS of 10 or more passed over), and finally in the intention-to-treat population (α=0·00111 at this interim analysis). This study is registered with ClinicalTrials.gov, NCT02819518, and is ongoing.Findings: Between Jan 9, 2017, and June 12, 2018, of 1372 patients screened, 847 were randomly assigned to treatment, with 566 patients in the pembrolizumab-chemotherapy group and 281 patients in the placebo-chemotherapy group. At the second interim analysis (data cutoff, Dec 11, 2019), median follow-up was 25·9 months (IQR 22·8-29·9) in the pembrolizumab-chemotherapy group and 26·3 months (22·7-29·7) in the placebo-chemotherapy group. Among patients with CPS of 10 or more, median progression-free survival was 9·7 months with pembrolizumab-chemotherapy and 5·6 months with placebo-chemotherapy (hazard ratio [HR] for progression or death, 0·65, 95% CI 0·49-0·86; one-sided p=0·0012 [primary objective met]). Median progression-free survival was 7·6 and 5·6 months (HR, 0·74, 0·61-0·90; one-sided p=0·0014 [not significant]) among patients with CPS of 1 or more and 7·5 and 5·6 months (HR, 0·82, 0·69-0·97 [not tested]) among the intention-to-treat population. The pembrolizumab treatment effect increased with PD-L1 enrichment. Grade 3-5 treatment-related adverse event rates were 68% in the pembrolizumab-chemotherapy group and 67% in the placebo-chemotherapy group, including death in <1% in the pembrolizumab-chemotherapy group and 0% in the placebo-chemotherapy group.Interpretation: Pembrolizumab-chemotherapy showed a significant and clinically meaningful improvement in progression-free survival versus placebo-chemotherapy among patients with metastatic triple-negative breast cancer with CPS of 10 or more. These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic triple-negative breast cancer.Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. [ABSTRACT FROM AUTHOR]

This article investigated the solubility of platinum group metals (PGMs) in sodium borosilicate glass and its effect on the viscosity and electrical conductivity of melts. The role of PGMs in the viscosity and electrical conductivity of melts was examined using the rotating cylinder method and impedance spectroscopy, respectively. Moreover, XRD, XPS, and SEM were used to measure the phase compositions, valence states, and microstructures, respectively, of the glass samples with different PGMs contents. The results showed that the solubility of Pd and Rh in sodium borosilicate glass was estimated to be less than 110 ppm by weight. The higher concentrations of Pd and Rh resulted in Pd-rich and Rh-rich inclusions in the glass matrix, which eventually agglomerated to form metallic Pd, Rh and Rh 2 O 3. The evolution of viscosity and electrical conductivity with different temperatures followed the Arrhenius equation with a fairly good linear relationship between ln η and ln κ. • The solubility of PGMs in borosilicate glass was less than 110 ppm by weight. • The aggregation and crystallization trends of PGMs in glass were investigated. • The temperature dependence of viscosity and conductivity of glass melts obeyed Arrhenius equation at high temperature region. • The viscous/electrical activation energy of glass melts containing 0–1 wt% PGMs was calculated. • The impact of PGMs concentration on the structure of PGMs aggregates had a nonlinear threshold effect. [ABSTRACT FROM AUTHOR]

