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Objective: To describe characteristics of U.S. contraceptive non-users to inform tailored contraceptive access initiatives., Study Design: We used National Survey of Family Growth data from 2011 to 2017 to identify characteristics of contraceptive non-users compared to other women ages 15-44 at risk for unintended pregnancy. We also examined reasons for not using contraception by when non-users expected their next birth. We calculated unadjusted and adjusted prevalence ratios using two definitions of contraceptive non-use: (1) contraceptive non-use during the interview month, and (2) a more refined definition based on contraception use during the most recent month of sexual intercourse and expectation of timing of next birth. We considered p-values < 0.05 statistically significant., Results: Approximately 20% ( n  = 2844) of 12,071 women at risk of unintended pregnancy were classified as standard contraceptive non-users. After adjusting for all other variables, non-users were more likely to be low-income, uninsured, never married, expect a birth within 2 years, and have zero or one parity. The top reasons for contraceptive non-use were not minding if they got pregnant (22.6%), worried about contraceptive side effects (21.0%), and not thinking they could get pregnant (17.6%). After applying the more refined non-user definition, we identified 5.7% ( n  = 721) of women as non-users; expecting a birth within 2-5 years and having a parity of one were associated with non-use after adjustment of all other factors., Conclusion: Our more refined definition of non-users could be used in future studies examining the causes of unintended pregnancy and to inform programmatic interventions to reduce unintended pregnancy., Implications: Describing contraceptive non-users and reasons for contraceptive non-use could help us better understand reasons for unintended pregnancy and inform tailored contraceptive access initiatives., Competing Interests: The authors have no conflicts of interest to disclose., (© 2020 The Authors.)

We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10(-9) across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10(-4)). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.

Background: Timing of solid food introduction in infancy has been associated with several chronic diseases. To explore potential mechanisms, we investigated the relationship between timing of solid food introduction and F2-isoprostanes-a marker of oxidative stress., Methods: Urinary F2-isoprostanes were assessed in 336 healthy children aged less than 11.5 y with 1,266 clinic visits (mean = 3.8 visits per child) in the Diabetes Autoimmunity Study in the Young. We analyzed the association between F2-isoprostane concentrations and infant diet exposures using linear mixed models adjusted for age, age(2), HLA-DR3/4,DQB1*0302 genotype, first-degree relative with type 1 diabetes, maternal age, maternal education, sex, and exposure to in utero cigarette smoke., Results: Later solid food introduction was associated with lower F2-isoprostane concentrations in childhood (on average, 0.10 ng/mg per month of age at introduction; estimate: -0.10 (95% confidence interval (CI): -0.18, -0.02) P value = 0.02). Moreover, childhood F2-isoprostane concentrations were, on average, 0.24 ng/mg lower in individuals breastfed at solid food introduction (estimate: -0.24 (95% CI: -0.47, -0.01) P value = 0.04) compared with those who were not. Associations remained significant after limiting analyses to F2-isoprostanes after 2 y of age., Conclusion: Our results suggest a long-term protective effect of later solid food introduction and breastfeeding at solid food introduction against increased F2-isoprostane concentrations throughout childhood.

Type 1 diabetes (T1D), a chronic autoimmune disease, is often preceded by a preclinical phase of islet autoimmunity (IA) where the insulin-producing beta cells of the pancreas are destroyed and circulating autoantibodies can be detected. The goal of this study was to demonstrate methods for identifying exposures that differentially influence the disease process at certain ages by assessing age-related heterogeneity. The Diabetes Autoimmunity Study in the Young (DAISY) has followed 2,547 children at increased genetic risk for T1D from birth since 1993 in Denver, Colorado, 188 of whom developed IA. Using the DAISY population, we evaluated putative determinants of IA, including non-Hispanic white (NHW) ethnicity, maternal age at birth, and erythrocyte membrane n-3 fatty acid (FA) levels, for age-related heterogeneity. A supremum test, weighted Schoenfeld residuals, and restricted cubic splines were used to assess nonproportional hazards, that is, an age-related association of the exposure with IA risk. NHW ethnicity, maternal age, and erythrocyte membrane n-3 FA levels demonstrated a significant age-related association with IA risk. Assessing heterogeneity in disease etiology enables researchers to identify associations that may lead to better understanding of complex chronic diseases.

