Chemical Source Profiles and Toxicity Assessment of Urban Fugitive Dust PM2.5 in Guanzhong Plain, China.

Urban fugitive dust is a significant contributor to atmospheric PM2.5 and a potential risk to humans. In 2019, both road dust and construction dust were collected from four cities, including Xi'an, Xianyang, Baoji, and Tongchuan, in Guanzhong Plain, China. Elements, water-soluble ions, and carbonaceous fractions were determined to establish the chemical source profile. High enrichment degrees of Se, Sc, Cl, and Zn in both road dust and construction dust indicated that the industrial system and energy consumption influenced Guanzhong Plain strongly. According to the coefficient of divergence, the two datasets within Xianyang and Tongchuan were similar. Combined with the chemical profile, road dust was affected by more stationary emission sources than construction dust in Xi'an, while biomass burning and vehicle exhaust contributed more to road dust than construction dust in Baoji. Moreover, the health risk of heavy metal was assessed, and corresponding influencing factors were identified. Road dust in all cities showed a non-negligible non-carcinogenic risk for children. Ingestion and inhalation were the main exposure pathways to which As and Co contributed the most, respectively. The land-use regression model revealed that the first-class road in a 100 m radius impacted all high-risk level metals, and the commercial building material and enterprises weakly influenced Co and Pb, respectively.

Fabrication of a label-free electrochemical cell-based biosensor for toxicity assessment of thiram.

Thiram has been widely used in agriculture and may invades the food chain, posing a threat to human health. In this research, a label-free electrochemical cell-based biosensor was presented for in vitro toxicity assessment of thiram. HepG2 cells were cultured on poly-l-lysine@gold nano-flowers functionalized indium tin oxide coated glass electrode (PLL@AuNFs/ITO) to serve as biorecognition elements. AuNFs were electrodeposited on ITO to provide an enlarged specific surface area and benefited the output signal amplification. PLL was selected as an effective biocompatible coating material to facilitate cell adhesion and proliferation, thereby realizing one-step recording of electrochemical signals from thiram-treated cells. With the aid of the differential pulse voltammetry method, the fabricated biosensor was applied to assess the cytotoxicity of thiram. Results showed that the cytotoxicity measured by the fabricated biosensor exhibited a linear relationship related to thiram concentration ranging from 5 to 50 µM with a detection limit of 2.23 µM. The IC50 of thiram obtained by the biosensor was 29.5 µM, which was close to that of conventional MTT assay (30.8 µM). The effects of thiram on HepG2 cells were also investigated via SEM and flow cytometry. Meanwhile, the proposed biosensor was used to evaluate the toxicity of thiram in fruit samples. Results indicated that the toxicity of thiram cannot be ignored even at a low residual concentration in food (≤5 mg/kg). In conclusion, the developed sensor showed excellent sensitivity, stability, and reliability, which provided a great capacity for the convenient toxicity evaluation of thiram residue in food.

Estimating the health burden of aflatoxin attributable stunting among children in low income countries of Africa.

Numerous population-based studies have documented high prevalence of aflatoxin associated childhood stunting in low income countries. We provide an estimate of the disease burden of aflatoxin related stunting using data from the four African countries. For this empirical analysis, we obtained blood aflatoxin albumin adduct biomarker based exposure data as measured using ELISA technique and anthropometric measurement data from surveys done over a 12-year period from 2001 to 2012 in four low income countries in Africa. We used these data to calculate population attributable risk (PAR), life time disease burden for children under five by comparing two groups of stunted children using both prevalence and incidence-based approaches. We combined prevalence estimates with a disability weight, measuring childhood stunting and co-occurrence of stunting-underweight to produce years lived with disability. Using a previously reported mortality, years of life lost were estimated. We used probabilistic analysis to model these associations to estimate the disability-adjusted life-years (DALYs), and compared these with those given by the Institute for Health Metrics and Evaluation's Global Burden of Disease (GBD) 2016 study. The PAR increased from 3 to 36% for aflatoxin-related stunting and 14-50% for co-occurrence of stunting and underweight. Using prevalence-based approach, children with aflatoxin related stunting resulted in 48,965.20 (95% uncertainty interval (UI): 45,868.75-52,207.53) DALYs per 100,000 individuals. Children with co-occurrence of stunting and underweight due to exposure to aflatoxin resulted in 40,703.41 (95% UI: 38,041.57-43,517.89) DALYs per 100,000 individuals. Uncertainty analysis revealed that reducing aflatoxin exposure in high exposure areas upto non-detectable levels could save the stunting DALYs up to 50%. The burden of childhood all causes stunting is greater in countries with higher aflatoxin exposure such as Benin. In high exposure areas, these results might help guide research protocols and prioritisation efforts and focus aflatoxin exposure reduction. HEFCE Global Challenge Research Fund Aflatoxin project.

