Dr Christopher Oldmeadow

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.

Previous reports have shown that quantification of high tumour grade is of prognostic significance for patients with prostate cancer. In particular, percent Gleason pattern 4 (GP4) has been shown to predict outcome in several studies, although conflicting results have also been reported. A major issue with these studies is that they rely on surrogate markers of outcome rather than patient survival. We have investigated the prognostic predictive value of quantifying GP4 in a series of prostatic biopsies containing Gleason score 3+4=7 and 4+3=7 tumours. It was found that the length of GP4 tumour determined from the measurement of all biopsy cores from a single patient, percent GP4 present and absolute GP4 were all significantly associated with distant progression of tumour, all-cause mortality and cancer-specific mortality over a 10-year follow-up period. Assessment of the relative prognostic significance showed that these parameters outperformed division of cases according to Gleason score (3+4=7 versus 4+3=7). International Society of Urological Pathology (ISUP) Grade Groups currently divide these tumours, according to Gleason grading guidelines, into grade 2 (3+4=7) and grade 3 (4+3=7). Our results indicate that this simple classification results in the loss of important prognostic information. In view of this we would recommend that ISUP Grade Groups 2 and 3 be amalgamated as grade 2 tumour with the percentage of GP4 carcinoma being appended to the final grade, e.g., 3+4=7 carcinoma with 40% pattern 4 tumour would be classified as ISUP Grade Group 2 (40%).

Globally, there has been a renewed focus on addressing gestational weight gain (GWG). In Australia, the Department of Health pregnancy care guidelines recommend women be offered routine weighing and receive brief nutritional and physical activity support during antenatal care visits. Women gaining weight outside the Institute of Medicine (IOM)¿s weight gain reference values are further recommended to be referred to a dietitian. However, professional and organizational barriers, including an absence of weight gain referral pathways and limited workforce resources, exist with the translation and scaling of these recommendations into practice. This study aimed to explore patterns of GWG among a cohort of Australian pregnant women and to determine if pregnancy weight gains of above or below 2 kg or 5 kg in the second and third trimester can be used to predict total GWG outside recommendations. Sensitivity, specificity, negative, and positive likelihood ratios were calculated. The most predictive time point was 24 weeks¿ gestation using the minimum weight change parameter of +/-2 kg, demonstrating reasonable sensitivity (0.81, 95% CI 0.61¿0.83) and specificity (0.72, 95% CI 0.61¿0.83), resulting in 55% (n = 72/131) of the cohort qualifying for dietetic referral. Given the current health service constraints, a review of dietetic services within maternity care is warranted.

Objectives: High blood pressure (BP) is a major risk factor for cardiovascular disease and prevalence rates continue to rise with ageing populations. Polypharmacy remains a burden among the ageing, thus alternative effective strategies are warranted. This study investigated the effects of a polyphenols rich dietary supplement containing Pinus massoniana bark extract (PMBE) for modulating BP in healthy Australian adults. Design: This study is a secondary analysis of data from a double-blinded, placebo-controlled clinical trial. Methods: Sixty-two healthy adults aged 55¿75 years were randomized to receive 50 mL dietary supplement containing placebo (0 mg PMBE) or PMBE (1322 mg PMBE) daily for 12 weeks. Seated systolic BP (SBP) and diastolic (DBP) were measured at baseline, 6 weeks and 12 weeks. Effects of PMBE on modulating BP was also explored in this study stratified for SBP status (optimal v high) as well as by SBP medication status. Mixed effect regression modelling was employed involving fixed categorical effects for elapsed time, treatment assignment and their interaction as well as random subject-level intercept to account for within-subject correlations resulting from repeated measurements. Significant models were further examined by addition of covariates and power calculations were performed since this study was a secondary analysis. Results: SBP significantly reduced (-3.29 mmHg, p = 0.028) after PMBE at 12 weeks compared to baseline. SBP in individuals with normal-high SBP (>120 mmHg) in the PMBE group reduced by - 6.46 mmHg (p = 0.001) at 12 weeks compared to baseline. No significant changes were reported for individuals with optimal (=120 mmHg) SBP nor did DBP significantly change in either study groups. In individuals with non-medicated normal-high SBP, SBP significantly reduced by - 7.49 mmHg (p = 0.001) and DBP by - 3.06 mmHg (p = 0.011) at 12 weeks compared to baseline after PMBE. Cross-group comparisons were not statistically different. Conclusions: A polyphenol-rich dietary supplement derived from PMBE led to a clinically and statistically significant reduction in SBP in adults. Future studies to investigate the effects of PMBE-polyphenol supplementation on BP are warranted to confirm and explore optimal dose and impact on hypertension.

Objectives: Evidence-based treatment protocols are currently lacking for immune-mediated necrotizing myopathy (IMNM). In this multicentre retrospective study, we examined baseline clinical characteristics and treatment variables that may predict short-Term outcomes of patients with IMNM. Methods: Muscle biopsies from the John Hunter Hospital and the Royal Adelaide Hospital obtained between 2012 and 2019 were reviewed at a single laboratory at South Australia Pathology. All biopsies with histological features of IMNM were identified. Demographics of study subjects, clinical information and myositis-specific antibody status were recorded along with muscle strength, serum creatine kinase (CK) and treatment regimens at baseline and 3 and 6 months. Primary outcome measures were muscle strength and serum CK at 3 and 6 months. Mixed-effects regression models in a Bayesian framework were performed using the R statistical package. Results: Female sex, older age, initial prednisone dose and i.v. methylprednisolone were associated with greater improvement in serum CK. In patients with moderate-severe disease at baseline, early IVIG was associated with greater improvement in hip flexor strength at 6 months. Conclusion: Early IVIG was associated with clinical improvement in the short-Term follow-up in IMNM. Female sex, older age, initial oral prednisone dose and initial use of i.v. methylprednisolone were associated with better biochemical improvement.

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.

A range of anxiety measures is used in oncology but their comparability is unknown. We examined variations in measurement across three commonly used instruments: Hospital Anxiety and Depression-Anxiety subscale (HADS-A); Depression, Anxiety, Stress Scale - Anxiety subscale (DASS-A); and Generalised Anxiety Disorder scale (GAD-7). Participants (n = 164) completed the self-report measures and the Generalised Anxiety Disorder module of the Structured Clinical Interview for DSM-IV (SCID). We performed Rasch analysis and calculated diagnostic accuracy statistics. Instruments measured similar constructs of anxiety, but had different ranges of measurement, with the HADS-A including lower severity symptoms than the other two measures. Anxiety severity was similar for GAD-7 ¿mild¿ and HADS-A ¿possible¿ categories, but ¿mild¿ anxiety on the DASS-A represented more severe symptoms. Conversely, DASS-A ¿severe¿ anxiety represented less intense symptoms than GAD-7 ¿severe¿ anxiety. Co-calibration indicated a score of eight on the HADS-A was equivalent in anxiety severity to scores of three on the DASS-A and six on the GAD-7. Area under the curve (AUC) was just acceptable for HADS-A and GAD-7 but not DASS-A. The HADS-A, DASS-A and GAD-7 displayed important differences in how they measured anxiety. In particular, categorical classifications of anxiety severity (mild/moderate/severe) were not equivalent across instruments. Thus, prevalence estimates of anxiety symptoms will vary as a consequence of the instrument used. The GAD-7 and HADS-A obtained more similar results and better AUC than the DASS-A. Our co-calibration could be used in future studies and meta-analyses of individual participant data to set cut-off points that provide more consistent classification of anxiety severity.

Background: Detecting anxiety in oncology patients is important, requiring valid yet brief measures. One increasingly popular approach is the Patient Reported Outcomes Measurement Information System (PROMIS); however, its validity is not well established in oncology. We assessed the convergent and criterion validity of PROMIS anxiety measures in an oncology sample. Methods: 132 oncology/haematology outpatients completed the PROMIS Anxiety Computer Adaptive Test (PROMIS-A-CAT) and the 7 item (original) PROMIS Anxiety Short Form (PROMIS-A-SF) along with six well-established measures: Hospital Anxiety and Depression Scale-Anxiety (HADS-A); Generalised Anxiety Disorder-7 (GAD-7); Depression, Anxiety and Stress Scale-Anxiety (DASS-A) and Stress (DASS-S); Distress Thermometer (DT) and PSYCH-6. Correlations, area under the curve (AUC) and diagnostic accuracy statistics were calculated with Structured Clinical Interview as the reference standard. Results: Both PROMIS measures correlated with all legacy measures at p <.001 (Rho =.56¿.83). AUCs (>.80) were good for both PROMIS measures and comparable to or better than all legacy measures. At the recommended mild cut-point (55), PROMIS-A-SF had sensitivity (.67) comparable to or better than all the legacy measures, whereas PROMIS-A-CAT sensitivity (.59) was lower than GAD-7 (.67) and HADS-A (.62), but comparable to PSYCH-6 and higher than DASS-A, DASS-S and DT. Sensitivity for both was.79. A reduced cut-point of 51 on both PROMIS measures improved sensitivity (.83¿.84) although specificity was only adequate (.61¿.62). Conclusions: The convergent and criterion validity of the PROMIS anxiety measures in cancer populations was confirmed as equivalent, but not superior to, established measures (GAD-7 and HADS-A). The PROMIS-A-CAT did not demonstrate clear advantages over PROMIS-A-SF.

Objectives Some online, personally tailored, text-based physical activity interventions have proven effective. However, people tend to ¿ skim' and ¿ scan' web-based text rather than thoroughly read their contents. In contrast, online videos are more engaging and popular. We examined whether web-based personally tailored physical activity videos were more effective in promoting physical activity than personally tailored text and generic information. Methods 501 adults were randomised into a video-tailored intervention, text-tailored intervention or control. Over a 3-month period, intervention groups received access to eight sessions of web-based personally tailored physical activity advice. Only the delivery method differed between intervention groups: tailored video versus tailored text. The primary outcome was 7-day ActiGraph-GT3X+ measured moderate-to-vigorous physical activity (MVPA) assessed at 0, 3 and 9 months. Secondary outcomes included self-reported MVPA and website engagement. Differences were examined using generalised linear mixed models with intention-to-treat and multiple imputation. Results Accelerometer-assessed MVPA increased 23% in the control (1.23 (1.06, 1.43)), 12% in the text-tailored (1.12 (0.95, 1.32)) and 28% in the video-tailored (1.28 (1.06, 1.53)) groups at the 3-month follow-up only, though there were no significant between-group differences. Both text-tailored (1.77 (1.37, 2.28]) and video-tailored (1.37 (1.04, 1.79)) groups significantly increased self-reported MVPA more than the control group at 3 months only, but there were no differences between video-tailored and text-tailored groups. The video-tailored group spent significantly more time on the website compared with text-tailored participants (90 vs 77 min, p=0.02). Conclusions The personally tailored videos were not more effective than personally tailored text in increasing MVPA. The findings from this study conflict with pilot study outcomes and previous literature. Process evaluation and mediation analyses will provide further insights. Trial registration number ACTRN12615000057583

Problem: Studies investigating the direct and indirect relationships between psychosocial factors (i.e. attitudes, beliefs and values), health related behaviour (diet and physical activity) and gestational weight gain are increasing. To date heterogeneity of psychosocial measurement tools has limited research progress in this area, preventing measurement of effects by meta-analysis techniques. Aim: To conduct a revalidation analysis of a Weight Related Behaviours Questionnaire, originally developed by Kendall, Olson and Frangelico within the United States of America and assess its performance for use within the Australian context. Methods: A revalidation study using Exploratory Factor Analysis was undertaken to assess the factor structure and internal consistency of the six psychosocial scales of the Weight Related Behaviours Questionnaire, within the Woman and Their Children's Health (WATCH), pregnancy cohort. The questionnaire was self-completed between 18 ¿ 20 weeks gestation. Psychosocial factors included; Weight locus of control; Self-efficacy; Attitudes towards weight gain; Body image, Feelings about the motherhood role; and Career orientation. Findings: Weight locus of control, Self-efficacy and Body image, retained the same factor structure as the original analysis. The remaining psychosocial factors observed a different factor structure in terms of loadings or number of factors. Deleted items modelling suggests the questionnaire could be strengthened and shortened. Conclusion: Weight Locus of control, Self-efficacy and Body image were observed as consistent, valid and reliable psychosocial measures for use within the Australian context. Further research is needed to confirm the model and investigate the potential for combining these scales into a shorter psychosocial measurement tool.

Background: There is an established association between fast-food consumption and metabolic diseases. Some studies also suggest that calorie-dense food promotes a proinflammatory response, which is itself linked with myocardial infarction (MI). Whether increased fast-food availability is a risk factor for MI remains unknown. Aim: To investigate the role of fast-food outlet density (FFD) as a novel environmental risk factor for MI in the Hunter region, New South Wales (NSW). Methods: We conducted a retrospective cohort study using a database of all MI events between 1996 and 2013, extracted from the Hunter Cardiac and Stroke Outcomes unit. FFD was calculated for each local government area (LGA) of the Hunter region, allowing for a comparative analysis. Stratification by fast-food outlet data and LGA resulted in a total of 3070 cases. Weighted linear regression was used to investigate the role of FFD on incidence of MI in regional and rural Australia. Results: FFD was positively correlated with rates of MI, remaining consistent in both single and multivariate predictor models adjusting for age, obesity, hyperlipidaemia, hypertension, smoking status, diabetes and socioeconomic status (P < 0.001). An increase of one fast-food outlet corresponded with four additional cases of MI per 100 000 people per year (4.07, 95% confidence interval, 3.86¿4.28). Conclusions: FFD was positively associated with incidence of MI in both rural and metropolitan areas of NSW. This relationship remained consistent after multivariate adjustment for standard cardiovascular risk factors, highlighting the importance of an individual's food environment as a potential contributor towards their health.

Background: There is significant opportunity to improve the nutritional quality of foods packed in children's school lunchboxes. Interventions that are effective and scalable targeting the school and home environment are therefore warranted. Objective: This study aimed to assess the effectiveness of a multicomponent, mobile health-based intervention, SWAP IT, in reducing the energy contribution of discretionary (ie, less healthy) foods and drinks packed for children to consume at school. Methods: A type I effectiveness-implementation hybrid cluster randomized controlled trial was conducted in 32 primary schools located across 3 local health districts in New South Wales, Australia, to compare the effects of a 6-month intervention targeting foods packed in children's lunchboxes with those of a usual care control. Primary schools were eligible if they were not participating in other nutrition studies and used the required school communication app. The Behaviour Change Wheel was used to co-design the multicomponent SWAP IT intervention, which consisted of the following: school lunchbox nutrition guidelines, curriculum lessons, information pushed to parents digitally via an existing school communication app, and additional parent resources to address common barriers to packing healthy lunchboxes. The primary outcome, mean energy (kilojoules) content of discretionary lunchbox foods and drinks packed in lunchboxes, was measured via observation using a validated school food checklist at baseline (May 2019) and at 6-month follow-up (October 2019). Additional secondary outcomes included mean lunchbox energy from discretionary foods consumed, mean total lunchbox energy packed and consumed, mean energy content of core lunchbox foods packed and consumed, and percentage of lunchbox energy from discretionary and core foods, all of which were also measured via observation using a validated school food checklist. Measures of school engagement, consumption of discretionary foods outside of school hours, and lunchbox cost were also collected at baseline and at 6-month follow-up. Data were analyzed via hierarchical linear regression models, with controlling for clustering, socioeconomic status, and remoteness. Results: A total of 3022 (3022/7212, 41.90%) students consented to participate in the evaluation (mean age 7.8 years; 1487/3022, 49.22% girls). There were significant reductions between the intervention and control groups in the primary trial outcome, mean energy (kilojoules) content of discretionary foods packed in lunchboxes (-117.26 kJ; 95% CI -195.59 to -39.83; P=.003). Relative to the control, the intervention also significantly reduced secondary outcomes regarding the mean total lunchbox energy (kilojoules) packed (-88.38 kJ; 95% CI -172.84 to -3.92; P=.04) and consumed (-117.17 kJ; 95% CI -233.72 to -0.62; P=.05). There was no significant difference between groups in measures of student engagement, consumption of discretionary foods outside of school hours, or cost of foods packed in children's lunchboxes. Conclusions: The SWAP IT intervention was effective in reducing the energy content of foods packed for and consumed by primary school-aged children at school. Dissemination of the SWAP IT program at a population level has the potential to influence a significant proportion of primary school-aged children, impacting weight status and associated health care costs.

