| 1. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 2. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 3. |
- Gei, Maga, et al.
(författare)
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Legume abundance along successional and rainfall gradients in Neotropical forests
- 2018
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Ingår i: Nature Ecology & Evolution. - : Springer Science and Business Media LLC. - 2397-334X. ; 2:7
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Tidskriftsartikel (refereegranskat)abstract
- The nutrient demands of regrowing tropical forests are partly satisfied by nitrogen-fixing legume trees, but our understanding of the abundance of those species is biased towards wet tropical regions. Here we show how the abundance of Leguminosae is affected by both recovery from disturbance and large-scale rainfall gradients through a synthesis of forest inventory plots from a network of 42 Neotropical forest chronosequences. During the first three decades of natural forest regeneration, legume basal area is twice as high in dry compared with wet secondary forests. The tremendous ecological success of legumes in recently disturbed, water-limited forests is likely to be related to both their reduced leaflet size and ability to fix N2, which together enhance legume drought tolerance and water-use efficiency. Earth system models should incorporate these large-scale successional and climatic patterns of legume dominance to provide more accurate estimates of the maximum potential for natural nitrogen fixation across tropical forests.
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| 4. |
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| 5. |
- Windhorst, Rogier A., et al.
(författare)
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JWST PEARLS. Prime extragalactic areas for reionization and lensing science : project overview and first results
- 2023
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Ingår i: Astronomical Journal. - : Institute of Physics (IOP). - 0004-6256 .- 1538-3881. ; 165:1
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Tidskriftsartikel (refereegranskat)abstract
- We give an overview and describe the rationale, methods, and first results from NIRCam images of the JWST “Prime Extragalactic Areas for Reionization and Lensing Science” (PEARLS) project. PEARLS uses up to eight NIRCam filters to survey several prime extragalactic survey areas: two fields at the North Ecliptic Pole (NEP); seven gravitationally lensing clusters; two high redshift protoclusters; and the iconic backlit VV 191 galaxy system to map its dust attenuation. PEARLS also includes NIRISS spectra for one of the NEP fields and NIRSpec spectra of two high-redshift quasars. The main goal of PEARLS is to study the epoch of galaxy assembly, active galactic nucleus (AGN) growth, and First Light. Five fields—the JWST NEP Time-Domain Field (TDF), IRAC Dark Field, and three lensing clusters—will be observed in up to four epochs over a year. The cadence and sensitivity of the imaging data are ideally suited to find faint variable objects such as weak AGN, high-redshift supernovae, and cluster caustic transits. Both NEP fields have sightlines through our Galaxy, providing significant numbers of very faint brown dwarfs whose proper motions can be studied. Observations from the first spoke in the NEP TDF are public. This paper presents our first PEARLS observations, their NIRCam data reduction and analysis, our first object catalogs, the 0.9–4.5 μm galaxy counts and Integrated Galaxy Light. We assess the JWST sky brightness in 13 NIRCam filters, yielding our first constraints to diffuse light at 0.9–4.5 μm. PEARLS is designed to be of lasting benefit to the community.
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| 6. |
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| 7. |
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| 8. |
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| 9. |
- Duncan, Rebecca
(författare)
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Coda : Planetary Gothic: An Invitation
- 2023
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Ingår i: The Edinburgh Companion to Globalgothic. - Edinburgh : Edinburgh University Press. - 9781399510585 - 9781399510608 ; , s. 485-494
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Bokkapitel (refereegranskat)
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| 10. |
- Duncan, Rebecca
(författare)
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Contemporary South African Horror : On Meat, Neoliberalism and the Postcolonial Politics of a Global Form
- 2014
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Ingår i: Horror Studies. - : Intellect Ltd.. - 2040-3275 .- 2040-3283. ; 5:1, s. 85-106
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Tidskriftsartikel (refereegranskat)abstract
- Following the postapartheid encounter with neo-liberal economics, South African cultural production has begun to register the influence of global, popular forms borne into the country on the tide of multinational capital. Horror is one such commercial mode the manifestation of which, in contemporary South Africa, is thus bound up with processes of economic globalization. Its deployment in the country is also, however, committed to unveiling the brutalities and dehumanizations underpinning the neo-liberal operation of global capital. In these texts, economic deprivation and exploitation are made to resonate with the country’s history of racial oppression, and are given brutal form as evocations of the person become meat. The circumscribed position in which such narratives situate themselves – their critique of the processes which sustain them – is the focus of this article’s final stages: I suggest we read South Africa’s horror, not as complicit in some invalidating way, but as an experimental exploration of modes and voices in a postapartheid culture unrestrained by polarizing ethical demands to oppose the racist state. South African horror arises, then, in a context where the binary is losing purchase as a model for dissent, and this observation, I venture, may have implications not simply for the postapartheid production of such narratives, but for wider manifestations of the genre too.
