Professor John Attia

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

Background: Hepatocellular carcinoma (HCC) is the third most fatal cancer, with a 5-year survival rate of 18%. Standard frontline-therapy is multikinase inhibitors (MKIs), but accessibility is still limited, particularly in developing countries. This network meta-analysis (NMA) aimed to compare the efficacy of usual chemotherapy vs MKIs. Method: Randomised-controlled trials (RCTs) comparing any among chemotherapy vs MKIs in treatment-naïve patients with advanced HCCs were identified from MEDLINE and SCOPUS databases. Overall survival (OS) and progression-free survival (PFS) probabilities and times were extracted from Kaplan-Meier curves using Digitizer, and then converted to individual patient time-to-event data. A one-stage mixed-effect survival model was applied to estimate median OS and PFS. A two-stage NMA was applied for the overall response rate and adverse events (AEs) outcome. Results: A total of 20 RCTs were eligible for NMA. Lenvatinib was the best treatment among single MKIs, with median OS and PFS of 9 and 6.3 months, without significant differences in AEs relative to other MKIs. Median OS and PFS were 0.70 (-0.42, 1.83) and 2.17 (1.41, 2.93) months longer with Lenvatinib than Sorafenib. Among chemotherapy agents, FOLFOX4 had the longest median OS and PFS at 7.9 and 4.3 months, respectively, without significant AEs compared to other chemotherapies. The combination of Sorafenib+Doxorubicin prolonged median OS and PFS to 12.7 and 6.3 months, respectively. Conclusion: Use of the MKIs Lenvatinib or Sorafenib as first line systemic treatment for advanced HCC could be beneficial. However, FOLFOX4 might be the optimal choice in a developing country where the health-care budget is limited.

Background: Spirometry is commonly used to assess and monitor lung function. It may also be a useful tool to monitor maternal health during pregnancy. However, large studies examining lung function across gestation are limited. Also, whether spirometry values follow the same pattern during pregnancy in women with and without asthma is unknown. Objective: To investigate the effect of advancing gestation, and its interaction with asthma, on lung function in a large well-defined cohort of pregnant women. Methods: Data were obtained from prospective cohorts involving women with (n = 770) and without (n = 259) asthma (2004-2017), recruited between 12 and 22 weeks' gestation. Lung function (forced vital capacity [FVC], FEV , FEV :FVC%) was assessed periodically during pregnancy using spirometry. Multilevel mixed-effect regression models were used to assess changes in lung function over gestation. Results: Asthma had a significant effect on baseline lung function (FEV %, -9%; FVC%, -3%; FEV :FVC%, -4%). FVC% decreased with advancing gestation (-0.07%/wk; 95% CI, -0.10 to -0.04]), as did FEV %, but only among those without asthma (women without asthma: -0.14%/wk, 95% CI, -0.22 to -0.06%; compared with women with asthma: 0.02%/wk, 95% CI, -0.01 to 0.06). FEV :FVC% remained relatively stable for women without asthma (0.03%/wk; 95% CI, -0.08 to 0.02), but increased for women with asthma (0.06%/wk; 95% CI, 0.04 to 0.16). Conclusions: Data suggest that advancing gestation negatively affects FVC% and FEV %. This is consistent with extrapulmonary restriction from advancing pregnancy. Yet, the presence of asthma altered the trajectories of FEV % and FEV :FVC%. Optimal asthma management during pregnancy might have opposed the negative effects of gestation on lung function. 1 1 1 1 1 1 1 1 1

Objective: To determine whether brain volume is associated with functional outcome after acute ischemic stroke (AIS). Patients and Methods: This study was conducted between July 1, 2014, and March 16, 2019. We analyzed cross-sectional data of the multisite, international hospital-based MRI-Genetics Interface Exploration study with clinical brain magnetic resonance imaging obtained on admission for index stroke and functional outcome assessment. Poststroke outcome was determined using the modified Rankin Scale score (0-6; 0 = asymptomatic; 6 = death) recorded between 60 and 190 days after stroke. Demographic characteristics and other clinical variables including acute stroke severity (measured as National Institutes of Health Stroke Scale score), vascular risk factors, and etiologic stroke subtypes (Causative Classification of Stroke system) were recorded during index admission. Results: Utilizing the data from 912 patients with AIS (mean ± SD age, 65.3±14.5 years; male, 532 [58.3%]; history of smoking, 519 [56.9%]; hypertension, 595 [65.2%]) in a generalized linear model, brain volume (per 155.1 cm ) was associated with age (ß -0.3 [per 14.4 years]), male sex (ß 1.0), and prior stroke (ß -0.2). In the multivariable outcome model, brain volume was an independent predictor of modified Rankin Scale score (ß -0.233), with reduced odds of worse long-term functional outcomes (odds ratio, 0.8; 95% CI, 0.7-0.9) in those with larger brain volumes. Conclusion: Larger brain volume quantified on clinical magnetic resonance imaging of patients with AIS at the time of stroke purports a protective mechanism. The role of brain volume as a prognostic, protective biomarker has the potential to forge new areas of research and advance current knowledge of the mechanisms of poststroke recovery. 3

