| 1. |
- Manning, Alisa, et al.
(författare)
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
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Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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| 2. |
- Zschäpitz, David, et al.
(författare)
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Rupture risk parameters upon biomechanical analysis independently change from vessel geometry during abdominal aortic aneurysm growth
- 2023
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Ingår i: JVS-Vascular Science. - : Elsevier BV. - 2666-3503. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The indication for abdominal aortic aneurysm (AAA) repair is based on a diameter threshold. However, mechanical properties, such as peak wall stress (PWS) and peak wall rupture index (PWRI), influence the individual rupture risk. This study aims to correlate biomechanical and geometrical AAA characteristics during aneurysm growth applying a new linear transformation-based comparison of sequential imaging. Methods: Patients with AAA with two sequential computed tomography angiographies (CTA) were identified from a single-center aortic database. Patient characteristics included age, gender, and comorbidities. Semiautomated segmentation of CTAs was performed using Endosize (Therenva) for geometric variables (diameter, neck configuration, α/β angle, and vessel tortuosity) and for finite element method A4 Clinics Research Edition (Vascops) for additional variables (intraluminal thrombus [ILT]), vessel volume, PWS, PWRI). Maximum point coordinates from at least one CTA 6 to 24 months before their final were predicted for the final preoperative CTA using linear transformation along fix and validation points to estimate spatial motion. Pearson's correlation and the t test were used for comparison. Results: Thirty-two eligible patients (median age, 70 years) were included. The annual AAA growth rate was 3.7 mm (interquartile range [IQR], 2.25-5.44; P <.001) between CTs. AAA (+17%; P <.001) and ILT (+43%; P <.001) volume, maximum ILT thickness (+35%; P <.001), β angle (+1.96°; P =.017) and iliac tortuosity (+0.009; P =.012) increased significantly. PWS (+12%; P =.0029) and PWRI (+16%; P <.001) differed significantly between both CTAs. Both mechanical parameters correlated most significantly with the AAA volume increase (r = 0.68 [P <.001] and r = 0.6 [P <.001]). Changes in PWS correlated best with the aneurysm neck configuration. The spatial motion of maximum ILT thickness was 14.4 mm (IQR, 7.3-37.2), for PWS 8.4 mm (IQR, 3.8-17.3), and 11.5 mm (IQR, 5.9-31.9) for PWRI. Here, no significant correlation with any of the aforementioned parameters, patient age, or time interval between CTs were observed. Conclusions: PWS correlates highly significant with vessel volume and aneurysm neck configuration. Spatial motion of maximum ILT thickness, PWS, and PWRI is detectable and predictable and might expose different aneurysm wall segments to maximum stress throughout aneurysm growth. Linear transformation could thus add to patient-specific rupture risk analysis. Clinical Relevance: Abdominal aortic aneurysm rupture risk assessment is a key feature in future individualized therapy approaches for patients, since more and more data are obtained concluding a heterogeneous disease entity that might not be addressed ideally looking only at diameter enlargement. The approach presented in this pilot study demonstrates the feasibility and importance of measuring peak wall stress and rupture risk indices based on predicted and actual position of maximum stress points including intraluminal thrombus.
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| 3. |
- Ahlinder, Astrid
(författare)
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Degradable copolymers in additive manufacturing: controlled fabrication of pliable scaffolds
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inom vävnadsregenerering är produktionen av väldefinieradematriser med en porös arkitektur av nedbrytbara polymerer av stortintresse, dessa kan nu skapas genom additiva tillverkningsprocesser. Vidadditiv tillverkning krävs ett smalt munstycke för att skapa detaljrikastrukturer och detta ställer krav på att de reologiska egenskapernaanpassat. Lägre viskositet av smältan gör de lättare att använda, men enhög molmassa krävs för tillverka matriser där de mekaniska egenskapernakan bibehållas under tiden som krävs för vävnadsregenerering. Ytterligareen utmaning uppstår när nedbrytbara polymerer används i smältbaseradadditiva tillverkningsprocesser är att termisk nedbrytning ofta reducerarmolmassan redan under produktionsfasen. För att kunna användanedbrytbara polymerer av medicinsk kvalitet i smältbaserad additivtillverkning och samtidigt minimera den termiska nedbrytningen har, idenna avhandling, reologiska fingeravtryck av nedbrytbara syntetiskapolymerer med medicinsk kvalitet använts för att bestämmaprocessparametrar. Termisk nedbrytning beroende av processparamaterar har analyserats och minimeras i två smältbaserade additivatillverkningsprocesser.En additiv tillverkningsprocess var designad där nedbrytbarapolymerer av hög molmassa kunde användas utan termisk nedbrytning närprocessparametrar hade valts utifrån polymerens egenskaper. Kunskapenom användningen av dessa polymerer inom additiv tillverkning kundeappliceras på en sampolymer som utvecklats inom forskningsgruppen förmjukvävnad, poly(ε-kaprolakton-co-p-dioxanon) för att skapa böjbaramatriser. Genom att använda reologisk analys och polymerkarakteriseringerhölls processparametrar som möjliggjorde additiv tillverkning utantermisk nedbrytning. I tillägg till val av polymer och processparametrar såkan mekaniska egenskaper också styras av den strukturella designen.Poly(ε-kaprolakton) användes som modellmaterial för att reducerastyvheten med hjälp av designen, resultatet visade att det var möjligt medmer än en faktor 10 och mjuka böjbara matriser skapades.
