Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Assessing the Need for Semantic Data Integration for Surgical Biobanks—A Knowledge Representation Perspective

To improve patient outcomes after trauma, the need to decrypt the post-traumatic immune response has been identified. One prerequisite to drive advancement in understanding that domain is the implementation of surgical biobanks. This paper focuses on the outcomes of patients with one of two diagnoses: post-traumatic arthritis and osteomyelitis. In creating surgical biobanks, currently, many obstacles must be overcome. Roadblocks exist around scoping of data that is to be collected, and the semantic integration of these data. In this paper, the generic component model and the Semantic Web technology stack are used to solve issues related to data integration. The results are twofold: (a) a scoping analysis of data and the ontologies required to harmonize and integrate it, and (b) resolution of common data integration issues in integrating data relevant to trauma surgery

Comparative population genomics reveals key barriers to dispersal in Southern Ocean penguins

The mechanisms that determine patterns of species dispersal are important factors in the production and maintenance of biodiversity. Understanding these mechanisms helps to forecast the responses of species to environmental change. Here, we used a comparative framework and genomewide data obtained through RAD-Seq to compare the patterns of connectivity among breeding colonies for five penguin species with shared ancestry, overlapping distributions and differing ecological niches, allowing an examination of the intrinsic and extrinsic barriers governing dispersal patterns. Our findings show that at-sea range and oceanography underlie patterns of dispersal in these penguins. The pelagic niche of emperor (Aptenodytes forsteri), king (A. patagonicus), Adélie (Pygoscelis adeliae) and chinstrap (P. antarctica) penguins facilitates gene flow over thousands of kilometres. In contrast, the coastal niche of gentoo penguins (P. papua) limits dispersal, resulting in population divergences. Oceanographic fronts also act as dispersal barriers to some extent. We recommend that forecasts of extinction risk incorporate dispersal and that management units are defined by at-sea range and oceanography in species lacking genetic data.</p

Data from: Comparative population genomics reveals key barriers to dispersal in Southern Ocean penguins

The mechanisms that determine patterns of species dispersal are important factors in the production and maintenance of biodiversity. Understanding these mechanisms helps to forecast the responses of species to environmental change. Here we used a comparative framework and genome-wide data obtained through RAD-seq to compare the patterns of connectivity among breeding colonies for five penguin species with shared ancestry, overlapping distributions, and differing ecological niches, allowing an examination of the intrinsic and extrinsic barriers governing dispersal patterns. Our findings show that at-sea range and oceanography underlie patterns of dispersal in these penguins. The pelagic niche of emperor (Aptenodytes forsteri), king (A. patagonicus), Ad&eacute;lie (Pygoscelis adeliae) and chinstrap (P. antarctica) penguins facilitates gene flow over thousands of kilometres. In contrast, the coastal niche of gentoo penguins (P. papua) limits dispersal, resulting in population divergences. Oceanographic fronts also act as dispersal barriers to some extent. We recommend that forecasts of extinction risk incorporate dispersal and that management units are defined by at-sea range and oceanography in species lacking genetic data.,Adelie penguins - VCF of SNP datasetAdelie.vcfChinstrap penguins - VCF of SNP datasetChinstrap.vcfGentoo penguins - VCF of full SNP datasetincludes outlier lociGentoos_all-SNPs.vcfGentoo penguins - VCF of neutral SNP datasetoutlier loci removedGentoos_neutral-SNPs.vcfGentoo penguins - nexus file for BFD*Input file of SNPs for BFD* species delimitationGentoos_input_for_BFD.nexGentoo penguins - phylip file for RAxMLPhylip alignment of SNPs for phylogenetic inference in RAxMLGentoos_input_for_RAxML.phyGentoos_input_for_SNAPP_set1XML input file for SNAPP analysis of gentoo penguins - set 1Gentoos_input_for_SNAPP_set2XML input file for SNAPP analysis - set 2,</span

Cardiac echocardiogram findings of severe acute respiratory syndrome coronavirus-2-associated multi-system inflammatory syndrome in children

BACKGROUND: A novel paediatric disease, multi-system inflammatory syndrome in children, has emerged during the 2019 coronavirus disease pandemic. OBJECTIVES: To describe the short-term evolution of cardiac complications and associated risk factors in patients with multi-system inflammatory syndrome in children. METHODS: Retrospective single-centre study of confirmed multi-system inflammatory syndrome in children treated from 29 March, 2020 to 1 September, 2020. Cardiac complications during the acute phase were defined as decreased systolic function, coronary artery abnormalities, pericardial effusion, or mitral and/or tricuspid valve regurgitation. Patients with or without cardiac complications were compared with chi-square, Fisher\u27s exact, and Wilcoxon rank sum. RESULTS: Thirty-nine children with median (interquartile range) age 7.8 (3.6-12.7) years were included. Nineteen (49%) patients developed cardiac complications including systolic dysfunction (33%), valvular regurgitation (31%), coronary artery abnormalities (18%), and pericardial effusion (5%). At the time of the most recent follow-up, at a median (interquartile range) of 49 (26-61) days, cardiac complications resolved in 16/19 (84%) patients. Two patients had persistent mild systolic dysfunction and one patient had persistent coronary artery abnormality. Children with cardiac complications were more likely to have higher N-terminal B-type natriuretic peptide (p = 0.01), higher white blood cell count (p = 0.01), higher neutrophil count (p = 0.02), severe lymphopenia (p = 0.05), use of milrinone (p = 0.03), and intensive care requirement (p = 0.04). CONCLUSION: Patients with multi-system inflammatory syndrome in children had a high rate of cardiac complications in the acute phase, with associated inflammatory markers. Although cardiac complications resolved in 84% of patients, further long-term studies are needed to assess if the cardiac abnormalities (transient or persistent) are associated with major cardiac events

