| 1. |
- Lango Allen, Hana, et al.
(author)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Journal article (peer-reviewed)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 2. |
- Maccari, Maria Elena, et al.
(author)
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Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity.
- 2023
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In: The Journal of allergy and clinical immunology. - 1097-6825. ; 152:4
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Journal article (peer-reviewed)abstract
- Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking.This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS.Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs.The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS.APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients.
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| 3. |
- Alsabri, Mohamed, et al.
(author)
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Impact of Teamwork and Communication Training Interventions on Safety Culture and Patient Safety in Emergency Departments : A Systematic Review
- 2022
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In: Journal of patient safety. - : Lippincott Williams & Wilkins. - 1549-8417 .- 1549-8425. ; 18:1, s. E351-E361
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Research review (peer-reviewed)abstract
- Objectives: This study aimed to narratively summarize the literature reporting on the effect of teamwork and communication training interventions on culture and patient safety in emergency department (ED) settings.Methods: We searched PubMed, EMBASE, Psych Info CINAHL, Cochrane, Science Citation Inc, the Web of Science, and Educational Resources Information Centre for peer-reviewed journal articles published from January 1, 1988, to June 8, 2018, that assessed teamwork and communication interventions focusing on how they influence patient safety in the ED. One additional search update was performed in July 2019.Results: Sixteen studies were included from 8700 screened publications. The studies' design, interventions, and evaluation methods varied widely. The most impactful ED training interventions were End-of-Course Critique, Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS), and crisis resource management (CRM)-based training. Crisis resource management and TeamSTEPPS CRM-based training curriculum were used in most of the studies. Multiple tools, including the Kirkpatrick evaluation model, the Agency for Healthcare Research and Quality Hospital Survey on Patient Safety Culture, the TeamSTEPPS Teamwork Attitudes Questionnaire, the Safety Attitudes Questionnaire, and the Communication and Teamwork Skills Assessment, were used to assess the impact of such interventions. Improvements in one of the domains of safety culture and related domains were found in all studies. Four empirical studies established improvements in patient health outcomes that occurred after simulation CRM training (Kirkpatrick 4), but there was no effect on mortality.Conclusions: Overall, teamwork and communication training interventions improve the safety culture in ED settings and may positively affect patient outcome. The implementation of safety culture programs may be considered to reduce incidence of medical errors and adverse events.
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| 4. |
- Beauchesne, Benjamin, et al.
(author)
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A new step forward in realistic cluster lens mass modelling : analysis of Hubble Frontier Field Cluster Abell S1063 from joint lensing, X-ray, and galaxy kinematics data
- 2023
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In: Monthly notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 527:2, s. 3246-3275
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Journal article (peer-reviewed)abstract
- We present a new method to simultaneously and self-consistently model the mass distribution of galaxy clusters that combines constraints from strong lensing features, X-ray emission, and galaxy kinematics measurements. We are able to successfully decompose clusters into their collisionless and collisional mass components thanks to the X-ray surface brightness, as well as use the dynamics of cluster members, to obtain more accurate masses exploiting the fundamental plane of elliptical galaxies. Knowledge from all observables is included through a consistent Bayesian approach in the likelihood or in physically motivated priors. We apply this method to the galaxy cluster Abell S1063 and produce a mass model that we publicly release with this paper. The resulting mass distribution presents different ellipticities for the intra-cluster gas and the other large-scale mass components as well as deviation from elliptical symmetry in the main halo. We assess the ability of our method to recover the masses of the different elements of the cluster using a mock cluster based on a simplified version of our Abell S1063 model. Thanks to the wealth of mutliwavelength information provided by the mass model and the detected X-ray emission, we also found evidence for an ongoing merger event with gas sloshing from a smaller infalling structure into the main cluster. In agreement with previous findings, the total mass, gas profile, and gas mass fraction are all consistent with small deviations from the hydrostatic equilibrium. This new mass model for Abell S1063 is publicly available, as the LENSTOOL extension used to construct it.
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| 5. |
- Cenni, Enrico, et al.
(author)
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ESS MEDIUM BETA CAVITY PROTOTYPES MANUFACTURING
- 2016
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Conference paper (peer-reviewed)abstract
- The ESS elliptical superconducting Linac consists of two types of 704.42 MHz cavities, medium and high beta, to accelerate the beam from 216 MeV (spoke cavity Linac) up to the final energy at 2 GeV. The last Linac optimization, called Optimus+, has been carried out taking into account the limitations of SRF cavity performance (field emission). The medium and high-beta parts of the Linac are composed of 36 and 84 elliptical cavities, with geometrical beta values of 0.67 and 0.86 respectively. We describe here the procedures and numerical analysis leading from half-cells to a complete medium cavity assembly, which take into account not only the frequency of the fundamental accelerating mode but also the higher order modes near the machine line. The half-cell selection process to form dumb bells will be described, as well as the reshaping and trimming procedure.
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| 6. |
- Cenni, Enrico, et al.
