| 1. |
- Abel, I, et al.
(författare)
-
Overview of the JET results with the ITER-like wall
- 2013
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 53:10, s. 104002-
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Tidskriftsartikel (refereegranskat)abstract
- Following the completion in May 2011 of the shutdown for the installation of the beryllium wall and the tungsten divertor, the first set of JET campaigns have addressed the investigation of the retention properties and the development of operational scenarios with the new plasma-facing materials. The large reduction in the carbon content (more than a factor ten) led to a much lower Z(eff) (1.2-1.4) during L- and H-mode plasmas, and radiation during the burn-through phase of the plasma initiation with the consequence that breakdown failures are almost absent. Gas balance experiments have shown that the fuel retention rate with the new wall is substantially reduced with respect to the C wall. The re-establishment of the baseline H-mode and hybrid scenarios compatible with the new wall has required an optimization of the control of metallic impurity sources and heat loads. Stable type-I ELMy H-mode regimes with H-98,H-y2 close to 1 and beta(N) similar to 1.6 have been achieved using gas injection. ELM frequency is a key factor for the control of the metallic impurity accumulation. Pedestal temperatures tend to be lower with the new wall, leading to reduced confinement, but nitrogen seeding restores high pedestal temperatures and confinement. Compared with the carbon wall, major disruptions with the new wall show a lower radiated power and a slower current quench. The higher heat loads on Be wall plasma-facing components due to lower radiation made the routine use of massive gas injection for disruption mitigation essential.
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| 2. |
- Romanelli, F, et al.
(författare)
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Overview of the JET results
- 2011
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 51:9
-
Tidskriftsartikel (refereegranskat)abstract
- Since the last IAEA Conference JET has been in operation for one year with a programmatic focus on the qualification of ITER operating scenarios, the consolidation of ITER design choices and preparation for plasma operation with the ITER-like wall presently being installed in JET. Good progress has been achieved, including stationary ELMy H-mode operation at 4.5 MA. The high confinement hybrid scenario has been extended to high triangularity, lower ρ*and to pulse lengths comparable to the resistive time. The steady-state scenario has also been extended to lower ρ*and ν*and optimized to simultaneously achieve, under stationary conditions, ITER-like values of all other relevant normalized parameters. A dedicated helium campaign has allowed key aspects of plasma control and H-mode operation for the ITER non-activated phase to be evaluated. Effective sawtooth control by fast ions has been demonstrated with3He minority ICRH, a scenario with negligible minority current drive. Edge localized mode (ELM) control studies using external n = 1 and n = 2 perturbation fields have found a resonance effect in ELM frequency for specific q95values. Complete ELM suppression has, however, not been observed, even with an edge Chirikov parameter larger than 1. Pellet ELM pacing has been demonstrated and the minimum pellet size needed to trigger an ELM has been estimated. For both natural and mitigated ELMs a broadening of the divertor ELM-wetted area with increasing ELM size has been found. In disruption studies with massive gas injection up to 50% of the thermal energy could be radiated before, and 20% during, the thermal quench. Halo currents could be reduced by 60% and, using argon/deuterium and neon/deuterium gas mixtures, runaway electron generation could be avoided. Most objectives of the ITER-like ICRH antenna have been demonstrated; matching with closely packed straps, ELM resilience, scattering matrix arc detection and operation at high power density (6.2 MW m-2) and antenna strap voltages (42 kV). Coupling measurements are in very good agreement with TOPICA modelling. © 2011 IAEA, Vienna.
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| 3. |
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| 4. |
- Romagnoni, A, et al.
(författare)
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Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data
- 2019
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10351-
-
Tidskriftsartikel (refereegranskat)abstract
- Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
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| 5. |
- Craddock, Nick, et al.
(författare)
-
Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
-
Tidskriftsartikel (refereegranskat)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 6. |
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| 7. |
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| 8. |
- Momozawa, Y, et al.
(författare)
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IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
- 2018
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2427-
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Tidskriftsartikel (refereegranskat)abstract
- GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
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| 9. |
- Carter, Aarynn L., et al.
(författare)
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A benchmark JWST near-infrared spectrum for the exoplanet WASP-39 b
- 2024
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Ingår i: Nature Astronomy. - 2397-3366. ; In Press
-
Tidskriftsartikel (refereegranskat)abstract
- A combined analysis of datasets across four JWST instrument modes provides a benchmark transmission spectrum for the Saturn-mass WASP-39 b. The broad wavelength range and high resolution constrain orbital and stellar parameters to below 1%.
