Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10-8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10-6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

A genome-wide asociation study identifies new psoriasis susceptibility loci and an interaction betwEn HLA-C and ERAP1

To identify new susceptibility loci for psoriasis, we undertOk a genome-wide asociation study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified asociations at eight previously unreported genomic loci. Seven loci harbored genes with recognized iMune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These asociations were replicated in 9,079 European samples (six loci with a combined P < 5-10 -8 and two loci with a combined P < 5-10-7). We also report compeLing evidence for an interaction betwEn the HLA-C and ERAP1 loci (combined P = 6.95-10-6). ERAP1 plays an important role in MHC claS I peptide proceSing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk aLele. Our findings implicate pathways that integrate epidermal barrier dysfunction with iNate and adaptive iMune dysregulation in psoriasis pathogenesis.

Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region

Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P 1 × 10 5 were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 × 10 17), 16q22 (CDH1 and CDH3; P = 2.8 × 10 8) and 7q31 (LAMB1; P = 3.0 × 10 8). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis. © 2009 Nature America, Inc. All rights reserved.

Cost effectiveness of bone density measurements

Objective. To assess the cost-effectiveness of bone density screening programmes for osteoporosis. Study design. Using published and locally available data regarding fracture rates and treatment costs, the overall costs per fracture prevented, cost per quality of life year (QALY) saved and cost per year of life gained were estimated for different bone density screening and osteoporosis treatment programmes. Main outcome measures. Cost per fracture prevented, cost per QALY saved, and cost per year of life gained. Results. In women over the age of 50 years, the costs per fracture prevented of treating all women with hormone replacement therapy, or treating only if osteoporosis is demonstrated on bone density screening were £32,594 or £23,867 respectively. For alendronate therapy for the same groups, the costs were £171,067 and £14,067 respectively. Once the background rate of treatment with alendronate reaches 18%, bone density screening becomes cost-saving. Costs estimates per QALY saved ranged from £1,514 to £39,076 for osteoporosis treatment with alendronate following bone density screening. Conclusions. For relatively expensive medications such as alendronate, treatment programmes with prior bone density screening are far more cost effective than those without, and in some circumstances become cost-saving. Costs per QALY of life saved and per year of life gained for osteoporosis treatment with prior bone density screening compare favourably with treatment of hypertension and hypercholesterolemia.

Health Assessment and Physical Examination, 2nd Edition

Health Assessment and Physical Examination is designed to teach students to assess a patient’s physical, psychological, cultural and emotional dimensions of health as a foundation of nursing care. The skills of interviewing, inspection, percussion, palpation, auscultation, and documentation are refined to help students to make clinical judgements and promote healthy patient outcomes. A strong emphasis on science encompasses all the technical aspects of anatomy, physiology, and assessment, while highlighting clinically relevant information. Emphasis on caring is displayed through themes of assessment of the whole person, which also encourages nurses to think about care for themselves as well as patients.

Precarious Creativity: Global Media, Local Labor

Precarious Creativity examines the seismic changes confronting media workers in an age of globalization and corporate conglomeration. This pathbreaking anthology peeks behind the hype and supposed glamor of screen media industries to reveal the intensifying pressures and challenges confronting actors, editors, electricians, and others. The authors take on pressing conceptual and methodological issues while also providing insightful case studies of workplace dynamics regarding creativity, collaboration, exploitation, and cultural difference. Furthermore, it examines working conditions and organizing efforts on all six continents, offering broad-ranging and comprehensive analysis of contemporary screen media labor in such places as Lagos, Prague, Hollywood, and Hyderabad. The collection also examines labor conditions across a range of job categories that includes, for example, visual effects, production services, and adult entertainment. With contributions from such leading scholars as John Caldwell, Vicki Mayer, Herman Gray, and Tejaswini Ganti, Precarious Creativity offers timely critiques of media globalization while also intervening in broader debates about labor, creativity, and precarity.