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| 4. |
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| 5. |
- Alloisio, Marta, et al.
(författare)
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Fracture of porcine aorta-Part 1 : symconCT fracture testing and DIC
- 2023
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Ingår i: Acta Biomaterialia. - : Elsevier BV. - 1742-7061 .- 1878-7568. ; 167, s. 147-157
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Tidskriftsartikel (refereegranskat)abstract
- Tissue failure and damage are inherent parts of vascular diseases and tightly linked to clinical events. Additionally, experimental set-ups designed to study classical engineering materials are suboptimal in the exploration of vessel wall fracture properties. The classical Compact Tension (CT) test was augmented to enable stable fracture propagation, resulting in the symmetry-constraint Compact Tension (symconCT) test, a suitable set-up for fracture testing of vascular tissue. The test was combined with Digital Image Correlation (DIC) to study tissue fracture in 45 porcine aorta specimens. Test specimens were loaded in axial and circumferential directions in a physiological solution at 37 & DEG;C. Loading the aortic vessel wall in the axial direction resulted in mode I tissue failure and a fracture path aligned with the circumferential vessel direction. Circumferential loading resulted in mode I-dominated failure with multiple deflections of the fracture path. The aorta ruptured at a principal Green-Lagrange strain of approximately 0.7, and strain rate peaks that develop ahead of the crack tip reached nearly 400 times the strain rate on average over the test specimen. It required approximately 70% more external work to fracture the aorta by circumferential than axial load; normalised with the fracture surface, similar energy levels are, however, observed. The symconCT test resulted in a stable fracture propagation, which, combined with DIC, provided a set-up for the in-depth analysis of vascular tissue failure. The high strain rates ahead of the crack tip indicate the significance of rate effects in the constitutive description of vascular tissue fracture.
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| 6. |
- Alloisio, Marta, et al.
(författare)
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Fracture of porcine aorta. Part 2: FEM modelling and inverse parameter identification
- 2023
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Ingår i: Acta Biomaterialia. - : Acta Materialia Inc. - 1742-7061 .- 1878-7568. ; 167, s. 158-170
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Tidskriftsartikel (refereegranskat)abstract
- The mechanics of vascular tissue, particularly its fracture properties, are crucial in the onset and progression of vascular diseases. Vascular tissue properties are complex, and the identification of fracture mechanical properties relies on robust and efficient numerical tools. In this study, we propose a parameter identification pipeline to extract tissue properties from force-displacement and digital image correlation (DIC) data. The data has been acquired by symconCT testing porcine aorta wall specimens. Vascular tissue is modelled as a non-linear viscoelastic isotropic solid, and an isotropic cohesive zone model describes tissue fracture. The model closely replicated the experimental observations and identified the fracture energies of 1.57±0.82 kJ m−2 and 0.96±0.34 kJ m−2 for rupturing the porcine aortic media along the circumferential and axial directions, respectively. The identified strength was always below 350 kPa, a value significantly lower than identified through classical protocols, such as simple tension, and sheds new light on the resilience of the aorta. Further refinements to the model, such as considering rate effects in the fracture process zone and tissue anisotropy, could have improved the simulation results. Statement of significance: This paper identified porcine aorta's biomechanical properties using data acquired through a previously developed experimental protocol, the symmetry-constraint compact tension test. An implicit finite element method model mimicked the test, and a two-step approach identified the material's elastic and fracture properties directly from force-displacement curves and digital image correlation-based strain measurements. Our findings show a lower strength of the abdominal aorta as compared to the literature, which may have significant implications for the clinical evaluation of the risk of aortic rupture.
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| 7. |
- Alloisio, Marta, et al.