Introduction: Different endpoint criteria, different durations of follow-up and the completeness of follow-up can dramatically affect the perceived benefits of atrial fibrillation (AF) ablation. Methods: We defined three endpoints for recurrence of AF post ablation in a cohort of 200 patients with symptomatic AF, refractory to antiarrhythmic drugs (AADs). A ¿Strict Endpoint¿ where patients were considered to have a recurrence with any symptomatic or documented recurrence for =30 seconds with no blanking period, and off their AADs, a ¿Liberal Endpoint¿ where only documented recurrences after the blanking period, either on or off AADs were counted, and a ¿Patient-defined Outcome endpoint¿ which was the same as the Liberal endpoint but allowed for up to two recurrences and one repeat ablation or DCCV during follow-up. We also surveyed 50 patients on the waiting list for an AF ablation and asked them key questions regarding what they would consider to be a successful result for them. Results: Freedom from recurrence of atrial tachyarrhythmias (AT) at 5 years was 62% for the Strict Endpoint, 73% for the Liberal Endpoint, and 80% for the Patient-defined Outcome endpoint (p<0.001). Of the 50 patients surveyed awaiting AF ablation, 70% said they would still consider the procedure a success if it required one repeat ablation or one DCCV (p=0.004), and 76% would be accepting of one or two recurrences during follow-up (p<0.001). Conclusion: In this study, the majority of patients still considered AF ablation a successful treatment if they had up to two recurrences of AF, one repeat procedure or one DCCV. Furthermore, a ¿Patient-defined¿ definition of success lead to significantly different results in this AF ablation cohort when compared to conventionally used/guideline directed measures of success.

Background: Physical Activity 4 Everyone (PA4E1) is an evidence-based program effective at increasing adolescent physical activity (PA) and improving weight status. This study aimed to determine a) the effectiveness of an adapted implementation intervention to scale-up PA4E1 at 24-month follow-up, b) fidelity and reach, and c) the cost and cost-effectiveness of the implementation support intervention. Methods: A cluster randomised controlled trial using a type III hybrid implementation-effectiveness design in 49 lower socio-economic secondary schools, randomised to a program (n = 24) or control group (n = 25). An adapted implementation intervention consisting of seven strategies was developed to support schools to implement PA4E1 over 24-months. The primary outcome was the proportion of schools implementing at least four of the 7 PA practices, assessed via computer assisted telephone interviews (CATI) with Head Physical Education Teachers. Secondary outcomes included the mean number of PA practices implemented, fidelity and reach, cost and cost-effectiveness. Logistic regression models assessed program effects. Results: At baseline, no schools implemented four of the 7 PA practices. At 24-months, significantly more schools in the program group (16/23, 69.6%) implemented at least four of the 7 PA practices than the control group (0/25, 0%) (p < 0.001). At 24-months, program schools were implementing an average of 3.6 more practices than control schools (4.1 (1.7) vs. 0.5 (0.8), respectively) (P < 0.001). Fidelity and reach of the implementation intervention were high (> 75%). The total cost of the program was $415,112 AUD (2018) ($17,296 per school; $117.30 per student). Conclusions: The adapted implementation intervention provides policy makers and researchers with an effective and potentially cost-effective model for scaling-up the delivery of PA4E1 in secondary schools. Further assessment of sustainability is warranted. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12617000681358 prospectively registered 12th May 2017.

Introduction/Aims: We explored correlates of night-time and exercise-associated lower limb cramps in participants of the 1000 Norms Project. Methods: A volunteer community sample of healthy people aged =18 y underwent assessment of motor function and physical performance, and were questioned about muscle cramps in the previous 3¿mo. Results: Of 491 (221 female) participants age 18¿101 y (mean: 59.12; SD: 18.03), about 1 in 3 experienced night-time lower limb cramps, and about 1 in 4 experienced exercise-associated lower limb cramps. For night-cramps, a one unit increase in Beighton score (greater whole-body flexibility) was associated with a 31% reduced odds of cramps (odds ratio [OR]¿=¿0.69, 95% confidence interval [CI]:0.45, 0.99) and passing all three lesser-toe strength tests was associated with 50% reduced odds of cramps (OR¿=¿0.50, 95% CI: 0.32, 0.78). For exercise-associated cramps, participants in the fourth (lowest arch) quartile of Foot Posture Index were 2.1 times (95% CI: 1.11, 3.95) more likely to experience cramps than participants in the first (highest arch) quartile. Odds of experiencing both types of cramps versus no cramps were lower with passing all three lesser-toe strength tests (OR¿=¿0.40, 95% CI: 0.19, 0.85) and better performance in the six-minute walk test (OR¿=¿0.997, 95% CI: 0.996, 0.998). Discussion: People who experienced both exercise-associated and night-time cramps were less functional. The association between night-time cramps with less whole-body flexibility and reduced lesser-toe flexor strength should be explored to determine causation. Planovalgus (low-arched) foot type was independently associated with exercise-associated cramps. The effectiveness of foot orthoses for secondary prevention of exercise-associated cramps in people with low-arched feet should be explored.

Objective: To evaluate whether a safe medication strategy compared with usual care, provided to people with dementia during an unplanned admission, reduces readmissions to hospital and re-presentation to emergency departments within three months. Methods: A prospective, controlled pre-/post-trial conducted at two regional hospitals in New South Wales, Australia. Results: No treatment effect was seen for time to first re-presentation or readmission within three months (P¿=.3). Compliance with six strategies applicable for all participants in the intervention phase was 58%. There was no treatment effect for secondary outcomes including dose administration aid use, home medicines review (HMR) requests by general practitioners and completed HMRs; however, they were significantly higher at the intervention site in both phases. Conclusion: A bundle of care to improve medication safety in people with dementia did not reduce re-presentations or readmissions within three months.

Introduction. Aboriginal pregnant women who smoke experience barriers to quitting, including challenges to social and emotional well-being, but these are infrequently quantified. Finding an appropriate measurement tool in this setting is crucial to increase knowledge for holistic smoking cessation interventions. Aims. To pilot the Growth and Empowerment Measure (GEM) with a sample of pregnant Aboriginal women who smoke. Methods. Aboriginal women participating in the step-wedge ICAN QUIT in Pregnancy pilot study completed the GEM comprised of 14-item Emotional Empowerment Scale (EES14), 12 Scenarios (12S), and K6 items at baseline, 4 weeks, and 12 weeks. Qualitative interviews with service staff were held at the end of the study to assess feasibility. Results. 15 pregnant Aboriginal women took part between November 2016 and July 2017. At 12 weeks, n=8/12 (67%) of women reported an increase in both the EES14 and 12S scores. Total 12S scores were significantly higher at 12 weeks (p=0.0186). Total K6 had a nonsignificant trend for reduction (p=0.0547). Staff reported that the length of the survey presents challenges in this setting. Conclusions. A shortened, modified GEM is recommended in this setting. We recommend the GEM to be tested in a larger study, powered to assess its associations with smoking behaviours.

Background: Unhealthy lifestyle behaviours contribute to the poor health of people attending alcohol and other drug (AOD) treatment. Healthy Recovery is an 8-session group-based intervention that targets smoking, diet and physical inactivity as part of an integrated healthy lifestyle approach. The current study aimed to examine the effectiveness of Healthy Recovery when delivered within residential AOD treatment settings. Methods: The study design was a stepped-wedge cluster randomised trial. Participants were 151 current smokers attending residential AOD programs provided by the Australian Salvation Army (n = 71, Control condition; n = 80, Intervention condition). The primary outcome was number of cigarettes smoked per day. Secondary outcomes examined other smoking behaviours (7-day point prevalence, use of nicotine replacement therapy [NRT]), diet (servings and variety of fruit and vegetables), and physical activity. Results: The mean number of cigarettes smoked per day was significantly lower in the Intervention condition at 2-, 5-, and 8-month follow-up. There were also significant differences in favour of the Intervention condition for number of quit attempts, use of NRT and variety of fruit. There were no other significant differences for other dietary or physical activity variables. Conclusions: Healthy Recovery had a positive impact on smoking behaviours. Future research should consider strategies to further promote smoking cessation (e.g. promoting longer-term use of NRT), as well as addressing physical activity and dietary behaviours. The introduction of broader organisational approaches (e.g. smoke free policies, organised group exercise and cooking activities) might help to enhance healthy lifestyle approaches within AOD treatment settings.

Background and objective: COVID-19 is complicated by acute lung injury, and death in some individuals. It is caused by SARS-CoV-2 that requires the ACE2 receptor and serine proteases to enter AEC. We determined what factors are associated with ACE2 expression particularly in patients with asthma and COPD. Methods: We obtained lower AEC from 145 people from two independent cohorts, aged 2¿89 years, Newcastle (n = 115) and Perth (n = 30), Australia. The Newcastle cohort was enriched with people with asthma (n = 37) and COPD (n = 38). Gene expression for ACE2 and other genes potentially associated with SARS-CoV-2 cell entry was assessed by qPCR, and protein expression was confirmed with immunohistochemistry on endobronchial biopsies and cultured AEC. Results: Increased gene expression of ACE2 was associated with older age (P = 0.03) and male sex (P = 0.03), but not with pack-years smoked. When we compared gene expression between adults with asthma, COPD and healthy controls, mean ACE2 expression was lower in asthma patients (P = 0.01). Gene expression of furin, a protease that facilitates viral endocytosis, was also lower in patients with asthma (P = 0.02), while ADAM-17, a disintegrin that cleaves ACE2 from the surface, was increased (P = 0.02). ACE2 protein expression was also reduced in endobronchial biopsies from asthma patients. Conclusion: Increased ACE2 expression occurs in older people and males. Asthma patients have reduced expression. Altered ACE2 expression in the lower airway may be an important factor in virus tropism and may in part explain susceptibility factors and why asthma patients are not over-represented in those with COVID-19 complications.

Background: Spirometry is commonly used to assess and monitor lung function. It may also be a useful tool to monitor maternal health during pregnancy. However, large studies examining lung function across gestation are limited. Also, whether spirometry values follow the same pattern during pregnancy in women with and without asthma is unknown. Objective: To investigate the effect of advancing gestation, and its interaction with asthma, on lung function in a large well-defined cohort of pregnant women. Methods: Data were obtained from prospective cohorts involving women with (n = 770) and without (n = 259) asthma (2004-2017), recruited between 12 and 22 weeks' gestation. Lung function (forced vital capacity [FVC], FEV1, FEV1:FVC%) was assessed periodically during pregnancy using spirometry. Multilevel mixed-effect regression models were used to assess changes in lung function over gestation. Results: Asthma had a significant effect on baseline lung function (FEV1%, -9%; FVC%, -3%; FEV1:FVC%, -4%). FVC% decreased with advancing gestation (-0.07%/wk; 95% CI, -0.10 to -0.04]), as did FEV1%, but only among those without asthma (women without asthma: -0.14%/wk, 95% CI, -0.22 to -0.06%; compared with women with asthma: 0.02%/wk, 95% CI, -0.01 to 0.06). FEV1:FVC% remained relatively stable for women without asthma (0.03%/wk; 95% CI, -0.08 to 0.02), but increased for women with asthma (0.06%/wk; 95% CI, 0.04 to 0.16). Conclusions: Data suggest that advancing gestation negatively affects FVC% and FEV1%. This is consistent with extrapulmonary restriction from advancing pregnancy. Yet, the presence of asthma altered the trajectories of FEV1% and FEV1:FVC%. Optimal asthma management during pregnancy might have opposed the negative effects of gestation on lung function.

Nerve growth factor (NGF) and its receptors, the neurotrophic receptor tyrosine kinase 1 (NTRK1/TrkA) and the common neurotrophin receptor (NGFR/p75NTR), are increasingly implicated in cancer progression, but their clinicopathological significance in oesophageal cancer is unclear. In this study, the expression of NGF, NTRK1 and NGFR were analysed by immunohistochemistry in a cohort of 303 oesophageal cancers versus 137 normal adjacent oesophageal tissues. Immunostaining was digitally quantified and compared to clinicopathological parameters. NGF and NGFR staining were found in epithelial cells and at similar levels between oesophageal cancers and normal oesophageal tissue. NGFR staining was slightly increased with grade (p=0.0389). Interestingly, NTRK1 staining was markedly higher in oesophageal squamous cell carcinoma (OR 2.31, 95%CI 1.13¿4.38, p<0.0001) and significantly lower in adenocarcinoma (OR 0.50, 95%CI 0.44¿0.63, p<0.0001) compared to normal oesophageal tissue. In addition, NTRK1 staining was decreased in grade 2 and grade 3 (OR 0.51, 95%CI 0.21¿1.40, p<0.0001) compared to grade 1, suggesting a preferential involvement of this receptor in the more differentiated forms of oesophageal carcinomas. Together, these data point to NTRK1 as a biomarker and a candidate therapeutic target in oesophageal squamous cell carcinoma.

Objective: To examine general practitioners¿ views about how health assessments for older people should be conducted. Methods: General practitioners were randomly sampled from a national database of medical practitioners and invited to complete a survey. Survey items explored general practitioners¿ views about essential components of a 75+ Health Assessment and who should assess each component, consultation time, use of standardised templates and tools, and home visits. Results: Overall, 185 (19.2%) general practitioners participated. Of 61 items presented, 24 were rated ¿essential¿ by =70% of practitioners, with an average estimated consultation time of 65 minutes. Of the 24 essential items, it was perceived that 21 could be assessed by either a general practitioner or clinic nurse. Most practitioners indicated a standardised template (86%) and standardised tools for complex issues (79%) should be used, and home visits conducted (75%). Conclusions: General practitioners agreed on 24 items as essential for every health assessment, with assessments estimated to take more than one hour. Implications for public health: Increases to remuneration for prolonged assessments or mechanisms for improving efficiency and quality of assessments are needed. Acceptable mechanisms may include standardised patient-reported tools, standardised templates and the use of non-medical staff to assist with assessments.

Background: Severe asthma with fungal sensitization (SAFS) and allergic bronchopulmonary aspergillosis (ABPA) are important complications of severe asthma. The evidence for treating them with omalizumab is limited. Objective: To determine the effectiveness of treatment with omalizumab in patients with severe allergic asthma comparing those with and without evidence of fungal sensitization using data recorded in the Australian Xolair Registry. Methods: Data from 205 patients who received omalizumab and recorded in the Australian Xolair Registry were analyzed to determine change in the Juniper 5-item Asthma Control Questionnaire (ACQ-5) score, exacerbation frequency, and oral corticosteroid dose over a 24-month period of omalizumab treatment. Patients were grouped into cohorts on the basis of fungal sensitization, and an analysis of improvement in outcomes between baseline and 24 months was conducted within each group. A further subgroup analysis of patients with ABPA was also conducted. Results: Patients with SAFS (n = 62), including those with ABPA (ASAFS), were as likely to demonstrate significant improvements in ACQ-5 score and exacerbations and reduced regular oral corticosteroid dose over 24 months as those with severe asthma without sensitization to fungi (n = 156). After adjusting for age, sex, body mass index, smoking history, and baseline FEV1%, the effects still remained. A subgroup analysis of 11 patients with ABPA similarly demonstrated a significant improvement on omalizumab. Conclusions: Omalizumab is an effective therapy in ASAFS, leading to sustained improvements in symptoms and exacerbations for 24 months. The benefit for ABPA is less clear because of the small sample size.

