Search

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 LC

Glutamate metabolism may play a role in the pathophysiology of cardiometabolic disorders. However, there is limited evidence of an association between glutamate-related metabolites and, moreover, changes in these metabolites, and risk of cardiovascular disease (CVD). METHODS AND RESULTS: Plasma levels of glutamate and glutamine were measured at baseline and 1-year follow-up in a case-cohort study including 980 participants (mean age 68 years; 46% male) from the PREvención con DIeta MEDiterránea (PREDIMED) randomized trial, which assessed a Mediterranean diet intervention in the primary prevention of CVD. During median 4.8 years of follow-up, there were 229 incident CVD events (nonfatal stroke, nonfatal myocardial infarction, or CVD death). In fully adjusted models, per 1-SD, baseline glutamate was associated with 43% (95% CI: 16% to 76%) and 81% (39% to 137%) increased risk of composite CVD and stroke alone, respectively, and baseline glutamine-to-glutamate ratio with 25% (6% to 40%) and 44% (25% to 58%) decreased risk of composite CVD and stroke alone, respectively. Associations appeared linear for stroke (both Plinear trend≤0.005). Among participants with high baseline glutamate, the interventions lowered CVD risk by 37% compared to the control diet; the intervention effects were not significant when baseline glutamate was low (Pinteraction=0.02). No significant effect of the intervention on year-1 changes in metabolites was observed, and no effect of changes themselves on CVD risk was apparent. CONCLUSIONS: Baseline glutamate was associated with increased CVD risk, particularly stroke, and glutamine-to-glutamate ratio was associated with decreased risk. Participants with high glutamate levels may obtain greater benefits from the Mediterranean diet than those with

OBJECTIVE: We aimed to analyse the effect of the introduction of fingolimod, the first oral disease-modifying therapy, on treatment utilisation and persistence in an international cohort of patients with multiple sclerosis (MS). METHODS: MSBASIS, a prospective, observational sub-study of the MSBase registry, collects demographic, clinical and paraclinical data on patients followed from MS onset (n=4718). We conducted a multivariable conditional risk set survival analysis to identify predictors of treatment discontinuation, and to assess if the introduction of fingolimod has altered treatment persistence. RESULTS: A total of 2640 patients commenced immunomodulatory therapy. Following the introduction of fingolimod, patients were more likely to discontinue all other treatments (hazard ratio 1.64, p<0.001) while more patients switched to fingolimod than any other therapy (42.3% of switches). Patients switched to fingolimod due to convenience. Patients treated with fingolimod were less likely to discontinue treatment compared with other therapies (p<0.001). Female sex, country of residence, younger age, a high Expanded Disability Status Scale score and relapse activity were all independently associated with higher rates of treatment discontinuation. CONCLUSION: Following the availability of fingolimod, patients were more likely to discontinue injectable treatments. Those who switched to fingolimod were more likely to do so for convenience. Persistence was improved on fingolimod compared to other medications.

The relation between the consumption of sweetened beverages and metabolic syndrome (MetS) is controversial.This analysis evaluated the associations between intakes of sugar-sweetened beverages (SSBs), artificially sweetened beverages, and natural and bottled fruit juices and the incidence of MetS in elderly individuals at high risk of cardiovascular disease (CVD) and without MetS at baseline.We prospectively examined 1868 participants free of MetS at baseline from the PREDIMED (PREvención con DIeta MEDiterránea) study. MetS was defined by using the updated harmonized criteria of the International Diabetes Federation, the American Heart Association, and National Heart, Lung, and Blood Institute. Energy and nutrient intakes were evaluated at baseline and then yearly by using a validated 137-item food-frequency questionnaire. Multivariable-adjusted HRs for MetS and its components were estimated from mean intakes during follow-up. We compared the 2 highest consumption categories (1-5 and >5 servings/wk) with the lowest category (<1 serving/wk).A total of 930 incident cases of MetS were documented during a median follow-up of 3.24 y. When we compared consumption of >5 servings/wk with consumption of <1 serving/wk, multivariable HRs (95% CIs) for MetS incidence were 1.43 (1.00, 2.15), 1.74 (1.26, 2.41), 1.30 (1.00, 1.69), and 1.14 (1.04, 1.65) for SSBs, artificially sweetened beverages, natural fruit juices, and bottled fruit juices, respectively.The occasional consumption of SSBs and artificially sweetened beverages (1-5 servings/wk) was not associated with the incidence of MetS in middle-aged and elderly individuals at high risk of CVD. The consumption of >5 servings/wk of all of the types of beverages analyzed was associated with an increased risk of MetS and some of its c

