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Abstract Background Little data exists on the factors associated with health care seeking behaviour for primary symptoms of colorectal cancer (CRC). This study aimed to identify individual, provider and psychosocial factors associated with (i) ever seeking medical advice and (ii) seeking early medical advice for primary symptoms of colorectal cancer (CRC). Methods 1592 persons aged 56–88 years randomly selected from the Hunter Community Study (HCS) were sent a questionnaire. Results Males and those who had received screening advice from a doctor were at significantly higher odds of ever seeking medical advice for rectal bleeding. Persons who had private health coverage, consulted a doctor because the ‘symptom was serious’, or who did not wait to consult a doctor for another reason were at significantly higher odds of seeking early medical advice (< 2 weeks). For change in bowel habit, persons with lower income, within the healthy weight range, or who had discussed their family history of CRC irrespective of whether informed of ‘increased risk’ were at significantly higher odds of ever seeking medical advice. Persons frequenting their GP less often and seeing their doctor because the symptom persisted were at significantly higher odds of seeking early medical advice (< 2 weeks). Conclusions The seriousness of symptoms, importance of early detection, and prompt consultation must be articulated in health messages to at-risk persons. This study identified modifiable factors, both individual and provider-related to consultation behaviour. Effective health promotion efforts must heed these factors and target sub-groups less likely to seek early medical advice.

Abstract Background Chronic exposure to high level of inorganic arsenic in drinking water has been associated with Type 2 Diabetes (T2D). Most research has been ecological in nature and has focused on high levels of arsenic exposure with few studies directly measuring arsenic levels in drinking water as an index of arsenic exposure. The effect of low to moderate levels of arsenic exposure on diabetes risk is largely unknown thus our study is adding further knowledge over previous works. Methods This cross sectional study was conducted in 1004 consenting women and men from 1682 eligible participants yielding a participation rate of 60%. These participants are aged >30 years and were living in Bangladesh and had continuously consumed arsenic-contaminated drinking water for at least 6 months. T2D cases were diagnosed using glucometer following the new diagnostic criteria (Fasting Blood Glucose > 126 mg/dl) from the WHO guideline (WHO 2006), or a self-reported physician diagnosis of type 2 diabetes. Association between T2D and chronic arsenic exposure was estimated by multiple logistic regression with adjustment for age, sex, education, Body Mass Index (BMI) and family history of T2D. Results A total of 1004 individuals participated in the study. The prevalence of T2D was 9% (95% CI 7-11%). After adjustment for diabetes risk factors, an increased risk of type 2 diabetes was observed for arsenic exposure over 50 μg/L with those in the highest category having almost double the risk of type 2 diabetes (OR=1.9 ; 95% CI 1.1-3.5). For most levels of arsenic exposure, the risk estimates are higher with longer exposure; a dose–response pattern was also observed. Conclusions These findings suggest an association between chronic arsenic exposure through drinking water and T2D. Risks are generally higher with longer duration of arsenic exposure. The risk of T2D is highest among those who were exposed to the highest concentration of arsenic for more than 10 years.

Abstract Background Family history is a common risk factor for colorectal cancer (CRC), yet it is often underused to guide risk assessment and the provision of risk-appropriate CRC screening recommendation. The aim of this study was to identify from a patient perspective health care providers' current practice relating to: (i) assessment of family history of CRC; (ii) notification of "increased risk" to patients at "moderately/potentially high" familial risk; and (iii) recommendation that patients undertake CRC screening. Methods 1592 persons aged 56-88 years randomly selected from the Hunter Community Study (HCS), New South Wales, Australia were mailed a questionnaire. 1117 participants (70%) returned a questionnaire. Results Thirty eight percent of respondents reported ever being asked about their family history of CRC. Ever discussing family history of CRC with a health care provider was significantly more likely to occur for persons with a higher level of education, who had ever received screening advice and with a lower physical component summary score. Fifty one percent of persons at "moderately/potentially high risk" were notified of their "increased risk" of developing CRC. Thirty one percent of persons across each level of risk had ever received CRC screening advice from a health care provider. Screening advice provision was significantly more likely to occur for persons who had ever discussed their family history of CRC with a health care provider and who were at "moderately/potentially high risk". Conclusions Effective interventions that integrate both the assessment and notification of familial risk of CRC to the wider population are needed. Systematic and cost-effective mechanisms that facilitate family history collection, risk assessment and provision of screening advice within the primary health care setting are required.

