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The present study investigated the dissolution and oxidation corrosion behaviors of Hastelloy exposed to static liquid lead‐bismuth eutectic (LBE) at 500°C with an oxygen concentration of 1 × 10−6 mass%. Hastelloy exhibited better LBE corrosion resistance than the Monel alloy. Both dissolution and oxidation corrosion were observed in Hastelloy, and the maximum LBE penetration depth and spinel layer thickness in the corroded sample after 4000 h of exposure reached 120 ± 36 and 21 ± 12 µm, respectively. Annealing twin boundaries provided favorable paths of accelerated LBE penetration into the matrix, resulting in selective leaching of Ni. Microstructural characterization revealed that the spinel layer formed between penetrated LBE and base metal slowed down the elemental interdiffusion, thereby retarding the dissolution rate. Volumetric changes induced by LBE penetration promoted the formation of stacking faults and dislocations, which could provide more channels for elemental diffusion, leading to the propagation of dissolution attack. [ABSTRACT FROM AUTHOR]

This paper proposes a novel maximum power point tracking scheme for efficient and speedy extraction of maximum power from a pressure retarded osmosis process subject to rapid salinity variation. The scheme is designed using the Whale Optimization with Differential Evolution algorithm, a nature-inspired metaheuristic technique. The algorithm has facilitated the developed maximum power point tracking controller with features that have helped overcome limitations such as lower tracking efficiency and steady state oscillations as encountered in the conventional methods. Previously, a number of widely used algorithms including perturb & observe, incremental mass resistance and mass feedback controller were used to design maximum power point control schemes for a PRO process to reduce power loss due to rapid salinity variation. However, in using these techniques, a trade-off between the oscillations and the respond time was required to adjust the operation. The proposed scheme is used to solve this problem and is implemented in simulation on a scaled-up PRO system. The performance of the scheme is compared with some popularly used maximum power point tracking controllers. It is observed from results that the proposed method not only outperforms other widely used methods but is also more robust. [ABSTRACT FROM AUTHOR]

Abstract: Gefitinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase and is used for the treatment of non‐small‐cell lung cancer (NSCLC) with activating EGFR mutations. Gefitinib is metabolized by CYP2D6 and CYP3A4. This analysis compared the systemic exposure of gefitinib after oral administration in CYP2D6 ultrarapid metabolizers (UM) vs extensive metabolizers (EM). Physiologically based pharmacokinetic (PBPK) modeling was conducted using a population‐based simulator. The model was calibrated using itraconazole‐gefitinib clinical drug‐drug interaction data and validated with gefitinib data in CYP2D6 EM vs poor metabolizers (PM). System components of the PBPK model were evaluated using published clinical metoprolol pharmacokinetic data in CYP2D6 UM, EM, and PM. Our PBPK model predicted a gefitinib geometric least‐squares mean area under the plasma concentration‐time curve (AUC) from time 0 to 264 hours (AUC(0‐264)) ratio in the presence vs absence of itraconazole of 1.85, similar to the ratio of 1.78 from clinical study data. Predicted and observed metoprolol geometric least‐squares mean AUC(0‐24) ratios in UM vs EM were also similar (0.46 and 0.55, respectively), suggesting that system components related to CYP2D6 in the PBPK model were properly established. In addition, the PBPK model also captured gefitinib pharmacokinetic profiles in CYP2D6 polymorphic populations. The final PBPK model predicted a decrease in gefitinib AUC of ∼39% in CYP2D6 UM vs EM. Such changes in exposure will have limited impact as the reduced exposure is still above gefitinib's in vitro IC90 for EGFR activating mutations in NSCLC patients. [ABSTRACT FROM AUTHOR]

Creep behaviors of CNS-2 steel have been investigated under different conditions at 600–650 °C and 105–180 MPa, and the microstructures and precipitations of crept and aged specimens have been characterized. It is showed that the CNS-2 steels have remarkable creep resistance at 600°C/105MPa until at least 1500 h, and the accelerated creep occurs at the elevated temperature of 650 °C and applied stress of 180MPa. The CNS-2 steels are toughened after creep without hardening and embrittlement. Their grain microstructures are stable but the sub-structures change during the creep. The subgrains coarsen with creep strain and the density of dislocations decreases due to the recovery at elevated temperature. Three kinds of precipitations including M 23 C 6 , MX-type carbonitride and Laves phase are identified in the crept steels by TEM, EDS and SEAD analysis. It is also found that the applied stress promotes the precipitations formed at the grain or subgrain boundary. [ABSTRACT FROM AUTHOR]

