Estimation of the dietary requirement for vitamin D in adolescents aged 14-18 y: a dose-response, double-blind, randomized placebo-controlled trial. Dose Response to Vitamin D Supplementation in Postmenopausal Women Vitamin D supplementation increases calcium absorption without a threshold effect. Effect of vitamin D supplementation on inflammation: protocol for a systematic review Estimation of the dietary requirement for vitamin D in healthy adolescent white girls. Prospective study of dietary supplements, macronutrients, micronutrients, and risk of bladder cancer in US men. Estimation of the dietary requirement for vitamin D in free-living adults >=64 y of age. Vitamin D Receptor Fok-I Polymorphism Modulates Diabetic Host Response to Vitamin D Intake Fortified breakfast cereal consumed daily for 12 wk leads to a significant improvement in micronutrient intake and micronutrient status in adolescent girls: a randomised controlled trial Relation of Consumption of Vitamin E, Vitamin C, and Carotenoids to Risk for Stroke among Men in the United States Estimation of the dietary requirement for vitamin D in healthy adults. Dietary calcium and vitamin D intake in relation to osteoporotic fracture risk. Estimation of the dietary requirement for vitamin D in white children aged 4-8 y: a randomized, controlled, dose-response trial. Nutritional Intervention as a Preventive Approach for Cognitive-Related Outcomes in Cognitively Healthy Older Adults: A Systematic Review. Biomarker-calibrated protein intake and bone health in the Women's Health Initiative clinical trials and observational study. Vitamin C and risk of coronary heart disease in women. A systematic review protocol examining the effect of vitamin D supplementation on endothelial function Efficacy of vitamin D supplementation in depression in adults: a systematic review protocol Dietetic guidelines: diet in secondary prevention of cardiovascular disease. Concordance of randomized and nonrandomized studies was unrelated to translational patterns of two nutrient-disease associations. Optimal vitamin D status: a critical analysis on the basis of evidence-based medicine. Effect of dietary interventions in mild cognitive impairment: a systematic review. Intakes of Fruits, Vegetables, Vitamins A, C, and E, and Carotenoids and Risk of Renal Cell Cancer Incorporation of eicosapentaenoic and docosahexaenoic acids into lipid pools when given as supplements providing doses equivalent to typical intakes of oily fish1234 Vitamin D and calcium intakes and breast cancer risk in pre- and postmenopausal women. Lack of a relation between vitamin and mineral antioxidants and bone mineral density: results from the Women's Health Initiative. Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status. Estimation of the maternal vitamin D intake that maintains circulating 25-hydroxyvitamin D in late gestation at a concentration sufficient to keep umbilical cord sera ≥25–30 nmol/L: a dose-response, double-blind, randomized placebo-controlled trial in pregnant women at northern latitude Supplemental and Dietary Vitamin E Intakes and Risk of Prostate Cancer in a Large Prospective Study Genomic Response to Vitamin D Supplementation in the Setting of a Randomized, Placebo-Controlled Trial Antioxidants and basal cell carcinoma of the skin: A nested case–control study Nutrient intake and anemia risk in the women's health initiative observational study. The relationship between vitamin C intake, general health practices, and mortality in Alameda County, California. Effect of increasing fruit and vegetable intake by dietary intervention on nutritional biomarkers and attitudes to dietary change: a randomised trial
BACKGROUND Adolescents are a population group at high risk of low vitamin D status , yet the evidence base for establishing dietary vitamin D requirements remains weak . OBJECTIVE The aim was to establish the distribution of  vitamin D intakes required to maintain serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations above proposed cutoffs ( 25 , 30 , 40 , and 50 nmol/L ) during winter in white males and females ( 14 - 18 y of age ) in the United Kingdom ( 51 ° N ) . DESIGN In a dose-response trial , 110 adolescents ( aged 15.9 ± 1.4 y ; 43 % males ) were r and omly assigned to receive 0 , 10 , or 20 μg vitamin D3 supplements/d for 20 wk during winter . A nonlinear regression model was fit to total vitamin D intake and postintervention serum 25(OH)D concentrations , and regression-predicted values estimated the vitamin D intakes required to maintain serum 25(OH)D concentrations above specific cutoffs . RESULTS Mean ± SD serum 25(OH)D concentrations increased from 49.2 ± 12.0 to 56.6 ± 12.4 nmol/L and from 51.7 ± 13.4 to 63.9 ± 10.6 nmol/L in the 10- and 20-μg/d groups , respectively , and decreased in the placebo group from 46.8 ± 11.4 to 30.7 ± 8.6 nmol/L ( all P ≤ 0.001 ) . Vitamin D intakes required to maintain 25(OH)D concentrations > 25 and > 30 nmol/L in 97.5 % of adolescents were estimated to be 10.1 and 13.1 μg/d , respectively , and 6.6 μg/d to maintain 50 % of adolescents at concentrations > 40 nmol/L. Because the response of 25(OH)D reached a plateau at 46 nmol/L , there is uncertainty in estimating the vitamin D intake required to maintain 25(OH)D concentrations > 50 nmol/L in 97.5 % of adolescents , but it exceeded 30 μg/d . CONCLUSION Vitamin D intakes between 10 and ∼30 μg/d are required by white adolescents during winter to maintain serum 25(OH)D concentrations > 25 - 50 nmol/L , depending on the serum 25(OH)D threshold chosen . This trial was registered at clinical trials.gov as NCT02150122 and as International St and ard R and omized Controlled Trial Number IS RCT N40736890 BACKGROUND Serum 25-hydroxyvitamin D ( 25-[OH]D ) is considered the best biomarker of clinical vitamin D status . OBJECTIVE To determine the effect of increasing oral doses of vitamin D(3 ) on serum 25-(OH)D and serum parathyroid hormone ( PTH ) levels in postmenopausal white women with vitamin D insufficiency ( defined as a 25-[OH]D level ≤50 nmol/L ) in the presence of adequate calcium intake . These results can be used as a guide to estimate the Recommended Dietary Allowance ( RDA ) ( defined as meeting the needs of 97.5 % of the population ) for vitamin D(3 ) . DESIGN R and omized , placebo-controlled trial . ( Clinical Trials.gov registration number : NCT00472823 ) SETTING Creighton University Medical Center , Omaha , Nebraska . PARTICIPANTS 163 healthy postmenopausal white women with vitamin D insufficiency enrolled in the winter or spring of 2007 to 2008 and followed for 1 year . INTERVENTION Participants were r and omly assigned to receive placebo or vitamin D(3 ) , 400 , 800 , 1600 , 2400 , 3200 , 4000 , or 4800 IU once daily . Daily calcium supplements were provided to increase the total daily calcium intake to 1200 to 1400 mg . MEASUREMENTS The primary outcomes were 25-(OH)D and PTH levels at 6 and 12 months . RESULTS The mean baseline 25-(OH)D level was 39 nmol/L. The dose response was curvilinear and tended to plateau at approximately 112 nmol/L in patients receiving more than 3200 IU/d of vitamin D(3 ) . The RDA of vitamin D(3 ) to achieve a 25-(OH)D level greater than 50 nmol/L was 800 IU/d . A mixed-effects model predicted that 600 IU of vitamin D(3 ) daily could also meet this goal . Compared with participants with a normal body mass index ( < 25 kg/m(2 ) ) , obese women ( ≥30 kg/m(2 ) ) had a 25-(OH)D level that was 17.8 nmol/L lower . Parathyroid hormone levels at 12 months decreased with an increasing dose of vitamin D(3 ) ( P = 0.012 ) . Depending on the criteria used , hypercalcemia occurred in 2.8 % to 9.0 % and hypercalciuria in 12.0 % to 33.0 % of participants ; events were unrelated to dose . LIMITATION Findings may not be generalizable to other age groups or persons with substantial comorbid conditions . CONCLUSION A vitamin D(3 ) dosage of 800 IU/d increased serum 25-(OH)D levels to greater than 50 nmol/L in 97.5 % of women ; however , a model predicted the same response with a vitamin D(3 ) dosage of 600 IU/d . These results can be used as a guide for the RDA of vitamin D(3 ) , but prospect i ve trials are needed to confirm the clinical significance of these results . PRIMARY FUNDING SOURCE National Institute on Aging BACKGROUND The maximal calcium absorption in response to vitamin D has been proposed as a biomarker for vitamin D sufficiency . OBJECTIVE The objective was to determine whether there is a threshold beyond which increasing doses of vitamin D , or concentrations of serum 25-hydroxyvitamin D [ 25(OH)D ] , no longer increase calcium absorption . DESIGN This was a placebo-controlled , dose-response , r and omized , double-blind study of the effect of vitamin D on calcium absorption in healthy postmenopausal women . Seventy-six healthy postmenopausal women were r and omly assigned to placebo or 800 IU ( 20 μg ) , 2000 IU ( 50 μg ) , or 4000 IU ( 100 μg ) vitamin D₃ for 8 wk . The technique of dual isotopes of stable calcium was used with a calcium carrier to measure calcium absorption at baseline and after 8 wk . RESULTS Seventy-one women with a mean ± SD age of 58.8 ± 4.9 y completed the study . The mean calcium intake was 1142 ± 509 mg/d and serum 25(OH)D was 63 ± 14 nmol/L at baseline . A statistically significant linear trend of an increase in calcium absorption adjusted for age and body mass