Volume Of Distribution Research Articles

Population Pharmacokinetics of Xeligekimab: An Anti-IL-17A Monoclonal Antibody, in Patients with Moderate to Severe Plaque Psoriasis.

Xeligekimab, a recombinant fully human IgG4 monoclonal antibody, has been strategically developed to target IL-17A and is presently in the developmental phase for treating moderate to severe plaque psoriasis. This study aims to investigate the pharmacokinetic profile of Xeligekimab, utilizing data derived from clinical trials specifically conducted in Chinese patients. The study conducted a population pharmacokinetic (PopPK) analysis involving 614 patients with plaque psoriasis. Examined covariates encompassed demographics, baseline laboratory tests, anti-drug antibodies (ADA), injection site, and disease-related baseline characteristics. Model evaluation utilized goodness-of-fit, prediction-corrected visual prediction check, and bootstrap methods. The clinical significance of covariates statistically associated with Xeligekimab was assessed through simulation analysis. The PopPK model of Xeligekimab demonstrated characteristics of a two-compartment model with first-order absorption and linear elimination. Inter-individual variability (IIV) was estimated for clearance and volume of distribution. For a typical plaque psoriasis patient, the estimated values for absorption rate constant (Ka), apparent clearance (CL/F), central compartment volume (Vc/F), peripheral compartment volume (Vp/F), and inter-compartmental clearance (Q/F) was 0.225 per day, 2.223 L/day, 4.02 L, 4.13 L, and 1.11 L/day, respectively. The estimated IIV for CL/F and Vc/F was 25.8% and 49.8%, respectively. The elimination half-life (t1/2) was approximately 28.5 days. CL/F was significantly influenced by factors such as body weight, age, gender, and baseline total protein. Vc/F was significantly influenced by body weight, age, gender, and baseline albumin. However, the clinical relevance of these covariate effects on exposure parameters was determined to be limited.

Disposition kinetics and bioavailability of doxycycline after parenteral administrations in ewes

Doxycycline is a tetracycline, which have been marketed in different species for treating infections caused by susceptible bacteria. There is limited information on the disposition kinetics of this drug in ewes and this antimicrobial may be useful against several sheep pathogens that are common causes of morbidity and economic loss. Therefore, the aim of this work was to establish the pharmacokinetics of doxycycline after intravenous (IV) and extravascular (subcutaneous (SC) and intramuscular (IM)) administrations in this species. A cross-over model was designed (n = 6). Doxycycline was dosed at 5 mg/kg for IV administration and 20 mg/kg for extravascular administrations. Non-compartmental pharmacokinetic methods were used to calculate plasma concentration-time data. The value of apparent volume of distribution (Vz) suggests a moderate distribution of this antibiotic in sheep, with a value of 0.84 L/kg. The maximum concentrations achieved after extravascular administrations (Cmax) were similar, with no significant differences between the two routes of administration (IM and SC). However, doxycycline absorption was slower after SC administration than after IM administration, taking twice as long to reach maximum plasma concentration (tmax). Bioavailabilities after extravascular routes of administration were low and after IM administration doxycycline caused lameness in all animals. Therefore, the SC administration showed a better profile with respect to pharmacokinetic properties and safety. Future studies on the susceptibility of isolated sheep pathogens to doxycycline are needed to establish appropriate dosing regimens.

Pharmacokinetics of Piperacillin-Tazobactam in Critically Ill Patients with Open Abdomen and Vacuum-Assisted Wound Closure: Dosing Considerations Using Monte Carlo Simulation.

Open abdomen with vacuum-assisted wound closure therapy (OA/VAC) is frequently used in critically ill patients although the impact of OA/VAC on antibiotics pharmacokinetics (PK) remains unknown. We thus aimed to characterize the PK of piperacillin-tazobactam (PTZ) in critically ill patients with OA/VAC and assess the optimal dosing regimens based on pharmacodynamics (PD) target attainment. Over a 15-month study period, 45 patients with OA/VAC treated with PTZ administered continuously and adapted to 24 h creatinine clearance (CLCR) underwent measurements of free concentrations in their plasma, urine, VAC exudate, and peritoneal fluid. Population PK modeling was performed considering the effect of covariates, and Monte Carlo simulations were employed to determine the probability of target attainment (PTA) for the PK/PD targets (100% fT > 16 mg/L) in the plasma and at the peritoneal site at steady state. Piperacillin concentrations were described using a two-compartment model, with age and total body weight as significant covariates for central volume of distribution (V1) and estimated renal function for clearance (CL). Tazobactam concentrations were described using a two-compartment model with estimated renal function as a significant covariate. The central volume of distributions V1 of piperacillin and tazobactam were 21.2 and 23.2 L, respectively. The VAC-induced peritoneal clearance was negligible compared to renal clearance. Most patients achieved the desirable PK/PD target when using a CLCR-pondered PTZ dosing regimen from 12 g/1.5 g/day to 20 g/2.5 g/day. Despite a wide inter-individual variability, the influence of OA/VAC on piperacillin and tazobactam PK parameters is not straightforward. The use of a CLCR-pondered PTZ dosing regimen from 12 g/1.5 g/day to 20 g/2.5 g/day is needed to reach a PTA > 85%.