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| 11. |
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| 12. |
- Duncan, Rebecca
(författare)
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Decolonial Gothic : Beyond the Postcolonial in Gothic Studies
- 2022
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Ingår i: Gothic Studies. - : Edingburgh University Press. - 1362-7937 .- 2050-456X. ; 24:3, s. 304-322
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Tidskriftsartikel (refereegranskat)abstract
- This article theorises decolonial Gothic as a novel approach to Gothic fiction from formerly colonised regions and communities. It responds to an emerging body of Gothic production, which situates itself in a world shaped by persistently racialised distributions of social and environmental precarity, and where colonial power is thus an enduring material reality. To address such fiction, the article proposes, requires a reassessment of the hauntological frameworks through which Gothic and the (post)colonial have hitherto been brought into contact. Forged in the cultural climate of late-twentieth-century postmodernity, these hinge on the assumption of an epochal break, which renders colonial history a thing of the past; thus, they fall short of narratives that engage with active formations of colonial power. Accordingly, the article outlines an alternative approach, positioning Gothic fiction in the context of the capitalist world-system, which – into the present – is structured by colonial categories of race, heteropatriarchal categories of gender, and instrumentalising discourses of nature as plunderable resource.
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| 13. |
- Duncan, Rebecca, et al.
(författare)
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Decolonising the COVID-19 pandemic : On Being in this Together
- 2021
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Ingår i: Approaching Religion. - : Approaching Religion. - 1799-3121. ; 11:2, s. 115-131
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Tidskriftsartikel (refereegranskat)abstract
- At its inception, the COVID-19 pandemic was described as something inherently new, capable of crossing and erasing the economic, racial, gendered, and religious divides that stratify societies around the world. However, the ongoing pandemic is not new or egalitarian, but fuelled by, and fuelling, crises already under way on a global scale. In this article we examine on the one hand the relationship between the pandemic and still-active formations of racialised and gendered power, and on the other the pandemic's inextricability from a dispersed and uneven planetary emergency. As the environmental historian Jason W. Moore notes, this emergency disproportionately affects ‘women, people of colour and (neo)colonial populations’ (2019: 54), and the effects of COVID-19 are similarly unevenly allocated.
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| 14. |
- Duncan, Rebecca
(författare)
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Fiction from the Data Frontier
- 2024
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Ingår i: Interventions. - : Taylor & Francis Group. - 1369-801X .- 1469-929X.
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Tidskriftsartikel (refereegranskat)
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| 15. |
- Duncan, Rebecca
(författare)
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From Cheap Labour to Surplus Humanity : World-Ecology and the Postapartheid Speculative in Neill Blomkamp’s District 9
- 2018
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Ingår i: Science Fiction Film and Television. - : Liverpool University Press. - 1754-3770 .- 1754-3789. ; 11:1, s. 45-72
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Tidskriftsartikel (refereegranskat)abstract
- Conventions appropriated from certain forms of speculative fiction – sf, gothic and horror among them – have become increasingly discernible features of diverse contemporary postcolonial imaginaries. In this article, I consider Neill Blomkamp's District 9 (2009) in light of questions posed by these developments. Drawing on world-ecological thinking (Moore 2015) and highlighting legacies of South African political economy (Wolpe 1972), I suggest the film deploys sf and horror traditions alongside invocations of local history in response to the reorganisation of 'Nature' in South Africa in the wake of the transition from apartheid to neoliberal governance. I show that Blomkamp manipulates speculative forms to register the febrile climate of this anxious time, and to contest the logic undergirding historic and ongoing unevenness. In conclusion, I point to key limitations to his project in this last regard.
