| 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. |
- Xie, Meng, et al.
(författare)
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Secondary ossification center induces and protects growth plate structure
- 2020
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Ingår i: eLIFE. - : ELIFE SCIENCES PUBLICATIONS LTD. - 2050-084X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Growth plate and articular cartilage constitute a single anatomical entity early in development but later separate into two distinct structures by the secondary ossification center (SOC). The reason for such separation remains unknown. We found that evolutionarily SOC appears in animals conquering the land - amniotes. Analysis of the ossification pattern in mammals with specialized extremities (whales, bats, jerboa) revealed that SOC development correlates with the extent of mechanical loads. Mathematical modeling revealed that SOC reduces mechanical stress within the growth plate. Functional experiments revealed the high vulnerability of hypertrophic chondrocytes to mechanical stress and showed that SOC protects these cells from apoptosis caused by extensive loading. Atomic force microscopy showed that hypertrophic chondrocytes are the least mechanically stiff cells within the growth plate. Altogether, these findings suggest that SOC has evolved to protect the hypertrophic chondrocytes from the high mechanical stress encountered in the terrestrial environment.
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| 3. |
- Hyhlik-Dürr, A., et al.
(författare)
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Finite Element Analysis of Abdominal Aortic Aneurysms : Preliminary Results of Intra and Inter observer Validation
- 2010
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Konferensbidrag (refereegranskat)abstract
- Objective: Treatment of abdominal aortic aneurysm (AAA) is indicated if risk for rupture exceeds the risk for aortic repair. Estimation of the individual risk for rupture in AAA is therefore essential. The diameter of AAA is known as an independent risk factor for rupture and therefore the base of indication for surgical or endovascular therapy. For more sensitive patient selection, other morphological or hemodynamic predictors such as volume or peak wall stress have to be evaluated. The purpose of this study was to analyze the reproducibility of diameter measurement, volume estimation and peak wall stress calculation in AAA by finite element analysis. Methods: Computed tomography angiography (CTA) scans of 10 patients with AAA and 4 volunteers with healthy infrarenal aortas were analyzed by three independent investigators. A semiautomatic reconstruction using two- and three-dimensional deformable (active) contour models was used to segment vascular bodies from CTA data. Centreline calculated maximal diameter and volume measurements, as extracted from the reconstructed abdominal aorta, as well as peak wall stress, as predicted by three-dimensional non-linear finite element models, were analyzed. Specifically, aortic wall and thrombus tissue were captured by isotropic, non-linear and finite strain constitutive models. Likewise, mean arterial pressure was applied at the luminal surface, the vessels were fixed at the renal arteries and the aortic bifurcation and no contact with surrounding organs was considered. Inter- and intra-observer variabilities for diameter, volume and peak wall stress measurements were assessed by calculating the coefficient of variation (CV=SD*100/mean in %) of the five fold determinations. The methodological variation was expressed as deviation of diameter (mm), volume (ml) and peak wall stress (kPa) amongst the three observers. Results: Reproducibility measurements in healthy vessels of aortic diameters between 16.1mm to 16.6mm varied from CV=2.5% to CV=4.9%. Abdominal aortic volumes of 14ml to 15ml were measured in the healthy cohort with a reproducibility of CV=5.8% to CV=11.5%. Peak wall stress varied between 53 kPa and 55 kPa, where CV ranged from 3-13%. Inter-observer variation was <10% for diameter, volume and peak stress in healthy volunteers. Aortic diameter in three AAAs was measured to 58.9 mm; 54.6 mm; and 71.2 mm respectively. The coefficient of variation showed high agreement with values less than 5%. AAA volume varied between 130 ml and 300 ml (CV < 10%) and Peak wall stress was predicted between 172 kPa and 296 kPa (CV <10%). Variability between the 3 observers in AAA measurements was 0.7 mm – 6.0 mm for diameter, 11 – 28 ml for volume and 4-27 kPa for peak wall stress, respectively. Conclusions: Volume and diameter measurements based on geometrical models reconstructed from CTA scans showed quit good reproducibility for serial measurements in normal and degenerative arteries. Peak wall stress predictions exhibited high accordance between different observers, and in serial measurements within one observer. Volume and peak wall stress analysis could be an additionally module for assessment of individual rupture risk in AAA in the future, which however needs to be validated by additional studies.
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| 4. |
- Hyhlik-Dürr, A., et al.