Internal blood lead exposure levels in permanent residents of Jiangxi Province and its effects on routine hematological and biochemical indices.

Lead exposure levels are closely linked to human health and can cause damage to multiple organ systems, including the blood system and liver. However, due to insufficient evidence, the effects of lead exposure on hematological and biochemical indices have not been fully established. This study aims to explore the blood lead levels of permanent residents in Jiangxi Province and analyze the factors affecting blood lead levels and the impact of blood lead levels on hematological and biochemical indices. We conducted a cross-sectional study including questionnaires, health examinations, and blood sample examinations on 720 randomly selected permanent residents (3-79 years) in Jiangxi Province in 2018. The blood lead levels were measured using inductively coupled plasma mass spectrometry. Routine hematological and biochemical tests were determined by qualified medical institutions using automated hematology analyzers and biochemistry analyzers. The geometric mean of blood lead concentration in permanent residents of Jiangxi Province was 20.45 μg/L. Gender, age, annual household income, smoking, and hypertension were the influencing factors for blood lead levels. For each 1 μg/L increase in blood lead, the risks of elevated red blood cell count (from low to high), platelet volume distribution width, alkaline phosphatase (from low to high), and cholesterol increased by 2.4, 1.6, 3.6, and 2.3%, respectively, whereas the risks of elevation of direct bilirubin and total bilirubin both decreased by 1.7%. The blood lead level in permanent residents of Jiangxi Province is higher than the national average. Higher blood lead levels were found in men than in women; blood lead levels were positively correlated with age but negatively correlated with annual household income; smoking and hypertension are risk factors for elevated blood lead; and blood lead levels affect routine hematological and biochemical markers such as red blood cell count, platelet volume distribution width, direct bilirubin, total bilirubin, alkaline phosphatase, and cholesterol.

Numerical Simulation and Experimental Research of Spatial Volume Distribution and Velocity Changes of Abrasive Suspension Jet Based on LES + VOF + DEM

The machining accuracy and cutting ability of abrasive suspension jet (ASJ) are affected by the spatial volume distribution and velocity changes of jet flow and abrasives in the free jet area outside the nozzle. In this paper, large eddy simulation (LES) flow model, volume of fluid (VOF) multiphase flow model and discrete element model (DEM) were used to simulate the flow field characteristics of ASJ. The spatial volume distribution and velocity changes of jet flow and abrasives under 10[Formula: see text]MPa jet pressure were studied and the model validation experiments were carried out. In the comparison between the numerical simulation results and the experimental results, it was found that the average error of the percentage of central jet flow is 3.4%, the percentage of central abrasive particles is 3.0% and the velocity of abrasive particles is 4.2%. The physical structure of the numerical model is fixed (so it does not support abrasive injection jet (AIJ)), and the material physical parameters, initial conditions and boundary conditions are editable. Therefore, it can be used to predict the degree of water divergence, abrasives divergence and abrasives velocity attenuation of ASJ with different jet pressure and abrasive types. This numerical model can provide guidance for the parameter setting of ASJ machining process in order to obtain better machining accuracy and cutting ability.

