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Objectives To compare the accuracy and precision of 3D-Dixon and 2D-SSFP MR-imaging for assessment of aortic diameter in Marfan patients. Methods This prospective single-center study investigated respiratory-gated 3D-Dixon and breath-hold 2D-SSFP non-contrast MR-imaging at 3 T in 47 Marfan patients (36.0 ± 13.2 years, 28♀,19♂). Two radiologists performed individual diameter measurements at five levels of the thoracic aorta and evaluated image quality on a four-grade scale (1 = poor, 4 = excellent) and artifacts (1 = severe, 4 = none). Aortic root diameters acquired by echocardiography served as a reference standard. Intraclass correlation coefficient, Bland-Altman analyses, F-test, t-test, and regression analyses were used to assess agreement between observers and methods. Results Greatest aortic diameters were observed at the level of the sinuses of Valsalva (SOV) for 3D-Dixon (38.2 ± 6.8 mm) and 2D-SSFP (38.3 ± 7.1 mm) (p = 0.53). Intra- and interobserver correlation of diameter measurements was excellent at all aortic levels for both 3D-Dixon (r = 0.94–0.99 and r = 0.94–0.98) and 2D-SSFP (r = 0.96–1.00 and r = 0.95–0.99). 3D-Dixon-derived and 2D-SSFP-derived diameter measurements at the level of the SOV revealed a strong correlation with echocardiographic measurements (r = 0.92, p < 0.001 and r = 0.93, p < 0.001, respectively). The estimated mean image quality at the level of SOV was higher for 2D-SSFP compared to that for 3D-Dixon (3.3 (95%-CI: 3.1–3.5) vs. 2.9 (95%-CI: 2.7–3.1)) (p < 0.001). Imaging artifacts were less at all aortic levels for 3D-Dixon compared to 2D-SSFP (3.4–3.8 vs. 2.8–3.1) (all p < 0.002). Conclusion Respiratory-gated 3D-Dixon and breath-hold 2D-SSFP MR-imaging provide accurate and precise aortic diameter measurements. We recommend 3D-Dixon imaging for monitoring of aortic diameter in Marfan patients due to fewer imaging artifacts and the possibility of orthogonal multiplanar reformations of the aortic root. Key Points • Respiratory-gated 3D-Dixon and breath-hold 2D-SSFP imaging provide accurate and precise aortic diameter measurements in patients suffering from Marfan syndrome. • Imaging artifacts are stronger in 2D-SFFP imaging than in 3D-Dixon imaging. • We recommend 3D-Dixon imaging for monitoring of aortic diameter in Marfan patients due to fewer imaging artifacts and the possibility of orthogonal multiplanar reformations.

Über das richtige Lüften, die Auswahl von Raumluftreinigungsgeräten oder die richtige Betriebsweise von Lüftungsanlagen in Zeiten von Corona wurde bereits viel geschrieben. Der nachfolgende Beitrag gibt einen Überblick über den aktuellen Sachstand und zeigt auf, was die einzelnen Lösungen tatsächlich leisten können.

