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Purpose: Dietary nitrate intake is inversely related to numerous contributors towards frailty, including cardiovascular disease and poor physical function. Whether these findings extend to frailty remain unknown. We investigated if habitual nitrate intake, derived from plants or animal-based foods, was cross-sectionally associated with frailty in women. Methods: Community-dwelling older Australian women (n = 1390, mean age 75.1 ± 2.7 years) completed a validated semi-quantitative food frequency questionnaire (FFQ). Nitrate concentrations in food were obtained from international nitrate databases. We adopted the Rockwood frailty index (FI) of cumulative deficits comprising 33 variables across multiple health domains (scored 0 to 1), which predicts increased hospitalisation and mortality risk. A FI ≥ 0.25 indicated frailty. Cross-sectional associations between nitrate intake (total plant and animal nitrate, separately) and frailty were analysed using multivariable-adjusted logistic regression models (including lifestyle factors), as part of restricted cubic splines. Results: A non-linear inverse relationship was observed between total plant nitrate intake and frailty. Compared to women with the lowest plant nitrate intake (Quartile [Q]1), women with greater intakes in Q2 (OR 0.69 95%CI 0.56–0.84), Q3 (OR 0.67 95%CI 0.50–0.90) and Q4 (OR 0.66 95%CI 0.45–0.98) had lower odds for frailty. A nadir in the inverse association was observed once intakes reached ~ 64 mg/d (median Q2). No relationship was observed between total animal nitrate and frailty. Conclusion: Community-dwelling older women consuming low amounts of plant-derived nitrate were more likely to present with frailty. Consuming at least one daily serving (~ 75 g) of nitrate-rich green leafy vegetables may be beneficial in preventing frailty. [ABSTRACT FROM AUTHOR]

Purpose: Cancer survival is improving, making optimal management of long-term treatment-related adverse effects increasingly important. Exercise and a healthy diet are beneficial and regularly recommended in cancer survivorship guidelines; however, few cancer survivors meet these recommendations so there is a need to explore why. This study aimed to understand experiences receiving exercise and diet support among Australian breast and prostate cancer survivors during and following treatment, and to explore what support they would like to receive. Methods: Adults who completed active treatment for breast or prostate cancer were recruited via a private cancer care centre. Using a qualitative descriptive study design, participants attended in-person focus groups that were recorded, transcribed, then analysed using reflexive thematic analysis. Results: In total, 26 cancer survivors (15 breast, 11 prostate) participated in one of seven focus groups (4 breast, 3 prostate). Two themes were developed: 1) It was just brushed over, and 2) Wanting more. Theme 1 reports that exercise, and especially diet, were rarely discussed. If they were, it was often limited to general recommendations. Theme 2 shows that participants wanted more specific and personalised support, and information about how exercise and/or diet could benefit their cancer treatment. Conclusion: Despite strong interest in receiving personalised exercise and diet support, neither are routinely provided to Western Australian breast and prostate cancer survivors. If support was provided, there was inconsistency in the level and type of support provided. These findings identify important gaps in exercise and diet support provision to cancer survivors and will inform future strategies aiming to improve cancer survivorship care. [ABSTRACT FROM AUTHOR]

Activation of the mechanistic target of rapamycin (mTOR) is a key metabolic checkpoint of pro-inflammatory T-cell development that contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), however, the underlying mechanisms remain poorly understood. Here, we identify a functional role for Rab4A-directed endosome traffic in CD98 receptor recycling, mTOR activation, and accumulation of mitochondria that connect metabolic pathways with immune cell lineage development and lupus pathogenesis. Based on integrated analyses of gene expression, receptor traffic, and stable isotope tracing of metabolic pathways, constitutively active Rab4AQ72L exerts cell type-specific control over metabolic networks, dominantly impacting CD98-dependent kynurenine production, mTOR activation, mitochondrial electron transport and flux through the tricarboxylic acid cycle and thus expands CD4+ and CD3+CD4−CD8− double-negative T cells over CD8+ T cells, enhancing B cell activation, plasma cell development, antinuclear and antiphospholipid autoantibody production, and glomerulonephritis in lupus-prone mice. Rab4A deletion in T cells and pharmacological mTOR blockade restrain CD98 expression, mitochondrial metabolism and lineage skewing and attenuate glomerulonephritis. This study identifies Rab4A-directed endosome traffic as a multilevel regulator of T cell lineage specification during lupus pathogenesis. Activation of the mechanistic target of rapamycin (mTOR) is important in the metabolic function of proinflammatory T cells in autoimmunity. Here the authors characterise how Rab4A is involved with CD98 and endosome recycling which subsequently affects mTOR activation, autoimmunity and T cell expansion. [ABSTRACT FROM AUTHOR]

