Global strategies for the prevention of neural tube defects through the improvement of folate status in women of reproductive age.

INTRODUCTION: Neural tube defects represent a global public health problem, mainly in countries where effective prevention strategies are not yet in place. The global prevalence of neural tube defects is estimated at 18.6/10,000 (uncertainty interval: 15.3-23.0) live births, where ~ 75% of cases result in under-five mortality. Most of the mortality burden is in low- and middle-income countries. The main risk factor for this condition is insufficient folate levels in women of reproductive age. METHODS: This paper reviews the extent of the problem, including the most recent global information on folate status in women of reproductive age and the most recent estimates of the prevalence of neural tube defects. Additionally, we provide an overview of the available interventions worldwide to reduce the risk of neural tube defects by improving folate status in the population, including dietary diversification, supplementation, education, and fortification. RESULTS: Large-scale food fortification with folic acid is the most successful and effective intervention to reduce the prevalence of neural tube defects and associated infant mortality. This strategy requires the coordination of several sectors, including governments, the food industry, health services providers, the education sector, and entities that monitor the quality of the service processes. It also requires technical knowledge and political will. An international collaboration between governmental and non-governmental organizations is essential to succeed in saving thousands of children from a disabling but preventable condition. DISCUSSION: We propose a logical model for building a national-level strategic plan for mandatory LSFF with folic acid and explain the actions needed for promoting sustainable system-level change.

Rapid decline in lung function is temporally associated with greater metabolically active adiposity in a longitudinal study of healthy adults.

RATIONALE: Adiposity is associated with low lung function, but the longitudinal relationship between lung function and adiposity is inadequately studied. OBJECTIVE: To examine the bidirectional longitudinal associations between rapid decline in lung function and adiposity phenotypes in healthy adults. METHODS: This secondary analysis used a 25-year longitudinal dataset from the Coronary Artery Risk Development in Young Adults (CARDIA) study that enrolled 5115 participants. MEASUREMENTS: In the first analysis, metabolic syndrome at or before CARDIA year (Y) 10 (Y10) was the predictor, and subsequent rapid decline in forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1) between Y10 and Y20 was the outcome. In the second analysis, rapid decline was the predictor, and incident metabolic syndrome at Y20 and/or Y25 was the outcome. In the third analysis, rapid decline was the predictor, and subsequent CT-assessed regional fat depots at Y25 were the outcome. RESULTS: Metabolic syndrome at or before Y10 is temporally associated with rapid decline in FVC between Y10 and Y20 (adjusted p=0.04), but this association was explained by body mass index (BMI) at Y10. Rapid decline in FVC or FEV1 is temporally associated with greater incident metabolic syndrome at Y20 and/or Y25 (adjusted OR 2.10 (1.69, 2.61); p<0.001, and 1.56 (1.26, 1.94); p<0.001, respectively) and greater CT-assessed intrathoracic visceral adiposity at Y25 (adjusted standardised ß 0.09; p<0.001 for both analyses). These associations were not explained by BMI levels prior to the outcome measurement. CONCLUSIONS: Healthy adults with rapid decline in lung function are at risk for developing metabolic syndrome and for disproportionate accumulation of intrathoracic visceral fat. Metabolic abnormalities may be an early extrapulmonary manifestation of lung impairment that may be preventable by improving lung health.

Loss of Lung Health from Young Adulthood and Cardiac Phenotypes in Middle Age.