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Duncan, Rebecca
(författare)
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Haunted Technonature : Anthropocene Coloniality in Ng Yi-Sheng’s Lion City
- 2021
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Ingår i: Haunted Nature. - Cham : Palgrave Macmillan. - 9783030818685 - 9783030818692 - 9783030818715 ; , s. 135-158
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Bokkapitel (refereegranskat)abstract
- This chapter moves away from the established strand of literary ecocriticism in which haunted nature is situated in the Anthropocene and instead examines how Anthropocene thinking itself becomes subject to haunting in speculative fiction. To make this argument, it focuses on Ng Yi-Sheng’s collection Lion City (2018): a text that maps connections between Singapore’s colonial history and the nation’s contemporary status as a model for climate survival through geoengineering and “technonature.” This analysis proposes that rather than mobilizing the speculative to describe human effects on the biosphere (as much criticism suggests), Ng’s tales excavate legacies of environmental injustice repressed by the paradigm of anthropogenesis. In doing so, the narrative critiques Anthropocene accounts of emergency and highlights the necessity of decolonizing the narrative of crisis itself.
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| 20. |
- Duncan, Rebecca, et al.
(författare)
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Introduction : McGrath in the World: Gothic, Madness and Transnational Consciousness
- 2019
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Ingår i: Patrick McGrath and his Worlds. - London : Routledge. - 9781138311190 - 9781003007944 ; , s. 1-18
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Bokkapitel (refereegranskat)abstract
- This introduction identifies a transnational consciousness that runs through Patrick McGrath’s work. Locating this in relation to the author’s own migration from England to the United States, and considering it in the context of late-twentieth and early-twenty-first century transatlantic upheavals, the chapter explores McGrath’s established and related investments in the gothic and tropes of madness as registering and, at times, interrogating contemporary geopolitical shifts. To bring this relationship between madness, gothic, and the transnational into focus, the introduction examines a selection of fictions from across McGrath’s oeuvre through the lens of the imperial gothic—a mode that is frequently reflexively and critically engaged by these texts. Viewed in this way, McGrath’s gothic figurations of madness can—in certain of his narratives—be read to witness anxieties around the decline of British and US hegemony in the latter phases of the Cold War, for example, and in the aftermath of the attacks on the World Trade Center on 11 September 2001. To approach the author’s fiction from this vantage point is not, as we point out, to refuse the psychoanalytic perspectives so frequently applied to the McGrath canon; rather, it is to make visible the ways in which self-consciously summoned clinical paradigms articulate with gothic forms and a transnational sensibility to critique planetary formations of power. The introduction closes with an outline of the chapters collected in this volume.
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| 21. |
- Duncan, Rebecca, et al.
(författare)
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Introduction : The Body in Postcolonial Fiction after the Millennium
- 2020
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Ingår i: Interventions. - : Taylor & Francis Group. - 1369-801X .- 1469-929X. ; 22:5, s. 587-605
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Since the turn of the millennium, debates in postcolonial studies and world literature have repeatedly shown the realities of empire to be continuing, immediate and visceral. What has been overlooked thus far are the ways in which the bodily has re-emerged in postcolonial cultural production as a receptor to, and vocabulary for, these immanent violences. Fictions from across the global south are drawing with apparently increasing frequency on corporeal lexica in their imaginings of on-going imperial circumstances. At the same time, the new millennium has witnessed the rise, in multiple postcolonial contexts, of speculative genres - science fiction and horror pre-eminent among them - to which the body is central. Together, all of this suggests the need for renewed reflection on the poetics and functions of the bodily in contemporary fictional engagements with empire. This special issue takes up this imperative. Our interest lies with the grammars and technologies offered by the corporeal in postcolonial cultural production since the millennium, and in the possibilities and limitations of these bodily registers. Over the course of this introduction, we outline the material, narrative and theoretical contexts within which we see the body re-emerging as a site of renewed critical and literary or cinematic potential. We return to established analytical categories for the corporeal in postcolonial literary studies, and show that current fictional handlings of the body and embodiment appear resistant to interpretation via these rubrics. Taking our cue both from a materialist theoretical (re)turn that corresponds to the turn of the millennium and from aesthetic developments in literature and film of the same period, we go on to lay the groundwork for an approach to the body as this is currently emerging in contemporary postcolonial and peripheral imaginaries.
