83 research outputs found
A Multinational Study of Acute and LongâTerm Outcomes of Type 1 Galactosemia Patients Who Carry the S135L (c.404CÂ >âT) Variant of GALT
Patients with galactosemia who carry the S135L (c.404C > T) variant of galactose-1-P uridylyltransferase (GALT), documented to encode low-level residual GALT activity, have been under-represented in most prior studies of outcomes in Type 1 galactosemia. What is known about the acute and long-term outcomes of these patients, therefore, is based on very limited data. Here, we present a study comparing acute and long-term outcomes of 12 patients homozygous for S135L, 25 patients compound heterozygous for S135L, and 105 patients homozygous for two GALT-null (G) alleles. This is the largest cohort of S135L patients characterized to date. Acute disease following milk exposure in the newborn period was common among patients in all 3 comparison groups in our study, as were long-term complications in the domains of speech, cognition, and motor outcomes. In contrast, while at least 80% of both GALT-null and S135L compound heterozygous girls and women showed evidence of an adverse ovarian outcome, prevalence was only 25% among S135L homozygotes. Further, all young women in this study with even one copy of S135L achieved spontaneous menarche; this is true for only about 33% of women with classic galactosemia. Overall, we observed that while most long-term outcomes trended milder among groups of patients with even one copy of S135L, many individual patients, either homozygous or compound heterozygous for S135L, nonetheless experienced long-term outcomes that were not mild. This was true despite detection by newborn screening and both early and life-long dietary restriction of galactose. This information should empower more evidence-based counseling for galactosemia patients with S135L.info:eu-repo/semantics/publishedVersio
The diagnosis and management of patients with idiopathic osteolysis
Idiopathic osteolysis or disappearing bone disease is a condition characterized by the spontaneous onset of rapid destruction and resorption of a single bone or multiple bones. Disappearing bone disorder is a disease of several diagnostic types. We are presenting three patients with osteolysis who have different underlying pathological features. Detailed phenotypic assessment, radiologic and CT scanning, and histological and genetic testing were the baseline diagnostic tools utilized for diagnosis of each osteolysis syndrome. The first patient was found to have Gorham-Stout syndrome (non-heritable). The complete destruction of pelvic bones associated with aggressive upward extension to adjacent bones (vertebral column and skull base) was notable and skeletal angiomatosis was detected. The second patient showed severe and aggressive non-hereditary multicentric osteolysis with bilateral destruction of the hip bones and the tarsal bones as well as a congenital unilateral solitary kidney and nephropathy. The third patient was phenotypically and genotypically compatible with Winchester syndrome resulting in multicentric osteolysis (autosomal recessive). Proven mutation of the (MMP2-Gen) was detected in this third patient that was associated with 3MCC deficiency (3-Methylcrontonyl CoA Carboxylase deficiency). The correct diagnoses in our 3 patients required the exclusion of malignant osteoclastic tumours, inflammatory disorders of bone, vascular disease, and neurogenic arthropathies using history, physical exam, and appropriate testing and imaging. This review demonstrates how to evaluate and treat these complex and difficult patients. Lastly, we described the various management procedures and treatments utilized for these patients
Inferior outcome after hip resurfacing arthroplasty than after conventional arthroplasty: Evidence from the Nordic Arthroplasty Register Association (NARA) database, 1995 to 2007
Today, total hip arthroplasty (THA) is one of the safest and most efficient surgical treatments. New materials, surgical techniques and design concepts intended to improve THA have not always been successful. Thorough preclinical and early clinical investigations can detect some aspects of under-performing, while continuing surveillance is recommended to detect and analyze reasons for any later appearing flaws. In this thesis, several ways to monitor and assess THA performance are explored and carried out, using survival analysis in registry studies, radiostereometry (RSA), radiology and clinical outcome.
In Paper I, a study using the Nordic Arthroplasty Register Association (NARA) registry shows that HRA had an almost 3-fold increased early non-septic revision risk and that risk factors were found to be female sex, certain HRA designs and units having performed few HRA procedures. Papers II and III contain comparisons of highly cross-linked polyethylene (XLPE) and conventional polyethylene (PE). XLPE had a considerably lower wear rate up to 10 years but showed no obvious improvements regarding implant fixation, BMD or clinical outcome. In the NARA registry, in 2 of 4 studied cup designs the XLPE version had a lower risk of revision for aseptic loosening compared to the PE version. Paper IV describes that stem subsidence and retrotorsion measured with RSA at 2 years predicted later aseptic stem failure in an unfavorably altered, previously well-functioning cemented femoral stem. In Paper V and VI, a novel approach to measure articulation wear with RSA in radiodense hip arthroplasty articulations was presented and evaluated. Subsequently, a comparison between ceramic-on-ceramic (COC) and metal-on-conventional PE uncemented THA displayed a considerably lower wear rate, smaller periacetabular bone lesions and a relatively high squeaking rate, the latter with unknown long-term consequences, in the COC hips. Implant fixation, heterotopic ossification and clinical outcome did not differ between articulation types.