Aims: Perineural invasion (PNI) by prostatic adenocarcinoma is debated as a prognostic parameter. This study investigates the prognostic predictive value of PNI in a series of patients with locally advanced prostate cancer treated with radiotherapy and androgen deprivation using 10¿years outcome data from the TROG 03.04 RADAR trial. Methods: Diagnostic prostate biopsies from 976 patients were reviewed and the presence of PNI noted. Patients were followed for 10¿years according to the trial protocol or until death. The primary endpoint for the study was time to bone metastasis. Secondary endpoints included time to soft tissue metastasis, transition to castration resistance, prostate cancer-specific mortality and all-cause mortality. Results: PNI was detected in 449 cases (46%), with 234 cases (24%) having PNI in more than one core. The presence of PNI was significantly associated with higher ISUP grade, clinical T staging category, National Comprehensive Cancer Network risk group, and percent positive biopsy cores. The cumulative probability of bone metastases according to PNI status was significant over the 10¿years follow-up interval of the study (log-rank test P¿<¿0.0001). PNI was associated with all endpoints on univariable analysis. After adjusting for baseline clinicopathological and treatment factors, bone metastasis was the only endpoint in which PNI retained its prognostic significance (hazard ratio 1.42, 95% confidence interval 1.05¿1.92, P¿=¿0.021). Conclusions: The association between PNI and the development of bone metastases supports the inclusion of this parameter as a component of the routine histology report. Further this association suggests that evaluation of PNI may assist in selecting those patients who should be monitored more closely during follow-up.

Aim: This study aimed to explore clustering among individual eating behaviours in a sample of Australian university students, and explore associations between clustered eating behaviours and demographic characteristics. Methods: A cross-sectional analysis of data from the University of Newcastle (UON) Student Healthy Lifestyle Survey 2017 was conducted. Measures included eating behaviours (eg, vegetables, energy-dense nutrient poor [EDNP] food intakes) assessed using short diet questions, and demographic characteristics (eg, age, undergraduate/postgraduate student). Factor analysis was used to explore clustering of individual eating behaviours (ie, identify factors). Linear regression models were used to explore associations between eating behaviour factors identified and demographic characteristics. Results: A total of 3062 students (70% female; 56% aged 17-24 years) were included in the analysis. The six eating behaviour factors identified (characterised by higher consumption of the named foods/drinks) were; EDNP snack foods, meat and takeaway foods, fruit and vegetables, sugary drinks, breakfast, and breads and cereals. A higher fruit and vegetable factor score was associated with being female (P <.001), and a higher meat and takeaway foods factor score was associated with being male (P <.001) and of younger age (P <.001). Conclusions: Nutrient-rich foods clustered together and EDNP foods clustered together, that is, the identified factors represent either nutrient-rich or EDNP foods. Interventions in the university setting should target students with the poorest eating behaviours, including males and younger students.

Objective: To explore if better diet quality scores as a measure of adherence to the Australian Dietary Guidelines (ADG) and the Mediterranean diet (MedDiet) are associated with a lower incidence of hypertension and non-fatal CVD.Design: Prospective analysis of the 1946-1951 cohort of the Australian Longitudinal Study on Women's Health (ALSWH). The Australian Recommended Foods Score (ARFS) was calculated as an indicator of adherence to the ADG; the Mediterranean Diet Score (MDS) measured adherence to the MedDiet. Outcomes included hypertension and non-fatal CVD. Generalised estimating equations estimated OR and 95 % CI across quartiles of diet quality scores.Setting: Australia, 2001-2016.Participants: 1946-1951 cohort of the ALSWH (n 5324), without CVD, hypertension and diabetes at baseline (2001), with complete FFQ data.Results: There were 1342 new cases of hypertension and 629 new cases of non-fatal CVD over 15 years of follow-up. Multivariate analysis indicated that women reporting better adherence to the ARFS (=38/74) had 15 % (95 % CI 1, 28 %; P = 0·05) lower odds of hypertension and 46 % (95 % CI 6, 66 %; P = 0·1) lower odds of non-fatal CVD. Women reporting better adherence to the MDS (=8/17) had 27 % (95 % CI 15, 47 %; P = 0·0006) lower odds of hypertension and 30 % (95 % CI 2, 50 %; P = 0·03) lower odds of non-fatal CVD.Conclusions: Better adherence to diet quality scores is associated with lower risk of hypertension and non-fatal CVD. These results support the need for updated evidenced based on the ADG as well as public health nutrition policies in Australia.

Objective: The purpose of this study was to determine if there is a relationship between pain and movement kinematics during functional tasks, evaluated over time, in individuals with chronic idiopathic neck pain. Methods: Ten participants with chronic idiopathic neck pain performed 2 functional tasks (overhead reach to the right and putting on a seatbelt) while evaluated using 8 Oqus 300+ cameras. Kinematic variables included joint angles and range of motion (ROM) (°), head segment relative to neck segment (head-neck [HN]); and head/neck segment relative to upper thoracic segment (head/neck-trunk), velocity (m/s), and time (% of movement phase). Pain was quantified using a 100-mm visual analog scale. Linear mixed effects regression models were used to analyze associations between pain and kinematic variables adjusting for treatment group. Results: For overhead reach, higher pain was associated with less HN peak rotation at baseline (ß = ¿0.33; 95% CI -0.52 to ¿0.14, P = .003) and less HN total rotation ROM at 6 months (ß = ¿0.19; 95% CI ¿0.38 to ¿0.003, P = .048). For the seatbelt task, higher pain was associated with less HN peak rotation (ß = ¿0.52; 95% CI -0.74 to ¿0.30 to ¿0.74, P < .001) and less HN total rotation ROM at baseline (ß = ¿0.32; 95% CI ¿0.53 to ¿0.10, P = .006). No other movement variables demonstrated meaningful relationships with pain for the reach or seatbelt tasks. Conclusion: Higher pain is associated with less HN peak and total rotation during functional reaching tasks requiring head rotation. Recognizing altered functional kinematics in individuals with chronic neck pain may assist patient management.

Aim: To examine whether nurses' location of employment, demographics, or training influences their perceptions of what constitutes optimal care for dying patients in hospital. Design: Questionnaire-based, cross-sectional study. Methods: Between December 2016¿June 2018, 582 registered or enrolled nurses from Australia (N¿=¿153), South Korea (N¿=¿241), and Hong Kong (N¿=¿188) employed in a variety of hospital care units rated the extent to which they agreed with 29 indicators of optimal end-of-life care across four domains: patient, family, healthcare team, and healthcare system. Latent class analysis identified classes of respondents with similar responses. Results: Top five indicators rated by participants included: ¿physical symptoms managed well¿; ¿private rooms and unlimited visiting hours¿; ¿spend as much time with the patient as families wish¿; 'end-of-life care documents stored well and easily accessed¿ and ¿families know and follow patient's wishes¿. Four latent classes were generated: ¿Whole system/holistic¿ (Class 1); ¿Patient/provider-dominated¿ (Class 2); ¿Family-dominated¿ (Class 3) and ¿System-dominated¿ (Class 4). Class 1 had the highest proportion of nurses responding positively for all indicators. Location was an important correlate of perceptions, even after controlling for individual characteristics. Conclusion: Nurses' perceptions of optimal end-of-life care are associated with location, but perhaps not in the direction that stereotypes would suggest. Findings highlight the importance of developing and implementing location-specific approaches to optimize end-of-life care in hospitals. Impact: The findings may be useful to guide education and policy initiatives in Asian and Western countries that stress that end-of-life care is more than symptom management. Indicators can be used to collect data that help quantify differences between optimal care and the care actually being delivered, thereby determining where improvements might be made.

Background: Transbronchial lung cryobiopsy (TBLC) is a novel technique for sampling lung tissue for interstitial lung disease diagnosis. The aim of this study was to establish the diagnostic accuracy of TBLC compared with surgical lung biopsy (SLB), in the context of increasing use of TBLC in clinical practice as a less invasive biopsy technique. Methods: COLDICE was a prospective, multicentre, diagnostic accuracy study investigating diagnostic agreement between TBLC and SLB, across nine Australian tertiary hospitals. Patients with interstitial lung disease aged between 18 and 80 years were eligible for inclusion if they required histopathological evaluation to aid diagnosis, after detailed baseline evaluation. After screening at a centralised multidisciplinary discussion (MDD), patients with interstitial lung disease referred for lung biopsy underwent sequential TBLC and SLB under one anaesthetic. Each tissue sample was assigned a number between 1 and 130, allocated in a computer-generated random sequence. Encoded biopsy samples were then analysed by masked pathologists. At subsequent MDD, de-identified cases were discussed twice with either TBLC or SLB along with clinical and radiological data, in random non-consecutive order. Co-primary endpoints were agreement of histopathological features in TBLC and SLB for patterns of definite or probable usual interstitial pneumonia, indeterminate for usual interstitial pneumonia, and alternative diagnosis; and for agreement of consensus clinical diagnosis using TBLC and SLB at MDD. Concordance and ¿ values were calculated for each primary endpoint. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12615000718549. Findings: Between March 15, 2016, and April 15, 2019, we enrolled 65 patients (31 [48%] men, 34 [52%] women; mean age 66·1 years [SD 9·3]; forced vital capacity 83·7% [SD 14·2]; diffusing capacity for carbon monoxide 63·4% [SD 12·8]). TBLC (7·1 mm, SD 1·9) and SLB (46·5 mm, 14·9) samples were each taken from two separate ipsilateral lobes. Histopathological agreement between TBLC and SLB was 70·8% (weighted ¿ 0·70, 95% CI 0·55¿0·86); diagnostic agreement at MDD was 76·9% (¿ 0·62, 0·47¿0·78). For TBLC with high or definite diagnostic confidence at MDD (39 [60%] of 65 cases), 37 (95%) were concordant with SLB diagnoses. In the 26 (40%) of 65 cases with low-confidence or unclassifiable TBLC diagnoses, SLB reclassified six (23%) to alternative high-confidence or definite MDD diagnoses. Mild-moderate airway bleeding occurred in 14 (22%) patients due to TBLC. The 90-day mortality was 2% (one of 65 patients), following acute exacerbation of idiopathic pulmonary fibrosis. Interpretation: High levels of agreement between TBLC and SLB for both histopathological interpretation and MDD diagnoses were shown. The TBLC MDD diagnoses made with high confidence were particularly reliable, showing excellent concordance with SLB MDD diagnoses. These data support the clinical utility of TBLC in interstitial lung disease diagnostic algorithms. Further studies investigating the safety profile of TBLC are needed. Funding: University of Sydney, Hunter Medical Research Institute, Erbe Elektromedizin, Medtronic, Cook Medical, Rymed, Karl-Storz, Zeiss, and Olympus.

Aim: Aims were to test the effectiveness of an organizational change intervention integrating smoking cessation treatment into usual alcohol and other drug (AOD) treatment, compared with usual care, on (1) 7-day point prevalence abstinence (PPA) at 8¿weeks follow-up; (2) prolonged abstinence; (3) cigarettes smoked per day; (4) number of quit attempts; and (5) offer and use of nicotine replacement therapy (NRT). All outcomes were assessed at 8¿weeks and 6.5¿months follow-up. Design: Cluster-randomized controlled trial, with AOD service as unit of randomization, conducted January 2015¿March 2016. Setting: Thirty-two eligible services (provided face-to-face client sessions to =¿50 clients/year) in Australia were randomized to control (usual care; n¿=¿15) or intervention (n¿=¿17) groups by an independent blinded biostatistician. Participants: Eligible participants (= 16¿years, current smoker) completed surveys at the service at baseline (n¿=¿896) and telephone follow-up surveys (conducted by blinded assessors) at 8¿weeks (n¿=¿471; 53%) and 6.5¿months (n¿=¿427; 48%). Intervention: Intervention services received an intervention to establish routine screening, assessment and delivery of smoking cessation care. Measurements: Primary outcome was biochemically verified 7-day PPA at 8-week follow-up. Secondary outcomes included verified and self-reported prolonged abstinence, self-reported 7-day PPA, cigarettes/day, quit attempts and offer and use of NRT. Intention-to-treat analyses were performed, assuming missing participants were not abstinent. Findings: At 8¿weeks, the findings in verified 7-day PPA between groups [2.6 versus 1.8%, odds ratio (OR)¿=¿1.72, 95% confidence interval (CI)¿=¿0.5¿5.7, P¿=¿0.373] were inconclusive as to whether a difference was present. Significantly lower mean cigarettes/day were reported in the intervention group compared to the usual care group at 8¿weeks [incidence rate ratio (IRR)¿=¿0.88, 95% CI¿=¿0.8¿0.95, P¿=¿0.001] but were similar at 6.5 months (IRR¿=¿0.96, 95% CI¿=¿0.9¿1.02, P¿=¿0.240) follow-up. At both follow-ups the intervention group reported higher rates of NRT use. Conclusions: Integrating smoking cessation treatment into addiction services did not significantly improve short-term abstinence from smoking.

Background: Addressing smoking cessation during pregnancy among Aboriginal women is a national priority under the Closing the Gap campaign. There is a need to measure and report interventions to support Aboriginal women during pregnancy. Aim: To quantitatively assess women's smoking experiences over a 12 week ICAN QUIT in Pregnancy program. Methods: Aboriginal women and/or women expecting an Aboriginal baby reported their smoking experiences through repeated cross-sectional survey at baseline, four weeks, and 12 weeks. Self-reported nicotine dependence measures (heaviness of smoking index, strength of urges and frequency of urges to smoke), intentions to quit smoking, quit attempts, use of nicotine replacement therapy were gathered as well as a carbon-monoxide measure at each time point. Results: Expectant mothers (n = 22) of Aboriginal babies participated from six Aboriginal Community Controlled Health Services between November 2016 and July 2017. At 12 weeks women reported (n = 17) low heaviness of smoking index 1.21 with high strength of urges 2.64 and frequency of urges 3.00; 12/13 (92%) reported likely/very likely to quit smoking, made a mean 1.67 number of quit attempts, three women (13.6%) quit smoking (validated); 5/16 (31%) reported using nicotine replacement therapy. Discussion: Participating women made multiple quit attempts demonstrating motivation to quit smoking. Smoking cessation interventions should be tailored to address high strength and frequency of nicotine dependence despite low consumption. Conclusion: Prolonged smoking cessation support is recommended to address physical, behavioural and psychological aspect of smoking. Cessation support should address previous quitting experiences to assess smoking dependence and tailoring of support. Trial registration: Australian and New Zealand Clinicial Trials Registry (Ref #ACTRN12616001603404).

Purpose: To clarify the relative effects of duration of androgen suppression (AS) and radiation dose escalation (RDE) on distant progression (DP) in men with locally advanced prostate cancer. Methods and Materials: Participants with locally advanced prostate cancer in the TROG 03.04 RADAR trial were randomized to 6 or 18 months AS ± 18 months zoledronic acid (Z). The trial incorporated a RDE program by stratification at randomization and dosing options were 66, 70, or 74 Gy external beam radiation therapy (EBRT), or 46 Gy EBRT plus high-dose-rate brachytherapy boost (HDRB). The primary endpoint for this study was distant progression (DP). Secondary endpoints included local progression, bone progression, prostate cancer-specific mortality and all-cause mortality. Effect estimates for AS duration and RDE were derived using Fine and Gray competing risk models adjusting for use of Z, age, tumor stage, Gleason grade group, prostate-specific antigen, and treatment center. Cumulative incidence at 10 years was estimated for each RDE group. Results: A total of 1051 out of 1071 randomized subjects were eligible for inclusion in this analysis. Compared with 6 months AS, 18 months AS significantly reduced DP independently of radiation dose (subhazard ratio 0.70; 95% confidence interval [CI], 0.56-0.87; P =.002). No statistically significant interaction between effect of AS duration and RT dose was observed (Wald test P =.76). In subgroup analyses, DP was significantly reduced by the longer duration of AS in the 70 Gy and HDRB groups but not in the 66 Gy and 74 Gy. Compared with 70 Gy, HDRB significantly reduced DP (subhazard ratio 0.68 [95% CI, 0.57-0.80]; P <.0001) independently of AS duration. At 10 years, adjusted cumulative incidences were 26.1% (95% CI, 18.9%-33.2%), 26.7% (22.9%-30.6%), 24.9% (20.0%-29.8%) and 19.7% (15.5%-23.8%) for DPs in the respective radiation dose groups. Conclusions: Compared with 6 months AS, 18 months AS reduced DP independently of radiation dose. Men treated with HDRB gained a significant benefit from a longer duration of AS. Evidence of improved oncologic outcomes for HDRB compared with dose-escalated EBRT needs to be confirmed in a randomized trial.

