Professor John Attia

© 2018, The Author(s). 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.

© 2018 The Authors. 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.

© 2018 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ) Background: Heart failure (HF) is a common, costly condition with an increasing burden on Australian health care system resources. Knowledge of the burden of HF on patients and on the health system is important for resource allocation. This study is the first systematic review to estimate the mortality and readmission rates after hospitalisation for HF in the Australian population. Methods: We searched for studies of HF hospitalisation in Australia published between January 1990 and May 2016, using a systematic search of PubMed, Medline, Scopus, Web of Science, EMBASE and Cochrane Library databases. Studies reporting 30-day and/or 1-year outcomes for mortality or readmission following hospitalisation were eligible and included in this study. Results: Out of 2889 articles matching the initial search criteria, a total of 13 studies representing 67,255 patients were included in the final analysis. The pooled mean age of heart failure patients was 76.3 years and 51% were male (n = 34,271). The pooled estimated 30-day and 1-year all-cause mortality were 8% and 25% respectively. The pooled estimated 30-day and 1-year all-cause readmission rates were 20% and 56% respectively. There is a high prevalence of comorbidities in heart failure patients. There were limited data on readmission and mortality in rural patients and Indigenous people. Conclusions: Heart failure hospitalisations in Australia are followed by substantial readmission and mortality rates.

© 2018 Scandinavian Association for the Study of Pain. Published by Walter de Gruyter GmbH, Berlin/Boston. All rights reserved. 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.

© 2016 John Wiley & Sons Ltd Introduction: Prolonged use of systemic corticosteroids leads to reduced bone mineral density and osteoporosis, in turn increasing the risk of minimal trauma fractures with their associated morbidity and mortality in elderly populations. However, the effect of inhaled corticosteroids on bone mineral density has been debated in the medical literature. Objectives: We aimed to determine the effect of inhaled corticosteroids on bone mineral density measured using calcaneal quantitative ultrasonography in a cohort of older Australians. Methods: Data was collected from the Hunter Community Study, a longitudinal cohort of Australians aged 55-85. Simple and multiple linear regression methods were used to test the cross-sectional association between inhaled corticosteroids and calcaneal bone mineral density measured with quantitative ultrasound at baseline. A causal diagram was used to determine the minimally sufficient number of co-variates necessary to determine the unconfounded effect of inhaled corticosteroids on bone mineral density; these included gender, body mass index, smoking, asthma, alcohol use, age, physical activity, and diet. Results: There were 152 (6.8%) patients on inhaled corticosteroids and 2098 (93%) controls. Simple and multiple linear regression methods showed a non-significant effect of inhaled steroids on BMD with slight decrease of BMD -0.010 g/cm2(95% CI -0.042 to 0.022, P =.55) and -0.013 g/cm2(95% CI -0.062 to 0.036, P =.61) respectively. Age, gender, body mass index, and smoking were stronger predictors of BMD. Conclusions: No statistically significant relationship was detected between the use of inhaled corticosteroids and reduced bone mineral density in this observational study of a cohort of older Australians.

� 2017 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd. Background: First-generation cephalosporins (such as cefazolin) are recommended as antibiotic prophylaxis in groin hernia repair, but other broad-spectrum antibiotics have also been prescribed in clinical practice. This was a systematic review and network meta-analysis to compare the efficacy of different antibiotic classes for prevention of surgical-site infection (SSI) after hernia repair. Methods: RCTs were identified that compared efficacy of antibiotic prophylaxis on SSI after inguinal or femoral hernia repair from PubMed and Scopus databases up to March 2016. Data were extracted independently by two reviewers. Network meta-analysis was applied to assess treatment efficacy. The probability of being the best antibiotic prophylaxis was estimated using surface under the cumulative ranking curve (SUCRA) analysis. Results: Fifteen RCTs (5159 patients) met the inclusion criteria. Interventions were first-generation (7 RCTs, 1237 patients) and second-generation (2 RCTs, 532) cephalosporins, ß-lactam/ß-lactamase inhibitors (6 RCTs, 619) and fluoroquinolones (2 RCTs, 581), with placebo as the most common comparator (14 RCTs, 2190). A network meta-analysis showed that ß-lactam/ß-lactamase inhibitors and first-generation cephalosporins were significantly superior to placebo, with a pooled risk ratio of 0�44 (95 per cent c.i. 0�25 to 0�75) and 0�62 (0�42 to 0�92) respectively. However, none of the antibiotic classes was significantly different from the others. SUCRA results indicated that ß-lactam/ß-lactamase inhibitors and first-generation cephalosporins were ranked first and second respectively for best prophylaxis. Conclusion: ß-Lactam/ß-lactamase inhibitors followed by first-generation cephalosporins ranked as the most effective SSI prophylaxis for adult patients undergoing groin hernia repair.

© 2017 American Heart Association, Inc. Background and Purpose - This study aimed to assess the efficacy of modafinil, a wakefulness-promoting agent in alleviating post-stroke fatigue =3 months after stroke. We hypothesized that 200 mg of modafinil daily for 6 weeks would result in reduced symptoms of fatigue compared with placebo. Methods - This single-center phase 2 trial used a randomized, double-blind, placebo-controlled, crossover design. The key inclusion criterion was a multidimensional fatigue inventory score of =60. Patients were randomized to either modafinil or placebo for 6 weeks of therapy, then after a 1 week washout period swapped treatment arms for a second 6 weeks of therapy. The primary outcome was the multidimensional fatigue inventory; secondary outcomes included the Montreal cognitive assessment, the Depression, Anxiety, and Stress Scale (DASS), and the Stroke-Specific Quality of Life (SSQoL) scale. The multidimensional fatigue inventory is a self-administered questionnaire with a range of 0 to 100. Treatment efficacy was assessed using linear regression by estimating within-person, baseline-adjusted differences in mean outcomes after therapy. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000350527). Results - A total of 232 stroke survivors were screened and 36 were randomized. Participants receiving modafinil reported a significant decrease in fatigue (multidimensional fatigue inventory, -7.38; 95% CI, -21.76 to -2.99; P<0.001) and improved quality of life (SSQoL, 11.81; 95% CI, 2.31 to 21.31; P=0.0148) compared with placebo. Montreal cognitive assessment and DASS were not significantly improved with modafinil therapy during the study period (P>0.05). Conclusions - Stroke survivors with nonresolving fatigue reported reduced fatigue and improved quality of life after taking 200 mg daily treatment with modafinil.

© 2017 Daneshi et al. This study analyzed clinically actionable pharmacogenotypes for clopidogrel, warfarin, statins, thiopurines, and tacrolimus using microarray data for 2121 participants (55¿85 years) from the Australian Hunter Community Study (HCS). At least 74% of participants (95% confidence interval [CI]: 72%¿76%) had strong level evidence for at least one medium- or high-risk actionable genotype that would trigger a change in standard therapy under current international recommendations. About 14% of these participants (95% CI: 12%¿16%) were taking medication potentially affected by the genotype in question. Furthermore, ~2.6% of all participants with medication data (95% CI: 1.4%¿3.8%) had a high-risk clinically actionable genotype for a medication to which they were exposed. This represents a considerable number of people at the population level. Although relationships between genotype and health outcomes remain contentious, pharmacogenotyping of multiple variants simultaneously may have considerable potential to improve medication safety and efficacy for older people in the community.

© 2017 Diabetes UK 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. HbA1cin 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. HbA1cin 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.

© 2017 Diabetes UK Aim: To determine the glycaemic impact of increasing protein quantities when consumed with consistent amounts of carbohydrate in individuals with Type 1 diabetes on intensive insulin therapy. Methods: Participants with Type 1 diabetes [aged 10¿40 years, HbA1c= 64 mmol/mol (8%), BMI = 91st percentile] received a 30-g carbohydrate (negligible fat) test drink daily over 5 days in randomized order. Protein (whey isolate 0 g/kg carbohydrate, 0 g/kg lipid) was added in amounts of 0 (control), 12.5, 25, 50 and 75 g. A standardized dose of insulin was given for the carbohydrate. Postprandial glycaemia was assessed by 5 h of continuous glucose monitoring. Results: Data were collected from 27 participants (15 male). A dose¿response relationship was found with increasing amount of protein. A significant negative relationship between protein dose and mean excursion was seen at the 30- and 60-min time points (P = 0.007 and P = 0.002, respectively). No significant relationship was seen at the 90- and 120-min time points. Thereafter, the dose¿response relationship inverted, such that there was a significant positive relationship for each of the 150¿300-min time points (P < 0.004). Mean glycaemic excursions were significantly greater for all protein-added test drinks from 150 to 300 min (P < 0.005) with the 75-g protein load, resulting in a mean excursion that was 5 mmol/l higher when compared with the control test drink (P < 0.001). Conclusions: Increasing protein quantity in a low-fat meal containing consistent amounts of carbohydrate decreases glucose excursions in the early (0¿60-min) postprandial period and then increases in the later postprandial period in a dose-dependent manner.

© 2017 Elsevier Ltd 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 FiO2of 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.

� 2015, Springer-Verlag Berlin Heidelberg. 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.

© 2017 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.

© European Society of Cardiology. Objective Previous studies have reported discrepancy effects of education and income on cardiovascular diseases. This systematic review and meta-analysis was therefore conducted which aimed to summarize effects of education and income on cardiovascular diseases. Methods Studies were identified from Medline and Scopus until July 2016. Cohorts were eligible if they assessed associations between education/income and cardiovascular diseases, had at least one outcome including coronary artery diseases, cardiovascular events, strokes and cardiovascular deaths. A multivariate meta-analysis was applied to pool risk effects of these social determinants. Results Among 72 included cohorts, 39, 19, and 14 were studied in Europe, USA, and Asia. Pooled risk ratios of low and medium versus high education were 1.36 (95% confidence interval: 1.11-1.66) and 1.21 (1.06-1.40) for coronary artery diseases, 1.50 (1.17-1.92) and 1.27 (1.09-1.48) for cardiovascular events, 1.23 (1.06-1.43) and 1.17 (1.01-1.35) for strokes, and 1.39 (1.26-1.54) and 1.21 (1.12-1.30) for cardiovascular deaths. The effects of education on all cardiovascular diseases were still present in US and Europe settings, except in Asia this was present only for cardiovascular deaths. Effects of low and medium income versus high on these corresponding cardiovascular diseases were 1.49 (1.16-1.91) and 1.27 (1.10-1.47) for coronary artery diseases, 1.17 (0.96-1.44) and 1.05 (0.98-1.13) for cardiovascular events, 1.30 (0.99-1.72) and 1.24 (1.00-1.53) for strokes, and 1.76 (1.45-2.14) and 1.34 (1.17-1.54) for cardiovascular deaths. Conclusion Social determinants are risk factors of cardiovascular diseases in developed countries, although high heterogeneity in pooling. Data in Asia countries are still needed to update pooling.

© 2017 Elsevier B.V. Aims We compared the impact of new gestational diabetes (GDM) diagnostic criteria by IADPSG with previous criteria to ascertain concordance between the two criteria; and whether women discordant for GDM between the old and new criteria had increased pregnancy complications. Methods Oral glucose tolerance tests of pregnant women across time periods using old criteria and new criteria were collected. Maternal data and perinatal outcomes were compared between diagnostic concordant and discordant women. Results In total, 666/5178 (12.9%) women were diagnosed and treated for GDM. There was a significant increase in odds of any complication in concordant positive women (OR 3.91 95%CI 2.71¿5.63, p <.0001); in women only positive by new GDM criteria (OR 2.06, 95% CI 1.41¿2.99, p =.0002); and women only positive by old GDM criteria (OR 2.28, 95% CI 1.42¿3.66, p =.0006); compared to concordant negative women. This is mainly due to macrosomia and nursery admissions. Conclusion This study confirms that women diagnosed with GDM on both old and new criteria have a higher rate of birth complications than women without GDM. Women who have been missed out due to new criteria may still be at risk. Therefore, combination of both old and new criteria may be optimal for identifying high-risk pregnancies.

© 2017 Elsevier B.V. Aims To assess the relationship between insulin resistance (IR), retinopathy and maculopathy in young adults with Type 1 diabetes mellitus. Methods A cross-sectional study at a regional Australian tertiary hospital. Retinal pathology, assessed by colour fundus photography, was correlated with two surrogate measures of IR: estimated Glucose Disposal Rate (eGDR) and Insulin Sensitivity Score (ISS), where lower scores reflect greater IR. Results 107 patients were recruited, with mean age 24.7¿years, 53% male, and mean duration of disease 10.8¿years. Mean eGDR scores (5.6¿vs 8.0 p¿<¿0.001) and ISS (4.7¿vs 7.9, p¿<¿0.001) were lower in subjects having at least moderate non-proliferative diabetic retinopathy (NPDR; relative to nil/mild-NPDR). Similarly, mean eGDR (4.2¿vs 6.2, p¿=¿0.001) and ISS (3.8¿vs 6.1, p¿=¿0.003) were lower in patients with maculopathy. Multivariate logistic regression modelling was used to control for confounding. For retinopathy severity, a unit increase in eGDR or ISS (representing lower IR) was associated with a 50% decrease in odds of moderate-NPDR or worse (eGDR OR 0.5, 95%CI 0.32¿0.77, p¿=¿0.002; ISS OR 0.49, 95%CI 0.29¿0.84, p¿=¿0.01). A unit increase in eGDR or ISS was associated with a 46¿56% decrease in odds of maculopathy (eGDR OR 0.54, 95%CI 0.37¿0.81, p¿=¿0.003; ISS OR 0.44, 95%CI 0.22¿0.88, p¿=¿0.02). Conclusions IR correlates with more severe retinopathy in young adults with Type 1¿DM. This is the first description of a correlation between IR and maculopathy in Type 1¿DM, warranting further evaluation. Prospective studies examining whether reducing IR can improve microvascular complications are required.

© 2017 The Authors. International Dental Journal published by John Wiley & Sons Ltd on behalf of World Dental Federation. Objective: Dental plaque accumulation and inadequate personal oral hygiene (OH) are known major risk factors of periodontitis. Nevertheless, the magnitude of their effects has not yet been the subject of a meta-analysis. Material and methods: The Medline and Scopus databases were searched up to May 2016. Observational studies were eligible if they assessed associations between OH and periodontitis in adult subjects. A multivariate random-effects meta-analysis was used to pool the effects of fair/poor OH versus good OH on periodontitis across studies. The associations between oral care habits and periodontitis were also assessed. Results: A total of 50 studies were eligible; 15 were used for pooling the effect of fair OH versus good OH and poor OH versus good OH on periodontitis, with pooled odds ratios (ORs) of 2.04 [95% confidence interval (CI): 1.65¿2.53] and 5.01 (95% CI: 3.40¿7.39), respectively. Eleven studies examined oral care habits measured according to toothbrushing regularity and dental visit frequency; pooled ORs of 0.66 (95% CI: 0.47¿0.94) and 0.68 (95% CI: 0.47¿0.98) were obtained, respectively. Conclusions: Fair to poor OH increases the risk of periodontitis by two- to five-fold. This risk can be reduced by regular toothbrushing and dental visits.

© 2017 Elsevier Inc. Apolipoproteins play a crucial role in lipid metabolism with implications in cardiovascular disease, obesity, diabetes, Alzheimer's disease, and longevity. We quantified 7 apolipoproteins in plasma in 1067 individuals aged 56¿105 using immunoassays and explored relationships with APOE polymorphism e2/3/4, vascular health, frailty, and cognition. ApoA1, ApoA2, ApoB, ApoC3, ApoE, ApoH, and ApoJ decreased from mid-life, although ApoE and ApoJ had U-shaped trends. Centenarians had the highest ApoE levels and the lowest frequency of APOE e4 allele relative to younger groups. Apolipoprotein levels trended lower in APOE e4 homozygotes and heterozygotes compared with noncarriers, with ApoE and ApoJ being significantly lower. Levels of all apolipoproteins except ApoH were higher in females. Sex- and age-related differences were apparent in the association of apolipoproteins with cognitive performance, as only women had significant negative associations of ApoB, ApoE, ApoH, and ApoJ in mid-life, whereas associations at older age were nonsignificant or positive. Our findings suggest levels of some apolipoproteins, especially ApoE, are associated with lifespan and cognitive function in exceptionally long-lived individuals.

© 2017 The Authors 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).

© 2017 AMPCo Pty Ltd. Produced with Elsevier B.V. All rights reserved. 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.

