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Objectives: We assessed the joint effects of omega (n)-3 fatty acid supplementation and dietary fish intake on systemic lipid mediators of inflammation among adults., Methods: Within VITAL, a double-blind randomized controlled trial, adults were randomized to ω-3 fatty acids (460 mg EPA + 380 mg DHA/d) or placebo. We selected participants who reported low (<1 serving/mo) baseline dietary fish intake and matched them by age, sex, race, and trial arm to participants with self-reported highest fish intake (≥3.9 servings/wk). Baseline and 1-y plasma samples were tested for 9 ω-3 fatty acid-derived lipid mediators. Multivariable linear models assessed lipid mediator changes and joint effects of ω-3 fatty acid supplementation and dietary fish intake., Results: Forty-eight participants with low baseline fish intake were matched to 48 with high fish intake. Mean age was 64.6 (±7.26), 50% were female, and 85% non-Hispanic white. One-year lipid mediator changes in expected directions were observed in those receiving ω-3 fatty acids versus placebo: reductions in proinflammatory mediators, PGD2, 5-HETE, and 12-HETE; increases in proresolving mediators, EPA and DHA. Larger 1-y lipid biomarker changes were seen in those with low baseline fish intake randomized to active ω-3 fatty acids for DHA, EPA, PGD2, Resolvin D1, and Resolvin D4 were observed, although no significant multiplicative interactions were detected., Discussion: Beneficial changes in circulating proresolving and proinflammatory mediators were found with 1-y of ω-3 fatty acid supplementation versus placebo for all participants, with a trend toward larger effects among those with low baseline fish intake, although interactions were not significant., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Karen Costenbader reports financial support was provided by National Institutes of Health. Vadim Bubes reports financial support was provided by National Institutes of Health. Samia Mora reports financial support was provided by National Institutes of Health. JoAnn Manson reports financial support was provided by National Institutes of Health. JoAnn Manson reports equipment, drugs, or supplies was provided by Pharmavite LLC. JoAnn Manson reports equipment, drugs, or supplies was provided by BASF SE. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: In the 5.3-year randomized, 2 × 2 factorial, double-blind, placebo-controlled Vitamin D and Omega-3 Trial (VITAL), vitamin D supplementation reduced autoimmune disease (AD) incidence (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.61-0.99). Omega-3 (n-3) fatty acid supplementation showed a statistically nonsignificant reduction (HR 0.85, 95% CI 0.67-1.08). We aimed to confirm further AD cases arising during and after randomization and assess sustained effects with two years of postintervention observation., Methods: Of the 12,786 men aged ≥50 and 13,085 women aged ≥55 initially randomized, we observed surviving and willing participants for two more years. We continued to confirm annual participant-reported new AD by medical record review. Cox models calculated HRs for all confirmed incident AD, (and secondary endpoints, including probable cases, and individual ADs), during the observational and randomized periods., Results: A total of 21,592 participants (83.5%) were observed for two more years; 514 participants developed incident confirmed AD (236 since prior report), of whom 255 had been randomized to vitamin D versus 259 to vitamin D placebo (HR 0.98 [95% CI 0.83-1.17] at 7 years). AD was confirmed in 234 participants initially randomized to n-3 fatty acids versus 280 randomized to its placebo (HR 0.83 [95% CI 0.70-0.99] at 7 years). Of newly confirmed cases, 65 had onset during randomization; their inclusion changed randomized results as follows: HR 0.85 (95% CI 0.70-1.04) for vitamin D and HR 0.87 (95% CI 0.71-1.06) for n-3 fatty acids., Conclusion: Two years after trial termination, the protective effects of 2000 IU/day of vitamin D dissipated, but 1,000 mg/day of n-3 fatty acids had a sustained effect in reducing AD incidence., (© 2024 American College of Rheumatology.)