Abstract Background Training in the five steps of evidence-based practice (EBP) has been recommended for inclusion in entry-level health professional training. The effectiveness of EBP education has been explored predominantly in the medical and nursing professions and more commonly in post-graduate than entry-level students. Few studies have investigated longitudinal changes in EBP attitudes and behaviours. This study aimed to assess the changes in EBP knowledge, attitudes and behaviours in entry-level physiotherapy students transitioning into the workforce. Methods A prospective, observational, longitudinal design was used, with two cohorts. From 2008, 29 participants were tested in their final year in a physiotherapy program, and after the first and second workforce years. From 2009, 76 participants were tested in their final entry-level and first workforce years. Participants completed an Evidence-Based Practice Profile questionnaire (EBP2), which includes self-report EBP domains [Relevance, Terminology (knowledge of EBP concepts), Confidence, Practice (EBP implementation), Sympathy (disposition towards EBP)]. Mixed model analysis with sequential Bonferroni adjustment was used to analyse the matched data. Effect sizes (ES) (95% CI) were calculated for all changes. Results Effect sizes of the changes in EBP domains were small (ES range 0.02 to 0.42). While most changes were not significant there was a consistent pattern of decline in scores for Relevance in the first workforce year (ES -0.42 to -0.29) followed by an improvement in the second year (ES +0.27). Scores in Terminology improved (ES +0.19 to +0.26) in each of the first two workforce years, while Practice scores declined (ES -0.23 to -0.19) in the first year and improved minimally in the second year (ES +0.04). Confidence scores improved during the second workforce year (ES +0.27). Scores for Sympathy showed little change. Conclusions During the first two years in the workforce, there was a transitory decline in the self-reported practice and sense of relevance of EBP, despite increases in confidence and knowledge. The pattern of progression of EBP skills beyond these early professional working years is unknown.

Abstract Background Most previous studies of allied health professionals' evidence based practice (EBP) attitudes, knowledge and behaviours have been conducted with profession specific questionnaires of variable psychometric strength. This study compared the self-report EBP profiles of allied health professionals/trainees in an Australian university. Methods The Evidence-Based Practice Profile (EBP2) questionnaire assessed five domains (Relevance, Terminology, Practice, Confidence, Sympathy) in 918 subjects from five professional disciplines. One and 2-way factorial analysis of variance (ANOVA) and t-tests analysed differences based on prior exposure to EBP, stage of training, professional discipline, age and gender. Results There were significant differences between stages of training (p < 0.001) for all domains and between EBP exposure groups for all but one domain (Sympathy). Professional discipline groups differed for Relevance, Terminology, Practice (p < 0.001) and Confidence (p = 0.006). Males scored higher for Confidence (p = 0.002) and females for Sympathy (p = 0.04), older subjects (> 24 years) scored higher for all domains (p < 0.05). Age and exposure affected all domains (p < 0.02). Differences in stages of training largely explained age-related differences in Confidence and Practice (p ≤ 0.001) and exposure-related differences in Confidence, Practice and Sympathy (p ≤ 0.023). Conclusions Across five allied health professions, self-report EBP characteristics varied with EBP exposure, across stages of training, with profession and with age.

Abstract Background Endometrial cancer is the most common gynaecological malignancy in women of developed countries. Many risk factors implicated in endometrial cancer trigger inflammatory events; therefore, alterations in immune response may predispose an individual to disease. Toll-like receptors (TLRs) and nucleosome-binding oligomerization domain (NOD) genes are integral to the recognition of pathogens and are highly polymorphic. For these reasons, the aim of the study was to assess the frequency of polymorphic variants in TLR and NOD genes in an Australian endometrial cancer population. Methods Ten polymorphisms were genotyped in 191 endometrial cancer cases and 291 controls using real-time PCR: NOD1 (rs2075822, rs2907749, rs2907748), NOD2 (rs5743260, rs2066844, rs2066845), TLR2 (rs5743708), TLR4 (rs4986790) and TLR9 (rs5743836, rs187084). Results Haplotype analysis revealed that the combination of the variant alleles of the two TLR9 polymorphisms, rs5743836 and rs187084, were protective for endometrial cancer risk: OR 0.11, 95% CI (0.03-0.44), p = 0.002. This result remained highly significant after adjustment for endometrial cancer risk factors and Bonferroni correction for multiple testing. There were no other associations observed for the other polymorphisms in TLR2, TLR4, NOD1 and NOD2. Conclusions The variant 'C' allele of rs5743836 causes greater TLR9 transcriptional activity compared to the 'T' allele, therefore, higher TLR9 activity may be related to efficient removal of microbial pathogens within the endometrium. Clearly, the association of these TLR9 polymorphisms and endometrial cancer risk must be further examined in an independent population. The results point towards the importance of examining immune response in endometrial tumourigenesis to understand new pathways that may be implicated in disease.

