Purpose Inflammation could play a key role in tissue damage and bone metabolism. The modified dietary inflammatory score (M-DIS) is a validated tool to estimate the inflammatory potential of the diet. In the present study, we evaluate the associations between the M-DIS and bone mineral density (BMD) in a senior Mediterranean population with overweight/obesity and metabolic syndrome. Methods Baseline cross-sectional association between the M-DIS and bone mineral density was assessed in 1134 participants of the multicenter PREDIMED-Plus trial (aged 55-75 with overweight/obesity and metabolic syndrome). BMD was measured using Dual-energy X-ray Absorptiometry scans and participants answered a food frequency questionnaire to determine the M-DIS. BMD was categorized as low BMD when T score was equal or lower than -1 and normal BMD in another case. Associations between BMD and M-DIS were evaluated by using linear and logistic regressions adjusted by other co-variates. Results Participants in the top tertile of the M-DIS had a lower BMD at total femur [beta (95% CI) - 0.02 (- 0.04, - 0.01)], trochanter areas [beta (95% CI) - 0.03 (- 0.05, - 0.01)] and lumbar spine area [beta (95% CI) - 0.03 (- 0.07, 0.01)] (but in the last case, measures were less precise and hence not statistically significant) compared to those in the lower M-DIS tertile. Multiple logistic regression analyses showed that the odds of the total femur and femoral trochanter osteopenia/osteoporosis were higher in participants in the top tertile compared to those in the lowest tertile of M-DIS [OR (95% CI) 1.71 (1.12, 2.64), P for trend 0.015; 2.02 (1.29, 3.21), P for trend 0.002, respectively]. Conclusion A high pro-inflammatory diet, measured by the M-DIS, is associated with lower BMD in a senior Mediterranean population with metabolic syndrome.

Objectives: Although low-quality diets and smoking are independently associated with higher mortality risk, a joint analysis of both risk factors in relation to mortality has not been sufficiently studied. The aim of this study was to explore the effect modification between level of adherence to a Mediterranean dietary pattern (MedDiet) and smoking status on all-cause, cancer, and cardiovascular mortality.Methods: We conducted a prospective analysis to assess the association between diet and smoking status in the SUN (Seguimiento Universidad de Navarra) cohort study. Deaths were confirmed by review of the National Death Index. Participants were classified into six categories according to the MedDiet (adherence/non-adherence) and their exposure to smoking (never/former/current smoker). Multivariate-adjusted Cox regression models were fitted to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for mortality. During a mean follow-up of 11.5 y (SD 4.5), we observed 18 948 participants (mean age 38.4 y; SD 12.4) and 431 deaths (51.3% cancer deaths). Results: A higher risk for death was found among smokers with a low adherence to the MedDiet (HR, 2.20; 95% CI, 1.45-3.34) compared with never smokers with high adherence to the MedDiet. The P value for supra-multiplicative effect modification was not statistically significant, meaning that the effect of both factors is multiplicative. A higher risk for premature death from cancer was found in smokers and in those nonadherent with the MedDiet.Conclusion: Smoking and poor adherence to the MedDiet exerted a multiplicative effect in increasing allcause mortality and cancer-related mortality in a Spanish population of university graduates.(c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Background & aims: The quality of dietary carbohydrates rather than total carbohydrate intake may determine the accumulation of visceral fat; however, to date, few studies have examined the impact of diet on adiposity using specific imaging techniques. Thus, the aim of this prospective study was to investigate the association between concurrent changes in carbohydrate quality index (CQI) and objectively-quantified adiposity distribution over a year. Methods: We analyzed a cohort of 1476 participants aged 55-75 years with overweight/obesity and metabolic syndrome (MetS) from the PREDIMED-Plus randomized controlled trial. Dietary intake information was obtained at baseline, 6- and 12-months from a validated 143-item semi-quantitative food-frequency questionnaire, and CQI (range: 4 to 20) was calculated based on four dietary criteria: total dietary fibre, glycemic index, wholegrain/total grain carbohydrate ratio, and solid/total carbohydrate ratio. Overall and regional adiposity (total body fat, visceral fat and android-to-gynoid fat ratio) was quantified using dual-energy X-ray absorptiometry at all three time points. Multiple adjusted linear mixed-effects models were used to assess associations between concurrent changes in repeatedly measured CQI and adiposity over time. Results: After controlling for potential confounding factors, a 3-point increment in CQI over 12-month follow-up was associated with a decrease in visceral fat (beta-0.067 z-score, 95% CI-0.088;-0.046, p < 0.001), android-to-gynoid fat ratio (-0.038,-0.059;-0.017, p < 0.001), and total fat (-0.064,-0.080;-0.047, p < 0.001). Fibre intake and the ratio of wholegrain/total grain showed the strongest inverse associations with all adiposity indicators. Conclusions: In this prospective cohort of older adults with overweight/obesity and MetS, we found that improvements in dietary carbohydrate quality over a year were associated with concurrent favorable changes in visceral and overall fat deposition. These associations were mostly driven by dietary fibre and the wholegrain/total grain ratio.Trial registration: The trial was registered at the International Standard Randomized.

Introduction and objectives: Fatty acid metabolic dysregulation in mitochondria is a common mechanism involved in the development of heart failure (HF) and atrial fibrillation (AF). We evaluated the association between plasma acylcarnitine levels and the incidence of HF or AF, and whether the mediterranean diet (MedDiet) may attenuate the association between acylcarnitines and HF or AF risk. Methods: Two case-control studies nested within the Prevencion con dieta mediterranea (PREDIMED) trial. High cardiovascular risk participants were recruited in Spain: 326 incident HF and 509 AF cases individually matched to 1 to 3 controls. Plasma acylcarnitines were measured with high-throughput liquid chromatography-tandem mass spectrometry. Conditional logistic regression models were fitted to estimate multivariable OR and 95%CI. Additive and multiplicative interactions were assessed by intervention group, obesity (body mass index >= 30 kg/m(2)), and type 2 diabetes. Results: Elevated levels of medium- and long-chain acylcarnitines were associated with increased HF risk (adjusted ORper DE, 1.28; 95%CI, 1.09-1.51 and adjusted ORper DE, 1.21; 95%CI, 1.04-1.42, respectively). A significant association was observed for AF risk with long-chain acylcarnitines: 1.20 (1.06-1.36). Additive interaction of the association between long-chain acylcarnitines and AF by the MediDiet supplemented with extra virgin olive oil (P for additive interaction = .036) and by obesity (P = .022) was observed in an inverse and direct manner, respectively. Conclusions: Among individuals at high cardiovascular risk, elevated long-chain acylcarnitines were associated with a higher risk of incident HF and AF. An intervention with MedDiet + extra-virgin olive oil may reduce AF risk associated with long-chain acylcarnitines.

Purpose To assess the association between three different a priori dietary patterns adherence (17-item energy reduced-Mediterranean Diet (MedDiet), Trichopoulou-MedDiet and Dietary Approach to Stop Hypertension (DASH)), as well as the Protein Diet Score and kidney function decline after one year of follow-up in elderly individuals with overweight/obesity and metabolic syndrome (MetS). Methods We prospectively analyzed 5675 participants (55-75 years) from the PREDIMED-Plus study. At baseline and at one year, we evaluated the creatinine-based estimated glomerular filtration rate (eGFR) and food-frequency questionnaires-derived dietary scores. Associations between four categories (decrease/maintenance and tertiles of increase) of each dietary pattern and changes in eGFR (ml/min/1.73m(2)) or >= 10% eGFR decline were assessed by fitting multivariable linear or logistic regression models, as appropriate. Results Participants in the highest tertile of increase in 17-item erMedDiet Score showed higher upward changes in eGFR (beta: 1.87 ml/min/1.73m(2); 95% CI: 1.00-2.73) and had lower odds of >= 10% eGFR decline (OR: 0.62; 95% CI: 0.47-0.82) compared to individuals in the decrease/maintenance category, while Trichopoulou-MedDiet and DASH Scores were not associated with any renal outcomes. Those in the highest tertile of increase in Protein Diet Score had greater downward changes in eGFR (beta: - 0.87 ml/min/1.73m(2); 95% CI: - 1.73 to - 0.01) and 32% higher odds of eGFR decline (OR: 1.32; 95% CI: 1.00-1.75). Conclusions Among elderly individuals with overweight/obesity and MetS, only higher upward change in the 17-item erMedDiet score adherence was associated with better kidney function after one year. However, increasing Protein Diet Score appeared to have an adverse impact on kidney health. Trial Registration Number: ISRCTN89898870 (Data of registration: 2014).

Background: Recent evidence has indicated a greater number of protective factors are associated with a greater decreased risk for depression and depressive symptoms compared with individual factors alone. Moreover, adherence to healthy modifiable lifestyle behaviors may lower the risk of depression regardless of underlying genetic risk. Objectives: We longitudinally evaluated the association of the Mediterranean lifestyle (MEDLIFE) with the risk of depression. Methods: We prospectively analyzed data from 15,279 participants (6089 men and 9190 women, mean age 37 y) in the Seguimiento Universidad de Navarra cohort. The MEDLIFE index is composed of 28 items on food consumption, dietary habits, physical activity, rest, social habits, and conviviality, each of which was assigned 0 or 1 point. Final scores ranged from 0 to 28 points and were categorized into quartiles of MEDLIFE adherence. Cox proportional regression models determined the association of total MEDLIFE adherence, each item, and block with incident depression. Results: After a mean follow-up of 11.7 y, 912 (6%) incident cases of depression were reported. The mean +/- SD final score for MEDLIFE adherence was 11.9 +/- 2.7 points. The multivariable model showed that compared with the first quartile, the second and third quartiles of MEDLIFE adherence were significantly associated with a decreased relative risk for incident depression (HR: 0.82; 95% CI: 0.69, 0.96 and HR: 0.74; 95% CI: 0.61, 0.89, respectively). The fourth quartile did not show a statistically significant association with incident depression (HR: 0.89; 95% CI: 0.73, 1.09). Conclusions: MEDLIFE adherence may decrease the risk of depression in a Spanish cohort of university graduates. Given no clear association was observed among the highest MEDLIFE adherence, future studies are warranted to better understand the nature of this association. Evidence on MEDLIFE, beyond the Mediterranean diet, may contribute toward more effective prevention strategies for depression.

Background: The Traditional Mediterranean Diet (TMD) is known to have beneficial effects on several chronic diseases. However, data concerning the whole transcriptome modulation of the TMD are scarce. Objective: We aimed to explore the effects of the TMD on the whole transcriptome of individuals at high cardiovascular risk. Methods: Thirty-four participants at high cardiovascular risk were randomly assigned to a TMD enriched with extra-virgin olive oil (TMD + VOO), mixed nuts (TMD + Nuts), or a control diet based on low-fat diet recommendations. A microarray analysis in circulating peripheral blood mononuclear cells of the participants was conducted before and after 3 months of the intervention. The association of changes in gene expression was modeled into canonical pathways by conducting an untargeted functional analysis with the Ingenuity Pathway Analysis(R)(IPA). Effects were considered significant when the absolutez-score values were >= 2.0 and the logarithmP(adjusted by the Benjamini-Hochberg procedure [BH]) values were >= 1.30. Results: According to IPA, interventions with TMD + Nuts, TMD + VOO, and control diet downregulated neuroinflammation, triggering receptor expressed on myeloid cells 1 , and cholecystokinin/gastrin-mediated signaling pathways, respectively. The gene expression among these pathways included cytokines, T-cell activation receptors, nuclear factor kappa beta/inflammasome components, pro-inflammatory enzymes and cell cycle regulators. Conclusion: The current findings suggest that the TMD enriched with mixed nuts or VOO downregulate transcriptomic pathways, including those related to neuroinflammation, which could influence development of neurodegenerative diseases. Our data should be corroborated in other tissue cells, such as neurons and glial cells.

Background In the last years, evidence that dietary vitamin K could have a role in the cognitive domain has increased. However, data from large trials are limited. The objective of this study was to assess the association of 2 year changes in the dietary intake of vitamin K with cognitive function measured through neuropsychological performance tests. Methods In 5,533 participants of the multicentre PREDIMED-Plus study (48.1% women, age 65.1 +/- 4.9 years with overweight/obesity and metabolic syndrome), we assessed the adjusted odds ratios of cognitive function decline according to 2 year changes in vitamin K intake. Participants answered a battery of cognitive function tests and Food Frequency Questionnaires (FFQs) in order to estimate the vitamin K dietary intake. Results After adjusting for potential cofounders, the highest tertile of change of dietary vitamin K intake (median [IQR]; 194.4 mu g/d [120.9, 373.1]) was inversely associated with a Mini-Mental State Examination (MMSE) score <= 24 (OR [95% CI]; 0.53 [0.35, 0.79] P for trend = 0.002) compared with a decrease in the intake of vitamin K (median [IQR]; -97.8 mu g/d [-292.8, -51.5]). A significant positive association between changes in dietary vitamin K intake and the semantic verbal fluency test scores (OR [95% CI]; 0.69 [0.51, 0.94] P for trend = 0.019) was found. Conclusions An increase of the intake of dietary vitamin K was associated with better cognitive function scores, independently of recognised risk factors for cognitive decline, in an older adult Mediterranean population with high cardiovascular risk.

Background and aims: A healthy lifestyle is essential to prevent cardiovascular disease (CVD). However, beyond dietary habits, there is a scarcity of studies comprehensively assessing the typical traditional Mediterranean lifestyle with a multi-dimensional index. We assessed the association between the Mediterranean lifestyle (measured with the MEDLIFE index including diet, physical activity, and other lifestyle factors) and the incidence of CVD. Methods and results: The "Seguimiento Universidad de Navarra" (SUN) project is a prospective, dynamic and multipurpose cohort of Spanish university graduates. We calculated a MEDLIFE score, composed of 28 items on food consumption, dietary habits, physical activity, rest, social habits, and conviviality, for 18,631 participants by assigning 1 point for each typical Mediterranean lifestyle factor achieved, for a theoretically possible final score ranging from 0 to 28 points. During an average follow-up of 11.5 years, 172 CVD cases (myocardial infarction, stroke or cardiovascular death) were observed. An inverse association between the MEDLIFE score and the risk of primary cardiovascular events was observed, with multivariable-adjusted hazard ratio (HR) = 0.50; (95% confidence interval, 0.31-0.81) for the highest MEDLIFE scores (14-23 points) compared to the lowest scores (0-9 points), p (trend) = 0.004. Conclusion: A higher level of adherence to the Mediterranean lifestyle was significantly associated with a lower risk of CVD in a Spanish cohort. Public health strategies should promote the Mediterranean lifestyle to preserve cardiovascular health. (c) 2021 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.

Introduction and objectives: The ankle-brachial index (ABI) is an indicator of peripheral artery disease (PAD). The aim of this study was to assess the association between PAD, measured with the ABI, and cognitive function in persons with overweight or obesity and metabolic syndrome. Methods: Cross-sectional study conducted with baseline data from the PREDIMED-Plus study, which included 4898 participants (after exclusion of those without ABI measurements) aged between 55 and 75 years, and with overweight or obesity and metabolic syndrome. At the baseline assessment, we measured the ABI with a standardized protocol and assessed the presence of other cardiovascular risk factors (eg, diabetes, dyslipidemia, hypertension). Cognitive function was evaluated using several tests validated for the Spanish population (mini-mental state examination [MMSE], phonological and semantic verbal fluency test, WAIS-III working memory index [WMI], parts A and B of the trail making test (TMT), and clock drawing test). Generalized linear models were used to assess the association between the ABI and cognitive function. Results: Among the participants, 3.4% had PAD defined as ABI ¿ 0.9, and 3.3% had arterial calcification defined as ABI ¿ 1.4. PAD was associated with age, systolic blood pressure and obesity indicators, while arterial calcification was also associated with obesity and diabetes. No significant associations were observed between cognitive function and ABI or PAD. Conclusions: In our sample, the presence of PAD increased with age, blood pressure, and obesity. No significant association was observed between ABI, PAD, or cognitive function.

Background Evidence is limited about the joint health effects of the Mediterranean lifestyle on cardiometabolic health and mortality. The aim of this study was to evaluate the association of the Mediterranean lifestyle with the frequency of the metabolic syndrome (MS) and the risk of all-cause and cardiovascular mortality in Spain. Methods Data were taken from ENRICA study, a prospective cohort of 11,090 individuals aged 18+ years, representative of the population of Spain, who were free of cardiovascular disease (CVD) and diabetes at 2008-2010 and were followed-up to 2017. The Mediterranean lifestyle was assessed at baseline with the 27-item MEDLIFE index (with higher score representing better adherence). Results Compared to participants in the lowest quartile of MEDLIFE, those in the highest quartile had a multivariable-adjusted odds ratio 0.73 (95% confidence interval (CI) 0.5, 0.93) for MS, 0.63. (0.51, 0.80) for abdominal obesity, and 0.76 (0.63, 0.90) for low HDL-cholesterol. Similarly, a higher MELDIFE score was associated with lower HOMA-IR and highly-sensitivity C-reactive protein (P-trend < 0.001). During a mean follow-up of 8.7 years, 330 total deaths (74 CVD deaths) were ascertained. When comparing those in highest vs. lowest quartile of MEDLIFE, the multivariable-adjusted hazard ratio (95% CI) was 0.58 (0.37, 0.90) for total mortality and 0.33 (0.11, 1.02) for cardiovascular mortality. Conclusions The Mediterranean lifestyle was associated with lower frequency of MS and reduced all-cause mortality in Spain. Future studies should determine if this also applies to other Mediterranean countries, and also improve cardiovascular health outside the Mediterranean basin.

BACKGROUND: Few studies have examined the associations of trimethylamine-N-oxide (TMAO) and its precursors (choline, betaine, dimethylglycine, and L-carnitine) with the risk of atrial fibrillation (AF) and heart failure (HF). This study sought to investigate these associations. METHODS: Prospective associations of these metabolites with incident AF and HF were examined among participants at high cardiovascular risk in the PREDIMED study (PREvencion con DIeta MEDiterranea) after follow-up for about 10 years. Two nested case-control studies were conducted, including 509 AF incident cases matched to 618 controls and 326 HF incident cases matched to 426 controls. Plasma levels of TMAO and its precursors were semi-quantitatively profiled with liquid chromatography tandem mass spectrometry. Odds ratios were estimated with multivariable conditional logistic regression models. RESULTS: After adjustment for classical risk factors and accounting for multiple testing, participants in the highest quartile vs. the lowest quartile of baseline choline and betaine levels had a higher risk of AF [OR (95% CI): 1.85 (1.30-2.63) and 1.57 (1.09-2.24), respectively]. The corresponding OR for AF for extreme quartiles of dimethylglycine was 1.39 (0.99-1.96). One SD increase in log-transformed dimethylglycine was positively associated with AF risk (OR, 1.17; 1.03-1.33). The corresponding ORs for HF for extreme quartiles of choline, betaine, and dimethylglycine were 2.51 (1.57-4.03), 1.65 (1.00-2.71) and 1.65 (1.04-2.61), respectively. TMAO and L-carnitine levels were not associated with AF or HF. CONCLUSIONS: Our findings support the role of the choline metabolic pathway in the pathogenesis of AF and HF.

Background & aims: Ultra-processed food and drink products (UPF) consumption has been associated with obesity and its-related comorbidities. Excess of visceral fat, which appears with increasing age, has been considered as the culprit contributing to adiposity-associated adverse health outcomes. However, none of previous studies elucidated the link between UPF and directly quantified adiposity and its distribution. We aimed to prospectively investigate the association between concurrent changes in UPF consumption and objectively assessed adiposity distribution. Methods: A subsample of 1485 PREDIMED-Plus participants (Spanish men and women aged 55-75 years with overweight/obesity and metabolic syndrome) underwent body composition measurements. Consumption of UPF at baseline, 6 and 12 months was evaluated using a validated 143-item semiquantitative Food Frequency Questionnaire. Food items (g/day) were categorized according to their degree of processing using NOVA system. Regional adiposity (visceral fat (in g) and android-to-gynoid fat & nbsp; ratio) and total fat mass (in g) at three time points were measured with dual-energy X-ray absorpti-ometry (DXA) and were normalized using sex-specific z-scores. The association of changes in UPF consumption, expressed as the percentage of total daily intake (daily g of UPF/total daily g of food and beverage intake*10 0), with adiposity changes was evaluated using linear mixed-effects models. Results: On average, the consumption of UPF accounted for 8.11% (SD 7.41%) of total daily intake (in grams) at baseline. In multivariable-adjusted model, 10% daily increment in consumption of UPF was associated with significantly (all p-values <0.05) greater accumulation of visceral fat (b 0.09 z-scores, 95% CI 0.05; 0.13), android-to-gynoid fat ratio (0.05, 0.00; 0.09) and total fat (0.09, 0.06; 0.13). Conclusion: A higher consumption of UPF was associated with greater age-related visceral and overall adiposity accumulation. Further studies are warranted to confirm these results in other populations and settings. Trial registration: The trial was registered at the International Standard Randomized Controlled Trial (ISRCTN: http://www.isrctn.com/ISRCTN89898870) with number 89898870 and registration date of 24 July 2014, retrospectively registered . (c) 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. ratio) and total fat mass (in g) at three time points were measured with dual-energy X-ray absorptiometry (DXA) and were normalized using sex-specific z-scores. The association of changes in UPF consumption, expressed as the percentage of total daily intake (daily g of UPF/total daily g of food and beverage intake*10 0), with adiposity changes was evaluated using linear mixed-effects models. Results: On average, the consumption of UPF accounted for 8.11% (SD 7.41%) of total daily intake (in grams) at baseline. In multivariable-adjusted model, 10% daily increment in consumption of UPF was associated with significantly (all p-values <0.05) greater accumulation of visceral fat (b 0.09 z-scores, 95% CI 0.05; 0.13), android-to-gynoid fat ratio (0.05, 0.00; 0.09) and total fat (0.09, 0.06; 0.13). Conclusion: A higher consumption of UPF was associated with greater age-related visceral and overall adiposity accumulation. Further studies are warranted to confirm these results in other populations and settings. Trial registration: The trial was registered at the International Standard Randomized Controlled Trial

There is growing interest in natural antioxidants and their potential effects on breast cancer (BC). Epidemiological evidence, however, is inconsistent. We prospectively evaluated the association between dietary intake of vitamins A, C, and E, selenium, and zinc and BC among 9983 female participants from the SUN Project, a Mediterranean cohort of university graduates. Participants completed a food frequency questionnaire at baseline, and biennial follow-up information about incident BC diagnosis was collected. Cases were ascertained through revision of medical charts and consultation of the National Death Index. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI). During an average follow-up of 11.3 years, 107 incident BC cases were confirmed. The multivariable HRs (95% CI) for BC comparing extreme tertiles of energy-adjusted dietary intakes were 1.07 (0.64-1.77; P-trend = 0.673) for vitamin A, 1.00 (0.58-1.71; P-trend = 0.846) for vitamin C, 0.92 (0.55-1.54; P-trend = 0.728) for vitamin E, 1.37 (0.85-2.20; P-trend = 0.135) for selenium, and 1.01 (0.61-1.69; P-trend = 0.939) for zinc. Stratified analyses showed an inverse association between vitamin E intake and postmenopausal BC (HRT3 vs. T1 = 0.35; 95% CI, 0.14-0.86; P-trend = 0.027). Our results did not suggest significant protective associations between dietary vitamins A, C, and E, selenium, or zinc and BC risk.

Purpose Identification of dietary factors involved in the development and progression of nonalcoholic fatty liver disease (NAFLD) is relevant to the current epidemics of the disease. Dietary amino acids appear to play a key role in the onset and progression of NAFLD. The aim of this study was to analyze potential associations between specific dietary amino acids and variables related to glucose metabolism and hepatic status in adults with overweight/obesity and NAFLD. Methods One hundred and twelve individuals from the Fatty Liver in Obesity (FLiO) study were evaluated. Liver assessment was carried out by ultrasonography, magnetic resonance imaging and analysis of biochemical parameters. Dietary amino acid intake (aromatic amino acids (AAA); branched-chain amino acids (BCAA); sulfur amino acids (SAA)) was estimated by means of a validated 137-item food frequency questionnaire. Results Higher consumption of these amino acids was associated with worse hepatic health. Multiple adjusted regression models confirmed that dietary AAA, BCAA and SAA were positively associated with liver fat content. AAA and BCAA were positively associated with liver iron concentration. Regarding ferritin levels, a positive association was found with BCAA. Dietary intake of these amino acids was positively correlated with glucose metabolism (glycated hemoglobin, triglyceride and glucose index) although the significance disappeared when potential confounders were included in the model.

Introduction: Large randomized trials testing the effect of a multifactorial weight-loss lifestyle intervention including Mediterranean diet (MedDiet) on renal function are lacking. Here, we evaluated the 1-year efficacy of an intensive weight-loss intervention with an energy-reduced MedDiet (erMedDiet) plus increased physical activity (PA) on renal function. Methods: Randomized controlled "PREvencion con DIeta MEDiterranea-Plus" (PREDIMED-Plus) trial is conducted in 23 Spanish centers comprising 208 primary care clinics. Overweight/obese (n = 6,719) adults aged 55-75 years with metabolic syndrome were randomly assigned (1:1) to an intensive weight-loss lifestyle intervention with an erMedDiet, PA promotion, and behavioral support (intervention) or usual-care advice to adhere to an energy-unrestricted MedDiet (control) between September 2013 and December 2016. The primary outcome was 1-year change in estimated glomerular filtration rate (eGFR). Secondary outcomes were changes in urine albumin-to-creatinine ratio (UACR), incidence of moderately/severely impaired eGFR (<60 mL/min/1.73 m(2)) and micro- to macroalbuminuria (UACR >= 30 mg/g), and reversion of moderately (45 to <60 mL/min/1.73 m(2)) to mildly impaired GFR (60 to <90 mL/min/1.73 m(2)) or micro- to macroalbuminuria. Results: After 1 year, eGFR declined by 0.66 and 1.25 mL/min/1.73 m(2) in the intervention and control groups, respectively (mean difference, 0.58 mL/min/1.73 m(2); 95% CI: 0.15-1.02). There were no between-group differences in mean UACR or micro- to macroalbuminuria changes. Moderately/severely impaired eGFR incidence and reversion of moderately to mildly impaired GFR were 40% lower (HR 0.60; 0.44-0.82) and 92% higher (HR 1.92; 1.35-2.73), respectively, in the intervention group. Conclusions: The PREDIMED-Plus lifestyle intervention approach may preserve renal function and delay CKD progression in overweight/obese adults.

Evidence is still limited on the influence of sedentary lifestyles on breast cancer (BC) risk. Also, prospective information on the combined effects of both sedentariness and leisure-time physical activity (LTPA) is scarce. We aimed to assess the association of higher sedentary behavior and LTPA (separately and in combination) with the risk of BC in a middle-aged cohort of university graduates. The SUN Project is a follow-up study initiated in 1999 with recruitment permanently open. Baseline assessments included a validated questionnaire on LTPA and sedentary habits. Subsequently, participants completed biennial follow-up questionnaires. Multivariable adjusted Cox models were used to estimate the hazard ratios (HR) for incident BC according to LTPA, TV-watching, the joint classification of both, and a combined 8-item multidimensional active lifestyle score. We included 10,812 women, with 11.8 years of median follow-up of. Among 115,802 women-years of follow-up, we confirmed 101 incident cases of BC. Women in the highest category of LTPA ( 2 points) group. There was no significant supra-multiplicative interaction between TV-watching and LTPA. Both low LTPA and TV-watching 2 h/d may substantially increase BC risk, independently of each other.

