bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating 25-Hydroxyvitamin D Concentration and Risk of Breast, Prostate, and Colorectal Cancers: The Melbourne Collaborative Cohort Study
Authors: Heath Alicia K. , Hodge Allison M. , Ebeling Peter R. , Eyles Darryl W. , Kvaskoff David , Buchanan Daniel D. , Giles Graham G. , Williamson Elizabeth J. , English Dallas R.
Published: March 2019

Background:

The role of vitamin D in cancer risk remains controversial, and limited data exist on associations between vitamin D and subtypes of specific cancers. We investigated associations between circulating 25-hydroxyvitamin D (25(OH)D) and risk of colorectal, breast, and prostate cancers, including subtypes.

Methods:

A case–cohort study within the Melbourne Collaborative Cohort Study included 547 colorectal, 634 breast, and 824 prostate cancers, and a sex-stratified random sample of participants (n = 2,996). Concentration of 25(OH)D in baseline-dried blood spots was measured using LC-MS/MS. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for each cancer in relation to plasma-equivalent 25(OH)D concentration. Associations by stage and BRAF/KRAS status for colorectal cancer, estrogen receptor status for breast cancer, and aggressiveness for prostate cancer were examined in competing risks models.

Results:

25(OH)D concentrations were inversely associated with risk of colorectal cancer [highest vs. lowest 25(OH)D quintile: HR, 0.71; 95% confidence interval (CI), 0.51–0.98], which was limited to women (HR, 0.52; 95% CI, 0.33–0.82). Circulating 25(OH)D was also inversely associated with BRAF V600E–positive colorectal cancer (per 25 nmol/L increment: HR, 0.71; 95% CI, 0.50–1.01). There were no inverse associations with breast cancer (HR, 0.98; 95% CI, 0.70–1.36) or prostate cancer (HR, 1.11; 95% CI, 0.82–1.48).

Conclusions:

Circulating 25(OH)D concentration was inversely associated with colorectal cancer risk for women, but not with risk of breast cancer or prostate cancer.

Impact:

Vitamin D might play a role in preventing colorectal cancer. Further studies are required to confirm whether vitamin D is associated with specific tumor subtypes.
Potent Antineoplastic Effects of Combined PI3Kα–MNK Inhibition in Medulloblastoma
Authors: Eckerdt Frank , Bell Jonathan B. , Beauchamp Elspeth M. , Clymer Jessica , Blyth Gavin T. , Kosciuczuk Ewa M. , Ma Quanhong , Chen David Z. , Horbinski Craig , Goldman Stewart , Munshi Hidayatullah G. , Hashizume Rintaro , Platanias Leonidas C.
Published: March 2019

Medulloblastoma is a highly malignant pediatric brain tumor associated with poor outcome. Developing treatments that target the cancer stem cell (CSC) population in medulloblastoma are important to prevent tumor relapse and induce long-lasting clinical responses. We utilized medulloblastoma neurospheres that display CSC characteristics and found activation of the PI3K/AKT pathway in sphere-forming cells. Of all class IA PI3Ks, only the PI3Kα isoform was required for sphere formation by medulloblastoma cells. Knockdown of p110α, but not p110β or p110δ, significantly disrupted cancer stem cell frequencies as determined by extreme limiting dilution analysis (ELDA), indicating an essential role for the PI3Kα catalytic isoform in medulloblastoma CSCs. Importantly, pharmacologic inhibition of the MAPK-interacting kinase (MNK) enhanced the antineoplastic effects of targeted PI3Kα inhibition in medulloblastoma. This indicates that MNK signaling promotes survival in medulloblastoma, suggesting dual PI3Kα and MNK inhibition may provide a novel approach to target and eliminate medulloblastoma CSCs. We also observed a significant reduction in tumor formation in subcutaneous and intracranial mouse xenograft models, which further suggests that this combinatorial approach may represent an efficient therapeutic strategy for medulloblastoma.

Implications:

These findings raise the possibility of a unique therapeutic approach for medulloblastoma, involving MNK targeting to sensitize medulloblastoma CSCs to PI3Kα inhibition.
Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures
Authors: Zeng Dongqiang , Li Meiyi , Zhou Rui , Zhang Jingwen , Sun Huiying , Shi Min , Bin Jianping , Liao Yulin , Rao Jinjun , Liao Wangjun
Published: March 2019

Tumor microenvironment (TME) cells constitute a vital element of tumor tissue. Increasing evidence has elucidated their clinicopathologic significance in predicting outcomes and therapeutic efficacy. Nonetheless, no studies have reported a systematic analysis of cellular interactions in the TME. In this study, we comprehensively estimated the TME infiltration patterns of 1,524 gastric cancer patients and systematically correlated the TME phenotypes with genomic characteristics and clinicopathologic features of gastric cancer using two proposed computational algorithms. Three TME phenotypes were defined, and the TMEscore was constructed using principal component analysis algorithms. The high TMEscore subtype was characterized by immune activation and response to virus and IFNγ. Activation of transforming growth factor β, epithelial–mesenchymal transition, and angiogenesis pathways were observed in the low TMEscore subtype, which are considered T-cell suppressive and may be responsible for significantly worse prognosis in gastric cancer [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.33–0.54; P < 0.001]. Multivariate analysis revealed that the TMEscore was an independent prognostic biomarker, and its value in predicting immunotherapeutic outcomes was also confirmed (IMvigor210 cohort: HR, 0.63; 95% CI, 0.46–0.89; P = 0.008; GSE78220 cohort: HR, 0.25; 95% CI, 0.07–0.89; P = 0.021). Depicting a comprehensive landscape of the TME characteristics of gastric cancer may, therefore, help to interpret the responses of gastric tumors to immunotherapies and provide new strategies for the treatment of cancers.
Cancer Immunotherapy with T Cells Carrying Bispecific Receptors That Mimic Antibodies
Authors: Ahn Sarah , Li Jingjing , Sun Chuang , Gao Keliang , Hirabayashi Koichi , Li Hongxia , Savoldo Barbara , Liu Rihe , Dotti Gianpietro
Published: March 2019

