Effects of Supplemented Mediterranean Diets on Plasma-Phospholipid Fatty Acid Profiles and Risk of Cardiovascular Disease after 1 Year of Intervention in the PREDIMED Trial.

BACKGROUND: Plasma fatty acids (FAs) have been associated with cardiovascular disease (CVD) risk. Diet and endogenous metabolism influence the FA profile of the plasma phospholipid (PL) fraction. In the PREDIMED trial, we examined 1-year changes in the FA profile of plasma PL according to a nutritional intervention with Mediterranean diets, either supplemented with extra-virgin olive oil (MedDiet + EVOO) or mixed nuts (MedDiet + nuts), in a high cardiovascular risk population. We also analyzed if 1-year changes in PL FAs were associated with subsequent cardiovascular risk. METHODS: We included 779 participants in our case-cohort study: 185 incident cases and 594 participants in the subcohort (including 31 overlapping cases). The end point was the incidence of CVD. We measured the FAs of plasma PL at baseline and after 1 year of intervention. RESULTS: MedDiet + EVOO increased C17:0 and C20:3n9 in linear regression models [ß coefficientperSD : 0.215 (95% CI, 0.032-0.399) and 0.271 (0.107-0.434), respectively] and decreased 16:1n7 and C22:4n6 [ßperSD: -0.239 (95% CI, -0.416 to -0.061) and -0.287 (95% CI, -0.460 to -0.113), respectively] vs the control group. MedDiet + nuts increased C18:3n3 [ßperSD: 0.382 (95% CI, 0.225 - 0.539)], C18:2n6 [ßper SD: 0.250 (95% CI, 0.073 - 0.428)], C18:0 [ßperSD: 0.268 (95% CI, 0.085-0.452)], and C22:0 [ßper SD: 0.216 (95% CI, 0.031-0.402)]; and decreased the sum of six n6 FAs [ßper SD: -0.147 (95% CI, -0.268 to -0.027)] vs the control group. The 1-year increase in C18:2n6 was inversely associated with the subsequent CVD risk (HRperSD: 0.64 (95% CI, 0.44-0.92)). CONCLUSIONS: MedDiet interventions changed n6 FAs and C16:1n7c; other changes were specific for each group: MedDiet + EVOO increased C17:0 and C20:3n9, and MedDiet + Nuts C18:3n3, C18:2n6, C18:0, and C22:0 FAs.

Vitamin D and Risk of Obesity-Related Cancers: Results from the SUN ('Seguimiento Universidad de Navarra') Project.

Obesity is associated with a higher risk of several types of cancer, grouped as obesity-related cancers (ORC). Vitamin D deficiency is more prevalent in obese subjects, and it has been suggested to play a role in the association between obesity and cancer risk. The aim of the study was to analyze the association between vitamin D intake and the subsequent risk of ORC in a prospective Spanish cohort of university graduates. The SUN Project, initiated in 1999, is a prospective dynamic multipurpose cohort. Participants answered a 556-item lifestyle baseline questionnaire that included a validated food-frequency questionnaire. We performed Cox regression models to estimate the hazard ratios (HRs) of ORC according to quartiles of energy-adjusted vitamin D intake (diet and supplements). We included 18,017 participants (mean age = 38 years, SD = 12 years), with a median follow-up of 12 years. Among 206,783 person-years of follow-up, we identified 225 cases of ORC. We found no significant associations between vitamin D intake and ORC risk after adjusting for potential confounders: HRQ2vsQ1 = 1.19 (95% CI 0.81-1.75), HRQ3vsQ1 = 1.20 (95% CI 0.81-1.78), and HRQ4vsQ1 = 1.02 (95% CI 0.69-1.51). Dietary and supplemented vitamin D do not seem to be associated with ORC prevention in the middle-aged Spanish population.

Plasma acylcarnitines and risk of incident heart failure and atrial fibrillation: the Prevención con dieta mediterránea study.