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| 10. |
- Halliday, Alison, et al.
(författare)
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10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1) : A multicentre randomised trial
- 2010
-
Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 376:9746, s. 1074-1084
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Tidskriftsartikel (refereegranskat)abstract
- Background If carotid artery narrowing remains asymptomatic (ie, has caused no recent stroke or other neurological symptoms), successful carotid endarterectomy (CEA) reduces stroke incidence for some years. We assessed the long-term effects of successful CEA. Methods Between 1993 and 2003, 3120 asymptomatic patients from 126 centres in 30 countries were allocated equally, by blinded minimised randomisation, to immediate CEA (median delay 1 month, IQR 0·3-2·5) or to indefinite deferral of any carotid procedure, and were followed up until death or for a median among survivors of 9 years (IQR 6-11). The primary outcomes were perioperative mortality and morbidity (death or stroke within 30 days) and non-perioperative stroke. Kaplan-Meier percentages and logrank p values are from intention-to-treat analyses. This study is registered, number ISRCTN26156392. Findings 1560 patients were allocated immediate CEA versus 1560 allocated deferral of any carotid procedure. The proportions operated on while still asymptomatic were 89·7 versus 4·8 at 1 year (and 92·1 vs 16·5 at 5 years). Perioperative risk of stroke or death within 30 days was 3·0 (95 CI 2·4-3·9; 26 non-disabling strokes plus 34 disabling or fatal perioperative events in 1979 CEAs). Excluding perioperative events and non-stroke mortality, stroke risks (immediate vs deferred CEA) were 4·1 versus 10·0 at 5 years (gain 5·9, 95 CI 4·0-7·8) and 10·8 versus 16·9 at 10 years (gain 6·1, 2·7-9·4); ratio of stroke incidence rates 0·54, 95 CI 0·43-0·68, p<0·0001. 62 versus 104 had a disabling or fatal stroke, and 37 versus 84 others had a non-disabling stroke. Combining perioperative events and strokes, net risks were 6·9 versus 10·9 at 5 years (gain 4·1, 2·0-6·2) and 13·4 versus 17·9 at 10 years (gain 4·6, 1·2-7·9). Medication was similar in both groups; throughout the study, most were on antithrombotic and antihypertensive therapy. Net benefits were significant both for those on lipid-lowering therapy and for those not, and both for men and for women up to 75 years of age at entry (although not for older patients). Interpretation Successful CEA for asymptomatic patients younger than 75 years of age reduces 10-year stroke risks. Half this reduction is in disabling or fatal strokes. Net benefit in future patients will depend on their risks from unoperated carotid lesions (which will be reduced by medication), on future surgical risks (which might differ from those in trials), and on whether life expectancy exceeds 10 years. Funding UK Medical Research Council, BUPA Foundation, Stroke Association.
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| 11. |
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| 12. |
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| 13. |
- Bell, Taylor, et al.
(författare)
-
Nightside clouds and disequilibrium chemistry on the hot Jupiter WASP-43b
- 2024
-
Ingår i: Nature Astronomy. - 2397-3366. ; 8:7, s. 879-898
-
Tidskriftsartikel (refereegranskat)abstract
- Hot Jupiters are among the best-studied exoplanets, but it is still poorly understood how their chemical composition and cloud properties vary with longitude. Theoretical models predict that clouds may condense on the nightside and that molecular abundances can be driven out of equilibrium by zonal winds. Here we report a phase-resolved emission spectrum of the hot Jupiter WASP-43b measured from 5 μm to 12 μm with the JWST’s Mid-Infrared Instrument. The spectra reveal a large day–night temperature contrast (with average brightness temperatures of 1,524 ± 35 K and 863 ± 23 K, respectively) and evidence for water absorption at all orbital phases. Comparisons with three-dimensional atmospheric models show that both the phase-curve shape and emission spectra strongly suggest the presence of nightside clouds that become optically thick to thermal emission at pressures greater than ~100 mbar. The dayside is consistent with a cloudless atmosphere above the mid-infrared photosphere. Contrary to expectations from equilibrium chemistry but consistent with disequilibrium kinetics models, methane is not detected on the nightside (2σ upper limit of 1–6 ppm, depending on model assumptions). Our results provide strong evidence that the atmosphere of WASP-43b is shaped by disequilibrium processes and provide new insights into the properties of the planet’s nightside clouds. However, the remaining discrepancies between our observations and our predictive atmospheric models emphasize the importance of further exploring the effects of clouds and disequilibrium chemistry in numerical models.