Pharmacokinetics of methadone after intravenous and subcutaneous administration in domestic ferrets (Mustela putorius furo)

ObjectiveTo determine the pharmacokinetic profile of methadone after intravenous (IV) and subcutaneous (SC) administration in domestic ferrets (Mustela putorius furo). Study designCrossover experimental study. AnimalsA group of eight healthy adult ferrets weighing 1.01 ± 0.23 kg (mean ± standard deviation). MethodsMethadone hydrochloride (0.3 mg kg–1) was injected IV or SC to each ferret with a 3 week washout period. Blood samples were collected via a jugular catheter before and 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360 and 480 minutes after drug administration. Liquid chromatography–tandem mass spectrometry was used to determine plasma methadone concentrations. A nonlinear mixed effects model was used to analyze the data. ResultsAfter IV injection, systemic clearance (Clss) and volume of distribution (Vdss) were 78.9 mL min–1 kg–1 and 9.8 L kg–1, respectively. Elimination half-life was 2.0 hours and SC bioavailability was fixed at 1. The maximum observed plasma concentration after SC injection was 92.1 ± 76.8 ng mL–1. Behavioral changes were observed after both routes. Conclusions and clinical relevanceThe pharmacokinetic profile of IV methadone was characterized by a high Clss and large Vdss, with high bioavailability and absorption rate after SC administration. Half-life was short and mean plasma methadone concentrations stayed above the minimum effective concentration (MEC) reported in humans only after SC administration for 5 minutes, but remained above that reported in dogs for 45 minutes following both routes. Further studies investigating the MEC and pharmacodynamics of methadone in ferrets are warranted.

Changes in the equilibrium of the urban transport system of a large city following an urban flood

Urban floods are among the most frequent and destructive natural disasters. They generate enormous economic and non-economic losses, including damage to buildings and transportation infrastructure, which are critical systems supporting community well-being. The purpose of this paper was to assess the impact an urban flood would have on the urban road transport system in Łódź and to determine changes in potential accessibility that would accompany a flood. This paper introduces a novel approach in terms of combining the modelling of direct impact ranges of urban flooding in the area of Łódź and a macroscopic multi-motivational traffic model for the city (using PTV Visum software). This made it possible to identify mechanisms of changes made in as many intra-system relationships as possible, as well as between the system and its surroundings. The results showed that changes in the spatial distribution of traffic volume in the city are closely dependent on the water level. The sections of the network most affected by the load changes are those that form the framework for the entire system of Łódź, indicating a lack of resilience of the car transport subsystem in the critical segment for the functioning quality of the entire subsystem. Additionally, the study was conducted for public transport, and it was indicated that changes in its utilization are minimal. It was also found that the greatest impact on transport accessibility from an urban flood is for ultra-short trips. This is primarily due to the base effect (the initial quality of the infrastructure and its potential) – the internal potential of the transport area deteriorates drastically during a flood, severely affecting accessibility.

Insights into particle dispersion and damage mechanisms in functionally graded metal matrix composites with random microstructure-based finite element model

This study investigates the impact of Al2O3\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathrm {Al_2O_3}$$\\end{document} particle volume fraction and distribution on the deformation and damage of particle-reinforced metal matrix composites, particularly in the context of functionally graded metal matrix composites. In this study, a two-dimensional nonlinear random microstructure-based finite element modeling approach implemented in ABAQUS/Explicit with a Python-generated script to analyze the deformation and damage mechanisms in AA6061-T6/Al2O3\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathrm{AA6061\\mbox{-}T6/Al_2O_{3}}$$\\end{document} composites. The plastic deformation and ductile cracking of the matrix are captured using the Gurson–Tvergaard–Needleman model, whereas particle fracture is modelled using the Johnson–Holmquist II model. Matrix-particle interface decohesion is simulated using the surface-based cohesive zone method. The findings reveal that functionally graded metal matrix composites exhibit higher hardness values (HRB\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ extrm{HRB}$$\\end{document}) than traditional metal matrix composites. The results highlight the importance of functionally graded metal matrix composites. Functionally graded metal matrix composites with a Gaussian distribution and a particle volume fraction of 10% achieve HRB\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ extrm{HRB}$$\\end{document} values comparable to particle-reinforced metal matrix composites with a particle volume fraction of 20%, with only a 2% difference in HRB\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ extrm{HRB}$$\\end{document}. Thus, HRB\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ extrm{HRB}$$\\end{document} can be improved significantly by employing a low particle volume fraction and incorporating a Gaussian distribution across the material thickness. Furthermore, functionally graded metal matrix composites with a Gaussian distribution exhibit higher HRB\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ extrm{HRB}$$\\end{document} values and better agreement with experimental distribution functions when compared to those with a power-law distribution.