Previous studies have suggested that metabolite profiles of elevated acylcarnitines were associated with increased risk of cardiovascular disease (CVD) in populations with established coronary disease. However, to our knowledge, this association has not been evaluated in the context of primary cardiovascular prevention.We evaluated the association between 28 plasma acylcarnitine species and risk of incident CVD and the potential modifying effect of Mediterranean diet (MedDiet) interventions.We measured plasma acylcarnitines with the use of high-throughput liquid chromatography-tandem mass spectrometry at baseline and after 1 y of follow-up, both individually and classified into short-, medium-, or long-chain scores, in a case-cohort study within the Prevención con Dieta Mediterránea (PREDIMED) study, which is a randomized Mediterranean dietary intervention for primary cardiovascular prevention. A randomly selected subcohort (n = 751) and all available incident CVD cases (n = 229) after 4.8 y of follow-up were included in the current study.After adjustment for age, sex, body mass index, and other CVD risk factors, participants in the highest quartile of baseline short- and medium-chain acylcarnitines had a higher risk of CVD than did participants in the lowest quartile [HRs: 1.80 (95% CI: 1.11, 2.91; P-trend 0.01) and 1.55 (95% CI: 1.01, 2.48; P-trend = 0.04), respectively]. Increased short-chain acylcarnitines after 1 y were associated with higher risks of total CVD and stroke. Participants with higher baseline concentrations of short-, medium-, and long-chain acylcarnitines who were randomly assigned to the control group had a higher risk of CVD than did subjects with lower concentrations of acylcarnitines who were assigned to the MedDiet group.Our data support the con

Nutrigenetic studies analyzing gene-diet interactions of the TCF7L2-rs7903146 C > T polymorphism on type-2 diabetes (T2D) have shown controversial results. A reason contributing to this may be the additional modulation by obesity. Moreover, TCF7L2-rs7903146 is one of the most influential variants in T2D-genetic risk scores (GRS). Therefore, to increase the predictive value (PV) of GRS it is necessary to first see whether the included polymorphisms have heterogeneous effects. We comprehensively investigated gene-obesity interactions between the TCF7L2-rs7903146 C > T polymorphism on T2D (prevalence and incidence) and analyzed other T2D-polymorphisms in a sub-sample. We studied 7018 PREDIMED participants at baseline and longitudinally (8.7 years maximum follow-up). Obesity significantly interacted with the TCF7L2-rs7903146 on T2D prevalence, associations being greater in non-obese subjects. Accordingly, we prospectively observed in non-T2D subjects (n = 3607) that its association with T2D incidence was stronger in non-obese (HR: 1.81; 95% CI: 1.13-2.92, p = 0.013 for TT versus CC) than in obese subjects (HR: 1.01; 95% CI: 0.61-1.66; p = 0.979; p-interaction = 0.048). Accordingly, TCF7L2-PV was higher in non-obese subjects. Additionally, we created obesity-specific GRS with ten T2D-polymorphisms and demonstrated for the first time their higher strata-specific PV. In conclusion, we provide strong evidence supporting the need for considering obesity when analyzing the TCF7L2 effects and propose the use of obesity-specific GRS for T2D.

Glutamate metabolism may play a role in the pathophysiology of cardiometabolic disorders. However, there is limited evidence of an association between glutamate-related metabolites and, moreover, changes in these metabolites, and risk of cardiovascular disease (CVD).Plasma levels of glutamate and glutamine were measured at baseline and 1-year follow-up in a case-cohort study including 980 participants (mean age 68 years; 46% male) from the PREvención con DIeta MEDiterránea (PREDIMED) randomized trial, which assessed a Mediterranean diet intervention in the primary prevention of CVD. During median 4.8 years of follow-up, there were 229 incident CVD events (nonfatal stroke, nonfatal myocardial infarction, or CVD death). In fully adjusted models, per 1-SD, baseline glutamate was associated with 43% (95% CI: 16% to 76%) and 81% (39% to 137%) increased risk of composite CVD and stroke alone, respectively, and baseline glutamine-to-glutamate ratio with 25% (6% to 40%) and 44% (25% to 58%) decreased risk of composite CVD and stroke alone, respectively. Associations appeared linear for stroke (both Plinear trend?0.005). Among participants with high baseline glutamate, the interventions lowered CVD risk by 37% compared to the control diet; the intervention effects were not significant when baseline glutamate was low (Pinteraction=0.02). No significant effect of the intervention on year-1 changes in metabolites was observed, and no effect of changes themselves on CVD risk was apparent.Baseline glutamate was associated with increased CVD risk, particularly stroke, and glutamine-to-glutamate ratio was associated with decreased risk. Participants with high glutamate levels may obtain greater benefits from the Mediterranean diet than those with low levels.URL: www.controlled-trials.c

