Professor John Attia

Background: The need for better end-of-life care for people with dementia has been acknowledged. Existing literature suggests that people dying with dementia have less access to palliative care, yet little is known about the care provided to people with dementia at the end of life. This study aimed to establish evidence related to end-of-life care for people dying with dementia in hospital compared to other settings. Methods: A retrospective clinical audit of people who had a diagnosis of dementia and had accessed services within a local health district, who died between 2015 and 2019, was conducted. A total of 705 people were identified, and a subset of 299 people randomly selected for manual audit. Chi-square p-values were used to compare the place of death, and a t-test or non-parametric test was used to assess the significance of the difference, as appropriate. Measures of functional decline within one month of death were assessed using mixed effects logistic regression models. Results: The characteristics of people differed by place of death, with people who died in hospital more likely to be living at home and to not have a spouse. Less than 1 in 5 people had advance care directives or plans. Many were still being actively treated at the time of death: almost half of people who died in hospital had an investigation in their final 72¿hours, less than half of people were coded as receiving palliative care at death, and more than 2 in 3 people did not get access to specialist palliative care. Declining function was associated with the terminal phase. Conclusion: This study provides novel insights for those providing end-of-life care for people with dementia. Healthcare professionals and policy makers should consider how demographic characteristics relate to the places people with dementia receive end-of-life care. The care provided to people with dementia in the last year of their life highlights the need for more support to prepare advance care documentation and timely consideration for palliative care. Changes in markers of nutritional status and function in people with advanced dementia may help with identification of terminal phases.

Background: Improving the coordination and integration of health services is recognised nationally and internationally as a key strategy for improving the quality of diabetes care. The Australian Diabetes Alliance Program (DAP) is an integrated care model implemented in the Hunter New England Local Health District (HNELHD), New South Wales (NSW), in which endocrinologists and diabetes educators collaborate with primary care teams via case-conferencing, practice performance review, and education sessions. The objective of this study was to report on general practitioners¿ (GPs) perspectives on DAP and whether the program impacts on their skills, knowledge, and approach in delivering care to adult patients with type 2 diabetes. Methods: Four primary care practices with high rates of monitoring haemoglobin A1c (HbA1c) levels (> 90% of patients annually) and five practices with low rates of monitoring HbA1c levels (< 80% of patients annually) from HNELHD, NSW provided the sampling frame. A total of nine GPs were interviewed. The transcripts from the interviews were reviewed and analysed to identify emergent patterns and themes. Results: Overall, GPs were supportive of DAP. They considered that DAP resulted in significant changes in their knowledge, skills, and approach and improved the quality of diabetes care. Taking a more holistic approach to care, including assessing patients with diabetes for co-morbidities and risk factors that may impact on their future health was also noted. DAP was noted to increase the confidence levels of GPs, which enabled active involvement in the provision of diabetes care rather than referring patients for tertiary specialist care. However, some indicated the program could be time consuming and greater flexibility was needed. Conclusions: GPs reported DAP to benefit their knowledge, skills and approach for managing diabetes. Future research will need to investigate how to improve the intensity and flexibility of the program based on the workload of GPs to ensure long-term acceptability of the program.

This systematic review was conducted to explore natural language processing (NLP) focusing on text representation techniques and algorithms used previously to identify recurrent cancer diagnoses from electronic medical records (EMR), and an assessment of their detection performance. Relevant studies were identified from PubMed, Scopus, ACM Digital Library, and IEEE databases since inception to August 18, 2022. Data, including text representation methods, model algorithms and performance, and type of clinical notes, were extracted from individual studies by two independent reviewers. Study risk of bias was assessed using the prediction model risk of bias assessment tool. Of the 412 studies identified, 17 were eligible for inclusion, with 15 representing models that were not externally validated. Three text representations were used: statistical, context-free, and contextual representations (bidirectional encoder representations from transformers (BERT) and its variants), from 12, 6, and 3 studies, respectively. The corresponding median harmonic precision and recall means (F1 scores) for these representations were 0.43, 0.87, and 0.72, respectively. The algorithms applied included rule-based, machine learning, and deep learning approaches with median F1 scores of 0.71, 0.43, and 0.76, respectively. In conclusion, this systematic review suggests that deep learning models that use PubMedBERT as a text representation perform best. These findings are clinically informative for the selection of appropriate approaches for the detection of recurrent cancer from electronic medical records.