Rationale: Altered lipid metabolism has been implicated in heart failure (HF) development, but no prospective studies have examined comprehensive lipidomics data and subsequent risk of HF. Objective: We aimed to link single lipid metabolites and lipidomics networks to the risk of developing HF. Methods and results: Discovery analyses were based on 216 targeted lipids in a case-control study (331 incident HF cases and 507 controls, matched by age, sex, and study center), nested within the PREDIMED (Prevención con Dieta Mediterránea) study. Associations of single lipids were examined in conditional logistic regression models. Furthermore, lipidomics networks were linked to HF risk in a multistep workflow, including machine learning-based identification of the HF-related network clusters, and regression-based discovery of the HF-related lipid patterns within these clusters. If available, significant findings were externally validated in a subsample of the EPIC-Potsdam cohort (2414 at-risk participants, including 87 incident HF cases). After confounder-adjustments, 2 lipids were significantly associated with HF risk in both cohorts: CER (ceramide) 16:0 (relative risk [RR] per SD in PREDIMED, 1.28 [95% CI, 1.13-1.47]) and phosphatidylcholine 32_0 (RR per SD in PREDIMED, 1.23 [95% CI, 1.08-1.41]). Additionally, lipid patterns in several network clusters were associated with HF risk in PREDIMED. Adjusted for standard risk factors, an internally cross-validated score based on the significant HF-related lipids that were identified in the network analysis in PREDIMED was associated with a higher HF risk (20 lipids, RR per SD, 2.33 [95% CI, 1.93%-2.81%). Moreover, a lipid score restricted to the externally available lipids was significantly associated with HF incidence in both cohorts (6 lipids, RRs per SD, 1.30 [95% CI, 1.14-1.47] in PREDIMED, and 1.46 [95% CI, 1.17-1.82] in EPIC-Potsdam). Conclusions: Our study identified and validated 2 lipid metabolites and several lipidomics patterns as potential novel biomarkers of HF risk. Lipid profiling may capture preclinical molecular alterations that predispose for incident HF. Registration: URL: https://www.isrctn.com/ISRCTN35739639; Unique identifier: ISRCTN35739639.

Hypertension is the strongest independent modifiable risk factor for cardiovascular disease. We aimed to investigate the association of magnesium intake with incident hypertension in a Mediterranean population, and the potential modification of this association by body mass index (BMI). We assessed 14,057 participants of the SUN (Seguimiento Universidad de Navarra) prospective cohort (67.0% women) initially free of hypertension. At baseline, a validated 136-item food frequency questionnaire was administered. We used Cox models adjusted for multiple socio-demographic, anthropometric, and lifestyle factors, and prevalent conditions present at baseline. Among a mean 9.6 years of follow-up we observed 1406 incident cases of medically diagnosed hypertension. An inverse association in multivariable-adjusted models was observed for progressively higher magnesium intake up to 500 mg/d vs. intake < 200 mg/d, which was greater among those with a BMI > 27 kg/m(2). Lean participants with magnesium intake < 200 mg/d vs. >200 mg/d also had a higher risk of incident hypertension. Adherence to the Mediterranean diet did not modify these associations. In conclusion, dietary magnesium intake < 200 mg/d was independently associated with a higher risk of developing hypertension in a Mediterranean cohort, stronger for overweight/obese participants. Our results emphasize the importance of encouraging the consumption of magnesium-rich foods (vegetables, nuts, whole cereals, legumes) in order to prevent hypertension.

Background & aims: Epidemiological data on iron status and cardiovascular disease (CVD) are still controversial. The aim of this study was to determine whether low serum iron (SI) levels are associated with an increased odds of first CVD event in a population at high cardiovascular risk. Methods: Case-control study design nested within the "PREvención con DIeta MEDiterránea" (PREDIMED) trial. A total of 207 participants diagnosed with CVD (myocardial infarction, stroke or cardiovascular death) during follow-up period (2003-2010) were matched by sex, age and intervention group to 436 controls by incidence density sampling. Median time between serum sample collection and subsequent CVD event occurrence was 0.94 years. Inductively coupled plasma mass spectrometry analysis was used to determine SI levels. In-person interviews, medical record reviews, and validated questionnaires were used to assess covariates. Multivariable-adjusted odds ratios (ORs) of CVD were calculated with conditional logistic regression. Results: Mean SI levels were higher in men than in women (1224.0 ¿g/L vs. 1093.8 ¿g/L; p < 0.001). Among women, but not in men, the mean SI concentration was lower in cases than in controls (1008.5 ¿g/L vs. 1132.9 ¿g/L; p = 0.030). There was a gradual decrease in the multivariable-adjusted ORs of CVD with increasing SI levels (highest vs. lowest quartile: OR = 0.55, 95% CI: 0.32-0.93; ptrend = 0.020). This inverse relationship was more pronounced among women (highest vs. lowest quartile: OR = 0.15, 95% CI: 0.03-0.69; ptrend = 0.011). Conclusions: The present findings are consistent with previously reported inverse associations between SI and CVD. SI levels as an independent marker of short-term cardiovascular risk may be useful for risk assessment in older populations. Trial registration: www.controlled-trials.com; International Standard Randomized Controlled Trial Number (ISRCTN): 35,739,639. Registered 5 October 2005. Retrospectively registered.

Background: The quality of carbohydrate consumed, assessed by the glycemic index (GI), glycemic load (GL), or carbohydrate quality index (CQI), affects the postprandial glycemic and insulinemic responses, which have been implicated in the etiology of several chronic diseases. However, it is unclear whether plasma metabolites involved in different biological pathways could provide functional insights into the role of carbohydrate quality indices in health. Objectives: We aimed to identify plasma metabolomic profiles associated with dietary GI, GL, and CQI. Methods: The present study is a cross-sectional analysis of 1833 participants with overweight/obesity (mean age = 67 y) from 2 case-cohort studies nested within the PREDIMED (Prevencion con Dieta Mediterranea) trial. Data extracted from validated FFQs were used to estimate the GI, GL, and CQI. Plasma concentrations of 385 metabolites were profiled with LC coupled to MS and associations of these metabolites with those indices were assessed with elastic net regression analyses. Results: A total of 58, 18, and 57 metabolites were selected for GI, GL, and CQI, respectively. Choline, cotinine, gamma -butyrobetaine, and 36:3 phosphatidylserine plasmalogen were positively associated with GI and GL, whereas they were negatively associated with CQI. Fructose-glucose-galactose was negatively and positively associated with GI/GL and CQI, respectively. Consistent associations of 21 metabolites with both GI and CQI were found but in opposite directions. Negative associations of kynurenic acid, 22:1 sphingomyelin, and 38:6 phosphatidylethanolamine, as well as positive associations of 32:1 phosphatidylcholine with GI and GL were also observed. Pearson correlation coefficients between GI, GL, and CQI and the metabolomic profiles were 0.30, 0.22, and 0.27, respectively. Conclusions: The GI, GL, and CQI were associated with specific metabolomic profiles in a Mediterranean population at high cardiovascular disease risk. Our findings may help in understanding the role of dietary carbohydrate indices in the development of cardiometabolic disorders. This trial was registered at isrctn.com as ISRCTN35739639. J Nutr 2021;151:50-58. ABSTRACT Background: The quality of carbohydrate consumed, assessed by the glycemic index (GI), glycemic load (GL), or carbohydrate quality index (CQI), affects the postprandial glycemic and insulinemic responses, which have been implicated in the etiology of several chronic diseases. However, it is unclear whether plasma metabolites involved in different biological pathways could provide functional insights into the role of carbohydrate quality indices in health. Objectives: We aimed to identify plasma metabolomic profiles associated with dietary GI, GL, and CQI. Methods: The present study is a cross-sectional analysis of 1833 participants with overweight/obesity (mean age = 67 y) from 2 case-cohort studies nested within the PREDIMED (Prevencion con Dieta Mediterranea) trial. Data extracted from validated FFQs were used to estimate the GI, GL, and CQI. Plasma concentrations of 385 metabolites were profiled with LC coupled to MS and associations of these metabolites with those indices were assessed with elastic net regression analyses. Results: A total of 58, 18, and 57 metabolites were selected for GI, GL, and CQI, respectively. Choline, cotinine, gamma -butyrobetaine, and 36:3 phosphatidylserine plasmalogen were positively associated with GI and GL, whereas they were negatively associated with CQI. Fructose-glucose-galactose was negatively and positively associated with GI/GL and CQI, respectively. Consistent associations of 21 metabolites with both GI and CQI were found but in opposite directions. Negative associations of kynurenic acid, 22:1 sphingomyelin, and 38:6 phosphatidylethanolamine, as well as positive associations of 32:1 phosphatidylcholine with GI and GL were also observed. Pearson correlation coefficients between GI, GL, and CQI and the metabolomic profiles were 0.30, 0.22, and 0.27, respectively. Conclusions: The GI, GL, and CQI were associated with specific metabolomic profiles in a Mediterranean population at high cardiovascular disease risk. Our findings may help in understanding the role of dietary carbohydrate indices in the development of cardiometabolic disorders. This trial was registered at isrctn.com as ISRCTN35739639. J Nutr 2021;151:50-58.

The global growing rates of cognitive decline and dementia, together with the absence of curative therapies for these conditions, support the interest in researching potential primary prevention interventions, with particular focus on dietary habits. The aim was to assess the association between polyphenol intake and 6-year change in cognitive function in the 'Seguimiento Universidad de Navarra' (SUN) Project, a Spanish prospective cohort study. Changes (final - initial) in cognitive function were evaluated in a subsample of 806 participants (mean age 66 (sd 5) years, 69·7 % male) of the SUN Project using the validated Spanish Telephone Interview for Cognitive Status-modified score. Polyphenol intake was derived from a validated semi-quantitative FFQ and matching food composition data from the Phenol-Explorer database. Multivariable linear regression models were used to evaluate the association between total polyphenol intake, polyphenol subclasses and cognitive changes. No significant association between total polyphenol intake and changes in cognitive function was found. However, a higher intake of lignans (ßQuintile (Q) 5 v. Q1 0·81; 95 % CI 0·12, 1·51; Ptrend = 0·020) and stilbenes (ßQ5 v. Q1 0·82; 95 % CI 0·15, 1·49; Ptrend = 0·028) was associated with more favourable changes in cognitive function over time, particularly with respect to immediate memory and language domains. Olive oil and nuts were the major sources of variability in lignan intake, and wine in stilbene intake. The results suggest that lignan and stilbene intake was associated with improvements in cognitive function.

Goals To explore affective and cognitive status, later in life, in individuals with and without previous history of eating disorder (ED), and also its association with higher risk for metabolic syndrome (MetS) symptomatology. Methods A cross-sectional analysis of 6756 adults, aged 55-75 years with overweight/obesity and MetS participating in the Predimed-Plus study was conducted. Participants completed self-reported questionnaires to examine lifetime history of ED, according to DSM-5 criteria, and other psychopathological and neurocognitive factors. Anthropometric and metabolic measurements were also collected. Results Of the whole sample, 24 individuals (0.35%) reported a previous history of ED. In this subsample, there were more women and singles compared to their counterparts, but they also presented higher levels of depressive symptoms and higher cognitive impairment, but also higher body mass index (BMI) and severe obesity, than those without lifetime ED. Conclusions This is one of the first studies to analyse the cognitive and metabolic impact of a previous history of ED. The results showed that previous ED was associated with greater affective and cognitive impairment, but also with higher BMI, later in life. No other MetS risk factors were found, after controlling for relevant variables.

Objective: Quantify the impact of reducing the consumption of red/processed meats on cardiovascular mortality and all-cause mortality of the Spanish adult population based in 5 revisions published. Participants and main measurements: We defined exposure as consumption of >= 3 servings/week of red or processed meats and considered four possible scenarios of exposed population (30%-60%). Based on data from the Spanish National Statistics Institute, we calculated the weighted mortality between 40 and 80 years. Using the relative risks (RR) and 95% confidence intervals (CI) published by the referred revisions (RR= 0.88; IC 95%: 0.84-0.93 for all-cause mortality and RR =0.92; IC 95%: 0.90-0.93 for cardiovascular mortality), we calculated the expected mortality rate in both exposed and unexposed categories. By multiplying these rates by the number of exposed individuals, we estimated the attributable number of yearly deaths. Results: If 60% of the population was exposed, with a 95% CI, the number of cardiovascular deaths that could be averted each year if population consumed < 3 servings/week of red or processed meats was between 2.112 and 3.055. If was exposed that 30%, the difference in the yearly number of potentially averted deaths was between 1.079 and 1.577. Conclusions: Even under the most conservative assumption, the benefit, at the population level, of reducing red or processed meats consumption < 3 servings/week on cardiovascular mortality is important. The conclusions of the recently published reviews contradicted their own results and contributed to a state of confusion that can create substantial harm for public health.

Chronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine whether gain of function in FAO (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1A (CPT1A) in TECs. Cpt1a-knockin (CPT1A-KI) mice subjected to 3 models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy [FAN], and adenine-induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted proinflammatory response, and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restored oxidative metabolism and mitochondrial number and enhanced bioenergetics, increasing palmitate oxidation and ATP levels, changes that were also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients showed decreased CPT1 levels and increased accumulation of shortand middle chain acylcarnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD.

Background: The optimal distribution between physical activity (PA) levels and sedentary behaviour (SB) for the greatest benefits for body composition among older adults with overweight/obesity and chronic health conditions remains unclear. We aimed to determine the prospective association between changes in PA and in SB with concurrent changes in body composition and to examine whether reallocating inactive time into different physical activity levels was associated with 12-month change to body composition in older adults. Methods: Longitudinal assessment nested in the PREDIMED-Plus trial. A subsample (n = 1564) of men and women (age 55-75 years) with overweight/obesity and metabolic syndrome from both arms of the PREDIMED-Plus trial was included in the present analysis. Participants were followed up at 6 and 12 months. Physical activity and SB were assessed using validated questionnaires. Out of 1564 participants, 388 wore an accelerometer to objectively measure inactive time and PA over a 7-day period. At each time point, participants' body composition was measured using dual-energy X-ray absorptiometry (DXA). Standard covariate-adjusted and isotemporal substitution modelling were applied to linear mixed-effects models. Results: Increasing 30 min of total PA and moderate-to-vigorous physical activity (MVPA) was associated with significant reductions in body fat (beta - 0.07% and - 0.08%) and visceral adipose tissue (VAT) (- 13.9 g, and - 15.6 g) at 12 months (all p values < 0.001). Reallocating 30 min of inactive time to MVPA was associated with reductions in body fat and VAT and with an increase in muscle mass and muscle-to-fat mass ratio (all p values < 0.001). Conclusions: At 12 months, increasing total PA and MVPA and reducing total SB and TV-viewing SB were associated with improved body composition in participants with overweight or obesity, and metabolic syndrome. This was also observed when substituting 30 min of inactive time with total PA, LPA and MVPA, with the greatest benefits observed with MVPA.

The intervention with the Mediterranean diet (MD) pattern has evidenced short-term anti-inflammatory effects, but little is known about its long-term anti-inflammatory properties at molecular level. This study aims to investigate the 3-year effect of MD interventions compared to low-fat diet (LFD) on changes on inflammatory biomarkers related to atherosclerosis in a free-living population with a high-risk of cardiovascular disease (CD). Participants (n = 285) in the PREDIMED trial were randomly assigned into three intervention groups: MD with extra-virgin olive oil (EVOO) or MD-Nuts, and a LFD. Fourteen plasma inflammatory biomarkers were determined by Luminex assays. An additional pilot study of gene expression (GE) was determined by RT-PCR in 35 participants. After 3 years, both MDs showed a significant reduction in the plasma levels of IL-1 beta, IL-6, IL-8, TNF-alpha, IFN-gamma, hs-CRP, MCP-1, MIP-1 beta, RANTES, and ENA78 (p < 0.05; all). The decreased levels of IL-1 beta, IL-6, IL-8, and TNF-alpha after MD significantly differed from those in the LFD (p < 0.05). No significant changes were observed at the gene level after MD interventions, however, the GE of CXCR2 and CXCR3 tended to increase in the control LFD group (p = 0.09). This study supports the implementation of MD as a healthy long-term dietary pattern in the prevention of CD in populations at high cardiovascular risk.

Background & aims: The Mediterranean lifestyle (MEDLIFE), as an overall lifestyle pattern, may be associated with a lower prevalence of metabolic syndrome. We assessed the association of a validated MEDLIFE index with metabolic syndrome and its components in a non-Mediterranean working population. Methods: A cross-sectional analysis was conducted at baseline among 249 US career firefighters in Feeding America's Bravest 2016-2018. The MEDLIFE index consisted of 26 items on food consumption, dietary habits, physical activity, rest, and social interactions that scored 0 or 1 point. Thus, total scores could range from 0 to 26 points. Multivariable logistic regression models were used to determine the associations across tertiles of MEDLIFE adherence with metabolic syndrome and each of its individual components. Multivariable linear models further assessed each component as a continuous outcome. Results: The prevalence of metabolic syndrome was 17.7%. Participants with higher MEDLIFE adherence (T3: 11-17 points) had 71% lower odds of having metabolic syndrome compared to those with lower MEDLIFE adherence (T1: 2-7 points) (OR = 0.29; 95%CI: 0.10 to 0.90, p for trend = 0.04). Furthermore, significant inverse associations were found for T3 versus T1 on abdominal obesity (OR = 0.42; 95%CI: 0.18 to 0.99, p for trend = 0.07) and hypertriglyceridemia (OR = 0.24; 95%CI: 0.09 to 0.63, p for trend = 0.002). Significant inverse associations for continuous outcomes included total-cholesterol (total-c), low-density lipoprotein (LDL) cholesterol, and total-c:high-density lipoprotein (HDL) cholesterol (p for trend <0.05). Conclusion: Higher adherence to traditional Mediterranean lifestyle habits, as measured by a comprehensive MEDLIFE index, was associated with a lower prevalence of metabolic syndrome and a more favorable cardiometabolic profile in a non-Mediterranean working population. Future studies employing the MEDLIFE index in other populations are warranted to support this hypothesis.

Background: Tricarboxylic acid (TCA) cycle deregulation may predispose to cardiovascular diseases, but the role of TCA cycle-related metabolites in the development of atrial fibrillation (AF) and heart failure (HF) remains unexplored. This study sought to investigate the association of TCA cycle-related metabolites with risk of AF and HF. Methods: We used two nested case-control studies within the PREDIMED study. During a mean follow-up for about 10 years, 512 AF and 334 HF incident cases matched by age (±5 years), sex and recruitment center to 616 controls and 433 controls, respectively, were included in this study. Baseline plasma levels of citrate, aconitate, isocitrate, succinate, malate and d/l-2-hydroxyglutarate were measured with liquid chromatography-tandem mass spectrometry. Multivariable conditional logistic regression models were fitted to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for metabolites and the risk of AF or HF. Potential confounders included smoking, family history of premature coronary heart disease, physical activity, alcohol intake, body mass index, intervention groups, dyslipidemia, hypertension, type 2 diabetes and medication use. Results: Comparing extreme quartiles of metabolites, elevated levels of succinate, malate, citrate and d/l-2-hydroxyglutarate were associated with a higher risk of AF [ORQ4 vs. Q1 (95% CI): 1.80 (1.21-2.67), 2.13 (1.45-3.13), 1.87 (1.25-2.81) and 1.95 (1.31-2.90), respectively]. One SD increase in aconitate was directly associated with AF risk [OR (95% CI): 1.16 (1.01-1.34)]. The corresponding ORs (95% CI) for HF comparing extreme quartiles of malate, aconitate, isocitrate and d/l-2-hydroxyglutarate were 2.15 (1.29-3.56), 2.16 (1.25-3.72), 2.63 (1.56-4.44) and 1.82 (1.10-3.04), respectively. These associations were confirmed in an internal validation, except for aconitate and AF. Conclusion: These findings underscore the potential role of the TCA cycle in the pathogenesis of cardiac outcomes. Keywords: Atrial fibrillation; Heart failure; Hydroxyglutarate; PREDIMED; Tricarboxylic acid cycle metabolites.

Background: Short dietary assessment tools can be useful to estimate food intake and diet quality in large-scale epidemiological studies with time constraints. Objective: To determine the concurrent validity of the 17-item energy-restricted Mediterranean Adherence Screener (er-MEDAS) used in the PREDIMED (PREvencion con DIeta MEDiterranea)-Plus trial and to analyse its capacity to detect 1-year changes in diet and cardiometabolic risk factors. Methods: Validation study nested in the PREDIMED-Plus (n = 6760, 55-75 years). Dietary data were collected by the 17-item er-MEDAS and a 143-item validated semiquantitative food frequency questionnaire (FFQ) at baseline and after 1-year intervention. Cardiometabolic risk markers were measured at both time points. A Mediterranean diet (MedDiet) score was derived from both instruments. Concurrent validity was evaluated by Pearson and intra-class correlation coefficients (ICC) and Bland and Altman limits of agreement. Construct validity was evaluated by assessing 1-year changes in FFQ-reported dietary intake and cardiometabolic profile changes in relation to changes in er-MEDAS. Results: A moderate to good correlation between the MedDiet score calculated by both measurement instruments was found: r = 0.61 and ICC = 0.60 (both p < 0.001). Agreement of each of the er-MEDAS items ranged from 55.4% to 85.0% with a moderate mean concordance (kappa = 0.41). Between baseline and 1-year follow-up, energy intake measured by the FFQ decreased by 242 kcal, while Mediterranean food consumption increased in participants with the highest increase in the er-MEDAS MedDiet score. An increase in the er-MEDAS MedDiet score ratings was associated with a decrease in BMI, waist circumference, triglycerides, fasting glucose, diastolic blood pressure, and triglycerides/HDL-cholesterol ratio (p < 0.001 for all), and with an increase in HDL-cholesterol (p = 0.006). Conclusion: The er-MEDAS shows a modest to good concurrent validity compared with FFQ data. It shows acceptable construct validity, as a greater er-MEDAS score was associated with more favourable dietary and cardiometabolic profiles over time.

Background Walnut consumption is associated with lower risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). However, it is unknown whether plasma metabolites related to walnut consumption are also associated with lower risk of cardiometabolic diseases. Objectives The study aimed to identify plasma metabolites associated with walnut consumption and evaluate the prospective associations between the identified profile and risk of T2D and CVD. Methods The discovery population included 1833 participants at high cardiovascular risk from the PREvencion con DIeta MEDiterranea (PREDIMED) study with available metabolomics data at baseline. The study population included 57% women (baseline mean BMI (in kg/m(2)): 29.9; mean age: 67 y). A total of 1522 participants also had available metabolomics data at year 1 and were used as the internal validation population. Plasma metabolomics analyses were performed using LC-MS. Cross-sectional associations between 385 known metabolites and walnut consumption were assessed using elastic net continuous regression analysis. A 10-cross-validation (CV) procedure was used, and Pearson correlation coefficients were assessed between metabolite weighted models and self-reported walnut consumption in each pair of training-validation data sets within the discovery population. We further estimated the prospective associations between the identified metabolite profile and incident T2D and CVD using multivariable Cox regression models. Results A total of 19 metabolites were significantly associated with walnut consumption, including lipids, purines, acylcarnitines, and amino acids. Ten-CV Pearson correlation coefficients between self-reported walnut consumption and the plasma metabolite profile were 0.16 (95% CI: 0.11, 0.20) in the discovery population and 0.15 (95% CI: 0.10, 0.20) in the validation population. The metabolite profile was inversely associated with T2D incidence (HR per 1 SD: 0.83; 95% CI: 0.71, 0.97; P = 0.02). For CVD incidence, the HR per 1-SD was 0.71 (95% CI: 0.60, 0.85; P < 0.001). Conclusions A metabolite profile including 19 metabolites was associated with walnut consumption and with a lower risk of incident T2D and CVD in a Mediterranean population at high cardiovascular risk.

Background: The Prevention With Mediterranean Diet (PREDIMED) trial supported the effectiveness of a nutritional intervention conducted by a dietitian to prevent cardiovascular disease. However, the effect of a remote intervention to follow the Mediterranean diet has been less explored. Objective: This study aims to assess the effectiveness of a remotely provided Mediterranean diet-based nutritional intervention in obtaining favorable dietary changes in the context of a secondary prevention trial of atrial fibrillation (AF). Methods: The PREvention of recurrent arrhythmias with Mediterranean diet (PREDIMAR) study is a 2-year multicenter, randomized, controlled, single-blinded trial to assess the effect of the Mediterranean diet enriched with extra virgin olive oil (EVOO) on the prevention of atrial tachyarrhythmia recurrence after catheter ablation. Participants in sinus rhythm after ablation were randomly assigned to an intervention group (Mediterranean diet enriched with EVOO) or a control group (usual clinical care). The remote nutritional intervention included phone contacts (1 per 3 months) and web-based interventions with provision of dietary recommendations, and participants had access to a web page, a mobile app, and printed resources. The information is divided into 6 areas: Recommended foods, Menus, News and Online resources, Practical tips, Mediterranean diet classroom, and Your personal experience. At baseline and at 1-year and 2-year follow-up, the 14-item Mediterranean Diet Adherence Screener (MEDAS) questionnaire and a semiquantitative food frequency questionnaire were collected by a dietitian by phone. Results: A total of 720 subjects were randomized (365 to the intervention group, 355 to the control group). Up to September 2020, 560 subjects completed the first year (560/574, retention rate 95.6%) and 304 completed the second year (304/322, retention rate 94.4%) of the intervention. After 24 months of follow-up, increased adherence to the Mediterranean diet was observed in both groups, but the improvement was significantly higher in the intervention group than in the control group (net between-group difference: 1.8 points in the MEDAS questionnaire (95% CI 1.4-2.2; P<.001). Compared with the control group, the Mediterranean diet intervention group showed a significant increase in the consumption of fruits (P<.001), olive oil (P<.001), whole grain cereals (P=.002), pulses (P<.001), nuts (P<.001), white fish (P<.001), fatty fish (P<.001), and white meat (P=.007), and a significant reduction in refined cereals (P<.001), red and processed meat (P<.001), and sweets (P<.001) at 2 years of intervention. In terms of nutrients, the intervention group significantly increased their intake of omega-3 (P<.001) and fiber (P<.001), and they decreased their intake of carbohydrates (P=.02) and saturated fatty acids (P<.001) compared with the control group. Conclusions: The remote nutritional intervention using a website and phone calls seems to be effective in increasing adherence to the Mediterranean diet pattern among AF patients treated with catheter ablation.

