Otitis media: recent advances in otitis media vaccine development and model systems

Otitis media is an inflammatory disorder of the middle ear caused by airways-associated bacterial or viral infections. It is one of the most common childhood infections as globally more than 80% of children are diagnosed with acute otitis media by 3 years of age and it is a common reason for doctor’s visits, antibiotics prescriptions, and surgery among children. Otitis media is a multifactorial disease with various genetic, immunologic, infectious, and environmental factors predisposing children to develop ear infections. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the most common culprits responsible for acute otitis media. Despite the massive global disease burden, the pathogenesis of otitis media is still unclear and requires extensive future research. Antibiotics are the preferred treatment to cure middle ear infections, however, the antimicrobial resistance rate of common middle ear pathogens has increased considerably over the years. At present, pneumococcal and influenza vaccines are administered as a preventive measure against otitis media, nevertheless, these vaccines are only beneficial in preventing carriage and/or disease caused by vaccine serotypes. Otitis media caused by non-vaccine serotype pneumococci, non-typeable H. influenza, and M. catarrhalis remain an important healthcare burden. The development of multi-species vaccines is an arduous process but is required to reduce the global burden of this disease. Many novel vaccines against S. pneumoniae, non-typeable H. influenza, and M. catarrhalis are in preclinical trials. It is anticipated that these vaccines will lower the disease burden and provide better protection against otitis media. To study disease pathology the rat, mouse, and chinchilla are commonly used to induce experimental acute otitis media to test new therapeutics, including antibiotics and vaccines. Each of these models has its advantages and disadvantages, yet there is still a need to develop an improved animal model providing a better correlated mechanistic understanding of human middle ear infections, thereby underpinning the development of more effective otitis media therapeutics. This review provides an updated summary of current vaccines against otitis media, various animal models of otitis media, their limitations, and some future insights in this field providing a springboard in the development of new animal models and novel vaccines for otitis media

Sheep Updates 2003 - Economics

This session covers five papers from different authors: 1. Burping sheep are warming the planet. Anne Bennett, Department of Agriculture, Western Australia 2. When will the family owned farm make the Endangered Species List? Steve Dilley, 2001 Nuffield Farming Scholar, Donnybrook apple and beef producer 3. Recent trends and future climate in WA. Ian Foster, Department of Agriculture 4. Profitability of sheep systems in WA’s South Coast for various commodity price scenarios. Emma Kopke, John Young and Ross Kingwell. 5. How profitable are your pasture systems - Take the STEP to find out. Caroline Peek, Department of Agriculture Geraldto

Role of the AP2 β-Appendage Hub in Recruiting Partners for Clathrin-Coated Vesicle Assembly

Adaptor protein complex 2 α and β-appendage domains act as hubs for the assembly of accessory protein networks involved in clathrin-coated vesicle formation. We identify a large repertoire of β-appendage interactors by mass spectrometry. These interact with two distinct ligand interaction sites on the β-appendage (the “top” and “side” sites) that bind motifs distinct from those previously identified on the α-appendage. We solved the structure of the β-appendage with a peptide from the accessory protein Eps15 bound to the side site and with a peptide from the accessory cargo adaptor β-arrestin bound to the top site. We show that accessory proteins can bind simultaneously to multiple appendages, allowing these to cooperate in enhancing ligand avidities that appear to be irreversible in vitro. We now propose that clathrin, which interacts with the β-appendage, achieves ligand displacement in vivo by self-polymerisation as the coated pit matures. This changes the interaction environment from liquid-phase, affinity-driven interactions, to interactions driven by solid-phase stability (“matricity”). Accessory proteins that interact solely with the appendages are thereby displaced to areas of the coated pit where clathrin has not yet polymerised. However, proteins such as β-arrestin (non-visual arrestin) and autosomal recessive hypercholesterolemia protein, which have direct clathrin interactions, will remain in the coated pits with their interacting receptors

