Variability In Clearance Research Articles

Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders

BackgroundQuantitative measurements of cerebrospinal fluid to blood clearance has previously not been established for neurological diseases. Possibly, variability in cerebrospinal fluid clearance may affect the underlying disease process and may possibly be a source of under- or over-dosage of intrathecally administered drugs. The aim of this study was to characterize the cerebrospinal fluid to blood clearance of the intrathecally administered magnetic resonance imaging contrast agent gadobutrol (Gadovist, Bayer Pharma AG, GE). For this, we established a population pharmacokinetic model, hypothesizing that cerebrospinal fluid to blood clearance differs between cerebrospinal fluid diseases.MethodsGadobutrol served as a surrogate tracer for extra-vascular pathways taken by several brain metabolites and drugs in cerebrospinal fluid. We estimated cerebrospinal fluid to blood clearance in patients with different cerebrospinal fluid disorders, i.e. symptomatic pineal and arachnoid cysts, as well as tentative spontaneous intracranial hypotension due to cerebrospinal fluid leakage, idiopathic intracranial hypertension, or different types of hydrocephalus (idiopathic normal pressure hydrocephalus, communicating- and non-communicating hydrocephalus). Individuals with no verified cerebrospinal fluid disturbance at clinical work-up were denoted references.ResultsPopulation pharmacokinetic modelling based on 1,140 blood samples from 161 individuals revealed marked inter-individual variability in pharmacokinetic profiles, including differences in absorption half-life (time to 50% of tracer absorbed from cerebrospinal fluid to blood), time to maximum concentration in blood and the maximum concentration in blood as well as the area under the plasma concentration time curve from zero to infinity. In addition, the different disease categories of cerebrospinal fluid diseases demonstrated different profiles.ConclusionsThe present observations of considerable variation in cerebrospinal fluid to blood clearance between individuals in general and across neurological diseases, may suggest that defining cerebrospinal fluid to blood clearance can become a useful diagnostic adjunct for work-up of cerebrospinal fluid disorders. We also suggest that it may become useful for assessing clearance capacity of endogenous brain metabolites from cerebrospinal fluid, as well as measuring individual cerebrospinal fluid to blood clearance of intrathecal drugs.

Pediatric AIDS-Therapeutic Successes Built on a Foundation of Pediatric Clinical Pharmacology with Pharmacokinetic-Pharmacodynamic Modeling.

Pediatric AIDS-Therapeutic Successes Built on a Foundation of Pediatric Clinical Pharmacology with Pharmacokinetic-Pharmacodynamic Modeling.

Effect of variable chipping clearance and operational speed on the cassava chip geometry

Most cassava chipping machines adopt the fixed chipping clearance at different speeds accounting for inconsistencies in chip geometries. These irregularities influence drying time and may cause fermentation, culminating in poor quality and safety of dried chips. The need to develop a variable chipping machine capable of producing varied chip sizes for different uses necessitated this research. The main objective of this study was to develop and test the impact of a cassava chipping machine with a variable clearance and varying cutting speed on chip geometry. Drum operation speeds of 460 rpm, 730 rpm, and 800 rpm, and chipping clearances of 6 mm, 18 mm, and 28 mm were considered in this study. The study considered two twelve-month maturing varieties of cassava. These varieties were the Ampong (an improved variety) and Ankrah (a local variety). Processing time was varied between freshly harvested (FH) and 48 h after harvest (48AH). The initial moisture contents of the Ampong variety were 68.1% and 65.4% wet basis for the FH and 48AH samples, respectively. The Ankrah variety recorded 66.0% and 61.0% wet basis for FH and 48AH samples, respectively. Results from the performance evaluation test indicated that operational speed and chipping clearance had a significant effect (P<0.05) on the chips’ length, width, and thickness. Ankrah variety recorded the shortest mean chip length at 6 mm clearance and 730 rpm for the FH samples. On the other hand, Ampong samples at 730 rpm and 18 mm machine clearance recorded the shortest mean chip length for the 48AH samples.

