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Abstract: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR = 0.180; MAFEUR = 0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

Introduction: Plastic surgery residency programs leverage their websites as platforms for promoting their commitment to diversity and inclusion to potential candidates. Medical students who are seeking residency positions, including individuals from underrepresented backgrounds, place significant importance on the alignment of program culture and diversity. The authors assessed how these programs showcased diversity and inclusion efforts on their websites., Methods: The authors analyzed 89 plastic surgery integrated residency program websites for the presence of 12 elements, (1) nondiscrimination, (2) diversity and inclusion statement, (3) community resources, (4) extended resident biographies, (5) faculty biographies, (6) faculty photos, (7) resident photos, (8) additional financial resources for trainees, (9) wellness, (10) mental health resources, (11) health disparities/community engagement, and (12) presence of a diversity council. Additionally, we examined the presence of these 12 elements by geographic region (West, Midwest, South, and Northeast). Our analyzed use chi-squared, t-tests, and Mann-Whitney U; significance level was p = 0.005. The independent plastic surgery programs were excluded, considering their websites were combined with the integrated-residency programs., Results: We reviewed 89 websites from February 9, 2024 until February 24, 2024 and on average had 6.32 ± 1.1 diversity and inclusion elements. Resident photos (n = 84, 94.4%), community resources (n = 55, 61.8%), faculty photos (n = 63, 70.8%), and additional financial resources for trainees (n = 56, 62.9%) were the most common. The least common diversity and inclusion elements were diversity councils (n = 12, 13.5%), wellness resources (n = 36, 40.4%), and diversity and inclusion statements (n = 42, 47.2%). The primary analysis revealed that programs with higher number of incoming positions (3 or more) (5.2 ± 1.8) had a significantly higher diversity and inclusion scores when compared to programs with lower number of incoming positions (3.6 ± 2.1) (p = 0.002). Furthermore, based on the geographic regions from the U.S. Census, there was no significant difference between geographic regions., Conclusions: Characterizing the number of program websites and quantifying the number of diversity elements on each site provide an opportunity for more residency programs to further commit to diversity and inclusion. Displaying different diversity and inclusive initiatives on program websites may attract more diverse applicants, particularly individuals from underrepresented populations in medicine., (Copyright © 2024 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Abstract: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

Background and Aims: Assessing the relationship between vitamin K1 intakes, using region-specific food databases, with both all-cause, and cardiovascular disease (CVD) mortality warrants further investigation to inform future preventative strategies. Consequently, we examined the aforementioned associations in the Perth Longitudinal Study of Ageing Women (PLSAW)., Methods and Results: 1436 community-dwelling older Australian women (mean ± SD age 75.2 ± 2.7 years) completed a validated food frequency questionnaire at baseline (1998). Vitamin K1 intake was calculated based on an Australian vitamin K food database, supplemented with published data. All-cause and CVD mortality data was obtained from linked health records. Associations were examined using restricted cubic splines within Cox-proportional hazard models, adjusted for a range of cardiovascular and lifestyle related risk factors. Over 15 years of follow-up, 601 (41.9%) women died, with 236 deaths (16.4%) due to CVD. Compared to women with the lowest vitamin K1 intakes (Quartile 1, median 49.1 μg/day), those with the highest intakes (Quartile 4, median 119.3 μg/day) had lower relative hazards for all-cause mortality (HR 0.66 95%CI 0.51-0.86) and CVD mortality (HR 0.61 95%CI 0.41-0.92). A plateau in the inverse association was observed from vitamin K1 intakes of approximately ≥80 μg/day., Conclusion: Higher vitamin K1 intakes were associated with lower risk for both all-cause and CVD mortality in community-dwelling older women, independent of CVD related risk factors. A higher intake of vitamin K1 rich foods, such as leafy green vegetables, may support cardiovascular health., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: We previously reported that habitual consumption of dietary flavanol oligomers + polymers and anthocyanins is associated with a lower risk of ischemic stroke. However, no studies have investigated their relationship with ischemic stroke subtypes., Objectives: In this follow-up analysis, we aimed to examine the association of flavanol oligomers + polymers and anthocyanin intake with ischemic stroke subtypes, including the following: 1) large-artery atherosclerosis, 2) cardioembolism, 3) small-vessel occlusion, 4) other determined etiology, and 5) undetermined etiology., Methods: Participants (n = 55,094) from the Danish Diet, Cancer, and Health Study were followed up for <16 y for first-time ischemic stroke events, which were classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Intakes of flavanol oligomers + polymers and anthocyanins were calculated from food frequency questionnaires using the Phenol-Explorer database, and their relationships with ischemic stroke subtypes were investigated using restricted cubic splines within Cox proportional hazards models. After multivariable adjustment, higher habitual intakes (quintile 5 compared with quintile 1) of flavanol oligomers + polymers and anthocyanins were associated with a lower risk of specific ischemic stroke subtypes, including large-artery atherosclerosis [flavanol oligomers + polymers, hazard ratio {HR} (95% confidence interval {CI}): 0.64 (0.47, 0.87)], cardioembolism [anthocyanins, HR (95% CI): 0.45 (0.25, 0.82)], and small-vessel occlusion [flavanol oligomers + polymers, HR (95% CI): 0.65 (0.54, 0.80); anthocyanins, HR (95% CI): 0.79 (0.64, 0.97)], but not stroke of other determined or undetermined etiology., Conclusions: Higher habitual intakes of flavanols and anthocyanins are differentially associated with a lower risk of ischemic stroke from atherosclerosis and/or cardioembolism but not with other subtypes., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background and Aims: We and others have identified links between cardiovascular conditions