Training volume, intensity, and performance of world-class Chinese rowers prior to the 2019 world championships: A case study

Six world-class Chinese male rowers (age: 28.2 ± 3.2 years; height: 1.93 ± 0.02 m; body mass: 94.7 ± 3.9 kg) participated in the study. The training volume in different modalities and intensities were recorded over 44 weeks. To evaluate rowing performance, rowers completed four 2000 m and 5000 m maximum effort time trials and two incremental step tests. Total training time for the season was 907 h, which consisted of 67.5% of rowing training, 16.9% of strength training, 15.2% of warm-up and flexibility, and 0.4% of non-specific endurance training. The rowing training intensity distribution (TID) was 87.0% performed at low intensity (LIT), 8.4% at moderate intensity (MIT), and 4.6% at high intensity (HIT). There was no significant difference in average weekly rowing training volume (distance) at LIT across four phases (p = 0.12), as well as rowing training at MIT (p = 0.07) and HIT (p = 0.97). The fourth 2000 m time trials performance significantly improved from the first trial (−6.4 s, p = 0.02). The fourth 5000 m time trial performance was significantly improved from the first (−13.4 s, p = 0.02) and second trial (−14.1 s, p = 0.01). The final-step mean power output (W) in the second incremental step test improved significantly (p = 0.04). In the 2018–19 season, China's world-class rowers conducted considerable LIT rowing. The training volume distribution and rowing TID were similar in all phases.

Whole-Body Multiparametric PET in Clinical Oncology: Current Status, Challenges, and Opportunities.

The interpretation of clinical oncologic PET studies has historically used static reconstructions based on SUVs. SUVs and SUV-based images have important limitations, including dependence on uptake times and reduced conspicuity of tracer-avid lesions in organs with high background uptake. The acquisition of dynamic PET images enables additional PET reconstructions via Patlak modeling, which assumes that a tracer is irreversibly trapped by tissues of interest. The resulting multiparametric PET images capture a tracer's net trapping rate (Ki) and apparent volume of distribution (VD), separating the contributions of bound and free tracer fractions to the PET signal captured in the SUV. Potential benefits of multiparametric PET include higher quantitative stability, superior lesion conspicuity, and greater accuracy for differentiating malignant and benign lesions. However, the imaging protocols necessary for multiparametric PET are inherently more complex and time-intensive, despite the recent introduction of automated or semiautomated scanner-based reconstruction packages. In this Review, we examine the current state of multiparametric PET in whole-body oncologic imaging. We summarize the Patlak methodology and relevant tracer kinetics, discuss clinical workflows and protocol considerations, and highlight clinical challenges and opportunities. We aim to help oncologic imagers make informed decisions about whether to implement multiparametric PET in their clinical practices.

Predicting Human Subcutaneous Bioavailability of Therapeutic Monoclonal Antibodies from Systemic Clearance and Volume of Distribution.

Subcutaneous delivery of monoclonal antibody therapeutics is often preferred to intravenous delivery due to better patient compliance and overall lower cost to the healthcare system. However, the systemic absorption of biologics dosed subcutaneously is often incomplete. The aim of this work was to describe a human bioavailability prediction method for monoclonal antibodies delivered subcutaneously that utilizes intravenous pharmacokinetic parameters as input. A two-compartment pharmacokinetic model featuring a parallel-competitive absorption pathway and a presystemic metabolism pathway was employed. A training data set comprised 19 monoclonal antibodies (geometric mean bioavailability of 68%), with previously reported human pharmacokinetic parameters, while a validation set included data compiled from 5 commercial drug products (geometric mean bioavailability of 69%). A single fitted absorption rate constant, paired with compound-specific estimates of presystemic metabolism rate proportional to compound-specific systemic clearance parameters, resulted in calculations of human subcutaneous bioavailability closely mimicking clinical data in the training data set with a root-mean-square error of 5.5%. Application of the same approach to the validation data set resulted in predictions characterized by 12.6% root-mean-square error. Factors that may have impacted the prediction accuracy include a limited number of validation data set compounds and an uncertainty in the absorption rate, which were subsequently discussed. The predictive method described herein provides an initial estimate of the subcutaneous bioavailability based exclusively on pharmacokinetic parameters available from intravenous dosing.