Rotor Stability Effects of Tilting Pad Journal Bearings With Assembled Clearance Asymmetry

Abstract This paper presents component and system-level analyses to understand the stiffness, damping, and rotor stability effects of tilting pad journal bearings (TPJB) with assembled clearance variation across pads. This variation results from a normal manufacturing process of the bearing components, i.e., shaft, bearing shell, pad radius, and pad thickness, whose machining tolerances add in a closed-loop producing a different assembled clearance per pad. The results are compared to the standard analysis practice of uniformly setting all pads assembled clearance to its maximum and minimum stack-up values to find the worst case for stability. The component-level analysis follows a rigid rotor approach. While in the system-level analysis, a full rotor-bearings-seals model of a lightweight, high-speed centrifugal compressor is employed. A four-pad TPJB with a load between pads (LBP) configuration is considered. Large differences in stiffness and log dec are encountered, while almost negligible differences are found in damping. Also, some interesting observations related to rotor-bearing planar mode shapes are reported when the bearing pads have dissimilar assembled clearances. These modes disappear once the labyrinth seal force coefficients are incorporated into the full model.

Evaluation and selection of a lead diabody for interferon-γ PET imaging

IntroductionInterferon-γ (IFN-γ) is an appealing target to evaluate immune response in cancer immunotherapy as it is a hallmark of an active immune system. Imaging and detection via immunopositron emission tomography (immunoPET) of this soluble cytokine has been made feasible using a 89Zr-labeled (t 1/2 ~ 3.27 d) monoclonal antibody (mAb). Because of its size, using a full-length mAb as an imaging vector is not ideal for repeat serial imaging because of its prolonged blood pool residency and tumor accumulation resulting in lengthier wait times between administration and imaging. This consequently impacts the potential to image a dynamic immune response in real time. This work compares 89Zr-labeled diabodies (Db) designed with variable linker lengths between the VH and VL regions with the goal of selecting a lead Db for future studies. Methods and resultsFour Db fragments with various linker lengths (HL-n, n = 7–13 amino acids) were each conjugated to desferrioxamine (DFO). The number of attached chelates was analyzed via mass spectrometry with all immunoconjugates exhibiting one unit of DFO attached. Db-DFO conjugates were subsequently radiolabeled with zirconium-89. All constructs radiolabeled with high yields. Each radioimmunoconjugate was tested for reactivity to IFN-γ. All tracers except for [89Zr]Zr-DFO-NCS-anti-IFN-γ HL-9 exhibited comparable immunoreactivities (>90 %) to the radiolabeled parent mAb (95.8 %). At 24 h post-labeling, the IRF values were retained except for the HL-13 construct. Imaging scans and tissue distribution studies acquired in mice bearing CT26 syngeneic colorectal tumors between 1 and 24 h post-tracer administration demonstrated variable clearance kinetics and tumor localization of each radiotracer. HL-7 had higher binding in non-tumor tissues compared to HL-11 and HL-13 at 3 h p.i. Competitive binding studies versus unmodified parent mAb (AN-18) demonstrated blocking of radiolabeled HL-11 and HL-13. [89Zr]Zr-DFO-NCS-anti-IFN-γ HL-7 was inadequately blocked. ConclusionDespite nuanced differences in linker lengths, our data demonstrates that [89Zr]Zr-DFO-NCS-anti-IFN-γ HL-11 exhibited the best radiotracer properties for the assessment of IFN-γ production in vivo. Work is currently underway to test the potential of using shorter-lived isotopes, like copper-64 (t1/2 ~ 12.7 h) to match pharmacokinetics and half-lives.

Complex Assembly Analysis for Geometric and Dimensional Tolerance to Obtain Selective Assembly from Partitioned Bins Using a Multi-objective Approach to Control Clearance Variation of IC Engine

Complex Assembly Analysis for Geometric and Dimensional Tolerance to Obtain Selective Assembly from Partitioned Bins Using a Multi-objective Approach to Control Clearance Variation of IC Engine

Research on Contact and Wear Characteristics of the Planetary Roller Screw Mechanism with Screw Misalignments

Misalignments are unavoidable in most applications of the planetary roller screw mechanism (PRSM) due to many potential causes. However, the effect of screw misalignments on the contact characteristics for the PRSM have not been thoroughly investigated. In this paper, a comprehensive analytical procedure for the PRSM performance considering screw misalignments is proposed. First, the contact positions and clearances of the PRSM with screw misalignments are calculated. Next, an improved model is presented for evaluation of the load distribution, in which the variation of axial clearances is taken into consideration. The numerical results are validated by finite element analysis. Then, the precision loss model caused by wear is derived considering the variation of contact forces. The results indicate that the contact positions slightly change due to the misalignment angle of the screw, while the axial clearances and load distribution at the screw-roller interface are significantly affected. At the same time, the contact forces over thread vary periodically. In addition, the screw misalignment aggravates the wear of the PRSM, resulting in accuracy degradation. The theoretical investigations lay the foundation for the engineering application of the PRSM.

