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Correlation has become a fundamental method for information science. However, correlations are limited in making concrete decisions. In this article, we detail how causal inference could be utilised in the field of information science. There are six main steps of implementing matching for causal inference, namely, selecting candidate control variables, determining control variables, calculating similarities among all samples, forming control group, examining the performance of control group and estimating causal effects. As an example, this article applies causal inference to investigate whether Nobel Physics award increases the after-award citations. The method is presented in a step-by-step manner so that researchers can reproduce our analysis in the future.

We here perform a systematic bioinformatic analysis to uncover the role of sorting nexin (SNX) family in clinical outcome of gastric cancer (GC). Comprehensive bioinformatic analysis were realized with online tools such as TCGA, GEO, String, Timer, cBioportal and Kaplan–Meier Plotter. Statistical analysis was conducted with R language or Perl, and artificial neural network (ANN) model was established using Python. Our analysis demonstrated that SNX4/5/6/7/8/10/13/14/15/16/20/22/25/27/30 were higher expressed in GC, whereas SNX1/17/21/24/33 were in the opposite expression profiles. GSE66229 was employed as verification of the differential expression analysis based on TCGA. Clustering results gave the relative transcriptional levels of 30 SNXs in tumor, and it was totally consistent to the inner relevance of SNXs at mRNA level. Protein–Protein Interaction map showed closely and complex connection among 33 SNXs. Tumor immune infiltration analysis asserted that SNX1/3/9/18/19/21/29/33, SNX1/17/18/20/21/29/31/33, SNX1/2/3/6/10/18/29/33, and SNX1/2/6/10/17/18/20/29 were strongly correlated with four kinds of survival related tumor-infiltrating immune cells, including cancer associated fibroblast, endothelial cells, macrophages and Tregs. Kaplan–Meier survival analysis based on GEO presented more satisfactory results than that based on TCGA-STAD did, and all the 29 SNXs were statistically significant, SNX23/26/28 excluded. SNXs alteration contributed to microsatellite instability (MSI) or higher level of MSI-H (hyper-mutated MSI or high level of MSI), and other malignancy encompassing mutation of TP53 and ARID1A, as well as methylation of MLH1.The multivariate cox model, visualized as a nomogram, performed excellently in patients risk classification, for those with higher risk-score suffered from shorter overall survival (OS). Compared to previous researches, our ANN models showed a predictive power at a middle-upper level, with AUC of 0.87/0.72, 0.84/0.72, 0.90/0.71 (GSE84437), 0.98/0.66, 0.86/0.70, 0.98/0.71 (GSE66229), 0.94/0.66, 0.83/0.71, 0.88/0.72 (GSE26253) corresponding to one-, three- and five-year OS and recurrence free survival (RFS) estimation, especially ANN model built with GSE66229 including exclusively SNXs as input data. The SNX family shows great value in postoperative survival evaluation of GC, and ANN models constructed using SNXs transcriptional data manifesting excellent predictive power in both OS and RFS prediction works as convincing verification to that.

The purposes of this study were to analyse the spatiotemporal variations in greenhouse gas diffusive fluxes at the sediment–water interface of sewage-draining rivers and natural rivers, and investigate the factors responsible for the changes in greenhouse gas diffusive fluxes. Greenhouse gas diffusive fluxes at the sediment–water interface of rivers in Tianjin city (Haihe watershed) were investigated during July and October 2014, and January and April 2015 by laboratory incubation experiments. The influence of environmental variables on greenhouse gas diffusive fluxes was evaluated by Spearman’s correlation analysis and a multiple stepwise regression analysis. Sewage-draining rivers were more seriously polluted by human sewage discharge than natural rivers. The greenhouse gas diffusive fluxes at the sediment–water interface exhibited obvious spatiotemporal variations. The mean absolute value of the CO2 diffusive fluxes was seasonally variable with spring>winter>fall>summer, while the mean absolute values of the CH4 and N2O diffusive fluxes were both higher in summer and winter, and lower in fall and spring. The annual mean values of the CO2, CH4 and N2O diffusive fluxes at the sewage-draining river sediment–water interface were − 123.26 ± 233.78 μmol m−2 h−1, 1.88 ± 6.89 μmol m−2 h−1 and 1505.03 ± 2388.46 nmol m−2 h−1, respectively, which were 1.22, 4.37 and 134.50 times those at the natural river sediment–water interface, respectively. The spatial variation of the N2O diffusive fluxes in the sewage-draining rivers and the natural rivers was the most significant. As a general rule, the more serious the river pollution was, the greater the diffusive fluxes of the greenhouse gases were. On average for the whole year, the river sediment was the sink of CO2 and the source of CH4 and N2O. There were positive correlations among the CO2, CH4 and N2O diffusive fluxes. The main influencing factor for CO2 and N2O diffusive fluxes was the water temperature of the overlying water; however, the key factors for CH4 diffusive fluxes were the Eh of the sediment and the NH4+-N of the overlying water. River sediment can be either a sink or a source of greenhouse gases, which varies in different levels of pollution and different seasons. Human sewage discharge has greatly affected the carbon and nitrogen cycling of urban rivers.

For the environmental efficiency assessment of the plant nursery production system, the total CO2 eq emissions of 18 nurseries in China was calculated using the LCA “from cradle to gate” approach. The analysis revealed that the GHG emissions of potted plant production were higher than those of field-grown nurseries. The CO2 eq emissions were variable between 0.31 and 2.19 Mg ha−1 year−1 for field-grown nurseries, while the lowest and the highest emissions were 4.09 and 6.06 Mg ha−1 year−1, respectively, for potted plant nurseries. In 2015, the total CO2 eq emissions of the nursery production industry in China were approximately 1.59 Mt, which consisted of 1.07 Mt from field-grown nurseries and 0.52 Mt from pot-grown plant nurseries. In China, nursery production industry carbon emissions were 0.19% of the national agriculture emissions. The comparison showed that the GHG emissions of the nursery plant system have significant differences depending on region, production method, plant species and economic development level.

The distribution of high-quality customers (hereafter HQC) for taxis (including ride-hailing cars) has a significant impact on drivers’ revenue and taxis’ operation efficiency. Based on the taxi global positioning system data, we construct an evaluation model of passengers to discuss the imbalance of consumption in taxi market. The profit margin for each taxi order is calculated, and then a grid-based method is used to distinguish the HQC and the regions with potential higher benefits. We analyze the HQC’s distribution of taxis (including ride-hailing cars) in different areas and in different time periods. We find that the HQC are distributed mainly on the periphery of the main urban area, which indicates that traffic condition is even worse in the urban center because of factors such as congestion. The HQC are more concentrated on workdays and more scattered on nonworkdays, which implies that the public have different travel habits and demands on workdays and nonworkdays. The proportion of HQC in each administrative district or functional zone is not always positively correlated to either the proportion of total orders or the total HQC. This indicates that the distribution of HQC in each administrative district or functional zone is imbalanced. The proportion of orders and that of HQC are roughly the same in the temporal dimension, being higher in the morning and evening rush hours. Compared with the distribution of the HQC of ride-hailing, that of taxis is more imbalanced in the temporal dimension. Relevant departments should further coordinate taxi pricing, strengthen market control, and promote sustainable development in the taxi and ride-hailing markets.

Female Sex Workers (FSWs) are a high-risk group that not only are susceptible to, but also may contribute to the spread of, HIV/AIDS. How to effectively intervene the FSW population for HIV/AIDS prevention has been a public concern. In this paper, relied on a set of interview data of FSWs collected from a city in Yunnan Province, China, we first construct a social network based on if FSWs have been acquaint. We find that the network has the characteristics of “small world” with a small average shortest path and a big clustering coefficient. The network also shows a “small community” phenomenon with a low average density. In other words, individuals are close to each other in community, and their external connection is sparse. The degree of the FSW social network obeys an exponential distribution, indicating that few numbers of nodes have a large centrality (i.e. the important individuals). In addition, those nodes that is more passive in HIV/AIDS prevention have a higher level of clustering, but a lower similarity with their neighbors. Finally, we use individuals’ responses to the AIDS KAP questionnaire to predict one’s position (or status) in the social network, as the social network structure is invisible, observable individual responses to the questionnaire is easier to obtain. We then propose an efficient method to choose the nodes based on individuals’ responses to AIDS KAP questionnaire for intervention and network clogging. We found that, compared with a random node selection method, our method is more effective.