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 Prevención con dieta mediterránea (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/m2), and type 2 diabetes. RESULTS: Elevated levels of medium- and long-chain acylcarnitines were associated with increased HF risk (adjusted ORperDE, 1.28; 95%CI, 1.09-1.51 and adjusted ORperDE, 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. This trial was registered at controlled-trials.com (Identifier: ISRCTN35739639).

Circulating Amino Acids and Risk of Peripheral Artery Disease in the PREDIMED Trial.

Effective prevention and risk prediction are important for peripheral artery disease (PAD) due to its poor prognosis and the huge disease burden it produces. Circulating amino acids (AA) and their metabolites may serve as biomarkers of PAD risk, but they have been scarcely investigated. The objective was to prospectively analyze the associations of baseline levels of plasma AA (and their pathways) with subsequent risk of PAD and the potential effect modification by a nutritional intervention with the Mediterranean diet (MedDiet). A matched case-control study was nested in the PREDIMED trial, in which participants were randomized to three arms: MedDiet with tree nut supplementation group, MedDiet with extra-virgin olive oil (EVOO) supplementation group or control group (low-fat diet). One hundred and sixty-seven PAD cases were matched with 250 controls. Plasma AA was measured with liquid chromatography/mass spectrometry at the Broad Institute. Baseline tryptophan, serine and threonine were inversely associated with PAD (ORfor 1 SD increase = 0.78 (0.61-0.99); 0.67 (0.51-0.86) and 0.75 (0.59-0.95), respectively) in a multivariable-adjusted conditional logistic regression model. The kynurenine/tryptophan ratio was directly associated with PAD (ORfor 1 SD increase = 1.50 (1.14-1.98)). The nutritional intervention with the MedDiet+nuts modified the association between threonine and PAD (p-value interaction = 0.018) compared with the control group. However, subjects allocated to the MedDiet+EVOO group were protected against PAD independently of baseline threonine. Plasma tryptophan, kynurenine/tryptophan ratio, serine and threonine might serve as early biomarkers of future PAD in subjects at a high risk of cardiovascular disease. The MedDiet supplemented with EVOO exerted a protective effect, regardless of baseline levels of threonine.

Dietary vitamin D intake and colorectal cancer risk: a longitudinal approach within the PREDIMED study.

PURPOSE: We evaluated whether the intake of dietary vitamin D is associated with the incidence of both colorectal cancer (CRC) and colon cancer in the framework of the PREDIMED cohort of older adults at high cardiovascular risk. METHODS: We analyzed data from 7216 men and women (55-80 years) without CRC at baseline from the PREvención con DIeta MEDiterránea study. Baseline consumption of vitamin D was assessed using a validated 137-item food frequency questionnaire. Cox proportional hazards ratios (HRs) of CRC and colon cancer incidence were estimated for quartiles and per 1-SD of baseline vitamin D intake. RESULTS: During a median follow-up of 6 years, we documented 97 incident CRC cases after the exclusion of subjects with no baseline dietary data and/or outliers of energy intake. A non-significant HRs and 95% confidence intervals (CIs) of CRC for the comparison of extreme quartiles (4th vs 1st) of vitamin D intake were observed [0.55 (0.30-1.00), P for trend = 0.072], whereas it was significant for colon cancer incidence alone [0.44 (0.22-0.90), P for trend = 0.032]. However, this association became significant in CRC and colon cancer incidence, after excluding 391 subjects consuming baseline vitamin D and/or calcium medication or prescribed supplements [0.52 (0.28-0.96) and 0.41 (0.12-0.85), respectively]. CONCLUSION: A higher dietary intake of vitamin D was significantly associated with a reduced CRC risk in individuals at high cardiovascular risk.

Consumption of caffeinated beverages and kidney function decline in an elderly Mediterranean population with metabolic syndrome.

