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In some reactors, ammonia and its radiolytic product (H2) are used to scavenge the oxidizing species (H2O2, O2, and •OH). A reducing chemical environment is thus created and the pH of the coolant is regulated simultaneously. In the present study, the radiolytic behaviors of deoxygenated ammonia solution were studied in the γ-ray field. The impacts of N2 pressure, gas-liquid volume ratio, and temperature on deoxygenated ammonia solution radiolysis were investigated. The pH and the concentrations of residual ammonia, H2, and nitrogen oxides (NO2- and NO3-) were analyzed. The results revealed that the variation of N2 pressure (0.5~5.0 MPa) and gas-liquid volume ratio had no influence on the concentrations of residual ammonia and nitrogen oxides. NO2- and NO3- concentrations were approximately 1 mg/L at room temperature when the absorbed dose was 28.8 kGy. However, the apparent concentration of H2 significantly decreased with the N2 pressure and gas-liquid volume ratio. The loss fraction of ammonia considerably declined from 26.5% to 8.4% when the temperature increased from 25 to 200 ℃, demonstrating that the radiolysis of ammonia was suppressed at the elevated temperature. However, the concentrations of NO2- and NO3- increased to 34 and 3 times, respectively, at 200 ℃ compared to those at 25 ℃. In addition, a radiolysis model of ammonia-containing coolant was established in the present study. The maximum relative error between experimental data and calculation results at any temperature was 4.1%. The model was thereafter used to calculate residual ammonia concentration with the absorbed dose under different initial ammonia concentrations. The results revealed that it was necessary to replenish ammonia regularly when using it alone to inhibit oxidizing species.

As the decay daughter of 99Mo, 99mTc is the most widely used radioisotope in the field of nuclear medicine. Recently, the major 99Mo production reactors in the world are facing problems such as unplanned maintenance, shutdown and decommission, resulting in the unstable supply of 99Mo. Therefore, many developed countries have been actively exploiting alternative technologies for 99Mo production. In this paper, various 99Mo-production technologies by particle accelerator instead of reactor were introduced, and the research progress of producing 99Mo based on electron accelerator was summarized at home and abroad. The accelerator performance index and the key technologies in the production process were discussed in detail, such as the design of irradiation device and target, separation of 99mTc, recovery of 100Mo and waste management. In addition, some suggestions were put forward for the basic and applied research of relevant technologies in China and the commercialization of 99Mo production by electron accelerator.

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]

Copper and copper alloys are widely used in the field of nuclear materials. The effects of aqueous solutions that have undergone copper ion radiolysis on the generation of H2O2, O2, and H2 must be considered for material corrosion control and hydrogen explosion risk assessment. In this study, a γ-radiolysis experiment of an aqueous solution containing copper ions was conducted to explore the effects of different absorbed doses, absorption dose rates, and Cu2+ concentrations on the generation of H2O2, O2, and H2. The results showed that with an increase in the absorbed dose (0-1.80 kGy), the concentrations of H2O2 and H2(g) firstly increased and then tended to stabilize under steady-state concentrations of 5.41×10-6 and 7.91×10-5 mol/L, respectively, whereas the concentration of O2(g) remained at 9.04×10-4 mol/L. The presence of Cu2+ enhanced the equilibrium concentrations of H2 and H2O2 by one and two orders of magnitude, respectively, which in turn promoted the generation of H2O2 and H2; however, it had a negligible effect on O2 generation. The equilibrium concentrations of H2O2 and H2 increased with an increase in the absorption dose rate. Specifically, when the absorption dose rate was increased from 1.40 to 46.93 Gy/min, the equilibrium concentrations of H2O2 and H2 increased from 4.56×10-6 and 1.78×10-5 mol/L to 2.46×10-5 and 3.81×10-4 mol/L, respectively, whereas O2 remained essentially unaffected within this absorption dose rate range. In addition, based on the kinetics of water radiolysis and two-film theory of gas-liquid mass transfer, we constructed a calculation model for the radiolysis of aqueous solutions containing copper ions. Compared with the experimental data, the absolute values of the normalized mean bias in the simulation results were mostly between 1% and 7%, with a maximum of approximately 24%, thereby demonstrating the effectiveness and correctness of the calculation model. Accordingly, the model was used to calculate the radiolytic behavior of an aqueous solution containing copper ions under C6+ ion irradiation, and the simulation results matched well with the experimental data reported in the literature, indicating that the model can be expanded to other applications.

