Effects of Baseline Left Ventricular Hypertrophy and Decreased Renal Function on Cardiovascular and Renal Outcomes in Patients with Fabry Disease Treated with Agalsidase Alfa: A Fabry Outcome Survey Study

PURPOSE: The initiation of enzyme-replacement therapy prior to the occurrence of substantial and irreversible organ damage in patients with Fabry disease is of critical importance. The Fabry Outcome Survey is an international disease registry of patients with a confirmed diagnosis of Fabry disease. In this study, data from the Fabry Outcome Survey were used for the assessment of the risks for cardiovascular and renal events in patients who received agalsidase alfa treatment. METHODS: Eligible patients were males and females aged ≥18 years with Fabry disease treated with agalsidase alfa. Cardiovascular events included myocardial infarction, left ventricular hypertrophy (LVH), heart failure, arrhythmia, conduction abnormality, and cardiac surgery. Renal events included dialysis, transplantation, and renal failure. Kaplan-Meier curves and log-rank tests were used for comparing event-free probabilities and time to first cardiovascular or renal event, from agalsidase alfa initiation to a maximum of 120 months, in patients with LVH versus normal left ventricular mass index (LVMI; ≤50 g/m2.7 in males and ≤48 g/m2.7 in females) at treatment initiation (baseline), and in patients with a low estimated glomerular filtration rate (eGFR; <90 mL/min/1.73 m2) versus normal eGFR at baseline. Multivariate Cox regression analysis was used for examining the association between key study variables and the risks for cardiovascular and renal events. FINDINGS: Among the 560 patients (269 males; 291 females) with available LVMI data, 306 (55%) had LVH and 254 (45%) had normal LVMI at baseline. The risk for a cardiovascular event was higher in the subgroup with LVH versus normal LVMI at baseline (hazard ratio [HR] = 1.57; 95% CI, 1.21-2.05; P < 0.001), but the risk for a renal event was similar between the 2 subgroups (HR = 1.90; 95% CI, 0.94-3.85; P = 0.074). Among the 1093 patients (551 males; 542 females) with available eGFR data, 433 (40%) had a low eGFR and 660 (60%) had a normal eGFR at baseline. The subgroup with a low eGFR at baseline had a significantly higher risk for a cardiovascular event (HR = 1.33; 95% CI, 1.04-1.70; P = 0.021) or a renal event (HR = 5.88; 95% CI, 2.73-12.68; P < 0.001) compared with patients with a normal eGFR at baseline. IMPLICATIONS: In the present study, the presence of LVH and/or reduced renal function at agalsidase alfa initiation was associated with a significantly higher risk for a cardiovascular or renal event, indicating that cardiovascular and renal pathologies in Fabry disease may be inter-related. Early initiation of agalsidase alfa treatment prior to the onset of severe organ damage may improve outcomes. ClinicalTrials.gov identifier: NCT03289065

Sindarin: A Versatile Scripting API for the Pharo Debugger

International audienceDebugging is one of the most important and time consuming activities in software maintenance, yet mainstream debuggers are not well-adapted to several debugging scenarios. This has led to the research of new techniques covering specific families of complex bugs. Notably, recent research proposes to empower developers with scripting DSLs, plugin-based and moldable debuggers. However, these solutions are tailored to specific use-cases, or too costly for one-time-use scenarios. In this paper we argue that exposing a debugging scripting interface in mainstream debuggers helps in solving many challenging debugging scenarios. For this purpose, we present Sindarin, a scripting API that eases the expression and automation of different strategies developers pursue during their debugging sessions. Sindarin provides a GDB-like API, augmented with AST-bytecode-source code mappings and object-centric capabilities. To demonstrate the versatility of Sindarin, we reproduce several advanced breakpoints and non-trivial debugging mechanisms from the literature

