Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

The Epidemiology of Emergency In-Patient Hospitalisations Among Those with 'No Fixed Abode' (Homeless) 2005-2014: What Lessons Can Be Learnt.

Estimates show that homelessness is increasing in Ireland. This study analysed the epidemiology of emergency hospitalisations among those experiencing homelessness between 2005-2014. All in-patient admissions to acute hospitals classified with 'no fixed abode' were extracted from the Hospital In-patient Enquiry System. Data were analysed using JMP. There were 2,051 in-patient emergency admissions of people classified with 'no fixed abode' during the study period, an increase of 406% since 2005 (78 in 2005 vs. 395 in 2014). The mean age was 40.6 (S.D. 13.2). The majority of patients (1,176 /2,051; 57%) had a mental/ behavioural diagnosis. Over one in ten (280; 13.7%) were admitted for ambulatory care sensitive conditions (ACSCs) including convulsions/epilepsy (N=92/280; 32.9%), cellulitis (62/280; 22.1%) and COPD (29/280; 10.4%). The health of homeless people is a fundamental issue that needs addressing. Access to, and use of, community and preventative services is needed to reduce utilisation of emergency hospital services.

Irish Medical Students Understanding of the Intern Year.

Upon completion of medical school in Ireland, graduates must make the transition to becoming interns. The transition into the intern year may be described as challenging as graduates assume clinical responsibilities. Historically, a survey of interns in 1996 found that 91% felt unprepared for their role. However, recent surveys in 2012 have demonstrated that this is changing with preparedness rates reaching 52%. This can be partially explained by multiple initiatives at the local and national level. Our study aimed evaluate medical student understanding of the intern year and associated factors. An online, cross-sectional survey was sent out to all Irish medical students in 2013 and included questions regarding their understanding of the intern year. Two thousand, two hundred and forty-eight students responded, with 1,224 (55.4%) of students agreeing or strongly agreeing that they had a good understanding of what the intern year entails. This rose to 485 (73.7%) among senior medical students. Of junior medical students, 260 (42.8%) indicated they understood what the intern year, compared to 479 (48.7%) of intermediate medical students. Initiatives to continue improving preparedness for the intern year are essential in ensuring a smooth and less stressful transition into the medical workforce.

Interpreting biomarker data from the COPHES/DEMOCOPHES twin projects: Using external exposure data to understand biomarker differences among countries.

In 2011 and 2012, the COPHES/DEMOCOPHES twin projects performed the first ever harmonized human biomonitoring survey in 17 European countries. In more than 1800 mother-child pairs, individual lifestyle data were collected and cadmium, cotinine and certain phthalate metabolites were measured in urine. Total mercury was determined in hair samples. While the main goal of the COPHES/DEMOCOPHES twin projects was to develop and test harmonized protocols and procedures, the goal of the current paper is to investigate whether the observed differences in biomarker values among the countries implementing DEMOCOPHES can be interpreted using information from external databases on environmental quality and lifestyle. In general, 13 countries having implemented DEMOCOPHES provided high-quality data from external sources that were relevant for interpretation purposes. However, some data were not available for reporting or were not in line with predefined specifications. Therefore, only part of the external information could be included in the statistical analyses. Nonetheless, there was a highly significant correlation between national levels of fish consumption and mercury in hair, the strength of antismoking legislation was significantly related to urinary cotinine levels, and we were able to show indications that also urinary cadmium levels were associated with environmental quality and food quality. These results again show the potential of biomonitoring data to provide added value for (the evaluation of) evidence-informed policy making.

A review of bed utilisation in the west of Ireland.

To ensure efficient use of Irish acute hospitals, the study aimed to assess the appropriateness of admission and days of care. The Appropriateness Evaluation Protocol (AEP) was applied to a stratified random sample of 286 medical and surgical, elective and non-elective patients from four acute hospitals in the west of Ireland. A total of 23 patients (8%) were inappropriately admitted. Of these 15 (65%) could have been avoided. Of the 34 elective/booked admissions, seven (21%) were inappropriate in terms of location of surgery criteria. Over three quarters of elective patients (77%) were admitted one or more days prior to surgery which was not justified for 13 (57%) of these patients. Over a quarter of days of care (n = 73, 26%) were inappropriate. Evidence of discharge planning was found for 48% of patients. The study provides a benchmark to monitor progress. Existing policies and programmes should be implemented and monitored.

The association between sleep patterns and obesity in older adults.