RATIONALE: Chronic lung diseases are associated with cardiovascular disease. How these associations evolve from young adulthood forward is unknown. Understanding the preclinical history of these associations could inform prevention strategies for common heart-lung conditions. OBJECTIVES: To use the Coronary Artery Risk Development in Young Adults (CARDIA) study to explore the development of heart-lung interactions. METHODS: We analyzed cardiac structural and functional measurements determined by echocardiography at Year 25 of CARDIA and measures of pulmonary function over 20 years in 3,000 participants. MEASUREMENTS AND MAIN RESULTS: Decline in FVC from peak was associated with larger left ventricular mass (ß = 6.05 g per SD of FVC decline; P < 0.0001) and greater cardiac output (ß = 0.109 L/min per SD of FVC decline; P = 0.001). Decline in FEV1/FVC ratio was associated with smaller left atrial internal dimension (ß = -0.038 cm per SD FEV1/FVC decline; P < 0.0001) and lower cardiac output (ß = -0.070 L/min per SD of FEV1/FVC decline; P = 0.03). Decline in FVC was associated with diastolic dysfunction (odds ratio, 3.39; 95% confidence interval, 1.37-8.36; P = 0.006). CONCLUSIONS: Patterns of loss of lung health are associated with specific cardiovascular phenotypes in middle age. Decline in FEV1/FVC ratio is associated with underfilling of the left heart and low cardiac output. Decline in FVC with preserved FEV1/FVC ratio is associated with left ventricular hypertrophy and diastolic dysfunction. Cardiopulmonary interactions apparent with common complex heart and lung diseases evolve concurrently from early adulthood forward.

Quality Control and Reproducibility in M-Mode, Two-Dimensional, and Speckle Tracking Echocardiography Acquisition and Analysis: The CARDIA Study, Year 25 Examination Experience.

INTRODUCTION: Few large studies describe quality control procedures and reproducibility findings in cardiovascular ultrasound, particularly in novel techniques such as speckle tracking echocardiography (STE). We evaluate the echocardiography assessment performance in the Coronary Artery Risk Development in Young Adults (CARDIA) study Year 25 (Y25) examination (2010-2011) and report findings from a quality control and reproducibility program conducted to assess Field Center image acquisition and reading center (RC) accuracy. METHODS: The CARDIA Y25 examination had 3475 echocardiograms performed in 4 US Field Centers and analyzed in a RC, assessing standard echocardiography (LA dimension, aortic root, LV mass, LV end-diastolic volume [LVEDV], ejection fraction [LVEF]), and STE (two- and four-chamber longitudinal, circumferential, and radial strains). Reproducibility was assessed using intraclass correlation coefficients (ICC), coefficients of variation (CV), and Bland-Altman plots. RESULTS: For standard echocardiography reproducibility, LV mass and LVEDV consistently had CV above 10% and aortic root below 6%. Intra-sonographer aortic root and LV mass had the most robust values of ICC in standard echocardiography. For STE, the number of properly tracking segments was above 80% in short-axis and four-chamber and 58% in two-chamber views. Longitudinal strain parameters were the most robust and radial strain showed the highest variation. Comparing Field Centers with echocardiography RC STE readings, mean differences ranged from 0.4% to 4.1% and ICC from 0.37 to 0.66, with robust results for longitudinal strains. CONCLUSION: Echocardiography image acquisition and reading processes in the CARDIA study were highly reproducible, including robust results for STE analysis. Consistent quality control may increase the reliability of echocardiography measurements in large cohort studies.

Mortality After Major Cardiovascular Events in Survivors of Childhood Cancer.

BACKGROUND: Adult survivors of childhood cancer are at risk for cardiovascular events. OBJECTIVES: In this study, we sought to determine the risk for mortality after a major cardiovascular event among childhood cancer survivors compared with noncancer populations. METHODS: All-cause and cardiovascular cause-specific mortality risks after heart failure (HF), coronary artery disease (CAD), or stroke were compared among survivors and siblings in the Childhood Cancer Survivor Study (CCSS) and participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Cox proportional hazard regression models were used to estimate HRs and 95% CIs between groups, adjusted for demographic and clinical factors. RESULTS: Among 25,658 childhood cancer survivors (median age at diagnosis 7 years, median age at follow-up or death 38 years) and 5,051 siblings, 1,780 survivors and 91 siblings had a cardiovascular event. After HF, CAD, and stroke, 10-year all-cause mortalities were 30% (95% CI: 26%-33%), 36% (95% CI: 31%-40%), and 29% (95% CI: 24%-33%), respectively, among survivors vs 14% (95% CI: 0%-25%), 14% (95% CI: 2%-25%), and 4% (95% CI: 0%-11%) among siblings. All-cause mortality risks among childhood cancer survivors were increased after HF (HR: 7.32; 95% CI: 2.56-20.89), CAD (HR: 5.54; 95% CI: 2.37-12.93), and stroke (HR: 3.57; 95% CI: 1.12-11.37). CAD-specific mortality risk was increased (HR: 3.70; 95% CI: 1.05-13.02). Among 5,114 CARDIA participants, 345 had a major event. Although CARDIA participants were on average decades older at events (median age 57 years vs 31 years), mortality risks were similar, except that all-cause mortality after CAD was significantly increased among childhood cancer survivors (HR: 1.85; 95% CI: 1.16-2.95). CONCLUSIONS: Survivors of childhood cancer represent a population at high risk for mortality after major cardiovascular events.