Four-dimensional flow magnetic resonance imaging (4D flow MRI) provides volumetric and time-resolved visualization and quantification of blood flow. This review presents an overview of possible applications of 4D flow MRI for non-invasive assessment of abdominal hemodynamics. This review is based on the authors' experience and the current literature. A PubMed database literature research was performed in December 2019 focusing on abdominal applications of 4D flow MRI. We illustrated the review with exemplary figures and movies of clinical cases from our institution. 4D flow MRI offers the possibility of comprehensive assessment of abdominal blood flows in different vascular territories and organ systems. Results of recent studies indicate that 4D flow MRI improves understanding of altered hemodynamics in patients with abdominal disease and may be useful for monitoring therapeutic response. Future studies with larger cohorts aiming to integrate 4D flow MRI in the clinical routine setting are needed. · 4D flow MRI enables comprehensive visualization of the complex abdominal vasculature. · 4D flow MRI enables quantification of abdominal blood flow velocities and flow rates. · 4D flow MRI may enable deeper understanding of altered hemodynamics in abdominal disease. · Further validation studies are needed prior to broad distribution of abdominal 4D flow MRI.· Riedel C, Lenz A, Fischer L et al. Abdominal Applications of 4D Flow MRI. Fortschr Röntgenstr 2021; 193: 388 - 398. Die 4-dimensionale Fluss-Magnetresonanztomografie (4D-Fluss-MRT) erlaubt die zeitaufgelöste Darstellung und Quantifizierung des Blutflusses. Diese Übersichtsarbeit stellt die möglichen Anwendungen der 4D-Fluss-MRT zur nichtinvasiven Bildgebung der Hämodynamik im Abdomen zusammen. Diese Übersichtsarbeit basiert auf der Erfahrung der Autoren sowie einer aktuellen Literaturrecherche. Die Literaturrecherche wurde in der PubMed-Datenbank bezüglich abdomineller Anwendungen der 4D-Fluss-MRT im Dezember 2019 durchgeführt. Wir haben die Arbeit mit Abbildungen und Filmen klinischer Fälle aus unserer Institution illustriert. Die 4D-Fluss-MRT erlaubt die umfassende Beurteilung des abdominellen Blutflusses in verschiedenen Organsystemen und Gefäßterritorien. Die Ergebnisse neuerer Studien zeigen, dass die 4D-Fluss-MRT ein besseres Verständnis der veränderten Hämodynamik bei Patienten mit abdominellen Erkrankungen sowie die Überwachung des therapeutischen Ansprechens ermöglicht. Zukünftige Studien in größeren Kohorten sind nötig, um die 4D-Fluss-MRT in den klinischen Alltag zu integrieren. · Die 4D-Fluss-MRT ermöglicht eine umfassende Visualisierung der komplexen abdominellen Gefäßanatomie.. · Die 4D-Fluss-MRT ermöglicht die Quantifizierung der Geschwindigkeiten und der Flussraten in abdominellen Blutgefäßen.. · Die 4D-Fluss-MRT könnte zu einem besseren Verständnis der veränderten Hämodynamik bei unterschiedlichen abdominellen Erkrankungen beitragen.. · Weitere Studien zur Validierung der 4D-Fluss-MRT in der abdominellen Bildgebung sind vor der breiten Anwendung notwendig..

Background Aortic valve repair has become a treatment option for adults with symptomatic bicuspid (BAV) or unicuspid (UAV) aortic valve insufficiency. Our aim was to demonstrate the feasibility of 4D flow cardiovascular magnetic resonance (CMR) to assess the impact of aortic valve repair on changes in blood flow dynamics in patients with symptomatic BAV or UAV. Methods Twenty patients with adult congenital heart disease (median 35 years, range 18–64; 16 male) and symptomatic aortic valve regurgitation (15 BAV, 5 UAV) were prospectively studied. All patients underwent 4D flow CMR before and after aortic valve repair. Aortic valve regurgitant fraction and systolic peak velocity were estimated. The degree of helical and vortical flow was evaluated according to a 3-point scale. Relative flow displacement and wall shear stress (WSS) were quantified at predefined levels in the thoracic aorta. Results All patients underwent successful aortic valve repair with a significant reduction of aortic valve regurgitation (16.7 ± 9.8% to 6.4 ± 4.4%, p p = 0.014). Both helical flow (1.6 ± 0.6 vs. 0.9 ± 0.5, p p = 0.002) as well as both flow displacement (0.3 ± 0.1 vs. 0.25 ± 0.1, p = 0.031) and WSS (0.8 ± 0.2 N/m2 vs. 0.5 ± 0.2 N/m2, p Conclusions 4D flow CMR allows assessment of the impact of aortic valve repair on changes in blood flow dynamics in patients with bicuspid aortic valve disease.

Degradation at the modular head-neck interface in total hip arthroplasty (THA) is predominately expressed in the form of corrosion and fretting, potentially causing peri-prosthetic failure by adverse reactions to metal debris. This retrieval study aimed to quantify variations in stem taper surface topographies and to assess the influence on the formation of corrosion and/or fretting in titanium alloy stem tapers combined with metal and ceramic heads. Four hip stem designs (Alloclassic, CLS, Bicontact and SL-Plus) were characterized using high-resolution 3D microscopy, and corrosion and fretting were rated using the Goldberg scoring scheme. Quantification of the taper surface topographies revealed a high variability in surface characteristics between threaded stem tapers: Alloclassic and CLS tapers feature deeply threaded trapezoid-shaped profiles with thread heights over 65 µm. The sawtooth-shaped Bicontact and triangular SL-Plus taper are characterized by low thread heights below 14 µm. Significantly lower corrosion and fretting scores were observed in lightly threaded compared to deeply threaded tapers in ceramic head combinations. No significant differences in corrosion or fretting scores with thread height were found in pairings with metal heads. Understanding the relationship between stem taper surface topography and the formation of corrosion and fretting could help to improve the performance of modern THAs and lead to longer-lasting clinical results.