Background: Guideline recommendations for preoperative chest radiographs vary to the extent that individual patient benefit is unclear. We developed and validated a prediction score for abnormal preoperative chest radiographs in adult patients undergoing elective non-cardiothoracic surgery. Methods: Our prospective observational study recruited 703 adult patients who underwent elective non-cardiothoracic surgery at Ramathibodi Hospital. We developed a risk prediction score for abnormal preoperative chest radiographs with external validation using data from 411 patients recruited from Thammasat University Hospital. The discriminative performance was assessed by receiver operating curve analysis. In addition, we assessed the contribution of abnormal chest radiographs to perioperative management. Results: Abnormal preoperative chest radiographs were found in 19.5% of the 703 patients. Age, pulmonary disease, cardiac disease, and diabetes were significant factors. The model showed good performance with a C-statistics of 0.739 (95% CI, 0.691¿0.786). We classified patients into four groups based on risk scores. The posttest probabilities in the intermediate-, intermediate-high-, and high-risk groups were 33.2%, 59.8%, and 75.7%, respectively. The model fitted well with the external validation data with a C statistic of 0.731 (95% CI, 0.674¿0.789). One (0.4%) abnormal chest radiograph from the low-risk group and three (2.4%) abnormal chest radiographs from the intermediate-to-high-risk group had a major impact on perioperative management. Conclusions: Four predictors including age, pulmonary disease, cardiac disease, and diabetes were associated with abnormal preoperative chest radiographs. Our risk score demonstrated good performance and may help identify patients at higher risk of chest abnormalities.

Introduction: The cardiovascular benefits of multiple antihyperglycemic drugs as add-on therapies to metformin in the real-practice are unclear. This study aimed to directly compare major adverse cardiovascular events (CVE) associated with these multiple drugs. Methods: An emulation of a target trial was conducted using a retrospective-cohort data of type 2 diabetes mellitus (T2DM) prescribed with second-line drugs on top of metformin, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), thiazolidinediones (TZD) and sulfonylureas (SUs). We applied inverse probability weighting and regression adjustment using intention-to-treat (ITT), per-protocol analysis (PPA) and modified ITT. Average treatment effects (ATE) were estimated using SUs as the reference. Results and Discussion: Among 25,498 patients with T2DM, 17,586 (69.0%), 3,261 (12.8%), 4,399 (17.3%), and 252 (1.0%) received SUs, TZD, DPP4i, and SGLT2i. Median follow-up time was 3.56 (1.36-7.00) years. CVE was identified in 963 patients. The ITT and modified ITT approaches showed similar results; the ATE (i.e., the difference of CVE risks) for SGLT2i, TZD, and DPP4i compared to SUs were -0.020(-0.040, -0.0002), -0.010(-0.017, -0.003), and -0.004(-0.010, 0.002), respectively, indicating 2% and 1% significant absolute risk reduction in CVE in SGLT2i and TZD compared to SUs. These corresponding effects were also significant in the PPA with ATEs of -0.045(-0.060, -0.031), -0.015(-0.026, -0.004), and -0.012(-0.020, -0.004). In addition, SGLT2i had 3.3% significant absolute risk reduction in CVE relative to DPP4i. Our study demonstrated benefits of SGLT2i and TZD in reducing CVE in T2DM patients compared to SUs when added to metformin.