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| 14. |
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| 15. |
- Martin, P., et al.
(författare)
-
Overview of the RFX-mod fusion science programme
- 2013
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 53:10, s. 104018-
-
Forskningsöversikt (refereegranskat)abstract
- This paper reports the highlights of the RFX-mod fusion science programme since the last 2010 IAEA Fusion Energy Conference. The RFX-mod fusion science programme focused on two main goals: exploring the fusion potential of the reversed field pinch (RFP) magnetic configuration and contributing to the solution of key science and technology problems in the roadmap to ITER. Active control of several plasma parameters has been a key tool in this endeavour. New upgrades on the system for active control of magnetohydrodynamic (MHD) stability are underway and will be presented in this paper. Unique among the existing fusion devices, RFX-mod has been operated both as an RFP and as a tokamak. The latter operation has allowed the exploration of edge safety factor q edge < 2 with active control of MHD stability and studies concerning basic energy and flow transport mechanisms. Strong interaction has continued with the stellarator community in particular on the physics of helical states and on three-dimensional codes.
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| 16. |
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| 17. |
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| 18. |
- Jacobs, B., et al.
(författare)
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A strong H-opacity signal in the near-infrared emission spectrum of the ultra-hot Jupiter KELT-9b
- 2022
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 668
-
Tidskriftsartikel (refereegranskat)abstract
- We present the analysis of a spectroscopic secondary eclipse of the hottest transiting exoplanet detected to date, KELT-9b, obtained with the Wide Field Camera 3 aboard the Hubble Space Telescope. We complement these data with literature information on stellar pulsations and Spitzer/Infrared Array Camera and Transiting Exoplanet Survey Satellite eclipse depths of this target to obtain a broadband thermal emission spectrum. Our extracted spectrum exhibits a clear turnoff at 1.4 μm. This points to H- bound-free opacities shaping the spectrum. To interpret the spectrum, we perform grid retrievals of self-consistent 1D equilibrium chemistry forward models, varying the composition and energy budget. The model with solar metallicity and C/O ratio provides a poor fit because the H- signal is stronger than expected, requiring an excess of electrons. This pushes our retrievals toward high atmospheric metallicities ([M/H] = 1.98-0.21+0.19) and a C/O ratio that is subsolar by 2.4σ. We question the viability of forming such a high-metallicity planet, and therefore provide other scenarios to increase the electron density in this atmosphere. We also look at an alternative model in which we quench TiO and VO. This fit results in an atmosphere with a slightly subsolar metallicity and subsolar C/O ratio ([M/H] = -0.22-0.13+0.17, log (C/O) = -0.34-0.34+0.19). However, the required TiO abundances are disputed by recent high-resolution measurements of the same planet.
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| 19. |
- Martin, P., et al.
(författare)
-
Overview of the RFX fusion science program
- 2011
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 51:9, s. 094023-
-
Tidskriftsartikel (refereegranskat)abstract
- This paper summarizes the main achievements of the RFX fusion science program in the period between the 2008 and 2010 IAEA Fusion Energy Conferences. RFX-mod is the largest reversed field pinch in the world, equipped with a system of 192 coils for active control of MHD stability. The discovery and understanding of helical states with electron internal transport barriers and core electron temperature >1.5 keV significantly advances the perspectives of the configuration. Optimized experiments with plasma current up to 1.8 MA have been realized, confirming positive scaling. The first evidence of edge transport barriers is presented. Progress has been made also in the control of first-wall properties and of density profiles, with initial first-wall lithization experiments. Micro-turbulence mechanisms such as ion temperature gradient and micro-tearing are discussed in the framework of understanding gradient-driven transport in low magnetic chaos helical regimes. Both tearing mode and resistive wall mode active control have been optimized and experimental data have been used to benchmark numerical codes. The RFX programme also provides important results for the fusion community and in particular for tokamaks and stellarators on feedback control of MHD stability and on three-dimensional physics. On the latter topic, the result of the application of stellarator codes to describe three-dimensional reversed field pinch physics will be presented.
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| 20. |
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| 21. |
- McKeith, I, et al.