Background/Objectives: Few studies have investigated the association between dietary flavonoid intake, including all major subclasses, and the long-term risk of ischemic heart disease (IHD). We examined whether dietary flavonoid intake associated with IHD incidence, assessing the possible modifying role of sex and smoking, in participants from the Danish Diet, Cancer, and Health study. Subjects/Methods: In a cohort study design, 54,496 adults (46.8% male), aged 50–64 years, without a history of IHD, were followed for up to 23 years. Habitual dietary flavonoid intake was estimated from food frequency questionnaires using Phenol-Explorer. Incident cases of IHD were identified within Danish nationwide health registries. Restricted cubic splines in Cox proportional hazards models were used to examine associations between flavonoid intake and IHD risk. Results: During follow-up, 5560 IHD events were recorded. No overall association was seen between total flavonoid intake, nor any subclass, and IHD, following adjustment for demographics, lifestyle, and dietary confounders. Stratified by sex and smoking status, higher intakes of specific subclasses associated with lower IHD risk among ever-smokers [Q5 vs. Q1 flavonols HR (95% CI): 0.90 (0.82, 0.99); flavanol oligo+polymers: 0.88 (0.80, 0.97)], but not among never-smokers, nor either sex specifically. Conclusions: While we did not find clear evidence that higher habitual dietary flavonoid intake was associated with lower IHD risk, these results do not exclude the possibility that certain subclasses may have a protective role in prevention of IHD among population sub-groups; this was evident among smokers, who are at a higher risk of atherosclerosis. [ABSTRACT FROM AUTHOR]

We have previously shown that abdominal aortic calcification (AAC), a marker of advanced atherosclerotic disease, is weakly associated with reduced hip areal bone mineral density (aBMD). To better understand the vascular-bone health relationship, we explored this association with other key determinants of whole-bone strength and fracture risk at peripheral skeletal sites. This study examined associations of AAC with peripheral quantitative computed tomography (pQCT)-assessed total, cortical and trabecular volumetric BMD (vBMD), bone structure and strength of the radius and tibia among 648 community-dwelling older women (mean ± SD age 79.7 ± 2.5 years). We assessed associations between cross-sectional (2003) and longitudinal (progression from 1998/1999-2003) AAC assessed on lateral dual-energy X-ray absorptiometry (DXA) images with cross-sectional (2003) and longitudinal (change from 2003 to 2005) pQCT bone measures at the 4% radius and tibia, and 15% radius. Partial Spearman correlations (adjusted for age, BMI, calcium treatment) revealed no cross-sectional associations between AAC and any pQCT bone measures. AAC progression was not associated with any bone measure after adjusting for multiple comparisons, despite trends for inverse correlations with total bone area at the 4% radius (rs =  - 0.088, p = 0.044), 4% tibia (rs =  - 0.085, p = 0.052) and 15% radius (rs =  - 0.101, p = 0.059). Neither AAC in 2003 nor AAC progression were associated with subsequent 2-year pQCT bone changes. ANCOVA showed no differences in bone measures between women with and without AAC or AAC progression, nor across categories of AAC extent. Collectively, these finding suggest that peripheral bone density and structure, or its changes with age, are not associated with central vascular calcification in older women. [ABSTRACT FROM AUTHOR]

Purpose: Higher total fruit and vegetable (FV) intakes have been associated with lower perceived stress. The relationship between specific types of FV and perceived stress remains uncertain. The aims of this cross-sectional study were to explore the relationship between consumption of specific types of FV with perceived stress in a population-based cohort of men and women aged ≥ 25 years from the Australian Diabetes, Obesity and Lifestyle (AusDiab) Study. Methods: Dietary intake was assessed using a validated Food Frequency Questionnaire (n = 8,640). Perceived stress was evaluated using a validated Perceived Stress Questionnaire, with values ranging 0–1 (lowest to highest). High perceived stress cut-offs of ≥0.34 for men and ≥0.39 for women were obtained from the highest quartile of the perceived stress score for each sex. Multivariable-adjusted logistic regression was performed to investigate the associations. Results: The mean age of participants (50.1% females) was 47.8 (SD 15) years. Persons in the highest, versus lowest, quartiles of apples and pears, orange and other citrus, and banana intakes had a significantly lower odds (24–31%) of having high perceived stress. Similarly, persons with higher intakes of cruciferous, yellow/orange/red, and legume vegetables had significantly lower odds (25–27%) of having high perceived stress. Conclusion: In Australian adults, a higher consumption of apples and pears, oranges and other citrus, and bananas, as well as cruciferous, yellow/orange/red, and legume vegetables were associated with lower odds of having high perceived stress. The recommendations of "eating a rainbow" of colours may assist in preventing and/or reducing perceived stress. [ABSTRACT FROM AUTHOR]

Background: There is currently no treatment for attenuating progression of arterial calcification. 18F-sodium fluoride positron emission tomography (18F-NaF PET) locates regions of calcification activity. We tested whether vitamin-K1 or colchicine affected arterial calcification activity. Methods: 154 patients with diabetes mellitus and coronary calcification, as detected using computed tomography (CT), were randomized to one of four treatment groups (placebo/placebo, vitamin-K1 [10 mg/day]/placebo, colchicine [0.5 mg/day]/placebo, vitamin-K1 [10 mg/day]/ colchicine [0.5 mg/day]) in a double-blind, placebo-controlled 2x2 factorial trial of three months duration. Change in coronary calcification activity was estimated as a change in coronary maximum tissue-to-background ratio (TBRmax) on 18F-NaF PET. Results: 149 subjects completed follow-up (vitamin-K1: placebo = 73:76 and colchicine: placebo = 73:76). Neither vitamin-K1 nor colchicine had a statistically significant effect on the coronary TBRmax compared with placebo (mean difference for treatment groups 0·00 ± 0·16 and 0·01 ± 0·17, respectively, p > 0.05). There were no serious adverse effects reported with colchicine or vitamin-K1. Conclusions: In patients with type 2 diabetes, neither vitamin-K1 nor colchicine significantly decreases coronary calcification activity, as estimated by 18F-NaF PET, over a period of 3 months. Clinical trial registration: ACTRN12616000024448. [ABSTRACT FROM AUTHOR]