Tumors are inherently heterogeneous in antigen expression, and escape from immune surveillance due to antigen loss remains one of the limitations of targeted immunotherapy. Despite the clinical use of adoptive therapy with chimeric antigen receptor (CAR)–redirected T cells in lymphoblastic leukemia, treatment failure due to epitope loss occurs. Targeting multiple tumor-associated antigens (TAAs) may thus improve the outcome of CAR-T cell therapies. CARs developed to simultaneously target multiple targets are limited by the large size of each single-chain variable fragment and compromised protein folding when several single chains are linearly assembled. Here, we describe single-domain antibody mimics that function within CAR parameters but form a very compact structure. We show that antibody mimics targeting EGFR and HER2 of the ErbB receptor tyrosine kinase family can be assembled into receptor molecules, which we call antibody mimic receptors (amR). These amR can redirect T cells to recognize two different epitopes of the same antigen or two different TAAs in vitro and in vivo.
Ivabradine in Cancer Treatment-Related Left Ventricular Dysfunction
Authors: Sarocchi Matteo , Arboscello Eleonora , Ghigliotti Giorgio , Murialdo Roberto , Bighin Claudia , Gualandi Francesca , Sicbaldi Vera , Balbi Manrico , Brunelli Claudio , Spallarossa Paolo
Published: March 2019

Background: Patients developing cancer treatment-related left ventricular dysfunction (CTrLVD) require a prompt therapy. Hypotension, dizziness, and fatigue often limit the use of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and β-blockers (BB) in cancer patients who may already be afflicted by these symptoms. Ivabradine is a heart rate-lowering drug that does not cause hypotension and may be used in heart failure with reduced left ventricular ejection fraction (LVEF). Objective: The aim of this paper was to investigate the role of ivabradine to treat CTrLVD. Methods: A retrospective analysis in a cohort of 30 patients with CTrLVD (LVEF < 50%) receiving ivabradine on top of the maximal tolerated dose of ACEi/ARB and BB was performed. We evaluated cardiovascular treatment, oncologic treatment, LVEF, functional class (New York Heart Association [NYHA]), and fatigue during the study period. Results: Ivabradine was initially started at the dose of 2.5 mg/b.i.d. in most patients and then carefully titrated. Hypotension (70%) and fatigue (77%) were the main causes limiting the treatment with ACEi/ARB and BB. After a mean follow-up of 6.5 months, LVEF increased from 45.1% (SD = 6.4) to 53.2% (SD = 3.9; p < 0.001). When patients were analyzed according to the type of cancer therapy, no difference in LVEF changes across the groups was found. NYHA class ameliorated in 11 patients, while fatigue improved in 8 patients. No serious cardiovascular side effects were reported. Conclusions: The ability to improve symptoms and LVEF in unfit cancer patients makes ivabradine a reasonable pharmacological tool for treating CTrLVD.
Short-Term Fasting Induces Cell Cycle Arrest in Immature Hematopoietic Cells and Increases the Number of Naïve T Cells in the Bone Marrow of Mice
Authors: Takakuwa Teruhito , Nakashima Yasuhiro , Koh Hideo , Nakane Takahiko , Nakamae Hirohisa , Hino Masayuki
Published: March 2019

Calorie restriction (CR) has been studied as a way to prolong longevity, and CR before chemotherapy can reduce hematological toxicity in cancer patients. We investigated the influence of fasting on immune cells and immature hematopoietic cells. In fasted mice, there was a significant reduction in the hematopoietic stem cell count but no significant difference for progenitor cells. Colony assays showed no difference and the rates of early and late apoptosis were almost identical when comparing fasted and control mice. DNA cell cycle analysis of immature bone marrow (BM) cells showed that CR caused a significant increase in the percentage in the G0/G1 phase and decreases in the S and G2/M phases. We detected a remarkable increase of T cells in the BM of fasted mice. CD44– naïve CD8+ T cells were more numerous in fasted BM, as were naïve CD4+ T cells, and part of those T cells showed less tendency in the G0/G1 phase. Immature hematopoietic cells remained in a relatively quiescent state and retention of colony-forming capacity during CR. The number of naïve T cells in the BM of fasted mice increased. These findings imply immature hematopoietic cells and some lymphoid cells can survive starvation, whilst maintaining their function.
Complex Neurological Phenotype in Female Carriers of NHE6 Mutations
Authors: Pescosolido Matthew F. , Kavanaugh Brian C. , Pochet Nathalie , Schmidt Michael , Jerskey Beth A. , Rogg Jeffrey M. , De Jager Philip L. , Young-Pearse Tracy L. , Liu Judy S. , Morrow Eric M.
Published: March 2019

