| 1. |
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| 2. |
- Adam, A, et al.
(author)
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Abstracts from Hydrocephalus 2016.
- 2017
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In: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 14:Suppl 1
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Journal article (peer-reviewed)
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| 3. |
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| 4. |
- van Rheenen, W, et al.
(author)
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Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
- 2021
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 53:12, s. 1636-
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Journal article (peer-reviewed)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
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| 11. |
- van Rheenen, Wouter, et al.
(author)
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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
- 2016
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
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Journal article (peer-reviewed)abstract
- To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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| 12. |
- Bale, S. D., et al.
(author)
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The FIELDS Instrument Suite for Solar Probe Plus
- 2016
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In: Space Science Reviews. - : Springer Science and Business Media LLC. - 0038-6308 .- 1572-9672. ; 204:1-4, s. 49-82
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Research review (peer-reviewed)abstract
- NASA's Solar Probe Plus (SPP) mission will make the first in situ measurements of the solar corona and the birthplace of the solar wind. The FIELDS instrument suite on SPP will make direct measurements of electric and magnetic fields, the properties of in situ plasma waves, electron density and temperature profiles, and interplanetary radio emissions, amongst other things. Here, we describe the scientific objectives targeted by the SPP/FIELDS instrument, the instrument design itself, and the instrument concept of operations and planned data products.
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| 13. |
- Bauermeister, S, et al.
(author)
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The Dementias Platform UK (DPUK) Data Portal
- 2020
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In: European journal of epidemiology. - : Springer Science and Business Media LLC. - 1573-7284 .- 0393-2990. ; 35:6, s. 601-611
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Journal article (peer-reviewed)abstract
- The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure ‘lab’ using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.
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| 14. |
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| 15. |
- Tran, Thao Thanh, et al.
(author)
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Inhibition of the master regulator of Listeria monocytogenes virulence enables bacterial clearance from spacious replication vacuoles in infected macrophages
- 2022
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In: PLoS Pathogens. - : Public Library Science. - 1553-7366 .- 1553-7374. ; 18:1
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Journal article (peer-reviewed)abstract
- A hallmark of Listeria (L.) monocytogenes pathogenesis is bacterial escape from maturing entry vacuoles, which is required for rapid bacterial replication in the host cell cytoplasm and cell-to-cell spread. The bacterial transcriptional activator PrfA controls expression of key virulence factors that enable exploitation of this intracellular niche. The transcriptional activity of PrfA within infected host cells is controlled by allosteric coactivation. Inhibitory occupation of the coactivator site has been shown to impair PrfA functions, but consequences of PrfA inhibition for L. monocytogenes infection and pathogenesis are unknown. Here we report the crystal structure of PrfA with a small molecule inhibitor occupying the coactivator site at 2.0 Å resolution. Using molecular imaging and infection studies in macrophages, we demonstrate that PrfA inhibition prevents the vacuolar escape of L. monocytogenes and enables extensive bacterial replication inside spacious vacuoles. In contrast to previously described spacious Listeria-containing vacuoles, which have been implicated in supporting chronic infection, PrfA inhibition facilitated progressive clearance of intracellular L. monocytogenes from spacious vacuoles through lysosomal degradation. Thus, inhibitory occupation of the PrfA coactivator site facilitates formation of a transient intravacuolar L. monocytogenes replication niche that licenses macrophages to effectively eliminate intracellular bacteria. Our findings encourage further exploration of PrfA as a potential target for antimicrobials and highlight that intra-vacuolar residence of L. monocytogenes in macrophages is not inevitably tied to bacterial persistence.
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| 16. |
- Akdemir, KC, et al.
(author)
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Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer
- 2020
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 52:3, s. 294-
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Journal article (peer-reviewed)abstract
- Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.
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| 17. |
- Belay, Mulugeta, et al.
