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BACKGROUND: The psychological aftermath of the Chernobyl accident is regarded as the largest public health problem unleashed by the accident to date. Yet the mental health of the clean-up workers, who faced the greatest radiation exposure and threat to life, has not been systematically evaluated. This study describes the long-term psychological effects of Chernobyl in a sample of clean-up workers in Ukraine.MethodThe cohorts were 295 male clean-up workers sent to Chernobyl between 1986 and 1990 interviewed 18 years after the accident (71% participation rate) and 397 geographically matched controls interviewed as part of the Ukraine World Mental Health (WMS) Survey 16 years after the accident. The World Health Organization (WHO) Composite International Diagnostic Interview (CIDI) was administered. We examined group differences in common psychiatric disorders, suicide ideation and severe headaches, differential effects of disorder on days lost from work, and in the clean-up workers, the relationship of exposure severity to disorder and current trauma and somatic symptoms. Analyses were adjusted for age in 1986 and mental health prior to the accident. RESULTS: Relatively more clean-up workers than controls experienced depression (18.0% v. 13.1%) and suicide ideation (9.2% v. 4.1%) after the accident. In the year preceding interview, the rates of depression (14.9% v. 7.1%), post-traumatic stress disorder (PTSD) (4.1% v. 1.0%) and headaches (69.2% v. 12.4%) were elevated. Affected workers lost more work days than affected controls. Exposure level was associated with current somatic and PTSD symptom severity. CONCLUSIONS: Long-term mental health consequences of Chernobyl were observed in clean-up workers. [ABSTRACT FROM AUTHOR]

Background: Disabling hearing loss affects ∼430 million people globally. Fish consumption and long-chain n-3 polyunsaturated fatty acid (PUFA) intake were inversely associated with risk of hearing loss, but the association of plasma n-3 PUFAs and hearing loss is unclear., Objective: To examine the associations between plasma n-3 PUFA fractions (as % of total fatty acids), i.e., DHA % and Other n-3 PUFA % (defined as total n-3 PUFA minus DHA), with self-reported hearing difficulty in a population-based cohort in the UK., Methods: Our study includes 175,177 UK Biobank participants (40-69y, 54 % women) with data on plasma n-3 PUFA and hearing status. Baseline plasma PUFA levels were analyzed by nuclear magnetic resonance, and self-reported hearing difficulty was obtained by questionnaire between 2007 and 2010. Logistic regression was used to estimate age-adjusted odds ratios (ORs), multivariable-adjusted odds ratios (MVORs) by adjusting for 14 demographic, behavioral, biomarker and health-related potential confounders, and 95 % confidence intervals (CIs)., Results: Hearing difficulty was reported by 26.7 % of participants. Higher plasma n-3 PUFA levels were independently associated with lower odds of self-reported hearing difficulty. The prevalence of hearing difficulty rose across age strata (40-49y, 15.8 %; 50-59y, 24.9 % and 60+y, 34.4 %; p < 0.0001) and overall was higher in males (33.2 %) than females (21.3 %). Compared with those in the lowest quintile of plasma DHA % or Other n-3 PUFA %, the MVOR (95 % CI) for hearing difficulty was 0.88 (0.85, 0.92) in highest quintile of plasma DHA %, and 0.91 (0.87, 0.94) in the highest quintile of Other n-3 PUFA %. The associations with DHA % did not differ by age or sex (p-for-interaction 0.83 and 0.58, respectively). MVORs for DHA % and Other n-3 PUFA % were similar among the 44,486 individuals with data on noise exposure at work., Conclusions: Higher plasma n-3 PUFA levels were independently associated with lower odds of hearing difficulty., Competing Interests: Declaration of competing interest M.I. McBurney has held consulting agreements in the past 3 years with the Council for Responsible Nutrition; Church & Dwight; DSM Nutritional Products; McCormick; VitaMe Technologies; and World Health Organization. W.S. Harris holds an interest in OmegaQuant Analytics, a lab that offers n-3 blood testing. N.L. Tintle, J. Westra and S.E. Curhan have no conflicts to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The potential role of n-6 PUFAs in major health outcomes remains controversial., Objectives: To examine the relationship between the major plasma n6 PUFA, linoleic acid (LA), as well as the non-LA n6 PUFAs, and total and cause-specific mortality., Methods: This was a prospective, observational, biomarker-based study in the UK Biobank. Individuals with complete information on baseline demographic, covariate and plasma PUFA levels (percent ot total fatty acids) and mortality outcomes were included (n=257,925). Multivariable-adjusted, Cox-proportional hazards models were used to predict risk of death from all-causes, and from cardiovascular disease (CVD), cancer, and other causes as a function of plasma LA and non-LA n6 levels, both continuously and by PUFA quintile (Q)., Results: Comparing LA Q5 to Q1, the hazard ratio (HR, 95% CI) for total mortality was 0.80 (0.76, 0.84; p<0.001), and this was similar for all three cause-specific death categories. On the other hand, mortality HR for non-LA n6 was 1.12 (1.08,1.17; p<0.001), and this was primarily due to increased risk for non-CVD, noncancer deaths [HR 1.29 (1.19,1.40; p<0.001)]. Exploratory analyses among the eight next most common other causes of death suggested that both the decreased risk associated with higher LA and the increased risk associated with non-LA n6 were confined to deaths from respiratory and digestive diseases., Conclusions: These findings highlight the profound differences in mortality risk related to LA and non-LA n6 PUFA levels and underscore the inappropriateness of treating n-6 PUFAs as a homogenous class with respect to health outcomes. They also support recommendations to maintain (if not increase) current LA intakes., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Prediabetes and type 2 diabetes mellitus are growing global health concerns, predisposing individuals to various vascular complications. Lifestyle modifications, including dietary interventions, offer promising avenues for prevention and management. Using a multivariable-adjusted model, we analyzed the cross-sectional associations between plasma proportions (% of total fatty acids) of omega-3 polyunsaturated fatty acids (n3 PUFA, including total n3 PUFA, docosahexaenoic acid [DHA], non-DHA n3 PUFA), and glycated hemoglobin A1c (HbA1c) as well as the prevalence of prediabetes in a sample from the UK Biobank cohort. Our hypothesis was that proportions of n3 PUFA, especially DHA, would by inversely associated with the prediabetes prevalence. The sample (n = 92,762; 54.5% females) had an average age of 56 years and was overweight (mean body mass index = 27). The mean plasma DHA proportion in the sample was 2.03% (standard deviation [SD] = 0.67%), non-DHA n3 PUFA was 2.41% (SD = 1.02%) and total n3 PUFA was 4.43% (SD = 1.56%). Prediabetic individuals were identified by blood HbA1c proportions between 5.7% and 6.4% (39-46 mmol/mol) according to American Diabetes Association criteria. Each of the three n3 PUFA biomarkers was inversely associated with HbA1c proportions. In particular, DHA showed the strongest inverse association, with an OR of 0.62 (95% confidence intervals: 0.58, 0.67; P < .001) when comparing quintiles 5 to 1 in a fully adjusted model. These findings suggest a potential protective role of n3 PUFA, particularly DHA, in mitigating the risk of having prediabetes. Further prospective investigations are needed to clarify whether long-chain n3 PUFA could function as modifiable factors for prediabetes., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Cognitive decline, and more specifically Alzheimer's disease, continues to increase in prevalence globally, with few, if any, adequate preventative approaches. Several tests of cognition are utilized in the diagnosis of cognitive decline that assess executive function, short- and long-term memory, cognitive flexibility, and speech and motor control. Recent studies have separately investigated the genetic component of both cognitive health, using these measures, and circulating fatty acids., Objectives: We aimed to examine the potential moderating effect of main species of ω-3 polyunsaturated fatty acids (PUFAs) on an individual's genetically conferred risk of cognitive decline., Methods: The Offspring cohort from the Framingham Heart Study was cross-sectionally analyzed in this genome-wide interaction study (GWIS). Our sample included all individuals with red blood cell ω-3 PUFA, genetic, cognitive testing (via Trail Making Tests [TMTs]), and covariate data (N = 1620). We used linear mixed effects models to predict each of the 3 cognitive measures (TMT A, TMT B, and TMT D) by each ω-3 PUFA, single nucleotide polymorphism (SNP) (0, 1, or 2 minor alleles), ω-3 PUFA by SNP interaction term, and adjusting for sex, age, education, APOE ε4 genotype status, and kinship (relatedness)., Results: Our analysis identified 31 unique SNPs from 24 genes reaching an exploratory significance threshold of 1×10 -5 . Fourteen of the 24 genes have been previously associated with the brain/cognition, and 5 genes have been previously associated with circulating lipids. Importantly, 8 of the genes we identified, DAB1, SORCS2, SERINC5, OSBPL3, CPA6, DLG2, MUC19, and RGMA, have been associated with both cognition and circulating lipids. We identified 22 unique SNPs for which individuals with the minor alleles benefit substantially from increased ω-3 fatty acid concentrations and 9 unique SNPs for which the common homozygote benefits., Conclusions: In this GWIS of ω-3 PUFA species on cognitive outcomes, we identified 8 unique genes with plausible biology suggesting individuals with specific polymorphisms may have greater potential to benefit from increased ω-3 PUFA intake. Additional replication in prospective settings with more diverse samples is needed., (Copyright © 2023. Published by Elsevier Inc.)

