Kinetics of the incorporation of dietary fatty acids into serum cholesteryl esters, erythrocyte membranes, and adipose tissue: an 18-month controlled study. 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Plant- and marine-derived n-3 polyunsaturated fatty acids have differential effects on fasting and postprandial blood lipid concentrations and on the susceptibility of LDL to oxidative modification in moderately hyperlipidemic subjects. Linoleic-acid-enriched diet: long-term effects on serum lipoprotein and apolipoprotein concentrations and insulin sensitivity in noninsulin-dependent diabetic patients. Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol. Effects of altering the ratio of dietary n-6 to n-3 fatty acids on insulin sensitivity, lipoprotein size, and postprandial lipemia in men and postmenopausal women aged 45-70 y: the OPTILIP Study. Gamma-linolenate reduces weight regain in formerly obese humans. Effects of omega-3 supplementation in combination with diet and exercise on weight loss and body composition. 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A randomised controlled trial investigating the effect of n-3 long-chain polyunsaturated fatty acid supplementation on cognitive and retinal function in cognitively healthy older people: the Older People And n-3 Long-chain polyunsaturated fatty acids (OPAL) study protocol [ISRCTN72331636] Impact of high dose n-3 polyunsaturated fatty acid treatment on measures of microvascular function and vibration perception in non-alcoholic fatty liver disease: results from the randomised WELCOME trial Effects of Dietary n-3 Fatty Acids on Hepatic and Peripheral Insulin Sensitivity in Insulin-Resistant Humans Effects of Diet Composition and Insulin Resistance Status on Plasma Lipid Levels in a Weight Loss Intervention in Women The effects of flaxseed dietary supplement on lipid profile, bone mineral density, and symptoms in menopausal women: a randomized, double-blind, wheat germ placebo-controlled clinical trial. Efficacy of n-3 polyunsaturated fatty acids and feasibility of optimizing preventive strategies in patients at high cardiovascular risk: rationale, design and baseline characteristics of the Rischio and Prevenzione study, a large randomised trial in general practice Administration of omega-3 fatty acids and Raloxifene to women at high risk of breast cancer: interim feasibility and biomarkers analysis from a clinical trial Incorporation of eicosapentaenoic and docosahexaenoic acids into lipid pools when given as supplements providing doses equivalent to typical intakes of oily fish1234 Pro‐ and anti‐inflammatory cytokines in healthy volunteers fed various doses of fish oil for 1 year Mediterranean Diet Reduces 24-Hour Ambulatory Blood Pressure, Blood Glucose, and Lipids: One-Year Randomized, Clinical Trial Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). n-3 fatty acids in patients with multiple cardiovascular risk factors. Impact of foods enriched with n-3 long-chain polyunsaturated fatty acids on erythrocyte n-3 levels and cardiovascular risk factors. Dietary omega-3 fatty acids and fish consumption and risk of type 2 diabetes. Olive oil and reduced need for antihypertensive medications. The Age-Related Eye Disease Study 2 (AREDS2): study design and baseline characteristics (AREDS2 report number 1). Long-chain omega-3 fatty acids improve brain function and structure in older adults. Fish oil supplemented for 9 months does not improve glycaemic control or insulin sensitivity in subjects with impaired glucose regulation: a parallel randomised controlled trial. Higher body fat percentage is associated with enhanced temperature perception in NAFLD: results from the randomised Wessex Evaluation of fatty Liver and Cardiovascular markers in NAFLD with OMacor thErapy trial (WELCOME) trial The use of novel foods enriched with long-chain n-3 fatty acids to increase dietary intake: a comparison of methodologies assessing nutrient intake. Long-term effect of eicosapentaenoic acid ethyl (EPA-E) on albuminuria of non-insulin dependent diabetic patients. Foods, nutrients or whole diets: effects of targeting fish and LCn3PUFA consumption in a 12mo weight loss trial Additive benefits of long-chain n-3 polyunsaturated fatty acids and weight-loss in the management of cardiovascular disease risk in overweight hyperinsulinaemic women Identification of dietary patterns associated with blood pressure in a sample of overweight Australian adults Dietary n-3/long-chain n-3 polyunsaturated fatty acids for prevention of sporadic colorectal tumors: a randomized controlled trial in polypectomized participants. Rationale and study design of dietary intervention in patients polypectomized for tumors of the colorectum. Influence of a Mediterranean Dietary Pattern on Body Fat Distribution: Results of the PREDIMED–Canarias Intervention Randomized Trial Lack of benefit of dietary advice to men with angina: results of a controlled trial A randomized study of coconut oil versus sunflower oil on cardiovascular risk factors in patients with stable coronary heart disease Plasma n-3 fatty acids and clinical outcomes in recent-onset rheumatoid arthritis. Administration of highly purified eicosapentaenoic acid to statin-treated diabetic patients further improves vascular function. Diet and reinfarction trial (DART): design, recruitment, and compliance. Eicosapentaenoic acid reduces the progression of carotid intima-media thickness in patients with type 2 diabetes. Lack of effect of fish oil supplementation on coagulation and transcapillary escape rate of albumin in insulin-dependent diabetic patients with diabetic nephropathy. Effect of long-term, moderate-dose supplementation with omega-3 fatty acids on monocyte procoagulant activity and release of interleukin-6 in patients with coronary artery disease. Long-term effects of linoleic-acid-enriched diet on albuminuria and lipid levels in Type 1 (insulin-dependent) diabetic patients with elevated urinary albumin excretion Oily fish reduces plasma triacylglycerols: a primary prevention study in overweight men and women. Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional capacity in patients with dilated cardiomyopathy. Flaxseed on cardiovascular disease markers in healthy menopausal women: a randomized, double-blind, placebo-controlled trial. Including walnuts in a low-fat/modified-fat diet improves HDL cholesterol-to-total cholesterol ratios in patients with type 2 diabetes. Serum Lp(a) lipoprotein levels in patients with coronary artery disease and the influence of long-term n-3 fatty acid supplementation. Effects of n-3 pufas on fasting plasma glucose and insulin resistance in patients with impaired fasting glucose or impaired glucose tolerance. A 3 years follow-up of a Mediterranean diet rich in virgin olive oil is associated with high plasma antioxidant capacity and reduced body weight gain Influence of Obesity on Breast Density Reduction by Omega-3 Fatty Acids: Evidence from a Randomized Clinical Trial Fish consumption and cognitive function among older people in the UK: Baseline data from the OPAL study Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. Double-blind Randomized Placebo-controlled Clinical Trial of Omega 3 Fatty Acids for the Treatment of Diabetic Patients With Nonalcoholic Steatohepatitis Long‐term effects of n‐3 polyunsaturated fatty acids on haemostatic variables and bleeding episodes in patients with coronary artery disease Treatment for 6 months with fish oil-derived n-3 polyunsaturated fatty acids has neutral effects on glycemic control but improves dyslipidemia in type 2 diabetic patients with abdominal obesity: a randomized, double-blind, placebo-controlled trial Long-term safety and efficacy of TAK-085 in Japanese subjects with hypertriglyceridemia undergoing lifestyle modification: the omega-3 fatty acids randomized long-term (ORL) study. One-year treatment with ethyl esters of n-3 fatty acids in patients with hypertriglyceridemia and glucose intolerance: reduced triglyceridemia, total cholesterol and increased HDL-C without glycemic alterations. Structured dietary advice incorporating walnuts achieves optimal fat and energy balance in patients with type 2 diabetes mellitus. Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use Influence of supplementation with N-3 fatty acids on different coronary risk factors in men--a placebo controlled study. Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention). Improvement in non-alcoholic fatty liver disease severity is associated with a reduction in carotid intima-media thickness progression. Effect of DHA supplementation in a very low-calorie ketogenic diet in the treatment of obesity: a randomized clinical trial Effect of low doses of n-3 fatty acids on cardiovascular diseases in 4,837 post-myocardial infarction patients: design and baseline characteristics of the Alpha Omega Trial. EFFECTS OF CHANGES IN FAT, FISH, AND FIBRE INTAKES ON DEATH AND MYOCARDIAL REINFARCTION: DIET AND REINFARCTION TRIAL (DART) Favorable influences of linoleic acid on the progression of diabetic micro- and macroangiopathy in adult onset diabetes mellitus. Effect of dietary supplementation with n-3 fatty acids on coronary artery bypass graft patency. Efficacy and safety of prescription omega-3-acid ethyl esters for the prevention of recurrent symptomatic atrial fibrillation: a prospective study. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. Long-Term Effects of Fish Oil on Insulin Resistance and Plasma Lipoproteins in NIDDM Patients With Hypertriglyceridemia Long-term effects of n-3 fatty acids on serum lipids and glycaemic control. Fish Oil in Diabetic Nephropathy Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra‐Virgin Olive Oil or Nuts Effects of n‐3 Fatty Acid Supplements in Diabetes Mellitus Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia Creation of a database to assess effects of omega-3, omega-6 and total polyunsaturated fats on health: methodology for a set of systematic reviews Retraction and Republication: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. N Engl J Med 2013;368:1279-90. n-3 fatty acids and cardiovascular events after myocardial infarction. Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: Results from the WELCOME trial. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Effects of n-3 fatty acid supplements on glycemic traits in Chinese type 2 diabetic patients: A double-blind randomized controlled trial.
Tissue levels of n-3 fatty acids reflect dietary intake , but quantitative data about rate of incorporation and levels as a function of intake are scarce . We fed 58 men 0 , 3 , 6 , or 9 g/d of fish oil for 12 months and monitored fatty acids in serum cholesteryl esters , erythrocytes , and subcutaneous fat during and after supplementation .  Eicosapentaenoic acid ( EPA ) in cholesteryl esters plateaued after 4 - 8 weeks ; the incorporation half-life was 4.8 days . Steady-state levels increased by 3.9 + /- 0.3 mass % points ( + /- SE ) for each extra gram of EPA eaten per day . Incorporation of docosahexaenoic acid ( DHA ) was erratic ; plateau values were 1.1 + /- 0.1 mass % higher for every g/d ingested . Incorporation of EPA into erythrocyte membranes showed a half-life of 28 days ; a steady state was reached after 180 days . Each g/d increased levels by 2.1 + /- 0.1 mass % . C22:5n-3 levels increased markedly . Changes in DHA were erratic and smaller . EPA levels in adipose tissue rose also ; the change after 6 months was 67 % of that after 12 months in gluteal and 75 % in abdominal fat . After 12 months each gram per day caused an 0.11 + /- 0.01 mass % rise in gluteal fat for EPA , 0.53 + /- 0.07 for C22:5n-3 , and 0.14 + /- 0.03 for DHA . Thus , different ( n-3 ) fatty acids were incorporated with different efficiencies , possibly because of interconversions or different affinities of the enzymatic pathways involved . EPA levels in cholesteryl esters reflect intake over the past week or two , erythrocytes over the past month or two , and adipose tissue over a period of years . These findings may help in assessing the intake of ( n-3 ) fatty acids in epidemiological studies Background Whether and how n-3 and n-6 polyunsaturated fatty acids ( PUFAs ) are related to type 2 diabetes ( T2D ) is debated . Objective ly measured plasma PUFAs can help to clarify these associations . Methods and Findings Plasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospect i ve Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries .  Country-specific hazard ratios ( HRs ) were estimated using Prentice-weighted Cox regression and pooled by r and om-effects meta- analysis . We also systematic ally review ed published prospect i ve studies on circulating PUFAs and T2D risk and pooled the quantitative evidence for comparison with results from EPIC-InterAct . In EPIC-InterAct , among long-chain n-3 PUFAs , α-linolenic acid ( ALA ) was inversely associated with T2D ( HR per st and ard deviation [ SD ] 0.93 ; 95 % CI 0.88–0.98 ) , but eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) were not significantly associated . Among n-6 PUFAs , linoleic acid ( LA ) ( 0.80 ; 95 % CI 0.77–0.83 ) and eicosadienoic acid ( EDA ) ( 0.89 ; 95 % CI 0.85–0.94 ) were inversely related , and arachidonic acid ( AA ) was not significantly associated , while significant positive associations were observed with γ-linolenic acid ( GLA ) , dihomo-GLA , docosatetraenoic acid ( DTA ) , and docosapentaenoic acid ( n6-DPA ) , with HRs between 1.13 to 1.46 per SD . These findings from EPIC-InterAct were broadly similar to comparative findings from summary estimates from up to nine studies including between 71 to 2,499 T2D cases . Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs . Conclusions These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA ( ALA ) but no convincing association of marine-derived n3 PUFAs ( EPA and DHA ) with T2D . Moreover , they highlight that the most abundant n6-PUFA ( LA ) is inversely associated with T2D . The detection of associations with previously less well-investigated PUFAs points to the importance of considering individual fatty acids rather than focusing on fatty acid class Background : Epidemiologic evidence of an association between fish intake and  type 2 diabetes ( T2D )  is inconsistent and unresolved . Objective : The objective was to examine the association between total and type of fish intake and  T2D in 8 European countries . Design : This was a case-cohort study , nested within the European Prospect i ve Investigation into Cancer and Nutrition ( EPIC ) study , with 3.99 million person-years of follow-up , 12,403 incident diabetes cases , and a r and om subcohort of 16,835 individuals from 8 European countries . Habitual fish intake ( lean fish , fatty fish , total fish , shellfish , and combined fish and shellfish ) was assessed by country-specific dietary question naires . HRs were estimated in each country by using Prentice-weighted Cox regression models and pooled by using a r and om-effects meta- analysis . Results : No overall association was found between combined fish and shellfish intake and incident T2D per quartile ( adjusted HR : 1.00 ; 95 % CI : 0.94 , 1.06 ; P-trend = 0.99 ) . Total fish , lean fish , and shellfish intakes separately were also not associated with T2D , but fatty fish intake was weakly inversely associated with T2D : adjusted HR per quartile 0.97 ( 0.94 , 1.00 ) , with an HR of 0.84 ( 0.70 , 1.01 ) , 0.85 ( 0.76 , 0.95 ) , and 0.87 ( 0.78 , 0.97 ) for a comparison of the second , third , and fourth quartiles with the lowest quartile of intake , respectively ( P-trend = 0.06 ) . Conclusions : These findings suggest that lean fish , total fish , and shellfish intakes are not associated with incident diabetes but that fatty fish intake may be weakly inversely associated . Replication of these findings in other population s and investigation of the mechanisms underlying these associations are warranted . Meanwhile , current public health recommendations on fish intake should remain unchanged Background Some studies have suggested an association between omega-3 long-chain polyunsaturated fatty acids ( n-3 LC PUFAs ) and better cognitive outcomes in older adults . To date , only two r and omised , controlled trials have assessed the effect of n-3 LC PUFA supplementation on cognitive function in older cognitively healthy population s. Of these trials only one found a benefit , in the subgroup carrying the ApoE-ε4 allele . The benefits of n-3 LC PUFA supplementation on cognitive function in older normal population s thus still remain unclear . The main objective of the current study was to provide a comprehensive assessment of the potential of n-3 LC PUFAs to slow cognitive decline in normal elderly people , and included ApoE-ε4 allele carriage as a potential moderating factor . The detailed methodology of the trial is reported herein . Methods The study was a parallel , 18-month , r and omised , double-blind , placebo-controlled intervention with assessment at baseline and repeated 6-monthly . Participants ( N = 391 , 53.7 % female ) aged 65 - 90 years , English-speaking and with normal cognitive function , were recruited from metropolitan Adelaide , South Australia . Participants in the intervention arm received capsules containing fish-oil at a daily dosage of 1720 mg of docosahexaenoic acid and 600 mg of eicosapentaenoic acid while the placebo arm received the equivalent amount of olive oil in their capsules . The primary outcome is rate of change in cognitive performance , as measured by latent variables for the cognitive constructs ( encompassing Reasoning , Working Memory , Short-term Memory , Retrieval Fluency , Inhibition , Simple and Choice-Reaction Time , Perceptual Speed , Odd-man-out Reaction Time , Speed of Memory Scanning , and Psychomotor Speed ) and assessed by latent growth curve modeling . Secondary outcomes are change in the Mini-mental State Examination , functional capacity and well-being ( including health status , depression , mood , and self-report cognitive functioning ) , blood pressure , and biomarkers of n-3 LC PUFA status , glucose , lipid metabolism , inflammation , oxidative stress , and DNA damage . Trial registration Australia and New Zeal and Clinical Trials Register ( ANZCTR ) : Background The benefit of n-3 polyunsaturated fatty acids ( PUFA ) supplementation for mortality and cardiovascular events after myocardial infa rct ion is well documented , but the effect of n-3 PUFA in Caucasians without established cardiovascular disease is not known . Our aim was to examine the influence of supplementation with eicosapentaenoic acid and docosahexaenoic acid on all-cause mortality and cardiovascular events in elderly men at high-risk of cardiovascular disease . Design In the Diet and Omega-3 Intervention Trial , 563 Norwegian men , 64–76-year old and 72 % without overt cardiovascular disease , were r and omized to a 3-year 2 × 2 factorial design ed clinical trial of diet counseling and /or 2.4 g n-3 PUFA supplementation . The n-3 PUFA arm was placebo-controlled ( corn oil ) . Methods Demographic parameters and classical risk factors were obtained at baseline . Deaths and cardiovascular events were recorded through 3 years , and the effects of n-3 PUFA-intervention on these outcomes were evaluated in pooled groups of the n-3 PUFA-arm . Results There were 38 deaths and 68 cardiovascular events . The unadjusted hazard ratios of all-cause mortality and cardiovascular events were 0.57 ( 95 % confidence interval : 0.29–1.10 ) and 0.86 ( 0.57–1.38 ) , respectively . Adjusted for baseline age , current smoking , hypertension , body mass index and serum glucose , hazard ratios were 0.53 ( 0.27–1.04 , P = 0.063 ) and 0.89 ( 0.55–1.45 , P = 0.641 ) , respectively . Conclusion We observed a tendency toward reduction in all-cause mortality in the n-3 PUFA groups that , despite a low number of participants , reached borderline statistical significance . The magnitude of risk-reduction suggests that a larger trial should be considered in similar population BACKGROUND Epidemiological and clinical evidence suggests that an increased intake of long-chain n-3 fatty acids protects against mortality from coronary artery disease . We aim ed to test the hypothesis that long-term use of eicosapentaenoic acid ( EPA ) is effective for prevention of major coronary events in hypercholesterolaemic patients in Japan who consume a large amount of fish . METHODS 18 645 patients with a total cholesterol of 6.5 mmol/L or greater were recruited from local physicians throughout Japan between 1996 and 1999 . Patients were r and omly assigned to receive either 1800 mg of EPA daily with statin ( EPA group ; n=9326 ) or statin only ( controls ; n=9319 ) with a 5-year follow-up . The primary endpoint was any major coronary event , including sudden cardiac death , fatal and non-fatal myocardial infa rct ion , and other non-fatal events including unstable angina pectoris , angioplasty , stenting , or coronary artery bypass grafting . Analysis was by intention-to-treat . The study was registered at Clinical Trials.gov , number NCT00231738 . FINDINGS At mean follow-up of 4.6 years , we detected the primary endpoint in 262 ( 2.8 % ) patients in the EPA group and 324 ( 3.5 % ) in controls-a 19 % relative reduction in major coronary events ( p=0.011 ) . Post-treatment LDL cholesterol concentrations decreased 25 % , from 4.7 mmol/L in both groups . Serum LDL cholesterol was not a significant factor in a reduction of risk for major coronary events . Unstable angina and non-fatal coronary events were also significantly reduced in the EPA group . Sudden cardiac death and coronary death did not differ between groups . In patients with a history of coronary artery disease who were given EPA treatment , major coronary events were reduced by 19 % ( secondary prevention subgroup : 158 [ 8.7 % ] in the EPA group vs 197 [ 10.7 % ] in the control group ; p=0.048 ) . In patients with no history of coronary artery disease , EPA treatment reduced major coronary events by 18 % , but this finding was not significant ( 104 [ 1.4 % ] in the EPA group vs 127 [ 1.7 % ] in the control group ; p=0.132 ) . INTERPRETATION EPA is a promising treatment for prevention of major coronary events , and especially non-fatal coronary events , in Japanese hypercholesterolaemic patients BACKGROUND There is conflicting evidence on the benefits of foods rich in vitamin E ( alpha-tocopherol ) , n-3 polyunsaturated fatty acids ( PUFA ) , and their pharmacological substitutes . We investigated the effects of these substances as supplements in patients who had myocardial infa rct ion . METHODS From October , 1993 , to September , 1995 , 11,324 patients surviving recent ( < or = 3 months ) myocardial infa rct ion were r and omly assigned supplements of n-3 PUFA ( 1 g daily , n=2836 ) , vitamin E ( 300 mg daily , n=2830 ) , both ( n=2830 ) , or none ( control , n=2828 ) for 3.5 years . The primary combined efficacy endpoint was death , non-fatal myocardial infa rct ion , and stroke . Intention-to-treat analyses were done according to a factorial design ( two-way ) and by treatment group ( four-way ) . FINDINGS Treatment with n-3 PUFA , but not vitamin E , significantly lowered the risk of the primary endpoint ( relative-risk decrease 10 % [ 95 % CI 1 - 18 ] by two-way analysis , 15 % [ 2 - 26 ] by four-way analysis ) . Benefit was attributable to a decrease in the risk of death ( 14 % [ 3 - 24 ] two-way , 20 % [ 6 - 33 ] four-way ) and cardiovascular death ( 17 % [ 3 - 29 ] two-way , 30 % [ 13 - 44 ] four-way ) . The effect of the combined treatment was similar to that for n-3 PUFA for the primary endpoint ( 14 % [ 1 - 26 ] ) and for fatal events ( 20 % [ 5 - 33 ] ) . INTERPRETATION Dietary supplementation with n-3 PUFA led to a clinical ly important and statistically significant benefit . Vitamin E had no benefit . Its effects on fatal cardiovascular