| 1. |
- Manning, Alisa, et al.
(författare)
-
A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
-
Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
-
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.
|
|
| 2. |
- Singh, T. P., et al.
(författare)
-
Systematic review and meta-analysis of the association between intraluminal thrombus volume and abdominal aortic aneurysm rupture
- 2019
-
Ingår i: Journal of Vascular Surgery. - : Mosby Inc.. - 0741-5214 .- 1097-6809. ; 70:6, s. 2065--2073.e10
-
Forskningsöversikt (refereegranskat)abstract
- Background: Intraluminal thrombus (ILT) is present in most abdominal aortic aneurysms (AAAs), although its role in AAA progression is controversial. Methods: A literature search was performed to identify studies that investigated the association between ILT volume and AAA rupture. A study assessment tool was developed to assess the methodologic quality of included studies. A meta-analysis was conducted using an inverse variance-weighted random-effects model to compare the ILT volume in ruptured and asymptomatic intact AAAs. Leave-one-out sensitivity analyses were conducted to assess the robustness of the findings. A subanalysis was performed including studies in which patients with asymptomatic intact and ruptured AAAs were matched for aortic diameter. Interstudy heterogeneity was assessed using the I2 statistic. Results: Eight studies involving 672 patients were included in this systematic review. Meta-analysis of all studies found a greater ILT volume in patients with ruptured AAAs than in patients with asymptomatic intact AAAs (standardized mean difference, 0.56; 95% confidence interval, 0.17-0.96; P =.005; I2 = 79.8%). Sensitivity analyses suggested that the findings were robust; however, aortic diameter was significantly larger in ruptured than in asymptomatic intact AAAs (mean ± standard deviation, 78 ± 18 and 64 ± 15 mm, respectively; P <.001). In the subanalysis of studies that matched for diameter, no significant difference in ILT volume between groups was found (standardized mean difference, 0.03; 95% confidence interval, −0.27 to 0.33; P =.824; I2 = 0%). Conclusions: This meta-analysis suggests that ILT volume is greater in patients with ruptured AAAs than in patients with asymptomatic intact AAAs, although this is most likely due to the larger diameter of ruptured AAAs.
|
|
| 3. |
- Comellas, E., et al.
(författare)
-
A homeostatic-driven turnover remodelling constitutive model for healing in soft tissues
- 2016
-
Ingår i: Journal of the Royal Society Interface. - : Royal Society of London. - 1742-5689 .- 1742-5662. ; 13:116
-
Tidskriftsartikel (refereegranskat)abstract
- Remodelling of soft biological tissue is characterized by interacting biochemical and biomechanical events, which change the tissue's microstructure, and, consequently, its macroscopic mechanical properties. Remodelling is a well-defined stage of the healing process, and aims at recovering or repairing the injured extracellular matrix. Like other physiological processes, remodelling is thought to be driven by homeostasis, i.e. it tends to re-establish the properties of the uninjured tissue. However, homeostasis may never be reached, such that remodelling may also appear as a continuous pathological transformation of diseased tissues during aneurysm expansion, for example. A simple constitutive model for soft biological tissues that regards remodelling as homeostatic-driven turnover is developed. Specifically, the recoverable effective tissue damage, whose rate is the sum of a mechanical damage rate and a healing rate, serves as a scalar internal thermodynamic variable. In order to integrate the biochemical and biomechanical aspects of remodelling, the healing rate is, on the one hand, driven by mechanical stimuli, but, on the other hand, subjected to simple metabolic constraints. The proposed model is formulated in accordance with continuum damage mechanics within an open-system thermodynamics framework. The numerical implementation in an in-house finite-element code is described, particularized for Ogden hyperelasticity. Numerical examples illustrate the basic constitutive characteristics of the model and demonstrate its potential in representing aspects of remodelling of soft tissues. Simulation results are verified for their plausibility, but also validated against reported experimental data.
|
|
| 4. |
- Erhart, P., et al.
(författare)
-
Finite-Elemente-Analyse abdomineller Aortenaneurysmen : Aktuelle Wertigkeit als Ergänzung zur herkömmlichen Diagnostik
- 2015
-
Ingår i: Gefässchirurgie. - : Springer Science and Business Media LLC. - 0948-7034 .- 1434-3932. ; 20:7, s. 503-507
-
Tidskriftsartikel (refereegranskat)abstract
- Finite element analysis (FEA) of abdominal aortic aneurysms (AAA) could enable a more precise patient-specific risk assessment of AAA rupture. Further clinical studies are needed to validate this model as a clinical decision-making tool. The A4clinics™ software provides a simple and detailed FEA simulation. After implementation of a FEA workstation in a high volume university vascular center, relevant studies for further model validation are expected to be carried out.
|
|
| 5. |
- Gasser, T. Christian, et al.