index with increasing vitamin D₃ dose or serum 25(OH)D concentration was observed . A 6.7 % absolute increase in calcium absorption was found in the highest vitamin D₃ group ( 100 μg ) . No evidence of nonlinearity was observed in the dose-response curve . CONCLUSIONS No evidence of a threshold of calcium absorption was found with a serum 25(OH)D range from 40 to 130 nmol/L. Calcium absorption in this range is not a useful biomarker to determine nutritional recommendations for vitamin Introduction The extraskeletal role of vitamin D is being increasingly recognised . This has important clinical implication s , as vitamin D deficiency has reached epidemic proportions worldwide . Vitamin D has proposed anti-inflammatory properties , yet the role of vitamin D supplementation in reducing inflammation remains largely unknown . The purpose of this review is to investigate the impact of vitamin D supplementation on inflammation , and to identify relevant knowledge gaps in the field . Methods and analysis Medline , CINAHL , EMBASE and All EBM will be systematic ally search ed for r and omised controlled trials ( RCTs ) and systematic review s of RCTs , comparing vitamin D supplementation with placebo , usual care or other pharmacological or non-pharmacological interventions . One review er will assess articles for eligibility according to prespecified selection criteria , after which 2 independent review ers will perform data extraction and quality appraisal . Meta-analyses will be conducted where appropriate . Ethics and dissemination Formal ethical approval is not required as no primary data is collected . This systematic review will identify potential clinical implication s of vitamin D deficiency and supplementation , and will be disseminated through a peer- review ed publication and at conference meetings , to inform future research on the efficacy of vitamin D supplementation for inflammation and inflammatory diseases . PROSPERO registration number CRD42016037104 BACKGROUND Knowledge gaps have contributed to considerable variation ( between 0 and 15 μg/d ) in international dietary recommendations for  vitamin D in adolescents . OBJECTIVE We aim ed to establish the distribution of dietary vitamin D required to maintain serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations above several proposed cutoffs ( 25 , 37.5 , 40 , and 50 nmol/L ) during wintertime in adolescent white girls . DESIGN Data ( baseline and 6 mo ) from 2 r and omized ,  placebo-controlled  , double-blind , 12-mo intervention studies in Danish ( 55 ° N ) and Finnish ( 60 ° N ) girls ( n = 144 ; mean age : 11.3 y ; mean vitamin D intake : 3.7 μg/d ) at vitamin D(3 ) supplementation amounts of 0 , 5 , and 10 μg/d were used . Serum 25(OH)D was measured with an HPLC assay in a central ized laboratory . RESULTS Clear dose-related increments ( P < 0.0001 ) in serum 25(OH)D with increasing supplemental vitamin D(3 ) were observed . The slope of the relation between vitamin D intake and serum 25(OH)D at the end of winter was 2.43 nmol ⋅ L(-1 ) ⋅ μg intake(-1 ) , and no difference in the slopes between Finnish and Danish girls was observed . The vitamin D intakes that maintained serum 25(OH)D concentrations at > 25 , > 37.5 , and > 50 nmol/L in 97.5 % of the sample were 8.3 , 13.5 , and 18.6 μg/d , respectively , whereas an intake of 6.3 μg/d maintained a serum 25(OH)D concentration > 40 nmol/L in 50 % of the sample . CONCLUSION The vitamin D intakes required to ensure that adequate vitamin D status [ defined variably as serum 25(OH)D > 25 and > 50 nmol/L ] is maintained during winter in the vast majority ( > 97.5 % ) of adolescent girls ( mean age : 11.3 y ) at northern latitudes ( > 55 ° N ) are 8.3 and 18.6 μg/d , respectively . This trial was registered at clinical trials.gov as NCT00267540 Data derived from laboratory investigations suggest that a number of dietary variables may contribute to bladder carcinogenesis . Although bladder cancer is the fourth leading cause of cancer in men in the United States , dietary studies are few . The authors examined the relations between intakes of macro- and micronutrients and the  risk of bladder cancer among men in the prospect i ve Health Professionals Follow-Up Study . Each participant completed a 131-item food frequency question naire in 1986 and in 1990 , from which nutrient intakes were calculated . During 12 years of follow-up , 320 cases of bladder cancer were diagnosed . No association was observed for total caloric or macronutrient intake and bladder cancer risk . Similarly , we found no relation for dietary intake of potassium , sodium , calcium , magnesium , phosphorus , iron , or water-soluble vitamins and bladder cancer risk . Total vitamin E intake and vitamin E supplements  were inversely associated with risk . In addition , a dose-response relation was observed for duration of vitamin E supplement use . A suggestive inverse association was seen with dose of vitamin C supplement use . More studies are needed to determine the role of vitamins E and C supplement intake in bladder carcinogenesis BACKGROUND Older adults may be more prone to developing vitamin D deficiency than younger adults . Dietary requirements for vitamin D in older adults are based on limited evidence . OBJECTIVE The objective was to establish the dietary intake of vitamin D required to maintain serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations above various cutoffs between 25 and 80 nmol/L during wintertime , which accounted for the effect of summer sunshine exposure and diet . DESIGN A r and omized , placebo-controlled , double-blind , 22-wk intervention was conducted in men and women aged > /=64 y ( n = 225 ) at supplemental levels of 0 , 5 , 10 , and 15 microg vitamin D(3)/d from October 2007 to March 2008 . RESULTS Clear dose-related increments ( P < 0.0001 ) in serum 25(OH)D were observed with increasing supplemental vitamin D(3 ) intakes . The slope of the relation between total vitamin D intake and serum 25(OH)D was 1.97 nmol . L(-1 ) . microg intake(-1 ) . The vitamin D intake that maintained serum 25(OH)D concentrations > 25 nmol/L in 97.5 % of the sample was 8.6 microg/d . Intakes were 7.9 and 11.4 microg/d in those who reported a minimum of 15 min daily summer sunshine exposure or less , respectively . The intakes required to maintain serum 25(OH)D concentrations of > 37.5 , > 50 , and > 80 nmol/L in 97.5 % of the sample were 17.2 , 24.7 , and 38.7 microg/d , respectively . CONCLUSION To ensure that the vitamin D requirement is met by the vast majority ( > 97.5 % ) of adults aged > /=64 y during winter , between 7.9 and 42.8 microg vitamin D/d is required , depending on summer sun exposure and the threshold of adequacy of 25(OH)D. This trial was registered at http://www.controlled-trials.com/IS RCT N20236112 as IS RCT N registration no. IS RCT N20236112 OBJECTIVE Inter population as well as interindividual variations in response to vitamin D intake commonly observed in subjects with type 2 diabetes may be related to genetic makeup . One of the c and i date genes potentially responsible for this diversity is vitamin D receptor ( VDR ) . This study aim ed to investigate the interactive effect of VDR Fok-I polymorphism and vitamin D intake on diverse aspects of diabetic host response . RESEARCH DESIGN AND METHODS Glycemic status , lipid profiles , inflammatory biomarkers , and VDR Fok-I genotypes were determined in diabetic subjects ( n = 140 ) who participated in a r and omized controlled trial . Participants consumed two 250-mL bottles per day of yogurt drink ( doogh ) fortified with 500 IU vitamin D/250 mL for 12 weeks . RESULTS Mean serum 25(OH)D increased by ~30 nmol/L ( P < 0.001 ) . The time × intervention effect was significant for 25(OH)D ( P = 0.030 ) , HDL ( P = 0.011 ) , high-sensitivity C-reactive protein ( hsCRP ) ( P < 0.001 ) , interleukin (IL)-4 ( P = 0.008 ) , and IL-6 ( P = 0.017 ) among the genotypic groups . The alleles were defined as ‘ ‘ F ’ ’ or ‘ ‘ f ’ ’ depending on the absence or presence of the restriction site , respectively . The least increment in 25(OH)D was in ff ( 23.0 ± 3.8 nmol/L ) compared with Ff ( 31.2 ± 3.4 nmol/L ) and FF ( 35.6 ± 2.7 nmol/L ) ( P for trend = 0.009 ) , but only the difference between ff and FF was significant ( P = 0.023 ) . FF group had the largest decrement of both hsCRP and IL-6 compared with Ff ( P < 0.001 and P = 0.038 ) and ff ( P = 0.010 and P = 0.048 ) , respectively . CONCLUSIONS We concluded that those of VDR ff genotype may be regarded as “ low responders ” to vitamin D intake in terms of response of circulating 25(OH)D and certain inflammatory biomarkers . A nutrigenetic approach may , therefore , be needed to protect diabetic patients from vitamin D deficiency Background Poor micronutrient status is reported among adolescents across Europe and USA . This may be related to the well-documented decline in the regular consumption of breakfast by this group . The regular consumption of a breakfast cereal offers a possible means to improve micronutrient status ; fortified cereal is likely to have enhanced benefit . A study was conducted to determine the efficacy of the regular consumption of a fortified cereal with milk , compared with unfortified cereal , consumed either as a breakfast or a supper , in improving micronutrient intake and micronutrient status of adolescent girls . Methods A r and omised , double-blind , placebo-controlled intervention trial was conducted in girls recruited at ages 16–19 years , from schools and colleges in Sheffield , UK . Girls were r and omised to receive 50 g fortified or unfortified cereal , with 150 ml semi-skimmed milk , daily , for 12 weeks , as a breakfast or as a supper .  