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BACKGROUND: Reduced 25-hydroxyvitamin D (25[OH]D) metabolism and secondary hyperparathyroidism are common with lower estimated glomerular filtration rate (eGFR) and may contribute to cardiovascular disease and cancer risk. METHODS: We assessed for heterogeneity by baseline eGFR of the effects of vitamin D(3) on cardiovascular and cancer outcomes in the Vitamin D and Omega-3 Trial (VITAL). Participants were randomized to 2000 IU vitamin D(3) and/or 1 g Ω-3 fatty acids daily using a placebo-controlled, two-by-two factorial design (5.3 years follow-up). Primary study end points were incident major cardiovascular events and invasive cancer. Changes in serum 25(OH)D and parathyroid hormone (PTH) were examined. RESULTS: Baseline eGFR was available for 15,917 participants. Participants’ mean age was 68 years, and 51% were women. Vitamin D(3) resulted in higher serum 25(OH)D compared with placebo (difference in change 12.5 ng/ml; 95% CI, 12 to 13.1 ng/ml), without heterogeneity by eGFR (P interaction, continuous eGFR=0.2). Difference in change in PTH between vitamin D(3) and placebo was larger with lower eGFR (P interaction=0.05): –6.9 (95% CI, –10.5 to –3.4), –5.8 (95% CI, –8.3 to –3.4), –4 (95% CI, –5.9 to –2.2), and –3.8 (95% CI, –5.6 to –2) pg/ml for eGFR

In the United States, Black and Hispanic children have higher rates of asthma and asthma-related morbidity compared with White children and disproportionately reside in communities with economic deprivation.To determine the extent to which neighborhood-level socioeconomic indicators explain racial and ethnic disparities in childhood wheezing and asthma.The study population comprised children in birth cohorts located throughout the United States that are part of the Children's Respiratory and Environmental Workgroup consortium. Cox proportional hazard models were used to estimate hazard ratios (HRs) of asthma incidence, and logistic regression was used to estimate odds ratios of early and persistent wheeze prevalence accounting for mother's education, parental asthma, smoking during pregnancy, child's race and ethnicity, sex, and region and decade of birth.Neighborhood-level socioeconomic indicators defined by US census tracts calculated as z scores for multiple tract-level variables relative to the US average linked to participants' birth record address and decade of birth. The parent or caregiver reported the child's race and ethnicity.Prevalence of early and persistent childhood wheeze and asthma incidence.Of 5809 children, 46% reported wheezing before age 2 years, and 26% reported persistent wheeze through age 11 years. Asthma prevalence by age 11 years varied by cohort, with an overall median prevalence of 25%. Black children (HR, 1.47; 95% CI, 1.26-1.73) and Hispanic children (HR, 1.29; 95% CI, 1.09-1.53) were at significantly increased risk for asthma incidence compared with White children, with onset occurring earlier in childhood. Children born in tracts with a greater proportion of low-income households, population density, and poverty had increased asthma incidence. Results for early and persistent wheeze were similar. In effect modification analysis, census variables did not significantly modify the association between race and ethnicity and risk for asthma incidence; Black and Hispanic children remained at higher risk for asthma compared with White children across census tracts socioeconomic levels.Adjusting for individual-level characteristics, we observed neighborhood socioeconomic disparities in childhood wheeze and asthma. Black and Hispanic children had more asthma in neighborhoods of all income levels. Neighborhood- and individual-level characteristics and their root causes should be considered as sources of respiratory health inequities.

Aims Cardiac arrhythmias have been associated with intense solar and geomagnetic activity (SGA) and exposures to air pollution. Methods and results We examined whether oscillations of SGA can modify the effect of hourly exposures to air pollutants on atrial fibrillation ≥30 s (AF) risk in patients with dual-chamber implantable cardioverter-defibrillators. The effects of SGA on ambient particulate matter 50th percentile in IMF, SW, and Kp index) enhanced the effects of all three air pollutants on AF, while during periods of reduced SGA the associations were considerably weaker or absent. During periods of intense SW 6 h prior to an AF event, the odds ratio (OR) for PM2.5 exposure per interquartile range (IQR) of 5.6 µg/m3 was 1.7 [95% confident interval (CI) 1.3–2.3, P = 0.0001]. For periods of reduced SW, the OR for PM2.5 exposure per IQR was 1.2 (95% CI 0.9–1.5; P = 0.27). There were similar effects for PN and BC exposures. In patients with multiple AF events per hour, the associations with air pollutants during intense SGA were even greater. Conclusion The effects of air pollutants up to 24 h before AF events were enhanced during periods of increased SGA. Our results suggest that these effects may account for variation in AF risk.

Background: To clarify the mechanisms underlying physical activity (PA)-related cardioprotection, we examined the association of PA with plasma bioactive lipids (BALs) and cardiovascular disease (CVD) events. We additionally performed genome-wide associations. Methods: PA-bioactive lipid associations were examined in VITAL (VITamin D and OmegA-3 TriaL)-clinical translational science center (REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01169259; N=1032) and validated in JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)-NC (REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00239681; N=589), using linear models adjusted for age, sex, race, low-density lipoprotein-cholesterol, total-C, and smoking. Significant BALs were carried over to examine associations with incident CVD in 2 nested CVD case-control studies: VITAL-CVD (741 case-control pairs) and JUPITER-CVD (415 case-control pairs; validation). Results: We detected 145 PA-bioactive lipid validated associations (false discovery rate Conclusions: We identified a PA-related bioactive lipidome profile out of which 12 BALs also had opposite associations with incident CVD events.