(författare)
-
Biomechanical modeling the adaptation of soft biological tissue
- 2017
-
Ingår i: Current Opinion in Biomedical Engineering. - : Elsevier B.V.. - 2468-4511. ; 1, s. 71-77
-
Tidskriftsartikel (refereegranskat)abstract
- External (mechanical) stimuli influence cell function at the level of gene expression and thereby contribute to the overall control of Soft Biological Tissues' (SBT) structure and function. SBT seem to adapt towards stable homeostatic mechanical conditions, and failure of reaching homeostasis may result in pathologies. SBT adaptation has to obey basic physical principles, and even within these constraints, a large number of SBT adaptation models have been proposed. Recent SBT models integrated the tissue's microstructure and directly addressed length scales of individual tissue constituents, which in turn allowed linking biomechanical and biochemical adaptation aspects. Despite adaptation models being based on very different hypotheses, many of them lead to physically reasonable results. Most interestingly, the recently developed homogenized Constrained Mixture Model reported very similar predictions than the original Constrained Mixture Model. This key observation indicates that the simpler kinematics-based approach is indeed able to capture the overall consequences of the continuous production and degradation of SBT constituents. However, mainly due to the scarcity of relevant experiment data, not a single model has been thoroughly validated against clearly specified modeling objectives. Consequently, much more interdisciplinary experimental work is required to guide SBT modeling activities. Nevertheless, predictive biomechanical SBT adaption models would not only be of considerable scientific interest, but would also have a large number of practical applications.
|
|
| 6. |
- Gasser, T. Christian
(författare)
-
Biomechanical Rupture Risk Assessment
- 2016
-
Ingår i: AORTA. - : Thieme Medical Publishers, Inc.. - 2325-4637. ; 4:2, s. 42-60
-
Tidskriftsartikel (refereegranskat)abstract
- Abdominal aortic aneurysm (AAA) rupture is a local event in the aneurysm wall that naturally demands tools to assess the risk for local wall rupture. Consequently, global parameters like the maximum diameter and its expansion over time can only give very rough risk indications; therefore, they frequently fail to predict individual risk for AAA rupture. In contrast, the Biomechanical Rupture Risk Assessment (BRRA) method investigates the wall's risk for local rupture by quantitatively integrating many known AAA rupture risk factors like female sex, large relative expansion, intraluminal thrombus-related wall weakening, and high blood pressure. The BRRA method is almost 20 years old and has progressed considerably in recent years, it can now potentially enrich the diameter indication for AAA repair. The present paper reviews the current state of the BRRA method by summarizing its key underlying concepts (i.e., geometry modeling, biomechanical simulation, and result interpretation). Specifically, the validity of the underlying model assumptions is critically disused in relation to the intended simulation objective (i.e., a clinical AAA rupture risk assessment). Next, reported clinical BRRA validation studies are summarized, and their clinical relevance is reviewed. The BRRA method is a generic, biomechanics-based approach that provides several interfaces to incorporate information from different research disciplines. As an example, the final section of this review suggests integrating growth aspects to (potentially) further improve BRRA sensitivity and specificity. Despite the fact that no prospective validation studies are reported, a significant and still growing body of validation evidence suggests integrating the BRRA method into the clinical decision-making process (i.e., enriching diameter-based decision-making in AAA patient treatment).
|
|
| 7. |
- Gasser, T. Christian
(författare)
-
Damage in vascular tissues and its modeling
- 2017
-
Ingår i: CISM International Centre for Mechanical Sciences, Courses and Lectures. - Cham : Springer International Publishing. ; , s. 85-118
-
Bokkapitel (refereegranskat)abstract
- The present chapter reviews vessel wall histology and summarizes relevant continuum mechanical concepts to study mechanics-induced tissue damage. As long as the accumulated damage does not trigger strain localizations, the standard nonpolar continuum mechanical framework is applicable. As an example, a damage model for collagenous tissue is discussed and used to predict collagen damage in the aneurysm wall at supra-physiologic loading. The physical meaning of model parameters allow their straight forward identification from independent mechanical and histological experimental data. In contrast, if damage accumulates until the material’s stiffness looses its strong ellipticity, more advanced continuum mechanical approaches are required. Specifically, modeling vascular failure by a fracture process zone is discussed, such that initialization and coalescence of micro-defects is mechanically represented by a phenomenological cohesive traction separation law. Failure of ventricular tissue due to deep penetration illustrates the applicability of the model. Besides appropriate continuum mechanical approaches, laboratory experiments that are sensitive to constitutive model parameters and ensure controlled failure propagation are crucial for a robust parameter identification of failure models.