Dietary intake was estimated using a 4-d food diary and blood collected for the assessment of nutritional status . Within-group changes were tested using a paired sample t test ; two-way ANOVA was used to analyse effects of the intervention , with cereal type and time of consumption as factors , correcting for baseline values . The analysis was conducted on 71 girls who completed the study . Results Consumption of unfortified cereal elicited an increase in the intake of vitamins B1 , B2 and B6 ; consumption of fortified cereal elicited increases in vitamins B1 , B2 , B6 , B12 , folate and iron ( P < 0.001 ) and of vitamin D ( P = 0.007 ) , all increases were significantly greater than for unfortified cereal . Consumption of the fortified cereal also led to a significant improvement in biomarkers of status for vitamins B2 , B12 , folate and of iron , compared with girls receiving the unfortified cereal , and maintained vitamin D status , in contrast with the girls receiving the unfortified cereal ( P < 0.001 ) . Conclusions The daily consumption of cereal with milk for 12 weeks by adolescent girls , increased intakes of micronutrients . The consumption of fortified cereal elicited greater increases than for unfortified cereal and improved biomarkers of micronutrient status . The findings justify strategies to encourage the consumption of fortified cereal with milk by adolescents , either as a breakfast or a supper . Trial registration Registered with Current Controlled Trials ( Registration : IS RCT N55141306 Considerable evidence supports the hypothesis that vitamin E reduces the risk for atherosclerosis ( 1 ) . Vitamin E inhibits the proliferation of smooth-muscle cells in vitro ( 2 ) and increases the resistance of low-density lipoprotein to oxidation when it is added to plasma or administered to humans ( 3 , 4 ) . Furthermore , platelets from persons taking vitamin E supplements  had markedly reduced adhesiveness to collagen ( 5 ) . Consistent with these findings , vitamin E intake has been inversely associated with risk for coronary heart disease ( 6 - 8 ) and for peripheral arterial disease ( 9 ) and with carotid artery wall thickness ( 10 , 11 ) . Risk for ischemic stroke also increases with atherosclerosis and might therefore be reduced by vitamin E. However , few studies have addressed the relation between vitamin E and risk for ischemic stroke , and those that have been done were small , had little variation in vitamin E intake , or did not distinguish between ischemic and hemorrhagic stroke ( 12 - 15 ) . Risk for hemorrhagic stroke is unlikely to be reduced by high doses of vitamin E and could even be increased by the reduced platelet adhesion that these doses cause ( 5 ) . The most informative previous studies a large r and omized trial in men ( 16 , 17 ) and a prospect i ve investigation in women (6)supported a modest beneficial effect of vitamin E with respect to ischemic stroke , but the results were not statistically significant . Moreover , in the trial in men ( 16 ) , this apparent benefit was offset by an increased risk for hemorrhagic stroke . Like vitamin E , vitamin C and carotenoids have antioxidant properties ( 18 , 19 ) and have been hypothesized to reduce risk for stroke , but epidemiologic evidence to support these hypotheses is limited ( 14 - 17 , 20 - 22 ) . Of the carotenoids , we considered -carotene , -carotene , lutein , and lycopene because they are present in relatively large amounts in the diet and have distinct antioxidant properties ( 23 ) . Our primary hypothesis was that high intake of these antioxidants would reduce risk for ischemic stroke . We report here the associations between intakes of vitamin E , vitamin C , and specific carotenoids and risks for ischemic and hemorrhagic stroke in a large cohort of men in the United States . Methods Study Sample The Health Professionals Follow-up Study began in 1986 , when 51 529 health professionals 40 to 75 years of age [ 24 ] completed a 131-item food-frequency question naire and supplied information about medical history and lifestyle . Follow-up question naires were sent every 2 years so that we could up date information on potential risk factors , including use of vitamin supplements , and identify newly diagnosed cases of stroke and other diseases . We excluded from analysis 1595 men who did not have 1 ) a daily caloric intake between 800 and 4200 kcal and 2 ) fewer than 70 blanks ( among 131 listed food items ) on the food-frequency question naire . We also excluded men with previous myocardial infa rct ion , angina , coronary artery surgery , stroke , transient ischemic attack , peripheral arterial disease , or diabetes . We followed the 43 738 eligible men for incidence of stroke for 8 years . The average response rate for the 2-year follow-up cycles was more than 94 % . Nonresponding participants who were not matched to the National Death Index were assumed to be alive . This study was approved by the institutional review board of the Harvard School of Public Health . Assessment of Diet and Other Exposure Variables On the 1986 question naire , we asked about 1 ) the average frequency of intake over the previous year of specified portions of 131 foods and 2 ) the use of vitamin and mineral supplements . We specifically asked about dose and duration of use of multivitamin , vitamin E , and vitamin C supplements . Nutrient calculations took into account the specific br and s of breakfast cereal and multivitamin supplements reported by each participant . We assessed the question naire 's validity in a r and om sample of 127 men who completed two 1-week diet records ( 25 ) ; 121 of these men also provided blood sample s ( 26 , 27 ) . The correlations between the food-frequency assessment s of intake and plasma concentrations were 0.51 for -tocopherol , 0.47 for -carotene and lycopene , 0.35 for -carotene , and 0.40 for lutein . These correlations were similar to those seen between plasma levels of these nutrients and intake of these nutrients as estimated by the two 1-week diet records ( 25 ) , and they support the validity of the food-frequency question naire . Even if dietary measurements were perfect , vitamin intake and plasma levels would not be highly correlated because multiple factors contribute to between-person variations in plasma vitamin levels . The correlation between the food-frequency and diet-record assessment s was 0.92 for both vitamin C and vitamin E ( 25 ) . In 1986 , in addition to reporting on diet , participants were asked to report their usual systolic and diastolic blood pressures and whether they had physician-diagnosed hypertension . The validity of these variables has been documented ( 28 ) . Other potential risk factors for stroke that were assessed at baseline and in the follow-up question naire included smoking history , body mass index , history of hypercholesterolemia , physical activity , parental history of myocardial infa rct ion , and alcohol consumption . Events End points were fatal or nonfatal stroke occurring between the return of the baseline question naire and 31 January 1994 . If a participant reported an incident stroke on a follow-up question naire , we asked for permission to review that participant 's medical records . Strokes were confirmed if they were characterized by a typical neurologic defect of sudden or rapid onset that lasted at least 24 hours and was attributable to a cerebrovascular event . Strokes caused by infection or neoplasia were excluded . Review s were conducted by physicians who had no knowledge of participants ' risk factor status . Strokes were subclassified , according to the criteria of the National Survey of Stroke , as due to ischemia ( embolism or thrombosis ) , subarachnoid hemorrhage , intracerebral hemorrhage , or an unknown cause ( 29 ) . If no records could be obtained , a stroke was considered probable if it necessitated hospitalization and was corroborated by additional information provided in a letter or interview . Deaths were initially reported by next-of-kin , coworkers , postal authorities , or the National Death Index . Fatal strokes were confirmed by medical records ( 84 % ) or autopsy reports ( 2 % ) or were considered probable if medical records or autopsy reports could not be obtained and stroke was listed as the underlying cause of death on the death certificate ( 14 % ) . Statistical Analysis Participants contributed follow-up time from the return of the 1986 question naire to the occurrence of a confirmed stroke or death or 31 January 1994 . Men who had nonfatal myocardial infa rct ion or coronary surgery during the follow-up period were retained in the analysis . Intake of vitamin E and other nutrients was energy-adjusted to 2000 kcal/d ( 30 ) . Relative risks were calculated by dividing the incidence of stroke among men in each quintile of energy-adjusted vitamin E intake at baseline by the incidence of stroke among men in the lowest quintile of intake . Similar calculations were done for the other nutrients . Quintiles were used to