Introduction The debate regarding euthanasia and physician-assisted suicide (E/PAS) raises key issues about the role of the doctor, and the professional, ethical, and clinical dimensions of the doctor-patient relationship. This review aimed to examine the published evidence regarding the response of doctors who have participated in E/PAS.Methods Original research papers were identified reporting either qualitative or qualitative data published in peer-reviewed literature between 1980 and March 2018, with a specific focus on the impact on, or response from, physicians to their participation in E/PAS. PRISMA and CASP guidelines were followed.Results Nine relevant papers met selection criteria. Given the limited published data, a descriptive synthesis of quantitative and qualitative findings was performed. Quantitative surveys were limited in scope but identified a mixed set of responses. Where studies measured psychological impact, 30-50% of doctors described emotional burden or discomfort about participation, while findings also identified a comfort or satisfaction in believing the request of the patient was met. Significant, ongoing adverse personal impact was reported between 15% to 20%. A minority of doctors sought personal support, generally from family or friends, rather than colleagues. The themes identified from the qualitative studies were summarized as: 1) coping with a request; 2) understanding the patient; 3) the doctor's role and agency in the death of a patient; 4) the personal impact on the doctor; and 5) professional guidance and support.Significance of results Participation in E/PAS can have a significant emotional impact on participating clinicians. For some doctors, participation can contrast with perception of professional roles, responsibilities, and personal expectations. Despite the importance of this issue to medical practice, this is a largely neglected area of empirical research. The limited studies to date highlight the need to address the responses and impact on clinicians, and the support for clinicians as they navigate this challenging area.

Background: Inadequate or excessive gestational weight gain is associated with both short and long-term adverse maternal and infant health outcomes. The practice of routine maternal weight monitoring has been suggested as an effective health promotion intervention, both as a screening tool for adverse maternal and infant outcomes and as a weight management strategy for addressing gestational weight gain. Discussion: The effectiveness of routine maternal weighing as part of maternity care has been debated for more than 30 years. The National Health and Medical Research Council of Australia have recently revised their pregnancy care clinical practice guidelines recommending maternal weight monitoring (clinician and/or self-weighing) be reintroduced into clinical practice. This paper presents a timely discussion of the topic that will contribute new insights to the debate. Conclusion: Weight gain in pregnancy is complex. Evaluation of the translation, implementation, acceptability and uptake of the newly revised guidelines is warranted, given that evidence on the practice remains inconclusive. Future research exploring social ecological interventions to assist pregnant women achieve optimal gestational weight gains are suggested to expand the evidence base.

Background & aims: Chronic inflammation drives the development of insulin resistance and type 2 diabetes. Long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) eicosapentaenoic acid (EPA, c20:5n-3) and docosahexaenoic acid (DHA, c22:6n-3) may protect against type 2 diabetes development. The aim of this current study is to determine whether LCn-3PUFA status is associated with type 2 diabetes in the Hunter Community Study. Methods: Men and women aged 55¿85 years were randomly selected from the electoral roll and invited to participate. Participants were included in the current study if they had plasma phospholipid fatty acid composition data available and diabetes status could be determined. LCn-3PUFA status was determined by fatty acid composition of plasma phospholipids (EPA + DHA, %,w/w). Diabetes was determined according to World Health Organisation criteria. Insulin was measured in n = 251 participants and HOMA-IR calculated. Results: In total, n = 2092 (diabetes: n = 249) participants were included. After adjusting for confounders of diabetes, LCn-3PUFA status was inversely associated with diabetes in overweight/obese females (OR [95%CI]: 0.90 [0.80, 1.00], p = 0.045) but not males (p-interaction = 0.041). Overweight/obese females with diabetes had significantly lower levels of DHA than those without diabetes (mean difference [95%CI]: -0.53 [-0.87, -0.20], p = 0.002), with no difference in EPA. LCn-3PUFA was inversely associated with HOMA-IR (r = -0.175, p = 0.005). Conclusions: This study provides further evidence of a sex-dependent association between LCn-3PUFA and type 2 diabetes. Causal pathways between LCn-3PUFA and type 2 diabetes merits delineation. sex

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

Objective:To determine how timing of surgery affects transfusion, major complications, and mortality in patients who sustain a geriatric hip fracture while taking dual antiplatelet therapy (DAPT; typically aspirin and clopidogrel).Design:Retrospective cohort study.Setting:University-affiliated Level 1 Trauma Center.Patients:Patients 65 years of age or older on DAPT with a geriatric hip fracture were investigated at a single institution between 2002 and 2017. Demographic and perioperative data were collected from patient records, institutional databases, and national hip fracture registry.Intervention:Fixation or arthroplasty.Main Outcome Measurement:Transfusion, major complications, and 30-day mortality.Results:Of the 6724 patients sustaining a geriatric hip fracture, 122 patients were taking DAPT on admission. Timing of surgery did not influence transfused units (incidence rate ratio 1.00, 95% confidence interval: 0.87-1.15, P = 0.968) but did affect major complications (time modeled as quadratic term; odds ratios ranging from 0.20 to 7.91, ptime = 0.001, ptime*time<0.001) and 30-day mortality (odds ratio 1.32, 95% confidence interval: 1.03-1.68, P = 0.030).Conclusion:Surgical delay does not change the need for transfusion of hip fracture patients on DAPT, but it is associated with increased probabilities of major complications and 30-day mortality.Level of Evidence:Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0¿1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0¿2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4¿6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10¿2·03]; p=0·011), with low heterogeneity across studies (I =27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05¿1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06¿2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4¿6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52¿1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03¿4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22¿25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None. 2

