Plasma metabolite profile of legume consumption and future risk of type 2 diabetes and cardiovascular disease.

BACKGROUND: Legume consumption has been linked to a reduced risk of type 2 diabetes (T2D) and cardiovascular disease (CVD), while the potential association between plasma metabolites associated with legume consumption and the risk of cardiometabolic diseases has never been explored. Therefore, we aimed to identify a metabolite signature of legume consumption, and subsequently investigate its potential association with the incidence of T2D and CVD. METHODS: The current cross-sectional and longitudinal analysis was conducted in 1833 PREDIMED study participants (mean age 67 years, 57.6% women) with available baseline metabolomic data. A subset of these participants with 1-year follow-up metabolomics data (n = 1522) was used for internal validation. Plasma metabolites were assessed through liquid chromatography-tandem mass spectrometry. Cross-sectional associations between 382 different known metabolites and legume consumption were performed using elastic net regression. Associations between the identified metabolite profile and incident T2D and CVD were estimated using multivariable Cox regression models. RESULTS: Specific metabolic signatures of legume consumption were identified, these included amino acids, cortisol, and various classes of lipid metabolites including diacylglycerols, triacylglycerols, plasmalogens, sphingomyelins and other metabolites. Among these identified metabolites, 22 were negatively and 18 were positively associated with legume consumption. After adjustment for recognized risk factors and legume consumption, the identified legume metabolite profile was inversely associated with T2D incidence (hazard ratio (HR) per 1 SD: 0.75, 95% CI 0.61-0.94; p = 0.017), but not with CVD incidence risk (1.01, 95% CI 0.86-1.19; p = 0.817) over the follow-up period. CONCLUSIONS: This study identified a set of 40 metabolites associated with legume consumption and with a reduced risk of T2D development in a Mediterranean population at high risk of cardiovascular disease. TRIAL REGISTRATION: ISRCTN35739639.

A Walnut-Enriched Diet for 2 Years Changes the Serum Oxylipin Profile in Healthy Older Persons.

BACKGROUND: Oxylipins are products derived from polyunsaturated fatty acids (PUFAs) that play a role in cardiovascular disease and aging. Fish oil-derived n-3 PUFAs promote the formation of anti-inflammatory and vasodilatory oxylipins; however, there are little data on oxylipins derived from α-linolenic acid (C18:3n-3), the primary plant-derived n-3 PUFA. Walnuts are a source of C18:3n-3. OBJECTIVES: To investigate the effect on serum oxylipins of a diet enriched with walnuts at 15% energy (30-60 g/d; 2.6-5.2 g C18:3n-3/d) for 2 y compared to a control diet (abstention from walnuts) in healthy older males and females (63-79 y). METHODS: The red blood cell proportion of α-linolenic acid was determined by gas chromatography as a measure of compliance. Ultra-performance liquid chromatography-tandem mass spectrometry was used to measure serum concentrations of 53 oxylipins in participants randomly assigned to receive the walnut diet (n = 64) or the control diet (n = 51). Two-year concentration changes (final minus baseline) were log-transformed (base log-10) and standardized (mean-centered and divided by the standard deviation of each variable). Volcano plots were then generated (fold change ≥1.5; false discovery rate ≤0.1). For each oxylipin delta surviving multiple testing, we further assessed between-intervention group differences by analysis of covariance adjusting for age, sex, BMI, and the baseline concentration of the oxylipin. RESULTS: The 2-y change in red blood cell C18:3n-3 in the walnut group was significantly higher than that in the control group (P < 0.001). Compared to the control diet, the walnut diet resulted in statistically significantly greater increases in 3 C18:3n-3-derived oxylipins (9-HOTrE, 13-HOTrE, and 12,13-EpODE) and in the C20:5n-3 derived 14,15-diHETE, and greater reductions of the C20:4n-6-derived 5-HETE, 19-HETE, and 5,6-diHETrE. CONCLUSIONS: Long-term walnut consumption changes the serum oxylipin profile in healthy older persons. Our results add novel mechanistic evidence on the cardioprotective effects of walnuts. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01634841.