We evaluate the parameter effects of the laser source, coupling lens and turbulence on the fiber coupling efficiency. Our results indicate that there are optimal radius of the wave-front curvature and transmitting radius of laser beam and optimal focal length of a coupling lens for specific turbulence strength and propagation distance. By utilizing the optimal wave-front curvature, optimal focal length and optimal transmitting beam radius, one can maximize the coupling efficiency.

Background Gastric cancer (GC) represents a major malignancy and is the third deathliest cancer globally. Several lines of evidence indicate that the epithelial-mesenchymal transition (EMT) has a critical function in the development of gastric cancer. Although plentiful molecular biomarkers have been identified, a precise risk model is still necessary to help doctors determine patient prognosis in GC. Methods Gene expression data and clinical information for GC were acquired from The Cancer Genome Atlas (TCGA) database and 200 EMT-related genes (ERGs) from the Molecular Signatures Database (MSigDB). Then, ERGs correlated with patient prognosis in GC were assessed by univariable and multivariable Cox regression analyses. Next, a risk score formula was established for evaluating patient outcome in GC and validated by survival and ROC curves. In addition, Kaplan-Meier curves were generated to assess the associations of the clinicopathological data with prognosis. And a cohort from the Gene Expression Omnibus (GEO) database was used for validation. Results Six EMT-related genes, including CDH6, COL5A2, ITGAV, MATN3, PLOD2, and POSTN, were identified. Based on the risk model, GC patients were assigned to the high- and low-risk groups. The results revealed that the model had good performance in predicting patient prognosis in GC. Conclusions We constructed a prognosis risk model for GC. Then, we verified the performance of the model, which may help doctors predict patient prognosis.

With the expansion of urban scale and the growth of urban population, the bicycle-sharing system has been greatly helping grease the wheels of convenience and diversity of citizens' travel. Nevertheless, there are a set of additional problems, including imbalance of supply and demand at rental stations and low utilization of system operation, which have disrupted the travel experience of consumers, the profitability of businesses, and the coordination of government. In this study, we take Nanjing as an example to measure the operating efficiency of bicycle-sharing by calculating the capacity utilization rate (CUR). Afterwards, based on the IC card data of bicycle-sharing users, we statistically analyzed the traffic inflow and outflow at rental stations. Besides, this paper discusses the factors influencing the use of bicycle-sharing, by introducing the method of sampling stepwise regression into the study of rental situation and geographical environment. The results are as follows: (1) demand for bicycle-sharing is higher on weekdays than on weekends, especially during the morning and evening rush hours. (2) The daily average capacity utilization rate of bicycle-sharing is less than 0.08, indicating that the system is not efficient enough. During morning and evening rush hours, only less than 10% of rental stations have high inflow and outflow, and there is an imbalance of inflow and outflow for the same rental station at different times of the day. (3) The stepwise regression results show that the inflow and outflow of bicycle-sharing rental stations are mainly affected by the distribution of traffic, education, entertainment, medical, and other functional zones near the stations. These findings could provide relevant government departments and enterprises with strategies and suggestions for the efficient and healthy operation of the urban bicycle-sharing system.

In recent times, China has emphasized five major development concepts to promote high-quality development: coordination, green, innovation, openness, and sharing. As a metamorphosis of these ideas, Chinese science and technology parks (STPs) are gathering areas of high-tech industries and represent advanced productive forces. Their greenness, openness, and innovative developments herald the future development trends of China. Based on the data of 52 STPs in China from 2011 to 2018, this study analyzes the impact of foreign direct investment (FDI) quantity and quality on the low-carbon development of the STPs. We use Hansen’s nonlinear panel threshold regression model with knowledge accumulation as the threshold variable. The results show the following: First, there are complex nonlinear relationships between FDI quantity, FDI quality, and the low-carbon development of the STPs. Second, FDI quantity has a significant positive impact on the low-carbon development of the STPs only when the level of knowledge accumulation is below a certain threshold. Beyond this threshold the effect is no longer significant. Third, FDI quality has a significant positive impact on the low-carbon development of STPs only when the level of knowledge accumulation is lower than a certain threshold; beyond which, the impact is no longer significant. These results can serve as a reference for China to effectively promote economic low-carbon growth of STPs and achieve green, open, and innovative development.

The emergence and development of car-sharing has not only satisfied people&rsquo, s diverse travel needs, but also brought new solutions for improving urban traffic conditions and achieving low-carbon and green sustainable development. In recent years, car-sharing has had competition with other ways of getting around, as the acceptance of car-sharing has grown, notably taxis. Therefore, it is particularly important to explore car-sharing travel costs advantages from the perspective of consumers and discover the competitive and complementary spaces between car-sharing and other modes. Therefore, taking Beijing as an example, this paper uses GPS trajectory data based on car-sharing orders to design a travel cost framework of car-sharing and taxis. We calculate and compare the travel cost difference between these two modes under different travel characteristics. The results indicate that car-sharing is a more economical way for consumers to travel for short or medium lengths of time, while people are more inclined to take taxis for distances of long duration. Compared with on workdays, at the weekend, the cost advantage of car-sharing is greater for long-distance trips. Moreover, the cost advantage of car-sharing increases gradually with the increase in travel distance. In addition, the travel costs of car-sharing and taxis are also affected by peak and off-peak traffic periods. Compared with off-peak periods, it is more cost-effective for travelers to take taxis during peak traffic periods for various travel distances. From the perspective of the travel cost, it is of great theoretical significance to discuss the substitution (market competition) and complementary relationship (market cooperation) between car-sharing and taxis in a detailed and systematic way. It provides methods and ideas for the comparative cost calculation of car-sharing and other travel modes. This paper also provides enlightenment and guidance for the development of car-sharing. Enterprises should implement differentiated pricing, designing different charging methods for different traffic periods, travel miles, and rental times, and set up additional stations in the surrounding areas of the city. Relevant government departments should also strictly manage the market access of car-sharing, and add or open car-sharing parking lots in centralized areas and for specific periods.

The distribution and composition of polychlorinated biphenyls (PCBs) within soil-plant systems around a notorious e-waste recycling site were investigated. The average total PCB concentrations in rhizospheric soils (RSs) and nonrhizospheric soils (NRSs) were 2160 and 1270 pg g

Talents are not only an important strategic resource for promoting regional development but also a core element for maintaining competitiveness. We organize the evaluation index system of regional talent attraction into the following four aspects: regional development, industry development, income and regional environment. Combined with the talent possession of 31 provinces (cities) from 2010 to 2018, we establish a regression equation of the relationship between the evaluation index and talent possession by using a stepwise regression and the Bayesian prior function. Simultaneously, we apply the spatial autocorrelation analysis method to measure the correlation and agglomeration degree of the talent attraction level of provinces and municipalities in China. The results reveal the following. (1) From 2010 to 2018, the talent attractiveness level of China's provinces shows a steady upward trend with an average annual growth rate of 5.804%. The regional environment has the highest score, and the income level has the lowest score. (2) The level of talent attraction in China shows a decreasing trend from east to west, and the ranking in 2018 was "East Coast > North Coast > Southern Coast > Middle Yangtze River > Middle Yellow River > Southwest > Northeast > Greater Northwest". The trend of spatial agglomeration is apparent and gradually increases over the years. The numbers of hot and cold spots are relatively large and concentrated in the eastern coast and western region, respectively. (3) The level of economic development, quality of people's life, and level of the development of the tertiary industry have a great impact on the attractiveness of talents. Talents also pay more attention to regional medical, education and transportation indicators. These research results can provide some guidance and references for the formulation of talent introduction policies in various provinces and municipalities.

Purpose: This study examined safety, pharmacokinetics, and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors. Patients and Methods: The 3 + 3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on day 1) and etoposide (100 mg/m2 on days 1–3) in 21-day cycles. Veliparib dose was explored from 80 to 240 mg b.i.d. on 7-day, 14-day, or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400 mg b.i.d.) until disease progression or unacceptable toxicity. Results: Thirty-nine patients were enrolled to determine the recommended phase II dose of 240 mg veliparib for 14 days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in 1 patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg b.i.d. for 7 days. Most common adverse events related to veliparib were nausea (39%), fatigue (39%), and hematologic toxicities. Continuous dosing of veliparib 240 mg b.i.d. with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17 of 39 (44%) and 16 of 25 (64%) of all enrolled and ED SCLC patients, respectively. At the RP2D, confirmed responses occurred in 6 of 13 (46%) and 5 of 6 (83%) of all enrolled and ED SCLC patients, respectively. Conclusions: Veliparib (240 mg b.i.d. 14 days) plus carboplatin/etoposide can be safely combined. Phase II of this study is ongoing in first-line patients with ED SCLC.