It remains unclear whether caffeinated beverages could have deleterious renal effects in elderly population with underlying comorbid conditions. We investigated the associations between coffee, tea, or caffeine intake and 1-year changes in glomerular filtration rate (eGFR) in a large Spanish cohort of overweight/obese elderly with metabolic syndrome (MetS). This prospective analysis includes 5851 overweight/obese adults (55-75 years) with MetS from the PREDIMED-Plus study. We assessed coffee, tea, and caffeine consumption from a validated food-frequency questionnaire and creatinine-based eGFR using the Chronic Kidney Disease Epidemiology Collaboration equation. Multivariate-adjusted regression models were applied to test associations between baseline coffee, tea, or caffeine intake and 1-year eGFR changes. Caffeinated coffee (> 2 cups/day) and tea (at least 1 cup/day) drinkers had 0.88 and 0.93 mL/min/1.73 m2 greater eGFR decrease respectively, compared to those with less than 1 cup/day of coffee consumption or non-tea drinkers. Furthermore, caffeinated coffee consumption of > 2 cups/day was associated with 1.19-fold increased risk of rapid eGFR decline > 3 mL/min/1.73 m2 (95% CI 1.01-1.41). Similarly, individuals in the highest (median, 51.2 mg/day) tertile of caffeine intake had a 0.87 mL/min/1.73 m2 greater eGFR decrease. Decaffeinated coffee was not associated with eGFR changes. In conclusion, higher consumption of caffeinated coffee, tea, and caffeine was associated with a greater 1-year eGFR decline in overweight/obese adults with MetS.

Dietary calcium, vitamin D, and breast cancer risk in women: findings from the SUN cohort.

PURPOSE: Epidemiological evidence concerning the relationship between calcium and vitamin D intake and breast cancer (BC) is inconclusive. Moreover, the association according to menopausal status remains unclear. We aimed to assess whether total intakes from dietary and supplemental sources of calcium and vitamin D were associated with the incidence of BC in a Mediterranean cohort. METHODS: We prospectively evaluated the association between intakes of calcium and vitamin D and BC risk among 10,812 women in the Seguimiento Universidad de Navarra (SUN) Project, a Spanish cohort of university graduates. RESULTS: During a mean follow-up of 10.7 years, 101 incident BC cases were confirmed. Evidence of a non-linear association between total calcium intake and BC risk was found (Pnon-linearity = 0.011) with risk reductions associated with higher intake up to approximately 1400 mg/day. Moderate intake [Tertile 2 (T2)] of total calcium was associated with lower overall BC risk [HR for T2 vs. Tertile 1 (T1): 0.55; 95% CI 0.33-0.91] and also among postmenopausal women (HRT2 vs. T1 = 0.38; 95% CI 0.16-0.92). Intake of vitamin D was not associated with BC risk. CONCLUSIONS: Our findings suggest an L-shaped association between total calcium intake and BC incidence. Moderate calcium intake may be associated with lower BC risk among overall and postmenopausal women, but not among premenopausal women. No evidence for any association between vitamin D intake and BC was found. Adherence to current guidelines recommendations for calcium intake may help to reduce BC risk.

Association of calprotectin with other inflammatory parameters in the prediction of mortality for ischemic stroke.

