Conjoint Associate Professor Mark McEvoy

Among plasma metabolites linked with a health-conscious food pattern (HCFP) identified in the Malmö Diet and Cancer epidemiological study, circulating ergothioneine (ERT) concentrations exhibited the strongest independent association with reduced risk of cardiometabolic disease and all-cause mortality and were also related to alcohol consumption. Thus, we first assessed whether alcohol intake and ERT were similarly associated in participants of the Hunter Community Study (HCS) that did not follow an HCFP-based diet. Then, we sought to identify the presence of associations with some biomarkers associated with cardiovascular disease. In a multivariable adjusted, robust regression analysis, compared to non-drinkers, safe drinkers had, on average, a serum ERT concentration 0.112 (95% CI: 0.0¿0.225; P = 0.051) units higher and moderate-hazardous drinkers had a serum ERT concentration 0.240 (95% CI: 0.093¿0.387; P = 0.001) units higher. Moreover, stepwise multiple linear regression shows that age (P = 0.025), and asymmetric dimethyl-L-arginine (ADMA) (P = 0.001) were independently associated with serum ERT concentrations, independently of age, sex, education, household income, marital status, and health status of participants, or possible alcohol-induced organ damage. The relationship between ERT and ADMA offers a potential explanation for the interplay between ERT, and decreased risk of cardiometabolic disease and all-cause mortality. Also, it provides new mechanistic insights into the association between alcohol consumption and cardiovascular diseases, possibly mediated by ADMA metabolic pathways.

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.

There is a lack of evidence to determine if diet quality is associated with cognitive performance in older adults. Therefore, the aim of this study was to examine whether diet quality is associated with cognitive performance among older adults. A cross-sectional, secondary analysis of baseline data from the Hunter Community Study (HCS), comparing diet quality, measured using the Australian Recommended Food Score (ARFS), along with validated cognitive performance instruments the Audio Recorded Cognitive Screen (ARCS) and the Mini-Mental State Examination (MMSE) were undertaken in adults aged 55¿85 years, living in Newcastle, NSW, Australia. Adjusted linear regression analyses showed that, compared with the lowest ARFS quintile, those in the highest quintile had an ARCS score 5.883 units greater (p < 0.001; R2 = 0.0098). Furthermore, when quintiles of ARFS score were tested against each ARCS sub-scale score, statistically significant associations were observed with the greatest effect for the Memory (ß = 4.055; p = 0.001; R2 = 0.0065) and Attention (ß = 4.136; p = 0.002; R2 = 0.0047) domains. No statistically significant associations were observed between quintiles of ARFS and MMSE score in the adjusted linear regression analyses. In conclusion, a positive association was observed between diet quality and cognitive performance within this sample of older Australian adults. Further investigation of the above association over time, when follow-up data becomes available, in longitudinal analysis is recommended.

Body composition (fat, skeletal muscle and bone mass) is an important determinant of overall health and risk of endocrine disorders such as type 2 diabetes and osteoporosis. Although diet and physical activity are strongly implicated, body composition is also heritable. We conducted a discovery genome-wide association study on 31 phenotypes from the three-compartment body composition model (fat, lean and bone mass) in a set of 4 386 individuals (n = 2 109 males, n = 2 294 females) from the UK Biobank pilot imaging enhancement program that underwent a dual energy X-ray absorptiometry (DXA) scan for assessment of body composition and genetic screening. From 6 137 607 imputed single nucleotide polymorphisms (SNPs) we identified 17 body composition loci (P<5.0 x 10-8). GWAS from the combined dataset identified four statistically significant SNPs (rs7592270, rs145972737, rs13212044, rs77772562). In sex-stratified GWAS, 10 male specific SNPs across all traits were identified and five female specific SNPs. Of the 17 SNPs, six were in or close to a gene where there was a plausible functional connection. Three SNPs (rs7592270, rs77772562 and rs7552312) were correlated with obesity phenotypes, one SNP (rs2236705) with lean phenotypes and two with bone mass phenotypes (rs112098641 and rs113380185). These results highlight candidate genes and biological pathways related to body composition, including glucose metabolism and estrogen regulation, that are of interest to replicate in future studies.