We theoretically study the fiber-coupling efficiency of Gaussian–Schell model beams propagating through oceanic turbulence. The expression of the fiber-coupling efficiency is derived based on the spatial power spectrum of oceanic turbulence and the cross-spectral density function. Our work shows that the salinity fluctuation has a greater impact on the fiber-coupling efficiency than temperature fluctuation does. We can select longer λ in the “ocean window” and higher spatial coherence of light source to improve the fiber-coupling efficiency of the communication link. We also can achieve the maximum fiber-coupling efficiency by choosing design parameter according specific oceanic turbulence condition. Our results are able to help the design of optical communication link for oceanic turbulence to fiber sensor.

Bicycle-sharing is an eco-friendly transportation operating model in the context of “Internet Plus” and the sharing economy. It not only meets the short-distance travel needs of residents but has great significance for promoting the sustainable development of urban public transportation. However, a series of problems have appeared in the bicycle-sharing market, such as unreasonable resource allocation, low operating efficiency and management difficulties. Based on booking data and GPS trajectory data in Beijing of Mobike, this paper statistically analyzes the spatial and temporal distribution characteristics of residents’ bicycle-sharing trips. Then, we construct a multi-factor influence model of bicycle-sharing demand based on a negative binomial regression and variable selection model, which quantifies a series of factors that influence bicycle-sharing trips, such as population and the regional economy, building land attributes, transportation accessibility, weather, and climatic conditions, etc. The results show that, firstly, there is a spatial imbalance in the distribution of bicycle-sharing demand among different districts in Beijing. Bicycle-sharing demand is mainly concentrated in the six core districts of the city, with more than 80% of all demand. We also find that the bicycle-sharing demand has different distribution characteristics on working days and nonworking days. Compared with nonworking days, residents’ demand for bicycle-sharing on weekdays shows obvious peak periods in the morning, noon, and evening. Secondly, factors that have a major impact on the demand for bicycle-sharing include: per capita disposable income, pass facilities, parking lots etc. Among them, factors such as per capita disposable income, pass facilities, parking lots and bus/subway stations have a significant positive influence on bicycle-sharing demand. However, the number of functional zones such as airports, ports and marinas, tourist attraction and automobile sales has a significant negative influence. In addition, a comfortable temperature and good air quality encourage residents to use bicycle-sharing more for travel, while high humidity is not conducive to bicycle-sharing. We suggest that companies and related departments should jointly participate in the regulation and management of the bicycle-sharing industry, in various aspects such as bicycle scheduling, bicycle management and industry systems. In this way, cities can allocate bicycle-sharing resources reasonably and improve overall operating efficiency. The advantages of bicycle-sharing can be better used to promote the sustainable development of urban public transportation in the future.

Carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) concentration, saturation and fluxes in rivers (Beitang drainage river, Dagu drainage rive, Duliujianhe river, Yongdingxinhe river and Nanyunhe river) of Tianjin city (Haihe watershed) were investigated during July and October in 2014, and January and April in 2015 by static headspace gas chromatography method and the two-layer model of diffusive gas exchange. The influence of environmental variables on greenhouse gases (GHGs) concentration under the disturbance of anthropogenic activities was discussed by Spearman correlative analysis and multiple stepwise regression analysis. The results showed that the concentration and fluxes of CO2, CH4 and N2O were seasonally variable with >winter>fall>summer, spring>summer>winter>fall and summer>spring>winter>fall for concentrations and spring>summer>fall>winter, spring>summer>winter>fall and summer>spring>fall>winter for fluxes respectively. The GHGs concentration and saturation were higher in comprehensively polluted river sites and lower in lightly polluted river sites. The three GHGs emission fluxes in two sewage draining rivers of Tianjin were clearly higher than those of other rivers (natural rivers) and the spatial variation of CH4 was more obvious than the others. CO2 and N2O air-water interface emission fluxes of the sewage draining rivers in four seasons were about 1.20-2.41 times and 1.13-3.12 times of those in the natural rivers. The CH4 emission fluxes of the sewage draining rivers were 3.09 times in fall to 10.87 times in spring of those in the natural rivers in different season. The wind speed, water temperature and air temperature were related to GHGs concentrations. Nitrate and nitrite (NO3-+NO2--N) and ammonia (NH4+-N) were positively correlated with CO2 concentration and CH4 concentration; and dissolved oxygen (DO) concentration was negatively correlated with CH4 concentration and N2O concentration. The effect of human activities on carbon and nitrogen cycling in river is great.

Under the background of greenhouse gases emission reduction, the measurement of carbon emissions from the tourism industry has attracted increasing academic attention. Tourism is not a traditional sector in the System of National Accounts, and as a result the statistics of carbon dioxide emissions of the tourism industry on a national scale is difficult to calculate. The measurement methodology of a bottom-up approach and a top-down approach were mainly used in others studies. Utilizing a boundary that includes domestic tourism consumption, inbound tourism consumption, and tourism consumption incurring domestically in relation to outbound travel and airfares paid to the national carriers, a top-down approach is used to measure the national tourism dioxide emissions combining the Tourism Satellite Account and the Input–Output model from productive industry. Using this case study, it was calculated that the total carbon emissions of the Chinese tourism industry in 2002, 2005, 2007 and 2010 were 111.49 Mt, 141.88 Mt, 169.76 Mt and 208.4 Mt respectively, accounting for 2.489%, 2.425%, 2.439% and 2.447% respectively of the total carbon emission of all industries in China. The indirect carbon emissions by other tourism sectors except the transport sector were 3–4 times their direct carbon emissions. Compared with the manufacturing industry, the tourism industry is an industry of low pollution and low energy consumption. We discuss the advantage and shortcoming of the two approaches and put forward some suggestions to assist the research of tourism carbon emissions.

We present the models of the Strehl ratio (SR) and the spread rate of Gaussian–Schell model (GSM) beams in the long slant path of marine–atmosphere turbulence. The models are developed based on the extended Rytov theory which permits us extending the results of weak scintillation into the moderate-to-strong scintillation regimes. Our results show that there exists a minimum of SR for selected waist radiuses and the minimum SR is dependent on the transverse coherent width of light source. The spread rate increases with increasing the light wavelength but it decreases with increasing the waist radius and the inner scale. The effects of turbulence on the peak received irradiance can be reduced by selecting larger waist radius of transmitting aperture and longer light wavelength.

The bit-error rate (BER) and outage probability of optical wireless communication (OWC) link for the ground-to-train of the curved track in turbulence with rain is evaluated. Considering the re-modulation effects of raining fluctuation on optical signal modulated by turbulence, we set up the models of average BER and outage probability in the present of pointing errors, based on the double inverse Gaussian (IG) statistical distribution model. The numerical results indicate that, for the same covered track length, the larger curvature radius increases the outage probability and average BER. The performance of the OWC link in turbulence with rain is limited mainly by the rain rate and pointing errors which are induced by the beam wander and train vibration. The effect of the rain rate on the performance of the link is more severe than the atmospheric turbulence, but the fluctuation owing to the atmospheric turbulence affects the laser beam propagation more greatly than the skewness of the rain distribution. Besides, the turbulence-induced beam wander has a more significant impact on the system in heavier rain. We can choose the size of transmitting and receiving apertures and improve the shockproof performance of the tracks to optimize the communication performance of the system.

Coastal reclamation is the gain of land from the sea or coastal wetlands for agricultural purposes, industrial use or port expansions. Large-scale coastal land reclamation can have adverse effects on the coastal environment, including loss of marine habitats and deterioration of coastal water quality. In recent decades, coastal land reclamation has occurred extensively to meet the increasing needs of rapid economic development and urbanization in China. The overall objective of this study is to understand the coastal reclamation status of China from 1979 to 2014 and analyzed its driving factors for mitigating negative ecological effects. The data of coastal reclamation were done with the ERDAS Imagine V9.2 platform and ArcGIS software based on remote images including Landsat, SPOT, ZY-2 and ZY-3. Potential driving factors for sea reclamation were selected based on statistics bulletins and the knowledge of experts in coastal management. In order to understand the relationships among possible impact factors and coastal reclamation, the Partial Least-Squares Regression models was constructed. The analysis results indicated that the total area of reclamation was 11162.89 km2 based on remote sensing images between 1979 and 2014. Shandong Province is the largest reclamation area, reaching 2736.54 km2, and the reclamation is mainly concentrated in Zhejiang, Jiangsu and Liaoning, where the reclamation areas were all more than 1000 km2. According to the remote sensing images, there are three coastal reclamation hotspot regions including Bohai bay (in which is located Liaoning, Tianjin and Hebei), Jiangsu province coastal area and Hangzhou bay (in Zhejiang province). A large scale land reclamation plan of more than 5880 km2 has been made by local government and 2469 km2 has approved by the State Council. From the analyzed results, there is a significant collinearity between these indicators, and no significant correlation between the area of reclamation and selected indicators. Economic development and employees in marine industries have weak positive correlation and correspondingly, the area of cultivated land (ACL) had a negative correlation. Because of the weak correlation, there is an assumption that economic development, outcome of coastal reclamation and population growth were not only was the direct driving factor, but also the outcome of coastal reclamation and population growth was not the direct driving indicator. Construction land quota and huge economic returns to local government may be the direct driving factors according to our field investigation. To resolve the contradiction between the need for land and coastal wetland conservation, it is recommended that China should establish a special management agency and coordination mechanisms, reconsidered the implementation of the reclamation plans and projects that have been approved, enhance law enforcement and increase penalties and strengthen public participation in reclamation management.

