Toll-like receptor 4 and CD14 polymorphisms in ankylosing spondylitis: Evidence of a weak association in finns

Objective To investigate the association of CD14 and Toll-like receptor (TLR4) with ankylosing spondylitis (AS). Methods A promoter variant in CD14 and 2 coding polymorphisms in TLR4 were investigated in UK and Finnish families with AS and in a UK case-control study. A metaanalysis of published TLR4 and CD14 studies was performed. Results In the Finnish study the CD74-260bp T variant showed an association (p = 0.006), and the common 2-marker TLR4 haplotype showed a weak association (global p = 0.03), with AS. No associations were seen in the UK based studies or in the metaanalyses. Conclusion CD14 and TLR4 showed an association with AS in the Finns only.

Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990–2013: Quantifying the epidemiological transition

Background The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age–sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development. Methods We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time. Findings Worldwide, from 1990 to 2013, life expectancy at birth rose by 6·2 years (95% UI 5·6–6·6), from 65·3 years (65·0–65·6) in 1990 to 71·5 years (71·0–71·9) in 2013, HALE at birth rose by 5·4 years (4·9–5·8), from 56·9 years (54·5–59·1) to 62·3 years (59·7–64·8), total DALYs fell by 3·6% (0·3–7·4), and age-standardised DALY rates per 100 000 people fell by 26·7% (24·6–29·1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non–communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries. Interpretation Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition—in which increasing sociodemographic status brings structured change in disease burden—is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions.

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Background The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. Methods Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk–outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990–2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. Findings All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8–58·5) of deaths and 41·6% (40·1–43·0) of DALYs. Risks quantified account for 87·9% (86·5–89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. Interpretation Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.

Groucho homologue Grg5 interacts with the transcription factor Runx2-Cbfa1 and modulates its activity during postnatal growth in mice

Runx2-Cbfal, a Runt transcription factor, plays important roles during skeletal development. It is required for differentiation and function of osteoblasts. In its absence, chondrocyte hypertrophy is severely impaired and there is no vascularization of cartilage templates during skeletal development. These tissue-specific functions of Runx2 are likely to be dependent on its interaction with other proteins. We have therefore searched for proteins that may modulate the activity of Runx2. The yeast two-hybrid system was used to identify a groucho homologue, Grg5, as a Runx2-interacting protein. Grg5 enhances Runx2 activity in a cell culture-based assay and by analyses of postnatal growth in mice we demonstrate that Grg5 and Runx2 interact genetically. We also show that Runx2 haploinsufficiency in the absence of Grg5 results in a more severe delay in ossification of cranial sutures and fontanels than occurs with Runx2 haploinsufficiency on a wild-type background. Finally, we find shortening of the proliferative and hypertrophic zones, and expansion of the resting zone in the growth plates of Runx2(+/-)Grg5(-/-) mice that are associated with reduced Ihh expression and Indian hedgehog (Ihh) signaling. We therefore conclude that Grg5 enhances Runx2 activity in vivo.

Does the size of subsamples taken from multispecies trawl catches affect estimates of catch composition and abundance?

Although subsampling is a common method for describing the composition of large and diverse trawl catches, the accuracy of these techniques is often unknown. We determined the sampling errors generated from estimating the percentage of the total number of species recorded in catches, as well as the abundance of each species, at each increase in the proportion of the sorted catch. We completely partitioned twenty prawn trawl catches from tropical northern Australia into subsamples of about 10 kg each. All subsamples were then sorted, and species numbers recorded. Catch weights ranged from 71 to 445 kg, and the number of fish species in trawls ranged from 60 to 138, and invertebrate species from 18 to 63. Almost 70% of the species recorded in catches were "rare" in subsamples (less than one individual per 10 kg subsample or less than one in every 389 individuals). A matrix was used to show the increase in the total number of species that were recorded in each catch as the percentage of the sorted catch increased. Simulation modelling showed that sorting small subsamples (about 10% of catch weights) identified about 50% of the total number of species caught in a trawl. Larger subsamples (50% of catch weight on average) identified about 80% of the total species caught in a trawl. The accuracy of estimating the abundance of each species also increased with increasing subsample size. For the "rare" species, sampling error was around 80% after sorting 10% of catch weight and was just less than 50% after 40% of catch weight had been sorted. For the "abundant" species (five or more individuals per 10 kg subsample or five or more in every 389 individuals), sampling error was around 25% after sorting 10% of catch weight, but was reduced to around 10% after 40% of catch weight had been sorted.

Spin it to win it: A comparison of constraints-led versus traditional coaching approaches

This thesis aimed to compare the effects of constraints-led and traditional coaching approaches on young cricket spin bowlers, with a specific research focus on increasing spin rates (i.e., Revolutions per Minute). Participants were 22 spin bowlers from either an Australia state youth squad or an academy in England. Results indicate that adopting a constraints-led approach can benefit younger, inexperienced bowlers, whilst a traditional approach may assist more skilled, older bowlers. The findings are discussed with regards to how they may inform the learning design of training programs by cricket coaches.