Background: Mesh can be used to prevent incisional hernia (IH) occurrence. However, the effect of various mesh positions has never been compared. This study aimed to compare and rank the effect and safety of various mesh-augmented fascia closure techniques on hernia prophylaxis in midline laparotomy. Methods: MEDLINE and SCOPUS were searched from inception to December 2019. Randomized clinical trials (RCTs) were eligible if they met the following criteria: comparison of any of the following interventions: onlay (OM), retrorectus (RM), preperitoneal (PM), intraperitoneal mesh (IM) augmentation, and primary suture closure (PSC); and reporting on any of these outcomes: IH, wound infection, seroma, hematoma, and dehiscence. Two independent reviewers extracted data and assessed the risk of bias. A two-stage random-effect network meta-analysis was performed, then intervention effects were pooled and ranked accordingly. Results: A total of 20 RCTs were eligible. Only OM and RM showed a significantly lower risk of IH than PSC with pooled risk ratios (RRs), 95% confidence intervals (95%CI) of 0.24 (0.12, 0.46) and 0.32 (0.16, 0.66), and number needed to treat (NNTs) of 4 and 5, respectively. However, OM showed a significantly higher risk of seroma than PSC (RR 2.21 (1.44, 3.39) with a number needed to harm (NNH) of 14). Most mesh placements showed a higher risk of wound infection, except for RM, but none of these was significantly different. All mesh techniques, except RM, showed a reduction in dehiscence, but again these were not significantly different. Conclusions: OM and RM provided the most effective IH prevention relative to PSC. However, OM had a higher rate of seroma than RM and PSC. Other complications, including wound infection, hematoma, and dehiscence, were not significantly observed among these fascia closure techniques.

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

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

Rationale: There are no prospective observational studies exploring the relationship between relative hypotension and adverse kidneyrelated outcomes among critically ill patients with shock. Objectives: To investigate the magnitude of relative hypotension during vasopressor support among critically ill patients with shock and to determine whether such relative hypotension is associated with new significant acute kidney injury (AKI) or major adverse kidney events (MAKE) within 14 days of vasopressor initiation. Methods: At seven multidisciplinary ICUs, 302 patients, aged >40 years and requiring >4 hours of vasopressor support for nonhemorrhagic shock, were prospectively enrolled.Weassessed the time-weighted average of the mean perfusion pressure (MPP) deficit (i.e., the percentage difference between patients' preillness basal MPP and achievedMPP)during vasopressor support and the percentage of time points with an MPP deficit.20% as key exposure variables. New significant AKI was defined as an AKI-stage increase of two or more (Kidney Disease: Improving Global Outcome creatinine-based criteria). Measurements and Main Results: The median MPP deficit was 19% (interquartile range, 13-25), and 54% (interquartile range, 19-82) of time points were spent with an MPP deficit.20%. Seventy-three (24%) patients developed new significant AKI; 86 (29%) patients developed MAKE. For every percentage increase in the time-weighted average MPP deficit, multivariable-adjusted odds of developing new significant AKI and MAKE increased by 5.6% (95% confidence interval, 2.2-9.1; P = 0.001) and 5.9% (95% confidence interval, 2.2-9.8; P = 0.002), respectively. Likewise, for every one-unit increase in the percentage of time points with an MPP deficit.20%, multivariable-adjusted odds of developing new significant AKI andMAKEincreased by 1.2% (0.3-2.2; P = 0.008) and 1.4% (0.4-2.4; P = 0.004), respectively. Conclusions: Vasopressor-treated patients with shock are often exposed to a significant degree and duration of relative hypotension, which is associated with new-onset, adverse kidney-related outcomes.

BACKGROUND Laparoscopic appendectomy (LA) has been popular for decades because of shorter hospitalization and return to routine activity. However, complications (e.g., surgical site infection [SSI] and intra-abdominal abscess [IAA]) relative to open appendectomy (OA) are still debated. We therefore conducted an umbrella review to systematically appraise meta-analyses (MAs) comparing SSI and IAA between LA and OA. METHODS Meta-analyses that included only randomized controlled trials were identified from MEDLINE and Scopus databases from inception until July 2018. Their findings were described, the number of overlapping studies was assessed using corrected covered area, and excess significant tests were also assessed. Finally, effect sizes of SSI and IAA were repooled. RESULTS Ten MAs were eligible; SSI was reported in all MAs and IAA in 8 MAs. Surgical site infection rate was 48% to 70% lower in LA than OA, but conversely, IAA rate was 1.34 to 2.20 higher in LA than OA. Overlapping included studies for SSI and IAA were 61% and 54%, respectively, indicating that less information was added across MAs. However, there was no evidence of bias from excess significant tests when pooling SSI or IAA estimates. The risk ratios (95% confidence interval) comparing LA versus OA were repooled in adults and children yielding risk ratios of 0.56 (0.47-0.67) and 0.40 (0.25-0.65) for SSI, and 1.20 (0.88-1.63) and 1.05 (0.61-1.80) for IAA. CONCLUSION Evidence from this umbrella review indicates that LA carries a significantly lower risk of SSI but likely a higher risk of IAA than OA. LEVEL OF EVIDENCE Systematic review/meta-analysis, level I.

Persistent immune thrombocytopenia (ITP) patients require second-line treatments, for which information on clinical outcomes are lacking. A systematic review and network meta-analysis (NMA) were conducted. Only randomised controlled trials (RCT) of second-line drugs in adult persistent ITP patients with platelet response, platelet count, any bleeding or serious adverse events (SAE) outcome were eligible. Twelve RCTs (n¿=¿1313) were included in NMA. For platelet response outcome, eltrombopag and romiplostin were the best relative to placebo; the former had a non-significant advantage [risk ratio (RR)¿=¿1·10 (95% confidence interval: 0·46, 2·67)]. Both treatments were superior to rituximab and recombinant human thrombopoietin (rhTPO)+rituximab, with corresponding RRs of 4·56 (1·89, 10·96) and 4·18 (1·21, 14·49) for eltrombopag; 4·13 (1·56, 10·94) and 3·79 (1·02, 14·09) for romiplostim. For platelet count, romiplostim ranked highest, followed by eltrombopag, rhTPO+rituximab, and rituximab. For bleeding, rituximab had lowest risk, followed by eltrombopag and romiplostim. For SAEs, rhTPO+rituximab had highest risk, followed by rituximab, eltrombopag and romiplostim. From clustered ranking, romiplostim had the best balance between short-term efficacy and SAEs, followed by eltrombopag. In conclusion, romiplostim and eltrombopag may yield high efficacy and safety. Rituximab may not be beneficial due to lower efficacy and higher complications compared with the thrombopoietin receptor agonists. RCTs with long-term clinical outcomes are required.

