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

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme

Crop Updates 1999 - Cereals

This article covers sixty papers FOREWORD ACKNOWLEDGMENTS PLENARY PAPERS 1. Western Australia’s climate: trends and opportunities, Len W. Broadbridge, Director, Bureau of Meterorology 2. Managing seasonal variations in agriculture, Dr Doug Abrecht, Director, Dryland Research Institute, Merredin CROP ESTABLISHMENT 3. Soil management to prevent waterlogging on duplex soils in the Great Southern, D. Bakker, Greg Hamilton, Cliff Spann and Doug Rowe, Agriculture Western Australia 4. The influence of no-till and press wheels on crop production for heavy soils, Peter Fisher, Jennifer Bignell, Matthew Braimbridge, Greg Hamilton, Agriculture Western Australia NUTRITION 5. Fertiliser nitrogen, applied late, needs rain to increase grain nitrogen and protein levels in wheat, Bill Bowden1, Ross Brennan1, Reg Lunt1 and Senthold Asseng2 1 Agriculture Western Australia, 2 CSIRO 6. Canola upsets the nutrition of the next cereal crop? Bill Bowden1, Garren Knell1, Cherie Rowles 1, Simon Bedbrook\u27, Chris Gazey 1,Mike Bolland1, Ross Brennan 1, Lyn Abbott2, Zed Rengel2 and Wayne Pluske3, 1 Agriculture Western Australia, 2 UWA Soil Science, 3 CSBP 7. Comparisons between high analysis nitrogen sources, Erin Cahill, CSBP 8. Urea additives for reduced drilled urea toxicity for canola and wheat, Bill Crabtree, WANTFA 9. Fertiliser placement, Matthew Evans, CSBP 9. The profitability of variable rate nitrogen applications on wheat, Tim Nielsen, CSBP Technical Services DISEASE 10. Fungicide for wheat leaf disease: boon or bane? Jat Bhathal, Rob Loughman and D. Rasmussen, Plant Pathology, Agriculture Western Australia 11. Role of retained wheat stubbles in disease carryover in wheat/lupin rotations, Jat Bhathal and Rob Loughman, Plant Pathology, Agriculture Western Australia 12. Comparison of aerial and ground application of fungicide for lead disease control ion wheat, Jat Bhathal and Rob Loughman, Plant Pathology, Agriculture Western Australia 13. Bean yellow mosaic virus infection of alternative pasture legume species, Roger Jones, CRC for legumes in Mediterranean Agriculture and Agriculture Western Australia 14. Survey of cereal root nematodes in cropping soils in Western Australia, Sean Kelly1, Ian Riley2 and Robert Loughman1, 1 Agriculture Western Australia,2 University of Adelaide 15. Crop management options for root lesion nematode, Robert Loughman 1, Sharyn Taylor2, Vivien Vanstone 3, Ian Riley3 and Dominie Wright1, 1 Agriculture Western Australia, 2SARDI Plant Research Centre, Glen Osmond, South Australia 3 University of Adelaide, Glen Osmond, South Australia 16. Forecasting barley yellow dwarf risk in cereals, Debbie Thackray and Roger Jones, Agriculture Western Australia and CRC for Legumes in Mediterranean Agriculture 17. Managing barley yellow dwarf virus in cereal crops, Debbie Thackray, Roger Jones and Simon McKirdy, Agriculture Western Australia and CRC for Legumes in Mediterranean Agriculture 18. Broadacre diagnostic service, Dominie Wright, Agriculture Western Australia, AGWEST Plant Laboratories 19. Using twist fungus (Dilophospora alopecuri) to reduce the risk of annual ryegrass toxicity, Dr George Yan1 and Dr Ian Riley2, 1 Plant Research and Development Service, Agriculture Western Australia, 2 Applied and Molecular Ecology, Waite Campus, The University of Adelaide, South Australia NEW VARIETIES 20. New wheat and oat varieties for 1999, Robin Wilson, lain Barclay, Robyn Mclean, Dean Diepeveen, Robert Loughman, and Bill Lambe, Agriculture Western Australia 21. Performance in 1998 of recently released wheat varieties, Robin Wilson, lain Barclay, Robyn Mclean, Dean Diepeveen, Robert Loughman and Bill Lambe, Agriculture Western Australia WHEAT AGRONOMY 22. Increasing the noodle ‘strike rate’, Wal Anderson, Brenda Shackley and Mechelle Owen, Agriculture Western Australia, Quality Wheat CRC 23. Variety trials: wheat and barley, Peter Burgess, Lamond Burgess & Associates 24. South coast wheat variety farmer survey, Ben Curtis, Agriculture Western Australia 25. Residual effects of deep ripping, gypsum and nutrients on grain yields and soil properties, Mohammed A. Hamza and W.K. Anderson, Agriculture Western Australia 26. How to ensure durum wheat profitability! Jamie Henderson, Frank Boetel and Alfredo lmpiglia, Agriculture Western Australia 27. Agronomic evaluation of new wheat varieties for 1999 in the Northern Agricultural Region, Frances Hoyle, Agriculture Western Australia 28. The influence of on-farm management and variety of grain screening levels, Frances Hoyle, Agriculture Western Australia 29. Variety response of hard wheats to management, Darshan Sharma and Wal Anderson, Agriculture Western Australia BARLEY AND OATS 30. Studies into production of export oaten hay, Pierre Fievez, Pierre Fievez and Associates 31. Gairdner barley in the Central and Northern Regions, Blakely Paynter, Agriculture Western Australia 32. Improving milling oat quality, Glenn McDonald, Agriculture Western Australia 33. Gairdner barley in the Southern Region, Kevin Young, Agriculture Western Australia