(author)
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Detection of Mycobacterium tuberculosis complex DNA in CD34-positive peripheral blood mononuclear cells of asymptomatic tuberculosis contacts : an observational study
- 2021
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In: The Lancet Microbe. - 2666-5247. ; 2:6, s. 267-275
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Journal article (peer-reviewed)abstract
- Background: Haematopoietic stem cells expressing the CD34 surface marker have been posited as a niche for Mycobacterium tuberculosis complex bacilli during latent tuberculosis infection. Our aim was to determine whether M tuberculosis complex DNA is detectable in CD34-positive peripheral blood mononuclear cells (PBMCs) isolated from asymptomatic adults living in a setting with a high tuberculosis burden. Methods: We did a cross-sectional study in Ethiopia between Nov 22, 2017, and Jan 10, 2019. Digital PCR (dPCR) was used to determine whether M tuberculosis complex DNA was detectable in PBMCs isolated from 100 mL blood taken from asymptomatic adults with HIV infection or a history of recent household or occupational exposure to an index case of human or bovine tuberculosis. Participants were recruited from HIV clinics, tuberculosis clinics, and cattle farms in and around Addis Ababa. A nested prospective study was done in a subset of HIV-infected individuals to evaluate whether administration of isoniazid preventive therapy was effective in clearing M tuberculosis complex DNA from PBMCs. Follow-up was done between July 20, 2018, and Feb 13, 2019. QuantiFERON-TB Gold assays were also done on all baseline and follow-up samples. Findings: Valid dPCR data (ie, droplet counts >10 000 per well) were available for paired CD34-positive and CD34-negative PBMC fractions from 197 (70%) of 284 participants who contributed data to cross-sectional analyses. M tuberculosis complex DNA was detected in PBMCs of 156 of 197 participants with valid dPCR data (79%, 95% CI 74–85). It was more commonly present in CD34-positive than in CD34-negative fractions (154 [73%] of 197 vs 46 [23%] of 197; p<0·0001). Prevalence of dPCR-detected M tuberculosis complex DNA did not differ between QuantiFERON-negative and QuantiFERON-positive participants (77 [78%] of 99 vs 79 [81%] of 98; p=0·73), but it was higher in HIV-infected than in HIV-uninfected participants (67 [89%] of 75 vs 89 [73%] of 122, p=0·0065). By contrast, the proportion of QuantiFERON-positive participants was lower in HIV-infected than in HIV-uninfected participants (25 [33%] of 75 vs 73 [60%] of 122; p<0·0001). Administration of isoniazid preventive therapy reduced the prevalence of dPCR-detected M tuberculosis complex DNA from 41 (95%) of 43 HIV-infected individuals at baseline to 23 (53%) of 43 after treatment (p<0·0001), but it did not affect the prevalence of QuantiFERON positivity (17 [40%] of 43 at baseline vs 13 [30%] of 43 after treatment; p=0·13). Interpretation: We report a novel molecular microbiological biomarker of latent tuberculosis infection with properties that are distinct from those of a commercial interferon-γ release assay. Our findings implicate the bone marrow as a niche for M tuberculosis in latently infected individuals. Detection of M tuberculosis complex DNA in PBMCs has potential applications in the diagnosis of latent tuberculosis infection, in monitoring response to preventive therapy, and as an outcome measure in clinical trials of interventions to prevent or treat latent tuberculosis infection. Funding: UK Medical Research Council.
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| 18. |
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| 19. |
- Dand, Nick, et al.
(author)
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Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling
- 2017
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In: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 26:21, s. 4301-4313
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Journal article (peer-reviewed)abstract
- Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 x 10(-8), OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency amp;lt; 0.01) via gene-wide aggregation testing (IFIH1: p(burden) = 2.53 x 10(-7), OR = 0.707; TYK2: p(burden) = 6.17 x 10(-4), OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.
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| 20. |
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| 21. |
- Ferrari, S. L., et al.
(author)
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Diagnosis and management of bone fragility in diabetes : an emerging challenge
- 2018
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In: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 29:12, s. 2585-2596
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Journal article (peer-reviewed)abstract
- Fragility fractures are increasingly recognized as a complication of both type 1 and type 2 diabetes, with fracture risk that increases with disease duration and poor glycemic control. Yet the identification and management of fracture risk in these patients remains challenging. This review explores the clinical characteristics of bone fragility in adults with diabetes and highlights recent studies that have evaluated bone mineral density (BMD), bone microstructure and material properties, biochemical markers, and fracture prediction algorithms (i.e., FRAX) in these patients. It further reviews the impact of diabetes drugs on bone as well as the efficacy of osteoporosis treatments in this population. We finally propose an algorithm for the identification and management of diabetic patients at increased fracture risk.