(författare)
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Dementia with Lewy bodies
- 2004
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Ingår i: The Lancet. Neurology. - 1474-4422. ; 3:1, s. 19-28
-
Tidskriftsartikel (refereegranskat)
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| 22. |
- Teede, Helena J., et al.
(författare)
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Recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome
- 2023
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Ingår i: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 189
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Tidskriftsartikel (refereegranskat)abstract
- Study question: What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? Summary answer: International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. What is known already: The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from 6 continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low-to low-quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus-based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, the evidence quality was low, and evidence-practice gaps persist. Study design, size, and duration: The 2023 International Evidence-based Guideline update re-engaged the 2018 network across professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation, and ultimately recommendation strength, and diversity and inclusion were considered throughout. Participants/materials, setting, and methods: This summary should be read in conjunction with the full guideline for detailed participants and methods. Governance included a 6-continent international advisory and management committee, 5 guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health, and other experts, alongside consumers, project management, evidence synthesis, statisticians, and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and 5 face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across 5 guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council. Main results and the role of chance: The evidence in the assessment and management of PCOS has generally improved in the past 5 years but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpin 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include the following: (1) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm, and inclusion of anti-Müllerian hormone levels as an alternative to ultrasound in adults only; (2) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnoea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; (3) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care, and shared decision-making to improve patient experience, alongside greater research; (4) maintained emphasis on healthy lifestyle, emotional well-being, and quality of life, with awareness and consideration of weight stigma; and (5) emphasizing evidence-based medical therapy and cheaper and safer fertility management. Limitations and reasons for caution: Overall, recommendations are strengthened and evidence is improved but remains generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. Wider implications of the findings: The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input, and consumer preferences. Research recommendations have been generated, and a comprehensive multifaceted dissemination and translation programme supports the guideline with an integrated evaluation programme.
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| 23. |
- Teede, Helena J, et al.
(författare)
-
Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome.
- 2023
-
Ingår i: The Journal of clinical endocrinology and metabolism. - 1945-7197. ; 108:10, s. 2447-2469
-
Tidskriftsartikel (refereegranskat)abstract
- What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference?International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS.The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist.The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout.This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC).The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management.Overall, recommendations are strengthened and evidence is improved, but remain generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided.The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation programme supports the Guideline with an integrated evaluation program.This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and the European Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the sponsoring organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC.
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| 24. |
- Zuin, M., et al.
(författare)
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Overview of the RFX-mod fusion science activity
- 2017
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Ingår i: Nuclear Fusion. - : Institute of Physics Publishing (IOPP). - 0029-5515 .- 1741-4326. ; 57:10
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Tidskriftsartikel (refereegranskat)abstract
- This paper reports the main recent results of the RFX-mod fusion science activity. The RFX-mod device is characterized by a unique flexibility in terms of accessible magnetic configurations. Axisymmetric and helically shaped reversed-field pinch equilibria have been studied, along with tokamak plasmas in a wide range of q(a) regimes (spanning from 4 down to 1.2 values). The full range of magnetic configurations in between the two, the so-called ultra-low q ones, has been explored, with the aim of studying specific physical issues common to all equilibria, such as, for example, the density limit phenomenon. The powerful RFX-mod feedback control system has been exploited for MHD control, which allowed us to extend the range of experimental parameters, as well as to induce specific magnetic perturbations for the study of 3D effects. In particular, transport, edge and isotope effects in 3D equilibria have been investigated, along with runaway mitigations through induced magnetic perturbations. The first transitions to an improved confinement scenario in circular and D-shaped tokamak plasmas have been obtained thanks to an active modification of the edge electric field through a polarized electrode. The experiments are supported by intense modeling with 3D MHD, gyrokinetic, guiding center and transport codes. Proposed modifications to the RFX-mod device, which will enable further contributions to the solution of key issues in the roadmap to ITER and DEMO, are also briefly presented.
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| 25. |
- Keppie, Stuart J, et al.