This study examined the prevalence of and sociodemographic characteristics associated with elevated symptoms of depression among clients seeking alcohol or other drug (AOD) treatment. Consenting clients attending two AOD outpatient clinics answered demographics, treatment questions and the Patient Health Questionnaire to assess depressive symptoms. Counts and percentages were calculated to determine the prevalence of elevated depressive symptoms. Logistic regression was used to model the odds of having elevated depressive symptoms for client demographics. Of the 203 clients who completed the survey (87% consent rate), 55% (n = 111) demonstrated elevated depressive symptoms. Females were twice as likely to experience elevated symptoms of depression compared to males (OR 2.07; 95% CI 1.05, 4.08; P = 0.037). The high rates of elevated depressive symptoms among individuals seeking AOD treatment highlight the importance of ongoing research to provide effective treatments for this comorbidity. Routine screening and clear treatment pathways may assist with providing high quality care.

Background: Young adults born preterm have remodeled hearts, i.e., altered cardiac shape and size with impaired cardiac function. At present, the natural history and pattern of prematurity related cardiac remodeling are not clearly established. The aim of this study was to compare the left ventricle (LV) geometry and function of preterm infants at 36 weeks postmenstrual age (PMA) with gestation matched newborn infants. Methods: LV end diastolic volume index (LV EDVI), LV mass index (LVMI), relative wall thickness (RWT), and sphericity index (SI) were prospectively obtained with echocardiography. LV geometry was classified according to the Gaasch method. LV function was assessed by determining ejection fraction (EF), longitudinal strain (LS), mitral annulus systolic motion (s¿), and estimated LV filling pressure (E/e¿). Results: Eighty-three preterm infants between 23 and 29 weeks gestation, and 40 infants of 36 weeks gestation at birth were analysed. LV EDVI, LVMI, SI, LS, s¿, and E/e¿ were higher in preterm group while RWT and EF were comparable between groups. LV showed normal geometry in 55.4%, physiological enlargement in 23% and dilated hypertrophy in 21.6% preterm infants. Conclusion: At 36 week, preterm infants have significantly dilated, hypertrophied, and more spherical LV with impaired diastolic function compared with PMA matched newborn infants.

The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). TrkA was expressed in cancer epithelial and myoepithelial cells, with higher levels of TrkA positively associated with IDC (39% of cases) (p < 0.0001). Interestingly, TrkA was significantly increased in tumours expressing the human epidermal growth factor receptor-2 (HER2), with expression in 49% of HER2-positive compared to 25% of HER2-negative tumours (p = 0.0027). A panel of breast cancer cells were used to confirm TrkA protein expression, demonstrating higher levels of TrkA (total and phosphorylated) in HER2-positive cell lines. Functional investigations using four different HER2-positive breast cancer cell lines indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability, through decreased phospho-TrkA (Tyr490) and downstream AKT (Ser473) activation, but did not display synergy with Herceptin. Overall, these data highlight a relationship between the tyrosine kinase receptors TrkA and HER2 and suggest the potential of TrkA as a novel or adjunct target for HER2-positive breast tumours.

Background: Regular methamphetamine use is associated with increased rates of psychiatric symptoms. Although there has been a substantial body of research reporting on the effectiveness of psychological treatments for reducing methamphetamine use, there is a paucity of research examining the effects of these treatments on co-occurring psychiatric symptoms. We addressed this gap by undertaking a systematic review of the evidence of the effectiveness of psychological treatments for methamphetamine use on psychiatric symptom outcomes in randomized controlled trials. Methods: A narrative synthesis of studies was conducted following the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement to inform methodology. Eight electronic peer-reviewed databases were searched. Ten eligible studies were assessed. Results: Most studies found an overall reduction in levels of methamphetamine use and psychiatric symptoms among samples as a whole. Although brief interventions were effective, there is evidence that more intensive interventions have greater impact on methamphetamine use and/or psychiatric symptomatology. Intervention attendance was variable. Conclusions: The evidence suggests that a variety of psychological treatments are effective in reducing levels of methamphetamine use and improving psychiatric symptoms. Future research should consider how psychological treatments could maximize outcomes in the co-occurring domains of methamphetamine use and psychiatric symptoms, with increasing treatment attendance as a focus. PROSPERO registration number: CRD42016043657.

Purpose: Very little is known about the genetic risk factors associated with triple-negative breast cancer (TNBC), an aggressive clinical subtype characterised by the absence of ER, PR and HER2. p53, the tumour suppressor gene, is essential for maintaining genomic stability in response to cellular stress. In breast cancer, the mutation rates of TP53 vary depending on the subtype, such that ER-negative tumours have a high rate, and in ER-positive tumours they are less common. Previous studies have implicated the intronic polymorphism in TP53 (rs17878362; or PIN3) with an increased risk of developing breast cancer, although little has been discerned on its prevalence in different subtypes. In this study, we investigated the prevalence of the PIN3 genotype in the blood of cohorts with ER-positive and the ER-negative subtype TNBC, and assessed its association with outcome. Methods: We genotyped 656 TNBC and 648 ER-positive breast cancer patients, along with 436 controls, and compared the prevalence of polymorphism rs17878362 in these cohorts. Results: We found there to be no differences in the prevalence of the PIN3 genotype between the ER-positive and TNBC cohorts. Furthermore, no statistically significant difference was observed in the outcome of patients in either cohort with respect to their PIN3 genotype. Conclusions: Taken together, our results do not support an association of the PIN3 genotype with increased breast cancer risk, either in ER-positive or ER-negative patients.

Background: The optimal duration of androgen suppression for men with locally advanced prostate cancer receiving radiotherapy with curative intent is yet to be defined. Zoledronic acid is effective in preventing androgen suppression-induced bone loss, but its role in preventing castration-sensitive bone metastases in locally advanced prostate cancer is unclear. The RADAR trial assessed whether the addition of 12 months of adjuvant androgen suppression, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive 6 months of androgen suppression and prostatic radiotherapy. This report presents 10-year outcomes from this trial. Methods: For this randomised, phase 3, 2 × 2 factorial trial, eligible men were 18 years or older with locally advanced prostate cancer (either T2b-4, N0 M0 tumours or T2a, N0 M0 tumours provided Gleason score was =7 and baseline prostate-specific antigen [PSA] concentration was =10 µg/L). We randomly allocated participants in a 2 × 2 factorial design by computer-generated randomisation (using the minimisation technique, and stratified by centre, baseline PSA concentration, clinical tumour stage, Gleason score, and use of a brachytherapy boost) in a 1:1:1:1 ratio to four treatment groups. Patients in the control group received 6 months of neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) and radiotherapy alone (short-term androgen suppression [STAS]); this treatment was either followed by another 12 months of adjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly; intermediate-term androgen suppression [ITAS]), or accompanied by 18 months of zoledronic acid (4 mg every 3 months, intravenously) starting at randomisation (STAS plus zoledronic acid), or both (ITAS plus zoledronic acid). All patients received radiotherapy to the prostate and seminal vesicles, starting from the end of the fifth month of androgen suppression; dosing options were 66, 70, and 74 Gy in 2-Gy fractions per day, or 46 Gy in 2-Gy fractions followed by a high-dose-rate brachytherapy boost dose of 19·5 Gy in 6·5-Gy fractions. Treatment allocation was open label. The primary endpoint was prostate cancer-specific mortality and was analysed according to intention-to-treat using competing-risks methods. The trial is closed to follow-up and this is the final report of the main endpoints. This trial is registered with ClinicalTrials.gov, number NCT00193856. Findings: Between Oct 20, 2003, and Aug 15, 2007, 1071 men were enrolled and randomly assigned to STAS (n=268), ITAS (n=268), STAS plus zoledronic acid (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 10·4 years (IQR 7·9¿11·7). At this 10-year follow-up, no interactions were observed between androgen suppression and zoledronic acid so the treatment groups were collapsed to compare treatments according to duration of androgen suppression: 6 months of androgen suppression plus radiotherapy (6AS+RT) versus 18 months of androgen suppression plus radiotherapy (18AS+RT) and to compare treatments according to whether or not patients received zoledronic acid. The total number of deaths was 375 (200 men receiving 6AS+RT and 175 men receiving 18AS+RT), of which 143 (38%) were attributable to prostate cancer (81 men receiving 6AS+RT and 62 men receiving 18AS+RT). When analysed by duration of androgen suppression, the adjusted cumulative incidence of prostate cancer-specific mortality was 13·3% (95% CI 10·3¿16·0) for 6AS+RT versus 9·7% (7·3¿12·0) for 18AS+RT, representing an absolute difference of 3·7% (95% CI 0·3¿7·1; sub-hazard ratio [sHR] 0·70 [95% CI 0·50¿0·98], adjusted p=0·035). The addition of zoledronic acid did not affect prostate cancer-specific mortality; the adjusted cumulative incidence of prostate cancer-specific mortality was 11·2% (95% CI 8·7¿13·7) with zoledronic acid vs 11·7% (9·2¿14·1) without, representing an absolute difference o...

Background: Transient ischemic attacks are common and place patients at risk of subsequent stroke. The 2007 EXPRESS and SOS-TIA studies demonstrated the efficacy of rapid treatment initiation. We hypothesized that with these findings having informed subsequent transient ischemic attacks management protocols, transient ischemic attacks prognosis in contemporary (2008 and later) patient cohorts would be more favorable than in historical cohorts. Methods: A systematic review and meta-analysis of cohort studies and randomized control trial placebo-arms of transient ischemic attack (published 2008¿2015). The primary outcome was stroke. Secondary outcomes were mortality, transient ischemic attack, and myocardial infarction. Studies were excluded if the outcome of transient ischemic attack patients was not reported separately. The systematic review included all studies of transient ischemic attack. The meta-analysis excluded studies of restricted transient ischemic attack patient types (e.g. only patients with atrial fibrillation). The pooled cumulative risks of stroke recurrence were estimated from study-specific estimates at 2, 7, 30, and 90 days post-transient ischemic attack, using a multivariate Bayesian model. Results: We included 47 studies in the systematic review and 40 studies in the meta-analysis. In the systematic review (191,202 patients), stroke at 2 days was reported in 13/47 (27.7%) of studies, at 7 days in 20/47 (42.6%), at 30 days in 12/47 (25.5%), and at 90 days in 33/47 (70.2%). Studies included in the meta-analysis recruited 68,563 patients. The cumulative risk of stroke was 1.2% (95% credible interval (CI) 0.6¿2.2), 3.4% (95% CI 2.0¿5.5), 5.0% (95% CI 2.9¿8.9), and 7.4% (95% CI 4.3¿12.4) at 2, 7, 30, and 90 days post-transient ischemic attack, respectively. Conclusion: In contemporary settings, transient ischemic attack prognosis is more favorable than reported in historical cohorts where a meta-analysis suggests stroke risk of 3.1% at two days.

National and international guidelines recommend opportunistic screening for chronic kidney disease to allow for early detection and management. Despite these guidelines, screening for chronic kidney disease in general practice settings is often suboptimal. This paper reports the results of a study that evaluated: (a) the effect of an asynchronous web-based e-learning module on general practice nurses' knowledge about chronic kidney disease risk factors and screening practices and (b) general practice nurses' perceived satisfaction with the e-learning module. Changes in chronic kidney disease knowledge were assessed using a pre-test and post-test evaluative design, and satisfaction scores were measured on completion of the module. Participants' baseline knowledge scores were poor, with mean pre-test scores of 3.77 (s.d. 1.66) out of 10. Post-test scores revealed a significant improvement (mean difference 1.81, (95% CI: 1.53-2.09), P < 0.01) however, overall final scores remained inadequate. Participants highly rated their satisfaction with the design of the module. Our results suggest that an asynchronous web-based e-learning module can improve general practice nurses' knowledge about chronic kidney disease risk factors and screening practice. Efforts are required to increase practice nurses' access to educational opportunities designed to improve knowledge in this area with the aim of increasing opportunistic screening for chronic kidney disease in the general practice setting.

Background: The burden of Chronic Kidney Disease (CKD) on the Australian health system is growing. Efforts to reverse this trend have not been successful. This paper evaluates the effectiveness of a targeted asynchronous web based e-learning module on general practice nurses¿ behavioural intentions in relation to opportunistic screening practices for people at risk of CKD. Design: Double blinded pre-post interventional randomised control design. Methods: Participants were nurses working in general practice settings in Australia. Participants were randomised to a knowledge based active control or targeted behavioural based intervention which were delivered using asynchronous e-learning modules. The intervention was designed to influence the behavioural constructs of the theory of planned behaviour (TPB): attitude, subjective norm and perceived behavioural control (PBC). Results: Of the 420 participants, we analysed the primary and secondary outcomes for 212 (50.47%) who had complete follow up data. There were no significant differences (p 0.424, [d] 0.04) in behavioural intention between the intervention and control groups at follow-up, when controlling for baseline values. However, regression models assessing the relationship between the change in the TPB constructs and behavioural intention at follow-up for all participants, regardless of study arm, demonstrated a significant change in intention to initiate a kidney health check. Although these changes could not be attributed to the effect of the intervention. Attitude (r2 = 0.3525, p 0.0004) and PBC (r2 = 0.3510, p 0.0005) models accounted for approximately 35% of the explained variance in behavioural intentions and social norm (r2 = 0.3297, p 0.0171) accounted for approximately 33% of the variance. When all TPB constructs were included in the model, 37% of the variance in intention was explained. Conclusion: A targeted behavioural online intervention was no more effective than a knowledge based online program to improve primary health care nurses¿ intention to initiate a kidney health check in people at risk of chronic kidney disease. Relevance to clinical practice: Collaborative efforts are required by all staff working in general practice to develop models of care to improve screening practices for chronic kidney disease. Future research should focus on interventions that improve collaboration between health care professionals in the primary care setting and public health campaigns to increase awareness of risks of CKD and the importance of screening in the primary care setting.

Background: Why adolescents' drinking is associated with their parents' drinking remains unclear. We examined associations in a prospective cohort study, adjusting for socio-demographic characteristics and family factors. Methods: We recruited 1927 children from grade 7 classes (mean age 13 years), and one of their parents, in three Australian states, contacted participants annually from 2010 to 2014, and analysed data from assessments at ages 13, 14, 15 and 16 years. We used the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) subscale to identify hazardous drinking in parents (score =5) and children (score =3) and constructed mixed-effect logistic regression models, accounting for clustering within school and adjusting for likely confounders. We evaluated the sensitivity of estimates by imputing missing values assuming the data were missing at random vs. missing not at random. Results: Parent hazardous drinking predicted mid-adolescent hazardous drinking, e.g. 15 years olds whose parents [adjusted odds ratio (aOR) 2.00; 95% confidence interval 1.51-2.64] or parents' partners (aOR 1.94; 1.48-2.55) were hazardous drinkers had higher odds of being hazardous drinkers at age 16. The magnitude of univariate associations changed little after adjusting for covariates, and sensitivity analyses confirmed the robustness of the association, across a wide range of assumptions about the missing data. Conclusions: The associations between parents' and their adolescent children's hazardous drinking are unlikely to be due to confounding by socio-demographic and family factors. Parents should be encouraged, and supported by public policy, to reduce their own alcohol consumption in order to reduce their children's risk of becoming hazardous drinkers.