Background: The most frequent complications from percutaneous electrophysiology procedures relate to vascular access. We sought to perform the first randomised controlled trial for femoral venous haemostasis utilising a simple and novel purse string suture (PSS) technique. Methods: We randomised 200 consecutive patients who were referred for electrophysiology procedures at two different hospitals to either 10 minutes of manual pressure or a PSS over the femoral vein and determined the incidence of vascular access site complications. Results: The mean age was 61.8 ± 12.1 years and 138 (69%) were male. Bleeding requiring addition pressure or a FemStop (Abbott Laboratories, Abbott Park, IL, USA) for complete haemostasis occurred in 17/99 (17%) patients in the PSS arm and 19/101 (19%) patients in the manual pressure arm (p = 0.72). There were no cases of haematoma prolonging hospital stay, arterio-venous fistula, pseudoaneurysm or retroperitoneal bleeding. The mean duration to achieve haemostasis was 45 seconds in the PSS arm and 10 minutes 44 seconds in the manual pressure arm (p < 0.001). Pain/discomfort associated with haemostasis occurred in 15/99 (15%) patients in the PSS arm and in 29/101 (29%) patients receiving manual pressure (p = 0.03). Conclusions: In this randomised trial we demonstrate that an easy to perform PSS is as effective at achieving haemostasis as 10 minutes of manual pressure for catheter ablation procedures. The PSS is considerably faster to perform and is more comfortable for patients than manual pressure.

Background and aims This study aims to (i) examine the effectiveness of internet-based smoking cessation programs; (ii) describe the number and type of behavior change techniques (BCTs) employed; and (iii) explore whether BCTs included in internet-based smoking cessation programs are related to program effectiveness. Methods MEDLINE, CINAHL, EMBASE, PsycINFO, and CENTRAL databases were searched. Randomized controlled trials were included if they described the study of a smoking cessation program delivered via the internet; included current adult tobacco smokers from the general population; and were written in English. Random effects meta-analyses and meta-regressions were used to examine program effectiveness (pooled odds ratios, by outcome measure, i.e., 7 day point prevalence abstinence [PPA], 30 day PPA, other abstinence measure) in short- and long-term outcomes, and examine the associations between BCT number and type (individual BCTs and BCT domain) and program effectiveness. Results Results from 45 studies were included (n = 65,736). Intervention effectiveness was found in the short term for all outcome measures (OR = 1.29, 95% CI 1.12, 1.50, p = .001), for "prolonged abstinence" (OR = 1.43, 95% CI 1.09, 1.87, p = .009), and "30 day PPA" (OR = 1.75, 95% CI 1.13, 2.72, p = .013). Internet-based programs were effective in the long term for all outcome measures (OR = 1.19, 95% CI = 1.06, 1.35, p = .004) and for "prolonged abstinence" (OR = 1.40, 95% CI 1.19, 1.63, p < .001). On average, interventions used more BCTs than comparison groups (6.6 vs. 3.1, p = .0002). The impact of specific individual BCTs and BCT domains on effectiveness was examined and is reported. Conclusions Internet-based smoking cessation interventions increased the odds of cessation by 29 per cent in the short term and by 19 per cent in the long term. Internet-based smoking cessation intervention development should incorporate BCTs to increase effectiveness. Registration CRD42015014676.

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

Evidence-based standardised diabetes care is difficult to achieve in the community due to resource limitations, and lack of equitable access to specialist care leads to poor clinical outcomes. This study reports a quality improvement program in diabetes health care across a large health district challenged with significant rural and remote geography and limited specialist workforce. An integrated diabetes care model was implemented, linking specialist teams with primary care teams through capacity enhancing case-conferencing in general practice supported by comprehensive performance feedback with regular educational sessions. Initially, 20 practices were recruited and 456 patients were seen over 14 months, with significant improvements in clinical parameters. To date 80 practices, 307 general practitioners, 100 practice nurses and 1400 patients have participated in the Diabetes Alliance program and the program envisages enrolling 40 new practices per year, with a view to engage all 314 practices in the health district over time. Diabetes care in general practice appears suboptimal with significant variation in process measures. An integrated care model where specialist teams are engaged collaboratively with primary care teams in providing education, capacity enhancing case-conferences and performance monitoring may achieve improved health outcomes for people with diabetes.

OBJECTIVES: To pool prevalence of nonconvulsive seizure, nonconvulsive status epilepticus, and epileptiform activity detected by different electroencephalography types in critically ills and to compare detection rates among them. DATA SOURCES: MEDLINE (via PubMed) and SCOPUS (via Scopus) STUDY SELECTION:: Any type of study was eligible if studies were done in adult critically ill, applied any type of electroencephalography, and reported seizure rates. Case reports and case series were excluded. DATA EXTRACTION: Data were extracted independently by two investigators. Separated pooling of prevalence of nonconvulsive seizure/nonconvulsive status epilepticus/epileptiform activity and odds ratio of detecting outcomes among different types of electroencephalography was performed using random-effect models. This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and also adhered to the Meta-analyses Of Observational Studies in Epidemiology guidelines. Quality of evidence was assessed with the Newcastle-Ottawa Quality Assessment Scale for observational studies and Cochrane methods for randomized controlled trial studies. DATA SYNTHESIS: A total of 78 (16,707 patients) and eight studies (4,894 patients) were eligible for pooling prevalence and odds ratios. For patients with mixed cause of admission, the pooled prevalence of nonconvulsive seizure, nonconvulsive status epilepticus, either nonconvulsive seizure or nonconvulsive status epilepticus detected by routine electroencephalography was 3.1%, 6.2%, and 6.3%, respectively. The corresponding prevalence detected by continuous electroencephalography monitoring was 17.9%, 9.1%, and 15.6%, respectively. In addition, the corresponding prevalence was high in post convulsive status epilepticus (33.5%, 20.2%, and 32.9%), CNS infection (23.9%, 18.1%, and 23.9%), and post cardiac arrest (20.0%, 17.3%, and 22.6%). The pooled conditional log odds ratios of nonconvulsive seizure/nonconvulsive status epilepticus detected by continuous electroencephalography versus routine electroencephalography from studies with paired data 2.57 (95% CI, 1.11-5.96) and pooled odds ratios from studies with independent data was 1.57 (95% CI, 1.00-2.47). CONCLUSIONS: Prevalence of seizures detected by continuous electroencephalography was significantly higher than with routine electroencephalography. Prevalence was particularly high in post convulsive status epilepticus, CNS infection, and post cardiac arrest.

