22 research outputs found

    Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

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    Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.This work was supported by the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (FIS; PI16/00425 and PI19/00321), Centro de Investigaci贸n Biom茅dica en Red Enfermedades Raras (CIBERER, 06/07/0036), IIS-FJD BioBank (PT13/0010/0012), Comunidad de Madrid (CAM, RAREGenomics Project, B2017/BMD-3721), European Regional Development Fund (FEDER), the Organizaci贸n Nacional de Ciegos Espa帽oles (ONCE), Fundaci贸n Ram贸n Areces, Fundaci贸n Conchita R谩bago and the University Chair UAM-IIS-FJD of Genomic Medicine. Irene Perea-Romero is supported by a PhD fellowship from the predoctoral Program from ISCIII (FI17/00192). Ionut F. Iancu is supported by a grant from the Comunidad de Madrid (CAM, PEJ-2017-AI/BMD7256). Marta del Pozo-Valero is supported by a PhD grant from the Fundaci贸n Conchita R谩bago. Berta Almoguera is supported by a Juan Rodes program from ISCIII (JR17/00020). Pablo Minguez is supported by a Miguel Servet program from ISCIII (CP16/00116). Marta Corton is supported by a Miguel Servet program from ISCIII (CPII17/00006). The funders played no role in study design, data collection, data analysis, manuscript preparation and/or publication decisions

    Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

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    Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

    Preparing Phase 4 of the n_TOF/CERN facility

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    After CERN鈥檚 Long Shutdown 2, the n_TOF facility infrastructure was largely upgraded. The biggest change is the installation of a new lead spallation target, the performance of which needs to be carefully examined. During Summer 2021, the facility鈥檚 two flight paths were characterised in terms of neutron beam energy distribution, profile and resolution. In this work, the characterisation of the facility is described and the first results are given

    Chiral Microneedles from an Achiral Bis(boron dipyrromethene): Spontaneous Mirror Symmetry Breaking Leading to a Promising Photoluminescent Organic Material

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    Supramolecular self-assembly of a highly flexible and achiral meso bis(boron dipyrromethene) [bis(BODIPY)] dye straightforwardly yields fluorescent microfibers, exhibiting an intriguing anisotropic photonic behavior. This performance includes the generation of chiroptical activity owing to spontaneous mirror symmetry breaking (SMSB). Repetition of several self-assembly experiments demonstrates that the involved SMSB is not stochastic but quasi deterministic in the direction of the induced chiral asymmetry. The origin of these intriguing (chiro)photonic properties is revealed by fluorescent microspectroscopy studies of individual micrometric objects, combined with X-ray diffraction elucidation of microcrystals. Such a study demonstrates that J-like excitonic coupling between bis(BODIPY) units plays a fundamental role in their supramolecular organization, leading to axial chirality. Interestingly, the photonic behavior of the obtained fibers is ruled by inherent nonradiative pathways from the involved push-pull chromophores, and mainly by the complex excitonic interactions induced by their anisotropic supramolecular organization

    Ibiza Absolute Calibration Experiment : Survey and Preliminary Results

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    International audienceWithin the framework of a project comprising part of the Spanish Space Program related to the JASON-1 CNES (Centre National d'Etudes Spatiales)/NASA (National Aeronautics and Space Administration) mission, a campaign was conducted from June 9-17, 2003, on the Absolute Calibration Site of the island of Ibiza. The objective was to determine the local marine geoid slope under the ascending (187) and descending (248) Jason-1 ground tracks, in order to allow a better extrapolation of the open-ocean altimetric data with on-shore tide gauge locations, and thereby improve the overall precision of the calibration process. For this we have used a catamaran with two GPS antennas onboard, following the Corsica/Senetosa design (Bonnefond et al. 2003a). Five GPS reference stations were deployed in order to reduce the distance between the areas covered by the catamaran and the fixed GPS receiver used in the kinematic process. The geodetic activities (e.g., GPS, leveling) have enabled the building of a very accurate (few mm) network in a reference frame compatible with the satellite altimetry missions (ITRF 2000). The GPS kinematic data were processed using two different software programmes, allowing checking of the consistency of the solutions. If the standard deviation of the differences (3.3 cm) is close to the kinematic process precision, they exhibit some large values (up to 14 cm). These large discrepancies have been reduced using a weighting based on the crossover differences. Inasmuch as the distances between the tide gauges and the areas covered by the GPS catamaran were becoming large, we have used the MOG2D ocean model (Carregravere and Lyard 2003) to correct the sea surface from tides. In the farthest areas, the crossover differences show an improvement by a factor of two. Finally, we also present preliminary results on Jason-1 altimeter calibration using the derived marine geoid. From this analysis, the altimeter bias is estimated to be 120 卤 5 mm. The quality of this first result validates the whole GPS-based marine geoid processing, for which the accuracy is estimated to be better than 3 cm rms at crossovers