Purpose Cardiovascular disease remains the global leading cause of death. We evaluated at baseline the association between the adherence to eight a priori high-quality dietary scores and the prevalence of individual and clustered cardiovascular risk factors (CVRF) in the PREDIMED-Plus cohort. Methods All PREDIMED-Plus participants (6874 men and women aged 55-75 years, with overweight/obesity and metabolic syndrome) were assessed. The prevalence of 4 CVRF (hypertension, obesity, diabetes, and dyslipidaemia), using standard diagnoses criteria, were considered as outcomes. The adherence to eight a priori-defined dietary indexes was calculated. Multivariable models were fitted to estimate differences in mean values of factors and prevalence ratios for individual and clustered CVRF. Results Highest conformity to any dietary pattern did not show inverse associations with hypertension. The modified Mediterranean Diet Score (PR = 0.95; 95% CI 0.90-0.99), Mediterranean Diet Adherence Score (MEDAS) (PR = 0.94; 95% CI 0.89-0.98), the pro-vegetarian dietary pattern (PR = 0.95; 95% CI 0.90-0.99) and the Alternate Healthy Eating Index 2010 (PR = 0.92; 95% CI 0.87-0.96) were inversely associated with prevalence of obesity. We identified significant inverse trend among participants who better adhered to the MEDAS and the Prime Diet Quality Score (PDQS) in the mean number of CVRF across categories of adherence. Better adherence to several high-quality dietary indexes was associated with better blood lipid profiles and anthropometric measures. Conclusions Highest adherence to dietary quality indexes, especially Mediterranean-style and PDQS scores, showed marginal associations with lower prevalence of individual and clustered CVRF among elderly adults with metabolic syndrome at high risk of cardiovascular disease

While growing evidence exists on the independent associations between anthocyanins and physical activity on cardiovascular disease (CVD) risk determinants, the possible interaction between these exposures has not yet been studied. We aimed to study the potential synergism between anthocyanin intake and physical activity on lipid profile measures. This cross-sectional study was conducted among 249 US career firefighters participating in the Feeding America's Bravest trial. Anthocyanin intake was calculated using a validated food frequency questionnaire (FFQ) and physical activity level by a validated questionnaire. Multivariable linear regression models determined the extent to which anthocyanin intake and physical activity predicted lipid parameters. Generalized linear models were used for joint effect and interaction analyses on the multiplicative and additive scales. Both anthocyanins and physical activity were independently inversely associated with total cholesterol:high density lipoprotein (HDL) cholesterol. Only physical activity was inversely associated with triglycerides, low density lipoprotein (LDL) cholesterol:HDL, and triglycerides (TG):HDL. Although the combined exposure of low anthocyanin intake and low physical activity was associated with lower (RR = 2.83; 95% CI: 1.42 to 5.67) HDL cholesterol <40 mg/dL, neither multiplicative (p = 0.72) nor additive interactions were detected (relative excess risk due to interaction (RERI): 0.02; 95% CI: -1.63 to 1.66; p = 0.98). Our findings provide insight on the potential synergism between anthocyanin intake and physical activity on the lipid profile.

Background and aims: The prevalence of hyperuricemia has increased substantially in recent decades. It has been suggested that it is an independent risk factor for weight gain, hypertension, hypertriglyceridemia, metabolic syndrome (MetS), and cardiovascular disease. Results from epidemiological studies conducted in different study populations have suggested that high consumption of dairy products is associated with a lower risk of developing hyperuricemia. However, this association is still unclear. The aim of the present study is to explore the association of the consumption of total dairy products and their subtypes with the risk of hyperuricemia in an elderly Mediterranean population with MetS. Methods and results: Baseline cross-sectional analyses were conducted on 6329 men/women (mean age 65 years) with overweight/obesity and MetS from the PREDIMED-Plus cohort. Dairy consumption was assessed using a food frequency questionnaire. Multivariable-adjusted Cox regressions were fitted to analyze the association of quartiles of consumption of total dairy products and their subtypes with the prevalence of hyperuricemia. Participants in the upper quartile of the consumption of total dairy products (multiadjusted prevalence ratio (PR) = 0.84; 95% CI: 0.75-0.94; P-trend 0.02), low-fat dairy products (PR = 0.79; 95% CI: 0.70-0.89; P-trend <0.001), total milk (PR = 0.81; 95% CI: 0.73-0.90; P-trend<0.001), low-fat milk (PR = 0.80; 95% CI: 0.72-0.89; P-trend<0.001, respectively), low-fat yogurt (PR = 0.89; 95% CI: 0.80-0.98; P-trend 0.051), and cheese (PR = 0.86; 95% CI: 0.77-0.96; P-trend 0.003) presented a lower prevalence of hyperuricemia. Whole-fat dairy, fermented dairy, and yogurt consumption were not associated with hyperuricemia. Conclusions: High consumption of total dairy products, total milk, low-fat dairy products, low-fat milk, low-fat yogurt, and cheese is associated with a lower risk of hyperuricemia.

Limited longitudinal studies have been conducted to evaluate colorectal cancer (CRC) incidence based on the updated 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations or other global lifestyle indices, and none in aged populations at high cardiovascular risk. We aimed to assess the association between CRC incidence and adherence to two emerging lifestyles indices (2018 WCRF/AICR score and another low-risk lifestyle (LRL) score comprising smoking status, alcohol consumption, physical activity, diet, and body mass index) in the Spanish PREvencion con DIeta MEDiterranea (PREDIMED) cohort. We studied 7216 elderly men and women at high cardiovascular risk. The 2018 WCRF/AICR and LRL scores were calculated. Multivariable Cox proportional regression models were fitted to estimate the HRs (hazard ratios) and 95% confidence intervals (CIs) for incident CRC events. During a median interquartile range (IQR) follow-up of 6.0 (4.4-7.3) years, 97 CRC events were considered. A significant linear association was observed between each 1-point increment in the WCRF/AICR score (score range from 0 to 7) and CRC risk (HR (95% CI) = 0.79 (0.63-0.99)). Similarly, each 1-point increment in the LRL score (score range from 0 to 5) was associated with a 22% reduction in CRC risk (0.78 (0.64-0.96)). Adhering to emergent lifestyle scores might substantially reduce CRC incidence in elderly individuals. Further longitudinal studies, which take different lifestyle indexes into account, are warranted in the future.

Background: Overall quality of dietary carbohydrate intake rather than total carbohydrate intake may determine the risk of cardiovascular disease (CVD). Objective: We examined 6- and 12-mo changes in carbohydrate quality index (CQI) and concurrent changes in several CVD risk factors in a multicenter, randomized, primary-prevention trial (PREDIMED-Plus) based on an intensive weight-loss lifestyle intervention program. Methods: Prospective analysis of 5373 overweight/obese Spanish adults (aged 55-75 y) with metabolic syndrome (MetS). Dietary intake information obtained from a validated 143-item semiquantitative food-frequency questionnaire was used to calculate 6- and 12-mo changes in CQI (categorized in quintiles), based on 4 criteria (total dietary fiber intake, glycemic index, whole grain/total grain ratio, and solid carbohydrate/total carbohydrate ratio). The outcomes were changes in intermediate markers of CVD. Results: During the 12-mo follow-up, the majority of participants improved their CQI by increasing their consumption of fruits, vegetables, legumes, fish, and nuts and decreasing their consumption of refined cereals, added sugars, and sugar-sweetened beverages. After 6 mo, body weight, waist circumference (WC), systolic and diastolic blood pressure (BP), fasting blood glucose, glycated hemoglobin (HbA1c), triglyceride levels, triglycerides and glucose (TyG) index, and TyG-WC decreased across successive quintiles of improvement in the CQI. After 12 mo, improvements were additionally observed for HDL cholesterol and for the ratio of total to HDL cholesterol. Favorable improvements (expressed in common units of SD and 95% CI) for quintile 5 compared with quintile 1 of CQI change were observed for most risk factors, including TyG-WC (SD -0.20; 95% CI -0.26, -0.15), HbA1c (SD -0.16; 95% CI -0.23, -0.10), weight (SD -0.12; 95% CI -0.14, -0.09), systolic BP (SD -0.11; 95% CI -0.19, -0.02) and diastolic BP (SD -0.11; 95% CI -0.19, -0.04). Conclusions: Improvements in CQI were strongly associated with concurrent favorable CVD risk factor changes maintained over time in overweight/obese adults with MetS. This trial was registered as ISRCTN 89898870.

After publication of our article [1] we have been notified that Table 2 was incorrectly formatted.

Purpose: To assess the association between the consumption of non-soy legumes and different subtypes of non-soy legumes and serum uric acid (SUA) or hyperuricemia in elderly individuals with overweight or obesity and metabolic syndrome. Methods: A cross-sectional analysis was conducted in the framework of the PREDIMED-Plus study. We included 6329 participants with information on non-soy legume consumption and SUA levels. Non-soy legume consumption was estimated using a semi-quantitative food frequency questionnaire. Linear regression models and Cox regression models were used to assess the associations between tertiles of non-soy legume consumption, different subtypes of non-soy legume consumption and SUA levels or hyperuricemia prevalence, respectively. Results: Individuals in the highest tertile (T3) of total non-soy legume, lentil and pea consumption, had 0.14 mg/dL, 0.19 mg/dL and 0.12 mg/dL lower SUA levels, respectively, compared to those in the lowest tertile (T1), which was considered the reference one. Chickpea and dry bean consumption showed no association. In multivariable models, participants located in the top tertile of total non-soy legumes [prevalence ratio (PR): 0.89; 95% CI 0.82-0.97; p trend = 0.01, lentils (PR: 0.89; 95% CI 0.82-0.97; p trend = 0.01), dry beans (PR: 0.91; 95% C: 0.84-0.99; p trend = 0.03) and peas (PR: 0.89; 95% CI 0.82-0.97; p trend = 0.01)] presented a lower prevalence of hyperuricemia (vs. the bottom tertile). Chickpea consumption was not associated with hyperuricemia prevalence. Conclusions: In this study of elderly subjects with metabolic syndrome, we observed that despite being a purine-rich food, non-soy legumes were inversely associated with SUA levels and hyperuricemia prevalence.

Background and objectives: Cured ham is one of the most characteristic foods in the Spanish diet. Because it is a red processed meat and due to its nutritional composition, including high sodium content, a potential association between cured ham consumption and a higher risk of hypertension could be expected. However, epidemiological studies evaluating this association are scarce. We prospectively assessed the association between cured ham consumption and the incidence of hypertension. Methods: The "Seguimiento Universidad de Navarra" (SUN) study is a cohort of Spanish middle-aged adult university graduates (average age: 38 (SD: 12) years, 60% women). We included 13,900 participants of the SUN cohort free of hypertension at baseline. One serving of cured ham is 50g. They were classified into 4 categories of cured ham consumption: <1; 1; 2-4 and ¿5servs/week. Multivariable-adjusted Cox regression models were fitted to assess the association between cured ham consumption and subsequent hypertension risk using the category of lowest consumption as the reference. Results: After a median follow-up of 10.9 years, 1465 incident self-reported cases of hypertension were identified. After adjusting for potential confounders, including dietary confounders, a high consumption of cured ham (¿5servs/week vs. <1serv/week) was not significantly associated with hypertension risk in this prospective cohort (HR=0.88, 95% CI: 0.70-1.10, p linear trend=0.40). Conclusions: Our results showed that cured ham consumption was not associated with a significantly higher or lower risk of hypertension in a prospective cohort of Spanish middle-aged adult university graduates. Further longitudinal and experimental studies are needed to disentangle the association between cured ham consumption and the risk of hypertension.

Background: Socioeconomic disparities and lifestyle factors are likely to determine the overall quality of the diet. In addition, overeating is compatible with inadequate micronutrient intake and it can lead to adverse health outcomes. Objective: To assess adequacy of dietary nutrient intake and to investigate the influence of socioeconomic and lifestyle factors on nutrient density in a large primary cardiovascular prevention trial conducted in healthy participants with metabolic syndrome (MetS) to assess the cardiovascular effects of an energy-restricted Mediterranean diet (PREDIMED-Plus). Methods: Baseline cross-sectional analysis of the PREDIMED-Plus trial with 6646 Spanish participants (aged 55-75 years in men and 60-75 years in women) with overweight/obesity and MetS. Energy and nutrient intake (for 10 nutrients) were calculated using a validated 143-item Food Frequency Questionnaire (FFQ) and nutrient density was estimated dividing the absolute nutrient intake by total energy intake. The prevalence of inadequate intake was estimated according to dietary reference intakes. Multivariable linear regression models were fitted to examine associations between socioeconomic status or lifestyle factors and nutrient density. Results: A considerable proportion of the screened participants showed a deficient intake of vitamins A, D, E, B9, calcium, magnesium and dietary fibre. Inadequate intake of four or more of the ten nutrients considered was present in 17% of participants. A higher nutrient density was directly and significantly associated with female sex, higher educational level and a better adherence to the Mediterranean diet. Lifestyle factors such as non-smoking and avoidance of sedentary lifestyles were also independently associated with better nutrient density. Conclusions: Patients with MetS, despite being overweight, exhibited suboptimal nutrient intake, especially among men. Low nutrient density diet can be largely explained by differences in socioeconomic and lifestyle factors. These results highlight the importance of focussing on nutritional education in vulnerable populations, taking into account nutrient requirements.

Dietary polyphenol intake is associated with improvement of metabolic disturbances. The aims of the present study are to describe dietary polyphenol intake in a population with metabolic syndrome (MetS) and to examine the association between polyphenol intake and the components of MetS. This cross-sectional analysis involved 6633 men and women included in the PREDIMED (PREvencion con DIeta MEDiterranea-Plus) study. The polyphenol content of foods was estimated from the Phenol-Explorer 3.6 database. The mean of total polyphenol intake was 846 +/- 318 mg/day. Except for stilbenes, women had higher polyphenol intake than men. Total polyphenol intake was higher in older participants (>70 years of age) compared to their younger counterparts. Participants with body mass index (BMI) >35 kg/m(2) reported lower total polyphenol, flavonoid, and stilbene intake than those with lower BMI. Total polyphenol intake was not associated with a better profile concerning MetS components, except for high-density lipoprotein cholesterol (HDL-c), although stilbenes, lignans, and other polyphenols showed an inverse association with blood pressure, fasting plasma glucose, and triglycerides. A direct association with HDL-c was found for all subclasses except lignans and phenolic acids. To conclude, in participants with MetS, higher intake of several polyphenol subclasses was associated with a better profile of MetS components, especially HDL-c.

BackgroundAn inverse association between total leisure-time physical activity (LTPA) and depression has been previously documented in the scientific literature. Our objective was to prospectively assess the association of LTPA with the risk of depression, focusing on several dimensions of LTPA (intensity, duration and type).MethodsThe SUN (Seguimiento Universidad de Navarra) project is a prospective cohort study formed by Spanish university graduates. A total of 15,488 adults (40.2% men, mean age 3712years) initially free of depression were assessed. A report of a validated medical diagnosis of depression or the habitual use of antidepressants (any of both) were considered as incident cases of depression. LTPA was estimated through previously validated self-reported questionnaires. Participants were classified following Physical Activity recommendations from the World Health Organization, and according to the intensity, duration and type of LTPA. Cox proportional hazards regression models were run, adjusted for demographic, lifestyle, and dietary factors, to estimate adjusted hazard ratios (HR) of depression and 95% confidence intervals (CI).ResultsDuring 163,059 person-years of follow-up we registered 870 incident cases of depression. Participants with higher total LTPA (METs-h/wk) and higher duration of LTPA (hours/wk) exhibited a lower risk of depression HR=0.84 (95% CI: 0.72-0.99) and HR=0.83 (0.70-0.99) respectively, whereas intensity of LTPA (MET) did not show any association with depression.Conclusion p id=Par Participants with higher LTPA had a lower risk of depression. The inverse association was stronger for total LPTA time than for its intensity. Higher duration of LTPA should be encouraged to prevent depression.

Background: Studies have failed to establish a clear link between high-density lipoprotein (HDL) cholesterol and cardiovascular disease, leading to the hypothesis that the atheroprotective role of HDL lies in its biological activity rather than in its cholesterol content. However, to date, the association between HDL functional characteristics and acute coronary syndrome has not been investigated comprehensively. Methods: We conducted a case-control study nested within the PREDIMED (Prevencion con Dieta Mediterranea) cohort, originally a randomized trial in which participants followed a Mediterranean or low-fat diet. Incident acute coronary syndrome cases (N=167) were individually matched (1:2) to control patients by sex, age, intervention group, body mass index, and follow-up time. We investigated 2 individual manifestations (myocardial infarction, unstable angina) as secondary outcomes. We measured the following functional characteristics: HDL cholesterol concentration (in plasma); cholesterol efflux capacity; antioxidant ability, measured by the HDL oxidative-inflammatory index; phospholipase A2 activity; and sphingosine-1-phosphate, apolipoproteins A-I and A-IV, serum amyloid A, and complement 3 protein (in apolipoprotein B-depleted plasma). We used conditional logistic regression models adjusted for HDL cholesterol levels and cardiovascular risk factors to estimate odds ratios (ORs) between 1-SD increments in HDL functional characteristics and clinical outcomes. Results: Low values of cholesterol efflux capacity (OR1SD, 0.58; 95% CI, 0.40-0.83) and low levels of sphingosine-1-phosphate (OR1SD, 0.70; 95% CI, 0.52-0.92) and apolipoprotein A-I (OR1SD, 0.58; 95% CI, 0.42-0.79) were associated with higher odds of acute coronary syndrome. Higher HDL oxidative inflammatory index values were marginally linked to acute coronary syndrome risk (OR1SD, 1.27; 95% CI, 0.99-1.63). Low values of cholesterol efflux capacity (OR1SD, 0.33; 95% CI, 0.18-0.61), sphingosine-1-phosphate (OR1SD: 0.60; 95% CI: 0.40-0.89), and apolipoprotein A-I (OR1SD, 0.59; 95% CI, 0.37-0.93) were particularly linked to myocardial infarction, whereas high HDL oxidative-inflammatory index values (OR1SD, 1.53; 95% CI, 1.01-2.33) and low apolipoprotein A-I levels (OR1SD, 0.52; 95% CI, 0.31-0.88) were associated with unstable angina. Conclusions: Low cholesterol efflux capacity values, pro-oxidant/proinflammatory HDL particles, and low HDL levels of sphingosine-1-phosphate and apolipoprotein A-I were associated with increased odds of acute coronary syndrome and its manifestations in individuals at high cardiovascular risk.

Purpose We aimed to evaluate associations between compliance with recommendations for total water intake (TWI) and total water intake from fluids (TWIF), and some socio-demographic and lifestyle factors of a senior Mediterranean population at high cardiovascular risk. Methods Cross-sectional analysis with data of 1902 participants from the PREDIMED-Plus study. A validated 32-item Spanish fluid-intake questionnaire was used to assess beverage consumption and water intake. Multivariable logistic regression models were used to assess the odds ratio (OR) and the 95% confidence interval (CI) for complying with European Food Safety Agency recommendations for TWI and TWIF according to various socio-demographic and lifestyle factors, and for the joint associations of Mediterranean diet (MedDiet) adherence and moderate-vigorous physical activity (MVPA). Results The mean total volume of fluid intake in the population studied was 1934 +/- 617 mL/day. Water was the most frequently consumed beverage. Significant differences between sex were only observed in alcoholic and hot beverage consumption. Compliance with TWIF was associated with being women (OR 3.02; 2.40, 3.80), high adherence to MedDiet (OR 1.07; 1.02, 1.12), and participants who were more engaged in physical activity (PA) (OR 1.07; 1.02, 1.13). Age was inversely associated (OR 0.96; 0.94, 0.98). Similar results for TWI recommendations compliance were observed in relation to being women (OR 5.34; 3.85, 7.42), adherence to MedDiet (OR 1.16; 1.02, 1.31) and PA (OR 1.07; 1.00, 1.15). The joint association of PA and MedDiet, showed that participants with higher adherence to MedDiet and meeting WHO recommendations for MVPA complied better with the TWI recommendations (OR 1.66; 1.19, 2.32). Conclusions High compliance with recommendations for TWI was associated with being a woman, and a healthy lifestyle characterized by high adherence to the MedDiet and PA.

Background: Glycolysis/gluconeogenesis and tricarboxylic acid (TCA) cycle metabolites have been associated with type 2 diabetes (T2D). However, the associations of these metabolites with T2D incidence and the potential effect of dietary interventions remain unclear. Objectives: We aimed to evaluate the association of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with insulin resistance and T2D incidence, and the potential modifying effect of Mediterranean diet (MedDiet) interventions. Methods: We included 251 incident T2D cases and 638 noncases in a nested case-cohort study within the PREDIMED Study during median follow-up of 3.8 y. Participants were allocated to MedDiet + extra-virgin olive oil. MedDiet + nuts, or control diet. Plasma metabolites were measured using a targeted approach by LC-tandem MS. We tested the associations of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with subsequent T2D risk using weighted Cox regression models and adjusting for potential confounders. We designed a weighted score combining all these metabolites and applying the leave-oneout cross-validation approach. Results: Baseline circulating concentrations of hexose monophosphate. pyruvate, lactate, alanine, glycerol-3 phosphate, and isocitrate were significantly associated with higher T21) risk (17-44% higher risk for each 1-SD increment). The weighted score including all metabolites was associated with a 30% (95% CI: 1.12, 1.51) higher relative risk of T2D for each 1-SD increment. Baseline lactate and alanine were associated with baseline and 1-y changes of homeostasis model assessment of insulin resistance. One-year increases in most metabolites and in the weighted score were associated with higher relative risk of T2D after 1-y of follow-up. Lower risks were observed in the MedDiet groups than in the control group although no significant interactions were found after adjusting for multiple comparisons. Conclusions: We identified a panel of glycolysis/gluconeogenesisrelated metabolites that was significantly associated with T2D risk in a Mediterranean population at high cardiovascular disease risk. A MedDiet could counteract the detrimental effects of these metabolites.

Background: Although the association between glutamate and glutamine in relation to cardiometabolic disorders has been evaluated, the role of these metabolites in the development of atrial fibrillation (AF) and heart failure (HF) remains unknown. Objectives: We examined associations of glutamate, glutamine, and the glutamine-to-glutamate ratio with AF and HF incidence in a Mediterranean population at high cardiovascular disease (CVD) risk. Methods: The present study used 2 nested case-control studies within the PREDIMED (Prevencion con Dieta Mediterranea) study. During similar to 10 y of follow-up, there were 509 AF incident cases matched to 618 controls and 326 HF incident cases matched to 426 controls. Plasma concentrations of glutamate and glutamine were semiquantitatively profiled with LC-tandem MS. ORs were estimated with multivariable conditional logistic regression models. Results: In fully adjusted models, per 1-SD increment, glutamate was associated with a 29% (95% CI: 1.08, 1.54) increased risk of HF and glutamine-to-glutamate ratio with a 20% (95% CI: 0.67, 0.94) decreased risk. Glutamine-to-glutamate ratio was also inversely associated with HF risk (OR per 1-SD increment: 0.80; 95% CI: 0.67, 0.94) when comparing extreme quartiles. Higher glutamate concentrations were associated with a worse cardiometabolic risk profile, whereas a higher glutamine-to-glutamate ratio was associated with a better cardiometabolic risk profile. No associations between the concentrations of these metabolites and AF were observed. Conclusions: Our findings suggest that high plasma glutamate concentrations possibly resulting from alterations in the glutamate-glutamine cycle may contribute to the development of HF in Mediterranean individuals at high CVD risk.

Healthy lifestyle factors, such as physical activity (PA) and Mediterranean diet (MD), decrease the likelihood of developing metabolic syndrome (MetS). The aim of this study was to report main lifestyle components and related factors according to the MetS severity. Cross-sectional analysis was done of baseline lifestyle factors from 5739 participants with overweight/obesity and MetS features (aged 55-75 years) included in the PREDIMED-PLUS primary cardiovascular prevention randomized trial. Participants were categorized in tertiles according to a validated MetS severity score (MetSSS). Anthropometrics, visceral adiposity index, dietary nutrient intake, biochemical marker levels, as well as a Dietary Inflammatory Index and depression symptoms (Beck Depression Inventory-II) were measured. Diet quality was assessed using a 17-item energy-restricted MD questionnaire. Duration and intensity of PA was self-reported using the Minnesota-REGICOR Short Physical Activity Questionnaire. Sedentary behaviours were measured using the Spanish version of the Nurses' Health Study questionnaire. The 30 s chair stand test was also assessed. Participants with highest MetSSS showed higher values of cardiovascular risk factors (except for total cholesterol and LDL cholesterol), depression risk, sedentary and TV viewing time, and lower moderate and vigorous leisure-time physical activity (LTPA). Highest MetSSS participants tended to a pro-inflammatory dietary pattern and tended to lower MD adherence. In addition, they showed lower carbohydrate and nut intake and higher intake of protein, saturated and trans fatty acids, cholesterol, iodine, sodium, red and processed meat products, other oils different from olive oil and spirit alcoholic drinks. The highest MetS severity score was associated with lower moderate and vigorous LTPA and higher sedentary time and depression risk, as they tended to a pro-inflammatory dietary pattern and lower MD adherence.

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia. Catheter ablation aims to restore sinus rhythm. However, relapses occur in up to 30% of patients. A Mediterranean diet (MedDiet) enriched with extra-virgin olive oil (EVOO) substantially reduced the incidence of AF in the PREDIMED trial. The PREDIMAR will test a similar intervention in secondary prevention. Methods PREDIMAR is a multicenter, randomized, single-blind trial testing the effect of a MedDiet enriched with EVOO to reduce tachyarrhythmia relapses after AF ablation. The primary outcome is the recurrence of any sustained atrial tachyarrhythmia after ablation (excluding those occurring only during the first 3 months after ablation). The target final sample size is 720 patients (360 per group) recruited from 4 Spanish hospitals. A remote intervention, maintained for 2 years, is delivered to the active intervention group including periodic phone calls by a dietitian and free provision of EVOO. The control group will receive delayed intervention after trial completion. Routine electrocardiogram (ECG) and Holter ECG are performed, and a portable cardiac rhythm monitoring device is provided to be worn by participants during 15 months. Results Recruitment started in March 2017. Up to July 2019, 609 patients were randomized (average inclusion rate: 5.3 patients/wk). Retention rates after 18 months are >94%. Conclusions If our hypothesis is confirmed, the utility of the MedDiet enriched with EVOO in slowing the progression of AF will be proven, preventing recurrences and potentially reducing complications.

Scope The plasma metabolomics profiles of protein intake have been rarely investigated. The aim is to identify the distinct plasma metabolomics profiles associated with overall intakes of protein as well as with intakes from animal and plant protein sources. Methods and results A cross-sectional analysis using data from 1833 participants at high risk of cardiovascular disease is conducted. Associations between 385 identified metabolites and the intake of total, animal protein (AP), and plant protein (PP), and plant-to-animal ratio (PR) are assessed using elastic net continuous regression analyses. A double 10-cross-validation (CV) procedure is used and Pearson correlations coefficients between multi-metabolite weighted models and reported protein intake in each pair of training-validation datasets are calculated. A wide set of metabolites is consistently associated with each protein source evaluated. These metabolites mainly consisted of amino acids and their derivatives, acylcarnitines, different organic acids, and lipid species. Few metabolites overlapped among protein sources (i.e., C14:0 SM, C20:4 carnitine, GABA, and allantoin) but none of them toward the same direction. Regarding AP and PP approaches, C20:4 carnitine and dimethylglycine are positively associated with PP but negatively associated with AP. However, allantoin, C14:0 SM, C38:7 PE plasmalogen, GABA, metronidazole, and trigonelline (N-methylnicotinate) behave contrarily. Ten-CV Pearson correlation coefficients between self-reported protein intake and plasma metabolomics profiles range from 0.21 for PR to 0.32 for total protein. Conclusions Different sets of metabolites are associated with total, animal, and plant protein intake. Further studies are needed to assess the contribution of these metabolites in protein biomarkers' discovery and prediction of cardiometabolic alterations.