events require further exploration R and omised , controlled trials have been retracted after publication because of data fabrication and inadequate ethical approval . Fabricated data have included baseline variables , for instance , age , height or weight . Statistical tests can determine the probability of the distribution of means , given their st and ard deviation and the number of participants in each group . R and omised , controlled trials have been retracted after the data distributions have been calculated as improbable . Most retracted trials have been written by anaesthetists and published by specialist anaesthetic journals . I wanted to explore whether the distribution of baseline data in trials was consistent with the expected distribution . I wanted to determine whether trials retracted after publication had distributions different to trials that have not been retracted . I wanted to determine whether data distributions in trials published in specialist anaesthetic journals have been different to distributions in non‐specialist medical journals . I analysed the distribution of 72,261 means of 29,789 variables in 5087 r and omised , controlled trials published in eight journals between January 2000 and December 2015 : Anaesthesia ( 399 ) ; Anesthesia and Analgesia ( 1288 ) ; Anesthesiology ( 541 ) ; British Journal of Anaesthesia ( 618 ) ; Canadian Journal of Anesthesia ( 384 ) ; European Journal of Anaesthesiology ( 404 ) ; Journal of the American Medical Association ( 518 ) and New Engl and Journal of Medicine ( 935 ) . I chose these journals as I had electronic access to the full text . Trial p values were distorted by an excess of baseline means that were similar and an excess that were dissimilar : 763/5015 ( 15.2 % ) trials that had not been retracted from publication had p values that were within 0.05 of 0 or 1 ( expected 10 % ) , that is , a 5.2 % excess , p = 1.2 × 10−7 . The p values of 31/72 ( 43 % ) trials that had been retracted after publication were within 0.05 of 0 or 1 , a rate different to that for unretracted trials , p = 1.03 × 10−10 . The difference between the distributions of these two subgroups was confirmed by comparison of their overall distributions , p = 5.3 × 10−15 . Each journal exhibited the same abnormal distribution of baseline means . There was no difference in distributions of baseline means for 1453 trials in non‐anaesthetic journals and 3634 trials in anaesthetic journals , p = 0.30 . The rate of retractions from JAMA and NEJM , 6/1453 or 1 in 242 , was one‐quarter the rate from the six anaesthetic journals , 66/3634 or 1 in 55 , relative risk ( 99%CI ) 0.23 ( 0.08–0.68 ) , p = 0.00022 . A probability threshold of 1 in 10,000 identified 8/72 ( 11 % ) retracted trials ( 7 by Fujii et al. ) and 82/5015 ( 1.6 % ) unretracted trials . Some p values were so extreme that the baseline data could not be correct : for instance , for 43/5015 unretracted trials the probability was less than 1 in 1015 ( equivalent to one drop of water in 20,000 Olympic‐sized swimming pools ) . A probability threshold of 1 in 100 for two or more trials by the same author identified three authors of retracted trials ( Boldt , Fujii and Reuben ) and 21 first or corresponding authors of 65 unretracted trials . Fraud , unintentional error , correlation , stratified allocation and poor methodology might have contributed to the excess of r and omised , controlled trials with similar or dissimilar means , a pattern that was common to all the surveyed journals . It is likely that this work will lead to the identification , correction and retraction of hitherto unretracted r and omised , controlled trials BACKGROUND The provision of sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events , but such a possibility has not been formally tested . METHODS We r and omly assigned 12,537 people ( mean age , 63.5 years ) with cardiovascular risk factors plus impaired fasting glucose , impaired glucose tolerance , or type 2 diabetes to receive insulin glargine ( with a target fasting blood glucose level of ≤95 mg per deciliter [ 5.3 mmol per liter ] ) or st and ard care and to receive n-3 fatty acids or placebo with the use of a 2-by-2 factorial design . The results of the comparison between insulin glargine and st and ard care are reported here . The co primary outcomes were nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes and these events plus revascularization or hospitalization for heart failure . Microvascular outcomes , incident diabetes , hypoglycemia , weight , and cancers were also compared between groups . RESULTS The median follow-up was 6.2 years ( interquartile range , 5.8 to 6.7 ) . Rates of incident cardiovascular outcomes were similar in the insulin-glargine and st and ard-care groups : 2.94 and 2.85 per 100 person-years , respectively , for the first co primary outcome ( hazard ratio , 1.02 ; 95 % confidence interval [ CI ] , 0.94 to 1.11 ; P=0.63 ) and 5.52 and 5.28 per 100 person-years , respectively , for the second co primary outcome ( hazard ratio , 1.04 ; 95 % CI , 0.97 to 1.11 ; P=0.27 ) . New diabetes was diagnosed approximately 3 months after therapy was stopped among 30 % versus 35 % of 1456 participants without baseline diabetes ( odds ratio , 0.80 ; 95 % CI , 0.64 to 1.00 ; P=0.05 ) . Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years . Median weight increased by 1.6 kg in the insulin-glargine group and fell by 0.5 kg in the st and ard-care group . There was no significant difference in cancers ( hazard ratio , 1.00 ; 95 % CI , 0.88 to 1.13 ; P=0.97 ) . CONCLUSIONS When used to target normal fasting plasma glucose levels for more than 6 years , insulin glargine had a neutral effect on cardiovascular outcomes and cancers . Although it reduced new-onset diabetes , insulin glargine also increased hypoglycemia and modestly increased weight . ( Funded by Sanofi ; ORIGIN Clinical Trials.gov number , NCT00069784 . ) BACKGROUND Dietary alpha-linolenic acid ( ALA ) can be converted to long-chain n-3 polyunsaturated fatty acids ( PUFAs ) in humans and may reproduce some of the beneficial effects of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) on cardiovascular disease risk factors . OBJECTIVE This study aim ed to compare the effects of increased dietary intakes of ALA and EPA+DHA on a range of atherogenic risk factors . DESIGN This was a placebo-controlled , parallel study involving 150 moderately hyperlipidemic subjects r and omly assigned to 1 of 5 interventions :  0.8 or 1.7 g EPA+DHA/d  , 4.5 or 9.5 g ALA/d , or an n-6 PUFA control for 6 mo . Fatty acids were incorporated into 25 g of fat spread and 3 capsules to be consumed daily . RESULTS The change in fasting or postpr and ial lipid , glucose , or insulin concentrations or in blood pressure was not significantly different after any of the n-3 PUFA interventions compared with the n-6 PUFA control . The mean ( + /- SEM ) change in fasting triacylglycerols after the 1.7-g/d EPA+DHA intervention ( -7.7 + /- 4.99 % ) was significantly ( P < 0.05 ) different from the change after the 9.5-g/d ALA intervention ( 10.9 + /- 4.5 % ) . The ex vivo susceptibility of LDL to oxidation was higher after the 1.7-g/d EPA+DHA intervention than after the control and ALA interventions ( P < 0.05 ) . There was no significant change in plasma alpha-tocopherol concentrations or in whole plasma antioxidant status in any of the groups . CONCLUSION At estimated biologically equivalent intakes , dietary ALA and EPA+DHA have different physiologic effects Long-term ( 30 wk ) effects on serum lipoproteins and insulin sensitivity of two diets , one with a low polyunsaturated to saturated fat ratio ( P : S 0.3 ) and one with a P : S of 1.0 , were compared in 14 patients with noninsulin-dependent diabetes mellitus ( NIDDM ) in a crossover study . Total and LDL-cholesterol levels declined by 7.6 % ( p less than 0.01 ) and 9.8 % ( p less than 0.01 ) , respectively , during the high P : S diet . VLDL- , HDL2- , and HDL3-cholesterol ; triacylglycerol ; and apolipoprotein A1 , A2 , and B levels were not affected by the change in P : S. Despite a modest increase of insulin-mediated glucose disposal at physiologic insulinemia during the high P : S diet , no influence was seen on glycemic control , and on blood glucose , plasma insulin , and C peptide responses to mixed meals . In conclusion , a linoleic-enriched diet in patients with NIDD causes a less atherogenic lipoprotein profile but does not influence glycemic control and carbohydrate tolerance BACKGROUND Results of epidemiologic studies and clinical trials indicate that moderate doses of n-3 fatty acids reduce the risk of cardiovascular disease and may improve prognosis . OBJECTIVE The objective was to evaluate the effect of a high-dose ethylester concentrate of n-3 fatty acids administered early after an acute myocardial infa rct ion ( MI ) on subsequent cardiac events and serum lipids . DESIGN Three hundred patients with acute MI were r and omly assigned to a daily dose of either 4 g highly concentrated n-3 fatty acids or corn oil , administered in a double-blind manner over 12 - 24 mo . Median follow-up time was 1.5 y. Clinical follow-up , including the drawing of blood sample s , was performed after 6 wk of treatment and later at 0.5-year intervals . RESULTS Forty-two ( 28 % ) patients in the n-3 group and 36 ( 24 % ) in the corn oil group experienced at least one cardiac event ( cardiac death , resuscitation , recurrent MI , or unstable angina ) . No significant difference in prognosis was observed between groups for single or combined cardiac events . Total cholesterol concentrations decreased in both groups , with no significant intergroup differences . On average , the monthly increase in HDL cholesterol was 1.11 % in the n-3 group and 0.55 % in the corn oil group ( P = 0.0016 ) . Triacylglycerol concentrations decreased by 1.30%/mo in the n-3 group , whereas they increased by 0.35%/mo in the corn oil group ( P < 0.0001 ) . CONCLUSION No clinical benefit of a high-dose concentrate of n-3 fatty acids compared with corn oil was found despite a favorable effect on serum lipids BACKGROUND Insulin resistance is associated with elevated plasma triacylglycerol , low HDL concentrations , elevated postpr and ial lipemia , and a predominance of small , dense LDLs ( sdLDLs ) . It has been hypothesized that the dietary ratio of n-6 to n-3 ( n-6:n-3 ) polyunsaturated fatty acids ( PUFAs ) may have favorable effects on these risk factors by increasing insulin sensitivity . OBJECTIVE The objective was to measure changes in insulin sensitivity , lipoprotein size , and postpr and ial lipemia after a 6-mo alteration in n-6:n-3 . DESIGN In a r and omized , parallel design in 258 subjects aged 45 - 70 y , we compared 4 diets providing 6 % of energy as PUFAs with an n-6:n-3 between 5:1 and 3:1 with a control diet that had an n-6:n-3 of 10:1 . The diets were enriched in alpha-linolenic acid , eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) , or both . Insulin sensitivity was assessed with the homeostatic model assessment of insulin resistance and the revised quantitative insulin sensitivity test . RESULTS Dietary intervention did not influence insulin sensitivity or postpr and ial lipase activities . Fasting and postpr and ial triacylglycerol concentrations were lower , and the proportion of sdLDLs decreased ( by 12.7 % ; 95 % CI : -22.9 % , 2.4 % ) , with an n-6:n-3 of approximately 3:1 , which was achieved by the addition of long-chain n-3 PUFAs ( EPA and DHA ) . CONCLUSIONS Decreasing the n-6:n-3 does not influence insulin sensitivity or lipase activities in older subjects . The reduction in plasma triacylglycerol after an increased intake of n-3 long-chain PUFAs results in favorable changes in LDL size The purpose of this study was to determine whether gamma-linolenate ( GLA ) supplementation would suppress weight regain following major weight loss . Fifty formerly obese humans were r and omized into a double-blind study and given either 890 mg/d of GLA ( 5 g/d borage oil ) or 5 g/d olive oil ( controls ) for 1 y. Body weight and composition and adipose fatty acids of fasting subjects were assessed at 0 , 3 , 12 , and 33 mo . After 12 subjects in each group had completed 1 y of supplementation , weight regain differed between the GLA ( 2.17 + /- 1.78 kg ) and control ( 8.78 + /- 2.78 kg ) groups ( P < 0.03 ) . The initial study was terminated , and all remaining subjects were assessed over a 6-wk period . Unblinding revealed weight regains of 1.8 + /- 1.6 kg in the GLA group and 7.6 + /- 2.1 kg in controls for the 13 and 17 subjects , respectively , who completed a minimum of 50 wk in the study . Weight regain did not differ in the remaining 10 GLA and 5 control subjects who completed < 50 wk in the study . In a follow-up study , a subgroup from both the original GLA ( GLA-GLA , n = 9 ) and the original control ( Control-GLA , n = 14 ) population s either continued or crossed over to GLA supplementation for an additional 21 mo . Interim weight regains between 15 and 33 mo were 6.48 + /- 1.79 kg and 6.04 + /- 2.52 kg for the GLA-GLA and Control-GLA groups , respectively . Adipose triglyceride GLA levels increased 152 % ( P < 0.0001 ) in the GLA group at 12 mo , but did not increase further after 33 mo of GLA administration . In conclusion , GLA reduced weight regain  in humans following major weight loss , suggesting a role for essential fatty acids in fuel partitioning in humans prone to obesity BACKGROUND In addition to the metabolic and cardiovascular benefits of omega-3 ( n-3 ) fatty acids , several studies have suggested an added weight loss-enhancing benefit to this supplement . OBJECTIVE The objective was to assess whether supplemental omega-3 fatty acids in conjunction with diet and exercise augment weight loss over a 6-mo period . DESIGN In a single-institution , placebo-controlled , r and omized clinical trial , 128 individuals with a body mass index ( in kg/m(2 ) ) between 26 and 40 were assigned to receive 5 omega-3 [ 3.0 g eicosapentaenoic acid ( EPA ) plus docosahexaenoic acid ( DHA ) at a 5:1 ratio ( EPA : DHA ) ] or placebo capsules daily in conjunction with lifestyle modification . The primary endpoint was weight loss ; secondary endpoints included metabolic and psychometric variables . Analyses were by intention-to-treat . RESULTS Overweight and obese individuals were assigned to the omega-3 arm ( n = 64 ) or to the placebo arm ( n = 64 ) . Subjects in both arms received dietary and exercise counseling . Eighty-one individuals completed the 24-wk study , and the dropout rate was 27 % . Subjects in both arms lost an average of > 5 % of their body weight . No significant differences in weight loss were observed between the omega-3 ( -5.2 kg ; 95 % CI : -6.0 , -4.4 kg ) and placebo ( -5.8 kg ; 95 % CI : -6.7 , -5.1 kg ) arms . The absolute mean ( ±SEM ) change difference was 0.61 ± 0.58 kg ( P = 0.29 ) . In addition , no significant differences in the other factors assessed were observed . CONCLUSION Omega-3 fatty acids were not effective as an adjunct for weight loss in this otherwise healthy , overweight population BACKGROUND Age-associated declines in muscle mass and function are major risk factors for an impaired ability to carry out activities of daily living , falls , prolonged recovery time after hospitalization , and mortality in older adults . New strategies that can slow the age-related loss of muscle mass and function are needed to help older adults maintain adequate performance status to reduce these risks and maintain independence . OBJECTIVE We evaluated the efficacy of fish oil-derived n-3 ( ω-3 ) PUFA therapy to slow the age-associated loss of muscle mass and function . DESIGN Sixty healthy 60 - 85-y-old men and women were r and omly assigned to receive n-3 PUFA ( n = 40 ) or corn oil ( n = 20 ) therapy for 6 mo . Thigh muscle volume , h and grip strength , one-repetition maximum ( 1-RM ) lower- and upper-body strength , and average power during isokinetic leg exercises were evaluated before and after treatment . RESULTS Forty-four subjects completed the study [ 29 subjects ( 73 % ) in the n-3 PUFA group ; 15 subjects ( 75 % ) in the control group ] . Compared with the control group , 6 mo of n-3 PUFA therapy increased thigh muscle volume ( 3.6 % ; 95 % CI : 0.2 % , 7.0 % ) , h and grip strength ( 2.3 kg ; 95 % CI : 0.8 , 3.7 kg ) , and 1-RM muscle strength ( 4.0 % ; 95 % CI : 0.8 % , 7.3 % ) ( all P < 0.05 ) and tended to increase average isokinetic power ( 5.6 % ; 95 % CI : -0.6 % , 11.7 % ; P = 0.075 ) . CONCLUSION Fish oil-derived n-3 PUFA therapy slows the normal decline in muscle mass and function in older adults and should be considered a therapeutic approach for preventing sarcopenia and maintaining physical independence in older adults . This study was registered at clinical trials.gov as NCT01308957 Marine oils are rich in polyunsaturated fatty acids ( PUFAs ) , including docosahexaenoic and eicosapentaenoic acid . These PUFAs are associated with health benefits and additional sustainable sources of marine oils are desirable . One of the source organisms is Calanus finmarchicus , a copepod endemic to the North Atlantic . PUFAs in the lipid fraction of this organism are largely in the form of wax esters . To assess the safety of these wax esters as a source of PUFAs , a r and omized , double-blinded , placebo-controlled clinical trial was conducted whereby 64 subjects consumed 2 g Calanus oil in capsule form daily for a period of one year . A group of 53 subjects consumed placebo capsules . At baseline , 6- , and 12-months , series of evaluations were conducted , including : vital signs , clinical chemistry and hematological evaluations , and adverse event reporting . Food intake and physical exercise were controlled by means of a question naire . There were no effects on Calanus oil treatment on any of the safety parameters measured . A slight increase in the incidence of eczema was reported in the Calanus oil group , but the response was minor in nature , not statistically significant after controlling for multiple comparisons , and could not be attributed to treatment OBJECTIVE We carried out a secondary analysis in high-risk patients with a previous myocardial infa rct ion ( MI ) and diabetes in the Alpha Omega Trial . We tested the hypothesis that in these patients an increased intake of the n-3 fatty acids eicosapentaenoic acid ( EPA ) , docosahexaenoic acid ( DHA ) , and α-linolenic acid ( ALA ) will reduce the incidence of ventricular arrhythmias and fatal MI . RESEARCH DESIGN AND METHODS A subgroup of 1,014 post-MI patients with diabetes aged 60–80 years was r and omly allocated to receive one of four trial margarines , three with an additional amount of n-3 fatty acids and one placebo for 40 months . The end points were ventricular arrhythmia – related events and fatal MI . The data were analyzed according to the intention-to-treat principle , using multivariable Cox proportional hazards models . RESULTS The patients consumed on average 18.6 g of margarine per day , which result ed in an additional intake of 223 mg EPA plus 149 mg DHA and /or 1.9 g ALA in the active treatment groups . During follow-up , 29 patients developed a ventricular arrhythmia – related events and 27 had a fatal MI . Compared with placebo patients , the EPA-DHA plus ALA group experienced less ventricular arrhythmia – related events ( hazard ratio 0.16 ; 95 % CI 0.04–0.69 ) . These n-3 fatty acids also reduced the combined end-point ventricular arrhythmia – related events and fatal MI ( 0.28 ; 0.11–0.71 ) . CONCLUSIONS Our results suggest that low-dose supplementation of n-3 fatty acids exerts a protective effect against ventricular arrhythmia – related events in post-MI patients with diabetes BACKGROUND The effects of eicosapentaenoic acid ( EPA ) on coronary artery disease have been previously reported ; however , those of the addition of EPA to strong statins on coronary plaque components and local inflammatory cytokines are not known . METHODS AND RESULTS A total of 95 patients who had been treated with strong statin for at least 6 months were r and omized into 2 groups : an EPA group ( additional treatment with EPA at 1,800 mg/day , n=48 ) or a control group ( no additional treatment , n=47 ) , for 6 months . The tissue characteristics of target coronary plaque in each patient were analyzed using IB-IVUS before and after treatment . We also measured plasma levels of inflammatory cytokines sample d in the coronary sinus ( CS ) and peripheral vein . A significant reduction in lipid volume ( 18.5 ± 1.3 to 15.0 ± 1.5 mm(3 ) , P=0.007 ) and a significant increase in fibrous volume ( 22.9 ± 0.8 to 25.6 ± 1.1 mm(3 ) , P=0.01 ) were observed in IB-IVUS image analyses in the EPA group , but no significant changes in the plaque components in the control group . CS levels of pentraxin 3 and monocyte chemoattractant protein-1 were lower after than before treatment with EPA ( 3.3 ± 2.1 to 2.6 ± 1.2 ng/ml , 120.4 ± 26.2 to 110.2 ± 26.8 pg/ml , P=0.015 and P=0.008 , respectively ) ; however , there were no significant changes in those inflammatory cytokines between pre- and post-treatment in the control group . CONCLUSIONS The addition of EPA was associated with reduced lipid volume in coronary plaques and decreased inflammatory cytokines OBJECTIVE To compare the effects of placebo and GLA on the course of mild diabetic neuropathy over 1 yr . RESEARCH DESIGN AND METHODS We entered 111 patients with mild diabetic neuropathy from seven centers into a r and omized , double-blind , placebo-controlled parallel study of GLA at a dose of 480 mg/day .  MNCV , SNAP , CMAP , hot and cold thresholds , sensation , tendon reflexes , and muscle strength were assessed by st and ard tests in upper and lower limbs . RESULTS For all 16 parameters , the change over 1 yr in response to GLA was more favorable than the change with placebo , and for 13 parameters , the difference was statistically significant . Sex , age , and type of diabetes did not influence the result , but treatment was more effective in relatively well-controlled than in poorly-controlled diabetic patients . CONCLUSIONS GLA had a beneficial effect on the course of diabetic neuropathy Diabetic control as judged by five criteria did not deteriorate after 6 months of fish oil compared to 6 months of olive oil supplementation in 16 patients with NIDDM who were eating a low fat , high complex carbohydrate diet .  