1298-P: Metabolic Clearance of Insulin Is Altered after Gastric Bypass and Sleeve Gastrectomy

Roux-en-Y gastric bypass (GB) surgery and sleeve gastrectomy (SG) improve glucose tolerance, in part, by enhancing prandial insulin levels. Post-meal hyperinsulinemia after GB is caused by larger insulin secretion and lower metabolic clearance rate of insulin (MCRI) . Reduced prandial MCRI after GB is exaggerated in those with post-GB complication of hypoglycemia, suggesting that altered MCRI is a pathogenic factor. We investigated the role of GB or SG on insulin kinetics in fasting and fed states. The MCRI were measured during a mixed meal text (MMT) in 9 GB and 7 SG subjects: and during MMT combined with hyperinsulinemic hypoglycemic clamp in 9 GB, 7 SG, and 5 CN. Three groups were matched for age and BMI and surgical groups for time and weight loss since surgery; none had diabetes or liver disease. Fasting MCRI was greater in GB and SC than CN (p<0.05) . Meal ingestion diminished MCRI to a larger extent in GB subjects compared to SG reaching nadir values in 20-50 min (relative reduction in GB vs. SG: 82±3% vs. 74±3%, p<0.05) . The relative postprandial reduction in MCRI was inversely associated with the glycemic excursion and insulin response. During the clamp hepatic insulin clearance was larger in GB and SG compared to CN (p<0.05) . There was no association between hepatic insulin clearance and peripheral insulin sensitivity (M/I) . Induced hyperinsulinemia approximating 300 µU/ml reduced MCRI in 3 groups despite a larger M/I in surgical subjects. Meal ingestion during hyperinsulinemic hypoglycemia clamp raised MCRI in 3 groups (p<0.05) returning to pre-meal values in an hour. These findings demonstrate that the differences in basal MCRI among GB, SG and CN are mainly attributed to variations in insulin clearance in the liver and independent on peripheral insulin sensitivity. Further, prandial reduction in MCRI is greater after GB than SG in proportion to the rates of nutrient influx.; the effect of nutrient ingestion on insulin kinetics is altered during hyperinsulinemic hypoglycemia. Disclosure M.S.Rayas: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker's Bureau; AstraZeneca. A.Gastaldelli: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Boehringer Ingelheim International GmbH, Inventiva Pharma, Other Relationship; Eli Lilly and Company, Gilead Sciences, Inc., Pfizer Inc., Speaker's Bureau; Novo Nordisk. M.Salehi: None. Funding National Institute of Diabetes, Digestive, and Kidney Diseases (DK105379)

Probabilistic CFD analysis on the flow field and performance of the FDA centrifugal blood pump

The present study is set out to systematically investigate the combined impact of operational, geometrical, and model uncertainties on the hemodynamics and performance characteristics in the U.S. Food and Drug Administration (FDA) benchmark centrifugal blood pump. Non-intrusive Polynomial Chaos Expansion (NIPCE) has been utilized to propagate the uncertainty of 12 random input variables in the flow field and the performance characteristics of the blood pump at three working conditions. The global sensitivity of the Quantities of Interest (QoI) to the uncertain input parameters was measured through the Sobol’ indices. The Multiple Reference Frames (MRF) approach and the SST k−ω turbulence model were employed to conduct the 3D CFD computations of the pump. In addition, we quantified the device-related hemolysis using the semi-empirical power-law model. The stochastic CFD results of the pump velocity field and hydraulic performance parameters showed a satisfactory agreement with measurements. Statistical analysis indicated that the effect of operational and geometrical uncertainties on the velocity field of the blood pump chiefly emerges at the outlet diffuser region, more specifically along the center-line of the fluid jet formed inside the diffuser. This study has also clarified that the uncertainties in the flow field and the hydraulic performance of the blood pump are mainly due to the variations of impeller diameter, rotational speed, radial clearance, and flow rate. By contrast, the hemolysis index is profoundly affected by the model parameters. Additionally, higher robustness against uncertainties was observed for hydraulic efficiency compared to the pump head. Eventually, it was shown that the maximum value of the distribution function of the relative hemolysis index lies within the bounds of the measurements.