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| 22. |
- Duncan, Rebecca
(författare)
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Introduction : Decolonising Gothic
- 2022
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Ingår i: Gothic Studies. - : Edingburgh University Press. - 1362-7937 .- 2050-456X. ; 24:3, s. 219-227
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- This introduction to the special issue – ‘Decolonising Gothic’ – provides an overview of major existing approaches to gothic in the international context – namely postcolonial- and globalgothic – and highlights developments in contemporary Gothic production that demand a critical shift beyond these frameworks. The article outlines decolonial thinking as one productive response to this situation, and reflects both on what it might mean to ‘decolonise’ Gothic Studies, and on Gothic fiction’s own decolonising possibilities. The article concludes by introducing the essays collected in the special issue, foregrounding how each takes up the questions of decoloniality and decolonising in relation to gothic imaginaries from different regions of the world.
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| 23. |
- Duncan, Rebecca
(författare)
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Introduction : Globalgothic Beyond Globalisation
- 2023
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Ingår i: The Edinburgh Companion to Globalgothic. - Edinburgh : Edinburgh University Press. - 9781399510585 - 9781399510608 ; , s. 1-22
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Bokkapitel (refereegranskat)
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| 24. |
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| 25. |
- Duncan, Rebecca
(författare)
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'My Skin, a Parchment of Tales' : Trauma, Wounding and the Postapartheid Gothic in Terry Westby-Nunn's Sea of Wise Insects
- 2013
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Ingår i: Current Writing. - : Taylor & Francis. - 1013-929X .- 2159-9130. ; 25:1, s. 76-87
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, I read Terry Westby-Nunn's The Sea of Wise Insects as an example of the literary mode identified increasingly by scholars as South African postcolonial Gothic. In line with existing research, I work from a definition of the gothic genre which casts it as highly culturally specific and shaped by the anxieties of the society in which it arises. In Westby-Nunn's narrative these fears are enmeshed in the South African past, and revolve, more specifically, around the extent to which history's bearing on the present has become a dangerous point of repression. My argument traces a transgenerational logic of traumatic transmission, which situates the unspoken crimes of an old generation at the psychic nerve-centre of Westby-Nunn's contemporary protagonist, a strategy which disrupts any illusion of a stable boundary between the injustice of ‘then’ and the liberation of ‘now’. Finally, I suggest that through the deployment of an aesthetic which draws on the gothic sub-genre of horror-writing, Westby-Nunn develops a narrative which, to paraphrase Tabish Khair, does not operate “only in words”. Instead, the text relies in part on visceral reader reactions so that the novel admits of silence in a way that avoids replicating the exclusionary logic underpinning the institutionalised discrimination in South Africa's history.
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| 26. |
- Duncan, Rebecca
(författare)
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Shades of Dissent : Notes on Haunting in South African Literary History
- 2017
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Ingår i: Routledge Handbook to the Ghost Story. - London : Routledge. - 9781138184763 - 9781315644417
-
Bokkapitel (refereegranskat)abstract
- This chapter suggests encountering gradations—or, perhaps more appropriately, shades—of dissent. It explores the idea in respect of haunting figures emergent across the twentieth century in South African literatures. The tale of South African politics is, Antjie Krog suggests, something akin to a haunted house: narratives of liberal empire—elaborately extended as apartheid from the middle of the twentieth century—are populated by restless, revenant things. To read Perceval Gibbon’s ghost stories as haunted by that which their imperial premises cannot acknowledge is to engage in a particular historical praxis. The ability of the ghost to interrupt ‘modern’ knowledges becomes especially important if it is considered that, in South Africa, the epistemologies have unfolded with the processes of imperial expansion. Discourses inherited from Enlightenment modernity inform British imperial governance, and they live on as the founding premise of apartheid rule, which began with the election of the National Party in 1948.
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| 27. |
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| 28. |
- Duncan, Rebecca
(författare)
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South African Gothic
- 2019
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Ingår i: Twenty-First-Century Gothic. - Edinburgh : Edinburgh University Press. - 9781474440929 - 9781474440950 - 9781474440943 ; , s. 233-248
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Bokkapitel (refereegranskat)
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| 29. |
- Duncan, Rebecca, et al.