Plasma total and VLDL triglyceride and cholesterol decreased significantly after fish oil supplementation ;  plasma total and HDL cholesterol concentrations did not change . The LDL cholesterol level was significantly increased with fish oil supplementation , suggesting that patients with NIDDM who are given a fish oil supplement to decrease the plasma total and VLDL triglyceride levels may also need further dietary and /or pharmaceutical therapy to maintain an LDL cholesterol level compatible with a low risk of coronary disease . The study emphasizes the safe use of fish oil over a 6-month period in diabetic patients Background Hypertension can be prevented by adopting healthy dietary patterns . Our aim was to assess the 4-year effect on blood pressure ( BP ) control of a r and omized feeding trial promoting the traditional Mediterranean dietary pattern . Methods The PREDIMED primary prevention trial is a r and omized , single-blinded , controlled trial conducted in Spanish primary healthcare centers . We recruited 7,447 men ( aged 55 to 80 years ) and women ( aged 60 to 80 years ) who had high risk for cardiovascular disease . Participants were assigned to a control group or to one of two Mediterranean diets . The control group received education on following a low-fat diet , while the groups on Mediterranean diets received nutritional education and also free foods ; either extra virgin olive oil , or nuts . Trained personnel measured participants ’ BP at baseline and once yearly during a 4-year follow-up . We used generalized estimating equations to assess the differences between groups during the follow-up . Results The percentage of participants with controlled BP increased in all three intervention groups ( P-value for within-group changes : P<0.001 ) . Participants allocated to either of the two Mediterranean diet groups had significantly lower diastolic BP than the participants in the control group ( −1.53 mmHg ( 95 % confidence interval ( CI ) −2.01 to −1.04 ) for the Mediterranean diet supplemented with extra virgin olive oil , and −0.65 mmHg ( 95 % CI -1.15 to −0.15 ) mmHg for the Mediterranean diet supplemented with nuts ) . No between-group differences in changes of systolic BP were seen . Conclusions Both the traditional Mediterranean diet and a low-fat diet exerted beneficial effects on BP and could be part of advice to patients for controlling BP . However , we found lower values of diastolic BP in the two groups promoting the Mediterranean diet with extra virgin olive oil or with nuts than in the control group . Trial registration Current Controlled Trials IS RCT Residual cardiovascular risk persists despite statins , yet outcome studies of lipid‐targeted therapies beyond low‐density lipoprotein cholesterol ( LDL‐C ) have not demonstrated added benefit . Triglyceride elevation is an independent risk factor for cardiovascular events . High‐dose eicosapentaenoic acid ( EPA ) reduces triglyceride‐rich lipoproteins without raising LDL‐C. Omega‐3s have postulated pleiotropic cardioprotective benefits beyond triglyceride‐lowering . To date , no large , multinational , r and omized clinical trial has proved that lowering triglycerides on top of statin therapy improves cardiovascular outcomes . The Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial ( REDUCE‐IT ; NCT01492361 ) is a phase 3b r and omized , double‐blinded , placebo‐controlled trial of icosapent ethyl , a highly purified ethyl ester of EPA , vs placebo . The main objective is to evaluate whether treatment with icosapent ethyl  reduces ischemic events in statin‐treated patients with high triglycerides at elevated cardiovascular risk . REDUCE‐IT enrolled men or women age ≥45 years with established cardiovascular disease or age ≥50 years with diabetes mellitus and 1 additional risk factor . R and omization required fasting triglycerides ≥150 mg/dL and < 500 mg/dL and LDL‐C > 40 mg/dL and ≤100 mg/dL with stable statin ( ± ezetimibe ) ≥4 weeks prior to qualifying measurements . The primary endpoint is a composite of cardiovascular death , nonfatal myocardial infa rct ion , nonfatal stroke , coronary revascularization , or unstable angina . The key secondary endpoint is the composite of cardiovascular death , nonfatal myocardial infa rct ion , or nonfatal stroke . Several secondary , tertiary , and exploratory endpoints will be assessed . Approximately 8000 patients have been r and omized at approximately 470 centers worldwide . Follow‐up will continue in this event‐driven trial until approximately 1612 adjudicated primary ‐efficacy endpoint events have occurred IMPORTANCE Dietary supplements have been proposed as a mechanism to improve health and prevent disease . OBJECTIVE To determine if supplementing diet with long-chain ω-3 polyunsaturated fatty acids or with macular xanthophylls results in a reduced rate of  cardiovascular disease  ( CVD ) . DESIGN , SETTING , AND PARTICIPANTS The Cardiovascular Outcome Study ( COS ) was an ancillary study of the Age-Related Eye Disease Study 2 ( AREDS2 ) , a factorial- design ed r and omized clinical trial of 4203 participants recruited from 82 US academic and community ophthalmology clinics , who were followed up for a median of 4.8 years . Individuals were eligible to participate if they were between the ages of 50 and 85 years , had intermediate or advanced age-related macular degeneration in 1 eye , and were willing to be r and omized . Participants with stable , existing CVD ( > 12 months since initial event ) were eligible to participate . Participants , staff , and outcome assessors were masked to intervention . INTERVENTIONS Daily supplementation with long-chain ω-3 polyunsaturated fatty acids ( 350-mg docosahexaenoic acid [ DHA ] + 650-mg eicosapentaenoic acid [ EPA ] ) , macular xanthophylls ( 10-mg lutein + 2-mg zeaxanthin ) , combination of the two , or matching placebos . These treatments were added to background therapy of the AREDS vitamin and mineral formulation for macular degeneration . MAIN OUTCOMES AND MEASURES A composite outcome of myocardial infa rct ion , stroke , and cardiovascular death with 4 prespecified secondary combinations of the primary outcome with hospitalized heart failure , revascularization , or unstable angina . RESULTS Study participants were primarily white , married , and highly educated , with a median age at baseline of 74 years . A total of 602 cardiovascular events were adjudicated , and 459 were found to meet 1 of the study definitions for a CVD outcome . In intention-to-treat analysis , no reduction in the risk of CVD or secondary CVD outcomes was seen for the DHA +  EPA ( primary outcome : hazard ratio [ HR ] , 0.95 ; 95 % CI , 0.78 - 1.17 ) or lutein + zeaxanthin  ( primary outcome : HR , 0.94 ; 95 % CI , 0.77 - 1.15 ) groups . No differences in adverse events or serious adverse event were seen by treatment group . The sample size was sufficient to detect a 25 % reduction in CVD events with 80 % power . CONCLUSIONS AND RELEVANCE Dietary supplementation of long-chain ω-3 polyunsaturated fatty acids or macular xanthophylls in addition to daily intake of minerals and vitamins did not reduce the risk of CVD in elderly participants with age-related macular degeneration . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00345176 OBJECTIVE To investigate the association between macronutrient intake and  type 2 diabetes risk in middle-aged Australian women . DESIGN A prospect i ve cohort study , with 6 years ( 2002 - 2007 ) of follow up . Dietary intake was assessed with a vali date d FFQ . Relative risks with 95 % confidence intervals were used to examine risk associations . SETTING Australian Longitudinal Study on Women 's Health , Australia . SUBJECTS Australian women ( n 8370 ) from the Australian Longitudinal Study on Women 's Health aged 45 - 50 years and free of type 2 diabetes at baseline . RESULTS After 6 years of follow-up , 311 women developed type 2 diabetes . After adjusting for sociodemographic , lifestyle and other dietary risk factors , MUFA , total n-3 PUFA , α-linolenic acid and total n-6 PUFA intakes were positively associated with the incidence of type 2 diabetes . The relative risks for type 2 diabetes for the highest compared with the lowest quintiles were 1·64 ( 95 % CI 1·06 , 2·54 ) , P = 0·04 for MUFA ; 1·55 ( 95 % CI 1·03 , 2·32 ) , P = 0·01 for n-3 PUFA ; 1·84 ( 95 % CI 1·25 , 2·71 ) , P < 0·01 for α-linolenic acid ; and 1·60 ( 95 % CI 1·03 , 2·48 ) , P = 0·04 for n-6 PUFA . Other dietary macronutrients were not significantly associated with diabetes risk . CONCLUSIONS The data indicate that consumption of MUFA , n-3 PUFA and n-6 PUFA may influence the risk of developing type 2 diabetes in women The number of individuals with age-related cognitive impairment  is rising dramatically in the UK and globally . There is considerable interest in the general hypothesis that improving the diet of older people may slow the progression of cognitive decline . To date , there has been little attention given to the possible protective role of n-3 long-chain polyunsaturated fatty acids ( n-3 LCPs ) most commonly found in oily fish , in age-related loss of cognitive function . The main research hypothesis of this study is that an increased dietary intake of n-3 LCPs will have a positive effect on cognitive performance in older people in the UK.To test this hypothesis , a double-blind r and omised placebo-controlled trial will be carried out among adults aged 70–79 years in which the intervention arm will receive daily capsules containing n-3 LCP ( 0.5 g/day docosahexaenoic acid and 0.2 g/day eicosapentaenoic acid ) while the placebo arm will receive daily capsules containing olive oil . The main outcome variable assessed at 24 months will be cognitive performance and a second major outcome variable will be retinal function . Retinal function tests are included as the retina is a specifically differentiated neural tissue and therefore represents an accessible window into the functioning of the brain . The overall purpose of this public-health research is to help define a simple and effective dietary intervention aim ed at maintaining cognitive and retinal function in later life . This will be the first trial of its kind aim ing to slow the decline of cognitive and retinal function in older people by increasing daily dietary intake of n-3 LCPs . The link between cognitive ability , visual function and quality of life among older people suggests that this novel line of research may have considerable public health importance Abstract Aims /hypothesisThe effect of n-3 fatty acid treatment on vibration perception thresholds ( VPTs ) and cutaneous microvascular reactivity is not known . We tested whether : ( 1 ) a 15–18 month treatment with high dose ( 4 g/day ) docosahexaenoic ( DHA ) plus eicosapentaenoic ( EPA ) acid improved VPT and microvascular reactivity in patients with non-alcoholic fatty liver disease ; and ( 2 ) there are associations between VPT , microvascular reactivity and metabolic variables . Methods In the completed single centre , r and omised , parallel group , placebo controlled Wessex Evaluation of fatty Liver and Cardiovascular markers in non-alcoholic fatty liver disease with OMacor thErapy ( WELCOME ) trial , we tested the effect of DHA+EPA on VPT at 125 Hz ( big toe ) and the cutaneous hyperaemic response ( forearm ) to arterial occlusion ( ratio of maximum to resting blood flux [ MF/RF ] ) . Allocation and dispensing was carried out by an independent research pharmacist ; all participants and research team members were blinded to group assignment . Results In all , 51 and 49 patients were r and omised to placebo and DHA+EPA  , respectively ( mean age 51.4 years ) . Of these , 32 had type 2 diabetes . Forty-six ( placebo ) and 47 ( DHA+EPA ) patients completed the study ; there were no important adverse ( or unexpected ) effects or side effects . In multivariable-adjusted regression models ( intention-to-treat analyses ) , DHA+EPA treatment was associated with an increase in VPT ( β coefficient 1.49 [ 95 % CI 0.04 , 2.94 ] , p = 0.04 ) . For VPT , the adjusted mean differences ( 95 % CIs ) in the placebo and DHA+EPA treatment groups were −0.725 ( −1.71 , 0.25 ) and 0.767 ( −0.21 , 1.75 ) m/s2 , respectively . With DHA+EPA treatment , there was no change in MF/RF ( β coefficient 0.07 [ 95 % CI −0.56 , 0.70 ] , p = 0.84 ) , the adjusted mean differences ( 95 % CIs ) in the placebo and DHA+EPA treatment groups were −0.549 ( −1.03 , −0.07 ) and −0.295 ( −0.77 , 0.18 ) respectively . VPT was independently associated with age ( β coefficient 0.019 [ 95 % CI 0.010 , 0.029 ] , p < 0.0001 ) and MF/RF ( β coefficient −0.074 [ 95 % CI −0.132 , −0.016 ] , p = 0.013 ) , but not with diabetes ( p = 0.38 ) . Conclusions /interpretationHigh dose n-3 fatty acid treatment did not improve measures of microvascular function or vibration perception . Ageing and microvascular reactivity are associated with a measure of peripheral nerve function . Trial registration : Clinical Trials.gov NCT00760513 Funding : The study was funded by the National Institute for Health Research UK and Diabetes UK OBJECTIVE Dietary n-3 polyunsaturated fatty acids , including eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) , prevent insulin resistance and stimulate mitochondrial biogenesis in rodents , but the findings of translational studies in humans are thus far ambiguous . The aim of this study was to evaluate the influence of EPA and DHA on insulin sensitivity , insulin secretion , and muscle mitochondrial function in insulin-resistant , nondiabetic humans using a robust study design and gold-st and ard measurements . RESEARCH DESIGN AND METHODS Thirty-one insulin-resistant adults received 3.9 g/day  EPA+DHA or placebo for 6 months in a r and omized double-blind study . Hyperinsulinemic-euglycemic clamp with somatostatin was used to assess hepatic and peripheral insulin sensitivity . Postpr and ial glucose disposal and insulin secretion were measured after a meal . Measurements were performed at baseline and after 6 months of treatment . Abdominal fat distribution was evaluated by MRI . Muscle oxidative capacity was measured in isolated mitochondria using high-resolution respirometry and noninvasively by magnetic resonance spectroscopy . RESULTS Compared with placebo , EPA+DHA did not alter peripheral insulin sensitivity , postpr and ial glucose disposal , or insulin secretion . Hepatic insulin sensitivity , determined from the suppression of endogenous glucose production by insulin , exhibited a small but significant improvement with EPA+DHA compared with placebo .  Muscle mitochondrial function was unchanged by EPA+DHA or placebo . CONCLUSIONS This study demonstrates that dietary EPA+DHA does not improve peripheral glucose disposal , insulin secretion , or skeletal muscle mitochondrial function in insulin-resistant nondiabetic humans . There was a modest improvement in hepatic insulin sensitivity with EPA+DHA , but this was not associated with any improvements in clinical ly meaningful outcomes Background Optimal macronutrient distribution of weight loss diets has not been established . The distribution of energy from carbohydrate and fat has been observed to promote differential plasma lipid responses in previous weight loss studies , and insulin resistance status may interact with diet composition and affect weight loss and lipid responses . Methods and Results Overweight and obese women ( n=245 ) were enrolled in a 1‐year behavioral weight loss intervention  and r and omly assigned to 1 of 3 study groups : a lower fat ( 20 % energy ) , higher carbohydrate ( 65 % energy ) diet ; a lower carbohydrate ( 45 % energy ) , higher fat ( 35 % energy ) diet ; or a walnut‐rich , higher fat ( 35 % energy ) , lower carbohydrate ( 45 % energy ) diet . Blood sample s and data available from 213 women at baseline and at 6 months were the focus of this analysis . Triglycerides , total cholesterol , and high‐ and low‐density lipoprotein cholesterol were quantified and compared between and within groups . Triglycerides decreased in all study arms at 6 months ( P<0.05 ) . The walnut‐rich diet increased high‐density lipoprotein cholesterol more than either the lower fat or lower carbohydrate diet ( P<0.05 ) . The walnut‐rich diet also reduced low‐density lipoprotein cholesterol in insulin‐sensitive women , whereas the lower fat diet reduced both total cholesterol and high‐density lipoprotein cholesterol in insulin‐sensitive women ( P<0.05 ) . Insulin sensitivity and C‐reactive protein levels also improved . Conclusions Weight loss was similar across the diet groups , although insulin‐sensitive women lost more weight with a lower fat , higher carbohydrate diet versus a higher fat , lower carbohydrate diet . The walnut‐rich , higher fat diet result ed in the most favorable changes in lipid levels . Clinical Trial Registration URL : http://www . clinical trials.gov . Unique identifier : NCT01424007 Phytoestrogens are increasingly incorporated into the diet of menopausal women . However , there are limited data on the efficacy of flaxseed on the consequences of estrogen deficiency in menopausal women . The purpose of the study was to assess the effects of flaxseed incorporation into the diet of healthy menopausal women . One hundred and ninety-nine menopausal women were r and omly assigned to consume 40 g flaxseed/d ( n = 101 ) or wheat germ placebo ( n = 98 ) for 12 months . At baseline and at month 12 , serum levels of lipids , bone mineral density ( BMD ) , and menopausal symptoms were evaluated . Statistical analysis was performed under the intention to treat principle . Flaxseed reduced serum total ( -0.20 + /- 0.51 mmol/liter ; P = 0.012 ) and high-density lipoprotein ( -0.08 + /- 0.24 mmol/liter ; P = 0.031 ) cholesterol concentrations compared with wheat germ placebo .  BMD did not differ significantly between the two arms . Both flaxseed and wheat germ reduced ( P < 0.0001 ) the severity scores of menopausal symptoms , but no statistical difference was found between the two arms . Our findings suggest that 1-yr incorporation of flaxseed into the diet produced a favorable , but not clinical ly significant , effect on blood cholesterol and caused no significant change in BMD or symptoms in healthy menopausal women Background The optimization of preventive strategies in patients at high risk of cardiovascular events and the evaluation of bottlenecks and limitations of transferring current guidelines to the real world of clinical practice are important limiting steps to cardiovascular prevention . Treatment with n-3 polyunsaturated fatty acids improves prognosis after myocardial infa rct ion , but evidence of this benefit is lacking in patients at high cardiovascular risk , but without a history of myocardial infa rct ion . Methods / design Patients were eligible if their general practitioner ( GP ) considered them at high cardiovascular risk because of a cardiovascular disease other than myocardial infa rct ion , or multiple risk factors ( at least four major risk factors in non-diabetic patients and one in diabetics ) . Patients were r and omly allocated to treatment with n-3 polyunsaturated fatty acids ( 1 g daily ) or placebo in a double-blind study and followed up for five years by their GPs to assess the efficacy of the treatment in preventing cardiovascular mortality ( including sudden death ) and hospitalization for cardiovascular reasons . The secondary , epidemiological , aim of the study is to assess whether it is feasible to adopt current guidelines in everyday clinical practice , with a view to optimizing all the available preventive strategies in people at high cardiovascular risk . A nation-wide network of 860 GPs admitted 12,513 patients to the study between February 2004 and March 2007 . The mean age was 64 years and 62 % were males . Diabetes mellitus plus one or more cardiovascular risk factors was the main inclusion criterion ( 47 % ) . About 30 % of patients were included because of a history of atherosclerotic cardiovascular disease , 21 % for four or more risk factors , and less than 1 % for other reasons . Discussion The Rischio and Prevenzione ( R&P ) project provides a feasible model to test the efficacy of n-3 polyunsaturated fatty acid therapy in patients at high cardiovascular risk with no history of myocardial infa rct ion , and to assess how to implement recommended preventive strategies in general practice .Trial registration Clinical Trials.gov Background / Objectives : The antiestrogen , Raloxifene ( Ral ) is an effective breast cancer chemopreventive agent . Omega-3 fatty acids ( n-3FA ) may inhibit mammary carcinogenesis . On the basis of their mechanisms of action , we test the hypothesis that a combination of n-3FA and Ral may be superior in reducing select biomarkers of breast cancer risk in women . Subjects/ Methods : Postmenopausal women at increased risk for breast cancer ( breast density ⩾25 % ) were r and omized to : ( 1 ) no intervention ; ( 2 ) Ral 60 mg ; ( 3 ) Ral 30 mg ; ( 4 ) n-3FA ( Lovaza ) 4 g and ( 5 ) Lovaza 4 g+Ral 30 mg for 2 years . Reduction in breast density is the primary end point of the study . We report preliminary data on feasibility , compliance and changes in secondary end points related to IGF-I signaling , estrogen metabolism , oxidative stress and inflammation in the first group of 46 women who completed 1 year of the study . Results : All interventions were well tolerated with excellent compliance ( 96±1 % overall ) by pill count and also supported by the expected rise in both serum n-3FA and n-3FA/Omega-6 fatty acids ( n-6FA ) ratio in women r and omized to groups 4 and 5 ( P<0.05 ) . Lovaza  decreased serum triglycerides and increased high-density lipoprotein ( HDL ) cholesterol compared with control ( P<0.05 for both ) . Ral  reduced serum IGF-1 in a dose-dependent manner ( P<0.05 ) while Lovaza did not . Lovaza had no effect on IGF-1 or IGFBP-3 . None of the other biomarkers were affected by our treatment . Conclusion : The combination of Lovaza and Ral is a feasible strategy that may be recommended in future breast cancer chemoprevention trials Background : Estimation of the intake of oily fish at a population level is difficult . The measurement of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) in biological sample s may provide a useful biomarker of intake . Objective : We identified the most appropriate biomarkers for the assessment of habitual oily fish intake and changes in intake by elucidating the dose- and time-dependent response of EPA and DHA incorporation into various biological sample s that represent roles in fatty acid transport , function , and storage . Design : This was a double-blind , r and omized , controlled intervention trial in 204 men and women that lasted 12 mo .  EPA and DHA capsules were provided in a manner to reflect sporadic consumption of oily fish ( ie , 1 , 2 , or 4 times/wk ) .  EPA and DHA  were assessed at 9 time points over 12 mo in 9 sample types ( red blood cells , mononuclear cells , platelets , buccal cells , adipose tissue , plasma phosphatidylcholine , triglycerides , cholesteryl esters , and nonesterified fatty acids ) . Results : A dose response ( P < 0.05 ) was observed for EPA and DHA in all pools except for red blood cell EPA ( P = 0.057 ) . EPA and DHA measures in plasma phosphatidylcholine and platelets were best for the discrimination between different intakes ( P < 0.0001 ) . The rate of incorporation varied between sample types , with the time to maximal incorporation ranging from days ( plasma phosphatidylcholine ) to months ( mononuclear cells ) to > 12 mo ( adipose tissue ) . Conclusions : Plasma phosphatidylcholine EPA plus DHA was identified as the most suitable biomarker of acute changes in  EPA and DHA intake , and platelet and mononuclear cell EPA plus DHA were the most suitable biomarkers of habitual intake . This trial was registered at Current Controlled Trials ( www.controlled-trials.com ) as IS RCT N48398526 Dietary supplementation with n‐3 fatty acids from fish oil alleviates inflammation in various chronic inflammatory disease states . Reductions in the production of pro‐inflammatory cytokines interleukin 1β ( IL‐1β ) , tumour necrosis factor alpha ( TNF‐α ) , and interleukin 6 ( IL‐6 ) have been seen in humans after short‐term n‐3 fatty acid supplementation . We investigated long‐term effects of dietary n‐3 fatty acids on circulating cytokine concentrations and on ex vivo stimulated whole‐blood production of IL‐1β , TNF‐α and interleukin 1 receptor antagonist ( IL‐1Ra ) , the naturally occurring antagonist of IL‐1 . A total of 58 monks with a mean age of 56 years were r and omized into four groups and their diets were supplemented with 0 , 3 , 6 , or 9 g of fish oil , providing 0 , 1.06 , 2.13 or 3.19 g of n‐3 fatty acids per day . Subjects received equal amounts of saturated fatty acids , vitamin E and cholesterol . Compliance was excellent and erythrocyte fatty acid profiles closely reflected the amounts of n‐3 fatty acids ingested . In the group receiving 9 g of fish oil per day , no influence of n‐3 fatty acids on circulating cytokine concentrations was observed relative to placebo . Endotoxin‐stimulated whole‐blood cytokine production was measured at 26 and 52 weeks after the start and at 4 , 8 and 26 weeks after cessation of supplementation . In all groups , the production of IL‐1β and IL‐1Ra was higher during supplementation than afterwards . However , no differences in cytokine production were noted between the placebo group and the various treatment groups at any point in time . Our results suggest that long‐term supplementation of fish oil does not affect ex vivo cytokine production in man & NA;The PREvención con DIeta MEDiterránea ( PREDIMED ) trial showed that Mediterranean diets ( MedDiets ) supplemented with either extravirgin olive oil or nuts reduced cardiovascular events , particularly stroke , compared with a control , lower fat diet . The mechanisms of cardiovascular protection remain unclear . We evaluated the 1-year effects of supplemented MedDiets on 24-hour ambulatory blood pressure ( BP ) , blood glucose , and lipids . R and omized , parallel- design , controlled trial was conducted in 2 PREDIMED sites .  