Prospective Trial of Monocyte Count as a Biomarker of Hand-Foot Syndrome Among Patients With Soft Tissue Sarcomas Treated With Pegylated Liposomal Doxorubicin and Ifosfamide.

Pegylated liposomal doxorubicin (PLD) is widely used and can be used for prolonged periods, with the limiting toxicity usually being hand-foot syndrome (HFS). The pharmacokinetics of PLD is variable between patients, leading to variability in the risk of developing HFS. Dosing based on body surface area does not decrease variability in PLD clearance; thus, other predictive markers could be useful. The peripheral blood absolute monocyte count (AMC) has been suggested as a possible marker of both reticuloendothelial system function and PLD pharmacokinetics. The present study examined the AMC as a potential predictive biomarker in a prospective trial of pre-operative PLD combined with ifosfamide in soft tissue sarcomas (STSs). While our results suggest a relationship between pre-treatment AMC and PLD-induced HFS, the association did not reach statistical significance. The clinical utility of the AMC as a predictor of PLD-induced HFS appears limited, at least when given with ifosfamide.

Influence of Fit Clearance and Tightening Torque on Contact Characteristics of Spindle–Grinding Wheel Flange Interface

The spindle and grinding wheel flange (GWF) adopt double positioning of a tapered surface and end face. Due to the processing quality, the contact state of the spindle–GWF interface cannot be determined accurately. Based on the theory of finite element and the Yoshimura integral method, an analysis method for the contact stiffness of the spindle–GWF interface was established. In addition, the effects of the spindle–GWF interface’s original clearance and tightening torque on the contact pressure, final contact state and contact stiffness of the spindle–GWF interface were investigated and experimentally verified. It was found that the final contact state of the spindle–GWF changed when the tightening torque increased, especially when the original contact state was tapered contact, and the final contact state changed significantly after assembly. The contact pressure and contact stiffness of the spindle–GWF interface are increased by increasing the tightening torque. The radial stiffness is more affected by the end clearance variation compared to the axial and angular stiffness. When the original contact state is tapered contact, the radial stiffness of the interface is at maximum in three contact states. This research provides theoretical guidance for GWF assembly on gear-grinding machines.

Aerodynamic performance of suction-side squealer tip in impulse/reaction turbine blade rows

In order to understand the impact of turbine reaction on the SS (suction-side squealer) tip loss, the loss map for the SS tip with the variations of both tip clearance and squealer height is completed in the blade row of medium turbine reaction (exit-to-inlet velocity ratio, VR = 2.0), and then the present SS tip losses are compared with the previous ones in the blade rows of weak and strong turbine reactions (VR = 1.2 and 2.4). The SS tip loss map shows that the loss change with squealer height is not so large and its maximum loss reduction is less than2.9% of flat tip loss. Regardless of tip clearance and squealer height, the present SS tip performs worse than the full squealer tip in the loss reduction for VR = 2.0, and this performance gap is more noticeable for wider tip clearance. The comparisons of the present SS tip losses for VR = 2.0 with those for VR = 1.2 and 2.4 show that the SS tip-to-flat tip loss ratio is influenced strongly by VR (reaction) of impulse/reaction turbine blade row. Irrespective of squealer height, the SS tip has a considerable loss reduction only in the blade row of VR = 2.4. Especially for low squealer heights without structural defect, the SS tip-to-flat tip loss ratio continues to decrease, as VR increases from 1.2 to 2.4. The present over-tip flow visualizations give a clear explanation about tip gap flow physics in the blade rows of different VR.

Can First-Dose Therapeutic Drug Monitoring Predict the Steady State Area Under the Blood Concentration-Time Curve of Busulfan in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation?

Busulfan has high intra-individual variability and possible time-dependent changes in clearance, which complicates therapeutic drug monitoring (TDM), as first dose sampling may not predict the steady state concentrations. In this study, we aimed to use Bayesian pharmacokinetic parameters estimated from the first dose to predict the steady state AUC for busulfan. This observational study was conducted among pediatric patients at King Abdullah Specialist Children’s Hospital. From each patient, we collected six blood samples (2, 2.25, 2.5, 3, 4, and 6 h after the start of IV infusion of the first dose). A subset of patients were also sampled at the steady state. First, we modeled the data using only the first dose. The model was used to estimate the empirical Bayesian estimates of clearance for each individual patient, then we used the empirical Bayesian estimates of clearance to predict the AUC0–tau at steady state (i.e., predicted AUC0–tau). Steady state AUC0–tau was also calculated for patients sampled at steady state using the trapezoidal method using raw time concentration data; this was considered the reference AUC0–tau.. Then, we compared the AUC0–tau predicted using the Bayesian approach with the reference AUC0–tau values. We calculated bias and precision to assess predictability. In total we had 33 patients sampled after first dose and at steady state. Using the Bayesian approach to predict the AUC0–tau, bias was −2.8% and precision was 33%. This indicates that first dose concentrations cannot accurately predict steady state busulfan concentrations; therefore, follow-up TDM may be required for optimal dosing.