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

© 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. Methods In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings Data were available for more than 550¿000 individuals and 51¿623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c(0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30). Interpretation PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. Funding British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

© 2016 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine Objective: Hypoxia is a recognised complication of procedural sedation. This study sought to determine whether there was an association between the use of high-flow oxygen delivery by a non-rebreather (NRB) mask during ED procedural sedation and decreased rates of hypoxia when compared with alternative oxygenation methods. Methods: Records of all procedural sedations performed over a 12 month period in an Australian tertiary ED were reviewed retrospectively. The primary outcome was whether recorded oxygen saturations fell below 90%. Specifics of the oxygen delivery method were noted and data collected included sex, age, indication for sedation, drugs and doses administered, time of day sedation was commenced and staff grade of sedationist. Results: A total of 755 procedural sedations were reviewed. Two hundred and five (27.1%) patients were administered oxygen via NRB mask from the outset of their sedation. NRB administration was associated with a statistically significant decreased rate of hypoxia (1/205 patients vs 23/550 [odds ratio: 0.112; 95% confidence interval: 0.003¿0.0702]; P = 0.0090). This association remained statistically significant when adjusted for confounders. Conclusions: This study demonstrates an association with a statistically significant reduction in hypoxia when high-flow oxygen via NRB mask is administered during emergency procedural sedation. This intervention is simple, safe and inexpensive, and we would advocate that it be evaluated further in prospective trials.

© 2017, BMJ Publishing Group. All rights reserved. Background Tobacco smoking can have negative health outcomes on recovery from surgery. Although it is recommended best practice to provide patients with advice to quit and follow-up support, provision of postdischarge support is rare. Developing an online smoking cessation program may help address this gap. Objectives This paper describes the development and pretesting of an online smoking cessation program (smoke-free recovery, SFR) tailored to the orthopaedic trauma population for use while in hospital and post-discharge. Methods Drawing on the DoTTI framework for developing an online program, the following steps were followed for program development: (1) design and development; (2) testing early iteration; (3) testing for effectiveness and (4) integration and implementation. This article describes the first two stages of SFR program development. Results SFR is a 10-module online smoking cessation program tailored for patients with orthopaedic trauma. Of the participants who completed testing early iterations, none reported any difficulties orientating themselves to the program or understanding program content. The main themes were that it was ¿helpful¿, provision of ¿help to quit¿ was low and SFR increased thoughts of ¿staying quit post discharge¿. Conclusions This study found that a theory and evidence-based approach as the basis for an online smoking cessation program for patients with orthopaedic trauma was acceptable to users. A randomised controlled trial will be conducted to examine whether the online smoking cessation program is effective in increasing smoking cessation and how it can be integrated and implemented into hospital practice (stages three and four of the DoTTI framework).

© 2017 National Stroke Association Background Cervical artery dissection (CAD) is a leading cause of stroke among middle-aged adults, but the etiology is unclear. Some reports of seasonal variation in CAD incidence have been suggested but may reflect extreme climatic conditions. Seasonal variation may implicate more transient seasonal causes such as proinflammatory or hypercoagulable states. This study aimed to assess whether CAD incidence varied with season between UK and Australian sites. Also, this study aimed to determine whether there was a different pattern of seasonal variation between arteries (carotid and vertebral) and any association between CAD incidence and clinical factors. Methods This was a retrospective observational study of patients older than 18 years with radiological diagnosis of internal carotid or vertebral arterial dissection, from sites in Australia and the UK. Clinical variables were compared between autumn-winter and spring-summer and site of dissection. Results A total of 133 CAD cases were documented in Australia and 242 in the UK. There was a seasonal pattern to CAD incidence in countries in both the northern and the southern hemispheres, with a trend for dissection to occur more commonly in autumn, winter, and spring than in summer (incidence rate ratios [IRR] 1.4-1.5, P¿<¿.05). CAD counts were also slightly higher in internal carotid than in vertebral artery (IRRs 1.168, 1.43, and 1.127, respectively). Neither systolic blood pressure nor pulse pressure was significantly associated with CAD counts. Conclusions CAD occurs more commonly in cooler months regardless of geographical location, suggesting transient seasonal causes may be important in the pathophysiology. This effect was slightly higher in internal carotid than in vertebral artery, suggesting differing trigger mechanisms between dissection sites.

© 2017, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. 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.

© 2017 Article author(s). Purpose To assess the 5-year progression from unilateral to bilateral age-related macular degeneration (AMD) and associated risk factors. Design Pooled data analyses of three prospective population-based cohorts, the Blue Mountains Eye Study, Beaver Dam Eye Study and Rotterdam Study. Methods Retinal photography and interview with comprehensive questionnaires were conducted at each visit of three studies. AMD was assessed following the modified Wisconsin AMD grading protocol. Progression to bilateral any (early and late) or late AMD was assessed among participants with unilateral involvement only. Factors associated with the progression were assessed using logistic regression models while simultaneously adjusting for other significant risk factors. Results In any 5-year duration, 19-28% of unilateral any AMD cases became bilateral and 27-68% of unilateral late AMD became bilateral. Factors associated with the progression to bilateral involvement of any AMD were age (per year increase, adjusted OR 1.07), carrying risk alleles of the complement factor H and age-related maculopathy susceptibility 2 genes (compared with none, OR 1.76 for 1 risk allele and OR 3.34 for 2+ risk alleles), smoking (compared with non-smokers, OR 1.64 for past and OR 1.67 for current smokers), and the presence of large drusen area or retinal pigmentary abnormalities in the first eye. Conclusion One in four to one in five unilateral any AMD cases, and up to one in two unilateral late AMD cases, progressed to bilateral in 5 years. Known AMD risk factors, including smoking, are significantly associated with the progression to bilateral involvement.

© 2017 American Heart Association, Inc. Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

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

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Objective: This study investigates orthopaedic trauma patients smoking cessation history, intentions to quit, receipt of smoking cessation care during hospital admission, and patient-related factors associated with receipt of smoking cessation care. Methods: An online cross-sectional survey of orthopaedic trauma patients was conducted in 2 public hospitals in New South Wales, Australia. Prevalence of smoking and associated variables were described. Logistic regressions were used to examine whether patient characteristics were associated with receipt of smoking cessation care. Results: Eight hundred nineteen patients (response rate 73%) participated. More than 1 in 5 patients (21.8%) were current smokers (n = 175). Of the current smokers, more than half (55.3%) indicated making a quit attempt in the last 12 months and the majority (77.6%) were interested in quitting. More than a third of smokers (37.4%) were not advised to quit; 44.3% did not receive any form of nicotine replacement therapy; and 24.1% reported that they did not receive any of these 3 forms of smoking cessation care during their admission. Provision of care was not related to patient characteristics. Conclusions: The prevalence of smoking among the sample was high. Respondents were interested in quitting; however, the provision of care during admission was low. Smoking cessation interventions need to be developed to increase the provision of care and to promote quit attempts in this Australian population.

© 2017 The Royal Society for Public Health Objective Malaysia has a high and rising prevalence of type 2 diabetes (T2D). While environmental (non-genetic) risk factors for the disease are well established, the role of genetic variations and gene¿environment interactions remain understudied in this population. This study aimed to estimate the relative contributions of environmental and genetic risk factors to T2D in Malaysia and also to assess evidence for gene¿environment interactions that may explain additional risk variation. Study design This was a case¿control study including 1604 Malays, 1654 Chinese and 1728 Indians from the Malaysian Cohort Project. Methods The proportion of T2D risk variance explained by known genetic and environmental factors was assessed by fitting multivariable logistic regression models and evaluating McFadden's pseudo R2and the area under the receiver-operating characteristic curve (AUC). Models with and without the genetic risk score (GRS) were compared using the log likelihood ratio Chi-squared test and AUCs. Multiplicative interaction between genetic and environmental risk factors was assessed via logistic regression within and across ancestral groups. Interactions were assessed for the GRS and its 62 constituent variants. Results The models including environmental risk factors only had pseudo R2values of 16.5¿28.3% and AUC of 0.75¿0.83. Incorporating a genetic score aggregating 62 T2D-associated risk variants significantly increased the model fit (likelihood ratio P-value of 2.50 × 10-4¿4.83 × 10-12) and increased the pseudo R2by about 1¿2% and AUC by 1¿3%. None of the gene¿environment interactions reached significance after multiple testing adjustment, either for the GRS or individual variants. For individual variants, 33 out of 310 tested associations showed nominal statistical significance with 0.001 < P < 0.05. Conclusion This study suggests that known genetic risk variants contribute a significant but small amount to overall T2D risk variation in Malaysian population groups. If gene¿environment interactions involving common genetic variants exist, they are likely of small effect, requiring substantially larger samples for detection.

© The Author(s) 2016. Focal hyperperfusion after acute ischaemic stroke could be of prognostic value depending upon its spatial localisation and temporal dynamics. Factors associated with late stage (12-24 h) perilesional hyperperfusion, identified using arterial spin labelling, are poorly defined. A prospective cohort of acute ischaemic stroke patients presenting within 4.5 h of symptom onset were assessed with multi-modal computed tomography acutely and magnetic resonance imaging at 24 ± 8 h. Multivariate logistic regression analysis and receiver operating characteristics curves were used. One hundred and nineteen hemispheric acute ischaemic stroke patients (mean age = 71 ± 12 years) with 24 h arterial spin labelling imaging were included. Forty-Two (35.3%) patients showed perilesional hyperperfusion on arterial spin labelling at 24 h. Several factors were independently associated with perilesional hyperperfusion: good collaterals (71% versus 29%, P < 0.0001; OR = 5, 95% CI = [1.6, 15.7], P = 0.005), major reperfusion (81% versus 48%, P = < 0.0001; OR = 7.5, 95% CI = [1.6, 35.1], P = 0.01), penumbral salvage (76.2% versus 47%, P = 0.002; OR = 6.6, 95% CI = [1.8, 24.5], P = 0.004), infarction in striatocapsular (OR = 9.5, 95% CI = [2.6, 34], P = 0.001) and in cortical superior division middle cerebral artery (OR = 4.7, 95% CI = [1.4, 15.7], P = 0.012) territory. The area under the receiver operating characteristic curve was 0.91. Our results demonstrate good arterial collaterals, major reperfusion, penumbral salvage, and infarct topographies involving cortical superior middle cerebral artery and striatocapsular are associated with perilesional hyperperfusion.

� 2016 Royal Australasian College of Physicians Observational studies of the effectiveness of clinical interventions are proliferating as more ¿real-world¿ clinical data (so called ¿big data¿) are gathered from clinical registries, administrative datasets and electronic health records. While well-conducted randomised controlled trials (RCT) remain the scientific standard in assessing the efficacy of clinical interventions, well-designed observational studies may add to the evidence base of effectiveness in situations where RCT are of limited value or very difficult to perform. Rather than dismissing observational studies, we need to determine what circumstances may justify doing an observational study and when the study is sufficiently rigorous to be considered reasonably trustworthy. This article proposes criteria by which users of the literature might make such determinations.

© 2016 Elsevier Ireland Ltd. Aims: There are a number of studies showing that zinc supplementation may improve glucose handling in people with established diabetes. We sought to investigate whether this zinc-dependent improvement in glucose handling could potentially be harnessed to prevent the progression of pre-diabetes to diabetes. In this double-blind randomized placebo-controlled trial, we determined participants' fasting blood glucose levels, (FBG) and Homeostasis Model Assessment (HOMA) parameters (beta cell function, insulin sensitivity and insulin resistance) at baseline and after 6 months of zinc supplementation. Methods: The Bangladesh Institute of Health Sciences Hospital (BIHS) (Mirpur, Dhaka, Bangladesh) database was used to identify 224 patients with prediabetes, of whom 55 met the inclusion criteria and agreed to participate. The participants were randomized either to the intervention or control group using block randomization. The groups received either 30 mg zinc sulphate dispersible tablet or placebo, once daily for six months. Results: After six months, the intervention group significantly improved their FBG concentration compared to the placebo group (5.37 ± 0.20 mmol/L vs 5.69 ± 0.26, p < 0.001) as well as compared to their own baseline (5.37 ± 0.20 mmol/L vs 5.8 ± 0.09, p < 0.001). Beta cell function, insulin sensitivity and insulin resistance all showed a statistically significant improvement as well. Conclusion: To our knowledge this is the first trial to show an improvement in glucose handling using HOMA parameters in participants with prediabetes. Larger randomized controlled trials are warranted to confirm these findings and to explore clinical endpoints.

© 2016 Elsevier Ltd. Background: The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes. Methods: To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis. Findings: We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50 × 10-8; joint OR 1·19, 1·12-1·26, p=1·30 × 10-9). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26 × 10-19; joint OR 1·37, 1·30-1·45, p=2·79 × 10-32) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93 × 10-7; joint OR 1·17, 1·11-1·23, p=2·29 × 10-10) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50 × 10-8; joint OR 1·24, 1·15-1·33, p=4·52 × 10-9) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82 × 10-8; joint OR 1·17, 1·11-1·23, p=2·92 × 10-9). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed. Interpretation: Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke. Funding: US National Institute of Neurological Disorders and Stroke, National Institutes of Health.

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

© 2016 Nature America, Inc. Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (P = 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.

© 2016 Nature America, Inc. We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r 2 = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

© 2016 Elsevier Ireland Ltd Background It remains unclear whether eradication of oligometastases by stereotactic body radiation therapy or other means will result in cure or prolongation of survival in some cases, or merely provide palliation. We address this issue with prospectively collected progression and treatment data from the TROG 03.04 RADAR randomised controlled trial for men with locally advanced prostate cancer (PC). Methods Three Fine and Gray competing risk survival models with time-dependent covariates were used to determine whether metastatic progression status at first diagnosis of bony metastases, i.e. number of bony sites involved and presence of prior or simultaneous other sites of progression, impacts on prostate cancer-specific mortality (PCSM) when adjusted for baseline prognostic factors and allocated primary treatment. Results Between 2003 and 2014, 176 of the 1071 subjects developed bone metastases, 152 developed other sites of progression and 91 died of PC. All subjects received secondary treatment using androgen suppression but none received extirpative treatments. The three models found evidence: 1 ¿ of a clear prognostic gradient according to number of bony metastatic sites; 2 ¿ that other sites of progression contributed to PCSM to a lesser extent than bone progression; and 3 ¿ that further bony metastatic progression in men with up to 3 bony metastases had a major impact on PCSM. Conclusion Randomised trials are essential to determine the value of extirpative treatment for oligometastatic bony metastases due to PC.

© The Author 2015. Published by Oxford University Press. Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels.We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ~120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indelswere examined.We identified 41 genome-wide significant fibrinogen loci; of which, 18were newly identified. Therewere no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

© Wolters Kluwer Health, Inc. All rights reserved. Disengagement from services is common before suicide, hence identifying factors at treatment presentation that predict future suicidality is important. This article explores risk profiles for suicidal ideation among treatment seekers with depression and substance misuse. Participants completed assessments at baseline and 6 months. Baseline demographics, psychiatric history, and current symptoms were entered into a decision tree to predict suicidal ideation at follow-up. Sixty-three percent of participants at baseline and 43.5% at follow-up reported suicidal ideation. Baseline ideation most salient when psychiatric illness began before adulthood, increasing the rate of follow-up ideation by 16%. Among those without baseline ideation, dysfunctional attitudes were the most important risk factor, increasing rates of suicidal ideation by 35%. These findings provide evidence of factors beyond initial diagnoses that increase the likelihood of suicidal ideation and are worthy of clinical attention. In particular, providing suicide prevention resources to those with high dysfunctional attitudes may be beneficial.

© 2016 The Author(s). Background: Cardiovascular disease (CVD) disproportionately affects disadvantaged people, but reliable quantitative evidence on socioeconomic variation in CVD incidence in Australia is lacking. This study aimed to quantify socioeconomic variation in rates of primary and secondary CVD events in mid-age and older Australians. Methods: Baseline data (2006-2009) from the 45 and Up Study, an Australian cohort involving 267,153 men and women aged = 45, were linked to hospital and death data (to December 2013). Outcomes comprised first event - death or hospital admission - for major CVD combined, as well as myocardial infarction and stroke, in those with and without prior CVD (secondary and primary events, respectively). Cox regression estimated hazard ratios (HRs) for each outcome in relation to education (and income and area-level disadvantage), separately by age group (45-64, 65-79, and = 80 years), adjusting for age and sex, and additional sociodemographic factors. Results: There were 18,207 primary major CVD events over 1,144,845 years of follow-up (15.9/1000 person-years), and 20,048 secondary events over 260,357 years (77.0/1000 person-years). For both primary and secondary events, incidence increased with decreasing education, with the absolute difference between education groups largest for secondary events. Age-sex adjusted hazard ratios were highest in the 45-64 years group: for major CVDs, HR (no qualifications vs university degree) = 1.62 (95% CI: 1.49-1.77) for primary events, and HR = 1.49 (1.34-1.65) for secondary events; myocardial infarction HR = 2.31 (1.87-2.85) and HR = 2.57 (1.90-3.47) respectively; stroke HR = 1.48 (1.16-1.87) and HR = 1.97 (1.42-2.74) respectively. Similar but attenuated results were seen in older age groups, and with income. For area-level disadvantage, CVD gradients were weak and non-significant in older people (> 64 years). Conclusions: Individual-level data are important for quantifying socioeconomic variation in CVD incidence, which is shown to be substantial among both those with and without prior CVD. Findings reinforce the opportunity for, and importance of, primary and secondary prevention and treatment in reducing socioeconomic variation in CVD and consequently the overall burden of CVD morbidity and mortality in Australia.