Losatuxizumab vedotin (formerly ABBV-221) is a second-generation antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). In this multicenter phase 1 study, eligible patients with EGFR-dependent solid tumors received losatuxizumab vedotin (3 + 3 design) intravenously at starting dose of 0.3 mg/kg over 3 h per 21-day cycle, with alternate dosing schedules utilized (2 weeks on/1 week off or weekly) to mitigate infusion reactions. Forty-five patients received ≥1 doses of losatuxizumab vedotin (13 colon, 6 non-small cell lung cancer, 5 head and neck [HNC], 5 glioblastoma multiforme, 2 breast, 14 other). Tumor samples were evaluated for EGFR protein expression by immunohistochemistry, EGFR and EGFR ligand mRNA expression by RNAseq, and results compared with outcome. Most common adverse events were infusion-related reaction (22/45; 49%) and fatigue (20/45; 44%). While most infusion reactions were grade ≤ 2, four patients experienced grade ≥3 infusion reactions. Several infusion reaction mitigation strategies were explored. Because of the high incidence of infusion reactions, the trial was stopped and the maximum tolerated dose was not reached. The last cleared dose: 6 mg/kg/cycle. Nineteen patients (42%) had stable disease; 4 remained on study >6 months. One HNC patient with increased levels of EGFR and EGFR ligands (amphiregulin, epiregulin) achieved a confirmed partial response. Pharmacokinetic analysis of losatuxizumab vedotin showed exposures appeared to be approximately dose-proportional. The high frequency of infusion reactions necessitated early closure of this trial. The detailed mitigation strategies used in this protocol for infusion-related reactions may provide beneficial information for trial design of agents with high infusion reaction rates.

Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics. A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child–Pugh scores), who received a single 50 mg dose of venetoclax with a low-fat meal. Blood samples were collected up to 120 h after venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) in subjects with mild or moderate hepatic impairment were similar to subjects with normal hepatic function. Mean venetoclax AUC in subjects with severe hepatic impairment was 2.3- to 2.7-fold higher than in subjects with normal hepatic function. The half-life of venetoclax in subjects with severe hepatic impairment was approximately two-fold longer than in subjects with normal hepatic function and subjects with mild or moderate hepatic impairment. Unbound fractions of venetoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. No significant adverse safety events were reported. No venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.

Purpose:Bromodomain and extraterminal (BET) proteins play important roles in transcriptional regulation relevant to cancer pathogenesis, and therapeutic targeting/inhibition of BET causes apoptosis of cancer cells in vitro. In this first-in-human study of the pan-BET inhibitor mivebresib (ABBV-075), the safety profile, MTD, and recommended phase II dose (RP2D) were determined in patients with advanced solid tumors.Patients and Methods:A 3 + 3 dose escalation for different mivebresib dosing schedules [daily, Monday/Wednesday/Friday (M-W-F), 4 days on/3 off (4/7)] was followed by dose expansion in patients with prostate cancer. Endpoints were safety, tolerability, pharmacokinetics, and preliminary antitumor activity.Results:Seventy-two patients with solid tumors (14% uveal melanoma; 11% colorectal; 11% breast; 8% pancreatic; 7% head/neck; 49% others) were treated with mivebresib during dose escalation, and 12 additional patients with prostate cancer in expansion cohort. Most common treatment-emergent adverse events (TEAE) related to mivebresib were dysgeusia (49%), thrombocytopenia (48%), fatigue (26%), and nausea (25%). Most common grade 3/4 TEAEs related to mivebresib were thrombocytopenia (35%) and anemia (6%). Dose-limiting toxicities included thrombocytopenia (2 mg daily; 4.5 mg M-W-F), gastrointestinal bleed (2 mg daily), hypertension (2–3 mg 4/7), fatigue, decreased appetite, and aspartate aminotransferase elevation (4 mg M-W-F). Of 61 evaluable patients from dose escalation, 26 (43%) had stable disease and 35 (57%) had progressive disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.8–1.9).Conclusions:On the basis of safety and tolerability, mivebresib RP2D is 1.5 mg for the daily schedule, 2.5 mg for 4/7, and 3 mg for M-W-F. Mivebresib has a tolerable safety profile, and stable disease was observed in some patients with malignant solid tumors.

BackgroundTreatment of patients coinfected with hepatitis C and human immunodeficiency viruses (HCV; HIV) requires careful consideration of potential drug-drug interactions between HCV direct-acting antiviral agents (DAA) and HIV antiretrovirals. Glecaprevir/pibrentasvir is a fixed-dose combination of an NS3/4A protease inhibitor and an NS5A inhibitor approved for the treatment of chronic HCV genotype 1–6 infection, including patients with HIV coinfection.MethodsA series of phase 1 studies was conducted to evaluate potential interactions of glecaprevir and pibrentasvir with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, abacavir/dolutegravir/lamivudine, raltegravir, rilpivirine, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, or efavirenz/emtricitabine/tenofovir disoproxil fumarate. Pharmacokinetics of the antiretrovirals and DAAs were characterized when administered alone and in combination to quantify changes in systemic drug exposure.ResultsGlecaprevir area under the curve increased >4-fold in the presence of ritonavir-boosted HIV protease inhibitors, while pibrentasvir concentrations were not significantly affected; elevations in alanine transaminase occurred in combination with atazanavir/ritonavir only. Exposures of glecaprevir and pibrentasvir may be significantly decreased by efavirenz. Coadministration with glecaprevir and pibrentasvir did not result in clinically significant changes in the exposure of any antiretroviral agents.ConclusionsAtazanavir is contraindicated with glecaprevir/pibrentasvir and use of boosted protease inhibitors or efavirenz is not recommended. No clinically significant interactions were observed with other studied antiretrovirals.

Aquaculture ponds are important anthropogenic sources of nitrous oxide (N2O). Direct N2O emissions arising from feed application to ponds have been widely investigated, but indirect emissions from N2O production from residual feeds in pond water are much less understood and characterized to refine the IPCC emission factor. In this study, we determined the concentrations and spatiotemporal variations of dissolved N2O and NO3--N in situ in three aquaculture ponds at the Min River Estuary in southeastern China during the culture period over two years, and calculated the indirect N2O emission factor (EF5) for aquaculture ponds using the N2O-N/NO3--N mass ratio methodology. Our results indicated that the EF5 values in the ponds over the culture period ranged between 0.0007 and 0.0543, with a clear seasonal pattern which closely followed that of the DOC:NO3-N ratio. We also observed significant spatial variations in EF5 among the three ponds, which could be attributed to the difference in feed conversion rate. In addition, we assessed the EF5 values from aquaculture ponds in five regions of the Chinese coastline across the latitudinal gradient from the tropical to the temperate zones. The average EF5 value from aquaculture ponds across the five coastal regions was 0.0093±0.0024, which was approximately 3.7 times of the IPCC default value for rivers and estuaries (0.0025). Moreover, the EF5 values demonstrated considerable spatial variations across these coastal regions with a coefficient of variation of 59%, which were largely related to the difference in water salinity. Our findings filled a key knowledge gap about the indirect N2O emission factor from aquaculture ponds, and provided field evidence for the refinement of EF5 value currently adopted by IPCC in the national greenhouse gas inventory.