|
|
| 8. |
- Gasser, T. Christian
(författare)
-
The biomechanical rupture risk assessment of abdominal aortic aneurysms—method and clinical relevance
- 2018
-
Ingår i: Lecture Notes in Applied and Computational Mechanics. - Cham : Springer Verlag. ; , s. 233-253
-
Konferensbidrag (refereegranskat)abstract
- An Abdominal Aortic Aneurysm (AAA) is an enlargement of the infrarenal aorta, a serious condition whose clinical treatment requires assessing its risk of rupture. This chapter reviews the current state of the Biomechanical Rupture Risk Assessment (BRRA), a non-invasive diagnostic method to calculate such AAA rupture risk, and emphasizes on constitutive modeling of AAA tissues. Histology and mechanical properties of the normal and aneurysmatic walls are summarized and related to proposed constitutive descriptions. Models for the passive vessel wall as well as their adaptation in time are discussed. Reported clinical BRRA validation studies are summarized and their clinical relevance is discussed. Despite open problems in AAA biomechanics, like robust modeling vascular tissue adaptation to mechanical and biochemical environments, a significant body of current validation evidence suggests integrating the BRRA method into the clinical decision-making process.
|
|
| 9. |
- Gasser, T. Christian
(författare)
-
Vascular tissue biomechanics : Constitutive modeling of the arterial wall
- 2018
-
Ingår i: Encyclopedia of Biomedical Engineering. - : Elsevier. - 9780128051443 - 9780128048290 ; , s. 265-274
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- The artery is a dynamic organ that is able to maintain conditions for optimal mechanical operation. Arterial properties are critical to the entire cardiovascular system, and the study of their biomechanics may, among others, help understand the role of tissue stress and strain in cardiovascular diseases. The present article reviews artery wall histology and morphology in relation to its key mechanical properties. Specifically, the role of cellular and extracellular components in artery biomechanics is discussed. Then, this information is related to reported constitutive descriptions with the focus on histomechanical and passive artery wall models. Concluding remarks relate to open problems in artery biomechanics like uncertainty and variability of input information.
|
|
| 10. |
- Grytsan, Andrii, 1986-
(författare)
-
Abdominal aortic aneurysm inception and evolution - A computational model
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abdominal aortic aneurysm (AAA) is characterized by a bulge in the abdominal aorta. AAA development is mostly asymptomatic, but such a bulge may suddenly rupture, which is associated with a high mortality rate. Unfortunately, there is no medication that can prevent AAA from expanding or rupturing. Therefore, patients with detected AAA are monitored until treatment indication, such as maximum AAA diameter of 55 mm or expansion rate of 1 cm/year. Models of AAA development may help to understand the disease progression and to inform decision-making on a patient-specific basis. AAA growth and remodeling (G&R) models are rather complex, and before the challenge is undertaken, sound clinical validation is required.In Paper A, an existing thick-walled model of growth and remodeling of one layer of an AAA slice has been extended to a two-layered model, which better reflects the layered structure of the vessel wall. A parameter study was performed to investigate the influence of mechanical properties and G&R parameters of such a model on the aneurysm growth.In Paper B, the model from Paper A was extended to an organ level model of AAA growth. Furthermore, the model was incorporated into a Fluid-Solid-Growth (FSG) framework. A patient-specific geometry of the abdominal aorta is used to illustrate the model capabilities.In Paper C, the evolution of the patient-specific biomechanical characteristics of the AAA was investigated. Four patients with five to eight Computed Tomography-Angiography (CT-A) scans at different time points were analyzed. Several non-trivial statistical correlations were found between the analyzed parameters.In Paper D, the effect of different growth kinematics on AAA growth was investigated. The transverse isotropic in-thickness growth was the most suitable AAA growth assumption, while fully isotropic growth and transverse isotropic in-plane growth produced unrealistic results. In addition, modeling of the tissue volume change improved the wall thickness prediction, but still overestimated thinning of the wall during aneurysm expansion.
|
|