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

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.

Context: Long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFAs) are widely considered as nootropic agents that may be beneficial in reversing cognitive impairment. Objective: The present systematic review of randomized controlled trials was conducted to determine the changes in cognitive function after intervention with LCn-3PUFA supplementation in non-demented adults, including those with mild cognitive impairment. Data Sources: Five databases (MEDLINE, CINAHL, Scopus, EMBASE, and the Cochrane Library) were searched systematically along with reference lists of selected articles. Study Selection: Studies were eligible for inclusion if they measured the effect of LCn-3PUFA supplementation on cognition in non-demented adults. Data Extraction: A total of 787 records were screened, of which 25 studies were eligible for inclusion. Treatment effects were summarized as global cognitive function for primary outcome and measured using the Mini-Mental State Examination and individual cognitive domains for secondary outcome. The pooled effect sizes were estimated using Hedge's g and random-effects modeling. Data Analysis: Results from randomized controlled trials indicate that LCn-3PUFAs have no effect on global cognitive function (Hedge's g = 0.02; 95% confidence interval, -0.12 to 0.154), and among the specific cognitive domains, only memory function showed a mild benefit (Hedge's g = 0.31; P = 0.003; z = 2.945). Conclusion: The existing literature suggests that LCn-3PUFA supplementation could provide a mild benefit in improving memory function in non-demented older adults. Systematic Review Registration: PROSPERO registration no. CRD42017078664.

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.

Objectives:The objective of this review was to pool and rank the efficacy of lifestyle intervention strategies targeting weight, body mass index, waist circumference and waist-to-hip ratio in people with psychosis by comparing the effect size of these weight outcomes. Secondary to this, the objective was to stratify the lifestyle interventions according to their inclusion of dietary information that adheres to Australian Dietary Guidelines.Introduction:People living with psychosis have a significantly increased risk of all-cause mortality, with cardiovascular disease a considerable contributor to this risk. Controlling lifestyle risk factors, which include smoking, poor diet and inadequate physical activity, leads to significant weight reduction and decreases cardiovascular disease risk. Previous reviews on this topic have not clearly identified essential components of lifestyle interventions in people with psychosis, mainly due to statistical limitations of analyses. This review employed a network meta-analysis, which compares more than two groups of interventions and ranks them according to efficacy, thus providing a global estimate of effect. Additionally, available reviews have not assessed compliance of dietary information offered in lifestyle interventions to established guidelines.Inclusion criteria:This review considered randomized controlled trials that delivered lifestyle interventions to community-dwelling adults with psychotic disorders. Outcomes of interest included weight, body mass index, waist circumference and waist-to-hip ratio.Methods:The Cochrane Library, MEDLINE/PreMEDLINE, Embase, CINAHL, Scopus and PsycINFO were searched for studies published in English from 1985 to June 2018. Data were qualitatively summarized, during which lifestyle intervention subgroups were created (based on key similarities) and then compared in direct meta-analyses and network meta-analyses. Assessment of study adherence to Australian Dietary Guidelines was conducted in a narrative format.Results:Thirty-two randomized controlled trials were included, and the overall quality of these studies ranged from what appeared to be low to moderate. Lifestyle intervention studies contained both a dietary and physical activity component, with the exception of two studies that focused solely on physical activity. Delivery of dietary and physical activity information was mainly through education; however, some studies provided additional structure to the intervention by offering tailored advice or helping participants to set goals, and providing regular review of progress for diet, physical activity or both. Results from network-meta-analyses showed that only studies with a structured approach for both diet and physical activity demonstrated significant decreases in weight (effect size =-4.12, 95% confidence interval =-7.772 to-2.760, P = 0.000) and body mass index (effect size =-2.94, 95% confidence interval =-1.78 to-0.357, P = 0.003). Waist circumference subgroup comparisons mainly comprised single studies; therefore, findings were inconclusive. Dietary information provided in studies generally complied with Australian Dietary Guidelines; however, none of the studies complied with all guidelines.Conclusions:Lifestyle interventions incorporating both dietary and physical activity components led to the greatest decreases in weight (4.1 kg) and body mass index (2.9 points) among people with psychosis. Important intervention strategies for both components are the personalization of education through tailored advice or goal setting, and a corresponding progress review. Dietary information in the included studies appeared to comply with the Australian Dietary Guidelines. However, these findings were weakened by an increased risk of bias, complex and multicomponent study designs, and lack of clarity in reporting of study methodology.