Objective: To assess the associations of docosahexaenoic acid (DHA), a marine omega-3 fatty acid, with long-term all-cause mortality, cardiovascular (CV) mortality, and cancer mortality., Patients and Methods: We analyzed data from UK Biobank, which included 117,702 subjects with baseline plasma DHA levels and 12.7 years of follow-up between April 2007 and December 2021. Associations with risk for mortality endpoints were analyzed categorically by quintile of DHA plasma levels., Results: Comparing the lowest to highest quintiles of circulating levels of DHA, there was 21% lower risk of all-cause mortality (HR, 0.79; 95% CI, 0.74 to 0.85; P<.0001). In a secondary analysis, we merged the UK Biobank findings with those from a recent FORCE (Fatty Acid and Outcome Research Consortium) meta-analysis that included 17 prospective cohort studies and 42,702 individuals examining DHA and mortality associations. The cumulative sample population included 160,404 individuals and 24,342 deaths during a median of 14 years of follow-up. After multivariable adjustment for relevant risk factors comparing the lowest to the highest quintiles of DHA, there was 17% lower risk of all-cause mortality (95% CI, 0.79 to 0.87; P<.0001), 21% lower risk for CV disease mortality (95% CI, 0.73 to 0.87; P<.001), 17% lower risk for cancer mortality (95% CI, 0.77 to 0.89; P<.0001), and 15% lower risk for all other mortality (95% CI, 0.79 to 0.91; P<.001)., Conclusion: Higher DHA levels were associated with significant risk reductions in all-cause mortality, as well as reduced risks for deaths due to CV disease, cancer, and all other causes. The findings strengthen the hypothesis that DHA, a marine-sourced omega-3, may support CV health and lifespan., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

n3-PUFA impact health in several ways, including cardiovascular protection and anti-inflammatory effects, but the underlying mechanisms are not fully understood. In this exploratory study involving 31 healthy subjects, we aimed to investigate the effects of 12 weeks of fish-oil supplementation (1500 mg EPA+DHA/day) on the physical properties of multiple blood cell types. We used deformability cytometry (DC) for all cell types and Laser-assisted Optical Rotational Red Cell Analysis (Lorrca) to assess red blood cell (RBC) deformability. We also investigated the correlation between changes in the physical properties of blood cells and changes in the Omega-3 Index (O3I), defined as the relative content of EPA+DHA in RBCs. Following supplementation, the mean±SD O3I increased from 5.3 %±1.5 % to 8.3 %±1.4 % (p < 0.001). No significant changes in RBC properties were found by both techniques. However, by DC we observed a consistent pattern of physical changes in lymphocytes, neutrophils and monocytes. Among these were significant increases in metrics correlated with the cells' deformability resulting in less stiff cells. The results suggest that leukocytes become softer and have an increased ability to deform under induced short-term physical stress such as hydrodynamic force in the circulation. These changes could impact immune function since softer leukocytes can potentially circulate more easily and could facilitate a more rapid response to systemic inflammation or infection. In conclusion, fish-oil supplementation modulates some physical properties of leukocyte-subfractions, potentially enhancing their biological function. Further studies are warranted to explore the impact of n3-PUFA on blood cell biology, particularly in disease states associated with leukocyte dysregulation., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The effect of marine omega-3 PUFAs on risk of stroke remains unclear., Methods: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome., Results: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P <0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P <0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P =0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P =0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD., Conclusions: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke., Competing Interests: Disclosures Dr O’Keefe reports major ownership interest in Cardiotabs. Dr Harris reports minor ownership interest in Omegaquant Analytics, LLC. Dr Sala-Vila reports travel and grant support from California Walnut Commission. Dr Mora reports compensation for consultant services from Quest Diagnostics. Dr Murphy reports compensation from Pharmavite for consultant services. Dr Bork reports grants from Karen Elise Jensens Fond. Dr Ärnlöv reports compensation from Astellas Pharma for other services; compensation from Boehringer Ingelheim for consultant services; compensation from AstraZeneca for other services; and compensation from Novartis for other services. Dr Geleijnse reports grants from National Institutes of Health to other; grants from Upfield Europe BV to other; and grants from The Dutch Heart Foundation to other. Dr Manson reports grants from National Institutes of Health and compensation from National Institutes of Health for other services. Dr Mora reports compensation from Pfizer for consultant services; employment by Brigham and Women’s Hospital; grants from National Institute of Diabetes and Digestive and Kidney Diseases; and grants from National Heart, Lung, and Blood Institute. Dr Melo van Lent reports grants from National Institutes of Health and grants from Alzheimer’s Association. Dr Mozaffarian reports grants from Rockefeller Foundation; compensation from Beren Therapeutics for other services; stock holdings in HumanCo; compensation from January Inc. for other services; compensation from Filtricine for other services; compensation from Perfect Day for other services; compensation from Tiny Organics for other services; grants from Bill and Melinda Gates Foundation; compensation from Calibrate for other services; grants from Vail Innovative Global Research; grants from Kaiser Permanente Fund at East Bay Community Foundation; compensation from DayTwo for other services; compensation from Instacart health for other services; compensation from Season Health for other services; grants from National Institutes of Health; compensation from Barilla for consultant services; stock holdings in Calibrate; compensation from Kaiser Permanente Fund for other services; compensation from HumanCo for other services

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the FADS locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of P < 5 × 10 -8 , we confirmed association of the FADS signal and found evidence of two additional signals (in DAGLA and BEST1) within 200 kb of the originally reported FADS signal. Outside of the FADS region, we identified novel signals for arachidonic acid (AA) in Hispanic Americans located in/near genes including TMX2, SLC29A2, ANKRD13D and POLD4, and spanning a > 9 Mb region on chromosome 11 (57.5 Mb ~ 67.1 Mb). Among these novel signals, we found associations unique to Hispanic Americans, including rs28364240, a POLD4 missense variant for AA that is common in CHARGE Hispanic Americans but absent in other race/ancestry groups. Our study sheds light on the genetics of PUFAs and the value of investigating complex trait genetics across diverse ancestry populations., (© 2023. Springer Nature Limited.)