BACKGROUND: Inflammatory response plays an important role in many processes related to acute ischemic stroke (AIS). Calprotectin (S100A8/S100A9), released by monocytes and neutrophils, is a key protein in the regulation of inflammation and thrombosis. The purpose of this study is to evaluate the association of circulating calprotectin with other inflammatory biomarkers and AIS prognosis, as well as the calprotectin content in stroke thrombi. METHODS: Among the 748 patients treated at a comprehensive stroke center between 2015 and 2017, 413 patients with confirmed acute ischemic injury were prospectively evaluated. Patients with systemic inflammation or infection at onset were excluded. Plasma calprotectin was measured by ELISA in blood samples of AIS patients within the first 24 h. Univariate and multivariate logistic regression models were performed to evaluate its association with mortality and functional independence (FI) at 3 months (defined as modified Rankin Scale < 3) and hemorrhagic transformation (HT) after ischemic stroke. Further, S100A9 was localized by immunostaining in stroke thrombi (n = 44). RESULTS: Higher calprotectin levels were associated with 3-month mortality, HT, and lower 3-month FI. After adjusting for potential confounders, plasma calprotectin remained associated with 3-month mortality [OR (95% CI) 2.31 (1.13-4.73)]. Patients with calprotectin ≥ 2.26 µg/mL were 4 times more likely to die [OR 4.34 (1.95-9.67)]. Addition of calprotectin to clinical variables led to significant improvement in the discrimination capacity of the model [0.91 (0.87-0.95) vs 0.89 (0.85-0.93); p < 0.05]. A multimarker approach demonstrated that patients with increased calprotectin, CRP, and NLR had the poorest outcome with a mortality rate of 42.3% during follow-up. S100A9 protein, as part of the heterodimer calprotectin, was present in all thrombi retrieved from AIS patients. Mean S100A9 content was 3.5% and tended to be higher in patients who died (p = 0.09). Moreover, it positively correlated with platelets (Pearson r 0.46, p < 0.002), leukocytes (0.45, p < 0.01), and neutrophil elastase (0.70, p < 0.001) thrombus content. CONCLUSIONS: Plasma calprotectin is an independent predictor of 3-month mortality and provides complementary prognostic information to identify patients with poor outcome after AIS. The presence of S100A9 in stroke thrombi suggests a possible inflammatory mechanism in clot formation, and further studies are needed to determine its influence in resistance to reperfusion.

Association between coffee consumption and total dietary caffeine intake with cognitive functioning: cross-sectional assessment in an elderly Mediterranean population.

PURPOSE: Coffee is rich in compounds such as polyphenols, caffeine, diterpenes, melanoidins and trigonelline, which can stimulate brain activity. Therefore, the possible association of coffee consumption with cognition is of considerable research interest. In this paper, we assess the association of coffee consumption and total dietary caffeine intake with the risk of poor cognitive functioning in a population of elderly overweight/obese adults with metabolic syndrome (MetS). METHODS: PREDIMED-plus study participants who completed the Mini-Mental State Examination test (MMSE) (n = 6427; mean age = 65 ± 5 years) or a battery of neuropsychological tests were included in this cross-sectional analysis. Coffee consumption and total dietary caffeine intake were assessed at baseline using a food frequency questionnaire. Logistic regression models were fitted to evaluate the association between total, caffeinated and decaffeinated coffee consumption or total dietary caffeine intake and cognitive impairment. RESULTS: Total coffee consumers and caffeinated coffee consumers had better cognitive functioning than non-consumers when measured by the MMSE and after adjusting for potential confounders (OR 0.63; 95% CI 0.44-0.90 and OR 0.56; 95% CI 0.38-0.83, respectively). Results were similar when cognitive performance was measured using the Clock Drawing Test (CDT) and Trail Making Test B (TMT-B). These associations were not observed for decaffeinated coffee consumption. Participants in the highest tertile of total dietary caffeine intake had lower odds of poor cognitive functioning than those in the reference tertile when screened by the MMSE (OR 0.64; 95% CI 0.47-0.87) or other neurophysiological tests evaluating a variety of cognitive domains (i.e., CDT and TMT-A). CONCLUSIONS: Coffee consumption and total dietary caffeine intake were associated with better cognitive functioning as measured by various neuropsychological tests in a Mediterranean cohort of elderly individuals with MetS. TRIAL REGISTRATION: ISRCTN89898870. Registration date: July 24, 2014.

Relationship between olive oil consumption and ankle-brachial pressure index in a population at high cardiovascular risk.