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

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

Laparoscopic totally extra-peritoneal inguinal hernia repair is the standard option for inguinal hernia treatment. However, there are various types of mesh fixation and their relative uses are still controversial. This network meta-analysis was conducted to compare and rank the different fixations available for TEP. Medline and Scopus databases were search until February 1, 2017 and using randomized controlled trials comparing outcomes between different mesh fixation techniques were included. The results demonstrated that fifteen RCTs (n = 1783) were eligible for pooling. Five types of mesh fixation were used; metallic tack, no-fixation, absorbable tack, suture, and glue. Network meta-analysis that use metallic tack as the reference, indicated that suture and glue both carried a lower risk of recurrence with pooled risk ratios (RR) of 0.29 (95% CI 0.00, 18.81) and 0.29 (0.07, 1.30), respectively. For overall complications, absorbable tack had lower risk (0.63, 95% CI: 0.02, 16.13). However, none of these estimates reached statistical significance. So, this network meta-analysis suggests that glue and absorbable tack might be best in lowering recurrence risk and complications. However, a large scale RCT is still needed to confirm these results.

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

Objective: We tested the hypothesis that participants who know the behavioral focus of a study and are thus aware that a particular behavior is being studied will modify that behavior, independently of any possible effect of assessment, thereby dismantling a Hawthorne effect into two putative components. Study Design and Setting: We undertook a three-arm individually randomized trial online among students: group A (control) were told they were completing a lifestyle survey; group B were told the focus of the survey was alcohol consumption; and group C additionally answered 20 questions on their alcohol use and its consequences before answering the same lifestyle questions as Groups A and B. Nondrinkers were excluded, and all groups were aware they would be followed up after 1 month. Results: Outcome data were obtained for 4,583 of 5,478 trial participants (84% follow-up rate). There were no differences between the three groups on primary (overall volume consumed) or secondary outcome measures (drinking frequency and amount per typical occasion) in the intervening 4 weeks. Conclusions: There is no evidence that any form of Hawthorne effect exists in relation to self-reported alcohol consumption online among university students in usual research practice. Attention to study contexts is warranted for investigating research participation effects.

Objectives: To examine the effectiveness of different strategies for recruiting participants for a large Australian randomised controlled trial (RCT), the Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE). Design, setting, participants: Men and women aged 55¿60 years with at least two cardiovascular risk factors (hypertension, hypercholesterolaemia, overweight/obesity) were recruited for a multicentre placebo-controlled RCT assessing the effectiveness of 23-valent pneumococcal polysaccharide vaccine (23vPPV) for preventing cardiovascular events. Methods: Invitations were mailed by the Australian Department of Human Services to people in the Medicare database aged 55¿60 years; reminders were sent 2 weeks later. Invitees could respond in hard copy or electronically. Direct recruitment was supplemented by asking invitees to extend the invitation to friends and family (snowball sampling) and by Facebook advertising. Main outcome: Proportions of invitees completing screening questionnaire and recruited for participation in the RCT. Results: 21¿526 of 154¿992 invited people (14%) responded by completing the screening questionnaire, of whom 4725 people were eligible and recruited for the study. Despite the minimal study burden (one questionnaire, one clinic visit), the overall participation rate was 3%, or an estimated 10% of eligible persons. Only 16% of eventual participants had responded within 2 weeks of the initial invitation letter (early responders); early and late responders did not differ in their demographic or medical characteristics. Socio-economic disadvantage did not markedly influence response rates. Facebook advertising and snowball sampling did not increase recruitment. Conclusions: Trial participation rates are low, and multiple concurrent methods are needed to maximise recruitment. Social media strategies may not be successful in older age groups. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12615000536561.

Background: Stroke thrombolysis with alteplase is currently recommended 0¿4·5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4·5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis. Methods: In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged =18 years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0¿1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036. Findings: We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI 1·15¿2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI 1·23¿76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81¿2·96, p=0·66). Interpretation: Patients with ischaemic stroke 4·5¿9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis. Funding: None.

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

Background: Many drugs have been used to treat scabies, but it is unclear which of them is the most efficacious. Objective: To evaluate the comparative efficacy and safety of antiscabietic agents. Methods: A systematic review of randomized controlled trials was conducted. Direct and network meta-analyses were applied to 13 antiscabietic agents on 3 outcomes (cure, persistent itching, and adverse events). Their probability of having highest efficacy and safety was estimated and ranked. Results: A network meta-analysis of 52 trials including 9917 patients indicated that permethrin (the reference treatment) had a significantly higher cure rate than sulfur, malathion, lindane, crotamiton, and benzyl benzoate. Combination permethrin plus oral ivermectin had a nonsignificantly higher cure rate than permethrin. Combination permethrin plus oral ivermectin was ranked highest in terms of cure, topical ivermectin in terms of persistent itching, and synergized pyrethrins in terms of adverse events. On the basis of clustered ranking, permethrin, oral ivermectin, and synergized pyrethrins seemed to retain balance between cure and adverse events. Limitations: There are small numbers of trials and patients in some comparisons and a high risk of bias in some trials. Conclusion: There is no 1 treatment that ranked highest in all aspects. Physicians should consider the drug's efficacy and safety profiles, along with ease of administration.