In this study, the γ-radiolysis of boric acid-lithium hydroxide-ammonia coolant was investigated under different conditions, including boric acid concentration, absorbed dose, and absorbed dose rate. The concentrations of H2O2, NO2-, and NO3- were determined using UV-visible spectroscopy and ion chromatography. With an increase in boric acid concentration, the concentrations of H2O2 and NO2- in the coolant system did not change significantly within a pH range commonly used in pressurized water reactor operation. Specifically, the concentration of H2O2 varied from 9.28×10-5 to 1.07×10-4 mol/L, while that of NO2- changed from 0.9×10-5 to 1.5×10-5 mol/L. In contrast, the concentration of NO3- fluctuated significantly, ranging from 4×10-5 to 8×10-5 mol/L. With an increase in the absorbed dose (1-30 kGy), the equilibrium concentration of H2O2 and NO2- in boric acid-lithium hydroxide-ammonia system increased to 1.28×10-4 mol/L and 1.30×10-5 mol/L, respectively. Meanwhile, the concentration of NO3- did not change significantly (4×10-5 to 6×10-5 mol/L). The concentrations of the three radiolytic products were not significantly affected within the given absorbed dose rate range (1.27 to 18.86 Gy/min). Overall, this work provides valuable basic data for optimizing the new boric acid-lithium hydroxide-ammonia coolant system.

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]

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]

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]

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]

Sequencing-based genetic association analysis is typically performed by first generating genotype calls from sequence data and then performing association tests on the called genotypes. Standard approaches require accurate genotype calling (GC), which can be achieved either with high sequencing depth (typically available in a small number of individuals) or via computationally intensive multi-sample linkage disequilibrium (LD)-aware methods. We propose a computationally efficient two-stage combination approach for association analysis, in which single-nucleotide polymorphisms (SNPs) are screened in the first stage via a rapid maximum likelihood (ML)-based method on sequence data directly (without first calling genotypes), and then the selected SNPs are evaluated in the second stage by performing association tests on genotypes from multi-sample LD-aware calling. Extensive simulation- and real data-based studies show that the proposed two-stage approaches can save 80% of the computational costs and still obtain more than 90% of the power of the classical method to genotype all markers at various depths  d ≥ 2 . [ABSTRACT FROM AUTHOR]

Group sequential design (GSD) is widely used in clinical trials in which correlated tests of multiple hypotheses are used. Multiple primary objectives resulting in tests with known correlations include evaluating (1) multiple experimental treatment arms, (2) multiple populations, (3) the combination of multiple arms and multiple populations, or (4) any asymptotically multivariate normal tests. In this paper, we focus on the first three of these and extend the framework of the weighted parametric multiple test procedure from fixed designs with a single analysis per objective to a GSD setting where different objectives may be assessed at the same or different times, each in a group sequential fashion. Pragmatic methods for design and analysis of weighted parametric group sequential design under closed testing procedures are proposed to maintain the strong control of the family‐wise Type I error rate when correlations between tests are incorporated. This results in the ability to relax testing bounds compared to designs not fully adjusting for known correlations, increasing power, or allowing decreased sample size. We illustrate the proposed methods using clinical trial examples and conduct a simulation study to evaluate the operating characteristics. [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]

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]

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]