Analysis of Cardiorespiratory Fitness in Early Adulthood and Midlife With All-Cause Mortality and Fatal or Nonfatal Cardiovascular Disease.

Importance: Optimizing cardiovascular fitness is a prevention strategy against premature death and cardiovascular disease (CVD) events. Since this evidence has largely been established in older populations, the importance of cardiorespiratory fitness during earlier periods of adulthood remains unclear. Objective: To examine the association of early-adulthood cardiorespiratory fitness and percentage of early-adulthood cardiorespiratory fitness retained during midlife with subsequent risk of all-cause mortality and CVD-related morbidity and mortality overall as well as by sex and race. Design, Setting, and Participants: This retrospective population-based cohort study analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, an ongoing prospective cohort study conducted at field center clinics in Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California. Participants in the CARDIA study were aged 18 to 30 years when they completed the baseline graded exercise test protocol in 1985 to 1986 and have since undergone follow-up examinations biannually and every 2 to 5 years. Data were collected through August 31, 2020, and were analyzed in October 2022. Exposures: Cardiorespiratory fitness was estimated from a symptom-limited, maximal graded exercise test protocol conducted at baseline and at year 7 and year 20 follow-up examinations. Main Outcomes and Measures: All-cause mortality and combined fatal and nonfatal CVD events were obtained since year 20 of follow-up examinations through August 31, 2020. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) for each primary exposure with each outcome. Results: A total of 4808 participants (mean [SD] age at baseline, 24.8 [3.7] years; 2670 females [56%]; 2438 Black individuals [51%]) were included in the sample. During 68 751 person-years of follow-up, there were 302 deaths (6.3%) and 274 CVD events (5.7%) since year 20. Every 1-minute increment in cardiorespiratory fitness at baseline was associated with a lower risk of all-cause mortality in females (HR, 0.73; 95% CI, 0.64-0.82) and males (HR, 0.87; 95% CI, 0.80-0.96). Every 5% increment in cardiorespiratory fitness retained through year 20 was associated with a lower risk of all-cause mortality (HR, 0.89; 95% CI, 0.79-0.99), but no evidence of effect modification by race or sex was found. Every 1-minute increment in cardiorespiratory fitness at baseline was associated with a lower risk of fatal or nonfatal CVD (HR, 0.89; 95% CI, 0.82-0.96), and the estimated HR per 5% increment in cardiorespiratory fitness retained throughout midlife was 0.89 (95% CI, 0.78-1.00), with no evidence for interaction by race or sex. Conclusions and Relevance: This cohort study found that higher early-adulthood cardiorespiratory fitness and greater retention of early-adulthood cardiorespiratory fitness throughout midlife were associated with a lower risk of premature death and CVD events. Additional research is needed to clarify the association of cardiorespiratory fitness timing across the life course with risk of clinical outcomes.

Racial differences in incident heart failure among young adults.