Modification of the ω\omega-Meson Lifetime in Nuclear Matter

The photo production of $\omega$ mesons on the nuclei C, Ca, Nb and Pb has been measured using the Crystal Barrel/TAPS detector at the ELSA tagged photon facility in Bonn. The dependence of the $\omega$ meson cross section on the nuclear mass number has been compared with three different types of models, a Glauber analysis, a BUU analysis of the Giessen theory group and a calculation by the Valencia theory group. In all three cases, the inelastic $\omega$ width is found to be $130-150 \rm{MeV/c^2}$ at normal nuclear matter density for an average 3-momentum of 1.1 GeV/c. In the restframe of the $\omega$ meson, this inelastic $\omega$ width corresponds to a reduction of the $\omega$ lifetime by a factor $\approx 30$. For the first time, the momentum dependent $\omega$N cross section has been extracted from the experiment and is in the range of 70 mb.Comment: 5 pages, 4 figure

Ocean Acidification-Induced Food Quality Deterioration Constrains Trophic Transfer

Our present understanding of ocean acidification (OA) impacts on marine organisms caused by rapidly rising atmospheric carbon dioxide (CO2) concentration is almost entirely limited to single species responses. OA consequences for food web interactions are, however, still unknown. Indirect OA effects can be expected for consumers by changing the nutritional quality of their prey. We used a laboratory experiment to test potential OA effects on algal fatty acid (FA) composition and resulting copepod growth. We show that elevated CO2 significantly changed the FA concentration and composition of the diatom Thalassiosira pseudonana, which constrained growth and reproduction of the copepod Acartia tonsa. A significant decline in both total FAs (28.1 to 17.4 fg cell−1) and the ratio of long-chain polyunsaturated to saturated fatty acids (PUFA:SFA) of food algae cultured under elevated (750 µatm) compared to present day (380 µatm) pCO2 was directly translated to copepods. The proportion of total essential FAs declined almost tenfold in copepods and the contribution of saturated fatty acids (SFAs) tripled at high CO2. This rapid and reversible CO2-dependent shift in FA concentration and composition caused a decrease in both copepod somatic growth and egg production from 34 to 5 eggs female−1 day−1. Because the diatom-copepod link supports some of the most productive ecosystems in the world, our study demonstrates that OA can have far-reaching consequences for ocean food webs by changing the nutritional quality of essential macromolecules in primary producers that cascade up the food web

Photoproduction of pi0 omega off protons for E(gamma) < 3 GeV

Differential and total cross-sections for photoproduction of gamma proton to proton pi0 omega and gamma proton to Delta+ omega were determined from measurements of the CB-ELSA experiment, performed at the electron accelerator ELSA in Bonn. The measurements covered the photon energy range from the production threshold up to 3GeV.Comment: 8 pages, 13 figure

Atom Interferometers

Interference with atomic and molecular matter waves is a rich branch of atomic physics and quantum optics. It started with atom diffraction from crystal surfaces and the separated oscillatory fields technique used in atomic clocks. Atom interferometry is now reaching maturity as a powerful art with many applications in modern science. In this review we first describe the basic tools for coherent atom optics including diffraction by nanostructures and laser light, three-grating interferometers, and double wells on AtomChips. Then we review scientific advances in a broad range of fields that have resulted from the application of atom interferometers. These are grouped in three categories: (1) fundamental quantum science, (2) precision metrology and (3) atomic and molecular physics. Although some experiments with Bose Einstein condensates are included, the focus of the review is on linear matter wave optics, i.e. phenomena where each single atom interferes with itself.Comment: submitted to Reviews of Modern Physic

In-medium ω\omega mass from the γ+Nb→π0γ+X\gamma + Nb \to \pi^{0}\gamma + X reaction

Data on the photoproduction of $\omega$ mesons on nuclei have been re-analyzed in a search for in-medium modifications. The data were taken with the Crystal Barrel(CB)/TAPS detector system at the ELSA accelerator facility in Bonn. First results from the analysis of the data set were published by D. Trnka et al. in Phys. Rev. Lett 94 (2005) 192303 \cite{david}, claiming a lowering of the $\omega$ mass in the nuclear medium by 14$$ at normal nuclear matter density. The extracted $\omega$ line shape was found to be sensitive to the background subtraction. For this reason a re-analysis of the same data set has been initiated and a new method has been developed to reduce the background and to determine the shape and absolute magnitude of the background directly from the data. Details of the re-analysis and of the background determination are described. The $\omega$ signal on the $Nb$ target, extracted in the re-analysis, does not show a deviation from the corresponding line shape on a $LH_2$ target, measured as reference. The earlier claim of an in-medium mass shift is thus not confirmed. The sensitivity of the $\omega$ line shape to different in-medium modification scenarios is discussed.Comment: 13 pages and 11 figures, submitted for publicatio