Mutations in NHE6 (also termed SLC9A6) cause the X-linked neurological disorder Christianson syndrome (CS) in males. The purpose of this study was to examine the phenotypic spectrum of female carriers of NHE6 mutations. Twenty female carriers from 9 pedigrees were enrolled, ranging from approximately age 2 to 65. A subset of female carriers was assessed using standardized neuropsychological measures. Also, the association of NHE6 expression with markers of brain age was evaluated using 740 participants in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). A majority, but not all, female carriers demonstrated a deficit in at least one neurocognitive domain (85%). A recognizable neuropsychological profile emerged, revealing impairments in visuospatial function, attention, and executive function. Common neuropsychiatric diagnoses included: intellectual disability/developmental delay (20%), learning difficulties (31%), speech/language delays (30%), and attention-deficit/hyperactivity disorder (20%). Notable neurological diagnoses in aging CS female carriers include corticobasal degeneration and atypical parkinsonism. In postmortem brains from the ROS/MAP dataset of normal and pathological aging, decreased NHE6 expression was correlated with greater tau deposition. Our study provides an examination of the phenotypic range in female carriers of NHE6 mutations. The findings indicate that NHE6-related disease in females represents a new neurogenetic condition.
Hemodynamic Stimulation Using the Biomimetic Cardiac Tissue Model (BCTM) Enhances Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Rogers Aaron J. , Kannappan Ramaswamy , Abukhalifeh Hadil , Ghazal Mohammed , Miller Jessica M. , El-Baz Ayman , Fast Vladimir G. , Sethu Palaniappan
Published: March 2019

Human induced pluripotent stem cell (hiPSC)-derived cardio­myocytes (hiPSC-CMs) hold great promise for cardiovascular disease modeling and regenerative medicine. However, these cells are both structurally and functionally ­immature, primarily due to their differentiation into cardiomyocytes occurring under static culture which only reproduces biomolecular cues and ignores the dynamic hemo­dynamic cues that shape early and late heart development during cardiogenesis. To evaluate the effects of hemodynamic stimuli on hiPSC-CM maturation, we used the biomimetic cardiac tissue model to reproduce the hemodynamics and pressure/volume changes associated with heart development. Following 7 days of gradually increasing stimulation, we show that hemodynamic loading results in (a) enhanced alignment of the cells and extracellular matrix, (b) significant increases in genes associated with physiological hypertrophy, (c) noticeable changes in sarcomeric organization and potential changes to cellular metabolism, and (d) a significant increase in fractional shortening, suggestive of a positive force frequency response. These findings suggest that culture of hiPSC-CMs under conditions that accurately reproduce hemodynamic cues results in structural orga­nization and molecular signaling consistent with organ growth and functional maturation.
Dehydroabietic Acid Induces Regeneration of Collagen Fibers in Ultraviolet B-Irradiated Human Dermal Fibroblasts and Skin Equivalents
Authors: Park Nok Hyun , Kang Young-Gyu  , Kim Se-Hwa , Bae Il-Hong , Lee Sung Hoon , Kim Dae-Yong , Hwang Jae Sung , Kim Yong Jin , Lee Tae Ryong , Lee Eun-Soo
Published: March 2019

Background/Aims: Dehydroabietic acid (DAA) is a natural phytochemical found in red pine trees and herbal plants. While DAA and its derivatives are known for improving diabetes and hyperlipidemia, the antiaging effect and its underlying mechanisms of DAA on skin have not been fully examined. Here, we assessed the antiaging effects of DAA on human dermal fibroblasts and skin equivalents. Methods: We investigated the effect of DAA on the secretion of type I procollagen and matrix metalloproteinase-1 (MMP-1) in ultraviolet B (UVB)-irradiated neonatal normal human dermal fibroblasts (NHDFn). Using nonlinear optical imaging techniques, we visualized quantitative and qualitative changes of collagen fibers by DAA treatment in human skin equivalent models. Results: DAA induces increases in type I procollagen secretion when treated on UVB-irradiated NHDFn. DAA also downregulates secretion of MMP-1 through the inhibition of the JNK signaling pathway. In human skin equivalent models, we successfully visualized the spatial distribution of collagen fibers in the dermis and found that quantity, diameter, and arrangement of collagen fibers in the dermis were significantly improved by DAA treatment. Conclusion: Our results suggest that DAA could be a useful agent for improving skin photoaging through the protection and regeneration of collagen fibers in skin.
Abstract 001: Proteomic Signatures of Cardiovascular Risk Factors: A Cross-sectional Analysis of the Plasma Proteome in the Framingham Heart Study
Authors: Corlin Laura , Liu Chunyu , Larson Martin G , Vasan Ramachandran S
Published: March 2019

Introduction:
Proteomic biomarkers related to cardiovascular disease (CVD) risk factors may offer insights into the pathogenesis of subclinical and clinical CVD.

Hypothesis:
We hypothesized that 1) CVD risk factors may have distinctive proteomic signatures; and 2) select proteins are associated with multiple CVD risk factors indicating a central (pleiotropic) role in disease pathogenesis.

Methods:
We measured 1317 circulating plasma proteomic biomarkers (SomaScan; using the SomaLogic platform) in up to 897 Framingham Heart Study Generation 3 participants (mean age 46 years; 56% women) without hypertension, diabetes mellitus, or clinical CVD at the second examination (2008-2011). We used linear regression (or logistic for binary outcomes) to relate levels of each inverse-log transformed proteomic biomarker to age, sex, body mass index (BMI), waist circumference, systolic and diastolic blood pressure, blood lipid fractions, fasting blood sugar and insulin, coronary artery calcium (by computed tomography), left ventricular mass (by echocardiography), pre-hypertension, pre-diabetes, dyslipidemia, overweight, obesity, alcohol consumption, physical activity (by accelerometer), and smoking. All models adjusted for age, sex, and BMI. A Bonferroni-adjusted p-value <2.7E-5 indicated statistical significance.

Results:
Forty-one proteins were associated with ≥8 CVD risk factors and 13 proteins (Apo E, C5a, GHR, IGFBP-2, leptin, NG36, Notch-3, QORL1, RGMB, SHBG, TIG2, XTP3A, tPA) were associated with ≥10 risk factors. Illustrative volcano plots for proteomic signatures of smoking and physical activity show high representation of proteins related to tumor suppression, immunologic function, and cellular communication (Figure).