The precursor for nerve growth factor (proNGF) is expressed in some cancers but its clinicopathological significance is unclear. The present study aimed to define the clinicopathological significance of proNGF in thyroid cancer. ProNGF expression was analysed by immunohistochemistry in two cohorts of cancer versus benign tumors (adenoma) and normal thyroid tissues. In the first cohort (40 thyroid cancers, 40 thyroid adenomas and 80 normal thyroid tissues), proNGF was found overexpressed in cancers compared to adenomas and normal samples (p<0.0001). The area under the receiver-operating characteristic (ROC) curve was 0.84 (95% CI 0.75-0.93, p<0.0001) for cancers versus adenomas, and 0.99 (95% CI 0.98-1.00, p<0.0001) for cancers versus normal tissues. ProNGF overexpression was confirmed in a second cohort (127 cancers of various histological types and 55 normal thyroid tissues) and using a different antibody (p<0.0001). ProNGF staining intensity was highest in papillary carcinomas compared to other histological types (p<0.0001) and there was no significant association with age, gender, tumor size, stage and lymph node status. In conclusion, proNGF is increased in thyroid cancer and should be considered as a new potential diagnostic biomarker.

© The Author 2016. Published by Oxford University Press. All rights reserved. Background. Impaired health-related quality of life (HRQoL) post stroke is common, though prevalence estimates vary considerably. Few longitudinal studies explore post-stroke patterns of HRQoL and factors contributing to their change over time. Accurately identifying HRQoL after stroke is essential to understanding the extent of stroke effects. Objectives. This study aimed to assess change in levels of, and identify independent predictors of, HRQoL over the first 12-months post-stroke. Methods. Design. A prospective cohort study. Setting and participants. Community-dwelling stroke survivors in metropolitan Newcastle, New South Wales (NSW), Australia. Consecutively recruited stroke patients (n = 134) participated in face-to-face interviews at baseline, 3, 6, 9 and 12 months. Outcome measure. HRQoL (measured using the Assessment Quality-of-life).Independent measures. Physical and psycho-social functioning, including depression and anxiety (measured via Hospital Anxiety and Depression Scale), disability (Modified Rankin Scale), social support (Multi-dimensional Scale Perceived Social Support) and community participation (Adelaide Activities Profile).Analyses. A linear mixed model was used to establish the predictors of, change in HRQoL over time. Results. On multivariable analysis, HRQOL did not change significantly with time post-stroke. Higher HRQoL scores were independently associated with higher baseline HRQoL (P = 0.03), younger age (P = 0.006), lower disability (P = 0.003), greater community participation (P = 0.001) and no history of depression (P = 0.03). Conclusion. These results contribute to an understanding of HRQoL in the first year post-stroke. Community participation and stroke-related disability are potentially modifiable risk factors affecting post-stroke HRQoL. Interventions aimed at addressing participation and disability post-stroke should be developed and tested.

BACKGROUND Local infiltration analgesia (LIA) has emerged as an alternative treatment for postoperative pain after total knee arthroplasty (TKA). Its efficacy remains inconclusive with inconsistent results from previous studies and meta-analyses. There is no agreement on which local anaesthetic agent and infiltration technique is most effective and well tolerated. OBJECTIVE The objective was to compare LIA after primary TKA with placebo or no infiltration in terms of early postoperative pain relief, mobilisation, length of hospital stay (LOS) and complications when used as a primary treatment or as an adjunct to regional anaesthesia. The role of injection sites, postoperative injection or infusion and multimodal drug injection with ketorolac were also explored. DESIGN A systematic review and meta-analysis of randomised controlled trials (RCTs). DATA SOURCES A literature search was performed using PubMed and SCOPUS up to September 2015. ELIGIBILITY CRITERIA RCTs comparing LIA with placebo or no infiltration after primary TKA in terms of pain score and opioid consumption at 24 and 48 h, mobilisation, LOS and complications were included. RESULTS In total 38 RCTs were included. LIA groups had lower pain scores, opioid consumption and postoperative nausea and vomiting, higher range of motion at 24 h and shorter LOS than no injection or placebo. After subgroup analysis, intraoperative peri-articular but not intra-articular injection had lower pain score at 24 h than no injection or placebo with the pooled mean difference of pain score at rest of -0.89 [95% CI (-1.40 to -0.38); I2=92.0%]. Continuing with postoperative injection or infusion reduced 24-h pain score with the pooled mean difference at rest of -1.50 [95% CI (-1.92 to -1.08); I2=60.5%]. There was no additional benefit in terms of pain relief during activity, opioid consumption, range of movement or LOS when LIA was used as an adjunct to regional anaesthesia. Four out of 735 patients receiving LIA reported deep knee infection, three of whom had had postoperative catheter placement. CONCLUSION LIA is effective for acute pain management after TKA. Intraoperative peri-articular but not intra-articular injection may be helpful in pain control up to 24 h. The use of postoperative intra-articular catheter placement is still inconclusive. The benefit of LIA as an adjunctive treatment to regional anaesthesia was not demonstrated.

Copyright © The Authors 2016. There is increasing evidence for the role of nutrition in the prevention of depression. This study aims to describe changes in diet quality over 12 years among participants in the Australian Longitudinal Study on Women's Health in relation to changes in depressive symptoms. Women born between 1946 and 1951 were followed-up for 12 years (2001-2013). Dietary intake was assessed using the Dietary Questionnaire for Epidemiological Studies (version 2) in 2001, 2007 and every 2-3 years after that until 2013. Diet quality was summarised using the Australian Recommended Food Score (ARFS). Depressive symptoms were measured using the ten-item Centre for Epidemiologic Depression Scale at every 2-3-year intervals during 2001-2013. Linear mixed models were used to examine trends in diet quality and its sub-components. The same model including time-varying covariates was used to examine associations between diet quality and depressive symptoms adjusting for confounders. Sensitivity analyses were carried out using the Mediterranean dietary pattern (MDP) index to assess diet quality. Minimal changes in overall diet quality and its sub-components over 12 years were observed. There was a significant association between baseline diet quality and depression (ß=-0 24, P=0 001), but this was lost when time-varying covariates were added (ß=-0 04, P=0 10). Sensitivity analyses showed similar performance for both ARFS and MDP in predicting depressive symptoms. In conclusion, initial associations seen when using baseline measures of diet quality and depressive symptoms disappear when using methods that handle time-varying covariates, suggesting that previous studies indicating a relationship between diet and depression may have been affected by residual confounding.

© 2015, The Author(s). Summary: We assessed the ability of a fracture liaison service (FLS) to directly reduce re-fracture risk. Having a FLS is associated with a ~40¿% reduction in the 3-year risk of major bone and ~30¿% of any bone re-fracture. The number needed to treat to prevent a re-fracture is 20. Introduction: FLS have been promoted as the most effective interventions for secondary fracture prevention, and while there is evidence of increased rate of investigation and treatment at institutions with a FLS, only a few studies have considered fracture outcomes directly. We therefore sought to evaluate the ability of our FLS to reduce re-fracture risk. Methods: Historical cohort study of all patients =50¿years presenting over a 6-month period with¿a minimal trauma fracture (MTF) to the emergency departments of a tertiary hospital with a FLS, and one without a FLS. Baseline characteristics, mortality and MTFs over a 3-year follow-up were recorded. Results: Five hundred fifteen patients at the FLS hospital and 416 patients at the non-FLS hospital were studied. Over 3¿years, 63/515 (12¿%) patients at the FLS hospital and 70/416 (17¿%) at the non-FLS hospital had a MTF. All patients were analysed in an intention-to-treat analysis regardless of whether they were seen in the FLS follow-up clinic. Statistical analysis using Cox proportional hazard models in the presence of a competing risk of death from any cause was used. After adjustment for baseline characteristics, there was a ~30¿% reduction in rate of any re-fracture at the FLS hospital (hazard ratio (HR) 0.67, confidence interval (CI) 0.47-0.95, p value 0.025) and a ~40¿% reduction in major re-fractures (hip, spine, femur, pelvis or humerus) (HR 0.59, CI 0.39-0.90, p value 0.013). Conclusions: We found a ~30¿% reduction in any re-fractures and a ~40¿% reduction in major re-fractures at the FLS hospital compared with a similar non-FLS hospital. The number of patients needed to treat to prevent one new fracture over 3¿years is 20.

© 2016 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc. Background: We conducted a systematic review and meta-analysis of interferon regulatory factor 6 and 8q24 polymorphisms with nonsyndromic cleft lip with/without cleft palate (NSCL/P). Methods: Data extraction was independently performed by two reviewers. Genotypic effects of four polymorphisms from 31 studies were pooled separately by ethnicity using a mixed-effect logit model with accounting for heterogeneity. Results: For rs2235371, AA and GA carried, respectively, 51% (95% confidence interval [CI], 37%¿61%) and 42% (95% CI, 32%¿50%) lower risks of NSCL/P than GG genotypes in Asians, but these genotypes were not significant in Caucasians. For rs2013162, only AA was significant, that is, carried 0.65 (95% CI, 0.52¿0.82) times lower odds than CC in Caucasians but not for Asians. For rs642961, AA and GA genotypes, respectively, carried 2.47 (95% CI, 1.41¿4.35) and 1.40 (95% CI, 1.12¿1.75) times higher odds in Asian, and 2.03 (95% CI, 1.52¿2.71) and 1.58 (95% CI, 1.37¿1.82) times higher odds in Caucasians compare with GG genotypes. For rs987525, AA and CA genotypes carried 2.27 (95% CI, 1.43¿3.60) and 1.34 (95% CI, 1.02¿1.77) times higher odds in Asian, and 5.25 (95% CI, 3.98¿6.91) and 2.13 (95% CI¿1.82, 2.49) times higher odds in Caucasians, and 1.42 (95% CI, 1.10¿1.82) and 1.28 (95% CI, 1.09¿1.50) times higher odds in mixed ethnicities compared with CC genotypes. These variant effects remained significant based on applying Bonferroni corrected-thresholds, except in the mixed ethnicity. Conclusion: We show robust variant effects in NSCL/P. Considering them with other genes and risk factors might be useful to improve prediction of NSCL/P occurrence. Birth Defects Research (Part A) 106:773¿788, 2016. © 2016 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc.

© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2016. Indigenous Australians have high rates of chronic diseases, the causes of which are complex and include social and environmental determinants. Early experiences in utero may also predispose to later-life disease development. The Gomeroi gaaynggal study was established to explore intrauterine origins of renal disease, diabetes and growth in order to inform the development of health programmes for Indigenous Australian women and children. Pregnant women are recruited from antenatal clinics in Tamworth, Newcastle and Walgett, New South Wales, Australia, by Indigenous research assistants. Measures are collected at three time points in pregnancy and from women and their children at up to eight time points in the child's first 5 years. Measures of fetal renal development and function include ultrasound and biochemical biomarkers. Dietary intake, infant feeding and anthropometric measurements are collected. Standardized procedures and validated tools are used where available. Since 2010 the study has recruited over 230 women, and retained 66 postpartum. Recruitment is ongoing, and Gomeroi gaaynggal is currently the largest Indigenous pregnancy-through-early-childhood cohort internationally. Baseline median gestational age was 39.1 weeks (31.5-43.2, n=110), median birth weight was 3180 g (910-5430 g, n=110). Over one third (39.3%) of infants were admitted to special care or neonatal nursery. Nearly half of mothers (47.5%) reported tobacco smoking during pregnancy. Results of the study will contribute to knowledge about origins of chronic disease in Indigenous Australians and nutrition and growth of women and their offspring during pregnancy and postpartum. Study strengths include employment and capacity-building of Indigenous staff and the complementary ArtsHealth programme.

© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic risk remains unexplained. We present the meta-analysis results of four genome-wide association studies (4907 cases and 11 945 controls total) in women of European ancestry. We describe one new locus reaching genome-wide significance (P < 5 × 10 -8) at 6p22.3 (rs1740828; P = 2.29 × 10 -8, OR = 1.20), providing evidence of an additional region of interest for genetic susceptibility to endometrial cancer.

� 2016 Johnson et al. Objective: There have been no trials in healthcare settings of genetic susceptibility feedback in relation to alcohol consumption. The purpose of this study was to determine the feasibility and acceptability of conducting a full-scale randomised trial estimating the effect of personalised genetic susceptibility feedback on alcohol consumption in hospital outpatients with risky drinking. Methods: Outpatients =18 years of age who reported drinking more than 14 standard drinks in the past week or in a typical week were asked to provide a saliva sample for genetic testing. Genetic susceptibility feedback was posted to participants 6 months after recruitment. The co-primary outcomes were the proportion of participants who (i) provided a saliva sample that could be genotyped, and (ii) spoke with a genetic counsellor. Secondary outcomes included changes in patients' weekly alcohol consumption; scores on scales measuring readiness to change, importance of changing and confidence in ability to change drinking habits; knowledge about which cancers are alcohol-attributable; and acceptability of the saliva collection procedure and the genetic-feedback intervention. McNemar's test and paired t-tests were used to test for differences between baseline and follow-up in proportions and means, respectively. Results: Of 100 participants who provided a saliva sample, 93 had adequate DNA for at least one genotyping assay. Three participants spoke to a genetic counsellor. Patients' readiness to change their drinking, their views on the importance of changing and their stated confidence in their ability to change increased between baseline and follow-up. There was no increase in patients' knowledge about alcohol-attributable cancers nor any reduction in how much alcohol they drank 4 months after receiving the feedback. Most participants (80%) were somewhat comfortable or very comfortable with the process used to collect saliva, 84% understood the genetic feedback, 54% found it useful, 10% had sought support to reduce their drinking after receiving the feedback, and 37% reported that the feedback would affect how much they drink in the future. Conclusion: Results of this study suggest it would be feasible to conduct a methodologically robust trial estimating the effect of genetic susceptibility feedback on alcohol consumption in hospital outpatients with risky drinking.

© Copyright 2016 Wolters Kluwer Health, Inc. Elevations in postmortem vitreous sodium chloride (PMVSC) levels may help in differentiating saltwater/seawater drowning (SWD) deaths from immersion deaths not related to drowning (DNRD). It is unclear whether the elevation is related to blood/plasma electrolyte changes after inhalation of seawater as hypothesized in SWDs or possibly caused by electrolyte diffusion and/or osmosis across the outer coats of the eyeball during immersion. Aim: To investigate the changes in bovine PMVSC levels at different time points while immersed in seawater. Methods: Bovine eyeballs were obtained from an abattoir and randomized into 2 groups: A) submerged in seawater ("wet" group) or b) placed in an impermeable plastic bag that was immersed in seawater ("dry" group). The PMVSC levels from 6 eyeballs were measured from each group (without replacement) at 30 minutes, 1 hour, 6 hours, and 12 hours. Results: There was no significant difference in mean PMVSC levels between the 2 groups at 30-minute and 1-hour intervals. A significant difference was noted from 6 hours onward. Discussion: There is no statistically significant elevation in bovine PMVSC levels when immersed in seawater for up to 1 hour. Assuming similar physical properties in humans, any elevations in PMVSC levels in bodies immersed in seawater for less than 1 hour should not be caused by immersion.

© 2016 Background Previous studies in salt water drowning deaths (SWD) demonstrated an observable elevation of post mortem vitreous sodium and chloride (PMVSC) levels. It remains unclear what the underlying mechanism responsible for this change is: whether this is due to rapid electrolyte changes from salt water inhalation/ingestion during drowning or from electrolyte diffusion and/or osmosis across the outer coats of the eyeballs during immersion. A recent animal study using sacrificed bovine eyeballs immersed in salt water demonstrated no significant elevations in PMVSC when immersed for less than one hour. Assuming similar physical properties between human and bovine, we extrapolate that an elevation in PMVSC in SWD with immersion times of less than one hour (SWD-1) would not be from immersion, but from drowning. Aim Investigate whether there is an elevation in PMVSC in SWD-1. Methods Retrospective study comparing PMVSC in SWD-1 with controls from 2012 to 2015 inclusive. Results PMVSC in SWD-1 was significantly elevated compared with controls. A PMVSC of 259¿mmol/L has a sensitivity, specificity and likelihood ratio of 0.9, 0.9 and 7.6, respectively. Conclusion The elevation in PMVSC in SWD-1 is due to drowning. A PMVSC of 259¿mmol/L and above is a reliable ancillary test in diagnosing drowning in bodies immersed in salt water for less than one hour.