Abstract Background Cyclin D1 is integral for the G1 to S phase of the cell cycle as it regulates cellular proliferation. A polymorphism in cyclin D1, 870 G>A, causes overexpression and supports uncontrollable cellular growth. This polymorphism has been associated with an increased risk of developing many cancers, including endometrial cancer. Methods The 870 G>A polymorphisms (rs605965) in the cyclin D1 gene was genotyped in an Australian endometrial cancer case-control population including 191 cases and 291 controls using real-time PCR analysis. Genotype analysis was performed using chi-squared (χ2) statistics and odds ratios were calculated using unconditional logistic regression, adjusting for potential endometrial cancer risk factors. Results Women homozygous for the variant cyclin D1 870 AA genotype showed a trend for an increased risk of developing endometrial cancer compared to those with the wild-type GG genotype, however this result was not statistically significant (OR 1.692 95% CI (0.939–3.049), p = 0.080). Moreover, the 870 G>A polymorphism was significantly associated with family history of colorectal cancer. Endometrial cancer patients with the homozygous variant AA genotype had a higher frequency of family members with colorectal cancer in comparison to endometrial cancer patients with the GG and combination of GG and GA genotypes (GG versus AA; OR 2.951, 95% CI (1.026–8.491), p = 0.045, and GG+GA versus AA; OR 2.265, 95% CI (1.048–4.894), p = 0.038, respectively). Conclusion These results suggest that the cyclin D1 870 G>A polymorphism is possibly involved in the development of endometrial cancer. A more complex relationship was observed between this polymorphism and familial colorectal cancer.

Abstract Background Correct upright posture is considered to be a measure of good musculoskeletal health. Little is known about the usual variability of children's upright standing posture. The aim of this study was to assess differences between repeated measures of upright posture in a group of primary school children. Methods Sagittal plane photographs of usual, relaxed upright standing posture of 38 boys and girls aged 5–12 years were taken twice within an hour. Reflective markers were placed over the canthus, tragus, C7 spinous process, greater trochanter and lateral malleolus. Digitising software was used to calculate the x,y plane coordinates, from which five postural angles were calculated (trunk, neck, gaze, head on neck, lower limb). Height, weight, motor control estimates (as measured by the Brace Tests) and presence of recent pain were recorded for each child, and the association between the first test measure of posture angles and these factors was assessed using linear regression and ANOVA models. Multiple ANOVA models were applied to analyse the effect of repeated testing, and significant predictors on the angles. Results Four of the five postural angles (trunk, neck, head on neck, lower limb) were significantly influenced by age. As age was strongly associated with height (r2 = 0.84) and moderately associated with weight and motor control (r2 = 0.67, 0.56 respectively), these developmental parameters may well explain the age effect on angles. There was no relationship between age and pain reported on either the testing day, or recently, and there was no gender influence on any angle. There was no significant effect of repeated testing on any angle (ICC>0.93). None of the hypothesized predictors were associated with differences in angles from repeated testing. Conclusion This study outlined the variability of relaxed upright standing posture of children aged 5–12 years, when measured twice in an hour. Age influenced the size of the angles but not the variability. While the subject numbers in this study are small, the findings provide useful information on which further studies in posture and its development in pre-adolescent children can be based.

Abstract Background The on call service for health protection in most parts of the UK is provided by general public health consultants, registrars and nurses as the first tier of response backed up by medical consultants in health protection. The first tier responder usually carries a large bag of papers containing both local and national guidance on the management of common cases/incidents. An electronic on call pack may provide a suitable practical alternative to large paper based systems and help professionals deliver out of hours health protection advice and response to incidents. Methods We developed and piloted an electronic on call pack in Hertfordshire for use at the health protection unit level containing key local and national guidelines, contact information and useful references. The on-call pack was initially piloted using a laptop and more recently using a personal digital assistant (PDA). The use of the on-call pack was evaluated. Results Key advantages of the electronic system include reduced size, faster access to information that is clearly indexed and the relative ease of updating information. As part of the pilot, the electronic on call pack was presented to a local and regional training meeting with good response from participants using qualitative and quantitative methods. Conclusion It is anticipated that with suitable evaluation this system can be adapted and utilised by other health protection practitioners. This system provides a fast, reliable and easily maintained source of information for the public health on-call team.