Context: Declining muscle strength and performance in older adults are associated with falls, fractures, and premature death., Objective: To determine whether supplementation with vitamin D3 or omega-3 fatty acids vs. placebo for 2 years improves physical performance measures., Design: VITamin D and OmegA-3 TriaL (VITAL) was a double-blinded, placebo-controlled randomized trial of supplemental vitamin D3 and/or omega-3 fatty acids vs. placebo in the prevention of cancer and cardiovascular disease in 25,871 U.S. adults. This ancillary study was completed in a New England sub-cohort that had in-person evaluations at baseline and 2-year follow-up., Setting: Center for Clinical Investigations in Boston., Participants: 1,054 participants (men ≥50 and women ≥55 years)., Interventions: 2x2 factorial design of supplemental vitamin D3 (cholecalciferol, 2000 IU/day) and/or marine omega-3 fatty acids (1 g/day)., Main Outcome Measures: 2-year changes in physical performance measures of grip strength, walking speed, standing balance, repeated chair stands, and Timed-up and Go (TUG)., Results: At 2 years, all randomized groups showed worsening walking speeds and TUG. There were no differences in changes in grip strength, walking speeds, Short Physical Performance Battery (composite of walking speed, balance, and chair stands), and TUG between the vitamin D3-treated and the placebo-treated groups and between the omega-3-treated and the placebo-treated groups. Effects overall did not vary by sex, age, body mass index, or baseline measures of total or free 25-hydroxyvitamin D (25[OH]D) or plasma n-3 index; TUG slightly worsened with vitamin D supplementation, compared to placebo, in participants with baseline total 25(OH)D levels above the median (p=0.01, p for interaction=0.04)., Conclusions: Neither supplemental vitamin D3 nor marine omega-3 fatty acids for 2 years improved physical performance in this generally healthy adult population., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: Little is known about the effects of over-the-counter fish oil (FO) supplements on circulating omega-3 polyunsaturated fatty acid (n-3 PUFA)-derived specialized pro-resolving mediators (SPMs), nor about whether having a chronic inflammatory disease such as rheumatoid arthritis (RA) influences SPM levels. We investigated associations between over-the-counter n-3 PUFA FO supplementation and circulating SPMs among patients with vs. without RA., Methods: We studied 104 participants: 26 with RA taking FO matched by age and sex to 26 with RA not taking FO, 26 without RA taking FO, and 26 without RA not taking FO. Targeted-liquid chromatography-tandem mass spectroscopy was performed on patient plasma to identify and quantify 27 lipid mediators (including eicosanoids and SPMs). We performed t-tests and then multivariable linear regression analyses to assess whether having RA or taking FO supplements was associated with circulating lipid mediator concentrations, adjusting for age, race, sex, smoking, body mass index, and current medication use (statins, prednisone and immunomodulators among RA cases only). We tested for interactions between FO supplementation and RA status. We also conducted Spearman's correlations between EPA, DHA, and ARA and their downstream metabolites., Results: Among patients who were taking FO compared to those who were not, in multivariable- adjusted analyses, SPM substrates EPA and DHA were both elevated as were several of their pro-resolving bioactive products, including 15- and 18-HEPE from EPA, and 14- and 17-HDHA from DHA, which are substrates for specific SPMs. While E-series and D-series resolvins were present and identified, we did not find statistical elevations of other SPMs. Results were similar among patients with RA and patients without RA, taking vs. not taking FO supplementation (no formal statistical interaction observed). There was a strong positive correlation between EPA and DHA and their immediate downstream SPM precursors (18-HEPE and15-HEPE from EPA; 17-HDHA and 14-HDHA from DHA) among all patients., Conclusion: Patients taking FO supplements, regardless of RA status, not only had higher blood levels of EPA and DHA, but also of their enzymatic products 18-HEPE (E-series resolvin precursors), 15-HEPE and 17-HDHA (D-series resolvin and protectin precursors). Patients with RA, an inflammatory autoimmune disease, may be able to augment some SPM precursor reserves, similarly to matched controls without RA, by taking oral FO supplements., Competing Interests: Declaration of competing interest NM receives consulting fees from Pritikin Longevity Center. JL-S is on the scientific advisory board for Precion, Inc. All other authors report no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To investigate whether vitamin D and marine derived long chain omega 3 fatty acids reduce autoimmune disease risk., Design: Vitamin D and omega 3 trial (VITAL), a nationwide, randomized, double blind, placebo controlled trial with a two-by-two factorial design., Setting: Nationwide in the United States., Participants: 25 871 participants, consisting of 12 786 men ≥50 years and 13 085 women ≥55 years at enrollment., Interventions: Vitamin D (2000 IU/day) or matched placebo, and omega 3 fatty acids (1000 mg/day) or matched placebo. Participants self-reported all incident autoimmune diseases from baseline to a median of 5.3 years of follow-up; these diseases were confirmed by extensive medical record review. Cox proportional hazard models were used to test the effects of vitamin D and omega 3 fatty acids on autoimmune disease incidence., Main Outcome Measures: The primary endpoint was all incident autoimmune diseases confirmed by medical record review: rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and all others., Results: 25 871 participants were enrolled and followed for a median of 5.3 years. 