Controversy persists on the association between dairy products, especially milk, and cardiovascular diseases (CVD). Genetic proxies may improve dairy intake estimations, and clarify diet-disease relationships through Mendelian randomization. We meta-analytically (n???20,089) evaluated associations between a lactase persistence (LP) SNP, the minichromosome maintenance complex component 6 (MCM6)-rs3754686C>T (nonpersistence>persistence), dairy intake, and CVD biomarkers in American (Hispanics, African-American and Whites) and Mediterranean populations. Moreover, we analyzed longitudinal associations with milk, CVD and mortality in PREDIMED), a randomized Mediterranean diet (MedDiet) intervention trial (n?=?7185). The MCM6-rs3754686/MCM6-rs309180 (as proxy), LP-allele (T) was strongly associated with higher milk intake, but inconsistently associated with glucose and lipids, and not associated with CVD or total mortality in the whole population. Heterogeneity analyses suggested some sex-specific associations. The T-allele was associated with higher CVD and mortality risk in women but not in men (P-sex interaction:0.005 and 0.032, respectively), mainly in the MedDiet group. However, milk intake was not associated with CVD biomarkers, CVD or mortality either generally or in sub-groups. Although MCM6-rs3754686 is a good milk intake proxy in these populations, attributing its associations with CVD and mortality in Mediterranean women to milk is unwarranted, as other factors limiting the assumption of causality in Mendelian randomization may exist.

Epidemiological evidence suggests a cardioprotective role of ?-linolenic acid (ALA), a plant-derived ?-3 fatty acid. It is unclear whether ALA is beneficial in a background of high marine ?-3 fatty acids (long-chain n-3 polyunsaturated fatty acids) intake. In persons at high cardiovascular risk from Spain, a country in which fish consumption is customarily high, we investigated whether meeting the International Society for the Study of Fatty Acids and Lipids recommendation for dietary ALA (0.7% of total energy) at baseline was related to all-cause and cardiovascular disease mortality. We also examined the effect of meeting the society's recommendation for long-chain n-3 polyunsaturated fatty acids (?500 mg/day).We longitudinally evaluated 7202 participants in the PREvención con DIeta MEDiterránea (PREDIMED) trial. Multivariable-adjusted Cox regression models were fitted to estimate hazard ratios. ALA intake correlated to walnut consumption (r=0.94). During a 5.9-y follow-up, 431 deaths occurred (104 cardiovascular disease, 55 coronary heart disease, 32 sudden cardiac death, 25 stroke). The hazard ratios for meeting ALA recommendation (n=1615, 22.4%) were 0.72 (95% CI 0.56-0.92) for all-cause mortality and 0.95 (95% CI 0.58-1.57) for fatal cardiovascular disease. The hazard ratios for meeting the recommendation for long-chain n-3 polyunsaturated fatty acids (n=5452, 75.7%) were 0.84 (95% CI 0.67-1.05) for all-cause mortality, 0.61 (95% CI 0.39-0.96) for fatal cardiovascular disease, 0.54 (95% CI 0.29-0.99) for fatal coronary heart disease, and 0.49 (95% CI 0.22-1.01) for sudden cardiac death. The highest reduction in all-cause mortality occurred in participants meeting both recommendations (hazard ratio 0.63 [95% CI 0.45-0.87]).In participants without prior cardiovascula

