This study evaluated maintenance treatment with niraparib, a potent inhibitor of poly(ADP-ribose) polymerase 1/2, in patients with platinum-sensitive recurrent ovarian cancer.
In this phase III, ...double-blind, placebo-controlled study conducted at 30 centers in China, adults with platinum-sensitive recurrent ovarian cancer who had responded to their most recent platinum-containing chemotherapy were randomized 2 : 1 to receive oral niraparib (300 mg/day) or matched placebo until disease progression or unacceptable toxicity (NCT03705156). Following a protocol amendment, patients with a bodyweight <77 kg or a platelet count <150 × 103/μl received 200 mg/day, and all other patients 300 mg/day, as an individualized starting dose (ISD). Randomization was carried out by an interactive web response system and stratified by BRCA mutation, time to recurrence following penultimate chemotherapy, and response to most recent chemotherapy. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review.
Between 26 September 2017 and 2 February 2019, 265 patients were randomized to receive niraparib (n = 177) or placebo (n = 88); 249 patients received an ISD (300 mg, n = 14; 200 mg, n = 235) as per protocol. In the intention-to-treat population, median PFS was significantly longer for patients receiving niraparib versus placebo: 18.3 95% confidence interval (CI), 10.9-not evaluable versus 5.4 (95% CI, 3.7-5.7) months hazard ratio (HR) = 0.32; 95% CI, 0.23-0.45; P < 0.0001, and a similar PFS benefit was observed in patients receiving an ISD, regardless of BRCA mutation status. Grade ≥3 treatment-emergent adverse events occurred in 50.8% and 19.3% of patients who received niraparib and placebo, respectively; the most common events were neutrophil count decreased (20.3% versus 8.0%) and anemia (14.7% versus 2.3%).
Niraparib maintenance treatment reduced the risk of disease progression or death by 68% and prolonged PFS compared to placebo in patients with platinum-sensitive recurrent ovarian cancer. Individualized niraparib dosing is effective and safe and should be considered standard practice in this setting.
•Chinese patients with platinum-sensitive recurrent ovarian cancer received maintenance niraparib (n = 177) or placebo (n = 88).•Median PFS was longer for niraparib versus placebo: 18.3 versus 5.4 months (HR = 0.32; 95% CI, 0.23-0.45; P < 0.0001).•Niraparib had a similar PFS benefit for 249 patients receiving individualized dosing based on bodyweight and platelet count.•Grade ≥3 treatment-emergent adverse events occurred in 50.8% and 19.3% of patients who received niraparib and placebo, respectively.•In the niraparib group, Grade ≥3 platelet count decreased/thrombocytopenia occurred in 11.3% of patients.
A Nationwide Nitrogen Deposition Monitoring Network (NNDMN) containing 43 monitoring sites was established in China to measure gaseous NH3, NO2, and HNO3 and particulate NH4+ and NO3− in air and/or ...precipitation from 2010 to 2014. Wet/bulk deposition fluxes of Nr species were collected by precipitation gauge method and measured by continuous-flow analyzer; dry deposition fluxes were estimated using airborne concentration measurements and inferential models. Our observations reveal large spatial variations of atmospheric Nr concentrations and dry and wet/bulk Nr deposition. On a national basis, the annual average concentrations (1.3–47.0 μg N m−3) and dry plus wet/bulk deposition fluxes (2.9–83.3 kg N ha−1 yr−1) of inorganic Nr species are ranked by land use as urban > rural > background sites and by regions as north China > southeast China > southwest China > northeast China > northwest China > Tibetan Plateau, reflecting the impact of anthropogenic Nr emission. Average dry and wet/bulk N deposition fluxes were 20.6 ± 11.2 (mean ± standard deviation) and 19.3 ± 9.2 kg N ha−1 yr−1 across China, with reduced N deposition dominating both dry and wet/bulk deposition. Our results suggest atmospheric dry N deposition is equally important to wet/bulk N deposition at the national scale. Therefore, both deposition forms should be included when considering the impacts of N deposition on environment and ecosystem health.