Due to the urban industrial transformation and upgrading in China, the relationship between residential and employment spaces in large cities has changed significantly, resulting in an increasingly prominent job–housing separation phenomenon. Based on the taxi GPS trajectory data, this paper firstly analyzes the time and space distribution of job–housing–travel and the commuting characteristics of residents. Then, we construct the evaluation index systems of regional jobs–housing–taxi demand and regional social development level for Beijing. After calculating the weight of each index by using an entropy weight method, we analyze the coupling relationship between regional taxi demand and social development by building the coupling coordination degree model (CCDM). Conclusions are as follows: Firstly, it shows imbalance of space distribution of taxi orders in different administrative and functional areas. The order quantity gradually decreases from the main urban area to the edge, with the most in the living area, accounting for 46.23% of the total orders. Secondly, the daily variation trend of taxi orders in different functional areas is significantly different. During the morning rush hour, taxi orders flow out of residential areas and into office areas; however, during the evening rush hour, they flow out of the office and into the living area. For example, the residence area has a higher proportion of getting on passengers during the morning rush hour, which is 1.46 times that of the getting off ones. Thirdly, a low coupling coordination degree is observed between the regional social development level and the job–housing–taxi demand in Beijing, with a gradually decreasing from the main urban area to the outside, which is mainly caused by the imbalance between supply and demand. Therefore, it is suggested that the relevant government departments should formulate specific control schemes to traffic congestion according to local commuting features, and promote job–housing balance. Meanwhile, the taxi resources are supposed to be allocated reasonably by the striving to information symmetry, to promote the coordination and sustainability between the regional job–housing–taxi demand and social development level.

Aims To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax. Methods Twelve patients with non-Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open-label, fixed-sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5–11. Blood samples were collected predose and up to 96 h after each venetoclax dose on Day 1 and Day 8. Results Eleven patients had evaluable pharmacokinetic data and were therefore included in the statistical analyses. Compared to administration of a single 50 mg dose of venetoclax alone, ketoconazole increased the venetoclax mean maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve from time 0 to infinity (AUC∞) by 2.3-fold (90% confidence interval [CI]: 2.0–2.7) and 6.4-fold (90% CI: 4.5–9.2; range: 2- to 12-fold), respectively. Conclusions Coadministration of venetoclax with multiple doses of ketoconazole resulted in a significant increase of venetoclax exposures, strongly suggesting that CYP3A plays a major role in elimination of venetoclax in patients. These results suggest the need to avoid concomitant use with strong and moderate inhibitors or inducers of CYP3A during the venetoclax ramp-up phase in chronic lymphocytic leukaemia (CLL) patients. For patients who have completed the ramp-up phase, a modification in venetoclax dose for use with strong and moderate inhibitors or inducers of CYP3A is recommended.

Venetoclax is a selective, B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. In vitro data indicated weak cytochrome P450 (CYP) 2C9 inhibition by venetoclax; however, it is not predicted to cause clinically relevant inhibition due to high plasma protein binding. A Phase 1 study was conducted in healthy volunteers to evaluate the effect of venetoclax on warfarin pharmacokinetics. Subjects received a single oral dose of 5 mg warfarin on day 1 of both periods 1 and 2, separated by a 14 days washout. On day 1 of period 2, subjects concomitantly received a single 400 mg oral dose of venetoclax. Blood samples for warfarin concentration determination were collected after each dose administration for up to 9 days. Modest increases of 18 to 28% were observed in the maximum observed plasma concentration (C max) and area under the curve from time zero to infinity (AUC∞) of both R- and S-warfarin. Due to the narrow therapeutic window of warfarin, it is recommended that the international normalized ratio (INR) be monitored closely in patients receiving venetoclax and warfarin. Since similar increases in exposure were observed for both enantiomers, even though CYP2C9 is only involved in the metabolism of the S-enantiomer, and the half-life of both enantiomers remained the same, the interaction does not appear to be mediated via CYP2C9.

Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. A single-dose and multiple-dose rifampin study was conducted to evaluate the effect of CYP3A induction and transporter inhibition on the pharmacokinetics of venetoclax. Subjects received a single dose of venetoclax 200 mg on day 1 of period 1 and days 1 and 14 of period 2, a single dose of rifampin 600 mg on day 1 of period 2, and rifampin 600 mg once daily on days 5 through 17 of period 2. Blood samples were collected up to 96 hours after each venetoclax dose on day 1 of period 1 and days 1 and 14 of period 2. Compared with venetoclax alone, coadministration with a single dose of rifampin increased venetoclax Cmax and AUC∞ by 106% (90%CI, 73%-145%) and 78% (90%CI, 50%-111%), respectively, whereas coadministration with multiple doses of rifampin decreased venetoclax Cmax and AUC∞ by 42% (90%CI, 31%-52%) and 71% (90%CI, 66%-76%), respectively. It was possible to isolate the net effect of chronic CYP3A induction from acute P-glycoprotein (P-gp) inhibition by comparing venetoclax exposures following coadministration with multiple doses of rifampin versus a single dose of rifampin, which showed that CYP3A induction decreased venetoclax Cmax and AUC by 72% and 84%, respectively. These results are consistent with venetoclax being a P-gp substrate and indicate that CYP3A plays a major role in venetoclax metabolism. Prescribers should consider agents with little or no CYP3A induction during treatment with venetoclax.

Under the background of greenhouse gases emission reduction, the measurement of carbon emissions from the tourism industry has attracted increasing academic attention. Tourism is not a traditional sector in the System of National Accounts, and as a result the statistics of carbon dioxide emissions of the tourism industry on a national scale is difficult to calculate. The measurement methodology of a bottom-up approach and a top-down approach were mainly used in others studies. Utilizing a boundary that includes domestic tourism consumption, inbound tourism consumption, and tourism consumption incurring domestically in relation to outbound travel and airfares paid to the national carriers, a top-down approach is used to measure the national tourism dioxide emissions combining the Tourism Satellite Account and the Input–Output model from productive industry. Using this case study, it was calculated that the total carbon emissions of the Chinese tourism industry in 2002, 2005, 2007 and 2010 were 111.49 Mt, 141.88 Mt, 169.76 Mt and 208.4 Mt respectively, accounting for 2.489%, 2.425%, 2.439% and 2.447% respectively of the total carbon emission of all industries in China. The indirect carbon emissions by other tourism sectors except the transport sector were 3–4 times their direct carbon emissions. Compared with the manufacturing industry, the tourism industry is an industry of low pollution and low energy consumption. We discuss the advantage and shortcoming of the two approaches and put forward some suggestions to assist the research of tourism carbon emissions.

Due to the constraints of freshwater for agricultural irrigation, sewage water has been used in farmland irrigation as an important supplement and alternative water resources during the past three decades in China, especially in northern areas. However, there is increasing concern about food safety and health risks, hence, a case study was undertaken to understand the long-term effect of sewage irrigation on heavy metal concentrations in soil and plants. Sewage sludge, soil and plant samples were collected and analyzed for heavy metals concentrations. Results showed that sewage irrigated soil contained much higher concentrations of Cd, Cu, Pb, Zn, Ni, Cr, As and Hg compared to clean water irrigated soil. The heavy metal content of the topsoil (0–20 cm) was much higher than that of the subsoil. Significant heavy metal (Cd, Zn and Hg) pollution has occurred in soils of areas that had been using untreated waste water irrigation in Tianjin, China. There were significant accumulations of heavy metals in wheat that used sewage irrigation. Compared with the other parts of the wheat plants, the higher contents of Cd, Cr, Pb and As in the roots indicated that roots had a strong absorption ability and maybe cause an obvious barrier effect. Based on the soil to plant transfer factor of heavy metals, there is a strong accumulation effect of Cd in vegetables. Overall, the concentrations of Cd, Pb, Ni, Cr and As were lower than the national permitted safety limits in soil. Mean Cd, Pb and As concentrations in vegetables were higher than the national safety limits, whereas the mean concentrations of Cu, Zn and Cr were below Chinese national safety limits. Therefore, in order to ensure food safety and use of sewage for irrigation, continuous monitoring and pollution control is needed.