Aims/hypotheses: We previously reported that lower n-3 fatty acid intake and levels in erythrocyte membranes were associated with increased risk of islet autoimmunity (IA) but not progression to type 1 diabetes in children at increased risk for diabetes. We hypothesise that specific n-3 fatty acids and genetic markers contribute synergistically to this increased risk of IA in the Diabetes Autoimmunity Study in the Young (DAISY)., Methods: DAISY is following 2,547 children at increased risk for type 1 diabetes for the development of IA, defined as being positive for glutamic acid decarboxylase (GAD)65, IA-2 or insulin autoantibodies on two consecutive visits. Using a case-cohort design, erythrocyte membrane fatty acids and dietary intake were measured prospectively in 58 IA-positive children and 299 IA-negative children., Results: Lower membrane levels of the n-3 fatty acid, docosapentaenoic acid (DPA), were predictive of IA (HR 0.23; 95% CI 0.09, 0.55), while α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not, adjusting for HLA and diabetes family history. We examined whether the effect of dietary intake of the n-3 fatty acid ALA on IA risk was modified by fatty acid elongation and desaturation genes. Adjusting for HLA, diabetes family history, ethnicity, energy intake and questionnaire type, ALA intake was significantly more protective for IA in the presence of an increasing number of minor alleles at FADS1 rs174556 (pinteraction = 0.017), at FADS2 rs174570 (pinteraction = 0.016) and at FADS2 rs174583 (pinteraction = 0.045)., Conclusions/interpretation: The putative protective effect of n-3 fatty acids on IA may result from a complex interaction between intake and genetically controlled fatty acid desaturation.

Context: Vitamin D metabolism genes have been associated with type 1 diabetes (T1D) risk; however, these genes have not been investigated for association with the preclinical phase of T1D, islet autoimmunity (IA). Studies of vitamin D metabolism genes may elucidate the role of vitamin D in complex diseases., Objective: The objective of the study was to explore the association between seven vitamin D metabolism gene single-nucleotide polymorphisms (SNPs) and the risk of IA and progression to T1D., Design: The Diabetes Autoimmunity Study in the Young is a longitudinal, observational study., Setting: Newborn screening for human leukocyte antigen, sibling and offspring recruitment, and follow-up took place in Denver, Colorado., Participants: A total of 1708 children at increased genetic risk of T1D participated in the study: 148 developed IA and 62 IA-positive children progressed to T1D., Main Outcome Measures: IA, defined as positivity for glutamic acid decarboxylase, insulin, or IA-2 autoantibodies on two or more consecutive visits, and T1D, diagnosed by a physician, were the main outcome measures., Results: The risk of IA was associated with DHCR7/NADSYN1 rs12785878 and CYP27B1 rs4646536 [hazard ratio 1.36, 95% confidence interval 1.08-1.73 (for each additional minor allele) and hazard ratio 0.59, 95% confidence interval 0.39-0.89 (for A/G compared with the A/A genotype), respectively]. None of the vitamin D SNPs typed was associated with progression to T1D in IA-positive children. Six of the seven SNPs were significantly associated with 25-hydroxyvitamin D levels., Conclusions: DHCR7/NADSYN1 rs12785878 and CYP27B1 rs4646536 may play an important role in islet autoimmunity, the preclinical phase of T1D. These findings should be replicated in larger cohorts for confirmation.

Previously, we examined 20 non-HLA SNPs for association with islet autoimmunity (IA) and/or progression to type 1 diabetes (T1D). Our objective was to investigate fourteen additional non-HLA T1D candidate SNPs for stage- and age-related heterogeneity in the etiology of T1D. Of 1634 non-Hispanic white DAISY children genotyped, 132 developed IA (positive for GAD, insulin, or IA-2 autoantibodies at two or more consecutive visits); 50 IA positive children progressed to T1D. Cox regression was used to analyze risk of IA and progression to T1D in IA positive children. Restricted cubic splines were used to model SNPs when there was evidence that risk was not constant with age. C1QTNF6 (rs229541) predicted increased IA risk (HR: 1.57, CI: 1.20-2.05) but not progression to T1D (HR: 1.13, CI: 0.75-1.71). SNP (rs10517086) appears to exhibit an age-related effect on risk of IA, with increased risk before age 2 years (age 2 HR: 1.67, CI: 1.08-2.56) but not older ages (age 4 HR: 0.84, CI: 0.43-1.62). C1QTNF6 (rs229541), SNP (rs10517086), and UBASH3A (rs3788013) were associated with development of T1D. This prospective investigation of non-HLA T1D candidate loci shows that some SNPs may exhibit stage- and age-related heterogeneity in the etiology of T1D.