Background: Individuals are exposed to air pollution and ionizing radiation from natural sources through inhalation of particles. This study investigates the association between cardiac arrhythmias and short-term exposures to fine particulate matter (particulate matter ≤2.5 µm aerodynamic diameter; PM 2.5 ) and particle radioactivity. Methods: Ventricular arrhythmic events were identified among 176 patients with dual-chamber implanted cardioverter-defibrillators in Boston, Massachusetts between September 2006 and June 2010. Patients were assigned exposures based on residential addresses. Daily PM 2.5 levels were estimated at 1-km×1-km grid cells from a previously validated prediction model. Particle gross β activity was used as a surrogate for particle radioactivity and was measured from several monitoring sites by the US Environmental Protection Agency’s monitoring network. The association of the onset of ventricular arrhythmias (VA) with 0- to 21-day moving averages of PM 2.5 and particle radioactivity (2 single-pollutant models and a 2-pollutant model) before the event was examined using time-stratified case-crossover analyses, adjusted for dew point and air temperatures. Results: A total of 1,050 VA were recorded among 91 patients, including 123 sustained VA among 25 of these patients. In the single-pollutant model of PM 2.5 , each interquartile range increase in daily PM 2.5 levels for a 21-day moving average was associated with 39% higher odds of a VA event (95% CI, 12%–72%). In the single-pollutant model of particle radioactivity, each interquartile range increase in particle radioactivity for a 2-day moving average was associated with 13% higher odds of a VA event (95% CI, 1%–26%). In the 2-pollutant model, for the same averaging window of 21 days, each interquartile range increase in daily PM 2.5 was associated with an 48% higher odds of a VA event (95% CI, 15%–90%), and each interquartile range increase of particle radioactivity with a 10% lower odds of a VA event (95% CI, –29% to 14%). We found that with higher levels of particle radioactivity, the effect of PM 2.5 on VAs is reduced. Conclusions: In this high-risk population, intermediate (21-day) PM 2.5 exposure was associated with higher odds of a VA event onset among patients with known cardiac disease and indication for implanted cardioverter-defibrillator implantation independently of particle radioactivity.

BACKGROUND: Elevated postprandial triglycerides reflect a pro-atherogenic milieu, but underlying mechanisms are unclear. OBJECTIVE: We examined differences between fasting and nonfasting profiles of directly measured lipoprotein size and subfractions to assess if postprandial triglycerides reflected increases in very low density and intermediate density lipoproteins (VLDL and IDL) and remnants, or small dense lipid depleted LDL particles (sdLDL). METHODS: We conducted a cross-sectional analysis of 15,397 participants (10,135 fasting; 5262 nonfasting [0.05). CONCLUSIONS: Directly measured particle and cholesterol concentrations of VLDL, not sdLDL, were higher nonfasting and may partly contribute to the pro-atherogenicity of postprandial hypertriglyceridemia. These differences, although statistically significant, were small and may not fully explain the increased risk of postprandial hypertriglyceridemia. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov Unique identifier: NCT01169259.

ImportanceIn the Vitamin D and Omega-3 Trial (VITAL), the effects of randomized vitamin D supplementation (cholecalciferol), 2000 IU/d, reduced the risk of several health outcomes among participants with normal, but not elevated, body weights. It was unclear whether weight had any association with the outcomes of the supplementation.ObjectiveTo investigate whether baseline body mass index (BMI) modifies vitamin D metabolism and response to supplementation.Design, Setting, and ParticipantsVITAL is a completed randomized, double-blind, placebo-controlled trial for the primary prevention of cancer and cardiovascular disease. In the present cohort study, an analysis was conducted in a subset of VITAL participants who provided a blood sample at baseline and a subset with a repeated sample at 2 years’ follow-up. VITAL was conducted from July 1, 2010, to November 10, 2018; data analysis for the present study was conducted from August 1, 2021, to November 9, 2021.InterventionsTreatment outcomes of vitamin D, 2000 IU/d, supplementation vs placebo associated with clinical and novel vitamin D–related biomarkers by BMI category adjusted for other factors associated with vitamin D status.Main Outcomes and MeasuresMultivariable-adjusted means (SE) or 95% CIs of vitamin D–related serum biomarkers at baseline and follow-up: total 25-hydroxyvitamin D (25-OHD), 25-OHD3, free vitamin D (FVD), bioavailable vitamin D (BioD), vitamin D–binding protein (VDBP), albumin, parathyroid hormone (PTH), and calcium, and log-transformed as needed.ResultsA total of 16 515 participants (mean [SD] age, 67.7 [7.0] years; 8371 women [50.7%]; 12420 non-Hispanic White [76.9%]) were analyzed at baseline, including 2742 with a follow-up blood sample. Before randomization, serum total 25-OHD levels were incrementally lower at higher BMI categories (adjusted mean [SE]: underweight, 32.3 [0.7] ng/mL; normal weight, 32.3 [0.1] ng/mL; overweight, 30.5 [0.1] ng/mL; obesity class I, 29.0 [0.2] ng/mL; and obesity class II, 28.0 [0.2] ng/mL; P P P Conclusions and RelevanceIn this randomized cohort study, vitamin D supplementation increased serum vitamin D–related biomarkers, with a blunted response observed for participants with overweight or obesity at baseline. These longitudinal findings suggest that BMI may be associated with modified response to vitamin D supplementation and may in part explain the observed diminished outcomes of supplementation for various health outcomes among individuals with higher BMI.

The primary aim was to evaluate whether prevalent type 2 diabetes (T2D) modifies the effects of omega-3 supplementation on heart failure (HF) hospitalization. The secondary aim was to examine if race modifies the effects of omega-3 supplements on HF risk.It is unclear whether race and T2D modify the effects of omega-3 supplementation on the incidence of HF.In this ancillary study of the parent VITAL (Vitamin D and Omega-3 Trial)-a completed randomized trial testing the efficacy of vitamin D and omega-3 fatty acids on cardiovascular diseases and cancer, we assessed the role of T2D and race on the effects of omega-3 supplements on the incidence of HF hospitalization (adjudicated by a review of medical records and supplemented with a query of Centers for Medicare and Medicaid Services data).When omega-3 supplements were compared with placebo, the HR for first HF hospitalization was 0.69 (95% CI: 0.50-0.95) in participants with prevalent T2D and 1.09 (95% CI: 0.88-1.34) in those without T2D (P for interaction = 0.019). Furthermore, prevalent T2D modified the effects of omega-3 fatty acids on the incidence of recurrent HF hospitalization (HR: 0.53; 95% CI: 0.41-0.69 in participants with prevalent T2D vs HR: 1.07; 95% CI: 0.89-1.28 in those without T2D; P interaction 0.0001). In our secondary analysis, omega-3 supplementation reduced recurrent HF hospitalization only in Black participants (P interaction race × omega-3 = 0.0497).Our data show beneficial effects of omega-3 fatty acid supplements on incidence of HF hospitalization in participants with T2D but not in those without T2D, and such benefit appeared to be stronger in Black participants with T2D. (Intervention With Vitamin D and Omega-3 Supplements and Incident Heart Failure; NCT02271230; Vitamin D and Omega-3 Trial [VITAL]; NCT01169259 [parent study]).