and poor musculoskeletal health. However, the relationship between measures of carotid atherosclerosis such as focal carotid plaque and common carotid intima media thickness (CCA-IMT) and falls remains understudied. This study examined the association between measures of carotid atherosclerosis and fall-related hospitalization over 11.5 years in community dwelling older women., Methods and Results: 1116 older women recruited in 1998 to a five-year randomized controlled trial to examine the effect of calcium supplementation in preventing fracture and who had undertaken B-mode ultrasound in 2001 (three years after the baseline clinical visit) were included in this study. The participants were followed for over 11.5 years as Perth Longitudinal Study of Ageing Women (PLSAW). Over the follow up period, 428 (38.4%) women experienced a fall-related hospitalization. Older women with carotid plaque had 44% a higher relative hazard for fall-related hospitalization (HR 1.44; 95%CI, 1.18 to 1.76) compared to those without carotid plaque. The association persisted after adjustment for established falls risk factors such as measures of muscle strength and physical function.Each SD increase in the mean and maximum CCA-IMT was also associated with a higher risk of fall-related hospitalizations (HR 1.10; 95%CI, 1.00 to 1.21 and HR 1.11; 95%CI, 1.01 to 1.22, respectively)., Conclusions: Measures of carotid atherosclerosis are associated with a higher risk of fall-related hospitalization independent of established falls risk factors. These findings suggest the importance of vascular health when considering falls risk., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Coronary and aortic artery calcifications are generally slow to develop, and their burden predicts cardiovascular disease events. In patients with diabetes mellitus, arterial calcification is accelerated and calcification activity can be detected using 18F-sodium fluoride positron emission tomography (18F-NaF PET)., Objectives: We aimed to determine whether vitamin K1 supplementation inhibits arterial calcification activity in individuals with diabetes mellitus., Methods: This was a post hoc analysis of the ViKCoVaC (effect of Vitamin-K1 and Colchicine on Vascular Calcification activity in subjects with Diabetes Mellitus) double-blind randomized controlled trial conducted in Perth, Western Australia. Individuals with diabetes mellitus and established coronary calcification (coronary calcium score > 10), but without clinical coronary artery disease, underwent baseline 18F-NaF PET imaging, followed by oral vitamin K1 supplementation (10 mg/d) or placebo for 3 mo, after which 18F-NaF PET imaging was repeated. We tested whether individuals randomly assigned to vitamin K1 supplementation had reduced development of new 18F-NaF PET positive lesions within the coronary arteries and aorta., Results: In total, 149 individuals completed baseline and follow-up imaging studies. Vitamin K1 supplementation independently decreased the odds of developing new 18F-NaF PET positive lesions in the coronary arteries (OR: 0.35; 95% CI: 0.16, 0.78; P = 0.010), aorta (OR: 0.27; 95% CI: 0.08, 0.94; P = 0.040), and in both aortic and coronary arteries (OR: 0.28; 95% CI: 0.13, 0.63; P = 0.002)., Conclusions: In individuals with diabetes mellitus, supplementation with 10 mg vitamin K1/d may prevent the development of newly calcifying lesions within the aorta and the coronary arteries as detected using 18F-NaF PET. Further long-term studies are needed to test this hypothesis.This trial was registered at anzctr.org.au as ACTRN12616000024448., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: The COVID-19 pandemic created unprecedented pressure on hospitals globally. Digital tools developed before the crisis provided novel aspects of management, and new digital tools were rapidly developed as the crisis progressed. In our institution, a digitally mature NHS Trust in England which builds software systems, development during the early months of the crisis allowed increased patient safety and care, efficient management of the hospital and publication of data. The aim of this paper is to present this experience as a case study, describing development and lessons learned applicable to wider electronic healthcare record development., Methods: Request, triage, build and test processes for the digital systems were altered in response to the pandemic. Senior Responsible Officers appointed for the emergency triaged all changes and were supported by expert opinion and research active clinicians. Build and test cycles were compressed. New tools were built or existing ones modified in the central Electronic Healthcare Record, PICS (Prescribing, Information and Communication System), Clinical Dashboards and video platforms for remote consultation were developed., Findings: 2236 patients were admitted to UHB with suspected COVID-19 between March and May 2020. Dashboards and visualisation tools enabled by efficient real-time data collection for all new patients, contributed to strategic, operational and clinical decision making.Over 70 urgent changes were made to digital systems, including a screening proforma, improved infection control functions, help and order panels, data dashboards, and updated prescribing features. Novel uses were found for existing functions., Interpretation: Digital tools contributed to a co-ordinated response to COVID-19 in an area with a high disease burden. Change management processes were modified during the pandemic and successfully delivered rapid software modifications and new tools. Principal benefits came from the ability to adapt systems to rapidly changing clinical situations. Lessons learned from this intense development period are widely applicable to EHR development., Lay Summary: Digital tools, which are well designed, can help clinicians and safeguard patients. Health crises such as the COVID pandemic drove rapid development of digital tools. This case study outlines accelerated development within a governance framework that successfully reused existing tools and built new ones. The lessons from this development are generalizable to digital developments in healthcare., Competing Interests: Professor Sapey reports grants from HDR-UK PIONEER Hub during the conduct of the study. She additionally declares grants from the Medical Research Council, the Wellcome Trust, the British Lung Foundation, NIHR, and the Alpha 1 Foundation, outside the submitted work. No other authors declare any competing interests., (Crown Copyright © 2021 Published by Elsevier Ltd on behalf of Fellowship of Postgraduate Medicine. All rights reserved.)