avoid assumptions about the shape of the dose-response relation and to provide sufficient power to compare men in the extreme categories of intake . For vitamin E , vitamin C , and -carotene , additional analyses separately considered supplemental and dietary intake . We adjusted relative risks for age ( in 5-year categories ) ( 31 ) and used the Mantel extension test ( 32 ) to test for linear trends . To adjust for other risk factors , we used pooled logistic regression with 2-year intervals . Where the probability of an event within an interval is small , this method is equivalent to a Cox proportional-hazards analysis ( 33 ) . The multivariate models included the following as covariates : calendar time ( in 2-year intervals ) , total energy intake ( continuous variable ) , smoking ( current ; past ; or 1 to 14 , 15 to 24 , and 25 cigarettes/d ) , alcohol consumption ( < 5 , 5 to 9 , 10 to 14 , 15 to 29 , or 30 g/d ) , history of hypertension , history of hypercholesterolemia , parental history of myocardial infa rct ion before 65 years of age , profession , and quintiles of body mass index and physical activity . In these models , we evaluated monotonic trends by using the median value of each category and modeling it as a continuous variable . Analyses were also conducted to up date dietary intake and other covariates during follow-up . In these analyses , the incidence of stroke in 1986 - 1990 was related to vitamin and carotenoid intake reported in 1986 , whereas the incidence of stroke in 1990 - 1994 was related to the average intake reported in 1986 and 1990 . Because dietary changes made after the development of intermediate end points , such as coronary heart disease , peripheral arterial disease , transient ischemic attacks , diabetes , and hypercholesterolemia , may confound the associations between diet and disease ( 34 ) , we repeated the analyses without updating information on diet for men who reached an intermediate end point before completing the 1990 dietary question naire . All P values are two-sided . Role of the Funding Source The National Institutes of Health had no role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the paper for publication . Results During 323 394 person-years of follow-up , we documented 328 strokes : 210 ischemic , 70 hemorrhagic , and 48 unclassified . Fifty of the 328 strokes were fatal . The distribution of risk factors for stroke differed somewhat by vitamin E , vitamin C , and -carotene intake ( Table 1 ) . Men in the top quintiles of vitamin E or vitamin C intakemost of whom used multivitamin or specific vitamin supplementswere less likely to smoke , were more likely to use aspirin , and were BACKGROUND Knowledge gaps have contributed to considerable variation among international dietary recommendations for vitamin D. OBJECTIVE We aim ed to establish the distribution of dietary vitamin D required to maintain serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations above several proposed cutoffs ( ie , 25 , 37.5 , 50 , and 80 nmol/L ) during wintertime after adjustment for the effect of summer sunshine exposure and diet . DESIGN A r and omized , placebo-controlled , double-blind 22-wk intervention study was conducted in men and women aged 20 - 40 y ( n = 238 ) by using different supplemental doses ( 0 , 5 , 10 , and 15 microg/d ) of vitamin D(3 ) throughout the winter .  Serum 25(OH)D concentrations were measured by using enzyme-linked immunoassay at baseline ( October 2006 ) and endpoint ( March 2007 ) . RESULTS There were clear dose-related increments ( P < 0.0001 ) in serum 25(OH)D with increasing supplemental vitamin D(3 ) . The slope of the relation between  vitamin D intake and serum 25(OH)D was 1.96 nmol x L(-1 ) x microg(-1 ) intake . The vitamin D intake that maintained serum 25(OH)D concentrations of > 25 nmol/L in 97.5 % of the sample was 8.7 microg/d . This intake ranged from 7.2 microg/d in those who enjoyed sunshine exposure , 8.8 microg/d in those who sometimes had sun exposure , and 12.3 microg/d in those who avoided sunshine . Vitamin D intakes required to maintain serum 25(OH)D concentrations of > 37.5 , > 50 , and > 80 nmol/L in 97.5 % of the sample were 19.9 , 28.0 , and 41.1 microg/d , respectively . CONCLUSION The range of vitamin D intakes required to ensure maintenance of wintertime vitamin D status [ as defined by incremental cutoffs of serum 25(OH)D ] in the vast majority ( > 97.5 % ) of 20 - 40-y-old adults , considering a variety of sun exposure preferences , is between 7.2 and 41.1 microg/d The etiologic role of dietary calcium and vitamin D intake in primary prevention of  osteoporotic fractures is uncertain , despite considerable research efforts . With the aim to examine these associations with an improved precision , we used data from a large population -based prospect i ve cohort study in central Sweden . We estimated nutrient intake from a self-administered food-frequency question naire filled in by 60,689 women , aged 40 - 74 years at baseline during 1987 - 1990 . During follow-up , we observed 3986 women with a fracture at any site and 1535 with a hip fracture .  Rate ratio of fractures ( RR ) and 95 % CI were estimated using Cox proportional hazards models . We found no dose-response association between dietary calcium intake and fracture risk . The age-adjusted RR of hip fracture was 1.01 ( 95 % CI 0.96 - 1.06 ) per 300 mg calcium/day and the corresponding risk of any osteoporotic fracture was 0.99 ( 95 % CI 0.96 - 1.03 ) . Furthermore , women with an estimated calcium intake below 400 mg/day and those with a calcium intake higher than 1200 mg/day both had a similar age-adjusted hip fracture risk as those with intermediate calcium intakes : RR 1.07 ( 95 % CI 0.92 - 1.24 ) and RR 1.00 ( 95 % CI 0.79 - 1.27 ) , respectively . Vitamin D intake was not associated with fracture risk . Furthermore , women in the highest quintiles compared to the lowest quintiles of both calcium and vitamin D intake had an age-adjusted RR of 1.02 for all fractures ( 95 % CI 0.88 - 1.17 ) . Dietary calcium or vitamin D intakes estimated at middle and older age do not seem to be of major importance for the primary prevention of osteoporotic fractures in women BACKGROUND Children in northern latitudes are at high risk of vitamin D deficiency during winter because of negligible dermal vitamin D3 production . However , to our knowledge , the dietary requirement for maintaining the nutritional adequacy of vitamin D in young children has not been investigated . OBJECTIVE We aim ed to establish the distribution of vitamin D intakes required to maintain winter serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations above the proposed cutoffs ( 25 , 30 , 40 , and 50 nmol/L ) in white Danish children aged 4 - 8 y living at 55 ° N. DESIGN In a double-blind , r and omized , controlled trial 119 children ( mean age : 6.7 y ) were assigned to 0 ( placebo ) , 10 , or 20 μg vitamin D3/d supplementation for 20 wk . We measured anthropometry , dietary vitamin D , and serum 25(OH)D with liquid chromatography-t and em mass spectrometry at baseline and endpoint . RESULTS The mean ± SD baseline serum 25(OH)D was 56.7 ± 12.3 nmol/L ( range : 28.7 - 101.4 nmol/L ) . Serum 25(OH)D increased by a mean ± SE of 4.9 ± 1.3 and 17.7 ± 1.8 nmol/L in the groups receiving 10 and 20 μg vitamin D3/d , respectively , and decreased by 24.1 ± 1.2 nmol/L in the placebo group ( P < 0.001 ) . A nonlinear model of serum 25(OH)D as a function of total vitamin D intake ( diet and supplements ) was fit to the data . The estimated vitamin D intakes required to maintain winter serum 25(OH)D > 30 ( avoiding deficiency ) and > 50 nmol/L ( ensuring adequacy ) in 97.5 % of participants were 8.3 and 19.5 μg/d , respectively , and 4.4 μg/d was required to maintain serum 25(OH)D > 40 nmol/L in 50 % of participants . CONCLUSIONS Vitamin D intakes between 8 and 20 μg/d are required by white 4- to 8-y-olds during winter in northern latitudes to maintain serum 25(OH)D > 30 - 50 nmol/L depending on chosen serum 25(OH)D threshold . This trial was registered at clinical trials.gov as NCT02145195 The link diet-cognitive function/dementia has been largely investigated in observational studies ; however , there was a lack of evidence from r and omized clinical trials ( RCTs ) on the prevention of late-life cognitive disorders though dietary intervention in cognitively healthy older adults . In the present article , we systematic ally review ed RCTs published in the last four years ( 2014 - 2017 ) exploring nutritional intervention efficacy in preventing the onset of late-life cognitive disorders and dementia in cognitively healthy subjects aged 60 years and older using different levels of investigation ( i.e. , dietary pattern changes/medical food/nutraceutical supplementation/multidomain approach and dietary macro- and micronutrient approaches ) as well as possible underlying mechanisms of nutritional prevention . From the 35 included RCTs , there was moderate evidence that intervention through dietary pattern changes , medical food/nutraceutical supplementation , and multidomain approach improved specific cognitive domains or cognitive-related blood biomarkers . There was high evidence that protein supplementation improved specific cognitive domains or functional status in prefrail older adults without effect on cognitive function . For