Purpose: Dietary flavonoids are bioactive compounds that have been widely investigated for their associations with vascular health outcomes. As the development of tinnitus has been linked to vascular pathways, dietary flavonoids may have role in the prevention of tinnitus symptoms. This study reports the associations between the intakes of major classes of dietary flavonoids and 10-year incidence of tinnitus. Methods: Of the 1753 participants (aged ≥ 50 years) from the Blue Mountains Hearing Study with complete baseline data on tinnitus symptoms and dietary intakes, 536 (31%) cases of tinnitus were identified and excluded from further analysis. Dietary data was collected using a semi-quantitative food frequency questionnaire and intakes of the five major classes of flavonoids were determined using U.S. Department of Agriculture flavonoid databases. Presence of prolonged tinnitus was assessed by a positive response to a single question administered by an audiologist. Results: Of the remaining 1217 participants without tinnitus at baseline, 222 (18%) incident cases of tinnitus were identified over 10 years. After age–sex adjustment, participants in the third versus first quartile of proanthocyanidin intake were significantly less likely to develop incident tinnitus by 36% (HR = 0.64; 95% CI 0.43–0.96, Ptrend = 0.04). Following multivariable adjustment, this protective trend was non-significant (HR = 0.60; 95% CI 0.39–0.92; Ptrend = 0.06). Similarly, a non-significant protective trend was observed when comparing the fourth versus first quartile of intake of all flavonoids (OR = 0.61; 95% CI 0.39–0.96). No other associations were observed. Conclusion: Our findings do not support the hypothesis that dietary flavonoids are protective against the development of tinnitus over 10 years. The weak significant association observed between proanthocyanidin and incident tinnitus may be a chance finding as there was no significant trend following multivariate adjustments and, therefore, requires further studies to investigate these associations. [ABSTRACT FROM AUTHOR]

Purpose: To assess whether dietary intake of flavonoids are associated with longitudinal treatment outcomes of patients with neovascular age-related macular degeneration (nAMD). Methods: 547 participants with nAMD were recruited at baseline, 494 were followed-up after receiving 12 months of anti-vascular endothelial growth factor (anti-VEGF) therapy. Baseline dietary intake of flavonoids was determined using a validated food frequency questionnaire. At follow-up, presence of intra-retinal and sub-retinal fluid (IRF and SRF), retinal pigment epithelium detachment and measurements of central macular thickness (CMT) were recorded from optical coherence tomography scans. Visual acuity (VA) was documented using LogMAR charts. Results: Participants in the first tertile of intake of the flavonol quercetin, and the flavan-3-ols epigallocatechin-3-gallate and epigallocatechin had significantly worse vision than participants in the third tertile—multivariable-adjusted least square (LS) mean VA: 14.68 vs. 19.53 (p = 0.04); 14.06 vs. 18.89 (p = 0.04); 13.86 vs. 18.86 (p = 0.03), respectively. Participants in the first compared to the third tertile of flavan-3-ol, epigallocatechin-3-gallate and epigallocatechin intake all had a twofold higher risk of IRF, multivariable-adjusted p trend of: 0.03, 0.01 and 0.02, respectively. The first vs. the third tertile of tea intake had significantly worse vision (LS mean VA: 13.49 vs. 19.04, p = 0.02), increased risk of IRF (OR 2.13, 95% CI 1.18–3.85) and greater mean CMT (279.59 μm vs. 256.52 μm, p = 0.04). Conclusions: Higher intakes of dietary flavonoids, specifically flavonols and flavan-3-ols, could be associated with better long-term treatment outcomes in nAMD patients receiving anti-VEGF therapy. Confirmation of these associations in interventional studies could result in promising new therapeutic approaches to the treatment of nAMD. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the relationship of habitual FV intake, different types of FV, and vegetable diversity with depressive symptoms. Methods: Australian men and women (n = 4105) aged > 25 years from the Australian Diabetes, Obesity and Lifestyle Study were included. Dietary intake was assessed using a Food Frequency Questionnaire at baseline, 5 and 12 years. Depressive symptoms were assessed using the validated 10-item Centre for Epidemiology Studies Short Depression Scale at 12 years. Multiple logistic regression models were used to investigate the association between the exposures of interest and depressive symptoms using odds ratios (OR) and 95% confidence intervals (CI) across quartiles of FV intake and vegetable diversity. Analyses were multivariable-adjusted for confounding factors. Results: At 12 years, 425 (10.4%) participants had "any depressive symptoms". Habitual FV intake was inversely associated with depressive symptoms at 12 years. After adjustment, participants in quartile 2 of FV intake (Q2; median 317 g/day) had a 20% lower odds of having any depressive symptoms (OR [95% CI] 0.80 [0.69, 0.95]) in comparison to those in the lowest quartile of FV intake (Q1; median 223 g/day). Yellow/orange/red and leafy green vegetables were the key vegetable types driving this association. Higher vegetable diversity (4–6 different vegetables/day) was associated with a 24–42% lower odds of having depressive symptoms when compared to < 3 different vegetables/day. The associations remained similar after further adjusting for diet quality. Conclusion: A FV-rich diet, consisting of a diverse range of vegetables, particularly yellow/orange/red and leafy green vegetables may help to lower depressive symptoms. Promoting such a diet, particularly in men and women with a low FV intake, may have a significant public health impact. [ABSTRACT FROM AUTHOR]