The study reported and analyzed the current state of wastewater treatment plants (WWTPs) in urban China from the perspective of treatment technologies, pollutant removals, operating load and effluent ...discharge standards. By the end of 2013, 3508 WWTPs have been built in 31 provinces and cities in China with a total treatment capacity of 1.48×108m3/d. The uneven population distribution between China's east and west regions has resulted in notably different economic development outcomes. The technologies mostly used in WWTPs are AAO and oxidation ditch, which account for over 50% of the existing WWTPs. According to statistics, the efficiencies of COD and NH3–N removal are good in 656 WWTPs in 70 cities. The overall average COD removal is over 88% with few regional differences. The average removal efficiency of NH3–N is up to 80%. Large differences exist between the operating loads applied in different WWTPs. The average operating loading rate is approximately 83%, and 52% of WWTPs operate at loadings of <80%, treating up to 40% of the wastewater generated. The implementation of discharge standards has been low. Approximately 28% of WWTPs that achieved the Grade I-A Discharge Standard of Pollutants for Municipal Wastewater Treatment Plant (GB 18918–2002) were constructed after 2010. The sludge treatment and recycling rates are only 25%, and approximately 15% of wastewater is inefficiently treated. Approximately 60% of WWTPs have capacities of 1×104m3/d–5×104m3/d. Relatively high energy consumption is required for small-scale processing, and the utilization rate of recycled wastewater is low. The challenges of WWTPs are discussed with the aim of developing rational criteria and appropriate technologies for water recycling. Suggestions regarding potential technical and administrative measures are provided.
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•3508 wastewater treatment plants (WWTPs) were summarized.•Population distribution and economic development caused regional difference of WWTPs.•Pollutant removal, operating load, discharge standards in 7 regions were presented.•Suggestions regarding potential technical and administrative measures were provided.
Organic Rankine Cycle (ORC) could be used to recover low-grade waste heat. When a vehicle is running, the engine exhaust gas states have a wide range of variance. Defining the operational conditions ...of the ORC that achieve the maximum utilization of waste heat is important. In this paper the performance of different working fluids operating in specific regions was analyzed using a thermodynamic model built in Matlab together with REFPROP. Nine different pure organic working fluids were selected according to their physical and chemical properties. The results were compared in the regions when net power outputs were fixed at 10
kW. Safety levels and environmental impacts were also evaluated. The outcomes indicate that R11, R141b, R113 and R123 manifest slightly higher thermodynamic performances than the others; however, R245fa and R245ca are the most environment-friendly working fluids for engine waste heat-recovery applications. The optimal control principle of ORC under the transient process is discussed based on the analytical results.
► R11, R141b, R113 and R123 manifest the best thermodynamic performances. ► R245fa and R245ca are the most environment-friendly working fluids for the engine waste heat-recovery application. ► The condensing temperature has more important effect than the evaporating pressure to the performance of ORC. ► The optimal control principle of ORC under the transient process was defined according to the calculation results for the vehicle engine waste heat-recovery application. ► ORC thermodynamic model was built in Matlab together with REFPROP.
Summary
What is known and objectives
Tacrolimus (TAC) is widely used as part of immunosuppressive regimens. There is great interindividual variation on the disposition of TAC. The aim of this study ...was to develop a population pharmacokinetic (PPK) model for Chinese liver transplant patients and evaluate genetic polymorphism and other possible factors on the PK parameters. The exposure of TAC is to be estimated through Bayesian modelling.
Methods
A total of 47 sets of rich‐time PK and 1234 conventional therapeutic drug monitoring (TDM) data were collected from 125 Chinese liver transplant patients. The pathophysiological data of these patients were recorded. CYP3A5*3 and ABCB1 genotypes were determined for each patient. The PPK model for TAC was established by nonlinear mixed‐effects modelling (nonmem). The impact of pathophysiology and genotype on PPK parameters was evaluated. Bayesian estimators for the area under concentration‐time curve (AUC) of TAC were validated.
Results
A two‐compartment model with lag time was found to be the most suitable model for the pooled full PK and TDM data for Chinese liver transplant patients. The CL/F, V2/F, Q/F, V3/F, Ka and lag time were 17.4±0.81 L/h, 165±44.1 L, 54.9±25.8L/h, 594±87.5 L, 0.51±0.095 L/h and 1.57±0.34 h. Post‐operative day (POD), creatinine clearance (CLcr) and ABCB1 C3435T genotypes were found to have significant influences on CL/F (P<.01). ABCB1 C3435T genotypes showed a significant correlation with V2/F (P<.01). C0–C2 and C0–C2–C4 were shown to be suitable for the estimation of AUC in Chinese liver transplant patients.