fatty acid supplementation , mainly long-chain polyunsaturated fatty acids , there was emerging evidence suggesting an impact of this approach in improving specific cognitive domains , magnetic resonance imaging ( MRI ) findings , and /or cognitive-related biomarkers also in selected subgroups of older subjects , although some results were conflicting . There was convincing evidence of an impact of non-flavonoid polyphenol and flavonoid supplementations in improving specific cognitive domains and /or MRI findings . Finally , there was only low evidence suggesting efficacy of intervention with homocysteine-related and antioxidant vitamins in improving cognitive functions , dementia incidence , or cognitive-related biomarkers in cognitively healthy older subjects BACKGROUND The effects of dietary protein on bone health are controversial . OBJECTIVE We examined the relation between protein intake with fracture and  bone mineral density ( BMD )  within the Women 's Health Initiative ( WHI ) . DESIGN This prospect i ve analysis included 144,580 women aged 50 - 79 y at baseline in the WHI clinical trials ( CTs ) and observational study ( OS ) that recruited participants in 1993 - 1998 with follow-up through 2011 . Self-reported clinical fractures were collected semiannually through the original end of the trials ( WHI CTs ) and annually ( WHI OS ) by question naires . Hip fracture was adjudicated by a central review of radiology reports . BMDs for total body , hip , and spine were measured at baseline and 3 and 6 y in 9062 women at 3 WHI clinics by using dual-energy X-ray absorptiometry .  Protein intake was assessed via food-frequency question naire and calibrated by using biomarkers of energy and protein intakes . Associations between protein intake and fracture were estimated by using Cox proportional hazards regression , and the relation between protein intake and BMD was estimated by using linear regression . RESULTS Median biomarker-calibrated protein intake was 15 % of energy intake . Per 20 % increase in calibrated protein intake ( percentage of energy ) , there was no significant association with total fracture ( HR : 0.99 ; 95 % CI : 0.97 , 1.02 ) or hip fracture ( HR : 0.91 ; 95 % CI : 0.84 , 1.00 ) , but there was an inverse association with forearm fracture ( HR : 0.93 ; 95 % CI : 0.88 , 0.98 ) . Each 20 % increase in calibrated protein intake was associated with a significantly higher BMD for total body ( mean 3-y change : 0.003 g/cm² ; 95 % CI : 0.001 , 0.005 g/cm² ) and hip ( mean 3-y change : 0.002 g/cm² ; 95 % CI : 0.001 , 0.004 g/cm² ) . CONCLUSIONS Higher biomarker-calibrated protein intake within the range of usual intake was inversely associated with forearm fracture and was associated with better maintenance of total and hip BMDs . These data suggest higher protein intake is not detrimental to bone health in postmenopausal women OBJECTIVES Our objective was to prospect ively examine the relation between vitamin C intake and risk of coronary heart disease ( CHD ) in women . BACKGROUND Results from prospect i ve investigations of the relation between vitamin C intake and risk of CHD have been inconsistent . The lack of clear evidence for a protective association despite a plausible mechanism indicates the need to evaluate further the association between vitamin C intake and risk of CHD . METHODS In 1980 , 85,118 female nurses completed a detailed semiquantitative food-frequency question naire that assessed their consumption of vitamin C and other nutrients . Nurses were followed up for 16 years for the development of incident CHD ( nonfatal myocardial infa rct ion and fatal CHD ) . RESULTS During 16 years of follow-up ( 1,240,566 person-years ) , we identified 1,356 incident cases of CHD . After adjustment for age , smoking , and a variety of other coronary risk factors , we observed a modest significant inverse association between total intake of vitamin C and risk of CHD ( relative risk [ RR ] = 0.73 ; 95 % confidence interval [ CI ] 0.57 to 0.94 ) . Among women who did not use vitamin C supplements or multivitamins  , the association between intake of vitamin C  from diet alone and incidence of CHD was weak and not significant ( RR = 0.86 ; 95 % CI 0.59 to 1.26 ) . In multivariate models adjusting for age , smoking , and a variety of other coronary risk factors , vitamin C supplement use was associated with a significantly lower risk of CHD ( RR = 0.72 ; 95 % CI 0.61 to 0.86 ) . CONCLUSIONS Users of vitamin C supplements appear to be at lower risk for CHD Introduction Vitamin D has potential benefits for extraskeletal health . These could include an anti-inflammatory effect as well as a reduction in endothelial dysfunction . We aim to provide quality evidence for the hypothesis that supplementation with vitamin D will improve endothelial function ( EF ) , possibly through the abrogation of systemic inflammation . Methods and analysis We will conduct a systematic review of all r and omised controlled trials on  vitamin D supplementation and EF lasting 12 weeks or more . The search will cover the period 2000–2015 and include studies that describe direct measures of EF  , markers of endothelial cell ( EC ) activation  and if concurrently reported , indicators of systemic inflammation  . Study selection will follow the Preferred Reporting Items for Systematic Review s and Meta-Analyses ( PRISMA ) guidelines and study quality will be assessed by the Jadad score in addition to an evaluation of allocation concealment and data analysis . If sufficient data are available , a meta- analysis will be conducted . The effect sizes will be generated using Hedges ’ g score , for both fixed and r and om effect models . I2 statistics and Galbraith plots will be used to assess heterogeneity and identify their potential sources . Potential publication and small sample size bias will be assessed by visual inspections of funnel plots and also Egger 's test . Meta-regression analysis ( if feasible ) will be conducted with restricted maximum likelihood ( REML ) estimation method , controlling for potential confounders ( demographics , study methods , location , etc ) . A backward elimination process will be applied in the regression modelling procedure . Subgroup analysis , conditional on number of studies retrieved and their sample size , will be stratified on participant disease category , total dose administered , degree of 25(OH)D change and type of supplement used . Ethics and dissemination Formal ethical approval is not required as primary data will not be collected . The results will be disseminated through a peer- review ed publication , conference presentation and the popular press . Trial registration number International Prospect i ve Register for Systematic Review s ( PROSPERO ) number CRD42014013523 Background The role of vitamin D in management of depression is unclear . Results from observational and emerging r and omized controlled trials ( RCTs ) investigating the efficacy of vitamin D in depression lack consistency - with some suggesting a positive association while others show a negative or inconclusive association . Methods / Design The primary aim of this study is to conduct a systematic review of RCTs to assess the effect of oral vitamin D supplementation versus placebo on depression symptoms measured by scales and the proportion of patients with symptomatic improvement according to the authors ’ original definition . Secondary aims include assessing the change in quality of life , adverse events and treatment discontinuation . We will conduct the systematic review and meta- analysis according to the recommendations of the Cochrane H and book for Systematic Review s of Interventions . We will search the Cochrane Central Register of Controlled Trials ( CENTRAL ) , MEDLINE ( 1966 to present ) , EMBASE ( 1980 to present ) , CINAHL ( 1982 to present ) , PsychINFO ( 1967 to present ) and Clinical Trials.gov . Unpublished work will be identified by search ing two major conferences : the International Vitamin Conference , the Anxiety Disorders and Depression Conference , while grey literature will be acquired by contacting authors of included studies . We will use the r and om-effects meta- analysis to synthesize the data by pooling the results of included studies . Discussion The results of this systematic review will be helpful in clarifying the efficacy of vitamin D supplementation and providing evidence to establish guidelines for implementation of vitamin D for depression in general practice and other relevant setting s. Study registration Unique identifier : CRD42013003849 AIM To produce dietetic guidelines summarizing the systematic review evidence on dietary advice for secondary prevention of cardiovascular disease . METHODS The Cochrane Library , MEDLINE and EMBASE were comprehensively search ed for systematic review s on aspects of diet and heart health . Review s were included if they search ed systematic ally for r and omised controlled trials relating to diet and secondary prevention of cardiovascular disease . Two members of the UK Heart Health and Thoracic Dietitians Group critically appraised each review . The quality and results of each review were discussed and summarized in a whole group meeting . The guidelines were trialled in seven dietetic departments and modified where necessary . RESULTS Providing evidence -based dietary information ( including increasing omega-3 fat plus fruit and vegetable intake ) to all people after myocardial infa rct ion will save more lives than concentrating dietary advice on those in need of weight loss or lipid lowering . The practice of prioritizing dietetic time to those with raised lipids is out of date since the advent of statin therapy . CONCLUSION There is good systematic review evidence that dietary advice to those with cardiovascular disease can reduce mortality and morbidity as well as modify risk factors .  