BACKGROUND: Reduced sleep duration has been increasingly reported to predict obesity. However, timing and regularity of sleep may also be important. In this study, the cross-sectional association between objectively measured sleep patterns and obesity was assessed in two large cohorts of older individuals. METHODS: Wrist actigraphy was performed in 3053 men (mean age: 76.4 years) participating in the Osteoporotic Fractures in Men Study and 2985 women (mean age: 83.5 years) participating in the Study of Osteoporotic Fractures. Timing and regularity of sleep patterns were assessed across nights, as well as daytime napping. RESULTS: Greater night-to-night variability in sleep duration and daytime napping were associated with obesity independent of mean nocturnal sleep duration in both men and women. Each 1 h increase in the standard deviation of nocturnal sleep duration increased the odds of obesity 1.63-fold (95% confidence interval: 1.31-2.02) among men and 1.22-fold (95% confidence interval: 1.01-1.47) among women. Each 1 h increase in napping increased the odds of obesity 1.23-fold (95% confidence interval: 1.12-1.37) in men and 1.29-fold (95% confidence interval: 1.17-1.41) in women. In contrast, associations between later sleep timing and night-to-night variability in sleep timing with obesity were less consistent. CONCLUSIONS: In both older men and women, variability in nightly sleep duration and daytime napping were associated with obesity, independent of mean sleep duration. These findings suggest that characteristics of sleep beyond mean sleep duration may have a role in weight homeostasis, highlighting the complex relationship between sleep and metabolism.

Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Review of acute cancer beds.

A review of admissions to cancer services at University Hospital Galway (UHG) was undertaken to assess the appropriateness of hospital usage. All cancer specialty patients admitted from 26-28 May 2009 were reviewed (n = 82). Chi square tests, Exact tests, and One-way ANOVA were utilised to analyse key issues emerging from the data. Fifty (61%) were classified as emergencies. Twenty three (67%) occupied a designated cancer bed with 24 (30%) in outlying non-oncology wards. The mean length of stay was 29.3 days. Possible alternatives to admission were identified for 15 (19%) patients. There was no evidence of discharge planning for 50 (60%) admissions. There is considerable potential to make more appropriate utilisation of UHG for cancer patients, particularly in terms of reducing bed days and length of stay and the proportion of emergency cancer admissions, and further developing integrated systems of discharge planning.

Childhood obesity: the extent of the problem among 6-year-old Irish national school children.

BACKGROUND: Childhood obesity is rapidly increasing worldwide. In Ireland, the number of overweight children has trebled over the last decade. The study aimed to provide an assessment of the prevalence of obesity of 6-year-old children in one region of Ireland. METHODS: Following training, School Public Health Nurses included the measurement of height and weight as part of the annual 'senior infants' school health check for 5453 6-year-old children in 189 schools between 2004 and 2007. Body mass index (BMI) was calculated using the International Obesity Taskforce cut-off points using lmsGrowth (a Microsoft Excel add-in), which uses a child's exact age. Kendall's Tau b was used to determine the reliability of measurements. Prevalence trends were tested using multinomial logistic regression. Pearson's chi-squared test was utilized to assess the statistical significance of differences in BMI by gender, school year, and to compare with similar other Irish studies. RESULTS: Out of the 5453 children measured, 3493 were aged 6 years old. A further 11 were excluded because of incomplete data. Data were analysed for 3482 6-year-old children. Overall, 27% of 6-year-olds were classified as either overweight or obese. A significantly greater proportion of girls are overweight or obese compared with boys (31% compared with 23%). Gender differences have remained relatively stable from 2004-2007. Overall, there have been no significant changes in the level of obesity from 2004-2007. In addition, when comparing with other Irish studies that collected data for 2001/2, there are no significant differences in obesity levels. CONCLUSIONS: There is a clear need to urgently prioritize the effective management of obesity. Resourses should now be targeted towards ensuring government policies in Ireland and elsewhere are implemented.

Sexuality and personal relationships for people with an intellectual disability. Part II: staff and family carer perspectives.

BACKGROUND: Recent ideological shifts in service provision promote appropriate sexual expression for people with an intellectual disability (ID), although there is little evidence that such advances in ideology are matched by current service provision. Part II of the current two-part study assessed the attitudes of staff and family carers to the sexuality of people with an ID. METHOD: A questionnaire survey which included case scenarios was carried out with family (n = 155) and staff carers (n = 153) of people with an ID in the west of Ireland. RESULTS: In general, staff carers were more inclined than family carers to openly discuss issues of sexuality with service users, and to suggest environmental, rather than service-user characteristics, as impediments to such discussions. Attitudinal differences emerged with significant differences between staff and family carers and between younger and older carers. Staff carers were more likely to support service-user engagement in intimate and non-intimate relationships whereas the majority of family carers (80%) showed a preference for low levels of intimacy in service-user relationships. CONCLUSION: When compared with the attitudes of family carers towards the sexuality of people with ID, the attitudes of staff carers more closely match those promoted by ideological developments. However, differences in attitudes between carer groups may lead to inconsistent approaches to the management of sexuality. As a consequence, we conclude that there is continued need to provide staff and family carers with opportunities for dialogue and an ongoing need for training in the area of sexuality.

