Genetic variants underlying risk of endometriosis: Insights from meta-analysis of eight genome-wide association and replication datasets

BACKGROUND Endometriosis is a heritable common gynaecological condition influenced by multiple genetic and environmental factors. Genome-wide association studies (GWASs) have proved successful in identifying common genetic variants of moderate effects for various complex diseases. To date, eight GWAS and replication studies from multiple populations have been published on endometriosis. In this review, we investigate the consistency and heterogeneity of the results across all the studies and their implications for an improved understanding of the aetiology of the condition. METHODS Meta-analyses were conducted on four GWASs and four replication studies including a total of 11 506 cases and 32 678 controls, and on the subset of studies that investigated associations for revised American Fertility Society (rAFS) Stage III/IV including 2859 cases. The datasets included 9039 cases and 27 343 controls of European (Australia, Belgium, Italy, UK, USA) and 2467 cases and 5335 controls of Japanese ancestry. Fixed and Han and Elkin random-effects models, and heterogeneity statistics (Cochran's Q test), were used to investigate the evidence of the nine reported genome-wide significant loci across datasets and populations. RESULTS Meta-analysis showed that seven out of nine loci had consistent directions of effect across studies and populations, and six out of nine remained genome-wide significant (P < 5 × 10(-8)), including rs12700667 on 7p15.2 (P = 1.6 × 10(-9)), rs7521902 near WNT4 (P = 1.8 × 10(-15)), rs10859871 near VEZT (P = 4.7 × 10(-15)), rs1537377 near CDKN2B-AS1 (P = 1.5 × 10(-8)), rs7739264 near ID4 (P = 6.2 × 10(-10)) and rs13394619 in GREB1 (P = 4.5 × 10(-8)). In addition to the six loci, two showed borderline genome-wide significant associations with Stage III/IV endometriosis, including rs1250248 in FN1 (P = 8 × 10(-8)) and rs4141819 on 2p14 (P = 9.2 × 10(-8)). Two independent inter-genic loci, rs4141819 and rs6734792 on chromosome 2, showed significant evidence of heterogeneity across datasets (P < 0.005). Eight of the nine loci had stronger effect sizes among Stage III/IV cases, implying that they are likely to be implicated in the development of moderate to severe, or ovarian, disease. While three out of nine loci were inter-genic, the remaining were in or near genes with known functions of biological relevance to endometriosis, varying from roles in developmental pathways to cellular growth/carcinogenesis. CONCLUSIONS Our meta-analysis shows remarkable consistency in endometriosis GWAS results across studies, with little evidence of population-based heterogeneity. They also show that the phenotypic classifications used in GWAS to date have been limited. Stronger associations with Stage III/IV disease observed for most loci emphasize the importance for future studies to include detailed sub-phenotype information. Functional studies in relevant tissues are needed to understand the effect of the variants on downstream biological pathways.

Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10−8) loci, some including known iron-related genes (​HFE, ​SLC40A1, ​TF, ​TFR2, ​TFRC, ​TMPRSS6) and others novel (​ABO, ​ARNTL, ​FADS2, ​NAT2, ​TEX14). SNPs at ​ARNTL, ​TF, and ​TFR2 affect iron markers in ​HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.

Can social resilience inform SA/SIA for adaptive planning for climate change in vulnerable regions?

This book represents a landmark effort to probe and analyze the theory and empirics of designing water disaster management policies. It consists of seven chapters that examine, in-depth and comprehensively, issues that are central to crafting effective policies for water disaster management. The authors use historical surveys, institutional analysis, econometric investigations, empirical case studies, and conceptual-theoretical discussions to clarify and illuminate the complex policy process. The specific topics studied in this book include a review and analysis of key policy areas and research priority areas associated with water disaster management, community participation in disaster risk reduction, the economics and politics of ‘green’ flood control, probabilistic flood forecasting for flood risk management, polycentric governance and flood risk management, drought management with the aid of dynamic inter-generational preferences, and how social resilience can inform SA/SIA for adaptive planning for climate change in vulnerable areas. A unique feature of this book is its analysis of the causes and consequences of water disasters and efforts to address them successfully through policy-rich, cross-disciplinary and transnational papers. This book is designed to help enrich the sparse discourse on water disaster management policies and galvanize water professionals to craft creative solutions to tackle water disasters efficiently, equitably, and sustainably. This book should also be of considerable use to disaster management professionals, in general, and natural resource policy analysts.