Objectives: Asthma is the leading cause of emergency room visits in children, and those with asthma tend to suffer from more severe consequences of respiratory tract infections. The aims of this study were among children who required hospitalization, compare differences between those admitted with or without respiratory infection, describe changes in yearly proportion of asthma among the children admitted with a respiratory infection in New York City from 2006 to 2012 and ascertain how asthma affected the average length of hospital stay for those with respiratory infection.Methods: We conducted an historical prospective study using data obtained from multiple electronic sources of patients discharged from a 200-bed pediatric hospital in a major metropolitan healthcare system between 2006 and 2012. Patient characteristics were obtained from electronic health records and billing codes.Results: Among 83 348 patient discharges, there were 5057 (6.1%) with a respiratory infection. In the multivariable model, children with the following characteristics were significantly more likely to be admitted with a respiratory infection as compared with other diagnoses: asthma [odds ratio (OR) 4.68 (95% confidence limits (CL): 4.31, 5.08], male sex [OR:1.11 (1.05, 1.18)], prior hospitalization [OR: 3.65 (3.43, 3.89)], renal failure [(OR: 2.14 (1.70, 2.70)] and Medicaid coverage [OR: 1.93 (1.81, 2.05)]. Children aged ≥5 years (OR: 0.44 (0.41, 0.47) and those with diabetes (OR: 0.32 (0.21, 0.51) were less likely to be admitted with a respiratory infection. Hospitalized patients with respiratory infection and asthma, identified by ICD-9 codes, had significantly shorter lengths of stay than patients without asthma, 5.3 and 9.0 days, respectively,p < 0.001. Asthma in patients admitted with a respiratory infection increased from 19.2% in 2006 to 28.2% in 2012, peaking at 34.1% in 2010 (p < 0.001).Conclusion: This study suggests that asthma is a significant risk factor for hospitalization of children with respiratory infection, and suggests that the prevalence of asthma is increasing over time among children hospitalized with respiratory infection in this urban setting. [ABSTRACT FROM AUTHOR]

Within the mean-field theory, we investigate the magnetic properties of a charged spin-1 Bose gas in two dimensions. In this system the diamagnetism competes with paramagnetism, where the Landé factor g is introduced to describe the strength of the paramagnetic effect. The system presents a crossover from diamagnetism to paramagnetism with the increasing of the Landé factor. denotes the critical value of the Landé factor. We get the same value of both in the low temperature and strong magnetic field limit. Our results also show that in very weak magnetic field no condensation happens in the two-dimensional charged spin-1 Bose gas. [ABSTRACT FROM AUTHOR]

Increasing urbanisation and population growth have caused depletion of freshwater resources leading to exacerbation of water scarcity in remote communities. Whilst much attention has been paid to improving industrial-scale desalination plants over the past decade, the development of small-scale off-grid desalination units to facilitate freshwater supply for remote communities has been overlooked. This study presents a novel method for coupling solar photovoltaic thermal (PVT) cells to reverse osmosis (RO) desalination introducing seawater as the cooling medium to increase the thermal efficiency of solar energy generation and subsequently maximising the rate of freshwater production. The inclusion of a battery unit will enable a constant rate of freshwater supply leading to minimisation of membrane fouling which often occurs in renewable energy powered membrane desalination units. The integrative system has been simulated for the seawater properties and climatic conditions in Alexandria, Egypt. Furthermore, the modelling results indicate that using the proposed method will lead to a reduction of 0.12 kWh/m3 in the specific electricity consumption rate of RO desalination, as well as increasing the electricity generation capacity of the PVT cells leading to a 6% reduction in the required solar panel surface area. • Novel off-grid solar PVT powered desalination for deployment in Alexandria, Egypt • Seawater feed used for cooling PVT modules prior to a 5 m3/day reverse osmosis unit • Results show increased efficiency for PVT due to cooling and fewer required panels. • Reduction in the specific energy consumption of reverse osmosis unit is 0.12 kWh/m3 • Increased RO efficiency is due to higher water viscosity and hence permeability. [ABSTRACT FROM AUTHOR]

