Contribution of Cytochrome P450 and ABCB1 Genetic Variability on Methadone Pharmacokinetics, Dose Requirements, and Response

Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements

Detailed Analysis of a Contiguous 22-Mb Region of the Maize Genome

Most of our understanding of plant genome structure and evolution has come from the careful annotation of small (e.g., 100 kb) sequenced genomic regions or from automated annotation of complete genome sequences. Here, we sequenced and carefully annotated a contiguous 22 Mb region of maize chromosome 4 using an improved pseudomolecule for annotation. The sequence segment was comprehensively ordered, oriented, and confirmed using the maize optical map. Nearly 84% of the sequence is composed of transposable elements (TEs) that are mostly nested within each other, of which most families are low-copy. We identified 544 gene models using multiple levels of evidence, as well as five miRNA genes. Gene fragments, many captured by TEs, are prevalent within this region. Elimination of gene redundancy from a tetraploid maize ancestor that originated a few million years ago is responsible in this region for most disruptions of synteny with sorghum and rice. Consistent with other sub-genomic analyses in maize, small RNA mapping showed that many small RNAs match TEs and that most TEs match small RNAs. These results, performed on ∼1% of the maize genome, demonstrate the feasibility of refining the B73 RefGen_v1 genome assembly by incorporating optical map, high-resolution genetic map, and comparative genomic data sets. Such improvements, along with those of gene and repeat annotation, will serve to promote future functional genomic and phylogenomic research in maize and other grasses

Tehran Air Pollution Modeling Using Long-Short Term Memory Algorithm: An Uncertainty Analysis

Air pollution is a major environmental issue in urban areas, and accurate forecasting of particles 10 μm or smaller (PM10) level is essential for smart public health policies and environmental management in Tehran, Iran. In this study, we evaluated the performance and uncertainty of long short-term memory (LSTM) model, along with two spatial interpolation methods including ordinary kriging (OK) and inverse distance weighting (IDW) for mapping the forecasted daily air pollution in Tehran. We used root mean square error (RMSE) and mean square error (MSE) to evaluate the prediction power of the LSTM model. In addition, prediction intervals (PIs), and Mean and standard deviation (STD) were employed to assess the uncertainty of the process. For this research, the air pollution data in 19 Tehran air pollution monitoring stations and temperature, humidity, wind speed and direction as influential factors were taken into account. The results showed that the OK had better RMSE and STD in the test (32.48 ± 9.8 μg/m3) and predicted data (56.6 ± 13.3 μg/m3) compared with those of the IDW in the test (47.7 ± 22.43 μg/m3) and predicted set (62.18 ± 26.1 μg/m3). However, in PIs, IDW ([0, 0.7] μg/m3) compared with the OK ([0, 0.5] μg/m3) had better performance. The LSTM model achieved in the predicted values an RMSE of 8.6 μg/m3 and a standard deviation of 9.8 μg/m3 and PIs between [2.7 ± 4.8, 14.9 ± 15] μg/m3

Subjective and physiological responses among racemic-methadone maintenance patients in relation to relative (S)- vs. (R)-methadone exposure

The definitive version is available at www.blackwell-synergy.comAIMS: To investigate the possibility that (S)-methadone influences therapeutic and adverse responses to rac-methadone maintenance treatment, by examining how subjective and physiological responses among rac-methadone maintenance patients vary in relation to relative exposure to (S)- vs. (R)-methadone. METHODS: Mood states (Profile of Mood States), opioid withdrawal (Methadone Symptoms Checklist), physiological responses (pupil diameter, heart rate, respiration rate, blood pressure), and plasma concentrations (CP) of (R)- and (S)-methadone were measured concurrently 11–12 times over a 24-h interdosing interval in 55 methadone maintenance patients. Average steady-state plasma concentrations (Cav) and pharmacodynamic responses were calculated using area under the curve (AUC). Linear regression was used to determine whether variability in pharmacodynamic responses was accounted for by (S)-methadone Cav controlling for (R)-methadone Cav and rac-methadone dose. Ratios of (S)-:(R)-methadone using AUCCP and trough values were correlated with pharmacodynamic responses for all subjects and separately for those with daily rac-methadone doses ≥ 100 mg. RESULTS: (S)-methadone Cav accounted for significant variability in pharmacodynamic responses beyond that accounted for by (R)-methadone Cav and rac-methadone dose, showing positive associations (partial r) with the intensity of negative mood states such as Tension (0.28), Fatigue (0.31), Confusion (0.32), and opioid withdrawal scores (0.30); an opposite pattern of relationships was evident for (R)-methadone. The plasma (S)-:(R)-methadone AUCCP ratio (mean ± SD 1.05 ± 0.21, range 0.65–1.51) was not significantly related to pharmacodynamic responses for the subjects as a whole but showed significant positive associations (r) with the intensity of negative mood states such as Total Mood Disturbance (0.61), Tension (0.69), Fatigue (0.65), Confusion (0.64), Depression (0.49) and heart rate (0.59) for the ≥ 100-mg dose range. CONCLUSIONS: These findings agree with previous evidence that (S)-methadone is associated with a significant and potentially adverse profile of responses distinct from that of (R)-methadone. Individual variability in relative (S)- vs. (R)-methadone exposure may be associated with variability in response to rac-methadone maintenance treatment.Timothy B. Mitchell, Kyle R. Dyer, David Newcombe, Amy Salter, Andrew A. Somogyi, Felix Bochner and Jason M. Whit

Evaluating scenarios toward zero plastic pollution

Plastic pollution is a pervasive and growing problem. To estimate the effectiveness of interventions to reduce plastic pollution, we modeled stocks and flows of municipal solid waste and four sources of microplastics through the global plastic system for five scenarios between 2016 and 2040. Implementing all feasible interventions reduced plastic pollution by 40% from 2016 rates and 78% relative to “business as usual” in 2040. Even with immediate and concerted action, 710 million metric tons of plastic waste cumulatively entered aquatic and terrestrial ecosystems. To avoid a massive build-up of plastic in the environment, coordinated global action is urgently needed to reduce plastic consumption; increase rates of reuse, waste collection, and recycling; expand safe disposal systems; and accelerate innovation in the plastic value chain

Evaluating scenarios toward zero plastic pollution

Plastic pollution is a pervasive and growing problem. To estimate the effectiveness of interventions to reduce plastic pollution, we modeled stocks and flows of municipal solid waste and four sources of microplastics through the global plastic system for five scenarios between 2016 and 2040. Implementing all feasible interventions reduced plastic pollution by 40% from 2016 rates and 78% relative to “business as usual” in 2040. Even with immediate and concerted action, 710 million metric tons of plastic waste cumulatively entered aquatic and terrestrial ecosystems. To avoid a massive build-up of plastic in the environment, coordinated global action is urgently needed to reduce plastic consumption; increase rates of reuse, waste collection, and recycling; expand safe disposal systems; and accelerate innovation in the plastic value chain