A numerical study of the effect of thrombus breakdown on predicted thrombus formation and growth.

Thrombosis is a complex biological process which involves many biochemical reactions and is influenced by blood flow. Various computational models have been developed to simulate natural thrombosis in diseases such as aortic dissection (AD), and device-induced thrombosis in blood-contacting biomedical devices. While most hemodynamics-based models consider the role of low shear stress in the initiation and growth of thrombus, they often ignore the effect of thrombus breakdown induced by elevated shear stress. In this study, a new shear stress-induced thrombus breakdown function is proposed and implemented in our previously published thrombosis model. The performance of the refined model is assessed by quantitative comparison with experimental data on thrombus formation in a backward-facing step geometry, and qualitative comparison with in vivo data obtained from an AD patient. Our results show that incorporating thrombus breakdown improves accuracy in predicted thrombus volume and captures the same pattern of thrombus evolution as measured experimentally and in vivo. In the backward-facing step geometry, thrombus breakdown impedes growth over the step and downstream, allowing a stable thrombus to be reached more quickly. Moreover, the predicted thrombus volume, height and length are in better agreement with the experimental measurements compared to the original model which does not consider thrombus breakdown. In the patient-specific AD, the refined model outperforms the original model in predicting the extent and location of thrombosis. In conclusion, the effect of thrombus breakdown is not negligible and should be included in computational models of thrombosis

Shear-driven modelling of thrombus formation in type B aortic dissection

Background: Type B aortic dissection (TBAD) is a dangerous pathological condition with a high mortality rate. TBAD is initiated by an intimal tear that allows blood to flow between the aortic wall layers, causing them to separate. As a result, alongside the original aorta (true lumen), a false lumen (FL) develops. TBAD compromises the whole cardiovascular system, in the worst case resulting in complete aortic rupture. Clinical studies have shown that dilation and rupture of the FL are related to the failure of the FL to thrombose. Complete FL thrombosis has been found to improve the clinical outcomes of patients with chronic TBAD and is the desired outcome of any treatment. Partial FL thrombosis has been associated with late dissection-related deaths and the requirement for re-intervention, thus the level of FL thrombosis is dominant in classifying the risk of TBAD patients. Therefore, it is important to investigate and understand under which conditions complete thrombosis of the FL occurs. Method: Local FL hemodynamics play an essential role in thrombus formation and growth. In this study, we developed a simplified phenomenological model to predict FL thrombosis in TBAD under physiological flow conditions. Based on an existing shear-driven thrombosis model, a comprehensive model reduction study was performed to improve computational efficiency. The reduced model has been implemented in Ansys CFX and applied to a TBAD case following thoracic endovascular aortic repair (TEVAR) to test the model. Predicted thrombus formation based on post-TEVAR geometry at 1-month was compared to actual thrombus formation observed on a 3-year follow-up CT scan. Results: The predicted FL status is in excellent agreement with the 3-year follow-up scan, both in terms of thrombus location and total volume, thus validating the new model. The computational cost of the new model is significantly lower than the previous thrombus model, with an approximate 65% reduction in computational time. Such improvement means the new model is a significant step towards clinical applicability. Conclusion: The thrombosis model developed in this study is accurate and efficient at predicting FL thrombosis based on patient-specific data, and may assist clinicians in choosing individualized treatments in the future

The necessity to seal the re-entry tears of aortic dissection after TEVAR: a hemodynamic indicator

Thoracic endovascular aortic repair (TEVAR) is a common treatment for Stanford type B aortic dissection (TBAD). However, re-entry tears might be found distal to the stented region which transports blood between the true and false lumens. Sealing the re-entry tears, especially for the thoracic tears, could further reduce blood perfusion to the false lumen; however, it might also bring risks by re-intervention or surgery. Wise determination of the necessity to seal the re-entry tears is needed. In this study, patient-specific models of TBAD were reconstructed, and the modified models were established by virtually excluding the thoracic re-entries. Computational hemodynamics was investigated, and the variation of the functional index and first balance position (FBP) of the luminal pressure difference, due to the sealing of the re-entries, was reported. The results showed that the direction of the net flow through the unstented thoracic re-entries varied among cases. Excluding the re-entries with the net flow toward the false lumen may induce the FBP moving distally and the relative particle residence time increasing in the false lumen. This study preliminarily demonstrated that the hemodynamic status of the re-entry tears might serve as an indicator to the necessity of sealing. By quantifying the through-tear flow exchange and shift of FBP, one can predict the hemodynamic benefit by sealing the thoracic re-entries and thus wisely determine the necessity of further interventional management