Background: Hypertension is a key risk factor for major adverse cardiovascular events but remains difficult to treat in many individuals. Dietary interventions are an effective approach to lower blood pressure (BP) but are not equally effective across all individuals. BP is heritable, and genetics may be a useful tool to overcome treatment response heterogeneity. We investigated whether the genetics of BP could be used to identify individuals with hypertension who may receive a particular benefit from lowering sodium intake and boosting potassium levels., Methods: In this observational genetic study, we leveraged cross-sectional data from up to 296 475 genotyped individuals drawn from the UK Biobank cohort for whom BP and urinary electrolytes (sodium and potassium), biomarkers of sodium and potassium intake, were measured. Biologically directed genetic scores for BP were constructed specifically among pathways related to sodium and potassium biology (pharmagenic enrichment scores), as well as unannotated genome-wide scores (conventional polygenic scores). We then tested whether there was a gene-by-environment interaction between urinary electrolytes and these genetic scores on BP., Results: Genetic risk and urinary electrolytes both independently correlated with BP. However, urinary sodium was associated with a larger BP increase among individuals with higher genetic risk in sodium- and potassium-related pathways than in those with comparatively lower genetic risk. For example, each SD in urinary sodium was associated with a 1.47-mm Hg increase in systolic BP for those in the top 10% of the distribution of genetic risk in sodium and potassium transport pathways versus a 0.97-mm Hg systolic BP increase in the lowest 10% ( P =1.95×10 -3 ). This interaction with urinary sodium remained when considering estimated glomerular filtration rate and indexing sodium to urinary creatinine. There was no strong evidence of an interaction between urinary sodium and a standard genome-wide polygenic score of BP., Conclusions: The data suggest that genetic risk in sodium and potassium pathways could be used in a precision medicine model to direct interventions more specifically in the management of hypertension. Intervention studies are warranted., Competing Interests: Disclosures Drs Reay and Cairns have filed a patent related to the use of the pharmagenic enrichment score framework in complex disorders (WIPO patent application WO/2020/237314), an approach used in a section of this study. Dr Cairns is director of a company that aims to commercialize the pharmagenic enrichment score platform (PolygenRx Pty Ltd), in which Dr Reay holds equity. The remaining authors declare no competing financial interests.

Objective: Irritable bowel syndrome (IBS) is a chronic disorder associated with an abnormal gastrointestinal microbiome. Microbiome-host interactions are known to influence organ function including in the central nervous system; thus, we sought to identify whether IBS may be a risk factor for the development of glaucoma., Design: Two prospective cohort studies., Subjects: The 1958 United Kingdom Birth Cohort (UKBC; 9091 individuals) and the Danish National Registry of Patients (DNRP; 62,541 individuals with IBS and 625,410 matched general population cohort members)., Methods: In the UKBC, participants were surveyed throughout life (including at ages 42 and 50). The DNRP contains records of hospital-based contacts and prescription data from the national prescription database., Main Outcome Measure: The main outcome measure was incidence of glaucoma. In the UKBC, incident glaucoma at age 50 (n = 48) was determined through comparison of survey responses at ages 42 and 50 years. In the DNRP, glaucoma was assessed by hospital diagnosis (n = 1510), glaucoma surgery (n = 582) and initiation of glaucoma medications (n = 1674)., Results: In the UKBC, the odds ratio (OR) of developing glaucoma between ages 42 and 50 in persons with a chronic IBS diagnosis was increased [OR: 5.84, 95% confidence interval (CI): 2.26-15.13]. People with an IBS diagnosis in the DNRP had a hazard ratio (HR) of 1.35 for developing physician-diagnosed glaucoma (95% CI: 1.16-1.56), an HR of 1.35 for undergoing glaucoma surgery (95% CI: 1.06-1.70) and an HR of 1.19 for initiating glaucoma medication (95% CI: 1.03-1.38)., Conclusions: In two large European cohort studies, IBS is a risk factor for glaucoma., (© 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

BACKGROUND & AIMS: Nitric oxide, a major inhibitory nonadrenergic, noncholinergic neurotransmitter that relaxes smooth muscle, may be implicated in the pathophysiology of visceral hypersensitivity in irritable bowel syndrome (IBS). Impaired bioavailability of the nitric oxide precursor molecule L-arginine and higher concentrations of methylarginines (endogenous inhibitors of nitric oxide synthesis) are known to impair nitric oxide synthesis in numerous gastrointestinal cell types. We therefore examined serum concentrations of L-arginine and the methylarginines in a nested case-control study, to assess whether these factors are associated with adult IBS., Methods: Data on clinical characteristics, methylarginines, and L-arginine (measured using LC-MS/MS) were collected from a random population-based cohort of Australian adults (median age = 64 years; IQR = 60-70). Cases of IBS, defined according to Rome III criteria (N = 156), and controls (N = 332) were identified from within the cohort at the 5-year follow-up., Results: In adjusted logistic regression analyses, L-arginine, asymmetric dimethylarginine, symmetric dimethylarginine, L-arginine/asymmetric dimethylarginine ratio, and Kessler-10 psychological distress scores were significantly associated with IBS (p < 0.05). [Correction added on 18 September 2021, after first online publication: In the preceding sentence, the value (p > 0.05) has been changed to (p < 0.05)]. Similar results were found for IBS subtypes. Higher serum L-arginine concentration had the strongest association with IBS diagnosis, with an odds ratio of 9.03 for those with serum L-arginine at the 75th (84 μmol/L) versus 25th (46 μmol/L) percentile (95% CI: 5.99-13.62). L-arginine had the best discriminative ability with a bias-adjusted area under the receiver operator characteristic curve of 0.859., Conclusions: Higher serum concentrations of L-arginine and endogenous methylarginines are strongly associated with IBS in adults., (© 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Measures of lung function are heritable, and thus, we sought to utilise genetics to propose drug-repurposing candidates that could improve respiratory outcomes. Lung function measures were found to be genetically correlated with seven druggable biochemical traits, with further evidence of a causal relationship between increased fasting glucose and diminished lung function. Moreover, we developed polygenic scores for lung function specifically within pathways with known drug targets and investigated their relationship with pulmonary phenotypes and gene expression in independent cohorts to prioritise individuals who may benefit from particular drug-repurposing opportunities. A transcriptome-wide association study (TWAS) of lung function was then performed which identified several drug-gene interactions with predicted lung function increasing modes of action. Drugs that regulate blood glucose were uncovered through both polygenic scoring and TWAS methodologies. In summary, we provided genetic justification for a number of novel drug-repurposing opportunities that could improve lung function., Competing Interests: WR, MC has filed a patent related to the use of the pharmagenic enrichment score methodology in complex disorders. This competing interest only applies to that section of the manuscript. WIPO Patent Application WO/2020/237314. SE, MG, CR, EH, MM, SH, RP, RS, JA No competing interests declared, (© 2021, Reay et al.)