Conclusions:
Our cross-sectional data from a relatively healthy community-based sample elucidated distinctive proteomic signatures of CVD risk factors. A small group of proteins were associated with multiple risk factors, suggesting their potential pleiotropic role in CVD.
Abstract 007: Actigraphy-Measured Sleep Regularity and Risk of Incident Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis
Authors: Huang Tianyi , Mariani Sara , Redline Susan
Published: March 2019

Background:
Prior studies have linked rotating night shift work to increased risk of cardiovascular disease (CVD). Irregular sleep schedules, characterized by high day-to-day variability in sleep duration or timing, represent possibly milder but much more common/chronic disruption of circadian rhythms in the general population. However, no prospective study to date has examined the association between sleep regularity and CVD outcomes.

Methods:
In the Multi-Ethnic Study of Atherosclerosis, 1,993 participants who were free of CVD completed 7-day wrist actigraphy at home for objective monitoring of sleep duration and quality between 2010 and 2013, and were prospectively followed through 2015. We assessed sleep regularity using the standard deviation (SD) of actigraphy-measured sleep duration and sleep onset timing across 7 days. Incident CVD was defined as total cardiovascular events including coronary heart disease, stroke, congestive heart failure, and cardiovascular death. Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for incident CVD according to SD of sleep duration and timing, adjusted for traditional CVD risk factors (e.g., sociodemographic factors, lifestyles and CVD biomarkers) and other sleep-related factors (e.g., average sleep duration, insomnia symptoms, daytime sleepiness, sleep-disordered breathing, chronotype and work schedules).

Results:
During a median follow-up of 4.0 years, 95 participants developed CVD events. Compared to participants with a 7-day sleep duration SD ≤60 min, the multivariable-adjusted HR (95% CI) for CVD was 1.12 (0.61, 2.07) for 61-90 min, 1.71 (0.94, 3.09) for 91-120 min, and 2.20 (1.22, 3.96) for >120 min. Every 1-hour increase in sleep duration SD was associated with 23% higher CVD risk (95% CI: 1.05, 1.45; p-trend=0.01). In contrast to this linear association with sleep duration variability, there appeared to be a threshold pattern for the association with SD of sleep onset timing. Compared to participants with a sleep timing SD ≤30 min, the multivariable-adjusted HR (95% CI) for CVD was 1.13 (0.60, 2.13) for 31-60 min, 1.15 (0.58, 2.31) for 61-90 min, and 2.07 (1.09, 3.94) for >90 min. CVD risk was 87% higher comparing sleep timing SD >90 min versus ≤90 min (95% CI: 1.19, 2.96; p=0.007). These associations did not differ significantly by age, sex, race/ethnicity, sleep duration or work schedules. Exclusion of current shift workers yielded similar results.

Conclusion:
Irregular sleep duration and timing may be novel risk factors for CVD, independent of traditional CVD risk factors and sleep quantity/quality. Given the increased prevalence of irregular sleep (e.g., due to mobile device use), our findings have important public health implications for CVD prevention and suggest value in evaluating the impact of sleep hygiene interventions aimed at improving sleep pattern consistency.
Abstract 009: Comparative Associations of Peripheral Artery Disease vs. Prevalent Myocardial Infarction or Stroke with Subsequent Mortality in the US Population, NHANES 1999-2004
Authors: Matsushita Kunihiro , Kwak Lucia , Ballew Shoshana H , Salameh Maya , Allison Matthew , Selvin Elizabeth , Coresh Josef
Published: March 2019

Background:
The FOURIER trial of a PCSK9 inhibitor in patients with prevalent cardiovascular disease reported that patients with peripheral artery disease (PAD) without myocardial infarction (MI) or stroke (MI/stroke) had worse prognosis than those with MI/stroke without PAD. However, whether this observation holds in the general population is unknown.

Methods:
We conducted a prospective analysis of 5,858 participants aged 40 years or older from the 1999-2004 National Health and Nutrition Examination Survey and compared overall mortality among four categories by PAD (ankle-brachial index ≤0.9) and MI/stroke (self-report) status at baseline using Kaplan-Meier curves and multivariable Cox models adjusted for potential confounders such as age, sex, race, diabetes, smoking, blood pressure, and lipids.

Results:
There were 125 participants (2.1%) with both PAD and MI/stroke, 323 (5.5%) with PAD without MI/stroke, and 571 (9.7%) with MI/stroke without PAD (4,785 participants without MI/stroke or PAD). During a median follow-up of 9.5 years, 1,133 participants died. Compared to those without PAD or MI/stroke, participants with both MI/stroke and PAD had the worst survival (36.8% at 10 years), followed by those with PAD without MI/stroke (56.4%) and then those with MI/stroke without PAD (71.0%) (Figure). Multivariable Cox models showed similar patterns: adjusted hazard ratios of 2.81 [95% CI 2.16-3.66] in MI/stroke with PAD, 1.85 (1.41-2.43) in PAD without MI/stroke, and 1.59 [1.30-1.95] in MI/stroke without PAD.

Conclusions:
In the general population, the presence of PAD contributed to significantly higher mortality in those with and without MI/stroke. PAD without MI/stroke showed similar or even worse prognosis than MI/stroke without PAD. These results suggest the importance of recognizing the presence of PAD in the community.
Abstract 011: Comprehensive Cardiovascular Risk Reduction Trial in Persons With Serious Mental Illness (IDEAL Trial)
Authors: Daumit Gail L , Appel Lawrence , Wang Nae-Yuh
Published: March 2019

Introduction:
Persons with serious mental illness (SMI) are at high risk for cardiovascular disease (CVD), with CVD mortality with rates at least twice those of the overall US. Potentially modifiable CV risk behaviors (tobacco smoking, obesity, physical inactivity, unhealthy diet) and risk factors (hypertension, diabetes, dyslipidemia) are all markedly elevated in persons with SMI. This vulnerable population often has substantial challenges related to cognitive impairment and psychiatric symptoms in addition to high prevalence of substance use, low income and social isolation. Accomplishing meaningful reductions in CVD risk for persons with SMI will require special efforts to develop interventions to promote CV health in this high-risk group. Our objective was to determine the effectiveness of an 18-month comprehensive CVD risk reduction intervention in adults with SMI.

