Serum retinol binding protein as a novel marker for clearance and dosage optimization: pharmacokinetics study of voriconazole in a cirrhosis population

Background and ObjectiveVoriconazole (VRC) exhibits nonlinear pharmacokinetic (PK) characteristics and a narrow therapeutic window. Consequently, standardized dosage regimens are insufficient to achieve the targeted therapeutic exposure in patients with cirrhosis. While numerous population pharmacokinetic (PPK) studies on VRC have been conducted, data on the cirrhosis demographic remain limited.This study aimed to explore the PK characteristics of VRC and its covariates in a cirrhosis population, with the objective of recommending individualized dosing regimens.MethodsData collected from routine therapeutic drug monitoring (TDM) of patients with recorded VRC plasma concentrations during a period of therapy between September 2022 and August 2024 were included. A population pharmacokinetic (PPK) model was constructed using nonlinear mixed-effects modeling (NONMEM). Monte Carlo simulation was used to predict the target trough concentrations of VRC under steady-state conditions based on the final model parameters, thereby facilitating tailored dosage recommendations.ResultsA total of 151 trough concentrations were obtained from 78 patients enrolled in the PPK study of VRC. A one-compartment model featuring first-order absorption and first-order elimination was optimal in describing the PK characteristics, additionally incorporating Child-Pugh grades and retinol-binding protein (RBP) as covariates affecting the central ventricular clearance rate (CL) of VRC. In the final model, the CL was determined as 6.96 L/h. For patients classified as Child-Pugh A and B with RBP ≥25 mg/L, the recommended dosages were 400 mg/d and 200 mg/d, respectively. At RBP levels <25 mg/L, the recommended dosages for Child-Pugh A and C patients were 200 mg/d and 100 mg/d, respectively, while for Child-Pugh B patients, both 200 mg/d and 100 mg/d were recommended.ConclusionOur results support the utility of RBP as a novel marker associated with VRC clearance. This biomarker may offer a practical option for VRC dosage optimization. The clinical dosage of VRC could be tailored according to the Child-Pugh grades and RBP levels of patients. While numerous unexplained factors potentially influence the pharmacokinetic properties of VRC, the application of PPK model-guided TDM is crucial for achieving precision in individualized medication regimens

Effective microorganisms input efficiently improves the vegetation and microbial community of degraded alpine grassland

Soil beneficial microorganism deficiency in the degraded grasslands have emerged as the major factors negatively impacting soil quality and vegetation productivity. EM (effective microorganisms) has been regarded as a good ameliorant in improving microbial communities and restoring degraded soil of agricultural systems. However, knowledge was inadequate regarding the effects of adding EM on the degraded alpine grassland. Four levels of EM addition (0, 150, 200, 250 mL m–2) were conducted to investigate the effects of EM addition on soil properties and microorganisms of degraded alpine grassland. The addition of EM increased aboveground biomass, soil organic carbon, total nitrogen, available phosphorus, and microbial biomass, but decreased soil electric conductivity. Meanwhile, the relative biomasses of gram-negative bacteria decreased, while the ectomycorrhizal fungi and arbuscular mycorrhizal fungi increased after EM addition. The relationship between microbial communities and environmental factors has been changed. The restore effect of EM increased with the increase of addition time. These results indicated that EM addition could be a good practice to restore the health of the degraded alpine grassland ecosystem

Influence of a groove-structured vortex generator on the drag reduction characteristics of a multiphase pump

The oil–gas mixture pump significantly contributes to marginal oil field extraction and remote transportation of deep-sea oil. Nevertheless, during the operation of the mixture pump, it is inevitable to encounter problems like the separation of the mixed media from the hydraulic components as well as the gas phase from the liquid phase, which leads to enhancing the flow resistance of the mixed media. Therefore, this study investigates the influence of a groove-structure vortex generator on the drag reduction characteristics of a helical axial-flow gas–liquid multiphase pump under the design flow rate condition and various inlet gas content rates. The findings show that the vortex generator with diverse groove depths can prevent the separation of the mixed media from the blade suction surface effectively and minimize the flow resistance of the media in the 1/10 of the blade inlet. In particular, excellent drag reduction results were gained with a maximum drag reduction rate of 36.7% when the relative depth was 3/40. In addition, the efficiency of the mixture pump increased by a maximum of 2.1%, and the head increased by a maximum of 4.3%. The significance of this study lies in its potential to further optimize the design and performance of gas–liquid multiphase pumps. It provides new insights into the design and application of vortex generators. It offers robust support for the optimization and enhancement of gas–liquid multiphase pumps

Hepatic dysfunction events associated with voriconazole: a real-world study from FDA adverse event reporting system (FAERS) database

Aims: Although voriconazole-induced hepatotoxicity has been reported previously, the direct cause-effect relationship in the real world remains to be established. The aim of this study was to investigate the association between voriconazole and hepatic dysfunction based on the FAERS database. Methods: Data from January 2004 to March 2022 in FAERS were retrieved. We estimate the association between the hepatic dysfunction and voriconazole using reporting odds ratios (RORs) for mining the adverse event report signals and compare voriconazole with the full database and other antifungal drugs. Results: 646 reports of hepatic dysfunction related to voriconazole as the primary suspect drug were collected totally. The median time to event of the hepatic dysfunction events was 8 (interquartile range [IQR] 2-28) days. 62.20% hepatic-related adverse events appeared within the first 15 days since the initiation of voriconazole administration. The overall ROR (95% CI) for hepatic-related adverse events was 6.82 (95% CI 6.26-7.42). Comparing to other antifungal drugs, the RORs for hepatic-related adverse events of fluconazole, isavuconazole and amphotericin B were 2.19 (95% CI 1.94-2.47), 2.31 (95% CI 1.66-3.33) and 1.26 (95% CI 1.08-1.48), respectively. Conclusions: We observed strong signals of higher frequency of reporting hepatic dysfunction events associated with voriconazole in the events of hepatic dysfunction. Since the risk of developing liver injury and possible hepatic dysfunction by voriconazole depends on several factors including underlying hepatic disease, close clinical and laboratory monitoring, including therapeutic drug monitoring (TDM), are essential to prevent or promptly recognize further deterioration of the hepatic function.</jats:p

Parameter identification for Hammerstein nonlinear systems using the maximum likelihood principle and Levenberg-Marquardt optimization method

This paper studies the parameter estimation problems of Hammerstein output error autoregressive (OEAR) systems. A maximum likelihood Levenberg-Marquardt recursive (ML-LM-R) algorithm using the varying interval input-output data is presented by using the maximum likelihood principle and Levenberg-Marquardt optimization method. The effectiveness of the algorithm is verified by a numerical example