Denosumab is a potent osteoclast inhibitor targeted to prevent osteoporotic bone loss and thereby reduce fractures in the aging population. Recently, an elevated risk of rebound fractures following denosumab discontinuation was identified, unless patients were transitioned to an alternative antiresorptive medication. How denosumab affects the interaction of mechanosensitive osteocytes and bone quality remains unknown. We hypothesized that denosumab influences osteocyte function contributing to bone reorganization and increased fractures during discontinuation. Bone quality and osteocytes were assessed in archived iliac crest bone biopsies obtained from patients with high fracture occurrence from 2011 to 2016. Biopsies were obtained due to high fracture occurrence prior and during osteoporosis therapy from (i) patients with at least two semiannual subcutaneous injections of 60 mg denosumab, (ii) patients with rebound fractures during discontinuation, and (iii) patients of a treatment-naive group. In total, biopsies from 43 individuals were analyzed (mean age, 65.5 ± 12.1 years). Our results showed that during denosumab treatment, iliac cortical bone had a higher bone tissue hardness compared to treatment-naive bone (p = 0.0077) and a higher percentage of mineralized osteocyte lacunae (p = 0.0095). The density of empty osteocyte lacunae was higher with denosumab compared to treatment-naive (p = 0.014) and remained high in trabecular bone during discontinuation (p = 0.0071). We conclude that during denosumab treatment, increased bone hardness may contribute to improved fracture resistance. In biopsies from patients with high fracture occurrence, denosumab treatment reduced osteocyte viability, an effect that persisted during treatment discontinuation. High-resolution imaging of osteocyte viability indicates a role for osteocytes as a potential future mechanistic target to understand rebound bone loss and increased fractures with denosumab discontinuation.

Bisphosphonates are the most widely prescribed pharmacologic treatment for osteoporosis and reduce fracture risk in postmenopausal women by up to 50%. However, in the past decade these drugs have been associated with atypical femoral fractures (AFFs), rare fractures with a transverse, brittle morphology. The unusual fracture morphology suggests that bisphosphonate treatment may impair toughening mechanisms in cortical bone. The objective of this study was to compare the compositional and mechanical properties of bone biopsies from bisphosphonate-treated patients with AFFs to those from patients with typical osteoporotic fractures with and without bisphosphonate treatment. Biopsies of proximal femoral cortical bone adjacent to the fracture site were obtained from postmenopausal women during fracture repair surgery (fracture groups, n = 33) or total hip arthroplasty (nonfracture groups, n = 17). Patients were allocated to five groups based on fracture morphology and history of bisphosphonate treatment [+BIS Atypical: n = 12, BIS duration: 8.2 (3.0) y; +BIS Typical: n = 10, 7.7 (5.0) y; +BIS Nonfx: n = 5, 6.4 (3.5) y; -BIS Typical: n = 11; -BIS Nonfx: n = 12]. Vibrational spectroscopy and nanoindentation showed that tissue from bisphosphonate-treated women with atypical fractures was harder and more mineralized than that from bisphosphonate-treated women with typical osteoporotic fractures. In addition, fracture mechanics measurements showed that tissue from patients treated with bisphosphonates had deficits in fracture toughness, with lower crack-initiation toughness and less crack deflection at osteonal boundaries than that of bisphosphonate-naive patients. Together, these results suggest a deficit in intrinsic and extrinsic toughening mechanisms, which contribute to AFFs in patients treated with long-term bisphosphonates.

Specific features of crack propagation in human cortical bone depend on many factors; bone micro-morphology is one of the main features. A bone compact-tension simulation model with zero-thickness cohesive element is employed in this study to investigate the effect of micro-morphology of cortical bone on fracture toughness and crack propagation. Various groups of bone sample – from young, senior, diseased and treated patients – were studied. It was found that the young group has the best performance in terms of fracture resistance, with the initiation fracture toughness (K0) and slope of 1.45 MPa(m)1/2 and 1.16 MPa(m)1/2/mm, respectively. The cracks in this group propagate mostly along the cement line to protect osteons from crack penetration.