© 2016 The authors. Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancerandwith estradiol (E2) concentrations.We analyzed2937singlenucleotidepolymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome widesignificant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10-11). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10-8). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by theobservedeffectonE2concentrations (1.09, CI=1.03-1.21), consistentwith the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associationswith rs727479 were stronger amongwomen with a higher BMI (PinteractionZ0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.

© 2016 Diabetes UK. Aim: To determine the effects of protein alone (independent of fat and carbohydrate) on postprandial glycaemia in individuals with Type¿1 diabetes mellitus using intensive insulin therapy. Methods: Participants with Type¿1 diabetes mellitus aged 7-40¿years consumed six 150¿ml whey isolate protein drinks [0¿g (control), 12.5, 25, 50, 75 and 100] and two 150¿ml glucose drinks (10 and 20¿g) without insulin, in randomized order over 8¿days, 4¿h after the evening meal. Continuous glucose monitoring was used to assess postprandial glycaemia. Results: Data were collected from 27 participants. Protein loads of 12.5 and 50¿g did not result in significant postprandial glycaemic excursions compared with control (water) throughout the 300¿min study period (P¿>¿0.05). Protein loads of 75 and 100¿g resulted in lower glycaemic excursions than control in the 60-120¿min postprandial interval, but higher excursions in the 180-300¿min interval. In comparison with 20¿g glucose, the large protein loads resulted in significantly delayed and sustained glucose excursions, commencing at 180¿min and continuing to 5¿h. Conclusions: Seventy-five grams or more of protein alone significantly increases postprandial glycaemia from 3 to 5¿h in people with Type¿1 diabetes mellitus using intensive insulin therapy. The glycaemic profiles resulting from high protein loads differ significantly from the excursion from glucose in terms of time to peak glucose and duration of the glycaemic excursion. This research supports recommendations for insulin dosing for large amounts of protein.

© 2016 Elsevier Inc. Antioxidants and fatty acids are associated with depression and inflammation, and inflammation appears to predict depression risk; hence, the associations between these nutrients and depression may be mediated by inflammation. We hypothesized that inflammatory markers interleukin (IL)-6 and C-reactive protein (CRP) mediate the associations between antioxidant and fatty acid intakes, and depression. Participants were from the Hunter Community Study, a longitudinal cohort of adults aged 55-85 years. Dietary intake was assessed using the Older Australian's Food Frequency Questionnaire. Fasting blood samples were drawn for analysis of nutrient and inflammatory biomarkers. Depressive symptoms were assessed using the 20-item Center for Epidemiologic Studies-Depression scale at baseline and at 5-year follow-up. Linear mixed models were used to investigate longitudinal associations between dietary intakes and depression, and mediation analyses were carried out to determine if IL-6 and/or CRP were the mediators. Analyses were conducted on men and women separately and adjusted for potential confounders. Fruit and monounsaturated fat intakes were negatively associated with depression, whereas total fat and saturated fat intakes were positively associated with depression in both sexes. Omega-3 polyunsaturated fat was inversely associated with depression in men only. IL-6 was a significant mediator of the association between fruits with low carotenoid content and depression in women. CRP significantly mediated the relationship between total fat, saturated fat, and monounsaturated fat intakes and depression in women, and saturated fat intake and depression in men. Our findings raise the possibility that the association between fatty acid intake and depression is partially mediated by inflammatory markers.

© 2016 Macmillan Publishers Limited All rights reserved. To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10 -8) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10 -9 after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10 -4). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10 -15), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10 -11) and neuron cell-cell adhesion (P-value=1.48 × 10 -13). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

© 2016 The Author(s). Background: The estrogen-induced gene 121 (EIG121) has been associated with breast and endometrial cancers, but its mechanism of action remains unknown. In a genome-wide search for tandem repeats, we found that EIG121 contains a short tandem repeat (STR) in its upstream regulatory region which has the potential to alter gene expression. The presence of this STR has not previously been analysed in relation to breast or endometrial cancer risk. Results: In this study, the lengths of this STR were determined by PCR, fragment analysis and sequencing using DNA from 223 breast cancer patients, 204 endometrial cancer patients and 220 healthy controls to determine if they were associated with the risk of developing breast or endometrial cancer. We found this repeat to be highly variable with the number of copies of the AG motif ranging from 27 to 72 and having a bimodal distribution. No statistically significant association was identified between the length of this STR and the risk of developing breast or endometrial cancer or age at diagnosis. Conclusions: The STR in the upstream regulatory region of EIG121 is highly polymorphic, but is not associated with the risk of developing breast or endometrial cancer in the cohorts analysed here. While this polymorphic STR in the regulatory region of EIG121 appears to have no impact on the risk of developing breast or endometrial cancer, its association with disease recurrence or overall survival remains to be determined.

© 2016, Alcohol Research Documentation Inc. All rights reserved. Objective: To investigate reporting of alcohol consumption, we manipulated the contexts of questions in ways designed to induce social desirability bias. Method: We undertook a two-arm, parallel-group, individually randomized trial at an Australian public university. Students were recruited by email to a web-based ¿Research Project on Student Health Behavior.¿ Respondents answered nine questions about their physical activity, diet, and smoking. They were unknowingly randomized to a group presented with either (A) three questions about their alcohol consumption or (B) seven questions about their alcohol dependence and problems (under a prominent header labeled ¿Alcohol Use Disorders Identification Test¿), followed by the same three alcohol consumption questions from (A). Results: A total of 3,594 students (mean age = 27, SD = 10) responded and were randomized: 1,778 to Group A and 1,816 to Group B. Outcome measures were the number of days they drank alcohol, the typical number of drinks they consumed per drinking day, and the number of days they consumed six or more drinks. The primary analysis included participants with any alcohol consumption in the preceding 4 weeks (1,304 in Group A; 1,340 in Group B) using between-group, two-tailed t tests. Results: In Groups A and B, respectively, means (and SDs) of the number of days drinking were 5.89 (5.92) versus 6.06 (6.12), p = .49; typical number of drinks per drinking day: 4.02 (3.87) versus 3.82 (3.76), p = .17; and number of days consuming six or more drinks: 1.69 (2.94) versus 1.67 (3.25), p = .56. Conclusions: We could not reject the null hypothesis because earlier questions about alcohol dependence and problems showed no sign of biasing the respondents¿ subsequent reports of alcohol consumption. These data support the validity of university students¿ reporting of alcohol consumption in web-based studies.

© 2016 AMPCo Pty Ltd. Objective: The system of care in the Hunter New England Local Health District for patients with ST-segment elevation myocardial infarction (STEMI) foresees pre-hospital thrombolysis (PHT) administered by paramedics to patients more than 60 minutes from the cardiac catheterisation laboratory (CCL), and primary percutaneous coronary intervention (PCI) at the CCL for others. We assessed the safety and effectiveness of the pre-hospital diagnosis strategy, which allocates patients to PHT or primary PCI according to travel time to the CCL. Design, setting and participants: Prospective, non-randomised, consecutive, single-centre case series of STEMI patients diagnosed on the basis of a pre-hospital electrocardiogram (ECG), from August 2008 to August 2013. All patients were treated at the tertiary referral hospital (John Hunter Hospital, Newcastle). Main outcome measures: The primary efficacy endpoint was all-cause mortality at 12 months; the primary safety endpoint was bleeding. Results: STEMI was diagnosed in 484 patients on the basis of pre-hospital ECG; 150 were administered PHT and 334 underwent primary PCI. The median time from first medical contact (FMC) to PHT was 35 minutes (IQR, 28¿43 min) and to balloon inflation 130 minutes (IQR, 100¿150 min). In the PHT group, 37 patients (27%) needed rescue PCI (median time, 4 h; IQR, 3¿5 h). The 12-month all-cause mortality rate was 7.0% (PHT, 6.7%; PCI, 7.2%). The incidence of major bleeding (TIMI criteria) in the PHT group was 1.3%; no patients in the primary PCI group experienced major bleeding. Conclusion: PHT can be delivered safely by paramedical staff in regional and rural Australia with good clinical outcomes.

� 2015 Diabetes UK Aims: To examine the prevalence and correlates of suicidal ideation (SI) in a community-based sample of adults with Type 1 or Type 2 diabetes. Methods: Participants were 3338 adults aged 18¿70 years with Type 1 diabetes (n = 1376) or Type 2 diabetes (non-insulin: n = 1238; insulin: n = 724) from a national survey administered to a random sample registered with the National Diabetes Services Scheme. Depression and SI were assessed using the Patient Health Questionnaire, and diabetes-specific distress with the Problem Areas In Diabetes scale. Separate logistic regression analyses by diabetes type/treatment were used to determine relative contribution to SI. Results: Overall, we observed a SI rate of 14% in our sample. Participants with Type 2 diabetes using insulin reported more frequent depressive symptoms, and were more likely to report recent SI (19%) compared with those with either Type 1 diabetes or Type 2 diabetes not using insulin (14 and 12%, respectively). After controlling for depression, there was little difference in the prevalence of SI between diabetes types/treatments, but higher diabetes-specific distress significantly increased the odds of SI. Conclusions: As SI is a significant risk factor for a suicide attempt, the findings have implications for healthcare professionals, pointing to the importance of adequate screening and action plans for appropriate follow-up of those reporting depression. Our findings are also indicative of the psychological toll of diabetes more generally, and the need to integrate physical and mental healthcare for people with diabetes.

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

© 2015 The Authors. Objectives: Telephone follow-up is not currently recommended as a strategy to improve retention in randomized trials. The aims of this study were to estimate the effect of telephone follow-up on retention, identify participant characteristics predictive of questionnaire completion during or after telephone follow-up, and estimate the effect of including participants who provided follow-up data during or after telephone follow-up on balance between randomly allocated groups in a trial estimating the effect of electronic alcohol screening and brief intervention on alcohol consumption in hospital outpatients with hazardous or harmful drinking. Method: Trial participants were followed up 6. months after randomization (June-December 2013) using e-mails containing a hyperlink to a web-based questionnaire when possible and by post otherwise. Telephone follow-up was attempted after two written reminders and participants were invited to complete the questionnaire by telephone when contact was made. Results: Retention before telephone follow-up was 62.1% (520/837) and 82.8% (693/837) afterward: an increase of 20.7% (173/837). Therefore, 55% (95% CI 49%-60%) of the 317 participants who had not responded after two written reminders responded during or after the follow-up telephone call. Age. <. 55. years, a higher AUDIT-C score and provision of a mobile/cell phone number were predictive of questionnaire completion during or after telephone follow-up. Balance between randomly allocated groups was present before and after inclusion of participants who completed the questionnaire during or after telephone follow-up. Conclusion: Telephone follow-up improved retention in this randomized trial without affecting balance between the randomly allocated groups.

© 2015 Kelly et al.; licensee BioMed Central. Background: Cardiovascular disease and cancer are leading causes of mortality for people with a history of alcohol or other substance use disorders. These chronic diseases share the same four primary behavioural risk factors i.e. excessive alcohol use, smoking, low intake of fruit and vegetables and physical inactivity. In addition to addressing problematic alcohol use, there is the potential for substance abuse treatment services to also address these other behaviours. Healthy Recovery is an 8-session group-based intervention that targets these multiple behavioural health risk factors and was developed specifically for people attending substance abuse treatment. This protocol describes a Cancer Institute NSW funded study that assesses the effectiveness of delivering Healthy Recovery for people who are attending residential alcohol and other substance abuse treatment. Methods/Design: The study uses a stepped wedge randomised controlled design, where randomisation occurs at the service level. Participants will be recruited from residential rehabilitation programs provided by The Australian Salvation Army. All participants who (1) currently smoke tobacco and (2) are expected to be in the residential program for the duration of the 5-week intervention will be asked to participate in the study. Those participants residing at the facilities assigned to the treatment condition will complete Healthy Recovery. The intervention is manual guided and will be delivered over a 5-week period, with participants attending 8 group sessions. All participants will continue to complete The Salvation Army residential program, a predominantly 12-step based, modified therapeutic community. Participants in the control condition will complete treatment as usual. Research staff blind to treatment allocation will complete the primary and secondary outcome assessments at baseline and then at weeks 8, 20 and 32 weeks post intervention. Discussion: This study will provide comprehensive data on the effect of delivering a healthy lifestyle intervention (i.e. Healthy Recovery) within a residential substance abuse setting. If shown to be effective, this intervention can be disseminated within other residential substance abuse programs. Trial registration: Australian and New Zealand Clinical Trials Register (ANZCTR): ACTRN12615000165583. Registered 19thFebruary 2015.

The neuronal membrane protein sortilin has been reported in a few cancer cell lines, but its expression and impact in human tumors is unclear. In this study, sortilin was analyzed by immunohistochemistry in a series of 318 clinically annotated breast cancers and 53 normal breast tissues. Sortilin was detected in epithelial cells, with increased levels in cancers, as compared to normal tissues (p = 0.0088). It was found in 79% of invasive ductal carcinomas and 54% of invasive lobular carcinomas (p < 0.0001). There was an association between sortilin expression and lymph node involvement (p = 0.0093), suggesting a relationship with metastatic potential. In cell culture, sortilin levels were higher in cancer cell lines compared to non-tumorigenic breast epithelial cells and siRNA knockdown of sortilin inhibited cancer cell adhesion, while proliferation and apoptosis were not affected. Breast cancer cell migration and invasion were also inhibited by sortilin knockdown, with a decrease in focal adhesion kinase and SRC phosphorylation. In conclusion, sortilin participates in breast tumor aggressiveness and may constitute a new therapeutic target against tumor cell invasion.

© 2015 Published by Elsevier Ireland Ltd. Background: The number of chemicals in household products has driven concern about potential adverse health through their use. Most research concentrates on product chemicals with reproductive and carcinogenic consequences, however some evidence exists that immune effects can lead to exacerbation of autoimmune illnesses such as lupus (SLE). Objectives: This paper examines household and personal product exposure patterns in a pilot case/control study of female Australians. We also examined associations between common product exposure and SLE symptom exacerbation over a year period. Methods: We enrolled 41 control and 80 SLE participants aged 18-80 years. Qualitative techniques of structured interview and thematic analysis retrospectively explored patterns of product use, and flare history data of SLE participants. Negative binomial regression models explored associations between self-reported flare (SRF) days and exposure to 34 common home product groups. Results: Mean product counts did not differ between participant groups (mean 33.1: SD 11.8), or flare groups (flare mean 32.6:SD 12, no-flare 31.8:SD 6.6). Products used for personal hygiene and general house cleaning were most frequently used.Significant association with increased SRF day relative risk (IRR) was seen for bath oil use (IRR 1.008, CI 1.00-1.02). Paradoxical "protective" effects, (reduced SRF days) were found for cleansing beauty (IRR 0.999, CI 0.998-0.999), make-up (IRR 0.998, CI 0.997-0.999); adhesives (IRR 0.994, CI 0.991-0.997) and paint (IRR 0.99, CI 0.986-0.995). Conclusions: Everyday product exposures can impact on symptom exacerbation in SLE. Some offering protection and others increased health risk. Identifying environmental associations offer the possibility of life-style interventions to reduce illness impact.

© 2015 American Academy of Neurology. Objectives: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease. Methods: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084). Results: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r2> 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes. Conclusions: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.

Copyright © 2015 Massachusetts Medical Society. Background: Trials of endovascular therapy for ischemic stroke have produced variable results. We conducted this study to test whether more advanced imaging selection, recently developed devices, and earlier intervention improve outcomes. Methods: We randomly assigned patients with ischemic stroke who were receiving 0.9 mg of alteplase per kilogram of body weight less than 4.5 hours after the onset of ischemic stroke either to undergo endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever or to continue receiving alteplase alone. All the patients had occlusion of the internal carotid or middle cerebral artery and evidence of salvageable brain tissue and ischemic core of less than 70 ml on computed tomographic (CT) perfusion imaging. The coprimary outcomes were reperfusion at 24 hours and early neurologic improvement (.8-point reduction on the National Institutes of Health Stroke Scale or a score of 0 or 1 at day 3). Secondary outcomes included the functional score on the modified Rankin scale at 90 days. Results: The trial was stopped early because of efficacy after 70 patients had undergone randomization (35 patients in each group). The percentage of ischemic territory that had undergone reperfusion at 24 hours was greater in the endovascular-therapy group than in the alteplase-only group (median, 100% vs. 37%; P<0.001). Endovascular therapy, initiated at a median of 210 minutes after the onset of stroke, increased early neurologic improvement at 3 days (80% vs. 37%, P = 0.002) and improved the functional outcome at 90 days, with more patients achieving functional independence (score of 0 to 2 on the modified Rankin scale, 71% vs. 40%; P = 0.01). There were no significant differences in rates of death or symptomatic intracerebral hemorrhage. Conclusions: In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retriever, as compared with alteplase alone, improved reperfusion, early neurologic recovery, and functional outcome. (Funded by the Australian National Health and Medical Research Council and others; EXTEND-IA ClinicalTrials.gov number, NCT01492725, and Australian New Zealand Clinical Trials Registry number, ACTRN12611000969965.)

