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| 513. |
- Ovadia, C., et al.
(author)
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Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis
- 2021
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In: Lancet Gastroenterology & Hepatology. - : Elsevier BV. - 2468-1253. ; 6:7
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Journal article (peer-reviewed)abstract
- Background Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. Methods In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 mu mol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. Findings The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67.8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0.7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0.6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1.04, 95% CI 0.35-3.07; p=0.95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0.29, 95% CI 0.04-2.42; p=0.25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1.28, 95% CI 0.86-1.91; p=0.22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0.60, 0.39-0.91; p=0.016). Interpretation Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. Copyright (C) 2021 The Authors(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
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| 515. |
- Pulit, SL, et al.
(author)
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Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.
- 2016
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In: The Lancet. Neurology. - 1474-4465. ; 15:2, s. 174-84
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Journal article (peer-reviewed)abstract
- The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16851 cases with state-of-the-art phenotyping data and 32473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20941 cases and 364736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50×10(-8); joint OR 1·19, 1·12-1·26, p=1·30×10(-9)). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26×10(-19); joint OR 1·37, 1·30-1·45, p=2·79×10(-32)) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93×10(-7); joint OR 1·17, 1·11-1·23, p=2·29×10(-10)) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50×10(-8); joint OR 1·24, 1·15-1·33, p=4·52×10(-9)) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82×10(-8); joint OR 1·17, 1·11-1·23, p=2·92×10(-9)). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.US National Institute of Neurological Disorders and Stroke, National Institutes of Health.
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| 517. |
- Rivero-Rodriguez, J. F., et al.
(author)
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Overview of fast particle experiments in the first MAST Upgrade experimental campaigns
- 2024
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In: Nuclear Fusion. - : Institute of Physics Publishing (IOPP). - 0029-5515 .- 1741-4326. ; 64:8
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Journal article (peer-reviewed)abstract
- MAST-U is equipped with on-axis and off-axis neutral beam injectors (NBI), and these external sources of super-Alfvénic deuterium fast-ions provide opportunities for studying a wide range of phenomena relevant to the physics of alpha-particles in burning plasmas. The MeV range D-D fusion product ions are also produced but are not confined. Simulations with the ASCOT code show that up to 20% of fast ions produced by NBI can be lost due to charge exchange (CX) with edge neutrals. Dedicated experiments employing low field side (LFS) gas fuelling show a significant drop in the measured neutron fluxes resulting from beam-plasma reactions, providing additional evidence of CX-induced fast-ion losses, similar to the ASCOT findings. Clear evidence of fast-ion redistribution and loss due to sawteeth (ST), fishbones (FB), long-lived modes (LLM), Toroidal Alfvén Eigenmodes (TAE), Edge Localised Modes (ELM) and neoclassical tearing modes (NTM) has been found in measurements with a Neutron Camera (NCU), a scintillator-based Fast-Ion Loss Detector (FILD), a Solid-State Neutral Particle Analyser (SSNPA) and a Fast-Ion Deuterium-α (FIDA) spectrometer. Unprecedented FILD measurements in the range of 1-2 MHz indicate that fast-ion losses can be also induced by the beam ion cyclotron resonance interaction with compressional or global Alfvén eigenmodes (CAEs or GAEs). These results show the wide variety of scenarios and the unique conditions in which fast ions can be studied in MAST-U, under conditions that are relevant for future devices like STEP or ITER.
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