Strontium ranelate and fluoride salts are therapeutic options to reduce fracture risk in osteoporosis. Incorporation of these elements in the physiological hydroxyapatite matrix of bone is accompanied by changes in bone remodeling, composition, and structure. However, a direct comparison of the effectiveness of strontium and fluoride treatment in human cortical bone with a focus on the resulting mechanical properties remains to be established. Study groups are composed of undecalcified specimens from healthy controls, treatment-naive osteoporosis cases, and strontium ranelate or fluoride-treated osteoporosis cases. Concentrations of both elements were determined using instrumental neutron activation analysis (INAA). Backscattered electron imaging was carried out to investigate the calcium content and the cortical microstructure. In comparison to osteoporotic patients, fluoride and strontium-treated patients have a lower cortical porosity indicating an improvement in bone microstructure. Mechanical properties were assessed via reference point indentation as a measure of bone's resistance to deformation. The strontium-incorporation led to significantly lower total indentation distance values compared to osteoporotic cases; controls have the highest resistance to indentation. In conclusion, osteoporosis treatment with strontium and fluoride showed positive effects on the microstructure and the mechanical characteristics of bone in comparison to treatment-naive osteoporotic bone. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 433-442, 2017.

Notch signaling is a key pathway controlling various cell fate decisions during embryogenesis and adult life. It is activated by binding of specific ligands to four different Notch receptors that are subsequently cleaved by presenilins to release an intracellular domain that enters the nucleus and activates specific transcription factors. While the skeletal analysis of various mouse models with activated or inactivated Notch signaling has demonstrated a general impact of this pathway on bone remodeling, the more recent identification of NOTCH2 mutations in individuals with Hajdu-Cheney syndrome (HCS) has highlighted its human relevance. Since HCS is primarily characterized by skeletal defects, these latter findings led us to analyze the specific role of Notch2 in skeletal remodeling. After observing Notch2 expression in osteoblasts and osteoclasts, we utilized Runx2-Cre and Lyz2-Cre mice to inactivate Notch2 in cells of the osteoblast or osteoclast lineage, respectively. Whereas Notch2(fl/fl)/Lyz2-Cre mice did not display significant alterations of skeletal growth, bone mass or remodeling, Notch2(fl/fl)/Runx2-Cre mice progressively developed skeletal abnormalities in long bones. More specifically, these mice displayed a striking increase of trabecular bone mass in the proximal femur and the distal tibia at 6 and 12months of age. Whereas undecalcified sectioning of the respective regions did not reveal impaired osteocyte differentiation as a potential trigger for the observed phenotype, ex vivo experiments with bone marrow cells identified an increased osteogenic capacity of Notch2(fl/fl)/Runx2-Cre cultures. Collectively, our findings demonstrate that Notch2 physiologically regulates bone remodeling by inhibiting trabecular bone formation in the appendicular skeleton. Understanding the underlying mechanisms may help to improve diagnosis and therapy of HCS.

In the spirit of Merton (1973) , we assert that temporary aggregate market illiquidity is compensated for in the form of higher conditional market returns. In order to test this hypothesis, we use two available liquidity proxies, namely versions of the Amihud illiquidity measure and a measure based on exchange traded fund prices. Our investigation is based on vector autoregressive models for the German stock market between July 2006 and June 2010. The fund-based illiquidity proxy dominates in capturing consistent results for the determination of time-varying market returns. Temporary illiquidity is indeed compensated for by higher market returns. We confirm a bidirectional relation between illiquidity and market returns, i.e. current returns depend on lagged illiquidity and current illiquidity can be determined by a combination of past returns as well as past illiquidity. The relation shows that illiquidity is persistent and driven by market declines.

We study the magnitude of tail risk – particularly lower tail downside risk – that is present in intraday versus overnight market returns and thereby examine the nature of the respective market risk borne by market participants. Using the Generalized Pareto Distribution for the return innovations, we use a GARCH model for the conditional market return components of major stock markets covering the U.S., France, Germany and Japan. Testing for fat-tails and tail index equality, we find that overnight return innovations exhibit significant tail risk, while intraday innovations do not. We illustrate this volatility versus tail risk trade-off based on conditional Value-at-Risk calculations. Our results show that overnight downside market risk is composed of a moderate volatility risk component and a significant tail risk component. We conclude that market participants face different intraday versus overnight risk profiles and that a risk assessment based on volatility only will severely underestimate overnight downside risk.