Dietary intervention success requires strong participant adherence, but very few studies have examined factors related to both short-term and long-term adherence. A better understanding of predictors of adherence is necessary to improve the design and execution of dietary intervention trials. This study was designed to identify participant characteristics at baseline and study features that predict short-term and long-term adherence with interventions promoting the Mediterranean-type diet (MedDiet) in the PREvención con DIeta MEDiterránea (PREDIMED) randomized trial.Analyses included men and women living in Spain aged 55-80 at high risk for cardiovascular disease. Participants were randomized to the MedDiet supplemented with either complementary extra-virgin olive oil (EVOO) or tree nuts. The control group and participants with insufficient information on adherence were excluded. PREDIMED began in 2003 and ended in 2010. Investigators assessed covariates at baseline and dietary information was updated yearly throughout follow-up. Adherence was measured with a validated 14-point Mediterranean-type diet adherence score. Logistic regression was used to examine associations between baseline characteristics and adherence at one and four years of follow-up.Participants were randomized to the MedDiet supplemented with EVOO (n?=?2,543; 1,962 after exclusions) or tree nuts (n?=?2,454; 2,236 after exclusions). A higher number of cardiovascular risk factors, larger waist circumference, lower physical activity levels, lower total energy intake, poorer baseline adherence to the 14-point adherence score, and allocation to MedDiet?+?EVOO each independently predicted poorer adherence. Participants from PREDIMED recruiting centers with a higher total workload (measured as total number o

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.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.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.Copyright © 2015 The Italian Society of Diabetology, the Italian S

The role of branched-chain amino acids (BCAAs) in cardiovascular disease (CVD) remains poorly understood. We hypothesized that baseline BCAA concentrations predict future risk of CVD and that a Mediterranean diet (MedDiet) intervention may counteract this effect.We developed a case-cohort study within the Prevención con Dieta Mediterránea (PREDIMED), with 226 incident CVD cases and 744 noncases. We used LC-MS/MS to measure plasma BCAAs (leucine, isoleucine, and valine), both at baseline and after 1 year of follow-up. The primary outcome was a composite of incident stroke, myocardial infarction, or cardiovascular death.After adjustment for potential confounders, baseline leucine and isoleucine concentrations were associated with higher CVD risk: the hazard ratios (HRs) for the highest vs lowest quartile were 1.70 (95% CI, 1.05-2.76) and 2.09 (1.27-3.44), respectively. Stronger associations were found for stroke. For both CVD and stroke, we found higher HRs across successive quartiles of BCAAs in the control group than in the MedDiet groups. With stroke as the outcome, a significant interaction (P = 0.009) between baseline BCAA score and intervention with MedDiet was observed. No significant effect of the intervention on 1-year changes in BCAAs or any association between 1-year changes in BCAAs and CVD were observed.Higher concentrations of baseline BCAAs were associated with increased risk of CVD, especially stroke, in a high cardiovascular risk population. A Mediterranean-style diet had a negligible effect on 1-year changes in BCAAs, but it may counteract the harmful effects of BCAAs on stroke.© 2016 American Association for Clinical Chemistry.

High dietary protein diets are widely used to manage overweight and obesity. However, there is a lack of consensus about their long-term efficacy and safety. Therefore, the aim of this study was to assess the effect of long-term high-protein consumption on body weight changes and death outcomes in subjects at high cardiovascular risk.A secondary analysis of the PREDIMED trial was conducted. Dietary protein was assessed using a food-frequency questionnaire during the follow-up. Cox proportional hazard models were used to estimate the multivariate-adjusted hazard ratio (HR) and 95% confidence intervals (95%CI) for protein intake in relation to the risk of body weight and waist circumference changes, cardiovascular disease, cardiovascular death, cancer death and total death.Higher total protein intake, expressed as percentage of energy, was significantly associated with a greater risk of weight gain when protein replaced carbohydrates (HR: 1.90; 95%CI: 1.05, 3.46) but not when replaced fat (HR: 1.69; 95%CI: 0.94, 3.03). However, no association was found between protein intake and waist circumference. Contrary, higher total protein intake was associated with a greater risk of all-cause death in both carbohydrate and fat substitution models (HR: 1.59; 95%CI: 1.08, 2.35; and HR: 1.66; 95%CI: 1.13, 2.43, respectively). A higher consumption of animal protein was associated with an increased risk of fatal and non-fatal outcomes when protein substituted carbohydrates or fat.Higher dietary protein intake is associated with long-term increased risk of body weight gain and overall death in a Mediterranean population at high cardiovascular risk.Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