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

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

Monitoring levels of alcohol-related harm in populations requires indicators that are robust to extraneous influence. We investigated the validity of an indicator for police-attributed alcohol-related assault. We summarized offence records from Queensland Police, investigated patterns of missing data, and considered the utility of a surrogate for alcohol-related assault. Of 242 107 assaults from 2004-2014, in 35% of cases the drug used by the offender was recorded as a ¿ unknown'. Under various assumptions about non-random missingness the proportion of assaults judged to be alcohol-related varied from 30%-65%. We found a sharp increase in missing data from 2007 suggesting the downward trend from that point is artefactual. Conversely, we found a stable and increasing trend using a time-based surrogate. The volume of missing data and other limitations preclude valid estimation of trends using the police indicator, and demonstrate how misleading results can be produced. Our analysis supports the use of an empirically-based surrogate indicator.

Background: To develop and validate a risk stratification model of severe injury (SI) and death to identify and prioritize road traffic injury (RTI) patients for transportation to an appropriate trauma center (TC). Methods: A 2-phase multicenter-cross-sectional study with prospective data collection was collaboratively conducted using 9 dispatch centers (DC) across Thailand. Among the 9 included DC, 7 and 2 DCs were used for development and validation, respectively. RTI patients who were treated and transported to hospitals by advanced life support (ALS) response units were enrolled. Multiple logistic regression was used to derive risk prediction score of death in 48 h and SI (new injury severity score = 16). Calibration/discrimination performances were explored. Results: A total of 5359 and 2097 RTIs were used for development and external validation, respectively. Seven and 9 predictors among demographic data, mechanism of injury, physic data, EMS operation, and prehospital managements were significant predictors of death and SI, respectively. Risk prediction models fitted well with the developed data (O/E ratios of 1.00 (IQR: 0.69, 1.01) and 0.99 (IQR: 0.95, 1.05) for death and SI, respectively); and the C statistics of 0.966 (0.961, 0.972) and 0.913 (0.905, 0.922). The risk scores were further stratified as low, moderate and high risk. The derive models did not fit well with external data but they were improved after recalibrating the intercepts. However, the model was externally good/excellent discriminated with C statistics from 0.896 (0.871, 0.922) to 0.981 (0.971, 0.991). Conclusion: Risk prediction models of death and SI were developed with good calibration and excellent discrimination. The model should be useful for ALS response units in proper allocation of patients.

Aim: To determine sequences and magnitude of causality among periodontitis, diabetes and chronic kidney disease (CKD) by mediation analysis. Methods: Ten-year-data were retrieved from the Electric Generation Authority of Thailand (EGAT) study. A cohort of 2,635 subjects was identified with no CKD at baseline. The interested outcome was CKD incidence defined as glomerular filtration rate <60¿ml/min/1.73¿m . The percentage of proximal sites with clinical attachment loss =5¿mm was used to represent periodontitis. Mediation analysis with 1,000-replication bootstrapping was applied to two causal diagrams, diagram A (Periodontitis¿¿¿Diabetes ¿ CKD) and diagram B (Diabetes¿¿¿Periodontitis ¿ CKD). Results: The cumulative incidence of CKD was 10.3 cases per 100 persons during 10-year period. In diagram A, each increasing percentage of proximal sites with severe periodontitis increased the adjusted odds ratio of CKD 1.010 (95% CI: 1.005, 1.015) and 1.007 (95% CI: 1.004, 1.013), by direct and indirect effect through diabetes, respectively. In diagram B, diabetes increased the odds of CKD twofold, with 6.5% of this effect mediated via periodontitis. Conclusions: Periodontitis had significant direct effect, and indirect effect through diabetes, on the incidence of CKD. Awareness about systemic morbidities from periodontitis should be emphasized. 2

Apolipoprotein E (APOE) genotype is an established genetic risk factor for sporadic Alzheimer's disease (AD) but the extent to which APOE genotype influences the plasma lipidome is unknown, even though lipids are potential diagnostic or prognostic biomarkers for AD. We quantified plasma lipids using untargeted liquid chromatography coupled mass spectrometry in a total of 152 non-demented participants aged 65-100 years carrying at least one ¿2 or ¿4 allele (¿2/¿2 or ¿2/¿3, n¿=¿38: ¿4/¿3 or ¿4/¿4, n¿=¿38), who were roughly matched to an ¿3/¿3 control by age, sex, and lipid-lowering medication (n¿=¿76). Low density lipoprotein cholesterol levels were genotype dependent (¿4/¿4> ¿4/¿3> ¿3/¿3> ¿2/¿3> ¿2/¿2). The greatest variation in lipids was related to the ¿2 isoform, where various lysophosphatidylcholines and all phosphatidylethanolamine (PE) subclasses were elevated relative to ¿3/¿3 and ¿4 carriers. APOE ¿4 carriers had reduced phosphatidylinositol relative to ¿3/¿3 and ¿2 carriers. Logistic regression revealed that ¿2 carriers were at least 4 times higher odds of being in the highest tertile of PE lipid level relative to ¿3/¿3. The elevation in PE and other phospholipids in ¿2 carriers may indicate the protective effect of ¿2 is linked to these phospholipids. Additionally, high baseline PE in cognitively normal participants predicted protection against cognitive decline six years later. Our data suggest substantial modulation of plasma lipids by APOE genotype and therefore indicates possible lipid targets and pathomechanisms involved in AD risk.