Purpose: To describe the phase 1 and population pharmacokinetic investigations that support dosing recommendations for elbasvir/grazoprevir (EBR/GZR) in hepatitis C virus-infected people with advanced chronic kidney disease. Methods: This was an open-label, two-part, multiple-dose trial (MK-5172 PN050; NCT01937975) in 24 non–HCV-infected participants with end-stage renal disease (ESRD) or severe renal impairment who received once-daily EBR 50 mg and GZR 100 mg for 10 days. Population pharmacokinetic analyses from the phase 3 C-SURFER study (PN052, NCT02092350) were also conducted. Results: When comparing haemodialysis (HD) and non-HD days in participants with ESRD, geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for EBR and GZR AUC0–24 were 1.14 (1.08–1.21) and 0.97 (0.87–1.09). When comparing ESRD and healthy participants, GMRs (90% CIs) for EBR and GZR AUC0–24 were 0.99 (0.75–1.30) and 0.83 (0.56–1.22) on HD days, and 0.86 (0.65–1.14) and 0.85 (0.58–1.25) on non-HD days. GMRs (90% CIs) for AUC0–24 in participants with severe renal impairment relative to healthy controls were 1.65 (1.09–2.49) for GZR and 1.86 (1.38–2.51) for EBR. In population modelling of data from C-SURFER, absolute geometric means of steady-state EBR AUC0–24 were 2.78 and 3.07 μM*h (HD and non-HD recipients) and GZR AUC0–24 were 1.80 and 2.34 μM*h (HD and non-HD recipients). Conclusions: EBR/GZR represents an important treatment option for HCV infection in people with severe renal impairment and those with ESRD. No dosage adjustment of EBR/GZR is required in people with any degree of renal impairment, including those receiving dialysis. [ABSTRACT FROM AUTHOR]

Abstract: Elbasvir (EBR)/grazoprevir (GZR) may be coadministered with immunosuppressant drugs in posttransplant people who are infected with hepatitis C virus. The aim of the present study was to assess the safety and pharmacokinetic interactions between EBR and GZR and single doses of cyclosporine, tacrolimus, mycophenolate mofetil (MMF), and prednisone. This was a 4‐part, open‐label study in 58 healthy volunteers. Participants received single doses of cyclosporine 400 mg, tacrolimus 2 mg, MMF 1 g, or prednisone 40 mg alone or in the presence of once‐daily EBR 50 mg/GZR 200 mg. Multiple oral doses of EBR + GZR had no significant effect on cyclosporine. However, in the presence of cyclosporine, the 24‐hour area under the concentration‐time curve of GZR was increased by approximately 15‐fold (geometric mean ratio [90%CI] 15.21 [12.83; 18.04]); the concentration of EBR was increased approximately 2‐fold in the presence of cyclosporine. Coadministration of EBR/GZR and tacrolimus did not affect the pharmacokinetics of EBR or GZR, but resulted in an increase in tacrolimus AUC (geometric mean ratio [90%CI] 1.43 [1.24; 1.64]). There were no clinically relevant interactions between EBR/GZR and either MMF or prednisone. Data from the present study indicate that EBR/GZR may be coadministered in people receiving tacrolimus, MMF, and prednisolone. EBR/GZR is contraindicated in people receiving cyclosporine because the significantly higher concentrations of GZR may increase the risk of transaminase elevations. [ABSTRACT FROM AUTHOR]

Purpose: Oral contraceptive pills (OCPs) are an important element of hepatitis C virus (HCV) treatment in women of childbearing potential. These studies evaluated the safety and pharmacokinetic interactions between elbasvir (EBR) and grazoprevir (GZR) and ethinyl estradiol/levonorgestrel (EE/LNG). Methods: Both studies were open-label, single-site, two-period, fixed-sequence, one-way interaction studies. In period 1, subjects received one tablet of EE/LNG (0.03 mg/0.15 mg). In period 2, subjects received EBR (50 mg once daily) for 13 days or GZR (200 mg once daily) for 10 days, with one tablet of EE/LNG on day 7 (GZR group) or 10 (EBR group). Each study enrolled 20 healthy, nonsmoking adult females. Results: There was no clinically meaningful effect of multiple doses of EBR or GZR on the pharmacokinetics of EE or LNG. Geometric mean ratios (GMRs) for AUC and C in the presence and absence of EBR were 1.01 and 1.10 for EE and 1.14 and 1.02 for LNG, with 90% confidence intervals (CIs) that were contained in the interval [0.80, 1.25]. Similarly, the AUC and C GMRs in the presence and absence of GZR were 1.10 and 1.05 for EE and 1.23 and 0.93 for LNG, respectively. The 90% CIs for EE AUC and for EE and LNG C were contained in the interval [0.80, 1.25]; however, the 90% CI for the LNG AUC [1.15, 1.32] slightly exceeded the upper bound. Conclusions: These results suggest that EBR/GZR can be co-administered to female patients with HCV of childbearing potential who are on OCPs to prevent pregnancy. [ABSTRACT FROM AUTHOR]