A low cost smart system to analyze different types of edible Bird's nest adulteration based on colorimetric sensor array.

This study was performed to develop a low-cost smart system for identification and quantification of adulterated edible bird's nest (EBN). The smart system was constructed with a colorimetric sensor array (CSA), a smartphone and a multi-layered network model. The CSA were used to collect the odor character of EBN and the response signals of CSA were captured by the smartphone systems. The principal component analysis (PCA) and hierarchical cluster analysis (HAC) were used to inquiry the similarity among authentic and adulterated EBNs. The multi-layered network model was constructed to analyze EBN adulteration. In this model, discrimination of authentic EBN and adulterated EBN was realized using back-propagation neural networks (BPNN) algorithm. Then, another BPNN-based model was developed to identify the type of adulterant in the mixed EBN. Finally, adulterated percentage prediction model for each kind of adulterate EBN was built using partial least square (PLS) method. Results showed that recognition rates of the authentic EBN and adulterated EBN was as high as 90%. The correlation coefficient of percentage prediction model for calibration set was 0.886, and 0.869 for prediction set. The low-cost smart system provides a real-time, nondestructive tool to authenticate EBN for customers and retailers.

A colorimetric hydrogen sulfide sensor based on gellan gum-silver nanoparticles bionanocomposite for monitoring of meat spoilage in intelligent packaging.

A colorimetric hydrogen sulfide (H2S) sensor based on gellan gum capped silver nanoparticles was developed to real-time monitor meat spoilage. The colorimetric sensor strategy was attributed to the ultrastrong binding ability of Ag with H2S to form Ag2S. The sensor enables the analysis of H2S with a limit of detection (LOD) of 0.81 µM, and it exhibited excellent selectivity toward H2S against other volatile components generated from chicken breast and silver carp during spoilage. By these virtues, the sensor presented visible color changes from yellow to colorless by in situ and nondestructively sensing H2S generated from chicken breast and silver carp in a packaging system. This strategy provided a simple but useful, non-destructive, robust, cost-effective, and user-friendly platform to real time monitor meat spoilage for intelligent food packaging.

Developmental trajectory of hope among late-adolescents: Population heterogeneity and the impact of gender and family socioeconomic status.

OBJECTIVE: To study the developmental trajectory of hope among late-adolescents, taking population heterogeneity and the impact of gender and family socioeconomic status (SES) into consideration. METHODS: The study used the Snyder Hope Scale to perform four surveys of a sample of 381 Chinese late-adolescents, both male and female, with a mean age of 17.69 ±â€¯1.12 years, over the course of one year, and employed a growth mixture model to perform data analysis. RESULTS: Although the levels of hope among the respondents who had high and moderate levels of hope at the outset of the study remained relatively stable over the course of the year, those with low levels of hope exhibited a significant decrease over time. CONCLUSIONS: There is significant population heterogeneity in late-adolescents' developmental trajectory of hope. Additionally, gender and family SES have a significant effect on the developmental trajectory of hope, as significantly more female students than male students reported high levels of hope. Furthermore, participants with high family SES outnumbered those with low family SES in the high-hope group, whereas those with low SES outnumbered those with high SES in the low-hope group.