What is new and conclusion
A PPK model for TAC was established successfully in Chinese liver transplant patients. POD, CLcr and ABCB1 C3435T genotypes were shown to have significant effects on CL/F. The AUC of TAC in Chinese liver transplant patients could be estimated through Bayesian modelling, based on which individualized immunosuppressive regimens can be designed.
Visual predictive check based on the final model in patients with ABCB1 CC (A), CT (B) and TT (C) genotypes. A population pharmacokinetic (PPK) model for tacrolimus (TAC) was established successfully based on 47 sets of rich time PK and 1234 conventional therapeutic drug monitoring (TDM) data Chinese liver transplant patients. ABCB1 C3435T genotypes were shown to have significant effects on CL/F. The area under concentration‐time curve (AUC) of TAC in Chinese liver‐transplant patients could be estimated through Bayesian modelling, based on which individualized immunosuppressive regimens can be designed.
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•Two amino acid derivatives (MPT and BPT) were tested as green inhibitors for carbon steel in CO2-saturated formation water.•MPT and BPT exhibit fairly high inhibition efficiency and ...stability of corrosion inhibition.•Both MPT and BPT act as mixed-type inhibitors for carbon steel in the test solution.•The adsorption of MPT and BPT on carbon steel surface follows the Langmuir adsorption isotherm.•Theoretical calculations were performed to in-depth explore the adsorption mechanism of MPT and BPT.
Amino acids are the promising biomolecules as eco-friendly inhibitors for the corrosion protection of materials. In this work, two amino acid derivatives (MPT and BPT) were synthesized as green inhibitors, and their corrosion inhibition performance for N80 carbon steel in CO2-saturated formation water was studied by electrochemical tests and surface analysis. It is found that both MPT and BPT exhibit outstanding inhibitive effect (inhibition efficiency of 99.26 % for MPT and 99.44 % for BPT), which is significantly higher than those already reported amino acid derivative inhibitors. The inhibition mechanism of MPT and BPT was also revealed by theoretical calculations.
The rock breaking mechanism is significantly affected by the joints in the rock mass. With the purpose to study the influence of joint characteristic parameters on cutting force and penetration, ...experimental explorations that contain miniature cutter head with double cutters are conducted in this paper on the basis of Rolling Indentation Abrasion Test (RIAT). In the present research, prefabricated joints of different forms are made in the rock samples. The experimental conclusions indicate that the optimal angle between horizontal and joint plane is equal to 30° for rock breaking process. In detail, the minimum thrust and the maximum penetration, which are related to the rock chipping angle for different joint orientations, are obtained at the optimal angle. Meanwhile, the improved theoretical formulas which are suitable for both intact and jointed rock are proposed. Besides, the change of thrust with penetration can be divided into four stages, which are the loading, starting, boring and stripping stages. Through simulating the rock breaking process by the rock rolling boring experimental method, this study measures the thrust, torque, penetration on the disc cutter, and reveals the influences of joint orientation and spacing on cutting forces and penetration. Furthermore, the penetration variation is summarized and the results are in good agreement with the field observation and numerical simulation results.
Agnathan fish hold a key position in vertebrate evolution, especially regarding the origin of the head and neural-crest-derived tissue. In contrast to amphioxus, lampreys and other vertebrates ...possess a complex brain and placodes that contribute to well-developed eyes, as well as auditory and olfactory systems. These sensory sytems were arguably a trigger to subsequent vertebrate diversifications. However, although they are known from skeletal impressions in younger Palaeozoic agnathans, information about the earliest records of these systems has been largely wanting. Here we report numerous specimens of the Lower Cambrian vertebrate Haikouichthys ercaicunensis, until now only known from the holotype. Haikouichthys shows significant differences from other fossil agnathans: key features include a small lobate extension to the head, with eyes and possible nasal sacs, as well as what may be otic capsules. A notochord with separate vertebral elements is also identifiable. Phylogenetic analysis indicates that this fish lies within the stem-group craniates. Although Haikouichthys somewhat resembles the ammocoete larva of modern lampreys, this is because of shared general craniate characters; adult lampreys and hagfishes (the cyclostomes if monophyletic) are probably derived in many respects.
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