[Display omitted] • This review focuses on representative works involving Ni-, Pd-, Fe-, and Co-based catalysts with high thermal stability for ethylene polymerization in the past five years. • Classified by the ligand structure, polymerization performance parameters under elevated temperatures are discussed. • Primary approaches to develop thermally robust late transition metal catalysts are outlined. • Designability and logicality of research should be highly improved to clarify the relationship between ligand structure and thermal stability, and the combination of experimental results and theoretical calculations may be helpful. Since the pioneering work of highly active α -diimine palladium/nickel catalysts in 1995 by Brookhart, late transition metal catalysts have been extensively and deeply investigated. Although late transition metal catalysts continue to emerge with unique catalytic properties, they still encounter many formidable challenges in the process of industrialization. One of the biggest obstacles is that the traditional late transition metal catalysts typically show poor thermal stability and thus are inapplicable to industrial polymerization conditions. In recent years, numerous thermally robust late transition metal catalysts have been constantly developed to enhance the possibility of their industrial application. This review focuses on representative works involving Ni-, Pd-, Fe-, and Co-based catalysts with high thermal stability for ethylene polymerization in the past five years. Classified by the ligand structure, polymerization performance parameters under elevated temperatures including catalytic activity and polyethylene properties are summarized and discussed. It reveals that thermally stable α -diimine palladium/nickel catalysts may be the most promising candidate for industrialization. This is due to their good balance between catalytic activities and molecular weights of produced polyethylene. Furthermore, primary approaches to develop thermally robust late transition metal catalysts are outlined, which sheds light on the rational design and application of catalysts with desirable polymerization performance. As one of the most useful methods for improving the thermal stability of catalysts, steric effect can effectively suppress chain transfer and catalyst decomposition and/or deactivation process by blocking the axial coordination sites of the active metal center. Noted that most previously reported thermal stable catalysts have been developed by trial-and-error method, thus a regular understanding of the structure–property relationship of catalysts is required. To achieve the objective of industrialization, the thermal stability of late transition metal catalysts deserves more attention and is expected to achieve a further breakthrough. [ABSTRACT FROM AUTHOR]

Background: Genetic risk scores (GRS) composed of single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD) have been shown to predict cardiovascular risk in primary and secondary prevention populations. We tested whether an expanded CAD-GRS predicted risk of recurrent coronary events in patients presenting with acute coronary syndrome (ACS). Methods: We genotyped 6,404 individuals from the genetics substudy of the IMPROVE-IT trial, which tested whether the addition of ezetimibe to statin therapy improves cardiovascular outcomes. We studied the association of an updated CAD-GRS that included 75 genetic variants, with a composite outcome of coronary heart disease death, myocardial infarction or urgent coronary revascularization, adjusting, importantly, for the clinical TIMI Risk Score for Secondary Prevention. Results: When divided into low (quintile 1), intermediate (quintiles 2-4) and high (quintile 5) genetic risk categories, a significant gradient in risk for recurrent cardiovascular events was observed such that, after adjusting for clinical risk factors, patients in the highest genetic risk category had a 44% greater risk compared to those in the lowest genetic risk category (P=0.0004) [Figure]. In terms of the benefit of ezetimibe vs. placebo, the hazard ratios and absolute risk reductions were 0.89 (95% CI 0.65-1.21) & 2.0%, 0.94 (95% CI 0.80-1.11) & 0.6% and 0.82 (95% CI 0.63-1.07) & 3.1% for the low, intermediate and high genetic risk categories, respectively. Conclusion: An expanded GRS composed of 75 CAD-associated SNPs identifies patients presenting with ACS who are at significantly increased risk of recurrent coronary events independent of clinical risk factors. Patients with the highest burden of genetic risk tended to derive the largest relative and absolute clinical benefit from ezetimibe therapy. [ABSTRACT FROM AUTHOR]

Purpose Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3. Methods These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3. Findings Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log 10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log 10 IU/mL for GT1- and GT3-infected participants. Implications The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose–response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protocol 8742-002). [ABSTRACT FROM AUTHOR]