Context The effect of daily vitamin D supplementation on the serum concentration of vitamin D (the parent compound) may offer insight into vitamin D disposition. Objective To assess the total serum vitamin D response to vitamin D3 supplementation and whether it varies according to participant characteristics. To compare results with corresponding results for total serum 25-hydroxyvitamin D [25(OH)D], which is used clinically and measured in supplementation trials. Design Exploratory study within a randomized trial. Intervention 2000 International Units of vitamin D3 per day (or matching placebo). Setting Community-based. Participants 161 adults (mean ± SD age 70 ± 6 years; 66% males) with type 2 diabetes. Main Outcome Measures Changes in total serum vitamin D and total serum 25(OH)D concentrations from baseline to year 2. Results At baseline, there was a positive, nonlinear relation between total serum vitamin D and total serum 25(OH)D concentrations. Adjusted effects of supplementation were a 29.2 (95% CI: 24.3, 34.1) nmol/L increase in serum vitamin D and a 33.4 (95% CI: 27.7, 39.2) nmol/L increase in serum 25(OH)D. Among those with baseline 25(OH)D < 50 compared with ≥ 50 nmol/L, the serum vitamin D response to supplementation was attenuated (15.7 vs 31.2 nmol/L; interaction P-value = 0.02), whereas the serum 25(OH)D response was augmented (47.9 vs 30.7 nmol/L; interaction P-value = 0.05). Conclusions Vitamin D3 supplementation increases total serum vitamin D and 25(OH)D concentrations with variation according to baseline 25(OH)D, which suggests that 25-hydroxylation of vitamin D3 is more efficient when serum 25(OH)D concentration is low.

Background Both elemental metals and particulate air pollution have been reported to influence adult blood pressure (BP). The aim of this study is to examine which elemental components of particle mass with diameter ≤2.5 μm (PM 2.5 ) are responsible for previously reported associations between PM 2.5 and neonatal BP. Methods and Results We studied 1131 mother‐infant pairs in Project Viva, a Boston‐area prebirth cohort. We measured systolic BP (SBP) and diastolic BP (DBP) at a mean age of 30 hours. We calculated average exposures during the 2 to 7 days before birth for the PM 2.5 components—aluminum, arsenic, bromine, sulfur, copper, iron, zinc, nickel, vanadium, titanium, magnesium, potassium, silicon, sodium, chlorine, calcium, and lead—measured at the Harvard supersite. Adjusting for covariates and PM 2.5 , we applied regression models to examine associations between PM 2.5 components and median SBP and DBP, and used variable selection methods to select which components were more strongly associated with each BP outcome. We found consistent results with higher nickel associated with significantly higher SBP and DBP, and higher zinc associated with lower SBP and DBP. For an interquartile range increase in the log Z score (1.4) of nickel, we found a 1.78 mm Hg (95% CI, 0.72–2.84) increase in SBP and a 1.30 (95% CI, 0.54–2.06) increase in DBP. Increased zinc (interquartile range log Z score 1.2) was associated with decreased SBP (−1.29 mm Hg; 95% CI, −2.09 to −0.50) and DBP (−0.85 mm Hg; 95% CI: −1.42 to −0.29). Conclusions Our findings suggest that prenatal exposures to particulate matter components, and particularly nickel, may increase newborn BP.

PMWe aimed to study associations of fine particulate matter PMWe conducted nasal epigenome-wide association analyses within 503 children from Project Viva (mean age 12.9 y), and examined various exposure durations (1-day, 1-week, 1-month, 3-months and 1-year) prior to nasal sampling. We used residential addresses to estimate average daily PMIn adjusted analyses, we found 362 CpGs associated with 1-year PMWe observed wide-spread DNAm variability associated with average past year PM

Omega-3 (n-3) treatment may lower cardiovascular risk, yet its effects on the circulating lipidome and relation to cardiovascular risk biomarkers are unclear. We hypothesized that n-3 treatment is associated with favorable changes in downstream fatty acids (FAs), oxylipins, bioactive lipids, clinical lipid and inflammatory biomarkers. We examined these VITAL200, a nested substudy of 200 subjects balanced on demographics and treatment and randomly selected from the Vitamin D and Omega-3 Trial (VITAL). VITAL is a randomized double-blind trial of 840 mg/d eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) vs. placebo among 25,871 individuals. Small polar bioactive lipid features, oxylipins and FAs from plasma and red blood cells were measured using three independent assaying techniques at baseline and one year. The Women&rsquo, s Health Study (WHS) was used for replication with dietary n-3 intake. Randomized n-3 treatment led to changes in 143 FAs, oxylipins and bioactive lipids (False Discovery Rate (FDR) &lt, 0.05 in VITAL200, validated (p-values &lt, 0.05)) in WHS with increases in 95 including EPA, DHA, n-3 docosapentaenoic acid (DPA-n3), and decreases in 48 including DPA-n6, dihomo gamma linolenic (DGLA), adrenic and arachidonic acids. N-3 related changes in the bioactive lipidome were heterogeneously associated with changes in clinical lipid and inflammatory biomarkers. N-3 treatment significantly modulates the bioactive lipidome, which may contribute to its clinical benefits.