As biobanks become increasingly popular, access to genotypic and phenotypic data continues to increase in the form of precomputed summary statistics (PCSS). Widespread accessibility of PCSS alleviates many issues related to biobank data, including that of data privacy and confidentiality, as well as high computational costs. However, questions remain about how to maximally leverage PCSS for downstream statistical analyses. Here we present a novel method for testing the association of an arbitrary number of single nucleotide variants (SNVs) on a linear combination of phenotypes after adjusting for covariates for common multimarker tests (e.g., SKAT, SKAT-O) without access to individual patient-level data (IPD). We validate exact formulas for each method, and demonstrate their accuracy through simulation studies and an application to fatty acid phenotypic data from the Framingham Heart Study., (© 2023 The Authors. Annals of Human Genetics published by University College London (UCL) and John Wiley & Sons Ltd.)

High red blood distribution width (RDW) is associated with decreased red blood cell deformability, and high neutrophil-lymphocyte ratio (NLR) is a biomarker of systemic inflammation and innate-adaptive immune system imbalance. Both RDW and NLR are predictors of chronic disease risk and mortality. Omega-3 index (O3I) values have previously been shown to be inversely associated with RDW and NLR levels. Our objective was to determine if total plasma long chain omega-3 fatty acids (Omega3%) measured in the UK Biobank cohort were associated with RDW and NLR values. RDW- and NLR- relationships with Omega3% were characterized in 109,191 adults (58.4% female). RDW- and NLR-Omega3% relationships were inversely associated with Omega3% (both p < 0.0001). These cross-sectional associations confirm previous findings that increasing RDW and NLR values are associated with low O3I. The hypothesis that RDW and/or NLR values can be reduced in individuals with less-than optimal long chain omega 3 values need to be tested in randomized controlled intervention trials using EPA and/or DHA., Competing Interests: Declaration of Competing Interest M.I. McBurney has or has held consulting agreements in the past 3 years with the Council for Responsible Nutrition; Church & Dwight; DSM Nutritional Products; McCormick; VitaMe Technologies; and World Health Organization. W.S. Harris holds an interest in OmegaQuant Analytics, a lab that offers omega-3 blood testing; and is a member of the RB Schiff Science and Innovation Advisory Board. N.L. Tintle has no conflicts to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The role of nutritional status and the risk of contracting and/or experiencing adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are unclear. Preliminary studies suggest that higher n-3 PUFA intakes are protective., Objectives: This study aimed to compare the risk of 3 coronavirus disease 2019 (COVID-19) outcomes (testing positive for SARS-CoV-2, hospitalization, and death) as a function of the baseline plasma DHA levels., Methods: The DHA levels (% of total fatty acids [FAs]) were measured by nuclear magnetic resonance. The 3 outcomes and relevant covariates were available for 110,584 subjects (hospitalization and death) and for 26,595 ever-tested subjects (positive for SARS-CoV-2) in the UK Biobank prospective cohort study. Outcome data between 1 January, 2020, and 23 March, 2021, were included. The Omega-3 Index (O3I) (RBC EPA + DHA%) values across DHA% quintiles were estimated. The multivariable Cox proportional hazards models were constructed, and linear (per 1 SD) relations with the risk of each outcome were computed as HRs., Results: In the fully adjusted models, comparing the fifth to the first DHA% quintiles, the HRs (95% confidence intervals) for testing positive, being hospitalized, and dying with COVID-19 were 0.79 (0.71, 0.89, P < 0.001), 0.74 (0.58, 0.94, P < 0.05), and 1.04 (0.69-1.57, not significant), respectively. On a per 1-SD increase in DHA% basis, the HRs for testing positive, hospitalization, and death, were 0.92 (0.89, 0.96, P < 0.001), 0.89 (0.83, 0.97, P < 0.01), and 0.95 (0.83, 1.09), respectively. The estimated O3I values across DHA quintiles ranged from 3.5% (quintile 1) to 8% (quintile 5)., Conclusions: These findings suggest that nutritional strategies to increase the circulating n-3 PUFA levels, such as increased consumption of oily fish and/or use of n-3 FA supplements, may reduce the risk of adverse COVID-19 outcomes., (Copyright © 2022 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Purpose: Hopelessness and rurality are each independently associated with increased mortality in adults with ischemic heart disease (IHD), yet there is no known research examining hopelessness in rural patients with IHD. The authors of this study evaluated the reliability and validity of the State-Trait Hopelessness Scale (STHS) in a primarily rural population of adults with IHD living in West North Central United States (US Great Plains)., Methods: Reliability, concurrent validity, and convergent validity were evaluated for 115 adults hospitalized for IHD. Rural-Urban Commuting Area codes were used to stratify participants by rurality level, with 66% categorized as rural. Principal component analysis was used to examine potential factor structure of the STHS., Findings: Cronbach α for the State and Trait Hopelessness subscales were 0.884 and 0.903, respectively. Concurrent validity was supported for the State and Trait subscales using the Patient Health Questionnaire-8 (State: r = 0.50, P < .001; Trait: r = 0.35, P < .001). Convergent validity was supported for the State subscale using the Duke Activity Status Index ( r = -0.23, P = .013). Principal component analysis showed 2 factors (hopelessness present and hopelessness absent) for the State and Trait subscales, accounting for 63% and 58% of variance, respectively., Conclusions: Findings support the reliability and validity of the STHS for evaluation of hopelessness in rural adults with IHD in clinical and research settings. Results replicated the same factor structure found in testing of the STHS in a primarily urban sample. Because of the prevalence of hopelessness in rural adults with IHD and association with increased mortality, hopelessness should be assessed during hospitalization and in the recovery period., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

There is inconsistency regarding the association between long-chain n -3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA; 20:5n3) and docosahexaenoic acid (DHA; 22:6n3) and the risk of type 2 diabetes. The present study aimed to investigate the association between the Omega-3 Index (erythrocyte EPA + DHA) and glycemic status as a function of body mass index (BMI). Cross-sectional data from routine clinical laboratory testing with a total of 100,572 people aged over 18 years and BMI ≥ 18.5 kg/m 2 were included. Of the patients, 10% were hyperglycemic (fasting plasma glucose levels ≥ 126 mg/dL) and 24.7% were of normal weight, 35.0% were overweight, and 40.3% were obese. Odds ratios (ORs) of being hyperglycemic were inversely associated with the Omega-3 Index, but weakened as BMI increased. Thus, ORs (95% CI) comparing quintile 5 with quintile 1 were 0.54 (0.44-0.66) in the normal weight group, 0.70 (0.61-0.79) in the overweight group, and 0.74 (0.67-0.81) in the obese group. Similar patterns were seen for EPA and DHA separately. The present study suggested that a low Omega-3 Index is associated with a greater risk of disordered glucose metabolism and this is independent of BMI.