Hypothesis:
The active intervention is more effective than the control condition in reducing CVD risk as assessed by the global Framingham Risk Score (FRS).

Methods:
We conducted a NHLBI-sponsored RCT in 269 adults with SMI who had at least one of the following CV risk behaviors/ factors: BMI≥25 kg/m
2
, tobacco smoking, hypertension, diabetes, or dyslipidemia. Participants were recruited from four locations of an outpatient community mental health organization. Those in the active intervention received an 18-month individual-level intervention delivered by a health coach and a nurse providing 1) tailored CVD risk reduction counseling; 2) collaboration with physicians to implement appropriate management of CVD health risks; and 3) coordination with mental health staff and social supports to encourage and motivate attainment of individual CV health goals. We also provided training and resources to promote group physical activity classes, and a dietician to consult with kitchen staff to provide healthier meals (accessible to all mental health program attendees).

Results:
At baseline, mean(SD) age was 48.8(11.9) years, range 21-71. Of 269, 48% (N=128) were male, 46% (125) were African-American, 84%(226) received disability, 59%(159) had schizophrenia/schizoaffective disorder, 25%(67) had bipolar disorder, and 14%(38) had depression. BMI was 33.7(7.2) kg/m
2
; 51% (138) smoked tobacco, 52% (141) had hypertension, 35% (93) had diabetes, 65%(175) had dyslipidemia. Mean(SD) baseline global FRS was 12.1(12.1)% overall, 16.9(14.6)% for men, 7.9(6.8)% for women. By October 15, 2018, 94%(253 of 269) participants completed the trial and had 18-month data collected. Eighteen-month data collection for the trial will conclude in November, 2018.

Conclusion:
Unless effective interventions that effect CV health outcomes are implemented, populations with SMI will continue to lag far behind the nation’s CVD goals. The IDEAL intervention is well positioned to address all CV risks in persons with SMI.
Abstract 012: Performance of Polygenic Risk Scores for Coronary Artery Disease in the Million Veteran Program
Authors: Tcheandjieu Catherine , Zhu Xiang , Ma Shining , Hilliard Austin , Clarke Shoa L , Lynch Julie A , Damrauer Scott M , Khera Amit V , Kathiresan Sekar , Tsao Philip S , Gaziano J. Michael , Wilson Peter W , O’Donnell Christopher , Assimes Themistocles L ,   on behalf of the VA Million Veteran Program
Published: March 2019

Introduction:
Recent studies suggest a substantial improvement in risk prediction of coronary artery disease (CAD) with polygenic risk scores (PRS). The degree to which this improvement is generalizable to other European (EUR) and non-EUR populations remains unclear.

Hypothesis:
We hypothesized that genome-wide PRSs trained and validated in the UK Biobank (UKBB) would perform best in external EUR populations and reduce the performance gap in prediction between EURs and African Americans (AA).

Methods:
We tested our hypothesis in ~91 000 EUR, AA, and Hispanic (HISP) Million Veteran Program (MVP) participants with CAD and ~225 000 non-cases as of July 2017. We created 5 separate weighted PRSs in all participants using: 1) 164 genome-wide significant SNPs for CAD (164SNPs), 2) 46 000 Metabochip SNPs (GRS46K), 3) 1.5 million (M) SNPs from standard pruning & thresholding of CARDIOGRAM+C4D (Khera_P&T), 4) 6.6M SNPs PRS created with LDpred (LDpred_Khera), and 5) 1.7M SNP PRS combining weights of 3 PRSs through meta-analysis (meta-GRS). We estimated age & sex adjusted Odds Ratios (OR) of CAD per standard deviation increase in each PRS using logistic regression and performed sensitivity analyses in subgroups of cases and non-cases.

Results:
LDpred and meta-GRS performed best among EURs (figure). However, the point estimate of the OR for these PRSs in MVP was notably lower than that observed in the UKBB (1.36 vs. ~1.7). ORs in MVP were higher among participants with early-onset disease (1.39), myocardial infarction (1.52), and revascularization (1.56) but lower for incident events after enrollment (1.27). Performance in HISP was mildly diluted but all PRS performed poorly among AA (figure).

Conclusion:
Genome-wide PRSs developed in the UKBB transfer best to external EUR populations but may over-estimate risk and do not close the performance gap in prediction between EURs and AAs. Our findings highlight a need for better calibrated PRSs specific to the cohort and race/ethnic group being tested prior to implementation in clinical practice.
Abstract 013: Cumulative Socioeconomic Disadvantage Across Life Course and Risk of Hospitalization for Heart Failure or Atrial Fibrillation and Mediating Pathways: Prospective Findings From the Moli-Sani Study
Authors: Bonaccio Marialaura , Di Castelnuovo Augusto , Costanzo Simona , De Curtis Amalia , Persichillo Mariarosaria , Cerletti Chiara , Donati Maria Benedetta , de Gaetano Giovanni , Iacoviello Licia ,   Moli-Sani Study Investigators
Published: March 2019

Introduction:
There is lack of data on the association of socioeconomic (SES) disadvantage experienced across life course with the risk of heart failure (HF) or atrial fibrillation (AF). Moreover, little is known on the mechanisms through which SES inequalities shape disease risk.

Hypothesis:
We assessed the hypothesis of an association between cumulative socioeconomic disadvantage (CSD) with risk of first hospitalization for HF or AF in a large general population-based cohort of Italians, and tested several sets of potential mediators in explaining such associations.