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| 22. |
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| 23. |
- Mittler, Eva, et al.
(author)
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Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses
- 2022
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In: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 14:636
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Journal article (peer-reviewed)abstract
- The rodent-borne hantavirus Puumala virus (PUUV) and related agents cause hemorrhagic fever with renal syndrome (HFRS) in humans. Other hantaviruses, including Andes virus (ANDV) and Sin Nombre virus, cause a distinct zoonotic disease, hantavirus cardiopulmonary syndrome (HCPS). Although these infections are severe and have substantial case fatality rates, no FDA-approved hantavirus countermeasures are available. Recent work suggests that monoclonal antibodies may have therapeutic utility. We describe here the isolation of human neutralizing antibodies (nAbs) against tetrameric Gn/Gc glycoprotein spikes from PUUV-experienced donors. We define a dominant class of nAbs recognizing the "capping loop" of Gn that masks the hydrophobic fusion loops in Gc. A subset of nAbs in this class, including ADI-42898, bound Gn/Gc complexes but not Gn alone, strongly suggesting that they recognize a quaternary epitope encompassing both Gn and Gc. ADI-42898 blocked the cell entry of seven HCPS- and HFRS-associated hantaviruses, and single doses of this nAb could protect Syrian hamsters and bank voles challenged with the highly virulent HCPS-causing ANDV and HFRS-causing PUUV, respectively. ADI-42898 is a promising candidate for clinical development as a countermeasure for both HCPS and HFRS, and its mode of Gn/Gc recognition informs the development of broadly protective hantavirus vaccines.
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| 24. |
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| 25. |
- van der Brug, MP, et al.
(author)
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RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways
- 2008
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 105:29, s. 10244-10249
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Journal article (peer-reviewed)abstract
- Parkinson's disease (PD) is a major neurodegenerative condition with several rare Mendelian forms. Oxidative stress and mitochondrial function have been implicated in the pathogenesis of PD but the molecular mechanisms involved in the degeneration of neurons remain unclear. DJ-1 mutations are one cause of recessive parkinsonism, but this gene is also reported to be involved in cancer by promoting Ras signaling and suppressing PTEN-induced apoptosis. The specific function of DJ-1 is unknown, although it is responsive to oxidative stress and may play a role in the maintenance of mitochondria. Here, we show, using four independent methods, that DJ-1 associates with RNA targets in cells and the brain, including mitochondrial genes, genes involved in glutathione metabolism, and members of the PTEN/PI3K cascade. Pathogenic recessive mutants are deficient in this activity. We show that DJ-1 is sufficient for RNA binding at nanomolar concentrations. Further, we show that DJ-1 binds RNA but dissociates after oxidative stress. These data implicate a single mechanism for the pleiotropic effects of DJ-1 in different model systems, namely that the protein binds multiple RNA targets in an oxidation-dependent manner.
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| 26. |
- Wec, Anna Z., et al.
(author)
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Longitudinal dynamics of the human B cell response to the yellow fever 17D vaccine
- 2020
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In: Proceedings of the National Academy of Sciences of the United States of America. - Washington : National Academy of Science. - 0027-8424 .- 1091-6490. ; 117:12, s. 6675-6685
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Journal article (peer-reviewed)abstract
- A comprehensive understanding of the development and evolution of human B cell responses duced by pathogen exposure will facilitate the design of next-generation vaccines. Here, we utilized a gh-throughput single B cell cloning technology to longitudinally track the human B cell response to the llow fever virus 17D (YFV-17D) vaccine. The earlymemory B cell (MBC) response was mediated by both assical immunoglobulin M (IgM) (IgM(+)CD27(+)) and switched immunoglobulin (swIg(+)) MBC pulations; however, classical IgM MBCs waned rapidly, whereas swIg(+) and atypical IgM(+) and IgD(+) MBCs were stable over time. Affinity maturation continued for 6 to 9 mo following vaccination, providing evidence for the persistence of germinal center activity long after the period of active viral replication in peripheral blood. Finally, a substantial fraction of the neutralizing antibody response was mediated by public clones that recognize a fusion loop-proximal antigenic site within domain II of the viral envelope glycoprotein. Overall, our findings provide a framework for understanding the dynamics and complexity of human B cell responses elicited by infection and vaccination.
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| 27. |
- Arul, A.J, et al.
