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| 2. |
- van Bragt, JJMH, et al.
(författare)
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Characteristics and treatment regimens across ERS SHARP severe asthma registries
- 2020
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 55:1
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m−2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day−1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day−1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.
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| 3. |
- Bauermeister, S, et al.
(författare)
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The Dementias Platform UK (DPUK) Data Portal
- 2020
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Ingår i: European journal of epidemiology. - : Springer Science and Business Media LLC. - 1573-7284 .- 0393-2990. ; 35:6, s. 601-611
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Abolhassani, H, et al.
(författare)
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Expanding Clinical Phenotype and Novel Insights into the Pathogenesis of ICOS Deficiency
- 2020
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Ingår i: Journal of clinical immunology. - : Springer Science and Business Media LLC. - 1573-2592 .- 0271-9142. ; 40:2, s. 277-288
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundInducible T cell co-stimulator (ICOS) deficiency has been categorized as a combined immunodeficiency often complicated by enteropathies, autoimmunity, lymphoproliferation, and malignancy. We report seven new patients and four novelICOSmutations resulting in a common variable immunodeficiency (CVID)–like phenotype and show that dysregulated IL-12 release, reduced cytotoxic T lymphocyte–associated protein 4 (CTLA4) expression, and skewing towards a Th1-dominant phenotype are all associated with inflammatory complications in this condition.MethodsA combination of whole exome and Sanger sequencing was used to identify novel mutations. Standard clinical and immunological evaluation was performed. FACS and ELISA-based assays were used to study cytokine responses and ICOS/ICOSL/CTLA4 expression following stimulation of whole blood and PBMCs with multiple TLR ligands, anti-CD3, and PHA.ResultsFour novel ICOS mutations included homozygous c.323_332del, homozygous c.451C>G, and compound heterozygous c.58+1G>A/c.356T>C. The predominant clinical phenotype was that of antibody deficiency associated with inflammatory complications in 4/7 patients. Six out of seven patients were treated with immunoglobulin replacement and one patient died from salmonella sepsis. All patients who were tested showed reduced IL-10 and IL-17 cytokine responses, normal IL-1β, IL6, and TNF release following LPS stimulation and highly elevated IL-12 production in response to combined LPS/IFNγ stimulation. This was associated with skewing of CD4+T cells towards Th1 phenotype and increased expression of ICOSL on monocytes. Lastly, reduced CTLA4 expression was found in 2 patients. One patient treated with ustekinumab for pancytopenia due to granulomatous bone marrow infiltration failed to respond to this targeted therapy.ConclusionsICOS deficiency is associated with defective T cell activation, with simultaneously enhanced stimulation of monocytes. The latter is likely to result from a lack of ICOS/ICOSL interaction which might be necessary to provide negative feedback which limits monocytes activation.
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| 5. |
- Lughadha, E. N., et al.
(författare)
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Extinction risk and threats to plants and fungi
- 2020
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Ingår i: Plants People Planet. - : Wiley. - 2572-2611. ; 2:5, s. 389-408
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Tidskriftsartikel (refereegranskat)abstract
- Societal Impact Statement There is increasing awareness that plants and fungi, as natural solutions, can play an important role in tackling ongoing global environmental challenges. We illustrate how understanding current and projected threats to plants and fungi is necessary to manage and mitigate risks, while building awareness of gaps and bias in current assessment coverage is essential to adequately prioritize conservation efforts. We highlight the state of the art in conservation science and point to current methods of assessment and future studies needed to mitigate species extinction. SummaryPlant and fungal biodiversity underpin life on earth and merit careful stewardship in an increasingly uncertain environment. However, gaps and biases in documented extinction risks to plant and fungal species impede effective management. Formal extinction risk assessments help avoid extinctions, through engagement, financial, or legal mechanisms, but most plant and fungal species lack assessments. Available global assessments cover c. 30% of plant species (ThreatSearch). Red List coverage overrepresents woody perennials and useful plants, but underrepresents single-country endemics. Fungal assessments overrepresent well-known species and are too few to infer global status or trends. Proportions of assessed vascular plant species considered threatened vary between global assessment datasets: 37% (ThreatSearch), and 44% (International Union for Conservation of Nature Red List of Threatened Species). Our predictions, correcting for several quantifiable biases, suggest that 39% of all vascular plant species are threatened with extinction. However, other biases remain unquantified, and may affect our estimate. Preliminary trend data show plants moving toward extinction. Quantitative estimates based on plant extinction risk assessments may understate likely biodiversity loss: they do not fully capture the impacts of climate change, slow-acting threats, or clustering of extinction risk, which could amplify loss of evolutionary potential. The importance of extinction risk estimation to support existing and emerging conservation initiatives is likely to grow as threats to biodiversity intensify. This necessitates urgent and strategic expansion of efforts toward comprehensive and ongoing assessment of plant and fungal extinction risk.