Determination of Demand for LNG in Poland

This study was aimed at improving the energy efficiency of the distribution of liquefied natural gas (LNG) as shipping fuel in the southern Baltic Sea. The objective of this study was to determine the demand for LNG for maritime shipping by analyzing the distribution of the resource from the water side (ship-to-ship). LNG was chosen due to the location of the LNG terminal in Świnoujście within the analyzed water area, where a problem has arisen in the southern part of the Baltic Sea regarding fuel supply for vessels due to the lack of developed infrastructure along the coast. An analysis was conducted to optimize the size of the LNG fleet and infrastructure facilities. Seeking compliance with Annex VI to the MARPOL 73/78 Convention, adopted by the International Maritime Organization (IMO), shipowners see potential in the switch from conventional fuels to LNG. As one of the alternative solutions, it will contribute to reducing harmful emissions. Determination of the LNG distribution volume requires the identification of LNG storage facility locations, specifying the number of LNG-powered ships (broken down by type) and the number of LNG bunkering ships. The first part of this study contains a detailed analysis of the number of sea-going ships that provide services in the southern part of the Baltic Sea and the world’s number of LNG bunkering ships. The database contains a set of the characteristics required to determine the optimal demand for LNG, where LNG bunkering vessels are capable of supplying fuel within the shortest possible time and covering the shortest possible distance to LNG-powered ships. The characteristics include the type of ship, requested LNG volume, the speed of LNG bunkering ships, the distance between LNG facilities, and the loading rate (the volume of fuel received per time unit). Based on the collected data, the volume of LNG distribution was determined using MATLAB R2019a software. The remainder of this study contains a description of the conducted research and results of an analysis of the traffic density in the Baltic Sea. The results were obtained on the basis of data from the Statistical Yearbook of Maritime Economy and IALA IWRAP Mk2 2020 software. The number of LNG-powered ships and number of LNG bunkering ships were specified, and the demand for LNG for the area under analysis was determined.

Comparing PEMFC state-of-health characteristics obtained by Galvanostatic Charge Method with and without nitrogen flush

Onboard determination of state-of-health (SoH) parameters becomes increasingly important with tightened lifetime requirements for automotive polymer electrolyte membrane (PEM) fuel cell systems. One way to electrochemically characterize SoH parameters like active catalyst surface area (roughness factor, RF), double layer capacitance and membrane permeability is the nitrogen-flush-requiring Galvanostatic Charge Method (GCM). In this publication, a nitrogen-flush-free and thus, onboard-compatible adapted version of GCM (AGCM from Möller et al. (2023)), is directly compared to its original method, GCM. A 20-cell automotive shortstack was frequently characterized with both GCM and AGCM methods as well as standard Cyclic Voltammetry (CV) during a degradation test. Additionally, the evaluation model for AGCM was varied in two aspects: Firstly, modeling the hydrogen partial pressure difference (ΔpH2) responsible for hydrogen crossover and secondly, modeling hydrogen diffusion in the cathode volume with a 0-D transport model. The characterization results prove that all investigated model variations of AGCM can reproduce double layer capacitance results from GCM and CV, as well as the decreasing trend in roughness factor results. RF-values characterized by AGCM agree with either GCM or CV results, depending on the evaluation model. A thorough analysis revealed the neglected short circuit resistance in combination with the chosen modeling approach of ΔpH2 in AGCM as the reason. The two modeling approaches for ΔpH2 base on extreme assumptions about the homogeneity of hydrogen distribution in the anode volume. Neither of them could reproduce the membrane permeability of GCM. Instead, one overestimates, one underestimates it, indicating the truth to be in between the two extreme models. However, AGCM measurement conditions are identified as a lever to improve the AGCM permeability results and their robustness, even if the modeling approaches remain unchanged. Furthermore, this study showed that neglecting hydrogen diffusion in the cathode volume in the AGCM evaluation model leads to overestimation of the membrane permeability.

Assessing masseter muscle volume and activity in relation to craniofacial morphology: a 3D CBCT study.

Understanding the factors influencing craniofacial structure growth is crucial for addressing craniofacial deformities. This study evaluates masseter muscle volume, activity, and maximum bite force across different skeletal malocclusion groups and aims to evaluate the masseter muscle volume, activity, and maximum bite force (BF) according to different skeletal malocclusion groups. This study aimed to assess masseter muscle volume, activity, and maximum bite force (BF) across different skeletal malocclusion groups in 60 young adults (18-30 years) seeking treatment at Kirikkale University Faculty of Dentistry. Cone-Beam Computed Tomography (CBCT) imaging, radiological measurements, surface electromyography (sEMG), and force sensor measurements were employed. Results revealed significant differences in sEMG measurements based on sagittal classification. Vertical direction groups showed notable results in muscle volume and BF, though no significant differences were observed in sEMG values. A correlation was identified between BF and sEMG, but no correlation was found between muscle volume and other parameters. The findings obtained in this study suggest that the significant relationship between EMG and sagittal skeletal classification could be a valuable diagnostic tool. However, concerns about reliability were raised due to uneven distribution in muscle volume and BF among vertical direction groups. The lack of significant results in muscle volume, sEMG, and BF was attributed to CBCT limitations in soft tissue imaging and the small sample size, emphasizing caution in interpreting the findings.