Reported associations between vitamin K1 and both all-cause and cause-specific mortality are conflicting. The 56,048 participants from the Danish Diet, Cancer, and Health prospective cohort study, with a median [IQR] age of 56 [52–60] years at entry and of whom 47.6% male, were followed for 23 years, with 14,083 reported deaths. Of these, 5015 deaths were CVD-related, and 6342 deaths were cancer-related. Intake of vitamin K1 (phylloquinone) was estimated from a food-frequency questionnaire (FFQ), and its relationship with mortality outcomes was investigated using Cox proportional hazards models. A moderate to high (87–192 µg/d) intake of vitamin K1 was associated with a lower risk of all-cause [HR (95%CI) for quintile 5 vs quintile 1: 0.76 (0.72, 0.79)], cardiovascular disease (CVD)-related [quintile 5 vs quintile 1: 0.72 (0.66, 0.79)], and cancer-related mortality [quintile 5 vs quintile 1: 0.80 (0.75, 0.86)], after adjusting for demographic and lifestyle confounders. The association between vitamin K1 intake and cardiovascular disease-related mortality was present in all subpopulations (categorised according to sex, smoking status, diabetes status, and hypertension status), while the association with cancer-related mortality was only present in current/former smokers (p for interaction = 0.002). These findings suggest that promoting adequate intakes of foods rich in vitamin K1 may help to reduce all-cause, CVD-related, and cancer-related mortality at the population level. [ABSTRACT FROM AUTHOR]

Whether the vascular effects of inorganic nitrate, observed in clinical trials, translate to a reduction in cardiovascular disease (CVD) with habitual dietary nitrate intake in prospective studies warrants investigation. We aimed to determine if vegetable nitrate, the major dietary nitrate source, is associated with lower blood pressure (BP) and lower risk of incident CVD. Among 53,150 participants of the Danish Diet, Cancer, and Health Study, without CVD at baseline, vegetable nitrate intake was assessed using a comprehensive vegetable nitrate database. Hazard ratios (HRs) were calculated using restricted cubic splines based on multivariable-adjusted Cox proportional hazards models. During 23 years of follow-up, 14,088 cases of incident CVD were recorded. Participants in the highest vegetable nitrate intake quintile (median, 141 mg/day) had 2.58 mmHg lower baseline systolic BP (95%CI − 3.12, − 2.05) and 1.38 mmHg lower diastolic BP (95%CI − 1.66, − 1.10), compared with participants in the lowest quintile. Vegetable nitrate intake was inversely associated with CVD plateauing at moderate intakes (~ 60 mg/day); this appeared to be mediated by systolic BP (21.9%). Compared to participants in the lowest intake quintile (median, 23 mg/day), a moderate vegetable nitrate intake (median, 59 mg/day) was associated with 15% lower risk of CVD [HR (95% CI) 0.85 (0.82, 0.89)]. Moderate vegetable nitrate intake was associated with 12%, 15%, 17% and 26% lower risk of ischemic heart disease, heart failure, ischemic stroke and peripheral artery disease hospitalizations respectively. Consumption of at least ~ 60 mg/day of vegetable nitrate (~ 1 cup of green leafy vegetables) may mitigate risk of CVD. [ABSTRACT FROM AUTHOR]

Resistance to ionizing radiation, a first-line therapy for many cancers, is a major clinical challenge. Personalized prediction of tumor radiosensitivity is not currently implemented clinically due to insufficient accuracy of existing machine learning classifiers. Despite the acknowledged role of tumor metabolism in radiation response, metabolomics data is rarely collected in large multi-omics initiatives such as The Cancer Genome Atlas (TCGA) and consequently omitted from algorithm development. In this study, we circumvent the paucity of personalized metabolomics information by characterizing 915 TCGA patient tumors with genome-scale metabolic Flux Balance Analysis models generated from transcriptomic and genomic datasets. Metabolic biomarkers differentiating radiation-sensitive and -resistant tumors are predicted and experimentally validated, enabling integration of metabolic features with other multi-omics datasets into ensemble-based machine learning classifiers for radiation response. These multi-omics classifiers show improved classification accuracy, identify clinical patient subgroups, and demonstrate the utility of personalized blood-based metabolic biomarkers for radiation sensitivity. The integration of machine learning with genome-scale metabolic modeling represents a significant methodological advancement for identifying prognostic metabolite biomarkers and predicting radiosensitivity for individual patients. Personalized prediction of tumor radiosensitivity would facilitate development of precision medicine workflows for cancer treatment. Here, the authors integrate machine learning and genome-scale metabolic modeling approaches to identify multi-omics biomarkers predictive of radiation response. [ABSTRACT FROM AUTHOR]

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p = 4 × 10−17), arthritis (GDF5p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing. Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases. [ABSTRACT FROM AUTHOR]

Purpose: Chronic inflammation plays a role in the pathogenesis of age-related renal disease and the diet can moderate systemic inflammation. The primary objective of this study was to examine the associations between a dietary inflammatory index (DII®) score and renal function, the trajectory of renal function decline, and renal disease-related hospitalizations and/or mortality over 10 years. Methods: The study was conducted in 1422 Western Australian women without prevalent chronic kidney disease and aged ≥ 70 years. Baseline dietary data, obtained from a validated food frequency questionnaire, were used to calculate a DII score for each individual. Results: In this cohort, the mean [range] DII score was 0.19 [− 6.14 to 6.39]. A higher DII score was associated with poorer renal function at baseline and a greater renal function decline over 10 years; after multivariable adjustments, a one-unit higher DII score was associated with a 0.55 mL/min/1.73 m2 lower eGFR at baseline (p = 0.01) and a 0.06 mL/min/1.73 m2 greater annual decline in eGFR over 10 years (p = 0.05). Restricted cubic splines provide evidence of a non-linear association between baseline DII score and risk of a renal disease-related event. Compared to participants in the lowest quintile, those in the highest quintile of DII score were at a higher risk of experiencing a renal disease-related event (adjusted HR 2.06, 95% CI 0.97, 4.37). Conclusion: Recommending an increased consumption of foods with a higher anti-inflammatory potential could form part of a multifaceted approach to reduce the risk of renal disease through diet and lifestyle changes. [ABSTRACT FROM AUTHOR]

