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Abiraterone acetate plus prednisone or prednisolone improves progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. Radium-223 improves overall survival and delays the onset of symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases. We assessed concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 in such patients. We did a randomised, double-blind, placebo-controlled, phase 3 trial at 165 oncology and urology centres in 19 countries. Eligible patients were aged 18 years or older, and had histologically confirmed, progressive, chemotherapy-naive, asymptomatic or mildly symptomatic castration-resistant prostate cancer and bone metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 6 months, and adequate haematological, renal, and liver function. Participants were randomly assigned (1:1) according to a permuted block design (block size 4) via interactive response technology to receive up to six intravenous injections of radium-223 (55 kBq/kg) or matching placebo once every 4 weeks. All patients were also scheduled to receive oral abiraterone acetate 1000 mg once daily plus oral prednisone or prednisolone 5 mg twice daily during and after radium-223 or placebo treatment. The primary endpoint was symptomatic skeletal event-free survival, which was assessed in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov, number NCT02043678. Enrolment has been completed, and follow-up is ongoing. Between March 30, 2014, and Aug 12, 2016, 806 patients were randomly assigned to receive radium-223 (n=401) or placebo (n=405) in addition to abiraterone acetate plus prednisone or prednisolone. The study was unblinded prematurely, on Nov 17, 2017, after more fractures and deaths were noted in the radium-223 group than in the placebo group (in an unplanned ad-hoc analysis), but all patients had completed radium-223 or placebo before this date. At the primary analysis (data cutoff Feb 15, 2018), 196 (49%) of 401 patients in radium-223 group had had at least one symptomatic skeletal event or died, compared with 190 (47%) of 405 patients in the placebo group (median follow-up 21·2 months [IQR 17·0–25·8]). Median symptomatic skeletal event-free survival was 22·3 months (95% CI 20·4–24·8) in the radium-223 group and 26·0 months (21·8–28·3) in the placebo group (hazard ratio 1·122 [95% CI 0·917–1·374]; p=0·2636). Fractures (any grade) occurred in 112 (29%) of 392 patients in the radium-223 group and 45 (11%) of 394 patients in the placebo group. The most common grade 3–4 treatment-emergent adverse events were hypertension (43 [11%] patients in the radium-223 group vs 52 [13%] patients in the placebo group), fractures (36 [9%] vs 12 [3%]) and increased alanine aminotransferase concentrations (34 [9%] vs 28 [7%]). Serious treatment-emergent adverse events occurred in 160 (41%) patients in the radium-223 group and 155 (39%) in the placebo group. Treatment-related deaths occurred in two (1%) patients in the radium-223 group (acute myocardial infarction and interstitial lung disease) and one (<1%) in the placebo group (arrhythmia). The addition of radium-223 to abiraterone acetate plus prednisone or prednisolone did not improve symptomatic skeletal event-free survival in patients with castration-resistant prostate cancer and bone metastases, and was associated with an increased frequency of bone fractures compared with placebo. Thus, we do not recommend use of this combination. Bayer.

The increase in blood nicotine after smoking a single cigarette is nicotine boost. We hypothesized that smokers with schizophrenia (SCZ) have a greater nicotine boost than controls without this disorder. Twenty-one subjects (11 SCZ and 10 controls, CON) had repeated venous blood sampling before, during, and after smoking a single cigarette after 12-hr abstinence to measure nicotine concentrations. Blood samples were drawn at baseline (before smoking) and 1, 2, 4, 6, 8, 10, 20, 30, 60, 90, and 120 min after the first puff. Groups were similar in baseline characteristics, including gender and level of dependence, and all smoked 20-30 cigarettes/day. Area under the serum nicotine concentration-time curve (AUC(20)) was calculated for time up to 20 min after the start of smoking. The mean difference in AUC(20) was significantly greater for SCZ versus CON (135.4 ng-min/ml; 95% CI = 0.45-283.80). The shape of the nicotine concentration-time curve for SCZ was significantly different compared with controls (p < .01). Nicotine boost in the first 4 min of smoking was higher in SCZ versus CON (25.2 vs. 11.1 ng/ml, p < .01) with no difference in the total time spent smoking. This technique improves on methods, which draw only two blood specimens to assess nicotine intake. Understanding how nicotine boost differs in SCZ from CON may explain high levels of addiction and low success in cessation in smokers with SCZ.