Background: Hypertriglyceridaemia (HTG; defined as =1.7 mmol/L) has a prevalence of 18¿33% with significant inter-regional variation. Despite meta-analysis demonstrating its association with increased risk of cardiovascular disease, only 40% of HTG is identified in the community resulting in underutilisation of lipid-lowering therapy and specialist clinics. An increase in awareness of its clinical risk factors is needed to improve the identification and management of HTG to prevent cardiovascular risk. Aims: To evaluate the prevalence, distribution and clinical predictors of HTG =1.7 mmol/L in a representative community group. Methods: Data were obtained from the Hunter Community Study (HCS), a longitudinal cohort of community-dwelling men and women aged 55-85 years residing in Newcastle, New South Wales. Fasting triglycerides were identified based on the availability of fasting blood glucose level and categorised according to normal (<1.7 mmol/L), mild (1.7 to <2.3 mmol/L) and moderate¿severe HTG (=2.3 mmol/L). Clinical predictors of HTG were assessed using linear and logistic regression models. Results: Of 2536 triglyceride levels, 2216 (87%) were in a fasting state and included in the study. Three hundred and two (13.6%) participants had mild HTG and 221 (10.0%) participants had moderate¿severe HTG. Significant clinical predictors of HTG included male gender, increasing body mass index, current smoking, decreasing daily step counts, increasing fasting glucose and higher thyroid-stimulating hormone. Alcohol intake and blood pressure were not significant in either adjusted regression model. Conclusions: HTG =1.7 mmol/L is common, affecting 24% of the HCS. Clinical predictors identify modifiable risk factors for cardiovascular risk management. Clinician education to promote awareness is required to improve patient outcomes.

Objectives: To develop an automated international classification of diseases (ICD) coding tool using natural language processing (NLP) and discharge summary texts from Thailand. Materials and methods: The development phase included 15,329 discharge summaries from Ramathibodi Hospital from January 2015 to December 2020. The external validation phase included Medical Information Mart for Intensive Care III (MIMIC-III) data. Three algorithms were developed: naïve Bayes with term frequency-inverse document frequency (NB-TF-IDF), convolutional neural network with neural word embedding (CNN-NWE), and CNN with PubMedBERT (CNN-PubMedBERT). In addition, two state-of-the-art models were also considered; convolutional attention for multi-label classification (CAML) and pretrained language models for automatic ICD coding (PLM-ICD). Results: The CNN-PubMedBERT model provided average micro- and macro-area under precision-recall curve (AUPRC) of 0.6605 and 0.5538, which outperformed CNN-NWE (0.6528 and 0.5564), NB-TF-IDF (0.4441 and 0.3562), and CAML (0.6257 and 0.4964), with corresponding differences of (0.0077 and -0.0026), (0.2164 and 0.1976), and (0.0348 and 0.0574), respectively. However, CNN-PubMedBERT performed less well relative to PLM-ICD, with corresponding AUPRCs of 0.7202 and 0.5865. The CNN-PubMedBERT model was externally validated using two subsets of MIMIC-III; MIMIC-ICD-10, and MIMIC-ICD-9 datasets, which contained 40,923 and 31,196 discharge summaries. The average micro-AUPRCs were 0.3745, 0.6878, and 0.6699, corresponding to directly predictive MIMIC-ICD-10, MIMIC-ICD-10 fine-tuning, and MIMIC-ICD-9 fine-tuning approaches; the average macro-AUPRCs for the corresponding models were 0.2819, 0.4219 and 0.5377, respectively. Discussion: CNN-PubMedBERT performed second-best to PLM-ICD, with considerable variation observed between average micro- and macro-AUPRC, especially for external validation, generally indicating good overall prediction but limited predictive value for small sample sizes. External validation in a US cohort demonstrated a higher level of model prediction performance. Conclusion: Both PLM-ICD and CNN-PubMedBERT models may provide useful tools for automated ICD-10 coding. Nevertheless, further evaluation and validation within Thai and Asian healthcare systems may prove more informative for clinical application.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common cause of chronic liver disease and can progress to nonalcoholic steatohepatitis and cirrhosis. This study aims to summarize the evidence for the effects of curcumin on MAFLD progression. Studies were identified from Medline and Scopus databases until April 2022. Systematic reviews and meta-analyses (SRMA) and randomized controlled trials (RCT) were selected based on pre-specified criteria. Three reviewers independently extracted data and assessed quality of included studies. Of the 427 identified records, 6 SRMAs and 16 RCTs were included in the analysis. Very high overlap was observed among SRMAs with corrected covered area of 21.9%. From an updated meta-analysis, curcumin demonstrated significant improvement in aspartate and alanine aminotransferase with pooled mean difference [95% confidence interval (CI)] of -3.90 (-5.97, -1.82) and -5.61 (-9.37, -1.85) units/L, respectively. Resolution and improvement of hepatic steatosis was higher in curcumin than control group with pooled relative risk (95% CI) of 3.53 (2.01, 6.22) and 3.41 (1.36, 8.56), respectively. Curcumin supplementation also led to lower fasting blood sugar, body mass index, and total cholesterol. Further trials should be conducted to assess the effect of curcumin on liver histology, especially regarding non-invasive hepatic fibrosis and steatosis.

