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Objectives: This study aimed to investigate the pharmacokinetic characteristics of siponimod in healthy volunteers and patients with MS based on aggregated data from published clinical trials, and to explore the factors influencing siponimod exposure.Methods: A total of 476 siponimod plasma concentrations aggregated from 28 dosage groups (corresponding to 294 healthy volunteers and 207 patients with MS) were collected from published clinical trials. Population pharmacokinetic (PPK) analysis was performed using a nonlinear, mixed-effect modeling approach. The pharmacokinetic properties of siponimod in healthy volunteers and patients with MS were compared, and the influence of covariates on siponimod exposure was evaluated using both PPK analysis and noncompartmental analysis (NCA).Results: A one-compartment model with first-order absorption and elimination adequately described siponimod pharmacokinetics. The typical population parameter estimates of clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (ka) were 3.17 L/h, 112.70 L, and 0.38 h−1, respectively. An 11.85% lower siponimod clearance was estimated for patients with MS relative to healthy volunteers. Subgroup analyses using NCA assessments revealed that siponimod presented an accumulation index of approximately 2 after multiple administration. Compared with nonobese participants, obese participants had a relatively lower dose-corrected area under the concentration-time curve (AUC0-∞/D) (0.31 vs. 0.42 h/L) and V/F (120.95 vs. 133.75 L), and a relatively higher CL/F (3.25 vs. 3.21 L/h). Participants with CYP2C9*2/*3, *1/*3, and *3/*3 genotypes experienced an increased (1.3- and 3.4-fold, respectively) AUC0-∞/D and a decreased (0.7- and 0.3-fold, respectively) CL/F compared with those in participants with the CYP2C9*1/*1, *1*2, and *2*2 genotypes. Fluconazole combination led to a decrease in CL/F (approximately 0.5 times) and an increase in AUC0-∞/D (approximately 1.3 times).Conclusion: Siponimod pharmacokinetic properties in healthy volunteers and patients with MS were explored using complementary model-based meta-analysis (MBMA) and NCA approaches. A slightly lower siponimod clearance was observed in patients with MS than in healthy volunteers. The dosage regimen, body mass index, CYP2C9 genetic polymorphism and fluconazole combination may had influences on siponimod pharmacokinetics. Such model paves the road to more population-based analyses in different patient populations with MS to quantify the effect of any influencing factors on siponimod pharmacokinetics.

The enzyme turnover rate, |${k}_{cat}$|⁠ , quantifies enzyme kinetics by indicating the maximum efficiency of enzyme catalysis. Despite its importance, |${k}_{cat}$| values remain scarce in databases for most organisms, primarily because of the cost of experimental measurements. To predict |${k}_{cat}$| and account for its strong temperature dependence, DLTKcat was developed in this study and demonstrated superior performance (log10-scale root mean squared error = 0.88, R -squared = 0.66) than previously published models. Through two case studies, DLTKcat showed its ability to predict the effects of protein sequence mutations and temperature changes on |${k}_{cat}$| values. Although its quantitative accuracy is not high enough yet to model the responses of cellular metabolism to temperature changes, DLTKcat has the potential to eventually become a computational tool to describe the temperature dependence of biological systems. [ABSTRACT FROM AUTHOR]

A unique configuration based on internally integrated electrodes is proposed for flexible hybrid zinc-ion capacitor (HZIC) devices. An in-depth charge storage process is studied, confirming the high electrochemical promise of HZICs for future practical applications. [ABSTRACT FROM AUTHOR]

Introduction: Nonsteroidal anti‐inflammatory drugs (NSAIDs) are regarded as nephrotoxins. Children commonly use NSAIDs and are susceptible to nephropathy, but the relationship between acute kidney injury (AKI) and use of NSAIDs is not well examined yet. Objective: To evaluate the relationship between AKI and use of NSAIDs in hospitalized pediatric patients who are susceptible to nephropathy. Methods: We conducted this systematic review and meta‐analysis of observational studies by searching PubMed, Embase, and Cochrane Database for articles published up to June 1, 2020. Reports included involved children (age < 18 years) who used NSAIDs for various reasons and were admitted in the hospital. The main outcome measure was whether AKI occurred, and pooled odds ratio (OR) and 95% confidence intervals (CI) were calculated using generic inverse variance methods. Results: Seven studies reporting risk of AKI in the hospitalized pediatric patients receiving NSAIDs were included applying a random‐effects model. In the hospitalized pediatric population, the pooled OR of AKI for present NSAID exposure was 1.55 (95%CI 1.26–1.92). Conclusions: NSAID exposure was associated with an approximate 1.6‐fold rise in the odds of developing AKI in hospitalized pediatric patients. Avoidance, cautious use of NSAIDs and further evidence are needed. This study was registered with PROSPERO (identifier: CRD42021219779). [ABSTRACT FROM AUTHOR]