Finite mixture models have been used to analyze data in a heterogeneous population. In this dissertation, we aimed to propose two statistical methodologies: one is the mixture regression model analysis accommodating repeated measures and observations under detection limits; the other is the GOF test for evaluating the model fit of mixture regression models, with and without random effects. Both methodologies were applied to the analysis of the 8-isoprostane data in the HEART study. A general framework for random effects finite mixture regression models was proposed to analyze repeatedly measured data with observations under a detection limit. The non-detectables were treated as left-censored observations and the regression parameters were estimated by the maximum likelihood method. Using normal mixture models as an example, we demonstrated that the parameter estimators are unbiased. In addition, we proposed a prototype goodness-of-fit test method based on the principle of cumulative residuals. Cumulative pseudo-residuals were defined based on the score functions and then a GOF test was proposed accordingly for two-component normal mixture models with and without random effects. Extensive simulation studies showed that the proposed GOF tests maintained the type I error rate, and had a reasonable power to detect model deviations.

A novel two-step ion exchange process was recently proposed to produce Engineered Stress Profile (ESP) glass. Important characteristics of ESP glass include high strength, relatively low strength variability and high surface damage resistance. It has been found that the mechanical reliability of ESP glass is mainly dependent on the processing conditions. Therefore, the primary objective of the current thesis is to quantitatively study the relationship between the mechanical properties of ESP glasses and the ion exchange processing conditions. Based on this relationship, processing conditions can be determined for any particular requirement of mechanical behavior for ion exchanged glass. To establish a property-processing relationship in ESP glasses, it is necessary to predict the stress profile in ion exchanged glass from the processing conditions. Since the residual stress profile in ion exchanged glass is mainly caused by the K/Na ion exchange and the stress relaxation, the diffusion process and the stress relaxation behavior of glass were studied. The K2O concentration profiles in singe-step and two-step ion exchanged soda lime silicate (SLS) glasses were calculated and found to be in a good agreement with the measured concentration profiles. The uniaxial compressive stress relaxation behavior of the SLS glass in the current thesis at typical ion exchange temperatures was studied. Since the surface composition in ion exchanged glass is significantly different from the composition of untreated glass, this composition difference could cause significant difference in glass properties including viscosity and stress relaxation. Therefore, properties of glasses with different K/Na ratios were studied, and empirical equations were obtained to estimate glass properties from the glass composition. Given the diffusion coefficient, surface concentration, composition-dependent dilation coefficient and stress relaxation data, residual stress profiles in ion-exchanged glasses could be calculated. These calculated stress profiles in single-step and two-step ion exchanged glasses have a reasonable agreement with the measured stress profiles using an optimized optical method. In addition, a variable temperature ion exchange process was used to produce ESP glass with a lower production cost than that for two-step ion exchange process. However, similar mechanical properties can be achieved by a variable temperature ion exchange process. Strength and strength variability of ion-exchanged glasses were predicted from the measured stress profile. Overall, an experimental methodology for predicting stress profiles in ion exchanged glasses is described. This methodology involves measuring the diffusion coefficient, stress relaxation behavior of SLS glass and other mixed alkali silicate glasses, calculating the stress profile in ion exchanged glass from the measured diffusivity data and stress relaxation data, and then comparing the calculated and experimentally measured stress profiles in glass.