Background: Limited ankle dorsiflexion, or equinus, is associated with elevated plantar pressures, which have been implicated in the development and non-healing of foot ulcer. A stretching intervention may increase ankle dorsiflexion and reduce plantar pressures in people with diabetes. Methods: Two arm parallel randomised controlled trial from September 2016 to October 2017. Adults with diabetes and ankle equinus (=5° dorsiflexion) were randomly allocated to receive an 8 week static calf stretching intervention or continue with their normal activities. Primary outcome measures were change in weight bearing and non-weight bearing ankle dorsiflexion and forefoot peak plantar pressure. Secondary outcome measures were forefoot pressure time integrals and adherence to the stretching intervention. Findings: 68 adults (mean (standard deviation) age and diabetes duration 67.4 (10.9) years and 14.0 (10.8) years, 64.7% male) were randomised to stretch (n = 34) or usual activity (n = 34). At follow up, no significant differences were seen between groups (adjusted mean difference) for non-weight (+1.3°, 95% CI:-0.3 to 2.9, p = 0.101) and weight bearing ankle dorsiflexion (+0.5°, 95% CI:-2.6 to 3.6, p = 0.743) or forefoot in-shoe (+1.5 kPa, 95% CI:-10.0 to 12.9, p = 0.803) or barefoot peak pressures (-19.1 kPa, 95% CI:-96.4 to 58.1, p = 0.628). Seven of the intervention group and two of the control group were lost to follow up. Interpretation: Our data failed to show a statistically significant or clinically meaningful effect of static calf muscle stretching on ankle range of motion, or plantar pressures, in people with diabetes and ankle equinus.

Background: Currently, there is no single validated biomarker which can prognosticate survival in patients with stage IV non-small cell lung cancer (NSCLC). This study examines the prognostic significance of four biomarkers: neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR) and advanced lung cancer inflammation index (ALI) in patients with stage IV NSCLC. Methods: This study aimed to establish the relationship between NLR, LMR, PLR, ALI and overall survival (OS) at baseline and post first cycle of treatment using Cox univariate PH models. We also studied these biomarkers in the elderly (age =70 years). Clinical data was sourced from Calvary Mater Newcastle between 2010 and 2015. Results: Baseline NLR, PLR, LMR and ALI showed strong association with OS. Five unit increase in NLR and PLR was associated with an 11% and 0.5% increase in the hazard of death respectively while 1 unit increase in ALI resulted in 4% increase in hazard of death. Five unit increase in LMR was associated with a 50% reduction in hazard of death. Post-treatment NLR and low ALI correlated with shorter OS but no statistically significant relationship could be demonstrated for PLR nor LMR. Similar prognostic trends were noted for elderly. Conclusions: High NLR, high PLR, low LMR and low ALI at baseline are significantly associated with poor OS. High NLR and low ALI are significantly associated with poor OS post treatment. Findings are similar regardless of age.

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.

Background Stroke events often result in long-term negative health outcomes. People who experience a first stroke event are 30%-40% more likely to experience a second stroke event within 5 years. An online secondary prevention programme for stroke survivors may help stroke survivors improve their health risk behaviours and lower their risk of a second stroke. Objectives This paper describes the development and early iteration testing of the usability and acceptability of an online secondary prevention programme for stroke survivors (Prevent 2nd Stroke, P2S). P2S aims to address six modifiable health risk behaviours of stroke: blood pressure, physical activity, nutrition, depression and anxiety, smoking, and alcohol consumption. Methods P2S was developed as an eight-module online secondary prevention programme for stroke survivors. Modelled on the DoTTI (Design and development, Testing early iterations, Testing for effectiveness, Integration and implementation) framework for the development of online programmes, the following stages were followed during programme development: (1) content development and design; and (2) testing early iteration. The programme was pilot-tested with 15 stroke survivors who assessed P2S on usability and acceptability. Results In stage 1, experts provided input for the content development of P2S. In stage 2, 15 stroke survivors were recruited for usability testing of P2S. They reported high ratings of usability and acceptability of P2S. P2S was generally regarded as easy to use' and relevant to stroke survivors'. Participants also largely agreed that it was appropriate to offer lifestyle advice to stroke survivors through the internet. Conclusions The study found that an online secondary prevention programme was acceptable and easily usable by stroke survivors. The next step is to conduct a randomised controlled trial to assess the effectiveness of the programme regarding behaviour change and determine the cost-effectiveness of the intervention.

Background and objective: Publicly funded therapy for idiopathic pulmonary fibrosis (IPF) relies on percentage predicted values from pulmonary function testing, for example Australian patients must have a forced vital capacity =50% (%FVC), transfer factor of the lung for carbon monoxide = 30% (%TLco) and forced expiratory volume in 1 s (FEV1)/FVC ratio > 0.7. Despite defined cut-off values, no jurisdiction prescribes a reference equation for use; multiple equations exist. We hypothesized that access to subsidized treatment varies depending on the chosen equation. The %FVC and %TLco from different commonly used reference equations across general respiratory patients, and IPF-specific patients, were compared. Methods: FVC and TLco measurements from a large general respiratory laboratory and the Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR) database were analysed using multiple equations. Differences between %FVC and %TLco for each equation were calculated, with particular interest in classification of patients (%) at the threshold for subsidized treatment. Results: A total of 20 378 general respiratory database results were analysed. The %FVC = 50% increased from 86% with the Roca equation to 96% with Quanjer (European Coal and Steal Community, ECSC) and %TLco=30% increased from 91% with Paoletti to 98% with Thompson. However, overall increase in eligibility for subsidized treatment was modest, varying from 48.2% to 49.2%. A total of 545 AIPFR database results were analysed. The %FVC = 50% increased from 73% with Roca to 94% with Quanjer (ECSC) and %TLco=30% increased from 87% with Paoletti to 96% with Miller. Overall eligibility for subsidized treatment in the AIPFR group varied from 73.6% to 82.8% between surveyed interstitial lung disease (ILD) centres based entirely on the equation used. Conclusion: Substantial variability exists between reference equations, impacting access to subsidized treatment. Treating clinicians should be aware of this when assessing patients around public funding thresholds.

Sensory over-reactivity may be related to atypical defecation habits in children with constipation. The Toileting Habit Profile Questionnaire-Revised (THPQ-R) is designed to identify defecation-related sensory issues. This study examined the discriminative and concurrent validity of the THPQ-R. Differentiating between children with and without constipation was used to establish discriminative validity. The relationship between scores on the THPQ-R and on the defecation scale of the Virginia Encopresis-Constipation Apperception Test (VECAT-S) was examined to establish concurrent validity. The difference in THPQ-R scores was statistically significant. There was a strong positive correlation between the over-reactivity section of the THPQ-R and VECAT-S scores. Results support using the THPQ-R to identify atypical defecation behaviors.

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.

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

Introduction: Health providers are lacking in their provision of smoking cessation care during pregnancy. The aim of this study was to systematically review all available global studies on the effectiveness of interventions in improving health providers¿ provision of smoking cessation care during pregnancy. Methods: Five databases were searched, Inclusion criteria included all intervention study types. Two reviewers screened abstracts and full texts independently. Interventions were characterized according to the Effective Practice Of Care taxonomy. Random-effects meta-analyses examined intervention effects on smoking cessation care components based on the 5As. Estimates were number of participants reporting each outcome, or mean score, transformed into Cohen's d. Crude meta-regressions, and meta-analysis subgrouping, were performed to examine whether intervention effects for ¿Ask¿ ¿Advise¿ and ¿Assist¿ differed by intervention components. Results: Of 3165 manuscripts, 16 fulfilled inclusion criteria. Pooled analysis showed significant small to large intervention effects on the different care components (Cohen's d ranging from 0.47 for ¿Ask¿ (95%CI 0.13¿0.81) to 1.12 (95%CI 0.45¿1.79) for ¿Setting a quit date¿). Crude meta-regression suggested that for ¿Ask¿ having a theoretical basis may improve effectiveness (Cohen's d difference 0.62, 95% CI 0.12¿1.1). Subgrouping the meta-analysis suggested that audit and feedback possibly increases intervention effectiveness for ¿Advise¿ and ¿Assist¿. Conclusion: Interventions designed to improve provision of smoking cessation care during pregnancy show a small increase in care components. Studies vary substantially in design, intervention components, and outcome measurement, impacting ability to synthesize available data. Audit and feedback and enhancing intervention design by using behaviour change theories may improve effectiveness. Registration: PROSPERO CRD42016030143.

This study evaluated discharge documentation for people with dementia who were discharged home, against expected discharge criteria and determined relationships between compliance scores and outcomes. This cross-sectional study audited discharge documentation and conducted a post discharge survey of carers. There were 73 eligible discharges and clinically significant documentation deficits for people with dementia included: risk assessments of confusion (48%), falls and pressure injury (56%); provision of medication dose-decision aids (53%), provision of contact information for patient support groups (6%) and advance care planning (9%). There was no significant relationship between compliance scores and outcomes. Carer strain was reported to be high for many carers. People with dementia and their carers are more vulnerable and at higher risk of poor outcomes after discharge. There are opportunities for improved provision of medications and risk assessment for people with dementia, provision of information for patient support groups and advanced care planning.

Background: Neoadjuvant systemic therapy (NAST)is used for large operable or highly proliferative breast cancers. It is not known whether psychological outcomes differ according to the treatment sequence (chemotherapy or surgery first)or tumour response. Methods: This was a planned analysis of a multi-institutional single arm longitudinal study of patients considering NAST for operable breast cancer. Participants completed patient reported outcome questionnaires before and after the decision about NAST, between chemotherapy and surgery, and 12 months after diagnosis. Results: Fifty-nine women enrolled. Fourteen of 51 (28%)who received NAST experienced pathological complete response (pCR). Patients who had surgery first (n = 7)had higher baseline anxiety, and a greater decrease in anxiety at 12 months follow up, compared with patients who received NAST (n = 50)(a decrease from baseline of 34 pts vs 17 points; p = 0.033). Distress declined at a similar rate in surgery first and NAST groups. Mean satisfaction with decision score post-decision was significantly lower in the adjuvant group compared with NAST (22 vs 26, p = 0.02). No differences were seen between patients with pCR vs residual cancer in: distress, anxiety, satisfaction with decision, fear of progression, and decision regret. Conclusion: Most patients in this study proceeded with NAST when their surgeon offered it as an option. This exploratory analysis suggests that patients who chose surgery first tended to be more anxious, and had lower satisfaction with their decision, than those who had NAST. In patients who had NAST, lack of pCR does not appear to correlate with adverse psychological outcomes.

The negative health consequences of tobacco and risky alcohol consumption are compounded when used concurrently. Australian preventative health guidelines recommend that general practitioners (GPs) assess and provide evidence-based intervention. No studies, however, have examined the accuracy of GP detection of concurrent tobacco use and risky alcohol consumption or the factors associated with accurate detection. This study aimed to examine the: (i) accuracy of GP detection of concurrent tobacco and risky alcohol use compared to patient self-report and (ii) GP and patient characteristics associated with accurate detection following a single clinical encounter. Patients attending 12 Australian general practices completed a survey assessing smoking and alcohol consumption. For each participating patient, GPs completed a checklist to indicate the presence of these risk factors. GP judgements were compared to patient self-report. Fifty-one GPs completed a health risk checklist for 1332 patients. Only 23% of patients who self-reported concurrent tobacco and risky alcohol use identified by their GP. Patients who visited their GP four to six times in the last year were most likely to have concurrent tobacco and risky alcohol use were identified. It is imperative to establish systems to increase detection of preventative health risks in general practice to enable the provision of evidence-based treatments.

The use of nicotine replacement therapy in pregnancy has been debated but evidence suggests that it is safer than smoking. A cross-sectional survey was conducted with: (i) general practitioners and obstetricians from a college database; and (ii) general practitioners with a special interest in Indigenous health. General practitioners had higher odds of prescribing compared to obstetricians. Reading guidelines, confidence, viewing nicotine replacement therapy as safe, effective and with good adherence, also significantly increased the odds of prescription. Clear guidance regarding safety and efficacy, with practical clinical protocols, are required in order to reduce variation in prescribing rates across these clinicians.

Objective: Chronic cerebrospinal venous insufficiency (CCSVI) is a condition associated with multiple sclerosis (MS). One mechanism that has been proposed is that the venous obstructions found in MS are due to a chronic persistent venulitis caused by the intra-cellular bacterial parasite, Chlamydophila pneumoniae (Cpn). The objective of the current study is to determine the effect of a combined antibiotic protocol (CAP) on the venous flow in MS patients as measured by a quantitative duplex ultrasound examination (QDUS). Method: A non-randomised before-after cohort study was conducted to investigate differences in blood flow volumes pre and 6-months post antibiotic treatment for Cpn infection. Flow volume data were measured by QDUS across affected and unaffected sides from multiple veins segments, including internal jugular vein (IJV) segments J2 and J3, and vertebral vein (VV), as well as global arterial blood flow (GABF). Results: 91 patients were included in the study. 64 (70%) were found to have positive Cpn serology. There was a statistically significant post-treatment difference seen for the affected side of Cpn infected patients (mean difference = 56 mL/min, p = 0.02). There was a non-significant increase seen for the affected side of uninfected patients (mean difference = 23 mL/min, p = 0.2). The difference in these effects (34 mL/min) was not statistically significant (p = 0.3). The mean flow rate decreased in the unaffected side for both infected (-27 mL/min, p = 0.5) and uninfected patients (-69 mL/min, p = 0.01). There was a statistically significant post-treatment increase in GABF for the infected patients (mean difference = 90 mL/min, p = 0.02) and a difference of 76 mL/min for non-infected patients (p = 0.01). Conclusion: A CAP appears to improve the extra-cranial circulation in patients diagnosed with MS. This effect is statistically significant in patients with positive Cpn serology, although patients with negative Cpn serology also show some benefit, betraying a lack of specificity of this effect.

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.

Introduction and Aims: This study aimed to compare current and ex-smokers' sociodemographic and psychosocial characteristics, use of cessation aids and abrupt versus gradual quitting approaches. Design and Methods: A cross-sectional survey of financially disadvantaged adults attending a community service organisation was conducted in New South Wales, Australia, between February 2012 and December 2013. Sociodemographic and psychosocial factors, use of cessation aids and gradual versus abrupt quit approach were assessed. ¿2 tests and logistic regression compared characteristics of current and ex-smokers. Results: Of 905 individuals who completed the survey, 639 (71%) were current smokers and 107 (12%) were ex-smokers. Ex-smokers were older [odds ratio (OR)¿=¿1.03, 95% confidence interval (CI)¿=¿1.01, 1.05], had higher odds of being female (OR¿=¿1.67, 95% CI¿=¿1.06, 2.65), lower odds of being financially stressed (OR¿=¿0.87, 95% CI¿=¿0.76, 0.99), lower odds of anxiety and depression symptoms (OR¿=¿0.91, 95% CI¿=¿0.84, 0.98) and lower odds of having friends and family who were smokers (ORs ranged from 0.30¿0.43). Ex-smokers had lower odds of using cessation aids and higher odds of reporting abrupt quitting during their last quit attempt (OR¿=¿4.48, 95% CI¿=¿2.66, 7.54). Conclusions: Lower levels of disadvantage, less smoking in social networks, less use of cessation aids and abrupt (vs. gradual) quitting approaches were associated with being an ex-smoker. Lower use of evidence based methods to quit by disadvantaged ex-smokers requires further exploration. [Twyman L, Bonevski B, Paul C, Bryant J, West R, Siahpush M, D'este C, Oldmeadow C, Palazzi K. What factors are associated with abstinence amongst socioeconomically disadvantaged smokers? A cross-sectional survey of use of cessation aids and quitting approach. Drug Alcohol Rev 2017;00:000-000].