(author)
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Reliability analysis of safety grade decay heat removal system of Indian prototype fast breeder reactor
- 2006
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In: Annals of Nuclear Energy. - : Elsevier BV. - 0306-4549. ; 33:2, s. 180-188
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Journal article (peer-reviewed)abstract
- The 500MW Indian pool type Prototype Fast Breeder Reactor (PFBR), is provided with two independent and diverse Decay Heat Removal (DHR) systems viz., Operating Grade Decay Heat Removal System (OGDHRS) and Safety Grade Decay Heat Removal System (SGDHRS). OGDHRS utilizes the secondary sodium loops and Steam–Water System with special decay heat removal condensers for DHR function. The unreliability of this system is of the order of 0.1–0.01. The safety requirements of the present generation of fast reactors are very high, and specifically for DHR function the failure frequency should be less than 1E-7/ry. Therefore, a passive SGDHR system using four completely independent thermo-siphon loops in natural convection mode is provided to ensure adequate core cooling for all Design Basis Events. The very high reliability requirement for DHR function is achieved mainly with the help of SGDHRS. This paper presents the reliability analysis of SGDHR system. Analysis is performed by Fault Tree method using "CRAFT" software developed at Indira Gandhi Centre for Atomic Research. This software has special features for compact representation and CCF analysis of high redundancy safety systems encountered in nuclear reactors. Common Cause Failures (CCF) are evaluated by beta-factor method. The reliability target for SGDHRS arrived from DHR reliability requirement and the ultimate number of demands per year (7/y) on SGDHRS is that the failure frequency should be <=1.4E-8/de. Since it is found from the analysis that the unreliability of SGDHRS with identical loops is 5.2E-6/de and dominated by leak rates of components like AHX, DHX and sodium dump and isolation valves, options with diversity measures in important components were studied. The failure probability of SGDHRS for a design consisting of 2 types of diverse loops (Diverse AHX, DHX and sodium dump and isolation valves) is 2.1E-8/de, which practically meets the reliability requirement.
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| 28. |
- Arul, A.J., et al.
(author)
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The power law character of off-site power failures
- 2003
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In: Annals of Nuclear Energy. - 0306-4549. ; 30:14, s. 1401-1408
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Journal article (peer-reviewed)abstract
- A study on the behavior of off-site AC power failure recovery times at three nuclear plant sites is presented. It is shown, that power law is appropriate for the representation of failure frequency–duration correlation function of off-site power failure events, based on simple assumptions about component failure and repair rates. It is also found that the annual maxima of power failure duration follow Frechet distribution, which is a type II asymptotic distribution, strengthening our assumption of power law for the parent distribution. The extreme value distributions obtained are used for extrapolation beyond the region of observation.
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| 29. |
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| 30. |
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| 31. |
- Bortz, Robert H., et al.
(author)
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Single-Dilution COVID-19 Antibody Test with Qualitative and Quantitative Readouts
- 2021
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In: mSphere. - : American Society for Microbiology. - 2379-5042. ; 6:2
-
Journal article (peer-reviewed)abstract
- The coronavirus disease 2019 (COVID-19) global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to place an immense burden on societies and health care systems. A key component of COVID-19 control efforts is serological testing to determine the community prevalence of SARS-CoV-2 exposure and quantify individual immune responses to prior SARS-CoV-2 infection or vaccination. Here, we describe a laboratory-developed antibody test that uses readily available research-grade reagents to detect SARS-CoV-2 exposure in patient blood samples with high sensitivity and specificity. We further show that this sensitive test affords the estimation of viral spike-specific IgG titers from a single sample measurement, thereby providing a simple and scalable method to measure the strength of an individual's immune response. The accuracy, adaptability, and cost-effectiveness of this test make it an excellent option for clinical deployment in the ongoing COVID-19 pandemic.IMPORTANCE Serological surveillance has become an important public health tool during the COVID-19 pandemic. Detection of protective antibodies and seroconversion after SARS-CoV-2 infection or vaccination can help guide patient care plans and public health policies. Serology tests can detect antibodies against past infections; consequently, they can help overcome the shortcomings of molecular tests, which can detect only active infections. This is important, especially when considering that many COVID-19 patients are asymptomatic. In this study, we describe an enzyme-linked immunosorbent assay (ELISA)-based qualitative and quantitative serology test developed to measure IgG and IgA antibodies against the SARS-CoV-2 spike glycoprotein. The test can be deployed using commonly available laboratory reagents and equipment and displays high specificity and sensitivity. Furthermore, we demonstrate that IgG titers in patient samples can be estimated from a single measurement, enabling the assay's use in high-throughput clinical environments.