EXO: A commons-based community network Internet Service Provider, description and subscribers usage patterns

The advent of Wi-Fi in the 1990s stimulated the creation of Community networks (CNs), a new networking paradigm deployed and maintained by their users. The non-profit and grassroots self-organization of CNs has shown significant potential in enhancing communication technologies grounded in ethical values, transcending mere Internet expansion to contribute to broader social impacts. Since its conception, hundreds of CNs have been deployed worldwide. However, many have faltered, primarily due to a lack of solid economic models and legal setup. This paper presents Expansió Xarxa Oberta (eXO) association, a commons Internet Service Provider (ISP). In contrast to commercial ISPs, eXO follows the same grassroots principles of CNs. Establishing a commons-based ISP is challenging, yet it is a key component for the sustainability and success of CNs. Therefore, our paper aims to dissect the complexity of a commons ISP by explaining eXO, a pioneering example that has already been in production for more than 14 years. To the best of our knowledge, this is the first time that a commons ISP is described in all its components.To describe eXO, we have proceeded in two parts. In the first one, we delineate the organizational structure, economics, funding mechanisms, activities, legal framework, and infrastructure. To gain more insight on eXO, in the second part, we conduct a technical analysis of traffic data collected from eXO’s core router, elucidating subscriber usage patterns. Our study encompasses various subscriber categories, including regular and financially subsidized users, Wi-Fi and optical fiber access, and traffic characteristics such as volume, TCP/UDP usage, services accessed, and traffic distribution across countries.

A steady-state distributed parameter ultrathin heat pipe model considering the unsaturated wick

Ultrathin heat pipes have become mainstream to address the heat dissipation issues of small electronic devices. Numerous numerical studies based on the saturated wick assumption have been proposed to analyze their heat transfer performance. In order to achieve a more accurate assessment, this study presents a three-dimensional model that quantitatively reflects the relationship between capillary pressure and medium volume, along with a corresponding correlation. Based on this, a steady-state distributed parameter ultrathin heat pipe model considering the retreating of medium volume in the wick and the unsaturation vapor-liquid interface was developed, whose accuracy was verified by the experimental data. The results demonstrated that the capillary pressure increased with the decrease of medium volume and contact angle. The evolution of the overall meniscus with medium volume was categorized into two stages, where capillary pressure dependent on the main and micro meniscus at different stage. The medium volume distribution, corresponding to capillary pressure, will automatically adjust to match the overall medium pressure drop. Comparative analysis against experimental data, the proposed model reduced the maximum temperature difference error by 8.43 % compared to the saturated wick assumption at a heat load of 6 W, revealing that the unsaturated liquid wick model exhibited higher accuracy.

Advances in CT-based lung function imaging for thoracic radiotherapy.

The objective of this review is to examine the potential benefits and challenges of CT-based lung function imaging in radiotherapy over recent decades. This includes reviewing background information, defining related concepts, classifying and reviewing existing studies, and proposing directions for further investigation. The lung function imaging techniques reviewed herein encompass CT-based methods, specifically utilizing phase-resolved four-dimensional CT (4D-CT) or end-inspiratory and end-expiratory CT scans, to delineate distinct functional regions within the lungs. These methods extract crucial functional parameters, including lung volume and ventilation distribution, pivotal for assessing and characterizing the functional capacity of the lungs. CT-based lung ventilation imaging offers numerous advantages, notably in the realm of thoracic radiotherapy. By utilizing routine CT scans, additional radiation exposure and financial burdens on patients can be avoided. This imaging technique also enables the identification of different functional areas of the lung, which is crucial for minimizing radiation exposure to healthy lung tissue and predicting and detecting lung injury during treatment. In conclusion, CT-based lung function imaging holds significant promise for improving the effectiveness and safety of thoracic radiotherapy. Nevertheless, challenges persist, necessitating further research to address limitations and optimize clinical utilization. Overall, this review highlights the importance of CT-based lung function imaging as a valuable tool in radiotherapy planning and lung injury monitoring.