18 046 self-identified as non-Hispanic white, 5106 as black, and 2152 as other racial and ethnic groups. The mean age was 67.1 years. For the vitamin D arm, 123 participants in the treatment group and 155 in the placebo group had a confirmed autoimmune disease (hazard ratio 0.78, 95% confidence interval 0.61 to 0.99, P=0.05). In the omega 3 fatty acids arm, 130 participants in the treatment group and 148 in the placebo group had a confirmed autoimmune disease (0.85, 0.67 to 1.08, P=0.19). Compared with the reference arm (vitamin D placebo and omega 3 fatty acid placebo; 88 with confirmed autoimmune disease), 63 participants who received vitamin D and omega 3 fatty acids (0.69, 0.49 to 0.96), 60 who received only vitamin D (0.68, 0.48 to 0.94), and 67 who received only omega 3 fatty acids (0.74, 0.54 to 1.03) had confirmed autoimmune disease., Conclusions: Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant). Both treatment arms showed larger effects than the reference arm (vitamin D placebo and omega 3 fatty acid placebo)., Study Registration: ClinicalTrials.gov NCT01351805 and NCT01169259., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the National Institutes of Health for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Although observational studies show inverse associations between vitamin D status and body weight/adiposity, there are few large randomized controlled trials (RCTs) investigating this relationship., Objective: To determine whether vitamin D3 supplementation lowers weight or improves body composition., Design: The VITamin D and OmegA-3 TriaL (VITAL) was a double-blinded, placebo-controlled RCT including 25 871 US adults. This ancillary study was completed in a sub-cohort that underwent body composition assessments at baseline and 2-year follow-up (89% retention)., Setting: Harvard Clinical and Translational Science Center in Boston., Participants: 771 participants (men ≥ 50 and women ≥ 55 years)., Interventions: 2 × 2 factorial design of supplemental vitamin D3 (2000 IU/day) and/or omega-3 fatty acids (1 g/day)., Main Outcome Measures: Endpoints were 2-year changes in weight, body mass index (BMI), waist circumference, and total and/or regional fat and lean tissue measures determined by dual-energy X-ray absorptiometry. Effect modification by clinical variables and total and free 25-hydroxyvitamin D (25[OH]D) levels was explored., Results: There were no effects of supplemental vitamin D3vs placebo on weight, BMI, or measures of adiposity and lean tissue. Effects did not vary by sex, race/ethnicity, fat mass index, or baseline total or free 25(OH)D levels. Vitamin D3 supplementation did slightly improve body fat percentage in participants with normal BMI at baseline, but not in the overweight or obese (P for interaction = 0.04)., Conclusions: Daily vitamin D3 supplementation vs placebo in the general older population did not improve weight or body composition. Whether supplemental vitamin D3 may benefit individuals with normal BMI warrants further study., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: A high incidence of asymptomatic atrial tachycardia and atrial fibrillation (AT/AF) has been recognized in patients with cardiac implantable devices (CIED). The clinical significance of these AT/AF episodes remains unclear. Some "device-detected AT/AF" was previously shown to be triggered by competitive atrial pacing (CAP)., Objective: To investigate and characterize a potential association between CAP and AT/AF in the largest series of observations to date., Methods: RATE, a multicenter registry, included 5379 patients with CIEDs followed for approximately 2 years. Electrograms (EGMs) from 1352 patients with AT/AF, CAP, or both were analyzed by experienced adjudicators to assess a causal relationship between AT/AF and CAP onset, duration, and morphology., Results: In 225 patients, 1394 episodes of both AT/AF and CAP were present in the same tracing. CAP and AT/AF were strongly associated (P ≤ .02). AT/AF occurred during the course of the study in 71% of patients with CAP. In 62% of the episodes, expert adjudication concluded that CAP triggered AT/AF. The duration and morphology of triggered and spontaneous AT/AF episodes differed. Spontaneous AT/AF episodes were associated with constant EGM morphology, and were either long or extremely short. CAP-triggered AT/AF more often had variable and shorter cycle length EGMs. The incidence