Higher omega-3 fatty acid blood levels, as assessed by the Omega-3 Index (O3I, erythrocyte eicosapentaenoic [EPA] + docosahexaenoic [DHA] percentage), have been linked with lower risk for cardiovascular disease and total mortality. Because seafood is an excellent source of EPA and DHA, we reasoned that people living on the coast with direct access to fresh seafood might have higher O3I levels than people living inland. Using O3I data originally collected for other purposes and an observational design, we compared the mean O3I from people in Newport, RI, with that of people living from 5 inland US cities (Indianapolis, IN; Charleston, WV; Lexington, KY; Oklahoma City, OK; and Memphis, TN). The Newport samples were collected at free, industry-sponsored health fairs, whereas the inland city samples were collected at free public health screenings sponsored by the Seafood Nutrition Partnership in 2014 through 2015. The mean (standard deviation) O3I in the Newport sample (n = 226) was 5.13% (1.34%) and the mean of the 5 cities (n = 1109) was 4.48% (1.08%) (P < .001). An O3I of ≥8% (considered optimal) was found in 3% of the Newport sample and in 1% of the pooled inland cities (P < .05). An O3I of ≤4% (considered low) was found in 22% of the Newport sample and in 41% of the pooled inland cities (P < .001). These data support our hypothesis, but because only 3% of those in the Newport sample had an O3I >8%, even greater seafood intake (or the use of fortified foods or dietary supplements) is needed to attain optimal omega-3 status., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The neutrophil-lymphocyte ratio (NLR) is a biomarker of systemic inflammation and measures innate-adaptive immune system balance. The omega-3-index (O3I) measures the amount of EPA+DHA in blood. Both a low O3I and an elevated NLR are associated with increased risk for chronic disease and mortality, including cardiovascular diseases and cancer. Hypothesizing that low O3I may partly contribute to systemic chronic inflammation, we asked if a relationship existed between O3I and NLR in healthy adults (≥18 y, n = 28,871, 51% female) without inflammation [C-reactive protein (CRP) <3 mg/mL)] who underwent a routine clinical assessment. NLR was inversely associated with O3I before (p < 0.0001) and after adjusting for age, sex, BMI, and CRP (p < 0.0001). Pearson correlations of other variables with NLR were r = 0.06 (CRP), r = 0.14 (age), and r = 0.01(BMI). In this healthy population, an O3I < 6.6% was associated with increasing NLR whereas NLR remained relatively constant (low) when O3I > 6.6%, suggestive of a quiescent, balanced immune system., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Low red blood cell (RBC) membrane content of EPA and DHA, i.e., the omega-3 index (O3I), and elevated RBC distribution width (RDW) are risk factors for all-cause mortality. O3I and RDW are related with membrane fluidity and deformability. Our objective was to determine if there is a relationship between O3I and RDW in healthy adults. Subjects without inflammation or anemia, and with values for O3I, RDW, high-sensitivity C-reactive protein (CRP), body mass index (BMI), age and sex were identified (n = 25,485) from a clinical laboratory dataset of  > 45,000 individuals. RDW was inversely associated with O3I in both sexes before and after (both p < 0.00001) adjusting models for sex, age, BMI and CRP. Stratification by sex revealed a sex-O3I interaction with the RDW-O3I slope (p < 0.00066) being especially steep in females with O3I ≤ 5.6%. In healthy adults of both sexes, the data suggested that an O3I of > 5.6% may help maintain normal RBC structural and functional integrity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: RBC long-chain omega-3 (n-3) fatty acid (FA) percentages (of total fatty acids) are associated with lower risk for total mortality, but it is unknown if a suite of FAs could improve risk prediction., Objectives: The objective of this study was to compare a combination of RBC FA levels with standard risk factors for cardiovascular disease (CVD) in predicting risk of all-cause mortality., Methods: Framingham Offspring Cohort participants without prevalent CVD having RBC FA measurements and relevant baseline clinical covariates (n = 2240) were evaluated during 11 y of follow-up. A forward, stepwise approach was used to systematically evaluate the association of 8 standard risk factors (age, sex, total cholesterol, HDL cholesterol, hypertension treatment, systolic blood pressure, smoking status, and prevalent diabetes) and 28 FA metrics with all-cause mortality. A 10-fold cross-validation process was used to build and validate models adjusted for age and sex., Results: Four of 28 FA metrics [14:0, 16:1n-7, 22:0, and omega-3 index (O3I; 20:5n-3 + 22:6n-3)] appeared in ≥5 of the discovery models as significant predictors of all-cause mortality. In age- and sex-adjusted models, a model with 4 FA metrics was at least as good at predicting all-cause mortality as a model including the remaining 6 standard risk factors (C-statistic: 0.778; 95% CI: 0.759, 0.797; compared with C-statistic: 0.777; 95% CI: 0.753, 0.802). A model with 4 FA metrics plus smoking and diabetes (FA + Sm + D) had a higher C-statistic (0.790; 95% CI: 0.770, 0.811) compared with the FA (P < 0.01) or Sm + D models alone (C-statistic: 0.766; 95% CI: 0.739, 0.794; P < 0.001). A variety of other highly correlated FAs could be substituted for 14:0, 16:1n-7, 22:0, or O3I with similar predicted outcomes., Conclusions: In this community-based population in their mid-60s, RBC FA patterns were as predictive of risk for death during the next 11 y as standard risk factors. Replication is needed in other cohorts to validate this FA fingerprint as a predictor of all-cause mortality., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background Rurality and hopelessness are each associated with increased mortality in adults with ischemic heart disease (IHD), yet there is no known research examining rurality as a risk factor for hopelessness in patients with IHD. This study evaluated rurality as a risk factor for state and trait hopelessness in adults hospitalized with IHD in samples drawn from the Great Lakes and Great Plains regions of the United States. Methods and Results A descriptive cross-sectional design was used. Data were collected from 628 patients hospitalized for IHD in the Great Lakes (n=516) and Great Plains (n=112). Rural-Urban Commuting Area codes were used to stratify study participants by level of rurality. Levels of state hopelessness (measured by the State-Trait Hopelessness Scale) were higher in rural patients (58.8% versus 48.8%; odds ratio [OR], 1.50; 95% CI, 1.03-2.18), a difference that remained statistically significant after adjusting for demographics, depression severity (measured by the Patient Health Questionnaire-8), and physical functioning (measured by the Duke Activity Status Index; OR, 1.59; 95% CI, 1.06-2.40; P =0.026). There was evidence of an interaction between marital status and rurality on state hopelessness after accounting for covariates ( P =0.02). Nonmarried individuals had an increased prevalence of state hopelessness (nonmarried 72.0% versus married 52.0%) in rural areas ( P =0.03). Conclusions Rural patients with IHD, particularly those who are nonmarried, may be at higher risk for state hopelessness compared with patients with IHD living in urban settings. Understanding rurality differences is important in identifying subgroups most at risk for hopelessness. Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT04498975.