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| 6. |
- Muxlow, T. W. B., et al.
(författare)
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The e-MERGE Survey (e-MERLIN Galaxy Evolution Survey): overview and survey description
- 2020
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 495:1, s. 1188-1208
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Tidskriftsartikel (refereegranskat)abstract
- We present an overview and description of the e-MERGE Survey (e-MERLIN Galaxy Evolution Survey) Data Release 1 (DR1), a large program of high-resolution 1.5-GHz radio observations of the GOODS-N field comprising similar to 140 h of observations with enhanced-Multi-Element Remotely Linked Interferometer Network (e-MERLIN) and similar to 40 h with the Very Large Array (VLA). We combine the long baselines of e-MERLIN (providing high angular resolution) with the relatively closely packed antennas of the VLA (providing excellent surface brightness sensitivity) to produce a deep 1.5-GHz radio survey with the sensitivity (similar to 1.5 mu Jy beam(-1)), angular resolution (0.2-0.7 arcsec) and field-of-view (similar to 15x15 arcmin(2)) to detect and spatially resolve star-forming galaxies and active galactic nucleus (AGN) at z greater than or similar to 1. The goal of e-MERGE is to provide new constraints on the deep, sub-arcsecond radio sky which will be surveyed by SKA1-mid. In this initial publication, we discuss our data analysis techniques, including steps taken to model in-beam source variability over an similar to 20-yr baseline and the development of newpoint spread function/primary beam models to seamlessly merge e-MERLIN and VLA data in the uv plane. We present early science results, including measurements of the luminosities and/or linear sizes of similar to 500 galaxies selected at 1.5 GHz. In combination with deep Hubble Space Telescope observations, we measure a mean radio-to-optical size ratio of r(e-MERGE)/r(HST) similar to 1.02 +/- 0.03, suggesting that in most high-redshift galaxies, the similar to GHz continuum emission traces the stellar light seen in optical imaging. This is the first in a series of papers that will explore the similar to kpc-scale radio properties of star-forming galaxies and AGN in the GOODS-N field observed by e-MERGE DR1.
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| 7. |
- Decin, L., et al.
(författare)
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(Sub)stellar companions shape the winds of evolved stars
- 2020
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 369:6509, s. 1497-1500
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Tidskriftsartikel (refereegranskat)abstract
- Binary interactions dominate the evolution of massive stars, but their role is less clear for low- and intermediate-mass stars. The evolution of a spherical wind from an asymptotic giant branch (AGB) star into a nonspherical planetary nebula (PN) could be due to binary interactions. We observed a sample of AGB stars with the Atacama Large Millimeter/submillimeter Array (ALMA) and found that their winds exhibit distinct nonspherical geometries with morphological similarities to planetary nebulae (PNe). We infer that the same physics shapes both AGB winds and PNe; additionally, the morphology and AGB mass-loss rate are correlated. These characteristics can be explained by binary interaction. We propose an evolutionary scenario for AGB morphologies that is consistent with observed phenomena in AGB stars and PNe.
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| 8. |
- Mahmoodi, Bakhtawar K., et al.
(författare)
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Association of Factor V Leiden With Subsequent Atherothrombotic Events A GENIUS-CHD Study of Individual Participant Data
- 2020
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 142:6, s. 546-555
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD.Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality.Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16];I-2=28%;P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity.Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
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| 9. |
- Richards, A.M.S., et al.