of short AT/AF events was higher among triggered episodes (25% vs 12.8%, P < .002)., Conclusion: Device-triggered AT/AF due to CAP is likely more common than previously recognized. This AT/AF entity differs from spontaneous AT/AF in duration and morphology. Clinical implications of spontaneous and device-triggered AT/AF may be different., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Context: It is unclear whether vitamin D supplementation reduces risk of falls, and results from randomized controlled trials (RCTs) are conflicting., Objective: The objective of this work is to determine whether 2000 IU/day of supplemental vitamin D3 decreases fall risk., Design: VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled RCT including 25 871 adults, randomly assigned November 2011 to March 2014 and treated for 5.3 years (median)., Setting: This is a nationwide study., Participants: Men 50 years or older and women 55 years or older (mean age, 67.1 years) without cancer or cardiovascular disease at baseline participated in this study., Interventions: Interventions included vitamin D3 (cholecalciferol; 2000 IU/day) and/or omega-3 fatty acids (1 g/day) or respective placebos in a 2 × 2 factorial design., Main Outcome Measures: Main outcome measures include 2 or more falls and falls resulting in a doctor or hospital visit., Results: Baseline serum total 25-hydroxyvitamin D (25[OH]D) level was 77 nmol/L; characteristics were well-balanced between groups. Numbers of participants with 2 or more falls were similar between active and placebo groups (9.8% vs 9.4%). Over 5 years, there were no differences in the proportion having 2 or more falls (odds ratio [OR] = 0.97; 95% CI, 0.90-1.05, P = .50), falls resulting in a doctor visit (OR = 1.03; 95% CI, 0.94-1.13, P = .46), or resulting in a hospital visit (OR = 1.04; 95% CI, 0.90-1.19, P = .61) between groups. Results did not differ between those with baseline 25(OH)D less than 50 vs 50 nmol/L or greater or other cut points., Conclusion: Daily supplemental vitamin D3 vs placebo did not decrease fall risk in generally healthy adults not selected for vitamin D insufficiency. This large RCT does not indicate that supplemental vitamin D should be used for primary prevention of falls in the US population., (© Endocrine Society 2020.)

Importance: Migraine with aura is known to increase the risk of cardiovascular disease (CVD). The absolute contribution of migraine with aura to CVD incidence in relation to other CVD risk factors remains unclear., Objective: To estimate the CVD incidence rate for women with migraine with aura relative to women with other major vascular risk factors., Design, Setting, and Participants: Female health professionals in the US (the Women's Health Study cohort) with lipid measurements and no CVD at baseline (1992-1995) were followed up through December 31, 2018., Exposures: Self-reported migraine with aura compared with migraine without aura or no migraine at baseline., Main Outcomes and Measures: The primary outcome was major CVD (first myocardial infarction, stroke, or CVD death). Generalized modeling procedures were used to calculate multivariable-adjusted incidence rates for major CVD events by risk factor status that included all women in the cohort., Results: The study population included 27 858 women (mean [SD] age at baseline, 54.7 [7.1] years), among whom 1435 (5.2%) had migraine with aura and 26 423 (94.8%) did not (2177 [7.8%] had migraine without aura and 24 246 [87.0%] had no migraine in the year prior to baseline). During a mean follow-up of 22.6 years (629 353 person-years), 1666 major CVD events occurred. The adjusted incidence rate of major CVD per 1000 person-years was 3.36 (95% CI, 2.72-3.99) for women with migraine with aura vs 2.11 (95% CI, 1.98-2.24) for women with migraine without aura or no migraine (P < .001). The incidence rate for women with migraine with aura was significantly higher than the adjusted incidence rate among women with obesity (2.29 [95% CI, 2.02-2.56]), high triglycerides (2.67 [95% CI, 2.38-2.95]), or low high-density lipoprotein cholesterol (2.63 [95% CI, 2.33-2.94]), but was not significantly different from the rates among those with elevated systolic blood pressure (3.78 [95% CI, 2.76-4.81]), high total cholesterol (2.85 [95% CI, 2.38-3.32]), or family history of myocardial infarction (2.71 [95% CI, 2.38-3.05]). Incidence rates among women with diabetes (5.76 [95% CI, 4.68-6.84]) or who currently smoked (4.29 [95% CI, 3.79-4.79]) were significantly higher than those with migraine with aura. The incremental increase in the incidence rate for migraine with aura ranged from 1.01 additional cases per 1000 person-years when added to obesity to 2.57 additional cases per 1000 person-years when added to diabetes., Conclusions and Relevance: In this study of female health professionals aged at least 45 years, women with migraine with aura had a higher adjusted incidence rate of CVD compared with women with migraine without aura or no migraine. The clinical importance of these findings, and whether they are generalizable beyond this study population, require further research.