Sexuality and personal relationships for people with an intellectual disability. Part I: service-user perspectives.

BACKGROUND: Despite a recent ideological shift towards the recognition of sexual autonomy for people with an intellectual disability (ID), there are continuing social and cultural barriers to sexual expression. Part I of the current two-part study assessed the sexual knowledge, experiences and aspirations of service users through focus groups and also examined their perceptions of impediments to achieving sexual autonomy. METHOD: Thirty-two participants (20 male, 12 female) attending an ID service participated in focus groups delineated by gender and age group (13-17 years; 18-30 years; 31+ years). RESULTS: Analysis of the focus groups showed that service users, especially those over the age of 18 years, had an understanding of their sexual rights but also identified a number of social and cultural barriers that they felt prevent them from achieving sexual autonomy. Those under the age of 18 years had only rudimentary knowledge of sexuality issues, for example pregnancy and sexual anatomy, but aspired to relationships and marriage similar to those over the age of 18 years. Family and staff attitudes appeared to be very influential in the views of respondents. All service users had received some form of sex education, although the benefits of such education appeared most enduring for those over 18 years. CONCLUSION: Service users had an understanding of their sexual rights and the social and environmental barriers that prevent them from fulfilling their rights. The provision of sex education training and promotion of positive attitudes towards appropriate sexual expression is critical to the realization of sexual autonomy for people with an ID.

Hormonal responses to a 160-km race across frozen Alaska.

BACKGROUND: Severe physical and environmental stress seems to have a suppressive effect on the hypothalamic-pituitary-gonadal (HPG) axis in men. Examining hormonal responses to an extreme 160-km competition across frozen Alaska provides a unique opportunity to study this intense stress. OBJECTIVE: To examine hormonal responses to an ultra-endurance race. METHODS: Blood samples were obtained from 16 men before and after racing and analyzed for testosterone, interleukin-6 (IL-6), growth hormone (GH) and cortisol. Six subjects (mean (SD) age 42 (7) years; body mass 78.9 (7.1) kg; height 1.78 (0.05) m raced by bicycle (cyclists) and 10 subjects (age 35 (9) years; body mass 77.9 (10.6) kg; height, 1.82 (0.05) m) raced by foot (runners). Mean (SD) finish times were 21.83 (6.27) and 33.98 (6.12) h, respectively. RESULTS: In cyclists there were significant (p< or =0.05) mean (SD) pre-race to post-race increases in cortisol (254.83 (135.26) to 535.99 (232.22) nmol/l), GH (0.12 (0.23) to 3.21 (3.33) microg/ml) and IL-6 (2.36 (0.42) to 10.15 (3.28) pg/ml), and a significant decrease in testosterone (13.81 (3.19) to 5.59 (3.74) nmol/l). Similarly, in runners there were significant pre-race to post-race increases in cortisol (142.09 (50.74) to 452.21 (163.40) ng/ml), GH (0.12 (0.23) to 3.21 (3.33) microg/ml) and IL-6 (2.42 (0.68) to 12.25 (1.78) pg/ml), and a significant decrease in testosterone (12.32 (4.47) to 6.96 (3.19) nmol/l). There were no significant differences in the hormonal levels between cyclists and runners (p>0.05). CONCLUSIONS: These data suggest a suppression of the hypopituitary-gonadal axis potentially mediated by amplification of adrenal stress responses to such an ultra-endurance race in environmentally stressful conditions.

Knowledge and attitudes of Irish Mental Health Professionals to the concept of recovery from mental illness - five years later.