(författare)
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Specimen width affects vascular tissue integrity for in-vitro characterisation
- 2024
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Ingår i: Journal of The Mechanical Behavior of Biomedical Materials. - : Elsevier BV. - 1751-6161 .- 1878-0180. ; 154
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Tidskriftsartikel (refereegranskat)abstract
- The preparation of slender specimens for in -vitro tissue characterisation could potentially alter mechanical tissue properties. To investigate this factor, rectangular specimens were prepared from the wall of the porcine aorta for uniaxial tensile loading. Varying strip widths of 16 mm, 8 mm, and 4 mm were achieved by excising zero, one, and three cuts within the specimen along the loading direction, respectively. While specimens loaded along the vessel's circumferential direction acquired consistent tissue properties, the width of test specimens influenced the results of axially loaded tissue; vascular wall stiffness was reduced by approximately 40% in specimens with strips 4 mm wide. In addition, the cross -loading stretch was strongly influenced by specimen strip width, and fiber sliding contributed to the softening of slender tensile specimens, an outcome from finite element analysis of test specimens. We may, therefore, conclude that cutting orthogonal to the main direction of collagen fibers introduces mechanical trauma that weakens slender tensile specimens, compromising the determination of representative mechanical vessel wall properties.
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| 8. |
- Auer, Martin, et al.
(författare)
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Automatic Displacement and Strain measuring in the Aorta from dynamic electrocardiographically-gated Computed Tomographic Angiography
- 2010
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Konferensbidrag (refereegranskat)abstract
- Introduction Image modalities like Duplex Ultrasound, Transesophageal Echocardiography, Intravascular Ultrasound, Computed Tomography and Magnetic Resonance provide vascular interventionists and surgeons with useful diagnostic information for treatment planning. Recent developments in cross-sectional imaging, including multi-modality image fusion and new contrast agents have resulted in improved spatial resolution. Specifically, dynamic Electrocardiographically-Gated Computed Tomographic Angiography (ECG-gated CTA) provides valuable information regarding motion and deformation of the normal and diseased aorta during the cardiac cycle. Extracting and presenting (visualization) of accurate quantitative information from the recorded image data, however remains a challenging task of image post processing. Method The algorithm proposed within this paper processes ECG-gated CTA data (here goes the scanner model and manufacturer) in DICOM (digital imaging and communication in medicine) format, within which the user manually defines an Eulerian Region of Interest (ROI). 2D deformable (active) contour models are used to pre-segment the luminal surfaces of the selected vessels at an arbitrary time point during the cardiac cycle. A tessellation algorithm is used to define the initial configuration of a 3D deformable (active) contour model, which in turn is used for the final segmentation of the luminal surfaces continuously during the cardiac cycle. Specifically, Finite Element (FE) formulations [1] for frames and shells, as known from structural mechanics, are used to define the deformable contour modes. This allows a direct mechanical interpretation of the applied set of reconstruction parameters and leads to an efficient FE implementation of the models [2]; parallel processor architecture is used to solve the global set of non-linear FE equations. Finally displacement and strain measures are derived from the dynamic segmentations and color coded plots are used to visualize them. Results and Conclusions The clinical relevance of dynamic imaging has not been fully exploited and accurate and fast image processing tools are critical to extract valuable information from ECG-gated CTA data. Such information is not only of direct clinical relevance but also critical to process our current understanding regarding normal and pathological aortic motions and deformations. The image processing concept proposed in this paper leads to efficient and clinically applicable software that facilitates an analysis of the entire aorta on a standard Personal Computer within a few minutes. Deformable (active) contour models are known to be more accurate compared to threshold based segmentation concepts [3] and the accuracy of the present approach is in the range of the in-plane image resolution. Apart from direct diagnostic information the extracted geometrical data could also be used (once enriched by accurate pressure measurements) for none invasive (minimal invasive) estimation of biomechanical aortic tissue properties. References [1] O. C. Zienkiewicz and R. L. Taylor, vol.1,2, 5th ed. Oxford: Butterworth Heinemann, 2000. [2] M. Auer and T. C. Gasser, IEEE T. Med. Imaging, 2010 (in press). [3] M. Sonka and J. M. Fitzpatrick, editors., Bellingham: Spie press, 2000
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| 9. |
- Auer, M., et al.
