Genetic determinants of heel bone properties: Genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n 5 14 260), velocity of sound (VOS; n 5 15 514) and BMD (n 5 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n 5 11 452) and new genotyping in 15 cohorts (de novo n 5 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 3 108) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 3 1014). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 3 106 also had the expected direction of association with any fracture (P < 0.05), including threeSNPswithP < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, thisGWAstudy reveals the effect of several genescommon to central DXA-derivedBMDand heel ultrasound/DXAmeasures and points to anewgenetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Runs of homozygosity and a cluster of vulvar cancer in young Australian Aboriginal women

Objective A cluster of vulvar cancer exists in young Aboriginal women living in remote communities in Arnhem Land, Australia. A genetic case–control study was undertaken involving 30 cases of invasive vulvar cancer and its precursor lesion, high-grade vulvar intraepithelial neoplasia (VIN), and 61 controls, matched for age and community of residence. It was hypothesized that this small, isolated population may exhibit increased autozygosity, implicating recessive effects as a possible mechanism for increased susceptibility to vulvar cancer. Methods Genotyping data from saliva samples were used to identify runs of homozygosity (ROH) in order to calculate estimates of genome-wide homozygosity. Results No evidence of an effect of genome-wide homozygosity on vulvar cancer and VIN in East Arnhem women was found, nor was any individual ROH found to be significantly associated with case status. This study found further evidence supporting an association between previous diagnosis of CIN and diagnosis of vulvar cancer or VIN, but found no association with any other medical history variable. Conclusions These findings do not eliminate the possibility of genetic risk factors being involved in this cancer cluster, but rather suggest that alternative analytical strategies and genetic models should be explored.

Prevalence and risk factors for oral HPV infection in young Australians

The prevalence of human papillomavirus (HPV)–associated head and neck cancers is increasing, but the prevalence of oral HPV infection in the wider community remains unknown. We sought to determine the prevalence of, and identify risk factors for, oral HPV infection in a sample of young, healthy Australians. For this study, we recruited 307 Australian university students (18–35 years). Participants reported anonymously about basic characteristics, sexual behaviour, and alcohol, tobacco and illicit drugs use. We collected oral rinse samples from all participants for HPV testing and typing. Seven of 307 (2.3%) students tested positive for oral HPV infection (3 HPV-18, one each of HPV-16, -67, -69, -90), and six of them were males (p = 0.008). Compared to HPV negative students, those with oral HPV infection were more likely to have received oral sex from more partners in their lifetime (p = 0.0004) and in the last year (p = 0.008). We found no statistically significant associations with alcohol consumption, smoking or numbers of partners for passionate kissing or sexual intercourse. In conclusion, oral HPV infection was associated with male gender and receiving oral sex in our sample of young Australians.

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Adverse childhood experiences and the health of university students in eight provinces of Vietnam

Recent systematic reviews have emphasized the need for more research into the health and social impacts of adverse childhood experiences (ACEs) in the Asia-Pacific region. This cross-sectional study was conducted with 2099 young adult students in 8 medical universities throughout Vietnam. An anonymous, self-report questionnaire included the World Health Organization ACE-International Questionnaire and standardized measures of mental and physical health. Three quarters (76%) of the students reported at least one exposure to ACEs; 21% had 4 or more ACEs. The most commonly reported adversities were emotional abuse, physical abuse, and witnessing a household member being treated violently (42.3%, 39.9%, and 34.6%, respectively). Co-occurrence of ACEs had dose–response relationships with poor mental health, suicidal ideation, and low physical health–related quality of life. This first multisite study of ACEs among Vietnamese university students provided evidence that childhood adversity is common and is significantly linked with impaired health and well-being into the early adult years

Genome-wide association study of intraocular pressure identifies the GLCCI1/ICA1 region as a glaucoma susceptibility locus

To discover quantitative trait loci for intraocular pressure, amajor risk factor for glaucoma and the only modifiable one,weperformed agenome-wide association studyonadiscoverycohort of2175individualsfromSydney, Australia. We found a novel association between intraocular pressure and a common variant at 7p21 near to GLCCI1 and ICA1. The findings in this region were confirmed through two UK replication cohorts totalling 4866 individuals (rs59072263, Pcombined = 1.10 × 10-8). A copy of the G allele at this SNP is associated with an increase in mean IOP of 0.45 mmHg (95%CI = 0.30-0.61 mmHg). These results lend support to the implication of vesicle trafficking and glucocorticoid inducibility pathways in the determination of intraocular pressure and in the pathogenesis of primary open-angle glaucoma.