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.

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.

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.

The elucidation of the metabolic pathways of the amino acid arginine and their role in health and disease have been an intensive focus of basic and clinical research for over a century. The recent advent of robust analytical techniques for biomarker assessment in large population cohorts has allowed the investigation of the pathophysiological role of specific arginine metabolites in key chronic disease states in old age, particularly those characterised by a reduced synthesis of endothelial nitric oxide, with consequent vascular disease and atherosclerosis. Two arginine metabolites have been increasingly studied in regard to their potential role in risk stratification and in the identification of novel therapeutic targets: the methylated arginine asymmetric dimethylarginine (ADMA) and the arginine analogue homoarginine. Higher circulating concentrations of ADMA, a potent inhibitor of nitric oxide synthesis, have been shown to predict adverse cardiovascular outcomes. By contrast, there is emerging evidence that homoarginine might exert cardioprotective effects. This review highlights recent advances in the biological and clinical role of ADMA and homoarginine in cardiovascular disease and other emerging fields, particularly chronic obstructive pulmonary disease, dementia, and depression. It also discusses opportunities for future research directions with the ultimate goal of translating knowledge of arginine metabolism, and its role in health and disease, into the clinical care of older adults.

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.

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.

Diabetes affects 9.8% of Australian women. Breakfast cereal consumption is potentially protective against diabetes. This study investigated the effects of breakfast cereal consumption on the 12-year risk of developing diabetes among mid-aged participants of the Australian Longitudinal Study of Women's Health (ALSWH). It was hypothesized that any breakfast cereal and higher-fiber breakfast cereals would be protective against the risk of developing diabetes. Data from Survey 3 (S3) to Survey 7 (S7) inclusive, from the 1946-51 ALSWH cohort were analyzed. Dietary data were obtained at S3 and the outcome was incident diabetes between S4-S7. Women were excluded if: they reported existing diabetes or impaired glucose tolerance at S3; dietary data were incomplete; or daily energy intake was <4,500 or >20,000 kJ. Logistic regression with discrete time survival analyses investigated the association between breakfast cereal intake and incident diabetes. Models were adjusted for income, BMI, smoking, physical activity, education, and dietary intakes and included a measure of time. There were 637 incident cases of diabetes. Breakfast cereal intake per se was not associated with incident diabetes (OR: 1.00; P =.98). Muesli consumption on its own (OR: 0.74; P =.00) or as a part of oats-based cereal (OR: 0.84; P =.047) was significantly associated with a decrease in the odds of developing diabetes. No other breakfast cereals were significantly associated with diabetes risk. Among mid-aged Australian women, muesli consumption was associated with a reduction in diabetes risk. This effect may be due to a particular profile of muesli eaters, but the relationship warrants further investigation.

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.

Objective:Age-related hearing loss is associated with endothelial dysfunction and increased cardiovascular risk, suggesting a vascular etiology. Methylarginines are endogenous nitric oxide synthase inhibitors that cause endothelial dysfunction and increase cardiovascular disease risk. This study is the first to examine the hypothesis that higher serum concentrations of methylarginines are associated with greater hearing loss prevalence.Study Design/Patients:Cross-sectional audiometric data on hearing levels, and serum methylarginines were collected from a population-based sample of 630 older community-dwelling adults.Results:Linear regression analysis showed a statistically significant association between higher serum concentrations of asymmetric dimethylarginine (ADMA) and L-arginine and greater degrees of hearing loss for males, particularly over 75 years. Higher body mass index and previous history of stroke were also associated with hearing loss. For females, ADMA concentration was not associated with hearing loss, but higher serum L-arginine concentrations were associated with reduced hearing loss prevalence in older females. Antihypertensive medication use was also associated with reduced hearing loss prevalence. LDL cholesterol and previous myocardial infarction were associated with greater hearing loss.Conclusion:This study showed a significant association between serum concentrations of ADMA and hearing loss for males, consistent with the association between endothelial dysfunction and hearing loss. The opposite effect of L-arginine on hearing loss in males versus females might reflect a different role of this precursor toward nitric oxide versus methylated arginines synthesis. These findings are potentially clinically significant if the association between ADMA and hearing loss is causal, as serum methylarginine levels are modifiable through pharmacotherapeutic/lifestyle interventions.