Although supplemental vitamin D is used to promote bone health in the general population, data from randomized controlled trials (RCTs) have been inconsistent. We determined whether daily, vitamin D 3 supplementation improves bone mineral density (BMD) and/or structure. VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled RCT of supplemental vitamin D 3 (2000 IU/d) and/or omega-3 fatty acids (1 g/d) in 25,871 adults nationwide. This ancillary study included a subcohort of 771 participants (men ≥50 and women ≥55 years; not taking bone active medications) evaluated at baseline and at 2-year follow-up (89% retention). Total 25(OH)D levels were measured by liquid chromatography tandem mass spectrometry (Quest Diagnostics, San Juan Capistrano, CA, USA). Free 25(OH)D (FVD) levels were measured using the ELISA assay by Future Diagnostics Solutions BV (Wijchen, Netherlands). Primary endpoints were 2-year changes in areal (a) BMD at the spine, hip, and whole body determined by dual-energy X-ray absorptiometry (DXA). Secondary endpoints were 2-year changes in volumetric (v) BMD and cortical thickness at the radius and tibia assessed by peripheral quantitative computed tomography. Supplemental vitamin D 3 versus placebo had no effect on 2-year changes in aBMD at the spine (0.33% versus 0.17%; p = 0.55), femoral neck (-0.27% versus -0.68%; p = 0.16), total hip (-0.76% versus -0.95%; p = 0.23), or whole body (-0.22% versus -0.15%; p = 0.60), or on measures of bone structure. Effects did not vary by sex, race/ethnicity, body mass index, or 25(OH)D levels. Among participants with baseline FVD levels below the median (<14.2 pmol/L), there was a slight increase in spine aBMD (0.75% versus 0%; p = 0.043) and attenuation in loss of total hip aBMD (-0.42% versus -0.98%; p = 0.044) with vitamin D 3 . Whether baseline FVD levels help to identify those more likely to benefit from supplementation warrants further study. Supplemental vitamin D 3 versus placebo for 2 years in general healthy adults not selected for vitamin D insufficiency did not improve BMD or structure. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research., (© 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.)

Background: Observational studies suggest vitamin D and marine ω-3 fatty acid (n-3 FA) supplements are associated with lower systemic inflammation. However, past trials have been inconsistent., Methods: The randomized, double-blind, placebo-controlled VITamin D and OmegA-3 TriaL (VITAL) tested vitamin D (2000 IU/day) and/or n-3 FA (1 g/day) supplementation in a 2 × 2 factorial design among women ≥55 and men ≥50 years of age. We assessed changes in interleukin (IL)-6, tumor necrosis factor receptor 2 (TNFR2), and high-sensitivity C-reactive protein (hsCRP) concentrations from baseline to 1 year among participants randomized to vitamin D + n-3 FA (392), vitamin D (392), n-3 FA (392), or placebo only (385). Geometric means and percent changes were compared, adjusting for baseline factors., Results: Baseline characteristics were well balanced. In the active arms, 25-OH vitamin D rose 39% and n-3 FA rose 55% vs minimal change in placebo arms. Neither supplement reduced biomarkers at 1 year. Vitamin D resulted in 8.2% higher IL-6 (95% CI, 1.5%-15.3%; adjusted P = 0.02), but TNFR2 and hsCRP did not. Among 784 receiving vitamin D, hsCRP increased 35.7% (7.8%-70.9%) in those with low (<20 ng/mL) but not with higher baseline serum 25(OH) vitamin D [0.45% (-8.9% to 10.8%); P interaction = 0.02]. Among 777 randomized to n-3 FA, hsCRP declined [-10.5% (-20.4% to 0.8%)] in those with baseline low (<1.5 servings/week), but not with higher fish intake [6.4% (95% CI, -7.11% to 21.8%); P interaction = 0.06]., Conclusions: In this large sample from a population-based randomized controlled trial, neither vitamin D nor n-3 FA supplementation over 1 year decreased these biomarkers of inflammation., Clinicaltrialsgov Identifier: NCT01169259; NCT01351805., (© 2019 American Association for Clinical Chemistry.)

