Professor Liz Holliday

Background: Physical inactivity and insomnia symptoms are independently associated with increased risk of depression and anxiety; however, few studies jointly examine these risk factors. This study aimed to prospectively examine the joint association of physical activity (PA) and insomnia symptoms with onset of poor mental health in adults. Methods: Participants from the 2013 to 2018 annual waves of the Household Income and Labour Dynamics in Australia panel study who had good mental health (Mental Health Inventory-5 >54) in 2013, and who completed at least 1 follow-up survey (2014¿2018), were included (n = 10,977). Poor mental health (Mental Health Inventory-5 = 54) was assessed annually. Baseline (2013) PA was classified as high/moderate/low, and insomnia symptoms (i.e., trouble sleeping) were classified as no insomnia symptoms/insomnia symptoms, with 6 mutually exclusive PA-insomnia symptom groups derived. Associations of PA¿insomnia symptom groups with onset of poor mental health were examined using discrete-time proportional-hazards logit-hazard models. Results: There were 2322 new cases of poor mental health (21.2%). Relative to the high PA/no insomnia symptoms group, there were higher odds (odds ratio and 95% confidence interval (95%CI)) of poor mental health among the high PA/insomnia symptoms (OR = 1.87, 95%CI: 1.57¿2.23), moderate PA/insomnia symptoms (OR = 1.93, 95%CI: 1.61¿2.31), low PA/insomnia symptoms (OR = 2.33, 95%CI: 1.96¿2.78), and low PA/no insomnia symptoms (OR = 1.14, 95%CI: 1.01¿1.29) groups. Any level of PA combined with insomnia symptoms was associated with increased odds of poor mental health, with the odds increasing as PA decreased. Conclusion: These findings highlight the potential benefit of interventions targeting both PA and insomnia symptoms for promoting mental health.

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12¿16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI¿s magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.

Background: Little is known about the physical and mental health impact of exposure to landscape fire smoke in women with asthma. This study examined the health impacts and information-seeking behaviours of women with asthma exposed to the 2019/2020 Australian fires, including women who were pregnant. Methods: Women with asthma were recruited from the Breathing for Life Trial in Australia. Following the landscape fire exposure period, self-reported data were collected regarding symptoms (respiratory and non-respiratory), asthma exacerbations, wellbeing, quality of life, information seeking, and landscape fire smoke exposure mitigation strategies. Participants¿ primary residential location and fixed site monitoring was used to geolocate and estimate exposure to landscape fire-related fine Particulate Matter (PM2.5). Results: The survey was completed by 81 pregnant, 70 breastfeeding and 232 non-pregnant and non-breastfeeding women with asthma. Participants had a median daily average of 17 µg/m3 PM2.5 and 105 µg/m3 peak PM2.5 exposure over the fire period (October 2019 to February 2020). Over 80% of participants reported non-respiratory and respiratory symptoms during the fire period and 41% reported persistent symptoms. Over 82% reported asthma symptoms and exacerbations of asthma during the fire period. Half the participants sought advice from a health professional for their symptoms. Most (97%) kept windows/doors shut when inside and 94% stayed indoors to minimise exposure to landscape fire smoke. Over two in five (43%) participants reported that their capacity to participate in usual activities was reduced due to prolonged smoke exposure during the fire period. Participants reported greater anxiety during the fire period than after the fire period (mean (SD) = 53(13) versus 39 (13); p < 0.001). Two in five (38%) pregnant participants reported having concerns about the effect of fire events on their pregnancy. Conclusion: Prolonged landscape fire smoke exposure during the 2019/2020 Australian fire period had a significant impact on the health and wellbeing of women with asthma, including pregnant women with asthma. This was despite most women taking actions to minimise exposure to landscape fire smoke. Effective and consistent public health messaging is needed during landscape fire events to guard the health of women with asthma.

Objective: To identify the optimal AUSDRISK threshold score to screen for pre-diabetes and diabetes. Methods: A total of 406 adult patients not diagnosed with diabetes were screened in General Practices (GP) between May and October 2019. All patients received a point of care (POC) HbA1c test. HbA1c test results were categorised into diabetes (=6.5% or =48 mmol/mol), pre-diabetes (5.7¿6.4% or 39¿47 mmol/mol), or normal (<5.7% or 39 mmol/mol). Results: Of these patients, 9 (2%) had undiagnosed diabetes and 60 (15%) had pre-diabetes. A Receiver Operator Characteristic (ROC) curve was constructed to predict the presence of pre-diabetes and diabetes; the area under the ROC curve was 0.72 (95%CI 0.65¿0.78) indicating modest predictive ability. The optimal threshold cut point for AUSDRISK score was 17 (sensitivity 76%, specificity 61%, + likelihood ratio (LR) 1.96, - likelihood ratio of 0.39) while the accepted cut point of 12 performed less well (sensitivity 94%, specificity 23%, +LR=1.22 -LR+0.26). Conclusions: The AUSDRISK tool has the potential to be used as a screening tool for pre-diabetes/diabetes in GP practices. A cut point of =17 would potentially identify 75% of all people at risk and three in 10 sent for further testing would be positive for prediabetes or diabetes. Implications for public health: Routine case-finding in high-risk patients will enable GPs to intervene early and prevent further public health burden from the sequelae of diabetes.

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

Whole blood viscosity (WBV) is the intrinsic resistance to flow developed due to the frictional force between adjacent layers of flowing blood. Elevated WBV is an independent risk factor for stroke. Poor microcirculation due to elevated WBV can prevent adequate perfusion of the brain and might act as an important secondary factor for hypoperfusion in acute ischaemic stroke. In the present study, we examined the association of WBV with basal cerebral perfusion assessed by CT perfusion in acute ischaemic stroke. Confirmed acute ischemic stroke patients (n = 82) presenting in hours were recruited from the single centre. Patients underwent baseline multimodal CT (non-contrast CT, CT angiography and CT perfusion). Where clinically warranted, patients also underwent follow-up DWI. WBV was measured in duplicate within 2¿h after sampling from 5-mL EDTA blood sample. WBV was significantly correlated with CT perfusion parameters such as perfusion lesion volume, ischemic core volume and mismatch ratio; DWI volume and baseline NIHSS. In a multivariate linear regression model, WBV significantly predicted acute perfusion lesion volume, core volume and mismatch ratio after adjusting for the effect of occlusion site and collateral status. Association of WBV with hypoperfusion (increased perfusion lesion volume, ischaemic core volume and mismatch ratio) suggest the role of erythrocyte rheology in cerebral haemodynamic of acute ischemic stroke. The present findings open new possibilities for therapeutic strategies targeting erythrocyte rheology to improve cerebral microcirculation in stroke.

Background Individualised music listening has been shown to reduce agitation and improve mood in people with dementia. However, there is a paucity of research describing the cost of implementing such interventions in residential care settings for older people. Aim To determine the cost of implementing an individualised music intervention for older people with dementia in residential aged care in Australia. Method A simple cost analysis was undertaken to determine the cost of delivering the individualised music intervention to 32 older people with dementia at two residential aged care facilities in New South Wales. The analysis took into consideration the operating, training and delivery costs, as well as the costs of purchasing the music equipment and downloads. Results The cost of delivering the individualised music intervention was found to be AU$6,623.76 per year ¿ or AU$3.98 per resident per week, at 2017 values. At 2022 values, this equates to an annual cost of AU$7,130.07 (£4,031.85) for 32 residents and a weekly cost of AU$4.28 (£2.42) per resident per week. Conclusion The cost of implementing the individualised music intervention was relatively low compared with the overall cost of residential aged care for older people with dementia.

Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85¿×¿10-9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n¿=¿27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Introduction: Continuous surveillance of stroke admissions has been conducted in the Hunter region, Australia, over the past two decades. We aimed to describe the trends in incidence rates of hospitalised stroke and case-fatality rates in this region, 2001-2019. Methods: From a hospital-based stroke registry, data for admitted adult stroke patients residing in the Hunter region were collected using ICD-10 codes for ischemic and haemorrhagic stroke. Negative binomial regression and logistic regression analysis were used to analyse trends for age-standardised and age-specific incidence rates of hospitalised stroke and 28-day case-fatality rates. Results: A total of 14,662 hospitalisations for stroke in 13,242 individuals were registered. The age-standardised incidence rate declined from 123 per 100,000 population in the 2001-2005 epoch to 96 in the 2016-2019 epoch (mean annual change -2.0%, incidence rate ratio (IRR) = 0.980 [95%CI: 0.976-0.984]). Age-specific analyses identified significant reduction in the group aged 75-84 (1039 per 100,000 population in 2001-2005 to 633 in 2016-2019, annual change -3.5%, IRR= 0.965 [95%CI: 0.960-0.970]). The 28-day case-fatality rates fluctuated over time (18.5% in 2001-2005, 20.8% in 2010-2015, and 17.8% in 2016-2019). Projected population aging suggests annual volume of patients with new stroke will increase by 77% by 2041 if incidence rates remain unchanged at the 2016-2019 level. Conclusion: Although age-standardised hospitalised stroke incidence rates have declined in the Hunter region, the health system will face an increase in stroke hospitalisations related to the aging population.

ABSTRACT: INTRODUCTION: Over-prescription of antibiotics for common infective conditions is an important health issue. Infective conjunctivitis represents one of the most common eye-related complaints in general practice. Despite its self-limiting nature, there is evidence of frequent general practitioner (GP) antibiotic prescribing for this condition, which is inconsistent with evidence-based guidelines. AIM: To investigate the prevalence and associations of GP registrars' (trainees') prescription of antibiotics for infective conjunctivitis. METHODS: We performed a cross-sectional analysis of the Registrar Encounters in Clinical Training (ReCEnT) ongoing prospective cohort study, which documents GP registrars' clinical consultations (involving collection of information from 60 consecutive consultations, at three points during registrar training). The outcome of the analyses was antibiotic prescription for a new diagnosis of conjunctivitis. Patient, registrar, practice and consultation variables were included in uni- and multivariable logistic regression analyses to test associations of these prescriptions. RESULTS: In total, 2333 registrars participated in 18 data collection rounds from 2010 to 2018. There were 1580 new cases of infective conjunctivitis (0.31% of all problems). Antibiotics (mainly topical) were prescribed in 1170 (74%) of these cases. Variables associated with antibiotic prescription included patients' Aboriginal or Torres Strait Islander status, registrar organisation of a follow up (both registrar and other GP follow up), and earlier registrar training term (more junior status). DISCUSSION: GP registrars, like established GPs, prescribe antibiotics for conjunctivitis in excess of guideline recommendations, but prescribing rates are lower in later training. These prescribing patterns have educational, social and economic consequences. Further educational strategies may enhance attenuation of registrars' prescribing during training.

Objective Examine the relationship between preconception stress and offspring birth weight. Setting Population-based cohort study linked with state-based administrative perinatal data. Participants 6100 births from 3622 women from the 1973-1978 cohort of the Australian Longitudinal Study of Women's Health who (1) recorded a singleton birth between January 1997 and December 2011; (2) returned at least one follow-up survey within 3 years of conception; and (3) had complete data on perceived stress prior to conception. Primary outcome measures Linear generalised estimating equations were used to examine the relationship between preconception stress and a continuous measure of birth weight, exploring differences based on birth order and stress chronicity. The minimal sufficient adjustment set of covariates was determined by a directed acyclic graph. Results For all births, there was no relationship between moderate/high acute or chronic stress and offspring birth weight in grams. Among first births only, there was a trend towards a relationship between moderate/high chronic stress and offspring birth weight. Offspring sex was associated with birth weight in all models, with female babies born lighter than male babies on average, after adjusting for covariates (p<0.0001). Conclusions Effects of preconception stress on birth weight was largely driven by time to conception. With the timing of stress critical to its impact on obstetrical outcomes, preconception care should involve not only reproductive life planning but the space to provide interventions at critical periods so that optimal outcomes are achieved.

Objectives: Sedentary behaviour research is a relatively new field, much of which has emerged since the widespread acceptance of clinical trial registration. The aim of this study was to investigate the trial registration and related issues in studies investigating the effect of frequent activity interruptions to prolonged sitting-time. Methods: Secondary analysis of a scoping review including systematic searches of databases and trial registries. We included experimental studies investigating the effects of frequent activity interruptions to prolonged sitting-time. Results: We identified 32 trials published in 45 papers. Only 16 (50%) trials were registered, with all 16 trials being completed and published. Of the unregistered trials, we identified three (19%) for which similarities in the sample size and participant demographics across papers was suggestive of duplicate publication. Identification of potential duplicate publications was difficult for the remaining 13 (81%). Results from 53 (76%) of the 70 registered outcomes were published, but 11 (69%) registered trials reported results from additional outcomes not prospectively registered. A total of 46 different outcomes (out of 53 reported outcome measures, similar measures were collated) were reported across all trials, 31 (67%) of which were collected in =2 trials. Conclusions: We found direct evidence of trial registration issues in experimental trials of breaking up sitting-time. The lack of prospective registration of all trials, and the large number of outcomes measured per trial are key considerations for future research in this field. These issues are unlikely to be confined to the field of sedentary behaviour research.