Crop Updates 2008 - Farming Systems

This session covers thirty nine papers from different authors: PLENARY 1. Developments in grain end use, Dr John de Majnik, New Grain Products, GRDC, Mr Paul Meibusch, New Farm Products and Services, GRDC, Mr Vince Logan, New Products Executive Manager, GRDC PRESENTATIONS 2. Global warming potential of wheat production in Western Australia: A life cycle assessment, Louise Barton1, Wahid Biswas2 and Daniel Carter3, 1School of Earth & Geographical Sciences, The University of Western Australia, 2Centre of Excellence in Cleaner Production, Division of Science and Engineering, Curtin University of Technology, 3Department of Agriculture and Food 3. How much fuel does your farm use for different farm operations? Nicolyn Short1, Jodie Bowling1, Glen Riethmuller1, James Fisher2 and Moin Salam1, 1Department of Agriculture and Food, 2Muresk Institute, Curtin University of Technology 4. Poor soil water storage and soil constraints are common in WA cropping soils, Stephen Davies, Jim Dixon, Dennis Van Gool and Alison Slade, Department of Agriculture and Food, Bob Gilkes, School of Earth and Geographical Sciences, University of Western Australia 5. Developing potential adaptations to climate change for low rainfall farming system using economic analysis tool. STEP, Megan Abrahams, Caroline Peek, Dennis Van Gool, Daniel Gardiner and Kari-Lee Falconer, Department of Agriculture and Food 6. What soil limitations affect the profitability of claying on non-wetting sandplain soils? David Hall1, Jeremy Lemon1, Harvey Jones1, Yvette Oliver2 and Tania Butler1, 1Department of Agriculture and Food, 2CSIRO Div Sustainable Ecology, Perth 7. Farming systems adapting to a variable climate; Two case studies, Kari-Lee Falconer, Department of Agriculture and Food 8. Importance of accounting for variation in crop yield potential when making fertiliser decisions, Michael Robertson and Yvette Oliver, CSIRO Sustainable Ecosystems, Floreat 9. Soil acidity is a widespread problem across the Avon River Basin, Stephen Carr1, Chris Gazey2, David York1 and Joel Andrew1, 1Precision SoilTech, 2Department of Agriculture and Food 10. The use of soil testing kits and ion-selective electrodes for the analysis of plant available nutrients in Western Australian soils, Michael Simeoni and Bob Gilkes School of Earth and Geographical Sciences, University of Western Australia 11. Redlegged earth mite resistance and integrated strategies for their control in Western Australia, Mangano G. Peter and Micic Svetlana, Department of Agriculture and Food 12. The economics of treating soil pH (liming), Chris Gazey, Steve Davies, Dave Gartner and Adam Clune, Department of Agriculture and Food, 13. Health benefits – A future differentiator for high value grains, Matthew Morell, Theme Leader, CSIRO Food Futures Flagship 14. Carbon in Sustralian cropping soils – We need to be realistic, Alan Umbers (M Rur Sc), GRDC/DAFF Sustainable Industries Initiative Project 15. AGWEST® Bartolo bladder clover (Trifolium spumosum) − a low cost annual pasture legume for the wheat/sheep zone, Angelo Loi, Brad Nutt and Clinton Revell, Department of Agriculture and Food 16. Maximising the value of point based soil sampling: Monitering trends in soil pH through time, Joel Andrew1, David York1, Stephen Carr1 and Chris Gazey2, 1Precision SoilTech, 2Department of Agriculture and Food 17. Improved crop root growth and productivity with deep ripping and deep placed lime, Stephen Davies1, Geoff Kew2*, Chris Gazey1, David Gartner1 and Adam Clune1, 1Department of Agriculture and Food, 2School of Earth and Geographical Sciences University of Western Australia, *Presenting author 18. The role of pastures in hosting Root Lesion Nematode (RLN, Pratylenchus neglectus), Vivien Vanstone, Ali Bhatti and Ming Pei You, Department of Agriculture and Food 19. To rip or not to rip. When does it pay? Imma Farre, Bill Bowden and Stephen Davies, Department of Agriculture and Food 20. Can yield be predicted from remotely sensed data, Henry Smolinski, Jane Speijers and John Bruce, Department of Agriculture and Food 21. Rotations for profit, David McCarthy and Gary Lang, Facey Group, Wickepin, WA 22. Rewriting rules for the new cropping economics, David Rees, Consultant, Albany 23. Reducing business risk in Binnu! – A case study, Rob Grima, Department of Agriculture and Food 24. Does improved ewe management offer grain farmers much extra profit? John Young, Farming Systems Analysis Service, Ross Kingwell, Department of Agriculture and Food, and UWA, Chris Oldham, Department of Agriculture and Food RESEARCH HIGHLIGHTS 25. Crop establishment and productivity with improved root zone drainage, Dr Derk Bakker, Research Officer, Department of Agriculture and Food 26. Will wheat production in Western Australia be more risky in the future? Imma Farre and Ian Foster, Department of Agriculture and Food PAPERS 27. Building farmers’ adaptive capacity to manage seasonal variability and climate change, David Beard, Department of Agriculture and Food 28. Precision placement increases crop phosphorus uptake under variable rainfall: Simulation studies, Wen Chen1 2, Richard Bell1, Bill Bowden2, Ross Brennan2, Art Diggle2 and Reg Lunt2, 1School of Environmental Science, Murdoch University, 2Department of Agriculture and Food 29. What is the role of grain legumes on red soil farms? Rob Grima, Department of Agriculture and Food 30. Fertiliser placement influences plant growth and seed yield of grain crops at different locations of WA, Qifu Ma1, Zed Rengel1, Bill Bowden2, Ross Brennan2, Reg Lunt2 and Tim Hilder2, 1Soil Science & Plant Nutrition, University of Western Australia, 2Department of Agriculture and Food 31. A review of pest and disease occurrences for 2007, Peter Mangano and Dusty Severtson, Department of Agriculture and Food 32. Effect of stocking rates on grain yield and quality of wheat in Western Australia in 2007, Shahajahan Miyan, Sam Clune, Barb Sage and Tenielle Martin, Department of Agriculture and Food 33. Storing grain is not ‘set and forget’ management, Chris Newman, Department of Agriculture and Food 34. Improving understanding of soil plant available water capacity (PAWC): The WA soil water database (APSoil), Yvette Oliver, Neal Dalgliesh and Michael Robertson, CSIRO Sustainable Ecosystems 35. The impact of management decisions in drought on a low rainfall northern wheatbelt farm, Caroline Peek and Andrew Blake, Department of Agriculture and Food 37. Cullen – A native pasture legume shows promise for the low-medium rainfall cropping zone, Megan Ryan, Richard Bennett, Tim Colmer, Daniel Real, Jiayin Pang, Lori Kroiss, Dion Nicol and Tammy Edmonds-Tibbett, School of Plant Biology, The University of Western Australia and Future Farm Industries CRC 38. Climate risk management tools – useful, or just another gadget? Lisa Sherriff, Kari-Lee Falconer, Daniel Gardiner and Ron McTaggart Department of Agriculture and Food 39. Benefits of crop rotation for management of Root Lesion Nematode (RLN, Pratylenchus neglectus), Vivien Vanstone, Sean Kelly and Helen Hunter, Department of Agriculture and Foo

