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In this paper, we used CALYPSO program which is conjuncted with DFT to investigate Li doped small-sized neutral Bn clusters. From ground-state and low energy structures, the properties and geometric significance of Li-doped boron clusters are greatly affected. Except for LiB9, which adds a B atom on preceding LiB8 boron wheel, the ground-state clusters of LiBn are formed by replacing the terminal boron atom of the Bn+1 clusters in the same size with a Li atom or by adding a Li atom to the Bn clusters. The transition point from 2 to 3D configuration of LiBn clusters appears at n = 5. The stability of LiBn clusters was analyzed by calculating the average binding energy, Gibbs free energy, first-order differential energy, second-order differential energy, HOMO–LUMO gap (the energy gap between the highest occupied and lowest unoccupied molecular orbital) and charge transfer. The results show that the LiB11 cluster with excellent symmetry and planar structure is the relative most stable structure. Molecular orbital and chemical bonding analysis indicated that the main reason for the stability of the LiB11 cluster is mainly due to the strong s-p bonding of B–B. [ABSTRACT FROM AUTHOR]

In this study, the unbiased crystal structure analysis by particle swarm optimisation (CALYPSO) combined with the density functional theory (DFT) method were used to perform a structure search for neutral Cs2Bn (n = 1–12) clusters, as well as the corresponding global minimum of the potential energy surface were determined. The ground-state structures of the Cs2Bn (n = 1–12) clusters have four types of geometries: planar, arch bridge, double pyramid, and shield shape. Subsequently, the relative stability of the ground-state structures was systematically analysed based on three effective rules, which indicates that the C7V Cs2B8 with a double pyramid structure has unusual stability. The results of the molecular orbitals (MOs) and density of states analysis (DOS) show that the B-2s and 2p atomic orbitals of Cs2B8 are the main components of MOs. In addition, from the results of adaptive natural density partitioning (AdNDP) and localised orbital locator (LOL), it can be seen that the excellent stability of Cs2B8 originates from the delocalised large π bonds with aromaticity and the s–p bonding of B–B. Our results reveal the structural growth mode of Cs2Bn clusters and enrich the chemical bonding properties of boron-based clusters. [ABSTRACT FROM AUTHOR]

• We predicted the acute toxicity of organophosphates based on chemical structure. • Large data were collected to develop quantitative structure-toxicity relationship models. • The random forest algorithm was used to develop these models. • Acute toxicity data from different administration routes could not be combined. • QSTR models achieve high predictive performance despite large variance in datasets. Organophosphates (OPs) are highly toxic compounds, with widespread application in agricultural and chemical industries, whose introduction into the environment poses serious hazards to humans and ecological systems. To assess and ultimately mitigate these hazards, this study predicted the acute toxicity of OPs according to their chemical structure and administration route. The acute toxicity data of 161 OPs in two species via six different administration routes were manually collected and used to develop a series of quantitative structure–toxicity relationship (QSTR) models with robust and practical predictive abilities. The random forest algorithm was used to develop the models, employing both quantum chemical and two-dimensional descriptors according to OECD guidelines. Correlation results and feature similarities indicated that whereas acute toxicity data from rats and mice via the same administration route were combinable for modeling, data from different routes were not. Six QSTR models for each route in a single species and two QSTR models for a single route in the two species were constructed, achieving practical predictive performance. Despite significant variances in their datasets, the prediction models could predict the acute toxicity of novel or unknown OPs, realize rapid assessment, and provide guidance for regulatory decisions to reduce the hazards of OPs. [ABSTRACT FROM AUTHOR]

Objectives: Several population pharmacokinetics (popPK) models for polymyxin B have been constructed to optimize therapeutic regimens. However, their predictive performance remains unclear when extrapolated to different clinical centers. Therefore, this study aimed to evaluate the predictive ability of polymyxin B popPK models. Methods: A literature search was conducted, and the predictive performance was determined for each selected model using an independent dataset of 20 patients (92 concentrations) from the Third Xiangya Hospital. Prediction- and simulation-based diagnostics were used to evaluate model predictability. The influence of prior information was assessed using Bayesian forecasting. Results: Eight published studies were evaluated. In prediction-based diagnostics, the prediction error within ± 30% was over 50% in two models. In simulation-based diagnostics, the prediction- and variability-corrected visual predictive check (pvcVPC) showed satisfactory predictivity in three models, while the normalized prediction distribution error (NPDE) tests indicated model misspecification in all models. Bayesian forecasting demonstrated a substantially improvement in the model predictability even with one prior observation. Conclusion: Not all published models were satisfactory in prediction- and simulation-based diagnostics; however, Bayesian forecasting improved the predictability considerably with priors, which can be applied to guide polymyxin B dosing recommendations and adjustments for clinicians. [ABSTRACT FROM AUTHOR]

