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The disintegration of near-limit flames propagating through the gap of Hele–Shaw cells has recently become a subject of active research. In this paper, the flamelets resulting from the disintegration of the continuous front are interpreted in terms of the Zeldovich flame balls stabilized by volumetric heat losses. A complicated free-boundary problem for 2D self-drifting near circular flamelets is reduced to a quasi-1D model. The quasi-1D formulation is then utilized to obtain the locus of the flamelet velocity, size, heat losses, and Lewis numbers at which the self-drifting flamelets may exist.

Given the obesity epidemic and the prevalence of comorbidities, there is an ongoing need to understand the health consequences of this disease state better. Understanding gene expression signals will facilitate the identification of mechanisms of kidney and liver dysfunction/disease often present in individuals with obesity. qPCR is the standard method for studying changes in relative gene expression. Reference genes (RGs) are obligatory for accurately normalizing mRNA transcript levels across samples. Despite the prevalence of qPCR, the reliability of the data is often compromised because RGs are still used without validation or have proven to be unstable in different tissues and various diseases. In this study, we validated seven reference genes ( ACTB , B2M , RPLP0 , HPRT1 , GAPDH , 18S rRNA , and PPIA ) using human liver tissue from 15 lean individuals and 17 individuals with a BMI ≥ 25 and human kidney tissue from 13 lean individuals and 15 individuals with a BMI ≥ 25. Cross-validation of expression stability was performed using the RefFinder platform with four algorithms: NormFinder, BestKeeper, geNorm, and the comparative ΔCt method. In obesity-related studies, the most suitable reference genes in gene expression studies are RPLP0 and HPRT1 in human kidney tissue and RPLP0 and GAPDH in the liver.

PurposeThe purpose of this work was to investigate the role of the lymphatic system in the pharmacokinetics of etanercept, a fusion protein.MethodsEtanercept 1 mg/kg was administered intravenously (IV) and subcutaneously (SC) to thoracic lymph duct-cannulated and sham-operated control rats. Blood and lymph samples were obtained for up to 6 days.ResultsModel-based SC bioavailability of etanercept was 65.2% in the control group. In lymph-cannulated rats, etanercept concentration in the lymph was consistently lower than in serum following IV dosing; and the concentration in the lymph was significantly higher than in serum after SC injection. The absorption occurred predominantly through the lymphatic pathway (82.7%), and only 17.3% by direct uptake into the central compartment (blood pathway). Lymphatic cannulation reduced the area under the serum concentration-time curve by 28% in IV group and by 91% in SC group. A mechanistic pharmacokinetic model that combined dual absorption pathways with redistribution of the systemically available protein drug into lymph was developed. The model successfully captured serum and lymph data in all groups simultaneously, and all parameters were estimated with sufficient precision.ConclusionsLymphatic system was shown to play an essential role in systemic disposition and SC absorption of etanercept.

Background/Objectives: Gabapentin has variable pharmacokinetics (PK), which contributes to difficulty in dosing and increased risk of adverse events. The objective of this study was to leverage gabapentin concentrations from therapeutic drug monitoring (TDM) to develop a population PK (popPK) model and characterize significant covariates that impact gabapentin PK. Methods: Data were retrospectively collected from 82 hospitalized adult patients with TDM gabapentin concentrations. Renal function indicators (i.e., estimated glomerular filtration rate, creatinine clearance, acute kidney injury), body weight parameters (i.e., actual body weight, ideal body weight, adjusted body weight, lean body weight, body mass index, obesity status), fasting plasma glucose levels, and diagnosis of type 2 diabetes were tested as potential covariates. A popPK model was developed in MONOLIX (2020R1, Lixoft, France). Results: A one-compartment model best described gabapentin PK with first-order absorption, dose-dependent bioavailability, first-order elimination, and no lag time. Population parameter estimates for the volume of distribution (Vd), and clearance (Cl) were 44.61 L, and 5.73 L/h, respectively. Serum creatinine was a significant covariate on Cl. Conclusions: The popPK model highlights the importance of renal function in the interindividual variability of gabapentin PK and suggests that diabetes and body weight parameters have no impact on gabapentin PK. Moreover, our study supports the utility of leveraging data obtained from clinical TDM for popPK model development.