The effect of varying aluminum (Al) levels on the high-temperature oxidation resistance of Alumina-Forming Austenitic stainless steels (AFA) has been investigated under dry air conditions at 800 °C and 900 °C. Mass gain assessments indicate that AFA stainless steel containing a higher concentration of Al, with a composition of Fe-20Ni-15Cr-2.4Al-1.6Mn, demonstrates enhanced resistance to oxidation when contrasted with steel of lower Al content, characterized as Fe-23Ni-15Cr-1.9Al. This phenomenon is attributed to the development of a compact CrMn 1.5 O 4 layer on the exterior and an Al 2 O 3 layer on the interior. The dense oxide layers that form on the high-Al steel impede the permeation of oxygen and deter the peeling of the oxide layer, thus preserving structural stability of the material upon exposure to high temperatures. Conversely, the steel with a lower Al content undergoes considerable chipping of its oxide layer. The morphology and distribution of Al 2 O 3 are determined by the relative rates of oxygen inward movement and aluminum outward movement. In the case of the Fe-20Ni-15Cr-2.4Al-1.6Mn steel, the tight oxide film significantly reduces the inward movement of oxygen and increases the outward movement of Al, leading to a denser Al 2 O 3 layer underneath the Cr 2 O 3. [Display omitted] • Al2O3 layer's compactness in high-Al AFA steels reduces oxygen permeation. • Oxide scale's adherence in 20Ni-15Cr-2.4Al-1.6Mn alloy deters spallation. • Oxidation studies identify Al's critical role in forming stable protective scales. • Comparative study unveils Al's impact on AFA steel's oxidation kinetics [ABSTRACT FROM AUTHOR]

Clarification of the relationship between oxygen diffusion and microstructural evolution in liquid lead-bismuth eutectic (LBE) is of great importance for understanding and consequently tailoring the oxidation process. In the present study, a Si-modified ferritic martensitic steel was exposed to oxygen-saturated LBE at 500°C at various times and the interface between the internal oxidation zone and matrix was investigated. Microstructural characterisation reveals that grain boundaries and martensitic lath boundaries provide a fast pathway for oxygen diffusion, resulting in the high amount of oxidation products, as well as cracks. The internal stress caused by the formation of oxidation products along grain boundary results in the proliferation of dislocations, which subsequently play as the new diffusion channel for oxygen. The chemical analysis demonstrates that Si preferably concentrates along the dislocations in a form of Si-rich oxide, suggesting the oxidation of Si is prior to the Cr-rich oxide. [ABSTRACT FROM AUTHOR]

• The corrosion behavior of three F/M steels with different Si and Y contents, 12Cr-Y, 11Cr-1Si, and 11Cr-1Si-Y in static liquid LBE with different temperature, oxygen concentration and test time was studied. • The oxide layer and dissolution corrosion features were observed and analysed. • The thin and dense oxide layer was formed in LBE with lower oxygen concentration. • Synergistic effect of Si and Y-addition significantly reduced the oxidation rate and dissolution corrosion performance of steels. Ferritic/martensitic (F/M) steels with (9–12)wt.% Cr are potential candidates for structural applications in Lead-cooled Fast Reactors (LFR) due to their low solubility in liquid Lead-Bismuth Eutectic (LBE) coolant. How to improve corrosion resistance of 9-12Cr F/M steels has been a challenge. Here we cast three steels by pre-laying yttrium (Y) powder on the bottom of mold to obtained Y-bearing steels. Precursory work on this family of Y-bearing steels has previously highlighted them with the longer steady state creep stage and the lower minimum creep rate at 650 °C under 120 MPa, which has motivated their study under more extreme conditions, such as corrosion behavior in liquid LBE. We find a synergistic effect of Si and Y on both optimizing structure and reducing thickness of oxide scale at various oxygen concentrations, exposing temperatures and test times. The oxide scale changed from dual layers to single spinel layer, the thickness reduced from 36 μm to 4 μm, dissolution corrosion and PbBi penetration were inhibited. Low diffusion coefficient of ions in SiO 2 and Y segregation on grain boundaries of steels hinder the outward diffusion of cations, and strong affinity between Y and O leads to the formation of Y 2 O 3 preferentially, acting as nucleation sites of SiO 2 and Cr 2 O 3 , accelerating a dense and continuous oxide scale. This work enables the development of structure steels with high corrosion resistance for various high temperature application, including boiler steel, gas turbine, and heat exchanger tubes. [ABSTRACT FROM AUTHOR]