Objective: To describe the prevalence and change in prevalence of electronic nicotine delivery systems (ENDS) use in youth by country and combustible smoking status. Methods: Databases and the grey literature were systematically searched to December 2015. Studies describing the prevalence of ENDS use in the general population aged =20 years in a defined geographical region were included. Where multiple estimates were available within countries, prevalence estimates of ENDS use were pooled for each country separately. Results: Data from 27 publications (36 surveys) from 13 countries were included. The prevalence of ENDS ever use in 2013¿2015 among youth were highest in Poland (62.1%; 95%CI: 59.9-64.2%), and lowest in Italy (5.9%; 95%CI: 3.3-9.2%). Among non-smoking youth, the prevalence of ENDS ever use in 2013¿2015 varied, ranging from 4.2% (95%CI: 3.8-4.6%) in the US to 14.0% in New Zealand (95%CI: 12.7-15.4%). The prevalence of ENDS ever use among current tobacco smoking youth was the highest in Canada (71.9%, 95%CI: 70.9-72.8%) and lowest in Italy (29.9%, 95%CI: 18.5-42.5%). Between 2008 and 2015, ENDS ever use among youth increased in Poland, Korea, New Zealand and the US; decreased in Italy and Canada; and remained stable in the UK. Conclusions: There is considerable heterogeneity in ENDS use among youth globally across countries and also between current smokers and non-smokers. Implications for public health: Population-level survey data on ENDS use is needed to inform public health policy and messaging globally.

Objective: To examine among people attending outpatient clinics aged 50¿74 at average risk of colorectal cancer (CRC): 1) The proportion who report: a) faecal occult blood test (FOBT) within the past two years; and b) colonoscopy within the past five years, including the reasons for undergoing colonoscopy; 2) characteristics associated with under-screening; 3) For those who are under-screened, the proportion who are: a) willing to receive help and the acceptability of different methods of receiving help, and; b) unwilling to receive help and reasons for this. Methods: Cross-sectional survey of 197 participants attending a major regional hospital in New South Wales, Australia. Multivariable logistic regression was used to determine correlates of under-screening. Results: A total of 59% reported either FOBT in the past two years or colonoscopy in the past five years. Of those reporting colonoscopy in the past five years, 21% were potentially over-screened. Males were more likely than females to be under-screened. Of those under-screened (41%), fewer than half were willing to receive screening advice. Conclusions and implications for public health: A significant proportion of people attending outpatient clinics are under-screened for CRC, with some people also over-screened. There is a need to explore strategies to overcome both under- and over-screening.

Excessive opioid prescribing can lead to adverse consequences including stockpiling, misuse, dependency, diversion and mortality. Increased prescriptions to post-operative inpatients as part of their discharge planning may be a significant contributor. Primary aims included comparing the amount of opioids prescribed, consumed, left unused and their relationship with pain and functionality. A total of 132 consecutive patients who underwent elective orthopaedic surgery were prospectively audited. Daily oral morphine equivalent (DME) of opioids prescribed was compared with opioids consumed and amount left unused 7-10 days after discharge. For analysis, patients were split into three groups: total knee replacement (TKR), hand surgery (Hands), and miscellaneous (Misc). The mean dose of opioid prescribed per patient was 108.5 mg DME. TKR consumed 33-35% more opioids than Misc (p=0.0283) and Hands (p=0.0975). Age was a significant independent factor for opioid consumption in the 50th and 75th percentiles of Hands (p=0.05). An average of 36 mg DME per patient was left unused with Hands having the highest median DME (37 mg) unused. In the total cohort, 26% of patients were discharged with more DME than their last 24 h as an inpatient and had at least 50% of their tablets left unused at follow-up. Over-prescription of opioids occurs at discharge which can increase the risk of harm. New intervention is needed to optimise prescribing practises. Changes to prescribing habits and workplace culture are required to minimise unnecessary opioid prescribing but will be challenging to implement. A multi-layered approach of electronic prescribing, opioid stewardship and targeted educational awareness programmes is recommended.

Background: The single-center double-blind, randomized controlled Managing Asthma in Pregnancy (MAP) trial in Newcastle, Australia, compared a treatment algorithm using the fraction of exhaled nitric oxide (FENO) in combination with asthma symptoms (FENO group) against a treatment algorithm using clinical symptoms only (clinical group) in pregnant asthmatic women (Australian New Zealand Clinical Trials Registry, no. 12607000561482). The primary outcome was a 50% reduction in asthma exacerbations during pregnancy in the FENO group. However, the effect of FENO-guided management on the development of asthma in the offspring is unknown. Objective: We sought to investigate the effect of FENO-guided asthma management during pregnancy on asthma incidence in childhood. Methods: A total of 179 mothers consented to participate in the Growing into Asthma (GIA) double-blind follow-up study with the primary aim to determine the effect of FENO-guided asthma management on childhood asthma incidence. Results: A total of 140 children (78%) were followed up at 4 to 6 years of age. FENO-guided as compared to symptoms-only approach significantly reduced doctor-diagnosed asthma (25.9% vs 43.2%; odds ratio [OR], 0.46, 95% CI, 0.22-0.96; P =.04). Furthermore, frequent wheeze (OR, 0.27; 95% CI, 0.09-0.87; P =.03), use of short-acting ß-agonists (OR, 0.49; 95% CI, 0.25-0.97; P =.04), and emergency department visits for asthma (OR, 0.17; 95% CI, 0.04-0.76; P =.02) in the past 12 months were less common in children born to mothers from the FENO group. Doctor-diagnosed asthma was associated with common risk alleles for early onset asthma at gene locus 17q21 (P =.01 for rs8069176; P =.03 for rs8076131), and higher airways resistance (P =.02) and FENO levels (P =.03). A causal mediation analysis suggested natural indirect effects of FENO-guided asthma management on childhood asthma through ¿any use¿ and ¿time to first change in dose¿ of inhaled corticosteroids during the MAP trial (OR: 0.83; 95% CI: 0.59-0.99, and OR: 0.90; 95% CI: 0.70-1.03, respectively). Conclusions: FENO-guided asthma management during pregnancy prevented doctor-diagnosed asthma in the offspring at preschool age, in part mediated through changes in use and dosing of inhaled corticosteroids during the MAP trial.

Background: Stroke survivors sit for long periods each day. Uninterrupted sitting is associated with increased risk of cardiovascular disease. Breaking up uninterrupted sitting with frequent, short bouts of light-intensity physical activity has an immediate positive effect on blood pressure and plasma clotting factors in healthy, overweight, and type 2 diabetic populations. Aim: We examined the effect of frequent, short bouts of light-intensity physical activity on blood pressure and plasma fibrinogen in stroke survivors. Methods: Prespecified secondary analyses from a three-armed randomized, within-participant, crossover trial. Participants were 19 stroke survivors (nine female, aged 68 years old, 90% able to walk independently). The experimental conditions were sitting for 8 h uninterrupted, sitting with 3 min bouts of light-intensity exercise while standing every 30 min, or sitting with 3 min of walking every 30 min. Blood pressure was measured every 30 min over 8 h and plasma fibrinogen at the beginning, middle, and end of each day. Intention-to-treat analyses were performed using linear mixed models including fixed effects for condition, period, and order, and a random intercept for participant to account for repeated measures and missing data. Results: Sitting with 3 min bouts of light-intensity exercise while standing every 30 min decreased systolic blood pressure by 3.5 mmHg (95% CI 1.7¿5.4) compared with sitting for 8 h uninterrupted. For participants not taking antihypertensive medications, sitting with 3 min of walking every 30 min decreased systolic blood pressure by 5.0 mmHg (95% CI -7.9 to 2.0) and sitting with 3 min bouts light-intensity exercise while standing every 30 min decreased systolic blood pressure by 4.2 mmHg (95% CI -7.2 to -1.3) compared with sitting for 8 h uninterrupted. There was no effect of condition on diastolic blood pressure (p = 0.45) or plasma fibrinogen levels (p = 0.91). Conclusion: Frequent, short bouts of light-intensity physical activity decreases systolic blood pressure in stroke survivors. However, before translation into clinical practice, the optimal duration and timing of physical activity bouts needs to be determined. Clinical trial registration: Australian and New Zealand Clinical Trials Registry http://www.anzctr.org.au ANZTR12615001189516.

Objectives: People with stroke sit for long periods each day, which may compromise blood glucose control and increase risk of recurrent stroke. Studies in other populations have found regular activity breaks have a significant immediate (within-day) positive effect on glucose metabolism. We examined the effects of breaking up uninterrupted sitting with frequent, short bouts of light-intensity physical activity in people with stroke on post-prandial plasma glucose and insulin. Methods: Randomized within-participant crossover trial. We included people between 3 months and 10 years post-stroke, ambulant with minimal assistance and not taking diabetic medication other than metformin. The three experimental conditions (completed in random order) were: sitting for 8 h uninterrupted, sitting with 3 min bouts of light-intensity exercise while standing every 30 min, or sitting with 3 min of walking every 30 min. Meals were standardized and bloods were collected half- to one-hourly via an intravenous cannula. Results: A total of 19 participants (9 female, mean [SD] age 68.2 [10.2]) completed the trial. The majority (n = 12, 63%) had mild stroke symptoms (National Institutes of Stroke Scale score 0¿13). There was no significant effect of experimental condition on glucose (mean [SD] positive incremental area [+iAUC] mmol·L·h-1 under the curve during sitting 42.3 [29.5], standing 47.4 [23.1], walking 44.6 [26.5], p = 0.563) or insulin (mean + iAUC pmol·L·h-1 sitting 14,161 [7,560], standing 14,043 [8,312], walking 14,008 [8,269], p = 0.987). Conclusion: Frequent, short bouts of light-intensity physical activity did not have a significant effect on post-prandial plasma glucose and insulin in this sample of people with stroke. Further studies are needed to identify strategies that improve inactivity-related glucose metabolism after stroke.

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.

Background: Preventable maternal mortality is related to delays in recognizing the problem, transport to a facility, and receiving appropriate care on arrival. Reducing maternal mortality in low-literacy settings is particularly challenging. In the rural villages of Nepal, the maternal mortality rate is among the highest in the world; the reasons include illiteracy and lack of knowledge of the needs of pregnant women. Culturally, singing and dancing are part of Nepalese daily life and present an opportunity to transmit knowledge of antenatal care and care at birth with a view to reducing the first 2 delays. Objective: We hypothesized that health messages regarding the importance of antenatal care and skilled birth assistance would be effectively transmitted by songs in the limited literacy environment of rural Nepal. Study Design: We randomly grouped 4 rural village development committees comprising 36 villages into 2 (intervention and control) clusters. In the intervention group, local groups were invited to write song lyrics incorporating key health messages regarding antenatal care to accompany popular melodies. The groups presented their songs and dances in a festival organized and judged by the community. The winning songs were performed by the local people in a song and dance progression through the villages, houses, and fields. A wall chart with the key health messages was also provided to each household. Knowledge of household decision makers (senior men and women) was assessed before and after the intervention and at 12 months using a structured questionnaire in all households that also assessed behavior change. Results: Structured interviews were conducted at baseline, immediately postintervention in the control and intervention areas (intervention n = 735 interviews, control n = 775), and at 12 months in the intervention area only (n = 867). Knowledge scores were recorded as the number of correct items out of 36 questions at baseline and postintervention, and of 21 questions at follow-up. Postintervention, test score doubled in the intervention group from a mean of 11.60/36¿22.33/36 (P <.001), with no practically significant change in the control population (17.48/36¿18.26/36). Improvement was greatest among the most illiterate members of the community (6.8/36¿19.8/36, P <.001). At 12 months follow-up, a majority of the participants (63.9%) indicated that they provided information learned from the songs to their neighbors and friends, and 41.3% reported still singing the songs from the intervention. Conclusion: The use of songs bypassed the limitations of literacy in communicating health messages that are key to improving maternal care in this low-literacy rural setting within a developing country. The improvements were maintained without further intervention for 12 months. With appropriate sociocultural adaptation to local contexts, this low-cost method of community education may be applicable to improving maternal health knowledge and behavior change in other low-resource and limited literacy settings that may lead to reductions in maternal mortality.

Globally, colorectal cancer (CRC) screening rates remain suboptimal. Primary care practitioners are supported by clinical practice guidelines which recommend they provide routine CRC screening advice. Published research can provide evidence to improve CRC screening in primary care, however this is dependent on the type and quality of evidence being produced. This review aimed to provide a snapshot of trends in the type and design quality of research reporting CRC screening among primary care patients across three time points: 1993¿1995, 2003¿2005 and 2013¿2015. Four databases were searched using MeSH headings and keywords. Publications in peer-reviewed journals which reported primary data on CRC screening uptake among primary care patients were eligible for inclusion. Studies meeting eligibility criteria were coded as observational or intervention. Intervention studies were further coded to indicate whether or not they met Effective Practice and Organisation of Care (EPOC) study design criteria. A total of 102 publications were included. Of these, 65 reported intervention studies and 37 reported observational studies. The proportion of each study type did not change significantly over time. The majority of intervention studies met EPOC design criteria at each time point. The majority of research in this field has focused on testing strategies to increase CRC screening in primary care patients, as compared to research describing rates of CRC screening in this population. Further research is needed to determine which effective interventions are most likely to be adopted into primary care.

Objectives: There remains a need to identify effective smoking cessation interventions in severely disadvantaged populations. This trial aimed to examine the effectiveness of an intervention (Call it Quits) developed to promote smoking cessation and delivered by community social service case-workers. Methods: Call it Quits was a pragmatic, parallel randomised trial of a case-worker delivered smoking cessation intervention conducted in a non-government community social service organisation in New South Wales (NSW), Australia. Adult smokers requiring financial assistance were randomly assigned to the five-session Call it Quits intervention or usual care control group. Of the 618 eligible individuals, 300 were randomised to the intervention group, of whom 187 (62%) consented and 318 were randomised to the control group, of whom 244 (77%) consented, resulting in 431 participants. The primary outcome measure was self-reported continuous abstinence up to 6-month follow-up with biochemical verification. Primary analysis was performed using all the available data from participants under the assumption the data is missing completely at random, followed by sensitivity analyses. Results: No statistically significant differences in the primary outcome were found (1.4% in the control group versus 1.0% in the intervention group, OR = 0.77, p = 0.828). Conclusions: A multi-component smoking cessation intervention delivering motivational interviewing-based counselling and free NRT by a trained case-worker within a community social service setting was not effective at achieving abstinence in a highly disadvantaged sample of smokers but increased attempts to stop and led to a reduction in number of cigarettes smoked daily.

Purpose: The majority of research on psychological outcomes for cancer patients has focussed on the role of individual characteristics, and disease and treatment factors. There has been very little exploration of the potential contribution of the treatment clinic to these outcomes. This study explored whether there is variation among clinics in cancer patients¿ psychological outcomes. Methods: Cancer outpatients were recruited from 22 medical oncology and haematology clinics in Australia. Participants completed a pen and paper survey including the Hospital Anxiety and Depression Scale (HADS), as well as sociodemographic, disease and treatment characteristics. Results: Of those eligible to participate, 4233 (82%) consented and 2811 (81% of consenters) returned the completed survey. There was no statistically significant variation in HADS depression scores across clinics. Some difference in anxiety scores derived from the HADS questionnaire between clinics (p = 0.03) was found with the percentage of between-clinic variation estimated to be 1.11%. However, once all demographic, disease and treatment predictors were adjusted for there was no statistical differences between clinics (percent of between-clinic variation = 0.53%; p = 0.1415). Conclusions: Psychological outcomes were not found to vary between clinics. Other sources of variation including patient characteristics may over-ride between-clinic variability, if it exists.