(författare)
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Masers: Precision probes of molecular gas
- 2020
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Ingår i: Advances in Space Research. - : Elsevier BV. - 1879-1948 .- 0273-1177. ; 65:2, s. 780-789
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Tidskriftsartikel (refereegranskat)abstract
- Maser emission from water, methanol, silicon monoxide and other molecules can reach brightness temperatures ≫1010 K. Such observations can achieve sub-pc precision for discs around black holes or sub-au scale interactions in protostellar discs and the regions where evolved star winds reach escape velocity. Ultra-high resolution maser observations also provide photon statistics, for fundamental physics experiments. RadioAstron has shown the success – and limitations – of cm-wave maser observations on scales ≪1 mas with sparse baseline coverage. ALMA, APEX and earlier single dish searches have found a wealth of mm and sub-mm masers, some of which probably also attain high brightness temperatures. Masers are ideal for high-resolution observations throughout the radio regime and we need to consider the current lessons for the best observational strategies to meet specific science cases.
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| 10. |
- Forgetta, V., et al.
(författare)
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Development of a polygenic risk score to improve screening for fracture risk: A genetic risk prediction study
- 2020
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Ingår i: PLoS medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 17:7
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Tidskriftsartikel (refereegranskat)abstract
- Background Since screening programs identify only a small proportion of the population as eligible for an intervention, genomic prediction of heritable risk factors could decrease the number needing to be screened by removing individuals at low genetic risk. We therefore tested whether a polygenic risk score for heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-can identify low-risk individuals who can safely be excluded from a fracture risk screening program. Methods and findings A polygenic risk score for SOS was trained and selected in 2 separate subsets of UK Biobank (comprising 341,449 and 5,335 individuals). The top-performing prediction model was termed "gSOS", and its utility in fracture risk screening was tested in 5 validation cohorts using the National Osteoporosis Guideline Group clinical guidelines (N= 10,522 eligible participants). All individuals were genome-wide genotyped and had measured fracture risk factors. Across the 5 cohorts, the average age ranged from 57 to 75 years, and 54% of studied individuals were women. The main outcomes were the sensitivity and specificity to correctly identify individuals requiring treatment with and without genetic prescreening. The reference standard was a bone mineral density (BMD)-based Fracture Risk Assessment Tool (FRAX) score. The secondary outcomes were the proportions of the screened population requiring clinical-risk-factor-based FRAX (CRF-FRAX) screening and BMD-based FRAX (BMD-FRAX) screening. gSOS was strongly correlated with measured SOS (r(2)= 23.2%, 95% CI 22.7% to 23.7%). Without genetic prescreening, guideline recommendations achieved a sensitivity and specificity for correct treatment assignment of 99.6% and 97.1%, respectively, in the validation cohorts. However, 81% of the population required CRF-FRAX tests, and 37% required BMD-FRAX tests to achieve this accuracy. Using gSOS in prescreening and limiting further assessment to those with a low gSOS resulted in small changes to the sensitivity and specificity (93.4% and 98.5%, respectively), but the proportions of individuals requiring CRF-FRAX tests and BMD-FRAX tests were reduced by 37% and 41%, respectively. Study limitations include a reliance on cohorts of predominantly European ethnicity and use of a proxy of fracture risk. Conclusions Our results suggest that the use of a polygenic risk score in fracture risk screening could decrease the number of individuals requiring screening tests, including BMD measurement, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention. Author summaryWhy was this study done? Osteoporosis screening identifies only a small proportion of the screened population to be eligible for intervention. The prediction of heritable risk factors using polygenic risk scores could decrease the number of screened individuals by reassuring those with low genetic risk. We investigated whether the genetic prediction of heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-could be incorporated into an established screening guideline to identify individuals at low risk for osteoporosis. What did the researchers do and find? Using UK Biobank, we developed a polygenic risk score (gSOS) consisting of 21,717 genetic variants that was strongly correlated with SOS ( = 23.2%). Using the National Osteoporosis Guideline Group clinical assessment guidelines in 5 validation cohorts, we estimate that reassuring individuals with a high gSOS, rather than doing further assessments, could reduce the number of clinical-risk-factor-based Fracture Risk Assessment Tool (FRAX) tests and bone-density-measurement-based FRAX tests by 37% and 41%, respectively, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention. What do these findings mean? We show that genetic pre-screening could reduce the number of screening tests needed to identify individuals at risk of osteoporotic fractures. Therefore, the potential exists to improve the efficiency of osteoporosis screening programs without large losses in sensitivity or specificity to identify individuals who should receive an intervention. Further translational studies are needed to test the clinical applications of this polygenic risk score; however, our work shows how such scores could be tested in the clinic.
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