Methods:
Longitudinal analysis on 21,756 HF- or AF-free men and women (aged≥35 y) recruited in the Moli-sani Study cohort, Italy (2005-2010). A score to estimate CSD over life-course was computed by using childhood SES factors (hot water, overcrowding, housing), 3-level educational attainment, and adulthood SES indicators (occupation, overcrowding, housing). Five sets of pathways were tested as potential mediators: baseline health conditions, lifestyles, and traditional, inflammatory and novel markers of CVD risk (listed in Table). First hospital admissions were recorded by direct linkage with hospital discharge forms. Hazard ratios with 95% confidence intervals (95% CIs) were calculated using multivariable Cox-proportional hazard models.

Results:
Over a median follow up of 8.2 years, we recorded 836 and 504 admissions to hospital for HF and AF, respectively. A 1-point increment in CSD was associated with 16% and 6% increased risk of HF and AF, respectively. Risk estimates associated with highest CSD, as compared to lowest CSD group, were 2.55 (1.76-3.70) and 1.60 (1.08-2.38) for risk of HF and AF, respectively. Part of such associations was explained by novel biomarkers of CVD risk and baseline lifestyles (Table).

Conclusions:
HF and AF risks are shaped by cumulative socioeconomic disadvantage across the life course in a large Mediterranean population. Lifestyles and novel markers of CVD risk account for the largest proportion of such associations.
Abstract 016: Lower Levels of County Housing Affordability Are Linked to Worse Cardiometabolic Risk Profiles in Middle-Aged and Older Adults
Authors: Rodgers Justin , Wallace Robert B , Briesacher Becky A , Baum Christopher F , Kim Daniel
Published: March 2019

Introduction:
Housing is a fundamental social determinant of health. Past studies have shown that high levels of unaffordable housing raise residents’ chances of moving, often redistributing individuals into socioeconomically disadvantaged neighborhoods and dwellings. This may simultaneously expose individuals to health-detrimental factors while limiting their exposure to health-promoting factors. Residents within unaffordable housing areas may also experience adverse physical and mental health outcomes through various psychosocial, behavioral and material pathways. Yet few studies have examined the relationship between housing affordability and risk factors for cardiovascular disease, the leading cause of morbidity and mortality among Americans.

Hypothesis:
We investigated the hypothesis that lower levels of county housing affordability are linked to higher odds of incident hypertension, diabetes, obesity, and depression.

Methods:
Using a nationally-representative sample of 3,722 middle-aged to older adults from the National Longitudinal Survey of Youths 1979 and exploiting quasi-experimental variation before and after the Great Recession, we estimated the associations between the change in median county-level percentage of household income spent on housing (rent, mortgage) between 2000 and 2008 and individual-level odds of incident hypertension, obesity, diabetes, and depression during the follow-up period 2008-2014. Incidence of hypertension and diabetes was assessed through survey-reported physician diagnosis. Obesity was defined as a BMI
≥
30 kg/m
2
, and depression was measured using the 7-item Center for Epidemiologic Studies Depression Scale and designated based on a cut-off score of 7. We employed fixed effects logistic regression models to reduce bias due to time-invariant confounding.

Results:
Each percentage point increase in the median county-level percentage of household income spent on rent or mortgage was associated with a 17% increase in the odds (OR = 1.17, 95% CI = 1.00 to 1.39; p = 0.047) of incident hypertension, a 37% increase in the odds (OR = 1.37, 95% CI = 1.00 to 1.87; p = 0.049) of obesity, and a 15% increased odds (OR = 1.15, 95% CI = 1.01 to 1.31; p = 0.030) of depression, controlling for individual- and area-level demographic and socioeconomic factors. No association was observed for diabetes. These associations were stronger among renters than among homeowners, and in men compared to women. In sensitivity analyses, these findings were robust when we limited the sample to non-movers and when we used alternative depression score cut-points.

Conclusions:
Our findings suggest that lower levels of housing affordability contribute to worse risk profiles for cardiovascular disease. Policies that make housing more affordable may help to reduce the population burden of cardiovascular disease.
Abstract 025: Association of Dietary Patterns and Lifetime Risk of Heart Failure: The Cardiovascular Disease Lifetime Risk Pooling Project
Authors: Khan Sadiya S , Zhong Wenze , Ning Hongyan , Paluch Amanda , Allen Norrina B , Yancy Clyde W , Wilkins John T , Lloyd-Jones Donald M
Published: March 2019

Introduction:
Modifiable healthy lifestyle factors have been associated with lower risk of developing heart failure (HF). However, the role of dietary patterns in relation to lifetime risk (LR) of HF and years lived free of HF is not established. We hypothesized that better diet quality scores would be associated with lower risk of HF and more years lived free of HF.

Methods:
We included individual-level pooled data from 7 US population-based cohorts stratified by index age groups (middle-aged [40-59 years] and older [60-79 years]), sex, and race. We calculated the alternate Healthy Eating Index-2010 (AHEI) score for all participants and performed (1) modified Kaplan-Meier analysis to estimate LR of HF, (2) competing Cox models (adjusted for age, smoking, education, body mass index, physical activity, hypertension, and diabetes) to estimate joint cumulative risks for HF or death, and (3) Irwin restricted mean to estimates years lived free of and with HF.

Results:
Of the 39,082 middle-aged participants free of HF at baseline, 15% of participants were black and 84% were women. Over 125,214 person-years of follow-up, LR for HF was highest in those with the lowest quality diet (quintile 1) compared with those in higher aHEI quintiles (
FIGURE
). Competing hazard ratios for HF among middle-aged black men and women in the lowest quintile were 2.56 (95% confidence interval [CI] 1.38, 4.76) and 2.33 (95% CI 1.34, 4.04) compared with individuals in the highest quintile, with similar findings in white adults. Participants in the lowest aHEI quintile lived significantly fewer healthy years free of HF compared with those in the highest aHEI quintile (p<0.05 for all sex-race groups). Similar patterns were observed in black and white older adults (index age 60-79 years).