Mandatory Reporting and the Difficulties Identifying and Responding to Risk of Severe Neglect: A Response Requiring a Rethink

Neglect of children is a significant social issue worldwide and is typically the most frequently reported form of maltreatment in Western nations, with its severe forms sometimes resulting in significant illness and disablement or death. Yet, paradoxically, it remains ‘neglected’ and largely in the shadow of physical and sexual abuse, often being viewed as less serious despite the real-life consequences of its insidious and compounding nature and the lasting damage it causes to intergenerational familial relationships and the life outcomes of those affected. This chapter explores the many complex forms of child neglect, its causes and impacts and the strategies to prevent it. In particular, a critical standpoint is taken in analysing the rationale and merits of mandatory reporting of neglect and their effects, systemically and for children.

Legislation Concerning Reporting of Child Sexual Abuse and Child Trafficking in India: A Closer Look

The increasing rate of child sexual abuse and child trafficking has become a serious concern for national and international policy makers. Because these acts are criminal, result in serious harms to the child, and occur in closed scenarios where the situation is concealed, it is very important for people who become aware of the acts to report the incidents to the appropriate authority. Reporting of incidents could help provide justice to the victim and penalize the perpetrators. In addition, it would help us to understand the nature and magnitude of the problem. The objective of this chapter is first to review the Indian legislation concerning mandatory reporting of child abuse and neglect, and second to consider the potential for mandatory reporting of two categories of child maltreatment in particular in the Indian context: sexual abuse and child trafficking.

Fine mapping of variants associated with endometriosis in the WNT4 region on chromosome 1p36

Genome-wide association studies show strong evidence of association with endometriosis for markers on chromosome 1p36 spanning the potential candidate genes WNT4, CDC42 and LINC00339. WNT4 is involved in development of the uterus, and the expression of CDC42 and LINC00339 are altered in women with endometriosis. We conducted fine mapping to examine the role of coding variants in WNT4 and CDC42 and determine the key SNPs with strongest evidence of association in this region. We identified rare coding variants in WNT4 and CDC42 present only in endometriosis cases. The frequencies were low and cannot account for the common signal associated with increased risk of endometriosis. Genotypes for five common SNPs in the region of chromosome 1p36 show stronger association signals when compared with rs7521902 reported in published genome scans. Of these, three SNPs rs12404660, rs3820282, and rs55938609 were located in DNA sequences with potential functional roles including overlap with transcription factor binding sites for FOXA1, FOXA2, ESR1, and ESR2. Functional studies will be required to identify the gene or genes implicated in endometriosis risk.

No evidence for genetic association with the let-7 microRNA-binding site or other common KRAS variants in risk of endometriosis

STUDY QUESTION Is there a contribution of the minor allele at the KRAS single nucleotide polymorphism (SNP) rs61764370 in the let-7 microRNA-binding site to endometriosis risk? SUMMARY ANSWER We found no evidence for association between endometriosis risk and rs61764370 or any other SNPs in KRAS. WHAT IS KNOWN ALREADY The rs61764370 SNP in the 3' untranslated region of the KRAS gene is predicted to disrupt a complementary binding site (LCS6) for the let-7 microRNA, and was recently reported to be at a high frequency (31%) in 132 women of varying ancestry with endometriosis compared with frequencies in a database of population controls (up to 7.6% depending on ancestry), suggesting a strong effect of this KRAS SNP in the aetiology of endometriosis. STUDY DESIGN, SIZE AND DURATION This was a case-control study with a total of 11 206 subjects. The study was performed between February 2012 and July 2012. PARTICIPANTS/MATERIALS, SETTINGAND METHODS We first investigated a possible association between common markers in KRAS and endometriosis risk from our genome-wide association (GWA) data in 3194 surgically confirmed endometriosis cases and 7060 controls of European ancestry. Although rs61764370 was not genotyped on the GWA arrays, five SNPs typed in the study were highly correlated with this variant. The rs61764370 and two SNPs highly correlated with rs61764370 were then genotyped in 933 endometriosis cases and 952 controls using the Sequenom MassARRAY platform. MAIN RESULTS AND THE ROLE OF CHANCE There was no evidence for an association between rs61764370 and endometriosis risk P = 0.411 and odds ratio = 1.10 (95% confidence intervals: 0.88-1.36). We also found no evidence for an association between the highly correlated SNP rs17387019 and endometriosis. Their minor allele frequencies in cases and controls were of 0.087-0.091 similar to the population frequency reported previously for this variant in controls. Analyses of endometriosis cases with revised American Fertility Society stage III/IV disease also showed no evidence for an association between these SNPs and endometriosis risk. LIMITATIONS AND REASONS FOR CAUTION The GWA and genotyped data sets were not independent since individuals and cases from some families overlap. Controls in our GWA study were not screened for endometriosis. WIDER IMPLICATIONS OF THE FINDINGS The key SNP, rs61764370, was genotyped in a subset of samples. Our results do not support the suggestion that carrying the minor allele at rs61764370 contributes to a significant number of endometriosis cases and rs61764370 is, therefore, unlikely to be a useful marker of endometriosis risk. STUDY FUNDING/COMPETING INTEREST(S) The research was funded by grants from the Australian National Health and Medical Research Council and Wellcome Trust. None of the authors has competing interests for the study.