(författare)
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Matrix-Bound Growth Factors are Released upon Cartilage Compression by an Aggrecan-Dependent Sodium Flux that is Lost in Osteoarthritis
- 2021
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Ingår i: Function. - : Oxford University Press (OUP). - 2633-8823. ; 2:5
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Tidskriftsartikel (refereegranskat)abstract
- Articular cartilage is a dense extracellular matrix-rich tissue that degrades following chronic mechanical stress, resulting in osteoarthritis (OA). The tissue has low intrinsic repair especially in aged and osteoarthritic joints. Here, we describe three pro-regenerative factors; fibroblast growth factor 2 (FGF2), connective tissue growth factor, bound to transforming growth factor-beta (CTGF-TGFβ), and hepatoma-derived growth factor (HDGF), that are rapidly released from the pericellular matrix (PCM) of articular cartilage upon mechanical injury. All three growth factors bound heparan sulfate, and were displaced by exogenous NaCl. We hypothesised that sodium, sequestered within the aggrecan-rich matrix, was freed by injurious compression, thereby enhancing the bioavailability of pericellular growth factors. Indeed, growth factor release was abrogated when cartilage aggrecan was depleted by IL-1 treatment, and in severely damaged human osteoarthritic cartilage. A flux in free matrix sodium upon mechanical compression of cartilage was visualised by 23Na -MRI just below the articular surface. This corresponded to a region of reduced tissue stiffness, measured by scanning acoustic microscopy and second harmonic generation microscopy, and where Smad2/3 was phosphorylated upon cyclic compression. Our results describe a novel intrinsic repair mechanism, controlled by matrix stiffness and mediated by the free sodium concentration, in which heparan sulfate-bound growth factors are released from cartilage upon injurious load. They identify aggrecan as a depot for sequestered sodium, explaining why osteoarthritic tissue loses its ability to repair. Treatments that restore matrix sodium to allow appropriate release of growth factors upon load are predicted to enable intrinsic cartilage repair in OA.Significance Statement: Osteoarthritis is the most prevalent musculoskeletal disease, affecting 250 million people worldwide.1 We identify a novel intrinsic repair response in cartilage, mediated by aggrecan-dependent sodium flux, and dependent upon matrix stiffness, which results in the release of a cocktail of pro-regenerative growth factors after injury. Loss of aggrecan in late-stage osteoarthritis prevents growth factor release and likely contributes to disease progression. Treatments that restore matrix sodium in osteoarthritis may recover the intrinsic repair response to improve disease outcome.
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| 26. |
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| 27. |
- Teede, Helena J, et al.
(författare)
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Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome.
- 2023
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Ingår i: Fertility and sterility. - 1556-5653. ; 120:4, s. 767-793
-
Tidskriftsartikel (refereegranskat)abstract
- What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference?International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS.The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist.The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout.This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC).The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management.Overall, recommendations are strengthened and evidence is improved, but remain generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided.The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation programme supports the Guideline with an integrated evaluation program.This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and the Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the sponsoring organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC.
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| 28. |
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| 29. |
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| 30. |
- Franke, Andre, et al.
(författare)
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Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1118-1125
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Tidskriftsartikel (refereegranskat)abstract
- We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
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| 31. |
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| 32. |
- Rubia-Rodríguez, Irene, et al.
(författare)
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Whither Magnetic Hyperthermia? : A Tentative Roadmap
- 2021
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Ingår i: Materials. - : MDPI AG. - 1996-1944. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- The scientific community has made great efforts in advancing magnetic hyperthermia for the last two decades after going through a sizeable research lapse from its establishment. All the progress made in various topics ranging from nanoparticle synthesis to biocompatibilization and in vivo testing have been seeking to push the forefront towards some new clinical trials. As many, they did not go at the expected pace. Today, fruitful international cooperation and the wisdom gain after a careful analysis of the lessons learned from seminal clinical trials allow us to have a future with better guarantees for a more definitive takeoff of this genuine nanotherapy against cancer. Deliberately giving prominence to a number of critical aspects, this opinion review offers a blend of state-of-the-art hints and glimpses into the future of the therapy, considering the expected evolution of science and technology behind magnetic hyperthermia.
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| 33. |
- Asherson, PJ, et al.