Background: Perfluoroalkyl substances (PFASs) are synthetic chemicals that may persist in the environment and in humans. There is a possible association between early-life PFAS exposure and metabolic dysfunction in later life, but data are limited. Methods: We studied 665 mother–child pairs in Project Viva, a Boston, Massachusetts-area cohort recruited 1999–2002. We quantified concentrations of PFASs [perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), perfluorohexane sulfonate (PFHxS), and perfluorodecanoate (PFDeA)] in maternal plasma collected at the first prenatal visit (median, 9.6 weeks gestation) and in child plasma from the mid-childhood research visit (median, 7.7 years). We assessed leptin, adiponectin, and homeostatic model assessment of insulin resistance (HOMA-IR) in mid-childhood. We fit covariate-adjusted linear regression models and conducted stratified analyses by child sex. Results: Children with higher PFAS concentrations had lower HOMA-IR [e.g., –10.1% (95% CI: –17.3, –2.3) per interquartile range increment in PFOA]. This inverse association between child PFAS and HOMA-IR was more pronounced in females [e.g., PFOA: –15.6% (95% CI: –25.4, –4.6) vs. –6.1% (95% CI: –16.2, 5.2) for males]. Child PFAS plasma concentrations were not associated with leptin or adiponectin. Prenatal PFAS plasma concentrations were not associated with leptin, adiponectin, or HOMA-IR in offspring. Conclusions: We found no evidence for an adverse effect of early-life PFAS exposure on metabolic function in mid-childhood. In fact, children with higher PFAS concentrations had lower insulin resistance. Antecedentes: las sustancias perfluoroalquilo (PFAS) son sustancias químicas sintéticas que pueden persistir en el medio ambiente y en los seres humanos. Existe una posible asociación entre la exposición temprana al PFAS y la disfunción metabólica en la edad adulta, pero los datos son limitados. Métodos: Estudiamos 665 parejas de madre e hijo en el Proyecto Viva, una cohorte del área de Boston, Massachusetts, reclutada en 1999-2002. Se cuantificaron las concentraciones de PFAS [perfluorooctanoato (PFOA), sulfonato de perfluorooctano (PFOS), perfluorononanoato (PFNA), sulfonato de perfluorohexano (PFHxS) y perfluorodecanoato (PFDeA)] en el plasma materno recolectado en la primera visita prenatal (mediana de 9,6 semanas), y en el plasma infantil de la visita de investigación de la niñez media (mediana, 7,7 años). Evaluamos la leptina, la adiponectina y la evaluación del modelo homeostático de la resistencia a la insulina (HOMA-IR) en la infancia media. Ajustamos modelos de regresión lineal ajustados por covariables y realizamos análisis estratificados por sexo del niño. Resultados: Los niños con concentraciones más altas de PFAS tenían HOMA-IR más bajo [por ejemplo, –10,1% (IC del 95%: –17,3, –2,3) por incremento de rango intercuartílico en PFOA]. Esta asociación inversa entre PFAS infantil y HOMA-IR fue más pronunciada en las mujeres [p. Ej., PFOA: –15,6% (IC del 95%: –25,4, –4,6) frente a –6,1% (IC del 95%: –16,2, 5,2) para machos]. Las concentraciones plasmáticas de PFAS en niños no se asociaron con leptina o adiponectina. Las concentraciones plasmáticas prenatales de PFAS no se asociaron con leptina, adiponectina o HOMA-IR en la descendencia. Conclusiones: No encontramos evidencia de un efecto adverso de la exposición temprana al PFAS sobre la función metabólica en la niñez media. De hecho, los niños con concentraciones más altas de PFAS tenían menor resistencia a la insulina. Antecedentes: As substâncias perfluoroalquílicas (PFASs) são produtos químicos sintéticos que podem persistir no meio ambiente e nos seres humanos. Há uma possível associação entre a exposição precoce ao PFAS e disfunção metabólica na vida adulta, mas os dados são limitados. Métodos: Estudamos 665 pares de mãe e filho no Projeto Viva, uma coorte da área de Boston, Massachusetts, recrutada em 1999–2002. Quantificamos as concentrações de PFASs [perfluorooctanoato (PFOA), perfluorooctano sulfonato (PFOS), perfluorononanoato (PFNA), sulfonato de perfluorohexano (PFHxS) e perfluorodecanoato (PFDeA)] no plasma materno coletado na primeira visita pré-natal (mediana). e no plasma infantil da visita de pesquisa do meio da infância (mediana, 7,7 anos). Avaliamos a leptina, a adiponectina e a avaliação do modelo homeostático de resistência à insulina (HOMA-IR) no meio da infância. Ajustamos modelos de regressão linear ajustados por covariável e conduzimos análises estratificadas por sexo da criança. Resultados: Crianças com concentrações mais altas de PFAS tiveram menor HOMA-IR [por exemplo, –10,1% (IC 95%: –17,3, –2,3) por incremento do intervalo interquartil no PFOA]. Esta associação inversa entre crianças PFAS e HOMA-IR foi mais pronunciada em mulheres [por exemplo, PFOA: –15,6% (IC 95%: –25,4, –4,6) vs. –6,1% (IC 95%: –16,2, 5,2) para machos]. As concentrações plasmáticas de crianças PFAS não foram associadas à leptina ou adiponectina. As concentrações plasmáticas de PFAS pré-natal não foram associadas à leptina, adiponectina ou HOMA-IR na prole. Conclusões: Não encontramos evidências de um efeito adverso da exposição precoce ao PFAS sobre a função metabólica na metade da infância. Na verdade, crianças com concentrações mais altas de PFAS apresentaram menor resistência à insulina. Boston Children’s Hospital, United States Harvard Medical School, United States Harvard Pilgrim Health Care Institute, United States Boston University School of Public Health, United States Universidad Nacional, Costa Rica National Center for Environmental Health, United States Harvard School of Public Health, United States University of California, United States Instituto Regional de Estudios en Sustancias Tóxicas

Background: Increasing empirical evidence suggests that exposure to nature (natural vegetation, or “greenness”) influences health. Studies have shown that greenness is related to lower diabetes risk possibly through mediation of physical activity, harmful environmental exposures, or mental health. However, to our knowledge, no previous study has reported on associations between greenness and insulin resistance in children. We hypothesize that children are more sensitive to environmental exposures particularly during critical windows of susceptibility. Our research aims to evaluate the early life association between greenness and insulin resistance and assess vulnerable life-periods in which individuals are more susceptible to their surroundings. Methods: We use data from Project Viva, a longitudinal cohort study designed to study prenatal factors, pregnancy outcomes, and child health. From 1999 to 2002, we recruited pregnant women from a multispecialty group practice in Massachusetts. Of the 1,036 who attended the early teen research visit, we considered 460 participants who provided fasting blood and had complete data for all covariates and exposure at infancy (less than one year), early childhood (median age 3.3 years), mid-childhood (median age 7.7 years) and early teens (median age 13.2). We defined greenness exposure surrounding each participant’s address using 30m resolution Landsat satellite imagery [Normalized Difference Vegetation Index] at infancy (under one year of age), early childhood, mid-childhood, and early teens. Our main outcome measurement was the homeostatic model assessment to estimate insulin resistance (HOMA-IR) at the early teen visit. Results: In models adjusted for age, race, sex, mother’s education, father’s education, household income and median household income from the census tract at delivery, living in the highest quintile of greenness in the 90-m area at the early teen visit was associated with 0.65 lower HOMA-IR (95%CI: -1.52, -0.40) than those in the lowest quintile. The observed association between higher greenness exposure and lower HOMA-IR in early teens was consistent for the 270-m area, although slightly attenuated, and no longer significant for the 1230-m area (mean HOMA-IR was 3.06, SD=2.08). We found no associations of exposure to greenness in the 90-m, 270-m or 1230-m areas around participants’ home at infancy, early childhood, or mid-childhood with early teenage HOMA-IR. Conclusions: Higher levels of green vegetation, especially closer to the home, at the early teen visit were associated with lower insulin resistance at the same time period. Early exposure to green space during infancy, early childhood and mid-childhood was not associated with HOMA-IR as an early teenager. Early childhood longitudinal studies including geographic contextual factors across diverse populations are needed to confirm or refute these findings.