Bone fracture risk is influenced by bone quality, which encompasses bone's composition as well as its multiscale organization and architecture. Aging and disease deteriorate bone quality, leading to reduced mechanical properties and higher fracture incidence. Largely unexplored is how bone quality and mechanical competence progress during longitudinal bone growth. Human femoral cortical bone was acquired from fetal (n = 1), infantile (n = 3), and 2- to 14-year-old cases (n = 4) at the mid-diaphysis. Bone quality was assessed in terms of bone structure, osteocyte characteristics, mineralization, and collagen orientation. The mechanical properties were investigated by measuring tensile deformation at multiple length scales via synchrotron X-ray diffraction. We find dramatic differences in mechanical resistance with age. Specifically, cortical bone in 2- to 14-year-old cases exhibits a 160% greater stiffness and 83% higher strength than fetal/infantile cases. The higher mechanical resistance of the 2- to 14-year-old cases is associated with advantageous bone quality, specifically higher bone volume fraction, better micronscale organization (woven versus lamellar), and higher mean mineralization compared with fetal/infantile cases. Our study reveals that bone quality is superior after remodeling/modeling processes convert the primary woven bone structure to lamellar bone. In this cohort of female children, the microstructural differences at the femoral diaphysis were apparent between the 1- to 2-year-old cases. Indeed, the lamellar bone in 2- to 14-year-old cases had a superior structural organization (collagen and osteocyte characteristics) and composition for resisting deformation and fracture than fetal/infantile bone. Mechanistically, the changes in bone quality during longitudinal bone growth lead to higher fracture resistance because collagen fibrils are better aligned to resist tensile forces, while elevated mean mineralization reinforces the collagen scaffold. Thus, our results reveal inherent weaknesses of the fetal/infantile skeleton signifying its inferior bone quality. These results have implications for pediatric fracture risk, as bone produced at ossification centers during children's longitudinal bone growth could display similarly weak points. © 2019 American Society for Bone and Mineral Research.

Within the mineralized bone, osteocytes form a multifunctional mechanosensitive network orchestrating bone remodelling. A preserved osteocyte population is a crucial determinant of bone quality. In human auditory ossicles, the early decrease in osteocyte numbers but maintained integrity remains an unexplained phenomenon that might serve for sound transmission from air to the labyrinth. Here we analysed the frequency, size and composition of osteocyte lacunae in the auditory ossicles of 22 individuals from early postnatal period to old age. Mineralization of the bone matrix was determined using backscattered electron imaging. No signs of bone remodelling were observed above the age of 1 year. We detected characteristics of early bone tissue aging, such as decrease in osteocytes, lower total lacunar density and lacunar area, as well as high matrix mineralization accompanied by distinct accumulation of micropetrotic lacunae and decreased indentation depths. The majority of these changes took place in the first months and years of life, while afterwards only minor reorganization was present. With osteocyte apoptosis potentially being a consequence of low mechanical stimuli, the early loss of osteocytes without initiation of bone remodelling indicates an adaptive response conserving the architecture of the auditory ossicles and ensuring stable sound transmission throughout life.

Strontium ranelate and fluoride salts are therapeutic options to reduce fracture risk in osteoporosis. Incorporation of these elements in the physiological hydroxyapatite matrix of bone is accompanied by changes in bone remodeling, composition, and structure. However, a direct comparison of the effectiveness of strontium and fluoride treatment in human cortical bone with a focus on the resulting mechanical properties remains to be established. Study groups are composed of undecalcified specimens from healthy controls, treatment-naïve osteoporosis cases, and strontium ranelate or fluoride-treated osteoporosis cases. Concentrations of both elements were determined using instrumental neutron activation analysis (INAA). Backscattered electron imaging was carried out to investigate the calcium content and the cortical microstructure. In comparison to osteoporotic patients, fluoride and strontium-treated patients have a lower cortical porosity indicating an improvement in bone microstructure. Mechanical properties were assessed via reference point indentation as a measure of bone's resistance to deformation. The strontium-incorporation led to significantly lower total indentation distance values compared to osteoporotic cases; controls have the highest resistance to indentation. In conclusion, osteoporosis treatment with strontium and fluoride showed positive effects on the microstructure and the mechanical characteristics of bone in comparison to treatment-naïve osteoporotic bone. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 433-442, 2017.