© 2015 Taylor & Francis Group, LLC. Acute lymphoblastic leukemia (ALL) and childhood brain tumors (CBT) are 2 of the most common forms of childhood cancer, but little is known of their etiology. In 2 nationwide case-control studies we investigated whether breastfeeding, age of food introduction, or early diet are associated with the risk of these cancers. Cases aged 0-14 years were identified from Australian pediatric oncology units between 2003 and 2007 (ALL) and 2005 and 2010 (CBT) and population-based controls through nationwide random-digit dialing. Mothers completed questionnaires giving details of infant feeding up to the age of 2 yr. Data from 322 ALL cases, 679 ALL controls, 299 CBT cases, and 733 CBT controls were analysed using unconditional logistic regression. Breastfeeding was associated with a reduced risk of ALL [odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.32, 0.84), regardless of duration. Introduction of artificial formula within 14 days of birth was positively associated with ALL (OR = 1.57, 95% CI: 1.03, 2.37), as was exclusive formula feeding to 6 mo (OR = 1.81, 95% CI: 1.07, 3.05). No associations were seen between breastfeeding or formula use and risk of CBT. Our results suggest that breastfeeding and delayed introduction of artificial formula may reduce the risk of ALL but not CBT.

© 2015 Informa Healthcare. Conclusion: The new mattress and pillow for prone positioning (MPP) is efficient in reducing the apnoea-hypopnoea index (AHI) and oxygen desaturation index (ODI) in most patients with obstructive sleep apnoea (OSA), with satisfactory compliance. Objective: The aim of the present study was to evaluate the effect of the prone body and head sleep position on severity of disease in patients with OSA after 4 weeks of adaptation to a mattress and pillow facilitating prone positioning. Methods: Fourteen patients with mild to severe OSA, 11 men and 3 women with a mean AHI of 26 (min, 6; max, 53) and mean ODI of 21 (min, 6; max, 51) were evaluated. Two polysomnographic (PSG) studies were performed. The first PSG study was without any treatment and the second was after 4 weeks of adaptation to the MPP for prone positioning of the body and the head. Results: Mean AHI and ODI decreased from 26 and 21 to 8 and 7, respectively (p < 0.001) with treatment. The mean time spent in the supine position was reduced from 128 to 10 min (p = 0.02) and the prone time increased from 42 to 174 min (p = 0.02) with the MPP. The mean total sleep time was 390 min during the first PSG study night without treatment and 370 min during the second night with the MPP (p = 0.7). Ten patients (71%) reduced their AHI by at least 50% and reached a value < 10 during treatment. All patients managed to sleep on the MPP for > 4 h per night during the 4-week study.

© 2015, American Aging Association. Hand grip strength (GS) is a predictor of mortality in older adults and is moderately to highly heritable, but no genetic variants have been consistently identified. We aimed to identify single nucleotide polymorphisms (SNPs) associated with GS in middle-aged to older adults using a genome-wide association study (GWAS). GS was measured using handheld dynamometry in community-dwelling men and women aged 55¿85 from the Hunter Community Study (HCS, N = 2088) and the Sydney Memory and Ageing Study (Sydney MAS, N = 541). Genotyping was undertaken using Affymetrix microarrays with imputation to HapMap2. Analyses were performed using linear regression. No genome-wide significant results were observed in HCS nor were any of the top signals replicated in Sydney MAS. Gene-based analyses in HCS identified two significant genes (ZNF295, C2CD2), but these results were not replicated in Sydney MAS. One out of eight SNPs previously associated with GS, rs550942, located near the CNTF gene, was significantly associated with GS (p = 0.005) in the HCS cohort only. Study differences may explain the lack of consistent results between the studies, including the smaller sample size of the Sydney MAS cohort. Our modest sample size also had limited power to identify variants of small effect. Our results suggest that similar to various other complex traits, many genetic variants of small effect size may influence GS. Future GWAS using larger samples and consistent measures may prove more fruitful at identifying genetic contributors for GS in middle-aged to older adults.

© 2014 American Association for Cancer Research. Background: Several studies suggest that maternal folic acid supplementation before or during pregnancy protects against childhood acute lymphoblastic leukemia (ALL). We investigated associations between ALL risk and folate pathway gene polymorphisms, and their modification by maternal folic acid supplements, in a population-based case-control study (2003-2007). Methods: All Australian pediatric oncology centers provided cases; controls were recruited by national random digit dialing. Data from 392 cases and 535 controls were included. Seven folate pathway gene polymorphisms (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756 A>G, MTR 5049 C>A, CBS 844 Ins68, and CBS 2199 T>C) were genotyped in children and their parents. Information on prepregnancy maternal folic acid supplement use was collected. ORs were estimated with unconditional logistic regression adjusted for frequency-matched variables and potential confounders. Case-parent trios were also analyzed. Results: There was some evidence of a reduced risk of ALL among children who had, or whose father had, the MTRR 66GG genotype: ORs 0.60 [95% confidence interval (CI) 0.39-0.91] and 0.64 (95% CI, 0.40-1.03), respectively. The ORs for paternal MTHFR 677CT and TT genotypes were 1.41 (95% CI, 1.02-1.93) and 1.81 (95% CI, 1.06-3.07). ORs varied little by maternal folic acid supplementation. Conclusions: Some folate pathway gene polymorphisms in the child or a parent may influence ALL risk. While biologically plausible, underlying mechanisms for these associations need further elucidation. Impact: Folate pathway polymorphisms may be related to risk of childhood ALL, but larger studies are needed for conclusive results.

© 2015 Kongtharvonskul et al.; licensee BioMed Central. Background: To conduct a systematic review and network meta-analysis of randomized controlled trials (RCTs) with the aims of comparing relevant clinical outcomes (that is, visual analog scores (VAS), total and sub-Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) scores, Lequesne algofunctional index, joint space width change, and adverse events) between diacerein, glucosamine, and placebo. Methods: Medline and Scopus databases were searched from inception to 29 August 2014, using PubMed and Scopus search engines and included RCTs or quasi-experimental designs comparing clinical outcomes between treatments. Data were extracted from original studies. A network meta-analysis was performed by applying weight regression for continuous outcomes and a mixed-effect Poisson regression for dichotomous outcomes. Results: Thirty-one of 505 identified studies were eligible. Compared to placebo, glucosamine showed a significant improvement with unstandardized mean differences (UMD) in total WOMAC, pain WOMAC, function WOMAC, and Lequesne score of -2.49 (95% confidence interval (CI) -4.14, -0.83), -0.75 (95% CI: -1.18, -0.32), -4.78 (95% CI: -5.96, -3.59), and -1.03 (95% CI: -1.34, -0.72), respectively. Diacerein clinically improves visual analog scores, function WOMAC, and stiffness WOMAC with UMD values of -2.23 (95% CI: -2.82, -1.64), -6.64 (95% CI: -10.50, -2.78), and -0.68 (95% CI: -1.20, -0.16) when compared to placebo. Conclusions: The network meta-analysis suggests that diacerein and glucosamine are equally efficacious for symptom relief in knee OA, but that the former has more side effects.

© 2015 Macmillan Publishers Limited. General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10^-9, MIR2113; rs17522122, P=2.55 × 10^-8, AKAP6; rs10119, P=5.67 × 10^-9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10^-6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10^-17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

© 2014 Wiley Periodicals, Inc. The aetiology of childhood brain tumours (CBT) is largely unknown. Damage to germ cells after parental exposure to airborne carcinogens, such as volatile organic compounds and polycyclic aromatic hydrocarbons is one plausible pathway. This analysis aimed to investigate whether parental refuelling of vehicles or the use of domestic wood heaters in key time periods relating to the child's birth was associated with an increased risk of CBT. Procedure: Cases <15 years of age were recruited through 10 paediatric oncology centres around Australia; controls were recruited through nationwide random-digit dialling, frequency matched to cases on age, sex and State of residence. Exposure to refuelling and wood heaters was ascertained through questionnaires from both parents. Odds ratios (ORs) and confidence intervals (CIs) were estimated using unconditional logistic regression, adjusting for relevant covariates. Results: Data were available for 306 case and 950 control families. Paternal refuelling =4times/month was associated with an increased risk of CBT (OR 1.59, 95% CI: 1.11, 2.29), and a dose-dependent trend was observed (P=0.004). No association was seen for maternal refuelling. Use of closed, but not open, wood heaters before (OR 1.51, 95% CI: 1.05, 2.15) and after (OR 1.44, 95% CI: 1.03, 2.01) the child's birth was associated with increased risk of CBT, but dose-response relationships were weak or absent. Conclusions: Paternal refuelling of vehicles =4times/month and the use of closed wood heaters before the child's birth may increase the risk of CBT. Replication in larger studies is needed.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. The prognostic information about CKD progression, particularly for GFR categories 1 and 2, is still limited. This cohort was therefore conducted to determine the CKD progression using a competing risk approach. We conducted a retrospective cohort study linking community health screening with hospitals and death registry data in a province of Thailand, from 1997 to 2011. A competing risk model was applied by treating death as a competing risk factor to estimate 2-, 5-, and 10-year probability of kidney failure and median time for CKD progression from lower to higher GFR category. There were 17,074 non-diabetic and 15,032 diabetic CKD subjects. Diabetic subjects progressed more rapidly through GFR categories with the median times for CKD progression from GFR categories G1 to G2, G2 to G3a, G3a to G3b, G3b to G4, and G4 to G5 of 4.4, 6.1, 4.9, 6.3, and 9.0 years, respectively. Non-diabetic subjects took longertoprogress with the corresponding median timeof9.4, 14.0, 11.0, 13.8, and >14.3 years. After adjusting for confounders, diabetic subjects were 49% (cause-specific hazard ratio (<inf>c</inf>HR) = 1.49, 95% CI: 1.37, 1.62) more likely to develop kidney failure than non-diabetic subjects. Albuminuria categories A3 and A2 were, respectively, 3.40 (95% CI: 3.07, 3.76) and 1.71 (95% CI: 1.53, 1.92) higher risk of kidney failure when compared to A1. For each albumin category, death rate increased as albuminuria increased particularly in diabetic subjects, which was approximately 2 times higher in A3 compared to A1. Considering GFR category, it gradually increased from G1 to G4 and sharply increased from G4 to G5 in both non-diabetic and diabetic subjects. This study has quantified CKD progression in an Asian population within ordinary practice. Diabetic subjects progress through GFR and albuminuria categories and reach kidney failure about twice as rapidly as non-diabetic subjects.

Copyright © 2015 Royal College of Pathologists of Australasia. All rights reserved. In 2014 a consensus conference convened by the International Society of Urological Pathology (ISUP) adopted amendments to the criteria for Gleason grading and scoring (GS) for prostatic adenocarcinoma. The meeting defined a modified grading system based on 5 grading categories (grade 1, GS 3+3; grade 2, GS 3+4; grade 3, GS 4+3; grade 4, GS 8; grade 5, GS 9-10). In this study we have evaluated the prognostic significance of ISUP grading in 496 patients enrolled in the TROG 03.04 RADAR Trial. There were 19 grade 1, 118 grade 2, 193 grade 3, 88 grade 4 and 79 grade 5 tumours in the series, with follow-up for a minimum of 6.5 years. On follow-up 76 patients experienced distant progression of disease, 171 prostate specific antigen (PSA) progression and 39 prostate cancer deaths. In contrast to the 2005 modified Gleason system (MGS), the hazards of the distant and PSA progression endpoints, relative to grade 2, were significantly greater for grades 3, 4 and 5 of the 2014 ISUP grading scheme. Comparison of predictive ability utilising Harrell's concordance index, showed 2014 ISUP grading to significantly out-perform 2005 MGS grading for each of the three clinical endpoints.

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

© 2015 Elsevier Ltd. Depression and inflammatory markers have a reliable cross-sectional association although less is known about the prospective relationship. The current study investigated whether pro-inflammatory markers are prospectively associated with depression, and whether indicators of unhealthy lifestyle, physical health and psychosocial functioning may drive this association. Participants were drawn from the Hunter Community Study, a community-dwelling cohort of individuals aged 55-85 years (N=1410). Participants completed baseline physiological assessment, health-related questionnaires, and blood sampling for the analysis of inflammatory markers, C-reactive protein (CRP) and interleukin (IL)-6. Participants completed the same depressive symptom questionnaire again after 3.5-5.5 years. Depression outcomes at follow-up were analysed dichotomously using established scale cut-off scores and continuously as a "residual score", representing the variation in follow-up depressive symptoms not explained by baseline symptoms and age. Analyses were conducted on males and females separately. At baseline, indicators of unhealthy lifestyle, physical health and psychosocial functioning were associated with depressive symptoms and inflammatory markers. For males, there were no relationships between inflammatory markers and follow-up depression outcomes. In females, IL-6 was significantly associated with depression outcomes in univariate, but not multivariate analyses. However, IL-6 significantly mediated the association between the predictors of waist-to-hip ratio, smoking and psychological coping at baseline, and follow-up depression outcomes. The results support the inflammatory hypothesis of depression, although females may be more vulnerable to effects. The findings raise the possibility that unhealthy lifestyle and psychosocial stress may drive inflammation and subsequent depressive symptoms.

© Kypri et al. Background: What participants think about the nature of a study might affect their behaviour and bias findings. We tested two hypotheses: (1) participants told they were in an intervention trial would report lower alcohol consumption at follow-up than those told they were in a cohort study; (2) participants told they were in the intervention group in a trial would have lower alcohol consumption at follow-up than those told they were in the control group. Methods: Students from four universities (N = 72,903) were invited to participate in a 'research project on student drinking'. Of 10,415 respondents, 6,788 were moderate to heavy drinkers and were randomized. Group A ('cohort') were informed their drinking would be assessed at baseline and again in one month. Group B ('control') were told the study was an intervention trial and they were in the control group. Group C ('intervention') were told the study was an intervention trial and they were to receive the intervention. All were assessed and directed to read identical online alcohol education material. Whether and how long they accessed the material were recorded. One month later, alcohol intake was reassessed. Results: In relation to hypothesis 1, there were no differences between the groups on the prespecified outcome measures. In relation to hypothesis 2, there were no differences though all point estimates were in the hypothesized direction (that is, 'intervention' < 'control'). The 'cohort' and 'control' groups accessed the material to a similar extent (59% versus 57%) while the 'intervention' group were more likely to access it (78%) and to read it for longer (median 35 s (25th and 75th percentiles: 6, 97) versus medians of 7 s (0, 28) and 8 s (4, 42) for the 'cohort' and 'control' groups, respectively). Conclusions: Although the context given to the research participants significantly influenced access to the online information and reading time, this did not translate into any effect on drinking behaviour, for either hypothesis. This might be because of failure in the experimental paradigm or the possibility of weaker effects using the online approach.

© 2015 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine. Objectives: To determine if medication review by a clinical pharmacist of older patients in the ED impacted on admission to hospital and other outcomes. Methods: A stratified, randomised controlled study comparing the intervention to current practice. A tertiary referral ED in New South Wales, Australia. Older people (>70 years) living at home who initially reported taking greater than five medications. Medication review by an experienced hospital pharmacist within the ED. Rate of admission, rate of readmission, length of stay and admission to an aged care facility at 4 months post presentation, and rate of general practitioner acceptance of pharmacist recommendations. Results: The odds of admission decreased for those receiving the intervention (odds ratio [OR] = 0.68, 95% confidence interval [CI]: 0.53, 0.87; P = 0.002). There was no evidence that the intervention affected hospital length of stay for admitted patients (0.09 days change, 95% CI -0.08, 0.25; P = 0.31), the rate of re-presentation (0.08% change, 95% CI -0.12, 0.28; P = 0.44) or admission to an aged care facility. The odds of admission to an aged care facility increased with the Identification of Seniors at Risk score. General practitioners adopted 49% of pharmacists' recommendations. Conclusions: The presence of an experienced pharmacist in the ED reduced hospital admissions. Further study is required to determine longer term impacts of General Medical Practitioner acceptance of pharmacists' recommendations.