Background: To examine if a composite activity-sleep behaviour index (ASI) mediates the effects of a combined physical activity and sleep intervention on symptoms of depression, anxiety, or stress, quality of life (QOL), energy and fatigue in adults. Methods: This analysis used data pooled from two studies: Synergy and Refresh. Synergy: Physically inactive adults (18¿65 years) who reported poor sleep quality were recruited for a two-arm Randomised Controlled Trial (RCT) (Physical Activity and Sleep Health (PAS; n = 80), or Wait-list Control (CON; n = 80) groups). Refresh: Physically inactive adults (40¿65 years) who reported poor sleep quality were recruited for a three-arm RCT (PAS (n = 110), Sleep Health-Only (SO; n = 110) or CON (n = 55) groups). The SO group was omitted from this study. The PAS groups received a pedometer, and accessed a smartphone/tablet ¿app¿ using behaviour change strategies (e.g., self-monitoring, goal setting, action planning), with additional email/SMS support. The ASI score comprised self-reported moderate-to-vigorous-intensity physical activity, resistance training, sitting time, sleep duration, efficiency, quality and timing. Outcomes were assessed using DASS-21 (depression, anxiety, stress), SF-12 (QOL-physical, QOL-mental) and SF-36 (Energy & Fatigue). Assessments were conducted at baseline, 3 months (primary time-point), and 6 months. Mediation effects were examined using Structural Equation Modelling and the product of coefficients approach (AB), with significance set at 0.05. Results: At 3 months there were no direct intervention effects on mental health, QOL or energy and fatigue (all p > 0.05), and the intervention significantly improved the ASI (all p < 0.05). A more favourable ASI score was associated with improved symptoms of depression, anxiety, stress, QOL-mental and of energy and fatigue (all p < 0.05). The intervention effects on symptoms of depression ([AB; 95%CI] -0.31; - 0.60,-0.11), anxiety (- 0.11; - 0.27,-0.01), stress (- 0.37; - 0.65,-0.174), QOL-mental (0.53; 0.22, 1.01) and ratings of energy and fatigue (0.85; 0.33, 1.63) were mediated by ASI. At 6 months the magnitude of association was larger although the overall pattern of results remained similar. Conclusions: Improvements in the overall physical activity and sleep behaviours of adults partially mediated the intervention effects on mental health and quality of life outcomes. This highlights the potential benefit of improving the overall pattern of physical activity and sleep on these outcomes. Trial registration: Australian New Zealand Clinical Trial Registry: ACTRN12617000680369; ACTRN12617000376347. Universal Trial number: U1111¿1194-2680; U1111¿1186-6588. Human Research Ethics Committee Approval: H-2016-0267; H-2016¿0181.

Background Cardiorespiratory fitness (CRF) is an important marker of current and future health status. The primary aim of our study was to evaluate the impact of a time-efficient school-based intervention on older adolescents' CRF. Methods Two-arm cluster randomised controlled trial conducted in two cohorts (February 2018 to February 2019 and February 2019 to February 2020) in New South Wales, Australia. Participants (N=670, 44.6% women, 16.0±0.43 years) from 20 secondary schools: 10 schools (337 participants) were randomised to the Burn 2 Learn (B2L) intervention and 10 schools (333 participants) to the control. Teachers in schools allocated to the B2L intervention were provided with training, resources, and support to facilitate the delivery of high-intensity interval training (HIIT) activity breaks during curriculum time. Teachers and students in the control group continued their usual practice. The primary outcome was CRF (20 m multi-stage fitness test). Secondary outcomes were muscular fitness, physical activity, hair cortisol concentrations, mental health and cognitive function. Outcomes were assessed at baseline, 6 months (primary end-point) and 12 months. Effects were estimated using mixed models accounting for clustering. Results We observed a group-by-time effect for CRF (difference=4.1 laps, 95% CI 1.8 to 6.4) at the primary end-point (6 months), but not at 12 months. At 6 months, group-by-time effects were found for muscular fitness, steps during school hours and cortisol. Conclusions Implementing HIIT during curricular time improved adolescents' CRF and several secondary outcomes. Our findings suggest B2L is unlikely to be an effective approach unless teachers embed sessions within the school day. Trial registration number Australian New Zealand Clinical Trials Registry (ACTRN12618000293268).

Objective A systematic review on meatal cleaning prior to urinary catheterisation and post catheterisation and reduces the risk catheter-associated urinary tract infections (CAUTIs) and bacteriuria was published in 2017, with further studies undertaken since this time. The objective of this paper is to present an updated systematic review on the effectiveness of antiseptic cleaning of the meatal area for the prevention of CAUTIs and bacteriuria in patients who receive a urinary catheter. Design Systematic review. Data sources Electronic databases Cochrane Library, PubMed, Embase, The Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medline and Academic Search Complete were searched from 1 January 2016 and 29 February 2020. Eligibility criteria Randomised controlled trials (RCTs) and quasi-experimental studies evaluating the use of antiseptic, antibacterial or non-medicated agents for cleaning the meatal, periurethral or perineal areas before indwelling catheter insertion or intermittent catheterisation or during routine meatal care. Data extraction and synthesis Data were extracted using the Cochrane Collaboration's data collection form for RCTs and non-RCTs. Data were extracted by one researcher and then checked for accuracy by a second researcher. Results A total of 18 studies were included. Some potential benefit of using antiseptics, compared with non-antiseptics for meatal cleaning to prevent bacteriuria and or CAUTI was identified (OR 0.84, 95% CI 0.69 to 1.02; p=0.071). Antiseptics (chlorhexidine or povidine-iodine) may be of value for meatal cleaning on the incidence of CAUTI, compared with comparator agents (saline, soap or antimicrobial cloths) (OR=0.65, 95% CI 0.42 to 0.99; p=0.047). Conclusion There is emerging evidence of the role of some specific antiseptics (chlorhexidine) prior to urinary catheterisation, in reducing CAUTIs, and some potential benefit to the role of antiseptics more generally in reducing bacteriuria. PROSPERO registration number CRD42015023741.

Background: Adverse childhood experiences have been linked to poor health and adverse health behavior in adulthood. Objective: This study aimed to estimate the prevalence of adverse childhood experiences among young Australian women (aged 20¿25) and examine associations between adverse childhood experiences and adult health behaviors and physical and mental health. Participants and Settings: Data were from the 1989-95 cohort of the Australian Longitudinal Study on Women's Health, who completed the Adverse Childhood Experiences Scale at Survey 3 in 2015 (N = 8609). Methods: Outcomes included: self-rated health, sexual health, psychological distress, depression, anxiety, suicide ideation, self-harm, substance abuse (drinking, smoking, illicit drugs), severe obesity, and exercise. Prevalence of childhood adversities were presented, with the association between childhood adversity and outcomes evaluated using log-binomial multivariable regressions (99% CI). Results: While 59% of women reported experiencing at least one childhood adversity, 10% of participants reported adverse childhood experiences across four or more categories, indicating a significant burden of risk for young Australian women. Women reporting four or more categories had higher rates of poor physical health (adjPR = 1.79, 99% CI = 1.51¿2.12), sexually transmitted infections (adjPR = 1.36, 99% CI = 1.11¿1.67), and poor mental health (adjPR = 2.78, 99% CI = 2.34¿3.32), and increased rates of severe obesity (adjPR = 2.14, 99% CI = 1.61¿2.86) and smoking (adjPR = 2.23, 99% CI = 1.89¿2.64). Conclusion: Using nationally representative data, this study shows adverse childhood experiences directly impact physical and mental health, and health behaviors in adulthood among young Australian women. The management of health and wellbeing in adulthood should look beyond the contemporaneous factors, incorporating a focus on how childhood adversity may negatively influence health behavior, health and wellbeing in later life.

Background: Interrupting prolonged sitting can attenuate postprandial glucose responses in overweight adults. The dose¿response effect in stroke survivors is unknown. The authors investigated the effects of interrupting 8 hours of prolonged sitting with increasingly frequent bouts of light-intensity standing-based exercises on the postprandial glucose response in stroke survivors. Methods: Within-participant, laboratory-based, dose-escalation trial. Participants completed three 8-hour conditions: prolonged sitting and 2 experimental conditions. Experimental conditions involved light-intensity standing-based exercises of increasing frequency (2 × 5 min to 6 × 5 min bouts). Postprandial glucose is reported. Results: Twenty-nine stroke survivors (aged 66 y) participated. Interrupting 8 hours of prolonged sitting with light-intensity standing-based exercises every 90 minutes significantly decreased postprandial glucose (positive incremental area under the curve; -1.1 mmol/L·7 h; 95% confidence interval, -2.0 to -0.1). In the morning (08:00¿11:00), postprandial glucose decreased during the 4 × 5 minutes and 6 × 5 minutes conditions (positive incremental area under the curve; -0.8 mmol/L·3 h; 95% confidence interval, -1.3 to -0.3 and -0.8 mmol/L·3 h; 95% confidence interval, -1.5 to -0.2, respectively) compared with prolonged sitting. Conclusion: Interrupting 8 hours of prolonged sitting at least every 90 minutes with light-intensity standing-based exercises attenuates postprandial glucose in stroke survivors. During the morning, postprandial glucose is attenuated when sitting is interrupted every 60 and 90 minutes.

Objectives Dizziness is a common and challenging clinical presentation in general practice. Failure to determine specific aetiologies can lead to significant morbidity and mortality. We aimed to establish frequency and associations of general practitioner (GP) trainees' (registrars') specific vertigo provisional diagnoses and their non-specific symptomatic problem formulations. Design A cross-sectional analysis of Registrar Clinical Encounters in Training (ReCEnT) cohort study data between 2010 and 2018. ReCEnT is an ongoing, prospective cohort study of registrars in general practice training in Australia. Data collection occurs once every 6 months midtraining term (for three terms) and entails recording details of 60 consecutive clinical consultations on hardcopy case report forms. The outcome factor was whether dizziness-related or vertigo-related presentations resulted in a specific vertigo provisional diagnosis versus a non-specific symptomatic problem formulation. Associations with patient, practice, registrar and consultation independent variables were assessed by univariate and multivariable logistic regression. Setting Australian general practice training programme. The training is regionalised and delivered by regional training providers (RTPs) (2010-2015) and regional training organisations (RTOs) (2016-2018) across Australia (from five states and one territory). Participants All general practice registrars enrolled with participating RTPs or RTOs undertaking GP training terms. Results 2333 registrars (96% response rate) recorded 1734 new problems related to dizziness or vertigo. Of these, 546 (31.5%) involved a specific vertigo diagnosis and 1188 (68.5%) a non-specific symptom diagnosis. Variables associated with a non-specific symptom diagnosis on multivariable analysis were lower socioeconomic status of the practice location (OR 0.94 for each decile of disadvantage, 95% CIs 0.90 to 0.98) and longer consultation duration (OR 1.02, 95% CIs 1.00 to 1.04). A specific vertigo diagnosis was associated with performing a procedure (OR 0.52, 95% CIs 0.27 to 1.00), with some evidence for seeking information from a supervisor being associated with a non-specific symptom diagnosis (OR 1.39, 95% CIs 0.92 to 2.09; p=0.12). Conclusions Australian GP registrars see dizzy patients as frequently as established GPs. The frequency and associations of a non-specific diagnosis are consistent with the acknowledged difficulty of making diagnoses in vertigo/dizziness presentations. Continuing emphasis on this area in GP training and encouragement of supervisor involvement in registrars' diagnostic processes is indicated.

Introduction: Little is known about the joint effects of physical activity and sleep difficulties on hypertension. The aim of this study was to examine the joint associations of physical activity and sleep difficulties with the incidence of hypertension in mid-aged women. Study Design: Prospective cohort study. Main Outcome Measures: Mid-aged participants (n = 5,300) in the Australian Longitudinal Study on Women's Health completed four triennial surveys starting in 2004, when they had a mean age of 55 years. The presence of hypertension, physical activity and the number of sleep difficulties (range 0-4) were reported at each survey. Total MET.min/week of physical activity was assessed, and dichotomised as inactive (<500 MET.min/wk) or active (=500 MET.min/wk). Joint categories of physical activity and sleep difficulties were created using six mutually exclusive groups. Associations of joint physical activity and sleep difficulty groups with incident hypertension were examined via discrete-time survival analysis using logit-hazard models. Results: There were 1,175 cases of incident hypertension (22.2%). Compared with the Active and No Difficulties group, women in the Inactive and 1 Difficulty (Odds Ratio (95% confidence interval) (1.31 (1.06, 1.62)) and Inactive and 2-4 Difficulties (1.44 (1.16, 1.78)) groups were more likely to develop hypertension. Sleep difficulties were not associated with hypertension among active women. Conclusions: Mid-aged inactive women with sleep difficulties were more likely to develop hypertension. Physical activity appeared to protect against the increased risk of hypertension in women with sleeping difficulties.

Objective: To summarise the evidence regarding the impact of individualised music listening on persons with dementia. Methods: Six electronic databases (CINAHL, Medline, ProQuest, PsycINFO, Music Periodicals and Cochrane) were searched up to July 2018 for randomised controlled trials (RCTs) evaluating the efficacy of individualised music listening compared to other music and non¿music-based interventions. Results: Four studies were included. Results showed evidence of a positive impact of individualised music listening on behavioural and psychological symptoms of dementia (BPSDs) including agitation, anxiety and depression and physiological outcomes. Evidence for other outcomes such as cognitive function and quality of life was limited. Conclusions: The limited evidence suggests individualised music listening has comparable efficacy to more resource-intensive interventions. However, there was a small number of RCTs and some outcomes were evaluated by a single study. This limits the conclusions drawn, warranting more RCTs evaluating other outcomes beyond the BPSDs.