Colonoscopy requirements of population screening for colorectal cancer in New Zealand

Aim: To estimate the colonoscopy burden of introducing population screening for colorectal cancer in New Zealand. Methods: Screening for colorectal cancer using biennial immunochemical faecal occult blood tests offered to people aged 50-74 years of age was modelled using population estimates from Statistics New Zealand for 2011-2031. Modelling to determine colonoscopy requirements was based on participation and test positivity rates from published results of screening programmes. Estimates of the number of procedures required for ongoing adenoma surveillance were calculated using screening literature results of adenoma yield, and New Zealand Guidelines for Adenoma Surveillance. Sensitivity analysis was undertaken on key parameters. Results: For a test positivity of 6.4%, biennial screening using immunochemical faecal occult blood testing with a 60% participation rate, would require 18,000 colonoscopies nationally, increasing to 28,000 by 2031. The majority of procedures are direct referrals from a positive FOBT, with surveillance colonoscopy numbers building over time. Conclusion: Colonoscopy requirements for immunochemical faecal occult blood based population screening for colorectal cancer are high. Significant expansion of services is required and careful management of surveillance procedures to ensure timely delivery of initial colonoscopies whilst maintaining symptomatic services. A model re-run informed by data from the screening pilot will allow improved estimates for the New Zealand setting.

The grapes of wrath: The Coonawarra dispute, geographical indications and international trade

The famous wine region of Coonawarra in South Australia has been promoted as ’Australia's other Red Centre', emphasizing its terra rossa soil and its cabernet sauvignon. In his atlas of the wine regions of Australia, John Beeston comments upon the rich and contested history of the region: ’Coonawarra is certainly the most famous cabernet sauvignon region in Australia, and some would argue, the most renowned wine region in Australia per se'. A reporter, Penelope Debelle, captures a sense of the legal conflict over the parameters of the boundaries of Coonawarra: ’Behind the name Coonawarra, an inglorious contest is being waged that pits the romance of South Australia's terra rossa cool-climate wine region against the cold commercial reality of the label.'This Chapter tells the story behind the Coonawarra litigation, addressing the parties to the dispute; the legal and historical context of the case; and the immediate impact case, as well as its lingering significance. It considers the ’Coonawarra' case as, very literally, a landmark in Australian jurisprudence in respect of intellectual property. This chapter engages in the methodology of ’legal storytelling'. In the field of new historicism, the use of anecdotes - petite histoire - has been seen as a useful way of challenging grand historical narratives. Joel Fineman has observed that the anecdote is ’the literary form or genre that uniquely refers to the real.' This chapter has three parts. Part 1 outlines the European Community - Australia Wine Agreement 1994, and the operation of the Australian Wine and Brandy Corporation Act 1980 (Cth). Part 2 considers the various stages of the dispute over the Coonawarra region - moving from the decision of the Geographical Indications Committee, to the ruling of the Administrative Appeals Tribunal; and the conclusive decision of the Full Court of the Federal Court of Australia. Part 3 examines the implications of the Coonawarra litigation for other wine regions of Australia - most notably, the King Valley in Victoria; but also the Hunter Valley in the New South Wales; and the Margaret River in Western Australia. The conclusion considers the ramifications of the European Community-Australia Wine Agreement 2007, which has been initialed by both sides.

Common genetic variants influence human subcortical brain structures

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08×10 -33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Identification of common variants associated with human hippocampal and intracranial volumes

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10 -16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10 -12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10 -7).