(författare)
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Randomised controlled trial of the short-term effects of osmotic-release oral system methylphenidate on symptoms and behavioural outcomes in young male prisoners with attention deficit hyperactivity disorder: CIAO-II study
- 2023
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Ingår i: The British journal of psychiatry : the journal of mental science. - : Royal College of Psychiatrists. - 1472-1465. ; 222:1, s. 7-17
-
Tidskriftsartikel (refereegranskat)abstract
- Research has shown that 20–30% of prisoners meet the diagnostic criteria for attention-deficit hyperactivity disorder (ADHD). Methylphenidate reduces ADHD symptoms, but effects in prisoners are uncertain because of comorbid mental health and substance use disorders.AimsTo estimate the efficacy of an osmotic-release oral system methylphenidate (OROS-methylphenidate) in reducing ADHD symptoms in young adult prisoners with ADHD.MethodWe conducted an 8-week parallel-arm, double-blind, randomised placebo-controlled trial of OROS-methylphenidate versus placebo in male prisoners (aged 16–25 years) meeting the DSM-5 criteria for ADHD. Primary outcome was ADHD symptoms at 8 weeks, using the investigator-rated Connors Adult ADHD Rating Scale (CAARS-O). Thirteen secondary outcomes were measured, including emotional dysregulation, mind wandering, violent attitudes, mental health symptoms, and prison officer and educational staff ratings of behaviour and aggression.ResultsIn the OROS-methylphenidate arm, mean CAARS-O score at 8 weeks was estimated to be reduced by 0.57 points relative to the placebo arm (95% CI −2.41 to 3.56), and non-significant. The responder rate, defined as a 20% reduction in CAARS-O score, was 48.3% for the OROS-methylphenidate arm and 47.9% for the placebo arm. No statistically significant trial arm differences were detected for any of the secondary outcomes. Mean final titrated dose was 53.8 mg in the OROS-methylphenidate arm.ConclusionsADHD symptoms did not respond to OROS-methylphenidate in young adult prisoners. The findings do not support routine treatment with OROS-methylphenidate in this population. Further research is needed to evaluate effects of higher average dosing and adherence to treatment, multi-modal treatments and preventative interventions in the community.
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| 34. |
- Baskaran, Karthikeyan, Senior Lecturer, 1983-, et al.
(författare)
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Scoring reading parameters : An inter-rater reliability study using the MNREAD chart
- 2019
-
Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 14:6, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Purpose First, to evaluate inter-rater reliability when human raters estimate the reading performance of visually impaired individuals using the MNREAD acuity chart. Second, to evaluate the agreement between computer-based scoring algorithms and compare them with human rating. Methods Reading performance was measured for 101 individuals with low vision, using the Portuguese version of the MNREAD test. Seven raters estimated the maximum reading speed (MRS) and critical print size (CPS) of each individual MNREAD curve. MRS and CPS were also calculated automatically for each curve using two different algorithms: the original standard deviation method (SDev) and a non-linear mixed effects (NLME) modeling. Intra-class correlation coefficients (ICC) were used to estimate absolute agreement between raters and/or algorithms. Results Absolute agreement between raters was ‘excellent’ for MRS (ICC = 0.97; 95%CI [0.96, 0.98]) and ‘moderate’ to ‘good’ for CPS (ICC = 0.77; 95%CI [0.69, 0.83]). For CPS, inter-rater reliability was poorer among less experienced raters (ICC = 0.70; 95%CI [0.57, 0.80]) when compared to experienced ones (ICC = 0.82; 95%CI [0.76, 0.88]). Absolute agreement between the two algorithms was ‘excellent’ for MRS (ICC = 0.96; 95%CI [0.91, 0.98]). For CPS, the best possible agreement was found for CPS defined as the print size sustaining 80% of MRS (ICC = 0.77; 95%CI [0.68, 0.84]). Absolute agreement between raters and automated methods was ‘excellent’ for MRS (ICC = 0.96; 95% CI [0.88, 0.98] for SDev; ICC = 0.97; 95% CI [0.95, 0.98] for NLME). For CPS, absolute agreement between raters and SDev ranged from ‘poor’ to ‘good’ (ICC = 0.66; 95% CI [0.3, 0.80]), while agreement between raters and NLME was ‘good’ (ICC = 0.83; 95% CI [0.76, 0.88]). Conclusion For MRS, inter-rater reliability is excellent, even considering the possibility of noisy and/or incomplete data collected in low-vision individuals. For CPS, inter-rater reliability is lower. This may be problematic, for instance in the context of multisite investigations or follow-up examinations. The NLME method showed better agreement with the raters than the SDev method for both reading parameters. Setting up consensual guidelines to deal with ambiguous curves may help improve reliability. While the exact definition of CPS should be chosen on a case-by-case basis depending on the clinician or researcher’s motivations, evidence suggests that estimating CPS as the smallest print size sustaining about 80% of MRS would increase inter-rater reliability.
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| 35. |
- Beal, Jacob, et al.
(författare)
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Robust estimation of bacterial cell count from optical density
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
-
Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 36. |
- Choi, S. G., et al.