BACKGROUND AND AIMS: The aim of this study was to ascertain the association between the consumption of different categories of edible olive oils (virgin olive oils and olive oil) and olive pomace oil and ankle-brachial pressure index (ABI) in participants in the PREDIMED-Plus study, a trial of lifestyle modification for weight and cardiovascular event reduction in individuals with overweight/obesity harboring the metabolic syndrome. METHODS: We performed a cross-sectional analysis of the PREDIMED-Plus trial. Consumption of any category of olive oil and olive pomace oil was assessed through a validated food-frequency questionnaire. Multivariable linear regression models were fitted to assess associations between olive oil consumption and ABI. Additionally, ABI ≤1 was considered as the outcome in logistic models with different categories of olive oil and olive pomace oil as exposure. RESULTS: Among 4330 participants, the highest quintile of total olive oil consumption (sum of all categories of olive oil and olive pomace oil) was associated with higher mean values of ABI (beta coefficient: 0.014, 95% confidence interval [CI]: 0.002, 0.027) (p for trend = 0.010). Logistic models comparing the consumption of different categories of olive oils, olive pomace oil and ABI ≤1 values revealed an inverse association between virgin olive oils consumption and the likelihood of a low ABI (odds ratio [OR] 0.73, 95% CI [0.56, 0.97]), while consumption of olive pomace oil was positively associated with a low ABI (OR 1.22 95% CI [1.00, 1.48]). CONCLUSIONS: In a Mediterranean population at high cardiovascular risk, total olive oil consumption was associated with a higher mean ABI. These results suggest that olive oil consumption may be beneficial for peripheral artery disease prevention, but longitudinal studies are needed.

Phenolic Acid Subclasses, Individual Compounds, and Breast Cancer Risk in a Mediterranean Cohort: The SUN Project.

BACKGROUND: Biological and epidemiological evidence supports an inverse association of phenolic acids with obesity-related chronic diseases. However, no previous study has prospectively evaluated the relationship between subclasses and individual compounds of phenolic acids and the risk of postmenopausal breast cancer, one of the most important and prevalent obesity-related cancer sites. OBJECTIVE: This study examined associations between subclasses of phenolic acids, including hydroxycinnamic and hydroxybenzoic acids intake, and risk of breast cancer. DESIGN: The Seguimiento Universidad de Navarra (SUN) Project is a dynamic, permanently open prospective cohort which started in 1999. PARTICIPANTS/SETTING: Participants were 10,812 middle-aged women. All of them were university graduates. MAIN OUTCOME MEASURES: Usual diet was assessed at baseline and after 10 years of follow-up with a 136-item food frequency questionnaire. Phenolic acid intake was calculated by matching food consumption with the Phenol-Explorer database on phenolic acids content of each reported food item. STATISTICAL ANALYSIS PERFORMED: Participants were classified according to tertiles of subclasses or individual compounds of phenolic acids. Cox regression models were fitted to estimate multivariable-adjusted hazard ratios and 95% CIs for breast cancer incidence. RESULTS: Over an average of 11.8 years of follow-up, 101 incident cases of breast cancer were confirmed. After multivariable adjustment, an inverse association between hydroxycinnamic acids intake and breast cancer was observed (hazard ratio third tertile vs first tertile 0.37, 95% CI 0.16 to 0.85; P for trend=0.029) among postmenopausal women. Specifically, chlorogenic acids (3-, 4-, and 5- caffeoylquinic acids) showed the strongest inverse association (hazard ratio third tertile vs first tertile 0.33, 95% CI 0.14 to 0.78; P for trend=0.012). CONCLUSIONS: A higher intake of hydroxycinnamic acids, especially from chlorogenic acids-present in coffee, fruits, and vegetables-was associated with a lower incidence of breast cancer among postmenopausal women. Future observational studies are needed to corroborate these results.

Coffee consumption and breast cancer risk in the SUN project.