Delayed or missed doses are unavoidable in the pharmacotherapy of epilepsy and significantly compromise the efficacy of antiepileptic drug treatment. An inappropriate remedial regimen can cause seizure relapse or serious adverse events. This study investigated the effect of delayed or missed doses on the pharmacokinetics (PK) of valproic acid (VPA) in patients with epilepsy and established remedial dosing recommendations for nonadherent patients. Monte Carlo simulations are based on all previous population pharmacokinetic models for pediatric, adult and elderly patients with epilepsy. The following four remedial strategies were investigated for each delayed dose: A) A partial dose or a regular dose is taken immediately; a regular dose is taken at the next scheduled time. B) The delayed dose was administered immediately, followed by a partial dose at the next scheduled time. C) The delayed dose and a partial dose are taken; the next scheduled time is skipped, and the regular regimen is resumed. D) Double doses are taken when missed one dose or two doses, and the regular regimen at the subsequent scheduled time is resumed. The recommended remedial dose was related to the delay duration and daily dose. Remedial dosing strategies A and B were almost equivalent, whereas Strategy C was recommended when the delayed dose was close to the next scheduled dose. Strategy D was only suggested for delayed two doses. Simulations provide quantitative insight into the remedial regimens for nonadherent patients, and clinicians should select the optimal regimen for each patient based on the individual's status. Unlabelled Image • Monte Carlo simulation based on population pharmacokinetics is used in the development of remedial dosing recommendation. • Optimal remedial regimen is mainly related to delay duration and daily dose. • Four remedial approaches are proposed and clinicians could select the regimen according to the patient status. [ABSTRACT FROM AUTHOR]

This study investigated the effect of delayed or missed doses on the pharmacokinetics (PK) of lamotrigine (LTG) in children with epilepsy and established remedial dosing recommendations for nonadherent patients. The Monte Carlo simulation based on a published LTG population PK model was used to assess the effect of different scenarios of nonadherence and the subsequently administered remedial regimens. The following three remedial approaches were investigated for each delayed dose: A) A partial dose was administered immediately, and the regular dose was administered at the next scheduled time. B) The delayed dose was administered immediately, followed by a partial dose at the next scheduled time. C) The delayed and partial doses were coadministered immediately, the next scheduled dose was skipped, and the regular dosing was resumed at the subsequent scheduled time. The most appropriate remedial regimen was that with the shortest deviation time from the individual therapeutic window. The effect of nonadherence on PK was dependent on the delay duration and daily dose, and the recommended remedial dose was related to the delay duration and concomitant antiepileptic drugs. Remedial dosing strategies A and B were almost equivalent, whereas C showed a larger PK deviation time. If one dose was missed, double doses were not recommended for the next scheduled time. Simulations provide quantitative insight into the remedial regimens for nonadherent patients, and clinicians should select the optimal regimen based on the status of patients. Three remedial strategies identified for a 12-year-old and 40-kg patient administered lamotrigine on 125 mg q12h regimen without an inducer or inhibitor when dose was delayed by 10 h. The dark pink shadow represents the distribution of the 5th–95th percentiles of the simulated concentrations in 90% of the virtual subjects, and the light pink shadows represent the distribution of the simulated concentrations outside the 5th–95th percentiles in the remaining 10% virtual subjects. Red solid line represents median of the simulated concentrations and dotted lines represent 0.5th and 99.5th percentiles of the simulated concentrations, respectively. Black dotted lines represent the individual therapeutic range (2.4–16.8 mg/L). Black solid line represents the deviation time. Unlabelled Image • Monte Carlo simulation was used to develop remedial regimens of nonadherence. • The remedial regimens were dependent on the delayed time and comedications. • Clinicians could select the optimal remedial strategy for individual patients. [ABSTRACT FROM AUTHOR]