Coronavirus disease 2019 is associated with long-term depressive symptoms in Spanish older adults with overweight/obesity and metabolic syndrome.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has serious physiological and psychological consequences. The long-term (>12 weeks post-infection) impact of COVID-19 on mental health, specifically in older adults, is unclear. We longitudinally assessed the association of COVID-19 with depression symptomatology in community-dwelling older adults with metabolic syndrome within the framework of the PREDIMED-Plus cohort. METHODS: Participants (n = 5486) aged 55-75 years were included in this longitudinal cohort. COVID-19 status (positive/negative) determined by tests (e.g. polymerase chain reaction severe acute respiratory syndrome coronavirus 2, IgG) was confirmed via event adjudication (410 cases). Pre- and post-COVID-19 depressive symptomatology was ascertained from annual assessments conducted using a validated 21-item Spanish Beck Depression Inventory-II (BDI-II). Multivariable linear and logistic regression models assessed the association between COVID-19 and depression symptomatology. RESULTS: COVID-19 in older adults was associated with higher post-COVID-19 BDI-II scores measured at a median (interquartile range) of 29 (15-40) weeks post-infection [fully adjusted ß = 0.65 points, 95% confidence interval (CI) 0.15-1.15; p = 0.011]. This association was particularly prominent in women (ß = 1.38 points, 95% CI 0.44-2.33, p = 0.004). COVID-19 was associated with 62% increased odds of elevated depression risk (BDI-II ≥ 14) post-COVID-19 when adjusted for confounders (odds ratio; 95% CI 1.13-2.30, p = 0.008). CONCLUSIONS: COVID-19 was associated with long-term depression risk in older adults with overweight/obesity and metabolic syndrome, particularly in women. Thus, long-term evaluations of the impact of COVID-19 on mental health and preventive public health initiatives are warranted in older adults.

Relationship between sex, APOE genotype, endocannabinoids and cognitive change in older adults with metabolic syndrome during a 3-year Mediterranean diet intervention.

BACKGROUND: The Mediterranean diet (MedDiet) has demonstrated efficacy in preventing age-related cognitive decline and modulating plasma concentrations of endocannabinoids (eCBs) and N-acylethanolamines (NAEs, or eCB-like compounds), which are lipid mediators involved in multiple neurological disorders and metabolic processes. Hypothesizing that eCBs and NAEs will be biomarkers of a MedDiet intervention and will be related to the cognitive response, we investigated this relationship according to sex and apolipoprotein E (APOE) genotype, which may affect eCBs and cognitive performance. METHODS: This was a prospective cohort study of 102 participants (53.9% women, 18.8% APOE-ɛ4 carriers, aged 65.6 ± 4.5 years) from the PREDIMED-Plus-Cognition substudy, who were recruited at the Hospital del Mar Research Institute (Barcelona). All of them presented metabolic syndrome plus overweight/obesity (inclusion criteria of the PREDIMED-Plus) and normal cognitive performance at baseline (inclusion criteria of this substudy). A comprehensive battery of neuropsychological tests was administered at baseline and after 1 and 3 years. Plasma concentrations of eCBs and NAEs, including 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and N-docosahexaenoylethanolamine (DHEA), were also monitored. Baseline cognition, cognitive changes, and the association between eCBs/NAEs and cognition were evaluated according to gender (crude models), sex (adjusted models), and APOE genotype. RESULTS: At baseline, men had better executive function and global cognition than women (the effect size of gender differences was - 0.49, p = 0.015; and - 0.42, p = 0.036); however, these differences became nonsignificant in models of sex differences. After 3 years of MedDiet intervention, participants exhibited modest improvements in memory and global cognition. However, greater memory changes were observed in men than in women (Cohen's d of 0.40 vs. 0.25; p = 0.017). In men and APOE-ε4 carriers, 2-AG concentrations were inversely associated with baseline cognition and cognitive changes, while in women, cognitive changes were positively linked to changes in DHEA and the DHEA/AEA ratio. In men, changes in the OEA/AEA and OEA/PEA ratios were positively associated with cognitive changes. CONCLUSIONS: The MedDiet improved participants' cognitive performance but the effect size was small and negatively influenced by female sex. Changes in 2-AG, DHEA, the OEA/AEA, the OEA/PEA and the DHEA/AEA ratios were associated with cognitive changes in a sex- and APOE-dependent fashion. These results support the modulation of the endocannabinoid system as a potential therapeutic approach to prevent cognitive decline in at-risk populations. TRIAL REGISTRATION: ISRCTN89898870.

The Impact of the Mediterranean Diet and Lifestyle Intervention on Lipoprotein Subclass Profiles among Metabolic Syndrome Patients: Findings of a Randomized Controlled Trial.