INTRODUCTION: Breast cancer prevalence is growing worldwide. Many factors, such as diet and lifestyle could be determinants of the incidence of breast cancer. Coffee has been extensively studied in relation to several chronic diseases because of its multiple effects in health maintenance and its elevated consumption. We studied the relationship between coffee intake and breast cancer risk in the SUN (Seguimiento Universidad de Navarra) prospective cohort. MATERIALS AND METHODS: We evaluated 10,812 middle-aged, Spanish female university graduates from the SUN Project, initially free of breast cancer. Coffee consumption was assessed with a 136-item validated food-frequency questionnaire (FFQ). Incident breast cancer cases were confirmed by a trained oncologist using medical records and by consultation of the National Death Index. We fitted Cox regression models to assess the relationship between baseline categories of coffee consumption and the incidence of breast cancer during follow-up. We stratified the analysis by menopausal status. RESULTS: During 115,802 person-years of follow-up, 101 new cases of breast cancer were confirmed. Among postmenopausal women, more than 1 cup of coffee per day was associated with a lower incidence of breast cancer (HR 0.44; 95% confidence interval: 0.21, 0.92) in the fully adjusted model, compared to women who consumed one cup of coffee or less per day. We observed no significant differences in regard to premenopausal women. CONCLUSION: Even though the number of cases was low, slight indications of an inverse association between coffee consumption and breast cancer risk among postmenopausal women were observed. Further longitudinal studies are warranted to confirm this finding.

Plasma Metabolites Associated with Coffee Consumption: A Metabolomic Approach within the PREDIMED Study.

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.

Naturally Lignan-Rich Foods: A Dietary Tool for Health Promotion?

Dietary guidelines universally advise adherence to plant-based diets. Plant-based foods confer considerable health benefits, partly attributable to their abundant micronutrient (e.g., polyphenol) content. Interest in polyphenols is largely focused on the contribution of their antioxidant activity to the prevention of various disorders, including cardiovascular disease and cancer. Polyphenols are classified into groups, such as stilbenes, flavonoids, phenolic acids, lignans and others. Lignans, which possess a steroid-like chemical structure and are defined as phytoestrogens, are of particular interest to researchers. Traditionally, health benefits attributed to lignans have included a lowered risk of heart disease, menopausal symptoms, osteoporosis and breast cancer. However, the intake of naturally lignan-rich foods varies with the type of diet. Consequently, based on the latest humans' findings and gathered information on lignan-rich foods collected from Phenol Explorer database this review focuses on the potential health benefits attributable to the consumption of different diets containing naturally lignan-rich foods. Current evidence highlight the bioactive properties of lignans as human health-promoting molecules. Thus, dietary intake of lignan-rich foods could be a useful way to bolster the prevention of chronic illness, such as certain types of cancers and cardiovascular disease.

Coffee consumption and total mortality in a Mediterranean prospective cohort.

Background: The relation of coffee consumption with total mortality is controversial, because the available evidence is still inconsistent. Objective: This study aimed to assess this association in a highly educated, middle-aged Mediterranean cohort. Design: We analyzed data from 201,055 person-years of follow-up arising from 19,888 participants. Coffee consumption was obtained at baseline with the use of a previously validated semiquantitative food-frequency questionnaire. Information on mortality was ascertained by permanent contact with the "Seguimiento Universidad de Navarra" (SUN) participants and their families, postal authorities, and consultation of the National Death Index. We used Cox regression models to estimate HRs and 95% CIs for mortality according to baseline total coffee consumption adjusted for potential confounders. Sex, age, and baseline adherence to the Mediterranean diet were considered as potential effect modifiers. Results: Among the 19,888 participants, 337 died. Overall, in the multivariable adjusted analysis, we found a 22% lower risk of all-cause mortality for each 2 additional cups of total coffee per day (HR: 0.78; 95% CI: 0.66, 0.93). This association was stronger for participants aged ≥55 y (HR: 0.67; 95% CI: 0.52, 0.86) than for younger participants, who showed no significant association (P-interaction = 0.002). Conclusion: In a Mediterranean cohort, we found an inverse linear association between total coffee consumption and the risk of all-cause mortality that was strongest among participants older than 54 y.