WHAT IS KNOWN ABOUT THE SUBJECT?: The Advancing Recovery in Ireland (ARI) project (Health Service Executive, 2012) promotes recovery-orientated services. A previous study of Irish mental health practitioners (Cleary & Dowling ) identified the need to improve knowledge and attitudes towards recovery. To facilitate implementation of ARI and monitor progress, this study provided a 'benchmark' of current knowledge and attitudes to recovery. WHAT THIS STUDY ADDS TO EXISTING KNOWLEDGE?: The study provides important baseline information on recovery knowledge and attitudes which can be used to assess the impact of the ARI Project. It also provides valuable information that can be compared to recovery approaches employed in other countries. Despite the increased emphasis on recovery in Ireland, knowledge and attitudes of health care practitioners towards recovery remain relatively unchanged between 2007 and 2013. Working in dual settings, being a non-nurse, and training was associated with better RKI scores. Training appears to be the strongest factor in predicting better recovery knowledge. The findings suggest that knowledge levels and attitude changes following education may not be sustained over time and ongoing training may be required. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: There is considerable scope to improve recovery knowledge. Key recommendations include the need for more recovery training, evaluate whether training translates into clinical practice, using 'Recovery Champions', introducing peer support workers and developing local policies and protocols to support recovery practice. ABSTRACT: Introduction A study of Irish mental health practitioners (Cleary & Dowling ) identified the need to improve knowledge and attitudes towards recovery. This led to the Advancing Recovery in Ireland Project (ARI) which promoted recovery-orientated services and a need to 'benchmark' progress. There is little evidence regarding the types of educational interventions that maintain positive recovery knowledge and attitudes in providers. Aim The study assessed current knowledge and attitudes to recovery. Methods The methodology of Cleary & Dowling () was replicated. A survey was administered to practitioners (n = 337) using the adapted Recovery Knowledge Inventory (RKI) (Cleary & Dowling ). Results No significant differences were found in recovery scores compared to Cleary & Dowling () or by level of experience. Working in dual settings, being a non-nurse, and training was associated with better recovery scores. Significantly more respondents had received training in recovery (40% versus 23%) compared to Cleary & Dowling (). Training appears to be the strongest factor predicting better recovery knowledge. Conclusions There is considerable scope to improve recovery knowledge. Key recommendations include the need for more recovery training, using 'Recovery Champions', introducing peer support workers and developing local policies and protocols to support recovery working.

Secondhand smoke exposure and risk following the Irish smoking ban: an assessment of salivary cotinine concentrations in hotel workers and air nicotine levels in bars.

OBJECTIVE: To investigate whether the Irish smoking ban has had an impact on secondhand smoke (SHS) exposures for hospitality workers. DESIGN, SETTING, AND PARTICIPANTS: Before and after the smoking ban a cohort of workers (n = 35) from a sample of city hotels (n = 15) were tested for saliva cotinine concentrations and completed questionnaires. Additionally, a random sample (n = 20) of city centre bars stratified by size (range 400-5000 square feet), were tested for air nicotine concentrations using passive samplers before and after the ban. MAIN OUTCOME MEASURES: Salivary cotinine concentrations (ng/ml), duration of self reported exposures to secondhand smoke, air nicotine (microg/cubic metre). RESULTS: Cotinine concentrations reduced by 69%, from 1.6 ng/ml to 0.5 ng/ml median (SD 1.29; p < 0.005). Overall 74% of subjects experienced decreases (range 16-99%), with 60% showing a halving of exposure levels at follow up. Self reported exposure to SHS at work showed a significant reduction from a median 30 hours a week to zero (p < 0.001). There was an 83% reduction in air nicotine concentrations from median 35.5 microg/m3 to 5.95 microg/m3 (p < 0.001). At baseline, three bars (16%) were below the 6.8 microg/m3 air nicotine significant risk level for lung cancer alone; at follow up this increased to 10 (53%). CONCLUSIONS: Passive smoking and associated risks were significantly reduced but not totally eliminated. Exposure to SHS is still possible for those working where smoking is still allowed and those working where smoke may migrate from outdoor areas. Further research is required to assess the true extent and magnitude of these exposures.

Investigation of optimum energies for chest imaging using film-screen and computed radiography.

The purpose of the study was to compare the image quality of film-screen (FS) and computed radiography (CR) for adult chest examinations across a range of beam energies. A series of images of the CDRAD threshold contrast detail detection phantom were acquired for a range of tube potential and exposure levels with both CR and FS. The phantom was placed within 9 cm of Perspex to provide attenuation and realistic levels of scatter in the image. Hardcopy images of the phantom were scored from a masked light-box by two scorers. Threshold contrast indices were used to calculate a visibility index (VI). The relationships between dose and image quality for CR and for FS are fundamentally different. The improvements in VIs obtained using CR at 75 kVp and 90 kVp were found to be statistically significant compared with 125 kVp at matched effective dose levels. The relative performance of FS and CR varies as a function of energy owing to the different k-edges of each system. When changing from FS to CR, the use of lower tube potentials may allow image quality to be maintained whilst reducing effective dose. A tube voltage of 90 kVp is indicated by this work, but may require clinical verification.