Metabolic syndrome (MetS) is associated with alterations of lipoprotein structure and function that can be characterized with advanced lipoprotein testing (ADLT). The effect of the Mediterranean diet (MedDiet) and weight loss on the lipoprotein subclass profile has been scarcely studied. Within the PREDIMED-Plus randomized controlled trial, a sub-study conducted at Bellvitge Hospital recruiting center evaluated the effects of a weight loss program based on an energy-reduced MedDiet (er-MedDiet) and physical activity (PA) promotion (intervention group) compared with energy-unrestricted MedDiet recommendations (control group) on ADLT-assessed lipoprotein subclasses. 202 patients with MetS (n = 107, intervention; n = 95, control) were included. Lipid profiles were determined, and ADLT was performed at baseline, 6, and 12 months. Linear mixed models were used to assess the effects of intervention on lipoprotein profiles. Compared to the control diet, at 12 months, the er-MedDiet+PA resulted in a significant additional 4.2 kg of body weight loss, a decrease in body mass index by 1.4 kg/m2, reduction in waist circumference by 2.2 cm, decreased triglycerides, LDL-cholesterol and non-HDL-cholesterol, and increased HDL-cholesterol. In er-MedDiet+PA participants, ADLT revealed a decrease in small dense-LDL-cholesterol (sd-LDL-C), intermediate-density lipoproteins, VLDL-triglyceride, and HDL-Triglyceride, and an increase in large LDL and large VLDL particles. In conclusion, compared to an ad libitum MedDiet (control group), er-MedDiet+PA decreased plasma triglycerides and the triglyceride content in HDL and VLDL particles, decreased sd-LDL-C, and increased large LDL particles, indicating beneficial changes against cardiovascular disease.

Higher circulating vitamin B12 is associated with lower levels of inflammatory markers in individuals at high cardiovascular risk and in naturally aged mice.

BACKGROUND: Vitamin B12 is an essential nutrient that is involved in numerous physiological processes, and its deficiency can lead to various complications, including neurological and haematological disorders. Some studies have suggested that vitamin B12 may have anti-inflammatory effects, but the mechanisms underlying this relationship are not yet fully understood. We investigated the relationship between circulating vitamin B12 and inflammatory markers interleukin (IL)-6 and C-reactive protein (CRP). The association of peripheral levels of vitamin B12 with IL-6 and CRP was assessed in 136 human samples from a high cardiovascular risk population. To corroborate the results from the human trial, the analysis was replicated in naturally aged mice. RESULTS: Individuals with higher serum levels of vitamin B12 showed lower concentrations of IL-6 and CRP after adjustment for potential confounders, and an inverse association was also found between serum IL-6 and vitamin B12 levels in naturally aged mice. CONCLUSION: Circulating vitamin B12 was inversely associated with IL-6 and CRP in humans and with IL-6 in mice, suggesting that it may exert an anti-inflammatory effect through modulation of these pro-inflammatory molecules. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Cytomegalovirus infection as a rare cause of colitis.

A 62 year-old-man with low anterior rectal resection and protective ileostomy, for low rectal neo and neoadjuvant QT +RT. Then ileostomy closure without incidences. On the 3rd postoperative day, he started with fever peaks and diarrhea. An abdominal CT scan showed diffuse thickening of the wall of the descending colon compatible with colitis and colonoscopy showed deep rectal ulcers with punch-like morphology with hyperemic mucosa with erythematous stippling of erosive appearance, showing this ulcerative pattern with numerous lesions and intensely edematous and congestive mucosa covered with abundant fibrinopurulent exudate in the descending colon. Biopsies and stool cultures were negative, but serologies were positive for CMV. Suspected CMV infection in a immunosuppressed by chemotherapy patient, he was treated with ganciclovir. The patient presented clinical improvement, without fever or diarrhea and improvement of the punch ulcers in the endoscopic controls, so he could be discharged from the hospital with follow-up in the outpatient consulting offices.

Association of adiposity and its changes over time with COVID-19 risk in older adults with overweight/obesity and metabolic syndrome: a longitudinal evaluation in the PREDIMED-Plus cohort.