Dissolved concentrations, saturation status, and emission fluxes of greenhouse gases (GHGs) in two reclamation mariculture ponds in the Bohai Gulf, China, were measured using the static headspace gas chromatography method and computed using a two-layer model of diffusive gas exchange. The study was conducted during August 2016 to assess diurnal variations in GHGs emissions. The main influencing factors of GHGs emissions from the ponds under the disturbance of artificial management were identified using Spearman correlation analyses and multiple stepwise regression analyses. Results showed that dissolved GHGs concentrations were stable throughout the day, whereas GHGs emission fluxes showed a clear diurnal variation with larger daytime values. The diurnal variation of N2O emission fluxes was greater than that of CO2 and that of CH4. Results also showed that pH of pond water was negatively correlated with CO2 and N2O emission fluxes and that air temperature was positively correlated with CH4 and N2O emission fluxes. In addition, ammonia (NH4+-N) was positively correlated with CH4 emission fluxes; water temperature and salinity were positively correlated with N2O emission fluxes. The estimated annual emissions from the reclamation aquaculture in Tianjin and the Bohai Rim region were 2.53 × 105 kg C–CO2, 6.94 × 103 kg C–CH4 and 1.11 × 103 kg N–N2O, and 3.42 × 107 kg C–CO2, 9.36 × 105 kg C–CH4 and 1.50 × 105 kg N–N2O respectively, indicating the important contribution of this fishery sector to GHGs emissions.

The fiber coupling efficiency of Gaussian-Schell model beams propagating through the oceanic turbulence of the Zernike tilt correction is studied. We derive the expression of the Zernike tilt corrected wave structure function. The numerical analysis reveals that a higher correction factor and spatial coherence of the laser beam increase the fiber coupling efficiency of the link. Our work shows that the increment of the fiber coupling efficiency caused by Zernike tilt correction under strong turbulence conditions is stronger than in the weak turbulence conditions, and the salinity fluctuation has a greater impact on it than temperature fluctuation does.

Dystonia is characterized by sustained muscle contractions, causing repetitive movements and abnormal postures. The epidemiological study of dystonia of Chinese population was limited reported. In this study, we investigated the epidemiology of primary dystonia, and its clinical characteristics in an adult population in China. We identified all dystonia patients from the movement disorders database and botulinum toxin clinic between 2009 and 2013. The medical records were reviewed to verify the diagnosis of dystonia, and demographic and clinical data were collected. A total of 1481 patients with primary dystonia were studied. The most common focal dystonia were blepharospasm (56.4 %), cervical dystonia (36.7 %), limb dystonia (3.4 %), oromandibular dystonia (2.9 %) and laryngeal dystonia (0.6 %). Males with primary dystonia were found to have an earlier age of onset. A female predominance was noted for most of the primary dystonia, with a men to women ratio (M:F) of 1:2.01. The minimum estimate of prevalence of primary dystonia was 27.0 (95 % confidence interval: 25.6-28.3) per million persons in this study. Despite the difference in genetic background and geographic area, the epidemiological features of dystonia in China from our study share most features around the world, such as women dystonia dominance, early-onset age of dystonia with women, etc. But East Asia countries (China and Japan) may share more common features of dystonia.

Background & AimsParitaprevir (administered with ritonavir, PTV/r), ombitasvir (OBV), and dasabuvir (DSV) are direct-acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection. Thirteen studies were conducted to characterize drug-drug interactions for the 3D regimen of OBV, PTV/r, and DSV and various medications in healthy volunteers to inform dosing recommendations in HCV-infected patients.MethodsMechanism-based drug-drug interactions were evaluated for gemfibrozil, ketoconazole, carbamazepine, warfarin, omeprazole, digoxin, pravastatin, and rosuvastatin. Drug-drug interactions with medications commonly used in HCV-infected patients were evaluated for amlodipine, furosemide, alprazolam, zolpidem, duloxetine, escitalopram, methadone, buprenorphine/naloxone, and oral contraceptives. Ratios of geometric means with 90% confidence intervals for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were used to determine the magnitude of interaction.ResultsCoadministration with the 3D regimen of OBV, PTV/r, and DSV resulted in a

Nowadays, ride-hailing services have been established as a part of the urban transportation. Their arrival has remade the profit structure and resulted in the unbalance of interest in taxi market. Here, we establish the service models of taxis, carpooling, and car-hailing under “Internet +” from the perspective of profit margins, to perform a comparative analysis among the different services. Results: First, Profit margins are generally higher for short trips than for long trips, though empty cruise fee to a certain degree make up for the driver’s decreased profit margins. Second, the profit margin for carpooling is roughly 1.85 times that of ride-hailing, and 1.75 times that of taxis. This shows that the sharing economy has a certain advantage. Third, Profit margins are higher and fluctuations are lower on non-work days than on work days. At last, Profit margins are roughly 1.3 times higher on non-congested roads than on congested roads. The reduced profitability on congested roads makes it even harder to catch a ride during rush hours and on congested roads. We suggest that the relevant departments make appropriate efforts to make it more attractive for drivers to take on passengers during rush hours and on congested roads, and promote the sharing in the taxi market.

We investigate the atmospheric turbulence effects on the propagation of vortex modes carried by Lommel beam. The analytic expression of the received signal and crosstalk mode intensity is derived based on the weak-to-strong non-Kolmogorov turbulence theory. The simulation results show that turbulence with small non-Kolmogorov spectrum parameter, small inner-scale factor and large outer-scale factor is more likely to induce modal crosstalk. With the increment of turbulence strength, the crosstalk spreads from adjacent modes to peripheral modes. The received signal intensity can be improved by use of Lommel beam with small asymmetry parameter, low orbital angular momentum quantum number and long wavelength. The results are helpful to the design of orbital angular momentum based free-space optical communication link.

Venetoclax is a selective BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). It is predominately metabolized by cytochrome P450 (CYP) 3A. The study objective was to determine the effect of different dosage regimens of ritonavir, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax in 20 healthy subjects. In cohorts 1 and 2, subjects received single 10 mg doses of venetoclax in periods 1 and 2 and a single 50- or 100-mg dose of ritonavir in period 2. In cohort 3, subjects received 10-mg venetoclax doses on day 1 of period 1 and days 1 and 11 of period 2, and 50 mg ritonavir daily on days 1 to 14 of period 2. Single doses of 50 and 100 mg ritonavir increased the venetoclax maximum concentration (Cmax) 2.3- to 2.4-fold compared to venetoclax alone and the area under the curve (AUC) 6.1- and 8.1-fold, respectively. Daily 50 mg ritonavir resulted in a 2.4- and 7.9-fold increase in venetoclax Cmax and AUC, respectively. Administration of 50 mg ritonavir daily saturated CYP3A inhibition and completely inhibited the formation of the major venetoclax metabolite M27. Time-dependent CYP3A inhibition with daily 50 mg ritonavir was offset by ritonavir CYP3A induction, resulting in a limited net increase in CYP3A inhibition with multiple doses. After completion of the dose ramp-up, venetoclax dose reductions of at least 75% are recommended when administered concomitantly with strong CYP3A inhibitors to maintain venetoclax exposures within the established therapeutic window for CLL treatment.

With the rapid development of the urban economy and transportation, the taxi market has presented a series of problems regarding unreasonable resource allocation, demand–supply imbalance, and driver income imbalance. Since the distribution of high-quality customers (hereafter HQC) affects drivers’ incomes and resource allocation in the taxi market, it is of great significance to study the HQC distribution to address these imbalance problems and understand the imbalance of the taxi market. In this paper, we calculate the profit margin of each order and construct a high-quality customer evaluation model from taxi GPS trajectory data. In analyzing the spatial–temporal distribution of HQC, our results indicate that HQC present a regional aggregation phenomenon in the spatial dimension, and HQC are mainly distributed in the main urban areas. The distribution of HQC is imbalanced in various administrative districts and functional zones. The daily change of orders in each administrative district is the same, but the temporal distribution of HQC is imbalanced. The temporal distribution of HQC in each functional zone is imbalanced, showing different daily change trend. According to these results, we suggest that the pricing of taxis and online ride-hailing services be coordinated based on the spatial–temporal distribution characteristics of HQC and that resources be rationally allocated to promote the sustainable and healthy development of urban transportation.