Coding on countably infinite alphabets

This paper describes universal lossless coding strategies for compressing sources on countably infinite alphabets. Classes of memoryless sources defined by an envelope condition on the marginal distribution provide benchmarks for coding techniques originating from the theory of universal coding over finite alphabets. We prove general upper-bounds on minimax regret and lower-bounds on minimax redundancy for such source classes. The general upper bounds emphasize the role of the Normalized Maximum Likelihood codes with respect to minimax regret in the infinite alphabet context. Lower bounds are derived by tailoring sharp bounds on the redundancy of Krichevsky-Trofimov coders for sources over finite alphabets. Up to logarithmic (resp. constant) factors the bounds are matching for source classes defined by algebraically declining (resp. exponentially vanishing) envelopes. Effective and (almost) adaptive coding techniques are described for the collection of source classes defined by algebraically vanishing envelopes. Those results extend ourknowledge concerning universal coding to contexts where the key tools from parametric inferenceComment: 33 page

Molecular control of nitric oxide synthesis through eNOS and caveolin-1 interaction regulates osteogenic differentiation of adipose-derived stem cells by modulation of Wnt/β-catenin signaling

BACKGROUND: Nitric oxide (NO) plays a role in a number of physiological processes including stem cell differentiation and osteogenesis. Endothelial nitric oxide synthase (eNOS), one of three NO-producing enzymes, is located in a close conformation with the caveolin-1 (CAV-1(WT)) membrane protein which is inhibitory to NO production. Modification of this interaction through mutation of the caveolin scaffold domain can increase NO release. In this study, we genetically modified equine adipose-derived stem cells (eASCs) with eNOS, CAV-1(WT), and a CAV-1(F92A) (CAV-1(WT) mutant) and assessed NO-mediated osteogenic differentiation and the relationship with the Wnt signaling pathway. METHODS: NO production was enhanced by lentiviral vector co-delivery of eNOS and CAV-1(F92A) to eASCs, and osteogenesis and Wnt signaling was assessed by gene expression analysis and activity of a novel Runx2-GFP reporter. Cells were also exposed to a NO donor (NONOate) and the eNOS inhibitor, l-NAME. RESULTS: NO production as measured by nitrite was significantly increased in eNOS and CAV-1(F92A) transduced eASCs +(5.59 ± 0.22 μM) compared to eNOS alone (4.81 ± 0.59 μM) and un-transduced control cells (0.91 ± 0.23 μM) (p < 0.05). During osteogenic differentiation, higher NO correlated with increased calcium deposition, Runx2, and alkaline phosphatase (ALP) gene expression and the activity of a Runx2-eGFP reporter. Co-expression of eNOS and CAV-1(WT) transgenes resulted in lower NO production. Canonical Wnt signaling pathway-associated Wnt3a and Wnt8a gene expressions were increased in eNOS-CAV-1(F92A) cells undergoing osteogenesis whilst non-canonical Wnt5a was decreased and similar results were seen with NONOate treatment. Treatment of osteogenic cultures with 2 mM l-NAME resulted in reduced Runx2, ALP, and Wnt3a expressions, whilst Wnt5a expression was increased in eNOS-delivered cells. Co-transduction of eASCs with a Wnt pathway responsive lenti-TCF/LEF-dGFP reporter only showed activity in osteogenic cultures co-transduced with a doxycycline inducible eNOS. Lentiviral vector expression of canonical Wnt3a and non-canonical Wnt5a in eASCs was associated with induced and suppressed osteogenic differentiation, respectively, whilst treatment of eNOS-osteogenic cells with the Wnt inhibitor Dkk-1 significantly reduced expressions of Runx2 and ALP. CONCLUSIONS: This study identifies NO as a regulator of canonical Wnt/β-catenin signaling to promote osteogenesis in eASCs which may contribute to novel bone regeneration strategies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13287-016-0442-9) contains supplementary material, which is available to authorized users

Beyond equilibrium climate sensitivity

ISSN:1752-0908ISSN:1752-089

Evaluation and verification of patient-specific modelling of type B aortic dissection

Quantitative assessment of the complex hemodynamic environment in type B aortic dissection (TBAD) through computational fluid dynamics (CFD) simulations can provide detailed insights into the disease and its progression. As imaging and computational technologies have advanced, methodologies have been developed to increase the accuracy and physiological relevance of CFD simulations. This study presents a patient-specific workflow to simulate blood flow in TBAD, utilising the maximum amount of in vivo data available in the form of CT images, 4D-flow MRI and invasive Doppler-wire pressure measurements, to implement the recommended current best practice methodologies in terms of patient-specific geometry and boundary conditions. The study aimed to evaluate and verify this workflow through detailed qualitative and quantitative comparisons of the CFD and in vivo data. Based on data acquired from five TBAD patients, a range of essential model inputs was obtained, including inlet flow waveforms and 3-element Windkessel model parameters, which can be utilised in further studies where in vivo flow data is not available. Local and global analysis showed good consistency between CFD results and 4D-MRI data, with the maximum velocity in the primary entry tear differing by up to 0.3 m/s, and 80% of the analysed regions achieving moderate or strong correlations between the predicted and in vivo velocities. CFD predicted pressures were generally well matched to the Doppler-wire measurements, with some deviation in peak systolic values. Overall, this study presents a validated comprehensive workflow with extensive data for CFD simulation of TBAD