Positioning the nursing librarian on the wards: nursing grand rounds with a difference

The concept nursing grand rounds (NGR) has been reported in the nursing literature since the 1960s. Many of the reported initiatives are based on a presentation forum in the manner of medical grand rounds, as an approach to undergraduate education, or as a means to monitor patients. Among the points of difference in the design of the pilot project undertaken in a busy surgical ward to investigate the effectiveness of NGR in increasing nurses work satisfaction was the inclusion of the nursing librarian as an integral part of the NGR team and processes which previously has not reported in the literature. The nursing librarian’s role was to search the literature and find the best evidence on the predetermined patient topic prior to the NGR to enable the nurse presenting to integrate the research findings into the presentation of the patient. The nursing librarian attended each NGR and commented where appropriate on the level of evidence. Nurses discussed current practice and the impact the retrieved literature would have on patient care comparing best practice with current practice. Outcomes of this project include in some cases change in practice, change in culture where NGRs are now embedded into ward culture, NGR extended to other wards, enthusiasm for EBP, the initiation of a “super searcher” model where the nursing librarian is more of a consultant and develops the searching skills of nominated nurses who become the resource on the ward.

Fundamental Tax Legislation [23nd Edition]

Fundamental Tax Legislation 2015 contains the essential provisions from the primary legislation that affects Australia’s taxation system. Updated and expanded for changes which occurred in 2014, this volume is an indispensable reference for undergraduate and postgraduate students of taxation. The Year in Review section has been updated to summarise the main legislative developments in taxation over the previous 12 months, a listing of the passage of tax related legislation during the last year and the inclusion of reference statistics (such as CPI quarterly figures and individual tax rates for residents and foreign residents). Also fully updated and revised to reflect the changes in 2014 is the Tax Rates and Tables section, which contains an accessible summary of the main tax rates and tables that students will need to refer to for their tax studies.

In vitro micro propagation of Nicotiana benthamiana via axillary shoots

Axillary shoots of Nicotiana benthamiana were regenerated from nodal explants in two weeks using MS media supplemented with the cytokinin, kinetin (0.5 mg/L), and the auxin, indole-3-butyric acid (IBA) (0.1 mg/L). Ninety two percent of shoots were 2.1-20 mm tall, a size ideal for root induction. After transfer to hormone-free MS they readily produced roots within seven days, with phenotypically normal, fully developed plants being obtained within four weeks. Leaf chlorosis due to iron deficiency was observed in plants over time, however, this was overcome by doubling the concentration of inorganic iron. This rapid micro-propagation system is particularly useful for the in vitro mass production of N. benthamiana plants for various biotechnological applications.

Planning, policy and you

The policy environment for regional natural resource management (NRM) has shifted considerably since it was first introduced in the early 2000s. This workshop will explore the impact of current policy on NRM planning and action through presentations and workshop discussion. To set the scene for the workshop discussion presentations will consider: 1) the impact of evolving national and state NRM policy in Australia; 2) how Australian NRM compares to other countries; 3) governance risks to NRM delivery; and 4) regional responses to NRM delivery. During the workshop element, participants from across regions will share their experiences and explore implications of current policy on the business of regional NRM.

A study of governance arrangements for land use and natural resource management planning in Cape York Peninsula

Complex intersecting social, economic and environmental dilemmas in Australia's Cape York Peninsula present a number of challenges for planners seeking to develop and implement land use and natural resource management (NRM) plans. There have been five different attempts at land use and NRM planning in Cape York Peninsula over the last 20 years. These processes have (to greater or lesser extents) failed to deliver community-owned and government-supported plans to guide development and/or the management of the region's natural resources. The region is remote, sparsely populated, and home to a significant Indigenous population. Much of the contestation within the region surrounds the access, use and ownership of the region's internationally valuable natural resources. This paper reviews, from the literature, the relevancy and applicability of criteria for best practice planning and governance. A range of identified best practice governance and planning principles are applied to assess the governance arrangements for planning in the Peninsula. The paper finds that decision-making arrangements for land use and NRM planning in the Peninsula are still in their infancy and are inadequate to support effective outcomes. The paper concludes that broader attention to best practice principles in governance for planning is needed to improve planning outcomes.