© 2013 APJPH. The aim of this research is to estimate the prevalence of excessive daytime sleepiness in an older population and associations with sociodemographic, health, and lifestyle factors using a cross-sectional, population-based study. Participants were men (1560) and women (1759), aged 55 to 85 years, enrolled in the Hunter Community Study, a longitudinal study of aging. Measurements were self-reported questionnaires, biochemical measures, and clinical measures. Of the 3319 participants, 3053 participants completed the Epworth Sleepiness Scale questionnaire. The prevalence of excessive daytime sleepiness was 15.3% overall and this was higher in males. In adjusted multivariate analysis, gender, working full time, body mass index, high-density and low-density lipoprotein cholesterol, Center for Epidemiologic Studies-Depression scale score, and Kessler psychological distress score were associated with excessive daytime sleepiness. Given the high prevalence of excessive daytime sleepiness observed in this study, further investigation and/or interventions to reduce adverse health outcomes, especially in males is warranted.

© 2015 Elsevier B.V.. Background: Nitric oxide synthase (NOS) mediated conversion of arginine (ARG) to citrulline (CIT) is a key pathway for nitric oxide synthesis. ARG is also metabolised by alternate pathways to ornithine (ORN), homoarginine (HMA), N^G-monomethyl-L-arginine (MMA), N^G,. N^G-dimethyl-L-arginine (ADMA) and N^G,. N^G'-dimethyl-L-arginine (SDMA), all of which have the capacity to alter NOS activity. Simultaneous assessment of these analytes, when assessing the impact of arginine metabolism in human disease states, is desirable. Methods: Analytes (ARG, ADMA, SDMA, MMA, HMA, CIT and ORN) were isolated from human plasma by solvent extraction, evaporated and reconstituted. Ultra-performance liquid chromatography (UPLC) was performed on a 150mm×2.1mm T3 HSS column using a gradient mobile phase comprising ammonium formate (10mM, pH3.8) in methanol (1% to 63%). Analytes were detected by time-of-flight mass spectrometry (Q-ToF-MS) in positive ion mode with electrospray ionisation (ESI+). Data were collected using MS^E. Results: Solvent extraction provided high recovery (>95%). UPLC-QToF-MS^E facilitated the separation and quantification of the 7 analytes in an analysis time of 6min. The approach has high sensitivity; LOQ range from 0.005µM (NMMA) to 0.25µM (ARG and ORN), and good precision; intra- and inter-day %RSD are <6% for all analytes. Conclusions: This approach provides the capacity to quantify 7 key compounds involved in ARG metabolism in a small sample volume, with a short total analysis time. These characteristics make this approach ideal for undertaking a comprehensive characterisation of this pathway in large data sets (e.g. population studies).

© 2015, Springer Science+Business Media New York. This study investigated whether inflammation may explain the relationship between depression and incident cardiovascular hospitalisations. Participants (55¿85¿years) completed baseline depression and physical assessment. Those without self-reported cardiovascular events were followed prospectively for hospital admissions for angina, myocardial infarction and cerebral infarction (median 937¿days). Across 5140 person-years of risk (N¿=¿1692), there were 47 incident cardiovascular hospitalisations (2.8¿%). Controlling for age and gender, interleukin (IL)-6, C-reactive protein (CRP), body mass index (BMI) and waist-to-hip ratio were associated with future cardiovascular events. Mediation analysis showed that CRP accounted for 8.1¿% and IL-6 10.9¿% of the effect of depression on cardiovascular events, and including the indirect effect in the model substantially reduced the direct relationship between depression and cardiovascular hospitalisations. BMI and waist-to-hip ratio accounted for indirect effects of 7.7 and 10.4¿%, respectively. Inflammatory markers partly explain the association between depression and cardiovascular events, although other shared factors also likely contribute.

� 2015 Society of Biological Psychiatry. BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged =45 years. Replication of suggestive associations (p < 5 � 10-6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 � 10-10) and replication cohorts (p = 5.65 � 10-8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 � 10-8, and rs6813517 [SPOCK3], p = 2.58 � 10-8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

© 2015, Taylor & Francis Group, LLC. It is biologically plausible that a paternal preconception diet low in nutrients related to DNA integrity could affect sperm DNA and subsequently risk of cancer in the offspring. The aim of this analysis was to investigate whether paternal preconception dietary folate, B6, or B12 intake was associated with the risk of childhood brain tumors (CBT) in an Australian case-control study. Cases <15 years of age were recruited from 10 Australian pediatric oncology centers between 2005 and 2010, and controls from random-digit dialing, frequency-matched to cases on age, sex, and state of residence. Paternal dietary information was obtained by food-frequency questionnaires. Nutrient values were energy adjusted and divided into tertiles for analysis by unconditional logistic regression. In fathers with relevant data (237 cases and 629 controls), no association with dietary folate and B6 and risk of CBT was seen; high B12 intake was associated with an increased risk of CBT (odds ratio highest vs. lowest tertile: 1.74, 95% confidence interval: 1.14, 2.66) without an increasing trend. These results do not support the hypothesis that paternal dietary folate intake influences the risk of CBT. The increased OR observed between dietary B12 intake and risk of CBT is without any certain explanation.

© 2015, Springer International Publishing Switzerland. Purpose: The etiology of childhood brain tumors (CBT) is poorly understood, but dietary factors could be involved. In this case¿control study of CBT, the possible associations of childhood intake of dietary and supplemental folate, vitamin B6, and vitamin B12 with the risk of CBT were investigated, along with various food groups. Methods: Cases diagnosed between 2005 and 2010 were identified from 10 pediatric oncology centers in Australia and controls by nationwide random-digit dialling. For study children of ages 3¿14¿years, diet in the year before diagnosis (or recruitment) was assessed using food frequency questionnaires. Folate intake was adjusted for bioavailability, and dietary micronutrient intake was energy-adjusted. Micronutrients and food groups were analyzed using logistic regression adjusting for relevant confounders. Principal components analysis was conducted to assess food group intake patterns for analysis. Results: Food and micronutrient data were available for 216 cases and 523 controls. Folate intake was associated with a reduced risk of CBT overall (odds ratio for highest tertile vs. lowest: 0.63, 95¿% confidence interval 0.41, 0.97) and particularly low-grade gliomas (odds ratio for highest tertile vs. lowest: 0.52, 95¿% confidence interval 0.29, 0.92). Vitamin B6 and B12 intake was not associated with CBT risk, nor was processed meat. Conclusions: High folate intake during childhood may reduce the risk of CBT. This potentially important finding needs to be corroborated in other studies. If replicated, these results could have important implications for public health recommendations regarding diet during childhood.

© 2014, Springer-Verlag Berlin Heidelberg. Endometrial cancer is the most common invasive gynaecological cancer in women, and relatively little is known about inherited risk factors for this disease. This is the first genome-wide study to explore the role of common and rare germline copy number variants (CNVs) in predisposition to endometrial cancer. CNVs were called from germline DNA of 1,209 endometrioid endometrial cancer cases and 528 cancer-unaffected female controls. Overall CNV load of deletions or DNA gains did not differ significantly between cases and controls (P¿>¿0.05), but cases presented with an excess of rare germline deletions overlapping likely functional genomic regions including genes (P¿=¿8¿×¿10^-10), CpG islands (P¿=¿1¿×¿10^-7) and sno/miRNAs regions (P¿=¿3¿×¿10^-9). On average, at least one additional gene and two additional CpG islands were disrupted by rare deletions in cases compared to controls. The most pronounced difference was that over 30 sno/miRNAs were disrupted by rare deletions in cases for every single disruption event in controls. A total of 13 DNA repair genes were disrupted by rare deletions in 19/1,209 cases (1.6¿%) compared to one gene in 1/528 controls (0.2¿%; P¿=¿0.007), and this increased DNA repair gene loss in cases persisted after excluding five individuals carrying CNVs disrupting mismatch repair genes MLH1, MSH2 and MSH6 (P¿=¿0.03). There were 34 miRNA regions deleted in at least one case but not in controls, the most frequent of which encompassed hsa-mir-661 and hsa-mir-203. Our study implicates rare germline deletions of functional and regulatory regions as possible mechanisms conferring endometrial cancer risk, and has identified specific regulatory elements as candidates for further investigation.

Copyright ©2015 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved. STUDY DESIGN: Cross-sectional case-control study. OBJECTIVES: To identify risk factors and clinical presentation of individuals with cervical arterial dissection. BACKGROUND: Cervical arterial dissection is a common cause of stroke in young people and has in rare cases been associated with cervical manipulative therapy. The mechanism is considered to involve pre-existing arterial susceptibility and a precipitating event, such as minor trauma. Identification of individuals at risk or early recognition of a dissection in progress could help expedite medical intervention and avoid inappropriate treatment. METHODS: Participants were individuals 55 years of age or younger from the Hunter region of New South Wales, Australia with radiologically confirmed vertebral or internal carotid artery dissection and an age- and sex-matched comparison group. Participants were interviewed about risk factors, preceding events, and clinical features of their stroke. Physical examination of joint mobility and soft tissue compliance was undertaken. RESULTS: Twenty-four participants with cervical arterial dissection and 21 matched comparisons with ischemic stroke but not dissection were included in the study. Seventeen (71%) of the 24 participants with dissection reported a recent history of minor mechanical neck trauma or strain, with 4 of these 17 reporting recent neck manipulative therapy treatment. Cardiovascular risk factors were uncommon, with the exception of diagnosed migraine. Among the participants with dissection, 67% reported transient ischemic features in the month prior to their admission for dissection. CONCLUSION: Recent minor mechanical trauma or strain to the head or neck appears to be associated with cervical arterial dissection. General cardiovascular risk factors, with the exception of migraine, were not important risk factors for dissection in this cohort. Preceding transient neurological symptoms appear to occur commonly and may assist in the identification of this serious pathology.

© 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Background: The development of effective orally administered medical therapy for pulmonary arterial hypertension (PAH) has made a significant impact on outcome in patients with PAH. Identification of patient groups likely to derive optimal benefit is important, given cost and potential side effects; the clinical effectiveness of these therapies in older patients with PAH is unclear as the presence of co-morbidity may limit benefits of therapy. Aims: We evaluated the epidemiology of PAH in a contemporary cohort to assess the influence of age on long-term outcome using PAH-specific therapies. Results: A total of 119 patients (88% female; mean age 65±12 years) were reviewed, comprising 52% with underlying connective tissue disease. Bosentan was the PAH specific agent most frequently used. The baseline 6MWT distance in the entire cohort was 304m with age associated with a significant decline in 6MWT. Conclusions: In a large cohort of patients treated with PAH-specific therapies, patients less than 55 years of age showed improvement in 6MWT with older patients demonstrating stabilisation or decline.

© 2015, Taylor & Francis. Background: As research focuses on the concept of resilience, evidence suggests that greater levels of personal hope may have a mitigating effect on the mental health impact of adversity. In view of the adversity affecting rural communities, a better understanding of factors influencing personal hope may help identify foci for mental health promotion and mental illness prevention research and interventions. Aim: To explore the relationship between demographic, socioeconomic and mental health factors and personal hopefulness, including the influence of locality and remoteness. Method: Using data from two community-based longitudinal cohorts from New SouthWales ¿ one urban and one rural ¿ we analysed cross-sectional relationships between a range of factors and personal hopefulness using logistic regression techniques, as part of a common follow-up. Personal hopefulness was measured using a 12-item scale and scores were categorised as low (<2.5), medium (2.5¿3.4) and high (=3.5). Results: Of 2774 participants (53% female, mean age 69.1 years [SD 7.3, range 58¿91 years], 36% living outside metropolitan areas) 32% had low, 51% had medium and 17% had high personal hopefulness scores. Several factors displayed univariate associations with personal hopefulness. In the multivariate model, five factors were independently associated with lower personal hopefulness: being older, having lower perceived prosperity, less frequent socialisation, experiencing high psychological distress or psychological impairment. Hopefulness was not associated with geographical location. Conclusion: The impact of current psychological distress and aspects of adversity on personal hopefulness over time should be further investigated in longitudinal research. Personal hopefulness did not differ across geographical location.

Background: Stroke is a leading cause of death and disability internationally. One of the three effective interventions in the acute phase of stroke care is thrombolytic therapy with tissue plasminogen activator (tPA), if given within 4.5 hours of onset to appropriate cases of ischaemic stroke.Objectives: To test the effectiveness of a multi-component multidisciplinary collaborative approach compared to usual care as a strategy for increasing thrombolysis rates for all stroke patients at intervention hospitals, while maintaining accepted benchmarks for low rates of intracranial haemorrhage and high rates of functional outcomes for both groups at three months.Methods and design: A cluster randomised controlled trial of 20 hospitals across 3 Australian states with 2 groups: multi- component multidisciplinary collaborative intervention as the experimental group and usual care as the control group. The intervention is based on behavioural theory and analysis of the steps, roles and barriers relating to rapid assessment for thrombolysis eligibility; it involves a comprehensive range of strategies addressing individual-level and system-level change at each site. The primary outcome is the difference in tPA rates between the two groups post-intervention. The secondary outcome is the proportion of tPA treated patients in both groups with good functional outcomes (modified Rankin Score (mRS <2) and the proportion with intracranial haemorrhage (mRS =2), compared to international benchmarks.Discussion: TIPS will trial a comprehensive, multi-component and multidisciplinary collaborative approach to improving thrombolysis rates at multiple sites. The trial has the potential to identify methods for optimal care which can be implemented for stroke patients during the acute phase. Study findings will include barriers and solutions to effective thrombolysis implementation and trial outcomes will be published whether significant or not.Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12613000939796. © 2014 Paul et al.; licensee BioMed Central Ltd.

Background: Despite the increasing interest towards the biological role of L-ergothioneine, little is known about the serum concentrations of this unusual aminothiol in older adults. We addressed this issue in a representative sample of community-dwelling middle-aged and older adults. Methods: Body mass index, estimated glomerular filtration rate, serum concentrations of L-ergothioneine, taurine, homocysteine, cysteine, glutathione, cysteinylglycine, and glutamylcysteine were evaluated in 439 subjects (age 55-85 years) randomly selected from the Hunter Community Study. Results: Median L-ergothioneine concentration in the entire cohort was 1.01 IQR 0.78-1.33 µmol/L. Concentrations were not affected by gender (P = 0.41) or by presence of chronic medical conditions (P = 0.15). By considering only healthy subjects, we defined a reference interval for L-ergothioneine serum concentrations from 0.36 (90% CI 0.31-0.44) to 3.08 (90% CI 2.45-3.76) µmol/L. Using stepwise multiple linear regression analysis L-ergothioneine was negatively correlated with age (rpartial = 20.15; P = 0.0018) and with glutamylcysteine concentrations (rpartial = 20.13; P = 0.0063). Conclusions: A thorough analysis of serum L-ergothioneine concentrations was performed in a large group of community-dwelling middle-aged and older adults. Reference intervals were established. Age and glutamylcysteine were independently negatively associated with L-ergothioneine serum concentration. © 2014 Sotgia et al.

Aim: To determine if there is a difference in serum zinc concentration between normoglycaemic, pre-diabetic and type-2 diabetic groups and if this is associated with pancreatic beta cell function and insulin sensitivity in the former 2 groups. Method: Cross sectional study of a random sample of older community-dwelling men and women in Newcastle, New South Wales, Australia. Beta cell function, insulin sensitivity and insulin resistance were calculated for normoglycaemic and prediabetes participants using the Homeostasis Model Assessment (HOMA-2) calculator. Result: A total of 452 participants were recruited for this study. Approximately 33% (N = 149) had diabetes, 33% (N = 151) had prediabetes and 34% (N = 152) were normoglycaemic. Homeostasis Model Assessment (HOMA) parameters were found to be significantly different between normoglycaemic and prediabetes groups (p<0.001). In adjusted linear regression, higher serum zinc concentration was associated with increased insulin sensitivity (p = 0.01) in the prediabetic group. There was also a significant association between smoking and worse insulin sensitivity. Conclusion: Higher serum zinc concentration is associated with increased insulin sensitivity. Longitudinal studies are required to determine if low serum zinc concentration plays a role in progression from pre-diabetes to diabetes. © 2014 Vashum et al.

Depression is a leading contributor to the global burden of diseases. Despite advances in research, challenges still exist in managing this disorder. Sufferers of autoimmune diseases are often observed to suffer from depression more often than healthy individuals, an association that cannot be completely accounted for by the impact of the disease on the individual. An association between autoimmunity and depressive symptoms also appears to exist in populations with subclinical symptoms. Moreover, researchers have successfully developed murine models illustrating the ability of autoantibodies to induce depressive-like symptoms. This paper will provide an overview of the association between autoantibodies and occurrence of depressive symptoms. Though current evidence appears to support a role for autoantibodies in the pathogenesis of depression, the majority of studies have examined this relationship cross-sectionally, therefore failing to establish a temporal association. Nonetheless, this novel theory meshes with older and newer neurochemical theories of depression. A better understanding of the immuno-pathogenesis underlying depression presents opportunities for more targeted treatment approaches and more timely and appropriate measures of detection. © 2014 Elsevier Ltd.

