Intravital Dynamic and Correlative Imaging of Mouse Livers Reveals Diffusion-Dominated Canalicular and Flow-Augmented Ductular Bile Flux.

BACKGROUND AND AIMS: Small-molecule flux in tissue microdomains is essential for organ function, but knowledge of this process is scant due to the lack of suitable methods. We developed two independent techniques that allow the quantification of advection (flow) and diffusion in individual bile canaliculi and in interlobular bile ducts of intact livers in living mice, namely fluorescence loss after photoactivation and intravital arbitrary region image correlation spectroscopy. APPROACH AND RESULTS: The results challenge the prevailing "mechano-osmotic" theory of canalicular bile flow. After active transport across hepatocyte membranes, bile acids are transported in the canaliculi primarily by diffusion. Only in the interlobular ducts is diffusion augmented by regulatable advection. Photoactivation of fluorescein bis-(5-carboxymethoxy-2-nitrobenzyl)-ether in entire lobules demonstrated the establishment of diffusive gradients in the bile canalicular network and the sink function of interlobular ducts. In contrast to the bile canalicular network, vectorial transport was detected and quantified in the mesh of interlobular bile ducts. CONCLUSIONS: The liver consists of a diffusion-dominated canalicular domain, where hepatocytes secrete small molecules and generate a concentration gradient and a flow-augmented ductular domain, where regulated water influx creates unidirectional advection that augments the diffusive flux.

Predicting the risk of post-hepatectomy portal hypertension using a digital twin: A clinical proof of concept.

BACKGROUND & AIMS: Despite improvements in medical and surgical techniques, post-hepatectomy liver failure (PHLF) remains the leading cause of postoperative death. High postoperative portal vein pressure (PPV) and portocaval gradient (PCG), which cannot be predicted by current tools, are the most important determinants of PHLF. Therefore, we aimed to evaluate a digital twin to predict the risk of postoperative portal hypertension (PHT). METHODS: We prospectively included 47 patients undergoing major hepatectomy. A mathematical (0D) model of the entire blood circulation was assessed and automatically calibrated from patient characteristics. Hepatic flows were obtained from preoperative flow MRI (n = 9), intraoperative flowmetry (n = 16), or estimated from cardiac output (n = 47). Resection was then simulated in these 3 groups and the computed PPV and PCG were compared to intraoperative data. RESULTS: Simulated post-hepatectomy pressures did not differ between the 3 groups, comparing well with collected data (no significant differences). In the entire cohort, the correlation between measured and simulated PPV values was good (r = 0.66, no adjustment to intraoperative events) or excellent (r = 0.75) after adjustment, as well as for PCG (respectively r = 0.59 and r = 0.80). The difference between simulated and measured post-hepatectomy PCG was ≤3 mmHg in 96% of cases. Four patients suffered from lethal PHLF for whom the model satisfactorily predicted their postoperative pressures. CONCLUSIONS: We demonstrated that a 0D model could correctly anticipate postoperative PHT, even using estimated hepatic flow rates as input data. If this major conceptual step is confirmed, this algorithm could change our practice toward more tailor-made procedures, while ensuring satisfactory outcomes. LAY SUMMARY: Post-hepatectomy portal hypertension is a major cause of liver failure and death, but no tool is available to accurately anticipate this potentially lethal complication for a given patient. Herein, we propose using a mathematical model to predict the portocaval gradient at the end of liver resection. We tested this model on a cohort of 47 patients undergoing major hepatectomy and demonstrated that it could modify current surgical decision-making algorithms.

Concentrations and pharmacokinetic parameters of MRI and SPECT hepatobiliary agents in rat liver compartments.