The aim of the present study was to assess the association between the dietary total antioxidant capacity, the dietary intake of different antioxidants and mortality in a Mediterranean population at high cardiovascular disease risk.A total of 7,447 subjects from the PREDIMED study (multicenter, parallel group, randomized controlled clinical trial), were analyzed treating data as an observational cohort. Different antioxidant vitamin intake and total dietary antioxidant capacity were calculated from a validated 137-item food frequency questionnaire at baseline and updated yearly. Deaths were ascertained through contact with families and general practitioners, review of medical records and consultation of the National Death Index. Cox regression models were fitted to assess the relationship between dietary total antioxidant capacity and mortality. Dietary total antioxidant capacity was estimated using ferric-reducing antioxidant power assays.A total of 319 deaths were recorded after a median follow-up of 4.3 years. Subjects belonging to the upper quintile of antioxidant capacity were younger, ex-smokers, with high educational level, and more active and had higher alcohol intake. Multivariable-adjusted models revealed no statistically significant difference between total dietary antioxidant capacity and mortality (Q5 vs. Q1 ref HR 0.85; 95% CI 0.60-1.20) neither for the intake of all the vitamins studied.No statistically significant association was found between antioxidant capacity and total mortality in elderly subjects at high cardiovascular risk.

Dietary fat quality and fat replacement are more important for cardiovascular disease (CVD) prevention than is total dietary fat intake.The aim was to evaluate the association between total fat intake and fat subtypes with the risk of CVD (myocardial infarction, stroke, or death from cardiovascular causes) and cardiovascular and all-cause death. We also examined the hypothetical effect of the isocaloric substitution of one macronutrient for another.We prospectively studied 7038 participants at high CVD risk from the PREvención con DIeta MEDiterránea (PREDIMED) study. The trial was conducted from 2003 to 2010, but the present analysis was based on an expanded follow-up until 2012. At baseline and yearly thereafter, total and specific fat subtypes were repeatedly measured by using validated food-frequency questionnaires. Time-dependent Cox proportional hazards models were used.After 6 y of follow-up, we documented 336 CVD cases and 414 total deaths. HRs (95% CIs) for CVD for those in the highest quintile of total fat, monounsaturated fatty acid (MUFA), and polyunsaturated fatty acid (PUFA) intake compared with those in the lowest quintile were 0.58 (0.39, 0.86), 0.50 (0.31, 0.81), and 0.68 (0.48, 0.96), respectively. In the comparison between extreme quintiles, higher saturated fatty acid (SFA) and trans-fat intakes were associated with 81% (HR: 1.81; 95% CI: 1.05, 3.13) and 67% (HR: 1.67; 95% CI: 1.09, 2.57) higher risk of CVD. Inverse associations with all-cause death were also observed for PUFA and MUFA intakes. Isocaloric replacements of SFAs with MUFAs and PUFAs or trans fat with MUFAs were associated with a lower risk of CVD. SFAs from pastries and processed foods were associated with a higher risk of CVD.Intakes of MUFAs and PUFAs were associated with a lower risk

Limited data suggest that multiple sclerosis (MS) in Latin America (LA) could be less severe than in the rest of the world. The objective was to compare the course of MS between LA and other regions. Methods Centers from 18 countries with >20 cases enrolled in the MSBase Registry participated. Patients with MS with a disease duration of >1 year and <30 years at time of EDSS measurement were evaluated. The MS Severity Score (MSSS) was used as a measure of disease progression. Comparisons among regions (North America, Europe, Australia and LA), hemispheres and countries were performed. Results A total of 9610 patients were included. Patients were from: Europe, 6290 (65.6%); North America, 1609 (16.7%); Australia, 1119 (11.6%); and LA, 592 (6.1%). The mean MSSS in patients from LA was 4.47 ± 2.8, 4.53 ± 2.8 in North America, 4.51 ± 2.8 in Europe and 4.49 ± 2.7 in Australia. Mean MSSS in the northern hemisphere was 4.51 ± 1.6 compared to 4.48 ± 1.9 in the southern hemisphere. No differences were found for MSSS among hemispheres ( p = 0.68), regions ( p = 0.96) or countries ( p = 0.50). Conclusions Our analyses did not discover any difference in mean MSSS among patients from different regions, hemispheres or countries.