BACKGROUND: Cross-sectionally, older age and obesity are associated with increased coronavirus disease-2019 (COVID-19) risk. We assessed the longitudinal associations of baseline and changes in adiposity parameters with COVID-19 incidence in older adults at high cardiovascular risk. METHODS: This analysis included 6874 men and women (aged 55-75 years) with overweight/obesity and metabolic syndrome in the PREDIMED-Plus lifestyle intervention trial for cardiovascular risk reduction. Body weight, body-mass-index (BMI), waist circumference, waist-to-height ratio (WHtR), and a body shape index (ABSI) were measured at baseline and annual follow-up visits. COVID-19 was ascertained by an independent Event Committee until 31 December 2021. Cox regression models were fitted to evaluate the risk of COVID-19 incidence based on baseline adiposity parameters measured 5-6 years before the pandemic and their changes at the visit prior to censoring. RESULTS: At the time of censoring, 653 incident COVID-19 cases occurred. Higher baseline body weight, BMI, waist circumference, and WHtR were associated with increased COVID-19 risk. During the follow-up, every unit increase in body weight (HRadj (95%CI): 1.01 (1.00, 1.03)) and BMI (HRadj: 1.04 (1.003, 1.08)) was associated with increased COVID-19 risk. CONCLUSIONS: In older adults with overweight/obesity, clinically significant weight loss may protect against COVID-19. TRIAL REGISTRATION: This study is registered at the International Standard Randomized Controlled Trial (ISRCT; http://www.isrctn.com/ISRCTN89898870 ).

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.

Plasma metabolite profiles associated with the World Cancer Research Fund/American Institute for Cancer Research lifestyle score and future risk of cardiovascular disease and type 2 diabetes.

BACKGROUND: A healthy lifestyle (HL) has been inversely related to type 2 diabetes (T2D) and cardiovascular disease (CVD). However, few studies have identified a metabolite profile associated with HL. The present study aims to identify a metabolite profile of a HL score and assess its association with the incidence of T2D and CVD in individuals at high cardiovascular risk. METHODS: In a subset of 1833 participants (age 55-80y) of the PREDIMED study, we estimated adherence to a HL using a composite score based on the 2018 Word Cancer Research Fund/American Institute for Cancer Research recommendations. Plasma metabolites were analyzed using LC-MS/MS methods at baseline (discovery sample) and 1-year of follow-up (validation sample). Cross-sectional associations between 385 known metabolites and the HL score were assessed using elastic net regression. A 10-cross-validation procedure was used, and correlation coefficients or AUC were assessed between the identified metabolite profiles and the self-reported HL score. We estimated the associations between the identified metabolite profiles and T2D and CVD using multivariable Cox regression models. RESULTS: The metabolite profiles that identified HL as a dichotomous or continuous variable included 24 and 58 metabolites, respectively. These are amino acids or derivatives, lipids, and energy intermediates or xenobiotic compounds. After adjustment for potential confounders, baseline metabolite profiles were associated with a lower risk of T2D (hazard ratio [HR] and 95% confidence interval (CI): 0.54, 0.38-0.77 for dichotomous HL, and 0.22, 0.11-0.43 for continuous HL). Similar results were observed with CVD (HR, 95% CI: 0.59, 0.42-0.83 for dichotomous HF and HR, 95%CI: 0.58, 0.31-1.07 for continuous HL). The reduction in the risk of T2D and CVD was maintained or attenuated, respectively, for the 1-year metabolomic profile. CONCLUSIONS: In an elderly population at high risk of CVD, a set of metabolites was selected as potential metabolites associated with the HL pattern predicting the risk of T2D and, to a lesser extent, CVD. These results support previous findings that some of these metabolites are inversely associated with the risk of T2D and CVD. TRIAL REGISTRATION: The PREDIMED trial was registered at ISRCTN ( http://www.isrctn.com/ , ISRCTN35739639).

Olive oil consumption, plasma metabolites, and risk of type 2 diabetes and cardiovascular disease.

BACKGROUND: Olive oil consumption has been inversely associated with the risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). However, the impact of olive oil consumption on plasma metabolites remains poorly understood. This study aims to identify plasma metabolites related to total and specific types of olive oil consumption, and to assess the prospective associations of the identified multi-metabolite profiles with the risk of T2D and CVD. METHODS: The discovery population included 1837 participants at high cardiovascular risk from the PREvención con DIeta MEDiterránea (PREDIMED) trial with available metabolomics data at baseline. Olive oil consumption was determined through food-frequency questionnaires (FFQ) and adjusted for total energy. A total of 1522 participants also had available metabolomics data at year 1 and were used as the internal validation sample. Plasma metabolomics analyses were performed using LC-MS. Cross-sectional associations between 385 known candidate metabolites and olive oil consumption were assessed using elastic net regression analysis. A 10-cross-validation (CV) procedure was used, and Pearson correlation coefficients were assessed between metabolite-weighted models and FFQ-derived olive oil consumption in each pair of training-validation data sets within the discovery sample. We further estimated the prospective associations of the identified plasma multi-metabolite profile with incident T2D and CVD using multivariable Cox regression models. RESULTS: We identified a metabolomic signature for the consumption of total olive oil (with 74 metabolites), VOO (with 78 metabolites), and COO (with 17 metabolites), including several lipids, acylcarnitines, and amino acids. 10-CV Pearson correlation coefficients between total olive oil consumption derived from FFQs and the multi-metabolite profile were 0.40 (95% CI 0.37, 0.44) and 0.27 (95% CI 0.22, 0.31) for the discovery and validation sample, respectively. We identified several overlapping and distinct metabolites according to the type of olive oil consumed. The baseline metabolite profiles of total and extra virgin olive oil were inversely associated with CVD incidence (HR per 1SD: 0.79; 95% CI 0.67, 0.92 for total olive oil and 0.70; 0.59, 0.83 for extra virgin olive oil) after adjustment for confounders. However, no significant associations were observed between these metabolite profiles and T2D incidence. CONCLUSIONS: This study reveals a panel of plasma metabolites linked to the consumption of total and specific types of olive oil. The metabolite profiles of total olive oil consumption and extra virgin olive oil were associated with a decreased risk of incident CVD in a high cardiovascular-risk Mediterranean population, though no associations were observed with T2D incidence. TRIAL REGISTRATION: The PREDIMED trial was registered at ISRCTN ( http://www.isrctn.com/ , ISRCTN35739639).