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; R 2 = 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 (β = 4.055; p = 0.001; R 2 = 0.0065) and Attention (β = 4.136; p = 0.002; R 2 = 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.

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.

The consumption of nitrate-rich vegetables can acutely lower blood pressure and improve mediators shown to optimise vascular health. However, we do not yet understand the impact of long-term habitual dietary nitrate intake and its association with CVD. Therefore, the aim of this investigation was to examine the relationship between habitual dietary nitrate intakes and risk of CHD in women from the Nurses' Health Study. We prospectively followed 62 535 women who were free from diabetes, CVD and cancer at baseline in 1986. Information on diet was updated every 4 years with validated FFQ. The main outcome was CHD defined by the occurrence of non-fatal myocardial infarction or fatal CHD. Cox proportional hazard regression models were used to estimate the relative risks (RR) and 95 % CI. During 26 years of follow-up, 2257 cases of CHD were identified. When comparing the highest quintile of nitrate intake with the lowest quintile, in aged-adjusted analysis there was a protective association for CHD (RR=0·77, 95 % CI 0·68, 0·97; P=0·0002) which dissipated after further adjustment for smoking, physical activity, BMI and race (RR=0·91; 95 % CI 0·80, 1·04; P=0·27). This magnitude of association was further attenuated once we adjusted for the Alternative Healthy Eating Index excluding vegetable and fruit consumption (RR=1·04, 95 % CI 0·91, 1·20; P=0·34). Dietary nitrate intake was not related to the risk of CHD after adjustment for other lifestyle and non-vegetable dietary factors in a large group of US women.

Nitric oxide (NO) facilitates anti-atherosclerotic effects. Vegetables are a major source of dietary nitrate. Experimental data indicates that dietary nitrate can significantly reduce major risk factors for atherosclerosis and subsequent cardiovascular disease (CVD), as nitrate can be metabolized to produce NO via the nitrate-nitrite-NO pathway. The purpose of this study was to prospectively investigate the association between habitual dietary nitrate intakes and the incidence of self-reported CVD-related complications within a representative sample of middle-aged Australian women (1946⁻1951 cohort of the Australian Longitudinal Study on Women's Health). Women free from disease at baseline who had completed the food frequency questionnaire data were included. Generalized estimating equations were used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) across quartiles for nitrate intakes. Of the 5324 women included for analysis, there were 1951 new cases of CVD-related complications over 15-years of follow-up. Women reporting higher total dietary nitrate intakes (Q4 > 78.2 mg/day) and vegetable nitrate intakes (Q4 > 64.4 mg/day) were 25% and 27% reduced risk of developing CVD-related complications respectively, compared with women reporting low total (Q1 < 45.5 mg/day) and vegetable nitrate intakes (Q1 < 34.8 mg/day). Our findings were consistent with other observational data indicating that dietary nitrate may explain some of the cardiovascular benefits of vegetable consumption., Competing Interests: The authors declare no conflict of interest.

We describe a robotic material that tightly integrates sensing, actuation, computation, and communication to perform autonomous shape change. The composite consists of multiple cells, each with the ability to control their local stiffness (by Joule heating of a thermoplastic) and communicate with their local neighbors. We also present a distributed algorithm for calculating the inverse kinematic solution of the resulting N-body system by iteratively solving a series of problems with reduced kinematics. We describe material design choices, mechanism design, algorithm, and manufacturing, emphasizing the interdisciplinary codesign problem that robotic materials pose, and demonstrate the results from a series of shape-changing experiments.