Diets were ad libitum , and no advice on increasing physical activity or reducing sodium intake was given . Participants were 235 subjects ( 56.5 % women ; mean age , 66.5 years ) at high cardiovascular risk ( 85.4 % with hypertension ) . Adjusted changes from baseline in mean systolic BP were −2.3 ( 95 % confidence interval [ CI ] , −4.0 to −0.5 ) mm Hg and −2.6 ( 95 % CI , −4.3 to −0.9 ) mm Hg in the MedDiets with olive oil and the MedDiets with nuts , respectively , and 1.7 ( 95 % CI , −0.1 to 3.5 ) mm Hg in the control group ( P<0.001 ) . Respective changes in mean diastolic BP were −1.2 ( 95 % CI , −2.2 to −0.2 ) , −1.2 ( 95 % CI , −2.2 to −0.2 ) , and 0.7 ( 95 % CI , −0.4 to 1.7 ) mm Hg ( P=0.017 ) . Daytime and nighttime BP followed similar patterns . Mean changes from baseline in fasting blood glucose were −6.1 , −4.6 , and 3.5 mg/dL ( P=0.016 ) in the MedDiets with olive oil , MedDiets with nuts , and control diet , respectively ; those of total cholesterol were −11.3 , −13.6 , and −4.4 mg/dL ( P=0.043 ) , respectively . In high-risk individuals , most with treated hypertension , MedDiets supplemented with extravirgin olive oil or nuts  reduced 24-hour ambulatory BP , total cholesterol , and fasting glucose . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : IS RCT N35739639 BACKGROUND Long-chain polyunsaturated fatty acid omega-3 levels are decreased in the hepatic tissue of patients with nonalcoholic fatty liver disease .  Polyunsaturated fatty acids are negative regulators of hepatic lipogenesis and attenuate the inflammatory response in mice . AIM To investigate whether polyunsaturated fatty acid may be effective in the treatment of nonalcoholic fatty liver disease . METHODS Forty patients with nonalcoholic fatty liver disease were r and omized into two groups for treatment of 6 months duration . Group DP ( n=20 ) received an AHA recommended diet and polyunsaturated fatty acid 2g/day ; Group D ( n=20 ) received only the AHA regular diet . Outcome measurements were fatty liver assessed by abdominal ultrasound , liver aminotransferase and tumour necrosis factor-alpha serum levels , and insulin resistance assessed by HOMA(IR ) . RESULTS After 6 months of treatment , the DP group displayed a decrease in alanine aminotransferase levels ( p<0.01 ) , as well as in triglyceride levels ( p<0.01 ) , serum tumour necrosis factor-alpha levels ( p<0.05 ) and in HOMA(IR ) ( p<0.05 ) . In the D group , no significant modification was observed . In the DP group , complete fatty liver regression was observed in 33.4 % of the patients , and an overall reduction in 50 % . In contrast , no patient achieved complete regression in the D group , whereas some amount of reduction occurred in 27.7 % of the patients ; the remaining 72.2 % did not change . CONCLUSION Our results indicate that alanine aminotransferase , triglyceride and serum tumour necrosis factor-alpha levels , as well as fatty liver improved after polyunsaturated fatty acid administration HYPOTHESIS The principle aim of the current study is to test the hypothesis that the long-term use of highly purified EPA ( eicosapentaenoic acid : 1800 mg/day ) , in addition to HMG-CoA reductase inhibitor , is effective in preventing cardiovascular events in Japanese patients with hypercholesterolemia . BACKGROUND Epidemiological and clinical evidence suggest that intake of long-chain polyunsaturated n-3 fatty acids ( PUFAs ) , which are abundant in fish , might have a significant role in the prevention of coronary artery disease , as marine PUFAs have multiple biological functions through lipid-dependent and lipid-independent mechanisms . METHODS The Japan EPA Lipid Intervention Study ( JELIS ) is a prospect i ve , r and omized , open-label , blinded end point trial including both primary and secondary prevention strata , with a maximum follow-up of 5 years . Its main purpose is to examine the clinical effectiveness of EPA oil given as an additional treatment to patients taking HMG-CoA reductase inhibitors for hypercholesterolemia . A primary end point is major coronary events : sudden cardiac death , fatal and nonfatal myocardial infa rct ion , and unstable angina pectoris including hospitalization for documented ischemic episodes , and events of angioplasty/stenting or coronary artery bypass grafting . Secondary end points include all-cause mortality , stroke , peripheral artery disease , and cancer . Baseline study composition comprises 15,000 participants ( 4204 men and 10,796 women ) in the primary prevention stratum and 3645 ( 1656 men and 1989 women ) in the secondary stratum . The minimum age is 40 years for men , women are required to be postmenopausal , and all patients must be < or = 75 years of age . The mean age of participants is 61 years , and 69 % are female . The schedule for plasma fatty acid composition measurement is as follows : at baseline , at 6 month , and yearly thereafter . The mean baseline total and low-density lipoprotein cholesterol levels were 275 mg/dL ( 7.1 mmol/L ) and 180 mg/dL ( 4.6 mmol/L ) . RESULTS Results are expected in 2005 . CONCLUSION JELIS is a large clinical trial that will evaluate whether EPA can make an additional improvement in mortality and morbidity of coronary artery disease beyond that of HMG-CoA reductase inhibitor treatment BACKGROUND Trials have shown a beneficial effect of n-3 polyunsaturated fatty acids in patients with a previous myocardial infa rct ion or heart failure . We evaluated the potential benefit of such therapy in patients with multiple cardiovascular risk factors or atherosclerotic vascular disease who had not had a myocardial infa rct ion . METHODS In this double-blind , placebo-controlled clinical trial , we enrolled a cohort of patients who were followed by a network of 860 general practitioners in Italy . Eligible patients were men and women with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infa rct ion . Patients were r and omly assigned to n-3 fatty acids ( 1 g daily ) or placebo ( olive oil ) . The initially specified primary end point was the cumulative rate of death , nonfatal myocardial infa rct ion , and nonfatal stroke . At 1 year , after the event rate was found to be lower than anticipated , the primary end point was revised as time to death from cardiovascular causes or admission to the hospital for cardiovascular causes . RESULTS Of the 12,513 patients enrolled , 6244 were r and omly assigned to n-3 fatty acids and 6269 to placebo . With a median of 5 years of follow-up , the primary end point occurred in 1478 of 12,505 patients included in the analysis ( 11.8 % ) , of whom 733 of 6239 ( 11.7 % ) had received n-3 fatty acids and 745 of 6266 ( 11.9 % ) had received placebo ( adjusted hazard ratio with n-3 fatty acids , 0.97 ; 95 % confidence interval , 0.88 to 1.08 ; P=0.58 ) . The same null results were observed for all the secondary end points . CONCLUSIONS In a large general- practice cohort of patients with multiple cardiovascular risk factors , daily treatment with n-3 fatty acids did not reduce cardiovascular mortality and morbidity . ( Funded by Società Prodotti Antibiotici and others ; Clinical Trials.gov number , NCT00317707 . ) Consumption of fish or fish oils rich in the n-3 long chain PUFA EPA and DHA may improve multiple risk factors for CVD . The objective of this study was to determine whether regular consumption of foods enriched with n-3 long-chain PUFA can improve n-3 long-chain PUFA status ( erythrocytes ) and cardiovascular health .  Overweight volunteers with high levels of triacylglycerols ( TG ; > 1.6 mmol/l ) were enrolled in a 6-month dietary intervention trial conducted in Adelaide ( n 47 ) and Perth ( n 39 ) , and r and omised to consume control foods or n-3-enriched foods  to achieve an EPA + DHA intake of 1 g/d . Test foods were substituted for equivalent foods in their regular diet .  Erythrocyte fatty acids , plasma TG and other CVD risk factors were monitored at 0 , 3 and 6 months . There were no significant differences between groups for blood pressure , arterial compliance , glucose , insulin , lipids , C-reactive protein ( CRP ) or urinary 11-dehydro-thromboxane B2 ( TXB2 ) over 6 months , even though regular consumption of n-3-enriched foods increased  EPA + DHA intake from 0.2 to 1.0 g/d . However , the n-3 long-chain PUFA content of erythrocytes increased by 35 and 53 % at 3 and 6 months , respectively , in subjects consuming the n-3-enriched foods . These increases were positively associated with measures of arterial compliance and negatively associated with serum CRP and urinary 11-dehydro-TXB2 excretion . Sustainable increases in dietary intakes and erythrocyte levels of n-3 long-chain PUFA can be achieved through regular consumption of suitably enriched processed foods . Such increases may be associated with reduced CV risk BACKGROUND Although dietary omega-3 ( n-3 ) fatty acids may confer some cardiovascular benefits , it is unclear whether these nutrients may also unfavorably affect risk of type 2 diabetes ( T2D ) . OBJECTIVE We evaluated whether dietary omega-3 fatty acids and fish consumption were associated with increased risk of T2D . DESIGN This was a prospect i ve study of 36,328 women ( mean age : 54.6 y ) who participated in the Women 's Health Study and who were followed from 1992 to 2008 .  Incident T2D was self-reported and vali date d primarily through the collection of supplementary information from participants . Information on omega-3 and fish intakes was obtained by using a vali date d food-frequency question naire . We used Cox proportional hazard models to estimate adjusted relative risks . RESULTS During an average follow-up of 12.4 y , 2370 women developed T2D .  Marine but not plant-based omega-3 fatty acids were positively associated with incident T2D . From the lowest to highest quintiles of marine omega-3 intake , the multivariable-adjusted hazard ratios ( 95 % CIs ) for T2D were 1.0 ( referent ) , 1.17 ( 1.03 , 1.33 ) , 1.20 ( 1.05 , 1.38 ) , 1.46 ( 1.28 , 1.66 ) , and 1.44 ( 1.25 , 1.65 ) , respectively ( P for trend < 0.0001 ) . A similar association was observed with fish intake , but additional adjustment for docosahexaenoic acid led to the elimination of the association . The relation between marine omega-3 fatty acids and T2D was observed in hypertensive and nonhypertensive subjects and in women who reported infrequent fish consumption . CONCLUSION Our data suggest an increased risk of T2D with the intake of long-chain omega-3 fatty acids , especially with higher intakes ( ≥ 0.20 g omega-3/d or ≥ 2 servings of fish/d ) . The Women 's Health Study was registered at clinical trials.gov as NCT00000479 BACKGROUND The blood pressure ( BP ) effects of changing the total fat intake and saturated-unsaturated fat ratio are still controversial , despite evidence that saturated fat-enriched diets are associated with higher BP levels . This double-blind , r and omized crossover study evaluated a possible difference between antihypertensive effects of monounsaturated ( MUFA ) ( extra-virgin olive oil ) and polyunsaturated fatty acids ( PUFA ) ( sunflower oil ) . METHODS Twenty-three hypertensive patients were assigned r and omly to MUFA or PUFA diet for 6 months and then crossed over to the other diet ; effects were evaluated on the basis of daily antihypertensives needed . RESULTS Diets high in MUFA and PUFA differed from the habitual diet for reduced total and saturated fats , whereas they differed from each other for MUFA ( 17.2 % vs 10.5 % ) and PUFA content ( 3.8 % vs 10.5 % ) . Resting BP was significantly lower ( P = .05 for systolic BP ; P = .01 for diastolic BP ) at the end of the MUFA diet compared with the PUFA diet .  Blood pressure responses during sympathetic stimulation with the cold pressor test and isometric exercise were similar . Daily drug dosage was significantly reduced during the MUFA but not the PUFA diet ( -48 % vs - 4 % , P<.005 ) . All patients receiving the PUFA diet required antihypertensive treatment , whereas 8 of those receiving the MUFA diet needed no drug therapy . CONCLUSIONS A slight reduction in saturated fat intake , along with the use of extra-virgin olive oil , markedly lowers daily antihypertensive dosage requirement , possibly through enhanced nitric oxide levels stimulated by polyphenols PURPOSE The Age-Related Eye Disease Study ( AREDS ) demonstrated beneficial effects of oral supplementation with antioxidant vitamins and minerals on the development of advanced age-related macular degeneration ( AMD ) in persons with at least intermediate AMD ( bilateral large drusen with or without pigment changes ) . Observational data suggest that other oral nutrient supplements might further reduce the risk of progression to advanced AMD . The primary purpose of the Age-Related Eye Disease Study 2 ( AREDS2 ) is to evaluate the efficacy and safety of lutein plus zeaxanthin ( L+Z ) and /or ω-3 long-chain polyunsaturated fatty acid ( LCPUFA ) supplementation in reducing the risk of developing advanced AMD . The study also assesses the reduction in zinc and the omission of β-carotene from original AREDS formulation . DESIGN Multicenter , phase III , r and omized , controlled clinical trial . PARTICIPANTS Persons aged 50 to 85 with bilateral intermediate AMD or advanced AMD in 1 eye . METHODS All participants were r and omly assigned to placebo ( n = 1012 ) , L+Z ( 10 mg/2 mg ; n = 1044 ) , ω-3 LCPUFAs ( eicosapentaenoic acid + docosahexaenoic acid [ 650 mg/350 mg ] ; n = 1069 ) , or the combination of L+Z and ω-3 LCPUFAs ( n = 1078 ) . All participants were offered a secondary r and omization to 1 of 4 variations of the original AREDS formulation keeping vitamins C ( 500 mg ) and E ( 400 IU ) and copper ( 2 mg ) unchanged while varying zinc and β-carotene as follows : Zinc remains at the original level ( 80 mg ) , lower only zinc to 25 mg , omit β-carotene only , or lower zinc to 25 mg and omit β-carotene . MAIN OUTCOME MEASURES Progression to advanced AMD determined by central ized grading of annual fundus photographs . RESULTS We enrolled 4203 participants at 82 clinical centers located in the United States . Population characteristics at baseline were as follows : Mean age , 74 years ; 57 % female ; 97 % white ; 7 % current smokers ; 19 % with prior cardiovascular disease ; and 44 % and 50 % taking statin-class cholesterol-lowering drugs and aspirin , respectively . Ocular characteristics include 59 % with bilateral large drusen , 32 % with advanced AMD in 1 eye and mean visual acuity of 20/32 in eyes without advanced AMD . CONCLUSIONS This report presents the AREDS2 study design and the participants ' baseline demographic and ocular characteristics Higher intake of seafish or oil rich in long-chain omega-3 polyunsaturated fatty acids ( LC-n3-FA ) may be beneficial for the aging brain . We tested in a prospect i ve interventional design whether high levels of supplementary LC-n3-FA would improve cognition , and addressed potential mechanisms underlying the effects . Sixty-five healthy subjects ( 50 - 75 years , 30 females ) successfully completed 26 weeks of either fish oil ( 2.2 g/day LC-n3-FA ) or placebo intake . Before and after the intervention period , cognitive performance , structural neuroimaging , vascular markers , and blood parameters were assayed . We found a significant increase in executive functions after LC-n3-FA compared with placebo ( P = 0.023 ) . In parallel , LC-n3-FA exerted beneficial effects on white matter microstructural integrity and gray matter volume in frontal , temporal , parietal , and limbic areas primarily of the left hemisphere , and on carotid intima media thickness and diastolic blood pressure . Improvements in executive functions correlated positively with changes in omega-3-index and peripheral brain-derived neurotrophic factor , and negatively with changes in peripheral fasting insulin . This double-blind r and omized interventional study provides first-time evidence that LC-n3-FA exert positive effects on brain functions in healthy older adults , and eluci date s underlying mechanisms . Our findings suggest novel strategies to maintain cognitive functions into old age The effects of fish oil ( FO ) supplementation on glycaemic control are unclear , and positive effects may occur only when the phospholipid content of tissue membranes exceeds 14 % as n-3 PUFA . Subjects ( n 36 , thirty-three completed ) were paired based on metabolic parameters and allocated into a parallel double-blind r and omised trial with one of each pair offered daily either 6 g of FO ( 3·9 g n-3 PUFA ) or 6 g of maize oil ( MO ) for 9 months . Hyperinsulinaemic-euglycaemic-euaminoacidaemic ( HIEGEAA ) clamps ( with [ 6,6 2H2 glucose ] ) were performed at the start and end of the intervention . Endogenous glucose production ( EGP ) and whole-body protein turnover ( WBPT ) were each measured after an overnight fast . The primary outcome involved the effect of oil type on insulin sensitivity related to glycaemic control . The secondary outcome involved the effect of oil type on WBPT . Subjects on  FO ( n 16 ) had increased erythrocyte n-3 PUFA concentrations > 14 % , whereas subjects on MO ( n 17 ) had unaltered n-3 PUFA concentrations at 9 % . Type of oil had no effect on fasting EGP , insulin sensitivity or total glucose disposal during the HIEGEAA clamp . In contrast , under insulin-stimulated conditions , total protein disposal ( P=0·007 ) and endogenous WBPT ( P=0·001 ) were both increased with FO . In an associated pilot study ( n 4 , three completed ) , although n-3 PUFA in erythrocyte membranes increased to > 14 % with the FO supplement , the enrichment in muscle membranes remained lower ( 8 % ; P<0·001 ) . In conclusion , long-term supplementation with FO , at amounts near the safety limits set by regulatory authorities in Europe and the USA , did not alter glycaemic control but did have an impact on WBPT Aims /hypothesisThe effect of n-3 fatty acid treatment on temperature perception as a sensory nerve function modality is uncertain . In patients with non-alcoholic fatty liver disease ( NAFLD ) both with and without type 2 diabetes , we : ( 1 ) tested whether 15–18 months ’ treatment with 4 g/day of docosahexaenoic plus eicosapentaenoic acid ( DHA+EPA ) improved hot ( HPT ) and cold ( CPT ) temperature perception thresholds and ( 2 ) explored factors associated with HPT and CPT , in a r and omised , double-blind , placebo-controlled trial . Methods The effect of treatment ( n = 44 ) on HPT , CPT and temperature perception index ( TPI : difference between HPT and CPT ) was measured at the big toe in 90 individuals without neuropathy ( type 2 diabetes ; n = 30 ) . Participants were r and omised 1:1 , using sequential numbering , by personnel independent from the trial team . All participants and all members of the research team were blinded to group assignment . Data were collected in the Southampton National Institute for Health Research Biomedical Research Centre . Treatment effects and the independence of associations were testing by regression modelling . Results Mean ± SD age was 50.9 ± 10.6 years . In men ( n = 53 ) and women ( n = 37 ) , HPTs ( ° C ) were 46.1 ± 5.1 and 43.1 ± 6.4 ( p = 0.02 ) , CPTs ( ° C ) were 22.7 ± 3.4 and 24.5 ± 3.6 ( p = 0.07 ) and TPIs ( ° C ) were 23.4 ± 7.4 and 18.7 ± 9.5 ( p = 0.008 ) , respectively . In univariate analyses , total body fat percentage ( measured by dual-energy x-ray absorptiometry [ DXA ] ) was associated with HPT ( r = –0.36 p = 0.001 ) , CPT ( r = 0.35 p = 0.001 ) and TPI ( r = 0.39 p = 0.0001 ) . In multivariable-adjusted regression models , adjusting for age , sex and other potential confounders , only body fat percentage was independently associated with HPT , CPT or TPI ( p = 0.006 , p = 0.006 and p = 0.002 , respectively ) . DHA+EPA treatment did not modify HPT , CPT or TPI ( p = 0.93 , p = 0.44 and p = 0.67 , respectively ) . There were no important adverse effects or side effects reported . Conclusions /interpretationHigher body fat percentage is associated with enhanced temperature perception . There was no benefit of treatment with high-dose n-3 fatty acids on the thresholds to detect hot or cold stimuli . Trial registration : Clinical Trials.gov NCT00760513 Funding : This work was supported by the National Institute for Health Research through the NIHR Southampton Biomedical Research Unit grant and by a Diabetes UK allied health research training fellowship awarded to KMcC ( Diabetes UK . BDA 09/0003937 ) OBJECTIVE To evaluate the effect of consuming a variety of foods enriched in long-chain n-3 fatty acids in low fish eaters . DESIGN Evaluation of reported dietary intakes in a 6-month , double-blind , r and omized , controlled parallel design trial . SUBJECTS/ SETTING Eighty-five men and women with overweight and mildly elevated triglyceride levels who have a low habitual intake of fish . INTERVENTION Subjects were r and omized to consume foods either enriched in long-chain n-3 fats or control foods ( not enriched ) . Subjects were asked to consume eight portions per day ( equivalent to approximately 1 g/day long-chain n-3 fatty acid if r and omized to the intervention ) . MAIN OUTCOME MEASURE Reported energy , macronutrient , and fatty acid intakes were measured by diet history , 3-day food records , and body weight . STATISTICAL ANALYSES Repeated measures analysis of variance , Kruskall-Wallis test , Pearson 's correlation coefficient , and Bl and -Altman plots were conducted . RESULTS The two groups did not differ in mean dietary intake of long-chain n-3 fatty acid intake at baseline ( 258 mg and 313 mg for the intervention and control groups , respectively ) . At 6 months the intervention group members increased their intake of long-chain n-3 fats 4.5-fold compared with baseline and with the control group ( P<.001 ) . The data from the diet histories correlated well with the food records for all reported macronutrient and fatty acid values . Food pattern analysis showed that milk ( 13.8 % ) , cereal ( 12.1 % ) , and bread ( 11.3 % ) contributed the most to the overall long-chain n-3 fatty acid intake in the intervention group . CONCLUSIONS This long-term study in free-living subjects indicates that population intakes of long-chain n-3 fatty acids could be substantially increased through the availability of a variety of n-3 fatty acid-enriched processed foods Dietary cod-liver oil containing eicosapentaenoic acid is effective on microvascular albumin leakage in diabetic patients with albuminuria . We determined the long-term effects of oral pure eicosapentaenoic acid ethyl ( EPA-E : 900 mg/day ) administration on diabetic nephropathy in non-insulin dependent diabetic ( NIDDM ) patients . The effects of EPA-E were determined by observing the changes of the index of urine albumin excretion level/urine creatinine ( Cr ) excretion level ( UAI ) , the ratio of beta 2-microglobulin excretion level/urine Cr excretion level ( beta 2-MG/Cr ) and the ratio of N-acetyl-D-glucosaminidase excretion level/urine Cr excretion level ( NAG/Cr ) at 3 , 6 and 12 months after the start of the