In conclusion, it was confirmed that implant surveillance can be done with RSA, also in radiodense THA. Early migration predicts later aseptic implant failure. Prolonged surveillance can confirm long-term material and design performance, verify or contradict anticipated advantages as well as detect unanticipated long-term complications
Enhancement of CURB65 score with proadrenomedullin (CURB65-A) for outcome prediction in lower respiratory tract infections: Derivation of a clinical algorithm
Proadrenomedullin (ProADM) confers additional prognostic information to established clinical risk scores in lower respiratory tract infections (LRTI). We aimed to derive a practical algorithm combining the CURB65 score with ProADM-levels in patients with community-acquired pneumonia (CAP) and non-CAP-LRTI
The natural history of classic galactosemia: lessons from the GalNet registry.
BACKGROUND
Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients.
METHODS
Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018.
RESULTS
Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of â€â1% and strict galactose restriction were associated with a less favorable outcome.
CONCLUSION
This study describes the natural history of classic galactosemia based on the hitherto largest data set
The Physical Processes of CME/ICME Evolution
As observed in Thomson-scattered white light, coronal mass ejections (CMEs) are manifest as large-scale expulsions of plasma magnetically driven from the corona in the most energetic eruptions from the Sun. It remains a tantalizing mystery as to how these erupting magnetic fields evolve to form the complex structures we observe in the solar wind at Earth. Here, we strive to provide a fresh perspective on the post-eruption and interplanetary evolution of CMEs, focusing on the physical processes that define the many complex interactions of the ejected plasma with its surroundings as it departs the corona and propagates through the heliosphere. We summarize the ways CMEs and their interplanetary CMEs (ICMEs) are rotated, reconfigured, deformed, deflected, decelerated and disguised during their journey through the solar wind. This study then leads to consideration of how structures originating in coronal eruptions can be connected to their far removed interplanetary counterparts. Given that ICMEs are the drivers of most geomagnetic storms (and the sole driver of extreme storms), this work provides a guide to the processes that must be considered in making space weather forecasts from remote observations of the corona.Peer reviewe
Identification and reconstruction of low-energy electrons in the ProtoDUNE-SP detector
Measurements of electrons from interactions are crucial for the Deep
Underground Neutrino Experiment (DUNE) neutrino oscillation program, as well as
searches for physics beyond the standard model, supernova neutrino detection,
and solar neutrino measurements. This article describes the selection and
reconstruction of low-energy (Michel) electrons in the ProtoDUNE-SP detector.
ProtoDUNE-SP is one of the prototypes for the DUNE far detector, built and
operated at CERN as a charged particle test beam experiment. A sample of
low-energy electrons produced by the decay of cosmic muons is selected with a
purity of 95%. This sample is used to calibrate the low-energy electron energy
scale with two techniques. An electron energy calibration based on a cosmic ray
muon sample uses calibration constants derived from measured and simulated
cosmic ray muon events. Another calibration technique makes use of the
theoretically well-understood Michel electron energy spectrum to convert
reconstructed charge to electron energy. In addition, the effects of detector
response to low-energy electron energy scale and its resolution including
readout electronics threshold effects are quantified. Finally, the relation
between the theoretical and reconstructed low-energy electron energy spectrum
is derived and the energy resolution is characterized. The low-energy electron
selection presented here accounts for about 75% of the total electron deposited
energy. After the addition of lost energy using a Monte Carlo simulation, the
energy resolution improves from about 40% to 25% at 50~MeV. These results are
used to validate the expected capabilities of the DUNE far detector to
reconstruct low-energy electrons.Comment: 19 pages, 10 figure
Impact of cross-section uncertainties on supernova neutrino spectral parameter fitting in the Deep Underground Neutrino Experiment
A primary goal of the upcoming Deep Underground Neutrino Experiment (DUNE) is
to measure the MeV neutrinos produced by a Galactic
core-collapse supernova if one should occur during the lifetime of the
experiment. The liquid-argon-based detectors planned for DUNE are expected to
be uniquely sensitive to the component of the supernova flux, enabling
a wide variety of physics and astrophysics measurements. A key requirement for
a correct interpretation of these measurements is a good understanding of the
energy-dependent total cross section for charged-current
absorption on argon. In the context of a simulated extraction of
supernova spectral parameters from a toy analysis, we investigate the
impact of modeling uncertainties on DUNE's supernova neutrino
physics sensitivity for the first time. We find that the currently large
theoretical uncertainties on must be substantially reduced
before the flux parameters can be extracted reliably: in the absence of
external constraints, a measurement of the integrated neutrino luminosity with
less than 10\% bias with DUNE requires to be known to about 5%.
The neutrino spectral shape parameters can be known to better than 10% for a
20% uncertainty on the cross-section scale, although they will be sensitive to
uncertainties on the shape of . A direct measurement of
low-energy -argon scattering would be invaluable for improving the
theoretical precision to the needed level.Comment: 25 pages, 21 figure
Highly-parallelized simulation of a pixelated LArTPC on a GPU
The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on 10^3 pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype
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