Quasi-free photoproduction of eta-mesons of the neutron

Quasi-free photoproduction of eta-mesons off nucleons bound in the deuteron has been measured with the CBELSA/TAPS detector for incident photon energies up to 2.5 GeV at the Bonn ELSA accelerator. The eta-mesons have been detected in coincidence with recoil protons and recoil neutrons, which allows a detailed comparison of the quasi-free n(gamma,eta)n and p(gamma,eta)p reactions. The excitation function for eta-production off the neutron shows a pronounced bump-like structure at W=1.68 GeV (E_g ~ 1 GeV), which is absent for the proton.Comment: accepted for publication in Phys. Rev. Let

K^0 pi^0 Sigma^+ and K^*0 Sigma^+ photoproduction off the proton

The exclusive reactions $\gamma p \to K^{*0} \Sigma^+(1189)$ and $\gamma p \to K^{0} \pi^{0}\Sigma^+(1189)$, leading to the p 4$\pi^{0}$ final state, have been measured with a tagged photon beam for incident energies from threshold up to 2.5 GeV. The experiment has been performed at the tagged photon facility of the ELSA accelerator (Bonn). The Crystal Barrel and TAPS detectors were combined to a photon detector system of almost 4$\pi$ geometrical acceptance. Differential and total cross sections are reported. At energies close to the threshold, a flat angular distribution has been observed for the reaction $\gamma p\to K^{0} \pi^{0}\Sigma^+$ suggesting dominant s-channel production. $\Sigma^*(1385)$ and higher lying hyperon states have been observed. An enhancement in the forward direction in the angular distributions of the reaction $\gamma p \to K^{*0}\Sigma^+$ indicates a $t$-channel exchange contribution to the reaction mechanism. The experimental data are in reasonable agreement with recent theoretical predictions.Comment: 11 pages, 13 figures, submitted to EPJ

Calcium supplementation of bioinks reduces shear stress-induced cell damage during bioprinting

AbstractDuring bioprinting, cells are suspended in a viscous bioink and extruded under pressure through small diameter printing needles. The combination of high pressure and small needle diameter exposes cells to considerable shear stress, which can lead to cell damage and death. Approaches to monitor and control shear stress-induced cell damage are currently not well established. To visualize the effects of printing-induced shear stress on plasma membrane integrity, we add FM 1-43 to the bioink, a styryl dye that becomes fluorescent when bound to lipid membranes, such as the cellular plasma membrane. Upon plasma membrane disruption, the dye enters the cell and also stains intracellular membranes. Extrusion of alginate-suspended NIH/3T3 cells through a 200 µm printing needle led to an increased FM 1-43 incorporation at high pressure, demonstrating that typical shear stresses during bioprinting can transiently damage the plasma membrane. Cell imaging in a microfluidic channel confirmed that FM 1-43 incorporation is caused by cell strain. Notably, high printing pressure also impaired cell survival in bioprinting experiments. Using cell types of different stiffnesses, we find that shear stress-induced cell strain, FM 1-43 incorporation and cell death were reduced in stiffer compared to softer cell types and demonstrate that cell damage and death correlate with shear stress-induced cell deformation. Importantly, supplementation of the suspension medium with physiological concentrations of CaCl2 greatly reduced shear stress-induced cell damage and death but not cell deformation. As the sudden influx of calcium ions is known to induce rapid cellular vesicle exocytosis and subsequent actin polymerization in the cell cortex, we hypothesize that calcium supplementation facilitates the rapid resealing of plasma membrane damage sites. We recommend that bioinks should be routinely supplemented with physiological concentrations of calcium ions to reduce shear stress-induced cell damage and death during extrusion bioprinting