BACKGROUND Genetic, observational, and clinical intervention studies indicate that circulating levels of triglycerides and cholesterol transported in triglyceride-rich lipoproteins (remnant cholesterol) can predict cardiovascular events. OBJECTIVES This study evaluated the association of triglycerides and remnant cholesterol (remnant-C) with major cardiovascular events in a cohort of older individuals at high cardiovascular risk. METHODS This study determined the baseline lipid profile and searched for major adverse cardiovascular events (MACEs) in the high-risk primary prevention PREDIMED (Prevencion con Dieta Mediterranea) trial population (mean age: 67 years; body mass index: 30 kg/m(2); 43% men; 48% with diabetes) after a median follow-up of 4.8 years. Unadjusted and adjusted Cox proportional hazard models were used to assess the association between lipid concentrations (either as continuous or categorical variables) and incident MACEs (N = 6,901; n cases = 263). RESULTS In multivariable-adjusted analyses, triglycerides (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 1.02 to 1.06, per 10 mg/dl [0.11 mmol/l]; p < 0.001), non-high-density lipoprotein cholesterol (HDL-C) (HR: 1.05; 95% CI: 1.01 to 1.10, per 10 mg/dl [0.26 mmol/l]; p = 0.026), and remnant-C (HR: 1.21; 95% CI: 1.10 to 1.33, per 10 mg/dl [0.26 mmol/l]; p 0.001), but not low-density lipoprotein cholesterol (LDL-C) or HDL-C, were associated with MACEs. Atherogenic dyslipidemia (triglycerides 150 mg/dl [1.69 mmol/l] and HDL-C <40 mg/dl [1.03 mmol/l] in men or <50 mg/dl [1.29 mmol/l] in women) was also associated with MACEs (HR: 1.44; 95% CI: 1.04 to 2.00; p = 0.030). Remnant-C >= 30 mg/dl (0.78 mmol/l) differentiated subjects at a higher risk of MACEs compared with those at lower concentrations, regardless of whether LDL-C levels were on target at <= 100 mg/dl (2.59 mmol/l). CONCLUSIONS In overweight or obese subjects at high cardiovascular risk, levels of triglycerides and remnant-C, but not LDL-C, were associated with cardiovascular outcomes independent of other risk factors. (C) 2020 Published by Elsevier on behalf of the American College of Cardiology Foundation.

Introduction: Overall lifestyle patterns rather than individual factors may exert greater reductions on chronic disease risk and mortality. The objective is to study the association between a Mediterranean lifestyle index and all-cause and cause-specific mortality. Methods: Investigators analyzed data from 20,494 participants in the Seguimiento Universidad de Navarra cohort in 2019. The Mediterranean lifestyle index is composed of 28 items on food consumption, dietary habits, physical activity, rest, and social interactions that score 0 or 1 point; scores theoretically could range from 0 to 28 points. Results: After a median follow-up of 12.1 years, 407 deaths were observed. In the multivariable-adjusted model, high adherence (14 points) to the Mediterranean lifestyle was associated with a 41% relative reduction in all-cause mortality (hazard ratio=0.59, 95% CI=0.42, 0.83) compared with low adherence (3-10 points, p<0.001 for trend). For each additional point, the multivariable hazard ratios for all-cause mortality were 0.95 (95% CI=0.89, 1.02) for food consumption; 1.00 (95% CI=0.92, 1.08) for dietary habits; and 0.73 (95% CI=0.66, 0.80) for physical activity, rest, social habits, and conviviality. Significant interaction with age at last contact (p<0.001) suggested a lower risk for each additional point among participants aged >= 50 years (hazard ratio=0.50, 95% CI=0.34, 0.74), whereas no association was found for participants aged <50 years (hazard ratio=1.15, 95% CI=0.54, 2.44). Conclusions: Adherence to a Mediterranean lifestyle may reduce the risk of mortality in a Spanish cohort of university graduates. Inverse associations were found for the overall Mediterranean lifestyle score and lifestyle block, whereas no associations were observed for the dietary blocks. Future research should consider the Mediterranean lifestyle beyond the Mediterranean diet in different populations for the promotion of healthy longevity. Trial registration: This study is registered at www.clinicaltrials.gov NCT02669602. (c) 2020 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Metabolomics is improving the understanding of the mechanisms of the health effects of diet. Previous research has identified several metabolites associated with the Mediterranean Diet (MedDiet), but knowledge about longitudinal changes in metabolic biomarkers after a MedDiet intervention is scarce. A subsample of 48 firefighters from a cluster-randomized trial at Indianapolis fire stations was randomly selected for the metabolomics study at 12 months of follow up (time point 1), where Group 1 (n = 24) continued for another 6 months in a self-sustained MedDiet intervention, and Group 2 (n = 24), the control group at that time, started with an active MedDiet intervention for 6 months (time point 2). A total of 225 metabolites were assessed at the two time points by using a targeted NMR platform. The MedDiet score improved slightly but changes were non-significant (intervention: 24.2 vs. 26.0 points and control group: 26.1 vs. 26.5 points). The MedDiet intervention led to favorable changes in biomarkers related to lipid metabolism, including lower LDL-C, ApoB/ApoA1 ratio, remnant cholesterol, M-VLDL-CE; and higher HDL-C, and better lipoprotein composition. This MedDiet intervention induces only modest changes in adherence to the MedDiet and consequently in metabolic biomarkers. Further research should confirm these results based on larger study samples in workplace interventions with powerful study designs.

Aims To investigate whether metabolic signature composed of multiple plasma metabolites can be used to characterize adherence and metabolic response to the Mediterranean diet and whether such a metabolic signature is associated with cardiovascular disease (CVD) risk. Methods and results Our primary study cohort included 1859 participants from the Spanish PREDIMED trial, and validation cohorts included 6868 participants from the US Nurses' Health Studies I and II, and Health Professionals Follow-up Study (NHS/HPFS). Adherence to the Mediterranean diet was assessed using a validated Mediterranean Diet Adherence Screener (MEDAS), and plasma metabolome was profiled by liquid chromatography-tandem mass spectrometry. We observed substantial metabolomic variation with respect to Mediterranean diet adherence, with nearly one-third of the assayed metabolites significantly associated with MEDAS (false discovery rate<0.05). Using elastic net regularized regressions, we identified a metabolic signature, comprised of 67 metabolites, robustly correlated with Mediterranean diet adherence in both PREDIMED and NHS/HPFS (r=0.28-0.37 between the signature and MEDAS; P=3x10(-35) to 4x10(-118)). In multivariable Cox regressions, the metabolic signature showed a significant inverse association with CVD incidence after adjusting for known risk factors (PREDIMED: hazard ratio [HR] per standard deviation increment in the signature = 0.71, P<0.001; NHS/HPFS: HR=0.85, P=0.001), and the association persisted after further adjustment for MEDAS scores (PREDIMED: HR=0.73, P=0.004; NHS/HPFS: HR=0.85, P=0.004). Further genome-wide association analysis revealed that the metabolic signature was significantly associated with genetic loci involved in fatty acids and amino acids metabolism. Mendelian randomization analyses showed that the genetically inferred metabolic signature was significantly associated with risk of coronary heart disease (CHD) and stroke (odds ratios per SD increment in the genetically inferred metabolic signature = 0.92 for CHD and 0.91 for stroke; P<0.001). Conclusions We identified a metabolic signature that robustly reflects adherence and metabolic response to a Mediterranean diet, and predicts future CVD risk independent of traditional risk factors, in Spanish and US cohorts.

Introduction and objectives: The cardiovascular benefits of the Mediterranean diet have usually been assessed under assumptions of ad libitum total energy intake (ie, no energy restriction). In the recently launched PREDIMED-Plus, we conducted exploratory analyses to study the baseline associations between adherence to an energy-restricted Mediterranean diet (MedDiet) and the prevalence of cardiovascular risk factors (CVRF). Methods: Cross-sectional assessment of all PREDIMED-Plus participants (6874 older adults with overweight/obesity and metabolic syndrome) at baseline. The participants were assessed by their usual primary care physicians to ascertain the prevalence of 4 CVRF (hypertension, obesity, diabetes, and dyslipidemia). A 17-point PREDIMED-Plus score was used to measure adherence to the MedDiet. Multivariable models were fitted to estimate differences in means and prevalence ratios for individual and clustered CVRF. Results: Better adherence to a MedDiet pattern was significantly associated with lower average triglyceride levels, body mass index, and waist circumference. Compared with low adherence (<= 7 points in the 17-point score), better adherence to the MedDiet (11-17 points) showed inverse associations with hypertension (prevalence ratio = 0.97; 95%CI, 0.94-1.00) and obesity (prevalence ratio = 0.96; 95%CI, 0.92-1.00), but positive associations with diabetes (prevalence ratio = 1.19; 95%CI, 1.07-1.32). Compared with the lowest third of adherence, women in the upper third showed a significantly lower prevalence of the clustering of 3 or more CVRF (prevalence ratio = 0.91; 95%CI, 0.83-0.98). Conclusions: Among participants at high cardiovascular risk, better adherence to a MedDiet showed significant inverse associations with CVRF among women, and improved lipid profiles and adiposity measures. (C) 2018 Sociedad Espanola de Cardiologia. Published by Elsevier Espana, S.L.U. All rights reserved.

Overweight and obesity are important risk factors for type 2 diabetes (T2D). Moving towards healthier diets, namely, diets rich in bioactive compounds, could decrease the odds of suffering T2D. However, those individuals with high body mass index (BMI) may have altered absorption or metabolism of some nutrients and dietary components, including polyphenols. Therefore, we aimed to assess whether high intakes of some classes of polyphenols are associated with T2D in a population with metabolic syndrome and how these associations depend on BMI and sex. This baseline cross-sectional analysis includes 6633 participants from the PREDIMED-Plus trial. Polyphenol intakes were calculated from food frequency questionnaires (FFQ). Cox regression models with constant time at risk and robust variance estimators were used to estimate the prevalence ratios (PRs) for polyphenol intake and T2D prevalence using the lowest quartile as the reference group. Analyses were stratified by sex and BMI groups (overweight and obese) to evaluate potential effect modification. Catechins, proanthocyanidins, hydroxybenzoic acids, and lignans were inversely associated with T2D. Hydroxycinnamic acids were directly related in men. These associations were different depending on sex and BMI, that is, women and overweight obtained stronger inverse associations.

The associations between arginine-based metabolites and incident type 2 diabetes (T2D) are unknown. We employed a case-cohort design, nested within the PREDIMED trial, to examine six plasma metabolites (arginine, citrulline, ornithine, asymmetric dimethylarginine [ADMA], symmetric dimethylarginine [SDMA] and N-monomethyl-l-arginine [NMMA]) among 892 individuals (251 cases) for associations with incident T2D and insulin resistance. Weighted Cox models with robust variance were used. The 1-year changes in arginine (adjusted hazard ratio [HR] per SD 0.68, 95% confidence interval [CI] 0.49, 0.95; Q4 vs. Q1 0.46, 95% CI 0.21, 1.04; P trend = 0.02) and arginine/ADMA ratio (adjusted HR per SD 0.73, 95% CI 0.51, 1.04; Q4 vs. Q1 0.52, 95% CI 0.22, 1.25; P trend = 0.04) were associated with a lower risk of T2D. Positive changes of citrulline and ornithine, and negative changes in SDMA and arginine/(ornithine + citrulline) were associated with concurrent 1-year changes in homeostatic model assessment of insulin resistance. Individuals in the low-fat-diet group had a higher risk of T2D for 1-year changes in NMMA than individuals in Mediterranean-diet groups (P interaction = 0.02). We conclude that arginine bioavailability is important in T2D pathophysiology.

BACKGROUND & AIMS: Evidence on coffee consumption and its association with the incidence of hypertension is still inconsistent. The aim of this study was to examine the association of regular or decaffeinated coffee consumption with the risk of developing hypertension in a middle-aged Mediterranean cohort. METHODS: The SUN Project is a prospective open cohort with more than 22,500 Spanish university graduates. For the present study, we analyzed data from 13,374 participants initially free of hypertension (mean follow-up 9.1 years). The consumption of regular and decaffeinated coffee was obtained at baseline using a previously validated semi-quantitative food frequency questionnaire. Validated, self-reported medical diagnoses of hypertension were collected biennially. We used Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for incident hypertension according to baseline coffee consumption. We assessed the interaction with sex and baseline adherence to the Mediterranean diet. RESULTS: Among 121,397 person-years of follow-up, a total of 1757 participants developed hypertension. Overall, coffee consumption -either caffeinated or decaffeinated- was not significantly associated with the risk of hypertension. Only among women, higher consumption of regular coffee was associated with a 26% lower risk of hypertension (>=2 cups/d vs. never/seldom, 95% CI 9%-39%; p for interaction: 0.0236). Women with a low baseline adherence to the Mediterranean diet showed the strongest risk reduction (HR ¿ 2 cups/d vs. never/seldom 0.58, 95% CI (0.41-0.82) p for interaction = 0.0452). CONCLUSION: In the SUN project we found an inverse association between regular coffee consumption and the risk of hypertension in women, which was strongest among women with a suboptimal food pattern (low adherence to the Mediterranean diet).

Dietary guidelines emphasize the importance of a varied diet to provide an adequate nutrient intake. However, an older age is often associated with consumption of monotonous diets that can be nutritionally inadequate, increasing the risk for the development or progression of diet-related chronic diseases, such as metabolic syndrome (MetS). To assess the association between dietary diversity (DD) and nutrient intake adequacy and to identify demographic variables associated with DD, we cross-sectionally analyzed baseline data from the PREDIMED-Plus trial: 6587 Spanish adults aged 55-75 years, with overweight/obesity who also had MetS. An energy-adjusted dietary diversity score (DDS) was calculated using a 143-item validated semi-quantitative food frequency questionnaire (FFQ). Nutrient inadequacy was defined as an intake below 2/3 of the dietary reference intake (DRI) forat least four of 17 nutrients proposed by the Institute of Medicine (IOM). Logistic regression models were used to evaluate the association between DDS and the risk of nutritionally inadequate intakes. In the higher DDS quartile there were more women and less current smokers. Compared with subjects in the highest DDS quartile, those in the lowest DDS quartile had a higher risk of inadequate nutrient intake: odds ratio (OR) = 28.56 (95% confidence interval (CI) 20.80-39.21). When we estimated food varietyfor each of the food groups, participants in the lowest quartile had a higher risk of inadequate nutrient intake for the groups of vegetables, OR = 14.03 (95% CI 10.55-18.65), fruits OR = 11.62 (95% CI 6.81-19.81), dairy products OR = 6.54 (95% CI 4.64-9.22) and protein foods OR = 6.60 (95% CI 1.96-22.24). As DDS decreased, the risk of inadequate nutrients intake rose. Given the impact of nutrient intake adequacy on the prevention of non-communicable diseases, health policies should focus on the promotion of a healthy varied diet, specifically promoting the intake of vegetables and fruit among population groups with lower DDS such as men, smokers or widow(er)s.

Background & aims: Breast cancer (BC) is the most commonly diagnosed cancer, and diet is suspected to play a role in its development. Dietary factors may mediate this process through modulation of inflammation, though findings from previous studies have not been consistent. We aimed to longitudinally assess the association between the dietary inflammatory index (DII (R)), a frequently used method to assess the inflammatory potential of the diet, and incident BC. Methods: We included 10,713 middle-aged, Spanish female university graduates from the SUN cohort. DII (R) scores were derived from a validated 136-item food-frequency questionnaire, and it was based on scientific evidence on the relationship between diet and inflammatory biomarkers. Diagnosis of BC was reported by the participant or, if deceased, by the next of kin or identified from death certificates. Self-reports of BC were confirmed by revision of medical reports by an experienced oncologist. Cox proportional hazard models were used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association between quartiles of DII (R) and incident BC. Results: After 10.3 years of median follow-up, we identified 100 confirmed and 168 probable incident BC cases. The multivariable-adjusted HR for participants in the 4th quartile to the 1st quartile was 1.44 (95% CI 0.76-2.72; p-trend: 0.339) when confirmed cases were analyzed, and 1.20 (95% CI 0.72-1.99; p-trend: 0.757) for the probable cases. We neither observed statistically significant differences in regard to menopausal status. Conclusions: The apparent increase in risk between DII (R) scores and BC in our cohort was not statistically significant, which could be partly explained by the small number of observed cases. (C) 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

OBJECTIVE The long-term impact of intentional weight loss on cardiovascular events remains unknown. We describe 12-month changes in body weight and cardiovascular risk factors in PREvencion con DIeta MEDiterranea (PREDIMED)-Plus, a trial designed to evaluate the long-term effectiveness of an intensive weight loss lifestyle intervention on primary cardiovascular prevention. RESEARCH DESIGN AND METHODS Overweight/obese adults with metabolic syndrome aged 55-75 years (n = 626) were randomized to an intensive weight loss lifestyle intervention based on an energy-restricted Mediterranean diet, physical activity promotion, and behavioral support (IG) or a control group (CG). The primary and secondary outcomes were changes in weight and cardiovascular risk markers, respectively. RESULTS Diet and physical activity changes were in the expected direction, with significant improvements in IG versus CG. After 12 months, IG participants lost an average of 3.2 kg vs. 0.7 kg in the CG (P < 0.001), a mean difference of -2.5 kg (95% CI -3.1 to -1.9). Weight loss >= 5% occurred in 33.7% of IG participants compared with 11.9% in the CG (P < 0.001). Compared with the CG, cardiovascular risk factors, including waist circumference, fasting glucose, triglycerides, and HDL cholesterol, significantly improved in IG participants (P < 0.002). Reductions in insulin resistance, HbA(1c), and circulating levels of leptin, interleukin-18, and MCP-1 were greater in IG than CG participants (P < 0.05). IG participants with prediabetes/diabetes significantly improved glycemic control and insulin sensitivity, along with triglycerides and HDL cholesterol levels compared with their CG counterparts. CONCLUSIONS PREDIMED-Plus intensive lifestyle intervention for 12 months was effective in decreasing adiposity and improving cardiovascular risk factors in overweight/obese older adults with metabolic syndrome, as well as in individuals with or at risk for diabetes.

OBJECTIVE To examine the effects of two Mediterranean eating plans (Med-EatPlans) versus a low-fat eating plan on the need for glucose-lowering medications. RESEARCH DESIGN AND METHODS From the Prevencion con Dieta Mediterranea (PREDIMED) trial, we selected 3,230 participants with type 2 diabetes at baseline. These participants were randomly assigned to one of three eating plans: Med-EatPlan supplemented with extra-virgin olive oil (EVOO), Med-EatPlan supplemented with mixed nuts, or a low-fat eating plan (control). In a subgroup (15%), the allocation was done in small clusters instead of using individual randomization, and the clustering effect was taken into account in the statistical analysis. In multivariable time-to-event survival models, we assessed two outcomes: 1) introduction of the first glucose-lowering medication (oral or injectable) among participants on lifestyle management at enrollment and 2) insulin initiation. RESULTS After a median follow-up of 3.2 years, in multivariable analyses adjusting for baseline characteristics and propensity scores, the hazard ratios (HRs) of starting a first glucose-lowering medication were 0.78 (95% CI 0.62-0.98) for Med-EatPlan + EVOO and 0.89 (0.71-1.12) for Med-EatPlan + nuts, compared with the control eating plan. After a median follow-up of 5.1 years, the adjusted HRs of starting insulin treatment were 0.87 (0.68-1.11) for Med-EatPlan + EVOO and 0.89 (0.69-1.14) for Med-EatPlan + nuts compared with the control eating plan. CONCLUSIONS Among participants with type 2 diabetes, a Med-EatPlan + EVOO may delay the introduction of new-onset glucose-lowering medications. The Med-EatPlan did not result in a significantly lower need for insulin.

We assessed the relationship between a healthy lifestyle and the subsequent risk of developing metabolic syndrome. The "Seguimiento Universidad de Navarra" (SUN) Project is a prospective cohort study, focused on nutrition, lifestyle, and chronic diseases. Participants (n = 10,807, mean age 37 years, 67% women) initially free of metabolic syndrome were followed prospectively for a minimum of 6 years. To evaluate healthy lifestyle, nine habits were used to derive a Healthy Lifestyle Score (HLS): Never smoking, moderate to high physical activity (>20 MET-h/week), Mediterranean diet (>= 4/8 adherence points), moderate alcohol consumption (women, 0.1-5.0 g/day; men, 0.1-10.0 g/day), low television exposure (<2 h/day), no binge drinking (<= 5 alcoholic drinks at any time), taking a short afternoon nap (<30 min/day), meeting up with friends >1 h/day, and working at least 40 h/week. Metabolic syndrome was defined according to the harmonizing definition. The association between the baseline HLS and metabolic syndrome at follow-up was assessed with multivariable-adjusted logistic regressions. During follow-up, we observed 458 (4.24%) new cases of metabolic syndrome. Participants in the highest category of HLS adherence (7-9 points) enjoyed a significantly reduced risk of developing metabolic syndrome compared to those in the lowest category (0-3 points) (adjusted odds ratio (OR) = 0.66, 95% confidence interval (CI) = 0.47-0.93). Higher adherence to the Healthy Lifestyle Score was associated with a lower risk of developing metabolic syndrome. The HLS may be a simple metabolic health promotion tool.

Background and aims: Glutamate, glutamine are involved in energy metabolism, and have been related to cardiometabolic disorders. However, their roles in the development of type-2 diabetes (T2D) remain unclear. The aim of this study was to examine the effects of Mediterranean diet on associations between glutamine, glutamate, glutamine-to-glutamate ratio, and risk of new-onset T2D in a Spanish population at high risk for cardiovascular disease (CVD). Methods and results: The present study was built within the PREDIMED trial using a case-cohort design including 892 participants with 251 incident T2D cases and 641 non-cases. Participants (mean age 66.3 years; female 62.8%) were non diabetic and at high risk for CVD at baseline. Plasma levels of glutamine and glutamate were measured at baseline and after 1-year of intervention. Higher glutamate levels at baseline were associated with increased risk of T2D with a hazard ratio (HR) of 2.78 (95%CI, 1.43-5.41, P for trend = 0.0002). In contrast, baseline levels of glutamine (HR: 0.64, 95% CI, 0.36-1.12; P for trend = 0.04) and glutamine-to-glutamate ratio (HR: 0.31, 95% CI, 0.16-0.57; P for trend = 0.0001) were inversely associated with T2D risk when comparing extreme quartiles. The two Mediterranean diets (MedDiet + EVOO and MedDiet + mixed nuts) did not alter levels of glutamine and glutamate after intervention for 1 year. However, MedDiet mitigated the positive association between higher baseline plasma glutamate and T2D risk (P for interaction = 0.01). Conclusion: Higher levels of glutamate and lower levels of glutamine were associated with increased risk of T2D in a Spanish population at high risk for CVD. Mediterranean diet might mitigate the association between the imbalance of glutamine and glutamate and T2D risk. This trial is registered at http://www.controlled-trials.com, ISRCTN35739639. (C) 2019 The Italian Society of Diabetology, 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: This study explored the association between inactive time and measures of adiposity, clinical parameters, obesity, type 2 diabetes and metabolic syndrome components. It further examined the impact of reallocating inactive time to time in bed, light physical activity (LPA) or moderate-to-vigorous physical activity (MVPA) on cardio-metabolic risk factors, including measures of adiposity and body composition, biochemical parameters and blood pressure in older adults. Methods: This is a cross-sectional analysis of baseline data from 2189 Caucasian men and women (age 55-75 years, BMI 27-40 Kg/m(2)) from the PREDIMED-Plus study (http://www.predimedplus.com/). All participants had >= 3 components of the metabolic syndrome. Inactive time, physical activity and time in bed were objectively determined using triaxial accelerometers GENEActiv during 7 days (ActivInsights Ltd., Kimbolton, United Kingdom). Multiple adjusted linear and logistic regression models were used. Isotemporal substitution regression modelling was performed to assess the relationship of replacing the amount of time spent in one activity for another, on each outcome, including measures of adiposity and body composition, biochemical parameters and blood pressure in older adults. Results: Inactive time was associated with indicators of obesity and the metabolic syndrome. Reallocating 30min per day of inactive time to 30 min per day of time in bed was associated with lower BMI, waist circumference and glycated hemoglobin (HbA1c) (all p-values < 0.05). Reallocating 30 min per day of inactive time with 30 min per day of LPA or MVPA was associated with lower BMI, waist circumference, total fat, visceral adipose tissue, HbA1c, glucose, triglycerides, and higher body muscle mass and HDL cholesterol (all p-values < 0.05). Conclusions: Inactive time was associated with a poor cardio-metabolic profile. Isotemporal substitution of inactive time with MVPA and LPA or time in bed could have beneficial impact on cardio-metabolic health.

Background & aims: Limited prospective studies have examined the association between legumes consumption and mortality, whereas scarce, if at all, previous studies have evaluated such associations taking into consideration specific grain legumes. We aimed to investigate the association between total legumes consumption and grain legumes species (dry beans, chickpeas, lentils, and fresh peas) with all cause, cardiovascular disease (CVD), cancer and other-cause mortality among elderly Mediterranean individuals at high CVD risk. Methods: We prospectively assessed 7216 participants from the PREvencion con Dleta MEDiterranea study. Dietary intake was assessed at baseline and yearly during follow-up by using a validated food frequency questionnaire. Results: During a median follow-up of 6.0 years, 425 total deaths, 103 CVD deaths, 169 cancer deaths and 153 due to other-causes deaths occurred. Hazard ratios (HRs) [95% confidence interval (CI)] of CVD mortality were 1.52 (1.02-2.89) (P-trend = 0.034) and 2.23 (1.32-3.78) (P-trend = 0.002) for the 3rd tertile of total legumes and dry beans consumption, respectively, compared with the 1st tertile. When comparing extreme tertiles, higher total legumes and lentils consumption was associated with 49% (HR: 0.51; 95% CI: 0.31-0.84; P-trend = 0.009) and 37% (HR: 0.63; 95% CI: 0.40-0.98; P-trend = 0.049) lower risk of cancer mortality. Similar associations were observed for CVD death in males and for cancer death in males, obese and diabetic participants. Conclusions: These findings support the benefits of legumes consumption for cancer mortality prevention which may be counterbalanced by their higher risk for CVD mortality. Trial registration: The trial is registered at http://www.controlled-trials.com (ISRCTN35739639). Registration date: 5th October 2005. (C) 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Research examining associations between objectively-measured napping time and type 2 diabetes (T2D) is lacking. This study aimed to evaluate daytime napping in relation to T2D and adiposity measures in elderly individuals from the Mediterranean region. A cross-sectional analysis of baseline data from 2190 elderly participants with overweight/obesity and metabolic syndrome, in the PREDIMED-Plus trial, was carried out. Accelerometer-derived napping was measured. Prevalence ratios (PR) and 95% confidence intervals (CI) for T2D were obtained using multivariable-adjusted Cox regression with constant time. Linear regression models were fitted to examine associations of napping with body mass index (BMI) and waist circumference (WC). Participants napping >= 90 min had a higher prevalence of T2D (PR 1.37 (1.06, 1.78)) compared with those napping 5 to <30 min per day. Significant positive associations with BMI and WC were found in those participants napping >= 30 min as compared to those napping 5 to <30 min per day. The findings of this study suggest that longer daytime napping is associated with higher T2D prevalence and greater adiposity measures in an elderly Spanish population at high cardiovascular risk.