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| 32. |
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| 33. |
- Christianson, Helena C, et al.
(author)
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Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity
- 2017
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In: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:40, s. 66960-66974
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Journal article (peer-reviewed)abstract
- Aggressive cancers are characterized by hypoxia, which is a key driver of tumor development and treatment resistance. Proteins specifically expressed in the hypoxic tumor microenvironment thus represent interesting candidates for targeted drug delivery strategies. Carbonic anhydrase (CAIX) has been identified as an attractive treatment target as it is highly hypoxia specific and expressed at the cell-surface to promote cancer cell aggressiveness. Here, we find that cancer cell internalization of CAIX is negatively regulated by post-translational modification with chondroitin or heparan sulfate glycosaminoglycan chains. We show that perturbed glycosaminoglycan modification results in increased CAIX endocytosis. We hypothesized that perturbation of CAIX glycosaminoglycan conjugation may provide opportunities for enhanced drug delivery to hypoxic tumor cells. In support of this concept, pharmacological inhibition of glycosaminoglycan biosynthesis with xylosides significantly potentiated the internalization and cytotoxic activity of an antibody-drug conjugate (ADC) targeted at CAIX. Moreover, cells expressing glycosaminoglycan-deficient CAIX were significantly more sensitive to ADC treatment as compared with cells expressing wild-type CAIX. We find that inhibition of CAIX endocytosis is associated with an increased localization of glycosaminoglycan-conjugated CAIX in membrane lipid raft domains stabilized by caveolin-1 clusters. The association of CAIX with caveolin-1 was partially attenuated by acidosis, i.e. another important feature of malignant tumors. Accordingly, we found increased internalization of CAIX at acidic conditions. These findings provide first evidence that intracellular drug delivery at pathophysiological conditions of malignant tumors can be attenuated by tumor antigen glycosaminoglycan modification, which is of conceptual importance in the future development of targeted cancer treatments.
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| 34. |
- Dimov, Aleksandar, et al.
(author)
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Mutation testing framework for software reliability model analysis and reliability estimation
- 2010
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In: Central and Eastern European Software Engineering Conference (CEE-SECR). - 9781457706066 ; , s. 163-169
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Conference paper (peer-reviewed)abstract
- After several years of research, even today estimation of software reliability is extremely challenging. The undeterministic nature of the factors that contribute to the reliability estimation has led to the development of numerous statistical models for this purpose. One of the important factors that contribute to software reliability is testing. The aim of this paper is to use mutation testing for estimating the „true” reliability of a system and provide a framework for estimation of uncertainty bounds associated with testing and a measure for factors such as test coverage, time between failures and code coverage that contribute to the estimation of reliability and use mutation testing as a tool to create a software failure dataset. The approach is experimented with an open source search tool.
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| 35. |
- Ive, J., et al.
(author)
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KCL-Health-NLP@CLEF eHealth 2018 Task 1 : ICD-10 coding of French and Italian death certificates with character-level convolutional neural networks
- 2018
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In: CEUR Workshop Proceedings. - : CEUR-WS.
-
Conference paper (peer-reviewed)abstract
- In this paper we describe the participation of the KCL-Health-NLP team in the CLEF eHealth 2018 lab, specifically Task 1: Multilingual Information Extraction-ICD10 coding. The task involves the automatic coding of causes of death in death certificates in French, Italian and Hungarian according to the ICD-10 taxonomy. Choosing to work on the two Romance languages, we treated the task as a sequence-to-sequence prediction problem. Our system has an encoder-decoder architecture, with convolutional neural networks based on character em-beddings as encoders and recurrent neural network decoders. Our hypothesis was that a character-level representation would allow our model to generalise across two genealogically related languages. Results obtained by pre-training our Italian model on the French data set confirmed this intuition. We also explored the impact of character-level features extracted from dictionary-matched ICD codes. We obtained F-measures of 0.72/0.64 and 0.78 on the French aligned/raw and Italian raw internal test data, respectively. On the blind test set released by the task organisers, our top results were 0.65/0.52 and 0.69 F-measure, respectively.