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

Background: In the context of ever-growing health expenditure and limited resources, economic evaluations aid in making evidence-informed policy decisions. Cost-utility analysis (CUA) is often used, and CUA data synthesis is also desirable, but methodological issues are challenged. Hence, we aim to provide a step-by-step process to prepare the CUA data for meta-analysis. Methods: Data harmonisation methods were constructed specifically considering CUA methodology, including inconsistent reports, economic parameters, heterogeneity (i.e., country¿s income, time horizon, perspective, modelling approaches, currency, willingness to pay). An incremental net benefit (INB) and its variance were estimated and pooled across studies using a basic meta-analysis by COMER. Results: Five scenarios show how to obtain INB and variance with various reported data: Study reports the mean and variance (Scenario 1) or 95% confidence interval (Scenario 2) of ¿C, ¿E, and ICER for INB/variance calculations. Scenario 3: ¿C, ¿E, and variances are available, but not for the ICER; a Monte Carlo was used to simulate ¿C and ¿E data, variance and covariance can be then estimated leading INB calculation. Scenario-4: Only the CE plane was available, ¿C and ¿E data can be extracted; means of ¿C, ¿E, and variance/covariance can be estimated accordingly, leading to INB/variance estimates. Scenario-5: Only mean cost/outcomes and ICER are available but not for variance and the CE-plane. A variance INB can be borrowed from other studies which are similar characteristics, including country income, ICERs, intervention-comparator, time period, country region, and model type and inputs (i.e., discounting, time horizon). Conclusion: Out data harmonisation and meta-analytic methods should be useful for researchers for the synthesis of economic evidence to aid policymakers in decision making.

Background: Supporting women to achieve healthy gestational weight gain is a global health challenge. Inadequate and excessive gestational weight gains are associated with short and long-term adverse maternal and infant health outcomes. Qualitative studies suggest that symptoms of pregnancy, health professional attitudes, lack of guidance, personal knowledge and beliefs, lack of support, weight stigma, and lack of time and money, are barriers to achieving healthy weight gain. Less is known about women's perceptions and experience of gestational weight gain within normal body mass index categories with even less known about the experience of women motivated to participate in pregnancy weight management intervention trials. Aim: To describe the experience and perspectives of women participating in an Australian weight management pilot randomised controlled trial. Methods: Five women from regional New South Wales enrolled in the Eating 4 Two trial, participated in semi - structured interviews during the post-natal period. A qualitative descriptive methodology and inductive thematic analysis was applied. Findings: Two main themes emerged: 1) Addressing weight gain in pregnancy; and 2) Pregnancy weight the balancing act. Women identified weight gain as an important topic, the need for improvements within maternity services, responsive feedback and realistic support strategies. Women identified pregnancy symptoms, occurring during early and late pregnancy as barriers to achieving healthy weight gain. Conclusion: Further investigation into the effects of pregnancy symptoms on eating and physical activity patterns across pregnancy is warranted. Both qualitative and quantitative research is needed to monitor the translation of guideline recommendations into clinical practice.