OBJECTIVE: To assess demographic, clinical, magnetic resonance imaging, and treatment exposure predictors of time to 3 or 12-month confirmed disability worsening in clinically isolated syndrome (CIS) and early multiple sclerosis (MS). METHODS: We utilized the MSBase Incident Study (MSBasis), a prospective cohort study of outcome after CIS. Predictors of time to first 3 and 12-month confirmed expanded disability status scale worsening were analyzed using Cox proportional hazards regression. RESULTS: About 1989 patients were analyzed, the largest seen-from-onset cohort reported to-date. A total of 391 patients had a first 3-month confirmed disability worsening event, of which 307 were sustained for 12 months. Older age at CIS onset (adjusted hazard ratio: aHR 1.17, 95% 1.06, 1.30), pyramidal (aHR 1.45, 95% CI 1.13, 1.89) and ambulation (HR 1.60, 95% CI 1.09, 2.34) system dysfunction, annualized relapse rate (aHR 1.20, 95% CI 1.18, 1.22), and lower proportion of observation time on treatment were associated with 3-month confirmed worsening. Predictors of time to 12-month sustained worsening included pyramidal system dysfunction (Hazard ratio: aHR 1.38, 95% CI 1.05, 1.83), and older age at CIS onset (aHR 1.17, 95% CI 1.04, 1.31). Greater proportion of follow-up time exposed to treatment was associated with greater reductions in the rate of worsening. INTERPRETATION: This study provides class IV evidence for a strong protective effect of disease-modifying treatment to reduce disability worsening events in patients with CIS and early MS, and confirms age and pyramidal dysfunction at onset as risk factors.

Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in

Infantile spasms (IS) and Lennox-Gastaut syndrome (LGS) are epileptic encephalopathies characterized by early onset, intractable seizures, and poor developmental outcomes. De novo sequence mutations and copy number variants (CNVs) are causative in a subset of cases. We used exome sequence data in 349 trios with IS or LGS to identify putative de novo CNVs. We confirm 18 de novo CNVs in 17 patients (4.8%), 10 of which are likely pathogenic, giving a firm genetic diagnosis for 2.9% of patients. Confirmation of exome-predicted CNVs by array-based methods is still required due to false-positive rates of prediction algorithms. Our exome-based results are consistent with recent array-based studies in similar cohorts and highlight novel candidate genes for IS and LGS.

BACKGROUND: Multiple Sclerosis is more common in women than men and females have more relapses than men. In a large international cohort we have evaluated the effect of gender on disability accumulation and disease progression to determine if male MS patients have a worse clinical outcome than females. METHODS: Using the MSBase Registry, data from 15,826 MS patients from 25 countries was analysed. Changes in the severity of MS (EDSS) were compared between sexes using a repeated measures analysis in generalised linear mixed models. Kaplan-Meier analysis was used to test for sex difference in the time to reach EDSS milestones 3 and 6 and the secondary progressive MS. RESULTS: In relapse onset MS patients (n = 14,453), males progressed significantly faster in their EDSS than females (0.133 vs 0.112 per year, P<0.001,). Females had a reduced risk of secondary progressive MS (HR (95% CI) = 0.77 (0.67 to 0.90) P = 0.001). In primary progressive MS (n = 1,373), there was a significant increase in EDSS over time in males and females (P<0.001) but there was no significant sex effect on the annualized rate of EDSS change. CONCLUSION: Among registrants of MSBase, male relapse-onset patients accumulate disability faster than female patients. In contrast, the rate of disability accumulation between male and female patients with primary progressive MS is similar.