Dietary nitrate is increasingly linked to a variety of beneficial health outcomes. Our purpose was to estimate dietary nitrate consumption and identify key dietary changes which have occurred over time within a representative sample of Australian women. Women from the 1946⁻1951 cohort of the Australian Longitudinal Study on Women's Health with complete food frequency questionnaire data for both 2001 and 2013 were included for analysis. Dietary nitrate intakes were calculated using key published nitrate databases. Diet quality scores including the Australian Recommended Food Score, the Mediterranean Diet Score and the Nutrient Rich Foods Index were calculated along with food group serves as per the Australian Dietary Guidelines. Wilcoxon matched pairs tests were used to test for change in dietary intakes and Spearman's correlations were used to examine associations. In our sample of 8161 Australian women, dietary nitrate intakes were on average 65⁻70 mg/day, and we detected a significant increase in dietary nitrate consumption over time (+6.57 mg/day). Vegetables were the primary source of dietary nitrate (81⁻83%), in particular lettuce (26%), spinach (14⁻20%), beetroot (10⁻11%), and celery (7⁻8%) contributed primarily to vegetable nitrate intakes. Further, increased dietary nitrate intakes were associated with improved diet quality scores ( r = 0.3, p < 0.0001). Although there is emerging evidence indicating that higher habitual dietary nitrate intakes are associated with reduced morbidity and mortality, future work in this area should consider how dietary nitrate within the context of overall diet quality can facilitate health to ensure consistent public health messages are conveyed.

Context: Depleted nitric oxide levels in the human body play a major role in cardiovascular disease pathogenesis. Inorganic nitrate/nitrite (rich dietary sources include beetroot and spinach) can act as a nitric oxide donor because nitrate/nitrite can be metabolized to produce nitric oxide., Objective: This review and meta-analysis sought to investigate the role of inorganic nitrate/nitrite in preventing or treating cardiovascular disease risk factors in humans., Data Sources: Electronic databases, including Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane, and Scopus, were searched., Data Extraction: Experimental trials examining the effect of oral inorganic nitrate/nitrite intake on cardiovascular disease risk factors were included for systematic analysis., Results: Thirty-four studies were included for qualitative synthesis, 23 of which were eligible for meta-analysis. Included studies measured the following outcomes: blood pressure, endothelial function, arterial stiffness, platelet aggregation, and/or blood lipids. Inorganic nitrate intake was found to significantly reduce resting blood pressure (systolic blood pressure: -4.80 mmHg, P < 0.0001; diastolic blood pressure: -1.74 mmHg, P = 0.001), improve endothelial function (flow-mediated dilatation: 0.59%, P < 0.0001), reduce arterial stiffness (pulse wave velocity: -0.23 m/s, P < 0.0001; augmentation index: -2.1%, P = 0.05), and reduce platelet aggregation by 18.9% (P < 0.0001)., Conclusions: Inorganic nitrate consumption represents a simple strategy for targeting cardiovascular disease risk factors. Future studies investigating the long-term effects of inorganic nitrate on cardiovascular disease outcomes are warranted.

This corrects the article DOI: 10.1038/srep45040.

Total iron intake is not strongly associated with iron stores, but haem iron intake may be more predictive. Haem iron is not available in most nutrient databases, so experimentally determined haem contents were applied to an Australian Food Frequency Questionnaire (FFQ) to estimate haem iron intake in a representative sample of young women (25-30 years). The association between dietary haem iron intakes and incident self-reported diagnosed iron deficiency over six years of follow-up was examined. Haem iron contents for Australian red meats, fish, and poultry were applied to haem-containing foods in the Dietary Questionnaire for Epidemiological Studies V2 (DQESv2) FFQ. Haem iron intakes were calculated for 9076 women from the Australian Longitudinal Study on Women's Health (ALSWH) using the DQESv2 dietary data from 2003. Logistic regression was used to examine the association between haem iron intake (2003) and the incidence of iron deficiency in 2006 and 2009. Multiple logistic regression showed baseline haem iron intake was a statistically significant predictor of iron deficiency in 2006 (Odds Ratio (OR): 0.91; 95% Confidence Interval (CI): 0.84-0.99; p -value: 0.020) and 2009 (OR: 0.89; 95% CI: 0.82-0.99; p -value: 0.007). Using the energy-adjusted haem intake made little difference to the associations. Higher haem iron intake is associated with reduced odds of iron deficiency developing in young adult Australian women., Competing Interests: The authors declare no conflict of interest.