Few studies have examined associations between exposure to air pollution and childhood lung function after implementation of strict air quality regulations in the 1990s.To assess traffic-related pollution exposure and childhood lung function.We geocoded addresses for 614 mother-child pairs enrolled during pregnancy in the Boston area 1999-2002 and followed them until a mid-childhood visit (median age, 7.7). We calculated the proximity of the home to the nearest major roadway. We estimated first year of life, lifetime, and prior-year exposure to particulate matter with a diameter smaller than 2.5 μm (PM2.5) by a hybrid model using satellite-derived aerosol optical depth, and to black carbon (BC) by a land-use regression model.Residential proximity to roadway and prior-year and lifetime PM2.5 and BC exposure were all associated with lower FVC. Associations with FEV1 were also negative and proportionally similar. Pollution exposures were not associated with the FEV1/FVC ratio or bronchodilator response. Compared with distances greater than or equal to 400 m, living less than 100 m from a major roadway was associated with lower FVC (-98.6 ml; -176.3 to -21.0). Each 2 μg/m(3) increment in prior-year PM2.5 was associated with lower FVC (-21.8 ml; -43.9 to 0.2) and higher odds of FEV1 less than 80% predicted (1.41; 1.03-1.93). Each 0.2 μg/m(3) increment in prior-year BC was associated with a 38.9 ml (-70.4 to -7.3) lower FVC.Estimates of long-term exposure to ambient pollution, including proximity to major roadway, PM2.5, and BC (a traffic-related PM2.5 constituent), were associated with lower lung function in this Boston-area cohort of children with relatively low pollution exposures.

Laboratory and observational research studies suggest that vitamin D and marine omega-3 fatty acids may reduce risk for pneumonia, acute exacerbations of respiratory diseases including chronic obstructive lung disease (COPD) or asthma, and decline of lung function, but prevention trials with adequate dosing, adequate power, and adequate time to follow-up are lacking. The ongoing Lung VITAL study is taking advantage of a large clinical trial-the VITamin D and OmegA-3 TriaL (VITAL)--to conduct the first major evaluation of the influences of vitamin D and marine omega-3 fatty acid supplementation on pneumonia risk, respiratory exacerbation episodes, asthma control and lung function in adults. VITAL is a 5-year U.S.-wide randomized, double-blind, placebo-controlled, 2 × 2 factorial trial of supplementation with vitamin D3 ([cholecalciferol], 2000 IU/day) and marine omega-3 FA (Omacor® fish oil, eicosapentaenoic acid [EPA]+docosahexaenoic acid [DHA], 1g/day) for primary prevention of CVD and cancer among men and women, at baseline aged ≥50 and ≥55, respectively, with 5107 African Americans. In a subset of 1973 participants from 11 urban U.S. centers, lung function is measured before and two years after randomization. Yearly follow-up questionnaires assess incident pneumonia in the entire randomized population, and exacerbations of respiratory disease, asthma control and dyspnea in a subpopulation of 4314 randomized participants enriched, as shown in presentation of baseline characteristics, for respiratory disease, respiratory symptoms, and history of cigarette smoking. Self-reported pneumonia hospitalization will be confirmed by medical record review, and exacerbations will be confirmed by Center for Medicare and Medicaid Services data review.

SummaryBackground Prenatal exposure to traffic pollution has been associated with faster infant weight gain, but implications for cardiometabolic health in later childhood are unknown. Methods Among 1418 children in Project Viva, a Boston-area pre-birth cohort, we assessed anthropometric and biochemical parameters of cardiometabolic health in early (median age 3.3 years) and mid- (median age 7.7 years) childhood. We used spatiotemporal models to estimate prenatal and early life residential PM2.5 and black carbon exposure as well as traffic density and roadway proximity. We performed linear regression analyses adjusted for sociodemographics. Results Children whose mothers lived close to a major roadway at the time of delivery had higher markers of adverse cardiometabolic risk in early and mid-childhood. For example, total fat mass was 2.1 kg (95%CI: 0.8, 3.5) higher in mid-childhood for children of mothers who lived

IntroductionCurrent evidence indicates that older racial/ethnic minorities encounter disparities in depression care. Because late-life depression is common and confers major adverse health consequences, it is imperative to reduce disparities in depression care. Thus, the primary objectives of this protocol are to: (1) quantify racial/ethnic disparities in depression treatment and (2) identify and quantify the magnitude of these disparities accountable for by a multifactorial combination of patient, provider and healthcare system factors.Methods and analysisData will be derived from the Vitamin D and Omega-3 Trial-Depression Endpoint Prevention (VITAL-DEP) study, a late-life depression prevention ancillary study to the VITAL trial. A total of 25 871 men and women, aged 50+ and 55+ years, respectively, were randomised in a 2×2 factorial randomised trial of heart disease and cancer prevention to receive vitamin D and/or fish oil for 5 years starting from 2011. Most participants were aged 65+ years old at randomisation. Medicare claims data for over 19 000 VITAL/VITAL-DEP participants were linked to conduct our study.The major study outcomes are depression treatment (antidepressant use and/or receipt of psychotherapy services) and adherence to medication treatment (antidepressant adherence and acceptability). The National Academy of Medicine framework for studying racial disparities was leveraged to select patient-level, provider-level and healthcare system-level variables and to address their potential roles in depression care disparities. Blinder-Oaxaca regression decomposition methods will be implemented to quantify and identify correlates of racial/ethnic disparities in depression treatment and adherence.Ethics and disseminationThis study received Institutional Review Board (IRB) approval from the Partners Healthcare (PHS) IRB, protocol# 2010P001881. We plan to disseminate our results through publication of manuscripts patient engagement activities, such as study newsletters regularly sent out to VITAL participants, and presentations at scientific meetings.Trial registration numberNCT01696435.