Social influences on risky driving behaviours among young drivers in Oman

Young drivers represent approximately 20% of the Omani population, yet account for over one third of crash injuries and fatalities on Oman's roads. Internationally, research has demonstrated that social influences play an important role within young driver safety, however, there is little research examining this within Arab gulf countries. This study sought to explore young driver behaviour using Akers' social learning theory. A self-report survey was conducted by 1319 (72.9% male and 27.1% female) young drivers aged 17-25 years. A hierarchical regression model was used to investigate the contribution of social learning variables (norms and behaviour of significant others, personal attitudes towards risky behaviour, imitation of significant others, beliefs about the rewards and punishments offered by risky behaviour), socio-demographic characteristics (age and gender), driving experience (initial training, time driving and previous driving without supervision) and sensitivity to rewards and punishments upon the self-reported risky driving behaviours of young drivers. It was found that 39.6% of the young drivers reported that they have been involved in at least one crash since the issuance of their driving licence and they were considered ‘at fault’ in 60.7% of these crashes. The hierarchical multiple regression models revealed that socio-demographic characteristics and driving experience alone explained 14.2% of the variance in risky driving behaviour. By introducing social learning factors into the model a further 37.0% of variance was explained. Finally, 7.9% of the variance in risky behaviour could be explained by including individual sensitivity to rewards and punishments. These findings and the implications are discussed.

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense. © 2012 Nature America, Inc. All rights reserved.

Genome-wide association study identifies eight loci associated with blood pressure

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N 71,225 European ancestry, N 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10 24), CYP1A2 (P = 1 × 10 23), FGF5 (P = 1 × 10 21), SH2B3 (P = 3 × 10 18), MTHFR (P = 2 × 10 13), c10orf107 (P = 1 × 10 9), ZNF652 (P = 5 × 10 9) and PLCD3 (P = 1 × 10 8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

The sleep patterns of infants and young children with gastro-oesophageal reflux

Objective: Sleep disturbance in gastro-oesophageal reflux disease (GORD) in infants and young children has not been systematically studied nor has this manifestation been compared with population norms. Methods: Sleep patterns of 102 infants and children aged 1 to 36 months with and without GORD, defined by pH monitoring, were analysed using the same questionnaire as in recent studies of normal sleep behaviour in this age range. Main outcome measures included time taken to settle at night, the number of night time wakenings requiring parental intervention, day time sleep patterns and parents problems with their childs' sleep behaviour. Results: Compared with the population norms (n=3102), those with GORD (n=76) had greater prevalence of night time waking >3/night (50% vs 13% aged 3-12 months; 60% vs 10% aged 12-24 months, P<0.001), requirement of parental intervention (82% vs 55% aged 3-12 months, P < 0.05; 92% vs 55% aged 12-24 months, P < 0.001), significantly delayed onset of sleeping through the night, and greater prevalence of daytime sleep beyond 24 months. Similar but less striking differences were seen comparing those with (n = 76) and without GORD (n = 26). Conclusions: Sleep interruption occurs more frequently in infants and children with GORD than population norms. Objective evaluation of infants and children with sleep disturbance after the age of 3 months may avoid unnecessary over or under diagnosis of GORD. Systematic investigation of the contribution of GORD to sleep disturbance in infants and young children is warranted

A controlled trial comparing the efficacy of rice-based and hypotonic glucose oral rehydration solutions in infants and young children with gastroenteritis

A prospective randomized trial was conducted to compare the efficacy of a rice-based oral rehydration solution (ORS) with glucose ORS in infants and children under 5 years of age with acute diarrhoea and mild to moderate dehydration (<10%). One hundred children presenting to a large metropolitan teaching hospital were eligible for entry to the study and were randomized to receive rice ORS or glucose ORS. Outcome measures were stool output (SO), duration of illness (DD) and recovery time to introduction of other fluids (RTF) and diet (RTD). Significant differences were found for all outcome measures in favour of the rice ORS group. Mean SO was lower (160 vs 213 mt; P<0.02), mean DD was reduced (17.3 vs 24.3 h; P = 0.03) and median RTF was decreased (12.7 vs 18.1 h; P< 0.001) in the rice ORS group compared with the glucose ORS group. The median rime to introduction of diet and mean length of hospital stay showed similar significant reductions. Our study has shown rice ORS to be an acceptable alternative to glucose ORS in young children and have shown that it is significantly more effective in reducing the course of diarrhoeal illness and the time taken to return to normal drinking and eating habits.

Identity, image, and sexuality in young adults with cancer

The impact of disease and treatment on a young adult's self-image and sexuality has been largely overlooked. This is surprising given that establishing social and romantic relationships is a normal occurrence in young adulthood. This article describes three female patients' cancer journeys and demonstrates how their experiences have impacted their psychosocial function and self-regard. The themes of body image, self-esteem, and identity formation are explored, in relation to implications for relationship-building and moving beyond a cancer diagnosis. This article has been written by young cancer survivors, Danielle Tindle, Kelly Denver, and Faye Lilley, in an effort to elucidate the ongoing struggle to reconcile cancer into a normal young adult's life.