    Ikskile鈥檚 transformations and their reflections in virtual space

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    Ma模istra darba 鈥濱k拧姆iles transform膩cijas un to atspogu募ojums virtu膩l膩 telp膩鈥 m膿r姆is ir noskaidrot vietas transform膩cijas izpausmes Ik拧姆iles pils膿t膩 un lauku teritorij膩, k膩 ar墨 analiz膿t to cilv膿ku uztver膿 un atspogu募ojumu virtu膩l膩 telp膩. Ma模istra darba t膿mas izv膿le ir saist墨ta ar Ik拧姆iles k膩 vietas un telpas straujo att墨st墨bu R墨gas pils膿tas piev膩rt膿, pieaugo拧o moderno tehnolo模iju lomu cilv膿ku ikdien膩, k膩 ar墨 ar autora profesion膩lo darb墨bu Ik拧姆iles novad膩 - gandr墨z desmit gadus autors ir str膩d膩jis m膿rniec墨bas jom膩. Ma模istra darbs rakst墨ts ar m膿r姆i izp膿t墨t vietas transform膩cijas izpausmes no cilv膿ka 模eogr膩fijas konceptu膩l膩 skat墨juma, lielo pils膿tu re模ionu ietekm膿, analiz膿t ietekmes un atspogu募ojumu virtu膩l膩 telp膩.Master`s thesis 鈥 Ikskile鈥檚 transformations and their reflections in virtual space鈥 purpose is to elucidate expressions of place transformations in Ikskile and rural areas, analyze the perception of space transformations and it`s reflections in virtual space. The Masters theme is based on Ikskile`s space rapid development on the outskirts of Riga and the increasing role of modern technologies in everyday life. Based on the experience of the author`s professional activities in Ikskile 鈥 nearly ten years author has worked in the sphere of field surveying. The Masters Paper aim is to explore place transformations expressions from conceptual view of human geography, taking into context the influence of growth and development of major urban areas, analyze impact and reflections in virtual space

    Multiple Viral Ligands Naturally Presented by Different Class I Molecules in Transporter Antigen Processing-Deficient Vaccinia Virus-Infected Cells

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    The transporter associated with antigen processing (TAP) delivers the viral proteolytic products generated by the proteasome in the cytosol to the endoplasmic reticulum lumen that are subsequently recognized by cytotoxic T lymphocytes (CTLs). However, several viral epitopes have been identified in TAP-deficient models. Using mass spectrometry to analyze complex human leukocyte antigen (HLA)-bound peptide pools isolated from large numbers of TAP-deficient vaccinia virus-infected cells, we identified 11 ligands naturally presented by four different HLA-A, HLA-B, and HLA-C class I molecules. Two of these ligands were presented by two different HLA class I alleles, and, as a result, 13 different HLA-peptide complexes were formed simultaneously in the same vaccinia virus-infected cells. In addition to the high-affinity ligands, one low-affinity peptide restricted by each of the HLA-A, HLA-B, and HLA-C class I molecules was identified. Both high- and low-affinity ligands generated long-term memory CTL responses to vaccinia virus in an HLA-A2-transgenic mouse model. The processing and presentation of two vaccinia virus-encoded HLA-A2-restricted antigens took place via proteasomal and nonproteasomal pathways, which were blocked in infected cells with chemical inhibitors specific for different subsets of metalloproteinases. These data have implications for the study of the effectiveness of early empirical vaccination with cowpox virus against smallpox disease

    Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

    No full text
    Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations

    Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

    No full text
    Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations
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