| 1. |
- Sawcer, Stephen, et al.
(author)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Journal article (peer-reviewed)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 2. |
- Dawson, Deborah, et al.
(author)
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High-utility conserved avian microsatellite markers enable parentage and population studies across a wide range of species
- 2013
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 14:1, s. 176-
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Journal article (peer-reviewed)abstract
- Background: Microsatellites are widely used for many genetic studies. In contrast to single nucleotide polymorphism (SNP) and genotyping-by-sequencing methods, they are readily typed in samples of low DNA quality/concentration (e.g. museum/non-invasive samples), and enable the quick, cheap identification of species, hybrids, clones and ploidy. Microsatellites also have the highest cross-species utility of all types of markers used for genotyping, but, despite this, when isolated from a single species, only a relatively small proportion will be of utility. Marker development of any type requires skill and time. The availability of sufficient "off-the-shelf" markers that are suitable for genotypinga wide range of species would not only save resources but also uniquely enablenew comparisons of diversity among taxa at the same set of loci. No other marker types are capable of enabling this. We therefore developed a set of avianmicrosatellite markers with enhanced cross-species utility. Results: We selected highly-conserved sequences with a high number of repeat units in both of two genetically distant species. Twenty-four primer sets were designed from homologous sequences that possessed at least eight repeat units in both the zebra finch (Taeniopygia guttata) and chicken (Gallus gallus). Each primer sequence was a complete match to zebra finch and, after accounting for degenerate bases, at least 86% similar to chicken. We assessed primer-set utilityby genotyping individuals belonging to eight passerine and four non-passerinespecies. The majority of the new Conserved Avian Microsatellite (CAM) markersamplified in all 12 species tested (on average, 94% in passerines and 95% in non-passerines). This new marker set is of especially high utility in passerines, with amean 68% of loci polymorphic per species, compared with 42% in non-passerinespecies. Conclusions: When combined with previously described conserved loci, this new set of conserved markers will not only reduce the necessity and expense ofmicrosatellite isolation for a wide range of genetic studies, including avianparentage and population analyses, but will also now enable comparisons ofgenetic diversity among different species (and populations) at the same set of loci, with no or reduced bias. Finally, the approach used here can be applied to other taxa in which appropriate genome sequences are available.
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| 3. |
- Halliday, Alison, et al.
(author)
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10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1) : A multicentre randomised trial
- 2010
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In: The Lancet. - 0140-6736 .- 1474-547X. ; 376:9746, s. 1074-1084
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Journal article (peer-reviewed)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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| 4. |
- Ingrids, Henrik, 1972-
(author)
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Dilemmas in child custody disputes : the child's best interest in courtroom discourse
- 2014
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Doctoral thesis (other academic/artistic)abstract
- This thesis examines courtroom interactions involving child custody disputes, exploring how participants during courtroom hearings orient to and manage the task of presenting their own side, while contesting the opposing party, in matters like the child’s best interest, domestic violence, parental neglect and misconduct. Drawing on 42 audio-recorded courtroom examinations of litigating parents by the same side and opponent side attorneys, it examines authentic courtroom hearings. Theoretically and methodologically, the thesis primarily builds on discursive psychology and conversation analysis. It draws on and contributes to studies on institutional talk by explicating the subtle interactional work required by participants in this institutional setting.The overall aim is to examine how interactional dilemmas in child custody disputes, requiring participants to simultanously manage contradictory activities, are handled through discursive practices. A core dilemma concerns the child’s (lack of) participation in the proceeding. In this absence, litigants try to mobilize the child’s voice and experiences in order to support their own claims, in danger of having such attempts dismissed as mere reflections of their own interest. The child’s reported speech and reported affects are important discursive devices for handling this dilemma. Another dilemma arises when litigants blame each other. Although this is necessary to ‘win’, litigants are regularly blamed when doing so, which generates something of a blame machinery of never-ending blame. A final dilemma concerns domestic violence. While implicitly gendered social categorizations are invoked to support mothers' claims of fearing their ex-partners, such discursive work is undermined through contrasting social categorizations.By analyzing child custody disputes on the micro-level of courtroom interaction, this study contributes to an understanding of how disputes are built through participants’ discursive practices.
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| 7. |
- Wennberg, Karl, et al.
(author)
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The Missing Entrepreneurs 2014 : Policies for Inclusive Entrepreneurship in Europe
- 2014
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Reports (other academic/artistic)abstract
- OECD's LEED Programme and the European Commission's DG on Employment, Social Affairs and Inclusion recently published the second book as part of their programme of work on inclusive entrepreneurship. The Missing Entrepreneurs 2014 examines how public policies at national and local levels can support job creation by encouraging business start-ups and self-employment by people from disadvantaged or under-represented social groups in entrepreneurship. It shows that there is substantial potential to combat unemployment and stimulate social inclusion by promoting entrepreneurship in populations such as women, youth, seniors, the unemployed, and migrants, if the specific problems they face can be addressed and if entrepreneurship policies are opened up to all.
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