Dietary advice that does this most effectively should be prioritized OBJECTIVE There are several examples in nutrition of discordance between the results of observational studies and r and omized controlled trials ( RCTs ) . We hypothesized that this discordance is attributable to differences in the translational paths of nutrient-disease associations . Translational paths can be assessed using citation analysis . STUDY DESIGN AND SETTING We compared the characteristics of citation networks using examples , where RCTs and observational studies agreed ( long-chain n-3 polyunsaturated fatty acids [ n-3 PUFA ] ) or disagreed ( vitamin E ) . We performed systematic review s in each example , constructed citation networks , and compared them with respect to the number of articles and citation relationships between them , as well as the distribution of articles ' hub and authority scores . RESULTS For n-3 PUFA , meta-analyses of 14 RCTs and 10 observational studies both suggested that higher intake was associated with lower cardiovascular mortality . For vitamin E , the meta- analysis of 14 RCTs excluded a clinical ly significant effect , whereas 14 observational studies reported a significant inverse association . The respective citation networks consisted of 392 ( n-3 PUFA ) and 351 ( vitamin E ) articles . No differences between the characteristics of the two networks were identified . There was no evidence that the observational studies pre date d RCTs in the translational process in either example . CONCLUSION In the two examples , citation network characteristics do not predict concordance in the results of observational studies and RCTs CONTEXT Public health authorities around the world recommend widely variable supplementation strategies for adults , whereas several professional organizations , including The Endocrine Society , recommend higher supplementation . METHODS We analyzed published r and omized controlled clinical trials to define the optimal intake or vitamin D status for bone and extraskeletal health . CONCLUSIONS The extraskeletal effects of vitamin D are plausible as based on pre clinical data and observational studies . However , apart from the beneficial effects of 800 IU/d of vitamin D3 for reduction of falls in the elderly , causality remains yet unproven in r and omized controlled trials ( RCTs ) . The greatest risk for cancer , infections , cardiovascular and metabolic diseases is associated with 25-hydroxyvitamin D ( 25OHD ) levels below 20 ng/mL. There is ample evidence from RCTs that calcium and bone homeostasis , estimated from serum 1,25-dihydroxyvitamin D and PTH , calcium absorption , or bone mass , can be normalized by 25OHD levels above 20 ng/mL. Moreover , vitamin D supplementation ( 800 IU/d ) in combination with calcium can reduce fracture incidence by about 20 % . Such a dose will bring serum levels of 25OHD above 20 ng/mL in nearly all postmenopausal women . Based on calculations of the metabolic clearance of 25OHD , a daily intake of 500 - 700 IU of vitamin D3 is sufficient to maintain serum 25OHD levels of 20 ng/mL. Therefore , the recommendations for a daily intake of 1500 - 2000 IU/d or serum 25OHD levels of 30 ng or higher for all adults or elderly subjects , as suggested by The Endocrine Society Task Force , are premature . Fortunately , ongoing RCTs will help to guide us to solve this important public health question Diet has been investigated in relation to its ability to promote cognitive function . However , evidence is currently limited and has rarely been systematic ally review ed , particularly in a mild cognitive impairment ( MCI ) population . This review examined the effect of diet on cognitive outcomes in MCI patients . A total of five data bases were search ed to find r and omised controlled trial ( RCT ) studies , with diet as the main focus , in MCI participants . The primary outcome was incident dementia and /or Alzheimer 's disease ( AD ) and secondary outcomes included cognitive function across different domains using vali date d neuropsychological tests .  Sixteen studies met the inclusion criteria . There was a high degree of heterogeneity relating to the nature of the dietary intervention and cognitive outcomes measured , thus making study comparisons difficult . Supplementation with vitamin E ( one study , n 516 ) , ginkgo biloba ( one study , n 482 ) or Fortasyn Connect ( one study , n 311 ) had no significant effect on progression from MCI to dementia and /or AD . For cognitive function , the findings showed some improvements in performance , particularly in memory , with the most consistent results shown by B vitamins , including  folic acid  ( one study , n 266 ) ,  folic acid alone  ( one study , n 180 ) ,  DHA and EPA  ( two studies , n 36 and n 86 ) ,  DHA  ( one study , n 240 ) and  flavonol supplementation  ( one study , n 90 ) . The findings indicate that dietary factors may have a potential benefit for cognitive function in MCI patients . Further well- design ed trials are needed , with st and ardised and robust measures of cognition to investigate the influence of diet on cognitive status Background : Fruits and vegetables rich in antioxidants have been proposed to reduce the risk of  renal cell cancer .  However , few prospect i ve studies have examined the intakes of fruits , vegetables , and antioxidant vitamins in relation to the risk of  renal cell cancer .  Methods : We prospect ively examined the associations between the intakes of fruits , vegetables , vitamins A , C , and E , and carotenoids and risk of renal cell cancer in women and men . We followed 88,759 women in the Nurses ' Health Study from 1980 to 2000 , and 47,828 men in the Health Professionals Follow-up Study from 1986 to 2000 . We assessed dietary intake every 2 to 4 years using a vali date d semiquantitative food frequency question naire . The Cox proportional hazards model was used to estimate study -specific multivariate relative risks ( RR ) , which were pooled using a r and om effects model . Results : A total of 248 ( 132 women and 116 men ) incident renal cell cancer cases were ascertained during 2,316,525 person-years of follow-up . The consumption of fruits and vegetables was associated with a decreased risk of renal cell cancer in men ( multivariate RR , 0.45 ; 95 % CI , 0.25 - 0.81 , for ≥6 servings of fruit and vegetable intake/d versus <3 servings/d ; P test for trend = 0.02 ) , but not in women ( multivariate RR , 1.17 ; 95 % CI , 0.66 - 2.07 , for the same contrast ; P test for trend = 0.25 ; P test for between- studies heterogeneity = 0.02 ) . Intakes of vitamins A and C from food and carotenoids were inversely associated with the risk of renal cell cancer  in men only , but we can not exclude the possibility that this was due to other factors in fruit and vegetables . No clear association was observed for vitamin E in women or men . Conclusions : Fruit and vegetable consumption may reduce the risk of renal cell cancer in men . ( Cancer Epidemiol Biomarkers Prev 2006;12(24):2445–52 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 BACKGROUND Some evidence suggests that vitamin D may reduce  breast cancer risk . Despite the biological interaction between vitamin D and calcium , few studies have evaluated their joint effects on breast cancer risk . OBJECTIVE The objective was to evaluate the associations and potential interaction between vitamin D and calcium ( from food and supplements ) and breast cancer risk in a population -based case-control study . DESIGN Breast cancer cases aged 25 - 74 y ( diagnosed 2002 - 2003 ) were identified through the Ontario Cancer Registry . Controls were identified by using r and om digit dialing ; 3101 cases and 3471 controls completed epidemiologic and food-frequency question naires . Adjusted odds ratios ( ORs ) and 95 % CIs were estimated by using multivariate logistic regression . RESULTS Vitamin D and calcium intakes from food only and total combined intakes ( food and supplements ) were not associated with breast cancer risk , although the mean intake of vitamin D was low . Vitamin D supplement intake > 10 microg/d ( 400 IU/d ) compared with no intake was associated with a reduced risk of breast cancer ( adjusted OR : 0.76 ; 95 % CI : 0.59 , 0.98 ) . No categories of calcium supplement intake were significantly associated with reduced breast cancer risk , but a significant inverse trend was observed ( P = 0.04 ) . There were no significant interactions involving vitamin D , calcium , or menopausal status . CONCLUSIONS No associations were found between overall vitamin D or calcium intake and breast cancer risk .  