Background Poor sleep health is highly prevalent. Physical activity is known to improve sleep quality but not specifically targeted in sleep interventions. Purpose To compare the efficacy of a combined physical activity and sleep intervention with a sleep-only intervention and a wait-list control, for improving sleep quality in middle-aged adults without a diagnosed sleep disorder. Methods Three-arm randomized controlled trial (Physical Activity and Sleep Health (PAS), Sleep Health Only (SO), Wait-list Control (CON) groups; 3-month primary time-point, 6-month follow-up) of 275 (PAS = 110, SO = 110, CON = 55) inactive adults (40¿65 years) reporting poor sleep quality. The main intervention component was a smartphone/tablet ¿app¿ to aid goal setting and self-monitoring physical activity and/or sleep hygiene behaviors (including stress management), and a pedometer for PAS group. Primary outcome was Pittsburgh Sleep Quality Index (PSQI) global score. Secondary outcomes included several self-reported physical activity measures and PSQI subcomponents. Group differences were examined stepwise, first between pooled intervention (PI = PAS + SO) and CON groups, then between PAS and SO groups. Results Compared with CON, PI groups significantly improved PSQI global and subcomponents scores at 3 and 6 months. There were no differences in sleep quality between PAS and SO groups. The PAS group reported significantly less daily sitting time at 3 months and was significantly more likely to report =2 days/week resistance training and meeting physical activity guidelines at 6 months than the SO group. Conclusions PIs had statistically significantly improved sleep quality among middle-aged adults with poor sleep quality without a diagnosed sleep disorder. The adjunctive physical activity intervention did not additionally improve sleep quality.

Background: Emerging evidence links a poor diet with mental ill-health although the direction of this association is unclear. The aim was to examine the bidirectional prospective relationships between core (and non-core food consumption, and symptoms of depression. Methods: Depressive symptoms (Mental Health Index-5, MHI-5), current/prior depression and consumption of core (recommended food groups) and non-core (discretionary) foods were assessed in the population-based 2013 and 2017 Household Income and Labour Dynamics in Australia cohort study. Three cross-lagged linear models assessed associations between all three baseline variables in 2013, alternating 2017 variables as outcomes. Results: In the population (n = 10,003; 48.3% women; 48.5[15.7] years), core food score in 2013 was associated with MHI-5 (ß:0.102, 95%CI: 0.010,0.193) in 2017, while the non-core food score was not (ß:-0.030, 95%CI:-0.099,0.160). Depressive symptom score in 2013 was not associated with either food score in 2017. Current/prior diagnosis of depression in 2013 was associated with core (ß:-0.198, 95%CI:-0.329,-0.067) but not non-core (ß:-0.036, 95%CI: -0.151,0.080) food score in 2017. Limitations: Results may not be generalizable to the whole population due to some selection bias, self-report depression diagnosis may have led to misclassification of previous mental illness, and core and non-core food scores are not validated measures of diet quality. Conclusions: There is a prospective association between core food consumption and depressive symptoms. This association is of small magnitude and we cannot discount insufficient core food consumption reflecting an effect of prior mental illness. Our results suggest that, for depression, public health focus should be on improving core food intake.

Objectives: Supporting healthy ageing is a key priority worldwide. Physical activity, diet quality and sleep are all associated with health outcomes, but few studies have explored their independent associations with all-cause mortality in an older population in the same model. The study aim was to examine associations between step-count, self-reported diet quality, restless sleep, and all-cause mortality in adults aged 55¿85 years. Design: A prospective cohort study of adults in Newcastle, New South Wales, Australia. Method: Data were from 1697 participants (49.3% women; baseline mean age 65.4 ± 7.1 years). Daily steps (measured by pedometer), diet quality (from a modified Australian Recommended Food Score), and frequency of restless sleep (by self-report) were assessed in relation to all-cause mortality using Cox proportional hazard regression with adjustment for sex, age, household income and smoking. Baseline data were collected between January 2005 and April 2008, and last follow-up was in March 2017 (median follow-up 9.6 years). Results: Higher step count (HR: 0.93, 95%CI: 0.88¿0.98 per 1000-step increment) and higher diet quality (HR: 0.86, 95%CI: 0.74¿0.99 per 8-point increment in diet quality score) were associated with reduced mortality risk. Restless sleep for =3 nights/week was not associated with mortality risk (HR: 1.03, 95%CI: 0.78¿1.39). Sensitivity analyses, adjusting for chronic disease and excluding deaths <1 year after baseline, did not change these estimates. Conclusions: Increased daily steps and consumption of a greater variety of nutrient-dense foods every week would result in substantial health benefits for older people. Future research should include a greater variety of sleep measures.

Purpose: To explore whether there was a difference in objectively measured physical activity and study participation between people who received their preferred study group allocation (matched) and those who did not receive their preferred study group (mismatched). Design: Secondary data from the NewCOACH randomized controlled trial. Setting: Insufficiently active patients in the primary care settings in Sydney and Newcastle, Australia. Participants: One hundred seventy-two adults aged 20 to 81 years. Intervention: Participants indicated their intervention preference at baseline for (1) five face-to-face visits with an exercise specialist, (2) one face-to-face visit and 4 telephone follow-ups with an exercise specialist, (3) written material, or (4) slight-to-no preference. Participants were then allocated to an intervention group and categorized as either ¿matched¿ or ¿mismatched¿ based on their indications. Participants who reported a slight-to-no preference was categorized as ¿matched.¿ Measures: Daily step count as measured by pedometers and study participation. Analysis: Mean differences between groups in daily step count at 3 and 12 months (multiple linear regression models) and study participation at baseline, 3 months, and 12 months (¿2 tests). Results: Preference for an intervention group prior to randomization did not significantly (all P¿s >.05 using 95% confidence interval) impact step counts (differences of <600 steps/day between groups) or study participation. Conclusion: Future research should continue to address whether the strength of preferences influence study outcome and participation and whether the study preferences change over time.

Background: General practitioners play an important role in diagnosis and ongoing management of pregnancies. Some GP registrars entering GP training may have had no post-graduate experience in obstetrics and gynaecology. GP registrars¿ involvement in antenatal care is under-researched. Aims: This study aimed to determine the prevalence and associations of Australian GP registrars¿ clinical consultations involving antenatal care. Materials and Methods: A cross-sectional analysis from the Registrar Clinical Encounters in Training (ReCEnT) cohort study. GP registrars record details of 60 consecutive consultations during each of three six-month training terms. Associations of managing pregnancy-related problems (compared to all other problems) were analysed using univariate and multivariable logistic regression. Independent variables included registrar, practice, patient, consultation and educational factors. Results: Antenatal care comprised 3277 (1.1%) of registrar problems/diagnoses. Consultations involving pregnancy-related problems were significantly associated with registrars being female, in term three, younger, and having post-graduate qualifications in obstetrics/gynaecology. Patients were significantly more likely to be from a non-English speaking background. Pregnancy-related problems/diagnoses were more likely to be seen in lower socioeconomic areas. Consultation factors significantly associated with a pregnancy-related problem/diagnosis included ordering imaging, ordering pathology, arranging referrals, and a longer duration of consultation. Registrars were less likely to prescribe medication or generate learning goals. Conclusions: GP registrars see fewer antenatal problems compared to established GPs. Male registrars, especially, have significantly less exposure to antenatal care, suggesting potential limitation of opportunity to gain skills and experience in antenatal care.

The impact of pre-pregnancy obesity and maternal diet quality on the use of healthcare resources during the perinatal period is underexplored. We assessed the effects of body mass index (BMI) and diet quality on the use of healthcare resources, to identify whether maternal diet quality may be effectively targeted to reduce antenatal heath care resource use, independent of women¿s BMI. Cross-sectional data and inpatient medical records were gathered from pregnant women attending publicly funded antenatal outpatient clinics in Newcastle, Australia. Dietary intake was self-reported, using the Australian Eating Survey (AES) food frequency questionnaire, and diet quality was quantified from the AES subscale, the Australian Recommended Food Score (ARFS). Mean pre-pregnancy BMI was 28.8 kg/m2 (range: 14.7 kg/m2¿64 kg/m2). Mean ARFS was 28.8 (SD = 13.1). Higher BMI was associated with increased odds of caesarean delivery; women in obese class II (35.0¿39.9 kg/m2) had significantly higher odds of caesarean delivery compared to women of normal weight, (OR = 2.13, 95% CI 1.03 to 4.39; p = 0.04). Using Australian Refined Diagnosis Related Group categories for birth admission, the average cost of the birth admission was $1348 more for women in the obese class II, and $1952 more for women in the obese class III, compared to women in a normal BMI weight class. Higher ARFS was associated with a small statistically significant reduction in maternal length of stay (RR = 1.24, 95% CI 1.00, 1.54; p = 0.05). There was no evidence of an association between ARFS and mode of delivery or ¿midwifery-in-the-home-visits¿.

Diet quality, physical activity, alcohol use, smoking, sleep and sitting-time are behaviors known to influence health. The aims of this study were to identify how these behaviors co-occur to form distinct health-behavior patterns, and to investigate the relationship between these patterns, and mental and self-rated health. Members of the Australian 10,000 Steps project were invited to participate in an online survey in November¿December 2011. The participants self-reported demographic and behavioral characteristics (fruit and vegetable intake, fast food, soft drink and alcohol consumption, smoking, physical activity, sitting-time and sleep), frequency of mental distress and self-rated health. Latent Class Analysis was used to identify health-behavior patterns. Latent class regression was used to examine relationships between behavior patterns, mental and self-rated health, and socio-demographic and economic factors. Data were analyzed in October 2017. Complete datasets were obtained from 10,638 participants. Four latent classes were identified, characterized by ¿Low-Risk Behavior¿, ¿Poor Sleep, Low-Risk Daytime Behavior¿, 'sound Sleep, High-Risk Daytime Behavior¿ and ¿High-Risk Behavior¿. The latter two classes, both characterized by high-risk daytime behaviors, were associated with poor self-rated health. Participants in classes with high-risk daytime behaviors were more likely to be younger, non-partnered, non-university educated, from lower income households and work longer hours. Classes characterized by poor sleep quality were associated with higher frequency of mental distress. Findings suggest that experiencing poor sleep is partly independent of daytime behaviors, demographic and socioeconomic factors, but has a strong association with mental health.

Patients with mental health conditions commonly present in General Practice. Mental health curricula are broad. We do not know that trainees are exposed to the learning they require. This study aimed to establish the prevalence, characteristics and associations of GP trainees¿ management of mental health problems. This paper presents a cross-sectional analysis of the Registrar Clinical Encounters in Training (ReCEnT) study, an ongoing multisite cohort study of Australian GP trainees (registrars) documenting their clinical experiences over 60 consecutive consultations. Univariate and multivariable logistic regression analyses were conducted with outcome of the problem/diagnosis being a mental health condition. 1659 trainees provided data on 218,325 consultations and 340,453 problems/diagnoses. Mental health conditions were associated with patients being male, of Aboriginal or Torres Strait Islander or English-speaking background. Trainee characteristics were being more senior and having trained in Australia. Practice characteristics included being in low socioeconomic areas. Trainees sought less help for mental health concerns than they did for other problems. While early-career GPs see a broad range of mental health conditions, they may benefit from training to manage patients from cross-cultural contexts. They may also need support to generate appropriate learning goals and seek assistance if they are to continue to deepen competence.

Introduction: E-cigarette use is controversial worldwide. The majority of previous studies on e-cigarette use were not gender specific. This study aimed to identify the predictors of e-cigarette use among young Australian women. Methods: This study used cross-sectional data from the 1989¿1995 cohort of the Australian Longitudinal Study on Women's Health. In 2015, study participants (N=8,915) aged 19¿26 years completed an online survey. Multivariable logistic regression was used to identify predictors of e-cigarette use. Data were analyzed in 2018. Results: The prevalence of ever and past-year e-cigarette use among young Australian women was 11.1% and 6.4%, respectively. More than a quarter of past-year and ever e-cigarette users were never cigarette smokers. Use of e-cigarettes in the past year was associated with younger age (AOR per year increase=0.87, 95% CI=0.82, 0.93); financial difficulty (AOR=0.68, 95% CI=0.54, 0.87); being an ex-smoker (AOR=5.05, 95% CI=3.64, 7.01) or current cigarette smoker (AOR=10.01, 95% CI=7.77, 12.89); drinking at a level of lifetime risk of harm from alcohol-related disease or injury (AOR=1.23, 95% CI=1.01, 1.53). Ever e-cigarette use showed similar associations and was also associated with rural residence (AOR=0.74, 95% CI=0.60, 0.91) and intimate partner violence (AOR=1.44, 95% CI=1.17, 1.76). Conclusions: The high prevalence of e-cigarette use among never cigarette smokers has significant public health implications. Interventions to curb the use of e-cigarettes among young Australian women should focus on risk factors, such as early age, cigarette smoking, alcohol use, and intimate partner violence.

ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.