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| 36. |
- Kanis, J. A., et al.
(author)
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Algorithm for the management of patients at low, high and very high risk of osteoporotic fractures
- 2020
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In: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 31, s. 1-12
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Journal article (peer-reviewed)abstract
- Guidance is provided in an international setting on the assessment and specific treatment of postmenopausal women at low, high and very high risk of fragility fractures. Introduction The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2019. This manuscript seeks to apply this in an international setting, taking additional account of further categorisation of increased risk of fracture, which may inform choice of therapeutic approach. Methods Clinical perspective and updated literature search. Results The following areas are reviewed: categorisation of fracture risk and general pharmacological management of osteoporosis. Conclusions A platform is provided on which specific guidelines can be developed for national use to characterise fracture risk and direct interventions.
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| 37. |
- Kanis, J. A., et al.
(author)
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Use of age-dependent FRAX-based intervention thresholds for Singapore
- 2020
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In: Archives of Osteoporosis. - : Springer Science and Business Media LLC. - 1862-3522 .- 1862-3514. ; 15:1
-
Journal article (peer-reviewed)abstract
- The Summary Assessment and treatment pathways based on age-specific intervention thresholds in Singapore using FRAX paths can be used to identify patients at high risk of fracture and avoid unnecessary treatment in those at low risk. Purpose Intervention thresholds for the treatment of osteoporosis have been based historically on the measurement of bone mineral density. The development of FRAX (R) has permitted a more accurate assessment of fracture risk. The aim of the present study was to explore treatment paths and characteristics of women selected for treatment in Singapore based on FRAX. Methods The approach to the setting of intervention and assessment thresholds used the methodology adopted by the National Osteoporosis Guideline Group for FRAX-based guidelines in the UK but based on the epidemiology of fracture and death in Singapore. The methodology was applied to women age 50 years or more drawn from the population-based Singapore Chinese Health Study (SCHS) cohort. Missing data for the calculation of FRAX was simulated using data from Chinese cohorts from Hong Kong. Results Intervention thresholds expressed as a 10-year probability of a major osteoporotic fracture ranged from 2.9% at the age of 50 years increasing to 32% at the age of 90 years. A total of 1927 of 29,323 women (7%) had a prior fragility fracture and would be eligible for treatment for this reason. An additional 3019 women (10.3%) would be eligible for treatment on the basis of age-dependent thresholds. The mean BMD T-score of women so selected was -2.94. Conclusion Probability-based assessment of fracture risk using age-specific intervention thresholds was developed for Singapore to help guide decisions about treatment.
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| 38. |
- Kerkman, Priscilla, et al.
(author)
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Generation of plasma cells and CD27-IgD- B cells during hantavirus infection is associated with distinct pathological findings
- 2021
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In: Clinical & Translational Immunology (CTI). - : John Wiley & Sons. - 2050-0068. ; 10
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Journal article (peer-reviewed)abstract
- Objective: Human hantavirus infections can cause haemorrhagic fever with renal syndrome (HFRS). The pathogenic mechanisms arenot fully understood, nor if they affect the humoral immune system. The objective of this study was to investigate humoral immune responses to hantavirus infection and to correlate them to the typical features of HFRS: thrombocytopenia and transient kidney dysfunction.Methods: We performed a comprehensive characterisation of longitudinal antiviral B-cell responses of 26 hantavirus patients and combined this with paired clinical data. In addition, we measured extracellular adenosine triphosphate (ATP)and its breakdown products in circulation and performed in vitro stimulations to address its effect on B cells.Results: We found that thrombocytopenia was correlated to an elevated frequency of plasmablasts in circulation. In contrast, kidney dysfunction was indicative of an accumulation of CD27-IgD- B cells and CD27/low plasmablasts. Finally, we provide evidence that high levels of extracellular ATP and matrix metalloproteinase 8 can contribute to shedding of CD27 during human hantavirus infection.Conclusion: Our findings demonstrate that thrombocytopenia and kidneydysfunction associate with distinctly different effects on the humoral immune system. Moreover, hantavirus-infectedindividuals have significantly elevated levels of extracellular ATP incirculation.
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| 39. |
- Mathews, T.S, et al.