Background: Higher flavonoid intakes are hypothesized to confer protection against type 2 diabetes mellitus., Objectives: We aimed to 1) investigate associations between flavonoid intakes and diabetes, 2) examine the mediating impact of body fat, and 3) identify subpopulations that may receive the greatest benefit from higher flavonoid intakes in participants of the Danish Diet, Cancer, and Health Study followed up for 23 y., Methods: Cross-sectional associations between baseline flavonoid intake, estimated using FFQs and the Phenol Explorer database, and body fat, estimated by bioelectrical impedance, were assessed using multivariable-adjusted linear regression models. Nonlinear associations between flavonoid intake and incident diabetes were examined using restricted cubic splines with multivariable-adjusted Cox proportional hazards models., Results: Among 54,787 participants (median age: 56 y; IQR: 52-60 y; 47.3% men), 6700 individuals were diagnosed with diabetes. Participants in the highest total flavonoid intake quintile (median, 1202 mg/d) had a 1.52 kg lower body fat (95% CI: -1.74, -1.30 kg) and a 19% lower risk of diabetes (HR: 0.81; 95% CI: 0.75, 0.87) after multivariable adjustments and compared with participants in the lowest intake quintile (median: 174 mg/d). Body fat mediated 57% (95% CI: 42, 83%) of the association between flavonoid intake and incident diabetes. Of the flavonoid subclasses, moderate to high intakes of flavonols, flavanol monomers, flavanol oligo + polymers, and anthocyanins were significantly associated with a lower risk of diabetes. Although associations were not modified by sex, smoking status, BMI, or physical activity (Pinteraction > 0.05 for all), findings on an absolute scale suggest that those at a higher risk (those with obesity) may benefit the most from a higher flavonoid intake., Conclusions: The findings reported in this study suggest that a diet abundant in flavonoid-rich foods may help ameliorate diabetes risk, in part through a reduction in body fat., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Flavonoid-rich foods have antiinflammatory, antiatherogenic, and antithrombotic properties that may contribute to a lower risk of ischemic stroke., Objectives: We aimed to investigate the relationship between habitual flavonoid consumption and incidence of ischemic stroke in participants from the Danish Diet, Cancer and Health Study., Design: In this prospective cohort study, 55,169 Danish residents without a prior ischemic stroke [median (IQR) age at enrolment of 56 y (52-60)], were followed for 21 y (20-22). We used Phenol-Explorer to estimate flavonoid intake from food frequency questionnaires obtained at study entry. Incident cases of ischemic stroke were identified from Danish nationwide registries and restricted cubic splines in Cox proportional hazards models were used to investigate relationships with flavonoid intake., Results: During follow-up, 4237 individuals experienced an ischemic stroke. Compared with participants in Q1 and after multivariable adjustment for demographics and lifestyle factors, those in Q5-for intake of total flavonoids, flavonols, and flavanol oligo + polymers-had a 12% [HR (95% CI): 0.88 (0.81, 0.96)], 10% [0.90 (0.82, 0.98)], and 18% [0.82 (0.75, 0.89)] lower risk of ischemic stroke incidence, respectively. Multivariable (demographic and lifestyle) adjusted associations for anthocyanins and flavones with risk of ischemic stroke were not linear, with moderate but not higher intakes associated with lower risk [anthocyanins Q3 vs. Q1 HR (95% CI): 0.85 (0.79, 0.93); flavones: 0.90 (0.84, 0.97)]. Following additional adjustment for dietary confounders, similar point estimates were observed; however, significance was only retained for anthocyanins and flavanol oligo + polymers [anthocyanins Q3 vs. Q1 HR (95% CI): 0.86 (0.79, 0.94); flavanol oligo + polymers Q5 vs. Q1 0.86 (0.78, 0.94)]., Conclusions: These findings suggest that moderate habitual consumption of healthy flavonoid-rich foods is associated with a lower risk of ischemic stroke and further investigation is therefore warranted., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Backgrounds and Aims: Abdominal aortic calcification (AAC) is associated with weaker grip strength, an established risk factor for fall-related hospitalizations. However, its association with long-term fall-related hospitalisations remains unknown. This study investigated the association between AAC and long-term fall-related hospitalizations in community-dwelling older women., Methods: Fall-related hospitalizations were obtained from linked data over 14.5-years in a prospective cohort of 1053 older women (mean age 75.0 ± 2.6 years). At baseline (1998/99), AAC was assessed from lateral spine images obtained using dual-energy X-ray absorptiometry, and scored using a semi-quantitative method (AAC24, range 0-24). The presence of any AAC was defined by AAC24 ≥ 1., Results: Over 14.5-years, 413 (39.2%) women experienced a fall-related hospitalization. In the multivariable-adjusted model, each unit increase in baseline AAC24 was associated with a 3% increase in relative hazards for a fall-related hospitalization (HR 1.03 95%CI, 1.01 to 1.07). Compared to women with no AAC, women with any AAC had a 40% (HR 1.40 95%CI, 1.11 to 1.76) and 39% (HR 1.39 95%CI, 1.10 to 1.76) greater risk for fall-related hospitalizations in the minimal and multivariable-adjusted models, respectively. This relationship was not attenuated by including measures of muscle function such as grip strength and timed-up-and-go., Conclusions: The presence of AAC is associated with long-term fall-related hospitalizations risk, independent of muscle function, in community-dwelling older women. Concurrent assessment of AAC may be a simple and cost-effective way to identify older women at higher risk of falling as part of routine osteoporosis screening., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Nitrate supplements can improve vascular and muscle function. Whether higher habitual dietary nitrate is associated with better muscle function remains underexplored., Objective: The aim was to examine whether habitual dietary nitrate intake is associated with better muscle function in a prospective cohort of men and women, and whether the relation was dependent on levels of physical activity., Methods: The sample (n = 3759) was drawn from the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab) (56% female; mean ± SD baseline age: 48.6 ± 11.1 y). Habitual dietary intake was assessed over 12 y by obtaining an average [of at least 2 time points, e.g., baseline (2000/2001) and 2004/2005 and/or 2011/2012] from a food-frequency questionnaire. Nitrate intake was calculated from a validated nitrate database and other published literature. Muscle function was quantified by knee extension strength (KES) and the 8-ft-timed-up-and-go (8ft-TUG) test performed in 2011/2012. Physical activity was assessed by questionnaire. Generalized linear models and logistic regression were used to analyze the data., Results: Median (IQR) total nitrate intake was 65 (52-83) mg/d, with ∼81% derived from vegetables. Individuals in the highest tertile of nitrate intake (median intake: 91 mg/d) had 2.6 kg stronger KES (11%) and 0.24 s faster 8ft-TUG (4%) compared with individuals in the lowest tertile of nitrate intake (median intake: 47 mg/d; both P < 0.05). Similarly, individuals in the highest tertile of nitrate intake had lower odds for weak KES (adjusted OR: 0.69; 95% CI: 0.47, 0.73) and slow 8ft-TUG (adjusted OR: 0.63; 95% CI: 0.50, 0.78) compared with those in the lowest tertile. Physical activity did not influence the relationship between nitrate intake and muscle function (KES; P-interaction = 0.86; 8ft-TUG; P-interaction = 0.99)., Conclusions: Higher habitual dietary nitrate intake, predominantly from vegetables, could be an effective way to promote lower-limb muscle strength and physical function in men and women., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background & Aims: Poor nutritional habits are linked to higher perceived stress, but the relationship between fruit and vegetable (FV) intake and stress is uncertain. The primary aim of this cross-sectional study was to explore the relationship between FV intake and perceived stress in a population-based cohort of men and women aged ≥25 years from the Australian Diabetes, Obesity and Lifestyle (AusDiab) Study. A secondary aim was to investigate the relationship between serum carotenoids, biomarkers of FV intake, and perceived stress., Methods: In Australian men and women, dietary intake was assessed using a Food Frequency Questionnaire in 1999-2000 (n = 8689). Perceived stress was assessed using a validated Perceived Stress Questionnaire [PSQ index values ranging from 0 (lowest) to 1 (highest)]. Serum carotenoids were measured in a subset of participants (n = 1187) using high-performance liquid chromatography. Multivariable-adjusted linear and logistic regression were performed to investigate the associations between FV intake and perceived stress., Results: Mean age of participants was 47.4 (SD 14.1) years (49.8% females). Participants with the highest intakes of FV had 10% lower PSQ index values than those with the lowest intake [Q4: 0.27 ± 0.004 vs. Q1: 0.30 ± 0.004 (mean ± SE), p = 0.004]. Similar associations were found for fruits and vegetables, analysed separately. In subgroup analyses higher FV intake was associated with lower perceived stress in the middle-aged adults [≥45-<65 years (p = 0.004)], but not in the younger (<45 years) and older participants (≥65 years). Higher FV intake was also significantly associated with lower perceived stress in men (p = 0.009) and women (p = 0.012), separately. Serum carotenoid levels were inversely associated with perceived stress before, but not after adjusting for age and other confounding factors., Conclusion: In Australian adults, higher FV intake was associated with lower perceived stress, particularly in the middle-aged adults. These findings support current recommendations that fruit and vegetables are essential for health and well-being., Competing Interests: Conflict of interest CPB and JMH report grants from FruitWest, and from Department of Agriculture and Food WA, outside the submitted work. DJM and JES report grants from Abbott Australasia Pty Ltd, Alphapharm Pty Ltd, AstraZeneca, Bristol-Myers Squibb, Eli Lilly Australia, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Novartis Pharmaceuticals, Novo Nordisk Pharmaceuticals, Roche Diagnostics Australia, Sanofi Aventis and Sanofi-synthelabo, during the conduct of the study. RMD received a Primary Growth Partnership grant via the Ministry of Primary Industries in New Zealand with Fonterra Co-operative Group Ltd, outside the submitted work. All other authors have no potential conflicts of interest to report., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The role of nutrition in the primary prevention of peripheral artery disease (PAD), the third leading cause of atherosclerotic cardiovascular disease, is undetermined. Flavonoids may attenuate atherosclerosis and therefore persons who consume flavonoid-rich foods may have a lower risk of developing PAD., Objectives: We aimed to examine the association between flavonoid intake and PAD hospitalizations and investigate if the association differs according to established risk factors for PAD., Methods: Baseline data from 55,647 participants of the Danish Diet, Cancer, and Health Study without PAD, recruited from 1993 to 1997, were cross-linked with Danish nationwide registries. Flavonoid intake was calculated from FFQs using the Phenol-Explorer database. Associations were examined using multivariable-adjusted restricted cubic splines based on Cox proportional hazards models., Results: After a median [IQR] follow-up time of 21 [20-22] y, 2131 participants had been hospitalized for any PAD. The association between total flavonoid intake and total PAD hospitalizations was nonlinear, reaching a plateau at ∼750-1000 mg/d. Compared with the median flavonoid intake in quintile 1 (174 mg/d), an intake of 1000 mg/d was associated with a 32% lower risk of any PAD hospitalization (HR: 0.68; 95% CI: 0.60, 0.77), a 26% lower risk of atherosclerosis (HR: 0.74; 95% CI: 0.62, 0.88), a 28% lower risk of an aneurysm (HR: 0.72; 95% CI: 0.59, 0.88), and a 47% lower risk of a hospitalization for other peripheral vascular disease (HR: 0.53; 95% CI: 0.42, 0.67). A higher total flavonoid intake was also significantly associated with a lower incidence of revascularization or endovascular surgery and lower extremity amputation. The association between total flavonoid intake and PAD hospitalizations differed according to baseline smoking status, alcohol intake, BMI, and diabetes status., Conclusions: Ensuring the adequate consumption of flavonoid-rich foods, particularly in subpopulations prone to the development of atherosclerosis, may be a key strategy to lower the risk of PAD., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Conjugated proteins and enzymes are often formed using N-hydroxysuccinimide (NHS) chemistry, which reacts with free primary amines resulting in a loss of charge and a reduction in isoelectric point (pI). Measurement of the extent of reaction of these conjugates is critical for biopharmaceutical developers. Due to this change in protein charge state, denaturing capillary isoelectric focussing (cIEF) offers a potentially straightforward and convenient approach for extent-of-reaction quantification. Here, we demonstrate the potential of this technique with poly(ethylene glycol) (PEG) conjugates of Erwinia chrysanthemil-asparaginase (ErA). Development of an appropriate sample preparation technique is critical to achieving reproducible cIEF electropherograms, particularly for denaturation-resistant proteins such as ErA, and an emphasis was placed on this during development of the PEG-ErA cIEF method. cIEF electropherograms demonstrating a distribution of PEGylation states in a bell-shaped curve were obtained, and assignment of PEGylation states to these peaks was critical to routine use of the method. The method is sensitive enough to resolve non-lysine adducts of PEG (such as those conjugated to histidine residues) and was shown to give reproducible results over a 2 year period. Biopharmaceutical developers should consider cIEF for extent of reaction monitoring and measurement for conjugates of free amine groups., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background & Aims: Primary prevention of atrial fibrillation (AF) through behavioural and dietary modification is a critically important and unmet need. Flavonoids are bioactive dietary compounds with promising cardiovascular health benefits. Our aim was to investigate the association between flavonoid intake and clinically apparent AF., Methods: Baseline data from 55 613 participants of the Danish Diet, Cancer and Health Study, without AF, recruited between 1993 and 1997, were cross-linked with Danish nationwide registries. Total flavonoid and flavonoid subclass intakes were calculated from validated food frequency questionnaires using the Phenol-Explorer database. Associations between flavonoid intake and incident AF (first-time hospitalization or outpatient visit) were examined using restricted cubic splines based on Cox proportional hazards models., Results: During a median [IQR] follow-up of 21 [18-22] years, 7291 participants were diagnosed with AF. Total flavonoid intake was not statistically significantly associated with risk