(författare)
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Dielectric function spectra at 40 K and critical-point energies for CuIn0.7Ga0.3Se2
- 2012
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 101:26, s. 261903-
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Tidskriftsartikel (refereegranskat)abstract
- We report ellipsometrically determined dielectric function ε spectra for CuIn0.7Ga0.3Se2 thin film at 40 and 300 K. The data exhibit numerous spectral features associated with interband critical points (CPs) in the spectral range from 0.74 to 6.43 eV. The second-energy-derivatives of ε further reveal a total of twelve above-bandgap CP features, whose energies are obtained accurately by a standard lineshape analysis. The ε spectra determined by ellipsometry show a good agreement with the results of full-potential linearized augmented plane wave calculations. Probable electronic origins of the CP features observed are discussed.
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| 37. |
- Clementson, Joel, et al.
(författare)
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Experimental setup for tungsten transport studies at the NSTX tokamak
- 2010
-
Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 81:10
-
Konferensbidrag (refereegranskat)abstract
- Tungsten particles have been introduced into the National Spherical Torus Experiment (NSTX) in Princeton with the purpose to investigate the effects of tungsten injection on subsequent plasma discharges. An experimental setup for the study of tungsten particle transport is described where the particles are introduced into the tokamak using a modified particle dropper, otherwise used for lithium-powder injection. An initial test employing a grazing-incidence extreme ultraviolet spectrometer demonstrates that the tungsten-transport setup could serve to infer particle transport from the edge to the hot central plasmas of NSTX. (C) 2010 American Institute of Physics. [doi:10.1063/1.3499607]
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| 38. |
- Cleynen, Isabelle, et al.
(författare)
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Inherited determinants of Crohn's disease and ulcerative colitis phenotypes : a genetic association study
- 2016
-
Ingår i: The Lancet. - New York, USA : Elsevier. - 0140-6736 .- 1474-547X. ; 387:10014, s. 156-167
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Tidskriftsartikel (refereegranskat)abstract
- Background: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile.Findings: After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)).Interpretation: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time.Funding: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
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| 39. |
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| 40. |
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| 41. |
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| 42. |
- Eckhard, Ulrich, et al.
(författare)
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Discovery of a proteolytic flagellin family in diverse bacterial phyla that assembles enzymatically active flagella
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Bacterial flagella are cell locomotion and occasional adhesion organelles composed primarily of the polymeric protein flagellin, but to date have not been associated with any enzymatic function. Here, we report the bioinformatics-driven discovery of a class of enzymatic flagellins that assemble to form proteolytically active flagella. Originating by a metallopeptidase insertion into the central flagellin hypervariable region, this flagellin family has expanded to at least 74 bacterial species. In the pathogen, Clostridium haemolyticum, metallopeptidase-containing flagellin (which we termed flagellinolysin) is the second most abundant protein in the flagella and is localized to the extracellular flagellar surface. Purified flagellar filaments and recombinant flagellin exhibit proteolytic activity, cleaving nearly 1000 different peptides. With similar to 20,000 flagellin copies per similar to 10-mu m flagella this assembles the largest proteolytic complex known. Flagellum-mediated extracellular proteolysis expands our understanding of the functional plasticity of bacterial flagella, revealing this family as enzymatic biopolymers that mediate interactions with diverse peptide substrates.
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| 43. |
- Hammond, Mark, et al.
(författare)
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Two-dimensional Eclipse Mapping of the Hot-Jupiter WASP-43b with JWST MIRI/LRS
- 2024
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Ingår i: Astronomical Journal. - 1538-3881 .- 0004-6256. ; 168:1
-
Tidskriftsartikel (refereegranskat)abstract
- We present eclipse maps of the two-dimensional thermal emission from the dayside of the hot-Jupiter WASP-43b, derived from an observation of a phase curve with the JWST MIRI/LRS instrument. The observed eclipse shapes deviate significantly from those expected for a planet emitting uniformly over its surface. We fit a map to this deviation, constructed from spherical harmonics up to order ℓ max = 2 , alongside the planetary, orbital, stellar, and systematic parameters. This yields a map with a meridionally averaged eastward hot-spot shift of (7.75 ± 0.36)°, with no significant degeneracy between the map and the additional parameters. We show the latitudinal and longitudinal contributions of the dayside emission structure to the eclipse shape, finding a latitudinal signal of ∼200 ppm and a longitudinal signal of ∼250 ppm. To investigate the sensitivity of the map to the method, we fix the parameters not used for mapping and derive an “eigenmap” fitted with an optimized number of orthogonal phase curves, which yields a similar map to the ℓ max = 2 map. We also fit a map up to ℓ max = 3 , which shows a smaller hot-spot shift, with a larger uncertainty. These maps are similar to those produced by atmospheric simulations. We conclude that there is a significant mapping signal which constrains the spherical harmonic components of our model up to ℓ max = 2 . Alternative mapping models may derive different structures with smaller-scale features; we suggest that further observations of WASP-43b and other planets will drive the development of more robust methods and more accurate maps.