Vitamin D supplements are often used to benefit skeletal health, although data on effects of daily high-dose vitamin D alone on bone density and structure are lacking. The ongoing VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, randomized, placebo-controlled trial testing effects of high-dose supplemental vitamin D 3 (cholecalciferol; 2000 IU/day) and/or omega-3 fatty acids (FAs; 1 g/day) for the primary prevention of cancer and cardiovascular disease. The study has a mean treatment period of 5 years among 25,874 U.S. men ≥50 years and women ≥55 years old from all 50 states. The ancillary study, VITAL: Effects on Bone Structure and Architecture, is testing effects of vitamin D 3 and/or omega-3 FAs on musculoskeletal outcomes and body composition in a subcohort of 771 participants. At in-person visits at the Harvard Catalyst Clinical and Translational Science Center (CTSC), participants completed bone density/architecture, body composition, and physical performance assessments at baseline and two-year follow-up. Baseline characteristics were evenly distributed among treatment groups, suggesting that any uninvestigated confounders will be evenly distributed; sex differences were also analyzed. Future analyses of the two-year follow-up visits will elucidate whether daily high-dose, supplemental vitamin D 3 and/or omega-3 FAs improve musculoskeletal outcomes, helping to advance clinical and public health recommendations., Clinical Trial Registration Number: NCT01747447., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Importance: Long-term multivitamin use had no effect on risk of cardiovascular disease (CVD) in the Physicians' Health Study II. Baseline nutritional status may have modified the lack of effect., Objective: To investigate effect modification by various baseline dietary factors on CVD risk in the Physicians' Health Study II., Design, Setting, and Participants: The Physicians' Health Study II was a randomized, double-blind, placebo-controlled trial testing multivitamin use (multivitamin [Centrum Silver] or placebo daily) among US male physicians. The Physicians' Health Study II included 14 641 male physicians 50 years or older, 13 316 of whom (91.0%) completed a baseline 116-item semiquantitative food frequency questionnaire and were included in the analyses. This study examined effect modification by baseline intake of key foods, individual nutrients, dietary patterns (Alternate Healthy Eating Index and Alternate Mediterranean Diet Score), and dietary supplement use. The study began in 1997, with continued treatment and follow-up through June 1, 2011., Interventions: Multivitamin or placebo daily., Main Outcomes and Measures: Major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, and CVD mortality. Secondary outcomes included myocardial infarction, total stroke, CVD mortality, and total mortality individually., Results: In total, 13 316 male physicians (mean [SD] age at randomization, 64.0 [9.0] years in those receiving the active multivitamin and 64.0 [9.1] years in those receiving the placebo) were observed for a mean (SD) follow-up of 11.4 (2.3) years. There was no consistent evidence of effect modification by various foods, nutrients, dietary patterns, or baseline supplement use on the effect of multivitamin use on CVD end points. Statistically significant interaction effects were observed between multivitamin use and vitamin B6 intake on myocardial infarction, between multivitamin use and vitamin D intake on CVD mortality, and between multivitamin use and vitamin B12 intake on CVD mortality and total mortality. However, there were inconsistent patterns in hazard ratios across tertiles of each dietary factor that are likely explained by multiple testing., Conclusions and Relevance: The results suggest that baseline nutritional status does not influence the effect of randomized long-term multivitamin use on major CVD events. Future studies are needed to investigate the role of baseline nutritional biomarkers on the effect of multivitamin use on CVD and other outcomes., Trial Registration: clinicaltrials.gov Identifier: NCT00270647.

Background: Markers of systemic inflammation (high-sensitivity C-reactive protein [hsCRP], soluble intercellular adhesion molecule 1 [sICAM-1], and fibrinogen) have been associated with a greater risk of total and ischemic stroke, in addition to elevated blood pressure. However, the role of these inflammatory markers on stroke pathophysiology by hypertension status is uncertain., Methods: Blood samples were collected and assayed for hsCRP, sICAM-1, and fibrinogen among 27,330 initially healthy women from the Women's Health Study, and women were followed up from 1992 to 2013. Prior to randomization, the baseline questionnaire collected self-reported hypertension status, cardiovascular risk factors, and lifestyle factors. New cases of total, ischemic, and hemorrhagic stroke were updated annually through questionnaires and confirmed by medical records according to the National Survey of Stroke criteria. Multivariable Cox models estimated overall associations between each inflammatory marker and stroke and separately stratified by hypertension status., Results: We observed 629 incident total strokes over 477,278 person-years. In adjusted analyses, extreme quartiles of hsCRP and sICAM-1 were each associated with a significantly greater risk of total stroke (hsCRP: hazard ratios [HR] = 1.77, 95% confidence interval [CI]: 1.39-2.26; sICAM-1: HR = 1.28, 95% CI: 1.00-1.63). Fibrinogen was not associated with a significantly greater stroke risk. In analyses stratified by hypertension status, elevated hsCRP was associated with a nonstatistically significant greater risk of total stroke among prehypertensive and hypertensive women., Conclusions: These data indicate that hsCRP and sICAM-1 are associated with hypertension status and stroke risk among women. Further work should examine the role of inflammatory markers on ischemic stroke subtypes and clarify mechanisms., (© American Journal of Hypertension, Ltd 2016. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: To compare the efficacy and accuracy of rotational angiography with three-dimensional reconstruction (3DATG) image merged with electro-anatomical mapping (EAM) vs. CT-EAM., Methods: A prospective, randomized, parallel, two-center study conducted in 36 patients (25 men, age 65 ± 10 years) undergoing AF ablation (33 % paroxysmal, 67 % persistent) guided by 3DATG (group 1) vs. CT (group 2) image fusion with EAM. 3DATG was performed on the Philips Allura Xper FD 10 system. Procedural characteristics including time, radiation exposure, outcome, and navigation accuracy were compared between two groups., Results: There was no significant difference between the groups in total procedure duration or time spent for various procedural steps. Minor differences in procedural characteristics were present between two centers. Segmentation and fusion time for 3DATG or CT-EAM was short and similar between both centers. Accuracy of navigation guided by either method was high and did not depend on left atrial size. Maintenance of sinus rhythm between the two groups was no different up to 24 months of follow-up., Conclusion: This study did not find superiority of 3DATG-EAM image merge to guide AF ablation when compared to CT-EAM fusion. Both merging techniques result in similar navigation accuracy.