Discussion:
A higher (better) diet quality score is independently associated with lower risk of HF and greater proportion of life lived without HF. Public health policies supporting adherence to the AHEI dietary recommendations may decrease the growing burden of HF.
Abstract 030: Dietary Inflammatory Potential is Associated with Cardiovascular Disease Risk in Two Large Prospective Cohort Studies of US Men and Women
Authors: Li Jun , Lee Donghoon , Li Yanping , Tabung Fred , Bhupathiraju Shilpa , Giovannucci Edward L , Manson JoAnn E , Rimm Eric B , Willett Walter C , Rexrode Kathryn M , Hu Frank
Published: March 2019

Introduction:
Chronic inflammation plays a pathogenic role in cardiovascular disease (CVD) development. Dietary factors have been implicated in CVD etiology and may have an impact on chronic inflammation.

Hypothesis:
Proinflammatory diets are associated with higher CVD risk.

Methods:
We include74,544 women in the Nurses’ Health Study (from 1984 through 2012) and 43,904 men in the Health Professionals Follow-up Study (from 1986 through 2012), who were free of heart disease, stroke, and cancer at baseline. Dietary inflammatory potentials were assessed using an empirical dietary inflammatory pattern (EDIP) score that has been pre-defined by 18 food components based on their associations with circulating levels of systemic inflammation markers C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 2. Adjusted hazard ratios (HRs) and 95% confidence internals (CIs) for CVD were calculated using Cox regressions.

Results:
During 2,831,128 person-years of follow-up, we documented 13,249 incident CVD cases, including 8,178 coronary heart disease cases and 5,182 stroke cases. After adjusting for established risk factors and potential confounders including body-mass index and aspirin or other nonsteroidal anti-inflammatory medication use, a higher EDIP score was associated with an increased risk of CVD (in pooled analyses, HR [95% CI] comparing the highest to the lowest quintiles were 1.29 [1.22 to 1.37];

P
trend

<0.001), CHD (HR = 1.32[1.23 to 1.42];

P
trend

<0.001), and stroke (HR = 1.25 [1.14 to 1.37];

P
trend

<0.001). Associations were similar among subgroups of participants, including by age, sex, family history, BMI, physical activity, and alcohol intake; but were stronger among non/past-smoking than current smoking women (

P
interaction

<0.002).

Conclusions:
Findings from two large US prospective cohort studies suggest that inflammation may be a potential mechanism linking dietary patterns to CVD progression. Reducing the proinflammatory potentials of the diet may assist CVD prevention.
Abstract 033: Directly Measured Triglyceride-Rich Lipoprotein Cholesterol and Small Dense LDL-Cholesterol Concentrations Associate With Incident Cardiovascular Disease: Prospective Data From the Women’s Health Study
Authors: Duran Edward K , Aday Aaron W , Cook Nancy , Buring Julie E , Ridker Paul M , Pradhan Aruna D
Published: March 2019

Background:
Elevated triglyceride rich lipoproteins (TRLs) and small dense LDL (sdLDL) levels are hallmarks of atherogenic dyslipidemia and the cholesterol content of these particles is hypothesized to drive atherosclerotic risk. However, laboratory quantitation has thus far been impractical with limited prospective clinical data utilizing directly measured levels of this cholesterol burden.

Methods:
We conducted a prospective case-cohort study within the Women’s Health Study. Randomly selected CVD case subjects (n=500) were compared to a reference subcohort (n=496). TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens. Cox proportional hazards models were used to compute quartile-specific multivariable-adjusted HRs for total CVD and individual outcomes of coronary and cerebrovascular disease (CCVD) and peripheral artery disease (PAD). Clinical models also adjusted for LDL-C and hsCRP.

Results:
TRL-C and sdLDL-C were strongly correlated (
ρ
=0.716, p<0.001) and levels were higher in case subjects than in the reference risk set. The risk of each outcome increased across quartiles of TRL-C (HR
adj
Q4 vs Q1: total events 1.87, 95% CI 1.14 - 3.06, p=0.012; CCVD 1.81, 95% CI 1.05 - 3.09, p = 0.030; PAD 2.43, 95% CI 1.11 - 5.31, p=0.039). In contrast, elevated sdLDL-C associated with incident CCVD but not PAD (HR
adj
Q4 vs Q1: total events 1.85, 95% CI 1.04 - 3.31, p=0.014; CCVD 2.17, 95% CI 1.14 - 4.13, p = 0.006; PAD 1.34, 95% CI 0.54 - 3.33, p=0.389).

Conclusion:
Directly measured TRL-C and sdLDL-C concentrations are strongly linked to incident CVD with potentially differential effects for PAD. These findings may indicate a greater potential benefit of therapeutics targeting TRL-C rather than LDL in the prevention of PAD.
Abstract 037: The U.S. Food and Drug Administration’s Metformin Label Change Reduces Racial Disparity in Metformin Use by Increasing Its Use Among Black Patients With Type 2 Diabetes and Moderately Impaired Kidney Function
Authors: Shin Jung-Im , Chang Alex , Coresh Josef , Inker Lesley A , Selvin Elizabeth , Grams Morgan
Published: March 2019

Introduction:
Historically, metformin was contraindicated in people with type 2 diabetes (T2D) and kidney disease due to concerns of lactic acidosis. The U.S. Food and Drug Administration (FDA) recently changed metformin label from serum creatinine (sCr)-based to estimated glomerular filtration (eGFR)-based indication, expanding its use for people with eGFR≥30 mL/min/1.73 m
2
. The purpose of our study is to assess the effects of the label change on metformin use among people with T2D, stratified by race and eGFR.