Development and validation of an LC-MS/MS method for the quantification of free and total doxorubicin in human plasma and its clinical application for a novel doxorubicin hydrochloride liposome injection in Chinese patients with breast cancer

AbstractA novel doxorubicin hydrochloride liposome injection was prepared to reduce toxicity and side effects, as well as extend plasma half-life in the treatment of breast cancer. In this study, a rapid and sensitive bioanalytical method was developed and validated to characterize the pharmacokinetic profile of total and free doxorubicin in plasma of 3 Chinese patients after intravenous infusion of this injection. Plasma samples were prepared by protein precipitation for the determination of total doxorubicin, while solid phase extraction was used to determine free doxorubicin. After plasma sample pre-treatment, total and free concentrations were quantified individually using a validated LC-MS/MS method. The calibration curves were found to be linear in the range of 0.20–500.0 ng mL−1 for total doxorubicin and in the range of 1.00–1,000 ng mL−1 for free doxorubicin. The free concentrations in plasma were only one sixth to one quarter of the total levels. Liposomal doxorubicin had a longer apparent half-life (>50 h) than the non-targeted drug (<10 h) reported in the reference. and a lower volume of distribution. This novel injectable formulation steadily released free doxorubicin from liposomes over a long period of time to reduce cardiac toxicity and side effects, while ensuring a clinical curative effect.

Documento nacional de consenso de monitorización terapéutica de antibióticos y antifúngicos en el paciente pediátrico y neonatal de la Sociedad Española de Farmacia Hospitalaria (SEFH) y la Sociedad Española de Infectología Pediátrica (SEIP)

Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic param- eters, is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised host.In neonates and children, infections account for a high percentage of hospital admissions and anti-infectives are the most used drugs. However, pediatric pharmacokinetic and pharmacodynamic studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals -usually used off-label in pediatrics- to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the pharmacokinetic parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treat- ment success. In addition, pediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring.The aim of this document, developed jointly between the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Pediatric Infectious Diseases (SEIP), is to describe the available evidence on the indications for therapeutic drug monitoring of antibiotics and antifungals in newborn and pediatric patients and to provide prac- tical recommendations for therapeutic drug monitoring in routine clinical practice to optimize pharmacokinetic and pharmacodynamic parameters, efficacy and safety of antibiotics and antifungals in the pediatric population.

Integrated Population Pharmacokinetics of Daprodustat in Patients with Chronic Kidney Disease with Anemia.

Daprodustat is a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) approved in the USA for treatment of anemia owing to chronic kidney disease (CKD) in dialysis-dependent adults and in Japan for treatment of CKD in dialysis- and non-dialysis dependent adults. This analysis characterized the population pharmacokinetics (PopPK) of daprodustat in adults with CKD and evaluated the influence of intrinsic and extrinsic factors. This PopPK analysis included data from one phase 2B and four phase 3 studies comprising 707 CKD subjects dose titrated to prespecified target hemoglobin levels with daprodustat doses ranging from 1 to 24 mg once daily and 2 to 48 mg given three times a week (TIW). Model development leveraged a previous phase 1/2 PopPK model. Stepwise covariate analysis included 20 extrinsic and intrinsic factors. Model evaluation used standard goodness-of-fit and visual predictive checks. Daprodustat PopPK was adequately characterized using a three-compartment distribution model with first-order elimination. The absorption phase was described using five transit compartments. Oral clearance and volume of distribution was 24.6 L/h and 26.9 L, respectively. Body weight dependence (with fixed allometric coefficients) of clearance and volume terms was a statistically significant covariate. Concomitant use of clopidogrel (moderate CYP2C8 inhibitor) decreased oral clearance, resulting in higher area under the plasma concentration-timecurve (AUC) ratio of 1.59 (90% CI: 1.39-1.82), subjects' dialysis status (non-dialysis versus dialysis) had an effect on absorption, with Cmax ratio of 1.19 (90% CI: 1.09-1.30). None of the other investigated intrinsic or extrinsic covariates, including concomitant administration with phosphate binders, oral iron and acid reducing agents resulted in a significant change in daprodustat systemic exposure. The PopPK of daprodustat in theCKD population with anemia was adequately characterized. Allometrically-scaled body weight on clearance and volume, dialysis status on absorption and clopidogrel on clearance were statistically significant covariates.