BACKGROUND: The antecedents and epidemiology of heart failure in young adults are poorly understood. METHODS: We prospectively assessed the incidence of heart failure over a 20-year period among 5115 blacks and whites of both sexes who were 18 to 30 years of age at baseline. Using Cox models, we examined predictors of hospitalization or death from heart failure. RESULTS: Over the course of 20 years, heart failure developed in 27 participants (mean [+/-SD] age at onset, 39+/-6 years), all but 1 of whom were black. The cumulative incidence of heart failure before the age of 50 years was 1.1% (95% confidence interval [CI], 0.6 to 1.7) in black women, 0.9% (95% CI, 0.5 to 1.4) in black men, 0.08% (95% CI, 0.0 to 0.5) in white women, and 0% (95% CI, 0 to 0.4) in white men (P=0.001 for the comparison of black participants and white participants). Among blacks, independent predictors at 18 to 30 years of age of heart failure occurring 15 years, on average, later included higher diastolic blood pressure (hazard ratio per 10.0 mm Hg, 2.1; 95% CI, 1.4 to 3.1), higher body-mass index (the weight in kilograms divided by the square of the height in meters) (hazard ratio per 5.7 units, 1.4; 95% CI, 1.0 to 1.9), lower high-density lipoprotein cholesterol (hazard ratio per 13.3 mg per deciliter [0.34 mmol per liter], 0.6; 95% CI, 0.4 to 1.0), and kidney disease (hazard ratio, 19.8; 95% CI, 4.5 to 87.2). Three quarters of those in whom heart failure subsequently developed had hypertension by the time they were 40 years of age. Depressed systolic function, as assessed on a study echocardiogram when the participants were 23 to 35 years of age, was independently associated with the development of heart failure 10 years, on average, later (hazard ratio for abnormal systolic function, 36.9; 95% CI, 6.9 to 198.3; hazard ratio for borderline systolic function, 3.5; 95% CI, 1.2 to 10.2). Myocardial infarction, drug use, and alcohol use were not associated with the risk of heart failure. CONCLUSIONS: Incident heart failure before 50 years of age is substantially more common among blacks than among whites. Hypertension, obesity, and systolic dysfunction that are present before a person is 35 years of age are important antecedents that may be targets for the prevention of heart failure. (ClinicalTrials.gov number, NCT00005130.)

Thyroid autoantibodies and thyroid function in subjects exposed to Chernobyl fallout during childhood: evidence for a transient radiation-induced elevation of serum thyroid antibodies without an increase in thyroid autoimmune disease.

CONTEXT: An increase in the prevalence of thyroid autoantibodies (ATAs) was reported 6-8 yr after the Chernobyl accident in radiation-exposed children and adolescents. OBJECTIVE: Our objective was to reassess the effects of childhood radiation exposure on ATAs and thyroid function 13-15 yr after the accident. DESIGN AND SETTING: We measured the antithyroglobulin (TgAbs) and antithyroperoxidase (TPOAbs) antibodies and TSH in 1433 sera collected between 1999 and 2001 from 13- to 17-yr-old adolescents born between January 1982 and October 1986 in paired contaminated and noncontaminated villages of Belarus, Ukraine, and Russia. A total of 1441 sera was collected from age- and sex-matched controls living in Denmark and Sardinia (Italy). Free T(4) and free T(3) were measured when TSH was abnormal. RESULTS: TPOAb prevalence was higher in contaminated than in noncontaminated Belarusian children (6.4 vs. 2.4%; P = 0.02) but lower than previously reported (11%) in a different contaminated Belarus village. No difference in TPOAb prevalence was found in Ukrainian and Russian villages. TgAbs showed no difference between contaminated and noncontaminated Belarus and Ukraine, whereas in Russia they showed a relative increase in the exposed subjects with respect to the unexposed, who showed an unexpectedly lower prevalence of TgAbs. Besides radiation exposure, female gender was the only variable significantly correlated with ATAs in all groups. ATA prevalence in nonexposed villages of Belarus, Ukraine, and Russian Federation did not differ from that found in Sardinia and Denmark. With few exceptions, thyroid function was normal in all study groups. CONCLUSIONS: TPOAb prevalence in adolescents exposed to radioactive fallout was still increased in Belarus 13-15 yr after the Chernobyl accident. This increase was less evident than previously reported and was not accompanied by thyroid dysfunction. Our data suggest that radioactive fallout elicited a transient autoimmune reaction, without triggering full-blown thyroid autoimmune disease. Longer observation periods are needed to exclude later effects.