(author)
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Functional reliability analysis of Safety Grade Decay Heat Removal System of Indian 500 MWe PFBR
- 2008
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In: Nuclear Engineering and Design. - : Elsevier BV. - 0029-5493 .- 1872-759X. ; 238:9, s. 2369-2376
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Journal article (peer-reviewed)abstract
- Passive systems are increasingly deployed in nuclear industry with an objective of increasing reliability and safety of operations with reduced cost. Methods for assessing the reliability of thermal-hydraulic passive systems, that is systems with moving working fluid, address the issues in natural buoyancy-driven flow that could result in a failure to meet the design safety limits under accident scenarios. This is referred as design functional reliability. This paper presents the results of functional reliability analysis carried out for the passive Safety Grade Decay Heat Removal System (SGDHRS) of IndianPrototype Fast Breeder Reactor (PFBR). The analysis is carried out based on the overall approach reported in the Reliability Methods for Passive System (RMPS, European Commission) project. Functionalfailure probability is calculated using Monte-Carlo method and also with method of moments.
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| 40. |
- Menard, Julien A., et al.
(author)
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Metastasis Stimulation by Hypoxia and Acidosis-Induced Extracellular Lipid Uptake Is Mediated by Proteoglycan-Dependent Endocytosis
- 2016
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In: Cancer Research. - 0008-5472 .- 1538-7445. ; 76:16, s. 4828-4840
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Journal article (peer-reviewed)abstract
- Hypoxia and acidosis are inherent stress factors of the tumor microenvironment and have been linked to increased tumor aggressiveness and treatment resistance. Molecules involved in the adaptive mechanisms that drive stress-induced disease progression constitute interesting candidates of therapeutic intervention. Here, we provide evidence of a novel role of heparan sulfate proteoglycans (HSPG) in the adaptive response of tumor cells to hypoxia and acidosis through increased internalization of lipoproteins, resulting in a lipid-storing phenotype and enhanced tumor-forming capacity. Patient glioblastoma tumors and cells under hypoxic and acidic stress acquired a lipid droplet (LD)-loaded phenotype, and showed an increased recruitment of all major lipoproteins, HDL, LDL, and VLDL. Stress-induced LD accumulation was associated with increased spheroid-forming capacity during reoxygenation in vitro and lung metastatic potential in vivo. On a mechanistic level, we found no apparent effect of hypoxia on HSPGs, whereas lipoprotein receptors (VLDLR and SR-B1) were transiently upregulated by hypoxia. Importantly, however, using pharmacologic and genetic approaches, we show that stress-mediated lipoprotein uptake is highly dependent on intact HSPG expression. The functional relevance of HSPG in the context of tumor cell stress was evidenced by HSPG-dependent lipoprotein cell signaling activation through the ERK/MAPK pathway and by reversal of the LD-loaded phenotype by targeting of HSPGs. We conclude that HSPGs may have an important role in the adaptive response to major stress factors of the tumor microenvironment, with functional consequences on tumor cell signaling and metastatic potential.
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| 41. |
- Mittler, Eva, et al.
(author)
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Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody
- 2023
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 15:700
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Journal article (peer-reviewed)abstract
- Emerging rodent-borne hantaviruses cause severe diseases in humans with no approved vaccines or therapeutics. We recently isolated a monoclonal broadly neutralizing antibody (nAb) from a Puumala virus-experienced human donor. Here, we report its structure bound to its target, the Gn/Gc glycoprotein heterodimer comprising the viral fusion complex. The structure explains the broad activity of the nAb: It recognizes conserved Gc fusion loop sequences and the main chain of variable Gn sequences, thereby straddling the Gn/Gc heterodimer and locking it in its prefusion conformation. We show that the nAb's accelerated dissociation from the divergent Andes virus Gn/Gc at endosomal acidic pH limits its potency against this highly lethal virus and correct this liability by engineering an optimized variant that sets a benchmark as a candidate pan-hantavirus therapeutic.
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| 42. |
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| 43. |
- Ramesh, S., et al.