In addition to synthetic drug carriers, the author also introduced how endogenous lymphotropic macromolecules, such as lipoproteins, may be exploited for lymphatic drug delivery. In addition to providing potential benefit through enhanced delivery to pharmacological targets in the lymphatic system, lymphatic drug transport also offers a route for orally administered drugs to avoid hepatic first-pass metabolism and therefore enhance systemic bioavailability (Shackleford, Faassen et al., 2003). Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The active form of vitamin D, calcitriol (1,25(OH)2D3), is produced from 25(OH)D3 via enzymes encoded by CYP2R1, CYP27A1, and CYP27B1. Polymorphisms in these genes may alter vitamin D metabolism and increase cardiovascular disease risk. This preliminary study investigated these polymorphisms in 27 patients with cardiovascular disease and 26 healthy volunteers using Polymerase Chain Reaction—Restriction Fragment Length Polymorphism (PCR-RFLP), while measuring 25(OH)D3 and 1,25(OH)2D3 concentrations by UPLC-MS/MS and ELISA, respectively. Among patients, those with the GT genotype of rs10877012 (CYP27B1) had higher 25(OH)D3 levels compared to other genotypes. Additionally, this polymorphism was associated with lower 1,25(OH)2D3 in TT homozygotes, suggesting reduced CYP27B1 activity. Furthermore, the TT genotype of rs6709815 (CYP27A1) was three times more prevalent in cardiac patients than in healthy controls, possibly indicating increased susceptibility to the disease. Although these findings suggest a genetic influence on vitamin D metabolism in cardiovascular disease, larger and more comprehensive studies are needed to confirm these associations.

Tuberculosis (TB) remains one of the leading global causes of mortality. Several methods have been established to detect anti-TB agents in human plasma and serum. However, there is a notable absence of studies analyzing TB drugs in urine. Thus, our objective was to validate a method for quantifying first-line anti-TB agents: isoniazid (INH), pyrazinamide (PZA), ethambutol (ETH), and rifampicin (RIF), along with its metabolite 25-desacetylrifampicin, and degradation products: rifampicin quinone and 3-formyl-rifampicin in 10 µL of urine. Chromatographic separation was achieved using a Kinetex Polar C18 analytical column with gradient elution (5 mM ammonium acetate and acetonitrile with 0.1% formic acid). Mass spectrometry detection was carried out using a triple-quadrupole tandem mass spectrometer operating in positive ion mode. The lower limit of quantification (LLOQ) was 0.5 µg/mL for INH, PZA, ETH, and RIF, and 0.1 µg/mL for RIF’s metabolites and degradation products. The method was validated following FDA guidance criteria and successfully applied to the analysis of the studied compounds in urine of TB patients. Additionally, we conducted a stability study of the anti-TB agents under various pH and temperature conditions to mimic the urine collection process in different settings (peripheral clinics or central laboratories).

Within the Boussinesq approximation, an elementary model for the deflagration-to-detonation transition triggered by self-acceleration of an expanding flame is formulated and explored. The self-acceleration is sustained by the intrinsic Rayleigh–Taylor instability until the Deshaies–Joulin deflagrability threshold is reached, followed by an abrupt transition to detonation. Emergence of the threshold is caused by positive feedback between the accelerating flame and the flame-driven pressure shock that results in the thermal runaway when the flame speed reaches a critical level. The model offers a simple mechanism that may be responsible for the transition to detonation in thermonuclear supernovae.

Background The primary objective of this study aims to test patient factors, with a focus on cardiometabolic disease, influencing the performance of the Cockcroft-Gault equation in estimating glomerular filtration rate. Methods A cohort study was performed using data from adult patients with both a 24-h urine creatinine collection and a serum creatinine available. Creatinine clearance was calculated for each patient using the Cockcroft-Gault, Modified Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations and estimates were compared to the measured 24-h urine creatinine clearance. In addition, new prediction equations were developed. Results In the overall study population ( n  = 484), 44.2% of patients were obese, 44.0% had diabetes, and 30.8% had dyslipidemia. A multivariable model which incorporating patient characteristics performed the best in terms of correlation to measured 24-h urine creatinine clearance, accuracy, and error. The modified Cockcroft-Gault equation using lean body weight performed best in the overall population, the obese subgroup, and the dyslipidemia subgroup in terms of strength of correlation, mean bias, and accuracy. Conclusions Regardless of strategy used to calculate creatinine clearance, residual error was present suggesting novel methods for estimating glomerular filtration rate are urgently needed.

Purpose To investigate the effect of dose level and anatomical site of injection on the pharmacokinetics of rituximab in mice, and to evaluate the utility of a pharmacokinetic model for describing interspecies differences in subcutaneous absorption between mice and rats. Methods Rituximab serum concentrations were measured following intravenous and subcutaneous administration at the back and abdomen of mice. Several approaches were compared for scaling model parameters from estimated values in rats. Results The bioavailability of rituximab following subcutaneous injection was inversely related to the dose level and was dependent on the site of injection in mice. The overall rate of absorption was faster in mice as compared to rats. Subcutaneous absorption profiles were well described using the proposed structural model, in which the total receptor concentration, the affinity of rituximab to the receptor, and the degradation rate constant were assumed to be species independent. Conclusions Subcutaneous absorption processes show similar trends in rats and mice, although the magnitude differs between species. A mathematical model that combines the absorption of free and bound antibody with presystemic degradation successfully captured rituximab pharmacokinetics in both species, and approaches for sharing and scaling parameters between species were identified.