Background: Extreme weather and air pollution are associated with increased cardiovascular risk in people with diabetes. Objectives: In a population with diabetes, we conducted a novel assessment of vascular brachial artery responses both to ambient pollution and to weather (temperature and water vapor pressure, a measure of humidity). Methods: Sixty-four 49- to 85-year-old Boston residents with type 2 diabetes completed up to five study visits (279 repeated measures). Brachial artery diameter (BAD) was measured by ultrasound before and after brachial artery occlusion [i.e., flow-mediated dilation (FMD)] and before and after nitroglycerin-mediated dilation (NMD). Ambient concentrations of fine particulate mass (PM2.5), black carbon (BC), organic carbon (OC), elemental carbon, particle number, and sulfate were measured at our monitoring site; ambient concentrations of carbon monoxide, nitrogen dioxide, and ozone were obtained from state monitors. Particle exposure in the home and during each trip to the clinic (home/trip exposure) was measured continuously and as a 5-day integrated sample. We used linear models with fixed effects for participants, adjusting for date, season, temperature, and water vapor pressure on the day of each visit, to estimate associations between our outcomes and interquartile range increases in exposure. Results: Baseline BAD was negatively associated with particle pollution, including home/trip–integrated BC (–0.02 mm; 95% CI: –0.04, –0.003, for a 0.28 μg/m3 increase in BC), OC (–0.08 mm; 95% CI: –0.14, –0.03, for a 1.61 μg/m3 increase) as well as PM2.5, 5-day average ambient PM2.5, and BC. BAD was positively associated with ambient temperature and water vapor pressure. However, exposures were not consistently associated with FMD or NMD. Conclusion: Brachial artery diameter, a predictor of cardiovascular risk, decreased in association with particle pollution and increased in association with ambient temperature in our study population of adults with type 2 diabetes. Citation: Zanobetti A, Luttmann-Gibson H, Horton ES, Cohen A, Coull BA, Hoffmann B, Schwartz JD, Mittleman MA, Li Y, Stone PH, de Souza C, Lamparello B, Koutrakis P, Gold DR. 2014. Brachial artery responses to ambient pollution, temperature, and humidity in people with type 2 diabetes: a repeated-measures study. Environ Health Perspect 122:242–248; http://dx.doi.org/10.1289/ehp.1206136

BACKGROUND The VITamin D and OmegA-3 TriaL (VITAL) is a completed randomized, placebo-controlled trial of vitamin D3 (2000 IU/day) and marine omega-3 (1 g/day) supplements in the primary prevention of cancer and cardiovascular disease. Here we examine baseline and change in 25-hydroxyvitamin D (25(OH)D) and related biomarkers with randomized treatment and by clinical factors. METHODS Baseline 25(OH)D was measured in 15,804 participants (mean age 68 years.; 50.8% women; 15.7% African Americans) and in 1660 1-year follow-up samples using liquid chromatography-tandem mass spectrometry and chemiluminescence. Calcium and parathyroid hormone (iPTH) were measured by chemiluminescence and spectrophotometry respectively. RESULTS Mean baseline total 25(OH)D (ng/mL ± SD) was 30.8 ± 10.0 ng/mL, and correlated inversely with iPTH (r = -0.28), p

Outdoor ambient weather has been hypothesized to be responsible for the seasonal distribution of cardiac arrhythmias. Because people spend most of their time indoors, we hypothesized that weather-related arrhythmia risk would be better estimated using an indoor measure or an outdoor measure that correlates well with indoor conditions, such as absolute humidity. The clinical records of 203 patients in eastern Massachusetts, USA, with an implantable cardioverter-defibrillator were abstracted for arrhythmias between 1995 and 2002. We used case-crossover methods to examine the association between weather and ventricular arrhythmia (VA). Among 84 patients who experienced 787 VAs, lower estimated indoor temperature (odds ratio (OR) = 1.16, 95% confidence interval (CI) 1.05–1.27 for a 1 °C decrease in the 24-h average) and lower absolute humidity (OR = 1.06, 95% CI 1.03–1.08 for a 0.5 g/m3 decrease in the 96-h average) were associated with increased risk. Lower outdoor temperature increased risk only in warmer months, likely attributable to the poor correlation between outdoor and indoor temperature during cooler months. These results suggest that lower temperature and drier air are associated with increased risk of VA onset among implantable cardioverter-defibrillator patients.

Introduction: People with diabetes are susceptible to increased cardiovascular morbidity and mortality with increases in ambient particle mass. Questions remain regarding the specific particle mass...

Introduction: Per- and polyfluoroalkyl substances (PFASs) are synthetic stain and grease repellents that may persist in the environment and in humans. Data on metabolic effects among children expos...

Introduction: Air pollution exposure has been associated with increased blood pressure (BP) in adults. Previously, we found that higher exposures to particle mass (PM2.5) and black carbon in the th...

In a population with type 2 diabetes mellitus (T2DM), we examined the associations of short-term air pollutant exposures with pulmonary inflammation, measured as fraction of exhaled pulmonary nitric oxide (FeNO). Sixty-nine Boston Metropolitan residents with T2DM completed up to five biweekly visits with 321 offline FeNO measurements. We measured ambient concentrations of particle mass, number, and components at our stationary central site. Ambient concentrations of gaseous air pollutants were obtained from state monitors. We used linear models with fixed effects for participants, adjusting for 24-h mean temperature, 24-h mean water vapor pressure, season, and scrubbed room NO the day of the visit, to estimate the associations between FeNO and interquartile range (IQR) increases in exposure. Interquartile increases in the 6-h averages of black carbon (BC) (0.5 μg/m3) and particle number (PN) (1000 particles/cm3) were associated with increases in FeNO of 3.84 % (95 % CI = 0.60 to 7.18 %) and 9.86 % (95 % CI = 3.59 to 16.52 %), respectively. We also found significant associations of increases in FeNO with increases in 24-h moving averages of BC, PN, and nitrogen oxides (NOx). Recent studies have focused on FeNO as a marker for eosinophilic pulmonary inflammation in asthmatic populations. This study adds support to the relevance of FeNO as a marker for pulmonary inflammation in diabetic populations, whose underlying chronic inflammatory status is likely to be related to innate immunity and proinflammatory adipokines.