Background The pandemic of cardiovascular disease (CVD) and type 2 diabetes (T2D) requires the identification of new predictor biomarkers. Biomarkers potentially modifiable with lifestyle changes deserve a special interest. Our aims were to analyze: (a) The associations of lysine, 2-aminoadipic acid (2-AAA) or pipecolic acid with the risk of T2D or CVD in the PREDIMED trial; (b) the effect of the dietary intervention on 1-year changes in these metabolites, and (c) whether the Mediterranean diet (MedDiet) interventions can modify the effects of these metabolites on CVD or T2D risk. Methods Two unstratified case-cohort studies nested within the PREDIMED trial were used. For CVD analyses, we selected 696 non-cases and 221 incident CVD cases; for T2D, we included 610 non-cases and 243 type 2 diabetes incident cases. Metabolites were quantified using liquid chromatography-tandem mass spectrometry, at baseline and after 1-year of intervention. Results In weighted Cox regression models, we found that baseline lysine (HR+1 SD increase = 1.26; 95% CI 1.06-1.51) and 2-AAA (HR+1 SD increase = 1.28; 95% CI 1.05-1.55) were both associated with a higher risk of T2D, but not with CVD. A significant interaction (p = 0.032) between baseline lysine and T2D on the risk of CVD was observed: subjects with prevalent T2D and high levels of lysine exhibited the highest risk of CVD. The intervention with MedDiet did not have a significant effect on 1-year changes of the metabolites. Conclusions Our results provide an independent prospective replication of the association of 2-AAA with future risk of T2D. We show an association of lysine with subsequent CVD risk, which is apparently diabetes-dependent. No evidence of effects of MedDiet intervention on lysine, 2-AAA or pipecolic acid changes was found. Trial registration ISRCTN35739639; registration date: 05/10/2005; recruitment start date 01/10/2003

Background and aims: There is ongoing controversy about the effect of a low to moderate alcohol consumption on atrial fibrillation (AF). Our aim is to assess the association between adherence to a Mediterranean alcohol drinking pattern and AF incidence. Methods and results: A total 6527 out of the 7447 participants in the PREDIMED trial met our inclusion criteria. A validated frequency food questionnaire was used to measure alcohol consumption. Participants were classified as non-drinkers, Mediterranean alcohol drinking pattern (MADP) (10-30 g/d in men and 5-15 g/day in women, preferably red wine consumption with low spirits consumption), low-moderate drinking (< 30 g/day men y and < 15 g/day women), and heavy drinking. We performed multivariable Cox regression models to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) of incident AF according to alcohol drinking patterns. After a mean follow up of 4.4 years, 241 new incident AF cases were confirmed. Alcohol consumption was not associated to AF incidence among low-moderate drinkers (HR: 0.96; 95% CI: 0.67-1.37), adherents to MADP (HR: 1.15 95% CI: 0.75-1.75), or heavy drinkers (HR: 0.92; 95% CI: 0.53-1.58), compared with non-drinkers. Conclusions: In a high cardiovascular risk adult population, a Mediterranean alcohol consumption pattern (low to moderate red wine consumption) was not associated with an increased incidence of AF. (C) 2019 The Italian Society of Diabetology, 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.

Studies examining associations between purine metabolites and type 2 diabetes (T2D) are limited. We prospectively examined associations between plasma levels of purine metabolites with T2D risk and the modifying effects of transcription factor-7-like-2 (TCF7L2) rs7903146 polymorphism on these associations. This is a case-cohort design study within the PREDIMED study, with 251 incident T2D cases and a random sample of 694 participants (641 non-cases and 53 overlapping cases) without T2D at baseline (median follow-up: 3.8 years). Metabolites were semi-quantitatively profiled with LC-MS/MS. Cox regression analysis revealed that high plasma allantoin levels, including allantoin-to-uric acid ratio and high xanthine-to-hypoxanthine ratio were inversely and positively associated with T2D risk, respectively, independently of classical risk factors. Elevated plasma xanthine and inosine levels were associated with a higher T2D risk in homozygous carriers of the TCF7L2-rs7903146 T-allele. The potential mechanisms linking the aforementioned purine metabolites and T2D risk must be also further investigated.

PurposeAlthough evidence indicates that both physical activity and adherence to the Mediterranean diet (MedDiet) reduce the risk of all-cause mortality, a little is known about optimal intensities of physical activity and their combined effect with MedDiet in older adults. We assessed the separate and combined associations of leisure-time physical activity (LTPA) and MedDiet adherence with all-cause mortality.MethodsWe prospectively studied 7356 older adults (676.2years) at high vascular risk from the PREvencion con DIeta MEDiterranea study. At baseline and yearly thereafter, adherence to the MedDiet and LTPA were measured using validated questionnaires.ResultsAfter 6.8years of follow-up, we documented 498 deaths. Adherence to the MedDiet and total, light, and moderate-to-vigorous LTPA were inversely associated with all-cause mortality (p<0.01 for all) in multiple adjusted Cox regression models. The adjusted hazard of all-cause mortality was 73% lower (hazard ratio 0.27, 95% confidence interval 0.19-0.38, p<0.001) for the combined category of highest adherence to the MedDiet (3rd tertile) and highest total LTPA (3rd tertile) compared to lowest adherence to the MedDiet (1st tertile) and lowest total LTPA (1st tertile). Reductions in mortality risk did not meaningfully differ between total, light intensity, and moderate-to-vigorous LTPA.ConclusionsWe found that higher levels of LTPA, regardless of intensity (total, light and moderate-to-vigorous), and greater adherence to the MedDiet were associated separately and jointly with lower all-cause mortality. The finding that light LTPA was inversely associated with mortality is relevant because this level of intensity is a feasible option for older adults.

BACKGROUND AND AIMS: A Mediterranean-type diet enriched with extra virgin olive oil has been associated with a reduction in the incidence of atrial fibrillation (AF) in a population at high cardiovascular risk. However, no study has replicated these findings. In our study, we analyzed the association between olive oil consumption and AF in the SUN project, a cohort with young Spanish adults at low cardiovascular risk. METHODS AND RESULTS: We included all participants without prevalent AF at baseline (18,118 participants). Incident AF cases were confirmed by a cardiologist following a prespecified protocol. We used multivariable repeated-measurement Cox models adjusted for possible confounders (sex, age, BMI, and several classic cardiovascular risk factors). After a mean follow-up of 10.1 years, 94 AF incident cases were confirmed. Comparing to the lowest category of consumption (<7.9 g/d), the multivariable models showed hazard ratios (IC 95%) of 1.52 (0.93-2.48) for low-to-moderate, 1.44 (0.83-2.47) for moderate-to-high and 1.27 (0.56-2.86) for high olive oil intake. In a subgroup analysis stratified by overweight, an inverse although non-significant association was found only among overweight participants when we compared the highest vs the lowest category of consumption (p for interaction = 0.043). CONCLUSION: No association between olive oil and AF was found in this low-risk cohort, although the effect of extra-virgin olive oil on AF prevention especially among people with overweight deserves further investigation.

Context: The potential associations between acylcarnitine profiles and incidence of type 2 diabetes (T2D) and whether acylcarnitines can be used to improve diabetes prediction remain unclear. Objective: To evaluate the associations between baseline and 1-year changes in acylcarnitines and their diabetes predictive ability beyond traditional risk factors. Design, Setting, and Participants: We designed a case-cohort study within the PREDIMED Study including all incident cases of T2D (n = 251) and 694 randomly selected participants at baseline (follow-up, 3.8 years). Plasma acylcarnitines were measured using a targeted approach by liquid chromatography-tandem mass spectrometry. We tested the associations between baseline and 1-year changes in individual acylcarnitines and T2D risk using weighted Cox regression models. We used elastic net regressions to select acylcarnitines for T2D prediction and compute a weighted score using a cross-validation approach. Results: An acylcarnitine profile, especially including short-and long-chain acylcarnitines, was significantly associated with a higher risk of T2D independent of traditional risk factors. The relative risks of T2D per SD increment of the predictive model scores were 4.03 (95% CI, 3.00 to 5.42; P < 0.001) for the conventional model and 4.85 (95% CI, 3.65 to 6.45; P < 0.001) for the model including acylcarnitines, with a hazard ratio of 1.33 (95% CI, 1.08 to 1.63; P < 0.001) attributed to the acylcarnitines. Including the acylcarnitines into the model did not significantly improve the area under the receiver operator characteristic curve (0.86 to 0.88, P = 0.61). A 1-year increase in C4OH-carnitine was associated with higher risk of T2D [per SD increment, 1.44 (1.03 to 2.01)]. Conclusions: An acylcarnitine profile, mainly including short-and long-chain acylcarnitines, was significantly associated with higher T2D risk in participants at high cardiovascular risk. The inclusion of acylcarnitines into the model did not significantly improve the T2D prediction C-statistics beyond traditional risk factors, including fasting glucose.

Few studies have examined the association of a wide range of metabolites with total and subtypes of coffee consumption. The aim of this study was to investigate associations of plasma metabolites with total, caffeinated, and decaffeinated coffee consumption. We also assessed the ability of metabolites to discriminate between coffee consumption categories. This is a cross-sectional analysis of 1664 participants from the PREDIMED study. Metabolites were semiquantitatively profiled using a multiplatform approach. Consumption of total coffee, caffeinated coffee and decaffeinated coffee was assessed by using a validated food frequency questionnaire. We assessed associations between 387 metabolite levels with total, caffeinated, or decaffeinated coffee consumption (50 mL coffee/day) using elastic net regression analysis. Ten-fold cross-validation analyses were used to estimate the discriminative accuracy of metabolites for total and subtypes of coffee. We identified different sets of metabolites associated with total coffee, caffeinated and decaffeinated coffee consumption. These metabolites consisted of lipid species (e.g., sphingomyelin, phosphatidylethanolamine, and phosphatidylcholine) or were derived from glycolysis (alpha-glycerophosphate) and polyphenol metabolism (hippurate). Other metabolites included caffeine, 5-acetylamino-6-amino-3-methyluracil, cotinine, kynurenic acid, glycocholate, lactate, and allantoin. The area under the curve (AUC) was 0.60 (95% CI 0.56-0.64), 0.78 (95% CI 0.75-0.81) and 0.52 (95% CI 0.49-0.55), in the multimetabolite model, for total, caffeinated, and decaffeinated coffee consumption, respectively. Our comprehensive metabolic analysis did not result in a new, reliable potential set of metabolites for coffee consumption.

Scope The relationship between red wine (RW) consumption and metabolism is poorly understood. It is aimed to assess the systemic metabolomic profiles in relation to frequent RW consumption as well as the ability of a set of metabolites to discriminate RW consumers. Methods and results A cross-sectional analysis of 1157 participants is carried out. Subjects are divided as non-RW consumers versus RW consumers (>1 glass per day RW [100 mL per day]). Plasma metabolomics analysis is performed using LC-MS. Associations between 386 identified metabolites and RW consumption are assessed using elastic net regression analysis taking into consideration baseline significant covariates. Ten-cross-validation (CV) is performed and receiver operating characteristic curves are constructed in each of the validation datasets based on weighted models. A subset of 13 metabolites is consistently selected and RW consumers versus nonconsumers are discriminated. Based on the multi-metabolite model weighted with the regression coefficients of metabolites, the area under the curve is 0.83 (95% CI: 0.80-0.86). These metabolites mainly consisted of lipid species, some organic acids, and alkaloids. Conclusions A multi-metabolite model identified in a Mediterranean population appears useful to discriminate between frequent RW consumers and nonconsumers. Further studies are needed to assess the contribution of these metabolites in health and disease.

Background: Insulin resistance is a complex metabolic disorder and is often associated with type 2 diabetes (T2D). Objectives: The aim of this study was to test whether baseline metabolites can additionally improve the prediction of insulin resistance beyond classical risk factors. Furthermore, we examined whether a multimetabolite model predicting insulin resistance in nondiabetics can also predict incident T2D. Methods: We used a case-cohort study nested within the Prevencion con Dieta Mediterranea (PREDIMED) trial in subsets of 700, 500, and 256 participants without T2D at baseline and 1 and 3 y. Fasting plasma metabolites were semiquantitatively profiled with liquid chromatography-tandem mass spectrometry. We assessed associations between metabolite concentrations and the homeostasis model of insulin resistance (HOMA-IR) through the use of elastic net regression analysis. We subsequently examined associations between the baseline HOMA-IR-related multimetabolite model and T2D incidence through the use of weighted Cox proportional hazard models. Results: We identified a set of baseline metabolites associated with HOMA-IR. One-year changes in metabolites were also significantly associated with HOMA-IR. The area under the curve was significantly greater for the model containing the classical risk factors and metabolites together compared with classical risk factors alone at baseline [0.81 (95% CI: 0.79, 0.84) compared with 0.69 (95% CI: 0.66, 0.73)] and during a 1-y period [0.69 (95% CI: 0.66, 0.72) compared with 0.57 (95% CI: 0.53, 0.62)]. The variance in HOMA-IR explained by the combination of metabolites and classical risk factors was also higher in all time periods. The estimated HRs for incident T2D in the multimetabolite score (model 3) predicting high HOMA-IR (median value or higher) or HOMA-IR (continuous) at baseline were 2.00 (95% CI: 1.58, 2.55) and 2.24 (95% CI: 1.72, 2.90), respectively, after adjustment for T2D risk factors. Conclusions: The multimetabolite model identified in our study notably improved the predictive ability for HOMA-IR beyond classical risk factors and significantly predicted the risk of T2D.

An effective strategy to quit smoking should consider demographic aspects, smoking-related characteristics and psychological factors. This study examined potential predictors of smoking cessation in Spanish college students. A total of 255 college student smokers (18¿24 years old), recruited to a cessation trial (Spain, 2013¿2014), comprised an observational cohort. The main outcome was biochemically verified (urine cotinine) abstinence at the 6-month follow-up. Baseline potential predictors included socio-demographic, smoking-related and psychological variables (Fagerström Test for Nicotine Dependence (FTND), expired monoxide level (CO), intention to quit, previous quit attempts, participation in previous multicomponent programmes and confidence in quitting). Logistic regression models were used to identify potential predictors, the area under the ROC curve (AUC) was used to discriminate the capacity of the predictors and the Hosmer¿Lemeshow goodness-of-fit test was used to assess model calibration. After 6 months of follow-up, variables related to high nicotine dependence, FTND and expired CO levels were associated with lower odds of quitting smoking (OR¿=¿0.69 [95% CI 0.54¿0.89] and 0.84 [0.77¿0.92], respectively). Furthermore, being prepared to change (OR¿=¿3.98 [1.49¿10.64], p¿=¿0.006) and being confident to quit (OR¿=¿4.73 [2.12¿10.55], p¿<¿0.001) were also potential predictors of smoking cessation. The model that combined all these variables had the best predictive validity (AUC¿=¿0.84 [0.78¿0.91], p¿=¿0.693) and showed good predictive capacity (¿2¿=¿10.36, p¿=¿0.241). Findings highlight that, in this population of college student smokers, having a lower level of nicotine dependence, being prepared to quit and having the confidence in the ability to quit were associated with smoking cessation, and these factors had good predictive capacity.

BACKGROUND: Suspicion of allergic drug reaction can cause important disturbances in the patient's life. OBJECTIVE: We evaluated in a prospective multicenter study the quality of life of patients who suffered a possible allergic drug reaction, and analyzed the effect of a drug allergy evaluation. METHODS: Patients (>18 years old) answered the specific questionnaire twice: before the drug allergy evaluation, and 1 month after it was completed. Statistics were performed using STATA. RESULTS: A total of 360 patients (240, 66.6% female; mean age, 45.4 years; standard deviation [SD], 15.6 years) completed the first questionnaire. After the evaluation, 150 of 346 patients (43.4%) were diagnosed as allergic to the drug (115 of 150 immediate; 35 of 150 delayed) and 196 of 346 patients (56.6%) as nonallergic. The mean value of the first questionnaire was 32.14 (SD, 11.84); patients with anaphylaxis, nonanaphylactic immediate reaction, with more than 1 drug reaction, or a chronic osteoarticular disease, had a statistically significant higher score in Q0 (worse quality of life). After the allergy study, the mean of the second questionnaire was 27.27 (SD, 9.96), showing a global improvement (P < .001). No statistically significant difference was found between drug allergic and non-drug allergic patients (P = .340); however, being >40 years old (P = .030), having a chronic osteoarticular disease (P = .003) and having more than 1 reaction to drugs (P < .001) were associated with a statistically significant worse quality of life after the evaluation. CONCLUSIONS: Having suffered anaphylaxis, more than 1 reported drug allergy or presenting a musculoskeletal disease are factors that worsen the quality of life. Quality of life improved significantly after completing a drug allergy evaluation. (C) 2019 American Academy of Allergy, Asthma & Immunology

The aim of the study was to evaluate sleep duration and sleep variability in relation to serum uric acid (SUA) concentrations and SUA to creatinine ratio. This is a cross-sectional analysis of baseline data from 1842 elderly participants with overweight/obesity and metabolic syndrome in the (Prevencion con Dieta Mediterranea) PREDIMED-Plus trial. Accelerometry-derived sleep duration and sleep variability were measured. Linear regression models were fitted to examine the aforementioned associations. A 1 hour/night increment in sleep duration was inversely associated with SUA concentrations ( = -0.07, p = 0.047). Further adjustment for leukocytes attenuated this association (p = 0.050). Each 1-hour increment in sleep duration was inversely associated with SUA to creatinine ratio ( = -0.15, p = 0.001). The findings of this study suggest that longer sleep duration is associated with lower SUA concentrations and lower SUA to creatinine ratio.

Lifestyles may influence the risk of hypertension. Our objective was to assess the association between a healthy-lifestyle score and the incidence of hypertension. The SUN Project is a dynamic, prospective cohort of Spanish university graduates (1999-2014). Among 14,057 participants initially free of hypertension, we assessed the influence of lifestyle-related factors based on a 10-item score that we previously reported to be associated with lower risk of major cardiovascular events. However, we focused on factors related to hypertension risk according to previous scientific evidence and international clinical guidelines and constructed a 6-item score including: no smoking, moderate-to-high physical activity, Mediterranean diet adherence, healthy body mass index, moderate alcohol intake and no binge drinking. We fitted Cox regression models to adjust for potential confounders. During a median follow-up of 10.2 years, we identified 1406 incident cases of medically diagnosed hypertension. The risk of developing hypertension was linearly reduced as participants better adhered to a healthy lifestyle pattern built by summing up these 6 factors (p for trend < 0.001). The highest category (5-6 factors) exhibited a significant 46% relative reduction in the risk of developing hypertension compared to the lowest category (0-1 factors) (multivariable-adjusted hazard ratio = 0.54; 95% CI: 0.42-0.68). Among the components of the score, BMI was apparently the main factor driving the association between the HLS and lower risk of hypertension. A healthy-lifestyle score including six simple healthy habits was longitudinally and linearly associated with a substantially reduced risk of hypertension. This index may be a useful tool for hypertension prevention.

Background: The effect of dietary fat intake on the metabolic syndrome (MetS) and in turn on cardiovascular disease (CVD) remains unclear in individuals at high CVD risk. Objective: To assess the association between fat intake and MetS components in an adult Mediterranean population at high CVD risk. Design: Baseline assessment of nutritional adequacy in participants (n = 6560, men and women, 55-75 years old, with overweight/obesity and MetS) in the PREvencion con DIeta MEDiterranea (PREDIMED)-Plus randomized trial. Methods: Assessment of fat intake (total fat, monounsatured fatty acids: MUFA, polyunsaturated fatty acids: PUFA, saturated fatty acids: SFA, trans-fatty acids: trans-FA, linoleic acid, alpha-linolenic acid, and omega-3 FA) using a validated food frequency questionnaire, and diet quality using 17-item Mediterranean dietary questionnaire and fat quality index (FQI). Results: Participants in the highest quintile of total dietary fat intake showed lower intake of energy, carbohydrates, protein and fiber, but higher intake of PUFA, MUFA, SFA, TFA, LA, ALA and omega-3 FA. Differences in MetS components were found according to fat intake. Odds (5th vs. 1st quintile): hyperglycemia: 1.3-1.6 times higher for total fat, MUFA, SFA and omega-3 FA intake; low high-density lipoprotein cholesterol (HDL-c): 1.2 higher for LA; hypertriglyceridemia: 0.7 lower for SFA and omega-3 FA intake. Conclusions: Dietary fats played different role on MetS components of high CVD risk patients. Dietary fat intake was associated with higher risk of hyperglycemia.

Introduction and objective: Our aim was to examine the secular trends in obesity prevalence among Spanish adults with diabetes. Material and methods: Data were collected from 8 waves (from 1987 to 2012) of the National Health Surveys (NHS). NHS are cross-sectional studies conducted in representative samples of the Spanish adult population. Data of 7378 adults (>= 16 years) who reported having been diagnosed of diabetes were analyzed. Previously validated self-reported weight and height were used to estimate body mass index (BMI). Obesity was defined as a BMI of 30 kg/m(2) or greater. Age-adjusted obesity prevalence for each wave was calculated by the direct standardization method. Results: From 1987 to 2012 age-adjusted prevalence of obesity among persons with diabetes increased from 18.2% (95% confidence interval [CI]: 14.2-22.2%) to 39.8% (95% CI: 36.8-42.8%). Age-adjusted prevalence of obesity in males with diabetes increased from 13.2% (95% CI: 7.3-19.1%) to 38.0% (95% CI: 33.8-42.1%) and in females from 23.0% (95% CI: 17.6-28.4%) to 42.3% (95% CI: 38.0-46.6%). Conclusions: Between 1987 and 2012 the prevalence of obesity markedly increased in Spain among adults with diabetes. (C) 2018 Elsevier Espana, S.L.U. All rights reserved.

Introduction and objectives: A healthy lifestyle (HLS) is essential to attaining optimal cardiovascular health. Our objective was to assess the association between a HLS score and the incidence of hard cardiovascular disease (CVD) events. Methods: The SUN project is a dynamic, prospective, multipurpose cohort of Spanish university graduates with a retention proportion of 92%. In 19 336 participants, we calculated a HLS score ranging from 0 to 10 points: never smoking, physical activity (> 20 METs-h/wk), Mediterranean diet adherence (¿ 4/8 points), low body mass index (¿ 22), moderate alcohol intake (women, 0.1-5g/d; men, 0.1-10g/d), low television exposure (¿ 2h/d), no binge drinking (¿ 5 alcoholic drinks anytime), taking a short afternoon nap (< 30min/d), meeting up with friends> 1h/d and working> 40h/wk. Results: After a median follow-up of 10.4 years, we identified 140 incident cases of CVD. After adjustment for potential confounders, the highest category of HLS score adherence (7-10 points) showed a significant 78% relative reduction in the risk of primary CVD compared with the lowest category (0-3 points) (adjusted HR, 0.22; 95%CI, 0.11-0.46). Each healthy habit was individually associated with a lower risk of CVD. Conclusions: A HLS score including several simple healthy habits was associated with a lower risk of developing primary CVD. This index may be useful to reinforce CVD prevention without the need to include traditional risk factors.

A few studies have assessed the association between omega-3 polyunsaturated fatty acids (n-3 PUFA) and cognitive impairment (CI) in very old adults. The aim of this study was to evaluate the effect of a multinutrient supplementation rich in n-3 PUFA on the cognitive function in an institutionalized >= 75-year-old population without CI or with mild cognitive impairment (MCI). A multicenter placebo-controlled double-blind randomized trial was conducted between 2012 and 2013. Cognitive function was assessed at baseline and after one year using 4 neuropsychological tests. Nutritional status was assessed using Mini Nutritional Assessment (MNA). Interaction between Mini-Mental State Examination (MMSE) score and nutritional status were analyzed using linear regression models. A total of 99 participants were randomized to receive placebo or pills rich in n-3 PUFA. After 1-year follow-up, both groups decreased their MMSE score (-1.18, SD:0.53 and-0.82, SD:0.63, p = 0.67 for the control and the intervention group respectively). The memory subscale of the MMSE showed an improvement (+0.26, SD:0.18) in the intervention group against a worsening in the control group (-0.11, SD: 0.14; p = 0.09 for differences between groups). Patients at intervention group with normal nutritional status (MNA >= 24) showed an improvement in the MMSE (+1.03, p = 0.025 for differences between 1-y and baseline measurements) against a worsening in the group with malnutrition (MNA<24) (-0.4, p = 0.886 for differences between 1-y and baseline; p of interaction p = 0.05). Supplementation with n-3 PUFA did not show an improvement in the global cognitive function in institutionalized elderly people without CI or with MCI. They only suggest an apparent improvement in memory loss if previously they were well nourished.

BACKGROUND: Metabolites of the tryptophan-kynurenine pathway (i.e., tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxyanthranilic) may be associated with diabetes development. Using a case-cohort design nested in the Prevencion con Dieta Mediterranea (PREDIMED) study, we studied the associations of baseline and 1-year changes of these metabolites with incident type 2 diabetes (T2D). METHODS: Plasma metabolite concentrations were quantified via LC-MS for n = 641 in a randomly selected subcohort and 251 incident cases diagnosed during 3.8 years of median follow-up. Weighted Cox models adjusted for age, sex, body mass index, and other T2D risk factors were used. RESULTS: Baseline tryptophan was associated with higher risk of incident T2D (hazard ratio = 1.29; 95% CI, 1.04-1.61 per SD). Positive changes in quinolinic acid from baseline to 1 year were associated with a higher risk of T2D (hazard ratio = 1.39; 95% CI, 1.09-1.77 per SD). Baseline tryptophan and kynurenic acid were directly associated with changes in homeostatic model assessment for insulin resistance (HOMA-IR) from baseline to 1 year. Concurrent changes in kynurenine, quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine/tryptophan ratio were associated with baseline-to-1-year changes in HOMA-IR. CONCLUSIONS: Baseline tryptophan and 1-year increases in quinolinic acid were positively associated with incident T2D. Baseline and 1-year changes in tryptophan metabolites predicted changes in HOMA-IR. Tryptophan levels may initially increase and then deplete as diabetes progresses in severity. (C) 2018 American Association for Clinical Chemistry

Background & aims: To assess the possible association between a validated Dietary Inflammatory Index (DII) and specific dietary components with suitable non-invasive markers of liver status in overweight and obese subjects within the PREDIMED study. Methods: A cross-sectional study encompassing 794 randomized overweight and obese participants (mean +/- SD age: 67.0 +/- 5.0 y, 55% females) from the PREDIMED (PREvencion con Dleta MEDiterranea) trial was conducted. DII is a validated tool evaluating the effect of diet on six inflammatory biomarkers (IL-1b, IL-4, IL-6, IL-10, TNF-alpha and C-reactive protein). Furthermore, a validated 137-item food-frequency-questionnaire was used to obtain the information about the food intake. In addition, anthropometric measurements and several non-invasive markers of liver status were assessed and the Fatty Liver Index (FLI) score was calculated. Results: A higher DII and lower adherence to Mediterranean diet (MeDiet) were associated with a higher degree of liver damage (FLI > 60) in obese as compared to overweight participants. Furthermore, the DII score was positively associated with relevant non-invasive liver markers (ALT, AST, GGT and FLI) and directly affected FLI values. Interestingly, a positive correlation was observed between liver damage (>50th percentile FLI) and nutrients and foods linked to a pro-inflammatory dietary pattern. Conclusions: This study reinforced the concept that obesity is associated with liver damage and revealed that the consumption of a pro-inflammatory dietary pattern might contribute to obesity and fatty liver disease features. These data suggest that a well-designed precision diet including putative anti-inflammatory components could specifically prevent and ameliorate non-alcoholic fatty liver manifestations in addition to obesity. (C) 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

BackgroundThe development and implementation of effective physical activity (PA) intervention programs is challenging, particularly in older adults. After the first year of the intervention program used in the ongoing PREvencion con DIeta MEDiterranea (PREDIMED)-Plus trial, we assessed the initial effectiveness of the PA component.MethodsPREDIMED-Plus is an ongoing randomized clinical trial including 6874 participants randomized to an intensive weight-loss lifestyle intervention based on an energy-restricted Mediterranean diet (MedDiet), physical activity promotion and behavioral support and to a control group using MedDiet recommendations but without calorie restriction or PA advice. Body mass index (BMI) and waist circumference (WC) are measured by standard clinical protocols. Duration and intensity of PA is self-reported using the validated REGICOR Short Physical Activity Questionnaire. The primary endpoint of the PREDIMED-Plus trial is a combined cardiovascular outcome: myocardial infarction (acute coronary syndromes with positive troponin test), stroke, or cardiovascular mortality. The present study involved secondary analysis of PA data (n=6059; mean age 654.9years) with one-year changes in total, light, and moderate-to-vigorous PA within and between intervention groups as the outcome. Generalized estimating equation models were fitted to evaluate time trends of PA, BMI, and WC within groups and differences between intervention and control groups.ResultsAfter 12months, average daily MVPA increased by 27.2 (95%CI 5.7;48.7) METs-min/day and 123.1 (95%CI 109.7-136.6) METs-min/day in the control and intervention groups, respectively. Total-PA, light-PA, and MVPA increased significantly (p<0.01) in both groups. A significant (p<0.001) time*intervention group interaction was found for Total-PA and MVPA, meaning the PA trajectory over time differed between the intervention and control groups. Age, sex, education level, and BMI did not moderate the effectiveness of the PA intervention. BMI and WC decreased significantly with increasing MVPA, compared with participants who reported no changes in MVPA.ConclusionAfter one year of follow-up, the PREDIMED-Plus PA intervention has been effective in increasing daily PA in older adults.Trial registration Retrospectively registered at the International Standard Randomized Controlled Trial (http://www.isrctn.com/ISRCTN89898870), registration date: 24 July 2014.