Drink and drug driving in Australian young adult users and non-users of illicit stimulants

- Introduction There is limited understanding of how young adults’ driving behaviour varies according to long-term substance involvement. It is possible that regular users of amphetamine-type stimulants (i.e. ecstasy (MDMA) and methamphetamine) may have a greater predisposition to engage in drink/drug driving compared to non-users. We compare offence rates, and self-reported drink/drug driving rates, for stimulant users and non-users in Queensland, and examine contributing factors. - Methods The Natural History Study of Drug Use is a prospective longitudinal study using population screening to recruit a probabilistic sample of amphetamine-type stimulant users and non-users aged 19-23 years. At the 4 ½ year follow-up, consent was obtained to extract data from participants’ Queensland driver records (ATS users: n=217, non-users: n=135). Prediction models were developed of offence rates in stimulant users controlling for factors such as aggression and delinquency. - Results Stimulant users were more likely than non-users to have had a drink-driving offence (8.7% vs. 0.8%, p < 0.001). Further, about 26% of ATS users and 14% of non-users self-reported driving under the influence of alcohol during the last 12 months. Among stimulant users, drink-driving was independently associated with last month high-volume alcohol consumption (Incident Rate Ratio (IRR): 5.70, 95% CI: 2.24-14.52), depression (IRR: 1.28, 95% CI: 1.07-1.52), low income (IRR: 3.57, 95% CI: 1.12-11.38), and male gender (IRR: 5.40, 95% CI: 2.05-14.21). - Conclusions Amphetamine-type stimulant use is associated with increased long-term risk of drink-driving, due to a number of behavioural and social factors. Inter-sectoral approaches which target long-term behaviours may reduce offending rates.

Indigenous Intellectual Property: A Handbook of Contemporary Research

Taking an interdisciplinary approach unmatched by any other book on this topic, this thoughtful Handbook considers the international struggle to provide for proper and just protection of Indigenous intellectual property (IP). In light of the United Nations Declaration on the Rights of Indigenous Peoples 2007, expert contributors assess the legal and policy controversies over Indigenous knowledge in the fields of international law, copyright law, trademark law, patent law, trade secrets law, and cultural heritage. The overarching discussion examines national developments in Indigenous IP in the United States, Canada, South Africa, the European Union, Australia, New Zealand, and Indonesia. The Handbook provides a comprehensive overview of the historical origins of conflict over Indigenous knowledge, and examines new challenges to Indigenous IP from emerging developments in information technology, biotechnology, and climate change. Practitioners and scholars in the field of IP will learn a great deal from this Handbook about the issues and challenges that surround just protection of a variety of forms of IP for Indigenous communities. Preface The Legacy of David Unaipon Matthew Rimmer Introduction: Mapping Indigenous Intellectual Property Matthew Rimmer PART I INTERNATIONAL LAW 1. The United Nations Declaration on the Rights of Indigenous Peoples: A Human Rights Framework for Indigenous Intellectual Property Mauro Barelli 2. The WTO, The TRIPS Agreement and Traditional Knowledge Tania Voon 3. The World Intellectual Property Organization and Traditional Knowledge Sara Bannerman 4. The World Indigenous Network: Rio+20, Intellectual Property, Indigenous Knowledge, and Sustainable Development Matthew Rimmer PART II COPYRIGHT LAW AND RELATED RIGHTS 5. Government Man, Government Painting? David Malangi and the 1966 One-Dollar Note Stephen Gray 6. What Wandjuk Wanted Martin Hardie 7. Avatar Dreaming: Indigenous Cultural Protocols and Making Films Using Indigenous Content Terri Janke 8. The Australian Resale Royalty for Visual Artists: Indigenous Art and Social Justice Robert Dearn and Matthew Rimmer PART III TRADE MARK LAW AND RELATED RIGHTS 9. Indigenous Cultural Expression and Registered Designs Maree Sainsbury 10. The Indian Arts and Crafts Act: The Limits of Trademark Analogies Rebecca Tushnet 11. Protection of Traditional Cultural Expressions within the New Zealand Intellectual Property Framework: A Case Study of the Ka Mate Haka Sarah Rosanowski 12 Geographical Indications and Indigenous Intellectual Property William van Caenegem PART IV PATENT LAW AND RELATED RIGHTS 13. Pressuring ‘Suspect Orthodoxy’: Traditional Knowledge and the Patent System Chidi Oguamanam, 14. The Nagoya Protocol: Unfinished Business Remains Unfinished Achmad Gusman Siswandi 15. Legislating on Biopiracy in Europe: Too Little, too Late? Angela Daly 16. Intellectual Property, Indigenous Knowledge, and Climate Change Matthew Rimmer PART V PRIVACY LAW AND IDENTITY RIGHTS 17. Confidential Information and Anthropology: Indigenous Knowledge and the Digital Economy Sarah Holcombe 18. Indigenous Cultural Heritage in Australia: The Control of Living Heritages Judith Bannister 19. Dignity, Trust and Identity: Private Spheres and Indigenous Intellectual Property Bruce Baer Arnold 20. Racial Discrimination Laws as a Means of Protecting Collective Reputation and Identity David Rolph PART VI INDIGENOUS INTELLECTUAL PROPERTY: REGIONAL PERSPECTIVES 21. Diluted Control: A Critical Analysis of the WAI262 Report on Maori Traditional Knowledge and Culture Fleur Adcock 22. Traditional Knowledge Governance Challenges in Canada Jeremy de Beer and Daniel Dylan 23. Intellectual Property protection of Traditional Knowledge and Access to Knowledge in South Africa Caroline Ncube 24. Traditional Knowledge Sovereignty: The Fundamental Role of Customary Law in Protection of Traditional Knowledge Brendan Tobin Index