Evaluation of polymorphisms in predicted target sites for micro RNAs differentially expressed in endometriosis

Previous microarray analyses identified 22 microRNAs (miRNAs) differentially expressed in paired ectopic and eutopic endometrium of women with and without endometriosis. To investigate further the role of these miRNAs in women with endometriosis, we conducted an association study aiming to explore the relationship between endometriosis risk and single-nucleotide polymorphisms (SNPs) in miRNA target sites for these differentially expressed miRNAs. A panel of 102 SNPs in the predicted miRNA binding sites were evaluated for an endometriosis association study and an ingenuity pathway analysis was performed. Fourteen rare variants were identified in this study. We found SNP rs14647 in the Wolf-Hirschhorn syndrome candidate gene1 (WHSC1) 3'UTR (untranslated region) was associated with endometriosis-related infertility presenting an odds ratio of 12.2 (95% confidence interval = 2.4-60.7, P = 9.03 x 10(-5)). SNP haplotype AGG in the solute carrier family 22, member 23 (SLC22A23) 3'UTR was associated with endometriosis-related infertility and more severe disease. With the individual genotyping data, ingenuity pathways analysis identified the tumour necrosis factor and cyclin-dependant kinase inhibitor as major factors in the molecular pathways. Significant associations between WHSC1 alleles and endometriosis-related infertility and SLC22A23 haplotypes and the disease severe stage were identified. These findings may help focus future research on subphenotypes of this disease. Replication studies in independent large sample sets to confirm and characterize the involvement of the gene variation in the pathogenesis of endometriosis are needed.

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.

Access To Justice In The ASEAN The Key Role Of UNCITRAL

UNCITRAL’s operation as a subsidiary of the UN General Assembly, tasked to unify and harmonise international trade law is a necessary and indispensable element of the UN’s mandate to maintain international peace and security. Strong legal frameworks which are compatible with those of international trading partners often accompany accelerated growth in economic capacity and stability. Over time, access to markets and resultant growth in economic and human development creates a disincentive for instability as incomes and standards of living rise. Human and economic development, facilitated by a modernised and just legal framework that is available to the broadest range of recipients goes hand in hand with the maintenance of domestic and regional peace, particularly in regions such as the ASEAN , one of the fastest growing in the world covering approximately 30% of global population and with a number of strong global economic neighbours including Japan, Korea, China (to the north), Australia (to the south) and Singapore (to the west). In an increasingly interconnected world, the ability of government, enterprise and individuals to participate in the global supply chain offers opportunities for economic growth and development. Over its almost 50 years of operations, UNCITRAL has produced a range of important texts that are designed to underpin world trade. A key implicit assumption underpinning the development of UNCITRAL texts is that the texts, once adopted can and will be applied in adopting states.

Intergenerational Perceptions and Conflicts in Multi-Age and Multigenerational Work Environments

One underappreciated consequence of the aging population phenomenon is that we are now experiencing what is arguably the most age-diverse workforce in modern history (Hanks & Icenogle, 2001; Newton, 2006; Toossi, 2004). As our workforce continues to age, shifts in the age demographic composition (i.e., the age diversity) of organizations and their subunits will become more apparent (Roth, Wegge, & Schmidt, 2007). Several factors have influenced and will continue to drive this trend. For example, in Western countries, younger people entering the workforce are more educated than ever before (Hussar & Bailey, 2013; Ryan & Siebens, 2012; Stoops, 2003) and could feasibly rise to positions of power in organizations more quickly than others have in the past (e.g., promotion rates vary as a function of age) (Rosenbaum, 1979; see also Clemens, 2012 conceptualization of the "fast track effect"). Furthermore, older workers are increasingly delaying retirement beyond the normative retirement age (Baltes & Rudolph, 2012; Burtless, 2012; Flynn, 2010), and already retired individuals are seeking re-employment in bridge employment roles in higher numbers than before (e.g., Adams & Rau, 2004; Kim & Feldman, 2000; Weckerle & Shultz, 1999).

A f/oxymoron? : Women, creativity and the suburbs

Donald Horne famously wrote, ‘Australia was born urban and quickly grew suburban’ (1964), an observation that carries a weight of assumptions about suburban living. Historically, the Australian suburbs have been regarded as places of retreat, family life and female activity, and subsequently as a place where not much of interest happens. By contrast, a city's central areas are seen as more dynamic spaces and, with recent creative city thinking and planning, as potential powerhouses of innovation and creativity. This article challenges assumptions about suburban living as passive places of retreat through an examination of women in the creative workforce who are living and working in the suburbs. It draws on historical accounts of creative suburban activity and a research project that mapped and investigated the experience of creative workers in the outer suburbs of Brisbane and Melbourne. The study finds that there is much creative work occurring in suburban localities, but this is not as unusual as might be expected.