Vitamin D from supplements was independently associated with reduced breast cancer risk . Further research is needed to investigate the effects of higher doses of vitamin D and calcium supplements BACKGROUND Antioxidant defenses are one possible mechanism for decreasing oxidative damage and its potentially negative effects on age-related bone mass . OBJECTIVE This study cross-sectionally examined whether higher dietary intakes , total intakes , and serum concentrations of antioxidants may be associated with higher  bone mineral density ( BMD ) . DESIGN Total hip ( and subregions ) , spine , and total-body BMDs were measured in 11,068 women aged 50 - 79 y enrolled in the Women 's Health Initiative Observational Study and Clinical Trial at 3 clinics .  Antioxidant intakes from diet ( vitamin A , retinol , beta-carotene , vitamin C , vitamin E , and selenium ) were estimated by using a self-reported food-frequency question naire . Antioxidants from supplements were estimated with an interviewer-administered question naire . A r and om subset ( n = 379 ) had serum concentrations of retinol , carotenoids , and tocopherols measured . RESULTS After adjustment for important BMD-related covariates , increasing intakes of antioxidants were not independently associated with BMD . A significant interaction effect was observed between intake of total vitamin C  ( lower three-fourths compared with highest one-fourth ) and use of  hormone therapy ( HT ) ( P < 0.01 ) . The beneficial effect of current HT use on femoral neck BMD appeared to be greater in women with higher concentrations of total vitamin C. This interaction was also significant for total-body ( P < 0.045 ) , spine ( P = 0.03 ) , and total-hip BMDs ( P = 0.029 ) . CONCLUSIONS Our results do not support independent associations between dietary intake , total intake , or serum concentrations of antioxidants and BMD in women participating in the Women 's Health Initiative . The extent to which HT use may interact with  vitamin C intake and BMD warrants further exploration BACKGROUND Cases of enhanced anticoagulant effect in response to high-dose vitamin E supplementation have been reported among patients taking oral anticoagulants .  Although a vitamin E-vitamin K interaction was proposed to underlie this effect , it has not been systematic ally investigated in adults with normal baseline coagulation status . OBJECTIVE The objective was to study the effect of 12 wk of supplementation with 1000 IU RRR-alpha-tocopherol/d on biochemical measures of vitamin K status in men and women not taking oral anticoagulants . DESIGN  Vitamin K status , which was assessed with the use of plasma phylloquinone concentrations , the degree of under-gamma-carboxylation of prothrombin ( proteins induced by vitamin K absence-factor II , PIVKA-II ) , and the percentage of undercarboxylated osteocalcin ( ucOC ) , was determined in 38 men and women with rheumatoid arthritis ( study A ) and in 32 healthy men ( study B ) participating in 2 independent , 12-wk r and omized clinical trials of vitamin E supplementation ( 1000 IU/d ) . RESULTS Mean ( + /- SD ) PIVKA-II increased from 1.7 + /- 1.7 to 11.9 + /- 16.1 ng/mL ( P < 0.001 ) in study A and from 1.8 + /- 0.6 to 5.3 + /- 3.9 ng/mL ( P < 0.001 ) in study B in response to 12 wk of vitamin E supplementation . An increase in PIVKA-II is indicative of poor vitamin K status . In contrast , the other measures of vitamin K status ( ie , plasma phylloquinone concentration and percentage of ucOC ) did not change significantly in response to the supplementation . CONCLUSIONS High-dose vitamin E supplementation increased PIVKA-II in adults not receiving oral anticoagulant therapy . The clinical significance of these changes warrants further investigation , but high doses of vitamin E may antagonize vitamin K. Whether such an interaction is potentially beneficial or harmful remains to be determined ABSTRACT Background In the absence of dose-response data , Dietary Reference Values for vitamin D in nonpregnant adults are extended to pregnancy . Objective The aim was to estimate vitamin D intake needed to maintain maternal 25-hydroxyvitamin D [ 25(OH)D ] in late gestation at a concentration sufficient to prevent newborn 25(OH)D < 25–30 nmol/L , a threshold indicative of increased risk of nutritional rickets . Design We conducted a 3-arm , dose-response , double-blind , r and omized placebo-controlled trial in Cork , Irel and ( 51.9oN ) . A total of 144 white-skinned pregnant women were assigned to receive 0 , 10 ( 400 IU ) , or 20 ( 800 IU ) µg vitamin D3/d from ≤18 wk of gestation . Vitamin D metabolites at 14 , 24 , and 36 wk of gestation and in cord sera , including 25(OH)D3 , 3-epi-25(OH)D3 , 24,25(OH)2D3 , and 25(OH)D2 were quantified by liquid chromatography – t and em mass spectrometry . A curvilinear regression model predicted the total vitamin D intake ( from diet and antenatal supplements plus treatment dose ) that maintained maternal 25(OH)D in late gestation at a concentration sufficient to maintain cord 25(OH)D at ≥25–30 nmol/L. Results Mean ± SD baseline 25(OH)D was 54.9 ± 10.7 nmol/L. Total vitamin D intakes at the study endpoint ( 36 wk of gestation ) were 12.1 ± 8.0 , 21.9 ± 5.3 , and 33.7 ± 5.1 µg/d in the placebo and 10-µg and 20-µg vitamin D3 groups , respectively ; and 25(OH)D was 24.3 ± 5.8 and 29.2 ± 5.6 nmol/L higher in the 10- and 20-µg groups , respectively , compared with placebo ( P < 0.001 ) . For maternal 25(OH)D concentrations ≥50 nmol/L , 95 % of cord sera were ≥30 nmol/L and 99 % were > 25 nmol/L. The estimated vitamin D intake required to maintain serum 25(OH)D at ≥50 nmol/L in 97.5 % of women was 28.9 µg/d . Conclusions Thirty micrograms of vitamin D per day safely maintained serum 25(OH)D concentrations at ≥50 nmol/L in almost all white-skinned women during pregnancy at a northern latitude , which kept 25(OH)D at > 25 nmol/L in 99 % and ≥30 nmol/L in 95 % of umbilical cord sera . This trial was registered at www . clinical trials.gov as NCT02506439 Supplemental vitamin E ( α-tocopherol ) has been linked to lower prostate cancer incidence in one r and omized trial and several , although not all , observational studies . The evidence regarding dietary intake of individual vitamin E isoforms and prostate cancer is limited and inconclusive , however . We prospect ively examined the relations of supplemental vitamin E and dietary intakes of α- , β- , γ- , and δ- tocopherols to prostate cancer risk among 295,344 men , ages 50 to 71 years and cancer-free at enrollment in 1995 to 1996 , in the NIH-AARP Diet and Health Study . At baseline , participants completed a question naire that captured information on diet , supplement use , and other factors . Proportional hazards models were used to estimate relative risks ( RR ) and 95 % confidence intervals ( 95 % CI ) of prostate cancer . During 5 years of follow-up , 10,241 incident prostate cancers were identified . Supplemental vitamin E intake was not related to prostate cancer risk ( for > 0 - 99 , 100 - 199 , 200 - 399 , 400 - 799 , and ≥800 IU/d versus never use : RR , 0.97 , 0.89 , 1.03 , 0.99 , and 0.97 ( 95 % CI , 0.87 - 1.07 ) respectively ; Ptrend = 0.90 ) . However , dietary γ-tocopherol , the most commonly consumed form of vitamin E in the United States , was significantly inversely related to the risk of advanced prostate cancer ( for highest versus lowest quintile : RR , 0.68 ; 95 % CI , 0.56 - 0.84 ; Ptrend = 0.001 ) . These results suggest that supplemental vitamin E does not protect against prostate cancer , but that increased consumption of γ-tocopherol from foods is associated with a reduced risk of clinical ly relevant disease . The potential benefit of γ-tocopherol for prostate cancer prevention deserves further attention . ( Cancer Epidemiol Biomarkers Prev 2007;16(6):1128–35 Background Vitamin D deficiency has been associated with multiple diseases , but the causal relevance and underlying processes are not fully understood . Elucidating the mechanisms of action of drug treatments in humans is challenging , but application of functional genomic approaches in r and omized trials may afford an opportunity to systematic ally assess molecular responses . Methods In the Biochemical Efficacy and Safety Trial of Vitamin D ( BEST-D ) , a double-blind , placebo-controlled , dose-finding , r and omized clinical trial , 305 community-dwelling individuals aged over 65 years were r and omly allocated to treatment with vitamin D3 4000 IU , 2000 IU or placebo daily for 12 months . Genome-wide genotypes at baseline , and transcriptome and plasma levels of cytokines ( IFN-γ , IL-10 , IL-8 , IL-6 and TNF-α ) at baseline and after 12 months , were measured . The trial had > 90 % power to detect 1.2-fold changes in gene expression . Findings Allocation to vitamin D for 12-months was associated with 2-fold higher plasma levels of 25-hydroxy-vitamin D ( 25[OH]D , 4000 IU regimen ) , but had no significant effect on whole-blood gene expression ( FDR < 5 % ) or on plasma levels of cytokines compared with placebo . In pre-specified analysis , rs7041 ( intron variant , GC ) had a significant effect on circulating levels of 25(OH)D in the low dose , but not in the placebo or high dose vitamin D regimen . A gene expression quantitative trait locus analysis ( eQTL ) demonstrated evidence of 31,568 cis-eQTLs ( unique SNP-probe pairs ) among individuals at baseline and 34,254 after supplementation for 12 months ( any dose ) . No significant associations involving vitamin D supplementation response eQTLs were found . Interpretation We performed a comprehensive functional genomics and molecular analysis of vitamin D supplementation in a r and omized , placebo-controlled trial . Although this study was limited to mostly Caucasian individuals aged over 65 years , the results differ from many previous studies and do not support a strong effect of vitamin D on long-term transcriptomic changes in blood or on plasma cytokine levels . The trial demonstrates the feasibility of applying functional genomic and genetic approaches in r and omized trials to assess molecular and individual level responses . Key Result Supplementation with high-dose vitamin D in older people for 12 months in a r and omized , placebo-controlled trial had no significant effect on gene expression or on plasma concentrations of selected cytokines . Trial Registration S RCT N registry ( Number 07034656 ) and the European Clinical Trials Data base ( EudraCT Number 2011 - 005763 - 24 ) Objective To investigate the relationship between basal cell carcinoma ( BCC ) and antioxidant nutrients , specifically carotenoids , vitamin E and selenium . Methods The Nambour Skin Cancer Study is an ongoing , community-based study of r and omly selected adult residents of a township in sub-tropical Queensl and , Australia . Using a nested case – control design , incident cases of BCC ( n=90 ) were compared with age and sex matched controls ( n=90 ) .  