Qualification of Fiber Reinforced Polymer materials (FRP’s) for manufacturing of structural components in the aerospace industry is usually associated with extensive and costly experimental ...campaigns. The burden of testing is immense and materials should be characterized under different loading states (tension, compression, shear) and environmental conditions (temperature, humidity) to probe their structural integrity during service life. Recent developments in multiscale simulation, together with increased computational power and improvements in modeling tools, can be used to alleviate this scenario. In this work, high-fidelity simulations of the material behavior at the micro level are used to predict ply properties and ascertain the effect of ply constituents and microstructure on the homogenized ply behavior. This approach relies on the numerical analysis of representative volume elements equipped with physical models of the ply constituents. Its main feature is the ability to provide fast predictions of ply stiffness and strength properties for different environmental conditions of temperature and humidity, in agreement with the experimental results, showing the potential to reduce the time and costs required for material screening and characterization.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary
Background
Autoimmune hepatitis requires long‐term therapy, and systemic corticosteroids are the backbone of therapeutic management. Prolonged use of corticosteroids may lead to adverse ...events but data from long‐term studies are mainly derived from studies in rheumatic diseases.
Aim
To assess cataract, diabetes and fractures in relation to corticosteroid doses in the long‐term maintenance treatment of patients with autoimmune hepatitis.
Methods
We retrospectively collected data on 476 patients (77% women) with an established diagnosis of autoimmune hepatitis. Binary logistic regression with a generalised estimating equation was used to analyse the association between current corticosteroid use and the incidence of cataract, diabetes and fractures with onset after autoimmune hepatitis diagnosis. We corrected for sex, age, cirrhosis at diagnosis and predniso(lo)ne use in the prior 3 years to account for possible ongoing effects.
Results
A total of 6634 years, with a median of 13 (range 1‐40) per patient were recorded. The median age at diagnosis was 44 years (range 2‐88). Adverse events were documented in 120 (25%) patients. Low‐dose predniso(lo)ne (0.1‐5.0 mg/d) increased the odds of fractures whereas higher doses (>5.0 mg/d) increased the odds of cataracts and diabetes. Budesonide increased the odds of cataract and fractures; this effect was independent of predniso(lo)ne use in the prior 1, 2 or 3 years.
Conclusions
Even low doses of corticosteroids frequently lead to substantial adverse events refuting the assumption that adverse events are prevented by administering low doses.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The determination of ply properties of Fiber Reinforced Polymers (FRP) for particular operational environmental conditions in aeronautical applications is mandatory in order to fulfill current ...industry stringent certification requirements. However, the traditional experimental approach requires massive investments of resources and time. From the behaviour obtained experimentally, constitutive equations including failure criteria are then devised to be used in the design of FRP structures. The ply longitudinal behaviour under compression is generally the most difficult to measure and characterize. In this work, an alternative coupled experimental-computational micromechanics approach is proposed to determine the longitudinal compression properties of unidirectional FRP plies under different environmental conditions. This methodology includes experimental characterization of matrix and fiber/matrix interface, combined with numerical simulations of realistic microstructures. The interface decohesion is simulated using cohesive-frictional interactions. A pressure dependent, elasto-plastic model that includes tensile damage is employed to capture the matrix nonlinear behaviour. The numerical predictions match the experimentally-obtained ply properties available in the literature in a remarkable way and suggest that virtual ply property characterization is a mature and reliable approach to conduct screening of materials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The foodborne pathogen Listeria monocytogenes has the ability to produce biofilms in food-processing environments and then contaminate food products, which is a major concern for food safety. The ...biofilm forming behavior of 143 L. monocytogenes strains was determined in four different media that were rich, moderate or poor in nutrients at 12°C, 20°C, 30°C and 37°C. The biofilm formation was mostly influenced by temperature, resulting in decreased biofilm formation with decreasing temperature. Biofilm formation was enhanced in nutrient-poor medium rather than in nutrient-rich medium, and especially in nutrient-poor medium significantly enhanced biofilm production was observed early in biofilm maturation underlining the effect of medium on biofilm formation rate. Also serotype had a significant effect on biofilm formation and was influenced by medium used because strains from both serotype 1/2b and 1/2a formed more biofilm than serotype 4b strains in nutrient-rich medium at 20°C, 30°C and 37°C, whereas in nutrient-poor medium the biofilm production levels of serotype 1/2a and 4b strains were rather similar and lower than serotype 1/2b strains. The strains used originated from various origins, including dairy, meat, industrial environment, human and animal, and the level of biofilm formation was not significantly affected by the origin of isolation, irrespective of medium used and temperature tested. A linear model was used to correlate crystal violet staining of biofilm production to the number of viable cells within the biofilm. This showed that crystal violet staining was poorly correlated to the number of viable cells in nutrient-poor medium, and LIVE/DEAD staining and DNase I treatment revealed that this could be attributed to the presence of non-viable cells and extracellular DNA in the biofilm matrix. The significant impact of intrinsic and extrinsic factors on biofilm production of L. monocytogenes underlined that niche-specific features determine the levels of biofilm produced, and insights in biofilm formation characteristics will allow us to further optimize strategies to control the biofilm formation of L. monocytogenes.