Background: The factors other than dietary intake that determine tissue concentrations of EPA and DHA remain obscure. Prior studies suggested that, in women, endogenous estrogen may accelerate synthesis of DHA from ɑ-linolenic acid (ALA), but the effects of exogenous estrogen on RBC n-3 (ɷ-3) PUFA concentrations are unknown., Objective: We tested the hypothesis that menopausal hormone therapy (HT) would increase RBC n-3 PUFA concentrations., Methods: Postmenopausal women (ages 50-79 y) were assigned to HT or placebo in the Women's Health Initiative (WHI) randomized trial. The present analyses included a subset of 1170 women (ages 65-79 y) who had RBC PUFA concentrations measured at baseline and at 1 y as participants in the WHI Memory Study. HT included conjugated equine estrogens (E) alone for women without a uterus (n = 560) and E plus medroxyprogesterone acetate (P) for those with an intact uterus (n = 610). RBC n-3 and n-6 (ɷ-6) PUFAs were quantified., Results: Effects of E alone and E+P on PUFA profiles were similar and were thus combined in the analyses. Relative to the changes in the placebo group after 1 y of HT, docosapentaenoic acid (DPA; n-3) concentrations decreased by 10% (95% CI: 7.3%, 12.5%), whereas DHA increased by 11% (95% CI: 7.4%, 13.9%) in the HT group. Like DHA, DPA n-6 increased by 13% from baseline (95% CI: 10.0%, 20.3%), whereas linoleic acid decreased by 2.0% (95% CI: 1.0%, 4.1%; P values at least <0.01 for all). EPA and arachidonic acid concentrations were unchanged., Conclusions: HT increased RBC concentrations of the terminal n-3 and n-6 PUFAs (DHA and DPA n-6). These findings are consistent with an estrogen-induced increase in DHA and DPA n-6 synthesis, which is consistent with an upregulation of fatty acid elongases and/or desaturases in the PUFA synthetic pathway. The clinical implications of these changes require further study. The Women's Health Initiative Memory Study is registered at clinicaltrials.gov as NCT00685009. Note that the data presented here were not planned as part of the original trial, and therefore are to be considered exploratory., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.

Hopelessness is associated with decreased physical activity (PA) and increased adverse events and death in patients with ischemic heart disease (IHD). Rates of PA in patients with IHD continue to be low in both hospital-based cardiac rehabilitation and home settings. While researchers have investigated strategies to increase PA among patients with IHD, interventions to promote PA specifically in IHD patients who report hopelessness are lacking. We describe the protocol for a NIH-funded randomized controlled trial designed to establish the effectiveness of a 6-week intervention (Heart Up!) to promote increased PA in IHD patients who report hopelessness. Participants (n = 225) are randomized to one of three groups: (1) motivational social support (MSS) from a nurse, (2) MSS from a nurse plus significant other support (SOS), or (3) attention control. Aims are to: (1) test the effectiveness of 6 weeks of MSS and MSS with SOS on increasing mean minutes per day of moderate to vigorous PA; (2) determine the effects of change in moderate to vigorous PA on hopelessness; and (3) determine if perceived social support and motivation (exercise self-regulation) mediate the effects of the intervention on PA. A total of 69 participants have been enrolled to date. The protocol has been consistently and accurately used by research personnel. We address the protocol challenges presented by the COVID-19 pandemic and steps taken to maintain fidelity to the intervention. Findings from this study could transform care for IHD patients who report hopelessness by promoting self-management of important PA goals that can contribute to better health outcomes., (© 2021 Wiley Periodicals LLC.)

Very-long chain omega-3 fatty acids (EPA and DHA) have anti-inflammatory properties that may help reduce morbidity and mortality from COVID-19 infection. We conducted a pilot study in 100 patients to test the hypothesis that RBC EPA+DHA levels (the Omega-3 Index, O3I) would be inversely associated with risk for death by analyzing the O3I in banked blood samples drawn at hospital admission. Fourteen patients died, one of 25 in quartile 4 (Q4) (O3I ≥5.7%) and 13 of 75 in Q1-3. After adjusting for age and sex, the odds ratio for death in patients with an O3I in Q4 vs Q1-3 was 0.25, p = 0.07. Although not meeting the classical criteria for statistical significance, this strong trend suggests that a relationship may indeed exist, but more well-powered studies are clearly needed., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The association between long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) and prostate cancer (PC) remains unclear., Methods: We compared incident PC rates as a function of the Omega-3 Index [O3I, erythrocyte eicosapentaenoic and docosahexaenoic acids (EPA + DHA)] in 5607 men (40-80 years of age) seen at the Cooper Clinic who were free of PC at baseline. The average follow-up was 5.1 ± 2.8 years until censoring or reporting a new PC diagnosis. Proportional hazards regression was used to model the linear association between baseline O3I and the age-adjusted time to diagnosis. A meta-analysis of n-3 PUFA biomarker-based studies and incident PC was updated with the present findings., Results: A total of 116 cases of incident PC were identified. When O3I was examined as a continuous variable, the age-adjusted hazard ratio (HR) (95% CI) was 0.98 (0.89, 1.07; p = 0.25) for each 1% increment in the O3I. The updated meta-analysis with 10 biomarker-based studies found no significant relationship between EPA or DHA levels and risk for PC., Conclusions: We find no evidence in this study nor in a meta-analysis of similar studies that consuming n-3 PUFA-rich fish or using fish oil supplements affects the risk of PC.

Objective: To evaluate perceived social support (PSS) in ischemic heart disease (IHD) patients who report hopelessness., Methods: Using a cross-sectional design, 156 patients were screened during their hospitalization for moderate to severe state hopelessness. Twenty patients who reported hopelessness during hospitalization and maintained hopelessness one week after hospital discharge were included., Results: A moderately strong negative correlation was identified between PSS and state hopelessness (r = -0.54, p = .014). PSS was significantly higher in married/partnered patients (26.7 ± 4.85) compared to unmarried/unpartnered patients (18 ± 9.18; t = 2.45, p = .035)., Conclusions: Social support may help reduce hopelessness in vulnerable cardiac patients, especially those who are unpartnered., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to evaluate the reliability and validity of the State-Trait Hopelessness Scale (STHS) in patients with heart disease who report moderate to severe state hopelessness., Methods: Reliability, concurrent validity, and convergent validity were evaluated for 20 patients., Results: Cronbach's α for the State and Trait subscales were .81 and .79, respectively. Strong correlations between the State Hopelessness Subscale and Patient Health Questionnaire-9 (r = 0.77, P < .001), State Hope Scale (r = -0.75, P < .001), EQ-5D-5L (r = 0.59, P < .005), and PROMIS-29 domains of depression (P = .72, P < .001), fatigue (P = .61, P < .001), and social roles (P = .45, P = .047) were found. There were strong correlations between the Trait Hopelessness Subscale and Trait Hope Scale (r = -0.58, P < .005), State Hope Scale (r = -0.49, P = .03), and PROMIS-29 fatigue domain (r = 0.54, P = .015)., Conclusions: Findings support the reliability and validity of the STHS for evaluation of hopelessness in patients with heart disease.