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10 -8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development., Competing Interests: Dr. BM Psaty serves on the DSMB for a clinical trial of a device funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Steno Diabetes Center and Synlab Holding Deutschland GmbH provided support in the form of salaries for authors T.S.A. and W.M. respectively, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

Tightly integrating sensing, actuation, and computation into composites could enable a new generation of truly smart material systems that can change their appearance and shape autonomously. Applications for such materials include airfoils that change their aerodynamic profile, vehicles with camouflage abilities, bridges that detect and repair damage, or robotic skins and prosthetics with a realistic sense of touch. Although integrating sensors and actuators into composites is becoming increasingly common, the opportunities afforded by embedded computation have only been marginally explored. Here, the key challenge is the gap between the continuous physics of materials and the discrete mathematics of computation. Bridging this gap requires a fundamental understanding of the constituents of such robotic materials and the distributed algorithms and controls that make these structures smart., (Copyright © 2015, American Association for the Advancement of Science.)

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., (© 2013 APJPH.)

Background: Methylarginines are endogenous nitric oxide synthase inhibitors that have been implicated in depression. This study measured serum concentrations of l-arginine, asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in a representative sample of older community-dwelling adults and determined their association with incident depression over 6-years of follow-up., Methods: Data on clinical, lifestyle, and demographic characteristics, methylated arginines, and l-arginine (measured using LC-MS/MS) were collected from a population-based sample of older Australian adults (Median age=64 years; IQR=60-70) from the Hunter Community Study. Clinical depression was defined as a Centre for Epidemiological Studies Depression Scale (CES-D) score ≥16 or use of antidepressant medications., Results: In adjusted analyses ADMA (Q3), SDMA (Q2), l-arginine (Q2), gender, and asthma remained statistically significant predictors of incident depression at follow-up. Quartile 3 of ADMA concentration was associated with 3.5 times the odds of developing depression compared with Q1 (OR=3.54; 95% CI: 1.25-9.99)., Limitations: Limitations of our study include the use of a subjective self-reported questionnaire tool using a dichotomous cut-off, together with use of antidepressant medications, as proxies for clinical depression. Moreover, similarly to most population studies on methylated arginines, the measurement of ADMA and SDMA from blood does not necessarily reflect intracellular concentrations of these compounds. Finally, there were no measures of nitric oxide metabolites to determine if these levels were altered in the presence of elevated methylarginines and depression., Conclusions: After adjusting for clinical, demographic, biochemical, and pharmacological confounders, higher serum ADMA was independently associated with incident depression at 6-years follow-up., (© 2013 Elsevier B.V. All rights reserved.)

Rationale: Methylarginines are endogenous nitric oxide synthase inhibitors that have been implicated in animal models of lung disease but have not previously been examined for their association with spirometric measures of lung function in humans., Objectives: This study measured serum concentrations of asymmetric and symmetric dimethylarginine in a representative sample of older community-dwelling adults and determined their association with spirometric lung function measures., Methods: Data on clinical, lifestyle, and demographic characteristics, methylated arginines, and L-arginine (measured using LC-MS/MS) were collected from a population-based sample of older Australian adults from the Hunter Community Study. The five key lung function measures included as outcomes were Forced Expiratory Volume in 1 second, Forced Vital Capacity, Forced Expiratory Volume in 1 second to Forced Vital Capacity ratio, Percent Predicted Forced Expiratory Volume in 1 second, and Percent Predicted Forced Vital Capacity., Measurements and Main Results: In adjusted analyses there were statistically significant independent associations between a) higher asymmetric dimethylarginine, lower Forced Expiratory Volume in 1 second and lower Forced Vital Capacity; and b) lower L-arginine/asymmetric dimethylarginine ratio, lower Forced Expiratory Volume in 1 second, lower Percent Predicted Forced Expiratory Volume in 1 second and lower Percent Predicted Forced Vital Capacity. By contrast, no significant associations were observed between symmetric dimethylarginine and lung function., Conclusions: After adjusting for clinical, demographic, biochemical, and pharmacological confounders, higher serum asymmetric dimethylarginine was independently associated with a reduction in key measures of lung function. Further research is needed to determine if methylarginines predict the decline in lung function.

Objectives: To determine current colorectal cancer (CRC) screening rates and the level of adherence to screening guidelines @a community level., Setting: A cross-sectional cohort of at-risk people aged 56-88 years randomly selected from the Hunter Community Study (HCS), Australia., Main Outcome Measures: Proportion ever reporting undertaking any CRC testing; current screening rates for each CRC screening modality; level of screening in accordance with national screening guidelines., Results: Of the 1117 participants (70%) who returned a questionnaire, 777 were deemed asymptomatic and eligible for analysis. Overall, 63% of respondents had ever received any CRC testing. Forty-three per cent had ever had a faecal occult blood test (20% screened in the previous 2 years); 30% had ever had a colonoscopy (16% screened in the previous 5 years); and 7% had ever had a sigmoidoscopy (1% screened in the previous 5 years). Rates of adherence to screening guidelines were 21% for respondents who were @or slightly above average risk, and 45% for respondents who were @moderately increased or potentially high risk., Conclusions: Rates of CRC screening remain low. The screening rate for colonoscopy was particularly high among people who were @or slightly above average risk, despite such screening not being endorsed in the guidelines. Effective strategies to improve rates of CRC screening and appropriate use of colonoscopy are required across the entire at-risk population.