Assessment of an In Silico Mechanistic Model for Proarrhythmia Risk Prediction Under the CiPA Initiative.

The International Council on Harmonization (ICH) S7B and E14 regulatory guidelines are sensitive but not specific for predicting which drugs are pro-arrhythmic. In response, the Comprehensive In Vitro Proarrhythmia Assay (CiPA) was proposed that integrates multi-ion channel pharmacology data in vitro into a human cardiomyocyte model in silico for proarrhythmia risk assessment. Previously, we reported the model optimization and proarrhythmia metric selection based on CiPA training drugs. In this study, we report the application of the prespecified model and metric to independent CiPA validation drugs. Over two validation datasets, the CiPA model performance meets all pre-specified measures for ranking and classifying validation drugs, and outperforms alternatives, despite some in vitro data differences between the two datasets due to different experimental conditions and quality control procedures. This suggests that the current CiPA model/metric may be fit for regulatory use, and standardization of experimental protocols and quality control criteria could increase the model prediction accuracy even further.

Mechanistic Model-Informed Proarrhythmic Risk Assessment of Drugs: Review of the "CiPA" Initiative and Design of a Prospective Clinical Validation Study.

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a mechanistic-based assessment of the proarrhythmic risk of drugs. CiPA proposes to assess a drug's effect on multiple ion channels and integrate the effects in a computer model of the human cardiomyocyte to predict proarrhythmic risk. Unanticipated or missed effects will be assessed with human stem cell-derived cardiomyocytes and electrocardiogram (ECG) analysis in early phase I clinical trials. This article provides an overview of CiPA and the rationale and design of the CiPA phase I ECG validation clinical trial, which involves assessing an additional ECG biomarker (J-Tpeak) for QT prolonging drugs. If successful, CiPA will 1) create a pathway for drugs with hERG block / QT prolongation to advance without intensive ECG monitoring in phase III trials if they have low proarrhythmic risk; and 2) enable updating drug labels to be more informative about proarrhythmic risk, not just QT prolongation.

Uncertainty Quantification Reveals the Importance of Data Variability and Experimental Design Considerations for in Silico Proarrhythmia Risk Assessment.

The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a global initiative intended to improve drug proarrhythmia risk assessment using a new paradigm of mechanistic assays. Under the CiPA paradigm, the relative risk of drug-induced Torsade de Pointes (TdP) is assessed using an in silico model of the human ventricular action potential (AP) that integrates in vitro pharmacology data from multiple ion channels. Thus, modeling predictions of cardiac risk liability will depend critically on the variability in pharmacology data, and uncertainty quantification (UQ) must comprise an essential component of the in silico assay. This study explores UQ methods that may be incorporated into the CiPA framework. Recently, we proposed a promising in silico TdP risk metric (qNet), which is derived from AP simulations and allows separation of a set of CiPA training compounds into Low, Intermediate, and High TdP risk categories. The purpose of this study was to use UQ to evaluate the robustness of TdP risk separation by qNet. Uncertainty in the model parameters used to describe drug binding and ionic current block was estimated using the non-parametric bootstrap method and a Bayesian inference approach. Uncertainty was then propagated through AP simulations to quantify uncertainty in qNet for each drug. UQ revealed lower uncertainty and more accurate TdP risk stratification by qNet when simulations were run at concentrations below 5× the maximum therapeutic exposure (Cmax). However, when drug effects were extrapolated above 10× Cmax, UQ showed that qNet could no longer clearly separate drugs by TdP risk. This was because for most of the pharmacology data, the amount of current block measured was <60%, preventing reliable estimation of IC50-values. The results of this study demonstrate that the accuracy of TdP risk prediction depends both on the intrinsic variability in ion channel pharmacology data as well as on experimental design considerations that preclude an accurate determination of drug IC50-values in vitro. Thus, we demonstrate that UQ provides valuable information about in silico modeling predictions that can inform future proarrhythmic risk evaluation of drugs under the CiPA paradigm.

Corrigendum: Optimization of an In silico Cardiac Cell Model for Proarrhythmia Risk Assessment.