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

Background: The efficacy of antibiotics in appendicitis remains controversial, and physicians are not confident in prescribing antibiotics as the first line treatment. This network meta-analysis was conducted to assess the efficacy and safety of individual antibiotics in uncomplicated appendicitis. Methods: Randomized controlled trials (RCTs) were identified from MEDLINE and SCOPUS databases since inception to July 2017. Studies. Network meta-analysis was applied to estimate treatment effects and safety. Probability of being the best treatment was estimated using surface under the cumulative ranking curve (SUCRA). Results: Among 9 RCTs meeting our inclusion criteria. A network meta-analysis indicated that those receiving antibiotics had about 12¿32% lower chance of treatment success and lower risk of complication about 23¿86%, especially Beta-lactamase than appendectomy. The overall appendicitis recurrence rate in the antibiotic group was about 18.2%. The SUCRA indicated that appendectomy was ranked first for treatment success and least complications, followed by Beta-lactamase. Conclusions: Appendectomy is still the most effective treatment in uncomplicated appendicitis but it carries complications. Beta-lactamase, might be an alternative treatment if there are any contraindications for operation.

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

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

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

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.

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.

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

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

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

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/cm (95% CI -0.042 to 0.022, P =.55) and -0.013 g/cm (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. 2 2

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

Introduction: Atrial fibrillation (AF) is increasing in prevalence and is associated with significant morbidity and mortality. The optimal diagnostic and treatment strategies for AF are continually evolving and care for patients requires confidence in integrating these new developments into practice. These clinical practice guidelines will assist Australian practitioners in the diagnosis and management of adult patients with AF. Main recommendations: These guidelines provide advice on the standardised assessment and management of patients with atrial fibrillation regarding:¿ screening, prevention and diagnostic work-up; acute and chronic arrhythmia management with antiarrhythmic therapy and percutaneous and surgical ablative therapies; stroke prevention and optimal use of anticoagulants; and¿ integrated multidisciplinary care. Changes in management as a result of the guideline: Opportunistic screening in the clinic or community is recommended for patients over 65 years of age. The importance of deciding between a rate and rhythm control strategy at the time of diagnosis and periodically thereafter is highlighted. b-Blockers or non-dihydropyridine calcium channel antagonists remain the first line choice for acute and chronic rate control. Cardioversion remains first line choice for acute rhythm control when clinically indicated. Flecainide is preferable to amiodarone for acute and chronic rhythm control. Failure of rate or rhythm control should prompt consideration of percutaneous or surgical ablation. The sexless CHA DS -VA score is recommended to assess stroke risk, which standardises thresholds across men and women; anticoagulation is not recommended for a score of 0, and is recommended for a score of = 2. If anticoagulation is indicated, non-vitamin K oral anticoagulants are recommended in preference to warfarin. An integrated care approach should be adopted, delivered by multidisciplinary teams, including patient education and the use of eHealth tools and resources where available. Regular monitoring and feedback of risk factor control, treatment adherence and persistence should occur. 2 2

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

New oral anticoagulants (NOACs; ie, direct thrombin inhibitor [DTI] and factor Xa [FXa] inhibitors) were used as alternatives to warfarin. Specific antidotes (idarucizumab for dabigatran and andexanet alfa for FXa inhibitors) and hemostatic reversal agents were used for lowering bleeding, but their efficacies were still uncertain. The objectives of this study were to estimate and compare the efficacy of NOAC antidotes on bleeding reversal and death. Studies were identified from MEDLINE and Scopus databases until May 2018. Case reports/series and cohorts were selected if they assessed reversal or death rates. Data were independently extracted by 2 reviewers. Individual patient data and aggregated data of outcomes were extracted from case reports/series and cohorts. Binary regression was used to estimate outcome rates, risk ratio (RR) along with 95% confidence interval (CI). Interventions were NOACs and reversal agents (ie, DTI-specific, DTI-standard, FXa-specific, and FXa-standard). Among 220 patients of 93 case reports/series, reversal rates were 95.9%, 77.6%, and 71.5% for DTI-specific, FXa-standard, and DTI-standard. Pooled RRs for DTI-specific and FXa-standard versus DTI-standard, respectively, were 1.34 (CI: 1.13-1.60) and 1.09 (CI: 0.84-1.40). Death rate was 0.18 (CI: 0.06-0.57) times lower in DTI-specific versus DTI-standard. For pooling 10 subcohorts, pooled RRs were 1.08 (CI: 1.00-1.16), 1.29 (CI: 1.20-1.39), and 1.13 (CI: 1.01-1.25) for DTI-specific, FXa-specific, and FXa-standard versus DTI-standard. In conclusion, specific reversal agents might be useful for reversal of bleeding and lowering the risk of death than standard reversal agents. Our findings were based on case reports/series and selected cohorts, further comparative studies are thus needed.

Background: Most trials of electronic alcohol screening and brief intervention (e-SBI) have been conducted in young people. The aim of this study was to evaluate the effect of e-SBI in adults with hazardous or harmful drinking. Methods: This individually randomized, parallel, two-group, double-blind controlled trial was conducted in the outpatient department of a large public hospital in Australia. Consenting adults who scored 5¿9 on the AUDIT-C (837/3225; 26%) were randomized in a 1:1 ratio by computer to screening alone (442/837; 53%) or to 10 min of assessment and personalized feedback on their alcohol consumption (comparisons with medical guidelines and age and sex-specific norms), peak blood alcohol concentration, expenditure on alcohol, and risk of alcohol dependence (395/837; 47%). The two primary outcomes, assessed six months after randomization, were the number of standard drinks (10 g ethanol) consumed by participants in the last seven days and their AUDIT score. Results: 693/837 (83%) and 635/837 (76%) participants were followed-up at 6 and 12 months, respectively. There was no statistically significant difference between the groups in the median number of standard drinks consumed in the last seven days (intervention: 12; control: 10.5; rate ratio, 1.12 [95% confidence interval, 0.96¿1.31]; P =.17) or in their median AUDIT score (intervention: 7; control: 7; mean difference, 0.28 [-0.42 to 0.98]; P =.44). Conclusion: These results do not support the implementation of an e-SBI program comprising personalized feedback and normative feedback for adults with hazardous or harmful drinking in the hospital outpatient setting.