Population pharmacokinetics and toxicodynamics of continuously infused linezolid in critically ill patients

Linezolid is a treatment option against multi-drug-resistant Gram-positive pathogens. Continuous infusion of linezolid has been proposed to optimize antimicrobial exposure, although pharmacokinetic data from large patient cohorts are lacking. Population pharmacokinetics and the time-dependent association between linezolid exposure and the occurrence of thrombocytopenia in 120 critically ill patients were described. Monte Carlo simulations evaluated pharmacokinetic/pharmacodynamic/toxicodynamic target attainment in relation to body weight and creatinine clearance for continuously infused doses of 300-2400 mg/day. Linezolid pharmacokinetics were highly variable (interindividual variability of clearance: 52.8% coefficient of variation). Non-linear clearance was quantified, which decreased from 6.82 to 3.82 L/h within 3-6 days in the population. A relationship between linezolid exposure and platelet count over time was established. For standard dosing (1200 mg/day), the model predicted Grade 2, 3 or 4 thrombocytopenia (<75×103/µL, <50×103/µL and <25×103/µL) in 21.7%, 10.4% and 2.5% of patients at day 14, respectively. Patients with impaired renal function displayed higher risk. The overall probability of Grade 3 thrombocytopenia could be reduced from 10.4% using standard dosing to 6.3% if a linezolid steady state plasma concentration of 7 mg/L is targeted, suggesting a value of therapeutic drug monitoring (TDM). Dosing linezolid by continuous infusion should include considerations of creatinine clearance and body weight to maximize the achievement of therapeutic exposures. However, due to the high variability in individual dose, optimization using TDM seems necessary to optimize linezolid dosing under continuous infusion to avoid toxicity, particularly if longer treatment courses are expected.

Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision Dosing

We develop a population pharmacokinetic model to describe Busulfan pharmacokinetics in paediatric patients and investigate by simulations the impact of various sampling schedules on the calculation of AUC. Seventy-six children had 2 h infusions every 6 h. A two-compartment linear model was found to adequately describe the data. A lag-time was introduced to account for the delay of the administration of the drug through the infusion pump. The mean values of clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 10.7 L/h, 39.5 L, 4.68 L/h and 17.5 L, respectively, normalized for a Body Weight (BW) of 70 kg. BW was found to explain a portion of variability with an allometric relationship and fixed exponents of 0.75 on clearance parameters and 1 on volumes. Interindividual variability for clearance and volume of distribution was found to be 28% and 41%, respectively, and interoccasion variability for clearance was found to be 11%. Three sampling schedules were assessed by simulations for bias and imprecision to calculate AUC by a non-compartmental and a model-based method. The latter was found to be superior in all cases, while the non-compartmental was unbiased only in sampling up to 12 h corresponding to a once-daily dosing regimen.

Aeroengine transient performance simulation integrated with generic heat soakage and tip clearance model

AbstractThe simulations and assessment of transient performance of gas turbine engines during the conceptual and preliminary design stage may be conducted ignoring heat soakage and tip clearance variations due to lack of detailed geometrical and structural information. As a result, problems with transient performance stability may not be revealed correctly, and corresponding design iterations would be necessary and costly when those problems are revealed at a detailed design stage. To make an engine design more cost and time effective, it has become important to require better transient performance simulations during the conceptual and preliminary design stage considering all key impact factors such as fuel control schedule, rotor dynamics, inter-component volume effect as well as heat soakage and tip clearance variation effects. In this research, a novel transient performance simulation approach with generically simplified heat soakage and tip clearance models for major gas path components of gas turbine engines including compressors, turbines and combustors has been developed to support more realistic transient performance simulations of gas turbine engines at conceptual and preliminary design stages. Such heat soakage and tip clearance models only require thermodynamic design parameters as input, which is normally available during such design stages. The models have been implemented into in-house transient performance simulation software and applied to a model twin-spool turbojet engine to test their effectiveness. Comparisons between transient performance simulated with and without the heat soakage and tip clearance effects demonstrate that the results are promising. Although the introduced heat soakage and tip clearance models may not be as accurate as that using detailed component geometrical information, it is able to include the major heat soakage and tip clearance effects and make the transient performance simulations and analysis more realistic during conceptual and preliminary engine design stage.