Squalene Stimulates a Key Innate Immune Cell to Foster Wound Healing and Tissue Repair.

Anti-inflammatory effects of virgin olive oil (VOO) have been described recently, along with its wound healing effect. One of the main minor compounds found in VOO is squalene (SQ), which also possesses preventive effects against skin damage and anti-inflammatory properties. The inflammatory response is involved in wound healing and manages the whole process by macrophages, among others, as the main innate cells with a critical role in the promotion and resolution of inflammation for tissue repair. Because of that, this work is claimed to describe the role that squalene exerts in the immunomodulation of M1 proinflammatory macrophages, which are the first cells implicate in recent injuries. Pro- and anti-inflammatory cytokines were analysed using TPH1 cell experimental model. SQ induced an increase in the synthesis of anti-inflammatory cytokines, such as IL-10, IL-13, and IL-4, and a decrease in proinflammatory signals, such as TNF-α and NF-κB in M1 proinflammatory macrophages. Furthermore, SQ enhanced remodelling and repairing signals (TIMP-2) and recruitment signals of eosinophils and neutrophils, responsible for phagocytosis processes. These results suggest that SQ is able to promote wound healing by driving macrophage response in inflammation. Therefore, squalene could be useful at the resolution stage of wound healing.

Coffee Consumption and the Risk of Depression in a Middle-Aged Cohort: The SUN Project.

Coffee is one of the most widely consumed drinks around the world, while depression is considered the major contributor to the overall global burden of disease. However, the investigation on coffee consumption and depression is limited and results may be confounded by the overall dietary pattern. We assessed the relationship between coffee intake and the risk of depression, controlling for adherence to the Mediterranean diet. We studied 14,413 university graduates of the 'Seguimiento Universidad de Navarra' (SUN) cohort, initially free of depression. We evaluated coffee consumption using a validated food-frequency questionnaire (FFQ). Incident depression cases were adjudicated only if the participant met two criteria simultaneously: (a) validated physician-diagnosed depression together with (b) new onset of habitual antidepressant use. Both criteria were needed; participants meeting only one of them were not classified as cases. Participants who drank at least four cups of coffee per day showed a significantly lower risk of depression than participants who drank less than one cup of coffee per day (HR: 0.37 (95% CI 0.15⁻0.95)). However, overall, we did not observe an inverse linear dose⁻response association between coffee consumption and the incidence of depression (p for trend = 0.22).

Potato Consumption Does Not Increase Blood Pressure or Incident Hypertension in 2 Cohorts of Spanish Adults.

Background: Potatoes have a high glycemic load but also antioxidants, vitamins, and minerals. It is unclear what mechanisms are involved in relation to their effect on blood pressure (BP) and hypertension.Objectives: This study aimed to assess the association between potato consumption, BP changes, and the risk of hypertension in 2 Spanish populations.Methods: Separate analyses were performed in PREDIMED (PREvención con DIeta MEDiterránea), a multicenter nutrition intervention trial of adults aged 55-80 y, and the SUN (Seguimiento Universidad de Navarra) project, a prospective cohort made up of university graduates and educated adults with ages (means ± SDs) of 42.7 ± 13.3 y for men and 35.1 ± 10.7 y for women. In PREDIMED, generalized estimating equations adjusted for lifestyle and dietary characteristics were used to assess changes in BP across quintiles of total potato consumption during a 4-y follow-up. Controlled BP values (systolic BP <140 mm Hg and diastolic BP <90 mm Hg) during follow-up were also assessed. For SUN, multivariate-adjusted HRs for incident hypertension during a mean 6.7-y follow-up were calculated.Results: In PREDIMED, the total potato intake was 81.9 ± 40.6 g/d. No overall differences in systolic or diastolic BP changes were detected based on consumption of potatoes. For total potatoes, the mean difference in change between quintile 5 (highest intake) and quintile 1 (lowest intake) in systolic BP after multivariate adjustment was -0.90 mm Hg (95% CI: -2.56, 0.76 mm Hg; P-trend = 0.1) and for diastolic BP was -0.02 mm Hg (95% CI: -0.93, 0.89 mm Hg; P-trend = 0.8). In SUN, the total potato consumption was 52.7 ± 33.6 g/d, and no significant association between potato consumption and hypertension incidence was observed in the fully adjusted HR for total potato consumption (quintile 5 compared with quintile 1: 0.98; 95% CI: 0.80, 1.19; P-trend = 0.8).Conclusions: Potato consumption is not associated with changes over 4 y in blood pressure among older adults in Spain or with the risk of hypertension among Spanish adults. This trial was registered at www.controlled-trials.com as ISRCTN35739639.

