Prompt Agalsidase Alfa Therapy Initiation is Associated with Improved Renal and Cardiovascular Outcomes in a Fabry Outcome Survey Analysis

BACKGROUND: The timing of enzyme replacement therapy initiation in patients with Fabry disease is hypothesized to be critical. In this study, we used Fabry Outcome Survey data to assess the impact of prompt versus delayed initiation of treatment with agalsidase alfa on cardiovascular and renal events in patients with Fabry disease. METHODS: Available genetic data at baseline were used to define patients with mutations associated with classical versus late-onset Fabry disease. Time to cardiovascular or renal events, from treatment initiation until 120 months, was compared for patients in prompt versus delayed groups. “Prompt” was defined as treatment initiation < 24 months from symptom onset (analysis A) or diagnosis (analysis B), and “delayed” was defined as ≥ 24 months from symptom onset (analysis A) or diagnosis (analysis B). Kaplan–Meier curves and Log rank tests compared event-free probabilities and time to first event. Multivariate Cox regression estimated hazard ratios (HRs). RESULTS: Analysis by time from symptom onset included 1374 patients (172 prompt, 1202 delayed). In a multivariate Cox regression analysis, prompt versus delayed treatment initiation significantly reduced the probability of cardiovascular (HR=0.62; P< 0.001) and renal (HR=0.57; P=0.001) events. History of cardiovascular or renal events was associated with increased risk of respective events. Analysis by time from diagnosis included 2051 patients (1006 prompt, 1045 delayed). In a multivariate Cox regression analysis, prompt treatment initiation significantly reduced the probability of cardiovascular events (HR=0.83; P=0.003) after adjusting for history of cardiovascular events, sex, and age at treatment initiation. Univariate analysis showed that the probability of renal events was significantly lower in the prompt group (P=0.018); this finding was attenuated in the multivariate Cox regression analysis. CONCLUSIONS: This analysis suggests that prompt treatment initiation with agalsidase alfa provided better renal and cardiovascular outcomes than delayed treatment in patients with Fabry disease

Relationship between spermatozoa motility parameters, sperm/egg ratio, and fertilization and hatching rates in pufferfish (Takifugu niphobles)

[EN] The use of high quality gametes from both males and females during in vitro fertilization (IVF) trials is an essential step in order to achieve high fertilization and hatching rates. Although aquaculture hatcheries have focused more on egg rather than spermatozoa quality, some studies have demonstrated that sperm quantity and quality have a great influence both on fertilization/hatching success and the subsequent development of the embryo and larvae. In this study we have demonstrated that sperm/egg ratio and sperm quality are factors strongly related to each other in the pufferfish (Takifugu niphobles). Our results suggest that both factors should be taken into account as unique interrelated elements, making possible to obtain high fertilization rates using a successful combination of small amount of high quality sperm or high amount of low quality sperm. In addition, coefficients of correlation and determination among all the sperm motion parameters provided by a CASA system and fertilization/hatching rates were estimated for the first time in a marine species. Positive significant correlations were found in some parameters such as total and progressive motility (0.68 and 0.7 respectively). However, curvilinear velocity (VCL), straight line velocity (VSL) and average velocity (VAP) showed the highest coefficients of correlation (0.82, 0.8, and 0.81, respectively). In this respect, spermatozoa velocity appears to be a key factor in the fertilization process, especially when the number of spermatozoa per egg is limited in the aqueous environment. (C) 2013 Elsevier B.V. All rights reserved.Funded by the Spanish Ministry of Economy and Competitiveness (MINECO; AGL2010-16009). Victor Gallego has a predoctoral grant (MINECO; BES-2009-020310) and has been granted a fellowship (EEBB-I-12-05858) of the MINECO's Spanish Personnel Research Training Programme to carry out this research in the Misaki Marine Biological Station (Miura, Japan). We would like to thank to Dr. Kurokawa for the help and knowledge supplied during this study.Gallego Albiach, V.; Pérez Igualada, LM.; Asturiano Nemesio, JF.; Yoshida, M. (2013). Relationship between spermatozoa motility parameters, sperm/egg ratio, and fertilization and hatching rates in pufferfish (Takifugu niphobles). Aquaculture. 416:238-243. https://doi.org/10.1016/j.aquaculture.2013.08.035S23824341

Timing performance of a double layer diamond detector

In order to improve the time precision of detectors based on diamonds sensors we have built a detector with two scCVD layers connected in parallel to the same amplifier. This work describes the design and the first measurements of such a prototype performed on a particle beam at CERN. With this different configuration we have obtained an improvement larger than a factor of 1.6-1.7 for the timing precision of the measurement when compared to a one layer scCVD diamond detector.Peer reviewe