Purpose: Numerous studies have been conducted on the population pharmacokinetics of tacrolimus in adult renal transplant recipients. It has been reported that the cytochrome P450 (CYP) 3A5 genotype is an important cause of variability in tacrolimus pharmacokinetics. However, the predictive performance of population pharmacokinetic (PK) models of tacrolimus should be evaluated prior to their implementation in clinical practice. The aim of the study reported here was to test the predictive performance of these published PK models of tacrolimus.Methods: A literature search of the PubMed and Web of Science databases ultimately led to the inclusion of eight one-compartment models in our analysis. We collected a total of 1715 trough concentrations from 174 patients. Predictive performance was assessed based on visual and numerical comparison bias and imprecision and by the use of simulation-based diagnostics and Bayesian forecasting.Results: Of the eight one-compartment models assessed, seven showed better predictive performance in CYP3A5 extensive metabolizers in terms of bias and imprecision. Results of the simulation-based diagnostics also supported the findings. The model based on a Chinese population in 2013 (model 3) showed the best and most stable predictive performance in all the tests and was more informative in CYP3A5 extensive metabolizers. As expected, Bayesian forecasting improved model predictability. Diversity among models and between different CYP3A5 genotypes of the same model was also narrowed by Bayesian forecasting.Conclusions: Based on our results, we recommend using model 3 in CYP3A5 extensive metabolizers in clinical practice. All models had a poor predictive performance in CYP3A5 poor metabolizers, and they should be used with caution in this patient population. However, Bayesian forecasting improved the predictability and reduced differences, and thus the models could be applied in this latter patient population for the design of maintenance dose. [ABSTRACT FROM AUTHOR]

To understand the effects of Cs on pure boron clusters, the growth mode, electronic properties, and bonding characteristics of CsB n 0/− (n = 2–12) clusters were discussed by CALYPSO combined with DFT method. Photoelectron spectra of the ground-state structures are reliable and efficient based on the accurate structure search method, which can provide theoretical information for future related studies. Through the study of the three valid criteria, we conclude that the CsB 8 and CsB 8 − with point group symmetry C 7V have outstanding stability and electronic properties. The orbital composition analysis indicates that the molecular orbitals of these two clusters are mainly composed of B-2 s and B-2 p atomic orbitals (AOs), and there is a strong interaction between these two AOs. Furthermore, we also found that the high stability of CsB 8 and CsB 8 − clusters mainly originates from the s - p bonding, σ and π bonds of B–B, especially the CsB 8 − cluster has (σ+π) double aromaticity. • The evolution of the structures for CsB n (n = 2-12) clusters has be elucidated. • The corresponding ground state structures are determined. • It is found that the most stable isomer is a double pyramid structure with double aromaticity. • The molecular orbitals and bonding characteristics of the most stable structure are discussed by various methods. [ABSTRACT FROM AUTHOR]

[Display omitted] • This study used sesquiterpenoids with 97 carbon skeletons for model construction. • The scheme based on the DFT method combined with triple correction can accurately calculate Δ c H of sesquiterpenoid HEDFs. • We developed the MLR equation with only 4 features for predicting Δ c H for sesquiterpenoid HEDFs. • The proposed DFT-QSPR scheme can effectively guide the design of novel sesquiterpenoid HDEFs. Sesquiterpenoids that are renewable and have high energy density and low freezing point are promising biomass high-energy–density fuels (HEDFs). The enthalpy of combustion (Δ c H) is the key characteristic to measure the heat energy content of HEDFs. Its accurate theoretical prediction and evaluation is essential for designing novel sesquiterpenoid HEDFs. Combining the screened and optimized density functional theory (DFT) method with triple computational correction, we presented a standardized calculation scheme for Δ c H with an average absolute error of only 2.6 % by 295 structurally diverse sesquiterpenoid HEDFs. Then, the extreme gradient boosting (XGBoost) algorithm was used to determine the correlation between the calculated Δ c H and 54 quantum chemical (QC) descriptors and the shapley additive explanation (SHAP) method to elucidate the key factors affecting Δ c H. Lastly, a quantitative structure–property relationship (QSPR) prediction model with only four QC features was constructed by using the SHAP results via the multiple linear regression (MLR) algorithms. Notably, the model has excellent prediction performance, decreased complexity, and improved applicability. The coefficient of determination (R 2) of the internal training set and external test set of the model are 0.957 and 0.956, while the root mean square error (RMSE) are 8.626 kcal/mol and 9.012 kcal/mol, respectively. The proposed DFT-QSPR (the ingenious combination of DFT and QSPR) scheme can effectively guide the design of Δ c H of novel sesquiterpenoid HDEFs. [ABSTRACT FROM AUTHOR]