Objectives Short-term elevation of ambient particulate air pollution has been associated with autonomic dysfunction and increased systemic inflammation, but the interconnections between these pathways are not well understood. We examined the association between inflammation and autonomic dysfunction and effect modification of inflammation on the association between air pollution and heart rate variability (HRV) in elderly subjects. Methods 25 elderly subjects in Steubenville, Ohio, were followed up to 24 times with repeated 30-min ECG Holter monitoring (545 observations). C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), soluble inter-cellular adhesion molecule 1 (sICAM-1), and white blood cell and platelet counts were measured in peripheral blood samples collected in the first month of the study. Increased systemic inflammation was defined for subjects within the upper 20% of the distribution for each marker. A central ambient monitoring station provided daily fine particle (PM2.5) and sulphate (SO42−) data. Linear mixed models were used to identify associations between inflammatory markers and HRV and to assess effect modification of the association between air pollution and HRV due to inflammatory status. Results A 5.8 mg/l elevation in CRP was associated with decreases of between −8% and –33% for time and frequency domain HRV outcomes. A 5.1 μg/m3 increase in SO42− on the day before the health assessment was associated with a decrease of −6.7% in the SD of normal RR intervals (SDNN) (95% CI −11.8% to −1.3%) in subjects with elevated CRP, but not in subjects with lower CRP (p value interaction=0.04), with similar findings for PM2.5. Conclusions Increased systemic inflammation is associated with autonomic dysfunction in the elderly. Air pollution effects on reduced SDNN are stronger in subjects with elevated systemic inflammation.

In this area where air quality is within EPA standards, living close to a major road was associated with early- and mid-childhood asthma, and lifetime exposure to particles was associated with early asthma, and also, mid-childhood asthma among girls only.

BACKGROUND: Living in a damp or mouldy home reportedly damages children's respiratory health, yet mould appears not to be a prominent risk factor in the public's perception. Analyses of data on over 58,000 children from the Pollution and the Young (PATY) study are presented. In this collaboration, researchers from 12 cross-sectional studies pooled their data to assess the effects of air quality on a spectrum of children's respiratory disorders. METHOD: Original studies were conducted in Russia, North America and 10 countries in Eastern and Western Europe. Pooled analyses were restricted to children aged 6-12 years. Associations between visible mould reported in the household and a spectrum of eight respiratory and allergic symptoms were estimated within each study. Logistic regressions were used, controlling for individual risk factors and for study area. Heterogeneity between study-specific results and mean effects (allowing for heterogeneity) were estimated using meta-analysis. RESULTS: Visible mould was reported by 13.9% of respondents in Russia, increasing to 39.1% in North America. Positive associations between exposure to mould and children's respiratory health were seen with considerable consistency across studies and across outcomes. Confounder-adjusted combined ORs ranged from 1.30 (95% CI 1.22 to 1.39) for "nocturnal cough" to 1.50 (1.31 to 1.73) for "morning cough". Evidence of stronger effects in more crowded households was statistically significant for only asthma and sensitivity to inhaled allergens. No consistent interactions between mould and age, sex or parental smoking were found. CONCLUSION: Indoor mould exposure was consistently associated with adverse respiratory health outcomes in children living in these diverse countries.

We examined the association between ambient air pollution levels and heart rate variability (HRV) in a panel study of 32 subjects.We used linear mixed models to analyze the effects of fine particles (PM2.5), sulfate (SO4), elemental carbon (EC), and gases on log-transformed standard deviation of normal RR intervals (SDNN), mean square of differences between adjacent RR intervals (r-MSSD), and high- and low-frequency power (HF, LF).An interquartile range (IQR) increase of 5.1 mug/m in SO4 on the previous day was associated with a decrease of -3.3% SDNN (95% confidence = -6.0% to -0.5%), -5.6% r-MSSD (-10.7% to -0.2%), and -10.3% HF (-19.5% to -0.1%). Associations with total PM2.5 were similar. HRV was not associated with EC, NO2, SO2, or O3.In addition to traffic-related particles, elevated levels of sulfate particles may also adversely affect autonomic function.

Both prenatal and postnatal passive smoking have been linked with respiratory symptoms and asthma in childhood. Their differential contributions to lung function growth in the general children's population are less clear.To study the relative impact of pre- and postnatal exposure on respiratory functions of primary school children in a wide range of geographic settings, we analyzed flow and volume data of more than 20,000 children (aged 6-12 yr) from nine countries in Europe and North America.Exposure information had been obtained by comparable questionnaires, and spirometry followed a protocol of the American Thoracic Society/European Respiratory Society. Linear and logistic regressions were used, controlling for individual risk factors and study area. Heterogeneity between study-specific results and mean effects were estimated using meta-analytic tools.Smoking during pregnancy was associated with decreases in lung function parameters between -1% (FEV1) and -6% maximal expiratory flow at 25% of vital capacity left (MEF25). A 4% lower maximal midexpiratory flow (MMEF) corresponded to a 40% increase in the risk of poor lung function (MMEF75% of expected). Associations with current passive smoking were weaker though still measurable, with effects ranging from -0.5% (FEV1) to -2% maximal expiratory flow (MEF50).Considering the high number of children exposed to maternal smoking in utero and the even higher number exposed to passive smoking after birth, this risk factor for reduced lung function growth remains a serious pediatric and public health issue.

Objectives: We reported previously that 24-hr moving average ambient air pollution concentrations were positively associated with ventricular arrhythmias detected by implantable cardioverter defibrillators (ICDs). ICDs also detect paroxysmal atrial fibrillation episodes (PAF) that result in rapid ventricular rates. In this same cohort of ICD patients, we assessed the association between ambient air pollution and episodes of PAF. Design: We performed a case–crossover study. Participants: Patients who lived in the Boston, Massachusetts, metropolitan area and who had ICDs implanted between June 1995 and December 1999 (n = 203) were followed until July 2002. Evaluations/Measurements: We used conditional logistic regression to explore the association between community air pollution and 91 electrophysiologist-confirmed episodes of PAF among 29 subjects. Results: We found a statistically significant positive association between episodes of PAF and increased ozone concentration (22 ppb) in the hour before the arrhythmia (odds ratio = 2.08; 95% confidence interval = 1.22, 3.54; p = 0.001). The risk estimate for a longer (24-hr) moving average was smaller, thus suggesting an immediate effect. Positive but not statistically significant risks were associated with fine particles, nitrogen dioxide, and black carbon. Conclusions: Increased ambient O3 pollution was associated with increased risk of episodes of rapid ventricular response due to PAF, thereby suggesting that community air pollution may be a precipitant of these events.