(author)
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Direct conversion of eggshell to hydroxyapatite ceramic by a sintering method
- 2016
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In: Ceramics International. - : Elsevier BV. - 0272-8842 .- 1873-3956. ; 42:6, s. 7824-7829
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Journal article (peer-reviewed)abstract
- Nanocrystalline hydroxyapatite derived from eggshell (HA-Es) was successfully prepared via a direct solid-state sintering method. The process involved mixing calcined eggshell powder and dicalcium hydrogen phosphate di-hydrate followed by a heat treatment at 800 degrees C. The resulting flower-like HA-Es powder was sintered at various temperatures ranging from 1050 degrees C to 1350 degrees C for 2 h in air atmosphere. The material was characterized to determine the thermal stability and the effect of sintering on the microstructure as well as properties of the resulting HA derived from eggshell. The results showed that sintering beyond 1250 degrees C resulted in the HA phase decomposition to tricalcium phosphate and tetra calcium phosphate. However, these secondary phases did not disrupted the densification process as the samples exhibited densities above 98% when sintered at 1300-1350 degrees C. A maximum fracture toughness of 1.51 MPam(1/2) was measured for HA-ES sample sintered at 1250 degrees C with a concomitant small grain size, below 1 pm coupled with high hardness of 5.62 GPa and high relative density of 98% being measured. The study also revealed that the relative density and grain size played a significant role in governing the properties of the HA-Es samples.
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| 44. |
- Simon, Sanu Mathew, et al.
(author)
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Morphological and thermal studies of mesoporous TiO2-ZrO2 and TiO2-ZrO2-polymer composites as potential self cleaning surface
- 2020
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In: Materials Today. - : Elsevier. - 2214-7853. ; 33:part 2, s. 1327-1332
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Journal article (peer-reviewed)abstract
- Inorganic-organic composites have significant importance in various fields including self cleaning displays, photocatalysis, solar energy conversion etc. The synthesis of polymer capped inorganic frameworks consisting oxides of Ti and Zr had been accomplished in a straightforward cost effective method. In this work, TiO2-ZrO2-Pluronic F127 composites were synthesized using sol-gel process in the presence of chelating ligand diethanolamine, which acts as a reaction inhibitor for hydrolysis and condensation of Ti and Zr alkoxide. For comparative studies, TiO2-ZrO2 composite sample under the same atmospheric conditions were also prepared. The structural and thermal properties were investigated using scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), water contact angle measurement (WCA) and thermogravimetric analysis (TGA-DTA). The textural parameters such as surface area, pore volume and pore diameter were analyzed using nitrogen sorption analysis. The water contact angle measurements have shown that the synthesized polymer-based composite material was superhydrophilic.
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| 45. |
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| 46. |
- Tsoi, Lam C., et al.
(author)
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Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants
- 2017
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
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Journal article (peer-reviewed)abstract
- Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size amp;gt;39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFkB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8(+) T-cells and CD4(+) T-cells including T(H)0, T(H)1 and T(H)17). The identified loci explain similar to 28% of the genetic heritability and generate a discriminatory genetic risk score (AUC = 0.76 in our sample) that is significantly correlated with age at onset (p = 2 x 10(-89)). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis.
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| 47. |
- Visser, Gerard H A, et al.
(author)
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FIGO opinion paper: Drivers and solutions to the cesarean delivery epidemic with emphasis on the increasing rates in Africa and Southeastern Europe.
- 2023
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In: International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. - 1879-3479. ; 163:Suppl 2, s. 5-9
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Journal article (peer-reviewed)abstract
- Cesarean delivery rates are rapidly increasing in Southeastern Europe (to more than 60%), North Africa (with a rate as high as 72% in Egypt), and in urban areas in Southern Africa (a rate of over 50% in Lagos, Nigeria). Data on the background to these increases are scarce, but likely to include poor birthing facilities in general hospitals, convenience for the doctor, private medicine, fear of litigation, socioeconomic status, shortage of midwives and nurses, and disappearance of vaginal instrumental deliveries. Options to reverse cesarean delivery trends are discussed. In this context there is a need to be better informed about how women are being counseled regarding vaginal or cesarean delivery. The long-term consequences in subsequent pregnancies for mothers and children may well be largely ignored, while these risks are highest in LMICs where higher birth numbers are desired. FIGO has begun discussions with obstetric and gynecologic societies, healthcare bodies, and governments in several countries discussed in this article, to find ways to lower the cesarean delivery rate. The requests came from the countries themselves, which may prove beneficial in helping advance progress.
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