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10−8). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Algorithm of medication review in frail older people: Focus on minimizing the use of high-risk medications

Aim Frail older people typically suffer several chronic diseases, receive multiple medications and are more likely to be institutionalized in residential aged care facilities. In such patients, optimizing prescribing and avoiding use of high-risk medications might prevent adverse events. The present study aimed to develop a pragmatic, easily applied algorithm for medication review to help clinicians identify and discontinue potentially inappropriate high-risk medications. Methods The literature was searched for robust evidence of the association of adverse effects related to potentially inappropriate medications in older patients to identify high-risk medications. Prior research into the cessation of potentially inappropriate medications in older patients in different settings was synthesized into a four-step algorithm for incorporation into clinical assessment protocols for patients, particularly those in residential aged care facilities. Results The algorithm comprises several steps leading to individualized prescribing recommendations: (i) identify a high-risk medication; (ii) ascertain the current indications for the medication and assess their validity; (iii) assess if the drug is providing ongoing symptomatic benefit; and (iv) consider withdrawing, altering or continuing medications. Decision support resources were developed to complement the algorithm in ensuring a systematic and patient-centered approach to medication discontinuation. These include a comprehensive list of high-risk medications and the reasons for inappropriateness, lists of alternative treatments, and suggested medication withdrawal protocols. Conclusions The algorithm captures a range of different clinical scenarios in relation to potentially inappropriate medications, and offers an evidence-based approach to identifying and, if appropriate, discontinuing such medications. Studies are required to evaluate algorithm effects on prescribing decisions and patient outcomes.

Geriatrician interventions on medication prescribing for frail older people in residential aged care facilities

Objective: In Australian residential aged care facilities (RACFs), the use of certain classes of high-risk medication such as antipsychotics, potent analgesics, and sedatives is high. Here, we examined the prescribed medications and subsequent changes recommended by geriatricians during comprehensive geriatric consultations provided to residents of RACFs via videoconference. Design: This is a prospective observational study. Setting: Four RACFs in Queensland, Australia, are included. Participants: A total of 153 residents referred by general practitioners for comprehensive assessment by geriatricians delivered by video-consultation. Results: Residents’ mean (standard deviation, SD) age was 83.0 (8.1) years and 64.1% were female. They had multiple comorbidities (mean 6), high levels of dependency, and were prescribed a mean (SD) of 9.6 (4.2) regular medications. Ninety-one percent of patients were taking five or more medications daily. Of total medications prescribed (n=1,469), geriatricians recommended withdrawal of 9.8% (n=145) and dose alteration of 3.5% (n=51). New medications were initiated in 47.7% (n=73) patients. Of the 10.3% (n=151) medications considered as high risk, 17.2% were stopped and dose altered in 2.6%. Conclusion: There was a moderate prevalence of potentially inappropriate high-risk medications. However, geriatricians made relatively few changes, suggesting either that, on balance, prescription of these medications was appropriate or, because of other factors, there was a reluctance to adjust medications. A structured medication review using an algorithm for withdrawing medications of high disutility might help optimize medications in frail patients. Further research, including a broader survey, is required to understand these dynamics.