of incident AF in the whole cohort. However, compared to the lowest quintile, a total flavonoid intake of 1000 mg/day was associated with a lower risk of AF in smokers [0.86 (0.77, 0.96)] but not in non-smokers [0.96 (0.88, 1.06)], and a lower risk of AF in high alcohol consumers [>20 g/d: 0.84 (0.75, 0.95)] but not in low-to-moderate alcohol consumers [<20 g/d: 0.97 (0.89, 1.07)]., Conclusion: Intake of flavonoids was not significantly associated with a lower risk of incident AF. However, higher intakes of flavonoids may be beneficial for those at a higher risk of developing AF., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background and Aims: Abdominal aortic calcification (AAC) and low ankle-brachial index (ABI) are markers of multisite atherosclerosis. We sought to estimate their associations in older men with health care costs and utilization adjusted for each other, and after accounting for CVD risk factors and prevalent CVD diagnoses., Methods: This was an observational cohort study of 2393 community-dwelling men (mean age 73.6 years) enrolled in the Osteoporotic Fractures in Men (MrOS) study and U.S. Medicare Fee for Service (FFS). AAC was scored on baseline lateral lumbar spine X-rays using a 24-point scale. ABI was measured as the lowest ratio of arm to right or left ankle blood pressure. Health care costs, hospital stays, and SNF stays were identified from Medicare FFS claims over 36 months following the baseline visit., Results: Men with AAC score ≥9 (n = 519 [21.7% of analytic cohort]) had higher annualized total health care costs of $1473 (95% C.I. 293, 2654, 2017 U S. dollars) compared to those with AAC score 0-1, after multivariable adjustment. Men with ABI <0.90 (n = 154 [6.4% of analytic cohort]) had higher annualized total health care costs of $2705 (95% CI 634, 4776) compared to men with normal ABI (≥0.9 and < 1.4), after multivariable adjustment., Conclusions: High levels of AAC and low ABI in older men are associated with higher subsequent health care costs, after accounting for clinical CVD risk factors, prevalent CVD diagnoses, and each other. Further investigations of whether preventing progression of peripheral vascular disease and calcification reduces subsequent health care costs are warranted., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Higher intakes of flavonoids provide health benefits, however, the importance of each flavonoid class and which population groups may receive the greatest protection from higher flavonoid intake warrants further investigation., Objective: To explore the associations of flavonoid and flavonoid-rich wholefood intakes with all-cause mortality and the moderating effects of early mortality risk factors., Design: The study included 2349 participants of The Blue Mountains Eye Study, with a mean ± SD age at baseline of 64.7 ± 9.2 years. Flavonoid intake was calculated from baseline food frequency questionnaires using US Department of Agriculture food composition databases. Associations were examined using adjusted Cox proportional hazards models., Results: After 14 years of follow-up, 677 participants died. There was a flavonoid threshold effect with the greatest risk reduction seen between low and moderate intakes of total flavonoids, flavonoid classes and flavonoid-rich foods. Amongst the whole cohort, participants in the highest tertile of anthocyanidin intake had a significantly lower risk of all-cause mortality [multivariable adjusted HR (95%CI): 0.76 (0.61, 0.94)] when compared to those in the lowest tertile. Amongst participants with at least one early mortality risk factor (smoking, high alcohol consumption, no regular exercise or obesity), risk of all-cause mortality was lower in those in the highest intake tertile for total flavonoids [adjusted HR: 0.77 (0.59, 1.00)], flavan-3-ols [0.75 (0.58, 0.98)], anthocyanidins [0.70 (0.54, 0.92)], and proanthocyanidins [0.69 (0.52, 0.92)], compared to those in the lowest tertile. No similar associations were observed among those without any risk factors. Similarly, consumption of apples, tea and the individual flavonoid compounds, quercetin and epicatechin, were associated with a lower risk of all-cause mortality among participants with at least one risk factor, but not amongst other participants., Conclusion: Moderate to high intakes of flavonoids and certain flavonoid subclasses may provide health benefits, particularly for individuals with at least one early mortality risk factor., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass., Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci., Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms)., Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection., Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

Objectives: To investigate the relationship of 4 sarcopenia definitions with long-term all-cause mortality risk in older Australian women., Design: Data from the Perth Longitudinal Study in Aging Women from 2003 to 2013 was examined in this prospective cohort study. The 4 sarcopenia definitions were the United States Foundation for the National Institutes of Health (FNIH), the European Working Group on Sarcopenia in Older People (EWGSOP), and adapted FNIH (AUS-POP F ) and EWGSOP (AUS-POP E ) definitions using Australian population-specific cut-points [<2 standard deviation (SD)] below the mean of young healthy Australian women. All-cause mortality was captured via linked data systems., Setting and Participants: In total, 903 community-dwelling older Australian women (baseline mean age 79.9 ± 2.6 years) with concurrent measures of muscle strength (grip strength), physical function (timed-up-and-go; TUG) and appendicular lean mass (ALM) were included., Measures: Cox-proportional hazards modeling was used to examine the relationship between sarcopenia definitions and mortality over 5 and 9.5 years., Results: Baseline prevalence of sarcopenia by the 4 definitions differed substantially [FNIH (9.4%), EWGSOP (24.1%), AUS-POP F (12.0%), AUS-POP E (10.7%)]. EWGSOP and AUS-POP E had increased age-adjusted hazard ratios (aHRs) for mortality over 5 years [aHR 1.88 95% confidence interval (CI) (1.24‒2.85), P < .01; aHR 2.52 95% CI (1.55‒4.09), P < .01, respectively] and 9.5 years (aHR 1.39 95% CI (1.06‒1.81), P = .02; aHR 1.94 95% CI (1.40‒2.69), P < .01, respectively). No such associations were observed for FNIH or AUS-POP F . Sarcopenia components including weaker grip strength (per SD, 4.9 kg; 17%) and slower TUG (per SD, 3.1 seconds; 40%) but not ALM adjusted-variants (ALM/body mass index or ALM/height 2 ) were associated with greater relative hazards for mortality over 9.5 years., Conclusions/relevance: Unlike FNIH, the EWGSOP sarcopenia definition incorporating weak muscle strength and/or poor physical function was related to prognosis, as was the regionally adapted version of EWGSOP. Although sarcopenia definitions were not developed based on prognosis, this is an important consideration for globally standardizing the sarcopenia framework., (Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Postprandial lipemia (PPL), defined as a prolonged or elevated rise in triglycerides that accompanies fat feeding, is a significant risk factor for coronary heart disease and associated comorbidities. The impact of PPL on coronary heart disease risk is underscored by the preponderance of each day spent in the postprandial state., Objective: In this study, we evaluated cross-sectionally the association between usual (ie, noninterventional) physical activity and the 6-hour triglyceride response to a standardized high-fat meal., Methods: The high-fat meal intervention was carried out in 671 apparently healthy individuals as part of the Heredity and Phenotype Intervention Heart Study. Triglyceride levels were measured in