BACKGROUND AND OBJECTIVES: Acne is a common chronic condition. The aim of this study was to establish the frequency and associations of consultations for acne by early-career general practitioners (general practice registrars). METHOD: The study was a cross-sectional analysis of data from the Registrar Clinical Encounters in Training study. RESULTS: During 2010-18, 2234 registrars contributed data for 289,594 consultations and 453,344 problems/diagnoses. Acne comprised 0.38% (95% confidence interval [CI]: 0.36, 0.40) of all problems/diagnoses. Nine per cent of patients were new to the practice (odds ratio [OR] 1.82; 95% CI: 1.62, 2.05) and 61% were existing patients of the practice but new to the registrar (OR 1.78; 95% CI: 1.46, 2.18). There was a lower frequency of acne presentations by Aboriginal and Torres Strait Islander patients (OR 0.29; 95% CI: 0.14, 0.58) and by patients in regional/remote/very remote areas (OR 0.75; 95% CI: 0.58, 0.95). DISCUSSION: The majority of the patients had an existing diagnosis of acne. That Aboriginal and Torres Strait Islander patients and patients in rural/remote areas present less frequently with acne requires further study.

Background: The obesity-cataract association has been inconsistently reported. The fat mass and obesity-related (FTO) single-nucleotide polymorphism (SNP) rs9939609 is a major SNP associated with obesity and has been used as an instrumental variable for obesity in a Mendelian randomization (MR) approach. An interaction between the FTO SNP and macronutrient intake for obesity was suggested previously. Objective: The aim of this study was to assess the associations between obesity and cataract, using FTO SNP rs9939609 as an instrumental variable in an MR approach, and explore interactions of this SNP with macronutrient intake in relation to risk of cataract in a population-based cohort. Methods: The Blue Mountains Eye Study (BMES) is a longitudinal population-based study of common eye disease. Of 3654 baseline participants of the BMES (1992-1994), 2334 (75.8% of survivors) and 1952 (76.7% of survivors) were followed 5 and 10 y later. During the 5-y follow-up, 1174 new participants were examined. Cumulative cataract was defined as the presence of cortical, nuclear, or posterior subcapsular (PSC) cataract at any visit, following the Wisconsin Cataract Grading System. Imputed dosage of the FTO SNP rs9939609 was used. Quintiles of macronutrient intake (carbohydrates, protein, fats) were derived from an FFQ. ORs and 95% CIs were estimated using multivariable-adjusted logistic regression models. Results: After multivariable adjustment, there were no associations between BMI and any cataract types in MR models using rs9939609 as an instrumental variable. However, an interaction between rs9939609 and protein intake for PSC cataract risk was suggested (P = 0.03). In analyses stratified by quintiles of protein intake, each minor allele of rs9939609 was associated with increased odds of PSC (OR: 2.14; 95% CI: 1.27, 3.60) in the lowest quintile subgroup only. Conclusions: Obesity was not causally associated with age-related cataract. However, among persons in the lowest quintile of protein intake, obesity may be associated with PSC cataract.

Objective: Limited international evidence suggests general practice registrars' emergency department (ED) referral rates exceed those of established general practitioners (GPs). The aim of the present study was to fill an evidence gap by establishing the prevalence, nature and associations of Australian GP registrar ED referrals. Methods: A cross-sectional analysis was performed of the Registrar Clinical Encounters in Training (ReCEnT) cohort study of GP registrars' consultation experiences, between 2010 and 2015. The outcome factor in logistic regression analysis was referral to an ED. Independent variables included patient-level, registrar-level, practice-level and consultation-level factors. Results: In all, 1161 GP registrars (response rate 95.5%) contributed data from 166 966 consultations, comprising 258 381 individual problems. Based on responses, 0.5% of problems resulted in ED referral, of which nearly 25% comprised chest pain, abdominal pain and fractures. Significant (P < 0.05) associations of ED referral included patient age <15 and >34 years, the patient being new to the registrar, one particular regional training provider (RTP), in-consultation information or assistance being sought and learning goals being generated. Outer regional-, remote-or very remote-based registrars made significantly fewer ED referrals than more urban registrars. Of the problems referred to the ED, 45.5% involved the seeking of in-consultation information or assistance, predominantly from supervisors. Conclusions: Registrars' ED referral rates are nearly twice those of established GPs. The findings of the present study suggest acute illnesses or injuries present registrars with clinical challenges and real learning opportunities, and highlight the importance of continuity of care, even for acute presentations. What is known about the topic?: A GP's decision concerning continued community-versus hospital-based management of acute presentations demands careful consideration of a suite of factors, including implications for patient care and resource expenditure. General practice vocational training is a critical period for the development of GP registrars' long-term patterns of practice. Although limited international evidence suggests GP registrars and early career GPs refer patients to the ED at a higher rate than their more experienced peers, these studies involved small subject numbers and did not investigate associations of registrars making an ED referral. Relevant Australian studies focusing on GP registrars' ED referral patterns are lacking. What does this paper add?: The present ongoing cohort study is the first to establish the patterns of ED referrals made by Australian GP registrars, encompassing five general practice RTPs across five states, with participating registrars practising in urban, rural, remote and very remote practices. Several significant associations were found with GP registrars making ED referrals, including patient age, continuity of care, the registrar's RTP, assistance sought by the registrar and rurality of the registrar's practice. What are the implications for practitioners?: The higher likelihood of GP registrars seeing acute presentations than their more established practice colleagues, coupled with a demonstrated association of registrars seeking in-consultation assistance for such presentations, highlights the importance of GP supervisor accessibility in facilitating ED referral appropriateness and in the development of registrars' safe clinical practice.

Importance: Genome-wide association studies (GWASs) in European populations have identified more than 100 schizophrenia-associated loci. A schizophrenia GWAS in a unique Indian population offers novel findings. Objective: To discover and functionally evaluate genetic loci for schizophrenia in a GWAS of a unique Indian population. Design, Setting, and Participants: This GWAS included a sample of affected individuals, family members, and unrelated cases and controls. Three thousand ninety-two individuals were recruited and diagnostically ascertained via medical records, hospitals, clinics, and clinical networks in Chennai and surrounding regions. Affected participants fulfilled DSM-IV diagnostic criteria for schizophrenia. Unrelated control participants had no personal or family history of psychotic disorder. Recruitment, genotyping, and analysis occurred in consecutive phases beginning January 1, 2001. Recruitment was completed on February 28, 2018, and genotyping and analysis are ongoing. Main Outcomes and Measures: Associations of single-nucleotide polymorphisms and gene expression with schizophrenia. Results: The study population included 1321 participants with schizophrenia, 885 family controls, and 886 unrelated controls. Among participants with schizophrenia, mean (SD) age was 39.1 (11.4) years, and 52.7% were male. This sample demonstrated uniform ethnicity, a degree of inbreeding, and negligible rates of substance abuse. A novel genome-wide significant association was observed between schizophrenia and a chromosome 8q24.3 locus (rs10866912, allele A; odds ratio [OR], 1.27 [95% CI, 1.17-1.38]; P = 4.35 × 10-8) that attracted support in the schizophrenia Psychiatric Genomics Consortium 2 data (rs10866912, allele A; OR, 1.04 [95% CI, 1.02-1.06]; P = 7.56 × 10-4). This locus has undergone natural selection, with the risk allele A declining in frequency from India (approximately 72%) to Europe (approximately 43%). rs10866912 directly modifies the abundance of the nicotinate phosphoribosyltransferase gene (NAPRT1) transcript in brain cortex (normalized effect size, 0.79; 95% CI, 0.6-1.0; P = 5.8 × 10-13). NAPRT1 encodes a key enzyme for niacin metabolism. In Indian lymphoblastoid cell lines, (risk) allele A of rs10866912 was associated with NAPRT1 downregulation (AA: 0.74, n = 21; CC: 1.56, n = 17; P =.004). Preliminary zebrafish data further suggest that partial loss of function of NAPRT1 leads to abnormal brain development. Conclusions and Relevance: Bioinformatic analyses and cellular and zebrafish gene expression studies implicate NAPRT1 as a novel susceptibility gene. Given this gene's role in niacin metabolism and the evidence for niacin deficiency provoking schizophrenialike symptoms in neuropsychiatric diseases such as pellagra and Hartnup disease, these results suggest that the rs10866912 genotype and niacin status may have implications for schizophrenia susceptibility and treatment..

Background: Low birthweight is more common in infants of indigenous (Aboriginal and/or Torres Strait Islander) than of White Australian mothers. Controversy exists on whether fetal growth is normally different in different populations. Objective: We sought to determine the relationships of birthweight, birthweight percentiles, and smoking with perinatal outcomes in indigenous vs nonindigenous infants to determine whether the White infant growth charts could be applied to indigenous infants. Study Design: Data were analyzed for indigenous status, maternal age and smoking, and perinatal outcomes in 45,754 singleton liveborn infants of at least 20 weeks gestation or 400 g birthweight delivered in New South Wales, Australia, between June 2010 and July 2015. Results: Indigenous infants (n=6372; 14%) had a mean birthweight 67 g lower than nonindigenous infants (P<.0001; with adjustment for infant sex and maternal body mass index). Indigenous mean birthweight percentile was 4.2 units lower (P<.0001). Adjustment for maternal age, smoking, body mass index, and infant sex reduced the difference in birthweight/percentiles to nonsignificance (12 g; P=.07). Conclusion: Disparities exist between indigenous and non-indigenous Australian infants for birthweight, birthweight percentile, and adverse outcome rates. Adjustment for smoking and maternal age removed any significant difference in birthweights and birthweight percentiles for indigenous infants. Our data indicate that birthweight percentiles should not be adjusted for indigenous ethnicity because this normalizes disadvantage; because White and indigenous Australians have diverged for approximately 50,000 years, it is likely that the same conclusions apply to other ethnic groups. The disparities in birthweight percentiles that are associated with smoking will likely perpetuate indigenous disadvantage into the future because low birthweight is linked to the development of chronic noncommunicable disease and poorer educational attainment; similar problems may affect other indigenous populations.

Objectives: We examined the development of disease and disability in a large cohort of older women, the extent to which these conditions exempt them from being classified as successful agers and different trajectories of disease, disability and longevity across women's later life. Methods: We used survey data from 12,432 participants of the 1921-26 birth cohort of the Australian Longitudinal Study of Women's Health from 1996 (age 70-75) to 2016 (age 90-95). Repeated measures latent class analysis (RMLCA) identified trajectories of the development of disease with or without disability and according to longevity. Bivariate analyses and multivariable multinomial logistic regression models were used to examine the association between participants' baseline characteristics and membership of the latent classes. Results: Over one-third of women could be considered to be successful agers when in their early 70s, few women could still be classified in this category throughout their later life or by the end of the study when they were in their 90s (~1%). RMLCA identified six trajectory groups including managed agers long survivors (9.0%) with disease but little disability, usual agers long survivors (14.9%) with disease and disability, usual agers (26.6%) and early mortality (25.7%). A small group of women having no major disease or disability well into their 80s were identified as successful agers (5.5%). A final group, missing surveys (18.3%), had a high rate of non-death attrition. Groups were differentiated by a number of social and health factors including marital status, education, smoking, body mass index, exercise and social support. Conclusions: The study shows different trajectories of disease and disability in a cohort of ageing women, over time and through to very old ages. While some women continue into very old age with no disease or disability, many more women live long with disease but little disability, remaining independent beyond their capacity to be classified as successful agers.

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated (|r^ g| ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.

Introduction: Having a low level of physical activity is an established risk factor for stroke, but little is known about the importance of common sedentary behavior¿television viewing¿to stroke risk. Methods: We conducted a retrospective analysis of data that were collected as part of the longitudinal Australian Diabetes, Obesity, and Lifestyle study. Stroke events reported during the study (between baseline assessment in 1999-2000 and April 2011) were confirmed using adjudication based on medical records. Baseline data on minutes per week spent watching television were used as the exposure variable. Other variables were collected in assessments at wave 2 (2004-05) and wave 3 (2011-2012). Univariable and multivariable logistic regression analyses were performed. Results: Among the full Australian Diabetes, Obesity, and Lifestyle study population (n = 11,247), there were 153 participants with confirmed stroke during the study period, and 9207 participants with no stroke in this period. Participants who went on to have their first stroke during the study had significantly higher levels of TV viewing time at baseline than those who did not have a stroke (P =.001). This association was not present (P =.83), however, when age and sex were included in the regression model. Conclusion: In the Australian Diabetes, Obesity, and Lifestyle study dataset, there was no evidence that more TV viewing is independently associated with risk of stroke, although analyses may have been underpowered.

Background: In Australia, more than 50% of end-stage kidney disease patients start haemodialysis treatment with a central venous catheter (CVC). While there are benefits of CVC access, they are associated with a high risk of bacteraemia infection. National guidelines for prevention of catheter-related infections advocate the importance of hand hygiene and asepsis practices, and for this reason, many dialysis units have regular auditing on hand hygiene and aseptic technique. Aim: To report the relationship between hygiene audit results and infection rates in our facility. Method: A hygiene audit tool was developed with 17 hygiene measures, categorised into three domains: environment, aseptic technique, and dressing care. This tool was used to observe nursing staff's hand hygiene compliance and aseptic technique during CVC care across five regional and remote units. Audit results were collected from 2011 to 2015. Results: A total of 350 audits were analysed, and the overall hygiene compliance was consistently high (85-99%). The relationship between mean hygiene score and infection rates was negative and the association was non-significant (p=0.7). Conclusion: The overall infection rates have decreased in our facility, by an average of 76% across sites. The decrease in infection was correlated to interventions such as minimising catheter utilisation, implementation of antimicrobial dressings and streamlining protocols but not hygiene audit results. Good hygiene is fundamental in the care of a CVC; however, whilst all facilities should strive for excellent audit results, it should not be the sole focus to prevent catheter infection.