A Bruch’s membrane substitute fabricated from silk fibroin supports the function of retinal pigment epithelial cells in vitro

Silk fibroin provides a promising biomaterial for ocular tissue reconstruction including the damaged outer blood-retinal barrier of patients afflicted with age-related macular degeneration (AMD). The aim of the present study was to evaluate the function of retinal pigment epithelial (RPE) cells in vitro, when grown on fibroin membranes manufactured to a similar thickness as Bruch’s membrane (3 μm). Confluent cultures of RPE cells (ARPE-19) were established on fibroin membranes and maintained under conditions designed to promote maturation over 4 months. Control cultures were grown on polyester cell culture well inserts (Transwell). Cultures established on either material developed a cobblestoned morphology with partial pigmentation within 12 weeks. Immunocytochemistry at 16 weeks revealed a similar distribution pattern between cultures for F-actin, ZO-1, ezrin, cytokeratin pair 8/18, RPE-65 and Na+/K+-ATPase. Electron microscopy revealed that cultures grown on fibroin displayed a rounder apical surface with a more dense distribution of microvilli. Both cultures avidly ingested fluorescent microspheres coated with vitronectin and bovine serum albumin (BSA), but not controls coated with BSA alone. VEGF and PEDF were detected in the conditioned medium collected from above and below both membrane types. Levels of PEDF were significantly higher than for VEGF on both membranes and a trend was observed towards larger amounts of PEDF in apical compartments. These findings demonstrate that RPE cell functions on fibroin membranes are equivalent to those observed for standard test materials (polyester membranes). As such, these studies support advancement to studies of RPE cell implantation on fibroin membranes in a preclinical model.

Incorporation of human recombinant tropoelastin into silk fibroin membranes with the view to repairing Bruch’s membrane

Bombyx mori silk fibroin membranes provide a potential delivery vehicle for both cells and extracellular matrix (ECM) components into diseased or injured tissues. We have previously demonstrated the feasibility of growing retinal pigment epithelial cells (RPE) on fibroin membranes with the view to repairing the retina of patients afflicted with age-related macular degeneration (AMD). The goal of the present study was to investigate the feasibility of incorporating the ECM component elastin, in the form of human recombinant tropoelastin, into these same membranes. Two basic strategies were explored: (1) membranes prepared from blended solutions of fibroin and tropoelastin; and (2) layered constructs prepared from sequentially cast solutions of fibroin, tropoelastin, and fibroin. Optimal conditions for RPE attachment were achieved using a tropoelastin-fibroin blend ratio of 10 to 90 parts by weight. Retention of tropoelastin within the blend and layered constructs was confirmed by immunolabelling and Fourier-transform infrared spectroscopy (FTIR). In the layered constructs, the bulk of tropoelastin was apparently absorbed into the initially cast fibroin layer. Blend membranes displayed higher elastic modulus, percentage elongation, and tensile strength (p < 0.01) when compared to the layered constructs. RPE cell response to fibroin membranes was not affected by the presence of tropoelastin. These findings support the potential use of fibroin membranes for the co-delivery of RPE cells and tropoelastin.

The application of building information modeling to enhance organisational learning

The construction industry is a knowledge-based industry where various actors with diverse expertise create unique information within different phases of a project. The industry has been criticized by researchers and practitioners as being unable to apply newly created knowledge effectively to innovate. The fragmented nature of the construction industry reduces the opportunity of project participants to learn from each other and absorb knowledge. Building Information Modelling (BIM), referring to digital representations of constructed facilities, is a promising technological advance that has been proposed to assist in the sharing of knowledge and creation of linkages between firms. Previous studies have mainly focused on the technical attributes of BIM and there is little evidence on its capability to enhance learning in construction firms. This conceptual paper identifies six ‘functional attributes’ of BIM that act as triggers to stimulate learning: (1) comprehensibility; (2) predictability; (3) accuracy; (4) transparency; (5) mutual understanding and; (6) integration.