The objective of this study was to elucidate micromechanical properties of Biodentine and two experimental calcium silicate cements (CSCs) using Reference Point Indentation (RPI). Biomechanical characteristics of the cement type and the effects of a radiopacifier, liquid components, acid etching treatment and bioactivation in simulated body fluid (SBF) were investigated by measuring the microhardness, average unloading slope (Avg US) and indentation distance increase (IDI). Biodentine had a greater microhardness than the experimental CSCs, while the Avg US and IDI values were not significantly different among investigated materials. There was a statistically significant difference in microhardness and IDI values between pure CSCs and radiopacified cements (p

Bisphosphonates are a common treatment to reduce osteoporotic fractures. This treatment induces osseous structural and compositional changes accompanied by positive effects on osteoblasts and osteocytes. Here, we test the hypothesis that restored osseous cell behavior, which resembles characteristics of younger, healthy cortical bone, leads to improved bone quality. Microarchitecture and mechanical properties of young, treatment-naïve osteoporosis and bisphosphonate-treated cases were investigated in femoral cortices. Tissue strength was measured using three-point bending. Collagen fibril-level deformation was assessed in non-traumatic and traumatic fracture states using synchrotron small-angle x-ray scattering (SAXS) at low and high strain rates. The lower modulus, strength and fibril deformation measured at low strain rates reflects susceptibility for osteoporotic low-energy fragility fractures. Independent of age, disease and treatment status, SAXS revealed reduced fibril plasticity at high strain rates, characteristic of traumatic fracture. The significantly reduced mechanical integrity in osteoporosis may originate from porosity and alterations to the intra/extrafibrillar structure, while the fibril deformation under treatment indicates improved nano-scale characteristics. In conclusion, losses in strength and fibril deformation at low strain rates correlate with the occurrence of fragility fractures in osteoporosis, while improvements in structural and mechanical properties following bisphosphonate treatment may foster resistance to fracture during physiological strain rates.

Health risks due to chronic exposure to highly fluoridated groundwater could be underestimated because fluoride might not only influence the teeth in an aesthetic manner but also seems to led to dentoalveolar structure changes. Therefore, we studied the tooth and alveolar bone structures of Dorper sheep chronically exposed to very highly fluoridated and low calcium groundwater in the Kalahari Desert in comparison to controls consuming groundwater with low fluoride and normal calcium levels within the World Health Organization (WHO) recommended range. Two flocks of Dorper ewes in Namibia were studied. Chemical analyses of water, blood and urine were performed. Mineralized tissue investigations included radiography, HR-pQCT analyses, histomorphometry, energy-dispersive X-ray spectroscopy and X-ray diffraction-analyses. Fluoride levels were significantly elevated in water, blood and urine samples in the Kalahari group compared to the low fluoride control samples. In addition to high fluoride, low calcium levels were detected in the Kalahari water. Tooth height and mandibular bone quality were significantly decreased in sheep, exposed to very high levels of fluoride and low levels of calcium in drinking water. Particularly, bone volume and cortical thickness of the mandibular bone were significantly reduced in these sheep. The current study suggests that chronic environmental fluoride exposure with levels above the recommended limits in combination with low calcium uptake can cause significant attrition of teeth and a significant impaired mandibular bone quality. In the presence of high fluoride and low calcium-associated dental changes, deterioration of the mandibular bone and a potential alveolar bone loss needs to be considered regardless whether other signs of systemic skeletal fluorosis are observed or not.

Structural integrity of bone tissue plays an important role in daily activities of humans. However, traumatic incidents such as sports injuries, collisions and falls can cause bone fracture, servere pain and mobility loss. In addition, ageing and degenerative bone diseases such as osteoporosis can increase the risk of fracture [1]. As a composite-like material, a cortical bone tissue is capable of tolerating moderate fracture/cracks without complete failure. The key to this is its heterogeneously distributed microstructural constituents providing both intrinsic and extrinsic toughening mechanisms. At micro-scale level, cortical bone can be considered as a four-phase composite material consisting of osteons, Haversian canals, cement lines and interstitial matrix. These microstructural constituents can directly affect local distributions of stresses and strains, and, hence, crack initiation and propagation. Therefore, understanding the effect of micromorphology of cortical bone on crack initiation and propagation, especially under dynamic loading regimes is of great importance for fracture risk evaluation. In this study, random microstructures of a cortical bone tissue were modelled with finite elements for four groups: healthy (control), young age, osteoporosis and bisphosphonate-treated, based on osteonal morphometric parameters measured from microscopic images for these groups. The developed models were loaded under the same dynamic loading conditions, representing a direct impact incident, resulting in progressive crack propagation. An extended finite-element method (X-FEM) was implemented to realize solution-dependent crack propagation within the microstructured cortical bone tissues. The obtained simulation results demonstrate significant differences due to micromorphology of cortical bone, in terms of crack propagation characteristics for different groups, with the young group showing highest fracture resistance and the senior group the lowest.