The Dietary Inflammatory Index (DII) was designed to measure the inflammatory potential of one's diet. Evidence from observational studies supports that a higher (ie, more proinflammatory) DII score is associated with inflammation and cardiometabolic diseases. We hypothesized that reduction in DII score would improve inflammatory cytokines. To test this hypothesis, we assessed data from a dietary intervention trial in patients with diagnosed coronary heart disease (CHD) to determine whether reduction in DII scores through healthy diets is linked to improvement in inflammatory and related cardiometabolic risk markers. Participants (n = 65, 83% male) were randomized to a Mediterranean diet or low-fat diet intervention for 6-months. Anthropometry, body composition and blood markers were measured and DII scores were calculated from 7-day food diaries. After 6-months, in participants who completed the intervention (n = 56), reduction in DII score correlated significantly with reduction in high sensitivity interleukin-6 (hs-IL-6) (r = 0.34, 95% CI 0.05, 0.56) and triglycerides (r = -0.30, 95% CI -0.51, -0.06) but not with C-reactive protein, adiponectin, glucose, body composition or anthropometry. The adjusted mean difference in hs-IL-6 and triglycerides between the highest and lowest tertiles of DII improvement was -0.47 pg/mL (95% CI 0.41, 1.10) and +0.30 mmol/L (95% CI 1.06, 1.59), respectively. The present study found that improvement in DII score through healthy diet intervention was linked with reduced levels of hs-IL-6, but also increased triglycerides, in adult Australian patients with CHD. Future research is warranted to investigate the impact of change in DII on cardiometabolic risk markers in larger cohorts, other disease populations or healthy subjects and with longer-term follow up. (C) 2018 Elsevier Inc. All rights reserved.

Laparoscopic arcuate ligament release has been demonstrated a valid therapeutic option for arcuate ligament syndrome. Nevertheless, long-term follow-up and predictive factors have not been described for this treatment. Clinical and surgical data and short- and long-term outcomes together with the impact of the degree of stenosis of the celiac trunk were analyzed in 13 consecutive patients who underwent laparoscopic arcuate ligament release between 2001 and 2013. Thirteen patients (12 F/1 M) underwent surgery. The median age was 32 years old, and their mean body mass index was 20.7 (range 14.7-25). The 13 patients presented with intense postprandial abdominal pain. Ten cases were associated with weight loss. The median duration of symptoms was 24 months (range 2-240). Three patients presented symptoms associated with superior mesenteric artery syndrome. Median operative time was 120 min (range 90-240), and there were no conversions to open surgery. Median hospital stay was 3 days (range 2-14). Over a median follow-up of 117 months (range 45-185), nine patients had excellent results although two required endovascular procedures at 70 and 24 months after surgery. Four patients (30.7%) experienced poor outcomes. When we analyzed the impact of the degree of occlusion of the celiac trunk, we observed that in patients with severe occlusion (> 70%), better results were obtained, with complete resolution of symptoms in 71% of cases. Laparoscopic arcuate ligament release constitutes an excellent treatment for arcuate ligament syndrome. The degree of occlusion of the celiac trunk may be a factor predictive of long-term outcomes.

Background: Perturbed lipid metabolic pathways may play important roles in the development of cardiovascular disease (CVD). However, existing epidemiological studies have focused more on discovering individual lipid metabolites for CVD risk prediction rather than assessing metabolic pathways. Methods: This study included a subcohort of 787 participants and all 230 incident CVD cases from the PREDIMED trial. Applying a network-based analytical method, we identified lipid subnetworks and clusters from a global network of 200 lipid metabolites and linked these subnetworks/clusters to CVD risk. Results: Lipid metabolites with more double bonds clustered within one subnetwork, whereas lipid metabolites with fewer double bonds clustered within other subnetworks. We identified 10 lipid clusters that were divergently associated with CVD risk. The hazard ratios [HRs, 95% confidence interval (Cl)] of CVD per a 1-standard deviation (SD) increment in cluster score were 1.39 (1.17-1.66) for the hydroxylated phosphatidylcholine (HPC) cluster and 1.24 (1.11-1.37) for a cluster that included diglycerides and a monoglyceride with stearic acyl chain. Every 1-SD increase in the score of cluster that included highly unsaturated phospholipids and cholesterol esters was associated with an HR for CVD of 0.81 (95% Cl, 0.67-0.98). Despite a suggestion that MedDiet modified the association between a subnetwork that included most lipids with a high degree of unsaturation and CVD, changes in lipid subnetworks/clusters during the first-year follow-up were not significantly different between intervention groups. Conclusions: The degree of unsaturation was a major determinant of the architecture of lipid metabolic network. Lipid clusters that strongly predicted CVD risk, such as the HPC cluster, warrant further functional investigations.

The Mediterranean Dietary (MedDiet) Pattern has been linked to many beneficial health effects. This review summarizes the main findings of a prospective cohort study, the Seguimiento Universidad de Navarra (SUN) cohort, specifically focused on MedDiet and the risk of major chronic disease. It is an open cohort in which 22,786 Spanish university graduates have participated since 1999 until February 2018. Data on diet, lifestyle and clinical diagnosis are collected at baseline and every two years. After reviewing 21 publications from the SUN cohort on the effects of the MedDiet, we conclude that this cohort has provided good evidence that a high MedDiet adherence is associated with a reduced incidence of all-cause mortality, fatal and non-fatal major cardiovascular disease (CVD), type 2 diabetes, weight gain, metabolic syndrome, depression, cognitive decline, and nephrolithiasis. An inverse dose-response relationship was found for many of these associations. The MedDiet was also associated with lower average heart rate, a mitigation of the harmful effects of overweight/obesity on the risk of CVD, and an attenuation of the effects of obesity on type 2 diabetes. A suggestion that the MedDiet may enhance fertility was also found.

The health benefits of the Mediterranean diet (MedDiet) and of physical activity (PA) have been widely documented. However, no longitudinal studies have investigated their combined effect on mortality. We assessed the individual and combined effects of adherence to the MedDiet and PA on all-cause mortality. We used data from 19,467 participants from a prospective cohort of Spanish university graduates, the SUN cohort, followed-up between December 1999 and February 2016. Adherence to the MedDiet was assessed using four different dietary scores, categorizing the quantitative scores into tertiles of adherence. To assess multiple dimensions of PA, an 8-item score was built. Multivariable Cox regression models were used to study the individual and combined relationship of adherence to the MedDiet and PA with all-cause mortality. During a median follow-up of 10.3 years, we registered 305 deaths. Compared with the lowest adherence to the MedDiet (< 20 in the modified Mediterranean diet score), better adherence (23¿30 points) was associated with lower mortality (multivariable-adjusted hazard ratio [HR] = 0.66, 95% confidence interval [CI]: 0.46¿0.96). Engaging in moderate or high levels of PA (versus lower levels) was associated with 44% and 52% relative reductions in mortality, respectively. High adherence to the MedDiet combined with engaging in higher amounts of PA showed a HR = 0.36 (95% CI: 0.19¿0.67). We documented that the combined effect of better adherence to the MedDiet and increased PA had multiplicative effects on mortality risk reduction.

The association between the intensity of physical activity and the incidence of cardiovascular diseases (CVD), irrespective of energy expenditure (EE), requires further study. Our objective is to examine this relationship using data from a large Spanish cohort. The Seguimiento Universidad de Navarra cohort is formed of university graduates recruited from March 1999 to October 2015. We included 18,737 adults free of CVD (mean age 38 years, 61 % women), with a median follow-up of 10.3 years. We estimated the average intensity of leisure time physical activity (LTPA) using a validated questionnaire. We classified respondents into 3 groups: Inactive, < 6 average metabolic equivalents (METs) and >= 6 average METs. We used Cox proportional hazards models adjusted by the EE in LTPA (MET-h/week) and other confounding factors, to examine this association. During 1,72,299 person-years of follow-up, we registered 127 cases of CVD (myocardial infarction, stroke, and death due to cardiovascular causes). The adjusted hazard ratio for CVD was 0.76 (95% CI 0.48 to 1.21) in the lower intensity group, and 0.31 (95% CI 0.12 to 0.79) in the higher intensity group, compared with the inactive, with a linear trend (p = 0.03). In conclusion, given the same level of EE, those respondents engaged in higher intensity LTPA, had a lower risk of CVD.

Aims/hypothesis Branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) are associated with type 2 diabetes. However, repeated measurements of BCAA/AAA and their interactions with dietary interventions have not been evaluated. We investigated the associations between baseline and changes at 1 year in BCAA/AAA with type 2 diabetes in the context of a Mediterranean diet (MedDiet) trial. Methods We included 251 participants with incident type 2 diabetes and a random sample of 694 participants (641 participants without type 2 diabetes and 53 overlapping cases) in a case-cohort study nested within the PREvencin con DIeta MEDiterranea (PREDIMED) trial. Participants were randomised to a MedDiet+extra-virgin olive oil (n = 273), a MedDiet+nuts (n = 324) or a control diet (n = 295). We used LC-MS/MS to measure plasma levels of amino acids. Type 2 diabetes was a pre-specified secondary outcome of the PREDIMED trial. Results Elevated plasma levels of individual BCAAs/AAAs were associated with higher type 2 diabetes risk after a median follow-up of 3.8 years: multivariable HR for the highest vs lowest quartile ranged from 1.32 for phenylalanine ([95% CI 0.90, 1.92], p for trend = 0.015) to 3.29 for leucine ([95% CI 2.03, 5.34], p for trend<0.001). Increases in BCAA score at 1 year were associated with higher type 2 diabetes risk in the control group with HR per SD = 1.61 (95% CI 1.02, 2.54), but not in the MedDiet groups (p for interaction <0.001). The MedDiet+extra-virgin olive oil significantly reduced BCAA levels after 1 year of intervention (p = 0.005 vs the control group). Conclusions/interpretation Our results support that higher baseline BCAAs and their increases at 1 year were associated with higher type 2 diabetes risk. A Mediterranean diet rich in extra-virgin olive oil significantly reduced the levels of BCAA and attenuated the positive association between plasma BCAA levels and type 2 diabetes incidence.

Background: The study of the plasma lipidome may help to better characterize molecular mechanisms underlying cardiovascular disease. The identification of new lipid biomarkers could provide future targets for prevention and innovative therapeutic approaches. In the frame of the PREDIMED trial, our aim was to examine the associations of baseline lipidome patterns or their changes with the risk of clinical CVD events. Methods: We included 983 participants in our case-cohort study. The end-point was the incidence of major CVD during 4.8 years of median follow-up. We repeatedly measured 202 plasma known lipid metabolites at baseline and after 1-year of intervention. Principal component analysis was used to identify lipidome factors. Among the 15 identified factors, 7 were significantly associated with CVD. Considering common patterns among factors, lipids were grouped (summed) into scores. Results: After adjustment for traditional CVD risk factors, scores of baseline polyunsaturated phosphatidylcholines (PC)/lysoPC/PC-plasmalogens and polyunsaturated cholesterol esters (CE) showed inverse associations with CVD (p = 0,036 and 0.012, respectively); whereas scores of monoacylglycerols (MAGs)/diacylglycerols (DAGs) and short triacylglycerols (TAGs) showed a direct association with CVD (p = 0,026 and 0.037, respectively). Baseline phosphatidylethanolamines (PEs) and their 1-y changes tended to be associated with higher CVD risk (p = 0.066 and 0.081, respectively). We did not find a significant effect of the intervention with the Mediterranean Diet on these scores. Conclusions: Our study suggests that polyunsaturated PCs and CEs may confer protection against CVD. In contrast, MAGs, DAGs, TAGs and PEs appeared to be associated with higher CVD risk. (c) 2017 Elsevier B.V. All rights reserved.

OBJECTIVE Specific lipid molecular changes leading to type 2 diabetes (T2D) are largely unknown. We assessed lipidome factors associated with future occurrence of T2D in a population at high cardiovascular risk. RESEARCH DESIGN AND METHODS We conducted a case-cohort study nested within the PREDIMED trial, with 250 incident T2D cases diagnosed during 3.8 years of median follow-up, and a random sample of 692 participants (639 noncases and 53 overlapping cases) without T2D at baseline. We repeatedly measured 207 plasma known lipid metabolites at baseline and after 1 year of follow-up. We built combined factors of lipid species using principal component analysis and assessed the association between these lipid factors (or their 1-year changes) and T2D incidence. RESULTS Baseline lysophosphatidylcholines and lysophosphatidylethanolamines (lysophospholipids [LPs]), phosphatidylcholine-plasmalogens (PC-PLs), sphingomyelins (SMs), and cholesterol esters (CEs) were inversely associated with risk of T2D (multivariable-adjusted P for linear trend <0.001 for all). Baseline triacylglycerols (TAGs), diacylglycerols (DAGs), and phosphatidylethanolamines (PEs) were positively associated with T2D risk (multivariable-adjusted P for linear trend <0.001 for all). One-year changes in these lipids showed associations in similar directions but were not significant after adjustment for baseline levels. TAGs with odd-chain fatty acids showed inverse associations with T2D after adjusting for total TAGs. CONCLUSIONS Two plasma lipid profiles made up of different lipid classes were found to be associated with T2D in participants at high cardiovascular risk. A profile including LPs, PC-PLs, SMs, and CEs was associated with lower T2D risk. Another profile composed of TAGs, DAGs, and PEs was associated with higher T2D risk.

Background: The role of trimethylamine-N-oxide (TMAO) in type 2 diabetes (T2D) is currently partially understood and controversial. Objective: The aim of this study was to investigate associations between TMAO and related metabolites with T2D risk in subjects at high risk of cardiovascular disease. Design: This is a case-cohort design study within the Prevencion con Dieta Mediterranea (PREDIMED) study, with 251 incident T2D cases and a random sample of 694 participants (641 noncases and 53 overlapping cases) without T2D at baseline (median follow-up: 3.8 y). We used liquid chromatography-tandem mass spectrometry to measure plasma TMAO, l-carnitine, betaine, lyso-phosphatidylcholine (LPC) and lyso-phosphatidylethanolamine (LPE) species, phosphocholine, a-glycerophosphocholine, and choline at baseline and after 1 y. We examined associations with the use of weighted Cox proportional hazard models, accounting for the weighted case-cohort design by the Barlow method. Results: After adjustment for recognized T2D risk factors and multiple testing, individuals in the highest quartile of baseline TMAO and a-glycerophosphocholine had a lower risk of T2D [HR (95% CI): 0.52 (0.29, 0.89) and 0.46 (0.24, 0.89), respectively]. The HR (95% CI) comparing the extreme quartiles of betaine was 0.41 (0.23, 0.74). Similar trends were observed for C16: 0 LPC, C18: 1 LPC, C18: 0 LPC, C20: 4 LPC, C22: 6 LPC, C18: 1 LPC plasmalogen, and C16: 0 LPE. After correcting for multiple comparisons, participants in the highest quartile of 1-y changes in oleic acid LPC plasmalogen concentrations had a lower T2D risk than the reference quartile. Conclusion: Whether the associations between plasma TMAO and certain metabolite concentrations with T2D risk reflect its pathophysiology or represent an epiphenomenon needs to be elucidated.

A higher dietary inflammatory index (DII (R)) score is associated with inflammation and incidence of coronary heart disease (CHD). We hypothesized that a Mediterranean diet (MedDiet) intervention would reduce DII score. We assessed dietary data from a randomized controlled trial comparing 6-month MedDiet versus low-fat diet intervention, in patients with CHD. We aimed to determine the DII scores of the prescribed diets' model meal plans, followed by whether dietary intervention led to lower (i.e., more anti-inflammatory) DII scores and consequently lower high sensitivity C-reactive protein (hs-CRP) and interleukin-6 (hs-IL-6). DII scores were calculated from 7-day food diaries. The MedDiet meal plan had a markedly lower DII score than the low-fat diet meal plan (-4.55 vs. -0.33, respectively). In 56 participants who completed the trial (84% male, mean age 62 +/- 9 years), the MedDiet group significantly reduced DII scores at 6 months (n = 27; -0.40 +/- 3.14 to -1.74 +/- 2.81, P = .008) and the low-fat diet group did not change (n = 29; -0.17 +/- 2.27 to 0.05 +/- 1.89, P = .65). There was a significant Post-intervention adjusted difference in DII score between groups (compared to low-fat, MedDiet decreased by -1.69 DII points; P = .004). When compared to the low-fat diet, the MedDiet non-significantly reduced hs-IL-6 (-0.32 pg/mL, P = .29) and increased hs-CRP (+0.09 mg/L, P = .84). These findings demonstrated that MedDiet intervention significantly reduced DII scores compared to a low-fat diet. However, in this small cohort of patients with CHD this did not translate to a significant improvement in measured inflammatory markers. The effect of improvement in DII with MedDiet should be tested in larger intervention trials and observational cohorts. (C) 2018 Elsevier Inc. All rights reserved.

Background and aims: The PREDIMED (PREvencion con Dleta MEDiterranea) is a multicentre trial analyzed as a prospective cohort study. A total of 7122 participants (aged 55-80 years) at high risk of cardiovascular disease in the PREDIMED trial were recruited in 11 centres in Spain. The prevalence of subjects with type 2 diabetes was 50%. Our objective was to determine the contribution of lifestyle factors to the development of peripheral artery disease (PAD). Methods: Incident clinical PAD in relation to a healthy lifestyle 5-point score defined as adherence to a Mediterranean diet (MedDiet), moderate alcohol intake, regular physical activity, normal weight (BMI<25) and non-smoking was measured. Results: Eighty-seven incident PAD cases were diagnosed during a median follow-up of 4.8 years. Compared with participants with 0 or 1 healthy lifestyle factor, the multivariable hazard ratio for PAD was 0.65 (95% confidence interval (CI) 0.37 to 1.14) for 2 factors, and 0.40 (0.22-0.72) for 3 or more. Moderate alcohol consumption, non-smoking, physical activity and following a MedDiet were significantly inversely associated with PAD whereas no association was found for normal weight (BMI<25 kg/m(2)). PAD risk monotonically decreased with an increasing number of lifestyle factors, and the greatest reduction was found for a score combining moderate alcohol consumption, MedDiet and physical activity or non-smoking. The multivariable-adjusted population attributable risk percent for the combination of these 4 factors was 80.5% (95% CI: 21.3%-95.1%). Conclusions: Our results demonstrate that a simple healthy lifestyle score is associated with a substantially reduced risk of PAD in a high cardiovascular risk population with a high prevalence (50%) of subjects with type 2 diabetes. (C) 2018 Elsevier B.V. All rights reserved.

Background: The aim of this analysis was to ascertain the type of relationship between fish and seafood consumption, omega-3 polyunsaturated fatty acids (-3 PUFA) intake, and depression prevalence. Methods: Cross-sectional analyses of the PREDIMED-Plus trial. Fish and seafood consumption and -3 PUFA intake were assessed through a validated food-frequency questionnaire. Self-reported life-time medical diagnosis of depression or use of antidepressants was considered as outcome. Depressive symptoms were collected by the Beck Depression Inventory-II. Logistic regression models were used to estimate the association between seafood products and -3 PUFA consumption and depression. Multiple linear regression models were fitted to assess the association between fish and long-chain (LC) -3 PUFA intake and depressive symptoms. Results: Out of 6587 participants, there were 1367 cases of depression. Total seafood consumption was not associated with depression. The odds ratios (ORs) (95% confidence intervals (CIs)) for the 2nd, 3rd, and 4th quintiles of consumption of fatty fish were 0.77 (0.63-0.94), 0.71 (0.58-0.87), and 0.78 (0.64-0.96), respectively, and p for trend = 0.759. Moderate intake of total LC -3 PUFA (approximately 0.5-1 g/day) was significantly associated with a lower prevalence of depression. Conclusion: In our study, moderate fish and LC -3 PUFA intake, but not high intake, was associated with lower odds of depression suggesting a U-shaped relationship.

Background Inverse associations of the Mediterranean diet (MedDiet) and physical activity with cardiovascular disease have been previously reported. We investigated the individual and combined contributions of both to this inverse association in a Mediterranean cohort. Design We used data from 19,536 participants from a prospective cohort of Spanish university graduates, the 'Seguimiento Universidad de Navarra' (SUN) cohort, followed up between December 1999 and December 2016. Methods Adherence to the MedDiet was obtained from a 136-item validated food-frequency questionnaire and categorized in tertiles using four previously reported dietary scores. A validated questionnaire assessed the physical activity levels according to volume, intensity and frequency. Results Participants were followed up during a median time of 10.4 years. Compared with the lowest category of adherence to the MedDiet (¿3 in the Mediterranean Diet Score), higher adherence (6-9 points) was strongly inversely associated with cardiovascular disease (multivariable adjusted hazard ratio¿=¿0.33; 95% confidence interval (CI) 0.20-0.55). Also, engaging in an active lifestyle (6-8 points in an eight-item score) compared with low activity (<2 points) was associated with a reduced risk of incident cardiovascular disease (hazard ratio¿=¿0.43; 95% CI 0.20-0.90). Greater adherence to the MedDiet and engaging in high levels of active lifestyle showed a 75% relatively reduced risk of cardiovascular disease (hazard ratio¿=¿0.25; 95% CI 0.13-0.48). Conclusions The combined effect of adherence to the MedDiet and adopting an active lifestyle showed a synergistic inverse association with cardiovascular disease risk.

IMPORTANCE Cataract, one of the most frequent causes of blindness in developed countries, is strongly associated with aging. The exact mechanisms underlying cataract formation are still unclear, but growing evidence suggests a potential role of inflammatory and oxidative processes. Therefore, antioxidant and anti-inflammatory factors of the diet, such as vitamin K-1, could play a protective role. OBJECTIVE To examine the association between dietary vitamin K-1 intake and the risk of incident cataracts in an elderly Mediterranean population. DESIGN, SETTING, AND PARTICIPANTS A prospective analysis was conducted in 5860 participants from the Prevencion con Dieta Mediterranea Study, a randomized clinical trial executed between 2003 and 2011. Participants were community-dwelling men (44.2%) and women (55.8%), and the mean (SD) age was 66.3 (6.1) years. MAIN OUTCOMES AND MEASURES Dietary vitamin K-1 intake was evaluated using a validated food frequency questionnaire. The time to the cataract event was calculated as the time between recruitment and the date of the occurrence to cataract surgery, the time to the last visit of the follow-up, date of death, or the end of the study. Hazard ratios and 95% CIs for cataract incidence were estimated with a multivariable Cox proportional hazards model. RESULTS Participants were community-dwelling men (44.2%; n = 868) and women (55.8%; n = 1086), and the mean (SD) age was 66.3 (6.1) years. After a median of 5.6 years follow-up, we documented a total of 768 new cataracts. Participants in the highest tertile of dietary vitamin K1 intake had a lower risk of cataracts than those in the lowest tertile (hazard ratio, 0.71; 95% CI, 0.58-0.88; P =.002), after adjusting for potential confounders. CONCLUSIONS AND RELEVANCE High intake of dietary vitamin K-1 was associated with a reduced risk of cataracts in an elderly Mediterranean population even after adjusting by other potential confounders.

Background The study of dietary patterns is gaining interest. Although the health benefits of yogurt and lignans have been investigated separately, to our knowledge there are no studies on their associative effects. Objective The aim of this study was to evaluate a possible association between yogurt and lignans using biomarkers of cardiovascular disease risk in an elderly population. Design We conducted a cross-sectional analysis of the association between baseline dietary information and cardiovascular risk parameters using food frequency questionnaires. Participants We enrolled 7,169 Spanish participants of the PREDIMED (Prevencion con Dieta Mediterranea) study (elderly men and women at high cardiovascular risk) from June 2003 to June 2009. Main outcome measures Cardiovascular risk parameters, including cholesterol, tri-glycerides, glucose, body mass index, weight, waist circumference, and blood pressure were measured. Statistical analysis General linear models were used to assess the relationship between categorical variables (yogurt, total dairy intake, lignans, and yogurt plus lignans) and cardiovascular risk parameters. Results The consumption of either yogurt or lignans seems to have beneficial effects on human health, but the consumption of both showed greater improvement in some cardiovascular health parameters. Indeed, participants with a higher consumption of both yogurt and lignans showed lower total cholesterol (estimated beta-coefficients= -6.18; P=0.001) and low-density lipoprotein cholesterol levels (beta=-4.92; P=0.005). In contrast, participants with lower yogurt and lignan consumption had a higher body mass index (beta=0.28; P=0.007) and weight (beta=1.20; P=0.008). Conclusions High lignan and yogurt consumption is associated with a better cardiovascular risk parameters profile in an elderly Mediterranean population. Further research is warranted to determine the mechanisms and consequences of this potential effect.

The role of yogurt consumption in the risk of developing overweight, obesity, or metabolic syndrome has been the subject of epidemiologic studies over the last 10 y. A comprehensive literature search on MEDLINE and ISI Web of Knowledge from 1966 through June 2016 was conducted to examine the relation between yogurt consumption and weight gain, as well as the risk of overweight, obesity, or metabolic syndrome, in prospective cohort studies. Ten articles met all the inclusion criteria and were included in our systematic review. Of the 10 cohort studies, 3 analyzed the relation between yogurt consumption and the risk of overweight or obesity, 8 analyzed changes in waist circumference or weight changes, 3 studied the association with the risk of developing metabolic syndrome, and 1 studied the probability of abdominal obesity reversion. Although an inverse association between yogurt consumption and the risk of developing overweight or obesity was not fully consistent or always statistically significant, all studies but one showed in their point estimates inverse associations between yogurt consumption and changes in waist circumference, changes in weight, risk of overweight or obesity, and risk of metabolic syndrome during follow-up, although not all estimates were statistically significant ( 2 studies). Prospective cohort studies consistently suggested that yogurt consumption may contribute to a reduction in adiposity indexes and the risk of metabolic syndrome. Therefore, there is a need for more prospective studies and high-quality randomized clinical trials to confirm this apparent inverse association.