treatment . Oral EPA-E administration immediately improved the increased UAI at 3 months after the start of treatment . A significant improvement of the UAI by EPA-E was sustained 12 months later . EPA E administration also tended to decrease the urine beta 2-MG/Cr ratio from 6 months , but the difference was statistically not significant . However , the urine NAG/Cr ratio was not changed by EPA-E administration . EPA-E administration did not affect blood pressure levels , glycemic control and lipid metabolism in these patients . The present data indicated that EPA-E administration improved increased albumin excretion in NIDDM patients with nephropathy and its effects on albuminuria sustained for at least 12 months after the start of treatment . However , tubular factors were not influenced by EPA-E administration Background There is some evidence in the literature that emphasising fish consumption may assist with weight loss . The aim was to assess the effects of advice to consume 2 fish meals per week in a weight loss diet . Methods A parallel r and omised placebo-controlled trial was conducted in 118 obese Australian adults ( mean BMI ± SD 31.3 ± 3.5 kg/m2 ; mean age ± SD 45 ± 10 y ; 28 % male ) . Participants received low calorie dietary advice + placebo ( 1 g olive oil ; Control ) , low calorie dietary advice emphasising fish + placebo ( Fish ) , or low calorie dietary advice emphasising fish diet + LCn3PUFA supplements ( Fish + S ) . Individualised advice targeted 2 MJ energy deficit ( 30%E fat , 45%E carbohydrate and 25%E protein ) with or without two servings ( 180 g ) fatty fish/wk . Results All groups lost weight at 12 months ( Control −4.5 kg vs. Fish −4.3 kg vs. Fish + S −3.3 kg ; p < 0.001 ) and percentage body fat ( Control : -1.5 % vs. Fish : -1.4 % vs. Fish + S : -0.7 % ; p < 0.001 ) but there were no significant differences between groups . Cardiovascular disease risk factors changed as expected from weight loss . Conclusions Advice to consume 2 fish meals per week did not enhance the effects on weight loss of a healthy low calorie diet . Trial registration ACTRN12608000425392 Background : Obesity , inflammation , insulin resistance and cardiovascular disease ( CVD ) risk are inter-related . Both weight-loss and long-chain n-3 polyunsaturated fatty acids ( LC n-3 PUFA ) are independently known to reduce metabolic risk , but the combined effects are unclear . Objective : This study examines whether addition of LC n-3 PUFA to a low fat/high carbohydrate weight-loss programme results in greater improvements in inflammation , insulin sensitivity and CVD risk , than weight-loss alone . Design : One hundred and sixteen overweight insulin-resistant women entered a 24-week r and omised intervention study . Thirty-nine women were r and omised to a weight-loss programme , with LC n-3 PUFA ( WLFO ) , 38 to a weight-loss programme with placebo oil ( WLPO ) , and 39 to receive placebo oil , with no weight-loss programme ( control ) . Results : Ninety-three women completed the study ( 35 WLFO , 32 WLPO and 26 control ) , with significant weight-loss in WLFO ( 10.8±1.0 % ) and WLPO ( 12.4±1.0 % ) compared to the control group ( P<0.0001 ) . The WLFO , but not WLPO or control group , showed significant increases in adipose tissue LC n-3 PUFA ( 0.34±0.20 vs 0.17±0.10 and 0.16±0.10 % DHA , P<0.0001 ) . Weight-loss showed significant improvements in insulin sensitivity ( P<0.001 ) , lipid profile ( triglycerides P<0.05 ) and inflammation ( sialic acid P<0.05 ) . Time*group effects showed significant decreases in triglycerides ( P<0.05 ) and increases in adiponectin ( P<0.01 ) with LC n-3 PUFA , in the WLFO vs WLPO groups . Conclusions : Weight-loss improved risk factors associated with CVD , with some additional benefits of LC n-3 PUFA on triglycerides and adiponectin . Given the current low dietary intake of LC n-3 PUFA , greater attention should be given to increase these fatty acids in the treatment of obesity The dietary approaches to stop hypertension ( DASH ) diet provides strong evidence for an optimal dietary pattern for blood pressure ( BP ) control ; however , investigation at the level of key foods in a dietary pattern is sparse . This study aim ed to assess the relationship between dietary patterns driven by key foods with BP in a sample of obese Australian adults . Secondary analysis was conducted on baseline data of 118 participants ( 45.1±8.4 years , mean BP=124.1±15.8/72.6±9.2 mm Hg ) recruited in a weight reduction r and omized controlled trial ( ACTRN12608000425392 ) . Dietary assessment was by a vali date d diet history interview . The average of three office BP measurements was taken . Factor analysis extracted dietary patterns and their relation to systolic BP ( SBP ) and diastolic BP ( DBP ) was analysed using multiple linear regression . Eight dietary patterns were identified based on leading foods : meat and alcohol ; seafood ; fats ; fruits and nuts ; legumes ; confectionery ; sweet foods ; and yeast extracts and seasonings . A lower SBP was associated with alignment with the fruit and nuts pattern ( β=−4.1 ( 95 % confidence interval −7.5 to −0.7 ) mm Hg ) and with seafood for DBP ( β=−2.4 ( −4.6 to −0.3 ) mm Hg ) . SBP and DBP were higher with yeast extract and seasonings ( β=4.3 ( 1.4–7.3 ) ; 2.5 ( 0.9–4.0 ) mm Hg , respectively ) . In obese adults attending for weight loss , dietary patterns that included larger amounts of fruits and nuts and /or seafood were associated with lower BP at baseline , whereas patterns that were characterised by yeast extract and seasonings were associated with higher BP To address preventive effects of n-3 PUFAs/LC n-3 PUFAs on CRTs , a r and omized controlled trial was conducted . One-hundred four experimental group participants were advised to increase intake of n-3 PUFAs , including fish/shell fish , fish oil supplements and perilla oils , and to decrease consumption of n-6 PUFAs and fats/oils as a whole for 24 months .  One-hundred one control group participants were only caution ed to reduce consumption of fats/oils as a whole . R and om allocation was satisfactorily attained , and participants sufficiently complied with our regimen . Intakes , plasma concentrations , and compositions of the RBC and sigmoid colon membranes of n-3 PUFAs , LC n-3 PUFAs , EPA and DHA increased , and the ratios of n-6 PUFAs/n-3 PUFAs and AA/LC n-3 PUFAs decreased without any adverse response . Twenty-four months after the intervention , the multivariate-adjusted hazard ratio ( 95 % confidence intervals ) was estimated to be 0.805 ( 0.536 - 1.209 ) with a signal towards the reduced CRT incidence We have implemented a r and omized controlled dietary intervention in patients polypectomized for tumors of the colorectum to eluci date potential beneficial effects of n-3 polyunsaturated fatty acids ( PUFAs ) on the development of colorectal tumors . Those individuals in the experimental group were advised not only to decrease their consumption of fats/oils as a whole and foods supplying n-6 PUFAs but also to increase intake of foods and supplements containing n-3 PUFAs , while those in the comparison group were caution ed to reduce intake of fats/oils as a whole . Patients ' compliance/adherence was monitored with a semi-quantitative food frequency question naire and by assessment of fatty acid concentrations in plasma , membranes of red blood cells and sigmoid colon sample s. As for endpoints to assess tumor suppressive effects of n-3 PUFAs , the number/multiplicity , sizes and incidence rates of colorectal tumors were compared between the experimental and comparison groups after 12 and 24 months of the dietary intervention . On the specified assumption , the number of pairs needed for achieving statistical significance was calculated to be approximately 60 - 80 . A r and omized controlled trial is under way to secure enough patients , sustain compliance/adherence and minimize dropouts Objective : To assess the influence of a Mediterranean dietary pattern ( MeDiet ) on anthropometric and body composition parameters in one of the centers of the PREDIMED r and omized dietary trial . Subjects/ Setting s : 351 Canarian free-living subjects aged 55 to 80 years , with type 2 diabetes or ≥3 cardiovascular risk factors . Intervention : Participants were r and omly assigned to one of 3 different dietary interventions : MeDiet + extra-virgin olive oil ( EVOO ) , MeDiet + nuts ( walnuts , almonds , and hazelnuts ) , or a control low-fat diet . Total energy intake was ad libitum . Outcome measures : Measures included changes in anthropometric measures ( weight , body mass index [ BMI ] and waist circumference [ WC ] ) , body fat distribution , energy , and nutrient intake after 1 year . Body composition ( percentage of total body fat [ % TBF ] , total fat mass [ TFM ] , free fat mass [ FFM ] , percentage of truncal fat [ % TrF ] , truncal fat mass [ TrFM ] ) and total body water ( TBW ) were estimated by octapolar electrical impedance analysis . Statistical analyses : Paired t tests were conducted to assess within-group changes . Analyses of variance ( ANOVAs ) were used to assess the effect of the dietary intervention on the percentage change in anthropometric variables , body composition , and dietary intake profile . All pairwise comparisons that were statistically significant in ANOVA were subsequently adjusted using the Benjamini-Hochberg test , which penalizes for multiple comparisons . Results : After 1 year of intervention , significant within-group reductions in all anthropometric variables were observed for the MeDiet + EVOO and the control group . The MeDiet + nuts group exhibited a significant reduction in WC and TBW . The control group showed a significant increase in % TBF and a reduction in TBW . The control group showed a significant increase in the percentage of total body fat and a reduction in TBW . However , we did not find any between-group significant difference in anthropometric or body composition changes . Conclusions : Mediterranean diets enriched with EVOO or specific mixed nuts ( walnuts , almonds , hazelnuts ) that contain approximately 40 % total fat can be alternative options to low-fat diets for weight maintenance regimes in older overweight or obese adults Objective : To see whether mortality among men with angina can be reduced by dietary advice . Design : A r and omized controlled factorial trial . Setting : Male patients of general practitioners in south Wales . Subjects : A total of 3114 men under 70 y of age with angina . Interventions : Subjects were r and omly allocated to four groups : ( 1 ) advised to eat two portions of oily fish each week , or to take three fish oil capsules daily ; ( 2 ) advised to eat more fruit , vegetables and oats ; ( 3 ) given both the above types of advice ; and ( 4 ) given no specific dietary advice .  Mortality was ascertained after 3–9 y. Results : Compliance was better with the fish advice than with the fruit advice . All-cause mortality was not reduced by either form of advice , and no other effects were attributable to fruit advice . Risk of cardiac death was higher among subjects advised to take oily fish than among those not so advised ; the adjusted hazard ratio was 1.26 ( 95 % confidence interval 1.00 , 1.58 ; P=0.047 ) , and even greater for sudden cardiac death ( 1.54 ; 95 % CI 1.06 , 2.23 ; P=0.025 ) . The excess risk was largely located among the subgroup given fish oil capsules . There was no evidence that it was due to interactions with medication . Conclusion : Advice to eat more fruit was poorly complied with and had no detectable effect on mortality . Men advised to eat oily fish , and particularly those supplied with fish oil capsules , had a higher risk of cardiac death . This result is unexplained ; it may arise from risk compensation or some other effect on patients ' or doctors ' behaviour . Sponsorship : British Heart Foundation , Seven Seas Limited , Novex Pharma Limited , The Fish Foundation Background and rationale Coronary artery disease ( CAD ) and its pathological atherosclerotic process are closely related to lipids . Lipids levels are in turn influenced by dietary oils and fats . Saturated fatty acids increase the risk for atherosclerosis by increasing the cholesterol level . This study was conducted to investigate the impact of cooking oil media ( coconut oil and sunflower oil ) on lipid profile , antioxidant mechanism , and endothelial function in patients with established CAD . Design and methods In a single center r and omized study in India , patients with stable CAD on st and ard medical care were assigned to receive coconut oil ( Group I ) or sunflower oil ( Group II ) as cooking media for 2 years . Anthropometric measurements , serum , lipids , Lipoprotein a , apo B/A-1 ratio , antioxidants , flow-mediated vasodilation , and cardiovascular events were assessed at 3 months , 6 months , 1 year , and 2 years . Results Hundred patients in each arm completed 2 years with 98 % follow-up . There was no statistically significant difference in the anthropometric , biochemical , vascular function , and in cardiovascular events after 2 years . Conclusion Coconut oil even though rich in saturated fatty acids in comparison to sunflower oil when used as cooking oil media over a period of 2 years did not change the lipid-related cardiovascular risk factors and events in those receiving st and ard medical care A r and omised controlled trial ( RCT ) of high-dose v. low-dose fish oil in recent-onset rheumatoid arthritis ( RA ) demonstrated that the group allocated to high-dose fish oil had increased remission and decreased failure of disease-modifying anti-rheumatic drug ( DMARD ) therapy . This study examines the relationships between plasma phospholipid levels of the n-3 fatty acids in fish oil , EPA and DHA , and remission and DMARD use in recent-onset RA .  EPA and DHA  were measured in blood sample s from both groups of the RCT . The data were analysed as a single cohort , and Cox proportional hazards models were used to examine relationships between plasma phospholipid ( PL ) EPA and DHA and various outcome measures . When analysed as a single cohort , plasma PL EPA was related to time to remission , with a one unit increase in EPA ( 1 % total fatty acids ) associated with a 12 % increase in the probability of remission at any time during the study period ( hazard ratio (HR)=1.12 ; 95 % CI 1.02 , 1.23 ; P=0.02 ) . Adjustment for smoking , anti-cyclic citrullinated peptide antibodies and ' shared epitope ' HLA-DR allele status did not change the HR . Plasma PL EPA , adjusted for the same variables , was negatively related to time to DMARD failure ( HR=0.85 ; 95 % CI 0.72 , 0.99 ; P=0.047 ) . The HR for DHA and time to remission or DMARD failure were similar in magnitude to those for EPA , but not statistically significant . Biomarkers of n-3 status , such as plasma PL EPA , have the potential to predict clinical outcomes relevant to st and ard drug treatment of RA patients We prospect ively examined the additional effects of highly purified eicosapentaenoic acid ( EPA ) particularly on the vascular function of diabetic patients with hypercholesterolemia receiving statin therapy . We enrolled 28 patients with type 2 diabetes complicated by dyslipidemia who had been treated with statins for at least one year . The patients were r and omly assigned to 2 groups : administration of statin alone ( group S : n = 13 ) and addition of EPA to the current statin therapy ( group SE : n = 15 ) . The highly purified EPA was administered at a dose of 1,800 mg/day for 6 months . To evaluate vascular function , the duration of reactive hyperemia ( DRH ) , which is the time required for forearm blood flow to return to the basal level after inducing reactive hyperemia , was measured using strain gauge plethysmography . There were no significant differences in the clinical background factors between the 2 groups . Low-density lipoprotein cholesterol ( LDL-C ) , and non-high-density lipoprotein cholesterol levels significantly decreased after 6 months only in group SE . Compared with the baseline data , no significant change in DRH was observed after 6 months in group S. By contrast , DRH was significantly prolonged after 6 months in group SE , indicating that the addition of highly purified EPA improved vascular function . Our results showed that in patients with type 2 diabetes and receiving statin therapy whose LDL-C level was less than 100 mg/dL , the addition of highly purified EPA for 6 months significantly improved vascular function A r and omized controlled trial has been set up to examine the effect of diet on the secondary prevention of myocardial infa rct ion , involving 2033 men . The trial has a factorial design , subjects being r and omized independently to receive advice or no advice regarding three dietary factors : 1 . a reduction in total fat and an increase in polyunsaturated fat intake ; 2 . an increase in fatty fish intake ; 3 . an increase in cereal fibre intake .  Nearly half the men under 70 years of age who survived myocardial infa rct ion during the recruitment period entered the trial , the commonest reason for exclusion being that the subject was already eating ( or intended to eat ) a diet which included one or more of the regimens being investigated . Detailed dietary question naires were completed by each subject after 6 months in the trial . The results suggest that compliance with the advice is reasonably good . The differences between the diets of the groups given and not given advice on fish and fibre were substantial ; the difference attributable to advice on fat has been somewhat less than anticipated , partly because of failure to comply with advice and partly because of spontaneous changes in the diets of control subjects To investigate the effect of highly purified eicosapentaenoic acid ( EPA ) on the progression of diabetic macroangiopathy , we performed an open-label r and omized prospect i ve trial . A total of 81 Japanese type 2 diabetes were r and omly assigned to the EPA ( 1800 mg/day ) treated group or the control group . Carotid intima-media thickness ( IMT ) and brachial-ankle pulse wave velocity ( baPWV ) were evaluated before and after treatment in both groups . Sixty patients ( EPA group , n=30 ; control group , n=30 ) completed this study . During the study period of 2.1+/-0.2 years , the mean IMT and max IMT of the EPA treated group showed a significant annual decrease compared with that of the control group ( mean IMT , -0.029+/-0.112 mm versus 0.016+/-0.109 mm , respectively , P=0.029 ; max IMT , -0.084+/-0.113 mm versus -0.005+/-0.108 mm , respectively , P=0.0008 ) . The baPWV was also improved significantly in the EPA treated group compared with the control group ( -22.1+/-127.9 cm/s versus 62.3+/-223 cm/s , respectively , P=0.021 ) . Multiple regression analysis showed that the administration of EPA was a significant and independent factor associated with an annual improvement of mean IMT ( R2=0.067 ) . In summary , this is the first demonstration that administration of purified EPA improves the carotid IMT and the baPWV in patients with type 2 diabetes OBJECTIVE We studied the effect of a diet supplementation with fish oil in insulin-dependent diabetic patients with nephropathy in order to evaluate whether abnormal transcapillary escape rate of albumin and procoagulant activity in these patients could be modified . METHODS A double-blind , r and omized , controlled study was carried out at a tertiary referral centre . The subjects were 29 insulin-dependent diabetic patients with nephropathy . One year of fish oil supplementation ( 4.6 g n-3 fatty acids/day ) was compared with placebo ( olive oil ) . The main outcome measures were N-3 fatty acid proportions of platelet lipids , transcapillary escape rate of albumin , prothrombin fragment 1 + 2 , thrombin-antithrombin complexes , markers of fibrinolysis , fibrinogen , factor VII antigen and activity , thrombomodulin , von Willebr and factor , platelet factor 4 and beta-thromboglobulin . These were measured every 6 months . RESULTS Neither transcapillary escape rate of albumin ( 7.4 ( median ) ( 5.0 - 9.8 ) ( range ) % vs. 7.0 ( 4.6 - 10.6 ) % ) nor prothrombin fragment 1 + 2 ( 0.97 ( 0.72 - 2.40 ) nmol/L vs. 1.01 ( 0.59 - 3.11 ) nmol/L ) changed after 12 months of fish oil supplementation . CONCLUSION Increased transcapillary escape rate of albumin and activity could not be modified during diet supplementation with fish oil in insulin-dependent diabetic patients with nephropathy The influence of a moderate dietary supplementation with omega-3 polyunsaturated fatty acids ( omega-3 PUFAs ) ( 3.4 g eicosapentaenoic and docosahexaenoic acids per day ) for six months on lipopolysaccharide ( LPS ) stimulated monocyte procoagulant activity ( PCA ) was studied in two series of experiments , evaluating the plasma and cellular phases , respectively . In the first series , st and ard cryopreserved monocyte cultures were examined in heparin plasma of atherosclerotic patients ( n = 24 , 12 given omega-3 PUFAs , 12 controls ) . In the second series , monocytes from patients ( n = 32 , 16 given omega-3 PUFAs , 16 controls ) were investigated in a st and ard plasma milieu . Plasma and monocytes were obtained from the test subjects before as well as after six months of omega-3 PUFA supplementation . Monocyte PCA , measured by the formation of fibrinopeptide A , was not significantly different when comparing plasma and monocytes from the subjects supplemented with omega-3 PUFAs with plasma and monocytes , respectively , from the control subjects . In the second series of experiments we also determined the LPS induced release of interleukin-6 ( IL-6 ) , which was not significantly different in the two groups . However , a strong correlation between the stimulated monocyte IL-6 release and PCA was demonstrated ( r = 0.70 , p = 0.00001 ) , probably reflecting an individual inflammatory response pattern Summary We conducted a 2-year prospect i ve r and omised study to investigate the effects of a linoleic-acid-enriched diet on albuminuria and lipid levels in Type 1 ( insulin-dependent ) diabetic patients with elevated urinary albumin excretion ( overnight urinary albumin excretion rate between 10 and 200 μg/min ) . Thirty-eight patients were r and omly assigned to increase dietary polyunsaturated : saturated fatty acids ratio to 1.0 by replacement of saturated fat with linoleic-acid-rich products ( n=18 , two dropouts , analysis was performed in n=16 ) or to continue their usual diet ( n=20 ) . The total fat and protein content of the diet was unaltered . Clinical characteristics , albuminuria , blood pressure , glomerular filtration rate , metabolic control and dietary composition were similar in the two groups at baseline . In the high linoleic acid diet group , linoleic intake rose from 7±4 to 11±2 energy % and polyunsaturated : saturated fatty acids ratio rose from 0.60±0.28 to 0.96±0.16 ( p<0.001 compared to usual diet group ) . The median increase albuminuria was 58 % ( 95 % confidence interval , 13 to 109 ) during the first year ( p<0.02 ) and 55 % ( 95 % confidence interval , 11 to 127 ) ( p<0.01 ) during the second year . Glomerular filtration rate remained unaltered and filtration fraction tended to rise ( p<0.05 compared to usual diet group ) . In the usual diet group , albuminuria did not significantly increase by 16 % ( 95 % confidence interval , -17 to 38 ) and glomerular filtration rate declined during the second year . Blood pressure tended to rise similarly in both groups . Multiple regression analysis showed an independent effect of the high linoleic acid diet on the progression of albuminuria as well as the lack of decrease in glomerular filtration rate . Low density lipoprotein cholesterol and apolipoprotein B levels decreased in the high linoleic acid diet group ( p<0.05 ) . High density lipoprotein cholesterol declined in both groups ( p<0.05 ) . It is concluded that a linoleic-acid-enriched diet reduces atherogenic lipoproteins but does not have a beneficial effect on and might even promote renal functional abnormalities in Type 1 diabetic patients with elevated urinary albumin excretion OBJECTIVE Previous studies have demonstrated benefits of high-dose long-chain omega-3 polyunsaturated fatty acid ( LC omega-3 PUFA ) supplements on  metabolic risk .  