•Temperature was the most important factor influencing biofilm production.•Nutrient-poor rather than nutrient-rich medium enhanced biofilm production.•Effect of serotype on biofilm production was significant and influenced by medium.•Biofilm production was not significantly affected by the origin of isolation.•Poor correlation of CV staining and viable biofilm cells due to non-viable cells and eDNA
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Myeloperoxidase (MPO) is a heme-containing peroxidase abundantly expressed in neutrophils and to a lesser extent in monocytes. Enzymatically active MPO, together with hydrogen peroxide and chloride, ...produces the powerful oxidant hypochlorous acid and is a key contributor to the oxygen-dependent microbicidal activity of phagocytes. In addition, excessive generation of MPO-derived oxidants has been linked to tissue damage in many diseases, especially those characterized by acute or chronic inflammation. It has become increasingly clear that MPO exerts effects that are beyond its oxidative properties. These properties of MPO are, in many cases, independent of its catalytic activity and affect various processes involved in cell signaling and cell-cell interactions and are, as such, capable of modulating inflammatory responses. Given these diverse effects, an increased interest has emerged in the role of MPO and its downstream products in a wide range of inflammatory diseases. In this article, our knowledge pertaining to the biologic role of MPO and its downstream effects and mechanisms of action in health and disease is reviewed and discussed.
Treatment of Fabry disease (FD) with recombinant alpha-galactosidase A (r-αGAL A) is complicated by the formation of anti-drug antibodies in the majority of male patients with the classical disease ...phenotype. Detailed information regarding antibody subtypes, onset and persistence of antibody development and their effect on treatment efficacy is sparse.
A retrospective study was carried out in 39 male patients with classical FD, treated with either agalsidase-alfa or agalsidase-beta (mean follow up of 10 years). With six to twelve months intervals plasma-induced in vitro inhibition of enzyme activity, lysoglobotriaosylsphingosine (lysoGb3) levels and renal function were assessed. In a subset of 12 patients, additionally anti- r-αGAL A IgM, IgA and IgG1, 2, 3 and 4 levels were analyzed.
In 23 out of 39 patients, plasma-induced in vitro inhibition of r-αGAL A activity was observed (inhibition-positive). The inhibition titer was strongly negatively correlated to the decrease in lysoGb3: agalsidase-alfa (FElog10(inhibition) = −10.3, P ≤.001), agalsidase-beta (FElog10(inhibition) = −4.7, P ≤.001). Inhibition-positive patients had an accelerated decline in renal function (FE = 1.21, p = .042). During treatment IgG1 anti-r-αGAL A levels increased only in inhibition-positive patients (p = .0045). IgG4 anti-r-αGAL A antibodies developed in 7 out of 9 inhibition-positive patients. Other antibody subclasses were either not present or too low to quantify.
Development of inhibiting antibodies against r-αGAL A negatively affects the biochemical response to ERT and resulted in an accelerated decline in renal function. The presence of IgG1 and IgG4 anti-r-αGAL A antibodies is associated with in vitro αGAL A activity inhibition.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ABSTRACT
The mergers of two neutron stars are typically accompanied by broad-band electromagnetic emission from either a relativistic jet or a kilonova. It has also been long predicted that coherent ...radio emission will occur during the merger phase or from a newly formed neutron star remnant; however, this emission has not been seen to date. This paper presents the deepest limits for this emission from a neutron star merger, following triggered LOFAR observations of the short gamma-ray burst 181123B, starting 4.4 min after the GRB occurred. During the X-ray plateau phase, a signature of ongoing energy injection, we detect no radio emission to a 3σ limit of 153 mJy at 144 MHz (image integration time of 136 s), which is significantly fainter than the predicted emission from a standard neutron star. At a redshift of 1.8, this corresponds to a luminosity of 2.5 × 1044 erg s−1. Snapshot images were made of the radio observation on a range of time-scales, targeting short-duration radio flashes similar to fast radio bursts. No emission was detected in the snapshot images at the location of GRB 181123B enabling constraints to be placed on the prompt coherent radio emission model and emission predicted to occur when a neutron star collapses to form a black hole. At the putative host redshift of 1.8 for GRB 181123B, the non-detection of the prompt radio emission is two orders of magnitude lower than expected for magnetic reconnection models for prompt GRB emission and no magnetar emission is expected.