Objective: Interventions to promote physical activity for sedentary patients seen in general practice may be a way to reduce the burden of chronic disease. Coaching by an exercise physiologist is publicly funded in Australia, but cost effectiveness has not been documented. Methods: In a three-arm randomised controlled trial, face-to-face coaching and telephone coaching over 12 weeks were compared with a control group using the outcome of step count for one week at baseline, three months and twelve months. Program costs and time-based costs were considered. Quality of life was measured as a secondary outcome. Results: At 12 months, the intervention groups were more active than controls by 1,002 steps per day (95%CI 244, 1,759). This was achieved at a cost of AUD$245 per person. There was no change in reported quality of life or utility values. Conclusion: Coaching achieved a modest increase in activity equivalent to 10 minutes walking per day, at a cost of AUD$245 per person. Face-to-face and telephone counselling were both effective. Implication for public health: Persistence of increases nine months after the end of coaching suggests it creates long-term change and is a good value health intervention.

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11¿13% of the variance in educational attainment and 7¿10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

Australian general practitioners (GPs) commonly manage dermatological conditions requiring procedures. GP registrars have limited pre-vocational training exposure to dermatology and find skin problems challenging. We aimed to establish the prevalence, nature and associations of GP registrars¿ performance of skin procedures. We conducted a cross-sectional analysis from the Registrar Clinical Encounters in Training cohort study. Multivariable logistic regression was used to establish associations of our outcome (skin procedures, both including and excluding cryotherapy). Independent variables included patient and doctor demographics, diagnoses/problems managed and registrars¿ recourse to in-consultation assistance/information. A total of 1161 registrars provided data on 166,988 consultations, recording 2927 skin procedures (16.7% of all procedures; performed in 1.7% of consultations). Cryotherapy, excision, punch biopsy and shave biopsy were most common. More complex procedures were performed infrequently. Significant associations of performing procedures included rural/remote location (compared to major city), male patients, patient age 65+ (compared to age 15¿34) and registrars seeking in-consultation information/assistance. Skin procedures were less likely for Aboriginal patients or those from non-English-speaking backgrounds. For non-cryotherapy procedures, rurality was not significantly associated, but significant differences were found between training regions. In summary, GP registrars perform fewer dermatological procedures compared to established GPs. Findings will inform GP vocational training in skin procedures.

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

Objectives. Expanding learner cohorts of medical students and general practitioner (GP) vocational trainees and the impending retirement of the 'baby boomer' GP cohort threaten the teaching and supervisory capacity of the Australian GP workforce. Engaging newly qualified GPS is essential to sustaining this workforce training capacity. The aim of the present study was to establish the prevalence and associations of in-practice clinical teaching and supervision in early career GPS. Methods. The present study was a cross-sectional questionnaire-based study of recent (within 5 years) alumni of three of Australia's 17 regional general practice training programs. The outcome factor was whether the alumnus taught or supervised medical students, GP registrars or other learners in their current practice. Logistic regression analysis was used to establish associations of teaching and supervision with independent variables comprising alumnus demographics, current practice characteristics and vocational training experiences. Results. In all, 230 alumni returned questionnaires (response rate 37.4%). Of currently practising alumni, 52.4% (95% confidence interval (CI) 45.6-59.0%) reported current teaching or supervisory activities. Factors significantly (P < 0.05) associated with alumni currently undertaking in-practice clinical teaching and supervision were: Australian medical graduation (odds ratio (OR) for international graduates 0.36; 95% CI 0.14-0.92), working in a regional or remote area (OR 2.75; 95% CI 1.24-6.11) and currently undertaking nursing home visits, home visits or after-hours work (OR 2.01; CI 1.02-3.94).

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

Background: The pneumococcal polysaccharide vaccine (PPV) has been associated with reduced risk of cardiovascular events in human observational studies. Animal studies suggest that the phosphorylcholine epitope in the Streptococcus pneumoniae cell wall is structurally similar to oxidized low-density lipoprotein (oxLDL), hence PPV induces the production of antibodies that cross-react with anti-oxLDL and may cause regression of atherosclerotic plaque. We set out to determine the strength of association between PPV administration and reduction in cardiovascular events. Methods: A longitudinal, population-based cohort study of older Australians, from the Hunter Community Study, with up to 11 years of follow-up. We included participants aged = 65 years at baseline (2004¿2008), without a history of cardiovascular disease (CVD). History of PPV administration at baseline was the main exposure of interest. ¿Total number of hospital bed-days with CVD primary diagnosis¿ was one of the main outcomes measured. Models were adjusted for age, diabetes, alcohol intake, and smoking status. Influenza vaccine was the control exposure used and fracture bed-days was the control outcome used, to investigate the potential for residual confounding. Results: 91 of the total 1074 participants (mean age = 72, male = 45%) experienced a CVD event during follow-up. PPV (regardless of influenza vaccine) was associated with a significant reduction in CVD bed-day, (n = 863, incident rate ratio, IRR = 0.65, 95%CI: 0.45¿0.94, p = 0.02), but influenza vaccine (regardless of PPV) was not (n = 864, IRR = 0.86, 95%CI: 0.54¿1.35, p = 0.51). Furthermore, PPV adjusted for influenza vaccine remained associated with CVD bed-days (IRR = 0.64, 95%CI: 0.43¿0.96, p = 0.03) but was not associated with fracture bed-days (IRR = 0.75, 95%CI: 0.28¿2.00, p = 0.56). Conclusion: PPV demonstrated a 35% reduction in CVD bed-days. This finding was robust to residual confounding, using a control exposure and a control outcome, eliminating the concern for healthy-user bias. A large double-blinded placebo-controlled RCT is underway to confirm our finding and to explore the proposed mechanism of action (ACTRN12615000536561).

Background and Purpose - This study aimed to assess the efficacy of modafinil, a wakefulness-promoting agent in alleviating post-stroke fatigue =3 months after stroke. We hypothesized that 200 mg of modafinil daily for 6 weeks would result in reduced symptoms of fatigue compared with placebo. Methods - This single-center phase 2 trial used a randomized, double-blind, placebo-controlled, crossover design. The key inclusion criterion was a multidimensional fatigue inventory score of =60. Patients were randomized to either modafinil or placebo for 6 weeks of therapy, then after a 1 week washout period swapped treatment arms for a second 6 weeks of therapy. The primary outcome was the multidimensional fatigue inventory; secondary outcomes included the Montreal cognitive assessment, the Depression, Anxiety, and Stress Scale (DASS), and the Stroke-Specific Quality of Life (SSQoL) scale. The multidimensional fatigue inventory is a self-administered questionnaire with a range of 0 to 100. Treatment efficacy was assessed using linear regression by estimating within-person, baseline-adjusted differences in mean outcomes after therapy. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000350527). Results - A total of 232 stroke survivors were screened and 36 were randomized. Participants receiving modafinil reported a significant decrease in fatigue (multidimensional fatigue inventory, -7.38; 95% CI, -21.76 to -2.99; P<0.001) and improved quality of life (SSQoL, 11.81; 95% CI, 2.31 to 21.31; P=0.0148) compared with placebo. Montreal cognitive assessment and DASS were not significantly improved with modafinil therapy during the study period (P>0.05). Conclusions - Stroke survivors with nonresolving fatigue reported reduced fatigue and improved quality of life after taking 200 mg daily treatment with modafinil.

This study analyzed clinically actionable pharmacogenotypes for clopidogrel, warfarin, statins, thiopurines, and tacrolimus using microarray data for 2121 participants (55¿85 years) from the Australian Hunter Community Study (HCS). At least 74% of participants (95% confidence interval [CI]: 72%¿76%) had strong level evidence for at least one medium- or high-risk actionable genotype that would trigger a change in standard therapy under current international recommendations. About 14% of these participants (95% CI: 12%¿16%) were taking medication potentially affected by the genotype in question. Furthermore, ~2.6% of all participants with medication data (95% CI: 1.4%¿3.8%) had a high-risk clinically actionable genotype for a medication to which they were exposed. This represents a considerable number of people at the population level. Although relationships between genotype and health outcomes remain contentious, pharmacogenotyping of multiple variants simultaneously may have considerable potential to improve medication safety and efficacy for older people in the community.

Objective: To assess the number of pathology tests ordered by general practice registrars during their first 18e24 months of clinical general practice. Design: Longitudinal analysis of ten rounds of data collection (2010e2014) for the Registrar Clinical Encounters in Training (ReCEnT) study, an ongoing, multicentre, cohort study of general practice registrars in Australia. The principal analysis employed negative binomial regression in a generalised estimating equations framework (to account for repeated measures on registrars). Setting, participants: General practice registrars in training posts with five of 17 general practice regional training providers in five Australian states. The registrar participation rate was 96.4%. Main outcome measure: Number of pathology tests requested per consultation. The time unit foranalysiswas the registrar training term (the 6-month full-time equivalent component of clinical training); registrars contributed data for up to four training terms. Results: 876 registrars contributed data for 114 584 consultations. The number of pathology tests requested increased by 11% (95% CI, 8e15%; P < 0.001) per training term. Conclusions: Contrary to expectations, pathology test ordering by general practice registrars increased significantly during their first 2 years of clinical practice. This causes concerns about overtesting. As established general practitioners order fewer tests than registrars, test ordering may peak during late vocational training and early career practice. Registrars need support during this difficult period in the development of their clinical practice patterns.

Context: Tolerance for ambiguity is essential for optimal learning and professional competence. General practice trainees must be, or must learn to be, adept at managing clinical uncertainty. However, few studies have examined associations of intolerance of uncertainty in this group. Objectives: The aim of this study was to establish levels of tolerance of uncertainty in Australian general practice trainees and associations of uncertainty with demographic, educational and training practice factors. Methods: A cross-sectional analysis was performed on the Registrar Clinical Encounters in Training (ReCEnT) project, an ongoing multi-site cohort study. Scores on three of the four independent subscales of the Physicians' Reaction to Uncertainty (PRU) instrument were analysed as outcome variables in linear regression models with trainee and practice factors as independent variables. Results: A total of 594 trainees contributed data on a total of 1209 occasions. Trainees in earlier training terms had higher scores for ¿Anxiety due to uncertainty¿, ¿Concern about bad outcomes¿ and ¿Reluctance to disclose diagnosis/treatment uncertainty to patients¿. Beyond this, findings suggest two distinct sets of associations regarding reaction to uncertainty. Firstly, affective aspects of uncertainty (the ¿Anxiety¿ and ¿Concern¿ subscales) were associated with female gender, less experience in hospital prior to commencing general practice training, and graduation overseas. Secondly, a maladaptive response to uncertainty (the ¿Reluctance to disclose¿ subscale) was associated with urban practice, health qualifications prior to studying medicine, practice in an area of higher socio-economic status, and being Australian-trained. Conclusions: This study has established levels of three measures of trainees¿ responses to uncertainty and associations with these responses. The current findings suggest differing ¿phenotypes¿ of trainees with high ¿affective¿ responses to uncertainty and those reluctant to disclose uncertainty to patients. More research is needed to examine the relationship between clinical uncertainty and clinical outcomes, temporal changes in tolerance for uncertainty, and strategies that might assist physicians in developing adaptive responses to clinical uncertainty.

Aims We compared the impact of new gestational diabetes (GDM) diagnostic criteria by IADPSG with previous criteria to ascertain concordance between the two criteria; and whether women discordant for GDM between the old and new criteria had increased pregnancy complications. Methods Oral glucose tolerance tests of pregnant women across time periods using old criteria and new criteria were collected. Maternal data and perinatal outcomes were compared between diagnostic concordant and discordant women. Results In total, 666/5178 (12.9%) women were diagnosed and treated for GDM. There was a significant increase in odds of any complication in concordant positive women (OR 3.91 95%CI 2.71¿5.63, p <.0001); in women only positive by new GDM criteria (OR 2.06, 95% CI 1.41¿2.99, p =.0002); and women only positive by old GDM criteria (OR 2.28, 95% CI 1.42¿3.66, p =.0006); compared to concordant negative women. This is mainly due to macrosomia and nursery admissions. Conclusion This study confirms that women diagnosed with GDM on both old and new criteria have a higher rate of birth complications than women without GDM. Women who have been missed out due to new criteria may still be at risk. Therefore, combination of both old and new criteria may be optimal for identifying high-risk pregnancies.