Heart failure (HF) is one of the leading causes of hospitalization and death in the United States and throughout Europe. Although a higher risk for HF with antecedent myocardial infarction (MI) has been reported in offspring whose parents had MIs before age 55 years, it is unclear whether adherence to healthful behaviors can mitigate that risk. The aim of the present study was therefore to prospectively examine if adherence to healthy weight, regular exercise, moderate alcohol consumption, and abstinence from smoking can attenuate such increased HF risk. Information on parental history of MI and lifestyle factors was collected using questionnaires. Subjects adhering to ≥3 healthy lifestyle factors were classified as having good versus poor lifestyle scores. Incident HF was assessed via yearly follow-up questionnaires and validated in a subsample. During an average follow up of 21.7 ± 6.5 years, 1,323 new HF cases (6.6%), of which 190 (14.4%) were preceded by MI, occurred. Compared to subjects with good lifestyle scores and no parental histories of premature MI, multivariate adjusted hazard ratios for incident HF with antecedent MI were 3.21 (95% confidence interval 1.74 to 5.91) for subjects with good lifestyle score and parental histories of premature MI, 1.52 (95% confidence interval 1.12 to 2.07) for those with poor lifestyle score and no parental histories of premature MI, and 4.60 (95% confidence interval 2.55 to 8.30) for those with poor lifestyle scores and parental histories of premature MI. In conclusion, our data suggest that even in subjects at higher risk for HF because of genetic predisposition, adherence to healthful lifestyle factors may attenuate such an elevated HF risk., (Published by Elsevier Inc.)

Purpose: We prospectively determined whether preimplant myocardial perfusion imaging (MPI) predicts outcome with biventricular pacing (BiVP)., Methods: Single-photon emission computed tomography (SPECT) MPI, left ventricular (LV) volumes, ejection fraction (EF), 6-min hall walk (6MW) were assessed at baseline and at 4 months in 19 patients with ischemic cardiomyopathy undergoing BiVP. Clinical and hemodynamic responses were correlated with MPI., Results: Lower global myocardial scar burden predicted hemodynamic response to BiVP, while higher burden was associated with poor response. Clinical improvement with BiVP occurred in 12 (63%) of the patients. Clinical BiVP responders had lower rest/stress MPI score difference. There was a close negative correlation between MPI reversibility and increased 6MW distance., Conclusions: Baseline MPI is associated with clinical and hemodynamic response to BiVP: greater myocardial scar burden is predictive of poor hemodynamic response, while higher ischemic burden is predictive of poor clinical response. There is a differential response to BiVP by clinical and hemodynamic criteria.

Background & Aims: Previous studies of lower intestinal bleeding (LIB) have limited power to study mortality. We sought to identify characteristics associated with in-hospital mortality in a large cohort of patients with LIB., Methods: We used the 2002 Healthcare Cost and Utilization Project Nationwide Inpatient Sample to study a cross-sectional cohort of 227,022 hospitalized patients with discharge diagnoses indicating LIB. Predictors of mortality were identified by using multiple logistic regression., Results: In 2002, an estimated 8737 patients with LIB (3.9%) died while hospitalized. Independent predictors of in-hospital mortality were age (age >70 vs <50 years; odds ratio [OR], 4.91; 95% confidence interval [CI], 2.45-9.87), intestinal ischemia (OR, 3.47; 95% CI, 2.57-4.68), comorbid illness (>or=2 vs 0 comorbidities, OR, 3.00; 95% CI, 2.25-3.98), bleeding while hospitalized for a separate process (OR, 2.35; 95% CI, 1.81-3.04), coagulation defects (OR, 2.34; 95% CI, 1.50-3.65), hypovolemia (OR, 2.22; 95% CI, 1.69-2.90), transfusion of packed red blood cells (OR, 1.60; 95% CI, 1.23-2.08), and male gender (OR, 1.52; 95% CI, 1.21-1.92). Colorectal polyps (OR, 0.26; 95% CI, 0.15-0.45), and hemorrhoids (OR, 0.42; 95% CI, 0.28-0.64) were associated with a lower risk of mortality, as was diagnostic testing for LIB when added to the multivariate model (OR, 0.37; 95% CI, 0.28-0.48). Hospital characteristics were not significantly related to mortality. Predictors of mortality were similar in an analysis restricted to patients with diverticular bleeding., Conclusions: The all-cause in-hospital mortality rate in LIB was low (3.9%). Advanced age, intestinal ischemia, and comorbid illness were the strongest predictors of mortality.