Background MicroRNAs act as tumor suppressors or oncogenes. The pathological roles of miRNAs in gastric tumorigenesis are largely unknown. Although miR-10b was identified as an miRNA deregulator expressed in gastric cancer (GC), there also exists some debate on whether miR-10b is acting as tumor suppressor or oncogene in GC. Methods Quantitative RT-PCR was employed to investigate the level of miR-10b in GC tissues and matched adjacent normal tissues ( n  = 100). In vitro cell proliferation, apoptosis assays, cell migration, and invasion assays were performed to elucidate the biological effects of miR-10b. Because silencing of miRNA by promoter CpG island methylation may be an important mechanism in tumorigenesis, GC cells were treated with 5-aza-2′-deoxycytidine and trichostatin A, and expression changes of miR-10b were subsequently examined by quantitative RT-PCR. Furthermore, the methylation status of the CpG island upstream of miR-10b was analyzed by methylation-specific PCR in GC tissues ( n  = 29). Results We showed here that miR-10b was significantly downregulated in GC cell lines and tissues as demonstrated by quantitative real-time PCR. Overexpression of miR-10b in MGC-803 and HGC-27 dramatically suppressed cell proliferation, migration, invasion, and induced apoptosis. Moreover, we demonstrated that T-cell lymphoma invasion and metastasis (Tiam1) was a target of miR-10b. Furthermore, 5-aza-2′-deoxycytidine and trichostain A increased miR-10b expression, and the methylation level was high in the CpG islands upstream of miR-10b gene. Conclusions Taken together, these findings suggest that miR-10b may function as a novel tumor suppressor and is partially silenced by DNA hypermethylation in GC.

The present study aimed to investigate the adverse effects of the antithyroid drugs propylthiouracil (PTU) and methimazole (MMI)/carbimazole (CMZ) in treating hyperthyroidism. Qualitative analysis was performed for studies identified in a literature search up to April 20, 2019, and 30 studies were selected for meta-analysis. The study designs included case-control, randomized controlled, and retrospective cohort. Patients were in four age groups: childhood, gestating mothers, older adults, and other ages, and all were receiving PTU or MMI/CMZ. Adverse reactions to MMI/CMZ and PTU were evaluated and compared. Odds of liver function injury were higher in the PTU group than in the MMI/CMZ group (odds ratio [OR], 2.40; 95% confidence interval [CI], 1.16 to 4.96; = .02). Odds of elevated transaminase were much higher in the PTU group than in the MMI/CMZ group (OR, 3.96; 95% CI, 2.49 to 6.28; <.00001). No significant between-group differences were found in odds of elevated bilirubin, agranulocytosis, rash, or urticaria; incidence of other adverse events; or in children. Odds of birth defects during the first trimester of pregnancy were higher in the MMI/CMZ group than in the PTU group (OR, 1.29; 95% CI, 1.09 to 1.53; = .003). The impact of PTU on liver injury and transaminase levels is greater than that of MMI/CMZ, but no significant between-group differences are found in the drugs' effects on bilirubin, agranulocytosis and rash, urticaria, or in children. In treating pregnancy-related hyperthyroidism, PTU should be used in the first trimester and MMI reserved for use in late pregnancy. = alanine aminotransferase; = antithyroid drug; = confidence interval; = carbimazole; = Graves disease; = methimazole; = methylthiouracil; = Newcastle-Ottawa Scale; = odds ratio; = propylthiouracil; = radioactive iodine.

The fast development of mid-wave infrared photonics has increased the demand for high-performance photodetectors that operate in this spectral range. However, the signal-to-noise ratio, regarded as a primary figure of merit for mid-wave infrared detection, is strongly limited by the high dark current in narrow-bandgap materials. Therefore, conventional mid-wave infrared photodetectors such as HgCdTe require cryogenic temperatures to avoid excessively high dark current. To address this challenge, we report an avalanche photodiode design using photon-trapping structures to enhance the quantum efficiency and minimize the absorber thickness to suppress the dark current. The device exhibits high quantum efficiency and dark current density that is nearly three orders of magnitude lower than that of the state-of-the-art HgCdTe avalanche photodiodes and nearly two orders lower than that of previously reported AlInAsSb avalanche photodiodes that operate at 2 µm. Additionally, the bandwidth of these avalanche photodiodes reaches ~7 GHz, and the gain–bandwidth product is over 200 GHz; both are more than four times those of previously reported 2 µm avalanche photodiodes.We demonstrate an avalanche photodiode design using photon-trapping structures to enhance the quantum efficiency and minimizing the absorber thickness, yielding high quantum efficiency, suppressed dark current density and bandwidth of ~7 GHz.