(författare)
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Reconstruction and Finite Element Mesh Generation of Abdominal Aortic Aneurysms From Computerized Tomography Angiography Data With Minimal User Interactions
- 2010
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Ingår i: IEEE Transactions on Medical Imaging. - : Institute of Electrical and Electronics Engineers (IEEE). - 0278-0062 .- 1558-254X. ; 29:4, s. 1022-1028
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Tidskriftsartikel (refereegranskat)abstract
- Evaluating rupture risk of abdominal aortic aneurysms is critically important in reducing related mortality without unnecessarily increasing the rate of elective repair. According to the current clinical practice aneurysm rupture risk is (mainly) estimated from its maximum diameter and/or expansion rate; an approach motivated from statistics but known to fail often in individuals. In contrast, recent research demonstrated that patient specific biomechanical simulations can provide more reliable diagnostic parameters, however current structural model development is cumbersome and time consuming. This paper used 2D and 3D deformable models to reconstruct aneurysms from computerized tomography angiography data with minimal user interactions. In particular, formulations of frames and shells, as known from structural mechanics, were used to define deformable modes, which in turn allowed a direct mechanical interpretation of the applied set of reconstruction parameters. Likewise, a parallel finite element implementation of the models allows the segmentation of clinical cases on standard personal computers within a few minutes. The particular topology of the applied 3D deformable models supports a fast and simple hexahedral-dominated meshing of the arising generally polyhedral domain. The variability of the derived segmentations (luminal: 0.50(SD 0.19) mm; exterior 0.89(SD 0.45) mm) with respect to large variations in elastic properties of the deformable models was in the range of the differences between manual segmentations as performed by experts (luminal: 0.57(SD 0.24) mm; exterior: 0.77(SD 0.58) mm), and was particularly independent from the algorithm's initialization. The proposed interaction of deformable models and mesh generation defines finite element meshes suitable to perform accurate and efficient structural analysis of the aneurysm using mixed finite element formulations.
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| 10. |
- Biasetti, Jacopo, et al.
(författare)
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A Blood Flow based model for Platelet Activation in Abdominal Aortic Aneurisms
- 2010
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Konferensbidrag (refereegranskat)abstract
- Introduction Thrombus formation is the physiological response to vascular injury, it prevents loss of blood and permits wound healing, however, it is also associated with pathological conditions like hypoxia, anoxia and infarction [1]. Consequently, thrombus development must be carefully modulated to avoid uncontrolled growth, which in turn could lead to organ malfunctions. Specifically, an Intra-Luminal Thrombus (ILT) is found in almost all larger (clinically relevant) Abdominal Aortic Aneurysms (AAAs) and multiple biochemical [2] and biomechanical [3] implications on the underlying wall tissue have been reported. Despite the dominant role played by the ILT in AAA disease little is known regarding its development, and hence, the present study investigates ILT formation with particular emphasis on platelet activation triggered by biomechanical and biochemical field variables. Method The proposed model assumes that platelet activation is defined by a single field variable representing the accumulation of mechanical [4] and chemical [5] factors as the platelet moves along its path line. Platelet activation is given as soon asovercomes a certain threshold thought to be a constitutive property of blood. Specifically, the rate of the activation variable is determined by the maximum shear stress and the local concentrations of agonists and antagonists. To implement the model the fluid mechanical problem was solved in (COMSOL, COMSOL AB) and a particle tracking analysis (MATLAB, The MathWorks) was applied as a post processing step. The flow in a circular tube and the Backward Facing Step (BFS) problem under varying initial conditions were used for a basic investigation of the model and to relate its predictions to available data in the literature. Finally, platelet activation in patient specific AAAs was predicted and related to ILT development, which was estimated from Computer Tomography-Angiography (CT-A) data recorded from patient follow-up studies. Results and Conclusions The platelet activation variable is complex distributed (highly heterogeneous) in the flow field, where, specifically, at the boundary of vortexes [6] and in the boundary layer of the non- endothelialized wall highest values were predicted. Continuous release of antagonists from the endothelialized wall lowers in its vicinity, and hence, despite the high shear stress platelet activation is prevented. The proposed model links biomechanical and biochemical mechanisms of platelet activation and is able to predict the onset of thrombus formation of the BFS problem. The model is also able to predict some features of ILT development in the AAA, however, the change in luminal geometry is a cumulative effect of ILT growth, wall growth and their mechanical interactions, and hence, data recorded form patient follow-up studies needs to be analyzed carefully when validating the present model. References [1] J. D. Humphrey, Springer-Verlag, New York, 2002. [2] M. Kazi, et. al. J. Vasc. Surg., 38:1283-1292, 2003. [3] W. R. Mower et. al., J. Vasc. Surg., 33:602-608, 1997. [4] J. D. Hellums, Ann. Biomed. Eng., 22: 445-455, 1994. [5] B. Alberts et. al. Molecular Biology of the cell, 2002. [6] J. Biasetti et. al. Ann. Biomed. Eng., 38: 380–390 2010.
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