The association between consumption of dairy products and the risk of developing metabolic syndrome (MetS) is unclear.The purpose of this study was to evaluate the associations between consumption of dairy products (total and different subtypes) and incident MetS in a Mediterranean population at high cardiovascular disease risk.We prospectively analyzed 1868 men and women (55-80 y old) without MetS at baseline, recruited from different PREDIMED (Prevención con Dieta Mediterránea) centers between October 2003 and June 2009 and followed up until December 2010. MetS was defined according to updated, harmonized criteria. At baseline and yearly thereafter, we determined anthropometric variables, dietary habits by a 137-item validated food-frequency questionnaire, and blood biochemistry. Multivariable-adjusted HRs of MetS or its components were estimated for each of the 2 upper tertiles (vs. the lowest one) of mean consumption of dairy products during the follow-up.During a median follow-up of 3.2 y, we documented 930 incident MetS cases. In the multivariable-adjusted model, HRs (95% CIs) of MetS for the comparison of extreme tertiles of dairy product consumption were 0.72 (0.61, 0.86) for low-fat dairy, 0.73 (0.62, 0.86) for low-fat yogurt, 0.78 (0.66, 0.92) for whole-fat yogurt, and 0.80 (0.67, 0.95) for low-fat milk. The respective HR for cheese was 1.31 (1.10, 1.56).Higher consumption of low-fat dairy products, yogurt (total, low-fat, and whole-fat yogurt) and low-fat milk was associated with a reduced risk of MetS in individuals at high cardiovascular disease risk from a Mediterranean population. Conversely, higher consumption of cheese was related to a higher risk of MetS. This trial was registered at controlled-trials.com as ISRCTN35739639.© 2015 American Society for N

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): HR(quartile2) = 1.42 (95%CI = 0.97-2.09); HR(quartile3) = 1.85 (1.27-2.71); and HR(quartile4) = 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.

We tested the hypothesis that an intervention with a Mediterranean diet (MeDiet) could mitigate the well-known harmful effects of abdominal obesity on cardiovascular health.We assessed the relationship between baseline waist-to-height ratio (WHtR) and major cardiovascular events during a median follow-up of 4.8 years in the Prevention with Mediterranean Diet (PREDIMED) randomized primary prevention trial, which tested a MeDiet against a control diet (advice on a low-fat diet). We also examined whether the MeDiet intervention was able to counteract the detrimental cardiovascular effects of an increased WHtR. The trial included 7447 participants (55-80 years old, 57% women) at high cardiovascular risk but free of cardiovascular disease (CVD) at enrollment. An increased risk of CVD events (myocardial infarction, stroke, or cardiovascular death) was apparent for the highest versus the lowest quartile of WHtR (multivariable-adjusted hazard ratio: 1.98) (95% confidence interval: 1.10-3.57; linear trend: p = 0.019) only in the control-diet group, but not in the two groups allocated to intervention with MeDiet (p for interaction = 0.034). This apparent interaction suggesting that the intervention counterbalanced the detrimental cardiovascular effects of adiposity was also significant for body mass index (BMI) (p = 0.01) and waist circumference (p = 0.043).The MeDiet may counteract the harmful effects of increased adiposity on the risk of CVD.Copyright © 2015 Elsevier B.V. All rights reserved.

To date no clinical trials have evaluated the role of dietary patterns on the incidence of microvascular diabetes complications. We hypothesized that a nutritional intervention based on the Mediterranean diet (MedDiet) would have greater protective effect on diabetic retinopathy and nephropathy than a low-fat control diet.This was a post hoc analysis of a cohort of patients with type 2 diabetes participating in the PREvención con DIeta MEDiterránea (PREDIMED) study, a multicenter randomized nutritional intervention trial conducted in a population at high cardiovascular risk. Individuals with type 2 diabetes who were free of microvascular complications at enrollment (n = 3,614, aged 55-80 years) were randomly assigned to one of three dietary interventions: MedDiet supplemented with extravirgin olive oil (MedDiet+EVOO), MedDiet supplemented with mixed nuts (MedDiet+Nuts), or a low-fat control diet. Two independent outcomes were considered: new onset of diabetic retinopathy and nephropathy. Hazard ratios (HRs) were calculated using multivariable-adjusted Cox regression.During a median follow-up of 6.0 years, we identified 74 new cases of retinopathy and 168 of nephropathy. Compared with the control diet, multivariable-adjusted HRs for diabetic retinopathy were 0.56 (95% CI 0.32-0.97) for the MedDiet+EVOO and 0.63 (0.35-1.11) for the MedDiet+Nuts. No between-group differences were found for nephropathy. When the yearly updated information on adherence to the MedDiet was considered, the HR for retinopathy in the highest versus the lowest quintile was 0.34 (0.13-0.89; P = 0.001 for trend). No significant associations were found for nephropathy.A MedDiet enriched with EVOO may protect against diabetic retinopathy but not diabetic nephropathy.© 2015 by the American Diabetes Ass

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 PREvención con DIeta MEDiterránea 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.