Yearly attained adherence to Mediterranean diet and incidence of diabetes in a large randomized trial.

BACKGROUND: Several large observational prospective studies have reported a protection by the traditional Mediterranean diet against type 2 diabetes, but none of them used yearly repeated measures of dietary intake. Repeated measurements of dietary intake are able to improve subject classification and to increase the quality of the assessed relationships in nutritional epidemiology. Beyond observational studies, randomized trials provide stronger causal evidence. In the context of a randomized trial of primary cardiovascular prevention, we assessed type 2 diabetes incidence according to yearly repeated measures of compliance with a nutritional intervention based on the traditional Mediterranean diet. METHODS: PREDIMED (''PREvención con DIeta MEDiterránea'') was a Spanish trial including 7447 men and women at high cardiovascular risk. We assessed 3541 participants initially free of diabetes and originally randomized to 1 of 3 diets: low-fat diet (n = 1147, control group), Mediterranean diet supplemented with extra virgin olive (n = 1154) or Mediterranean diet supplemented with mixed nuts (n = 1240). As exposure we used actual adherence to Mediterranean diet (cumulative average), yearly assessed with the Mediterranean Diet Adherence Screener (scoring 0 to 14 points), and repeated up to 8 times (baseline and 7 consecutive follow-up years). This score was categorized into four groups: < 8, 8-< 10, 10- < 12, and 12-14 points. The outcome was new-onset type 2 diabetes. RESULTS: Multivariable-adjusted hazard ratios from time-varying Cox models were 0.80 (95% confidence interval, 0.70-0.92) per + 2 points in Mediterranean Diet Adherence Screener (linear trend p = .001), and 0.46 (0.25-0.83) for the highest (12-14 points) versus the lowest (< 8) adherence. This inverse association was maintained after additionally adjusting for the randomized arm. Age- and sex-adjusted analysis of a validated plasma metabolomic signature of the Mediterranean Diet Adherence Screener (constituted of 67 metabolites) in a subset of 889 participants also supported these results. CONCLUSIONS: Dietary intervention trials should quantify actual dietary adherence throughout the trial period to enhance the benefits and to assist results interpretation. A rapid dietary assessment tool, yearly repeated as a screener, was able to capture a strong inverse linear relationship between Mediterranean diet and type 2 diabetes. Trial registration ISRCTN35739639.

Lysosomal acid lipase deficiency manifestations in children and adults: Baseline data from an international registry.

BACKGROUND AND AIMS: Lysosomal acid lipase deficiency (LAL-D) is a rare, autosomal recessive disease involving lysosomal accumulation of cholesteryl esters and triglycerides. The International Lysosomal Acid Lipase Deficiency Registry (NCT01633489), established in 2013 to understand LAL-D natural history and long-term outcomes, is accessible to centres caring for patients diagnosed by deficient LAL activity and/or biallelic pathogenic LIPA variants. We describe the registry population enrolled through 2 May 2022. METHODS: In this prospective observational study, we analysed demographic and baseline clinical characteristics of children (ages ≥6 months to <18 years) and adults diagnosed with LAL-D. RESULTS: Of 228 patients with confirmed disease, 61% were children; 202/220 (92%) with data on race were white. Median age was 5.5 years at sign/symptom onset and 10.5 years at diagnosis; median time from sign/symptom onset to diagnostic testing was 3.3 years. The most common manifestations raising suspicion of disease were elevated alanine (70%) and aspartate aminotransferase levels (67%) and hepatomegaly (63%). Among 157 with reported LIPA mutations, 70 were homozygous and 45 were compound heterozygous for the common exon 8 splice junction pathogenic variant (E8SJM-1). Seventy percent (159/228) of patients had dyslipidaemia. Among 118 with liver biopsies, 63% had microvesicular steatosis exclusively, 23% had mixed micro- and macrovesicular steatosis and 47% had lobular inflammation. Of 78 patients with fibrosis-stage data, 37% had bridging fibrosis and 14% had cirrhosis. CONCLUSIONS: Although LAL-D signs/symptoms occur early, diagnosis is often delayed. Abnormal transaminase levels associated with hepatomegaly and dyslipidaemia should raise suspicion and prompt earlier diagnosis of LAL-D. TRIAL REGISTRATION NUMBER: NCT01633489.