PASTURE 34. The herbicide tolerance of some annual pasture legumes, Andrew Blake, Agriculture Western Australia 35. Pasture systems for cropping rotations in the northern wheatbelt, Keith Devenish, Agriculture Western Australia 36. Perennial pastures reduce recharge and acidification, Perry Dolling, Agriculture Western Australia 37. It’s time to include Lucerne in the pasture-crop system, Roy Latta 1, Lisa-Jane Blacklow2 and Chris Matthews 1,1 Agriculture Western Australia, 2 University of Western Australia, 38. New alternative pasture legume for fine textured soils, Angelo Loi, Brad Nutt and Rochelle McRobb, National Australian Pasture Legumes Improvement Program (NAPLIP) and Centre for Legumes in Mediterranean Agriculture (CLIMA) 39. Increasing pasture productivity on acid wodjil soils, Brad Nutt, David Webb and Andrew McRobb, Centre for Legumes in Mediterranean Agriculture (CLIMA) 40. Annual legume pasture species now available for use in cropping systems. Clinton Revell, Agriculture Western Australia 41. Herbicide and cultural management of Cadiz serradella in ‘phase’ pastures, Clinton Revell, Agriculture Western Australia 42. Spring spraying for redlegged earth mite, James Ridsdill-Smith and Celia Pavri, CSIRO Entomology and CLIMA 43. Water use and water extraction by recently developed pasture legume species and cultivars, David Tennant1, Darryl McClements2, Ross Thompson 1 and Mike Ewing2, 1 Natural Resource Management Services, Soil Management, 2 Plant Research and Development, Pasture Sciences 44. Death knell to doublegees? Tim Woodburn· and Paul Yeoh, CSIRO Entomology/CRC Weed Management Systems, Floreat LIMING 45. Calculated lime requirements for rotations, James Fisher1, Art Diggle 1•2 and Bill Bowden 1•2, 1 Centre for Legumes in Mediterranean Agriculture 2 Agriculture Western Australia 46. The RH lime reactivity test and RH of typical WA limes, Mark Whitten and Andrew Rate, Soil Science and Plant Nutrition, University of Western Australia YIELD MAPPING 47. Benchmarking target yields for wheat, Senthold Asseng 1, Bill Bowden2 and Paul Carlile3, 1 CSIRO Plant Industry, 2 Agriculture Western Australia, 3 UWA 48. Getting the most information from farm scale trial, Ed Blanchard, Agricultural Engineering and Precision Farming Consultant, Merredin, WA 49. Measuring nutrient changes using yield maps, Ed Blanchard, Agricultural engineering and precision farming consultant; Precision Farming Demonstration Project Coordinator for the Kondinin Group, Merredin WA BREEDING 50. Crop improvement royalties – investing in the future, Bevan Buirchell and Dean Diepeveen, Agriculture Western Australia 51. Screening cereals for genotypic variation in phosphorus efficiency, Lorraine Osborne and Zed Rengel, Soil Science and Plant Nutrition, University of Western Australia ON FARM TESTING 52. Test as you grow pays dividends, John Blake, Tress Walmsley, Terry Piper, Wal Anderson, Dean Diepeveen, Cameron Weeks, Michael Dodd, Amanda Falconer, Caroline Peek, Glenn Adam, Agriculture Western Australia 53. How useful is on-farm testing, Camray Gethin 1, Richard Guinness2, Simon Bedbrook1, Dean Diepeveen4, 1 TopCrop Development Officer, Agriculture Western Australia, 2 Farmer, Kunjin TopCrop Group, Corrigin, 3 Agricultural Consultant, Farmanco, York, 4 CVT service, Crop Industries, Agriculture Western Australia, ECONOMICS 54. The impact of farm practices on sustainability costs of rotations, Pierre Fievez, Pierre Fievez and Associates 55. Right rotations for TopCrop, Daniel Fels, Agriculture Western Australia 56. Dollars of water use efficiency, Andrew Rintoul, FAST National, GRDC funded project, Planfarm 57. Farm business structures, Andrew Rintoul, FAST National, GRDC funded project, Planfarm CLIMATE 58. Broadscale weather aspects affecting Western Australia during 1998 and prospects for 1999, Mal Lamond, Lamond Weather Services 59. An updated look at aspects of rainfall trends and variability in the south-west of Western Australia, Roger Tapp, Climate and Consultancy Section, Bureau of Meteorology, Perth WA 60. Frost research in the eastern wheatbelt, Craig White, Research Officer, Agriculture Western Australia, Presented by D.G. Abrech

Stem Cell and Advanced Nano Bioceramic Interactions

Bioceramics are type of biomaterials generally used for orthopaedic applications due to their similar structure with bone. Especially regarding to their osteoinductivity and osteoconductivity, they are used as biodegradable scaffolds for bone regeneration along with mesenchymal stem cells. Since chemical properties of bioceramics are important for regeneration of tissue, physical properties are also important for cell proliferation. In this respect, several different manufacturing methods are used for manufacturing nano scale bioceramics. These nano scale bioceramics are used for regeneration of bone and cartilage both alone or with other types of biomaterials. They can also act as carrier for the delivery of drugs in musculoskeletal infections without causing any systemic toxicity

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

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

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