(författare)
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The Emergency Has Already Happened
- 2023
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Ingår i: Environment and History. - : White Horse Press. - 0967-3407 .- 1752-7023. ; 29:4, s. 476-482
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Tidskriftsartikel (refereegranskat)
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| 30. |
- Duncan, Rebecca
(författare)
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Writing Ecological Revolution from Millennial South Africa : History, Nature and the Postapartheid Present
- 2020
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Ingår i: Ariel. - : Johns Hopkins University Press. - 0004-1327. ; 51:4, s. 65-97
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Tidskriftsartikel (refereegranskat)abstract
- This article does two key things. Firstly, it offers a perspective on histories of South African political economy refracted through the lens of "world-ecological" thinking (Moore, Capitalism 2-5). It maps the organisations of institutionalised apartheid and the liberal democracy that has succeeded it in terms of capital's cyclical regimentations of nature. This approach sheds new light on the entanglements of politics, economics, and environments, which, in specific ways over the course of the twentieth century and into the millennial present, have shaped and characterised unevenness in South Africa. Secondly, in light of these ideas, the article considers Zinaid Meeran's Tanuki Ichiban (2012), Henrietta Rose-Innes' Nineveh (2011), and Lauren Beukes' Maryland (2008), twenty-first-century texts exemplary of an increasingly prominent "speculative" impulse in contemporary South African literary production. I situate the extraordinary human and extra-human vocabularies of these fictions as responsive to shifting historical constructions of "Nature" in neoliberalising South Africa. I further argue that the narratives are sensitive to the structures of these historical and ongoing regimentations-to how they concatenate and overlay one another in the millennial present. Finally, I suggest that with recourse to speculative poetics, the texts seek to offer alternative conceptual vocabularies to those from which systematic violences continue to proceed.
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| 31. |
- Ercan, Ayse Bahar, et al.
(författare)
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Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.
- 2024
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Ingår i: The Lancet. Oncology. - 1474-5488. ; 25:5, s. 668-682
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Tidskriftsartikel (refereegranskat)abstract
- Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD.In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions.We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions.The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD.The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.
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| 32. |
- Estrada, Karol, et al.
(författare)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Tidskriftsartikel (refereegranskat)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 33. |
- Foley, Matt, et al.
(författare)
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Patrick McGrath and Passion : the Gothic modernism of Asylum and Beyond
- 2020
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Ingår i: Patrick McGrath and his Worlds. - London : Routledge. - 9781138311190 - 9781003007944 ; , s. 103-115
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Bokkapitel (refereegranskat)abstract
- This chapter reads Asylum (1996) and Port Mungo (2004) to suggest the centrality of passion to McGrath’s writing and, more specifically, to argue for the importance of modernist aesthetics and influences to mediating and locating these representations. There is still much to be said about the complex influences that modernism has on McGrath’s signature first-person narration and regarding the ways in which his fiction explores and critiques modernist concerns. As a starting point for further investigations, our argument makes the case that some of McGrath’s work can be understood as “gothic modernist:” that is, as drawing together modernist technique and concerns with images of gothic excess. Important intertexts for McGrath include first-person modes of narration drawn from modernism, for example from Ford Madox Ford’s The Good Solder: a Tale of Passion (1914), as well the “primtivist” turn to modernist aesthetics, evident in the writing of D. H. Lawrence, and in the post-Impressionist paintings of Paul Gauguin.
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| 34. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 35. |
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| 36. |
- Lozano, Rafael, et al.
(författare)
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Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017
- 2018
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Ingår i: The Lancet. - : Elsevier. - 1474-547X .- 0140-6736. ; 392:10159, s. 2091-2138
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Tidskriftsartikel (refereegranskat)abstract
- Background: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. Methods: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2·5th percentile and 100 as the 97·5th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings: The global median health-related SDG index in 2017 was 59·4 (IQR 35·4–67·3), ranging from a low of 11·6 (95% uncertainty interval 9·6–14·0) to a high of 84·9 (83·1–86·7). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030.
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| 37. |
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Patrick McGrath and his Worlds : Madness and the Transnational Gothic
- 2020
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Samlingsverk (redaktörskap) (refereegranskat)abstract
- Following the publication of Ghost Town (2005), a complex, globally conscious genealogy of millennial Manhattan, McGrath’s transnational status as an English author resident in New York, his pointed manipulation of British and American contexts, and his clear apprehension of imperial legacies have all come into sharper focus. By bringing together readings cognizant of this transnational and historical sensitivity with those that build on existing studies of McGrath’s engagements with the gothic and madness, Patrick McGrath and his Worlds sheds new light on an author whose imagined realities reflect the anxieties, pathologies, and power dynamics of our contemporary world order. McGrath’s fiction has been noted as parodic (The Grotesque, 1989), psychologically disturbing (Spider, 1990), and darkly sexual (Asylum, 1996). Throughout, his corpus is characterized by a preoccupation with madness and its institutions and by a nuanced relationship to the gothic. With its international range of contributors, and including a new interview with McGrath himself, this book opens up hitherto underexplored theoretical perspectives on the key concerns of McGrath’s ouevre, moving conversations around McGrath’s work decisively forward. Offering the first sustained exploration of his fiction’s transnational and world-historical dimensions, Patrick McGrath and his Worlds seeks to situate, reflect upon, and interrogate McGrath’s role as a key voice in Anglophone letters in our millennial global moment.