BACKGROUND: In hepatobiliary imaging, systems detect the total amount of agents originating from extracellular space, bile canaliculi, and hepatocytes. They add in situ concentration of each compartment corrected by its respective volume ratio to provide liver concentrations. In vivo contribution of each compartment to liver concentration is inaccessible. Our aim was to quantify the compartmental distribution of two hepatobiliary agents in an ex vivo model and determine how their liver extraction ratios and cholestasis (livers lacking canalicular transporters) might modify it. METHODS: We perfused labelled gadobenate dimeglumine (Bopta, 200 µM, 7% liver extraction ratio) and mebrofenin (Meb, 64 µM, 94% liver extraction ratio) in normal (n = 18) and cholestatic (n = 6) rat livers. We quantified liver concentrations with a gamma counter placed over livers. Concentrations in hepatocytes and bile canaliculi were calculated. Mann-Whitney and Kruskal-Wallis tests were used. RESULTS: Hepatocyte concentrations were 2,043 ± 333 µM (Meb) versus 360 ± 69 µM (Bopta, p < 0.001). Meb extracellular concentrations did not contribute to liver concentrations (1.3 ± 0.3%). The contribution of Bopta extracellular concentration was 12.4 ± 1.9% (p < 0.001 versus Meb). Contribution of canaliculi was similar for both agents (16%). Cholestatic livers had no Bopta in canaliculi but their hepatocyte concentrations increased in comparison to normal livers. CONCLUSION: Hepatocyte concentrations are correlated to liver extraction ratios of hepatobiliary agents. When Bopta is not present in canaliculi of cholestatic livers, hepatocyte concentrations increase in comparison to normal livers. This new understanding extends the interpretation of clinical liver images.

Partial orthotopic liver transplantation in combination with two-stage hepatectomy: A proof-of-concept explained by mathematical modeling.

BACKGROUND: Resection And Partial Liver Segment 2/3 Transplantation with Delayed total hepatectomy (RAPID) includes total hepatectomy in 2 steps with small graft transplantation at first stage. To avoid graft portal hyperperfusion, portal vein pressure monitoring is required after revascularization and right portal vein clamping. To date, portal flow modulation has not been reported but simulating hemodynamics in RAPID patients would be useful to anticipate these procedures. Our team developed hemodynamic 0D modeling; we aimed to assess if this mathematical model could be accurately used in the RAPID setting. METHODS: The modified 0D model was retrospectively tested on 3 patients. We compared our estimated portal vein pressures and portocaval gradients to those intraoperatively measured, as indication to modulate portal flow relies on these measures. FINDINGS: Portal pressures measured after right portal vein clamping (end of RAPID procedure) in patients 1, 2 and 3 were respectively of 14, 16 and 12 mmHg while the simulated pressures were of 13.1, 14.8 and 11.5 mmHg (p = 0.25). Portocaval gradients measured after right portal vein clamping in the 3 patients were respectively of 10, 11 and 7 mmHg while the simulated gradients were of 9.9, 11.6 and 8.3 mmHg (p = 0.5). INTERPRETATION: We succeeded to predict portal vein pressures and portocaval gradients after RAPID. This promising report demonstrates that 0D simulation could be a useful tool for human decision-making. Moreover, such a patient-specific model could be of importance if we transpose RAPID experience to hepatocellular carcinoma bearing cirrhotics, a population with high probability of portal hypertension after RAPID.

A Cohort Longitudinal Study Identifies Morphology and Hemodynamics Predictors of Abdominal Aortic Aneurysm Growth.

Abdominal aortic aneurysms (AAA) are localized, commonly occurring aortic dilations. Following rupture only immediate treatment can prevent morbidity and mortality. AAA maximal diameter and growth are the current metrics to evaluate the associated risk and plan intervention. Although these criteria alone lack patient specificity, predicting their evolution would improve clinical decision. If the disease is known to be associated with altered morphology and blood flow, intraluminal thrombus deposit and clinical symptoms, the growth mechanisms are yet to be fully understood. In this retrospective longitudinal study of 138 scans, morphological analysis and blood flow simulations for 32 patients with clinically diagnosed AAAs and several follow-up CT-scans, are performed and compared to 9 control subjects. Several metrics stratify patients between healthy, low and high risk groups. Local correlations between hemodynamic metrics and AAA growth are also explored but due to their high inter-patient variability, do not explain AAA heterogeneous growth. Finally, high-risk predictors trained with successively clinical, morphological, hemodynamic and all data, and their link to the AAA evolution are built from supervise learning. Predictive performance is high for morphological, hemodynamic and all data, in contrast to clinical data. The morphology-based predictor exhibits an interesting effort-predictability tradeoff to be validated for clinical translation.

Direct conversion of uranium dioxide UO2 to uranium tetrafluoride UF4 using the fluorinated ionic liquid [Bmim][PF6].

The industrial fluorination of UO2 to UF4 is based on a complex process involving the manipulation of a large amount of HF, a very toxic and corrosive gas. We present here a safer way to accomplish this reaction utilizing ionic liquid [Bmim][PF6] as a unique reaction medium and fluoride source.

The effects of ten weeks resistance training on sticking region in chest-press exercises.