Dietary intake of polychlorinated dibenzo-p-dioxins and furans, adiposity and obesity status.

INTRODUCTION: The principal source of exposure to Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans (PCDD/Fs) in humans comes from food intake. PCDD/Fs, are a family of potential endocrine disruptors and have been associated with different chronic diseases such as diabetes and hypertension. However, studies assessing the relationship between dietary exposure to PCDD/Fs and adiposity or obesity status in a middle-aged population are limited. OBJECTIVE: To assess cross-sectionally and longitudinally the associations between estimated dietary intake (DI) of PCDD/Fs and body mass index (BMI), waist circumference, and the prevalence/incidence of obesity and abdominal obesity in a middle-aged population. METHODS: In 5899 participants aged 55-75 years (48% women) living with overweight/obesity from the PREDIMED-plus cohort, PCDD/Fs DI was estimated using a 143-item validated food-frequency questionnaire, and the levels of food PCDD/F expressed as Toxic Equivalents (TEQ). Consequently, cross-sectional and prospective associations between baseline PCDD/Fs DI (in pgTEQ/week) and adiposity or obesity status were assessed at baseline and after 1-year follow-up using multivariable cox, logistic or linear regression models. RESULTS: Compared to participants in the first PCDD/F DI tertile, those in the highest tertile presented a higher BMI (ß-coefficient [confidence interval]) (0.43kg/m2 [0.22; 0.64]; P-trend <0.001), a higher waist circumference (1.11 cm [0.55; 1.66]; P-trend <0.001), and a higher prevalence of obesity and abdominal obesity (1.05 [1.01; 1.09] and 1.02 [1.00; 1.03]; P-trend = 0.09 and 0.027, respectively). In the prospective analysis, participants in the top PCDD/F DI baseline tertile showed an increase in waist circumference compared with those in the first tertile after 1-year of follow-up (ß-coefficient 0.37 cm [0.06; 0.70]; P-trend = 0.015). CONCLUSION: Higher DI of PCDD/Fs was positively associated with adiposity parameters and obesity status at baseline and with changes in waist circumference after 1-year of follow-up in subjects living with overweight/obesity. Further large prospective studies using a different population with longer follow-up periods are warranted in the future to strengthen our results.

Carbon dioxide (CO2) emissions and adherence to Mediterranean diet in an adult population: the Mediterranean diet index as a pollution level index.

BACKGROUND: Research related to sustainable diets is is highly relevant to provide better understanding of the impact of dietary intake on the health and the environment. AIM: To assess the association between the adherence to an energy-restricted Mediterranean diet and the amount of CO2 emitted in an older adult population. DESIGN AND POPULATION: Using a cross-sectional design, the association between the adherence to an energy-reduced Mediterranean Diet (erMedDiet) score and dietary CO2 emissions in 6646 participants was assessed. METHODS: Food intake and adherence to the erMedDiet was assessed using validated food frequency questionnaire and 17-item Mediterranean questionnaire. Sociodemographic characteristics were documented. Environmental impact was calculated through greenhouse gas emissions estimations, specifically CO2 emissions of each participant diet per day, using a European database. Participants were distributed in quartiles according to their estimated CO2 emissions expressed in kg/day: Q1 (≤2.01 kg CO2), Q2 (2.02-2.34 kg CO2), Q3 (2.35-2.79 kg CO2) and Q4 (≥2.80 kg CO2). RESULTS: More men than women induced higher dietary levels of CO2 emissions. Participants reporting higher consumption of vegetables, fruits, legumes, nuts, whole cereals, preferring white meat, and having less consumption of red meat were mostly emitting less kg of CO2 through diet. Participants with higher adherence to the Mediterranean Diet showed lower odds for dietary CO2 emissions: Q2 (OR 0.87; 95%CI: 0.76-1.00), Q3 (OR 0.69; 95%CI: 0.69-0.79) and Q4 (OR 0.48; 95%CI: 0.42-0.55) vs Q1 (reference). CONCLUSIONS: The Mediterranean diet can be environmentally protective since the higher the adherence to the Mediterranean diet, the lower total dietary CO2 emissions. Mediterranean Diet index may be used as a pollution level index.