Active Detectors for Plasma Soft X-Ray Detection at PALS

This paper summarizes the work carried out for an experimental study of low-energy nuclear excitation by laser-produced plasma at the PALS Prague laser facility. We describe the adaptation and shielding of single-quantum active radiation detectors developed at IEAP CTU Prague to facilitate their operation inside the laser interaction chamber in the vicinity of the plasma target. The goal of this effort is direct real-time single-quantum detection of plasma soft X-ray radiation with energy above a few keV and subsequent identification of the decay of the excited nuclear states via low-energy gamma rays in a highly radiative environment with strong electromagnetic interference

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

Optical markers of magnetic phase transition in CrSBr

Here, we investigate the role of the interlayer magnetic ordering of CrSBr in the framework of $\textit{ab initio}$ calculations and by using optical spectroscopy techniques. These combined studies allow us to unambiguously determine the nature of the optical transitions. In particular, photoreflectance measurements, sensitive to the direct transitions, have been carried out for the first time. We have demonstrated that optically induced band-to-band transitions visible in optical measurement are remarkably well assigned to the band structure by the momentum matrix elements and energy differences for the magnetic ground state (A-AFM). In addition, our study reveals significant differences in electronic properties for two different interlayer magnetic phases. When the magnetic ordering of A-AFM to FM is changed, the crucial modification of the band structure reflected in the direct-to-indirect band gap transition and the significant splitting of the conduction bands along the $\Gamma-Z$ direction are obtained. In addition, Raman measurements demonstrate a splitting between the in-plane modes $B^2_{2g}$/$B^2_{3g}$, which is temperature dependent and can be assigned to different interlayer magnetic states, corroborated by the DFT+U study. Moreover, the $B^2_{2g}$ mode has not been experimentally observed before. Finally, our results point out the origin of interlayer magnetism, which can be attributed to electronic rather than structural properties. Our results reveal a new approach for tuning the optical and electronic properties of van der Waals magnets by controlling the interlayer magnetic ordering in adjacent layers.Comment: 33 pages, 15 figure

Test of Ultra Fast Silicon Detectors for the TOTEM upgrade project

This paper describes the performance of a prototype timing detector, based on 50 mu m thick Ultra Fast Silicon Detector, as measured in a beam test using a 180 GeV/c momentum pion beam. The dependence of the time precision on the pixel capacitance and bias voltage is investigated in this paper. A timing precision from 30 ps to 100 ps (RMS), depending on the pixel capacitance, has been measured at a bias voltage of 180 V.Peer reviewe

Diamond Detectors for the TOTEM Timing Upgrade

This paper describes the design and the performance of the timing detector developed by the TOTEM Collaboration for the Roman Pots (RPs) to measure the Time-Of-Flight (TOF) of the protons produced in central diffractive interactions at the LHC. The measurement of the TOF of the protons allows the determination of the longitudinal position of the proton interaction vertex and its association with one of the vertices reconstructed by the CMS detectors. The TOF detector is based on single crystal Chemical Vapor Deposition (scCVD) diamond plates and is designed to measure the protons TOF with about 50 ps time precision. This upgrade to the TOTEM apparatus will be used in the LHC run 2 and will tag the central diffractive events up to an interaction pileup of about 1. A dedicated fast and low noise electronics for the signal amplification has been developed. The digitization of the diamond signal is performed by sampling the waveform. After introducing the physics studies that will most profit from the addition of these new detectors, we discuss in detail the optimization and the performance of the first TOF detector installed in the LHC in November 2015.Comment: 26 pages, 18 figures, 2 tables, submitted for publication to JINS

Evidence for non-exponential elastic proton-proton differential cross-section at low |t| and sqrt(s) = 8 TeV by TOTEM

The TOTEM experiment has made a precise measurement of the elastic proton-proton differential cross-section at the centre-of-mass energy sqrt(s) = 8 TeV based on a high-statistics data sample obtained with the beta* = 90 optics. Both the statistical and systematic uncertainties remain below 1%, except for the t-independent contribution from the overall normalisation. This unprecedented precision allows to exclude a purely exponential differential cross-section in the range of four-momentum transfer squared 0.027 < |t| < 0.2 GeV^2 with a significance greater than 7 sigma. Two extended parametrisations, with quadratic and cubic polynomials in the exponent, are shown to be well compatible with the data. Using them for the differential cross-section extrapolation to t = 0, and further applying the optical theorem, yields total cross-section estimates of (101.5 +- 2.1) mb and (101.9 +- 2.1) mb, respectively, in agreement with previous TOTEM measurements.Comment: Final version published in Nuclear Physics