Plasma lipidomic profiles and cardiovascular events in a randomized intervention trial with the Mediterranean diet.

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 (PREvención con DIeta MEDiterránea) 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.

Dietary Marine ω-3 Fatty Acids and Incident Sight-Threatening Retinopathy in Middle-Aged and Older Individuals With Type 2 Diabetes: Prospective Investigation From the PREDIMED Trial.

IMPORTANCE: Diabetic retinopathy (DR) is a devastating complication of individuals with type 2 diabetes mellitus. The retina is rich in long-chain ω-3 polyunsaturated fatty acids (LCω3PUFAs), which are substrate for oxylipins with anti-inflammatory and antiangiogenic properties. Experimental models support dietary LCω3PUFA protection against DR, but clinical data are lacking. OBJECTIVE: To determine whether LCω3PUFA intake relates to a decreased incidence of sight-threatening DR in individuals with type 2 diabetes older than 55 years. DESIGN, SETTING, AND PARTICIPANTS: In late 2015, we conceived a prospective study within the randomized clinical trial Prevención con Dieta Mediterránea (PREDIMED), testing Mediterranean diets supplemented with extra virgin olive oil or nuts vs a control diet for primary cardiovascular prevention. The trial was conducted in primary health care centers in Spain. From 2003 to 2009, 3614 individuals aged 55 to 80 years with a previous diagnosis of type 2 diabetes were recruited. Full data were available for 3482 participants (48% men; mean age 67 years). EXPOSURES: Meeting the dietary LCω3PUFA recommendation of at least 500 mg/d for primary cardiovascular prevention, as assessed by a validated food-frequency questionnaire. MAIN OUTCOMES AND MEASURES: The main outcome was incident DR requiring laser photocoagulation, vitrectomy, and/or antiangiogenic therapy confirmed by an external adjudication committee. RESULTS: Of the 3482 participants, 48% were men and the mean age was 67 years. A total of 2611 participants (75%) met target LCω3PUFA recommendation. During a median follow-up of 6 years, we documented 69 new events. After adjusting for age, sex, intervention group, and lifestyle and clinical variables, participants meeting the LCω3PUFA recommendation at baseline (≥500 mg/d) compared with those not fulfilling this recommendation (<500 mg/d) showed a 48% relatively reduced risk of incident sight-threatening DR, with a hazard ratio of 0.52 (95% CI, 0.31-0.88; P = .001). This association was slightly stronger for yearly updated LCω3PUFA intake (relative risk, 0.48; 95% CI, 0.28-0.82; P = .007). CONCLUSIONS AND RELEVANCE: In middle-aged and older individuals with type 2 diabetes, intake of at least 500 mg/d of dietary LCω3PUFA, easily achievable with 2 weekly servings of oily fish, is associated with a decreased risk of sight-threatening DR. Our results concur with findings from experimental models and the current model of DR pathogenesis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: http://www.controlled-trials.com/ISRCTN35739639.