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| 38. |
- Piponiot, Camille, et al.
(författare)
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Distribution of biomass dynamics in relation to tree size in forests across the world
- 2022
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Ingår i: New Phytologist. - : Wiley. - 0028-646X .- 1469-8137. ; 234, s. 1664-1677
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Tidskriftsartikel (refereegranskat)abstract
- Tree size shapes forest carbon dynamics and determines how trees interact with their environment, including a changing climate. Here, we conduct the first global analysis of among-site differences in how aboveground biomass stocks and fluxes are distributed with tree size. We analyzed repeat tree censuses from 25 large-scale (4–52 ha) forest plots spanning a broad climatic range over five continents to characterize how aboveground biomass, woody productivity, and woody mortality vary with tree diameter. We examined how the median, dispersion, and skewness of these size-related distributions vary with mean annual temperature and precipitation. In warmer forests, aboveground biomass, woody productivity, and woody mortality were more broadly distributed with respect to tree size. In warmer and wetter forests, aboveground biomass and woody productivity were more right skewed, with a long tail towards large trees. Small trees (1–10 cm diameter) contributed more to productivity and mortality than to biomass, highlighting the importance of including these trees in analyses of forest dynamics. Our findings provide an improved characterization of climate-driven forest differences in the size structure of aboveground biomass and dynamics of that biomass, as well as refined benchmarks for capturing climate influences in vegetation demographic models.
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| 39. |
- Richter, Katharina N., et al.
(författare)
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Glyoxal as an alternative fixative to formaldehyde in immunostaining and super-resolution microscopy
- 2018
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Ingår i: EMBO Journal. - : WILEY. - 0261-4189 .- 1460-2075. ; 37:1, s. 139-159
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Tidskriftsartikel (refereegranskat)abstract
- Paraformaldehyde (PFA) is the most commonly used fixative for immunostaining of cells, but has been associated with various problems, ranging from loss of antigenicity to changes in morphology during fixation. We show here that the small dialdehyde glyoxal can successfully replace PFA. Despite being less toxic than PFA, and, as most aldehydes, likely usable as a fixative, glyoxal has not yet been systematically tried in modern fluorescence microscopy. Here, we tested and optimized glyoxal fixation and surprisingly found it to be more efficient than PFA-based protocols. Glyoxal acted faster than PFA, cross-linked proteins more effectively, and improved the preservation of cellular morphology. We validated glyoxal fixation in multiple laboratories against different PFA-based protocols and confirmed that it enabled better immunostainings for a majority of the targets. Our data therefore support that glyoxal can be a valuable alternative to PFA for immunostaining.
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| 40. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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| 41. |
- Strittmatter, Nicole, et al.
(författare)
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Method To Visualize the Intratumor Distribution and Impact of Gemcitabine in Pancreatic Ductal Adenocarcinoma by Multimodal Imaging
- 2022
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 94:3, s. 1795-1803
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Tidskriftsartikel (refereegranskat)abstract
- Gemcitabine (dFdC) is a common treatment for pancreatic cancer; however, it is thought that treatment may fail because tumor stroma prevents drug distribution to tumor cells. Gemcitabine is a pro-drug with active metabolites generated intracellularly; therefore, visualizing the distribution of parent drug as well as its metabolites is important. A multimodal imaging approach was developed using spatially coregistered mass spectrometry imaging (MSI), imaging mass cytometry (IMC), multiplex immunofluorescence microscopy (mIF), and hematoxylin and eosin (H&E) staining to assess the local distribution and metabolism of gemcitabine in tumors from a genetically engineered mouse model of pancreatic cancer (KPC) allowing for comparisons between effects in the tumor tissue and its microenvironment. Mass spectrometry imaging (MSI) enabled the visualization of the distribution of gemcitabine (100 mg/kg), its phosphorylated metabolites dFdCMP, dFdCDP and dFdCTP, and the inactive metabolite dFdU. Distribution was compared to small-molecule ATR inhibitor AZD6738 (25 mg/kg), which was codosed. Gemcitabine metabolites showed heterogeneous distribution within the tumor, which was different from the parent compound. The highest abundance of dFdCMP, dFdCDP, and dFdCTP correlated with distribution of endogenous AMP, ADP, and ATP in viable tumor cell regions, showing that gemcitabine active metabolites are reaching the tumor cell compartment, while AZD6738 was located to nonviable tumor regions. The method revealed that the generation of active, phosphorylated dFdC metabolites as well as treatment-induced DNA damage primarily correlated with sites of high proliferation in KPC PDAC tumor tissue, rather than sites of high parent drug abundance.