Objective To assess the effectiveness of the introduction of a trainee specialist physician into the workforce mix of a rural hospital in the Northern Territory. Methods A retrospective review comparing clinical and non-clinical outcomes during two corresponding 6-month periods in 2011 and 2012, before and after a FRACP Trainee in General and Acute Care Medicine commenced employment in the hospital. Results There was a significant reduction of 18% in total length of stay of admitted adult patients, with a 23% reduction of inter-hospital transfers and a 43% reduction of total aeromedical evacuations after the introduction of the trainee specialist. Although there was a 9% increase in patients presenting to the emergency department, there was a 9% reduction in total adult admissions. There was no change in the overall in-patient mortality rate; however, there was a significant change in the location of death, with an increase in patients dying in Katherine Hospital and a reciprocal decrease in death rate in those who had been transferred to Royal Darwin Hospital after the arrival of the trainee Conclusions The addition of an Advanced Trainee in General Medicine led to a significant change in the capacity of the hospital to care for unwell and complex patients. The role of the hospital in the care of dying patients was redefined and allowed many more people to pass away closer to their community and families. There were considerable savings at Katherine Hospital in terms of reduced bed pressure, reduced hospital bypass behaviour and reduced inter-hospital transfers, and these translated into significant benefits for the tertiary referral hospital in Darwin. A rural general physician can greatly value add to the capacity of a rural hospital and is a highly effective mechanism for reducing the disparities in healthcare access for rural and Indigenous patients. What is known about this topic? There is little research about the clinical and non-clinical impact of the addition of general speciality clinicians into the workforce of rural hospitals. Although there are several regional hospitals in Australia that have general specialists (i.e. emergency department physicians, general physicians and surgeons) and sub-specialists where the volume of patients is adequate to support such a workforce, there has been no published assessment of the impact of the addition of such speciality services. What does this paper add? This paper provides evidence of the cost-effectiveness of the addition of a specialist general physician to the workforce of a remote hospital servicing a large Indigenous population with very high burdens of acute and chronic illnesses in the Northern Territory. The paper demonstrates the potential to significantly add capacity to a rural or regional hospital by moving general speciality care to the hospital rather than, or in addition to, providing other methods of speciality and sub-speciality health care delivery. What are the implications for practitioners? The implications of this paper are that a significantly cost-effective means of addressing health care delivery to rural and remote populations is through the addition of appropriately trained general specialists such as emergency department physicians, general physicians and general surgeons. The implications extend to broader workforce development policies for education providers, speciality colleges and state and federal governments. © AHHA 2014.

Objective To examine effect modification between genetic susceptibility to age-related macular degeneration (AMD) and dietary antioxidant or fish consumption on AMD risk. Design Pooled data analysis of population-based cohorts. Participants Participants from the Blue Mountains Eye Study (BMES) and Rotterdam Study (RS). Methods Dietary intakes of antioxidants (lutein/zeaxanthin [LZ], ß-carotene, and vitamin C), long-chain omega-3 polyunsaturated fatty acids, and zinc were estimated from food frequency questionnaires. The AMD genetic risk was classified according to the number of risk alleles of CFH (rs1061170) or ARMS2 (rs10490924) as low (no or 1 risk allele) or high (=2 risk alleles). Interactions between dietary intake and genetic risk levels were assessed. Associations between dietary intake and AMD risk were assessed comparing the highest with the 2 lower intake tertiles by genetic risk subgroups using discrete logistic regression, conducted in each study separately and then using pooled data. Participants without AMD lesions at any visit were controls. We adjusted for age and sex in analyses of each cohort sample and for smoking status and study site in pooled-data analyses. Main Outcome Measures All 15-year incident late AMD cases were confirmed by chief investigators of the Beaver Dam Eye Study, BMES, and RS. Intergrader reproducibility was assessed in an early AMD subsample, with 86.4% agreement between BMES and RS graders, allowing for a 1-step difference on a 5-step AMD severity scale. Results In pooled data analyses, we found significant interaction between AMD genetic risk status and LZ intake (P = 0.0009) but nonsignificant interactions between genetic risk status and weekly fish consumption (P = 0.05) for risk of any AMD. Among participants with high genetic risk, the highest intake tertile of LZ was associated with a >20% reduced risk of early AMD, and weekly consumption of fish was associated with a 40% reduced risk of late AMD. No similar association was evident among participants with low genetic risk. No interaction was detected between ß-carotene or vitamin C and genetic risk status. Conclusions Protection against AMD from greater LZ and fish consumption in persons with high genetic risk based on 2 major AMD genes raises the possibility of personalized preventive interventions. ©2014 by the American Academy of Ophthalmology.

Childhood brain tumors (CBT) are the second most common childhood cancers, yet their etiology is largely unknown. We investigated whether maternal gestational intake of folate and vitamins B6 and B12 was associated with CBT risk in a nationwide case-control study conducted 2005-2010. Case children 0-14 years were recruited from all 10 Australian pediatric oncology centers. Control children were recruited by national random digit dialing, frequency matched to cases on age, sex, and state of residence. Dietary intake was ascertained using food frequency questionnaires and adjusted for total energy intake. Data from 293 case and 726 control mothers were analyzed using unconditional logistic regression. The odds ratio (OR) for the highest versus lowest tertile of folate intake was 0.70 [95% confidence interval (CI): 0.48, 1.02]. The ORs appeared lower in mothers who drank alcohol during pregnancy (OR = 0.45, 95% CI: 0.22, 0.93), mothers who took folic acid (OR = 0.67, 95% CI: 0.42, 1.06) or B6/B12 supplements (OR = 0.51, 95% CI: 0.25, 1.06) and in children younger than 5 years (OR = 0.50, 95% CI: 0.27, 0.93). These findings are consistent with folate's crucial role in maintenance of genomic integrity and DNA methylation. Dietary intake of B6 and B12 was not associated with risk of CBT. © 2014 Copyright © Taylor & Francis Group, LLC.

Objective Fetuin-A is associated with body mass index (BMI) as well as components of the metabolic syndrome. However, it is unclear if fetuin-A affects BMI or the other way around. We therefore assessed the causal association between fetuin-A and BMI or vice versa, utilizing a bidirectional Mendelian randomization approach. Design and Methods This was a study of 2558 subjects from the Electricity Generating Authority of Thailand (EGAT) cohort. Two polymorphisms, that is, rs2248690 in the alpha2-Hereman-Schmid glycoprotein (AHSG) gene and rs9939609 in the fat mass and obesity-Associated (FTO) gene were genotyped. Bidirectional causal models were constructed using a two-stage least-square instrumental variable (IV) regression. First, rs2248690 locus was used as the instrumental variable for the effect of circulating fetuin-A on BMI, and then, the FTO rs9939609 locus was used as the instrumental variable for the effect of BMI on circulating fetuin-A. Results Among the 2558 subjects, the prevalence of the minor AHSG (T) and FTO (A) alleles was 17·9% and 22·1%, respectively. The AHSG rs2248690 locus was highly related to serum fetuin-A levels (P < 0·001). Likewise, the FTO rs9939609 locus and BMI were highly associated (P < 0·001). Mendelian randomization analyses showed that circulating fetuin-A, instrumented by the AHSG rs2248690 locus, was associated with BMI (coefficient = 2·26; 95% CI: 0·39, 4·12). In contrast, BMI, instrumented by the FTO rs9939609 locus, was not associated with circulating fetuin-A (coefficient = 0·0007; 95% CI: -0·0242, 0·0256). Conclusion Our findings suggest a causal association leading from circulating fetuin-A to BMI. There was no evidence of reverse causality from BMI to fetuin-A. © 2013 John Wiley & Sons Ltd.

Objective: To investigate the relationship between fine gradations in body mass index (BMI) and risk of hospitalisation for different types of cardiovascular disease (CVD). Design, Subjects and Methods: The 45 and Up Study is a large-scale Australian cohort study initiated in 2006. Self-reported data from 158 546 individuals with no history of CVD were linked prospectively to hospitalisation and mortality data. Hazard ratios (HRs) of incident hospitalisation for specific CVD diagnoses in relation to baseline BMI categories were estimated using Cox regression, adjusting for age, sex, region of residence, income, education, smoking, alcohol intake and health insurance status. Results: There were 9594 incident CVD admissions over 583 100 person-years among people with BMI=20 kg m-2, including 3096 for ischaemic heart disease (IHD), 1373 for stroke, 411 for peripheral vascular disease (PVD) and 320 for heart failure. The adjusted HR of hospitalisation for all CVD diagnoses combined increased significantly with increasing BMI (P(trend) <0.0001)). The HR of IHD hospitalisation increased by 23% (95% confidence interval (95% CI): 18-27%) per 5 kg m-2increase in BMI (compared to BMI 20.0-22.49 kg m-2, HR (95% CI) for BMI categories were: 22.5-24.99=1.25 (1.08-1.44); 25-27.49=1.43 (1.24-1.65); 27.5-29.99=1.64 (1.42-1.90); 30-32.49=1.63 (1.39-1.91) and 32.5-50=2.10 (1.79-2.45)). The risk of hospitalisation for heart failure showed a significant, but nonlinear, increase with increasing BMI. No significant increase was seen with above-normal BMI for stroke or PVD. For other specific classifications of CVD, HRs of hospitalisation increased significantly with increasing BMI for: hypertension; angina; acute myocardial infarction; chronic IHD; pulmonary embolism; non-rheumatic aortic valve disorders; atrioventricular and left bundle-branch block; atrial fibrillation and flutter; aortic aneurysm; and phlebitis and thrombophlebitis. Conclusion: The risk of hospitalisation for a wide range of CVD subtypes increases with relatively fine increments in BMI. Obesity prevention strategies are likely to benefit from focusing on bringing down the mean BMI at the population level, in addition to targeting those with a high BMI. © 2014 Macmillan Publishers Limited All rights reserved.

Perthes disease is an osteonecrosis of the femoral epiphysis with unclear etiology. This study aimed to systematically review the association between genetic determinants of hypercoagulability (Factor V Leiden, prothrombin II, and methylenetetrahydrofolate reductase; MTHFR) and Perthes disease. PubMed and Scopus searched from inception to January 2012, data extraction and quality assessment were performed. The odds ratio (OR) for the allele effect was pooled, and heterogeneity and publication bias were assessed. Twelve case-control studies met inclusion criteria and had sufficient data for extraction. There were 824 cases and 2,033 controls with a mean age range of 6.1-14.7 years. The prevalence of the minor allele in controls was 0.015 (95% confidence interval (CI): 0.008, 0.023), 0.012 (95% CI: 0.008, 0.017), and 0.105 (95% CI: 0.044, 0.167) for factor V Leiden, prothrombin II, and MTHFR, respectively. The factor V Leiden allele increased the risk of Perthes with a pooled OR of 3.10 (95% CI: 1.68, 5.72), while prothrombin II and MTHFR had non-significantly pooled OR 1.48 (95% CI: 0.71, 3.08), and 0.97 (95% CI: 0.72, 1.30), respectively. The factor V Leiden mutation is significantly related to Perthes disease, and its screening in at-risk children might be useful in the future. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Background Platelets with high hemostatic activity play an important role in the pathophysiology of coronary artery disease(CAD) and mean platelet volume(MPV) has been proposed as an indicator of platelet reactivity. Thus, MPV may emerge as a potential marker of CAD risk. The aim of this study was to conduct a systematic review and meta-analysis comparing mean difference in MPV between patients with CAD and controls and pooling the odds ratio of CAD in those with high versus low MPV. Methods Medline and Scopus databases were searched up to 12 March 2013. All observational studies that considered MPV as a study's factor and measured CAD as an outcome were included. Two reviewers independently selected the studies and extracted the data. Results Forty studies were included in this meta-analysis. The MPV was significantly larger in patients with CAD than controls with the unstandardized mean difference of 0.70 fL (95% CI: 0.55, 0.85). The unstandardized mean difference of MPV in patients with acute coronary event and in patients with chronic stable angina was 0.84 fL (95% CI: 0.63, 1.04) and 0.46 fL (95% CI: 0.11, 0.81) respectively. Patients with larger MPV (= 7.3 fL) also had a greater odds of having CAD than patients with smaller MPV with a pooled odds ratio of 2.28 (95% CI: 1.46, 3.58). Conclusion Larger MPV was associated with CAD. Thus, it might be helpful in risk stratification, or improvement of risk prediction if combining it with other risk factors in risk prediction models. © 2014 Elsevier Ireland Ltd. All rights reserved.

Purpose: Rural populations face numerous barriers to mental health care. Although internet-delivered mental health treatments may offer an accessible and cost-effective answer to these barriers, there has been little evaluation of the feasibility of this approach among rural communities. Methods: Data were obtained from a random rural community sample through the third wave of the Australian Rural Mental Health Study. Attitudes towards internet-delivered mental health treatments and availability of internet access were explored. Data were analysed to identify sub-groups in whom internet-delivered treatments may be usefully targeted. Results: Twelve hundred and forty-six participants completed the survey (mean age 59 years, 61 % females, 22 % from remote areas). Overall, 75 % had internet access and 20 % would consider using internet-based interventions, with 18 % meeting both of these feasibility criteria. Logistic regression revealed feasibility for internet-delivered mental health treatment was associated with younger age, male gender, being a carer, and a 12-month mental health problem. Participants who had used internet-delivered services in the past were significantly more likely to endorse these treatments as acceptable. Conclusions: There is considerable potential for internet-delivered treatments to increase service accessibility to some sub-groups, particularly among people with mental health problems who are not currently seeking help. Resistance to internet treatments appears to be largely attitudinal, suggesting that enhancing community education and familiarity with such programs may be effective in improving perceptions and ultimately access. © 2013 Springer-Verlag Berlin Heidelberg.

Purpose The causes of childhood brain tumors (CBT) are largely unknown, but gestational diet may influence this risk. The aim of this analysis was to investigate whether maternal coffee or tea consumption during pregnancy was associated with the risk of CBT. Methods The Australian Study of the Causes of Childhood Brain Tumours was a population-based, Australian case-control study conducted between 2005 and 2010. Case children were recruited from 10 pediatric oncology centers and control children by nationwide random-digit dialing, frequency matched to cases on the basis of age, sex and state of residence. Coffee and tea intake were assessed using a food frequency questionnaire. Results Data on coffee and tea consumption during pregnancy were available from 293 case mothers and 726 control mothers. Odds ratios (ORs) and confidence intervals (CIs) were calculated using multivariable unconditional logistic regression. There was little evidence of an association between gestational consumption of any coffee (OR 1.23, 95 % CI 0.92, 1.64) or tea (OR 1.00, 95 % CI 0.74, 1.36) and CBT risk. Among children aged under 5 years, the OR for any coffee consumption during pregnancy was 1.76 (95 % CI 1.09, 2.84) and for =2 cups per day during pregnancy was 2.52 (95 % CI 1.26, 5.04). There was little evidence that associations with coffee or tea intake differed by parental smoking status. Conclusions These results suggest a positive association between coffee intake =2 cups per day and risk of CBT in younger children, although some estimates are imprecise. There was no association between maternal tea drinking and risk of CBT. © 2014 Springer International Publishing Switzerland.

Purpose: Childhood brain tumors (CBT) are the second most common type of childhood cancer and the leading cause of childhood cancer mortality. Few causes of CBT are known, but parental, fetal, and early life exposures are likely to be important given the early age at diagnosis of many cases. We aimed to investigate whether parents' diagnostic radiological procedures before conception, in the mother during pregnancy or the child's procedures were associated with an increased risk of CBT. Methods: This population-based case-control study was conducted between 2005 and 2010. Cases were identified through all ten Australian pediatric oncology centers, and controls via nationwide random-digit dialing; frequency-matched to cases on age, sex and state of residence. Information on radiological exposures in the time periods of interest was obtained for 306 case and 950 control families through mailed questionnaires. Analysis used unconditional logistic regression, adjusting for matching variables and potential confounders. Results: We found no evidence of positive associations between risk of CBT overall and childhood or parental pre-pregnancy radiological procedures. Increased ORs for high-grade gliomas associated with childhood radiological procedures were based on small numbers and may be due to chance. Conclusions: Given the evidence for an increased risk of CBT in cohort studies of computed tomography (CT) in childhood, the lack of such an association in our study may be due to the reduced intensity of CTs after 2001. Future research to investigate the safety of fetal exposure to more intense procedures like CT scans is needed. © 2014 Springer International Publishing Switzerland.