Chronic pain can pose a serious challenge in everyday life for many individuals globally, especially in developing countries, but studies explicitly exploring risk factors of chronic pain beyond demographic characteristics using survey data have been scarce. To address this problem, this study analyzed World Health Organization data on chronic pain in Ukraine to explore demographic, psychological, and treatment perception-related risk factors to chronic pain. We replicated previous reports of older age, female sex, married status, inadequate financial resources, and comorbidity of other physical conditions as significant demographic risk factors for chronic pain diagnosis but not necessarily for severe pain. We also found evidence for psychological risk factors and treatment perceptions as significant predictors for chronic pain diagnosis and its severity. These results provide a first step in examining beyond demographic risk factors for chronic pain diagnosis and severity and, instead, assessing potential psychological risk factors., Competing Interests: The authors have declared that no competing interests exist.

Background: Supplemental long-chain omega-3 (n-3) fatty acids (EPA and DHA) raise erythrocyte EPA + DHA [omega-3 index (O3I)] concentrations, but the magnitude or variability of this effect is unclear., Objective: The purpose of this study was to model the effects of supplemental EPA + DHA on the O3I., Methods: Deidentified data from 1422 individuals from 14 published n-3 intervention trials were included. Variables considered included dose, baseline O3I, sex, age, weight, height, chemical form [ethyl ester (EE) compared with triglyceride (TG)], and duration of treatment. The O3I was measured by the same method in all included studies. Variables were selected by stepwise regression using the Bayesian information criterion., Results: Individuals supplemented with EPA + DHA (n = 846) took a mean ± SD of 1983 ± 1297 mg/d, and the placebo controls (n = 576) took none. The mean duration of supplementation was 13.6 ± 6.0 wk. The O3I increased from 4.9% ± 1.7% to 8.1% ± 2.7% in the supplemented individuals ( P < 0.0001). The final model included dose, baseline O3I, and chemical formulation type (EE or TG), and these explained 62% of the variance in response (P < 0.0001). The model predicted that the final O3I (and 95% CI) for a population like this, with a baseline concentration of 4.9%, given 850 mg/d of EPA + DHA EE would be ∼6.5% (95% CI: 6.3%, 6.7%). Gram for gram, TG-based supplements increased the O3I by about 1 percentage point more than EE products., Conclusions: Of the factors tested, only baseline O3I, dose, and chemical formulation were significant predictors of O3I response to supplementation. The model developed here can be used by researchers to help estimate the O3I response to a given EPA + DHA dose and chemical form., (Copyright © American Society for Nutrition 2019.)

Background: The Omega-3 Index (O3I; erythrocyte EPA+DHA as a percent of total fatty acids) is inversely related to risk for cardiovascular disease (CVD). The cardioprotective target O3I is 8%-12%. O3I levels in American regions with high CVD risk are poorly characterized., Purpose: To determine the O3I in individuals participating in a Seafood Nutrition Partnership (SNP) survey in seven US cities in the CVD "belt.", Methods: Fingerstick blood samples were analyzed for the O3I., Results: The SNP cohort (n = 2177) had a mean (SD) O3I of 4.42% (1.12%). Only 1.2% were in the desirable range, whereas 42% had an undesirable (<4%) O3I. The mean (SD) O3I in a subset of 772 SNP subjects who were matched for age and sex with the Framingham study was 4.6% (1.2%) compared 5.3% (1.6%) in the Framingham cohort (p < 0.0001)., Conclusions: Individuals in the CVD "belt" had relatively low O3I levels. Since in other settings, a low O3I is associated with increased risk for CVD, this may be one factor contributing to the higher risk for CVD in this region of the US., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: An Omega-3 Index (O3I; EPA+DHA as a % of erythrocyte total fatty acids) in the desirable range (8%-12%) has been associated with improved heart and brain health., Objective: To determine the combination of fish intake and supplement use that is associated with an O3I of >8%., Design: Two cross-sectional studies comparing the O3I to EPA+DHA/fish intake., Participants/setting: The first study included 28 individuals and assessed their fish and EPA+DHA intake using both a validated triple-pass 24-hr recall dietary survey and a single fish-intake question. The second study used de-identified data from 3,458 adults (84% from US) who self-tested their O3I and answered questions about their fish intake and supplement use., Statistical Analyses Performed: Study 1, chi-squared, one-way ANOVA, and Pearson correlations were computed. In Study 2, multi-variable regression models were used to predict O3I levels from reported fish/supplement intakes., Results: The mean ± SD O3I was 4.87 ± 1.32%, and 5.99 ± 2.29% in the first and second studies, respectively. Both studies showed that for every increase in fish intake category the O3I increased by 0.50-0.65% (p < 0.0001). In the second study, about half of the population was taking omega-3 supplements, 32% reported no fish intake and 17% reported eating fish >2 times per week. Taking an EPA+DHA supplement increased the O3I by 2.2% (p < 0.0001). The odds of having an O3I of ≥8% were 44% in the highest intake group (≥3 servings/week and supplementation) and 2% in the lowest intake group (no fish intake or supplementation); and in those consuming 2 fish meals per week but not taking supplements (as per recommendations), 10%., Conclusions: Current AHA recommendations are unlikely to produce a desirable O3I. Consuming at least 3 fish servings per week plus taking an EPA+DHA supplement markedly increases the likelihood of achieving this target level., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To examine differences in state and trait hopelessness between ethnic minority and White patients hospitalized with ischemic heart disease (IHD)., Methods: A descriptive cross-sectional design was used to enroll 517 patients at one Midwestern U.S. hospital. The State-Trait Hopelessness Scale measured hopelessness., Results: State hopelessness was higher in ethnic minority patients compared to Whites. Ethnic minority patients who had never been married had higher state hopelessness than those who were married or separated/divorced. There were no differences in trait hopelessness., Conclusions: Ethnic minority patients with IHD, who have never been married, may be at higher risk for state hopelessness., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Histopathology remains an important source of descriptive biological data in biomedical research. Recent petitions for enhanced reproducibility in scientific studies have elevated the role of tissue scoring (semiquantitative and quantitative) in research studies. Effective tissue scoring requires appropriate statistical analysis to help validate the group comparisons and give the pathologist confidence in interpreting the data. Each statistical test is typically founded on underlying assumptions regarding the data. If the underlying assumptions of a statistical test do not match the data, then these tests can lead to increased risk of erroneous interpretations of the data. The choice of appropriate statistical test is influenced by the study's experimental design and resultant data (eg, paired vs unpaired, normality, number of groups, etc). Here, we identify 3 common pitfalls in the analysis of tissue scores: shopping for significance, overuse of paired t-tests, and misguided analysis of multiple groups. Finally, we encourage pathologists to use the full breadth of resources available to them, such as using statistical software, reading key publications about statistical approaches, and identifying a statistician to serve as a collaborator on the multidisciplinary research team. These collective resources can be helpful in choosing the appropriate statistical test for tissue-scoring data to provide the most valid interpretation for the pathologist.