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| 42. |
- Sumaila, U. Rashid, et al.
(författare)
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WTO must ban harmful fisheries subsidies
- 2021
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 374:6567, s. 544-544
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 43. |
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| 44. |
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| 45. |
- Wulf Hanson, Sarah, et al.
(författare)
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A global systematic analysis of the occurrence, severity, and recovery pattern of long COVID in 2020 and 2021
- 2022
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Importance: While much of the attention on the COVID-19 pandemic was directed at the daily counts of cases and those with serious disease overwhelming health services, increasingly, reports have appeared of people who experience debilitating symptoms after the initial infection. This is popularly known as long COVID.Objective: To estimate by country and territory of the number of patients affected by long COVID in 2020 and 2021, the severity of their symptoms and expected pattern of recovery.Design: We jointly analyzed ten ongoing cohort studies in ten countries for the occurrence of three major symptom clusters of long COVID among representative COVID cases. The defining symptoms of the three clusters (fatigue, cognitive problems, and shortness of breath) are explicitly mentioned in the WHO clinical case definition. For incidence of long COVID, we adopted the minimum duration after infection of three months from the WHO case definition. We pooled data from the contributing studies, two large medical record databases in the United States, and findings from 44 published studies using a Bayesian meta-regression tool. We separately estimated occurrence and pattern of recovery in patients with milder acute infections and those hospitalized. We estimated the incidence and prevalence of long COVID globally and by country in 2020 and 2021 as well as the severity-weighted prevalence using disability weights from the Global Burden of Disease study.Results: Analyses are based on detailed information for 1906 community infections and 10526 hospitalized patients from the ten collaborating cohorts, three of which included children. We added published data on 37262 community infections and 9540 hospitalized patients as well as ICD-coded medical record data concerning 1.3 million infections. Globally, in 2020 and 2021, 144.7 million (95% uncertainty interval [UI] 54.8-312.9) people suffered from any of the three symptom clusters of long COVID. This corresponds to 3.69% (1.38-7.96) of all infections. The fatigue, respiratory, and cognitive clusters occurred in 51.0% (16.9-92.4), 60.4% (18.9-89.1), and 35.4% (9.4-75.1) of long COVID cases, respectively. Those with milder acute COVID-19 cases had a quicker estimated recovery (median duration 3.99 months [IQR 3.84-4.20]) than those admitted for the acute infection (median duration 8.84 months [IQR 8.10-9.78]). At twelve months, 15.1% (10.3-21.1) continued to experience long COVID symptoms.Conclusions and relevance: The occurrence of debilitating ongoing symptoms of COVID-19 is common. Knowing how many people are affected, and for how long, is important to plan for rehabilitative services and support to return to social activities, places of learning, and the workplace when symptoms start to wane.Key Points: Question: What are the extent and nature of the most common long COVID symptoms by country in 2020 and 2021?Findings: Globally, 144.7 million people experienced one or more of three symptom clusters (fatigue; cognitive problems; and ongoing respiratory problems) of long COVID three months after infection, in 2020 and 2021. Most cases arose from milder infections. At 12 months after infection, 15.1% of these cases had not yet recovered.Meaning: The substantial number of people with long COVID are in need of rehabilitative care and support to transition back into the workplace or education when symptoms start to wane.
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| 46. |
- Wulf Hanson, Sarah, et al.