Association between serum copper levels and risk of cardiovascular disease: A nested case-control study in the PREDIMED trial.

BACKGROUND AND AIM: Certain trace elements have been associated with increased cardiovascular risk. The aim of this study was to evaluate the association between serum copper (S-Cu) levels and the risk of a first event of cardiovascular disease (CVD) in a population of older adults with high cardiovascular risk. METHODS AND RESULTS: We conducted a case-control study nested within the PREDIMED trial. During a median follow-up of 4.8 years, a total of 207 incident cases diagnosed with CVD were matched for sex, age, and intervention group with 436 controls. Personal interviews, reviews of medical records, and validated questionnaires were used to assess known CVD risk factors. Biological serum samples were collected annually. Inductively coupled plasma mass spectrometry analysis was used to determine S-Cu levels. Adjusted odds ratios were calculated using multivariate conditional logistic regression models. All participants had S-Cu levels within the reference values, 750 µg/L to 1450 µg/L. Among men, but not among women, the mean S-Cu concentration was higher in cases 1014.1 µg/L than in controls 959.3 µg/L; (p = 0.004). In men, the multivariable-adjusted odds ratio for CVD was 2.36 (95% CI 1.07-5.20 for the comparison of the highest vs. the lowest quartile; p for trend = 0.02), in women, it was 0.43 (95% CI 0.11-1.70; p for trend = 0.165). CONCLUSION: In older Spanish men with high cardiovascular risk, a significant association was observed between high S-Cu levels, but still within the reference values, and an increased risk of a first event of CVD. Our findings suggest a sex difference in CVD risk and S-Cu levels. To confirm this relationship and to analyze the differences observed between men and women, further studies are needed.

American Heart Association's life simple 7 and the risk of atrial fibrillation in the PREDIMED study cohort.

BACKGROUND AND AIMS: The American Heart Association proposed 7 ideal cardiovascular health metrics (Life's Simple 7 [LS7]) namely, not smoking, body mass index <25 kg/m2, healthy diet, moderate physical activity ≥150 min/week, total blood cholesterol <200 mg/dL, blood pressure <120/80 mmHg and fasting blood glucose <100 mg/dL. Our objective was to assess the association between these LS7 metrics and the incidence of atrial fibrillation (AF). METHODS AND RESULTS: A total of 6,479 participants of the PREDIMED study were included. We calculated the participants' baseline LS7 index ranging 0-7 points to categorize them according to their adherence to these LS7 health metrics. Multivariable Cox regression models were used to estimate Hazard Ratios (HR) and their 95% Confidence Intervals (95% CI). After a median follow-up of 4.8 years, we identified 250 incident cases of AF. After adjusting for potential confounders, adherence to LS7 index was not associated with the incidence of AF (adjusted HR 0.90 [95% CI: 0.56-1.45] for highest vs. lowest LS7 categories). Body mass index <25 kg/m2 was the only health metric individually associated with a lower risk of AF (HR 0.36 [95% CI: 0.16-0.78]). CONCLUSIONS: In a high cardiovascular risk Spanish population, adherence to American Heart Association's LS7 metrics was not associated with the risk of incident AF. CLINICAL TRIALS NUMBER: ISRCTN35739639.

Metabolic syndrome criteria and severity and carbon dioxide (CO2) emissions in an adult population.

BACKGROUND: Metabolic syndrome (MetS) has become a growing risk factor of some non-communicable diseases. Increase of greenhouse gas emissions affects the planet. AIMS: To assess the association between MetS severity and amount of carbon dioxide (CO2) emitted in an adult population. DESIGN: Cross-sectional study (n = 6646; 55-76-year-old-men; 60-75-year-old-women with MetS). METHODS: Dietary habits were assessed using a pre-validated semi quantitative 143-item food frequency questionnaire. The amount of CO2 emitted due to the production of food consumed by person and day was calculated using a European database, and the severity of the MetS was calculated with the MetS Severity Score. RESULTS: Higher glycaemia levels were found in people with higher CO2 emissions. The risk of having high severe MetS was related to high CO2 emissions. CONCLUSIONS: Low CO2 emissions diet would help to reduce MetS severity. Advantages for both health and the environment were found following a more sustainable diet. TRIAL REGISTRATION: ISRCTN, ISRCTN89898870 . Registered 05 September 2013.