Introduction: Catheter stability is a key prerequisite for a successful EP procedure. Remote magnetic navigation system (RMNS) was recently introduced for the manipulation of EP catheters. It may provide an improved catheter stability but this has not been tested prospectively. We performed a prospective cross-over study which compares the amplitude and stability of the His-electrogram obtained by catheters using RMNS vs conventional manual catheter placement., Methods: His-electrograms were continuously recorded for 3 min with a conventional His mapping catheter and magnetically tipped catheter capable of alignment in the direction of an externally controlled magnetic field (0.08-0.1 Tesla) in the same patient. First 100 beats of each recording were used for data analysis. The amplitudes of each set of His-electrograms were measured and compared in microvolts. Coefficient of variation of the measured His-signal amplitude was calculated for each beat. Miller's test for the equality of the coefficients of variation and Levene's test of homogeneity of variance were used for statistical analysis., Results: Fourteen patients (6 males; aged 48+/-25 years) were included in the study. His-electrograms were more stable and homogenous with RMNS than manual method in 10/14 patients. Pooled variance of all RMNS recordings was significantly less than pooled variance of manual recordings (p=0.01)., Conclusion: His-electrogram recording using RMNS is more stable and homogeneous than traditional manual method in most patients. These data indicate a superior catheter stability with RMNS.

Objectives: Cytokines and growth factors play a major role in the dysregulated immune response in inflammatory bowel disease (IBD). We hypothesized that significant differences exist between the serum cytokine and growth factor profiles of pediatric IBD patients with active disease (AD) and those in remission, and that levels of some of these soluble mediators may be used to define regulators in IBD and determine disease activity., Methods: Eighty-eight consecutive patients with confirmed Crohn's disease (CD) and ulcerative colitis (UC) seen at the Duke Children's Hospital were prospectively enrolled and a serum sample was obtained. Data were recorded at the time of serum collection to calculate disease activity indices. The relative expression of 78 cytokines, growth factors, and soluble receptors was determined using proprietary antibody-based protein microarrays amplified by rolling circle amplification. SPSS 8 (SPSS Inc., Chicago, IL) was used to compare protein profiles for CD and UC patients in clinical remission (CR) versus AD., Results: Sixty-five CD patients and 23 UC patients were enrolled. Forty-one CD patients had available samples and PCDAI results. Twenty-two patients were in remission PCDAI < or = 12.5 (median 5), 19 patients had disease activity >15 (median 30). Univariate analysis revealed that PLGF, IL-7, IL-12p40, and TGF-beta1 cytokine levels were significantly elevated for patients in CR versus AD (p < 0.01). Twelve UC serum samples had Seo/Truelove Witt AI for analysis. Five patients were in remission by TW AI and Seo AI < or =110 and 7 patients had active mild-to-severe disease by TW and Seo AI >110. Only one cytokine, IL12p40, showed significance between CR versus AD (p < 0.02)., Conclusions: Surprisingly, we found no differences in circulating levels of proinflammatory cytokines but found that pediatric IBD patients in remission compared to those with AD had higher levels of specific circulating cytokines, including the regulatory cytokines IL-12p40 and TGF-beta1. It may be that these cytokines directly regulate intestinal inflammation in IBD or reflect the activity of T regulatory cells in negatively regulating the inflammatory response. Further studies will be needed to validate our results to define the molecular pathways involved in the intestinal immune response in man.

We report the development of an adjustable single-mode-fiber multiterminal directional coupler that exhibits efficient coupling and uniform terminal output over a wide range of coupling coefficients. The device is made using a new technique that employs silicon V-groove substrates in the fabrication of arrays of evanescently coupled taps on single-mode fibers. The coupler is highly directional and polarization independent and exhibits excess loss as low as 0.09 dB per terminal in a 1 x 7 device. The fabrication technique may be extended to produce devices having large numbers of terminals. Applications include use in fiber data-bus systems and as a tapped delay line for broadband signal processing.