Purpose: In this study, we assessed whether there are independent associations between dietary total flavonoid intake and major flavonoid classes with retinal arteriolar and venular calibre. Methods: Blue Mountains Eye Study participants aged 49+ years who had complete data on diet and retinal vessel measures were analysed (n = 2821). Dietary intake was assessed using a semi-quantitative Food-Frequency Questionnaire (FFQ). Flavonoid content of foods in the FFQ was estimated using the US Department of Agriculture Flavonoid, Isoflavone and Proanthocyanidin databases. Fundus photographs were taken and retinal vascular calibre was measured using validated computer-assisted techniques. The associations of intake of dietary flavonoids with retinal vessel calibre were examined in linear regression models and general linear model. Results: The highest quartile of intake was compared with the lowest quartile using multivariable-adjustment models. Participants with the highest proanthocyanidin intake had narrower retinal venules (223.9 ± 0.62 versus 226.5 ± 0.63, respectively; Ptrend = 0.01); and the highest isoflavone intake was associated with wider retinal arterioles (188.1 ± 0.55 versus 186.3 ± 0.56, respectively; Ptrend = 0.01). The highest apple/pear consumption (a dietary source of catechin) was associated with narrower retinal venules (223.8 ± 0.57 versus 226.1 ± 0.52; Ptrend = 0.01) and wider retinal arterioles (187.9 ± 0.51 versus 186.2 ± 0.51; Ptrend = 0.02). Further, participants who were in the highest versus lowest quartile of chocolate consumption had ~ 2.1 μm narrower retinal venules (multivariable-adjusted P = 0.03). Conclusions: This study shows that higher intakes of specific flavonoid subclasses are associated with a favourable retinal microvascular profile. Greater consumption of flavonoid-rich apples/pears and chocolate was also associated with beneficial variations in retinal vascular calibre. [ABSTRACT FROM AUTHOR]

Purpose: Existing research suggests that changes to retinal vascular caliber reflect nitric oxide (NO)-dependent endothelial dysfunction. Dietary nitrate is an important source of NO; however, studies on the link between dietary nitrate intake and retinal microvasculature are lacking. We aimed to assess the cross-sectional association between intake of dietary nitrate (from vegetable and non-vegetable sources) and retinal arteriolar and venular caliber among older adults. Methods: Participants from the Blue Mountains Eye Study aged 49+ years with complete data at baseline on diet and retinal vessel measures were analyzed (n = 2813). Dietary intake was assessed using a validated semi-quantitative food-frequency questionnaire. Nitrate intake from vegetable and non-vegetable sources was estimated using a validated comprehensive database and other published data where necessary. Fundus photographs were taken and retinal vascular caliber measured using validated computer-assisted techniques and summarized. Results: Participants in the lowest versus highest tertile of vegetable nitrate intake had significantly narrower retinal arterioles: 186.2 ± 0.48 versus 187.6 ± 0.48 µm (multivariable-adjusted p = 0.04). After multivariable adjustment, each 10-unit higher intake of total nitrate and vegetable nitrate was associated with 0.089 ± 0.004 and 0.090 ± 0.004 µm wider retinal arteriolar caliber, respectively, both p = 0.03. Each 10-unit higher vegetable nitrate intake was associated with 0.092 ± 0.005 µm narrower retinal venules (p = 0.05). Conclusion: Intake of dietary nitrate, particularly from vegetable sources, was associated with beneficial variations in both retinal arteriolar and venular caliber among older adults. Further research into associations between dietary nitrate and the retinal microvasculature could allow for greater understanding and possible prevention of clinical cardiovascular events. [ABSTRACT FROM AUTHOR]

Summary: Analyses using newly developed structural measures of minimal model (aBMD, W, Sigma, Delta) in a Chinese female age-matched cohort of femoral neck fracture patients and non-fracture community controls resulted in improved fracture prediction, suggesting the usefulness of new variables, extending the value of widely available DXA technology. Introduction: We have developed a new approach to evaluate 2D femoral neck (FN) structure, the minimal model (MM). This model includes FNaBMD and FNWidth with two new internal structural measures, the standard deviation of normalized mineral mass projection profile distribution (FNSigma) and the displacement between center of mineral (CoM) mass and geometric center of mineral mass projection profile (FNDelta). Methods: Differences in these four structural measurements together with age, weight, and height were compared in the contralateral hip of 285 FN fracture Chinese female patients and 261 age-matched community controls. Structural variables were calculated from DXA equivalent 2D images obtained from QCT scans analyzed using Mindways Software. Results: Review of FN scanned profiles of fracture patients and controls identified substantial reduction in mineral mass in the superior segment of FN. Fracture participants were taller, weighed less, and had lower FNaBMD and larger FNDelta, due to a larger inferior displacement in the CoM, consistent with greater reduction in superior segment bone. Logistic regression identified increased height, reduced FNaBMD, increased FNDelta, and reduced FNSigma per SD as significant independent contributors to differentiating fracture from non-fracture. Area under ROC analysis identified significant improvement in discrimination with the addition of FNDelta and FNSigma to the model including age, height, weight, and FNaBMD (C statistic 0.87 and 0.84 respectively). Conclusions: These data extend previous data that identified the benefit of 2D FN internal structural information in discriminating those at increased future fracture risk from recently fractured individuals. These data support continuing investigation of MM analysis as a straightforward analytical approach adding value to DXA hip aBMD in predicting fracture risk. [ABSTRACT FROM AUTHOR]