Examined the effects of cumulative prenatal substance exposure and cumulative environmental risk on the developmental trajectories of 278 infants, toddlers, and preschool children. Results indicated that both cumulative risk indexes were significantly correlated. Results also indicated that both indexes were related to decrements in developmental trajectories (intercept and slope) from 3 to 57 months of age. Both prenatal exposure and environmental risk added unique variance to the prediction of developmental level and rate of growth when entered after covariates (i.e., birth weight and sex). However, across a number of models with and without covariates, environmental risk accounted for more variance in developmental trajectories than did prenatal exposure. Implications are discussed.

High-probability requests were used to increase social interactions in 3 young boys with severe disabilities who had been identified as severely socially withdrawn. A multiple baseline design across participants was used to evaluate the effects of high-probability request intervention on (a) social initiations, (b) social responses, (c) continued interactions, and (d) performance of high- and low-probability requests. The students were observed in a second setting to examine generalization effects across peers who did not participate in the training sequence and settings. The results demonstrated that the high-probability requests increased the students' responsiveness to low-probability requests to initiate social behavior. Increases were also found in (a) unprompted initiations and extended interactions to the training peers, (b) unprompted initiations and extended interactions to peers who were not involved in the training procedure, and (c) generalized unprompted initiations and interactions in a second nontraining setting. The students maintained increased levels of initiations and interactions after all prompts were removed from both the training and nontraining settings.

Generalization and social validity are necessary aspects of any applied behavior analytic endeavor. They are especially critical to social-skills training research and practice. Investigators have demonstrated the effectiveness of various learning theory-based interventions in teaching social skills to and increasing peer interactions of children with and without disabilities. However, development of a technology for reliably transferring these changes across different situations or ensuring their persistence over time has proven to be more problematic. From both a conceptual and empirical standpoint, this article reviews progress in and barriers to assessing and enhancing generality of social behavior change and its relationship to social validity. If progress is to be made, then it will be necessary to (a) distinguish between generalization and generality in developing and evaluating social-skills interventions; (b) expand the concept of social validity to give more emphasis to objective measurement of social skills, interventions, and outcomes; and (c) pursue a systematic analysis of generality- and durability-programming tactics.

In a pilot study of the combination of epirubicin and chlorambucil in the treatment of chronic lymphocytic leukemia (CLL), 10 patients with advanced or progressive disease were treated in four centres. Up to a total of 15 courses in individual patients were given. Toxicity was relatively mild with nausea due to epirubicin being the most commonly reported side-effect. One patient developed a probable septicemia during a period of neutropenia. In another patient who died from probable Pneumocystis carinii pneumonia (PCP) after only one course of therapy, death could not be regarded as necessarily treatment-related. In seven previously untreated patients, one complete response and four partial remissions were seen. All three previously treated patients showed partial remissions.

A peer-initiation training procedure was implemented across multiple peer trainers to investigate social interactions between severely withdrawn autistic children and their nonhandicapped peers. For one subject, substantial increases in spontaneous interactions with training and nontraining peers occurred after the peer-initiation procedure was applied across two training exemplars. Spontaneous social interactions continued even after the training procedure was removed. Although experimental control was established with the second subject during training, spontaneous interactions during nontraining periods were primarily with training peers. The results contribute to an emerging data base on the social interactions of autistic and severely withdrawn handicapped children and on peer-initiation training procedures.

Group affection activities were used to increase the interaction of three autistic children with their nonhandicapped peers in an integrated early childhood setting. Peer interaction increased during free play when the affection activities were conducted, but not when similar activities without the affection component were used. This interaction included initiations by both the autistic and nonhandicapped children, with reciprocal interactions occurring more frequently with nonhandicapped peers who had participated in the affection activities.

A three-way design was used to determine whether teachers' judgments about mentally retarded children would be related to characteristics of the children, characteristics of the teacher, and/or characteristics of an integrated free-play setting. Independent variables were integration ratio, area of teacher's specialization, and target child. The dependent variable was teachers' judgments about handicapped children in an integrated setting. Subjects were 15 regular-education teachers and 15 special-education teachers who taught at the primary school level. Judgment ratings by regular-education teachers depended both on the characteristics of the target child and the integration ratio in the free-play activity. Special-education teachers' judgments also were influenced by characteristics of the child observed but not the integration ratio.