Background: The prognostic value of erythrocyte levels of n-6 fatty acids (FAs) for total mortality and cardiovascular disease (CVD) outcomes remains an open question., Methods: We examined cardiovascular (CV) outcomes and death in 2500 individuals in the Framingham Heart Study Offspring cohort without prevalent CVD (mean age 66 years, 57% women) as a function of baseline levels of different length n-6 FAs (18 carbon, 20 carbon, and 22 carbon) in the erythrocyte membranes. Clinical outcomes were monitored for up to 9.5 years (median follow up, 7.26 years). Cox proportional hazards models were adjusted for a variety of demographic characteristics, clinical status, and red blood cell (RBC) n-6 and long chain n-3 FA content., Results: There were 245 CV events, 119 coronary heart disease (CHD) events, 105 ischemic strokes, 58 CVD deaths, and 350 deaths from all causes. Few associations between either mortality or CVD outcomes were observed for n-6 FAs, with those that were observed becoming non-significant after adjusting for n-3 FA levels., Conclusions: Higher circulating levels of marine n-3 FA levels are associated with reduced risk for incident CVD and ischemic stroke and for death from CHD and all-causes; however, in the same sample little evidence exists for association with n-6 FAs. Further work is needed to identify a full profile of FAs associated with cardiovascular risk and mortality.

In the search for an understanding of how genetic variation contributes to the heritability of common human disease, the potential role of epigenetic factors, such as methylation, is being explored with increasing frequency. Although standard analyses test for associations between methylation levels at individual cytosine-phosphate-guanine (CpG) sites and phenotypes of interest, some investigators have begun testing for methylation and how methylation may modulate the effects of genetic polymorphisms on phenotypes. In our analysis, we used both a genome-wide and candidate gene approach to investigate potential single-nucleotide polymorphism (SNP)-CpG interactions on changes in triglyceride levels. Although we were able to identify numerous loci of interest when using an exploratory significance threshold, we did not identify any significant interactions using a strict genome-wide significance threshold. We were also able to identify numerous loci using the candidate gene approach, in which we focused on 18 genes with prior evidence of association of triglyceride levels. In particular, we identified GALNT2 loci as containing potential CpG sites that moderate the impact of genetic polymorphisms on triglyceride levels. Further work is needed to provide clear guidance on analytic strategies for testing SNP-CpG interactions, although leveraging prior biological understanding may be needed to improve statistical power in data sets with smaller sample sizes., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Although methylation data continues to rise in popularity, much is still unknown about how to best analyze methylation data in genome-wide analysis contexts. Given continuing interest in gene-based tests for next-generation sequencing data, we evaluated the performance of novel gene-based test statistics on simulated data from GAW20. Our analysis suggests that most of the gene-based tests are detecting real signals and maintaining the Type I error rate. The minimum p value and threshold-based tests performed well compared to single-marker tests in many cases, especially when the number of variants was relatively large with few true causal variants in the set., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: The rise in popularity and accessibility of DNA methylation data to evaluate epigenetic associations with disease has led to numerous methodological questions. As part of GAW20, our working group of 8 research groups focused on gene searching methods., Results: Although the methods were varied, we identified 3 main themes within our group. First, many groups tackled the question of how best to use pedigree information in downstream analyses, finding that (a) the use of kinship matrices is common practice, (b) ascertainment corrections may be necessary, and (c) pedigree information may be useful for identifying parent-of-origin effects. Second, many groups also considered multimarker versus single-marker tests. Multimarker tests had modestly improved power versus single-marker methods on simulated data, and on real data identified additional associations that were not identified with single-marker methods, including identification of a gene with a strong biological interpretation. Finally, some of the groups explored methods to combine single-nucleotide polymorphism (SNP) and DNA methylation into a single association analysis., Conclusions: A causal inference method showed promise at discovering new mechanisms of SNP activity; gene-based methods of summarizing SNP and DNA methylation data also showed promise. Even though numerous questions still remain in the analysis of DNA methylation data, our discussions at GAW20 suggest some emerging best practices.

GAW20 provided a platform for developing and evaluating statistical methods to analyze human lipid-related phenotypes, DNA methylation, and single-nucleotide markers in a study involving a pharmaceutical intervention. In this article, we present an overview of the data sets and the contributions analyzing these data. The data, donated by the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) investigators, included data from 188 families ( N  = 1105) which included genome-wide DNA methylation data before and after a 3-week treatment with fenofibrate, single-nucleotide polymorphisms, metabolic syndrome components before and after treatment, and a variety of covariates. The contributions from individual research groups were extensively discussed prior, during, and after the Workshop in groups based on discussion themes, before being submitted for publication., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rhizomes facilitate the wintering and vegetative propagation of many perennial grasses. Sorghum halepense (johnsongrass) is an aggressive perennial grass that relies on a robust rhizome system to persist through winters and reproduce asexually from its rootstock nodes. This study aimed to sequence and assemble expressed transcripts within the johnsongrass rhizome. A de novo transcriptome assembly was generated from a single johnsongrass rhizome meristem tissue sample. A total of 141,176 probable protein-coding sequences from the assembly were identified and assigned gene ontology terms using Blast2GO. Estimated expression analysis and BLAST results were used to reduce the assembly to 64,447 high-confidence sequences. The johnsongrass assembly was compared to Sorghum bicolor , a related nonrhizomatous species, along with an assembly of similar rhizome tissue from the perennial grain crop Thinopyrum intermedium . The presence/absence analysis yielded a set of 98 expressed johnsongrass contigs that are likely associated with rhizome development.

Background: The extent to which omega-3 fatty acid status is related to risk for death from any cause and for incident cardiovascular disease (CVD) remains controversial., Objective: To examine these associations in the Framingham Heart Study., Design: Prospective and observational., Setting: Framingham Heart Study Offspring cohort., Measurements: The exposure marker was red blood cell levels of eicosapentaenoic and docosahexaenoic acids (the Omega-3 Index) measured at baseline. Outcomes included mortality (total, CVD, cancer, and other) and total CVD events in participants free of CVD at baseline. Follow-up was for a median of 7.3 years. Cox proportional hazards models were adjusted for 18 variables (demographic, clinical status, therapeutic, and CVD risk factors)., Results: Among the 2500 participants (mean age 66 years, 54% women), there were 350 deaths (58 from CVD, 146 from cancer, 128 from other known causes, and 18 from unknown causes). There were 245 CVD events. In multivariable-adjusted analyses, a higher Omega-3 Index was associated with significantly lower risks (P-values for trends across quintiles) for total mortality (P = .02), for non-CVD and non-cancer mortality (P = .009), and for total CVD events (P = .008). Those in the highest (>6.8%) compared to those in the lowest Omega-3 Index quintiles (<4.2%) had a 34% lower risk for death from any cause and 39% lower risk for incident CVD. These associations were generally stronger for docosahexaenoic acid than for eicosapentaenoic acid. When total cholesterol was compared with the Omega-3 Index in the same models, the latter was significantly related with these outcomes, but the former was not., Limitations: Relatively short follow-up time and one-time exposure assessment., Conclusions: A higher Omega-3 Index was associated with reduced risk of both CVD and all-cause mortality., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Recent analyses have suggested a strong heritable component to circulating fatty acid (FA) levels; however, only a limited number of genes have been identified which associate with FA levels. In order to expand upon a previous genome wide association study done on participants in the Framingham Heart Study Offspring Cohort and FA levels, we used data from 2,400 of these individuals for whom red blood cell FA profiles, dietary information and genotypes are available, and then conducted a genome-wide evaluation of potential genetic variants associated with 22 FAs and 15 FA ratios, after adjusting for relevant dietary covariates. Our analysis found nine previously identified loci associated with FA levels (FADS, ELOVL2, PCOLCE2, LPCAT3, AGPAT4, NTAN1/PDXDC1, PKD2L1, HBS1L/MYB and RAB3GAP1/MCM6), while identifying four novel loci. The latter include an association between variants in CALN1 (Chromosome 7) and eicosapentaenoic acid (EPA), DHRS4L2 (Chromosome 14) and a FA ratio measuring delta-9-desaturase activity, as well as two loci associated with less well understood proteins. Thus, the inclusion of dietary covariates had a modest impact, helping to uncover four additional loci. While genome-wide association studies continue to uncover additional genes associated with circulating FA levels, much of the heritable risk is yet to be explained, suggesting the potential role of rare genetic variation, epistasis and gene-environment interactions on FA levels as well. Further studies are needed to continue to understand the complex genetic picture of FA metabolism and synthesis.