Hypothesis:
Because sCr levels are higher in blacks than in whites at the same level of eGFR, we hypothesized that the label change increases metformin use in people with T2D and kidney disease and magnitude of increase is greater in blacks than in whites.

Methods:
One-year period prevalence cohort was created for each of before and after the FDA’s label change (April 8, 2016) in Johns Hopkins Medicine, including people with T2D and eGFR≥30 mL/min/1.73 m
2
. We estimated the prevalence of metformin use in each cohort, stratified by eGFR within each race.

Results:
Mean age of study population (N=15,880) was 61 years, 52% were women, 48% were black, mean eGFR was 81 mL/min/1.73 m
2
, and mean HbA1c was 7.8%. Before the label change, blacks with eGFR 30-44 mL/min/1.73 m
2
were less likely to use metformin compared to whites, controlling for age, sex, eGFR, and HbA1c (odds ratio [OR]=0.49 [95% confidence interval: 0.37-0.65]). The label change did not increase metformin use among whites across all categories of eGFR, whereas it increased metformin use from 26.1% to 32.6% (P=0.03) among blacks with eGFR 30-44 ml/min/1.73 m
2
(
Figure
). As a result, magnitude of racial disparity in metformin use after the label change was attenuated (OR=0.75 [0.57-0.99]).

Conclusions:
The recent eGFR-based metformin label change increased its use in black people with T2D and moderately impaired kidney function, with reducing racial disparity of metformin use. Further studies to assess impact of metformin label change with longer study period are warranted.
Abstract 039: Low Levels of Moderate to Vigorous Physical Activity is Associated With Fewer Years Lived Free of Cardiovascular Disease: The Cardiovascular Lifetime Risk Pooling Project
Authors: Paluch Amanda , Ning Hongyan , Carnethon Mercedes , Pettee Gabriel Kelley , Allen Norrina , Lloyd-Jones Donald , Wilkins John
Published: March 2019

Background:
Quantifying the associations of moderate to vigorous intensity physical activity (MVPA) with years lived free of cardiovascular disease (CVD) allows for contextualization of the population burden and provides a metric for clinician-patient communication. We hypothesized that individuals with lower levels of MVPA during middle age will have fewer years lived free of CVD compared to those with higher levels.

Methods:
A standardized z-score for MVPA was created based on participant-reported physical activity in 28,466 middle aged adults aged 40-59 years (43.6% women) in 6 U.S. prospective cohort studies. Z-scores were then categorized into quartiles for each cohort. Rates (person-years) of incident CVD and death were summed for participants up to age 95 years, or to the oldest age of observation. Irwin’s restricted mean was used to calculate years lived free from CVD and overall survival stratified by sex.

Results:
Over 514,324 person-years of follow-up, 3,556 CVD events were observed. Whereas there was no difference in survival time among participants in the upper 3 quartiles, women in the lowest quartile vs. the next lowest quartile lived 3.2 fewer years and men lived 1.2 fewer years free of CVD. Survival after a CVD event was lower for women in the lowest MVPA quartile (mean±S.E: 0.07±0.32 years) compared to all other quartiles (Q2: 0.67±0.16 years to Q4: 0.96±0.16 years). Survival after CVD events was similar across all quartiles of MVPA for men, ranging from 1.1±0.05 to 1.4±0.05 years.

Conclusions:
The benefits of physical activity extend multiple decades into older ages. Even modest levels of physical activity during middle age is associated with longer CVD-free survival, particularly among women.
Abstract 040: Association of Physical Inactivity and Lifetime Risk of Heart Failure Among White and Black US Adults
Authors: Khan Sadiya S , Paluch Amanda E , Ning Hongyan , Berry Jarett D , Carnethon Mercedes , Wilkins John T , Lloyd-Jones Donald M
Published: March 2019

Introduction:
Adherence with the American Heart Association (AHA) guidelines for physical activity (AHA-PA) may reduce the risk of heart failure (HF). However, the association of AHA-PA in relation to sex and race-specific lifetime risk (LR) estimates of HF and years lived free of HF is not established. Therefore, we sought to examine the association of AHA-PA and burden of HF.

Methods:
We included individual-level pooled data from 5 population-based cohorts and stratified middle-aged participants (index age 40-59 years) free of cardiovascular disease (CVD) and HF at baseline by sex and race. We categorized AHA-PA as ideal (≥150 minutes/week), intermediate (1 to 149 minutes/week), or poor (0 minutes/week) and performed (1) modified Kaplan-Meier analysis to estimate LR of HF, (2) Irwin restricted mean to estimates years lived free of and with HF, and (3) competing Cox models (adjusted for age, smoking, education, body mass index [BMI], hypertension, and diabetes) to estimate joint cumulative risks for HF or death.

Results:
Of the 41,685 participants, 19% were black and 82% were women. Over median follow-up of 13.8 years, LR for incident HF was higher in individuals with poor compared with those who achieved ideal AHA-PA among women and black men, but not white men. Poor AHA-PA was associated with significantly fewer healthy years lived free of HF among black men (-4.9 years) compared with ideal AHA-PA, but was not significantly different among black women or white adults. Adjusted competing hazard ratios for incident HF among middle-aged black men with poor AHA-PA was 1.39 (95% confidence interval 1.02, 1.90) compared with individuals achieving ideal AHA-PA with similar findings among black (1.40 [1.07, 1.82]) or white women (1.79 [1.48, 2.17]) (
Table
).

Discussion:
Adherence with ideal AHA-PA is associated with lower risk of HF and greater proportion of life lived free of HF, particularly among black men. Public health policies promoting PA may mitigate the risk of HF in women and the racial disparities in HF in men.