© 2014, Springer International Publishing Switzerland. Purpose: We investigated whether paternal dietary intake of folate before conception is associated with the risk of childhood acute lymphoblastic leukemia (ALL) in a nationwide case¿control study.Methods: Data on dietary folate intake during the 6¿months before the child¿s conception were collected from 285 case fathers and 595 control fathers using a dietary questionnaire. Nutrient intake was quantified using a customized computer software package based on Australian food composition databases. Data on folate intake were analyzed using unconditional logistic regression, adjusting for study-matching variables, total energy, and potentially confounding variables. In a subset of 229 cases and 420 controls, data on vitamin B6 and vitamin B12 intake were also analyzed.Results: No consistent associations were seen with paternal dietary intake of folate or vitamin B6. Higher levels of paternal dietary vitamin B12 were appeared to be associated with an increased risk of childhood ALL, with those in the highest tertile of consumption having an OR of 1.51 (0.97, 2.36). The use of supplements containing folate and vitamins B6 or B12 was rare.Conclusions: We did not find any biologically plausible evidence that paternal nutrition in the period leading up to conception was associated with childhood ALL. Our finding for vitamin B12 may be a chance finding, given the number of analyses performed, or be attributable to participation bias because parents with a tertiary education had the lowest level of B12 intake and tertiary education was more common among control than case parents.

© 2014 Informa UK Ltd. Purpose: Few longitudinal studies explore post-stroke patterns of psychological morbidity and factors contributing to their change over time. We aimed to explore predictors of post-stroke depression (PSD) and post-stroke anxiety over a 12-month period. Methods: A prospective cohort study. Consecutively recruited stroke patients (n=134) participated in face-to-face interviews at baseline, 3, 6, 9, and 12 months. Primary outcome measures were depression and anxiety (measured via Hospital Anxiety and Depression Scale). Independent variables included disability (Modified Rankin Scale), Quality-of-life (Assessment Quality-of-life), social support (Multi-dimensional Scale Perceived Social Support) and community participation (Adelaide Activities Profile (AAP)). Secondary outcomes were predictors of resolution and development of PSD and anxiety. Results: Anxiety (47%) was more common than depression (22%) at baseline. Anxiety (but not depression) scores improved over time. Anxiety post-stroke was positively associated with baseline PSD (p<0.0001), baseline anxiety (p<0.0001) and less disability (p=0.042). PSD was associated with baseline anxiety (p<0.0001), baseline depression (p=0.0057), low social support (p=0.0161) and low community participation (p<0.0001). The only baseline factor predicting the resolution of PSD (if depressed at baseline) was increased social support (p=0.0421). Factors that predicted the onset of depression (if not depressed at baseline) were low community participation (p=0.0015) and higher disability (p=0.0057). Conclusion: While more common than depression immediately post-stroke, anxiety attenuates while the burden of depression persists over 12 months. Clinical programs should assess anxiety and depression, provide treatment pathways for those identified, and address modifiable risk factors, especially social support and social engagement.Implications for RehabilitationPsychological distress post stroke is persisting.Multi-disciplinary teams that establish goals with patients promoting social and community engagement could assist in managing psychological morbidity.A shift towards promoting longer-term monitoring and management of stroke survivors must be undertaken, and should consider the factors that support and hinder psychological morbidity.

© 2014 Macmillan Publishers Limited. All rights reserved. Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.

Background Many students find the peripheral sensory examination confusing. We set out to summarise the evidence base in order to provide guidance on the most useful manoeuvres. Methods We performed a literature review starting with 5 secondary sources, supplemented by a literature search on MEDLINE. Results A useful approach to neuropathy is to divide these into large fibre sensory neuropathy (LFSN) in which vibration and proprioception are affected, and small fibre sensory neuropathy (SFSN) in which pain and temperature are affected. Positive sensory symptoms such as burning, electric or sunburn pain point to a SFSN; negative symptoms such as loss of sensation, numbness or deep pain point to a LFSN. If LFSN is suspected, the most reproducible and best studied physical examination is a 10g monofilament, but vibration sense is also useful. There is much less data on the best physical examination for a SFSN. The most appropriate diagnostic test for SFSN is quantitative sensory testing, whereas for LFSN a nerve conduction study is indicated. Conclusions A modest amount of evidence is available to guide peripheral sensory examination but more research is needed. © 2014 John Wiley & Sons Ltd.

© 2014 - IOS Press and the authors. All rights reserved. There are a growing number of large cohorts of older persons with genome-wide genotyping data available, but APOE is not included in any of the common microarray platforms. We compared directly measured APOE genotypes with those imputed using microarray data and the '1000 Genomes' dataset in a sample of 320 Caucasians. We find 90% agreement for e2/e3/e4 genotypes and 93% agreement for predicting e4 status, yielding kappa values of 0.81 and 0.84, respectively. More stringent thresholds around allele number estimates can increase this agreement to 90-97% and kappas of 0.90-0.93.

© 2014 The British Editorial Society of Bone & Joint Surgery. There is a high rate of mortality in elderly patients who sustain a fracture of the hip. We aimed to determine the rate of preventable mortality and errors during the management of these patients. A 12 month prospective study was performed on patients aged > 65 years who had sustained a fracture of the hip. This was conducted at a Level 1 Trauma Centre with no orthogeriatric service. A multidisciplinary review of the medical records by four specialists was performed to analyse errors of management and elements of preventable mortality. During 2011, there were 437 patients aged > 65 years admitted with a fracture of the hip (85 years (66 to 99)) and 20 died while in hospital (86.3 years (67 to 96)). A total of 152 errors were identified in the 80 individual reviews of the 20 deaths. A total of 99 errors (65%) were thought to have at least a moderate effect on death; 45 reviews considering death (57%) were thought to have potentially been preventable. Agreement between the panel of reviewers on the preventability of death was fair. A larger-scale assessment of preventable mortality in elderly patients who sustain a fracture of the hip is required. Multidisciplinary review panels could be considered as part of the quality assurance process in the management of these patients.

© 2014 Elsevier Ireland Ltd. Background: Few studies have examined the prevalence of unhealthy alcohol use in the hospital outpatient setting. Our aim was to estimate the prevalence of unhealthy alcohol use among patients attending a broad range of outpatient clinics at a large public hospital in Australia. Methods: Adult hospital outpatients were invited to complete the Alcohol Use Disorders Identification Test Consumption questions (AUDIT-C) using an iPad as part of a randomised trial testing the efficacy of alcohol electronic screening and brief intervention. Unhealthy alcohol use was defined as an AUDIT-C score =5 among men and =4 among women. Results: Sixty percent (3616/6070) of invited hospital outpatients consented, of whom 89% (3206/3616) provided information on their alcohol consumption (either reported they had not consumed any alcohol in the last 12 months or completed the AUDIT-C). The prevalence of unhealthy alcohol use was 34.7% (95% confidence interval [CI]: 33.0-36.3%). The prevalence among men aged 18-24 years, 25-39 years, 40-59 years and 60 years and older, was 74.4% (95% CI: 68.4-80.4%), 54.3% (95% CI: 48.7-59.8%), 44.1% (95% CI: 39.9-48.3%), and 27.0% (95% CI: 23.6-30.4%), respectively (43.1% overall; 95% CI: 40.8-45.5%). The prevalence among women aged 18-24 years, 25-39 years, 40-59 years, and 60 years and older, was 48.6% (95% CI: 39.2-58.1%), 36.9% (95% CI: 31.2-42.6%), 25.2% (95% CI: 21.5-29.0%) and 14.5% (95% CI: 11.7-17.3%), respectively (24.9% overall; 95% CI: 22.7-27.1%). Conclusion: A large number of hospital outpatients who are not currently seeking treatment for their drinking could benefit from effective intervention in this setting.

The American Psychiatric Association estimates that 3 to 7 per cent of all school aged children are diagnosed with attention deficit hyperactivity disorder (ADHD). Even after correcting for general cognitive ability, numerous studies report a negative association between ADHD and educational achievement. With polygenic scores we examined whether genetic variants that have a positive influence on educational attainment have a protective effect against ADHD. The effect sizes from a large GWA meta-analysis of educational attainment in adults were used to calculate polygenic scores in an independent sample of 12-year-old children from the Netherlands Twin Register. Linear mixed models showed that the polygenic scores significantly predicted educational achievement, school performance, ADHD symptoms and attention problems in children. These results confirm the genetic overlap between ADHD and educational achievement, indicating that one way to gain insight into genetic variants responsible for variation in ADHD is to include data on educational achievement, which are available at a larger scale. © 2014 Wiley Periodicals, Inc.

Background: Although an overall public health target of 10,000 steps per day has been advocated, the dose-response relationship for each health benefit of physical activity may differ. Methods: A representative community sample of 2458 Australian residents aged 55-85 wore a pedometer for a week in 2005-2007 and completed a health assessment. Age-standardized steps per day were compared with multiple markers of health using locally weighted regression to produce smoothed dose-response curves and then to select the steps per day matching 60% or 80% of the range in each health marker. Results: There is a linear relationship between activity level and markers of inflammation throughout the range of steps per day; this is also true for BMI in women and high density lipoprotein in men. For other markers, including waist:hip ratio, fasting glucose, depression, and SF-36 scores, the benefit of physical activity is mostly in the lower half of the distribution. Conclusions: Older adults have no plateau in the curve for some health outcomes, even beyond 12,000 steps per day. For other markers, however, there is a threshold effect, indicating that most of the benefit is achieved by 8000 steps per day, supporting this as a suitable public health target for older adults. © 2014 Human Kinetics, Inc.

© 2014 Handley et al.; licensee BioMed Central Ltd. Background: Rural and remote Australians face a range of barriers to mental health care, potentially limiting the extent to which current services and support networks may provide assistance. This paper examines self-reported mental health problems and contacts during the last 12¿months, and explores cross-sectional associations between potential facilitators/barriers and professional and non-professional help-seeking, while taking into account expected associations with socio-demographic and health-related factors. Methods: During the 3-year follow-up of the Australian Rural Mental Health Study (ARMHS) a self-report survey was completed by adult rural residents (N = 1,231; 61% female 77% married; 22% remote location; mean age = 59¿years), which examined socio-demographic characteristics, current health status factors, predicted service needs, self-reported professional and non-professional contacts for mental health problems in the last 12¿months, other aspects of help-seeking, and perceived barriers. Results: Professional contacts for mental health problems were reported by 18% of the sample (including 14% reporting General Practitioner contacts), while non-professional contacts were reported by 16% (including 14% reporting discussions with family/friends). Perceived barriers to health care fell under the domains of structural (e.g., costs, distance), attitudinal (e.g., stigma concerns, confidentiality), and time commitments. Participants with 12-month mental health problems who reported their needs as met had the highest levels of service use. Hierarchical logistic regressions revealed a dose-response relationship between the level of predicted need and the likelihood of reporting professional and non-professional contacts, together with associations with socio-demographic characteristics (e.g., gender, relationships, and financial circumstances), suicidal ideation, and attitudinal factors, but not geographical remoteness. Conclusions: Rates of self-reported mental health problems were consistent with baseline findings, including higher rural contact rates with General Practitioners. Structural barriers displayed mixed associations with help-seeking, while attitudinal barriers were consistently associated with lower service contacts. Developing appropriate interventions that address perceptions of mental illness and attitudes towards help-seeking is likely to be vital in optimising treatment access and mental health outcomes in rural areas.

BACKGROUND AND PURPOSE - : Studies in rodent models suggest that upregulating angiopoietin-1 (Angpt1) improves stroke outcomes. The aims of this study were to assess the association of plasma Angpt1 with stroke occurrence and outcome. METHODS - : Plasma Angpt1 was measured in 336 patients who had experienced a recent stroke and 321 healthy controls with no stroke history. Patients with stroke (n=285) were reassessed at 3 months and plasma Angpt1 concentration on admission compared between those with severe and minor disability as assessed by the modified Rankin scale. In a separate cohort of 4032 community-acquired older men prospectively followed for a minimum of 6 years, the association of plasma Angpt1 with stroke incidence was examined. RESULTS - : Median plasma Angpt1 was 3-fold lower in patients who had experienced a recent stroke (6.42, interquartile range, 4.26-9.53 compared with 17.36; interquartile range, 14.01-22.46 ng/mL; P<0.001) and remained associated with stroke after adjustment for other risk factors. Plasma Angpt1 concentrations on admission were lower in patients who had severe disability or died at 3 months (median, 5.52; interquartile range, 3.81-8.75 ng/mL for modified Rankin scale 3-6; n=91) compared with those with minor disability (median, 7.04; interquartile range, 4.75-9.92 ng/mL for modified Rankin scale 0-2; n=194), P=0.012, and remained negatively associated with severe disability or death after adjusting for other risk factors. Plasma Angpt1 was not predictive of stroke incidence in community-dwelling older men. CONCLUSIONS - : Plasma Angpt1 concentrations are low after ischemic stroke particularly in patients with poor stroke outcomes at 3 months. Interventions effective at upregulating Angpt1 could potentially improve stroke outcomes. © 2014 American Heart Association, Inc.

Copyright © 2014 by Lippincott Williams & Wilkins. BACKGROUND: The Denver and Sequential Organ Failure Assessment (SOFA) scores have been used widely to describe the epidemiology of postinjury multiple-organ failure; however, differences in these scores make it difficult to compare incidence, duration, and mortality of multiple-organ failure. The study aim was to compare the performance of the Denver and SOFA scores with respect to the outcomes of mortality, intensive care unit length of stay (ICU LOS), and ventilator days.METHODS: A 60-month prospective epidemiologic study was undertaken at an Australian Level I trauma center. Data were collected on trauma patients that met inclusion criteria (ICU admission, Injury Severity Score [ISS] 9 15, age 9 18 years, head Abbreviated Injury Scale [AIS] score G 3, survival for 948 hours). Demographics, ISS, physiologic parameters, SOFA and Denver scores, and outcome data were prospectively collected. Sensitivity/specificity and receiver operating characteristic curve were calculated for both scores. Analysis was also completed for a Day 3 postinjury SOFA and Denver score.RESULTS: A total of 140 patients met the inclusion criteria (mean [SD] age, 47 [21] years; ISS, 30; male, 69%; mortality rate, 6%; mean [SD] ICU LOS, 9 [7] days; mean [SD] ventilation period, 6 [7] days). There was no difference in the score performance predicting mortality. Day 3 SOFA score of 4 or greater outperformed the Denver score of greater than 3 when predicting ICU LOS and ventilator days (area under the curve, 0.83 vs. 0.69, 0.86 vs. 0.73, respectively). The SOFA score was more sensitive and the Denver score was more specific when predicting mortality, ICU LOS, and ventilator days.CONCLUSION: Both scores had similar performance predicting mortality; however, the Day 3 SOFA score outperforms the Denver score when predicting ICU LOS and ventilator days. Either score could be superior based on whether one is seeking to optimize specificity or sensitivity. It is important to note that these findings are in a non-head-injured population and that there are practical difficulties using the SOFA in head-injured patients.LEVEL OF EVIDENCE: Diagnostic study, level II.

Objective: To investigate if maternal asthma is associated with an increased risk of maternal and placental complications in pregnancy. Methods: Electronic databases were searched for the following terms: (asthma or wheeze) and (pregnan* or perinat* or obstet*). Cohort studies published between January 1975 and March 2012 were considered for inclusion. Forty publications met the inclusion criteria, reporting at least one maternal or placental complication in pregnant women with and without asthma. Relative risk (RR) with 95% confidence intervals (CIs) was calculated. Results: Maternal asthma was associated with a significantly increased risk of cesarean section (RR=1.31, 95%CI=[1.22-1.39]), gestational diabetes (RR=1.39, 95%CI=[1.17-1.66]), hemorrhage (antepartum: RR=1.25, 95%CI=[1.10-1.42]; postpartum: RR=1.29, 95%CI=[1.18-1.41]), placenta previa (RR=1.23, 95%CI=[1.07-1.40]), placental abruption (RR=1.29, 95%CI=[1.14-1.47]) and premature rupture of membranes (RR=1.21, 95%CI=1.07-1.37). Moderate to severe asthma significantly increased the risk of cesarean section (RR=1.19, 95%CI=[1.09-1.31]) and gestational diabetes (RR=1.19, 95%CI=[1.06-1.33]) compared to mild asthma. Bronchodilator use was associated with a significantly lowered risk of gestational diabetes (RR=0.64, 95%CI=[0.57-0.72]). Conclusions: Pregnant women with asthma are at increased risk of maternal and placental complications, and women with moderate/severe asthma may be at particular risk. Further studies are required to elucidate whether adequate control of asthma during pregnancy reduces these risks. © 2014 Informa UK Ltd. All rights reserved.

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout. © 2013 Nature America, Inc. All rights reserved.