Background: Treatment options for malignant pleural mesothelioma are scarce. Tazemetostat, a selective oral enhancer of zeste homolog 2 (EZH2) inhibitor, has shown antitumour activity in several haematological cancers and solid tumours. We aimed to evaluate the anti-tumour activity and safety of tazemetostat in patients with measurable relapsed or refractory malignant pleural mesothelioma.Methods: We conducted an open-label, single-arm phase 2 study at 16 hospitals in France, the UK, and the USA. Eligible patients were aged 18 years or older with malignant pleural mesothelioma of any histology that was relapsed or refractory after treatment with at least one pemetrexed-containing regimen, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a life expectancy of greater than 3 months. In part 1 of the study, participants received oral tazemetostat 800 mg once on day 1 and then twice daily from day 2 onwards. In part 2, participants received oral tazemetostat 800 mg twice daily starting on day 1 of cycle 1, using a two-stage Green-Dahlberg design. Tazemetostat was administered in 21-day cycles for approximately 17 cycles. The primary endpoint of part 1 was the pharmacokinetics of tazemetostat and its metabolite at day 15 after administration of 800 mg tazemetostat, as measured by maximum serum concentration (Cmax), time to Cmax (Tmax), area under the concentration-time curve (AUC) to day 15 (AUC0-t), area under the curve from time 0 extrapolated to infinity (AUC0-∞), and the half-life (t1/2) of tazemetostat, assessed in all patients enrolled in part 1. The primary endpoint of part 2 was the disease control rate (the proportion of patients with a complete response, partial response, or stable disease) at week 12 in patients with malignant pleural mesothelioma per protocol with BAP1 inactivation determined by immunohistochemistry. The safety population included all the patients who had at least one post-dose safety assessment. This trial is now complete and is registered with ClinicalTrials.gov, NCT02860286.Findings: Between July 29, 2016, and June 2, 2017, 74 patients were enrolled (13 in part 1 and 61 in part 2) and received tazemetostat, 73 (99%) of whom had BAP1-inactivated tumours. In part 1, following repeat dosing of tazemetostat at steady state, on day 15 of cycle 1, the mean Cmax was 829 ng/mL (coefficient of variation 56·3%), median Tmax was 2 h (range 1-4), mean AUC0-twas 3310 h·ng/mL (coefficient of variation 50·4%), mean AUC0-∞ was 3180 h·ng/mL (46·6%), and the geometric mean t1/2 was 3·1 h (13·9%). After a median follow-up of 35·9 weeks (IQR 20·6-85·9), the disease control rate in part 2 in patients with BAP1-inactivated malignant pleural mesothelioma was 54% (95% CI 42-67; 33 of 61 patients) at week 12. No patients had a confirmed complete response. Two patients had a confirmed partial response: one had an ongoing partial response with a duration of 18 weeks and the other had a duration of 42 weeks. The most common grade 3-4 treatment-emergent adverse events were hyperglycaemia (five [7%] patients), hyponatraemia (five [7%]), and anaemia (four [5%]); serious adverse events were reported in 25 (34%) of 74 patients. Five (7%) of 74 patients died while on study; no treatment-related deaths occurred.Interpretation: Further refinement of biomarkers for tazemetostat activity in malignant pleural mesothelioma beyond BAP1 inactivation could help identify a subset of tumours that are most likely to derive prolonged benefit or shrinkage from this therapy.Funding: Epizyme. [ABSTRACT FROM AUTHOR]

Crevice corrosion is a significant form of localized corrosion that can lead to failures in structural components. However, there is a lack of research on this phenomenon in liquid lead-bismuth eutectic (LBE). In this study, the crevice corrosion behavior of 316 L exposed to stagnant LBE with the oxygen concentration of 1 × 10–6 wt.% at 550 °C for 500 h was examined for the first time. Microstructural characterizations indicated 316 L is susceptible to crevice corrosion and reducing the crevices size facilitates a transition from oxidation to dissolution corrosion. Grain boundaries are able to provide more diffusion channels for oxygen, thereby promoting the development of Cr-rich oxides and chemical segregations beneath the surface scale. A simplified model elucidating the transportation of dissolved oxygen within the crevice environment of LBE has been developed. [Display omitted] [ABSTRACT FROM AUTHOR]

KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrated robust efficacy against KRAS G12D -mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR-Cas9 screening, which unveiled proteasome as a sensitization target. We further observed that the proteasome inhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, either as a single agent or in combination with carfilzomib, reshaped the tumor microenvironment toward an immune-permissive one. In summary, this study provides potential therapies for patients with KRAS G12D -mutant cancers, for whom effective treatments are currently lacking. [Display omitted] • HRS-4642, a KRAS G12D inhibitor, demonstrated preclinical anti-tumor effects • HRS-4642 treatment led to objective responses in patients with KRAS G12D mutation • Proteasome serves as a sensitization target for HRS-4642 to enhance anti-tumor efficacy • HRS-4642 alone or combined with carfilzomib effectively shaped the tumor microenvironment Zhou et al. report the potent preclinical and clinical anti-tumor efficacy of a KRAS G12D-specific inhibitor, HRS-4642, and its sensitizing combinational strategy with carfilzomib. This work provides novel therapeutics for solid tumor patients harboring KRAS G12D mutation, for whom effective targeted therapies are lacking. [ABSTRACT FROM AUTHOR]

[Display omitted] • MIP film with 4,7-bis(thiophene-2-yl)benzo thiadiazole shows high selectivity to CPF. • Au@Cu:Tb-MOFs act as co-reaction promoters greatly improve the ECL emission signal. • Molecular docking technology has verified the binding of functional monomer to CPF. • The sensor has excellent selectivity, stability, and sensitivity for CPF detection. • The strategy has great potential for pesticide residues detection in actual samples. Herein, a self-enhanced molecularly imprinted polymer luminescence (MIP-ECL) sensing platform based on gold-copper doped Tb-MOFs (Au@Cu:Tb-MOFs) was constructed for ultra-sensitive detection of chlorpyrifos (CPF). In this work, Au@Cu:Tb-MOFs as co-reaction promoters greatly improve the ECL emission signal, while Au@Cu:Tb-MOFs were used as cathode emitters. And chlorpyrifos and 4,7-bis(thiophene-2-yl)benzo [c][1,2,5] thiadiazole were electropolymerized on electrode surface to form MIP, where this films with thiophene derivatives could greatly improve ECL signal. Notably, the introduction of MIP as recognition elements enabled specific identification of target analytes, in which molecular docking technique validated target analyte and functional monomers are tightly bound through Pi-alkyl interaction. As the concentration of CPF increases, the ECL signal gradually decreases, showing a good linear relationship in the range of 0.1–106 pg/mL with a low detection limit (LOD) of 0.029 pg/mL. Moreover, actual sample testing experiment of this method displayed a special correlation in organophosphorus detection and development potential in actual sample analysis. [ABSTRACT FROM AUTHOR]

In order to encourage innovative medicine to address Chinese unmet medical needs, China has changed its drug regulatory landscape to speed up access to new medicines. In order to understand the fast‐changing landscape and to enable planning of more global drug development programs and study designs in China, we reviewed 15 published clinical pharmacology‐related guidances by the National Medical Products Administration (NMPA), and compared them with reference guidances from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the International Conference on Harmonization (ICH), to understand the similarities and differences, especially any China‐specific requirements, such as ethnic sensitivity analysis. Overall, by reviewing these clinical pharmacology‐related NMPA guidances, it is clear that NMPA guidances are very similar to FDA, EMA, and ICH guidances. There are no relevant differences in the major principles, but some differences in structure, contents, and focus were noted. The NMPA is adapting flexibility statements into newly published guidances. Ethnic sensitivity analysis needs to be implemented early in drug development plans. The NMPA encourages sponsors to conduct early clinical trials in China or include China early in multiregional clinical trials, and to obtain safety, efficacy, and pharmacokinetic data for ethnic sensitivity analysis. Depending on the stage of development, ethnic sensitivity analysis can be conducted using in vitro or literature data, other Asian clinical data, or Chinese clinical data. [ABSTRACT FROM AUTHOR]