Background: The bromodomain and extra terminal (BET) family of proteins bind acetylated histone tails, leading to the regulation of oncogenic target genes. Mivebresib (ABBV-075; MIV) is a pan-BET inhibitor that has demonstrated antitumor activity in vitro and in xenograft models of acute myeloid leukemia (AML). This phase 1, first-in-human, 2-part study (NCT02391480) assessed the safety and pharmacokinetics (PK) of MIV at various monotherapy (MIV-mono) or combination dosing schedules with venetoclax (MIV-VEN). Here we report PK and pharmacodynamic (PD) data in correlation to biological activity in patients with relapsed/refractory AML. Methods: Gene expression analysis was performed on RNA extracted from whole blood samples collected at multiple time points (pre-and post-MIV-mono treatment). mRNA expression was analyzed from total RNA and sequenced on HiSeq 3000 (Illumina, San Diego, CA). Soluble cytokine modulation was evaluated in serum samples (pre- and post-MIV-mono treatment) on Myriad Rules-Based Medicine's ExplorerMAP® Panel (145 analytes; Myriad RBM, Austin, TX). Cytogenetic analysis was performed at each site using institutional guidelines. Molecular profiling was performed at the site and by AbbVie using targeted next-generation sequencing (myeloid-specific panel). PK sampling was done on cycle 1 day 1 (C1D1), C1D8 and C2D1. PK analyses were completed using non-compartmental analysis methods. A linear regression analysis was performed to determine association between drug exposure and percentage change in gene modulation from baseline at 6 hours on C1D1. Biologic activity was defined as measurable reduction in bone marrow (BM) blasts from baseline. Results: As of Jan 2019, 44 patients (median age: 68 y [range, 29-84]; 35 patients >2 prior therapies) were enrolled: 19 in MIV-mono (5 of whom switched to MIV-VEN) and 25 who began treatment in MIV-VEN cohorts. MIV (1-2.5 mg) exposures were dose proportional and MIV was rapidly absorbed with a Tmax of 2-6 hours and terminal half-life of ~15-20 hours. Concomitant administration of VEN did not show any clinically significant effect on MIV plasma PK at steady state. At 6 hours post-MIV-mono treatment, a significant correlation was observed between drug exposure and PD biomarker modulation, with a dose-dependent gene expression increase in DCXR and HEXIM1 and decrease in CD93 (p In patients treated with MIV-mono, measurable reduction in BM blast counts was observed in 7/19 (37%) patients (Figure): complete remission (CR) with incomplete blood count recovery (n=1), ≥50% blast reduction (n=4), modest blast reduction of The majority of patients (30/44; 68%) were classified as adverse risk per ELN 2017 criteria. At baseline, 6/19 (32%) MIV-mono and 17/30 (57%) MIV-VEN patients had mutations in signaling genes; FLT3-ITD/TKD were the most commonly mutated in MIV-VEN population (10/17, 59%). In the MIV-VEN group, 4/10 (40%) patients with FLT3-ITD/TKD mutations and 4/6 (67%) patients with PTPN11 mutations had reduction in BM blasts following treatment. At baseline, 12/30 (40%) patients had mutations in either SF3B1/U2AF1 or PTPN11; 8 (67%) of these patients had reduction in BM blasts, including 1 CR and 1 MLFS. Conclusions: MIV exposure was dose proportional and a significant correlation was identified between multiple biomarkers (HEXIM1, DCXR, CD93 gene modulation) and drug exposure at 6 hours post-MIV treatment. MIV treatment inhibited BCL-2, VEGF and Myc gene expression, while inducing expression of pro-apoptotic genes. Biologic activity was observed particularly in patients treated with MIV-VEN who had SF3B1/U2AF1 or PTPN11 mutations. Disclosures Borthakur: Arvinas: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cantargia AB: Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Merck: Research Funding; Janssen: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; PTC Therapeutics: Consultancy; Incyte: Research Funding; GSK: Research Funding. Odenike:Agios: Research Funding; Gilead Sciences: Research Funding; Incyte: Research Funding; NS Pharma: Research Funding; Oncotherapy: Research Funding; Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI/Baxalta: Research Funding; Astex Pharmaceuticals: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Research Funding. Aldoss:Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Agios: Consultancy, Honoraria; AUTO1: Consultancy; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses. Rizzieri:AbbVie: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Kite Pharma: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy; TEVA: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Amgen: Consultancy; Jazz Pharmaceuticals: Speakers Bureau; Millennium: Speakers Bureau. Prebet:Boehringer Ingelheim: Research Funding; pfizer: Honoraria; Tetraphase: Consultancy; Genentech: Consultancy; novartis: Honoraria; Boehringer Ingelheim: Research Funding; novartis: Honoraria; novartis: Honoraria; novartis: Honoraria; Agios: Consultancy, Research Funding; pfizer: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; novartis: Honoraria; Boehringer Ingelheim: Research Funding; pfizer: Honoraria; pfizer: Honoraria; pfizer: Honoraria. Modi:AbbVie: Employment, Other: Stock/stock options. Joshi:AbbVie: Employment, Other: Stock/stock options. Hu:AbbVie: Employment, Other: Stock/stock options. Sun:AbbVie: Employment, Other: Stock/stock options. Wolff:AbbVie Inc: Employment, Other: Stock/stock options. Jonas:AbbVie, Amgen, GlycoMimetics: Other: Travel expenses; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding.

With the development of social economy, a series of problems such as an imbalance of supply and demand, unreasonable resource allocation and low operation efficiency appear in the urban taxi market. Based on the GPS trajectory data of taxis, this paper calculates and analyzes the operation efficiency of taxis in terms of time and space dimensions in Chengdu, Sichuan Province by using the capacity utilization rate. The results show that, firstly, the weekly variation trend of taxi capacity utilization rate is obviously periodic and its daily variation trend is unbalanced, which is reflected in the morning peak, afternoon peak, evening peak and night peak. The daily variation trend of taxi capacity utilization rate is significantly different between workdays and weekends, and the capacity utilization rate on weekends is much lower. Secondly, there is a spatial imbalance in the distribution of taxi capacity utilization rate. The capacity utilization rate of the main urban district is relatively high, and that of the other urban districts negatively correlates with the economic level and population density. The supply and demand of taxis are balanced within the various functional zones but unbalanced between different functional zones. It is suggested that the relevant departments shall reasonably allocate taxi resources according to the imbalance of taxi capacity utilization rate in time and space to improve the overall operation efficiency, and integrate market mechanism with government regulations to promote the sustainable development of urban taxis.

We propose a model of the fiber coupling efficiency for a partially coherent collimating laser beam propagating through turbulent biological tissue to fiber. By studying the influence of link parameters on fiber coupling efficiency, we find that there are optimal focal length and transmitting beam radius for specific turbulent tissue. We also find that a larger characteristic length and small length-scale factor, or smaller fractal dimension and strength coefficient of refractive-index fluctuation will lead to larger fiber coupling efficiency. In order to improve the fiber coupling efficiency, we recommend select the optimum focal length, moderate transmitting beam radius, lower aperture diameter of the coupling lens, longer wavelength and higher coherent degree of light source. 2000 MSC: 41A05, 41A10, 65D05, Keywords: Fiber coupling efficiency, Biological tissue, Turbulence, Optimum parameter, Laser beam

e14526 Background: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Cell free DNA (cfDNA) is a non-invasive mechanism for monitoring malignancy in UM patients. BET proteins activate transcription of oncogenic genes, and mivebresib (ABBV-075) is a potent pan-BET inhibitor. In the first-in-human phase 1 study, safety and pharmacokinetics of mivebresib were assessed in patients with advanced cancer (NCT02391480). We compared cfDNA mutational dynamics with the survival of UM patients treated with mivebresib. Methods: Adult patients with metastatic solid tumors and ≥1 line of prior treatment were treated with mivebresib on a schedule of daily; 3 days/week; or 4 days on, 3 days off. Two mL of plasma cfDNA (≥10ng) in 5 patients (3 progressive disease [PD], 2 stable disease [SD]) were sequenced with a targeted 63-gene panel (68 Kb) to ≥800X unique depth after barcode-based error-suppression and genomic alterations discovered in all patients. Results: As of May 2018, 10 UM patients received ≥1 dose of mivebresib with median 8.1 weeks (range, 3.6–39.6) of treatment. The median age was 55 years (range, 37–73). 9 patients experienced a treatment-emergent adverse event (TEAE), most commonly (≥40% patient incidence), dysgeusia (60%), thrombocytopenia and nausea (40%, each). 9 patients were evaluable, 4 achieved a best response of SD and 5 PD (RECIST v1.1). The mean pretreatment cfDNA concentration was 21.0 ng/mL (N = 5 with plasma available). cfDNA levels increased in two patients by 0.6% (SD) and 64.4% (PD). In PD patients, elevated cfDNA concentration (32.7 ng/mL [PD] vs 3.5 ng/mL [SD]) was associated with shorter progression-free survival and overall survival. At baseline, the cfDNA mutational load (median mutant molecules/mL plasma) of pathogenic (COSMIC) mutations with AF ≥1% was highest in PD (893.9; range, 78-4951.5) vs SD patients (53.1; range, 9.3-606.2) and negatively correlated with the patient’s survival (R2= 0.531). In 1 PD patient, multiple TP53 (C23G, V203M) and CDKN2A (A148T, L63P) mutations were acquired by the time of progression. Conclusions: These data suggest cfDNA as a potential marker for survival of UM patients. Further investigation of BET inhibition in this population is warranted. Clinical trial information: NCT02391480.