Effects of increased dietary omega-3 PUFA , via oily fish and /or plant-derived omega-3 PUFAs , are less clear and may be modulated by the omega-6:omega-3 PUFA of the habitual diet . This study examined the effect on  cardiovascular disease risk markers of reducing dietary omega-6:omega-3 PUFA by changes in linoleic acid : alpha-linolenic acid ( LA : LNA ) and /or increasing LC omega-3 PUFA . It tested whether decreases in LA : LNA modulate effects of LC omega-3 PUFA . METHODS One hundred forty-two subjects , recruited to a 24-wk r and omized study , were assigned to a control group or one of four interventions . Intervention groups received two portions of oily fish ( 4.5 g eicosapentaenoic acid + docosahexanoic acid ) or white fish ( 0.7 g eicosapentaenoic acid + docosahexanoic acid ) per week , and replaced habitual household fats with ones high in sunflower ( high LA : LNA ) or rapeseed ( low LA : LNA ) oil . RESULTS Modest dietary manipulations of omega-6 and omega-3 PUFAs result ed in significant group x time interactions for serum triacylglycerols ( TAGs ; P = 0.05 ) ; at 24 wk the control and two oily fish groups showed lower TAG than did the white fish/sunflower group ( P = 0.05 ) . Reductions in TAG , associated with increased oily fish intakes , were maximized when combined with lower dietary LA : LNA . There were no significant changes in several other cardiovascular disease risk markers . CONCLUSIONS Two portions of oily fish per week led to significant reductions in TAG relative to consumption of two portions of white fish per week . Changes in TAG were maximized when combined with lower LA : LNA OBJECTIVES This study was design ed to test the effects of n-3 polyunsaturated fatty acids ( PUFAs ) on left ventricular ( LV ) systolic function in chronic heart failure ( HF ) due to nonischemic dilated cardiomyopathy ( NICM ) . BACKGROUND One hundred thirty-three patients with NICM and minimal symptoms on st and ard therapy were r and omized to 2 g of n-3 PUFAs or placebo .  LV function and functional capacity were assessed prospect ively by echocardiography and cardiopulmonary exercise testing at baseline and at 12 months after r and omization . METHODS Patients with chronic HF due to NICM and minimal symptoms while receiving evidence -based therapy were enrolled . LV function and functional capacity were assessed prospect ively by echocardiography , cardiopulmonary exercise test , and New York Heart Association functional class at baseline and at 12 months after r and omization to either 2 g of n-3 PUFAs or placebo . RESULTS At 12 months after r and omization , the n-3 PUFAs group and the placebo group differed significantly ( p < 0.001 ) in regard to : 1 ) LV ejection fraction ( increased by 10.4 % and decreased by 5.0 % , respectively ) ; 2 ) peak VO(2 ) ( increased by 6.2 % and decreased by 4.5 % , respectively ) ; 3 ) exercise duration ( increased by 7.5 % and decreased by 4.8 % , respectively ) ; and 4 ) mean New York Heart Association functional class ( decreased from 1.88 ± 0.33 to 1.61 ± 0.49 and increased from 1.83 ± 0.38 to 2.14 ± 0.65 , respectively ) . The hospitalization rates for HF were 6 % in the n-3 PUFAs and 30 % in the placebo group ( p = 0.0002 ) . CONCLUSIONS In patients with NICM and minimal symptoms in response to evidence -based medical therapy , n-3 PUFAs treatment increases LV systolic function and functional capacity and may reduce hospitalizations for HF . Given these promising results , larger studies are in order to confirm our findings OBJECTIVE Due to its high content of lignans , alpha-linolenic acid and fiber , flaxseed may reduce cardiovascular disease risk in humans . The present study evaluated the effect of flaxseed on markers of cardiovascular disease risk in healthy menopausal women . METHODS One hundred ninety-nine women were r and omly assigned to consume 40 g daily of flaxseed or wheat germ placebo for 12 mo . Fatty acids , apolipoproteins A-1 and B , lipoprotein(a ) , low-density lipoprotein particle size , fibrinogen , C-reactive protein , insulin , and glucose were measured at baseline and at 12 mo . RESULTS In total 179 women were available for the intention-to-treat analysis .  Flaxseed increased plasma alpha-linolenic ( P < 0.0001 ) , docosapentaenoic ( P = 0.001 ) , and total omega-3 fatty ( P = 0.0004 ) acids . Differences between flaxseed and wheat germ were observed for apolipoprotein A-1 ( -0.10 + /- 0.26 g/L , P = 0.011 ) and apolipoprotein B ( -0.05 + /- 0.16 g/L , P = 0.047 ) . From baseline , flaxseed raised apolipoproteins A-1 and B by 4.4 % ( P = 0.006 ) and 3 % ( P = 0.054 ) , whereas wheat germ increased these apolipoproteins by 11.6 % ( P < 0.0001 ) and 7 % ( P = 0.0001 ) , respectively . Both treatments increased lipoprotein(a ) ( P < 0.0001 ) and decreased low-density lipoprotein peak particle size ( P < 0.0001 ) . CONCLUSION In this large , long-term , placebo-controlled trial in healthy menopausal women , flaxseed increased some omega-3 fatty acids in plasma and had a limited effect on apolipoprotein metabolism OBJECTIVE The aim of this study was to examine the effect of a moderate-fat diet inclusive of walnuts on blood lipid profiles in patients with type 2 diabetes . RESEARCH DESIGN AND METHODS This was a parallel r and omized controlled trial comparing three dietary advice groups each with 30 % energy as fat : low fat , modified low fat , and modified low fat inclusive of 30 g of walnuts per day .  Fifty-eight men and women , mean age 59.3 + /- 8.1 years , started the trial . Dietary advice was given at baseline with monthly follow-up and fortnightly phone calls for support .  Body weight , percent body fat , blood lipids , HbA1c , total antioxidant capacity , and erythrocyte fatty acid levels were measured at 0 , 3 , and 6 months . Data were assessed by repeated- measures ANOVA with an intention-to-treat model . RESULTS The walnut group achieved a significantly greater increase in HDL cholesterol-to-total cholesterol ratio ( P=0.049 ) and HDL ( P=0.046 ) than the two other treatment groups . A 10 % reduction in LDL cholesterol was also achieved in the walnut group , reflecting a significant effect by group ( P=0.032 ) and time ( P=0.036 ) . There were no significant differences between groups for changes in body weight , percent body fat , total antioxidant capacity , or HbA1c levels . The higher dietary polyunsaturated fat-to-saturated fat ratio and intakes of omega-3 fatty acids in the walnut group were confirmed by erythrocyte biomarkers of dietary intake . CONCLUSIONS Structured " whole of diet " advice that included 30 g of walnuts/day delivering substantial amounts of polyunsaturated fatty acid improved the lipid profile of patients with type 2 diabetes The serum levels of  Lp(a ) lipoprotein ( Lp(a ) ) were determined preoperatively in 601 patients with coronary artery disease , undergoing bypass operations .  Compared with a reference group of 99 apparently healthy individuals , the Lp(a ) levels were higher in the patient group ( 7.7 mg dl-1 vs. 5.1 mg dl-1 , p = 0.012 ) . In the patient group , there was a weak , but significant negative correlation between the Lp(a ) levels and age ( r = -0.10 , p = 0.017 ) , and in both groups the women had higher Lp(a ) levels than the men . In the patients we found no significant correlations between Lp(a ) and other serum lipids or lipoproteins , nor between Lp(a ) and variables in the fibrinolytic system . We investigated the long-term effects of supplementation with n-3 polyunsaturated fatty acids ( n-3 PUFAs ) on the Lp(a ) concentrations . Postoperatively , in a r and omized fashion , 280 of the patients received 4 g of an n-3 PUFA concentrate ( containing > 85 % of long-chain n-3 PUFAs ) per day , whereas 269 patients comprised the control group . The fatty acids in serum phospholipids were monitored , and a significant increase in the phospholipid n-3 fatty acids was noted in the n-3 PUFA group , as opposed to the virtually unchanged amounts in the control group . The Lp(a ) levels were determined again after 6 months , and , compared with the control group , n-3 PUFA supplementation had no overall effect on the serum Lp(a ) levels AIM to evaluate if a supplementation with n-3 PUFAs at high doses could give a regression of the condition of impaired glycemia . METHODS we enrolled 281 overweight/obese patients with impaired fasting glucose ( IFG ) or impaired glucose tolerance ( IGT ) ; 138 subjects were r and omized to n-3 PUFAs group , 1 g three times a day , and 143 to placebo for 18 months . We assessed at baseline , and after 9 , and 18 months : circumferences , body mass index ( BMI ) , fasting plasma glucose ( FPG ) , fasting plasma insulin ( FPI ) , HOMA-index , lipid profile . At baseline and at the end of the study , all patients underwent an oral glucose tolerance test ( OGTT ) . RESULTS we observed a decrease of glycemia and HOMA-IR with n-3 PUFAs , compared to baseline , and to placebo .  Fasting plasma insulin decreased with n-3 PUFAs and increased with placebo .  HDL-cholesterol increased after 18 months of n-3 PUFAs , while triglycerides decreased compared to baseline and to placebo . After OGTT performed at the end of the study , more patients returned to a condition of euglycemia with n-3 PUFAs compared to placebo . CONCLUSIONS n-3 PUFAs were effective in reducing glycemia in patients affected by IFG or IGT and seem to be helpful to slow the development of type 2 diabetes mellitus . © 2016 BioFactors , 42(3):316 - 322 , 2016 Background / Objectives : The aim of this study was to analyze the influence of a Mediterranean dietary pattern on plasma total antioxidant capacity ( TAC ) after 3 years of intervention and the associations with adiposity indexes in a r and omized dietary trial ( PREDIMED trial ) with high cardiovascular risk patients .Subjects/ Methods : 187 subjects were r and omly selected from the PREDIMED-UNAV center after they completed 3-year intervention program . Participants were following a Mediterranean-style diet with high intake of virgin olive oil or high intake of nuts , or a conventional low-fat diet .  Adiposity indexes were measured at baseline and at year 3 . Plasma TAC was evaluated using a commercially available colorimetric assay kit . Results : Plasma TAC in the control , olive oil and nuts groups was 2.01±0.15 , 3.51±0.14 and 3.02±0.14 mM Trolox , respectively after adjusting for age and sex . The differences between the Mediterranean diet and control groups were statistically significant ( P<0.001 ) . Moreover higher levels of TAC were significantly associated with a reduction in body weight after 3 years of intervention among subjects allocated to the virgin olive oil group ( B=−1.306 ; 95 % CI=−2.439 to −0.173 ; P=0.025 , after adjusting for age , sex and baseline body mass index ) . Conclusions : Mediterranean diet , especially rich in virgin olive oil , is associated with higher levels of plasma antioxidant capacity . Plasma TAC is related to a reduction in body weight after 3 years of intervention in a high cardiovascular risk population with a Mediterranean-style diet rich in virgin olive oil Pre clinical data indicate that omega-3 fatty acids ( n-3FA ) potentiate the chemopreventive effect of the antiestrogen ( AE ) tamoxifen against mammary carcinogenesis . The role of n-3FA in breast cancer prevention in humans is controversial . Pre clinical and epidemiologic data suggest that n-3FA may be preferentially protective in obese subjects . To directly test the protective effect of n-3FA against breast cancer , we conducted a 2-year , open-label r and omized clinical trial in 266 healthy postmenopausal women ( 50 % normal weight , 30 % overweight , 20 % obese ) with high breast density ( BD ; ≥25 % ) detected on their routine screening mammograms . Eligible women were r and omized to one of the following five groups ( i ) no treatment , control ; ( ii ) raloxifene 60 mg ; ( iii ) raloxifene 30 mg ; ( iv ) n-3FA lovaza 4 g ; and ( v ) lovaza 4 g plus raloxifene 30 mg . The 2-year change in BD , a vali date d biomarker of breast cancer risk , was the primary endpoint of the study . In subset analysis , we tested the prespecified hypothesis that body mass index ( BMI ) influences the relationship between plasma n-3FA on BD . While none of the interventions affected BD in the intention-to-treat analysis , increase in plasma DHA was associated with a decrease in absolute breast density but only in participants with BMI > 29 . Our results suggest that obese women may preferentially experience breast cancer risk reduction from n-3FA administration . Cancer Prev Res ; 9(4 ) ; 275–82 . © 2015 AACR Background Observational epidemiological data suggest that habitual consumption in later life of oily fish , rich in n-3 long-chain polyunsaturated fatty acids ( n-3 LCPs ) , is associated with better cognitive function , slower rates of cognitive decline and a lower risk of dementia . In this paper we present data on baseline fish consumption and cognitive function in cognitively healthy older people r and omised onto the Older People And n-3 Long-chain polyunsaturated fatty acid ( OPAL ) study . Methods In total , 867 older people were recruited to join the OPAL study from 20 general practice s in Engl and and Wales . Participants were aged 70–79 years at baseline were free of dementia and diabetes , had a Mini-Mental State Examination score of 24 or greater and did not report daily fish oil supplement consumption . Self-reported habitual fish consumption was assessed at baseline via questions on frequency and type of fish consumption .  Cognitive function at baseline was assessed via vali date d cognitive tests assessing memory , executive function , psychomotor speed and attention , including the Californian Verbal Learning Test ( CVLT ) , the primary outcome of the OPAL study . Reported age at leaving full time education was recorded as a measure of educational achievement and psychological health was measured using the GHQ-30 question naire . Results Unadjusted analysis revealed significant positive associations between reported fish consumption and the CVLT scores with a mean increase of approximately 0.24 words remembered for each increase in level of reported fish consumption . These associations were noticeably attenuated on adjustment for age , gender and reported age at leaving full-time education and did not remain significant on further adjustment for GHQ-30 score . Similar associations were also observed between fish consumption and the global cognitive z-score , memory score , executive function score and delay scores in unadjusted analysis with the associations again attenuated on adjustment . Conclusions Baseline data from participants r and omised into the OPAL study provide support for the hypothesis that higher fish consumption is associated with better cognitive function in later life . However , although in the main associations remain after adjusting for education and psychological health , the data do not allow us to rule out the possibility of residual confounding e.g. from socioeconomic status or other health behaviours . Evidence is needed from r and omised clinical trials to clarify the role of n-3 LCPs in cognitive health in later life in the normal older person population BACKGROUND Increased consumption of n-3 ( omega-3 ) long-chain polyunsaturated fatty acids ( LC PUFAs ) , especially eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) , may maintain cognitive function in later life . OBJECTIVE We tested the hypothesis that n-3 LC PUFA supplementation would benefit cognitive function in cognitively healthy older people . DESIGN At total of 867 cognitively healthy adults , aged 70 - 79 y , from 20 general practice s in Engl and and Wales were r and omly assigned into a double-blind controlled trial of daily capsules providing 200 mg EPA plus 500 mg DHA or olive oil for 24 mo . Treatment-allocation codes were obtained from a central computerized r and omization service . Trained research nurses administered a battery of cognitive tests , including the primary outcome , the California Verbal Learning Test ( CVLT ) , at baseline and 24 mo . Intention-to-treat analysis of covariance , with adjustment for baseline cognitive scores , age , sex , and age at leaving full-time education , included 748 ( 86 % ) individuals who completed the study . RESULTS The mean age of participants was 75 y ; 55 % of the participants were men .  Withdrawals and deaths were similar in active ( n = 49 and n = 9 , respectively ) and placebo ( n = 53 and n = 8 , respectively ) arms . Mean ( + /-SD ) serum EPA and DHA concentrations were significantly higher in the active arm than in the placebo arm at 24 mo ( 49.9 + /- 2.7 mg EPA/L in the active arm compared with 39.1 + /- 3.1 mg EPA/L in the placebo arm ; 95.6 + /- 3.1 mg DHA/L in the active arm compared with 70.7 + /- 2.9 mg DHA/L in the placebo arm ) . There was no change in cognitive function scores over 24 mo , and intention-to-treat analysis showed no significant differences between trial arms at 24 mo in the CVLT or any secondary cognitive outcome . CONCLUSIONS Cognitive function did not decline in either study arm over 24 mo . The lack of decline in the control arm and the relatively short intervention period may have limited our ability to detect any potential beneficial effect of fish oil on cognitive function in this study . The Older People And n-3 Long-chain polyunsaturated fatty acids ( OPAL ) Study was registered at www.controlled-trials.com as IS RCT N 72331636 Background : Nonalcoholic steatohepatitis ( NASH ) is common and severe in patients with diabetes mellitus . Although , there are no effective treatments for NASH in diabetic patients , preliminary reports suggest that polyunsaturated fatty acids ( PUFA ) may be beneficial in these patients . Aim : A prospect i ve , r and omized , double-blind placebo-controlled study ( NCT 00323414 ) was performed in NASH patients with diabetes . Clinical trials.gov ( NCT 00323414 ) . Subjects and Methods : A total of 37 patients ( 50.6±9.8 y ) with well-controlled diabetes ( HbA1C<8.5 % ) were r and omized to receive either PUFA containing eicosapentaenoic acid ( 2160 mg ) and docosahexaenoic acid ( 1440 mg ) daily or an isocaloric , identical placebo containing corn oil for 48 weeks under CONSORT guidelines . Clinical , demographics , biochemical laboratory tests , body composition using DEXA , and liver biopsy were performed at r and omization and at the end of treatment . Liver biopsy was scored by the NASH CRN criteria . An intention-to-treat analysis was performed . Results : At inclusion , sex , age , body weight , biochemical tests , glucose control , and liver histology were similar in the 2 treatment groups . There was no change in liver enzymes , body weight , or body composition during the study in either group . At the end of the treatment , hepatic steatosis and the activity score improved ( P<0.05 ) and lobular inflammation worsened ( P<0.001 ) with placebo but was unchanged with PUFA . At the end of the treatment , insulin resistance ( serum glucose and HOMA ) worsened with PUFA but not placebo . Conclusions : PUFA provided no benefit over placebo in NASH patients with diabetes . The effects of PUFA on histology and insulin resistance were inferior to placebo . These data provide no support for PUFA supplements in NASH The long-term effects of fish-oil supplementation on haemostatic parameters and bleeding episodes were investigated in patients undergoing coronary artery bypass surgery . They were investigated before and 9 months after the operation . Following r and omization post-operatively , 260 patients received 4 g  fish-oil concentrate  per day , whereas 251 patients comprised the control group .  All patients received either aspirin ( 300 mg/day ) or warfarin ( international normalized ratio aim ed at 2.5–4.2 ) . Compliance was affirmed by determination of serum phospholipid fatty acids . No excess of bleeding episodes could be attributed to the use of fish oil , given in addition to either aspirin or warfarin . The supplementation of fish oil did not affect the bleeding time or plasma levels of beta-thromboglobulin , whereas an increase in the platelet count after the operation was slightly less pronounced in the fish-oil group . Apart from a small increase in PAI-1 antigen of borderline significance , no long-term effects by fish oil on parameters of coagulation and fibrinolysis were seen Purpose This study aim ed to determine the effects of fish oil-derived n-3 PUFA on glycemic control and lipid profiles in type 2 diabetic patients with abdominal obesity . Methods In a r and omized , double-blind , placebo-controlled trial , 100 type 2 diabetic patients with abdominal obesity were r and omized into two groups including 4 g/day of fish oil ( 2.4 g n-3 PUFA ) or placebo ( corn oil ) for 6 months . Serum fatty acid , body composition , as well as markers of glucose regulation and lipid parameters were measured before and after intervention . Results Thirty-five men and 64 women aged 65.4 ± 5.3 years completed the intervention . Although body composition was unchanged , serum EPA and DHA were higher in the fish oil group than those in the placebo group ( P < 0.001 and P < 0.001 , respectively ) . Serum triglyceride ( TG ) decreased ( P = 0.007 ) , whereas high-density lipoprotein cholesterol ( HDL-C ) increased ( P = 0.006 ) in the fish oil group compared with the placebo group after 6 months . Serum total cholesterol , low-density lipoprotein cholesterol ( LDL-C ) , the ratio of LDL-C to HDL-C , and glycemic control ( measured by serum glucose , glycated hemoglobin , insulin , and homeostasis model assessment –insulin resistance ) were not significantly different between the two groups after 6 months . Conclusions This study showed that 6 months of fish oil supplement had no statistically significant effects on glycemic control , but improved TG and HDL-C in type 2 diabetic patients with abdominal obesity . Trial registration Chictr.org ChiCTR-TRC-14005084 BACKGROUND TAK-085 is an omega-3 preparation that contains eicosapentaenoic acid ethyl-ester ( EPA-E ) and docosahexaenoic acid-ethyl ester used in the management of hypertriglyceridemia . OBJECTIVE The aim of the study was to evaluate the long-term safety ( adverse events [ AEs ] , laboratory parameters , vital signs , weight , and electrocardiograms ) and effects on lipid profiles , especially triglyceride levels , of TAK-085 in Japanese patients with hypertriglyceridemia ( triglyceride levels ≥150 mg/dL and < 750 mg/dL ) . METHODS In this multicenter , open-label , r and omized study , adults with hypertriglyceridemia undergoing lifestyle modification  received TAK-085 2 g ( 2 g once daily ; n = 165 ) or 4 g ( 2 g twice daily ; n = 171 ) , or EPA-E 1.8 g ( 0.6 g three times daily ; n = 167 ) for 52 weeks . Patients were stratified for co-administration of a statin . RESULTS TAK-085 was well tolerated throughout the 52-week study . Overall , no substantial differences were found in the tolerability  of TAK-085 2 g , TAK-085 4 g , and EPA-E 1.8 g with incidence rates for AEs of 83.6 % , 86.0 % , and 89.2 % , respectively . Most AEs were mild or moderate in severity . Triglyceride levels decreased from baseline in all groups by week 4 , and the decreases were maintained throughout the study . At week 52 the reduction in triglycerides  with TAK-085 2 g ( -13.9 % ) was similar to that with EPA-E 1.8 g ( -12.1 % ) , whereas the reduction seen with TAK-085 4 g ( -25.5 % ) was greater than that with EPA-E 1.8 g , as assessed by point estimates and 95 % confidence intervals . CONCLUSIONS TAK-085 was safe and well tolerated for up to 52 weeks of treatment in Japanese patients with hypertriglyceridemia undergoing lifestyle modification .  