(author)
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Vertical test results on ESS medium and high beta elliptical cavity prototypes equipped with helium tank
- 2017
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In: IPAC 2017 - Proceedings of the 8th International Particle Accelerator Conference. - 9783954501823 ; , s. 948-950
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Conference paper (peer-reviewed)abstract
- The ESS elliptical superconducting Linac consists of two types of 704.42 MHz cavities, medium and high beta, to accelerate the beam from 216 MeV (spoke cavity Linac) up to the final energy at 2 GeV. The last Linac optimization, called Optimus+[1], has been carried out taking into account the limitations of SRF cavity performance (field emission). The medium and high-beta parts of the Linac are composed of 36 and 84 elliptical cavities, with geometrical beta values of 0.67 and 0.86 respectively [2]. This work presents the latest vertical test results on ESS medium and high beta elliptical cavity prototypes equipped with helium tank. We describe the cavity preparation procedure from buffer chemical polishing to vertical test.
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| 7. |
- Cenni, Enrico, et al.
(author)
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Vertical test results on ESS medium beta elliptical cavity prototype
- 2016
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In: Proceedings of the 28th Linear Accelerator Conference, LINAC 2016. - 9783954501694 ; , s. 631-633
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Conference paper (peer-reviewed)abstract
- The ESS elliptical superconducting Linac consists of two types of 704.42 MHz cavities, medium and high beta, to accelerate the beam from 216 MeV (spoke cavity Linac) up to the final energy of 2 GeV. The last Linac optimization, called Optimus+ [1], has been carried out taking into account the limitations of SRF cavity performance (field emission). The medium and high-beta parts of the Linac are composed of 36 and 84 elliptical cavities, with geometrical beta values of 0.67 and 0.86 respectively. This work presents the latest vertical test results on ESS medium beta elliptical cavity prototypes. We describe the cavity preparation procedure from buffer chemical polishing to vertical test. Finally, magnetic probes (Fluxgate) were installed on the cavity to determine magnetic field background during vertical test. The latest vertical test results showed that the cavity design performance is beyond requirements.
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| 8. |
- Devos, David, et al.
(author)
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Trial of Deferiprone in Parkinson’s Disease
- 2022
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In: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 387:22, s. 2045-2055
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Journal article (peer-reviewed)abstract
- BACKGROUNDIron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear.METHODSWe conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome.RESULTSA total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants.CONCLUSIONSIn participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks.
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| 9. |
- Ibata, Rodrigo, et al.
(author)
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Charting the Galactic Acceleration Field. I. A Search for Stellar Streams with Gaia DR2 and EDR3 with Follow-up from ESPaDOnS and UVES
- 2021
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 914:2
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Journal article (peer-reviewed)abstract
- We present maps of the stellar streams detected in the Gaia Data Release 2 (DR2) and Early Data Release 3 (EDR3) catalogs using the STREAMFINDER algorithm. We also report the spectroscopic follow-up of the brighter DR2 stream members obtained with the high-resolution CFHT/ESPaDOnS and VLT/UVES spectrographs as well as with the medium-resolution NTT/EFOSC2 spectrograph. Two new stellar streams that do not have a clear progenitor are detected in DR2 (named Hrid and Gunnthra), and seven are detected in EDR3 (named Gaia-6 to Gaia-12). Several candidate streams are also identified. The software also finds very long tidal tails associated with the 15 globular clusters: NGC 288, NGC 1261, NGC 1851, NGC 2298, NGC 2808, NGC 3201, M68, omega Cen, NGC 5466, Palomar 5, M5, NGC 6101, M92, NGC 6397, and NGC 7089. These stellar streams will be used in subsequent contributions in this series to chart the properties of the Galactic acceleration field on similar to 100 pc to similar to 100 kpc scales.
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| 10. |
- Jalalvand, Farshid, et al.
(author)
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Protein domain-dependent vesiculation of Lipoprotein A, a protein that is important in cell wall synthesis and fitness of the human respiratory pathogen Haemophilus influenzae
- 2022
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In: Frontiers in cellular and infection microbiology. - : Frontiers Media SA. - 2235-2988. ; 12
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Journal article (peer-reviewed)abstract
- The human pathogen Haemophilus influenzae causes respiratory tract infections and is commonly associated with prolonged carriage in patients with chronic obstructive pulmonary disease. Production of outer membrane vesicles (OMVs) is a ubiquitous phenomenon observed in Gram-negative bacteria including H. influenzae. OMVs play an important role in various interactions with the human host; from neutralization of antibodies and complement activation to spread of antimicrobial resistance. Upon vesiculation certain proteins are found in OMVs and some proteins are retained at the cell membrane. The mechanism for this phenomenon is not fully elucidated. We employed mass spectrometry to study vesiculation and the fate of proteins in the outer membrane. Functional groups of proteins were differentially distributed on the cell surface and in OMVs. Despite its supposedly periplasmic and outer membrane location, we found that the peptidoglycan synthase-activator Lipoprotein A (LpoA) was accumulated in OMVs relative to membrane fractions. A mutant devoid of LpoA lost its fitness as revealed by growth and electron microscopy. Furthermore, high-pressure liquid chromatography disclosed a lower concentration (55%) of peptidoglycan in the LpoA-deficient H. influenzae compared to the parent wild type bacterium. Using an LpoA-mNeonGreen fusion protein and fluorescence microscopy, we observed that LpoA was enriched in “foci” in the cell envelope, and further located in the septum during cell division. To define the fate of LpoA, C-terminally truncated LpoA-variants were constructed, and we found that the LpoA C-terminal domain promoted optimal transportation to the OMVs as revealed by flow cytometry. Taken together, our study highlights the importance of LpoA for H. influenzae peptidoglycan biogenesis and provides novel insights into cell wall integrity and OMV production.
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