Background: Epidemiological data on chromium (Cr) exposure and the risk of cardiovascular disease (CVD) are still limited. Toenail Cr level (TCL) provides a time-integrated measure reflecting long-term Cr exposure. We measured TCL to assess the hypothesis that long-term Cr exposure was inversely associated with incident CVD in a population at high risk for CVD. Methods and Results: The associations between TCL and CVD were evaluated in a case-control study nested within the "PREvencion con Dleta MEDiterranea" (PREDIMED) trial. We randomly selected 147 of the 288 patients diagnosed with CVD during follow-up and matched them on age and sex to 271 controls. Instrumental neutron activation analysis was used to assess TCL. In-person interviews, medical record reviews, and validated questionnaires were used to assess covariates. The fully adjusted OR for the highest vs. lowest quartile of toenail Cr was 0.54 (95% CI: 0.26-1.14; P-trend=0.189) for the nested case-control study. On stratification for diabetes mellitus (DM), OR was 1.37 (95% CI: 0.54-3.46; P-trend=0.364) for the DM group, and 0.25 (95% CI: 0.08-0.80; P-trend=0.030) for the non-DM group (P for interaction=0.078). Conclusions: The present findings, although not statistically significant, are consistent with previously reported inverse associations between TCL and CVD. These results, especially for non-DM patients, increase the limited epidemiological knowledge about the possible protective role of Cr against CVD.

Fiber and fiber-rich foods have been inversely associated with cardiovascular disease (CVD), but the evidence is scarce in young and Mediterranean cohorts. We used Cox regression models to assess the association between quintiles of total fiber and fiber from different sources, and the risk of CVD adjusted for the principal confounding factors in a Mediterranean cohort of young adults, the SUN (Seguimiento Universidad de Navarra, Follow-up) cohort. After a median follow-up of 10.3 years, we observed 112 cases of CVD among 17,007 participants (61% female, mean age 38 years). We observed an inverse association between fiber intake and CVD events (p for trend = 0.024) and also between the highest quintile of fruit consumption (hazard ratio (HR) 0.51, 95% confidence interval (CI) 0.27-0.95) or whole grains consumption (HR 0.43 95% CI 0.20-0.93) and CVD compared to the lowest quintile, and also a HR of 0.58 (95% CI 0.37-0.90) for the participants who ate at least 175 g/day of fruit. Only the participants in the highest quintile of fruit-derived fiber intake had a significantly lower risk of CVD (HR 0.52, 95% CI 0.28-0.97). The participants who ate at least one serving per week of cruciferous vegetables had a lower risk than those who did not (HR 0.52, 95% CI 0.30-0.89). In conclusion, high fruit consumption, whole grain consumption, or consumption of at least one serving/week of cruciferous vegetables may be protective against CVD in young Mediterranean populations.

There is an emerging use of brief dietary questionnaires to investigate diet-health relation. We prospectively assess the association between eating attitudes (yes/no) and incident cardiovascular disease (CVD) in 19,138 participants of the Seguimiento Universidad de Navarra (SUN) Cohort. We calculated a baseline healthy-eating attitudes score (in quartiles), positively weighting answers on more fruit, vegetables, fish and fiber and less meat, sweets and pastries, fat, butter, fatty meats and added sugar in drinks. We observed 139 incident cases of CVD. A higher score was associated with a lower risk of CVD [3-5 points Hazard Ratio (HR): 0.38 (95% confidence interval: 0.18-0.81); 6-8 points: 0.57 (0.29-1.12); 9-10 points: 0.31 (0.15-0.67), compared to 0-2 points]. Key contributors were the attitude to increase fruit [HR: 0.59 (0.40-0.87)], vegetables [HR: 0.57 (0.29-1.12)] and fiber intake [HR: 0.69 (0.48-0.98)]. Brief questionnaire on attitudes towards healthy-eating may be a useful tool for the primary prevention of CVD.

Background: During development of cardiovascular disease (CVD), interferon-gamma-mediated inflammation accelerates degradation of tryptophan into downstream metabolites. A Mediterranean diet (MedDiet) consisting of a high intake of extravirgin olive oil (EVOO), nuts, fruits, vegetables, and cereals has been demonstrated to lower the risk of CVD. The longitudinal relation between tryptophan and its downstream metabolites and CVD in the context of a MedDiet is unstudied. Objective: We sought to investigate the relation between metabolites in the tryptophan-kynurenine pathway and CVD in the context of a MedDiet pattern. Methods: We used a case-cohort design nested in the Prevencion con DietaMediterranea randomized controlled trial. There were 231 CVD cases (stroke, myocardial infarction, cardiovascular death) among 985 participants over a median of 4.7 y of follow-up [mean +/- SD age: 67.6 +/- 6.1 y; 53.7% women; mean6 SD bodymass index (in kg/m(2)): 29.7 +/- 3.7]. We assessed plasma tryptophan, kynurenine, kynurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid concentrations at baseline and after 1 y of intervention with aMedDiet. We combined thesemetabolites in a kynurenine risk score (KRS) by weighting each metabolite by the adjusted coefficient of its associations with CVD. Cox models were used in the primary analysis. Results: Increases in tryptophan after 1 ywere associatedwith a lower risk of compositeCVD(HR per SD: 0.79; 95% CI: 0.63, 0.98). The baseline kynurenic acid concentration was associated with a higher risk of myocardial infarction and coronary artery disease death but not stroke. A higher KRSwas more strongly associatedwith CVD in the control group than in the 2 intervention groups (P-interaction = 0.003). Adjustment for changes in plasma tryptophan attenuated the inverse association between MedDiet+ EVOO and CVD. Conclusions: An increase in the plasma tryptophan concentrationwas significantly associated with a decreased risk of CVD. A MedDiet may counteract the deleterious effects of a high tryptophan risk score.

Objective: This study prospectively assessed the association of the inflammatory potential of a diet using the dietary inflammatory index (DII) with average yearly weight changes and incident overweight/obesity. Methods: Seven thousand and twenty-seven university graduates with body mass index <25 from the Seguimiento Universidad de Navarra (SUN) cohort were followed up during a median of 8.1 years. The DII, a validated tool based on scientific evidence to appraise the relationship between dietary parameters and inflammatory biomarkers, was used. A validated food-frequency questionnaire was used to assess intake of total energy, food, and nutrients, from which DII scores were calculated at baseline and after 10 years of follow-up. Results: After a median follow-up of 8.1 years, 1,433 incident cases of overweight or obesity were observed. Hazard ratios for overweight/obesity were calculated, including multivariable time-dependent Cox regression models with repeated measures of diet. The hazard ratio for subjects in the highest quartile (most pro-inflammatory diet) was 1.32 (95% confidence interval 1.08-1.60) compared with participants in the lowest quartile (most anti-inflammatory diet), with a significant linear dose-response relationship (P=0.004). Consistently, increases in average yearly weight gains were significantly associated with proinflammatory diets. Conclusions: A proinflammatory diet was significantly associated with a higher annual weight gain and higher risk of developing new-onset overweight or obesity.

Aims The aim of this study was to evaluate the effect of the Mediterranean diet (MedDiet) on the incidence of heart failure (HF), a pre-specified secondary outcome in the PREDIMED (PREvencion con DIeta MEDiterrnea) primary nutrition-intervention prevention trial. Methods and results Participants at high risk of cardiovascular disease were randomly assigned to one of three diets: MedDiet supplemented with extra-virgin olive oil (EVOO), MedDiet supplemented with nuts, or a low-fat control diet. Incident HF was ascertained by a Committee for Adjudication of events blinded to group allocation. Among 7403 participants without prevalent HF followed for a median of 4.8 years, we observed 29 new HF cases in the MedDiet with EVOO group, 33 in the MedDiet with nuts group, and 32 in the control group. No significant association with HF incidence was found for the MedDiet with EVOO and MedDiet with nuts, compared with the control group [hazard ratio (HR) 0.68; 95% confidence interval (CI) 0.41-1.13, and HR 0.92; 95% CI 0.56-1.49, respectively]. Conclusion In this sample of adults at high cardiovascular risk, the MedDiet did not result in lower HF incidence. However, this pre-specified secondary analysis may have been underpowered to provide valid conclusions. Further randomized controlled trials with HF as a primary outcome are needed to better assess the effect of the MedDiet on HF risk.

BACKGROUND: Although in vitro studies and investigations in animal models and small clinical populations have suggested that ceramides may represent an intermediate link between overnutrition and certain pathological mechanisms underlying cardiovascular disease (CVD), no prospective studies have investigated the association between plasma ceramides and risk of CVD. METHODS: The study population consisted of 980 participants from the PREDIMED trial (Prevencion con Dieta Mediterranea), including 230 incident cases of CVD and 787 randomly selected participants at baseline ( including 37 overlapping cases) followed for <= 7.4 years. Participants were randomized to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with nuts, or a control diet. Plasma ceramide concentrations were measured on a liquid chromatography tandem mass spectrometry metabolomics platform. The primary outcome was a composite of nonfatal acute myocardial infarction, nonfatal stroke, or cardiovascular death. Hazard ratios were estimated with weighted Cox regression models using Barlow weights to account for the case-cohort design. RESULTS: The multivariable hazard ratios (HR) and 95% confidence intervals (Cls) comparing the extreme quartiles of plasma concentrations of C16:0, C22:0, C24:0, and C24: 1 ceramides were 2.39 (1.49-3.83, P-trend < 0.001), 1.91 (1.21-3.01, P-trend = 0.003), 1.97 (1.21-3.20, P-trend = 0.004), and 1.73 (1.09-2.74, P-trend = 0.011), respectively. The ceramide score, calculated as a weighted sum of concentrations of four ceramides, was associated with a 2.18-fold higher risk of CVD across extreme quartiles (HR, 2.18; 95% Cl, 1.36-3.49; P-trend < 0.001). The association between baseline ceramide score and incident CVD varied significantly by treatment groups (P-interaction = 0.010). Participants with a higher ceramide score and assigned to either of the 2 active intervention arms of the trial showed similar CVD risk to those with a lower ceramide score, whereas participants with a higher ceramide score and assigned to the control arm presented significantly higher CVD risk. Changes in ceramide concentration were not significantly different between Mediterranean diet and control groups during the first year of follow-up. CONCLUSIONS: Our study documented a novel positive association between baseline plasma ceramide concentrations and incident CVD. In addition, a Mediterranean dietary intervention may mitigate potential deleterious effects of elevated plasma ceramide concentrations on CVD.

Background: Lipid metabolites may partially explain the inverse association between the Mediterranean diet (MedDiet) and cardiovascular disease (CVD). Objective: We evaluated the associations between 1) lipid species and the risk of CVD (myocardial infarction, stroke, or cardiovascular death); 2) a MedDiet intervention [supplemented with extra virgin olive oil (EVOO) or nuts] and 1-y changes in these molecules; and 3) 1-y changes in lipid species and subsequent CVD. Design: With the use of a case-cohort design, we profiled 202 lipid species at baseline and after 1 y of intervention in the PREDIMED (PREvencion con DIeta MEDiterranea) trial in 983 participants [230 cases and a random subcohort of 790 participants (37 overlapping cases)]. Results: Baseline concentrations of cholesterol esters (CEs) were inversely associated with CVD. A shorter chain length and higher saturation of some lipids were directly associated with CVD. After adjusting for multiple testing, direct associations remained significant for 20 lipids, and inverse associations remained significant for 6 lipids. When lipid species were weighted by the number of carbon atoms and double bonds, the strongest inverse association was found for CEs [HR: 0.39 (95% CI: 0.22, 0.68)] between extreme quintiles (P-trend = 0.002). Participants in the MedDiet + EVOO and MedDiet + nut groups experienced significant (P < 0.05) 1-y changes in 20 and 17 lipids, respectively, compared with the control group. Of these changes, only those in CE(20:3) in the MedDiet + nuts group remained significant after correcting for multiple testing. None of the 1-y changes was significantly associated with CVD risk after correcting for multiple comparisons. Conclusions: Although the MedDiet interventions induced some significant 1-y changes in the lipidome, they were not significantly associated with subsequent CVD risk. Lipid metabolites with a longer acyl chain and higher number of double bonds at baseline were significantly and inversely associated with the risk of CVD.

Background-The relationship between plasma concentrations of betaine and choline metabolism and major cardiovascular disease (CVD) end points remains unclear. We have evaluated the association between metabolites from the choline pathway and risk of incident CVD and the potential modifying effect of Mediterranean diet interventions. Methods and Results-We designed a case-cohort study nested within the PREDIMED (Prevention With Mediterranean Diet) trial, including 229 incident CVD cases and 751 randomly selected participants at baseline, followed up for 4.8 years. We used liquid chromatography-tandem mass spectrometry to measure, at baseline and at 1 year of follow-up, plasma concentrations of 5 metabolites in the choline pathway: trimethylamine N-oxide, betaine, choline, phosphocholine, and a-glycerophosphocholine. We have calculated a choline metabolite score using a weighted sum of these 5 metabolites. We used weighted Cox regression models to estimate CVD risk. The multivariable hazard ratios (95% confidence intervals) per 1-SD increase in choline and alpha-glycerophosphocholine metabolites were 1.24 (1.05-1.46) and 1.24 (1.03-1.50), respectively. The baseline betaine/choline ratio was inversely associated with CVD. The baseline choline metabolite score was associated with a 2.21-fold higher risk of CVD across extreme quartiles (95% confidence interval, 1.36-3.59; P<0.001 for trend) and a 2.27-fold higher risk of stroke (95% confidence interval, 1.24-4.16; P<0.001 for trend). Participants in the higher quartiles of the score who were randomly assigned to the control group had a higher risk of CVD compared with participants in the lower quartile and assigned to the Mediterranean diet groups (P= 0.05 for interaction). No significant associations were observed for 1-year changes in individual plasma metabolites and CVD. Conclusions-A metabolite score combining plasma metabolites from the choline pathway was associated with an increased risk of CVD in a Mediterranean population at high cardiovascular risk.

Background and objective: The prevalence of obesity and diabetes mellitus (DM) has increased worldwide. Our objective was to examine trends in the prevalence of overweight, obesity, morbid obesity and DM in Spain from 1987 to 2012. Participants and methods: Data were obtained from 8 waves of the national health surveys which are cross-sectional studies conducted in representative samples of the Spanish adult population. Self-reported data of 156,440 adults (>= 16 years) from 1987 to 2012 were used. Body mass index (BMI) was calculated from self-reported weight and height. Overweight was defined as a BMI of 25.0 to 29.9 kg/m(2), obesity as a BMI >= 30 kg/m(2) and morbid obesity as a BMI >= 40 kg/m(2). DM was considered present if the participant reported having been diagnosed. Age-adjusted prevalence was adjusted by the direct standardisation method to the 2003 survey population. Results: From 1987 to 2012 age-adjusted prevalence of overweight increased from 34.0% (95% confidence interval [95% CI] 33.2-34.8) to 35.8% (95% CI 35.0-36.6), prevalence of obesity from 8.0% (95% CI 7.5-8.5) to 16.5% (95% CI 15.7-17.1%) and DM prevalence from 4.2% (95% CI 3.9-4.5) to 7.1% (95% CI 6.7-7.4%). Morbid obesity increased from 0.20% (95% Cl 0.13-0.27) in 1993 to 0.88% (95% CI 0.70-1.05) in 2012. The growth rate was greater among males. Conclusions: An increasing trend of the prevalence of overweight, obesity, morbid obesity and DM was found in Spain from 1987 to 2012, particularly in males. (C) 2016 Elsevier Espana, S.L.U. All rights reserved.

Background: Hydroxytyrosol is a phenolic compound that is present in virgin olive oil (VOO) and wine. Hydroxytyrosol-related foods have been shown to protect against cardiovascular disease (CVD). Objective: We investigated the associations between hydroxytyrosol and its biological metabolite, 3-O-methyl-hydroxytyrosol, also known as homovanillyl alcohol (HVAL), with CVD and total mortality. Design: We included 1851 men and women with a mean +/- SD age of 66.8 +/- 6 y at high risk of CVD from prospective cohort data. The primary endpoint was a composite of myocardial infarction, stroke, and death from cardiovascular causes; the secondary endpoint was all-cause mortality. Twenty-four-hour urinary hydroxytyrosol and HVAL and catechol-O-methyltransferase (COMT) rs4680 genotypes were measured. Results: After multivariable adjustment, all biomarkers were associated, as a continuous variable, with lower CVD risk, but only HVAL showed a strong inverse association (HR: 0.44; 95% CI: 0.25, 0.80) for the comparison between quintiles. Only HVAL, as a continuous variable, was associated with total mortality (HR: 0.81; 95% CI: 0.70, 0.95). Individuals in the highest quintile of HVAL compared with the lowest had 9.2 (95% CI: 3.5, 20.8) and 6.3 (95% CI: 2.3, 12.1) additional years of life or years free of CVD, respectively, after 65 y. Individuals with the rs4680GG genotype had the highest HVAL concentrations (P = 0.05). There was no association between COMT genotypes and events or interaction between COMT genotypes and HVAL concentrations. Conclusions: We report, for the first time to our knowledge, an independent association between high urinary HVAL concentrations and a lower risk of CVD and total mortality in elderly individuals. VOO and wine consumption and a high metabolic COMT capacity for methylation are key factors for high HVAL concentrations. The association that stems from our results reinforces the benefits of 2 key components of the Mediterranean diet (wine and VOO).

Supplemental marine omega-3 eicosapentaenoic acid (EPA) has an anti-atherosclerotic effect. Clinical research on EPA supplied by the regular diet and atherosclerosis is scarce. In the framework of the PREvencion con DIeta MEDiterranea (PREDIMED) trial, we conducted a cross-sectional study in 161 older individuals at high vascular risk grouped into different stages of carotid atherosclerosis severity, including those without ultrasound-detected atheroma plaque (n = 38), with plaques <2.0 mm thick (n = 65), and with plaques >= 2.0 mm (n = 79). The latter were asked to undergo contrast-enhanced 3T magnetic resonance imaging (MRI) and were subsequently grouped into absence (n = 31) or presence (n = 27) of MRI-detectable plaque lipid, a main feature of unstable atheroma plaques. We determined the red blood cell (RBC) proportion of EPA (a valid marker of long-term EPA intake) at enrolment by gas chromatography. In multivariate models, EPA related inversely to MRI-assessed plaque lipid volume, but not to maximum intima-media thickness of internal carotid artery, plaque burden, or MRI-assessed normalized wall index. The inverse association between EPA and plaque lipid content in patients with advanced atherosclerosis supports the notion that this fatty acid might improve cardiovascular health through stabilization of advanced atheroma plaques.

Laparoscopic organ-sparing pancreatectomy (LOSP) is an ideal therapeutic option in selected cases of pancreatic neuroendocrine tumors (PNETs). Nevertheless, given the low frequency of PNETs, there is scarce evidence regarding short and particularly long-term outcomes of LOSP in this clinical setting. All patients with PNETs who underwent surgery (under a LOSP policy) were retrospectively reviewed from a prospective database maintained at our center. Preoperative characteristics, operative data, pathological features and postoperative outcomes were analyzed. Between December 2003 and December 2015, 36 patients with PNETs underwent laparoscopic resections. Ten were functional tumors, 26 non-functional and 16 were "incidental" cases. The following procedures were performed: one enucleation, eight central pancreatectomies (LCP), one resection of the uncinate process and 26 distal pancreatectomies (DP) (15 of them laparoscopic vessels-preserving). There were no conversions to open surgery, and no drains were routinely left. Mean operative time was 288 min (SD 99). Hospital stay was 6 days. Eighteen patients (50%) experienced some complication of which most were mild (Clavien-Dindo I/II). Three postoperative bleedings occurred: two grade B/one grade C; two required laparoscopic reoperation. Thirteen (36.1%) patients developed peripancreatic fluid collections: two were symptomatic and were managed with transgastric drainage (one presented post-puncture abscesification requiring surgical drainage and splenectomy). Four patients (11%)-one DP and three LCP-developed new-onset pancreatogenic diabetes mellitus (NODM) in the long term. According to the European Neuroendocrine Tumor Society, 19 cases were stage I, seven IIA, two IIIA, one IIIB and seven stage IV. Over a mean follow-up of 51 months, two patients died, one due to recurrence of the tumor and another due to cirrhosis. The existing different surgical options must be individually considered according to the location and particular characteristics of every tumor. Results from this single-center study document the effectiveness of LOSP in selected cases of PNETs.

Background: The associations between dietary fat and cardiovascular disease have been evaluated in several studies, but less is known about their influence on the risk of diabetes. Objective: We examined the associations between total fat, subtypes of dietary fat, and food sources rich in saturated fatty acids and the incidence of type 2 diabetes (T2D). Design: A prospective cohort analysis of 3349 individuals who were free of diabetes at baseline but were at high cardiovascular risk from the PREvencion con DIeta MEDiterranea (PREDIMED) study was conducted. Detailed dietary information was assessed at baseline and yearly during the follow-up using a food frequency questionnaire. Multivariable Cox proportional hazards models were used to estimate T2D HRs and 95% CIs according to baseline and yearly updated fat intake. Results: We documented 266 incident cases during 4.3 y of follow-up. Baseline saturated and animal fat intake was not associated with the risk of T2D. After multivariable adjustment, participants in the highest quartile of updated intake of saturated and animal fat had a higher risk of diabetes than the lowest quartile (HR: 2.19; 95% CI: 1.28, 3.73; and P-trend = 0.01 compared with HR: 2.00; 95% CI: 1.29, 3.09; and P-trend < 0.01, respectively). In both the Mediterranean diet and control groups, participants in the highest quartile of updated animal fat intake had anw2-fold higher risk of T2D than their counterparts in the lowest quartile. The consumption of 1 serving of butter and cheese was associated with a higher risk of diabetes, whereas whole-fat yogurt intake was associated with a lower risk. Conclusions: In a Mediterranean trial focused on dietary fat interventions, baseline intake of saturated and animal fat was not associated with T2D incidence, but the yearly updated intake of saturated and animal fat was associated with a higher risk of T2D. Cheese and butter intake was associated with a higher risk of T2D, whereas whole-fat yogurt intake was associated with a lower risk of T2D.

We thank Modesto Varas et al. for their opportune comments with regard to the oncologic outcomes of our series of patients undergoing surgery for pancreatic neuroendocrine tumors (PNET). We agree with Varas et al. in relation to the increase in non-functional tumors (73%) and the incidental form of presentation (44%). These figures are in line with those presented in most series.

Background: Pancreatic neuroendocrine tumors (pNETs) comprise a heterogeneous group of tumors with a varied biological behavior. In the present study, we analyzed the experience of 79 pNETs resected between 1993 and 2015. The pathologic prognostic factors (European Neuroendocrine Tumor Society, ENETS; and AJCC) classification, vascular invasion (VI), proliferation index (ki-67) and the presence of necrosis were retrospectively reviewed. Methods: The clinical data of 79 patients with pNETs who underwent surgery were retrospectively analyzed. Mortality rates and Kaplan-Meier estimates were used to evaluate survival over time for pathologic stages, tumor functionality, and vascular invasion. Cox proportional hazards models were used to calculate the hazard ratio regarding ENETS, AJCC staging, sex, tumor functionality and vascular invasion. Results: The male: female ratio was 40: 39. Twenty-one patients (26%) had functional tumors and 58 (73.4%) had nonfunctional tumors, of which 35 (44.3%) were diagnosed incidentally. Seventeen Whipple procedures, 46 distal pancreatectomies (including 26 laparoscopic and 20 open procedures), 8 laparoscopic central pancreatectomies, 1 laparoscopic resection of the uncinated process and 7 enucleations (one laparoscopic) were performed. Vascular invasion and necrosis were observed in 29 of 75 cases (38.6%) and in 16 cases (29%), respectively. The comparison between survivor functions of ENETS staging categories showed statistically significant differences (p = 0.042). Mortality rate was higher in patients with non-functioning tumors compared with hormonally functioning tumors (p = 0.052) and in those with vascular invasion (p = 0.186). Conclusions: In spite of the heterogeneity of pNETs, the ENETS TNM classification efficiently predicts long-term prognosis. The non-functioning tumors and the presence of vascular invasion are associated with poor prognosis.

BACKGROUND AND AIMS: Beyond the quantity of carbohydrate intake, further research is needed to know the relevance of carbohydrate quality following operational indices. No previous longitudinal study has assessed the association between an index for quality of dietary carbohydrate intake and the risk of cardiovascular disease (CVD). Here, we examined the association between a carbohydrate quality index (CQI) and the risk of CVD. METHODS AND RESULTS: We used a validated semi-quantitative 136-item food-frequency questionnaire (FFQ) in a prospective follow-up study of 17,424 middle-aged adults from Spain. The CQI was defined by four criteria: dietary fiber intake, glycemic index, whole-grain/total-grain carbohydrate ratio, and solid/total carbohydrate ratio. We observed 129 incident cases of CVD during 10.1 y of median follow-up. An inverse association for CQI was found (hazard ratio = 0.44, 95% confidence interval (CI): 0.25-0.78 for the highest versus the lowest tertile, p for trend = 0.008). Participants in the highest tertile of the whole-grain/total-grain carbohydrate ratio had 47% lower risk of CVD (95% CI: 0.33-0.85, p for trend = 0.008). Participants with higher baseline CQI and higher baseline energy from carbohydrates had the lowest risk of CVD. CONCLUSION: In this Mediterranean cohort, a better quality of dietary carbohydrates measured by the CQI, showed a significant inverse association with the incidence of CVD. Specially, a higher proportion of carbohydrates from whole grains was strongly inversely associated with CVD. "Heart-healthy" diets should be focused not only on carbohydrate quantity but also on a multidimensional assessment of the type and quality of carbohydrates.

Nutritional adequacy implies sufficient intake of essential nutrients needed to [...] Background The assessment of changes in dietary habits provides interesting information on whether or not the observed trends are in line with accepted nutritional guidelines. The objective was to evaluate within-subject longitudinal changes in food consumption and nutrient intake and in a 10-year follow-up study. Methods The SUN ( ) project is a prospective Spanish cohort study. Diet was assessed using a 136-item food-frequency questionnaire (FFQ), previously validated in Spain. The participants were 3036 university graduates (55.8 % women) of Spain and the main outcome measures the changes in dietary quality and in food consumption and nutrient intake. Paired t-tests and conditional logistic regression models were used to evaluate within-subject longitudinal dietary changes and the risk of inadequacy respectively, after 10 years of follow-up. Results During follow-up, participants showed a relevant and significant increase (p 0.001) in the consumption of fruits (7.4 %), vegetables (8.6 %), low-fat dairy products (35.2 %), lean meat (12.4 %), fish (2.9 %), whole grains (53.2 %), nuts (52.4 %) and a significant decrease in legumes (-7.4 %), whole-fat dairy products (-44.2 %), red meat (-17.6 %), sugar-sweetened beverages (-58.7 %) and wine (-11.9 %). With respect to nutrients, we found a higher proportion of carbohydrates (3.6 %) and fiber (7.4 %) and a decrease in total energy intake (2.7 %), total fat (-4.5 %), SFA (-9.4 %), MUFA (-4.9 %), PUFA (-12.7 %), w-3 and w-6 fatty acids (-9.1 and -20.5 % respectively) and cholesterol (-9.6 %). Conclusions In this Mediterranean cohort study, mainly beneficial changes in the consumption of most foods and macronutrients were observed after 10 years of follow-up.