Background: Many factors contribute to exceptional longevity, with genetics playing a significant role. However, to date, genetic studies examining exceptional longevity have been inconclusive. This comprehensive review seeks to determine the genetic variants associated with exceptional longevity by undertaking meta-analyses. Methods: Meta-analyses of genetic polymorphisms previously associated with exceptional longevity (85+) were undertaken. For each variant, meta-analyses were performed if there were data from at least three independent studies available, including two unpublished additional cohorts. Results: Five polymorphisms, ACE rs4340, APOE e2/3/4, FOXO3A rs2802292, KLOTHO KL-VS and IL6 rs1800795 were significantly associated with exceptional longevity, with the pooled effect sizes (odds ratios) ranging from 0.42 (APOE e4) to 1.45 (FOXO3A males). Conclusion: In general, the observed modest effect sizes of the significant variants suggest many genes of small influence play a role in exceptional longevity, which is consistent with results for other polygenic traits. Our results also suggest that genes related to cardiovascular health may be implicated in exceptional longevity. Future studies should examine the roles of gender and ethnicity and carefully consider study design, including the selection of appropriate controls.

Background: Neoadjuvant systemic therapy (NAST) is an increasingly used treatment option for women with large operable or highly proliferative breast cancer. With equivalent survival outcomes between NAST and up-front surgery, the situation-specific preference-sensitive nature of the decision makes it suitable for a decision aid (DA). This study aimed to develop and evaluate a DA for this population. Methods: A DA booklet was developed according to international standards, including information about adjuvant and neoadjuvant treatment, outcome probabilities, and a values clarification exercise. Eligible women, considered by investigators as candidates for NAST, were enrolled in a multi-institutional, single-arm, longitudinal study. Patient-reported outcome measure questionnaires were completed pre- and post-DA, between chemotherapy and surgery, and at 12 months. Outcomes were feasibility (percentage of eligible patients accessing the DA); acceptability to patients (percentage who would recommend it to others) and clinicians (percentage who would use the DA in routine practice); and decision-related outcomes. Results: From 77 eligible women, 59 were enrolled, of whom 47 (79.7%; 95% CI, 69.4-89.9) reported having read the DA; 51 completed the first post-DA questionnaire. Of these 51, 41 participants (80.4%; 95% CI, 69.5-91.3) found the DA useful for their decision about NAST. Of 18 responding investigators, 16 (88.9%; 95% CI, 74.4-103.4) indicated they would continue to use the DA in routine practice. Post-DA, decisional conflict decreased significantly (P<.01); anxiety and distress decreased significantly; and 86.3% (95% CI, 73.7-94.3) achieved at least as much decisional control as they desired. Conclusions: This DA was feasible and acceptable to patients and clinicians, and improvement in decision-related outcomes was demonstrated when used in combination with clinical consultations. This DA could safely be implemented into routine practice for women considering NAST for operable breast cancer.

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.

Objectives: Alcohol misuse and depression are commonly co-occurring conditions. To date, no review has examined the most efficacious treatment model for psychosocial treatment of co-occurring alcohol misuse and depression. This systematic review determined the: (i) methodological quality of publications examining psychosocial treatment of co-occurring alcohol misuse and depression using a sequential, parallel or integrated treatment model; and (ii) effectiveness of each dual treatment model compared to single treatment for those with co-occurring alcohol misuse and depression. Methods: PubMed, Medline and PsycInfo databases were searched for studies which were included if they involved treatment for alcohol misuse and depression and could be classified into one of the three treatment models. Included studies were assessed using the Cochrane¿s Effective Practice and Organisation of Care risk of bias criteria. Relevant study characteristics and outcomes were extracted and are presented in a narrative review format. Results: Seven studies met inclusion criteria. None were categorised as low risk on the risk of bias criteria. No studies examined a sequential model of treatment, three examined a parallel model and four examined an integrated model of dual-focussed treatment. The studies examining the parallel model and two out of four studies examining the effectiveness of an integrated model demonstrated greater improvement for alcohol or depression outcomes compared to control conditions. Conclusion: Evidence for the psychosocial treatment of co-occurring alcohol misuse and depression is limited to a handful of studies. The evidence has several methodological limitations, which impact the interpretation of the findings. Therefore, while international guidelines recommend integrated dual-focussed treatment for co-occurring conditions, there is little evidence supporting the superiority of this treatment format for co-occurring alcohol misuse and depression. High-quality research demonstrating improvements in patient outcomes is required to ensure recommendations for clinical practice are based on strong empirical evidence.

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).

Depression and alcohol misuse are common co-occurring conditions. This study aimed to determine the accuracy of general practitioner identification of depression and alcohol misuse. Participants from 12 Australian general practices reported demographic and health risk behaviour data. General practitioners were asked to indicate the presence or absence of six health risk factors for individual patients. Accuracy of general practitioner identification was low at 21 per cent. Those with severe alcohol misuse, no chronic diseases and lower education levels were more likely to be identified. Routine screening prior to patient appointments may be a simple and efficient way to increase identification rates.

Aim: There is a high incidence of neonatal hypoglycaemia in neonates born to mothers with pre-existing diabetes. This often necessitates admission to the neonatal intensive care. Guidelines suggest maintaining intrapartum blood glucose levels (BGLs) of 4¿7 mmol/l in women with diabetes to reduce the risk of neonatal hypoglycaemia. This study assessed whether intrapartum BGLs in women with pre-gestational Type 1 and 2 diabetes were predictive of neonatal hypoglycaemia. Methods: A retrospective analysis of 261 births delivered at a tertiary hospital in Australia from 2009 to 2014. Results: There were 122 cases of neonatal hypoglycaemia (glucose = 2.6 mmol/l) in 261 births (47%). The mothers in the neonatal hypoglycaemia group spent less time with BGL in the range 4¿7 mmol/l [55 ± 37% vs. 65 ± 35%, P = 0.02; odds ratio (OR) 0.992, P = 0.03] and more time with BGL in the 7¿10 mmol/l range (31 ± 34% vs. 18 ± 27%, P = 0.003; OR 1.013, P = 0.003) compared with those without neonatal hypoglycaemia. Although statistically significant, receiver operating characteristic (ROC) curve analysis showed that time spent with maternal BGLs in the range 4¿7 mmol/l [area under the curve (AUC) = 0.58] or 7¿10 mmol (AUC = 0.60) was not strong enough to be a useful clinical predictor of neonatal hypoglycaemia. HbA1c in the second trimester of pregnancy (P = 0.02, OR 1.42) and percentage time spent in BGL range of 7¿10 mmol/l (P = 0.001, OR 1.02) were both associated with a risk of neonatal hypoglycaemia in a logistic regression model. HbA1c in the third trimester (P = 0.07, OR 1.28) approached, but did not reach, significance. Conclusions: These data support a BGL range of 4¿7 mmol/l as an intrapartum target. Glycaemic control in the second trimester is associated with neonatal hypoglycaemia. Improvement in ante- and intrapartum glycaemic control may reduce neonatal hypoglycaemia in women with pre-existing diabetes.

Background Bronchiolitis is the most common lung infection in infants and treatment focuses on management of respiratory distress and hypoxia. High-flow warm humidified oxygen (HFWHO) is increasingly used, but has not been rigorously studied in randomised trials. We aimed to examine whether HFWHO provided enhanced respiratory support, thereby shortening time to weaning off oxygen. Methods In this open, phase 4, randomised controlled trial, we recruited children aged less than 24 months with moderate bronchiolitis attending the emergency department of the John Hunter Hospital or the medical unit of the John Hunter Children's Hospital in New South Wales, Australia. Patients were randomly allocated (1:1) via opaque sealed envelopes to HFWHO (maximum flow of 1 L/kg per min to a limit of 20 L/min using 1:1 air¿oxygen ratio, resulting in a maximum FiO2 of 0·6) or standard therapy (cold wall oxygen 100% via infant nasal cannulae at low flow to a maximum of 2 L/min) using a block size of four and stratifying for gestational age at birth. The primary outcome was time from randomisation to last use of oxygen therapy. All randomised children were included in the primary and secondary safety analyses. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12612000685819. Findings From July 16, 2012, to May 1, 2015, we randomly assigned 202 children to either HFWHO (101 children) or standard therapy (101 children). Median time to weaning was 24 h (95% CI 18¿28) for standard therapy and 20 h (95% CI 17¿34) for HFWHO (hazard ratio [HR] for difference in survival distributions 0·9 [95% CI 0·7¿1·2]; log rank p=0·61). Fewer children experienced treatment failure on HFWHO (14 [14%]) compared with standard therapy (33 [33%]; p=0·0016); of these children, those on HFWHO were supported for longer than were those on standard therapy before treatment failure (HR 0·3; 95% CI 0·2¿0·6; p<0·0001). 20 (61%) of 33 children who experienced treatment failure on standard therapy were rescued with HFWHO. 12 (12%) of children on standard therapy required transfer to the intensive care unit compared with 14 (14%) of those on HFWHO (difference -1%; 95% CI -7 to 16; p=0·41). Four adverse events occurred (oxygen desaturation and condensation inhalation in the HFWHO group, and two incidences of oxygen tubing disconnection in the standard therapy group); none resulted in withdrawal from the trial. No oxygen-related serious adverse events occurred. Secondary effectiveness outcomes are reported in the Results section. Interpretation HFWHO did not significantly reduce time on oxygen compared with standard therapy, suggesting that early use of HFWHO does not modify the underlying disease process in moderately severe bronchiolitis. HFWHO might have a role as a rescue therapy to reduce the proportion of children requiring high-cost intensive care. Funding Hunter Children's Research Foundation, John Hunter Hospital Charitable Trust, and the University of Newcastle Priority Research Centre GrowUpWell.

The aim of this study was to determine whether the regional implementation of prohibitive liquor legislation, introduced in order to limit the sale of and access to alcohol, can lead to a sustained reduction in the incidence of assault occasioning facial injury, as seen in patients presenting to a level 1 trauma hospital. A retrospective observational cohort study was conducted to document patients who were identified as an acute hospital presentation of assault occasioning facial injury. The period of study was 2003¿2015; this ensured a similar period of time before and after the implementation of the legislation in 2008. A statistical analysis was undertaken to assess the rates of change in oral and maxillofacial (OMF) assault admissions pre and post legislation. The study found that pre-legislation numbers of OMF assaults increased at a rate of 14% per annum and then decreased at a rate of 21% per annum post legislation (31% relative rate ratio reduction). Similar trends were seen for all males, males aged 18¿35 years, and males where alcohol was recorded at clinical presentation. The introduction of ¿last drinks¿ and ¿lock out¿ legislation has led to a significant and sustained reduction in assaultive alcohol-related facial injury in Newcastle.

Background and Purpose: In alteplase-treated patients with acute ischemic stroke, we investigated the relationship between penumbral reperfusion at 24 hours and clinical outcomes, with and without adjustment for baseline ischemic core volume. Methods: Data were collected from consecutive acute ischemic stroke patients with baseline and follow-up perfusion imaging presenting to hospital within 4.5 hours of symptom onset at 7 hospitals. Logistic regression models were used for predicting the effect of the reperfused penumbral volume on the dichotomized modified Rankin Scale (MRS) at 90 days and improvement of National Institutes of Health Stroke Scale at 24 hours, both adjusted for baseline ischemic core volume. Results: This study included 1507 patients. Reperfused penumbral volume had moderate ability to predict 90-day MRS 0 to 1 (area under the curve, 0.77; R2, 0.28; P<0.0001). However, after adjusting for baseline ischemic core volume, the reperfused penumbral volume was a strong predictor of good functional outcome (area under the curve, 0.946; R2, 0.55; P<0.0001). For every 1% increase in penumbral reperfusion, the odds of achieving MRS 0 to 1 at day 90 increased by 7.4%. Improvement in acute 24-hour National Institutes of Health Stroke Scale was also significantly related to the degree of reperfused penumbra (R2, 0.31; P<0.0001). This association was again stronger after adjustment for baseline ischemic core volume (R2, 0.41; P<0.0001). For each 1% of penumbra that was reperfused, the 24-hour National Institutes of Health Stroke Scale decreased by 0.069 compared with baseline. Conclusions: In patients treated with alteplase, the extent of the penumbra that is reperfused is a powerful predictor of early and late clinical outcomes, particularly when baseline ischemic core is taken into account.

Purpose: To examine the longitudinal association between diet quality and depression using prospective data from the Australian Longitudinal Study on Women¿s Health. Methods: Women born in 1946¿1951 (n¿=¿7877) were followed over 9¿years starting from 2001. Dietary intake was assessed using the Dietary Questionnaire for Epidemiological Studies (version 2) in 2001 and a shortened form in 2007 and 2010. Diet quality was summarised using the Australian Recommended Food Score. Depression was measured using the 10-item Centre for Epidemiologic Depression Scale and self-reported physician diagnosis. Pooled logistic regression models including time-varying covariates were used to examine associations between diet quality tertiles and depression. Women were also categorised based on changes in diet quality during 2001¿2007. Analyses were adjusted for potential confounders. Results: The highest tertile of diet quality was associated marginally with lower odds of depression (OR 0.94; 95¿% CI 0.83, 1.00; P¿=¿0.049) although no significant linear trend was observed across tertiles (OR 1.00; 95¿% CI 0.94, 1.10; P¿=¿0.48). Women who maintained a moderate or high score over 6¿years had a 6¿14¿% reduced odds of depression compared with women who maintained a low score (moderate vs low score¿OR 0.94; 95¿% CI 0.80, 0.99; P¿=¿0.045; high vs low score¿OR 0.86; 95¿% CI 0.77, 0.96; P¿=¿0.01). Similar results were observed in analyses excluding women with prior history of depression. Conclusion: Long-term maintenance of good diet quality may be associated with reduced odds of depression. Randomised controlled trials are needed to eliminate the possibility of residual confounding.

Background Access to opioid agonist treatment can be associated with extensive waiting periods with significant health and financial burdens. This study aimed to determine whether patients with heroin dependence dispensed buprenorphine-naloxone weekly have greater reductions in heroin use and related adverse health effects 12-weeks after commencing treatment, compared to waitlist controls and to examine the cost-effectiveness of this strategy. Methods An open-label waitlist RCT was conducted in an opioid treatment clinic in Newcastle, Australia. Fifty patients with DSM-IV-TR heroin dependence (and no other substance dependence) were recruited. The intervention group (n = 25) received take-home self-administered sublingual buprenorphine-naloxone weekly (mean dose, 22.7 ± 5.7 mg) and weekly clinical review. Waitlist controls (n = 25) received no clinical intervention. The primary outcome was heroin use (self-report, urine toxicology verified) at weeks four, eight and 12. The primary cost-effectiveness outcome was incremental cost per additional heroin-free-day. Results Outcome data were available for 80% of all randomized participants. Across the 12-weeks, treatment group heroin use was on average 19.02 days less/month (95% CI -22.98, -15.06, p < 0.0001). A total 12-week reduction in adjusted costs including crime of $A5,722 (95% CI 3299, 8154) in favor of treatment was observed. Excluding crime, incremental cost per heroin-free-day gained from treatment was $A18.24 (95% CI 4.50, 28.49). Conclusion When compared to remaining on a waitlist, take-home self-administered buprenorphine-naloxone treatment is associated with significant reductions in heroin use for people with DSM-IV-TR heroin dependence. This cost-effective approach may be an efficient strategy to enhance treatment capacity.