Targeted cancer therapy with monoclonal antibodies has proven successful for different cancer types but is limited by the availability of suitable antibody targets. CD43s, a unique sialylated form of ...CD43 expressed by hematologic malignancies, is a recently identified target and antibodies interacting with CD43s may have therapeutic potential against acute myeloid leukemia (AML) and myelodysplastic syndrome. CD43s is recognized by the human antibody AT1413, that was derived from a high-risk AML patient who successfully cleared leukemia after allogeneic stem cell transplantation. Here we observed that AT1413 binds also to certain non-hematopoietic tumor cells, particularly melanoma and breast cancer. AT1413 immune precipitated CD43s from melanoma cells confirming that it recognizes the same target on melanoma as on AML. AT1413 induced antibody-dependent cellular cytotoxicity against short-term cultured patient-derived melanoma samples. However, AT1413 was unable to affect the growth of melanoma cells in vivo. To increase the efficacy of AT1413 as a therapeutic antibody, we generated two different formats of bispecific T-cell engaging antibodies (TCEs): one binding bivalently (bTCE) and the other monovalently (knob-in-hole; KiH) to both CD43s and CD3ε. In vitro, these TCEs redirected T-cell cytotoxicity against melanoma cells with differences in potencies. To investigate their effects in vivo, we grafted mice that harbor a human immune system with the melanoma cell line A375. Treatment with both AT1413 bTCE and AT1413 KiH significantly reduced tumor outgrowth in these mice. These data indicate a broad therapeutic potential of AT1413 that includes AML and CD43s-expressing solid tumors that originate from CD43-negative tissues.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Enzyme replacement therapy (ERT) slows disease progression of Fabry disease (FD), especially when initiated before the onset of irreversible organ damage. However, with the clinically asymptomatic ...progression of renal, cardiac and cerebral disease manifestations spanning decades, optimal timing of ERT initiation remains unclear.
In this cross-sectional retrospective study, seven male FD patients with a classical disease phenotype (cFD) who started treatment with agalsidase-beta in childhood were evaluated after 10 years of treatment (median age at evaluation 24 years, range 14–26). Cardiac imaging (echocardiography and MRI), electrophysiological and biochemical data of these patients were compared to those of untreated male cFD patients (n = 23, median age 22 years, range 13–27).
Albuminuria was less common and less severe in treated patients (albumin to creatinine ratio, ACR 0–8.8 mg/mmol, median 0.4) compared to untreated patients (ACR 0–248 mg/mmol, median 3.7, p = 0.02). The treated group had a lower left ventricular mass, measured using echocardiography (median 80 g/m2 versus 94 g/m2, p = 0.02) and MRI (median 53 g/m2 versus 68 g/m2, p = 0.02). Myocardial fibrosis was absent in all included patients. eGFR was normal in all treated patients whereas 7/23 (30%) of untreated patients had abnormal eGFR. Cerebral manifestations did not differ.
Start of treatment with ERT before age 16, in male cFD patients is associated with reduced occurrence of renal and cardiac manifestations of FD, as assessed by intermediate endpoints. Confirmation that this approach delays or even prevents renal failure and cardiac events requires another decade of follow-up.
•Starting ERT early, before the age of 16, in male FD patients with a classical phenotype is associated with reduced risk and severity of albuminuria.•Starting ERT early, before the age of 16, in male FD patients with a classical phenotype slows down left ventricular hypertrophy.•This study provides clinical comparative evidence (early treated vs untreated) to support early start of ERT in male patients with classical FD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ABSTRACT
The nature of the central engines of gamma-ray bursts (GRBs) and the composition of their relativistic jets are still under debate. If the jets are Poynting flux dominated rather than baryon ...dominated, a coherent radio flare from magnetic reconnection events might be expected with the prompt gamma-ray emission. There are two competing models for the central engines of GRBs; a black hole or a newly formed millisecond magnetar. If the central engine is a magnetar it is predicted to produce coherent radio emission as persistent or flaring activity. In this paper, we present the deepest limits to date for this emission following LOFAR rapid response observations of GRB 180706A. No emission is detected to a 3σ limit of 1.7 mJy beam−1 at 144 MHz in a 2-h LOFAR observation starting 4.5 min after the gamma-ray trigger. A forced source extraction at the position of GRB 180706A provides a marginally positive (1σ) peak flux density of 1.1 ± 0.9 mJy. The data were time sliced into different sets of snapshot durations to search for FRB like emission. No short duration emission was detected at the location of the GRB. We compare these results to theoretical models and discuss the implications of a non-detection.
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