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| 44. |
- Heap, Graham A., et al.
(författare)
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HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants
- 2014
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:10, s. 1131-1134
-
Tidskriftsartikel (refereegranskat)abstract
- Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 x 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the H LA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.
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| 45. |
- Holmlund, Patrik, et al.
(författare)
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Effect of vibration magnitude, vibration spectrum and muscle tension on apparent mass and cross axis transfer functions during whole-body vibration exposure
- 2006
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Ingår i: Journal of Biomechanics. - : Elsevier BV. - 0021-9290 .- 1873-2380. ; 39:16, s. 3062-3070
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Tidskriftsartikel (refereegranskat)abstract
- Twelve seated male subjects were exposed to 15 vibration conditions to investigate the nature and mechanisms of the non-linearity in biomechanical response. Subjects were exposed to three groups of stimuli: Group A comprised three repeats of random vertical vibration at 0.5, 1.0 and 1.5 m s-2 r.m.s. with subjects sitting in a relaxed upright posture. Group B used the same vibration stimuli as Group A, but with subjects sitting in a ‘tense' posture. Group C used vibration where the vibration spectrum was dominated by either low-frequency motion (2-7 Hz), high-frequency motion (7-20 Hz) or a 1.0 m s-2 r.m.s. sinusoid at the frequency of the second peak in apparent mass (about 10-14 Hz) added to 0.5 m s-2 r.m.s. random vibration. In the relaxed posture, frequencies of the primary peak in apparent mass decreased with increased vibration magnitude. In the tense posture, the extent of the non-linearity was reduced. For the low-frequency dominated stimulus, the primary peak frequency was lower than that for the high-frequency dominated stimulus indicating that the frequency of the primary peak in the apparent mass is dominated by the magnitude of the vibration encompassing the peak. Cross-axis transfer functions showed peaks of about 15-20% and 5% of the magnitudes of the peaks in the apparent mass for x- and y-direction transfer functions, respectively, in the relaxed posture. In the tense posture, cross-axis transfer functions reduced in magnitude with increased vibration, likely indicating a reduced fore-aft pitching of the body with increased tension, supporting the hypothesis that pitching contributes to the non-linearity in apparent mass.
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| 46. |
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| 47. |
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| 48. |
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| 49. |
- Lie, X. H., et al.
(författare)
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Mesp1 controls the chromatin and enhancer landscapes essential for spatiotemporal patterning of early cardiovascular progenitors
- 2022
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Ingår i: Nature Cell Biology. - : Springer Science and Business Media LLC. - 1465-7392 .- 1476-4679. ; 24:7, s. 1114-1128
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Tidskriftsartikel (refereegranskat)abstract
- The mammalian heart arises from various populations of Mesp1-expressing cardiovascular progenitors (CPs) that are specified during the early stages of gastrulation. Mesp1 is a transcription factor that acts as a master regulator of CP specification and differentiation. However, how Mesp1 regulates the chromatin landscape of nascent mesodermal cells to define the temporal and spatial patterning of the distinct populations of CPs remains unknown. Here, by combining ChIP-seq, RNA-seq and ATAC-seq during mouse pluripotent stem cell differentiation, we defined the dynamic remodelling of the chromatin landscape mediated by Mesp1. We identified different enhancers that are temporally regulated to erase the pluripotent state and specify the pools of CPs that mediate heart development. We identified Zic2 and Zic3 as essential cofactors that act with Mesp1 to regulate its transcription-factor activity at key mesodermal enhancers, thereby regulating the chromatin remodelling and gene expression associated with the specification of the different populations of CPs in vivo. Our study identifies the dynamics of the chromatin landscape and enhancer remodelling associated with temporal patterning of early mesodermal cells into the distinct populations of CPs that mediate heart development.
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| 50. |
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