Rapid decline in lung function in healthy adults predicts incident excess urinary albumin excretion later in life.

INTRODUCTION: Chronic lung disease, often characterised by rapid decline in lung function, is associated with vascular endothelial dysfunction (characterised by moderate to severe excess urinary albumin excretion (eUAE) but their longitudinal relationship is inadequately studied. In a bidirectional longitudinal examination of healthy adults, we analysed the following two hypotheses: (1) rapid decline (ie, highest tertile of lung function decline) predicts eUAE and (2) eUAE predicts rapid decline. METHODS: We performed a secondary data analysis from 3052 eligible participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study. For analysis 1, the predictor was rapid decline in lung function between the peak value (attained at or before CARDIA visit year 10 or Y10 at a mean age of 35 years) and Y20; and the outcome was incident eUAE at Y20 and/or Y25. For analysis 2, the predictor was eUAE at Y10 and the outcome was rapid decline between Y10 and Y20. RESULTS: After adjustment for covariates in analysis 1, rapid decline in FEV1 or FVC between peak and Y20 predicted incident eUAE at Y20 and/or Y25 (OR 1.51 and 1.44, respectively; p≤0.05 for both analyses). In analysis 2, eUAE at Y10 did not predict subsequent rapid decline. CONCLUSIONS: Healthy adults with rapid decline in lung function are at risk for developing vascular endothelial dysfunction, as assessed by incident eUAE, later in life.

Adult-onset asthma becomes the dominant phenotype among women by age 40 years. the longitudinal CARDIA study.

RATIONALE: Although asthma is usually considered to originate in childhood, adult-onset disease is being increasingly reported. OBJECTIVES: To contrast the proportion and natural history of adult-onset versus pediatric-onset asthma in a community-based cohort. We hypothesized that asthma in women is predominantly of adult onset rather than of pediatric onset. METHODS: This study used data from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort in the United States over a 25-year period. Adult- and pediatric-onset asthma phenotypes were studied, as defined by age at onset of 18 years or older. Subjects with asthma were categorized by sex, obesity, atopy, smoking, and race by mean age/examination year, using a three-way analysis of covariance model. Natural history of disease was examined using probabilities derived from a Markov chain model. MEASUREMENTS AND MAIN RESULTS: Asthma of adult onset became the dominant (i.e., exceeded 50%) phenotype in women by age 40 years. The age by which adult-onset asthma became the dominant phenotype was further lowered for obese, nonatopic, ever-smoking, or white women. The prevalence trend with increasing time for adult-onset disease was greater among subjects with nonatopic than atopic asthma among both sexes. Furthermore, adult-onset asthma had remarkable sex-related differences in risk factors. In both sexes, the quiescent state for adult-onset asthma was less frequent and also "less stable" over time than for pediatric-onset asthma. CONCLUSIONS: Using a large national cohort, this study challenges the dictum that most asthma in adults originates in childhood. Studies of the differences between pediatric- and adult-onset asthma may provide greater insight into the phenotypic heterogeneity of asthma.

Lung function in young adults predicts airflow obstruction 20 years later.