Red blood cell omega-3 fatty acids and attention scores in healthy adolescents.

Omega-3 fatty acids are critical for brain function. Adolescence is increasingly believed to entail brain vulnerability to dietary intake. In contrast to the abundant research on the omega-3 docosahexaenoic acid (DHA) in cognition, research on DHA and attention in healthy adolescents is scarce. In addition, the role of alpha-linolenic acid (ALA), the vegetable omega-3 fatty acid, is unexplored. We examined associations between DHA and ALA and attention function among a healthy young population. In this cross-sectional study conducted in 372 adolescents (13.8 ± 0.9 years-old), we determined the red blood cell proportions of DHA and ALA by gas chromatography (objective biomarkers of their long-term dietary intake) and measured attention scores through the Attention Network Test. We constructed multivariable linear regression models to analyze associations, controlling for known confounders. Compared to participants at the lowest DHA tertile (reference), those at the highest DHA tertile showed significantly lower hit reaction time-standard error (higher attentiveness) (28.13 ms, 95% confidence interval [CI] = - 52.30; - 3.97), lower hit reaction time ( - 38.30 ms, 95% CI = - 73.28; - 3.33) and lower executive conflict response ( - 5.77 ms, 95% CI = - 11.44; - 0.09). In contrast, higher values were observed in those at the top tertile of ALA in hit reaction time compared to the lowest one (46.14 ms, 95% CI = 9.90; 82.34). However, a beneficial association was observed for ALA, with decreasing impulsivity index across tertiles. Overall, our results suggest that DHA (reflecting its dietary intake) is associated with attention performance in typically developing adolescents. The role of dietary ALA in attention is less clear, although higher blood levels of ALA appear to result in lower impulsivity. Future intervention studies are needed to determine the causality of these associations and to better shape dietary recommendations for brain health during the adolescence period.

Nut consumption is associated with a shift of the NMR lipoprotein subfraction profile to a less atherogenic pattern among older individuals at high CVD risk.

BACKGROUND: Scientific evidence has accumulated on the beneficial effects of nut consumption on cardiovascular risk and cholesterol reduction, but few studies have examined the effects of nuts on advanced measures of lipoprotein atherogenicity determined by nuclear magnetic resonance (NMR) spectroscopy. We analyzed associations between the amount and type of of nuts consumed and advanced measures of lipoprotein atherogenity and insulin resistance in older individuals at high cardiovascular risk. METHODS: The present observational study was carried out within the framework of the Prevención con Dieta Mediterránea (PREDIMED) trial. Cross-sectional and longitudinal analyses after 1-year of follow-up were conducted in 196 men and women recruited in the PREDIMED-Reus (Spain) center. Dietary intake was assessed using a validated semi-quantitative food questionnaire. Baseline and 1-year fasting plasma lipoprotein and metabolite profiling were performed in plasma using NMR spectra Vantera® Clinical Analyzer. Associations by tertiles of nut consumption between baseline and 1-year changes and advanced measures of lipoprotein atherogenicity, branched chain amminoacids, and measures of insulin resistance were tested by multivariable-adjusted ANCOVA models. RESULTS: Compared to paticipants in the bottom tertile, those in the top tertile of total nut consumption showed higher levels of large HDL particles and HDL-cholesterol, lower levels of branched-chain amino acids (BCAA) and GlycA, and reduced lipoprotein insulin resistance and diabetes risk index. Participants in the top tertile of walnut consumption disclosed lower levels of very large VLDL, total LDL particles, LDL-cholesterol, and GlycA. Participants in the top tertile of non-walnut nut consumption displayed higher levels of total HDL particles, HDL-cholesterol and apoliporotein A1, lower BCAA and GlycA, and reduced lipoprotein insulin resistance. Participants in the top tertile of 1-year changes in walnut consumption showed increases in medium-sized HDL particles in comparison to the bottom tertile. CONCLUSIONS: In older individuals at high cardiovascular risk, increasing nut consumption was associated with a shift of the NMR lipoprotein subfraction profile to a less atherogenic pattern, as well as lower circulating concentrations of BCAA and decreased insulin resistance. These results provide novel mechanistic insight into the cardiovascular benefit of nut consumption. Trial registration ISRCTN35739639; registration date: 05/10/2005; recruitment start date 01/10/2003.