The aim of the study was to compare the effects of a 10-week chest-press resistance training on lifting regions in a trained exercise and a none-trained exercise; the barbell bench press (BBP). Thirty-five resistance trained men with 4.2 (± 2.3) years of resistance training experience were recruited. The participants were randomized to attend a resistance program, performing the chest-press, twice per week using either, Smith machine, dumbbells or laying on Swiss ball using a barbell. A six-repetitions maximum (6RM) test was conducted pre- and post-training in the trained chest-press exercise and non-trained BBP to examine lifting velocity, load displacement and the time of the pre-sticking, sticking and post-sticking regions. Additionally, the muscle activity in pectoralis major, triceps brachii, biceps brachii and deltoid anterior was examined. In the post-test, all three chest-press groups decreased lifting velocity and increased the time to reach the sticking- and post-sticking region. Independent of the type of chest-press exercise trained, no differences were observed in vertical displacement or in the muscle activity for the three lifting regions. In general, similar changes in kinematics in trained exercise and those observed in the BBP were observed for all three groups. This indicates that none of the three chest-press exercises (Swiss ball, Smith machine or dumbbells) were specific regarding the lifting regions but displaced a transferability towards the non-trained BBP. However, improved strength altered the sticking region among resistance trained men.

Magnetic Resonance Navigation for Targeted Embolization in a Two-Level Bifurcation Phantom.

This work combines a particle injection system with our proposed magnetic resonance navigation (MRN) sequence with the intention of validating MRN in a two-bifurcation phantom for endovascular treatment of hepatocellular carcinoma (HCC). A theoretical physical model used to calculate the most appropriate size of the magnetic drug-eluting bead (MDEB, 200 µm) aggregates was proposed. The aggregates were injected into the phantom by a dedicated particle injector while a trigger signal was automatically sent to the MRI to start MRN which consists of interleaved tracking and steering sequences. When the main branch of the phantom was parallel to B0, the aggregate distribution ratio in the (left-left, left-right, right-left and right-right divisions was obtained with results of 8, 68, 24 and 0% respectively at baseline (no MRN) and increased to 84%, 100, 84 and 92% (p < 0.001, p = 0.004, p < 0.001, p < 0.001) after implementing our MRN protocol. When the main branch was perpendicular to B0, the right-left branch, having the smallest baseline distribution rate of 0%, reached 80% (p < 0.001) after applying MRN. Moreover, the success rate of MRN was always more than 92% at the 1st bifurcation in the experiments above.

Flow stagnation volume and abdominal aortic aneurysm growth: Insights from patient-specific computational flow dynamics of Lagrangian-coherent structures.

Abdominal aortic aneurysms (AAA) are localized, commonly-occurring dilations of the aorta. When equilibrium between blood pressure (loading) and wall mechanical resistance is lost, rupture ensues, and patient death follows, if not treated immediately. Experimental and numerical analyses of flow patterns in arteries show direct correlations between wall shear stress and wall mechano-adaptation with the development of zones prone to thrombus formation. For further insights into AAA flow topology/growth interaction, a workout of patient-specific computational flow dynamics (CFD) is proposed to compute finite-time Lyapunov exponents and extract Lagrangian-coherent structures (LCS). This computational model was first compared with 4-D phase-contrast magnetic resonance imaging (MRI) in 5 patients. To better understand the impact of flow topology and transport on AAA growth, hyperbolic, repelling LCS were computed in 1 patient during 8-year follow-up, including 9 volumetric morphologic AAA measures by computed tomography-angiography (CTA). LCS defined barriers to Lagrangian jet cores entering AAA. Domains enclosed between LCS and the aortic wall were considered to be stagnation zones. Their evolution was studied during AAA growth. Good correlation - 2-D cross-correlation coefficients of 0.65, 0.86 and 0.082 (min, max, SD) - was obtained between numerical simulations and 4-D MRI acquisitions in 6 specific cross-sections from 4 patients. In follow-up study, LCS divided AAA lumens into 3 dynamically-isolated zones: 2 stagnation volumes lying in dilated portions of the AAA, and circulating volume connecting the inlet to the outlet. The volume of each zone was tracked over time. Although circulating volume remained unchanged during 8-year follow-up, the AAA lumen and main stagnation zones grew significantly (8 cm3/year and 6 cm3/year, respectively). This study reveals that transient transport topology can be quantified in patient-specific AAA during disease progression by CTA, in parallel with lumen morphology. It is anticipated that analysis of the main AAA stagnation zones by patient-specific CFD on a yearly basis could help to predict AAA growth and rupture.