What is known and objective: Esomeprazole, the S‐isomer of omeprazole, is a proton pump inhibitor which has been approved by over 125 countries, also known as NEXIUM®. Esomeprazole was developed to provide further improvement on efficacy for acid‐related diseases with higher systemic bioavailability due to the less first‐pass metabolism and lower plasma clearance. Esomeprazole is primarily metabolized by CYP2C19. Approximately <1% of Caucasians and 5%‐10% of Asians have absent CYP2C19 enzyme activity. Although the influence of various CYP2C19 phenotypes on esomeprazole pharmacokinetics has been studied, this is the first report in the Japanese population where 27 low CYP2C19 metabolizers were included. Methods: In this study, a population PK model describing the PK of esomeprazole was developed to understand the difference of CYP2C19 phenotypes on clearance in the Japanese population. The model quantitatively assessed the influence of CYP2C19 phenotype on esomeprazole PK in healthy Japanese male subjects after receiving repeated oral dosing. The inhibition mechanism of esomeprazole on CYP2C19 activity was also included in the model. Results and discussion: CYP2C19 phenotype and dose were found as statistically significant covariates on esomeprazole clearance. The apparent clearance at 10‐mg dose was 17.32, 9.77 and 7.37 (L/h) for homozygous extensive metabolizer, heterozygous extensive metabolizer and poor metabolizer subjects, respectively. And the apparent clearance decreased as dose increased. What is new and conclusion: The established population PK model well described the esomeprazole PK and model‐predicted esomeprazole PK was in good agreement with external clinical data, suggesting the robustness and applicability of the current model for predicting esomeprazole PK. [ABSTRACT FROM AUTHOR]

Abstract Casting oxide dispersion strengthened (ODS) steel is difficult due to the coarsening and agglomeration of oxide particles during melting and solidification. In the present paper, a new method was developed to prepare 9Cr-ODS steel via the in situ reaction between elemental yttrium in molten Fe and activated oxygen from Fe 2 O 3 oxygen carrier. To identify whether coarsening and aggregation of yttrium oxides can be suppressed, the cast steels did not suffer plastic deformation. Finally, tempered martensite matrix was obtained accompanied with about 0.2–1.1 μm yttrium oxides. Some yttrium oxides suffered coarsening and agglomeration due to the high oxygen content. 9Cr-ODS steel exhibited higher ultimate tensile strength, yield strength and slight lower elongation compared to 9Cr steel. The results indicated that yttrium oxides could be effectively introduced into the steel matrix via this casting method, which provided an alternative method for ODS steel fabrication. Graphical abstract Image 1 Highlights • A new method was developed to prepare 9Cr-ODS F/M steel. • Elemental yttrium and Fe 2 O 3 were the sources of yttrium and oxygen. • Yttrium oxides of about 0.2–1.1 μm were introduced into the matrix effectively. • 9Cr-ODS steel exhibited higher yield strength compared to 9Cr steel at RT and 873 K. [ABSTRACT FROM AUTHOR]

Significant and reversible reductions in testosterone levels were observed with AZD4901 in both preclinical and clinical testing. A comprehensive population pharmacokinetic/pharmacodynamic (PK/PD) modeling of AZD4901 concentration and testosterone relationship from 3 phase 1 studies was performed using NONMEM to support dose selection for phase 2a development. A 2-compartment model with first-order absorption and first-order elimination best described AZD4901 PK. Circadian rhythm of baseline testosterone concentrations was well described by a cosine function. An indirect response model with inhibition of testosterone production was used to link the AZD4901 concentration to testosterone response. The AZD4901 concentration to yield 50% maximum testosterone suppression (IC50) was estimated to be 230 ng/mL. Based on simulations, following 40 mg twice daily (BID) treatment, the AZD4901 steady-state trough concentration will be much higher compared to 80 mg once daily (QD). The AZD4901 concentration time above IC50 after 40 mg BID is 84% of the time of the dosing interval compared to only 49% after 80 mg QD. The mean predicted testosterone concentrations at steady state are lower and overall less variable over 24 hours for 40 mg BID dosing compared to 80 mg QD dosing. Population PK and PK/PD analyses demonstrated that AZD4901 40 mg BID is a better dosing strategy to more consistently suppress testosterone during the entire dosing interval. Consequently, 40 mg BID dosing was suggested in a phase 2a trial in females with polycystic ovary syndrome, and the trial resulted in a positive outcome as shown by significant testosterone decrease compared to placebo. [ABSTRACT FROM AUTHOR]