Large artery atherosclerotic stroke (LAS) shows substantial heritability not explained by previous genome-wide association studies. Here, we explore the role of coding variation in LAS by analyzing variants on the HumanExome BeadChip in a total of 3,127 cases and 9,778 controls from Europe, Australia, and South Asia. We report on a nonsynonymous single-nucleotide variant in serpin family A member 1 (SERPINA1) encoding alpha-1 antitrypsin [AAT; p.V213A; P = 5.99E-9, odds ratio (OR) = 1.22] and confirm histone deacetylase 9 (HDAC9) as a major risk gene for LAS with an association in the 3?-UTR (rs2023938; P = 7.76E-7, OR = 1.28). Using quantitative microscale thermophoresis, we show that M1 (A213) exhibits an almost twofold lower dissociation constant with its primary target human neutrophil elastase (NE) in lipoprotein-containing plasma, but not in lipid-free plasma. Hydrogen/deuterium exchange combined with mass spectrometry further revealed a significant difference in the global flexibility of the two variants. The observed stronger interaction with lipoproteins in plasma and reduced global flexibility of the Val-213 variant most likely improve its local availability and reduce the extent of proteolytic inactivation by other proteases in atherosclerotic plaques. Our results indicate that the interplay between AAT, NE, and lipoprotein particles is modulated by the gate region around position 213 in AAT, far away from the unaltered reactive center loop (357-360). Collectively, our findings point to a functionally relevant balance between lipoproteins, proteases, and AAT in atherosclerosis.

We aimed to evaluate the effect of pain education on opioid prescribing by early-career general practitioners. A brief training workshop was delivered to general practice registrars of a single regional training provider. The workshop significantly reduced hypothetical opioid prescribing (in response to paper-based vignettes) in an earlier evaluation. The effect of the training on actual prescribing was evaluated using a nonequivalent control group design nested within the Registrar Clinical Encounters in Training (ReCEnT) cohort study: 4 other regional training providers were controls. In ReCEnT, registrars record detailed data (including prescribing) during 60 consecutive consultations, on 3 occasions. Analysis was at the level of individual problem managed, with the primary outcome factor being prescription of an opioid analgesic and the secondary outcome being opioid initiation. Between 2010 and 2015, 168,528 problems were recorded by 849 registrars. Of these, 71% were recorded by registrars in the nontraining group. Eighty-two percentages were before training. Opioid analgesics were prescribed in 4382 (2.5%, 95% confidence interval [CI]: 2.40-2.63) problems, with 1665 of these (0.97%, 95% CI: 0.91-1.04) representing a new prescription. There was no relationship between the training and total prescribing after training (interaction odds ratio: 1.01; 95% CI: 0.75-1.35; P value 0.96). There was some evidence of a reduction in initial opioid prescriptions in the training group (interaction odds ratio: 0.74; 95% CI: 0.48-1.16; P value 0.19). This brief training package failed to increase overall opioid cessation. The inconsistency of these actual prescribing results with hypothetical prescribing behavior suggests that reducing opioid prescribing in chronic noncancer pain requires more than changing knowledge and attitudes.

Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. Methods In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings Data were available for more than 550¿000 individuals and 51¿623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30). Interpretation PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. Funding British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

Objective: Hypoxia is a recognised complication of procedural sedation. This study sought to determine whether there was an association between the use of high-flow oxygen delivery by a non-rebreather (NRB) mask during ED procedural sedation and decreased rates of hypoxia when compared with alternative oxygenation methods. Methods: Records of all procedural sedations performed over a 12 month period in an Australian tertiary ED were reviewed retrospectively. The primary outcome was whether recorded oxygen saturations fell below 90%. Specifics of the oxygen delivery method were noted and data collected included sex, age, indication for sedation, drugs and doses administered, time of day sedation was commenced and staff grade of sedationist. Results: A total of 755 procedural sedations were reviewed. Two hundred and five (27.1%) patients were administered oxygen via NRB mask from the outset of their sedation. NRB administration was associated with a statistically significant decreased rate of hypoxia (1/205 patients vs 23/550 [odds ratio: 0.112; 95% confidence interval: 0.003¿0.0702]; P = 0.0090). This association remained statistically significant when adjusted for confounders. Conclusions: This study demonstrates an association with a statistically significant reduction in hypoxia when high-flow oxygen via NRB mask is administered during emergency procedural sedation. This intervention is simple, safe and inexpensive, and we would advocate that it be evaluated further in prospective trials.

Background Cervical artery dissection (CAD) is a leading cause of stroke among middle-aged adults, but the etiology is unclear. Some reports of seasonal variation in CAD incidence have been suggested but may reflect extreme climatic conditions. Seasonal variation may implicate more transient seasonal causes such as proinflammatory or hypercoagulable states. This study aimed to assess whether CAD incidence varied with season between UK and Australian sites. Also, this study aimed to determine whether there was a different pattern of seasonal variation between arteries (carotid and vertebral) and any association between CAD incidence and clinical factors. Methods This was a retrospective observational study of patients older than 18 years with radiological diagnosis of internal carotid or vertebral arterial dissection, from sites in Australia and the UK. Clinical variables were compared between autumn-winter and spring-summer and site of dissection. Results A total of 133 CAD cases were documented in Australia and 242 in the UK. There was a seasonal pattern to CAD incidence in countries in both the northern and the southern hemispheres, with a trend for dissection to occur more commonly in autumn, winter, and spring than in summer (incidence rate ratios [IRR] 1.4-1.5, P¿<¿.05). CAD counts were also slightly higher in internal carotid than in vertebral artery (IRRs 1.168, 1.43, and 1.127, respectively). Neither systolic blood pressure nor pulse pressure was significantly associated with CAD counts. Conclusions CAD occurs more commonly in cooler months regardless of geographical location, suggesting transient seasonal causes may be important in the pathophysiology. This effect was slightly higher in internal carotid than in vertebral artery, suggesting differing trigger mechanisms between dissection sites.

Underperforming trainees requiring remediation may threaten patient safety and are challenging for vocational training programs. Decisions to institute remediation are high-stakes¿remediation being resource-intensive and emotionally demanding on trainees. Detection of underperformance requiring remediation is particularly problematic in general (family) practice. We sought to establish early-training assessment instruments predictive of general practice (GP) trainees¿ subsequently requiring formal remediation. We conducted a retrospective cohort study of trainees from a large Australian regionally-based GP training organization. The outcome factor was requirement for formal remediation. Independent variables were demographic factors and a range of formative assessments conducted immediately prior to or during early-stage training. Analyses employed univariate and multivariate logistic regression of each predictor assessment modality with the outcome, adjusting for potential confounders. Of 248 trainees, 26 (10.5¿%) required formal remediation. Performance on the Colleague Feedback Evaluation Tool (entailing feedback from a trainee¿s clinical colleagues on clinical performance, communication and probity) and External Clinical Teaching Visits (half-day sessions of the trainee¿s clinical consultations observed directly by an experienced GP), along with non-Australian primary medical qualification, were significantly associated with requiring remediation. There was a non-significant trend for association with performance on the Doctors Interpersonal Skills Questionnaire (patient feedback on interpersonal elements of the consultation). There were no significant associations with entry-selection scores or formative exam or assessment scores. Our finding that ¿in vivo¿ assessments of complex behaviour, but not ¿in vitro¿ knowledge-based assessments, predict need for remediation is consistent with theoretical understanding of the nature of remediation decision-making and should inform remediation practice in GP vocational training.

Purpose To assess the 5-year progression from unilateral to bilateral age-related macular degeneration (AMD) and associated risk factors. Design Pooled data analyses of three prospective population-based cohorts, the Blue Mountains Eye Study, Beaver Dam Eye Study and Rotterdam Study. Methods Retinal photography and interview with comprehensive questionnaires were conducted at each visit of three studies. AMD was assessed following the modified Wisconsin AMD grading protocol. Progression to bilateral any (early and late) or late AMD was assessed among participants with unilateral involvement only. Factors associated with the progression were assessed using logistic regression models while simultaneously adjusting for other significant risk factors. Results In any 5-year duration, 19-28% of unilateral any AMD cases became bilateral and 27-68% of unilateral late AMD became bilateral. Factors associated with the progression to bilateral involvement of any AMD were age (per year increase, adjusted OR 1.07), carrying risk alleles of the complement factor H and age-related maculopathy susceptibility 2 genes (compared with none, OR 1.76 for 1 risk allele and OR 3.34 for 2+ risk alleles), smoking (compared with non-smokers, OR 1.64 for past and OR 1.67 for current smokers), and the presence of large drusen area or retinal pigmentary abnormalities in the first eye. Conclusion One in four to one in five unilateral any AMD cases, and up to one in two unilateral late AMD cases, progressed to bilateral in 5 years. Known AMD risk factors, including smoking, are significantly associated with the progression to bilateral involvement.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

BACKGROUND: Both perioperative chemotherapy (PECT) and postoperative chemoradiotherapy (POCRT) have a significant survival advantage over surgery alone for the treatment of patients with gastric cancer. However, to the best of our knowledge, these regimens have not been compared in a randomized clinical trial. The purpose of the current observational study was to compare overall survival among patients receiving PECT versus POCRT for the treatment of gastric/gastroesophageal junction (GEJ) adenocarcinomas. METHODS: Patients with resected clinical American Joint Committee on Cancer TNM stage II or III adenocarcinomas of the stomach or GEJ from 2004 through 2013 were identified utilizing the National Cancer Data Base. Hazard ratios (HRs), 95% confidence intervals, and P values were computed using a Cox proportional hazards procedure. Multivariable models were adjusted for treatment regimen, age, race, ethnicity, tumor size, TNM stage, Charlson comorbidity index, and tumor grade. RESULTS: Patients receiving PECT had a 72% survival advantage compared with those treated with POCRT (5058 patients; HR, 0.58 [adjusted P<.0001]). The 5-year actuarial survival rate for PECT was 44% compared with 38% for POCRT. A statistically significant survival advantage for PECT also was observed when the analysis was stratified by clinical stage of disease (stage II [3192 patients]: adjusted HR, 0.79 [P =.041]; and stage III [1866 patients]: adjusted HR, 0.49 [P<.0001]). This benefit was greatest among patients with lymph node-positive disease who converted to lymph node-negative status with PECT. CONCLUSIONS: In this large series of patients with stage II/III resected gastric/GEJ adenocarcinomas from >1500 American College of Surgeons Commission on Cancer-accredited facilities, patients receiving PECT were shown to survive longer than those receiving POCRT. Cancer 2017;123:2909¿17. © 2017 American Cancer Society.

Objective Malaysia has a high and rising prevalence of type 2 diabetes (T2D). While environmental (non-genetic) risk factors for the disease are well established, the role of genetic variations and gene¿environment interactions remain understudied in this population. This study aimed to estimate the relative contributions of environmental and genetic risk factors to T2D in Malaysia and also to assess evidence for gene¿environment interactions that may explain additional risk variation. Study design This was a case¿control study including 1604 Malays, 1654 Chinese and 1728 Indians from the Malaysian Cohort Project. Methods The proportion of T2D risk variance explained by known genetic and environmental factors was assessed by fitting multivariable logistic regression models and evaluating McFadden's pseudo R2 and the area under the receiver-operating characteristic curve (AUC). Models with and without the genetic risk score (GRS) were compared using the log likelihood ratio Chi-squared test and AUCs. Multiplicative interaction between genetic and environmental risk factors was assessed via logistic regression within and across ancestral groups. Interactions were assessed for the GRS and its 62 constituent variants. Results The models including environmental risk factors only had pseudo R2 values of 16.5¿28.3% and AUC of 0.75¿0.83. Incorporating a genetic score aggregating 62 T2D-associated risk variants significantly increased the model fit (likelihood ratio P-value of 2.50 × 10-4¿4.83 × 10-12) and increased the pseudo R2 by about 1¿2% and AUC by 1¿3%. None of the gene¿environment interactions reached significance after multiple testing adjustment, either for the GRS or individual variants. For individual variants, 33 out of 310 tested associations showed nominal statistical significance with 0.001 < P < 0.05. Conclusion This study suggests that known genetic risk variants contribute a significant but small amount to overall T2D risk variation in Malaysian population groups. If gene¿environment interactions involving common genetic variants exist, they are likely of small effect, requiring substantially larger samples for detection.

Background. Home visits (HVs) and nursing home visits (NHVs) are accepted as core elements of general practice. There is concern regarding declining rates of HVs and an increasing demand for NHVs together with a perceived decreased willingness of younger GPs to provide these services. Objectives. To establish the prevalence and associations of recently vocationally qualified GPs ('graduates') performing HVs and NHVs. Methods. A cross-sectional questionnaire-based study of recent (within 5 years) graduates of 3 of Australia's 17 regional general practice training programs. Outcome factors were performing, as part of current practice, HVs and NHVs. Factors associated with each outcome were assessed by logistic regression with graduate and current practice characteristics and vocational training experiences as independent variables. Results. Of 230 responding graduates, 48.1% performed HVs and 40.6% performed NHVs in their current clinical GP role. Factors associated with both HVs and NHVs were participating in in-practice clinical teaching/supervision [odds ratios (ORs) 2.65 and 2.66], conducting HVs/NHVs during training (ORs 5.05 and 10.8) and working full-time (ORs for part-time work 0.20 and 0.29). Further associations with performing HVs were older GP age (compared to < 36 years: ORs 3.65 for 36-40 and 2.53 for 41+), smaller practice size (OR 0.53 for larger practices), Australian undergraduate education (OR 0.31 for non-Australian) and greater number of years in their current practice as a qualified GP (OR 1.25 per year). Conclusions. Our findings of graduates' modest engagement with HVs and NHVs reinforce concerns regarding Australian general practice's capacity to accommodate the needs of an aging population.