Synthesis of triacylglycerol requires the glucose-derived glycerol component, and glucose uptake has been viewed as the rate-limiting step in glucose metabolism in adipocytes. Furthermore, adipose tissue contains all three isoforms of the glycolytic enzyme phosphofructokinase (PFK). We here report that mice deficient in the muscle isoform PFK-M have greatly reduced fat stores. Mice with disrupted activity of the PFK-M distal promoter were obtained from Lexicon Pharmaceuticals, developed from OmniBank OST#56064. Intra-abdominal fat was measured by magnetic resonance imaging of the methylene proton signal. Lipogenesis from labeled glucose was measured in isolated adipocytes. Lipolysis (glycerol and free fatty acid release) was measured in perifused adipocytes. Intra-abdominal fat in PFK-M–deficient female mice (5–10 months old) was 17 ± 3% of that of wild-type littermates (n = 4; P < 0.02). Epididymal fat weight in 15 animals (7–9.5 months) was 34 ± 4% of control littermate (P < 0.002), with 10–30% lower body weight. Basal and insulin-stimulated lipogenesis in PFK-M–deficient epididymal adipocytes was 40% of the rates in cells from heterozygous littermates (n = 3; P < 0.05). The rate of isoproterenol-stimulated lipolysis in wild-type adipocytes declined ~10% after 1 h and 50% after 2 h; in PFK-M–deficient cells it declined much more rapidly, 50% in 1 h and 90% in 2 h, and lipolytic oscillations appeared to be damped (n = 4). These results indicate an important role for PFK-M in adipose metabolism. This may be related to the ability of this isoform to generate glycolytic oscillations, because such oscillations may enhance the production of the triacylglycerol precursor α-glycerophosphate. [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]

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]

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)., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In an interim analysis of this phase 3 trial, the addition of pembrolizumab to chemotherapy resulted in longer progression-free survival than chemotherapy alone among patients with advanced triple-negative breast cancer whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS; the number of PD-L1-staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100) of 10 or more. The results of the final analysis of overall survival have not been reported., Methods: We randomly assigned patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer in a 2:1 ratio to receive pembrolizumab (200 mg) every 3 weeks plus the investigator's choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine-carboplatin) or placebo plus chemotherapy. The primary end points were progression-free survival (reported previously) and overall survival among patients whose tumors expressed PD-L1 with a CPS of 10 or more (the CPS-10 subgroup), among patients whose tumors expressed PD-L1 with a CPS of 1 or more (the CPS-1 subgroup), and in the intention-to-treat population. Safety was also assessed., Results: A total of 847 patients underwent randomization: 566 were assigned to the pembrolizumab-chemotherapy group, and 281 to the placebo-chemotherapy group. The median follow-up was 44.1 months. In the CPS-10 subgroup, the median overall survival was 23.0 months in the pembrolizumab-chemotherapy group and 16.1 months in the placebo-chemotherapy group (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.55 to 0.95; two-sided P = 0.0185 [criterion for significance met]); in the CPS-1 subgroup, the median overall survival was 17.6 and 16.0 months in the two groups, respectively (hazard ratio, 0.86; 95% CI, 0.72 to 1.04; two-sided P = 0.1125 [not significant]); and in the intention-to-treat population, the median overall survival was 17.2 and 15.5 months, respectively (hazard ratio, 0.89; 95% CI, 0.76 to 1.05 [significance not tested]). Adverse events of grade 3, 4, or 5 that were related to the trial regimen occurred in 68.1% of the patients in the pembrolizumab-chemotherapy group and in 66.9% in the placebo-chemotherapy group, including death in 0.4% of the patients in the pembrolizumab-chemotherapy group and in no patients in the placebo-chemotherapy group., Conclusions: Among patients with advanced triple-negative breast cancer whose tumors expressed PD-L1 with a CPS of 10 or more, the addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone. (Funded by Merck Sharp and Dohme; KEYNOTE-355 ClinicalTrials.gov number, NCT02819518.)., (Copyright © 2022 Massachusetts Medical Society.)

Aim: To evaluate the effect of SLCO1B1 genetic variants on grazoprevir pharmacokinetics and efficacy. Methods: A retrospective analysis of 1578 hepatitis C virus-infected participants from ten Phase II/III clinical trials. Results: Relative to noncarriers of the risk allele, geometric mean ratios (95% CI) of grazoprevir area under curve (AUC) 0-24 were: rs4149056 (risk allele C), one copy, 1.13 (1.06-1.21), two copies, 1.43 (1.16-1.77); and rs11045819 (risk allele A), one copy, 0.93 (0.87-1.00); two copies, 0.78 (0.61-1.00). The rs2306283 variant was not associated with grazoprevir exposure. None of the SLCO1B1 variants were associated with sustained virologic response. Conclusion: Genetic variants in SLCO1B1 were associated with modest changes in grazoprevir pharmacokinetics, but not with meaningful differences in efficacy.