Purpose:Microbial keratitis is an urgent condition in ophthalmology that requires prompt treatment. This study aimed to apply deep learning algorithms for rapidly discriminating between fungal keratitis (FK) and bacterial keratitis (BK).Methods:A total of 2167 anterior segment images retrospectively acquired from 194 patients with 128 patients with BK (1388 images, 64.1%) and 66 patients with FK (779 images, 35.9%) were used to develop the model. The images were split into training, validation, and test sets. Three convolutional neural networks consisting of VGG19, ResNet50, and DenseNet121 were trained to classify images. Performance of each model was evaluated using precision (positive predictive value), sensitivity (recall), F1 score (test's accuracy), and area under the precision-recall curve (AUPRC). Ensemble learning was then applied to improve classification performance.Results:The classification performance in F1 score (95% confident interval) of VGG19, DenseNet121, and RestNet50 was 0.78 (0.72-0.84), 0.71 (0.64-0.78), and 0.68 (0.61-0.75), respectively. VGG19 also demonstrated the highest AUPRC of 0.86 followed by RestNet50 (0.73) and DenseNet (0.60). The ensemble learning could improve performance with the sensitivity and F1 score of 0.77 (0.81-0.83) and 0.83 (0.77-0.89) with an AUPRC of 0.904.Conclusions:Convolutional neural network with ensemble learning showed the best performance in discriminating FK from BK compared with single architecture models. Our model can potentially be considered as an adjunctive tool for providing rapid provisional diagnosis in patients with microbial keratitis.

Objectives To assess cost-effectiveness of direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF) by pooling incremental net benefits (INBs). Design Systematic review and meta-analysis. Setting We searched PubMed, Scopus and Centre for Evaluation of Value and Risks in Health Registry from inception to December 2019. Participants Patients with AF. Main outcome measures The INB was defined as a difference of incremental effectiveness multiplied by willing to pay threshold minus the incremental cost; a positive INB indicated favour treatment. These INBs were pooled (stratified by level of country income, perspective, time-horizon, model types) with a random-effects model if heterogeneity existed, otherwise a fixed effects model was applied. Heterogeneity was assessed using Q test and I2 statistic. Risk of bias was assessed using the economic evaluations bias (ECOBIAS) checklist. Results A total of 100 eligible economic evaluation studies (224 comparisons) were included. For high-income countries (HICs) from a third-party payer (TPP) perspective, the pooled INBs for DOAC versus VKA pairs were significantly cost-effective with INBs (95% CI) of $6632 ($2961.67 to $10 303.72; I2=59.9%), $6353.24 ($4076.03 to $8630.45; I2=0%), $7664.58 ($2979.79 to $12 349.37; I2=0%) and $8573.07 ($1877.05 to $15 269.09; I2=0%) for dabigatran, apixaban, rivaroxaban and edoxaban relative to VKA, respectively but only dabigatran was significantly cost-effective from societal perspective (SP) with an INB of $11 746.96 ($2429.34 to $21 064.59; I2=52.4%). The pooled INBs of all comparisons for upper-middle income countries (UMICs) were not significantly cost-effective. The ECOBIAS checklist indicated that risk of bias was mostly low for most items with the exception of five items which should be less influenced on pooling INBs. Conclusions Our meta-analysis provides comprehensive economic evidence that allows policy makers to generalise cost-effectiveness data to their local context. All DOACs may be cost-effective compared with VKA in HICs with TPP perspective. The pooling results produced moderate to high heterogeneity particularly in UMICs. Further studies are required to inform UMICs with SP.