抗精神病薬によるジストニアの発現機序に関する実験的研究 σ (sigma) sites の関与について

Published ErratumBurkholderia pseudomallei (Bp) is the causative agent of the infectious disease melioidosis. To investigate population diversity, recombination, and horizontal gene transfer in closely related Bp isolates, we performed whole-genome sequencing (WGS) on 106 clinical, animal, and environmental strains from a restricted Asian locale. Whole-genome phylogenies resolved multiple genomic clades of Bp, largely congruent with multilocus sequence typing (MLST). We discovered widespread recombination in the Bp core genome, involving hundreds of regions associated with multiple haplotypes. Highly recombinant regions exhibited functional enrichments that may contribute to virulence. We observed clade-specific patterns of recombination and accessory gene exchange, and provide evidence that this is likely due to ongoing recombination between clade members. Reciprocally, interclade exchanges were rarely observed, suggesting mechanisms restricting gene flow between clades. Interrogation of accessory elements revealed that each clade harbored a distinct complement of restriction-modification (RM) systems, predicted to cause clade-specific patterns of DNA methylation. Using methylome sequencing, we confirmed that representative strains from separate clades indeed exhibit distinct methylation profiles. Finally, using an E. coli system, we demonstrate that Bp RM systems can inhibit uptake of non-self DNA. Our data suggest that RM systems borne on mobile elements, besides preventing foreign DNA invasion, may also contribute to limiting exchanges of genetic material between individuals of the same species. Genomic clades may thus represent functional units of genetic isolation in Bp, modulating intraspecies genetic diversity.Wellcome Trus

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society