Dietary exposure was measured using food frequency question naire estimates of intake as well as serum biomarkers . Other determinants of skin cancer including sun exposure were also considered . Dietary intakes were adjusted for energy intake , and serum carotenoids and vitamin E were adjusted for serum cholesterol . Odds ratios were calculated across quartiles of dietary intake and serum biomarkers and linear trends were assessed using logistic regression , adjusting for age , sex and supplement use . Results and conclusions In this prospect i ve study no significant associations were found between BCC and  carotenoids , vitamin E or selenium  , as measured by serum biomarkers or dietary intake , although there was a suggestion of a positive association with lutein intake BACKGROUND Nutrient-related anemia among postmenopausal women is preventable ; recent data on prevalence are limited . OBJECTIVE To investigate the association between nutrient intakes and anemia prevalence , in relation to both incidence and persistence , in a longitudinal sample of postmenopausal women . We hypothesized that anemia prevalence , incidence , and persistence would be greater among women reporting lower intake of vitamin B-12 , folate , and iron .  DESIGN Prospect i ve cohort analysis . PARTICIPANTS / SETTING The observational cohort of the Women 's Health Initiative , including 93,676 postmenopausal women , aged 50 to 79 years , who were recruited across the United States at 40 clinical study sites . Women were enrolled between 1993 and 1998 ; data collection for these analyses continued through 2000 . MAIN OUTCOME MEASURES Anemia was defined as a blood hemoglobin concentration of < 12.0 g/dL ( 120.0 g/L ) . Persistent anemia was defined as anemia present at each measurement time point . Diet was assessed by food frequency question naire for iron , folate , B-12 , red meat , and cold breakfast cereal ; inadequacies were based on dietary reference intakes for women older than age 50 years . STATISTICAL ANALYSIS Descriptive statistics ( mean ± st and ard deviation ) were used to characterize the population demographics , anemia rates , and diet . Unconditional logistic regression was used to investigate associations between diet and incident and persistent anemia . Associations are presented as odds ratio and 95 % confidence intervals . RESULTS Anemia was identified in 3,979 ( 5.5 % ) of the cohort . Inadequate intakes of multiple anemia-associated nutrients were less frequent in non-Hispanic whites ( 7.4 % ) than other race/ethnic groups ( inadequacies demonstrated in 14.6 % to 16.3 % of the sample ) . Age , body mass index , and smoking were associated with anemia . Women with anemia reported lower intakes of energy , protein , folate , vitamin B-12 , iron , vitamin C , and red meat . Multiple ( more than a single nutrient ) dietary deficiencies were associated with a 21 % greater risk of persistent anemia ( odds ratio 1.21 , 95 % confidence interval 1.05 to 1.41 ) and three deficiencies result ed in a 44 % increase in risk for persistent anemia ( odds ratio 1.44 , 95 % confidence interval 1.20 to 1.73 ) . CONCLUSIONS Inadequate nutrient intake , a modifiable condition , is associated with greater risk for anemia  in postmenopausal women participating in the Observational Study of the Women 's Health Initiative . Efforts to identify and up date incidence estimates for anemia-associated nutrient deficiencies in aging women should be undertaken To evaluate the relation between vitamin C intake and mortality , a prospect i ve follow-up study was carried out among 3,119 noninstitutionalized adult residents of Alameda County , California who had completed a detailed lifestyle question naire around the beginning of 1974 . During 10 years of follow-up , 276 deaths have been identified . The question naire information and mortality data indicate that this sample is fairly representative of the county population and similar to the United States population . There is no important relation between the estimated 1974 vitamin C intake at levels above and below 250 mg per day and subsequent mortality from cancer , circulatory disease , all other causes , or all causes combined . However , there is an inverse relation between combinations of several health habits and total mortality . The health habits include never smoking cigarettes , regular physical activity , moderate or no use of alcohol , 7 - 8 hours of sleep per day , and maintaining proper weight . The conclusions with regard to vitamin C are limited by the crudeness with which the dietary intake has been estimated and changes in intake over time . Nevertheless , these results are not consistent with any substantial relation between vitamin C intake and subsequent mortality Purpose Low fruit and vegetable consumption is linked with an increased risk of death from vascular disease and cancer . The benefit of eating fruits and vegetables is attributed in part to antioxidants , vitamins and phytochemicals . Whether increasing intake impacts on markers of disease remains to be established . This study investigates whether increasing daily intake of fruits , vegetables and juices from low ( approx . 3 portions ) , to high intakes ( approx . 8 portions ) impacts on nutritional and clinical biomarkers . Barriers to achieving the recommended fruit and vegetable intakes are also investigated . Method In a r and omised clinical trial , the participants [ 19 men and 26 women ( 39–58 years ) ] with low reported fruit , juice and vegetable intake ( <3 portions/day ) were r and omised to consume either their usual diet or a diet supplemented with an additional 480 g of fruit and vegetables and fruit juice ( 300 ml ) daily for 12 weeks . Nutritional biomarkers ( vitamin C , carotenoids , B vitamins ) , antioxidant capacity and genomic stability were measured pre-intervention , at 4- , 8- and 12 weeks throughout the intervention . Sample s were also taken post-intervention after a 6-week washout period . Glucose , homocysteine , lipids , blood pressure , weight and arterial stiffness were also measured . Intake  of fruit , fruit juice and vegetables was reassessed 12 months after conducting the study and a question naire was developed to identify barriers to healthy eating . Results Intake increased significantly in the intervention group compared to controls , achieving 8.4 portions/day after 12 weeks . Plasma vitamin C ( 35 % ) , folate ( 15 % ) and certain carotenoids [ α-carotene ( 50 % ) and β-carotene ( 70 % ) and lutein/zeaxanthin ( 70 % ) ] were significantly increased ( P < 0.05 ) in the intervention group . There were no significant changes in antioxidant capacity , DNA damage and markers of vascular health . Barriers to achieving recommended intakes of fruits and vegetables measured 12 months after the intervention period were amount , inconvenience and cost . Conclusion While increasing fruit , juice and vegetable consumption increases circulating level of beneficial nutrients in healthy subjects , a 12-week intervention was not associated with effects on antioxidant status or lymphocyte DNA damage . Trial registration This trial was registered at Controlled-Trials.com ; registration IS RCT N71368072
RESULTS The meta- analysis of observational studies showed a weaker slope of dose-response relations than the meta- analysis of RCTs .
The obtained dose-response estimate between vitamin B-12 intake and status provides complementary evidence to underpin recommendations for a vitamin B-12 intake of population
BACKGROUND Many r and omized controlled trials ( RCTs ) and observational studies have provided information on the association between vitamin B-12 intake and biomarkers .
The use of these data to estimate dose-response relations provides a useful means to summarize the body of evidence .
OBJECTIVE We systematic ally review ed studies that investigated vitamin B-12 intake and biomarkers of vitamin B-12  status and estimated dose-response relations with the use of a meta- analysis .