Reductions in triglyceride levels achieved after 4 weeks were maintained at 52 weeks n-3 Fatty acids in the form of ethyl esters ( EE ) allow lower daily doses and improved compliance . Administration of n-3 fatty acids to patients with glucose intolerance has led to controversial findings , some studies indicating worsening of the disorder , others no effect , or an improvement . A total of 935 patients with hypertriglyceridemia , associated with additional cardiovascular risk factors , i.e. glucose intolerance , NIDDM and /or arterial hypertension were entered a double blind ( DB ) protocol lasting 6 months with n-3 EE versus placebo , followed by a further 6 months of open study ( n = 868 ) on 2 g a day of n-3 EE . At the end of the DB period , triglyceridemia in the total group was reduced significantly more by n-3 EE , without alterations in glycemic parameters . In the 6 months open follow up , patients on n-3 EE with type IIB hyperlipoproteinemia showed a significant reduction of total cholesterol , both in cases with ( -4.15 % vs. the 6 month levels ) and without NIDDM ( -3.8 % ) . HDL-cholesterol had an overall mean rise of 7.4 % , maximal in type IV patients with ( + 9.1 % ) and without ( + 10.1 % ) NIDDM . No alterations in glycemic parameters were detected in treated patients . Administration of n-3 EE to patients with hypertriglyceridemia associated with NIDDM or impaired glucose tolerance appears safe and effective OBJECTIVE A cardioprotective dietary fat profile is recommended for the treatment of type 2 diabetes . The clinical feasibility of advice strategies targeting specific fatty acid intakes and the extent to which they can be achieved by free-living population s needs to be tested . Walnuts , with high n-3 polyunsaturated fatty acid ( PUFA ) content , may help optimize fatty acid intakes , but regular consumption might increase total fat and energy intakes . This study examined whether advice that refers to a total dietary pattern inclusive of walnuts would result in low-fat energy-controlled diets with optimal dietary fat proportions for patients with type 2 diabetes mellitus . RESEARCH DESIGN AND METHODS A parallel- design , controlled trial was completed by 55 free-living men and women with established type 2 diabetes mellitus . Participants were r and omly assigned to one of three groups : low-fat ( general advice ) , modified low-fat ( total diet advice using exchange lists to differentiate PUFA-rich foods ) , walnut-specific ( modified low fat including 30 g walnuts/day ) .  Dietary intakes and clinical outcomes were measured at baseline , and at 3 and 6 months . Dietary goals were : less than 10 % of energy from saturated fat , 7 % to 10 % of energy from PUFA , adequate n-3 PUFA ( > or=2.22 g alpha-linolenic acid , > or=0.65 g eicosapentaenoic acid [EPA]+docosahexaenoic acid [ DHA ] ) and n-6 to n-3 ratio less than 10 . The proportion of subjects achieving dietary goals and major food sources of fat were determined . RESULTS At baseline , dietary intakes were not significantly different between groups . No group and few individuals ( 10 % ) were consuming adequate PUFA , with meat the main source of dietary fat ( 22 % total dietary fat ) . At 3 and 6 months , energy and macronutrient intakes were similar among groups . The walnut group , however , was the only group to achieve all fatty acid intake targets ( P < .01 ) , and had the greatest proportion of subjects achieving targets ( P < .05 ) . Walnuts were the main source of dietary fat ( 31 % ) and n-3 PUFA ( 50 % ) , while 350 g oily fish/day provided a further 17 % n-3 PUFA consumed by this group . CONCLUSIONS Specific advice for the regular inclusion of walnuts in the context of the total diet helps achieve optimal fat intake proportions without adverse effects on total fat or energy intakes  in patients with type 2 diabetes mellitus Background The effects of fish oil ( FO ) in rheumatoid arthritis ( RA ) have not been examined in the context of contemporary treatment of early RA . This study examined the effects of high versus low dose FO in early RA employing a ‘ treat-to-target ’ protocol of combination disease-modifying anti-rheumatic drugs ( DMARDs ) . Methods Patients with RA < 12 months ’ duration and who were DMARD-naïve were enrolled and r and omised 2:1 to FO at a high dose or low dose ( for masking ) . These groups , design ated FO and control , were given 5.5 or 0.4 g/day , respectively , of the omega-3 fats , eicosapentaenoic acid + docosahexaenoic acid . All patients received methotrexate ( MTX ) , sulphasalazine and hydroxychloroquine , and DMARD doses were adjusted according to an algorithm taking disease activity and toxicity into account . DAS28-erythrocyte sedimentation rate , modified Health Assessment Question naire ( mHAQ ) and remission were assessed three monthly . The primary outcome measure was failure of triple DMARD therapy . Results In the FO group , failure of triple DMARD therapy was lower ( HR=0.28 ( 95 % CI 0.12 to 0.63 ; p=0.002 ) unadjusted and 0.24 ( 95 % CI 0.10 to 0.54 ; p=0.0006 ) following adjustment for smoking history , shared epitope and baseline anti – cyclic citrullinated peptide . The rate of first American College of Rheumatology ( ACR ) remission was significantly greater in the FO compared with the control group ( HRs=2.17 ( 95 % CI 1.07 to 4.42 ; p=0.03 ) unadjusted and 2.09 ( 95 % CI 1.02 to 4.30 ; p=0.04 ) adjusted ) . There were no differences between groups in MTX dose , DAS28 or mHAQ scores , or adverse events . Conclusions FO was associated with benefits additional to those achieved by combination ‘ treat-to-target ’ DMARDs with similar MTX use . These included reduced triple DMARD failure and a higher rate of ACR remission Recent epidemiological studies have shown some beneficial health effects of the long chain ( n-3 ) polyunsaturated fatty acids found in fatty fish . Although the results of these studies are often ambiguous and inconclusive , they have prompted many intervention trials to study the effects of n-3 fatty acids ( FA ) on the cardiovascular risk profile . However screening of the literature revealed that many of the beneficial effects of fish ( oil ) were obtained in intervention studies which had several serious shortcomings in their design . Therefore we started a placebo controlled r and omised trial with increasing doses of n-3FA ( respectively 0 ; 1.12 ; 2.24 and 3.37 g n-3 FA/day ) and in order to have a maximum compliance this study was done in healthy monks . Fifty eight subjects took the fish oil capsules during 12 months and were thereafter followed for another 6 months . We could n't detect any effect of n-3 FA supplementation on total cholesterol , HDL cholesterol , LDL cholesterol , apo A1 , Lp(a ) , HbA1C , glucose , fibrinogen , factor VIII , antithrombin III , plasminogen activator inhibitor , tissue plasminogen activator and von Willebr and factor concentration , on bleeding time or on systolic or diastolic blood pressure . A pronounced significant dose dependent decrease of triglyceride levels was seen , while a slight but statistical significant decrease of apo B levels was observed in the highest fish oil dose . As the importance of triglycerides in the pathogenesis of atherosclerosis is still under discussion , the clinical relevance of these finding is not clear at the moment . It seems therefore improbable that the anti-atherosclerotic action of n-3 FA is due to an effect on the lipid , apoprotein , coagulation or fibrinolysis parameters as measured in our study . Hence further research must be focused on other parameters ( prostagl and ins ) which can be influenced by n-3 FA and which probably play an equally important role in the atherosclerotic process AIMS Impaired fasting glucose ( IFG ) , impaired glucose tolerance ( IGT ) , and diabetes arise due to insufficient insulin secretion and are risk factors for cardiovascular ( CV ) events . Thus , targeting normal fasting glucose levels with insulin may reduce CV events . Previous studies suggest that omega-3 fatty acid supplements may reduce CV death ; however , their effect in high-risk dysglycemic individuals is not known . METHODS People aged > or = 50 years with evidence of CV disease and with IFG , IGT , newly detected or established diabetes ( on 0 or 1 oral agent ) , and a local glycated hemoglobin < 150 % of the upper limit of normal for that assay were recruited and allocated to ( a ) either 1 daily injection of insulin glargine with the dose titrated to achieve a fasting plasma glucose < or = 5.3 mmol/L ( 95 mg/dL ) , or st and ard glycemic care ; and ( b ) either omega-3-acid ethyl esters 90 ( 1 g consisting of EPA 465 mg and DHA 375 mg ) or identical placebo , according to a 2 x 2 factorial design . The 2 different primary outcomes for the insulin and omega-3 fatty acid arms are CV events and CV death , respectively . RESULTS A total of 12,612 ( mean age 64 , 35 % women ) people in 40 countries were r and omized during a 2-year period ending December 2005 . Eighty-two percent had established  diabetes  , 6 % had new diabetes  , and 12 % had IGT or IFG ;  the mean fasting plasma glucose was 7.3 mmol/L ( 131 mg/dL ) . CONCLUSIONS The ORIGIN trial will determine whether or not either or both of these interventions can reduce CV events BACKGROUND AND AIMS n-3 polyunsaturated fatty acid ( PUFA ) treatment may decrease liver fat in non-alcoholic fatty liver disease ( NAFLD ) , but uncertainty exists whether this treatment also decreases cardiovascular disease ( CVD ) risk in NAFLD . We tested whether 15 - 18 months n-3 PUFA [ docosahexaenoic acid ( DHA ) and eicosapentaenoic acid ] ( Omacor/Lovaza , 4 g/day ) vs placebo decreased carotid intima-media thickness ( CIMT ) progression , a surrogate marker of CVD risk . We also evaluated if improvement in markers of NAFLD severity was associated with decreased CIMT progression over time . METHODS In a pre-specified sub- study of the WELCOME ( Wessex Evaluation of fatty Liver and Cardiovascular markers in NAFLD with OMacor thErapy ) trial ( NCT00760513 ) , CIMT was measured using B-mode ultrasound while NAFLD severity was assessed by measuring liver fat percentage ( magnetic resonance spectroscopy ) and hepatic necro-inflammation ( serum cytokeratin-18 ( CK-18 ) concentration ) , at baseline and end of study . RESULTS 92 patients ( age 51.5 ± 10.7 years , 57.6 % men ) completed the study . In the treatment group ( n = 45 ) , CIMT progressed by 0.012 mm ( IQR 0.005 - 0.020 mm ) compared to 0.015 mm ( IQR 0.007 - 0.025 mm ) in the placebo group ( n = 47 ) ( p = 0.17 ) . Reduced CIMT progression in the entire cohort was independently associated with decreased liver fat ( st and ardized β-coefficient 0.32 , p = 0.005 ) , reduced CK-18 levels ( st and ardized β-coefficient 0.22 , p = 0.04 ) and antihypertensive usage ( st and ardized β-coefficient -0.31 , p = 0.009 ) in multivariable regression analysis after adjusting for all potential confounders . Decreased weight ( st and ardized β-coefficient 0.30 , p < 0.001 ) and increased DHA tissue enrichment during the 18-month study ( st and ardized β-coefficient -0.19 , p = 0.027 ) were both independently associated with decreased liver fat , but not with CK-18 . CONCLUSION Improvement in two markers of NAFLD severity is independently associated with reduced CIMT progression A VLCK diet supplemented with DHA , commercially available , was tested against an isocaloric VLCK diet without DHA . The main purpose of this study was to compare the effect of DHA supplementation in classic cardiovascular risk factors , adipokine levels , and inflammation-resolving eicosanoids . A total of obese patients were r and omized into two groups : a group supplemented with DHA ( n = 14 ) ( PnK-DHA group ) versus a group with an isocaloric diet free of supplementation ( n = 15 ) ( control group ) . The follow-up period was 6 months . The average weight loss after 6 months of treatment was 20.36 ± 5.02 kg in control group and 19.74 ± 5.10 kg in PnK-DHA group , without statistical differences between both groups . The VLCK diets induced a significant change in some of the biological parameters , such as insulin , HOMA-IR , triglycerides , LDL cholesterol , C-reactive protein , resistin , TNF alpha , and leptin . Following DHA supplementation , the DHA-derived oxylipins were significantly increased in the intervention group . The ratio of proresolution/proinflammatory lipid markers was increased in plasma of the intervention group over the entire study . Similarly , the mean ratios of AA/EPA and AA/DHA in erythrocyte membranes were dramatically reduced in the PnK-DHA group and the anti-inflammatory fatty acid index ( AIFAI ) was consistently increased after the DHA treatment ( p < 0.05 ) . The present study demonstrated that a very low-calorie ketogenic diet supplemented with DHA was significantly superior in the anti-inflammatory effect , without statistical differences in weight loss and metabolic improvement BACKGROUND Weekly fish consumption has been related to a lower risk of fatal coronary heart disease ( CHD ) and incident stroke in population s with a low fish intake . This relation has mainly been attributed to n-3 fatty acids in fish , that is , eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) . It is at present unclear whether alpha-linolenic acid ( ALA ) , a n-3 fatty acid from vegetable origin , could also be protective against cardiovascular diseases ( CVDs ) . There is a need for food-based trials to establish the efficacy of low doses of n-3 fatty acids in CVD prevention . OBJECTIVES The aim of the study was to evaluate the effect of an additional daily intake of 400 mg of EPA + DHA and 2 g of ALA on CVD morbidity and mortality in free-living subjects with a history of myocardial infa rct ion . DESIGN The multicenter Alpha Omega Trial is a r and omized , double-blind , placebo-controlled trial with a 2 x 2 factorial design . Between May 2002 and December 2006 , we enrolled a total of 4,837 men and women aged 60 through 80 who experienced a myocardial infa rct ion within 10 years before entering the study . Subjects were r and omized to 1 of 4 margarine spreads that were enriched with EPA + DHA and /or ALA , or placebo . Compliance was monitored via tub counts and assessment of n-3 fatty acids in plasma . Subjects were observed for 40 months for the occurrence of fatal and nonfatal CVD . RESULTS The cohort was on average 69 years old at the start of the study and comprised 22 % women . Subjects had their ( last ) myocardial infa rct ion approximately 4 years before enrollment . Mean body mass index was 27.7 kg/m(2 ) , and 17 % smoked . Average serum total and high-density lipoprotein cholesterol were 4.7 and 1.3 mmol/L , respectively , and 85 % used statins . Mean blood pressure was 142/80 mm Hg , and most subjects were on antihypertensive medication ( 88 % ) . Diabetes mellitus was reported by 17 % of the subjects , and 7 % reported a history of stroke . The overall mortality rate during the trial period was 23 per 1,000 person-years , with approximately 40 % due to CVD . CURRENT STATUS Follow-up of the patients was completed in November 2009 , and findings will be reported in the second part of 2010 A r and omised controlled trial with a factorial design was done to examine the effects of dietary intervention in the secondary prevention of myocardial infa rct ion ( MI ) . 2033 men who had recovered from MI were allocated to receive or not to receive advice on each of three dietary factors : a reduction in fat intake and an increase in the ratio of polyunsaturated to saturated fat , an increase in fatty fish intake , and an increase in cereal fibre intake . The advice on fat was not associated with any difference in mortality , perhaps because it produced only a small reduction ( 3 - 4 % ) in serum cholesterol . The subjects advised to eat fatty fish had a 29 % reduction in 2 year all-cause mortality compared with those not so advised . This effect , which was significant , was not altered by adjusting for ten potential confounding factors . Subjects given fibre advice had a slightly higher mortality than other subjects ( not significant ) . The 2 year incidence of reinfa rct ion plus death from ischaemic heart disease was not significantly affected by any of the dietary regimens . A modest intake of fatty fish ( two or three portions per week ) may reduce mortality in men who have recovered from MI Abstract A 6-year study of 2 diets on the progression of diabetic retinopathy was performed on 102 patients .  Diet I was composed of carboydrate 50 cal% , saturated fats 35 cal% , and proteins 15 cal% . Diet II consisted of carbohydrate 45 cal% , fats 40 cal% ( 1/3 linoleic acid ) and proteins 15 cal% . The linoleic acid content of diet II was 4 times that of diet I. The diabetics were matched 2 to 2 by 10 criteria and set at r and om on one of the 2 diets . During the observation period of 6 years , 5 patients of diet I died of a heart infa rct ion . Of the remaining 96 patients , 52 males and 44 females , of the linoleic acid-poor diet group I , 66 % of the males and 55 % of the females showed retinophaty . Of the linoleic acid-rich diet group II , 35 % of the males and 32 % of the females showed the retinopathy ( P ) . A strong inverse correlation was found between progression of retinopathy and serum cholesteryl-linoleate . Of diet group I , 14 males and 10 females showed signs of cardiac ischaemia , of diet group II , 4 males and 4 females ( P ) . Large differences were seen for the GTT 's and corresponding insulin values between males and females . Although the females of diet group II improved remarkably in respect to GTT and reactive serum insulin , a slow deterioration of both parameters was seen for diet group I. For the males , no differences between the 2 diet groups were seen . The improvements due to the treatment were similar . The serum lipid responses were significant for the females , diet group II having the lowest levels . No differences were seen for the males . In most cases of both sexes , the platelets aggregation was increased , and no effects of linoleic acid were seen . No explanation for the different contradictory facts was given Epidemiologic and experimental data suggest that a high dietary intake of long-chain polyunsaturated n-3 fatty acids may reduce the risk of atherothrombotic disease . In a r and omized , controlled study , 610 patients undergoing coronary artery bypass grafting were assigned either to a fish oil group , receiving 4 g/day of fish oil concentrate , or to a control group .  All patients received antithrombotic treatment , either aspirin or warfarin .  Their diet and serum phospholipid fatty acid profiles were monitored . The primary end point was 1-year graft patency , which was assessed by angiography in 95 % of patients . Vein graft occlusion rates per distal anastomoses were 27 % in the fish oil group and 33 % in the control group ( odds ratio 0.77 , 95 % confidence interval , 0.60 to 0.99 , p = 0.034 ) . In the fish oil group , 43 % of the patients had > or = 1 occluded vein graft(s ) compared with 51 % in the control group ( odds ratio 0.72 , 95 % confidence interval , 0.51 to 1.01 , p = 0.05 ) . Moreover , in the entire patient group , there was a significant trend to fewer patients with vein graft occlusions with increasing relative change in serum phospholipid n-3 fatty acids during the study period ( p for linear trend = 0.0037 ) . Thus , in patients undergoing coronary artery bypass grafting , dietary supplementation with n-3 fatty acids reduced the incidence of vein graft occlusion , and an inverse relation between relative change in serum phospholipid n-3 fatty acids and vein graft occlusions was observed BACKGROUND Atrial fibrillation ( AF ) continues to be one of the most common cardiac problems , placing an exp and ing burden on the public health system . In several circumstances , AF can increase the risk of stroke and heart failure . Current pharmacologic treatment options are associated with the potential for significant adverse events , which often outweigh the benefits of achieving sinus rhythm . There is evidence to suggest antiarrhythmic benefits of omega-3 polyunsaturated fatty acids ; however , the data are not conclusive . This study is design ed to further assess the effect of prescription omega-3 ethyl esters ( P-OM3 ) in the prevention of recurrent AF in patients with AF without ( significant ) structural heart disease . METHODS This trial is a 6-month r and omized , double-blind , placebo-controlled , parallel- study design . Patients with confirmed symptomatic paroxysmal or persistent AF ( 5:1 ratio ) will be r and omized to receive either 4 g/d P-OM3 ( Lovaza ; GlaxoSmithKline , Research Triangle Park , NC ) or placebo . The primary end point is the first recurrence of symptomatic AF among patients with paroxysmal AF . Secondary end points include the first recurrence of symptomatic AF among all patients . Safety will be assessed regularly . CONCLUSION This is the first r and omized blinded trial to assess the antiarrhythmic effects of 4 g/d P-OM3 in paroxysmal AF BACKGROUND The use of n-3 fatty acids may prevent cardiovascular events in patients with recent myocardial infa rct ion or heart failure . Their effects in patients with ( or at risk for ) type 2 diabetes mellitus are unknown . METHODS In this double-blind study with a 2-by-2 factorial design , we r and omly assigned 12,536 patients who were at high risk for cardiovascular events and had impaired fasting glucose , impaired glucose tolerance , or diabetes to receive a 1-g capsule containing at least 900 mg ( 90 % or more ) of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin glargine or st and ard care . The primary outcome was death from cardiovascular causes . The results of the comparison between n-3 fatty acids and placebo are reported here . RESULTS During a median follow up of 6.2 years , the incidence of the primary outcome was not significantly decreased among patients receiving n-3 fatty acids , as compared with those receiving placebo ( 574 patients [ 9.1 % ] vs. 581 patients [ 9.3 % ] ; hazard ratio , 0.98 ; 95 % confidence interval [ CI ] , 0.87 to 1.10 ; P=0.72 ) . The use of n-3 fatty acids also had no significant effect on the rates of major vascular events ( 1034 patients [ 16.5 % ] vs. 1017 patients [ 16.3 % ] ; hazard ratio , 1.01 ; 95 % CI , 0.93 to 1.10 ; P=0.81 ) , death from any cause ( 951 [ 15.1 % ] vs. 964 [ 15.4 % ] ; hazard ratio , 0.98 ; 95 % CI , 0.89 to 1.07 ; P=0.63 ) , or death from arrhythmia ( 288 [ 4.6 % ] vs. 259 [ 4.1 % ] ; hazard ratio , 1.10 ; 95 % CI , 0.93 to 1.30 ; P=0.26 ) . Triglyceride levels were reduced by 14.5 mg per deciliter ( 0.16 mmol per liter ) more among patients receiving n-3 fatty acids than among those receiving placebo ( P<0.001 ) , without a significant effect on other lipids . Adverse effects were similar in the two groups . CONCLUSIONS Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events . ( Funded by Sanofi ; ORIGIN Clinical Trials.gov number , NCT00069784 . ) OBJECTIVE The aim of this study was to evaluate the long-term ( 6-month ) effects of moderate fish oil supplementation on insulin sensitivity and plasma lipoproteins in NIDDM patients with hypertriglyceridemia . RESEARCH DESIGN AND METHODS The study has been performed according to a r and omized double-blind placebo-controlled design with a parallel group sequence . After a washout period of 4 weeks and a run-in period of 3 weeks , 16 NIDDM patients with hypertriglyceridemia ( triglyceride [ TG ] , 2.25–5.65 mmol/l ) were r and omly assigned to either fish oil ( 2.7 g/day eicosapentaenoic plus docosahexaenoic acid for 2 months , then 1.7 g/day for 4 more months ) ( n = 8) or placebo ( n = 8) .  