(författare)
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Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021
- 2022
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 328:16, s. 1604-1615
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: Some individuals experience persistent symptoms after initial symptomatic SARS-CoV-2 infection (often referred to as Long COVID).OBJECTIVE: To estimate the proportion of males and females with COVID-19, younger or older than 20 years of age, who had Long COVID symptoms in 2020 and 2021 and their Long COVID symptom duration.DESIGN, SETTING, AND PARTICIPANTS: Bayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. Of the 54 studies, 44 were published and 10 were collaborating cohorts (conducted in Austria, the Faroe Islands, Germany, Iran, Italy, the Netherlands, Russia, Sweden, Switzerland, and the US). The participant data were derived from the 44 published studies (10 501 hospitalized individuals and 42 891 nonhospitalized individuals), the 10 collaborating cohort studies (10 526 and 1906), and the 2 US electronic medical record databases (250 928 and 846 046). Data collection spanned March 2020 to January 2022.EXPOSURES: Symptomatic SARS-CoV-2 infection.MAIN OUTCOMES AND MEASURES: Proportion of individuals with at least 1 of the 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after SARS-CoV-2 infection in 2020 and 2021, estimated separately for hospitalized and nonhospitalized individuals aged 20 years or older by sex and for both sexes of nonhospitalized individuals younger than 20 years of age.RESULTS: A total of 1.2 million individuals who had symptomatic SARS-CoV-2 infection were included (mean age, 4-66 years; males, 26%-88%). In the modeled estimates, 6.2% (95% uncertainty interval [UI], 2.4%-13.3%) of individuals who had symptomatic SARS-CoV-2 infection experienced at least 1 of the 3 Long COVID symptom clusters in 2020 and 2021, including 3.2% (95% UI, 0.6%-10.0%) for persistent fatigue with bodily pain or mood swings, 3.7% (95% UI, 0.9%-9.6%) for ongoing respiratory problems, and 2.2% (95% UI, 0.3%-7.6%) for cognitive problems after adjusting for health status before COVID-19, comprising an estimated 51.0% (95% UI, 16.9%-92.4%), 60.4% (95% UI, 18.9%-89.1%), and 35.4% (95% UI, 9.4%-75.1%), respectively, of Long COVID cases. The Long COVID symptom clusters were more common in women aged 20 years or older (10.6% [95% UI, 4.3%-22.2%]) 3 months after symptomatic SARS-CoV-2 infection than in men aged 20 years or older (5.4% [95% UI, 2.2%-11.7%]). Both sexes younger than 20 years of age were estimated to be affected in 2.8% (95% UI, 0.9%-7.0%) of symptomatic SARS-CoV-2 infections. The estimated mean Long COVID symptom cluster duration was 9.0 months (95% UI, 7.0-12.0 months) among hospitalized individuals and 4.0 months (95% UI, 3.6-4.6 months) among nonhospitalized individuals. Among individuals with Long COVID symptoms 3 months after symptomatic SARS-CoV-2 infection, an estimated 15.1% (95% UI, 10.3%-21.1%) continued to experience symptoms at 12 months.CONCLUSIONS AND RELEVANCE: This study presents modeled estimates of the proportion of individuals with at least 1 of 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after symptomatic SARS-CoV-2 infection.
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| 47. |
- Zheng, Hou-Feng, et al.
(författare)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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| 48. |
- Öhrman, Caroline, et al.
(författare)
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Reorganized Genomic Taxonomy of Francisellaceae Enables Design of Robust Environmental PCR Assays for Detection of Francisella tularensis
- 2021
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Ingår i: Microorganisms. - : MDPI. - 2076-2607. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- In recent years, an increasing diversity of species has been recognized within the family Francisellaceae. Unfortunately, novel isolates are sometimes misnamed in initial publications or multiple sources propose different nomenclature for genetically highly similar isolates. Thus, unstructured and occasionally incorrect information can lead to confusion in the scientific community. Historically, detection of Francisella tularensis in environmental samples has been challenging due to the considerable and unknown genetic diversity within the family, which can result in false positive results. We have assembled a comprehensive collection of genome sequences representing most known Francisellaceae species/strains and restructured them according to a taxonomy that is based on phylogenetic structure. From this structured dataset, we identified a small number of genomic regions unique to F. tularensis that are putatively suitable for specific detection of this pathogen in environmental samples. We designed and validated specific PCR assays based on these genetic regions that can be used for the detection of F. tularensis in environmental samples, such as water and air filters.
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