A High Serum Level of Taurocholic Acid is Correlated with the Severity and Resolution of Drug-induced Liver Injury

Background & Aims Alterations in the serum levels of bile acids are associated with drug-induced liver injury (DILI). We investigated the association between serum levels of bile acids and the severity and outcome of DILI, along with the potential role of variants in the ATP binding cassette subfamily B member 11 ( ABCB11) gene and expression of its product, ABCB11 (also called BSEP). Methods We performed this prospective study of 95 patients (median age, 53 years; 73.7% female) with DILI from August 2018 through August 2019. Patients were matched for age, gender, and body mass index with healthy individuals (n=100; healthy controls) and patients with chronic hepatitis B (n=105; CHB controls). We collected demographic and biochemical data at baseline and 1 week, 1 month, 3 months, and 6 months after DILI onset and at the time of biochemical recovery, liver failure or liver transplantation. Serum levels of bile acids were measured using high-performance liquid-chromatography tandem mass-spectrometry. All 27 exons of ABCB11 were sequenced and expression of BSEP were analyzed by immunohistochemistry in liver biopsy specimens. Results Levels of 30 of the 37 bile acids analyzed differed significantly between patients with DILI and healthy controls. Changes in levels of taurocholic acid (TCA), glycocholic acid, taurochenodeoxycholate, and glycochenodeoxycholate associated with the increased levels of bilirubin and greater severity of DILI, and were also associated with CHB. Cox regression analysis showed that only change in the levels of TCA independently associated with biochemical resolution of DILI. Combination of TCA level (≥ 1955.41 nmol/L), patient age, and DILI severity was associated with abnormal blood biochemistry at 6 months after DILI onset (area under the curve, 0.81; 95% confidence interval, 0.71–0.88; sensitivity, 0.69; specificity, 0.81). ABCB11 missense variants were not associated with differences in the serum bile acid profiles, DILI severity, or clinical resolution. However, lower levels of BSEP in bile canaliculi in liver biopsies were associated with altered serum levels of bile acids. Conclusions In this prospective study performed in Chinese patients, we found that the serum levels of TCA were associated with the severity and clinical resolution of DILI. Reduced protein expression of BSEP in liver tissue, rather than variants of the ABCB11 gene were associated with altered serum levels of bile acids

Numerical modeling of fluid-particle interaction in granular media

Fluid-particle interaction underpins important behavior of granular media. Particle-scale simulation may help to provide key microscopic information governing the interaction and o er better understanding of granular media as a whole. This paper presents a coupled computational fluid dynamics and discrete element method (CFD-DEM) approach for this purpose. The granular particle system is modeled by DEM, while the fluid flow is simulated by solving the locally averaged Navier-Stokes equation with CFD. The coupling is considered by exchanging such interaction forces as drag force and buoyancy force between the DEM and CFD. The approach is benchmarked by two classic geomechanics problems for which analytical solutions are available, and is further applied to the prediction of sand heap formation in water through hopper flow. It is demonstrated that the key characteristic of granular materials interacting with pore water can be successfully captured by the proposed method

Coupled CFD-DEM simulation of fluid-particle interaction in geomechanics

This paper presents a coupled Computational Fluid Dynamics and Discrete Element Method (CFD-DEM) approach to simulate the behaviour of fluid-particle interaction for applications relevant to mining and geotechnical engineering. DEM is employed to model the granular particle system, whilst the CFD is used to simulate the fluid flow by solving the locally averaged Navier-Stokes equation. The particle-fluid interaction is considered by exchanging such interaction forces as drag force and buoyancy force between the DEM and the CFD computations. The coupled CFD-DEM tool is first benchmarked by two classic geomechanics problems where analytical solutions are available, and is then employed to investigate the characteristics of sand heap formed in water through hopper flow. The influence of fluid-particle interaction on the behaviour of granular media is well captured in all the simulated problems. It is shown in particular that a sand pile formed in water is more homogeneous in terms of void ratio, contact force and fabric anisotropy. The central pressure dip of vertical stress profile at the base of sandpile is moderately reduced, as compared to the dry case. The effects of rolling resistance and polydispersity in conjunction with the presence of water on the formation of sandpile are also discussed. (C) 2013 Elsevier B.V. All rights reserved

A coupled CFD-DEM analysis of granular flow impacting on a water reservoir

Massive debris flows or rock avalanches falling into a water reservoir may cause devastating hazards such as overtopping or dam breakage. This paper presents a coupled Computational Fluid Dynamics and Discrete Element Method (CFD-DEM) analysis on the impacting behaviour of a granular flow falling from an inclined slope into a water reservoir. The coupling between CFD and DEM considers such important fluid-particle interaction forces as the buoyancy force, the drag force and the virtual mass force. It is found that the presence of water in the reservoir can generally help to reduce direct impact of granular flow on the check dam behind the reservoir, minimizes the intense collisions and bouncing among particles and helps form a more homogeneous final deposited heap as compared to the dry case. While the interparticle/particle-wall frictions and collisions dominate the energy dissipation in the dry granular flow, the majority of kinetic energy of the granular system in the wet case is first transferred to the water body, which leaves the granular flow itself to become a contact-shearing dominant one and causes impulse wave travelling between the check dam and the slope surface for a rather sustained period before settling down. A power law distribution is found for the velocity profile of the granular flow travelling on both the slope and the reservoir ground surfaces, and it may change temporarily to a linear distribution at the transition point of the slope toe where the Savage number depicts a peak. The consideration of rolling friction among particles may homogeneously reduce the travelling velocity of the granular flow and alleviate the overall impact on the check dam. The impact on the check dam depends on both the initial debris releasing height and the reservoir water level. Medium water levels in the reservoir have been found to be generally safer when the initial debris height is relatively high

Evaluating the impact of debris flow: a coupled CFD/DEM approach

This paper presents a micromechanical study on the impacting behavior of debris flow. A coupled approach of Computational Fluid Dynamics and Discrete Element Method (CFD/DEM) is employed to capture the complicated interactions between granular particles and fluid in a debris flow. The coupling considers important interacting forces including the buoyancy force, the drag force and the virtual mass force. The calibrated CFD/DEM tool is used to simulate the following two cases. (a) A dry granular system runs down an inclined slope and impacts a water basin with check dam at the foot of the slope; (b) A mixing body of granular particles and water flows down an inclined slope and impacts on a rigid obstacle. For case (a), our study shows the presence of water in the basin can generally help to reduce the direct impact of the granular flow on the check dam, but may cause impulse surging wave travelling between the check dam and the slope surface for sustained period which exert rather high water pressure and overall impact force on the check dam. The overall impact to the check depends on both the initial releasing height and the water level in the basin where an optimal water level may exist to achieve minimized overall impact to the check dam. In Case (b) we aim to simulate the real behavior of debris flow and its impact on the barrier dam. A granular system with proper grain size distribution is treated by DEM to simulate the big-size boulders and gravels in a debris system, while a suitable fluid is handled by the CFD to model the viscous flow composed of water, fines and silts. Detailed analysis is made regarding all aspects of the flow behavior of the debris system, including its forefront speed, velocity profile, segregation, the impacting to the rigid barrier and the trajectory traveling beyond the barrier and final deposit. The results are compared to those obtained from a corresponding dry case