the fasting state and during 6 hours after administration of a standardized fat challenge. We defined PPL response as the triglyceride area under the fat load curve (AUC) and measured physical activity using accelerometers that were worn continuously over a 7-day period., Results: Physical activity levels decreased with increasing age and were higher in men than women (both P < .001). The triglyceride AUC increased with increasing age in both men and women (both P < .001) and was also higher in men than in women (age-adjusted P = 9.2 × 10 -12 ). Higher physical activity levels were associated with a lower triglyceride AUC (P = .003), adjusting for age, sex, body mass index, and fasting low-density lipoprotein., Conclusion: These results suggest that the protective benefits of physical activity on cardiovascular health may operate, at least in part, through reduction of the PPL triglyceride response., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Dietary nitrate, found predominantly in green leafy vegetables and beetroot, is a precursor of nitric oxide. Under- or overproduction of nitric oxide is implicated in the etiology of several eye diseases. However, the potential influence of dietary nitrate intake on age-related macular degeneration (AMD) risk has not been assessed., Objective: To investigate the temporal association between dietary nitrate intake (from both vegetable and nonvegetable sources) and the 15-year incidence of AMD, independent of potential confounders., Design: A longitudinal cohort study conducted from 1992-1994 to 2007-2009., Participants/setting: The Blue Mountains Eye Study is a population-based study of adults aged 49+ at baseline, from a region west of Sydney, Australia. At baseline, 2,856 participants with complete dietary data and AMD information were examined, and of these, 2,037 participants were re-examined 15 years later and thus included in incidence analysis., Main Outcomes Measured: Incidence of AMD (main outcome) was assessed from retinal photographs. Dietary intake was assessed using a semiquantitative food-frequency questionnaire. Nitrate intake from vegetables and nonvegetable sources was calculated by use of a validated comprehensive database., Results: After adjusting for age, sex, smoking, energy intake, fish consumption, and AMD risk alleles (complement factor H and age-related maculopathy susceptibility-2 single nucleotide polymorphisms), participants in the third quartile compared with those in the first quartile (reference group) of total nitrate and total vegetable nitrate intake had reduced risk of incident early AMD: odds ratio (OR) 0.61 (95% CI 0.41 to 0.90) and OR 0.65 (95% CI 0.44 to 0.96), respectively. Significant associations were not observed between the fourth vs first quartile of total nitrate and vegetable nitrate intake with incident early AMD: OR 0.74 (95% CI 0.51 to 1.08) and OR 0.69 (95% CI 0.47 to 1.00), respectively. Nonsignificant associations were also observed with 15-year incidence of late AMD and total nonvegetable nitrate intake., Conclusions: These novel findings could have important implications, if the association between total nitrate intake and vegetable nitrate intake and 15-year incidence of early AMD is confirmed in other observational or intervention studies., (Copyright © 2018 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Background: The majority of research performed to date has examined the effects of commonly known antioxidants such as vitamins C, E, and A and carotenoids on age-related macular degeneration (AMD) risk and progression. To date, there is limited research on promising phytochemicals with antioxidant and anti-inflammatory properties, including flavonoids., Objective: In this exploratory study, we aimed to assess the independent associations between dietary intake of total flavonoids and common flavonoid classes with the prevalence and 15-y incidence of AMD., Design: In this population-based cohort study, 2856 adults aged ≥49 y at baseline and 2037 followed up 15 y later were included in prevalence and incidence analyses, respectively. Dietary intake was assessed by using a semiquantitative food-frequency questionnaire (FFQ). Estimates of the flavonoid content of foods in the FFQ were assessed by using the USDA Flavonoid, Isoflavone, and Proanthocyanidin databases. AMD was assessed from retinal photographs., Results: In cross-sectional analysis, each 1-SD increase in total overall flavonoid intake was associated with a reduced likelihood of any AMD (multivariable-adjusted OR: 0.76; 95% CI: 0.58, 0.99). Each 1-SD increase in dietary intake of total flavonols and total flavanones was associated with reduced odds of the prevalence of any AMD [multivariable-adjusted OR (95% CI): 0.75 (0.58, 0.97) and 0.77 (0.60, 0.99), respectively]. A marginally significant trend (P = 0.05) was observed between increasing the intake of total flavanone and hesperidin (from the first to the fourth quartile) and reduced likelihood of incident late AMD, after multivariable adjustment. Participants who reported ≥1 serving of oranges/d compared with those who never consumed oranges at baseline had a reduced risk of late AMD 15 y later (multivariable-adjusted OR: 0.39; 95% CI: 0.18, 0.85)., Conclusions: Our findings suggest an independent and protective association between dietary intake of flavonoids and the likelihood of having AMD. Additional prospective cohort studies are needed to validate these findings.

Background: Emerging evidence suggests that increasing intakes of nitrate-rich vegetables may be an effective approach to reduce blood pressure., Objective: Our primary aim was to determine whether daily consumption of nitrate-rich vegetables over 4 wk would result in lower blood pressure., Design: Thirty participants with prehypertension or untreated grade 1 hypertension were recruited to a randomized controlled crossover trial with 4-wk treatment periods separated by 4-wk washout periods. Participants completed 3 treatments in random order: 1) increased intake (∼200 g/d) of nitrate-rich vegetables [high-nitrate (HN); ∼150 mg nitrate/d], 2) increased intake (∼200 g/d) of nitrate-poor vegetables [low-nitrate (LN); ∼22 mg nitrate/d], and 3) no increase in vegetables (control; ∼6 mg nitrate/d). Compliance was assessed with the use of food diaries and by measuring plasma nitrate and carotenoids. Nitrate metabolism was assessed with the use of plasma, salivary, and urinary nitrate and nitrite concentrations. The primary outcome was blood pressure assessed by using 24-h ambulatory, home, and clinic measurements. Secondary outcomes included measures of arterial stiffness., Results: Plasma nitrate and nitrite concentrations increased with the HN treatment in comparison to the LN and control treatments (P < 0.001). Plasma carotenoids increased with the HN and LN treatments compared with the control (P < 0.01). HN treatment did not reduce systolic blood pressure [24-h ambulatory-HN: 127.4 ± 1.1 mm Hg; LN: 128.6 ± 1.1 mm Hg; control: 126.2 ± 1.1 mm Hg (P = 0.20); home-HN: 127.4 ± 0.7 mm Hg; LN: 128.7 ± 0.7 mm Hg; control: 128.3 ± 0.7 mm Hg (P = 0.36); clinic-HN: 128.4 ± 1.3 mm Hg; LN: 130.3 ± 1.3 mm Hg; control: 129.8 ± 1.3 mm Hg (P = 0.49)] or diastolic blood pressure compared with LN and control treatments (P > 0.05) after adjustment for pretreatment values, treatment period, and treatment order. Similarly, no differences were observed between treatments for arterial stiffness measures (P > 0.05)., Conclusion: Increased intake of nitrate-rich vegetables did not lower blood pressure in prehypertensive or untreated grade 1 hypertensive individuals when compared with increased intake of nitrate-poor vegetables and no increase in vegetables. This trial was registered at www.anzctr.org.au as ACTRN12615000194561.