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

Background: 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.

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

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

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. HbA in the second trimester of pregnancy (P = 0.02, OR 1.42) and percentage time spent in BGL range of 7¿10 mmol/l (P = 0.001, OR 1.02) were both associated with a risk of neonatal hypoglycaemia in a logistic regression model. HbA in the third trimester (P = 0.07, OR 1.28) approached, but did not reach, significance. Conclusions: These data support a BGL range of 4¿7 mmol/l as an intrapartum target. Glycaemic control in the second trimester is associated with neonatal hypoglycaemia. Improvement in ante- and intrapartum glycaemic control may reduce neonatal hypoglycaemia in women with pre-existing diabetes. 1c 1c

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, HbA = 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. 1c

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 FiO of 0·6) or standard therapy (cold wall oxygen 100% via infant nasal cannulae at low flow to a maximum of 2 L/min) using a block size of four and stratifying for gestational age at birth. The primary outcome was time from randomisation to last use of oxygen therapy. All randomised children were included in the primary and secondary safety analyses. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12612000685819. Findings From July 16, 2012, to May 1, 2015, we randomly assigned 202 children to either HFWHO (101 children) or standard therapy (101 children). Median time to weaning was 24 h (95% CI 18¿28) for standard therapy and 20 h (95% CI 17¿34) for HFWHO (hazard ratio [HR] for difference in survival distributions 0·9 [95% CI 0·7¿1·2]; log rank p=0·61). Fewer children experienced treatment failure on HFWHO (14 [14%]) compared with standard therapy (33 [33%]; p=0·0016); of these children, those on HFWHO were supported for longer than were those on standard therapy before treatment failure (HR 0·3; 95% CI 0·2¿0·6; p<0·0001). 20 (61%) of 33 children who experienced treatment failure on standard therapy were rescued with HFWHO. 12 (12%) of children on standard therapy required transfer to the intensive care unit compared with 14 (14%) of those on HFWHO (difference -1%; 95% CI -7 to 16; p=0·41). Four adverse events occurred (oxygen desaturation and condensation inhalation in the HFWHO group, and two incidences of oxygen tubing disconnection in the standard therapy group); none resulted in withdrawal from the trial. No oxygen-related serious adverse events occurred. Secondary effectiveness outcomes are reported in the Results section. Interpretation HFWHO did not significantly reduce time on oxygen compared with standard therapy, suggesting that early use of HFWHO does not modify the underlying disease process in moderately severe bronchiolitis. HFWHO might have a role as a rescue therapy to reduce the proportion of children requiring high-cost intensive care. Funding Hunter Children's Research Foundation, John Hunter Hospital Charitable Trust, and the University of Newcastle Priority Research Centre GrowUpWell. 2

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

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

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.

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.

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.

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.

This corrects the article DOI: 10.1038/srep45040.

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.

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

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

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.

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, HbA , 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 HbA (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m , -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. 1c 1c 2

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

Background 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).

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.

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.

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

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

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

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.

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 R and the area under the receiver-operating characteristic curve (AUC). Models with and without the genetic risk score (GRS) were compared using the log likelihood ratio Chi-squared test and AUCs. Multiplicative interaction between genetic and environmental risk factors was assessed via logistic regression within and across ancestral groups. Interactions were assessed for the GRS and its 62 constituent variants. Results The models including environmental risk factors only had pseudo R values of 16.5¿28.3% and AUC of 0.75¿0.83. Incorporating a genetic score aggregating 62 T2D-associated risk variants significantly increased the model fit (likelihood ratio P-value of 2.50 × 10 ¿4.83 × 10 ) and increased the pseudo R by about 1¿2% and AUC by 1¿3%. None of the gene¿environment interactions reached significance after multiple testing adjustment, either for the GRS or individual variants. For individual variants, 33 out of 310 tested associations showed nominal statistical significance with 0.001 < P < 0.05. Conclusion This study suggests that known genetic risk variants contribute a significant but small amount to overall T2D risk variation in Malaysian population groups. If gene¿environment interactions involving common genetic variants exist, they are likely of small effect, requiring substantially larger samples for detection. 2 2 -4 -12 2

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.

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.

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.

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 ; joint OR 1·19, 1·12-1·26, p=1·30 × 10 ). 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 ; joint OR 1·37, 1·30-1·45, p=2·79 × 10 ) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93 × 10 ; joint OR 1·17, 1·11-1·23, p=2·29 × 10 ) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50 × 10 ; joint OR 1·24, 1·15-1·33, p=4·52 × 10 ) 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 ; joint OR 1·17, 1·11-1·23, p=2·92 × 10 ). 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. -8 -9 -19 -32 -7 -10 -8 -9 -8 -9

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

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

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

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

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

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.

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.

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.

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.

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

Background: 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.

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.

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.

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.

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

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.

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.

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 ). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10 ). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by theobservedeffectonE concentrations (1.09, CI=1.03-1.21), consistentwith the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associationswith rs727479 were stronger amongwomen with a higher BMI (PinteractionZ0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction. -11 -8 2

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.

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.

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

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

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.

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.

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 ). 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. -11

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.

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 19 February 2015. th

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.

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.

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; r > 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. 2