Background: Dog ownership has been associated with increased physical activity in the general adult population., Objective: The objective of this study was to examine dog ownership and dog walking and their relationship with home-based and phase II cardiac rehabilitation exercise, depression, and hopelessness in patients with ischemic heart disease., Methods: A total of 122 patients with ischemic heart disease were included in this prospective observational study. Patients completed dog ownership/walking questions during their hospitalization. The Cardiac Rehabilitation Exercise Participation Tool, Patient Health Questionnaire-9, and State-Trait Hopelessness Scale were completed by mail at 3, 8, or 12 months later. Regression modeling was used to evaluate the significance of dog ownership/walking on exercise, depression and hopelessness., Results: The sample was 34.4% female and had a mean age of 64.7 ± 9.1 years. Forty-two patients (34.4%) reported owning a dog. Patients who owned but did not walk their dog reported significantly lower levels of home exercise compared with patients who walked their dogs at least 1 day per week (36.8% for non-dog walkers vs 73.9% for dog walkers, P = .019). The odds of participating in home exercise were significantly higher for dog walkers compared with non-dog walkers (odds ratio, 8.1 [1.7, 38.5] vs 1.0). There were no differences in phase II cardiac rehabilitation exercise, depression, or hopelessness between dog owners and non-dog owners or between dog walkers and non-dog walkers., Conclusions: These findings show a beneficial effect on home-based exercise for those who dog-walk at least 1 day per week. Healthcare professionals should encourage dog walking to increase dog owners' physical activity levels.

Background: In 1986, Reactor 4 of the Chernobyl nuclear power plant near Pripyat, Ukraine exploded, releasing highly-radioactive materials into the surrounding environment. Although the physical effects of the disaster have been well-documented, a limited amount of research has been conducted on association of the disaster with long-term, clinically-diagnosable mental health disorders. According to the diathesis-stress model, the stress of potential and unknown exposure to radioactive materials and the ensuing changes to ones life or environment due to the disaster might lead those with previous vulnerabilities to fall into a poor state of mental health. Previous studies of this disaster have found elevated symptoms of stress, substance abuse, anxiety, and depression in exposed populations, though often at a subclinical level., Materials and Methods: With data from The World Mental Health Composite International Diagnostic Interview, a cross-sectional large mental health survey conducted in Ukraine by the World Health Organization, the mental health of Ukrainians was modeled with multivariable logistic regression techniques to determine if any long-term mental health disorders were association with reporting having lived in the zone affected by the Chernobyl nuclear disaster. Common classes of psychiatric disorders were examined as well as self-report ratings of physical and mental health., Results: Reporting that one lived in the Chernobyl-affected disaster zone was associated with a higher rate of alcohol disorders among men and higher rates of intermittent explosive disorders among women in a prevalence model. Subjects who lived in the disaster zone also had lower ratings of personal physical and mental health when compared to controls., Discussion: Stress resulting from disaster exposure, whether or not such exposure actually occurred or was merely feared, and ensuing changes in life circumstances is associated with increased rates of mental health disorders. Professionals assisting populations that are coping with the consequences of disaster should be aware of possible increases in psychiatric disorders as well as poorer perceptions regarding personal physical and mental health.

Background and Aims: A recent 19-cohort meta-analysis examined the relationships between biomarkers of omega-3 fatty acids and risk for coronary heart disease (CHD). That study did not, however, report hazard ratios (HRs) specifically as a function of erythrocyte eicosapentaenoic (EPA) plus docosahexaenoic (DHA) levels, a metric called the Omega-3 Index in which EPA + DHA content is expressed as a percent of total fatty acids. The Omega-3 Index has been used in several recent studies and is a validated biomarker of omega-3 fatty acid tissue levels, but additional data are needed to confirm (or refute) the originally-proposed clinical cut-points of <4% (higher risk) and 8%-12% (lower risk)., Methods: The present study was therefore undertaken using published data from this meta-analysis to estimate HRs per 1-SD increase in the Omega-3 Index and median quintile values for this metric across 10 of the cohorts for which the needed data were available., Results: The overall mean (SD) for the Omega-3 Index in these 10 cohort studies was 6.1% (2.1%), and the HR for a 1-SD increase was 0.85 (95% confidence interval, 0.80-0.91). Median quintile 1 and 5 levels were 4.2% vs. 8.3%, respectively. Based on these values, we estimate that risk for fatal CHD would have been reduced by about 30% moving from an Omega-3 Index of 4%-8%., Conclusions: These findings support the use of <4% and >8% as reasonable therapeutic targets for the Omega-3 Index., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Exercise reduces morbidity and mortality for patients with heart disease. Despite clear guidelines and known benefits, most cardiac patients do not meet current exercise recommendations. Physician endorsement positively affects patient participation in hospital-based Phase II cardiac rehabilitation programs, yet the importance of physician recommendation for home-based cardiac rehabilitation exercise is unknown. A prospective observational design was used to examine predictors of both home-based and Phase II rehabilitation exercise in a sample of 251 patients with coronary heart disease. Regression analyses were done to examine demographic and clinical characteristics, physical functioning, and patient's report of physician recommendation for exercise. Patients with a strong physician referral, who were married and older, were more likely to participate in Phase II exercise. Increased strength of physician recommendation was the unique predictor of home-based exercise. Further research is needed to examine how health professionals can motivate cardiac patients to exercise in home and outpatient settings.

Purpose: Hopelessness is associated with increased adverse events and decreased survival in patients with coronary heart disease (CHD). The purpose of this research was to examine the effect of regular home- and hospital-based cardiac rehabilitation (CR) exercise on hopelessness levels in patients with CHD, hypothesizing that increased exercise in either setting would lead to decreased state hopelessness., Methods: A descriptive longitudinal design was used at a large teaching hospital in Michigan. A total of 324 patients provided data during hospitalization and at least 1 followup time point (3, 8, and 12 months)., Results: The patients had persistent, modest levels of state and trait hopelessness across all time points. Among home exercisers with moderate to severe state hopelessness at baseline, both mean state (P = .002) and trait (P = .02) hopelessness were reduced at later time points compared with those who quit or did not start exercise. Multivariable models showed that when individuals had moderate to severe baseline state hopelessness, home exercise remained associated with decreases in state hopelessness compared with no exercise, even after adjusting for hospital exercise, depression, and demographic variables., Conclusions: Exercise may be effective in reducing moderate to severe hopelessness in patients with CHD. Moderate to severe baseline state hopelessness was a predictor of attrition in this cohort, especially for home exercisers, but this was mediated in hospital-based programs. Further research is needed to determine how hopeless individuals can be encouraged to exercise and whether home- or a hospital-based CR exercise is superior in impacting hopelessness.