Introduction: Sexually transmitted infections and unplanned pregnancies affect adolescent sexual health and are serious public health concerns. They result from sexual intercourse in adolescence, which is usually associated with multiple partners, unprotected sex, and condom misuse. This behavior is related to socio-ecological factors that influence lifestyles. The YOURLIFE project aims to find out what young people think and feel about relationships, love, and sexuality, and to assess the associations between these thoughts and attitudes, adolescents' social factors, and sexual health. Materials and Equipment: An international school-based study with a cross-sectional and optional subsequent longitudinal design. Three online questionnaires designed for adolescents aged 13/14, 15/16, and 17/18, respectively, will be used. A matching coding system will allow longitudinal follow-up when adolescents reply to follow-up surveys. Questionnaires will include questions related to sociodemographic data; information/communication technologies; leisure time; parental supervision; influences of parents/friends; information sources; messages perceived; and sexuality-related knowledge, attitudes, and opinions. The second and third questionnaires for participants aged 15/16 and 17/18 will also contain variables concerning sexual behavior. Schools will be able to use their results to tailor educational approaches targeting the needs of their students. Multivariate analyses will be performed using the larger international dataset. Expected Impact Of the Study On Public Health: The YOURLIFE project will collect comprehensive information about the socio-ecological determinants of the sexual risk-taking of schooled adolescents worldwide. Effective preventive programs could be subsequently designed and tailored to the specific determinants of adolescents from different schools and settings, and also, when analyzed globally, to public health professionals.

This research assessed the association between the adherence to a Mediterranean lifestyle beyond the Mediterranean diet and the risk of depression in a prospective cohort of Spanish university graduates. Through a dynamic cohort study method, diet was assessed with a validated semiquantitative food-frequency questionnaire. The baseline assessment included a validated questionnaire on physical activity and average time spent with friends (socializing). Mediterranean lifestyle was defined as the joint exposure to Mediterranean diet, level of physical activity, and level of socializing. After a median follow-up of 8.5 years, 806 cases of depression among 11,800 participants were observed. Participants with the highest adherence to the Mediterranean lifestyle showed a 50% relative risk reduction in depression risk as compared to those participants with the lowest adherence (multivariable hazard ratio = 0.50; 95% confidence interval = [0.32, 0.81]). The Mediterranean lifestyle might reduce depression risk in the Seguimiento Universidad de Navarra cohort study beyond the known effects of the Mediterranean diet.

Background and aims Evidence on the association yogurt consumption and obesity is not conclusive. The aim of this study was to prospectively evaluate the association between yogurt consumption, reversion of abdominal obesity status and waist circumference change in elderly. Methods and results 4545 individuals at high cardiovascular risk were prospectively followed. Total, whole-fat and low-fat yogurt consumption were assessed using food frequency questionnaires. Generalized estimating equations were used to analyze the association between yogurt consumption and waist circumference change (measured at baseline and yearly during the follow-up). Logistic regression models were used to evaluate the odds ratios (ORs) and 95% CIs of the reversion rate of abdominal obesity for each quintile of yogurt consumption compared with the lowest quintile. After multivariable adjustment, the average yearly waist circumference change in the quintiles of whole-fat yogurt consumption was: Q1: 0.00, Q2: 0.00 (¿0.23 to 0.23), Q3: ¿0.15 (¿0.42 to 0.13), Q4: 0.10 (¿0.21 to 0.42), and Q5: ¿0.23 (¿0.46 to ¿0.00) cm; p for trend = 0.05. The ORs for the reversion of abdominal obesity for whole-fat yogurt consumption were Q1: 1.00, Q2: 1.40 (1.04¿1.90), Q3: 1.33 (0.94¿1.89), Q4: 1.21 (0.83¿1.77), and Q5: 1.43 (1.06¿1.93); p for trend = 0.26. Conclusion Total yogurt consumption was not significantly associated with reversion of abdominal obesity status and a lower waist circumference. However, consumption of whole-fat yogurt was associated with changes in waist circumference and higher probability for reversion of abdominal obesity. Therefore, it seems that whole-fat yogurt has more beneficial effects in management of abdominal obesity in elderly population at high cardiovascular risk.

Background: Some studies have pointed out that several dietary patterns could be associated with a reduced risk of depression among adults. This association seems to be consistent across countries, cultures and populations. The objective of the study was to compare and to establish the type of relationship between three diet quality scores and depression in the SUN (Seguimiento Universidad de Navarra) Cohort study. Methods: We performed a dynamic cohort study based on Spanish university graduates free of depression at baseline. Dietary intake was repeatedly assessed at baseline and after 10years of follow-up with a validated semi-quantitative food-frequency questionnaire. Three previously described diet quality scores: Mediterranean Diet Score (MDS), Pro-vegetarian Dietary Pattern (PDP) and Alternative Healthy Eating Index-2010 (AHEI-2010) were built. Participants were classified as having depression if they reported a new clinical diagnosis of depression by a physician or initiated the use of an antidepressant drug during follow-up. Time-dependent Cox regression models with cumulative averages of diet and restricted cubic splines were used to estimate hazard ratios of depression according to quintiles of adherence to the MDS, PDP and AHEI-2010. Results: One thousand and fifty one incident cases of depression were observed among 15,093 participants from the SUN Cohort after a median follow-up of 8.5years. Inverse and significant associations were observed between the three diet quality scores and depression risk. The hazard ratios and 95% confidence intervals for extreme quintiles (fifth versus first) of updated adherence to MDS, PDP and AHEI-2010 were 0.84 (0.69-1.02), 0.74 (0.61-0.89) and 0.60 (0.49-0.72), respectively. The dose-response analyses showed non-linear associations, suggesting that suboptimal adherence to these dietary patterns may partially be responsible for increased depression risk. Conclusions: Better adherence to the MDS, PDP and AHEI-2010 was associated with a reduced risk of depression among Spanish adults. However, our data suggested a threshold effect so that although the risk of depression was reduced when comparing moderate versus lower adherence, there was not much extra benefit for the comparison between moderate and high or very high adherence.

The dietary inflammatory index (DII) is a new tool to assess the inflammatory potential of the diet. In the present study, we aimed to determine the association between the DII and BMI, waist circumference and waist:height ratio (WHtR). We conducted a cross-sectional study of 7236 participants recruited into the PREvencion con DIeta MEDiterranea trial. Information from a validated 137-item FFQ was used to calculate energy, food and nutrient intakes. A fourteen-item dietary screener was used to assess adherence to the Mediterranean diet (MeDiet). Sex-specific multivariable linear regression models were fitted to estimate differences (and 95% CI) in BMI, waist circumference and WHtR across the quintiles of the DII. All nutrient intakes, healthy foods and adherence to the MeDiet were higher in the quintile with the lowest DII score (more anti-inflammatory values) except for intakes of animal protein, saturated fat and monounsaturated fat. Although an inverse association between the DII and total energy was apparent, the DII was associated with higher average BMI, waist circumference and WHtR after adjusting for known risk factors. The adjusted difference in the WHtR for women and men between the highest and lowest quintiles of the DII was 1·60% (95% CI 0·87, 2·33) and 1·04% (95% CI 0·35, 1·74), respectively. Pro-inflammatory scores remained associated with obesity after controlling for the effect that adherence to a MeDiet had on inflammation. In conclusion, the present study shows a direct association between the DII and indices of obesity, and supports the hypothesis that diet may have a role in the development of obesity through inflammatory modulation mechanisms.

Previous studies have reported an association between a more pro-inflammatory diet profile and various chronic metabolic diseases. The Dietary Inflammatory Index (DII) was used to assess the inflammatory potential of nutrients and foods in the context of a dietary pattern. We prospectively examined the association between the DII and the incidence of cardiovascular disease (CVD: myocardial infarction, stroke or cardiovascular death) in the PREDIMED (Prevención con Dieta Mediterránea) study including 7216 high-risk participants. The DII was computed based on a validated 137-item food frequency questionnaire. Multivariate-adjusted hazard ratios (HR) and 95% confidence intervals of CVD risk were computed across quartiles of the DII where the lowest (most anti-inflammatory) quartile is the referent. Risk increased across the quartiles (i.e., with increasing inflammatory potential): HRquartile2 = 1.42 (95%CI = 0.97¿2.09); HRquartile3 = 1.85 (1.27¿2.71); and HRquartile4 = 1.73 (1.15¿2.60). When fit as continuous the multiple-adjusted hazard ratio for each additional standard deviation of the DII was 1.22 (1.06¿1.40). Our results provide direct prospective evidence that a pro-inflammatory diet is associated with a higher risk of cardiovascular clinical events.

Objectives To evaluate the prevalence of HIV-related misconceptions in an outpatient centre of Kinshasa (Democratic Republic of Congo) and analyse the association between these beliefs and HIV infection. Methods A case-control study was carried out from December 2010 until June 2012. We assessed 1630 participants aged 15-49 attending a primary outpatient centre in Kinshasa: 762 HIV Voluntary Counselling and Testing attendees and 868 blood donors. A 59-item questionnaire about knowledge, attitudes and practice was administered during a face-to-face interview, followed by an HIV test. Cases and controls were respondents with a newly diagnosed HIV-positive or HIV-negative test, respectively. Unconditional logistic regression was used to analyse the association between misconceptions and HIV seropositivity. Results 274 cases and 1340 controls were recruited. Cases were more likely than controls to have a low socioeconomic status, no education, to be divorced/separated or widowed. An association was found between the following variables and HIV seropositivity: having a poor HIV knowledge (adjusted OR=2.79; 95% CI 1.43 to 5.45), not knowing a virus is the cause of AIDS (adjusted OR=2.03; 95% CI 1.38 to 2.98) and reporting more than three HIV-transmission-related misconceptions (adjusted OR=3.30; 95% CI 1.64 to 6.64), such as thinking an HIV-positive person cannot look healthy and that HIV is transmitted by sorcery, God's punishment, a kiss on the mouth, mosquitoes, coughs/sneezes or undercooked food. Conclusions Despite having access to healthcare services, there are still many people in Kinshasa that have HIV-related misconceptions that increase their HIV risk. Our findings underscore the need for a culturally adapted and gender-orientated basic HIV information into Congolese HIV prevention programmes.

DESIGN: The SUN Project is a dynamic, prospective, multipurpose cohort of Spanish university graduates with an overall retention rate of 90%. The study population encompassed 8569 Spanish university graduates (mean age: 37 y) who were initially free of overweight or obesity. Self-reported weight (previously validated) was collected at baseline and updated every 2 y during the follow-up period. Fructan consumption and GOS consumption were assessed with the use of a validated semiquantitative 136-item food-frequency questionnaire and were updated after 10 y. Time-dependent Cox proportional hazards models were used to estimate HRs and 95% CIs for incident overweight and to adjust for potential confounding factors. RESULTS: During follow-up (median: 9 y), 1964 incident cases of overweight were identified. After potential confounders were adjusted for, risk of overweight was 15% lower in participants in the highest quartile of fructan consumption (¿2.3 g/d) (95% CI: 0.74, 0.97; P-trend = 0.019). Subjects in the highest quartile of GOS consumption (¿0.45 g/d) had 17% lower risk of overweight (95% CI: 0.74, 0.94; P-trend = 0.001). CONCLUSIONS: Higher prebiotic consumption was associated with lower risk of overweight in a cohort of initially normal-weight, middle-aged adults. This potential protection has been previously scarcely assessed; therefore, additional longitudinal studies are needed to confirm our results.

OBJECTIVES: This study intends to evaluate whether the belief that condoms are 100% effective in protecting against HIV infection is associated with sexual risk behaviours among youth. METHODS: A cross-sectional study was performed in representative samples of high-school students in the Philippines, El Salvador and Peru. Participants completed a self-administered questionnaire. Students were asked about the risk of HIV transmission if one has sex using condoms. They were also asked to indicate whether they had ever had sexual relations and whether they used a condom in their first sexual relation. The sample was composed of 8994 students, aged 13-18. RESULTS: One out of seven adolescents believed condoms are 100% effective (safe-sex believers). Those adolescents were 82% more likely to have had sex than those without such belief, after adjusting for confounders (OR=1.82; 95% CI 1.51 to 2.21). On the contrary, no association was found between risk perception and condom use. Subgroup and sensitivity analyses produced similar results. CONCLUSIONS: This is, to the best of our knowledge, the first study conducted specifically to evaluate this phenomenon and that has used the same questionnaire and the same data collection protocol in three different developing countries from Asia, Central and South America. These results reasonably suggest that there could be an association between safe sex beliefs and sexual initiation. Longitudinal studies are needed to better understand this possible association as it could influence how to better promote sexual health.

The Prevención con Dieta Mediterránea (PREDIMED) was a multicenter, randomized, primary prevention feeding trial with blinded assessment of end points conducted in Spain between October 2003 and December 2010. Eligible participants were men aged 55 to 80 years and women aged 60 to 80 years without clinical PAD or baseline cardiovascular disease but with type 2 diabetes mellitus or at least 3 cardiovascular risk factors. Participants were randomized in a 1:1:1 ratio to 1 of 3 groups: a Mediterranean diet supplemented with extra-virgin olive oil; a Mediterranean diet supplemented with nuts; or counseling on a low-fat diet (control group). All participants received a comprehensive dietary educational program on a quarterly basis. The intensity of the program delivered to the control group was increased in October 2006. The protocol was approved by institutional review boards and written informed consent was obtained from all participants. New symptomatic PAD events were confirmed by a central end-point adjudication committee that was blinded to the allocated group. A confirmed diagnosis of PAD in symptomatic patients required at least 1 of the following criteria: an ankle-brachial index of less than 0.9 at rest, a clinical diagnosis of arterial occlusive disease based on imaging tests (duplex ultrasonography, magnetic resonance angiography, computed tomographic angiography, or catheter-based radiocontrast angiography), or an endovascular or open surgical procedure (revascularization or amputation). We used Stata version 12.1 (StataCorp) for statistical analyses. Kaplan-Meier curves and Cox proportional hazards models adjusted for baseline factors were used to compare the risk of PAD for each diet group vs the control group on an intention-to-treat basis. The number needed to treat (NNT) was estimated for each diet group vs control group. As a sensitivity analysis, we used multiple imputation algorithms for participants without any events or study contact for at least 2 years.

The common statistical indicator "mean age of first sex" can be misinterpreted by youth to indicate that most of their peers of the same age are sexually initiated, when this is not usually the case. This can jeopardize efforts to delay sexual initiation. University students were randomly assigned to one of two versions of an anonymous survey. They were asked to estimate how common sexual initiation was at a given age upon being presented with statements with different wordings, such as the "mean age of first sex" or "proportions of youth at different ages having had sex." Their interpretations were compared using logistic regression. Students who were assigned surveys using the indicator "mean age" of sexual initiation had higher odds of overestimating the extent of sexual initiation compared to those assigned surveys using percentages as the indicator, even after adjusting for student's sex and degree. We encourage the use of the "percentage" of youth, at different ages, who are sexually initiated as a more reliable indicator.

Objective: To identify the factors associated to the number of medication changes (MC) in institutionalized elderly. Method: Prospective study conducted during four months. The number of MC was recorded weekly. We analyzed the factors associated with a high number of changes (four or more), calculating the Odds Ratio as a measure of association and the Fisher's exact test for statistical significance. Results: 997 MC were recorded in 234 elderly. 42.7% of the patients had four or more MC. The factors associated with a high number of MC were, chronic renal failure, immobility syndrome, loss of visual acuity, comorbidity, and polypharmacy. Conclusions: A high number of MC is associated with factors considered as risk indicators of drug-related problems. The number of MC in institutionalized patients may be an indicator to prioritize medication review.

. Purpose: To compile a multicenter normative database of retinal nerve fibre layer (RNFL) and macular thicknesses and macular volume values in healthy Caucasian children 417 years using spectral-domain optical coherence tomography (SD-OCT). To analyse variations in the OCT measurements as a function of age, sex, refraction, and axial length (AL). Methods: An observational, multicenter and cross-sectional study among 301 healthy Caucasian children recruited at three Spanish centres was performed. To compile the database, each child underwent a dilated eye examination and a cycloplegic refraction, five AL measurements (IOL Master; Carl Zeiss Meditec, Dublin, CA, USA), five OCT scans with Cirrus OCT: three peripapillary RNFL scans (Optic Disc Cube 200X200 protocol) and two macular scans (Macular Cube 512X128 protocol). One eye of each subject was selected randomly for analysis. Results: Two hundred eighty-three children (117 boys, 41.34%; 166 girls, 58.66%) were included in this study. The mean age of the children was 9.58 +/- 3.12 years (range, 417). The mean SE was +0.63 +/- 1.65 D; (range, -4.88 to +5.25). The mean AL was 22.94 +/- 1.10 mm (range, 20.1026.27). The mean global RNFL thickness was 97.40 +/- 9.0 mu m (range, 77121.7 mu m). Multivariate analysis showed a positive correlation between the RNFL and spherical equivalent (SE) (p = 0.014). The mean central macular thickness was 253.85 +/- 19.76 mu m, the average thickness 283.62 +/- 14.08 mu m, and the mean macular volume 10.22 +/- 0.49 mu m3. Multivariate analysis showed a positive correlation between central macular thickness and age (p < 0.001). Boys had a significantly thicker central macula than girls (p < 0.001). Conclusions: Normative paediatric SD-OCT data might facilitate use of SD-OCT for assessing childhood ophthalmic diseases. This study provides a multicenter paediatric normative database of SD-OCT peripapillary RNFL and macular data.

ICS Objetivo. El objetivo de este estudio es comprobar cómo influyen en el inicio de la actividad sexual de los jóvenes salvadoreños los mensajes que reciben sobre cuestiones de sexualidad, afectividad y ocio a través de la familia, los amigos y los medios de comunicación. Métodos. Estudio transversal a partir de una muestra representativa de 2 615 estudiantes (de 13 a 19 años) de El Salvador. Se utilizó un muestreo sistemático aleatorio para seleccionar 30 colegios. Se recogieron aspectos sociodemográficos, estilos de vida y fuentes de información sobre sexualidad y amor utilizadas por los jóvenes. Resultados. La edad media de los jóvenes fue de 15 años (DE = 1,8). En total 638 (24,4%) jóvenes afirmaron haber tenido relaciones sexuales. Los siguientes factores se asociaron con una mayor probabilidad de haber tenido relaciones sexuales: percibir que los hermanos (OR = 1,8, IC 95%: 1,2¿2,7) o los amigos (OR = 1,7, IC 95%: 1,3¿2,2) apoyan que se tengan relaciones sexuales. Como factores protectores se encontraron la supervisión de los padres (OR = 0,5, IC 95%: 0,4¿0,7); recibir mensajes que apoyan la abstinencia por parte de amigos (OR = 0,7, IC 95%: 0,6¿1,0) o hermanos (OR = 0,7, IC 95%: 0,5¿0,8) y recibir mensajes favorables al matrimonio por parte de los padres (OR = 0,4, IC 95%: 0,3¿0,6). Conclusiones. Los mensajes de la familia y amigos son factores que parecen influir en el inicio de las relaciones sexuales de los jóvenes. Los programas de promoción de la salud sexual en

Fast-food and commercial baked goods consumption may have a detrimental effect on depression risk

ICS Purpose Adolescents who engage in sex can be affected by a range of negative physical and psychological consequences. We intend to analyze the reasons behind first sex, regret, and the association between reasons and regret. Methods A questionnaire was implemented to 8,495 high schools students aged 14¿18 years residing in the Philippines, El Salvador, and Peru. Sexually active participants responded whether several circumstances were reasons involved in their first sexual relationship. They also responded whether they regretted having already had sexual relationships. Results More than one-third of respondents reported at least one external pressure leading to first sex, and about one-half reported at least one reason implying getting carried away by sexual arousal. More females affirmed they regret having already had sex. Logistic regression shows that reasons for first sex associated with regret were partner insistence, ¿uncontrolled situations,¿ and seeing sexual images. These reasons were associated with regret even when love was also reported as related to first sex. Conclusions Adolescent sexual experience is often motivated by pressure (such as external pressure [because most friends already had sex or because of partner insistence]) and circumstances (such as getting carried away by sexual arousal [through an ¿uncontrolled situation¿ or viewing sexual images]) that lower the control over their decisions concerning sex, rather than by mature decisions, and this ma

The available large prospective studies supporting an inverse association between better adherence to the Mediterranean diet and lower mortality have mainly included older adults. It is not clear whether this inverse association is also present among younger individuals at lower mortality risk. Our aim was to assess the association between adherence to the Mediterranean diet and total mortality in middle-aged adults from the Seguimiento Universidad de Navarra (SUN) Project. We followed 15,535 Spanish university graduates for a mean of 6.8 y. Their mean age was 38 ± 12 y, 59.6% were females, and all were initially free of cardiovascular disease, cancer, and diabetes. A validated FFQ was used to assess dietary habits. Adherence to the Mediterranean diet was categorized into 3 groups according to the Mediterranean Diet Score (low, 0-2 points; moderate, 3-5 points; and high, 6-9 points). The outcome variable was total mortality. Cox proportional hazards models were used to estimate HR and 95% CI. We adjusted the estimates for sex, age, years of university education, BMI, smoking, physical activity, television watching, history of depression and baseline hypertension, and hypercholesterolemia. We observed 125 deaths during 105,980 person-years of follow-up. The fully adjusted HR for moderate and high adherence were 0.58 (95% CI: 0.34, 0.99; P = 0.05) and 0.38 (95% CI: 0.21, 0.70; P = 0.002), respectively. For each 2-point increment in the Mediterranean Diet Score, the HR of death

Assessment of eating habits (EH) through closed questions could be an alternative tool to assess diet as a predictor of weight change in epidemiological studies. The aim was to assess the association between baseline EH and the risk of weight gain or becoming overweight/obese in a Spanish dynamic prospective cohort (the Seguimiento Universidad de Navarra Project) of 10 509 participants. The baseline questionnaire included ten short questions with two possible answers: yes or no. We calculated a baseline EH score, categorised in quartiles, positively weighting answers on more fruit, vegetables, fish and fibre and less meat, sweets and pastries, fat, butter, fatty meats and added sugar in drinks. Reducing the consumption of meat or fat and removing fat from meat were significantly associated with lower weight gain. The partial correlation coefficient between EH score and weight change was ¿ 0·033 (P = 0·001). We observed 1063 cases of incident overweight/obesity among 7217 participants without overweight/obesity at baseline. Trying to eat more fruit, fish or fibre and less meat was inversely significantly associated with incident overweight/obesity. Those participants in the upper quartile of the score were at a 38 % (adjusted OR 0·62; 95 % CI 0·48, 0·81) lower risk of developing overweight/obesity during the follow-up compared with those in the lower quartile. However, the receiver-operating characteristic curves for the model with and without the EH score were materially identical. Despite the apparent significant inverse association, this score had a low predictive value for future weight gain and for incident overweight/obesity in a Mediterranean population, although some EH were independently and positively associated with weight gain.

Mediterranean diet has been related with reduced morbidity and better well-being. The aim of this study was to assess whether the adherence to the Mediterranean diet were associated with mental and physical health related to quality of life.

Few studies have related nutritional factors with quality of life in healthy populations. The purpose of the study was to assess whether dietary fat intake is associated to mental and physical quality of life

Emerging evidence relates some nutritional factors to depression risk. However, there is a scarcity of longitudinal assessments on this relationship. Objective: To evaluate the association between fatty acid intake or the use of culinary fats and depression incidence in a Mediterranean population. Material and Methods: Prospective cohort study (1999-2010) of 12,059 Spanish university graduates (mean age: 37.5 years) initially free of depression with permanently open enrolment. At baseline, a 136-item validated food frequency questionnaire was used to estimate the intake of fatty acids (saturated fatty acids (SFA), polyunsaturated fatty acids (PUFA), trans unsaturated fatty acids (TFA) and monounsaturated fatty acids (MUFA) and culinary fats (olive oil, seed oils, butter and margarine) During follow-up participants were classified as incident cases of depression if they reported a new clinical diagnosis of depression by a physician and/or initiated the use of antidepressant drugs. Cox regression models were used to calculate Hazard Ratios (HR) of incident depression and their 95% confidence intervals (CI) for successive quintiles of fats. Results: During follow-up (median: 6.1 years), 657 new cases of depression were identified. Multivariable-adjusted HR (95% CI) for depression incidence across successive quintiles of TFA intake were: 1 (ref), 1.08 (0.82-1.43), 1.17 (0.88-1.53), 1.28 (0.97-1.68), 1.42 (1.09-1.84) with a significant dose-response relationship (p for trend = 0.003). Results did not substantially change after adjusting for potential lifestyle or dietary confounders, including adherence to a Mediterranean Dietary Pattern. On the other hand, an inverse and significant dose-response relationship was obtained for MUFA (p for trend = 0.05) and PUFA (p for trend = 0.03) intake. Conclusions: A detrimental relationship was found between TFA intake and depression risk, whereas weak inverse associations were found for MUFA, PUFA and olive oil. These findings suggest that cardiovascular disease and depression may share some common nutritional determinants related to subtypes of fat intake.

Ischemic heart disease is the leading cause of mortality worldwide. Many mechanistic reasons support that a high consumption of olive oil may provide a protection against myocardial infarction, the hallmark of ischemic heart disease.

The disclosure of individual genetic results has generated an ongoing debate about which rules should be followed. We aimed to identify factors related to research participants¿ preferences about learning the results of genomic studies using their donated

Objetivo: la obtención de muestras biológicas humanas requiere el consentimiento de los donantes. En este proceso, es fundamental proporcionar una información adecuada. El objetivo de este estudio es analizar la información incluida en las hojas de información al paciente (HIP) de estudios genómicos. Método: se realizó un análisis de contenido de las HIP que recibieron los donantes de muestras para estudios genómicos. Para ello se utilizó una hoja de recogida de datos con 51 ítems. Se incluyeron HIP de protocolos de investigaciones que incluían estudios genómicos aprobados por un Comité Ético de Investigación Clínica entre 2004 y 2007. Resultados: se revisó el contenido de las HIP de 68 estudios genómicos. De éstos, 58 (85%) correspondían a investigaciones promovidas por la industria farmacéutica y a estudios internacionales. En las HIP se encontraron omisiones en la información relativa a las muestras: en menos del 50% de las HIP se hacía referencia a cuestiones como la propiedad de la muestra, el carácter gratuito de la donación o el lugar de almacenamiento. Igualmente, se detectaron frecuentes omisiones relativas a los datos genéticos como la posibilidad de comunicar los datos a familiares, el derecho a conocer los resultados genéticos o su período de almacenamiento. Conclusiones: en las HIP evaluadas se han detectado deficiencias importantes en la información sobre el manejo de las muestras y la información genética. Es necesaria una mejora sustancial del contenido de las HIP para cumplir tanto con los requisitos exigidos en la ley de investigación biomédica como con las exigencias éticas.

This international self-administered survey describes the attitudes of 279 patients, who had previously donated samples, regarding informed consent for future genomic research on donated tissue and explores factors associated with these attitudes. Most of the patients supported a fairly broad consent unless research was industry-sponsored. In multivariate analysis, support for broad informed consent was highest among neurology patients and patients who had already given a broad informed consent. There was a trend for Spaniards to be more supportive for a broad informed consent than their US counterparts. Exploring these opinions may help improve consent and explain why some patients reject broader forms of consent.