[This corrects the article on p. 616 in vol. 8, PMID: 28878692.].

Risk assessment models for genetic risk predictors of lung cancer using two-stage replication for Asian and European populations.

In the past ten years, great successes have been accumulated by taking advantage of both candidate-gene studies and genome-wide association studies. However, limited studies were available to systematically evaluate the genetic effects for lung cancer risk with large-scale and different ethnic populations. We systematically reviewed relevant literatures and filtered out 241 important genetic variants identified in 124 articles. A two-stage case-control study within specific subgroups was performed to assess the effects [Training set: 2,331 cases vs. 3,077 controls (Chinese population); testing set: 1,937 cases vs. 1,984 controls (European population)]. Variable selection and model development were used LASSO penalized regression and genetic risk score (GRS) system. Further change in area under the receiver operator characteristic curves (AUC) made by the epidemiologic model with and without GRS was used to compare predictions. It kept 38 genetic variants in our study and the ratios of lung cancer risk for subjects in the upper quartile GRS was three times higher compared to that in the low quartile (odds ratio: 4.64, 95% CI: 3.87-5.56). In addition, we found that adding genetic predictors to smoking risk factor-only model improved lung cancer predictive value greatly: AUC, 0.610 versus 0.697 (P < 0.001). Similar performance was derived in European population and the combined two data sets. Our findings suggested that genetic predictors could improve the predictive ability of risk model for lung cancer and highlighted the application among different populations, indicating that the lung cancer risk assessment model will be a promising tool for high risk population screening and prediction.

Optimization of an In silico Cardiac Cell Model for Proarrhythmia Risk Assessment.

Drug-induced Torsade-de-Pointes (TdP) has been responsible for the withdrawal of many drugs from the market and is therefore of major concern to global regulatory agencies and the pharmaceutical industry. The Comprehensive in vitro Proarrhythmia Assay (CiPA) was proposed to improve prediction of TdP risk, using in silico models and in vitro multi-channel pharmacology data as integral parts of this initiative. Previously, we reported that combining dynamic interactions between drugs and the rapid delayed rectifier potassium current (IKr) with multi-channel pharmacology is important for TdP risk classification, and we modified the original O'Hara Rudy ventricular cell mathematical model to include a Markov model of IKr to represent dynamic drug-IKr interactions (IKr-dynamic ORd model). We also developed a novel metric that could separate drugs with different TdP liabilities at high concentrations based on total electronic charge carried by the major inward ionic currents during the action potential. In this study, we further optimized the IKr-dynamic ORd model by refining model parameters using published human cardiomyocyte experimental data under control and drug block conditions. Using this optimized model and manual patch clamp data, we developed an updated version of the metric that quantifies the net electronic charge carried by major inward and outward ionic currents during the steady state action potential, which could classify the level of drug-induced TdP risk across a wide range of concentrations and pacing rates. We also established a framework to quantitatively evaluate a system's robustness against the induction of early afterdepolarizations (EADs), and demonstrated that the new metric is correlated with the cell's robustness to the pro-EAD perturbation of IKr conductance reduction. In summary, in this work we present an optimized model that is more consistent with experimental data, an improved metric that can classify drugs at concentrations both near and higher than clinical exposure, and a physiological framework to check the relationship between a metric and EAD. These findings provide a solid foundation for using in silico models for the regulatory assessment of TdP risk under the CiPA paradigm.

Improving the In Silico Assessment of Proarrhythmia Risk by Combining hERG (Human Ether-à-go-go-Related Gene) Channel-Drug Binding Kinetics and Multichannel Pharmacology.