The trend toward pre-graduation professional work experience for Australian young planners: Essential experience or essentially exploitation

This paper explores the changing employment expectations that frame the early professional work experiences of young planners in Australia. In particular, it considers the rising popularity of pre-graduation professional work experience as a precursor to formal entry into the workforce as a practising planner. This shift is being driven in part by employer expectations that graduates will already have ‘real world’ and relevant work experience. However, an equally significant driver appears to be a growing desire for early career and graduate planners to find ways to distinguish themselves from their peers in an increasingly tight labour market. Using data from an ongoing research project into the formative work experiences of young people this paper describes the three main types of pre-graduation professional work experience undertaken by young planners. It highlights the potential challenges and benefits of pre-graduation work experience from a legal, social and ethical perspective as well as from the perspective of young planners themselves. The paper concludes by reflecting on the role of the planning profession – employers, peak bodies and planning educators – in managing the tensions between producing ‘work ready’ graduates and safeguarding the employment conditions of early career planning professionals.

Prevalence and characteristics of road traffic injuries among young drivers in Oman, 2009-2011

Objectives Studies from different parts of the world have indicated that the impact of road traffic incidents disproportionally affects young adults. Few known studies have been forthcoming from Arabian Gulf countries. Within Oman, a high proportion of the population is under the age of 20. Coupled with the drastic increase of motorization in recent years there is a need to understand the state of road safety among young people in Oman. The current research aimed to explore the prevalence and characteristics of road traffic injuries among young drivers aged 17-25 years. Methods Crash data from 2009-2011 was extracted from the Directorate General of Traffic, Royal Oman Police (ROP) database in Oman. The data was analyzed to explore the impact of road crashes on young people (17-25 years), the characteristics of young driver crashes and how these differ from older drivers and to identify key predictors of fatalities in young driver crashes. Results Overall, young people were over-represented in injuries and fatalities within the sample time period. While it is true that many young people in crashes were driving at the time, it was also evident that young people were often a victim in a crash caused by someone else. Thus, to reduce the impact of road crashes on young people, there is a need to generally address road safety within Oman. When young drivers were involved in crashes they were predominantly male. The types of crashes these drivers have can be broadly attributed to risk taking and inexperience. Speeding and night time driving were the key risk factors for fatalities. Conclusion The results highlight the need to address young driver safety in Oman. From these findings, the introduction of a graduated driver licensing system with night time driving restrictions could significantly improve young driver safety.

Destinations: 3 Large Cast Plays for Young People

This book is a collection of three large-cast plays written in response to a very specific problem. My work as a teacher of drama often required me to locate a script that would somehow miraculously work for a cast of unknown number and gender, and most likely uneven skills and enthusiasm, who I hadn’t even met yet. It’s a familiar dilemma for teachers and students of drama in education contexts, at whatever level you’re teaching. I’d first addressed this creative problem with scripts such as Gate 38 (2010). I had tried using scripts that already existed, but found they required such extensive editing to suit the parameters of cast and performance duration that I may as well have been writing them myself. Even in the setting of a closed studio, in altering these plays I felt I was bending the vision of the playwright, and certainly their narrative structure, out of shape. Everyone who’s attempted to stage a performance with a large cast of students in an educational setting knows it takes time to truly connect with a play, its social contexts, themes and characters. It also takes a lot of time to get on top of the practicalities of learning, rehearsing, directing and running a performance with young people. Often the curtain goes up on something unfinished and unstable. I was looking for ways to reduce the complexity of staging a script, while maintaining the potential of this process as a site of rich, enjoyable learning. Two of the plays (Duty Free and Please Be Seated) are comprised of multiple monologues, combined with music-driven ensemble sequences. The monologues enable individuals to develop and polish their own performances, work in small groups, and cut down on the laborious detail of directing naturalistic scenes based in character interaction. The third (Australian Drama) involves a lot of duologues, meaning that its rehearsal process can happily employ that mainstay of the drama classroom: small group work. There’s plenty of room to move in terms of gender-blind casting as well. Please be Seated is mainly young women. The scripts also contain ensemble-based interludes which are non-verbal, music driven, with a choreographic element. They have also springboarded further explorations in form. The ethical and aesthetic complexities of verbatim works; the interaction between music and theatre; and meta-concerns related to the performing of performance: ‘how can the act of acting ‘acted’. The narratives of all three of these plays are deliberately open, enabling the flexible casting and on-the hop editing that large-group, time-poor processes sometimes necessitate. Duty Free is about the overseas ‘adventures’ of young people. Please Be Seated is based in verbatim text about young people falling in and out of love. Australian Drama is about young people in a drama classroom trying to connect with each other and put their own shine on dull fragments of the theatrical canon. The plays were published as a collection in hardcopy and digital editions by Playlab Press in 2015. Please be Seated is a co-write with a large group. These co-author’s names are listed in the publication, and below in ‘additional information’.