Pooled Population Pharmacokinetic Analysis for Exploring Ciprofloxacin Pharmacokinetic Variability in Intensive Care Patients.

Background and ObjectivePrevious pharmacokinetic (PK) studies of ciprofloxacin in intensive care (ICU) patients have shown large differences in estimated PK parameters, suggesting that further investigation is needed for this population. Hence, we performed a pooled population PK analysis of ciprofloxacin after intravenous administration using individual patient data from three studies. Additionally, we studied the PK differences between these studies through a post-hoc analysis.MethodsIndividual patient data from three studies (study 1, 2, and 3) were pooled. The pooled data set consisted of 1094 ciprofloxacin concentration–time data points from 140 ICU patients. Nonlinear mixed-effects modeling was used to develop a population PK model. Covariates were selected following a stepwise covariate modeling procedure. To analyze PK differences between the three original studies, random samples were drawn from the posterior distribution of individual PK parameters. These samples were used for a simulation study comparing PK exposure and the percentage of target attainment between patients of these studies.ResultsA two-compartment model with first-order elimination best described the data. Inter-individual variability was added to the clearance, central volume, and peripheral volume. Inter-occasion variability was added to clearance only. Body weight was added to all parameters allometrically. Estimated glomerular filtration rate on ciprofloxacin clearance was identified as the only covariate relationship resulting in a drop in inter-individual variability of clearance from 58.7 to 47.2%. In the post-hoc analysis, clearance showed the highest deviation between the three studies with a coefficient of variation of 14.3% for posterior mean and 24.1% for posterior inter-individual variability. The simulation study showed that following the same dose regimen of 400 mg three times daily, the area under the concentration–time curve of study 3 was the highest with a mean area under the concentration–time curve at 24 h of 58 mg·h/L compared with that of 47.7 mg·h/L for study 1 and 47.6 mg·h/L for study 2. Similar differences were also observed in the percentage of target attainment, defined as the ratio of area under the concentration–time curve at 24 h and the minimum inhibitory concentration. At the epidemiological cut-off minimum inhibitory concentration of Pseudomonas aeruginosa of 0.5 mg/L, percentage of target attainment was only 21%, 18%, and 38% for study 1, 2, and 3, respectively.ConclusionsWe developed a population PK model of ciprofloxacin in ICU patients using pooled data of individual patients from three studies. A simple ciprofloxacin dose recommendation for the entire ICU population remains challenging owing to the PK differences within ICU patients, hence dose individualization may be needed for the optimization of ciprofloxacin treatment.

The Simulation Research on the Ferrofluid Boundary in the Eccentric Rotating Seals

The ferrofluid seals are widely used in rotating machinery, including some eccentric rotating machinery. However, few studies were conducted on the performance of ferrofluid seals with eccentric rotating shafts. In order to analyze the effect of eccentricity on the sealing performance quantitatively, a simulation method is presented for eccentric ferrofluid seals in this article. The magnetic-flow coupling model is calculated by the finite element method (FEM). Besides, the 3-D boundary variation in the seal clearance is calculated by the moving mesh method. The simulation result shows the inhomogeneous distributions of magnetic induction intensity, magnetic force, and magnetization pressure. Based on the analysis of weak points, the effect of eccentricity on the sealing performance of the ferrofluid seal is studied. The sealing performance decreases gradually with the increase of eccentricity.

A comparison of the population pharmacokinetics of rifampicin, isoniazid and pyrazinamide between hospitalized and non-hospitalized tuberculosis patients with or without HIV.

Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups. Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM ® was used to analyze the data. Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin's absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9% and 154% more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid's clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide's clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients. Conclusion. We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underexposed compared to their outpatient counterparts.

Variable Clearance Characteristics of High Subsonic Compressor Cascades with Blade Tip Winglets

Variable Clearance Characteristics of High Subsonic Compressor Cascades with Blade Tip Winglets