Using data from the farm household survey conducted in 2009, arable land use intensity (ALUI) and its influence factors at farm household level were investigated by the Tobit model. Suyu District of Suqian City and Taixing City of Jiansu Province, China were chosen as the regions for comparison. The results show that: 1) On the average, the ALUI, labor intensity, yield-increasing input, and labor-saving input are 15 238.14 yuan (RMB)/ha, 192 d/ha, 7233.01 yuan/ha, and 2451.32 yuan/ha in the less economically developed Suyu District, and 13 020.65 yuan/ha, 181 d/ha, 5871.82 yuan/ha, and 2625.97 yuan/ha in more economically developed Taixing City. The figures indicate that Suyu District has higher ALUI and labor intensity input but lower labor-saving input. 2) Comparing all the influence factors, the total arable land area in available and average plot size have bigger effects on arable land intensive use; to a small degree, family's non-farm income affects labor intensity, yield-increasing input, and labor-saving input; the yield-increasing input decreases significantly when the householder has higher education attainment; the commercialization rates of agricultural products and the planting proportion of cash crops both have unstable influence on ALUI; the share of arable land rented in has few impacts on labor intensity, yield-increasing input, and labor-saving input. 3) There are no differences found in the internal impact mechanism of influence factors on the arable land intensive use behaviors of farm households. However, there are conspicuous disparities in the impact degrees and statistical significance based on varying economic levels. 4) Using the results as bases, this study proposes that the government should implement land management and agricultural policies according to local condition. And these policies should decrease land fragmentation to promote scale management of land and arable land use intensification. [ABSTRACT FROM AUTHOR]

Background: Inhaled corticosteroids reduce inflammation in asthma but chronic use may cause adverse effects. AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, has the potential of an improved risk-benefit profile. We investigated the safety and efficacy of AZD7594 in asthma.Methods: This phase 2a multi-center, randomized, double-blind, placebo-controlled crossover study enrolled adults with asthma aged 18 to 75 years. Patients were treated with budesonide 200 μg twice daily for 2-3 3 weeks (run in part one). If controlled, as demonstrated by an asthma control questionnaire-5 score of < 1.5, patients entered a three-week run-in (part two) where they received a short acting bronchodilator alone. Thereafter, patients with a fractional exhaled nitric oxide (FENO) ≥25 ppb and pre-dose FEV1 40 to 90% predicted were randomized to one of nine treatment sequences. Each patient received placebo and two of three dose levels of AZD7594 (58, 250, 800 μg) once daily via inhalation, in 14-day treatment periods, separated by three-week washout periods. The primary endpoint was the change from baseline in morning trough FEV1 versus placebo on day 15. Secondary endpoints included measures of airway inflammation and asthma control.Results: Fifty-four patients were randomized and received at least 1 dose of treatment, 48 patients completed the study. Overall 52 patients received placebo, 34 received AZD7594 58 μg, 34 received AZD7594 250 μg, and 34 received AZD7594 800 μg. AZD7594 800 μg demonstrated a significant improvement in Day 15 morning trough FEV1versus placebo (LS means difference 0.148 L 95% CI 0.035-0.261, p = 0.011), with a dose-dependent response seen in the 250 μg (0.076 L -0·036-0·188, p = 0.183) and 58 μg (0·027 L -0·086-0·140, p = 0.683). All secondary endpoints showed statistically significant improvement at the 800 μg dose. All doses demonstrated a significant reduction in FENO at day 15 p < 0.01. No statistically significant difference in plasma cortisol level was observed between AZD7594 and placebo at any dose. AZD7594 was considered safe and well tolerated.Conclusions: Two-week treatment with AZD7594 demonstrated a favorable risk-benefit profile in patients with mild to moderate asthma. Further clinical studies are needed to fully characterize AZD7594.Trial Registration: ClinicalTrials.gov number NCT02479412 . [ABSTRACT FROM AUTHOR]