Background/Aim Web 2.0 internet technology has great potential in promoting physical activity. This trial investigated the effectiveness of a Web 2.0-based intervention on physical activity behaviour, and the impact on website usage and engagement. Methods 504 (328 women, 126 men) insufficiently active adult participants were randomly allocated to one f two web-based interventions or a paper-based Logbook group. The Web 1.0 group participated in the existing 10 000 Steps programme, while the Web 2.0 group participated in a Web 2.0-enabled physical activity intervention including user-to-user interaction through social networking capabilities. ActiGraph GT3X activity monitors were used to assess physical activity at four points across the intervention (0, 3, 12 and 18 months), and usage and engagement were assessed continuously through website usage statistics. Results Treatment groups differed significantly in trajectories of minutes/day of physical activity (p=0.0198), through a greater change at 3 months fo Web 2.0 than Web 1.0 (7.3 min/day, 95% CI 2.4 to 12.3). In the Web 2.0 group, physical activity increased at 3 (mean change 6.8 min/day, 95% CI 3.9 to 9.6) and 12 months (3.8 min/day, 95% CI 0.5 to 7.0), but not 18 months. The Logbook group also increased physical activity at 3 (4.8 min/day, 95% CI 1.8 to 7.7) and 12 months (4.9 min/day, 95% CI 0.7 to 9.1), but not 18 months. The Web 1.0 group increased physical activity at 12 months only (4.9 min/day, 95% CI 0.5 to 9.3). The Web 2.0 group demonstrated higher levels of website engagement (p=0.3964).Conclusions In comparison to a Web 1.0 intervention, a more interactive Web 2.0 intervention, as well as the paper-based Logbook intervention, improved physicalactivity in the short term, but that effect reduced over time, despite higher levels of engagement of the Web 2.0 group. Trial registration number ACTRN12611000157976.

Introduction and Aims: Guidelines recommend anxiolytics and hypnotics (A/H) as second-line, short-term medications. We aimed to establish prevalence and associations of A/H prescribing by Australian general practice (GP) trainees. Design and Methods: A cross-sectional analysis from a cohort study of vocational trainees from four GP Regional Training Providers during 2010¿2013. General practice trainees act as independent practitioners (including for prescribing purposes) while having recourse to advice from a GP supervisor. Practice and trainee demographic data were collected as well as patient, clinical and educational data from 60 consecutive consultations of each trainee each training term. Analysis was at the level of individual problem managed, with the outcome factor being prescription of any anxiolytic or hypnotic. Results: Overall, 645 registrars (response rate 94.0%) prescribed 68 582 medications in 69 621 consultations (with 112 890 problems managed). A/Hs were prescribed for 1.3% of problems managed and comprised 2.2% of all prescriptions. They were prescribed particularly for insomnia (28.2%) or anxiety (21.8%), but also for many ¿off-label¿ indications. Significant associations of A/H prescriptions were: patient-level (greater age, Aboriginal and Torres Strait Islander status, English-speaking background, being new to the trainee but not to the practice); trainee-level (male) and consultation-level (longer duration, pre-existing problem, specialist referral not being made). Prescribing was significantly lower in one of the four Regional Training Providers. Discussion and Conclusions: GP trainees, inconsistent with most guideline recommendations, prescribe A/Hs mainly as maintenance therapy to unfamiliar and older patients. Our results suggest that changes in management approaches are needed which may be facilitated by support for psychotherapeutic training. [Holliday SM, Morgan S, Tapley A, Henderson KM, Dunlop AJ, van Driel ML, Spike NA, McArthur LA, Ball J, Oldmeadow CJ, Magin PJ. The pattern of anxiolytic and hypnotic management by Australian general practice trainees. Drug Alcohol Rev 2017;36:261-269].

Isolated distal deep vein thrombosis (DVT) represents an important clinical problem but there is no consensus regarding its management. The aim of this review was to evaluate the safety, efficacy, and shorter versus longer duration of anticoagulation in patients with isolated distal DVT. A systematic search was conducted using MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systemic Reviews. Studies reporting rates of symptomatic pulmonary embolism (PE), recurrent DVT, proximal extension, and/or major bleeding were included. Fourteen studies (six randomized controlled trials, eight cohorts) involving 2,918 patients met the eligibility criteria (with a total of 13 meeting criteria for the meta-analysis). Compared with no anticoagulation, anticoagulation was associated with a significant reduction in proximal extension (odds ratio [OR]: 0.29; 95% confidence interval [CI]: 0.13-0.67; p < 0.004), recurrent DVT (OR: 0.16; 95% CI: 0.04-0.65; p = 0.01), and the composite end-point of proximal extension/PE (OR: 0.34; 95% CI: 0.16-0.72; p = 0.005); however, no significant differences in PE (OR: 0.47; 95% CI: 0.17-1.34; p = 0.16) or major bleeding (OR: 1.49; 95% CI: 0.33-6.86; p = 0.60) were observed. Anticoagulation for a longer duration (=8 vs. =6 weeks) was associated with a significant reduction in proximal extension (OR: 0.23; 95% CI: 0.11-0.48; p < 0.001) but not for other outcomes.

Background. Antibiotic resistance is a public health concern, and is linked to over-prescribing. In self-limiting infections such as acute otitis media (AOM) and acute sinusitis, prescribing remains high despite strong guideline recommendations against the routine use of antibiotics. Early career General Practitioners may find evidence-based prescribing challenging. Aim. To establish the prevalence and associations of antibiotic prescribing for AOM and acute sinusitis by Australian vocational trainees in General Practice. Method. A cross-sectional analysis of data from the Registrar Clinical Encounters in Training (ReCEnT) study. This ongoing, multicentre prospective cohort study documents trainees' consultation-based clinical experiences. Univariate and logistic regression analyses were conducted on data recorded in consultations for AOM or acute sinusitis in nine collection periods during 2010-2014. Results. Data from 856 individual trainees (response rate 95.2%) were analysed. AOM was managed in 0.9% of encounters. Antibiotics were prescribed in 78.8% of cases. Prescribing was significantly associated with longer consultation time and first presentation for this problem. There was no significant association with patient age group. Acute sinusitis was managed in 0.9% of encounters. Antibiotics were prescribed in 71.2% of cases. Later-stage trainees and trainees who did not receive their primary medical qualification in Australia were more likely to prescribe an antibiotic for acute sinusitis. Conclusion. Early career GPs are not prescribing in an evidence-based manner. The complexity of guidelines for AOM and acute sinusitis may be confusing for prescribers, especially early career doctors struggling with inexperience and diagnostic uncertainty. Educational interventions are necessary to bring prescribing rates closer to quality benchmarks.

Worldwide, 10¿20% of adolescents experience mental health problems. Strategies aimed at strengthening resilience protective factors provide a potential approach for reducing mental health problems in adolescents. This study evaluated the effectiveness of a universal, school-based intervention targeting resilience protective factors in reducing mental health problems in adolescents. A cluster randomised controlled trial was conducted in 20 intervention and 12 control secondary schools located in socio-economically disadvantaged areas of NSW, Australia. Data were collected from 3115 students at baseline (Grade 7, 2011), of whom 2149 provided data at follow up (Grade 10, 2014; enrolments in Grades 7 to 10 typically aged 12¿16 years; 50% male; 69.0% retention). There were no significant differences between groups at follow-up for three mental health outcomes: total SDQ, internalising problems, and prosocial behaviour. A small statistically significant difference in favour of the control group was found for externalising problems. Findings highlight the continued difficulties in developing effective, school-based prevention programs for mental health problems in adolescents. Trial registration ANZCTR (Ref no: ACTRN12611000606987).

Objectives: To determine the extent to which physical activity reduces the number of hospital bed-days for Australians over 55, using an objective measure of activity. Design, setting and participants: 9784 Newcastle residents aged 55 years or more were invited to participate. 3253 responders were eligible and wore pedometers for one week during 2005e2007; their hospital data from recruitment to 31 March 2015 were analysed (mean follow-up time: 8.2 years). Complete data for 2110 people were available for analysis. Main outcome measures: Mean annual hospital bed-days, according to individual step count. Results: There was a statistically significant reduction in the number of hospital bed-days associated with higher step counts; the incidence rate ratio per extra 1000 steps per day at baseline was 0.91 (95% CI, 0.90e0.94). The disease-specific reductions were significant for admissions for cancer and diabetes, but not for cardiovascular disease. The difference between 4500 and 8800 steps per day (the upper and lower quartile boundaries for step count) was 0.36 bed-days per person per year, after adjusting for age, sex, number of medications, number of comorbidities, smoking and alcohol status, and education. When analysis was restricted to hospital admissions after the first 2 years of follow-up, the difference was 0.29 bed-days per person per year. Conclusions: More active people require less hospital care, and an achievable extra 4300 steps per day would result in an average of one less day in hospital for each 3 years of life.

Objective Both computerised and telephone surveys have potential advantages for research data collection. The current study aimed to determine the: (i) feasibility, (ii) acceptability, and (iii) cost per completed survey of computer tablet versus telephone data collection for clients attending an outpatient drug and alcohol treatment clinic. Design Two-arm randomised controlled trial. Method Clients attending a drug and alcohol outpatient clinic in New South Wales, Australia, were randomised to complete a baseline survey via computer tablet in the clinic or via telephone interview within two weeks of their appointment. All participants completed a three-month follow-up survey via telephone. Results Consent and completion rates for the baseline survey were significantly higher in the computer tablet condition. The time taken to complete the computer tablet survey was lower (11¿min) than the telephone condition (17¿min). There were no differences in the proportion of consenters or completed follow-up surveys between the two conditions at the 3-month follow-up. Acceptability was high across both modes of data collection. The cost of the computer tablet condition was $67.52 greater per completed survey than the telephone condition. Conclusion There is a trade-off between computer tablet and telephone data collection. While both data collection methods were acceptable to participants, the computer tablet condition resulted in higher consent and completion rates at baseline, therefore yielding greater external validity, and was quicker for participants to complete. Telephone data collection was however, more cost-effective. Researchers should carefully consider the mode of data collection that suits individual study needs.

Background: Trends in the incidence of acute myocardial infarction (AMI) provide important information for healthcare providers and can allow for accurate planning of future health needs and targeted interventions in areas with an excess burden of cardiovascular disease. Aim: To investigate the regional variations in AMI incidence in the Hunter region. Methods: Incident cases of AMI identified between 1996 and 2013 from the Hunter New England Health Cardiac and Stroke Outcomes Unit were prospectively collected for this study. We calculated crude and age-adjusted incidence of AMI over an 18-year period and explored differences in remoteness, age, sex and indigenous status. Results: During 1996¿2013, a total of 15 480 cases of AMI were identified. There was a significantly higher incidence of AMI in patients from regional areas compared to patients from metropolitan areas. More importantly, while rates of AMI declined by 28% in metropolitan patients, they increased by 8% in regional patients. Males had higher rates of AMI throughout the study period than females, however there was trend over time towards a reduction in AMI incidence in males that was not seen in females. The age-adjusted incidence of AMI for indigenous patients increased by 48% from 2007 to 2013, compared to a 23% decrease in non-indigenous patients. Conclusion: Between 1996 and 2013 in the Hunter region, the adjusted incidence of AMI increased for regional patients compared to metropolitan patients with a trend towards a higher adjusted incidence of AMI in the indigenous population.

Purpose: This study aimed to explore the dyadic relationships between unmet need, depression, and anxiety in people diagnosed with haematological cancer and their support persons. Methods: Adult survivors (18¿years+) who had been diagnosed with a haematological cancer were recruited to a cross-sectional mailed survey via five state cancer registries in Australia. Participating survivors invited a support person to also complete a survey. Structural equation modelling was used to explore the relationships among survivor and support person self-reported depression, anxiety, and unmet needs. Results: Of the 4299 eligible haematological cancer survivors contacted by the registries, 1511 (35%) returned a completed survey as did 1004 support persons. There were 787 dyads with complete data. After adjusting for age, gender, rurality, cancer type, and whether the support person was a relative, positive correlations were found between survivor and support person scores for depression (p¿=¿0.0029) and unmet needs (p¿<¿0.001), but not anxiety scores (p¿=¿0.075). Survivor unmet needs were significantly related to support person depression (p¿=¿0.0036). Support person unmet needs were significantly related to a higher depression score for survivors (p¿=¿0.0067). Greater support person unmet needs were significantly related to a higher anxiety score for survivors (p¿=¿0.0083). Survivor unmet needs did not have a significant relationship to support person anxiety (p¿=¿0.78). Conclusion: Unmet needs may mediate the interdependence of psychosocial experiences for survivors and support persons, although a longitudinal study is required to confirm causality. Addressing unmet needs may be a potential target for improving outcomes for both groups.

Limited data exist regarding co-occurring alcohol misuse and depression among general practice patients. This study examined the prevalence of depression by level of alcohol misuse, and the sociodemographic factors associated with depression and increased alcohol misuse severity. A cross-sectional survey was administered to 3559 Australian general practice patients. Patients completed their demographic details, the Patient Health Questionnaire (9-item) and the Alcohol Use Disorder Identification Test (Consumption items). The prevalence of alcohol misuse and depression was 6.7%, and depression prevalence varied significantly according to level of alcohol misuse (P<0.001). Age, gender, Aboriginality and number of chronic diseases were associated with depression and higher levels of alcohol misuse. These findings may assist General Practitioners in identifying those at risk of experiencing co-morbid depression and alcohol use, and aid in effective treatment and referral.

Background/Objectives: Skin conditions are commonly encountered in general practice but dermatology is underrepresented in undergraduate medical courses. Australian and international studies have shown that the dermatological diagnostic ability of general practitioners (GPs) is suboptimal, contributing to increased dermatology outpatient referrals. Dermatological experience in GP vocational training is thus of particular importance. We aimed to document the prevalence of skin disease presentations and the range of skin diseases encountered by GP trainees. We also sought to establish associations of GP trainee's skin disease experience, including their personal characteristics, consultation factors, and the actions arising from the consultation. Methods: This study took place in the Registrars Clinical Encounters in Training (ReCEnT) study. ReCEnT is an ongoing, prospective, multi-site cohort study of Australian GP trainees' consultations. A descriptive cross-sectional analysis was performed on trainees' consultation data. Results: In total, 645 individual trainees contributed data from 84¿615 consultations. Altogether, 11% of all problems managed were skin problems. Infections, dermatitis, injury and wounds were the most common presentations. Associations of consultations for skin problems (compared with all other problems) included seeking in-consultation advice, planning patient follow up and generating learning goals. Conclusions: These findings suggest GP trainees find skin problems challenging and may indicate a need for more and better targeted undergraduate and GP trainee education.

Background: Halogenated anesthetics activate cardiac ryanodine receptor 2-mediated sarcoplasmic reticulum Ca 2+ release, leading to sarcoplasmic reticulum Ca 2+ depletion, reduced cardiac function, and providing cell protection against ischemia-reperfusion injury. Anesthetic activation of ryanodine receptor 2 is poorly defined, leaving aspects of the protective mechanism uncertain. Methods: Ryanodine receptor 2 from the sheep heart was incorporated into artificial lipid bilayers, and their gating properties were measured in response to five halogenated anesthetics. Results: Each anesthetic rapidly and reversibly activated ryanodine receptor 2, but only from the cytoplasmic side. Relative activation levels were as follows: halothane (approximately 4-fold; n = 8), desflurane and enflurane (approximately 3-fold,n = 9), and isoflurane and sevoflurane (approximately 1.5-fold, n = 7, 10). Half-activating concentrations (K a) were in the range 1.3 to 2.1 mM (1.4 to 2.6 minimum alveolar concentration [MAC]) with the exception of isoflurane (5.3 mM, 6.6 minimum alveolar concentration). Dantrolene (10 µM with 100 nM calmodulin) inhibited ryanodine receptor 2 by 40% but did not alter the K a for halothane activation. Halothane potentiated luminal and cytoplasmic Ca 2+ activation of ryanodine receptor 2 but had no effect on Mg 2+ inhibition. Halothane activated ryanodine receptor 2 in the absence and presence (2 mM) of adenosine triphosphate (ATP). Adenosine, a competitive antagonist to ATP activation of ryanodine receptor 2, did not antagonize halothane activation in the absence of ATP. Conclusions: At clinical concentrations (1 MAC), halothane desflurane and enflurane activated ryanodine receptor 2, whereas isoflurane and sevoflurane were ineffective. Dantrolene inhibition of ryanodine receptor 2 substantially negated the activating effects of anesthetics. Halothane acted independently of the adenine nucleotide-binding site on ryanodine receptor 2. The previously observed adenosine antagonism of halothane activation of sarcoplasmic reticulum Ca 2+ release was due to competition between adenosine and ATP, rather than between halothane and ATP.

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.