Background and aims: Observational studies have demonstrated that the pneumococcal polysaccharide vaccine (PPV) is associated with reduced risk of cardiovascular events. This may be mediated through IgM antibodies to OxLDL, which have previously been associated with cardioprotective effects. The Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE) is a double-blind, randomised controlled trial (RCT) of PPV in preventing ischaemic events. Participants received PPV or placebo once at baseline and are being followed-up for incident fatal and non-fatal myocardial infarction or stroke over 6 years. Methods: A subgroup of participants at one centre (Canberra; n = 1,001) were evaluated at 1 month and 2 years post immunisation for changes in surrogate markers of atherosclerosis, as pre-specified secondary outcomes: high-sensitive C-reactive protein (CRP), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT). In addition, 100 participants were randomly selected in each of the intervention and control groups for measurement of anti-pneumococcal antibodies (IgG, IgG2, IgM) as well as anti-OxLDL antibodies (IgG and IgM to CuOxLDL, MDA-LDL, and PC-KLH). Results: Concentrations of anti-pneumococcal IgG and IgG2 increased and remained high at 2 years in the PPV group compared to the placebo group, while IgM increased and then declined, but remained detectable, at 2 years. There were statistically significant increases in all anti-OxLDL IgM antibodies at 1 month, which were no longer detectable at 2 years; there was no increase in anti-OxLDL IgG antibodies. There were no significant changes in CRP, PWV or CIMT between the treatment groups at the 2-year follow-up. Conclusions: PPV engenders a long-lasting increase in anti-pneumococcal IgG, and to a lesser extent, IgM titres, as well as a transient increase in anti-OxLDL IgM antibodies. However, there were no detectable changes in surrogate markers of atherosclerosis at the 2-year follow-up. Long-term, prospective follow-up of clinical outcomes is continuing to assess if PPV reduces CVD events.

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

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

Aims This study aims to (1) define the characteristics of patients with a first admission for heart failure (HF), stratified by type (reduced (HFrEF) vs preserved (HFpEF) ejection fraction) in a regional Australian setting; (2) compare the outcomes in terms of mortality and rehospitalisation and (3) assess adherence to the treatment guidelines. Methods We identified all index hospitalisations with HF to John Hunter Hospital and Tamworth Rural Referral Hospital in the Hunter New England Local Health District over a 12 months. We used the recent Australian HF guidelines to classify HFrEF and HFpEF and assess adherence to guideline-directed therapy. The primary outcome of the study was to compare short-term (1 year) and long-term all-cause mortality and the composite of all-cause hospitalisation or all-cause mortality of patients with HFrEF and HFpEF. Results There were 664 patients who had an index HF admission to John Hunter and Tamworth hospitals in 2014. The median age was 80 years, 47% were female and 22 (3%) were Aboriginal. In terms of HF type, 29% had HFrEF, 37% had HFpEF, while the remainder (34%) did not have an echocardiogram within 1 year of admission and could not be classified. The median follow-up was 3.3 years. HFrEF patients were predominantly male (64%) and in 48% the aetiology was ischaemic heart disease. The 1-year all-cause mortality was 23% in HFpEF subgroup and 29% in HFrEF subgroup (p=0.15). Five-year mortality was 61% in HFpEF and HFrEF patients. Of the HFrEF patients, only 61% were on renin-angiotensin-aldosterone blockers, 74% were on ß-blockers and 39% were on aldosterone antagonist. Conclusion HF patients are elderly and about evenly split between HFrEF and HFpEF. In this regional cohort, both HF types are associated with similar 1-year and 5-year mortality following incident HF hospitalisation. Echocardiography and guideline-directed therapies were underused.