Background: Whether general practitioner (GP) registrars have adequate exposure to, and feel confident in, managing children's health during training is unknown. Objectives: To determine the prevalence and associations of GP registrars' paediatric vs. non-paediatric consultations. Methods: Cross-sectional analysis from a cohort study of Australian GP registrars' 2010-2014 consultations. Results: 889 registrars contributed details for 26,427 (21.8% (95% CI: 21.4-22.2) paediatric consultations. Paediatric patients were more likely to be male and new to the practice. Although paediatric patients were less likely to have a chronic disease (OR 0.38, 95% CI 0.36, 0.40) and presented with fewer problems (OR 0.59, 95% CI 0.57, 0.61), registrars were more likely to seek in-consultation advice (OR 1.25, 95% CI 1.19, 1.31) and generate learning goals (OR 1.12, 95% CI 1.07, 1.18) for paediatric consultations. Discussion: GP registrars appear to feel less confident in managing paediatric compared with adult consultations, suggesting an unmet training need.

Introduction Primary care physicians are well placed to offer physical activity counseling, but insufficient time is a barrier. Referral to an exercise specialist is an alternative. In Australia, exercise specialists are publicly funded to provide face-to-face counseling to patients who have an existing chronic illness. This trial aimed to (1) determine the efficacy of primary care physicians¿ referral of insufficiently active patients for counseling to increase physical activity, compared with usual care, and (2) compare the efficacy of face-to-face counseling with counseling predominantly via telephone. Study design Three-arm pragmatic RCT. Setting/participants Two hundred three insufficiently active (<7,000 steps/day) primary care practice patients (mean age 57 years; 70% female) recruited in New South Wales, Australia, in 2011¿2014. Intervention (1) Five face-to-face counseling sessions by an exercise specialist, (2) one face-to-face counseling session followed by four telephone calls by an exercise specialist, or (3) a generic mailed physical activity brochure (usual care). The counseling sessions operationalized social cognitive theory via a behavior change counseling framework. Main outcome measures Change in average daily step counts between baseline and 12 months. Data were analyzed in 2016. Results Forty (20%) participants formally withdrew; completion rates at 3 and 6 months were 64% and 58%, respectively. Intervention attendance was high (75% received five sessions). The estimated mean difference between usual care and the combined intervention groups at 12 months was 1,002 steps/day (95% CI=244, 1,759, p=0.01). When comparing face-to-face with predominantly telephone counseling, the telephone group had a non-significant higher mean daily step count (by 619 steps) at 12 months. Conclusions Provision of expert physical activity counseling to insufficiently active primary care patients resulted in a significant increase in physical activity (approximately 70 minutes of walking per week) at 12 months. Face-to-face only and counseling conducted predominantly via telephone were both effective. This trial provides evidence to expand public funding for expert physical activity counseling and for delivery via telephone in addition to face-to-face consultations. Trial registration This trial is registered at www.anzctr.org.au/ ACTRN12611000884909.

Objective: To investigate older patients' encounters with general practice registrars (GPRs) to inform training and clinical practice. Methods: Cross-sectional analysis of data from GPR consultations across five regional training providers in Australia. Data were analysed using simple and multiple logistic regression models. Results: Our analysis included details of 118 831 consultations, 20 555 (17.6%, 95% CI 17.4¿17.8) with patients aged =65 years. Older patient encounters had an increased likelihood of including chronic disease (OR 1.77, 95% CI 1.70, 1.86) and more problems (OR 1.24, 95% CI 1.20, 1.27). However, in-consultation information or advice was less likely to be sought (OR 0.92, 95% CI 0.88, 0.97), and consultations were briefer (OR 0.99, 95% CI 0.99, 1.00). Conclusion: Our results suggest relatively limited GPR exposure to older patients coupled with less complex consultations than expected. Solutions will need to be carefully constructed not only to increase caseloads, but also to address training and supervision concerns.

Background: The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes. Methods: To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis. Findings: We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50 × 10-8; joint OR 1·19, 1·12-1·26, p=1·30 × 10-9). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26 × 10-19; joint OR 1·37, 1·30-1·45, p=2·79 × 10-32) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93 × 10-7; joint OR 1·17, 1·11-1·23, p=2·29 × 10-10) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50 × 10-8; joint OR 1·24, 1·15-1·33, p=4·52 × 10-9) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82 × 10-8; joint OR 1·17, 1·11-1·23, p=2·92 × 10-9). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed. Interpretation: Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke. Funding: US National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. Methods: Logistic regression analysis and fixed effects metaanalysis were used to test for associations between endometrial cancer risk and (i) individual BMI orWHRSNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. Results: The BMIwGRS was significantly associated with endometrial cancer risk (P -= 3.4 × 10-17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR-=1.55; 95% CI, 1.44-1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR -= 1.22; 95% CI, 1.10-1.39; P -= 5.3 × 10-4). There was evidence of directional pleiotropy (P -= 1.5 × 10-4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10-4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling.

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (P = 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r 2 = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

© 2016 Nature America, Inc. part of Springer Nature, All Rights reserved. The genetic architecture of human reproductive behavior - age at first birth (AFB) and number of children ever born (NEB) - has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

Background It remains unclear whether eradication of oligometastases by stereotactic body radiation therapy or other means will result in cure or prolongation of survival in some cases, or merely provide palliation. We address this issue with prospectively collected progression and treatment data from the TROG 03.04 RADAR randomised controlled trial for men with locally advanced prostate cancer (PC). Methods Three Fine and Gray competing risk survival models with time-dependent covariates were used to determine whether metastatic progression status at first diagnosis of bony metastases, i.e. number of bony sites involved and presence of prior or simultaneous other sites of progression, impacts on prostate cancer-specific mortality (PCSM) when adjusted for baseline prognostic factors and allocated primary treatment. Results Between 2003 and 2014, 176 of the 1071 subjects developed bone metastases, 152 developed other sites of progression and 91 died of PC. All subjects received secondary treatment using androgen suppression but none received extirpative treatments. The three models found evidence: 1 ¿ of a clear prognostic gradient according to number of bony metastatic sites; 2 ¿ that other sites of progression contributed to PCSM to a lesser extent than bone progression; and 3 ¿ that further bony metastatic progression in men with up to 3 bony metastases had a major impact on PCSM. Conclusion Randomised trials are essential to determine the value of extirpative treatment for oligometastatic bony metastases due to PC.

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels.We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ~120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indelswere examined.We identified 41 genome-wide significant fibrinogen loci; of which, 18were newly identified. Therewere no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

Summary: We assessed the ability of a fracture liaison service (FLS) to directly reduce re-fracture risk. Having a FLS is associated with a ~40¿% reduction in the 3-year risk of major bone and ~30¿% of any bone re-fracture. The number needed to treat to prevent a re-fracture is 20. Introduction: FLS have been promoted as the most effective interventions for secondary fracture prevention, and while there is evidence of increased rate of investigation and treatment at institutions with a FLS, only a few studies have considered fracture outcomes directly. We therefore sought to evaluate the ability of our FLS to reduce re-fracture risk. Methods: Historical cohort study of all patients =50¿years presenting over a 6-month period with¿a minimal trauma fracture (MTF) to the emergency departments of a tertiary hospital with a FLS, and one without a FLS. Baseline characteristics, mortality and MTFs over a 3-year follow-up were recorded. Results: Five hundred fifteen patients at the FLS hospital and 416 patients at the non-FLS hospital were studied. Over 3¿years, 63/515 (12¿%) patients at the FLS hospital and 70/416 (17¿%) at the non-FLS hospital had a MTF. All patients were analysed in an intention-to-treat analysis regardless of whether they were seen in the FLS follow-up clinic. Statistical analysis using Cox proportional hazard models in the presence of a competing risk of death from any cause was used. After adjustment for baseline characteristics, there was a ~30¿% reduction in rate of any re-fracture at the FLS hospital (hazard ratio (HR) 0.67, confidence interval (CI) 0.47-0.95, p value 0.025) and a ~40¿% reduction in major re-fractures (hip, spine, femur, pelvis or humerus) (HR 0.59, CI 0.39-0.90, p value 0.013). Conclusions: We found a ~30¿% reduction in any re-fractures and a ~40¿% reduction in major re-fractures at the FLS hospital compared with a similar non-FLS hospital. The number of patients needed to treat to prevent one new fracture over 3¿years is 20.

Background. Inappropriate antibiotic prescription and subsequent antibacterial resistance are major threats to health worldwide. Objectives. We aimed to establish whether early-career 'apprenticeship-model' experience in family practice influences antibiotic prescribing for respiratory tract infections and to also establish other associations of antibiotic prescribing changes during this early-career experience. Methods. A longitudinal analysis (2010-2014) of a cohort study of Australian GP registrars' (vocational trainees') consultations. Registrars from five regional training programs recorded data from 60 consecutive consultations, once each 6-month training Term, including the diagnoses managed and medications prescribed. The outcomes were whether an antibiotic was prescribed for the diagnoses 'upper respiratory tract infection (URTI)' and 'acute bronchitis/bronchiolitis'. Generalized linear mixed modelling was used to account for repeated measures on registrars and to include the time component: 'Term'. Results. A total of 856 registrars recorded 108759 consultations, including 8715 'URTI' diagnoses (5.15% of diagnoses) and 2110 'acute bronchitis/bronchiolitis' diagnoses (1.25%). Antibiotics were prescribed in 16.3% [95% confidence interval (CI) 14.9-17.8] of URTI and 72.2% (95% CI 69.6-74.6) of acute bronchitis/bronchiolitis diagnoses. Moving from an earlier to later term did not significantly influence registrars' antibiotic prescribing for URTI [adjusted odds ratio (OR) 0.95; 95% CI 0.87, 1.04, P = 0.27] or acute bronchitis/bronchiolitis [OR 1.01 (95% CI 0.90-1.14), P = 0.86]. Significant associations of antibiotic prescribing for URTIs were the registrar being non-Australian educated, greater patient age, practices not privately billing patients, pathology being ordered, longer consultation duration and the registrar seeking in-consultation information or advice (including from their supervisor). Conclusions. Early-career experience/training failed to produce rational antibiotic prescribing for URTI and acute bronchitis/bronchiolitis. Our findings suggest that prescribing interventions could target the registrar-supervisor dyad.

Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ~17,000; UK Biobank, n = ~115,000; and the Estonian Biobank, n = ~6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members' polygenic profile score for education to predict their parents' longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ~2.7% lower mortality risk for both mothers (total ndeaths= 79,702) and ~2.4% lower risk for fathers (total ndeaths= 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity.

IMPORTANCE Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been shown to influence homocysteine levels; homocysteine has been implicated as a cataractogenic stressor. OBJECTIVE To investigate the associations of MTHFR polymorphisms and serum homocysteine levels with incident cortical cataract in an older population. DESIGN, SETTING, AND PARTICIPANTS From 1992 to 1994, a population-based cohort study, the Blue Mountains Eye Study, was conducted with 3654 residents (82.4%of eligible participants) of the Blue Mountains region aged 49 years and older. At the second (1997-1999, 5-year follow-up) and third (2002-2004, 10-year follow-up) surveys, 2334 (75.8% of survivors) and 1952 (76.7%of survivors) were examined, respectively. For this report, the second survey serves as baseline when homocysteine levels were assessed, and 5-year incidence of cataract refers to incidence estimated from the second to the third survey. After excluding participants with no follow-up data or DNA or who had previous cortical cataract or cataract surgery, 757 participants were included in gene and environment analyses. This current project on associations with cataract was designed initially March 19, 2013, and completed April 14, 2014. Cataract was assessed using the Wisconsin Cataract Grading system. Two MTHFR polymorphisms, C677T (rs1801133) and A1298C (rs1801131), were included. Serum homocysteine levels were assessed following standard methods. MAIN OUTCOMES AND MEASURES Logistic regression modelswere used to estimate odds ratios (ORs) and 95%confidence intervals for incident cortical cataract, after adjusting for age, sex, smoking status, hypertension, diabetes, education, andmyopia. Path analysis was performed to explore a possible pathway of MTHFR polymorphisms via homocysteine levels to cortical cataract. RESULTS The mean (SD) age of the 1726 participants in the Blue Mountains Eye Study 2 cohort with normal homocysteine levels was 68.3 (8.1) years and 73.2 (8.5) years for those with elevated homocysteine levels. Both the C677T polymorphism (CT/TT vs CC: OR = 1.50; 95%CI = 1.01-2.23) and elevated homocysteine levels (>15 ìmol/L: OR = 2.24; 95% CI = 1.38-3.63) were independently associated with increased risk of cortical cataract. Path analysis showed that the genetic effect on cortical cataract was partially mediated via homocysteine levels. Combined CT/TT genotypes and elevated homocysteine levels were associated with a 3-fold risk of cortical cataract (OR = 3.74; 95%CI = 1.79-7.80). The synergy index of both exposures was 1.34 (95%CI = 0.44-4.01). CONCLUSIONS AND RELEVANCE MTHFR polymorphism and elevated homocysteine levels contributed separately and jointly to increased risk of cortical cataract. If these findings are confirmed, homocysteine levels may be a therapeutic target to reduce risk of cortical cataract in persons carrying genetic risk.