Bi or Bi2S3 are commonly used to improve the photocatalytic performance of bismuth-based photocatalysts because of surface plasmon resonance (SPR) effect or visible light absorption efficiency. Nevertheless, the modified efficiency between Bi and Bi2S3 has never been compared. In addition, Bi and Bi2S3 modified semiconductors were usually prepared via two-step routes, where a semiconductor was firstly prepared and then reduced by a reducing reagent like NaBH4 or ethylene glycol and sulfurized by thiourea (TU), Na2S or thioacetamide (TAA). Herein, a facile one-step solid state reaction route was used to prepare Bi(Bi2S3)/BiOCl photocatalysts at room temperature through the reaction between Bi(NO3)3·5H2O and KCl followed by sulfur sources. More importantly, these sulfur sources not only acted as sulfurization reagents, but also showed reducibility to different extent. TU possessed the strongest reducibility, whereas Na2S presented the strongest sulfurization ability. The investigation on the photocatalytic activity of these composites for rhodamine B (RhB) and malachite green (MG) degradation under visible light irradiation shows that Bi-coupled BiOCl exhibits the highest degradation efficiency, which further demonstrates important role of SPR effect of Bi.

Background: Rapid eye movement (REM) sleep behavior disorder (RBD) predicts cognitive decline in Parkinson’s disease (PD) patients without dementia. However, underlying mechanisms remain unknown. Accumulating studies suggest glutamatergic system dysregulation is associated. Objective: To examine the effect of RBD on the rate of cognitive decline in early PD patients and investigate whether plasma levels of the neuroexosomal glutamate transporters VGLUT-1 and EAAT-2 are altered in PD patients with RBD. Methods: This study included 157 newly diagnosed treatment-naïve PD patients. Based on one-night polysomnography recordings, the subjects were divided into PD with RBD and PD without RBD groups. All participants received a complete evaluation of motor and nonmotor symptoms at baseline, which included evaluations of cognitive function and their psychiatric state. Plasma levels of neuroexosomal VGLUT-1 and EAAT-2 were measured by ELISA kits. After a three-year follow-up, we evaluated baseline plasma levels of neuroexosomal glutamate transporters in each group as a predictor of cognitive decline using MoCA score changes over three years in regression models. Results: A total of 157 PD patients completed the 3-year follow-up with complete serial assessments. Plasma levels of neuroexosomal EAAT-2 were significantly lower in PD patients with RBD at baseline. At the three-year follow-up, PD patients with RBD presented greater cognitive decline. Lower baseline blood neuroexosomal EAAT-2 predicted cognitive decline over 3 years in PD patients with RBD (β = 0.064, P = 0.003). Conclusion: These findings indicate that blood neuroexosomal EAAT-2 is associated with cognitive decline in early PD with RBD.

To accurately predict the construction costs of foundation pit projects, a model based on the stacked denoising autoencoder (SDAE) is constructed in this work. The influencing factors of foundation pit project construction costs are identified from the four attributes of construction cost management, namely, engineering, the environment, the market, and management. Combined with Chinese national standards and the practice of foundation pit project management, a method of the quantization of the influencing factors is presented. 60 deep foundation pit projects in China are selected to obtain 13 main characteristic factors affecting these project construction cost by using the rough set. Then, considering the advantages of the SDAE in dealing with complex nonlinear problems, a prediction model of foundation pit project construction costs is created. Finally, this paper employs these 60 projects for a case analysis. The case study demonstrates that, compared with the actual construction costs, the calculation error of the proposed method is less than 3%, and the average error is only 1.54%. In addition, three error analysis tools commonly used in machine learning (the determination coefficient, root mean square error, and mean absolute error) emphasize that the calculation accuracy of the proposed method is notably higher than those of other methods (Chinese national code, the multivariate return method, the BP algorithm, the BP model optimized by the genetic algorithm, the support vector machine, and the RBF model). The relevant research results of this paper provide a useful reference for the prediction of the construction costs of foundation pit projects.