Objective: To investigate associations between eating behavior constructs (social eating, perceived competence, habit automaticity, self-determined motivation) and diet quality among young adults. Design: Cross-sectional analysis. Participants: Young adults (n = 1,005; mean age, 21.7 ± 2.0 years; 85% female) enrolled in the Advice, Ideas, and Motivation for My Eating (Aim4Me) study. Main outcome measures: Four eating behavior measures collected via online surveys: Social Eating Scale, Perceived Competence in Healthy Eating Scale, Self-Report Behavioral Automaticity Index, and Regulation of Eating Behaviors scales. Diet quality was assessed using the Australian Recommended Food Score (ARFS) and percentage energy from energy-dense, nutrient-poor (EDNP) foods. Analysis: Multivariate linear regression investigating associations between eating behavior measures (independent variables) and ARFS and EDNP foods (dependent variables), adjusting for sociodemographic and lifestyle confounders. Results: Greater perceived competence in healthy eating and behavioral automaticity for consuming healthy foods, limiting EDNP food intake, and higher intrinsic motivation, integrated regulation, and identified regulation of eating behaviors were associated with higher ARFS and lower percentage energy EDNP foods (P < 0.001). Greater self-reported social influence on eating behaviors was associated with higher ARFS (P = 0.01). Higher amotivation was associated with greater % energy from EDNP foods (P < 0.001). Conclusions and Implications: Perceived competence, habit automaticity, and self-determined motivation are determinants of diet quality in young adults. These findings support the development of interventions that promote healthy eating habits by focusing on eating behavior constructs and evaluating their use in improving diet quality.

Background: no studies have compared the predictive validity of different dementia risk prediction models in Australia. Objectives: (i) to investigate the predictive validity of the Australian National University-Alzheimer's Disease Risk Index (ANU-ADRI), LIfestyle for BRAin Health (LIBRA) Index and cardiovascular risk factors, ageing and dementia study (CAIDE) models for predicting probable dementia/cognitive impairment in an Australian cohort. (ii) To develop and assess the predictive validity of a new hybrid model combining variables from the three models. Methods: the Hunter Community Study (HCS) included 3,306 adults aged 55-85 years with a median follow-up of 7.1 years. Probable dementia/cognitive impairment was defined using Admitted Patient Data Collection, dispensing of cholinesterase inhibitors or memantine, or a cognitive test. Model validity was assessed by calibration and discrimination. A hybrid model was developed using deep neural network analysis, a machine learning method. Results: 120 (3.6%) participants developed probable dementia/cognitive impairment. Mean calibration by ANU-ADRI, LIBRA, CAIDE and the hybrid model was 19, 0.5, 4.7 and 3.4%, respectively. The discrimination of the models was 0.65 (95% CI 0.60-0.70), 0.65 (95% CI 0.60-0.71), 0.54 (95% CI 0.49-0.58) and 0.80 (95% CI 0.78-0.83), respectively. Conclusion: ANU-ADRI and LIBRA were better dementia prediction tools than CAIDE for identification of high-risk individuals in this cohort. ANU-ADRI overestimated and LIBRA underestimated the risk. The new hybrid model had a higher predictive performance than the other models but it needs to be validated independently in longitudinal studies.

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.

Cytomegalovirus (CMV) infection is common in kidney transplantation (KT). Antiviral-agents are used as universal prophylaxis. Our purpose aimed to compare and rank efficacy and safety. MEDLINE, Embase, SCOPUS, and CENTRAL were used from inception to September 2020 regardless language restriction. We included randomized clinical trials (RCTs) comparing the CMV infection/disease prophylaxis among antiviral-agents in adult KT recipients. Of 24 eligible RCTs, prophylactic valganciclovir (VGC) could significantly lower the overall CMV infection and disease risks than placebo with pooled risk differences (RDs) [95% confidence interval (CI)] of -0.36 (-0.54, -0.18) and -0.28 (-0.48, -0.08), respectively. Valacyclovir (VAC) and ganciclovir (GC) significantly decreased risks with the corresponding RDs of -0.25 (-0.32, -0.19) and -0.30 (-0.37, -0.22) for CMV infection and -0.26 (-0.40, -0.12) and -0.22 (-0.31, -0.12) for CMV disease. For subgroup analysis by seropositive-donor and seronegative-recipient (D+/R-), VGC and GC significantly lowered the risk of CMV infection/disease with RDs of -0.42 (-0.84, -0.01) and -0.35 (-0.60, -0.12). For pre-emptive strategies, GC lowered the incidence of CMV disease significantly with pooled RDs of -0.33 (-0.47, -0.19). VGC may be the best in prophylaxis of CMV infection/disease follow by GC. VAC might be an alternative where VGC and GC are not available.