Background and Objectives:Several studies have suggested a difference in clinical features of intellectual ability and psychiatric illness in the Prader–Willi syndrome (PWS) with the 15q11-q13 paternal deletion and maternal uniparental disomy (mUPD). Our objective was to appraise evidence on this association through a meta-analysis. Methods:The electronic records PubMed and EMBASE from 1956 to 2012 were extracted for meta-analysis. Meta-analyses were performed by using fixed effect model. Mean difference, odds ratio, and 95% confidence interval were calculated. Results:We retrieved a total of 744 PWS cases from 13 studies. These include 423 cases with paternal 15q11-q13 deletions and 318 cases of mUPD. Compare to the PWS cases with mUPD, PWS patients with the paternal 15q11-q13 deletion associated with significantly lower full scale IQ (FSIQ) [mean difference (MD), -2.69; 95%CI, -4.86 to -0.52; p=0.02] and verbal IQ (VIQ) (MD, -7.5; 95%CI, -9.75 to -5.26; p<0.00001) but higher performance IQ (PIQ) (MD, 4.02; 95%CI, 1.13 to 6.91; p=0.006). In contrast, PWS patients with mUPD are associated with significantly higher risk of psychiatric illness [odds rate (OR), 0.14; 95%CI, 0.08 to 0.23; p<0.00001] and higher risk of bipolar disorder (OR, 0.04; 95%CI, 0.01 to 0.23; p=0.0002). Conclusions:Significant different clinical features of cognitive development and psychiatric illness are associated with PWS with different molecular defects. These findings provide support for evidence based practice to evaluate and manage the PWS syndrome with different molecular defects. [ABSTRACT FROM AUTHOR]

Tacrolimus is used clinically for the long-term treatment of antirejection of transplanted organs in liver and kidney transplant recipients, although dose optimization is poorly managed. The aim of this study was to examine the association between tacrolimus pharmacokinetic variability and CYP3A4 and CYP3A5 genotypes by a population pharmacokinetic analysis based on routine drug monitoring data in adult renal transplant recipients.Trough tacrolimus concentrations were obtained from 161 adult kidney transplant recipients after transplantation. The population pharmacokinetic analysis was carried out using the nonlinear mixed-effect modeling software NONMEM version 7.2. The CYP3A4∗1G and CYP3A5∗3 genetic polymorphisms from the patients studied were determined by direct sequencing using a validated automated genetic analyzer.A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. Covariates including CYP3A5∗3 and CYP3A4∗1G alleles and hematocrit were retained in the final model. The apparent clearance of tacrolimus was about two-fold higher in kidney transplant patients with higher enzymatic activity of CYP3A5∗1 and CYP3A4∗1G (with the CYP3A5∗1/∗1 or ∗1/∗3 and CYP3A4∗1/∗1G or CYP3A4∗1G/∗1G) compared with those with lower enzymatic activity (CYP3A5∗3/∗3 and CYP3A4∗1/∗1).This is the first study to extensively determine the effect of CYP3A4∗1G and CYP3A5∗3 genetic polymorphisms and hematocrit value on tacrolimus pharmacokinetics in Chinese renal transplant recipients. The findings suggest that CYP3A5∗3 and CYP3A4∗1G polymorphisms and hematocrit are determinant factors in the apparent clearance of tacrolimus. The initial dose design is mainly based on CYP3A5 and CYP3A4 genotypes as well as hematocrit. This result may also be useful for maintenance tacrolimus dose optimization and may help to avoid fluctuating tacrolimus levels and improve the efficacy and tolerability of tacrolimus in kidney transplant recipients. [ABSTRACT FROM AUTHOR]