BACKGROUND: The current proarrhythmia safety testing paradigm, although highly efficient in preventing new torsadogenic drugs from entering the market, has important limitations that can restrict the development and use of valuable new therapeutics. The CiPA (Comprehensive in vitro Proarrhythmia Assay) proposes to overcome these limitations by evaluating drug effects on multiple cardiac ion channels in vitro and using these data in a predictive in silico model of the adult human ventricular myocyte. A set of drugs with known clinical torsade de pointes risk was selected to develop and calibrate the in silico model. METHODS AND RESULTS: Manual patch-clamp data assessing drug effects on expressed cardiac ion channels were integrated into the O'Hara-Rudy myocyte model modified to include dynamic drug-hERG channel (human Ether-à-go-go-Related Gene) interactions. Together with multichannel pharmacology data, this model predicts that compounds with high torsadogenic risk are more likely to be trapped within the hERG channel and show stronger reverse use dependency of action potential prolongation. Furthermore, drug-induced changes in the amount of electronic charge carried by the late sodium and L-type calcium currents was evaluated as a potential metric for assigning torsadogenic risk. CONCLUSIONS: Modeling dynamic drug-hERG channel interactions and multi-ion channel pharmacology improves the prediction of torsadogenic risk. With further development, these methods have the potential to improve the regulatory assessment of drug safety models under the CiPA paradigm.

Latent classes of resilience and psychological response among only-child loss parents in China.

Only-child loss parents in China recently gained extensive attention as a newly defined social group. Resilience could be a probable solution out of the psychological dilemma. Using a sample of 185 only-child loss people, this study employed latent class analysis (a) to explore whether different classes of resilience could be identified, (b) to determine socio-demographic characteristics of each class, and (c) to compare the depression and the subjective well-being of each class. The results supported a three-class solution, defined as 'high tenacity-strength but moderate optimism class', 'moderate resilience but low self-efficacy class' and 'low tenacity but moderate adaption-dependence class'. Parents with low income and medical insurance of low reimbursement type and without endowment insurance occupied more proportions in the latter two classes. The latter two classes also had a significant higher depression scores and lower subjective well-being scores than high tenacity-strength but moderate optimism class. Future work should care those socio-economically vulnerable bereaved parents, and an elastic economic assistance policy was needed. To develop targeted resilience interventions, the emphasis of high tenacity-strength but moderate optimism class should be the optimism. Moderate resilience but low self-efficacy class should be self-efficacy, and low tenacity but moderate adaption-dependence class should be tenacity.

A temperature-dependent in silico model of the human ether-à-go-go-related (hERG) gene channel.

INTRODUCTION: Current regulatory guidelines for assessing the risk of QT prolongation include in vitro assays assessing drug effects on the human ether-à-go-go-related (hERG; also known as Kv11.1) channel expressed in cell lines. These assays are typically conducted at room temperature to promote the ease and stability of recording hERG currents. However, the new Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm proposes to use an in silico model of the human ventricular myocyte to assess risk, requiring as input hERG channel pharmacology data obtained at physiological temperatures. To accommodate current industry safety pharmacology practices for measuring hERG channel activity, an in silico model of hERG channel that allows for the extrapolation of hERG assay data across different temperatures is desired. Because temperature may have an effect on both channel gating and drug binding rate, such models may need to have two components: a base model dealing with temperature-dependent gating changes without drug, and a pharmacodynamic component simulating temperature-dependent drug binding kinetics. As a first step, a base mode that can capture temperature effects on hERG channel gating without drug is needed. METHODS AND RESULTS: To meet this need for a temperature-dependent base model, a Markov model of the hERG channel with state transition rates explicitly dependent on temperature was developed and calibrated using data from a variety of published experiments conducted over a range of temperatures. The model was able to reproduce observed temperature-dependent changes in key channel gating properties and also to predict the results obtained in independent sets of new experiments. DISCUSSION: This new temperature-sensitive model of hERG gating represents an attempt to improve the predictivity of safety pharmacology testing by enabling the translation of room temperature hERG assay data to more physiological conditions. With further development, this model can be incorporated into the CiPA paradigm and also be used as a tool for developing insights into the thermodynamics of hERG channel gating mechanisms and the temperature-dependence of hERG channel block by drugs.

Self-control and parental control mediate the relationship between negative emotions and emotional eating among adolescents.