Regenerative sustainability for the built environment – from vision to reality: An introductory chapter

Regenerative sustainability is emerging as an alternative discourse around the transition from a ‘mechanistic’ to an ‘ecological’ or living systems worldview. This view helps us to re-conceptualize relationships among humans’ technological, ecological, economic, social and political systems. Through exploration of ‘net positive’ or ‘regenerative’ development lenses and the traditional sustainability literature, the conceptualization and approaches to achieve sustainable development and ecological modernization are expanded to articulate and to explore the evolving sustainability discourse, ‘regenerative sustainability’. This Special Volume of Journal of Cleaner Production (SV) is focused upon various dimensions of regenerative sustainability (e.g. regenerative design, regenerative development, and positive development) applied to the urban built environment at scales, which range from individual buildings, neighborhoods, and urban developments to integrated regional sustainable development. The main focus is on how these approaches and developments are evolving, how they can help us to prevent or adapt to climate change and how these approaches are likely to evolve in the next two to three decades. These approaches are addressed in four themes: (1) reviewing the theoretical development of the discourse of regenerative sustainability, its emerging principles and practices, (2) explaining how it can be measured and monitored, (3) providing encouraging practical pathways and examples of its implementation in multiple cultural and climatic contexts, and (4) mapping obstacles and enablers that must be addressed to help to ensure that more rapid progress is made in implementing the transitions towards an urban built environment that supports genuinely sustainable societies.

Polypharmacy among inpatients aged 70 years or older in Australia

Objectives To investigate medication changes for older patients admitted to hospital and to explore associations between patient characteristics and polypharmacy. Design Prospective cohort study. Participants and setting Patients aged 70 years or older admitted to general medical units of 11 acute care hospitals in two Australian states between July 2005 and May 2010. All patients were assessed using the interRAI assessment system for acute care. Main outcome measures Measures of physical, cognitive and psychosocial functioning; and number of regular prescribed medications categorised into three groups: non-polypharmacy (0–4 drugs), polypharmacy (5–9 drugs) and hyperpolypharmacy (≥ 10 drugs). Results Of 1220 patients who were recruited for the study, medication records at admission were available for 1216. Mean age was 81.3 years (SD, 6.8 years), and 659 patients (54.2%) were women. For the 1187 patients with complete medication records on admission and discharge, there was a small but statistically significant increase in mean number of regular medications per day between admission and discharge (7.1 v 7.6), while the prevalence of medications such as statins (459 [38.7%] v 457 [38.5%] patients), opioid analgesics (155 [13.1%] v 166 [14.0%] patients), antipsychotics (59 [5.0%] v 65 [5.5%] patients) and benzodiazepines (122 [10.3%] v 135 [11.4%] patients) did not change significantly. Being in a higher polypharmacy category was significantly associated with increase in comorbidities (odds ratio [OR], 1.27; 95% CI, 1.20–1.34), presence of pain (OR, 1.31; 1.05–1.64), dyspnoea (OR, 1.64; 1.30–2.07) and dependence in terms of instrumental activities of daily living (OR, 1.70; 1.20–2.41). Hyperpolypharmacy was observed in 290/1216 patients (23.8%) at admission and 336/1187 patients (28.3%) on discharge, and the proportion of preventive medication in the hyperpolypharmacy category at both points in time remained high (1209/3371 [35.9%] at admission v 1508/4117 [36.6%] at discharge). Conclusions Polypharmacy is common among older people admitted to general medical units of Australian hospitals, with no clinically meaningful change to the number or classification (symptom control, prevention or both) of drugs made by treating physicians.