Background: The longitudinal relationship between HLA class I and II eplet mismatches, de novo donor-specific antibodies (dnDSA) development, and acute rejection after transplantation in childhood is unknown. Methods: Eplet mismatches at HLA class I and II loci were calculated retrospectively for each donor/recipient pair transplanted between 2005 and 2015 at a single Australian center. Logistic regression analyses were conducted to determine the association between the number of eplet mismatches, dnDSA, and acute rejection. Results: The cohort comprised 59 children (aged 0–18 years) who received their first kidney allograft and were followed for median (interquartile range) 4.5 (± 2.6) years. Overall, 32% (19/59) developed dnDSA (class I 3% (2/59), class II 14% (8/59), 15% class I and II (9/59)), and 24% (14/59) developed biopsy-proven acute rejection. Every unit increase in class I and II eplet mismatches corresponded to an increase in risk of class I (odds ratio (OR) 1.22, 95% CI 1.07–1.39, p < 0.01) and class II (OR 1.06, 95% CI 1.01–1.11, p = 0.02) dnDSA development. Compared with recipients without dnDSA, class I and II dnDSA were associated with direction of effect towards increased risk of acute cellular rejection (class I: OR 5.87, 95% CI 0.99–34.94, p = 0.05; class II: OR 12.00, 95% CI 1.25–115.36, p = 0.03) and acute antibody-mediated rejection (class I: OR 25.67, 95% CI 3.54–186.10, p < 0.01; class II: OR 9.71, 95% CI 1.64–57.72, p = 0.01). Conclusions: Increasing numbers of HLA class I or II eplet mismatches were associated with the development of dnDSA. Children who developed dnDSA were also more likely to develop acute rejection compared with children without dnDSA. [ABSTRACT FROM AUTHOR]

Purpose: Increasing vegetable intake and diversity are recommended to maintain better health. Evidence for the health benefits of vegetable diversity, separate from total intake, is scarce. We aimed to investigate the associations of vegetable diversity with subclinical measures of atherosclerosis and atherosclerotic vascular disease (ASVD) mortality. Methods: Vegetable diversity was assessed within a validated food frequency questionnaire using a single question, 'How many different vegetables do you usually consume each day (< 1 to ≥ 6 per day)'. Cox proportional hazards modelling was used to examine the association between vegetable diversity and ASVD mortality in 1226 women aged ≥ 70 years without clinical ASVD or diabetes mellitus at baseline (1998). In 2001, B-mode ultrasonography was used to measure common carotid artery intima–media thickness (CCA-IMT) (n = 954) and carotid plaque severity (n = 968). Results: Over 15 years (15,947 person-years) of follow-up, 238 ASVD-related deaths were recorded. For each additional different vegetable consumed per day, there was 17% lower hazard for ASVD mortality (HR = 0.83, 95% CI 0.78, 0.93, P = 0.001); a 1.7% lower mean CCA-IMT (B ± SE: − 0.013 ± 0.004, P < 0.001); and a 1.8% lower maximum CCA-IMT (B ± SE: − 0.017 ± 0.004, P < 0.001). Further adjustment for total vegetable intake attenuated the association between vegetable diversity and ASVD mortality (P = 0.114), but not CCA-IMT (P = 0.024). No association was observed between vegetable diversity and carotid plaque severity (P > 0.05). Conclusions: Vegetable diversity may contribute to benefits in lowering risk of ASVD in older women. The reduction in risk is partly explained by increased total vegetable consumption. Clinical trial registry: The Perth Longitudinal Study of Aging in Women (PLSAW) trial registration ID is ACTRN12617000640303. This study was retrospectively registered on the Australian New Zealand Clinical Trials Registry at http://www.anzctr.org.au. [ABSTRACT FROM AUTHOR]

Purpose: Short-term trials indicate inorganic nitrate and nitrate-rich vegetables may have vascular health benefits. However, few observational studies have explored the relationship between nitrate intake and long-term cardiovascular disease (CVD) outcomes. The primary aim of this study was to investigate the association of nitrate intake from vegetables with CVD mortality in a sample of older Australians. Methods: A subgroup of participants without diabetes or major CVD at baseline (1992–1994) were included from the Blue Mountains Eye Study, a population-based cohort study of men and women aged ≥ 49 years. Diets were evaluated using a validated food frequency questionnaire at baseline, 5 years and 10 years of follow-up. Vegetable nitrate intake was estimated using a comprehensive vegetable nitrate database. Cox proportional hazard regression was used to explore the association between vegetable nitrate intake and CVD mortality. Results: During 14 years of follow-up, 188/2229 (8.4%) participants died from CVD. In multivariable-adjusted analysis, participants in quartile 2 [69.5–99.6 mg/day; HR 0.53 (95% CI 0.35, 0.82)], quartile 3 [99.7–137.8 mg/day; HR 0.51 (95% CI 0.32, 0.80)], and quartile 4 [> 137.8 mg/day; HR 0.63 (95% CI 0.41, 0.95)] of vegetable nitrate intake had lower hazards for CVD mortality compared to participants in quartile 1 (< 69.5 mg/day). Conclusions: In older Australian men and women, vegetable nitrate intake was inversely associated with CVD mortality, independent of lifestyle and cardiovascular risk factors. These findings confirm a recent report that intake of vegetable nitrate lowers the risk of CVD mortality in older women and extend these findings to older men. [ABSTRACT FROM AUTHOR]