Background and Purpose - White matter hyperintensities (WMH) are increased in patients with lacunar stroke. Whether this is because of shared pathogenesis remains unknown. Using genetic data, we evaluated whether WMH-associated genetic susceptibility factors confer risk of lacunar stroke, and therefore whether they share pathogenesis. Methods - We used a genetic risk score approach to test whether single nucleotide polymorphisms associated with WMH in community populations were associated with magnetic resonance imaging-confirmed lacunar stroke (n=1,373), as well as cardioembolic (n=1,331) and large vessel (n=1,472) Trial of Org 10172 in Acute Stroke Treatment subtypes, against 9,053 controls. Second, we separated lacunar strokes into those with WMH (n=568) and those without (n=787) and tested for association with the risk score in these 2 groups. In addition, we evaluated whether WMH-associated single nucleotide polymorphisms are associated with lacunar stroke, or in the 2 groups. Results - The WMH genetic risk score was associated with lacunar stroke (odds ratio [OR; 95% confidence interval [CI]]=1.14 [1.06-1.22]; P=0.0003), in patients both with and without WMH (WMH: OR [95% CI]=1.15 [1.05-1.26]; P=0.003 and no WMH: OR [95% CI]=1.11 [1.02-1.21]; P=0.019). Conversely, the risk score was not associated with cardioembolic stroke (OR [95% CI]=1.03 [0.97-1.09]; P=0.63) or large vessel stroke (OR [95% CI]=0.99 [0.93,1.04]; P=0.39). However, none of the WMH-associated single nucleotide polymorphisms passed Bonferroni-corrected significance for association with lacunar stroke. Conclusions - Genetic variants that influence WMH are associated with an increased risk of lacunar stroke but not cardioembolic or large vessel stroke. Some genetic susceptibility factors seem to be shared across different radiological manifestations of small vessel disease.

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancerandwith estradiol (E2) concentrations.We analyzed2937singlenucleotidepolymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome widesignificant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10-11). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10-8). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by theobservedeffectonE2 concentrations (1.09, CI=1.03-1.21), consistentwith the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associationswith rs727479 were stronger amongwomen with a higher BMI (PinteractionZ0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10 -8) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10 -9 after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10 -4). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10 -15), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10 -11) and neuron cell-cell adhesion (P-value=1.48 × 10 -13). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Background: The estrogen-induced gene 121 (EIG121) has been associated with breast and endometrial cancers, but its mechanism of action remains unknown. In a genome-wide search for tandem repeats, we found that EIG121 contains a short tandem repeat (STR) in its upstream regulatory region which has the potential to alter gene expression. The presence of this STR has not previously been analysed in relation to breast or endometrial cancer risk. Results: In this study, the lengths of this STR were determined by PCR, fragment analysis and sequencing using DNA from 223 breast cancer patients, 204 endometrial cancer patients and 220 healthy controls to determine if they were associated with the risk of developing breast or endometrial cancer. We found this repeat to be highly variable with the number of copies of the AG motif ranging from 27 to 72 and having a bimodal distribution. No statistically significant association was identified between the length of this STR and the risk of developing breast or endometrial cancer or age at diagnosis. Conclusions: The STR in the upstream regulatory region of EIG121 is highly polymorphic, but is not associated with the risk of developing breast or endometrial cancer in the cohorts analysed here. While this polymorphic STR in the regulatory region of EIG121 appears to have no impact on the risk of developing breast or endometrial cancer, its association with disease recurrence or overall survival remains to be determined.

Background and Purpose - Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early-versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset < 60 years. Methods. The discovery stage of our genome-wide association studies included 4505 cases and 21968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10-6 and performed in silico association analyses in an independent sample of =1003 cases and 7745 controls. Results.One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10-9). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII.activating protease levels, a product of HABP2. Conclusions.HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

Apolipoprotein H (ApoH) is a multi-functional plasma glycoprotein that has been associated with negative health outcomes. ApoH levels have high heritability. We undertook a genome-wide association study of ApoH levels using the largest sample to date and replicated the results in an independent cohort (total N = 1,255). In the discovery phase, a meta-analysis of two cohorts, the Sydney Memory and Ageing Study (Sydney MAS) and the Older Australian Twins Study (OATS) (n = 942) revealed genome-wide significant results in or near the APOH gene on chromosome 17 (top SNP, rs7211380, p = 1 × 10-11). The results were replicated in an independent cohort, the Hunter Community Study (p < 0.002) (n = 313). Conditional and joint analysis (COJO) confirmed the association of the chromosomal 17 region with ApoH levels. The set of independent SNPs identified by COJO explained 23% of the variance. The relationships between the top SNPs and cardiovascular/lipid/cognition measures and diabetes were assessed in Sydney MAS, with suggestive results observed for diabetes and cognitive performance. However, replication of these results in the smaller OATS cohort was not found. This work provides impetus for future research to better understand the contribution of genetics to ApoH levels and its possible impacts on health.

Objectives: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease. Methods: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084). Results: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r2 > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes. Conclusions: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.

Background and Purpose-Evidence from epidemiological studies points to differences in factors predisposing to stroke by age and sex. Whether these arise because of different genetic influences remained untested. Here, we use data from 4 genome-wide association data sets to study the relationship between genetic influence on stroke with both age and sex. Methods-Using genomic-relatedness-matrix restricted maximum likelihood methods, we performed 4 analyses: (1) we calculated the genetic correlation between groups divided by age and (2) by sex, (3) we calculated the heritability of age-at-stroke-onset, and (4) we evaluated the evidence that heritability of stroke is greater in women than in men. Results-We found that genetic factors influence age at stroke onset (h2 [SE]=18.0 [6.8]; P=0.0038), with a trend toward a stronger influence in women (women: h2 [SE]=21.6 [3.5]; Men: h2 [SE]=13.9 [2.8]). Although a moderate proportion of genetic factors was shared between sexes (rG [SE]=0.68 [0.16]) and between younger and older cases (rG [SE]=0.70 [0.17]), there was evidence to suggest that there are genetic susceptibility factors that are specific to sex (P=0.037) and to younger or older groups (P=0.056), particularly for women (P=0.0068). Finally, we found a trend toward higher heritability of stroke in women although this was not significantly greater than in men (P=0.084). Conclusions-Our results indicate that there are genetic factors that are either unique to or have a different effect between younger and older age groups and between women and men. Performing large, well-powered genome-wide association study analyses in these groups is likely to uncover further associations.

Hand grip strength (GS) is a predictor of mortality in older adults and is moderately to highly heritable, but no genetic variants have been consistently identified. We aimed to identify single nucleotide polymorphisms (SNPs) associated with GS in middle-aged to older adults using a genome-wide association study (GWAS). GS was measured using handheld dynamometry in community-dwelling men and women aged 55¿85 from the Hunter Community Study (HCS, N = 2088) and the Sydney Memory and Ageing Study (Sydney MAS, N = 541). Genotyping was undertaken using Affymetrix microarrays with imputation to HapMap2. Analyses were performed using linear regression. No genome-wide significant results were observed in HCS nor were any of the top signals replicated in Sydney MAS. Gene-based analyses in HCS identified two significant genes (ZNF295, C2CD2), but these results were not replicated in Sydney MAS. One out of eight SNPs previously associated with GS, rs550942, located near the CNTF gene, was significantly associated with GS (p = 0.005) in the HCS cohort only. Study differences may explain the lack of consistent results between the studies, including the smaller sample size of the Sydney MAS cohort. Our modest sample size also had limited power to identify variants of small effect. Our results suggest that similar to various other complex traits, many genetic variants of small effect size may influence GS. Future GWAS using larger samples and consistent measures may prove more fruitful at identifying genetic contributors for GS in middle-aged to older adults.

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10-9, MIR2113; rs17522122, P=2.55 × 10-8, AKAP6; rs10119, P=5.67 × 10-9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10-6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10-17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Objective: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation. Methods: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping. Results: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p 6.4 × 10-28 for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p 2.7 × 10-20 for the CE score in MO). Conclusions: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14 949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15 138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884 105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on ~120 000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status.

Background: Patients who have suffered from cerebral ischemia have a high risk of recurrent vascular events. Predictive models based on classical risk factors typically have limited prognostic value. Given that cerebral ischemia has a heritable component, genetic information might improve performance of these risk models. Our aim was to develop and compare two models: one containing traditional vascular risk factors, the other also including genetic information. Methods and Results: We studied 1020 patients with cerebral ischemia and genotyped them with the Illumina Immunochip. Median follow-up time was 6.5 years; the annual incidence of new ischemic events (primary outcome, n=198) was 3.0%. The prognostic model based on classical vascular risk factors had an area under the receiver operating characteristics curve (AUC-ROC) of 0.65 (95% confidence interval 0.61-0.69). When we added a genetic risk score based on prioritized SNPs from a genome-wide association study of ischemic stroke (using summary statistics from the METASTROKE study which included 12389 cases and 62004 controls), the AUC-ROC remained the same. Similar results were found for the secondary outcome ischemic stroke. Conclusions: We found no additional value of genetic information in a prognostic model for the risk of ischemic events in patients with cerebral ischemia of arterial origin. This is consistent with a complex, polygenic architecture, where many genes of weak effect likely act in concert to influence the heritable risk of an individual to develop (recurrent) vascular events. At present, genetic information cannot help clinicians to distinguish patients at high risk for recurrent vascular events.

Contributors Hans Schanda (Austria), Kris Goethals (Belgium), Peter Marinov (Bulgaria), Neophytos Papaneophytou (Cyprus), Jan Vevera (Czech Republic), Tina Gram Larsen (Denmark), Andres Lehtmets (Estonia), Hanna Putkonen (Finland), Florence Thibaut (France), Norbert Nedopil (Germany), Giogos Alevizopoulos (Greece), Peter Silfin (Hungary), Enda Dooley (Ireland), Francesca Villanti (Italy), Ingrida Cera (Latvia), Hans-Gerd Gumprecht (Luxembourg), Anton Grech (Malta), Ellen van Lier (Netherlands), Knut Rypdal (Norway), Malgorzata Opio (Poland), Máximo Fernández Colón (Portugal), Nicoleta Tataru (Romania), Lubomira Izakova (Slovakia), Peter Pregelj (Slovenia), Esperanza Gomez (Spain), Per Lindqvist (Sweden), Marc Graf (Switzerland), Jenny Shaw, Christine Kennedy, John Crighton (England & Wales, Northern Ireland and Scotland respectively, United Kingdom [UK]). When a mental health service user kills, concerns arise about that service. Our aim was to examine consequent reviews of services across the European Union (EU), Norway, and Switzerland. A systematic review of published literature and a questionnaire survey with a psychiatrist with forensic expertise from each EU country, Switzerland, and Norway were completed. Collated findings were circulated to respondents for correction and/or further observations. There were no relevant journal publications from the EU outside the UK. Survey responses came from 28 of 30 countries surveyed. An inquiry almost always occurred in four countries and at least sometimes in all but five others. Where an inquiry occurred, it was generally internal rather than by an independent body. The UK has a national inquiry database; Norway, the Netherlands, and Finland collect similar data nationally, but most EU countries do not. Legal (civil or criminal) or disciplinary proceedings were uncommon anywhere, but in France and in Italy a treating psychiatrist has been convicted of manslaughter; service authorities appear more-or-less immune everywhere. Except where inquiry is invariable, victims' relatives generally drive actions. The concept of individual inquiry after homicide is widely recognised and often occurs, but practice varies. The impact of such process still requires evaluation.

Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m 2 or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged =45 years. Replication of suggestive associations (p < 5 × 10-6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10-10) and replication cohorts (p = 5.65 × 10-8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10-8, and rs6813517 [SPOCK3], p = 2.58 × 10-8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

Endometrial cancer is the most common invasive gynaecological cancer in women, and relatively little is known about inherited risk factors for this disease. This is the first genome-wide study to explore the role of common and rare germline copy number variants (CNVs) in predisposition to endometrial cancer. CNVs were called from germline DNA of 1,209 endometrioid endometrial cancer cases and 528 cancer-unaffected female controls. Overall CNV load of deletions or DNA gains did not differ significantly between cases and controls (P¿>¿0.05), but cases presented with an excess of rare germline deletions overlapping likely functional genomic regions including genes (P¿=¿8¿×¿10-10), CpG islands (P¿=¿1¿×¿10-7) and sno/miRNAs regions (P¿=¿3¿×¿10-9). On average, at least one additional gene and two additional CpG islands were disrupted by rare deletions in cases compared to controls. The most pronounced difference was that over 30 sno/miRNAs were disrupted by rare deletions in cases for every single disruption event in controls. A total of 13 DNA repair genes were disrupted by rare deletions in 19/1,209 cases (1.6¿%) compared to one gene in 1/528 controls (0.2¿%; P¿=¿0.007), and this increased DNA repair gene loss in cases persisted after excluding five individuals carrying CNVs disrupting mismatch repair genes MLH1, MSH2 and MSH6 (P¿=¿0.03). There were 34 miRNA regions deleted in at least one case but not in controls, the most frequent of which encompassed hsa-mir-661 and hsa-mir-203. Our study implicates rare germline deletions of functional and regulatory regions as possible mechanisms conferring endometrial cancer risk, and has identified specific regulatory elements as candidates for further investigation.