Diet and hypoglycemic drugs remained unchanged throughout the whole experiment . At baseline and after 6 months , insulin sensitivity was measured by euglycemic hyperinsulinemic clamp ( insulin infused , 2.0 mIU · kg−1 body wt · min−1 ) . At the same time , blood glucose control , fasting and postpr and ial serum insulin and nonesterified fatty acid ( NEFA ) concentrations , and fasting plasma lipoprotein concentrations were evaluated . RESULTS In the group treated with ffish oil compared with the baseline , there was : 1 ) a significant reduction in both plasma TG ( 2.92 ± 0.23 vs. 3.85 ± 0.32 [ mean ± SE ] mmol/l , P < 0.001 ) and VLDL-TG ( 2.35 ± 0.24 vs. 4.25 ± 0.66 mmol/l , P < 0.01 ) , without significant changes in blood glucose control ; 2 ) a significant reduction in fasting NEFA concentrations ( 572 ± 100 vs. 825 ± 131 μmol/l , P < 0.01 ) ; and 3 ) a significant enrichment in long-chain ω-3 fatty acids of erythrocyte membrane phospholipids . In the placebo group , there were no changes in any of the variables analyzed . The insulin-mediated glucose uptake was unchanged in both groups ( fish oil , 4.04 ± 0.82 mg · kg−1 · min−1 at baseline and 3.96 ± 0.50 mg · kg−1 · min−1 at 6 months ; placebo , 3.51 ± 0.62 mg · kg−1 · min−1 at baseline and 4.09 ± 0.49 mg · kg−1 · min−1 at 6 months ) . CONCLUSIONS In NIDDM patients with hypertriglyceridemia , moderate amounts of fish oil induce a long-term significant reduction in plasma triglycerides , VLDL triglycerides , and NEFA and a significant enrichment in the erythrocyte phospholipid content of long-chain ω-3 fatty acids , without deteriorating blood glucose control . However , this amount of ω-3 fatty acids was unable to improve insulin sensitivity in this group of patients The long-term influence of n-3 polyunsaturated fatty acids ( n-3 PUFAs ) on serum lipids and glucose homeostasis was studied in a group of non-diabetic , moderately hypertriglyceridaemic patients undergoing coronary artery bypass grafting .  They were investigated according to the same procedure before and 6 months after the operation . Following r and omization postoperatively , 28 patients received 3.4 g eicosapentaenoic and docosahexaenoic acid per day , whereas 29 patients comprised the control group . The decline in serum triglycerides after 6 months was significantly greater in the n-3 PUFA group than in the control group ( median decline , -33.2 % vs. -11.1 % , p = 0.002 ) , while no group difference was noted in serum total , HDL , or LDL cholesterol levels . Fasting plasma glucose levels decreased less in the n-3 PUFA group compared with the control group ( median change , -0.2 mmol l-1 vs. -0.5 mmol l-1 , p = 0.054 ) . The corresponding changes in fasting insulin levels were -2 mIU ml-1 in the n-3 PUFA group and no change in the control group ( p = 0.039 ) . In both groups combined , the recorded changes in serum triglyceride and serum insulin levels were negatively correlated with the change in serum phospholipid n-3 fatty acids ( r = -0.35 , p = 0.008 and r = -0.32 , p = 0.016 , respectively ) . An oral glucose tolerance test revealed no significant group differences after 6 months , neither in the peak levels , nor in the areas under the curves between 0 and 3h after the glucose load for glucose , insulin , and C-peptide . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVE Recent studies in nondiabetic kidney diseases suggest that dietary supplementation with n-3 polyunsaturated fatty acids ( fish oil ) may have beneficial effects on albuminuria , kidney function , arterial blood pressure , and dyslipidemia . Therefore , we evaluated the long-term effect of fish oil in diabetic nephropathy . RESEARCH DESIGN AND METHODS A 1-year double-blind r and omized controlled study comparing fish oil ( 4.6 g n-3 fatty acids/day ) with placebo ( olive oil ) was performed in an outpatient clinic in a tertiary referral center . Thirty-six normotensive IDDM patients with diabetic nephropathy were included ; 18 were treated with fish oil . Seven patients dropped out ( four received fish oil ) , and results for the remaining 29 are presented . Albuminuria ( enzyme immunoassay ) , glomerular filtration rate ( 51Cr-labeled EDTA plasma clearance ) , 24-h ambulatory blood pressure , and lipid profile were determined every 6 months . RESULTS Albuminuria increased by 22 % ( 1–46 % ) ( mean [ 95 % CI ] ) in the fish oil group vs. 15 % ( −11–49 % ) in the placebo group ( NS ) . Glomerular filtration rate decreased from 116 ± 7 to 105 ± 7 ml · min−1 · 1.73 m−2 ( mean ± SE ) vs. from 108 ± 6 to 103 ± 7 , fish oil and placebo , respectively ( NS ) . No significant changes occurred in 24-h ambulatory blood pressure : from 141 ± 4/82 ± 2 mmHg to 142 ± 5/83 ± 2 vs. from 140 ± 4/78 ± 2 to 144 ± 4/80 ± 3 , fish oil and placebo , respectively ( NS ) . In the fish oil group , serum triglycerides ( median [ range ] ) decreased from 0.97 ( 0.5–4.0 ) mmol/l to 0.8 ( 0.4–3.0 ) vs. from 1.01 ( 0.4–2.0 ) to 1.09 ( 0.4–2.0 ) in the placebo group ( P < 0.05 ) and VLDL cholesterol decreased from 0.45 ( 0.23–1.88 ) to 0.37 ( 0.21–1.43 ) mmol/l vs. from 0.44 ( 0.21–0.94 ) to 0.41 ( 0.17–1.94 ) ( P < 0.05 ) , but total and LDL cholesterol rose in the fish oil compared with the placebo group . CONCLUSIONS Our study does not suggest that fish oil has beneficial effects on albuminuria , kidney function , blood pressure , and dyslipidemia in normotensive IDDM patients suffering from diabetic nephropathy Background Observational cohort studies and a secondary prevention trial have shown inverse associations between adherence to the Mediterranean diet and cardiovascular risk . Methods In a multicenter trial in Spain , we assigned 7447 participants ( 55 to 80 years of age , 57 % women ) who were at high cardiovascular risk , but with no cardiovascular disease at enrollment , to one of three diets : a Mediterranean diet supplemented with extra‐virgin olive oil , a Mediterranean diet supplemented with mixed nuts , or a control diet ( advice to reduce dietary fat ) . Participants received quarterly educational sessions and , depending on group assignment , free provision of extra‐virgin olive oil , mixed nuts , or small nonfood gifts . The primary end point was a major cardiovascular event ( myocardial infa rct ion , stroke , or death from cardiovascular causes ) . After a median follow‐up of 4.8 years , the trial was stopped on the basis of a prespecified interim analysis . In 2013 , we reported the results for the primary end point in the Journal . We subsequently identified protocol deviations , including enrollment of household members without r and omization , assignment to a study group without r and omization of some participants at 1 of 11 study sites , and apparent inconsistent use of r and omization tables at another site . We have withdrawn our previously published report and now report revised effect estimates based on analyses that do not rely exclusively on the assumption that all the participants were r and omly assigned . Results A primary end‐point event occurred in 288 participants ; there were 96 events in the group assigned to a Mediterranean diet with extra‐virgin olive oil ( 3.8 % ) , 83 in the group assigned to a Mediterranean diet with nuts ( 3.4 % ) , and 109 in the control group ( 4.4 % ) . In the intention‐to‐treat analysis including all the participants and adjusting for baseline characteristics and propensity scores , the hazard ratio was 0.69 ( 95 % confidence interval [ CI ] , 0.53 to 0.91 ) for a Mediterranean diet with extra‐virgin olive oil and 0.72 ( 95 % CI , 0.54 to 0.95 ) for a Mediterranean diet with nuts , as compared with the control diet . Results were similar after the omission of 1588 participants whose study ‐group assignments were known or suspected to have departed from the protocol . Conclusions In this study involving persons at high cardiovascular risk , the incidence of major cardiovascular events was lower among those assigned to a Mediterranean diet supplemented with extra‐virgin olive oil or nuts than among those assigned to a reduced‐fat diet . ( Funded by Instituto de Salud Carlos III , Spanish Ministry of Health , and others ; Current Controlled Trials number , IS RCT N35739639 . BACKGROUND Increased intake of n‐3 fatty acids has been associated with a reduced risk of cardiovascular disease in observational studies , but this finding has not been confirmed in r and omized trials . It remains unclear whether n‐3 ( also called omega‐3 ) fatty acid supplementation has cardiovascular benefit in patients with diabetes mellitus . METHODS We r and omly assigned 15,480 patients with diabetes but without evidence of atherosclerotic cardiovascular disease to receive 1‐g capsules containing either n‐3 fatty acids ( fatty acid group ) or matching placebo ( olive oil ) daily . The primary outcome was a first serious vascular event ( i.e. , nonfatal myocardial infa rct ion or stroke , transient ischemic attack , or vascular death , excluding confirmed intracranial hemorrhage ) . The secondary outcome was a first serious vascular event or any arterial revascularization . RESULTS During a mean follow‐up of 7.4 years ( adherence rate , 76 % ) , a serious vascular event occurred in 689 patients ( 8.9 % ) in the fatty acid group and in 712 ( 9.2 % ) in the placebo group ( rate ratio , 0.97 ; 95 % confidence interval [ CI ] , 0.87 to 1.08 ; P=0.55 ) . The composite outcome of a serious vascular event or revascularization occurred in 882 patients ( 11.4 % ) and 887 patients ( 11.5 % ) , respectively ( rate ratio , 1.00 ; 95 % CI , 0.91 to 1.09 ) . Death from any cause occurred in 752 patients ( 9.7 % ) in the fatty acid group and in 788 ( 10.2 % ) in the placebo group ( rate ratio , 0.95 ; 95 % CI , 0.86 to 1.05 ) . There were no significant between‐group differences in the rates of nonfatal serious adverse events . CONCLUSIONS Among patients with diabetes without evidence of cardiovascular disease , there was no significant difference in the risk of serious vascular events between those who were assigned to receive n‐3 fatty acid supplementation and those who were assigned to receive placebo . ( Funded by the British Heart Foundation and others ; Current Controlled Trials number , IS RCT N60635500 ; Clinical Trials.gov number , NCT00135226 . BACKGROUND Patients with elevated triglyceride levels are at increased risk for ischemic events . Icosapent ethyl , a highly purified eicosapentaenoic acid ethyl ester , lowers triglyceride levels , but data are needed to determine its effects on ischemic events . METHODS We performed a multicenter , r and omized , double‐blind , placebo‐controlled trial involving patients with established cardiovascular disease or with diabetes and other risk factors , who had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg per deciliter ( 1.52 to 5.63 mmol per liter ) and a low‐density lipoprotein cholesterol level of 41 to 100 mg per deciliter ( 1.06 to 2.59 mmol per liter ) . The patients were r and omly assigned to receive 2 g of icosapent ethyl twice daily ( total daily dose , 4 g ) or placebo . The primary end point was a composite of cardiovascular death , nonfatal myocardial infa rct ion , nonfatal stroke , coronary revascularization , or unstable angina . The key secondary end point was a composite of cardiovascular death , nonfatal myocardial infa rct ion , or nonfatal stroke . RESULTS A total of 8179 patients were enrolled ( 70.7 % for secondary prevention of cardiovascular events ) and were followed for a median of 4.9 years . A primary end‐point event occurred in 17.2 % of the patients in the icosapent ethyl group , as compared with 22.0 % of the patients in the placebo group ( hazard ratio , 0.75 ; 95 % confidence interval [ CI ] , 0.68 to 0.83 ; P<0.001 ) ; the corresponding rates of the key secondary end point were 11.2 % and 14.8 % ( hazard ratio , 0.74 ; 95 % CI , 0.65 to 0.83 ; P<0.001 ) . The rates of additional ischemic end points , as assessed according to a prespecified hierarchical schema , were significantly lower in the icosapent ethyl group than in the placebo group , including the rate of cardiovascular death ( 4.3 % vs. 5.2 % ; hazard ratio , 0.80 ; 95 % CI , 0.66 to 0.98 ; P=0.03 ) . A larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation or flutter ( 3.1 % vs. 2.1 % , P=0.004 ) . Serious bleeding events occurred in 2.7 % of the patients in the icosapent ethyl group and in 2.1 % in the placebo group ( P=0.06 ) . CONCLUSIONS Among patients with elevated triglyceride levels despite the use of statins , the risk of ischemic events , including cardiovascular death , was significantly lower among those who received 2 g of icosapent ethyl twice daily than among those who received placebo . ( Funded by Amarin Pharma ; REDUCE‐IT Clinical Trials.gov number , NCT01492361 . Objective To create a data base of long-term r and omised controlled trials ( RCTs ) comparing higher with lower omega-3 , omega-6 or total polyunsaturated fatty acid ( PUFA ) , regardless of reported outcomes , and to develop methods to assess effects of increasing omega-6 , alpha-linolenic acid ( ALA ) , long-chain omega-3 ( LCn3 ) and total PUFA on health outcomes . Design Systematic review search , methodology and meta-analyses . Data sources Medline , Embase , CENTRAL , WHO International Clinical Trials Registry Platform , Clinical trials.gov and trials in relevant systematic review s. Eligibility criteria RCTs of ≥24 weeks ' duration assessing effects of increasing ALA , LCn3 , omega-6 or total PUFAs , regardless of outcomes reported . Data synthesis Methods included r and om-effects meta-analyses and sensitivity analyses . Funnel plots were examined , and subgrouping assessed effects of intervention type , replacement , baseline diabetes risk and use of diabetic medications , trial duration and dose . Quality of evidence was assessed using Grading of Recommendations Assessment , Development and Evaluation ( GRADE ) . Results Electronic search es generated 37 810 hits , de-duplicated to 19 772 titles and abstract s. We assessed 2155 full-text papers , conference abstract s and trials registry entries independently in duplicate . Included studies were grouped into 363 RCTs comparing higher with lower omega-3 , omega-6 and /or total PUFA intake of at least 6 months ’ duration —the Data base . Of these 363 included RCTs , 216 RCTs were included in at least one of our review s of health outcomes , data extracted and risk of bias assessed in duplicate . Ninety five RCTs were included in the Data base but not included in our current review s. Of these 311 completed trials , 27 altered ALA intake , 221 altered LCn3 intake and 16 trials altered omega-3 intake without specifying whether ALA or LCn3 . Forty one trials altered omega-6 and 59 total PUFA.The remaining 52 trials are ongoing though 13 ( 25 % ) appear to be outst and ing , or constitute missing data . Conclusions This extensive data base of trials is available to allow assessment of further health outcomes To the Editor : Because of irregularities in the r and omization procedures , we wish to retract the following article : Primary Prevention of Cardiovascular Disease with a Mediterranean Diet . N Engl J Med 2013;368:1279 - 90 . DOI : 10.1056/NEJMoa1200303.1 We have reanalyzed the data and have published a new report : Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts . N Engl J Med . DOI : 10.1056/NEJMoa1800389.2 . . BACKGROUND Results from prospect i ve cohort studies and r and omized , controlled trials have provided evidence of a protective effect of n-3 fatty acids against cardiovascular diseases . We examined the effect of the marine n-3 fatty acids eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) and of the plant-derived alpha-linolenic acid ( ALA ) on the rate of cardiovascular events among patients who have had a myocardial infa rct ion . METHODS In a multicenter , double-blind , placebo-controlled trial , we r and omly assigned 4837 patients , 60 through 80 years of age ( 78 % men ) , who had had a myocardial infa rct ion and were receiving state-of-the-art antihypertensive , antithrombotic , and lipid-modifying therapy to receive for 40 months one of four trial margarines : a margarine supplemented with a combination of EPA and DHA ( with a targeted additional daily intake of 400 mg of EPA-DHA ) , a margarine supplemented with ALA ( with a targeted additional daily intake of 2 g of ALA ) , a margarine supplemented with EPA-DHA and ALA , or a placebo margarine . The primary end point was the rate of major cardiovascular events , which comprised fatal and nonfatal cardiovascular events and cardiac interventions . Data were analyzed according to the intention-to-treat principle , with the use of Cox proportional-hazards models . RESULTS The patients consumed , on average , 18.8 g of margarine per day , which result ed in additional intakes of 226 mg of EPA combined with 150 mg of DHA , 1.9 g of ALA , or both , in the active-treatment groups . During the follow-up period , a major cardiovascular event occurred in 671 patients ( 13.9 % ) . Neither EPA-DHA nor ALA reduced this primary end point ( hazard ratio with EPA-DHA , 1.01 ; 95 % confidence interval [ CI ] , 0.87 to 1.17 ; P=0.93 ; hazard ratio with ALA , 0.91 ; 95 % CI , 0.78 to 1.05 ; P=0.20 ) . In the prespecified subgroup of women , ALA , as compared with placebo and EPA-DHA alone , was associated with a reduction in the rate of major cardiovascular events that approached significance ( hazard ratio , 0.73 ; 95 % CI , 0.51 to 1.03 ; P=0.07 ) . The rate of adverse events did not differ significantly among the study groups . CONCLUSIONS Low-dose supplementation with EPA-DHA or ALA did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infa rct ion and who were receiving state-of-the-art antihypertensive , antithrombotic , and lipid-modifying therapy . ( Funded by the Netherl and s Heart Foundation and others ; Clinical Trials.gov number , NCT00127452 . ) BACKGROUND & AIMS Genetic variation in both patatin-like phospholipase domain-containing protein-3 ( PNPLA3 ) ( I148 M ) and the transmembrane 6 superfamily member 2 protein ( TM6SF2 ) ( E167 K ) influences severity of liver disease , and serum triglyceride concentrations in non-alcoholic fatty liver disease ( NAFLD ) , but whether either genotype influences the responses to treatments is uncertain . METHODS One hundred three patients with NAFLD were r and omised to omega-3 fatty acids ( DHA+EPA ) or placebo for 15 - 18months in a double blind placebo controlled trial . Erythrocyte enrichment with DHA and EPA was measured by gas chromatography . PNPLA3 and TM6SF2 genotypes were measured by PCR technologies . Multivariable linear regression and analysis of covariance were undertaken to test the effect of genotypes on omega-3 fatty acid enrichment , end of study liver fat percentage and serum triglyceride concentrations . All models were adjusted for baseline measurements of each respective outcome . RESULTS Fifty-five men and 40 women ( Genotypes PNPLA3 I148 M , 148I/I=41 , 148I/M=43 , 148M/M=11 ; TM6SF2 E167 K 167E/E=78 , 167E/K+167K/K=17 participants ) ( mean ± SD age , 51 ± 11 years ) completed the trial . Adjusting for baseline measurement , measured covariates and confounders , PNPLA3 148M/M variant was independently associated with percentage of DHA enrichment ( B coefficient -1.02 ( 95 % CI -1.97 , -0.07 ) , p=0.036 ) but not percentage of EPA enrichment ( B coefficient -0.31 ( 95 % CI -1.38 , 0.75 ) , p=0.56 ) . This genotype was also independently associated with end of study liver fat percentage ( B coefficient 9.5 ( 95 % CI 2.53 , 16.39 ) , p=0.008 ) , but not end of study triglyceride concentration ( B coefficient -0.11 ( 95 % CI -0.64 , 0.42 ) , p=0.68 ) . CONCLUSIONS PNPLA3 148M/M variant influences the changes in liver fat and DHA tissue enrichment during the trial but not the change in serum triglyceride concentration BACKGROUND & AIMS n-3 polyunsaturated fatty acids reduce insulin resistance , lipogenesis , and inflammation , which are features of nonalcoholic steatohepatitis ( NASH ) . Ethyl-eicosapentanoic acid ( EPA-E ) is a synthetic polyunsaturated fatty acid that reduces hypertriglyceridemia . We report the final results of a phase 2b multicenter , prospect i ve , double-blind , r and omized , placebo-controlled trial of EPA-E for NASH . METHODS Our study , performed at 37 sites in North America , included subjects with NASH and nonalcoholic fatty liver disease ( NAFLD ) activity scores ≥ 4 , with minimum scores of 1 for steatosis and inflammation , along with either ballooning or at least stage 1a fibrosis . A total of 243 subjects were r and omly assigned to groups given placebo ( n = 75 ) , low-dosage EPA-E ( 1800 mg/d ; n = 82 ) , or high-dosage EPA-E ( 2700 mg/d ; n = 86 ) for 12 months . Subjects were examined at 4-week intervals for 3 months , 6-week intervals for the next 3 months , and every 3 months thereafter , until 1 month after the last dose was taken . Liver biopsies were collected 2 weeks after the last dose of EPA-E or placebo . The primary efficacy end point was NAFLD activity score ≤ 3 , without worsening of fibrosis ; or a decrease in NAFLD activity score by ≥ 2 with contribution from > 1 parameter , without worsening of fibrosis , 1 year after the last dose of EPA-E or placebo was given . RESULTS Similar proportions of subjects in each group met the primary end point ( 40 % , 37 % , and 35.9 % for placebo , low-dosage , and high-dosage EPA-E , respectively ) . EPA-E had no significant effects on steatosis , inflammation , ballooning , or fibrosis scores . There were no significant effects on levels of liver enzymes , insulin resistance , adiponectin , keratin 18 , high-sensitivity C-reactive protein , or hyaluronic acid . High-dosage EPA-E  reduced levels of triglyceride ( -6.5 mg/dL vs an increase of 12 mg/dL in the placebo group ; P = .03 ) . There were no treatment-related serious adverse events . CONCLUSIONS In a phase 2 trial , EPA-E had no significant effect on the histologic features of NASH  . EPA-E reduced subjects ' levels of triglyceride compared with placebo , without any increase in serious adverse events . Clinical trials.gov Number : 01154985 SCOPE To investigate the effects of n-3 fatty acid supplements , both marine and plant-based , on glycemic traits in Chinese type 2 diabetes patients . METHOD AND RESULTS In a double-blind r and omized controlled trial , 185 recruited Chinese type 2 diabetes patients were r and omized to either fish oil ( FO , n = 63 ) , flaxseed oil ( FSO , n = 61 ) , or corn oil group ( served as control group , n = 61 ) for 180 days . The patients were asked to take corresponding oil capsules ( four capsules/day ) , which totally provided 2 g/day of eicosapentaenoic acid + docosahexaenoic acid in FO group and 2.5 g/day of alpha-linolenic acid in FSO group . No group × time interaction was observed for homeostatic model assessment of insulin resistance , fasting insulin , or glucose . Significant group × time interaction ( P = 0.035 ) was observed for glycated hemoglobin A1c ( HbA1c ) , with HbA1c decreased in FO group compared with corn oil group ( P = 0.037 ) . We also found significant group × time interactions for lipid traits , including LDL cholesterol ( P = 0.043 ) , total cholesterol ( P = 0.021 ) , total cholesterol/HDL cholesterol ( P = 0.009 ) , and triacylglycerol ( P = 0.003 ) , with the lipid profiles improved in FO group . No significant effects of FSO on glycemic traits or blood lipids were observed . CONCLUSIONS Marine n-3 PUFA supplements may improve glycemic control and lipid profiles among Chinese type 2 diabetic patients
OBJECTIVE To assess effects of increasing omega-3 , omega-6 , and total polyunsaturated fatty acids ( PUFA ) on  diabetes diagnosis and glucose metabolism .