Background: Dietary nitrate is an important source of nitric oxide (NO), a molecule critical for cardiovascular health. Nitrate is sequentially reduced to NO through an enterosalivary nitrate-nitrite-NO pathway that involves the oral microbiome. This pathway is considered an important adjunct pathway to the classical l-arginine-NO synthase pathway., Objective: The objective of this study was to systematically assess the evidence for dietary nitrate intake and improved cardiovascular health from both human and animal studies., Design: A systematic literature search was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines by using key search terms in Medline and EMBASE databases and defined inclusion and exclusion criteria., Results: Thirty-seven articles on humans and 14 articles on animals were included from 12,541 screened references. Data on the effects of dietary nitrate on blood pressure, endothelial function, ischemic reperfusion injury, arterial stiffness, platelet function, and cerebral blood flow in both human and animal models were identified. Beneficial effects of nitrate on vascular health have predominantly been observed in healthy human populations, whereas effects in populations at risk of cardiovascular disease are less clear. Few studies have investigated the long-term effects of dietary nitrate on cardiovascular disease clinical endpoints. In animal studies, there is evidence that nitrate improves blood pressure and endothelial function, particularly in animal models with reduced NO bioavailability. Nitrate dose seems to be a critical factor because there is evidence of cross-talk between the 2 pathways of NO production., Conclusions: Evidence for a beneficial effect in humans at risk of cardiovascular disease is limited. Furthermore, there is a need to investigate the long-term effects of dietary nitrate on cardiovascular disease clinical endpoints. Further animal studies are required to elucidate the mechanisms behind the observed effects.

Objective: We aimed to study whether dietary fat composition (n-3 and n-6 polyunsaturated fatty acids ratio (PUFAs) and PUFAs and saturated fatty acids (SFAs) ratio) is associated with total body fat (TF) and body fat distribution and whether this association was modified by the presence of chronic disease in middle-aged and elderly women in two population-based cohorts in the Netherlands and Australia., Methods: The study was performed in the Rotterdam Study (RS), a prospective cohort study among subjects aged 55 years and older (N = 1182 women) and the Calcium Intake Fracture Outcome Study (CAIFOS), a 5-year randomized controlled trial among women age 70+ (N = 891). At baseline, diet (i.e. PUFAs and SFAs) was measured by validated food frequency questionnaires. TF was assessed using Dual-energy X-ray absorptiometry in both studies and android abdominal fat (AF), gynoid fat (GF) and the android/gynoid ratio (A/G ratio) in the RS but not the CAIFOS. Chronic disease was defined as the presence of cardiovascular disease, diabetes mellitus and cancer., Results: No association was found between dietary n-3/n-6 PUFAs ratio or SFA/PUFAs ratio with TF in both cohorts. In the RS, a high n-3/n-6 PUFAs ratio was associated with a higher AF (3rd vs. 2nd tertile (reference): β: 0.15; 95% CI: 0.05, 0.24) but not with the A/G ratio. A low SFA/PUFA ratio was associated with a lower AF (1st vs. 2nd tertile (reference): β: -0.12; 95% CI: -0.22, -0.06) but not with the A/G ratio. Presence of chronic disease was found to be a significant effect modifier in both cohorts with regard to n-3/n-6 PUFAs and TF (P < 0.05). In participants without chronic disease, a higher n-3/n-6 PUFAs ratio was associated with a higher TF in the RS cohort (3rd vs. 2nd tertile (reference): β: 0.94; 95% CI: 0.12, 1.76), but this was not replicated in CAIFOS., Conclusion: These findings do not support the hypothesis that dietary fat composition is consistently associated with TF and body fat distribution in women. Future studies should clarify to what extent these findings may be influenced by the presence of chronic disease., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Nitrate-rich vegetables lower blood pressure and improve endothelial function in humans. It is not known, however, whether increased consumption of nitrate-rich vegetables translates to a lower risk of atherosclerotic vascular disease (ASVD) mortality. Objective: The objective was to investigate the association of nitrate intake from vegetables with ASVD mortality. Design: A total of 1226 Australian women aged 70-85 y without prevalent ASVD and/or diabetes were recruited in 1998 and were studied for 15 y. We assessed demographic and ASVD risk factors at baseline (1998), and we used a validated food-frequency questionnaire to evaluate dietary intake. Nitrate intake from vegetables was calculated by use of a newly developed comprehensive database. The primary outcome was any death attributed to ASVD ascertained by using linked data that were provided via the Western Australian Data Linkage system. We used Cox proportional hazards modeling to examine the association between nitrate intake and ASVD mortality before and after adjustment for lifestyle and cardiovascular disease risk factors. Results: During a follow-up period of 15,947 person-years, 238 of 1226 (19.4%) women died of ASVD-related causes. The mean ± SD vegetable nitrate intake was 67.0 ± 29.2 mg/d. Each SD higher vegetable nitrate intake was associated with a lower risk of ASVD mortality in both unadjusted [HR: 0.80 (95% CI: 0.70, 0.92), P = 0.002] and multivariable-adjusted [HR: 0.79 (95% CI: 0.68, 0.93), P = 0.004] analyses. This relation was attenuated after further adjustment for diet quality [HR: 0.85 (95% CI: 0.72, 1.01), P = 0.072]. Higher vegetable nitrate intake (per SD) also was associated with a lower risk of all-cause mortality [multivariable-adjusted HR: 0.87 (95% CI: 0.78, 0.97), P = 0.011]. Conclusions: Nitrate intake from vegetables was inversely associated with ASVD mortality independent of lifestyle and cardiovascular disease risk factors in this population of older adult women without prevalent ASVD or diabetes. These results support the concept that nitrate-rich vegetables may reduce the risk of age-related ASVD mortality. This trial was registered at www.anzctr.org.au as ACTRN12617000640303., (© 2017 American Society for Nutrition.)