We study the magnitude of tail risk --- particularly lower tail downside risk --- that is present in intraday versus overnight market returns and thereby examine the nature of the respective market risk borne by market participants. Using the Generalized Pareto Distribution for the return innovations, we use a GARCH model for the conditional market return components of major stock markets covering the U.S., France, Germany and Japan. Testing for fat-tails and tail index equality, we find that overnight return innovations exhibit significant tail risk, while intraday innovations do not. We illustrate this volatility versus tail risk trade-off based on conditional Value-at-Risk calculations. Our results show that overnight downside market risk is composed of a moderate volatility risk component and a significant tail risk component. We conclude that market participants face different intraday versus overnight risk profiles and that a risk assessment based on volatility only will severely underestimate overnight downside risk.

We address credit cycle dependent sovereign credit risk determinants. In our model, the spread determinants' magnitude is conditional on an unobservable endogenous sovereign credit cycle as represented by the underlying state of a Markov regime switching process. Our explanatory variables are motivated in the tradition of structural credit risk models and include changes in asset prices, interest rates, implied market volatility, gold price changes and foreign exchange rates. We examine daily frequency variations of U.S. dollar denominated Eurobond credit spreads of four major Latin American sovereign bond issuers (Brazil, Colombia, Mexico and Venezuela) with liquid bond markets during March 2000 to June 2011. We find that spread determinants are statistically significant and consistent with theory, while their magnitude remarkably varies with the state of the credit cycle. Crisis states are characterized by high spread change uncertainty and high sensitivities with respect to the spread change determinants. We further document that not only changes of local currencies, but also changes of the Euro with respect to the U.S. dollar are significant spread drivers and argue that this is consistent with the sovereigns' ability to pay.

Mucopolysaccharidosis-I (MPS-I) is a lysosomal storage disease (LSD) caused by inactivating mutations of IDUA, encoding the glycosaminoglycan-degrading enzyme α-l-iduronidase. Although MPS-I is associated with skeletal abnormalities, the impact of IDUA deficiency on bone remodeling is poorly defined. Here we report that Idua-deficient mice progressively develop a high bone mass phenotype with pathological lysosomal storage in cells of the osteoblast lineage. Histomorphometric quantification identified shortening of bone-forming units and reduced osteoclast numbers per bone surface. This phenotype was not transferable into wild-type mice by bone marrow transplantation (BMT). In contrast, the high bone mass phenotype of Idua-deficient mice was prevented by BMT from wild-type donors. At the cellular level, BMT did not only normalize defects of Idua-deficient osteoblasts and osteocytes but additionally caused increased osteoclastogenesis. Based on clinical observations in an individual with MPS-I, previously subjected to BMT and enzyme replacement therapy (ERT), we treated Idua-deficient mice accordingly and found that combining both treatments normalized all histomorphometric parameters of bone remodeling. Our results demonstrate that BMT and ERT profoundly affect skeletal remodeling of Idua-deficient mice, thereby suggesting that individuals with MPS-I should be monitored for their bone remodeling status, before and after treatment, to avoid long-term skeletal complications.

This paper addresses conditional sovereign credit risk determinants. In our model, the spread determinants' magnitude is conditional on an unobservable endogenous sovereign credit cycle as represented by the underlying state of a Markov regime switching process. Our explanatory variables are motivated in the tradition of structural credit risk models and include changes in asset price, interest rate, volatility and foreign exchange variables. We examine daily frequency variations of U.S. dollar denominated Eurobond credit spreads of four major Latin American sovereign issuers with liquid bond markets. We nd that spread determinants are statistically signi cant and consistent with theory while their magnitude varies with the states of our cycle variable, which characterizes low and high spread change uncertainty.We also uncover the presence of additional premium under Regime 1 where the spread volatility is stable. This premium is negatively related to the changes in credit spreads. The term structure factors exhibit much higher economic magnitudes under the high volatility sate. The response from the asset price factor to changes in credit spread is rather stable. We document that not only changes of local currencies, but also changes of the Euro with respect to the U.S. dollar are signi cant spread drivers and show that this is consistent with the sovereigns ability to meet its obligations.