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

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], FEV1, FEV1:FVC%) was assessed periodically during pregnancy using spirometry. Multilevel mixed-effect regression models were used to assess changes in lung function over gestation. Results: Asthma had a significant effect on baseline lung function (FEV1%, -9%; FVC%, -3%; FEV1:FVC%, -4%). FVC% decreased with advancing gestation (-0.07%/wk; 95% CI, -0.10 to -0.04]), as did FEV1%, but only among those without asthma (women without asthma: -0.14%/wk, 95% CI, -0.22 to -0.06%; compared with women with asthma: 0.02%/wk, 95% CI, -0.01 to 0.06). FEV1:FVC% remained relatively stable for women without asthma (0.03%/wk; 95% CI, -0.08 to 0.02), but increased for women with asthma (0.06%/wk; 95% CI, 0.04 to 0.16). Conclusions: Data suggest that advancing gestation negatively affects FVC% and FEV1%. This is consistent with extrapulmonary restriction from advancing pregnancy. Yet, the presence of asthma altered the trajectories of FEV1% and FEV1:FVC%. Optimal asthma management during pregnancy might have opposed the negative effects of gestation on lung function.

It is well established that genetics, environment, and interplay between them play a crucial role in adult disease. We aimed to evaluate the role of genetics, early life nutrition, and the interaction between them, on optimal adult health. As part of a large international consortium (n ~ 154,000), we identified 60 SNPs associated with both birthweight and adult disease. Utilising the Raine Study, we developed a birthweight polygenic score (BW-PGS) based on the 60 SNPs and examined relationships between BW-PGS and adulthood cardiovascular risk factors, specifically evaluating interactions with early life nutrition. Healthy nutrition was beneficial for all individuals; longer duration of any breastfeeding was particularly associated with lower BMI and lower Systolic Blood Pressure in those with higher BW-PGS. Optimal breastfeeding offers the greatest benefit to reduce adult obesity and hypertension in those genetically predisposed to high birthweight. This provides an example of how precision medicine in early life can improve adult health.

Background: Uncontrolled hyperphosphatemia in chronic kidney disease (CKD) patients commonly results in vascular calcification leading to increased risk of cardiovascular disease. Phosphate binders (PBs) are used for hyperphosphatemia and can be calcium-based (CBPBs) or non-calcium-based (NCBPBs), the latter being more expensive than CBPBs. In this study, we used meta-analysis approaches to assess the cost-utility of PBs for hyperphosphatemia in CKD patients. Methods: Relevant studies published prior to June 2019 were identified from PubMed, Scopus, the Cochrane Library, the National Health Service Economic Evaluation Database, and the Cost-Effectiveness Analysis Registry. Studies were eligible if they included CKD patients with hyperphosphatemia, compared any PBs and reported economic outcomes. Meta-analysis was applied to pool incremental net benefit (INB) across studies stratified by country income. Results: A total of 25 studies encompassing 32 comparisons were eligible. Lanthanum carbonate, a NCBPB, was a more cost-effective option than CBPBs in high-income countries (HICs), with a pooled INB of $3984.4 (599.5¿7369.4), especially in pre-dialysis patients and used as a second-line option with INBs of $4860.2 (641.5¿9078.8), $4011.0 (533.7¿7488.3), respectively. Sevelamer, also a NCBPB, was not more cost-effective as a first-line option compared to CBPBs with a pooled INB of $6045.8 (-¿23,453.0 to 35,522.6) and $34,168.9 (-¿638.0 to 68,975.7) in HICs and upper middle-income countries, respectively. Conclusions: Lanthanum carbonate was significantly more cost-effective than CBPBs as a second-line option for hyperphosphatemia in pre-dialysis patients in HICs. However, the use of sevelamer is not more cost-effective as a first-line option compared to CBPBs.

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 cm3) 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.

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-interactionsex = 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.

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 (I2=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.

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 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.

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

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

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¿m2. 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.

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 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

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

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.

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.