The objective of the study was to determine the association between AAC and neuromuscular function over 5 years. Participants in this study were ambulant women over 70 years old residing in Perth, Western Australia who participated in the Calcium Intake Fracture Outcomes Study, a randomised controlled trial of calcium supplementation. 1046 women (mean age = 74.9 ± 2.6 years; BMI = 27.1 ± 4.4 kg/m2) were included. Lateral spine images captured during bone density testing were scored for AAC (AAC24; 0-24) at baseline. Severe AAC (AACsev) was defined using established cut points (AAC24 ≥ 6). At baseline and follow-up, isometric grip strength was assessed using a dynamometer. Mobility was assessed by the Timed-Up-and-Go (TUG) test. Using pre-defined criteria, muscle weakness was considered as grip strength < 22 kg and poor mobility defined as TUG > 10.2 s. A subset of women had appendicular lean mass (ALM) determined by dual-energy X-ray absorptiometry at baseline and follow-up (n = 261). AACsev was evident in 193 (18.5%) women. Average decline in grip strength after 5 years was greater in those with AACsev than those without (3.6 ± 3.7 vs. 2.9 ± 4.2 kg; p = 0.034). This remained significant after adjustment for age, treatment allocation, diabetes, smoking history, renal function, medical record-derived prevalent vascular disease, BMI and physical activity (β = - 0.184; 95% confidence interval: - 0.361, - 0.008; p = 0.040). AACsev was not associated with 5-year changes in TUG or ALM in univariable or multivariable analyses (all p > 0.05). In older women, severe aortic calcification was associated with greater 5-year decline in muscle strength, but not TUG or ALM. These findings support the concept that vascular disease may have an effect on the loss of muscular strength. [ABSTRACT FROM AUTHOR]

Claudin-6 (Cldn6) is a tetraspanin transmembrane protein that contributes to tight junctional complexes and has been implicated in the maintenance of lung epithelial barriers. In the present study, we tested the hypothesis that genetic up-regulation of Cldn-6 influences inflammation in mice exposed to short-term environmental diesel particulate matter (DPM). Mice were subjected to ten exposures of nebulized DPM (PM2.5) over a period of 20 days via a nose-only inhalation system (Scireq, Montreal, Canada). Using real-time RT-PCR, we discovered that the Cldn6 gene was up-regulated in control mice exposed to DPM and in lung-specific transgenic mice that up-regulate Cldn-6 (Cldn-6 TG). Interestingly, DPM did not further enhance Cldn-6 expression in Cldn-6 TG mice. DPM caused increased cell diapedesis into bronchoalveolar lavage fluid (BALF) from control mice; however, Cldn-6 TG mice had less total cells and PMNs in BALF following DPM exposure. Because Cldn-6 TG mice had diminished cell diapedesis, other inflammatory intermediates were screened to characterize the impact of increased Cldn-6 on inflammatory signaling. Cytokines that mediate inflammatory responses including TNF-α and IL-1β were differentially regulated in Cldn6 TG mice and controls following DPM exposure. These results demonstrate that epithelial barriers organized by Cldn-6 mediate, at least in part, diesel-induced inflammation. Further work may show that Cldn-6 is a key target in understanding pulmonary epithelial gateways exacerbated by environmental pollution. [ABSTRACT FROM AUTHOR]

Intrauterine growth restriction (IUGR) is a disease affecting 10% of all pregnancies. IUGR is associated with maternal, fetal, or placental abnormalities. Studies investigating the effects of secondhand smoke (SHS) exposure and IUGR are limited. The receptor for advanced glycation end-products (RAGE) is a pro-inflammatory transmembrane receptor increased by SHS in the placenta. We tested the hypothesis that inhibition of RAGE during SHS exposure protects from smoke-induced IUGR. C57BL/6 mice were exposed to SHS or SHS + semi-synthetic glycosaminoglycan ethers (SAGEs) known to inhibit RAGE signaling. Trophoblast cells were treated with cigarette smoke extract (CSE) with or without SAGEs in order to address the effects of RAGE inhibition during trophoblast invasion in vitro. SHS-treated mice demonstrated a significant reduction in fetal weight (7.35-fold, P ≤ 0.0001) and placental weight (1.13-fold, P ≤ 0.0001) compared with controls. Mice co-treated with SHS and SAGEs were protected from SHS-induced fetal weights decreases. SHS treatment of C57BL/6 mice activated placental extracellular signal-regulated kinase (ERK) (3.0-fold, P ≤ 0.05), JNK (2.4-fold, P ≤ 0.05) and p38 (2.1-fold, P ≤ 0.05) and the expression of inflammatory mediators including TNF-α (1.34-fold, P ≤ 0.05) and IL-1β (1.03-fold, P ≤ 0.05). SHS-mediated activation of these molecules was reduced to basal levels when SAGE was co-administered. Invasion of trophoblast cells decreased 92% ( P < 0.002) when treated with CSE and CSE-mediated invasion was completely reversed by SAGEs. We conclude that RAGE inhibition protects against fetal weight loss during SHS-induced IUGR. These studies provide insight into tobacco-mediated IUGR development and clarify avenues that may be helpful in the alleviation of placental complications. [ABSTRACT FROM AUTHOR]