OBJECTIVE: The burden of obstructive lung disease is increasing, yet there are limited data on its natural history in young adults. To determine in a prospective cohort of generally healthy young adults the influence of early adult lung function on the presence of airflow obstruction in middle age. METHODS: A longitudinal study was performed of 2496 adults who were 18 to 30 years of age at entry, did not report having asthma, and returned at year 20. Airflow obstruction was defined as an forced expiratory volume in 1 second/forced vital capacity ratio less than the lower limit of normal. RESULTS: Airflow obstruction was present in 6.9% and 7.8% of participants at years 0 and 20, respectively. Less than 10% of participants with airflow obstruction self-reported chronic obstructive pulmonary disease. In cross-sectional analyses, airflow obstruction was associated with less education, smoking, and self-reported chronic obstructive pulmonary disease. Low forced expiratory volume in 1 second, forced expiratory volume in 1 second/forced vital capacity ratio, and airflow obstruction in young adults were associated with low lung function and airflow obstruction 20 years later. Of those with airflow obstruction at year 0, 52% had airflow obstruction 20 years later. The forced expiratory volume in 1 second/forced vital capacity at year 0 was highly predictive of airflow obstruction 20 years later (c-statistic 0.91; 95% confidence interval, 0.89-0.93). The effect of cigarette smoking on lung function decline with age was most evident in young adults with preexisting airflow obstruction. CONCLUSION: Airflow obstruction is mostly unrecognized in young and middle-aged adults. Low forced expiratory volume in 1 second, low forced expiratory volume in 1 second/forced vital capacity ratio, airflow obstruction in young adults, and smoking are highly predictive of low lung function and airflow obstruction in middle age.

Spirometry guidelines influence lung function results in a longitudinal study of young adults.

RATIONALE: End of test criteria can influence spirometry results. Epidemiology studies initiated before adoption of the 1987 American Thoracic Society (ATS) guidelines typically used a 1 or 2 s plateau on the volume-time curve, not a minimum test duration of 6 s, to terminate a test. OBJECTIVES: To determine the effect of changing guidelines on FEV(1), FVC and FEV(1)/FVC during a longitudinal study of young adults. METHODS: Spirometry was performed on participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Values obtained at entry and 2, 5 and 10 years later using accepted procedures were re-evaluated using the 2005 ATS-ERS guidelines, which were in effect for the year 20 exam. Generalized estimating equations were used to adjust tests with short exhalations that were acceptable by then current end of test criteria. RESULTS: The percentage of participants at years 0, 2, 5, and 10 with exhalations less than 6 s but with an acceptable plateau was 33%, 29%, 9%, and 2%, respectively. Exhalations less than 6 s occurred more frequently in younger and female participants, and were associated with lower FVC and higher FEV(1)/FVC. For short exhalations the adjusted FVC was 47 ml and 110 ml higher than the measured FVC when 6 and 8 s exhalation times were used. CONCLUSIONS: In longitudinal studies of young adults, changing end of test criteria may affect lung function, especially among younger and female participants. Determining adjusted values for tests with short exhalations may better represent the lung health of participants.

Obesity-asthma association: is it explained by systemic oxidant stress?

BACKGROUND: The mechanism for the obesity-asthma association is unknown. This study evaluated the hypothesis that systemic oxidant stress explains this association. METHODS: This cross-sectional study used year-20 follow-up evaluation data of 2,865 eligible participants in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Current asthma was self-reported. Oxidant stress primarily was assessed by plasma F2-isoprostane concentrations. Obesity measures included categories of BMI and dual-energy x-ray absorptiometry-assessed fat mass index (FMI) and lean mass index (LMI). Logistic and linear regressions were used for analyses. RESULTS: Asthma was associated with higher plasma F2-isoprostane concentrations (p = 0.049); however, this association was not significant when adjusted for either gender or BMI. The BMI-asthma association was seen only among women (p = 0.03; gender-specific interaction, p = 0.01), and this association was not explained by plasma F2-isoprostane levels. Similarly, both FMI and LMI were positively associated with asthma in women (p = 0.20 and 0.01, respectively). These associations also were not explained by plasma F2-isoprostane levels. Similar results were obtained when plasma levels of oxidized low-density lipoprotein were used instead of F2-isoprostane levels to study the BMI-asthma association at the year-15 evaluation. CONCLUSIONS: Systemic oxidant stress, primarily assessed by plasma F2-isoprostane concentrations, was not independently associated with asthma and, therefore, may not explain the obesity-asthma association in women. The asthma-oxidant stress association is confounded by gender and obesity. This study is limited by the inability to measure airway oxidant stress. It is possible that another (as yet undetermined) measure of systemic oxidant stress may be more relevant in asthma.