Background: Observational studies have linked tea drinking, a major source of dietary flavonoids, with higher bone density. However, there is a paucity of prospective studies examining the association of tea drinking and flavonoid intake with fracture risk., Objective: The objective of this study was to examine the associations of black tea drinking and flavonoid intake with fracture risk in a prospective cohort of women aged >75 y., Design: A total of 1188 women were assessed for habitual dietary intake with a food-frequency and beverage questionnaire. Incidence of osteoporotic fracture requiring hospitalization was determined through the Western Australian Hospital Morbidity Data system. Multivariable adjusted Cox regression was used to examine the HRs for incident fracture., Results: Over 10 y of follow-up, osteoporotic fractures were identified in 288 (24.2%) women; 212 (17.8%) were identified as a major osteoporotic fracture, and of these, 129 (10.9%) were a hip fracture. In comparison with the lowest tea intake category (≤1 cup/wk), consumption of ≥3 cups/d was associated with a 30% decrease in the risk of any osteoporotic fracture (HR: 0.70; 95% CI: 0.50, 0.96). Compared with women in the lowest tertile of total flavonoid intake (from tea and diet), women in the highest tertile had a lower risk of any osteoporotic fracture (HR: 0.65; 95% CI: 0.47, 0.88), major osteoporotic fracture (HR: 0.66; 95% CI: 0.45, 0.95), and hip fracture (HR: 0.58; 95% CI: 0.36, 0.95). For specific classes of flavonoids, statistically significant reductions in fracture risk were observed for higher intake of flavonols for any osteoporotic fracture and major osteoporotic fracture, as well as flavones for hip fracture (P < 0.05)., Conclusion: Higher intake of black tea and particular classes of flavonoids were associated with lower risk of fracture-related hospitalizations in elderly women at high risk of fracture., (© 2015 American Society for Nutrition.)

Background: The reduction of saturated fatty acid (SFA) intake has been the basis of long-standing dietary recommendations. However, recent epidemiologic studies have reported conflicting evidence in the relation between SFA consumption and risk of atherosclerotic vascular disease (ASVD) mortality., Objective: We investigated the association of SFA intake with serum lipid profiles and ASVD mortality in a population-based 10-y cohort study., Design: At baseline (1998) 1469 women living in Perth, Western Australia, with a mean ± SD age of 75.2 ± 2.7 y had SFA intake measured by using a validated food-frequency questionnaire. Outcome data were serum lipids at baseline and ASVD deaths over 10 y (13,649 person-years of follow-up), retrieved from the Western Australian Data Linkage System. Other risk factors for ASVD were assessed and adjusted for in multivariable analyses., Results: ASVD deaths occurred in 9.1% (134) of participants. The highest quartile of SFA intake (>31.28 g/d) had an ~16% cumulative mortality risk compared with ~5% in the lowest quartile (<17.39 g/d) (HR: 3.07; 95% CI: 1.54, 6.11; P = 0.001). Baseline SFA intake was associated with baseline serum total and LDL cholesterol in multivariable-adjusted models (β: 0.199, SE: 0.056, P < 0.001 and β: 0.190, SE: 0.051, P < 0.001, respectively). However, baseline serum total and LDL cholesterol were not associated with ASVD mortality., Conclusions: High SFA intake was associated with the risk of ASVD mortality in this population of elderly women. Although there was a strong positive association between SFA intake and LDL cholesterol, LDL cholesterol was not associated with ASVD mortality in this cohort. Nevertheless, these data support dietary advice to reduce SFA intake., (© 2015 American Society for Nutrition.)

Background: Flavonoids are bioactive compounds found in foods such as tea, chocolate, red wine, fruit, and vegetables. Higher intakes of specific flavonoids and flavonoid-rich foods have been linked to reduced mortality from specific vascular diseases and cancers. However, the importance of flavonoids in preventing all-cause mortality remains uncertain., Objective: The objective was to explore the association between flavonoid intake and risk of 5-y mortality from all causes by using 2 comprehensive food composition databases to assess flavonoid intake., Design: The study population included 1063 randomly selected women aged >75 y. All-cause, cancer, and cardiovascular mortalities were assessed over 5 y of follow-up through the Western Australia Data Linkage System. Two estimates of flavonoid intake (total flavonoidUSDA and total flavonoidPE) were determined by using food composition data from the USDA and the Phenol-Explorer (PE) databases, respectively., Results: During the 5-y follow-up period, 129 (12%) deaths were documented. Participants with high total flavonoid intake were at lower risk [multivariate-adjusted HR (95% CI)] of 5-y all-cause mortality than those with low total flavonoid consumption [total flavonoidUSDA: 0.37 (0.22, 0.58); total flavonoidPE: 0.36 (0.22, 0.60)]. Similar beneficial relations were observed for both cardiovascular disease mortality [total flavonoidUSDA: 0.34 (0.17, 0.69); flavonoidPE: 0.32 (0.16, 0.61)] and cancer mortality [total flavonoidUSDA: 0.25 (0.10, 0.62); flavonoidPE: 0.26 (0.11, 0.62)]., Conclusions: Using the most comprehensive flavonoid databases, we provide evidence that high consumption of flavonoids is associated with reduced risk of mortality in older women. The benefits of flavonoids may extend to the etiology of cancer and cardiovascular disease., (© 2015 American Society for Nutrition.)

Impaired muscle function has been demonstrated to be an important predictor of frailty and fracture in elderly people. The aim of this cross-sectional study was to evaluate the association of dairy intake with body composition and physical performance in 1,456 older women aged 70 to 85 years. Participants were assessed for dairy consumption (milk, yogurt, and cheese) by a validated food frequency questionnaire, body composition by dual-energy x-ray absorptiometry, and physical performance using hand-grip strength and Timed Up and Go tests. Data on falls in the previous 3 months were collected. Women were categorized according to tertiles of dairy intake: first tertile (≤1.5 servings/day), second tertile (1.5 to 2.2 servings/day), and third tertile (≥2.2 servings/day). Main outcomes were compared using analysis of covariance adjusting for confounding factors. Odds ratios for self-reported falls and risk of poor Timed Up and Go were obtained by using binary logistic regression. The mean age was 75.2±2.7 years and body mass index was 27.2±4.7. Compared with those in the first tertile of dairy intake, women in the third tertile had significantly greater whole body lean mass (34.4±0.3 vs 32.9±0.3 kg; P=0.001) and appendicular skeletal muscle mass (15.3±0.2 vs 14.5±0.2 kg; P=0.002), greater hand-grip strength (20.9±0.2 vs 20.0±0.2 kg; P=0.02), and 26% lower odds for a poor Timed Up and Go test (P=0.04); however, the difference in prevalence of falls in the previous 3 months was not statistically significant (10.3% vs 14.4%; P=0.08). Our results suggest an association of higher dairy intake with greater whole body lean mass and better physical performance in older women., (Copyright © 2013 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)