Potential for redistribution of post‐moult habitat for Eudyptes penguins in the Southern Ocean under future climate conditions

Anthropogenic climate change is resulting in spatial redistributions of many species. We assessed the potential effects of climate change on an abundant and widely distributed group of diving birds, Eudyptes penguins, which are the main avian consumers in the Southern Ocean in terms of biomass consumption. Despite their abundance, several of these species have undergone population declines over the past century, potentially due to changing oceanography and prey availability over the important winter months. We used light-based geolocation tracking data for 485 individuals deployed between 2006 – 2020 across 10 of the major breeding locations for five taxa of Eudyptes penguins. We used Boosted Regression Tree modelling to quantify post-moult habitat preference for southern rockhopper (E. chrysocome), eastern rockhopper (E. filholi), northern rockhopper (E. moseleyi) and macaroni/royal (E. chrysolophus and E. schlegeli) penguins. We then modelled their redistribution under two climate change scenarios, Representative Concentration Pathways RCP4.5 and RCP8.5 (for the end of the century, 2071 – 2100). As climate forcings differ regionally, we quantified redistribution in the Atlantic, Central Indian, East Indian, West Pacific, and East Pacific regions. We found sea surface temperature and sea surface height to be the most important predictors of current habitat for these penguins; physical features that are changing rapidly in the Southern Ocean. Our results indicated that the less severe RCP4.5 would lead to less habitat loss than the more severe RCP8.5. The five taxa of penguin may experience a general poleward redistribution of their preferred habitat, but with contrasting effects in the i) change in total area of preferred habitat under climate change ii) according to geographic region and iii) the species (macaroni/royal vs rockhopper populations). Our results provide further understanding on the regional impacts and vulnerability of species to climate change

Potential for redistribution of post-moult habitat for Eudyptes penguins in the Southern Ocean under future climate conditions

Anthropogenic climate change is resulting in spatial redistributions of many species. We assessed the potential effects of climate change on an abundant and widely distributed group of diving birds, Eudyptes penguins, which are the main avian consumers in the Southern Ocean in terms of biomass consumption. Despite their abundance, several of these species have undergone population declines over the past century, potentially due to changing oceanography and prey availability over the important winter months. We used light-based geolocation tracking data for 485 individuals deployed between 2006 and 2020 across 10 of the major breeding locations for five taxa of Eudyptes penguins. We used boosted regression tree modelling to quantify post-moult habitat preference for southern rockhopper (E. chrysocome), eastern rockhopper (E. filholi), northern rockhopper (E. moseleyi) and macaroni/royal (E. chrysolophus and E. schlegeli) penguins. We then modelled their redistribution under two climate change scenarios, representative concentration pathways RCP4.5 and RCP8.5 (for the end of the century, 2071–2100). As climate forcings differ regionally, we quantified redistribution in the Atlantic, Central Indian, East Indian, West Pacific and East Pacific regions. We found sea surface temperature and sea surface height to be the most important predictors of current habitat for these penguins; physical features that are changing rapidly in the Southern Ocean. Our results indicated that the less severe RCP4.5 would lead to less habitat loss than the more severe RCP8.5. The five taxa of penguin may experience a general poleward redistribution of their preferred habitat, but with contrasting effects in the (i) change in total area of preferred habitat under climate change (ii) according to geographic region and (iii) the species (macaroni/royal vs. rockhopper populations). Our results provide further understanding on the regional impacts and vulnerability of species to climate change.Fil: Green, Cara Paige. University of Tasmania; AustraliaFil: Green, David B.. University of Tasmania; AustraliaFil: Ratcliffe, Norman. British Antarctic Survey; Reino UnidoFil: Thompson, David. National Institute Of Water And Atmospheric Research; Nueva ZelandaFil: Lea, Mary Anne. University of Tasmania; AustraliaFil: Baylis, Alastair M. M.. South Atlantic Environmental Research Institute; Islas Malvinas. Macquarie University; AustraliaFil: Bond, Alexander L.. Natural History Museum; Reino Unido. Royal Society For The Protection Of Birds; Reino UnidoFil: Bost, Charles-André. Centre Détudes Biologiques de Chizé; FranciaFil: Crofts, Sarah. Falklands Conservation; Islas MalvinasFil: Cuthbert, Richard J.. World Land Trust; Reino Unido. Royal Society For The Protection Of Birds; Reino UnidoFil: González Solís, Jacob. Universidad de Barcelona; EspañaFil: Morrison, Kyle W.. National Institute Of Water And Atmospheric Research; Nueva ZelandaFil: Poisbleau, Maud. Universiteit Antwerp; BélgicaFil: Pütz, Klemens. Antarctic Research Trust; AlemaniaFil: Raya Rey, Andrea Nélida. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Ryan, Peter G.. University of Cape Town; SudáfricaFil: Sagar, Paul M.. National Institute Of Water And Atmospheric Research; Nueva ZelandaFil: Steinfurth, Antje. Royal Society For The Protection Of Birds; Reino UnidoFil: Thiebot, Jean-Baptiste. Hokkaido University; Japón. National Institute Of Water And Atmospheric Research; Nueva ZelandaFil: Tierney, Megan. Joint Nature Conservation Committee; Islas Malvinas. South Atlantic Environmental Research Institute; Nueva ZelandaFil: Whitehead, Thomas Otto. University of Cape Town; SudáfricaFil: Wotherspoon, Simon. Australian Antarctic Division; AustraliaFil: Hindell, Mark A.. Institute For Marine And Antarctic Studies; Australi