In many problem domains data may come from multiple sources (or views), such as video and audio from a camera or text on and links to a web page. These multiple views of the data are often not directly comparable to one another, and thus a principled method for their integration is warranted. In this paper we develop a new algorithm to leverage information from multiple views for unsupervised clustering by constructing a custom kernel. We generate a multipartite graph (with the number of parts given by the number of views) that induces a kernel we then use for spectral clustering. Our algorithm can be seen as a generalization of co-clustering and spectral clustering and a relative of Kernel Canonical Correlation Analysis. We demonstrate the algorithm on four data sets: an illustrative artificial data set, synthetic fMRI data, voxels from an fMRI study, and a collection of web pages. Finally, we compare its performance to common alternatives. [ABSTRACT FROM AUTHOR]

Summary: Osteocalcin, the osteoblast-derived protein, has been shown to be modulated in patients with problematic glucose metabolism. Our systematic review and meta-analysis found that in humans, higher blood osteocalcin level is associated with lower body indices of fat. Purpose/introduction: Osteocalcin (OC) was found to be inversely correlated with measures of glucose and energy metabolism, with some groups suggesting the undercarboxylated form (ucOC) to be metabolically active, although the link is not clear, especially in humans. Given obesity is a major risk factor for metabolic disorders, we aimed to assess the correlation between OC and two measures of body weight: body mass index (BMI) and percentage body fat (%BF). Methods: MEDLINE and EMBASE were searched to identify observational studies in adult populations that reported the crude correlation coefficients (r) between OC and BMI and %BF. Pool r were obtained using random-effects models. Results: Fifty-one publications were included in this analysis. Both total OC (TOC) (pooled r = − 0.151, 95% CI – 0.17, − 0.130; I2 = 52%) and ucOC (pooled r = − 0.060, 95% CI – 0.103, − 0.016; I2 = 54%) were inversely correlated with BMI. The pooled r between TOC and BMI in Caucasian-and-other-regions (r = − 0.187) were stronger than those in Asian populations (r = − 0.126; intra-group p = 0.002; R2 = 0.21). The mean/median BMI of the reported cohort was the major contributor to between-study heterogeneity in correlation between TOC/ucOC and BMI (R2 = 0.28 and 0.77, respectively). Both TOC and ucOC were also inversely correlated with %BF (TOC: pooled r = − 0.185, 95% CI – 0.257 to − 0.112; ucOC: pooled r = − 0.181, 95% CI – 0.258 to − 0.101). Conclusion: Higher OC and ucOC were correlated with lower BMI and %BF. The inverse correlations between TOC/ucOC and BMI appear to be affected by ethnicity and obesity status. [ABSTRACT FROM AUTHOR]

Midkine (MDK), a heparin-binding growth factor cytokine, is involved in the pathogenesis of kidney diseases by augmenting leukocyte trafficking and activation. Animal models and small case control studies have implicated MDK as a pathological biomarker in chronic kidney diseases (CKD), however this is yet to be confirmed in prospective human studies. In a prospective study of 499 elderly, predominantly Caucasian women aged over 70 years the association between serum MDK collected in 1998, and renal function change and the risk of CKD-related hospitalisations and deaths at 5 and 14.5 years, respectively, was examined. Baseline serum MDK was not associated with 5-year change in estimated glomerular filtration rate using the CKD Epidemiology Collaboration creatinine and cystatin C equation (Standardised β = − 0.09, 95% confidence interval − 3.76–0.48, p = 0.129), 5-year rapid decline in renal function (odds ratio = 0.97, 95% confidence interval 0.46–2.02, p = 0.927) or the risk of 14.5-year CKD-related hospitalisations and deaths (hazard ratio = 1.27, 95% confidence interval.66–2.46, p = 0.470) before or after adjusting for major risk factors. In conclusion, in this cohort of elderly women with normal or mildly impaired renal function, serum MDK was not associated with renal function change or future CKD-related hospitalisations and deaths, suggesting that MDK may not be an early biomarker for progression of CKD. [ABSTRACT FROM AUTHOR]

Flavonoids, plant-derived polyphenolic compounds, have been linked with health benefits. However, evidence from observational studies is incomplete; studies on cancer mortality are scarce and moderating effects of lifestyle risk factors for early mortality are unknown. In this prospective cohort study including 56,048 participants of the Danish Diet, Cancer, and Health cohort crosslinked with Danish nationwide registries and followed for 23 years, there are 14,083 deaths. A moderate habitual intake of flavonoids is inversely associated with all-cause, cardiovascular- and cancer-related mortality. This strong association plateaus at intakes of approximately 500 mg/day. Furthermore, the inverse associations between total flavonoid intake and mortality outcomes are stronger and more linear in smokers than in non-smokers, as well as in heavy (>20 g/d) vs. low-moderate (<20 g/d) alcohol consumers. These findings highlight the potential to reduce mortality through recommendations to increase intakes of flavonoid-rich foods, particularly in smokers and high alcohol consumers. The studies showing health benefits of flavonoids and their impact on cancer mortality are incomplete. Here, the authors perform a prospective cohort study in Danish participants and demonstrate an inverse association between regular flavonoid intake and both cardiovascular and cancer related mortality. [ABSTRACT FROM AUTHOR]