OBJECTIVES: The study was conducted to simultaneously investigate the mediating effects of parental control and adolescents' self-control on the relationship between adolescents' negative emotions and emotional eating, and to determine pathways with the greatest effect among these variables. METHODS: Negative emotions, emotional eating, parental control, and self-control were investigated in 594 high school students (average age=16.70, SD=1.09) in Changsha City, China. RESULTS: High levels of negative emotions and parental control and low levels of self-control were strongly related to high levels of emotional eating in adolescents. In addition to the direct relationship between negative emotions and emotional eating, there was a mediating effect observed through low self-control and high parental control. The mediational effect of parental control was non-significant in adolescent boys. Furthermore, negative emotions related to emotional eating through the effect of parental control on adolescents' self-control. The degree to which both mediators explained the relationship between negative emotions and emotional eating ranged from 52.6% to 66.8%, and self-control had a stronger mediational effect than did parental control. CONCLUSION: The results indicate that both self-control and parental control should be considered in designing preventative measures against emotional eating in adolescents. Adolescent self-control training could also assist in preventing emotional eating.

[The burden caused by injury in countryside residents in Dongying, Shandong Province].

OBJECTIVE: To make clear the burden of injury in residents living in countryside of Dongying, Shandong Province. METHODS: A retrospective questionnaire survey was conducted among 15,276 residents in 20 villages of Dongying Municipality of Shandong Province with a multiphase cluster randomly sampling on cases of injury from March 1, 2002 to February 28, 2003. The injury was decided with three principles which had been carried out through the nation. The standardized incidence and mortality rates were calculated on base of the population data of Shandong Province in 2000. The burden of injury was evaluated by incidence rate, mortality rate, years of potential life lost (YPLL) system, disability adjusted life year (DALY), direct and indirect economic costs, et al. RESULTS: Totally 902 were injured cases in which the crude incidence rate was 5.90%, and the standardized incidence rate was 5.93%. It was shown higher in men (7.79%) than in women (4.03%). The crude death rate was 12.438 per million. And the standardized death rate was 11.257 per million. 27 cases were crippled. The years, the working years and the valued years of the potential life lost were 24, 19.6 and 8.7 years respectively for each death case. Disability adjusted life years was 566.61 years. Direct economic cost for medical expenses of all cases was 816.3 thousand RMB Yuan and 200.1 thousand RMB Yuan for else costs. Indirect economic cost was 5,492.9 thousand RMB Yuan according to DALY. CONCLUSION: Injury was common incidence in rural residents in Dongying which caused a heavy burden on them. Prevention and control of injuries would be enhanced.

[A cross-sectional study on injuries in residents from the countryside of Huanghe Delta rural areas].

OBJECTIVE: To study the incidence of injuries among residents living in the countryside of Huanghe delta area. METHODS: A household questionnaire survey was conducted to 15 276 residents in 20 villages of Dongying municipality of Shandong province with a stratified-cluster sampling on their injuries from March 1, 2002 to February 28, 2003. Data were analyzed with Excel 2000 and SPSS 11.0 software. RESULTS: The crude incidence of injuries was 5.90% in total, and the standardized incidence was 5.93%. It was higher in men (7.79%) than in women (4.03%). There were 19 deaths with 20 cripples. The standardized death rate was 122.56 per 100 000 with leading causes of injuries was blunt or by sharp articles (24.61%), traffic accident (24.17%), falls (22.62%) and animal bites (13.08%). Peak incidence of age group was high in 25 - 54 age group and 0 - 4 age group (> 6.0%). 267 cases (29.60%) inpatients had had about 15.89 days hospitalization for each case. Rest of each case with injury had 19.20 days of rest. Direct economic loss for treatment would cost 904.85 RMB Yuan and 10.15 days with care takers and 221.88 RMB for other cost. The potential years of life lost was 24 years, the working years of life lost was 19.6 year, the valued years of life lost was 8.7 year, and the standardized period expected years of life lost was 31.73 year. CONCLUSION: Injury was common and frequently occurred among residents in the countryside of rural Huanghe delta areas, that seriously endangered the health care systems and burden on families.