The authors evaluated the association between ventricular arrhythmias detected by implantable cardioverter defibrillators and ambient air pollution concentrations in the hours immediately before the arrhythmia. Patients given implantable cardioverter defibrillators at the New England Medical Center in Boston, Massachusetts, between mid-1995 and 1999 who lived within 40 km of a central monitoring site (n = 203) were followed until July 2002. The authors used a case-crossover design to study the association between ambient air pollution and up to 798 confirmed ventricular arrhythmias among 84 subjects. The authors found that interquartile range increases in 24-hour moving average particulate matter less than 2.5 mum in aerodynamic diameter and ozone were associated with 19% and 21% increased risks of ventricular arrhythmia, respectively. For each, there was evidence of a linear exposure response, and the associations appeared independent. These associations were stronger than associations with mean concentrations on the same calendar day and previous calendar days. The authors did not find associations with pollutant concentrations less than 24 hours before the arrhythmia. Cases with a prior ventricular arrhythmia within 72 hours had greater risk associated with air pollutants than did cases without a recent arrhythmia. These results confirm previous findings and suggest that matching of pollution periods to arrhythmias is important in detecting such associations.

Introduction: Atrial fibrillation (AF) is responsible for substantial morbidity and mortality, yet little is known about the environmental factors that may trigger AF episodes. Weather has been proposed as a potential precipitant of paroxysmal AF. Hypothesis: We assessed the hypothesis that changes in outdoor ambient temperature and outdoor absolute humidity may trigger paroxysmal AF in the following 24 hours. Methods: Patients with dual chamber implantable cardioverter defibrillators (ICDs) living in eastern Massachusetts were enrolled between September 2006 and March 2010 from the Tufts Medical Center Cardiac Arrhythmia Clinic (Boston, Massachusetts) and followed prospectively for episodes of paroxysmal AF lasting at least 30 seconds. Arrhythmias documented by the ICD were reviewed and interpreted by an electrophysiologist masked to exposure. The date and time of AF episodes were linked to hourly weather data measured at Boston Logan International Airport. We examined the hypothesis using a time-stratified case-crossover analysis matched on calendar month, day of week and time of day and adjusted for air pollution and barometric pressure. To reduce the possibility of over-representation of clustered events and to reflect the averaging time of the exposure, incident AF episodes were included in the analysis if at least 24 hours had passed since the previous AF episode. Results: Of 200 patients enrolled, 49 experienced at least one AF episode (n = 328 episodes). After excluding events with missing exposure or covariate information, analyses were confined to 230 AF episodes among 47 patients. The 47 patients with paroxysmal AF were followed for an average of 1.9 years, and 32 (68%) were male, 45 (96%) were Caucasian, the mean age was 67 years, 24 (51%) had a history of prior AF episodes, 27 (57%) had a pre-implantation ejection fraction < 35%, and 29 (62%) received the ICD for primary prophylaxis. Outdoor temperature in the previous 24 hours was not associated with AF (odds ratio (OR) = 1.13; 95% confidence interval (CI): 0.89, 1.43, p = 0.32, per interquartile range (IQR) decrease of 6.3°C). Lower absolute humidity in the previous 24 hours was associated with a higher risk of AF onset (OR = 1.33; 95% CI: 1.02, 1.74, p = 0.04, per IQR decrease of 3.5 g/m 3 ); this risk increased slightly for the previous 3 hours (OR = 1.39; 95% CI: 1.06, 1.82, p = 0.02, per IQR decrease of 3.7 g/m 3 ). Conclusions: In conclusion, drier air was associated with a transiently higher risk of paroxysmal AF in the following 24 hours among patients with dual chamber ICDs.

We examine whether ambient air pollution is associated with oxygen saturation in 32 elderly subjects in Steubenville, Ohio.We used linear mixed models to examine the effects of fine particulate matter less than 2.5 μm (PM(2.5)), sulfate (SO(4)(-2)), elemental carbon, and gases on median oxygen saturation.An interquartile range increase of 13.4 μg/m in PM(2.5) on the previous day was associated with a decrease of -0.18% (95% confidence interval: -0.31 to -0.06) and a 5.1 μg/m(3) interquartile range increase in SO(4)(-2) on the previous day was associated with a decrease of -0.16% (95% confidence interval: -0.27 to -0.04) in oxygen saturation during the initial 5-minute rest period of the protocol.Increased exposure to air pollution, including the nontraffic pollutant SO(4)(-2) from industrial sources, led to changes in oxygen saturation that may reflect particle-induced pulmonary inflammatory or vascular responses.

Background Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. The Vitamin D and Omega-3 Trial (VITAL) is randomizing >22,000 U.S. adults >50 years o...

Background and Aims: Implanted cardioverter defibrillators (ICD) monitor and treat arrhythmias and provide electrocardiographic records of the timing of ventricular and atrial arrhythmias. Diabetes...

Dr. Culic suggests that the associations that we reported [(1)][1] between particulate air pollution (PM2.5) and atrial fibrillation (AF) may be confounded by inadequate control of meteorology. There is a well-developed body of literature suggesting that acute particulate air pollution exposures

Studies of the relationships between low socio-economic status and impaired lung function were conducted mainly in Western European countries and North America. East–West differences remain unexplored. Associations between parental education and lung function were explored using data on 24,010 school-children from eight cross-sectional studies conducted in North America, Western and Eastern Europe. Parental education was defined as low and high using country-specific classifications. Country-specific estimates of effects of low parental education on volume and flow parameters were obtained using linear and logistic regression, controlling for early life and other individual risk factors. Meta-regressions were used for assessment of heterogeneity between country-specific estimates. The association between low parental education and lung function was not consistent across the countries, but showed a more pronounced inverse gradient in the Western countries. The most consistent decrease associated with low parental education was found for peak expiratory flow (PEF), ranging from −2.80 to −1.14%, with statistically significant associations in five out of eight countries. The mean odds ratio for low PEF (