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

This analysis aimed to examine the association of social dysfunction with food security status, fruit intake, vegetable intake, meal frequency and breakfast consumption in people with psychosis from the Hunter New England (HNE) catchment site of the Survey of High Impact Psychosis (SHIP). Social dysfunction and dietary information were collected using standardised tools. Independent binary logistic regressions were used to examine the association between social dysfunction and food security status, fruit intake, vegetable intake, meal frequency and breakfast consumption. Although social dysfunction did not have a statistically significant association with most diet variables, participants with obvious to severe social dysfunction were 0.872 (95% CI (0.778, 0.976)) less likely to eat breakfast than those with no social dysfunction p < 0.05. Participants with social dysfunction were therefore, 13% less likely to have breakfast. This paper highlights high rates of social dysfunction, significant food insecurity, and intakes of fruits and vegetables below recommendations in people with psychosis. In light of this, a greater focus needs to be given to dietary behaviours and social dysfunction in lifestyle interventions delivered to people with psychosis. Well-designed observational research is also needed to further examine the relationship between social dysfunction and dietary behaviour in people with psychosis.

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

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

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

Background and aims Despite worldwide reductions in active smoking, non-smokers continue to be exposed to environmental tobacco smoke, especially at home or workplace. There is a well-recognised association between active smoking and peripheral arterial disease, however, a relationship to environmental tobacco smoke exposure is less substantiated. The aims of this paper are to review the literature regarding the association between environmental tobacco smoke and peripheral arterial disease and identify the public health implications of the findings. Methods Selected electronic databases (Medline, EMBASE, CINAHL, PsychINFO and Scopus) were searched for studies published up to August 2017. Key words and inclusion/exclusion criteria applied. A manual search of reference lists of studies selected for review was also performed. Results Of the initial 150 studies identified, 12 met inclusion criteria for review. Three studies showed a positive association between environmental tobacco smoke exposure and definitive diagnosis of peripheral arterial disease, 6 studies demonstrated a positive association with features of vascular injury, and 3 studies found no significant positive or negative association. Conclusions An association between exposure to environmental tobacco smoke and development of peripheral arterial disease or clinically significant arterial injury in non-smokers is supported by moderate quality evidence in the literature. Larger, longitudinal observational studies addressing current limitations, including sources of bias, inconsistency and imprecision, are needed to provide more robust and consistent evidence. Regardless, evidence of potential detrimental impacts supports ongoing restrictions on freedom to smoke in public areas, including the workplace, and has implications for those exposed in the home environment.

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

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

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

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

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

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

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

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

Iron deficiency (ID) is the most prevalent nutrient deficiency within the developed world. This is of concern as ID has been shown to affect immunity, thermoregulation, work performance and cognition. Animal flesh foods provide the richest and most bioavailable source of dietary (haem) iron, however, it is unclear whether low animal flesh diets contribute to ID. This systematic review aimed to investigate whether a higher consumption of animal flesh foods is associated with better iron status in adults. CINAHL, Cochrane, EMBASE and MEDLINE were searched for published studies that included adults (¥18 years) from developed countries and measured flesh intakes in relation to iron status indices. Eight experimental and 41 observational studies met the inclusion criteria. Generally, studies varied in population and study designs and results were conflicting. Of the seven high quality studies, five showed a positive association between animal flesh intake (85¿300 g/day) and iron status. However, the optimum quantity or frequency of flesh intake required to maintain or achieve a healthy iron status remains unclear. Results show a promising relationship between animal flesh intake and iron status, however, additional longitudinal and experimental studies are required to confirm this relationship and determine optimal intakes to reduce ID development.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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