7030 Background: Bromodomain and extra-terminal (BET) proteins bind to acetyllysines and upregulate oncogenic target genes. Mivebresib (ABBV-075) is a pan-BET inhibitor with antitumor activity in vitro and xenograft models of AML. This 2-part phase 1 study evaluates the safety and pharmacokinetics of mivebresib at monotherapy or combination dosing schedules in patients with solid tumors (part 1) and acute myeloid leukemia (AML; part 2) (NCT02391480). Here, we report preliminary data from part 2 in patients with relapsed/refractory (RR) AML. Methods: Mivebresib monotherapy (MIV-mono), or combined with venetoclax (MIV-VEN), were administered daily to adult patients with AML. The dose-limiting toxicity (DLT) period was 28 d. Results: As of Dec 2018, 41 patients (median age: 69 y [range, 29–84]; 19 patients had > 2 prior therapies) were enrolled: 19 in MIV-mono (5 of whom switched to MIV-combo) and 22 who began treatment in MIV-VEN cohorts. 23 patients had high cytogenetic risk. Median time on treatment was 28 d (range, 8–562). There were no DLTs. All patients experienced a treatment-emergent adverse event (AE), most commonly (≥40% patient incidence), fatigue (56%), dysgeusia (46%), decreased appetite (44%), diarrhoea (42%), nausea (42%), vomiting (42%). 40 patients had grade ≥3 AEs (febrile neutropenia (37%), anemia (34%) and thrombocytopenia (32%). 33 patients had serious AEs, most commonly febrile neutropenia (19%). 25 deaths were reported; 15 patients died of causes unrelated to mivebresib and 10 patients due to AML progression. The median best % bone marrow blast change for 26 evaluable patients was -20% (range, -98% to +300%). Gene expression analysis in pre- and post-treatment peripheral blood samples showed that HEXIM1, DCXR and CD93 genes were reliable PD biomarkers of ABBV-075 which were consistently modulated in a dose-dependent manner. At the cutoff date, median overall survival for all patients was 2.6 m. Conclusions: Mivebresib was well tolerated and showed antileukemic effects in patients with RR AML. Clinical trial information: NCT02391480.

8510 Background: CRT is standard treatment (Tx) for pts with unresectable stage III NSCLC. Vel, a potent oral PARP1/2 inhibitor, interferes with repair of chemotherapy- or radiation-induced DNA damage. In a phase 2 study, Vel showed favorable efficacy vs placebo when added to C/P in stage IV NSCLC. The reported phase 1 trial assessed the safety and efficacy of Vel + C/P-based CRT in Tx of stage III NSCLC (NCT02412371). Methods: Eligible pts (≥18 yr, unresectable stage III NSCLC, no prior NSCLC therapy) received Vel + CRT of weekly C area under the curve (AUC) 2 + P 45 mg/m2 weekly + 60 Gy (2 Gy/day) RT over 6–9 weeks (wk). Vel was dose escalated from 60 mg twice daily (BID) to 240 mg BID followed by Vel 120 mg BID added to consolidation therapy (CON) once every 3 wk of C AUC 6 + P 200 mg/m2 for 2 cycles (cohort 1–5). Cohort 6 received Vel 240 mg BID + CRT followed by Vel 240 mg BID + CON. Samples for pharmacokinetic (PK) analysis were collected on wk 4 day –3. The primary endpoint was to establish the recommended phase 2 dose (RP2D) of Vel + CRT/Vel + CON. Results: As of Sep 2018, 48 pts enrolled into cohorts 1–6 at Vel 60 mg/120 mg (n = 7), 80 mg/120 mg (n = 9), 120 mg/120 mg (n = 7), 200 mg/120 mg (n = 8), 240 mg/120 mg (n = 12), and 240 mg/240 mg (n = 5) added to CRT/CON; median age 65 yr (range, 48–81). Vel PK was dose proportional; 39 (81.3%) pts completed therapy. Grade ≥3 Tx-emergent adverse events (AEs) were reported in 37 (77.1%) pts; anemia and febrile neutropenia (10.4% each) were the most common. Serious AEs were observed in 19 (39.6%) pts. Dose-limiting toxicities occurred at 200 mg/120 mg (n = 1; influenza and pneumonia), 240 mg/120 mg (n = 1; insomnia), and 240 mg/240 mg (n = 2; febrile neutropenia, neutropenia, thrombocytopenia, esophagitis, suprapubic pain, sepsis); Vel 240 mg BID + CRT/Vel 120 mg + CON was chosen as the maximum tolerated dose/RP2D. Of 41 pts evaluable for tumor assessment, 26 (63.4%) had a confirmed response. Interim median progression-free survival was 24.1 mo (range, 8.9 – not reached); updated results will be reported. Conclusions: Vel 240 + CRT/Vel 120 mg BID + CON was well tolerated with promising antitumor activity in stage III NSCLC and was determined as RP2D. Clinical trial information: NCT02412371.

With the rapid development of information technology, the travel mode of " Internet + Transportation " has brought convenience to residents while causing a series of urban traffic problems. Based on GPS data from Didi Chuxing, this paper relates the residents' travel behaviour to their daily activities, and studies the regularity of the pick-up and drop-off activities of residents from the dimensions of time and space. The results are as follows: Firstly, the daily variation trend of residents' travel is unbalanced. At the same time, the travel volume of residents is at a higher level during night. Secondly, the travel of urban residents is closely related to urban areas and urban functional structures. On the administrative scale, the distribution of residents' travel is concentric, and the farther the distance from the downtown area is, the smaller the number of orders is. On the functional scale, the hot functional areas of residents' travel are related to residents' needs. At last, mastering the distribution of residents' travel hot spots and time will help to understand the residents' travel mode and the current situation of urban traffic, and provide new ideas for solving traffic problems in big cities.

The aim of the study was to investigate heavy metals concentrations in wheat field soils of Tianjin sewage irrigation region, and evaluate the potential ecological risk of heavy metals pollution. ICP-OES was employed to analyze the heavy metals concentrations in wheat field soils of Tianjin sewage-irrigation region. The grading standard of Tianjin soil environmental quality was used as the assessment foundation for soils and Lars Hakanson’s potential ecological hazards index method was used to evaluate the heavy metals pollution potential ecological risk in soils. The results showed that: Cd concentrations in soils ranged from 0.03 mg•kg-1 to 1.17 mg•kg-1, with an average value of 0.46 mg•kg-1; Zn concentrations in the soils ranged from 62 mg•kg-1 to 307 mg•kg-1, with an average value of 129.08 mg•kg-1. The concentrations of Cd and Zn in the soils exceeded second grade standards of Tianjin soil environment quality, so the soil was polluted. The other heavy metal elements, such as Cu, Pb, Cr and Ni, were all lower than second level of Tianjin soil environment quality standards, meaning that the soil was not contaminated by these heavy metals. The heavy metal concentrations were relatively rich in saline wet fluvo-aquic soil and clayification fluvo-aquic soil. Based on Lars Hakanson’s potential ecological hazards index method, Cd had heavily ecological risk in soils and was the main pollutant, while the other heavy metals had lightly ecological risk. Ecological risk of total heavy metals pollution was moderate. The heavy metals were most likely from wastewater irrigation. The pollutants in the soils came mainly from sewage irrigation. The waste water treatment technology should involve steps to remove heavy metals causing risk to human health.

This paper reviewed and analyzed the development of our nation’s loan loss provision system, then studied the relations of commercial bank loan loss provision and earnings management and capital management through empirical study. This paper selected 14 domestic commercial banks of year 2001-2009 as data sample, using Kanagaretnam et al.’s (2003) research method, dividing the loan loss provision into two parts that is discretionary and nondiscretionary part, and empirically studied the relationship of discretionary part of loan loss provision and earnings before taxes and provisions (EBTP) and capital adequacy ratio (CAR). Empirical results show that: there is significant positive correlation between the discretionary loan loss provisions and earnings before taxes and provisions (EBTP), and there is significant negative correlation between the discretionary loan loss provisions and capital adequacy ratio (CAR). That provides evidence for the relation of bank loan loss provision and earnings management and capital management. In the last, combining with empirical research findings and the status of the loan loss provision system of China’s commercial banks, this paper made several suggestions to improve the system of loan loss provision.