(författare)
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Finite-Elemente-Analyse abdomineller Aortenaneurysmen : Erste Ergebnisse der Intra- und Interobserver Validierung
- 2010
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Konferensbidrag (refereegranskat)abstract
- Hintergrund: Die Therapie des abdominellen Aortenaneurysmas (AAA) ist indiziert, wenn das Rupturrisiko das Risiko der elektiven Operation übersteigt. Die Abschätzung des individuellen Rupturrisikos gilt als Basis der Indikationsstellung zur offenen oder endovaskulären Chirurgie. Bisher wird der Durchmesser des AAA als maßgeblicher Risikofaktor für die Ruptur herangezogen. Für eine sensitivere Indikationsstellung sollten jedoch andere morphologische oder biomechanische Faktoren wie die Volumenveränderung im Verlauf und/oder die Wandspannung im Aneurysma untersucht werden. Ziel dieser Studie ist die Analyse der Reproduzierbarkeit der Durchmesserbestimmung sowie der Volumen- und Wandspannungsberechnung anhand eines geometrischen Modells, basierend auf der Finite Elemente Methode. Methode: Computertomographische Daten von vier gesunden und zehn Patienten mit infrarenalen abdominellen Aneurysmen werden von drei unabhängigen Untersuchern analysiert. Die abdominelle Aorta wird semiautomatisch von Computertomographie-Angiographie (CTA) Bilddaten segmentiert, wobei zwei und drei-dimensionale aktive Konturmodelle, wie sie aus der Bildverarbeitung bekannt sind, zum Einsatz kommen. Der maximale Durchmesser (cernterline-basiert) sowie das aortale Volumen werden aus den rekonstruierten dreidimensionalen Modellen berechnet. Zusätzlich werden nicht-lineare Finite Elemente Modelle verwendet, um die mechanische Spannung in der Aortenwand zwischen der Aortenbifurkation und den Nierenarterien zu bestimmen. Zu diesen Zweck wird der mittlere arterielle Druck als Belastung angenommen und nicht-lineare isotrope Materialmodelle erfassen die mechanischen Eigenschaften der Aortenwand und des Thrombusgewebes. Die Intra- und Interobserver Variabilität der fünf Messungen des maximalen Durchmessers, des Volumens und der maximalen Wandspannung wurden durch die Berechnung des Variationskoeffizienten (CV=SD*100/Arithmethisches Mittel in %) ausgedrückt. Die methodische Variation berechnet sich aus der Abweichung des Duchmessers (mm), des Volumens (ml) und der maximalen Wandspannung (kPA) zwischen den drei Untersuchern. Ergebnisse: Die Reproduzierbarkeit gesunder Gefäßen lag bei einem Durchmesser zwischen 16.1mm und 16.6mm zwischen CV=2,5% und CV=4,9%. Das aortale Volumen lag zwischen 14ml und 15ml, die Reproduzierbarkeit bei den gesunden Gefäßen streute zwischen CV=5.8% und CV=11.5%. Die maximale Wandspannung variierte zwischen 53 kPA and 55 kPa, der CV% lag hierbei zwischen 3 und 13. Die Interobserver Variabilität lag < 10% für den Durchmesser, die Volumenbestimmung und die Bestimmung der maximale Wandspannung. Der maximale Durchmesser der Aorta bei 3 Patienten mit infrarenalem Aneurysma wurde mit durchschnittlich 58.9mm, 54.6mm und 71.2mm berechnet (Stand bei Abstracteinreichung). Der Variationskoeffizient zeigte dabei eine hohe Übereinstimmung mit Werten unter 5%. Das Volumen der Aneurysmen schwankte zwischen 130 ml und 300 ml (CV<10%), die berechnete Wandspannung lag zwischen 172 kPA und 296 kPA (CV<10%). Die Variabilität zwischen den drei Untersuchern betrug 0,7-6,0 mm für den Durchmesser, 11-28 ml für das Volumen und 4-27 kPA für die maximale Wandspannung. Zusammenfassung: Sowohl an gesunden als auch an degenerativ veränderten Gefäßen ergibt die Reproduzierbarkeit des Aortendurchmessers und des aortalen Volumens basierend auf dem dreidimensionalen rekonstruierten Modellen eine hohe Übereinstimmung. Die berechnete Wandspannung basierend auf den Finiten Elemente Modellen zeigt einen geringen Grad an Variabilität sowohl zwischen verschiedenen Untersuchern als auch bei wiederholter Messung. Daher könnten die Volumenbestimmung und die Analyse der Wandspannung zusätzliche Größen bei der Bestimmung des individuellen Rupturrisikos bei Patienten mit Aortenaneurysmen darstellen, um eine präzisere Indikationsstellung zu ermöglichen.
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| 5. |
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| 6. |
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| 7. |
- Singh, T. P., et al.
(författare)
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Comparison of peak wall stress and peak wall rupture index in ruptured and asymptomatic intact abdominal aortic aneurysms
- 2020
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 0007-1323 .- 1365-2168. ; 108:6, s. 652-658
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous studies have suggested that finite element analysis (FEA) can estimate the rupture risk of an abdominal aortic aneurysm (AAA); however, the value of biomechanical estimates over measurement of AAA diameter alone remains unclear. This study aimed to compare peak wall stress (PWS) and peak wall rupture index (PWRI) in participants with ruptured and asymptomatic intact AAAs. Methods: The reproducibility of semiautomated methods for estimating aortic PWS and PWRI from CT images was assessed. PWS and PWRI were estimated in people with ruptured AAAs and those with asymptomatic intact AAAs matched by orthogonal diameter on a 1 : 2 basis. Spearman's correlation coefficient was used to assess the association between PWS or PWRI and AAA diameter. Independent associations between PWS or PWRI and AAA rupture were identified by means of logistic regression analyses. Results: Twenty individuals were included in the analysis of reproducibility. The main analysis included 50 patients with an intact AAA and 25 with a ruptured AAA. Median orthogonal diameter was similar in ruptured and intact AAAs (82·3 (i.q.r. 73·5–92·0) versus 81·0 (73·2–92·4) mm respectively; P = 0·906). Median PWS values were 286·8 (220·2–329·6) and 245·8 (215·2–302·3) kPa respectively (P = 0·192). There was no significant difference in PWRI between the two groups (P = 0·982). PWS and PWRI correlated positively with orthogonal diameter (both P < 0·001). Participants with high PWS, but not PWRI, were more likely to have a ruptured AAA after adjusting for potential confounders (odds ratio 5·84, 95 per cent c.i. 1·22 to 27·95; P = 0·027). This association was not maintained in all sensitivity analyses. Conclusion: High aortic PWS had an inconsistent association with greater odds of aneurysm rupture in patients with a large AAA.
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| 8. |
- Singh, T. P., et al.
(författare)
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Systematic review and meta-analysis of the association between intraluminal thrombus volume and abdominal aortic aneurysm rupture
- 2019
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Ingår i: Journal of Vascular Surgery. - : Mosby Inc.. - 0741-5214 .- 1097-6809. ; 70:6, s. 2065--2073.e10
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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.
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| 9. |
- 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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| 10. |
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