Log-transformed Concentrations Research Articles

Association of Urinary Strontium Levels with Pregnancy-induced Hypertension.

Pregnancy-induced hypertension (PIH), including gestational hypertension and preeclampsia, accounts for the majority of maternal and perinatal morbidity and mortality. Strontium (Sr) has been recently associated with preeclampsia in a small group of women; however, the role of Sr in PIH is not fully understood and warrants further investigation. In this study, we examined the association between urinary Sr levels and PIH, and assessed the effect of maternal age on the association. Urinary Sr concentrations were measured in 5423 pregnant women before delivery by inductively coupled plasma mass spectrometry (ICP-MS). Logistic regression analysis adjusting for potential confounders was applied to explore the association between Sr and PIH, and to evaluate the Sr-PIH relationship stratified by maternal age. Among the participants, 200 (3.83%) women were diagnosed with PIH. Compared with non-PIH women, women who developed PIH had lower urinary Sr concentrations (131.26 vs. 174.98 μg/L creatinine, P<0.01). With the natural log-transformed urinary creatinine-standardized Sr concentrations increasing, the risk of PIH decreased significantly [adjusted OR=0.60 (95%CI: 0.51, 0.72)]. Furthermore, the significant association of Sr with PIH was found among women under 35 years (P<0.01). Our finding suggested that Sr may play a potential protective role in the pathogenesis of PIH, especially among young pregnant women under 35 years old.

Socioeconomic status, financial stress, and glucocorticoid resistance among youth with asthma: Testing the moderation effects of maternal involvement and warmth

ObjectivesChildren who grow up in more socioeconomically disadvantaged homes experience greater levels of inflammation and worse asthma symptoms than children from more advantaged families. However, recent evidence suggests that certain family-level factors can mitigate health disparities associated with socioeconomic status (SES). In a sample of youth with asthma, we investigated the potential buffering effects of maternal involvement and warmth on SES disparities in asthma-related immune responses, assessed via glucocorticoid resistance (GR) of immune cells. MethodsOne hundred and forty-three youth (10–16 years of age) with asthma completed measures of maternal involvement and warmth, and their primary caregivers reported their levels of education, income, and financial stress. Peripheral blood mononuclear cells from youth’s blood were isolated, cultured, and assayed to determine mitogen-stimulated (PMA/INO + Etho) and mitogen/hydrocortisone-stimulated (PMA/INO + Cort) levels of two Th-2 cytokines (i.e., interleukin-5, interleukin-13) and one Th-1 cytokine (i.e., interferon-γ). GR was calculated by subtracting log-transformed cytokine concentration in the PMA/INO + Etho samples from log-transformed cytokine concentration in the PMA/INO + Cort samples. ResultsBoth maternal involvement and warmth moderated the indirect pathway from family SES to GR of Th-2 cytokines via financial stress. Specifically, we found that low family SES was associated with elevated GR of Th-2 cytokines via increased financial stress among youth reporting low levels of maternal involvement and warmth, but not among those reporting high levels of maternal involvement or warmth. ConclusionsThese results highlight the protective role of maternal involvement and warmth in health-related biological processes modulated by family SES among youth with asthma.

Causal associations of serum matrix metalloproteinase-8 level with ischaemic stroke and ischaemic stroke subtypes: a Mendelian randomization study.

Elevated serum matrix metalloproteinase-8 (MMP-8) concentrations are associated with high risk of vascular disease, but the causality remains unclear. A two-sample Mendelian randomization (MR) study was performed to examine the causal effect of serum MMP-8 concentrations on the risk of ischaemic stroke, ischaemic stroke subtypes and coronary artery disease. Ten independent single-nucleotide polymorphisms related to serum MMP-8 concentrations were identified as instrumental variables from a genome-wide association study of 6049 European subjects. Genetic association estimates for ischaemic stroke were obtained from the Multiancestry Genome-wide Association Study of Stroke consortium with 446,696 European individuals. The inverse-variance weighted method was applied to assess the causal associations of serum MMP-8 with ischaemic stroke and its subtypes in the main analysis. No significant causal association was observed for MMP-8 levels with total ischaemic stroke, large artery stroke or cardioembolic stroke. Genetically determined 1 - unit higher log-transformed serum MMP-8 concentration was associated with an increased risk of small vessel stroke (odds ratio 1.25; 95% confidence interval 1.12-1.39; p<0.001). In secondary analysis, a similar adverse impact was reported for MMP-8 on coronary artery disease (odds ratio 1.05; 95% confidence interval 1.01-1.10; p=0.017). Sensitivity analyses further confirmed the relationship between serum MMP-8 level and small vessel stroke and coronary artery disease. Mendelian randomization Egger regression showed no evidence of pleiotropic bias. High serum MMP-8 concentrations were causally associated with increased risks of small vessel stroke and coronary artery disease. The mechanism underlying the effect of serum MMP-8 on the vascular system requires further investigation.

Umbilical Cord Blood Metal Mixtures and Birth Size in Bangladeshi Children.

Background:Studies have evaluated environmental exposure to toxic metals such as arsenic (As), cadmium (Cd), manganese (Mn), or lead (Pb) on birth size; however, information on potential effects of exposures to metal mixtures is limited.Objectives:We assessed the association between metal mixtures (As, Cd, Mn, Pb) in umbilical cord blood and neonate size in Bangladeshi children.Methods:In this birth cohort study, pregnant women who were of age with an ultrasound-confirmed singleton pregnancy of gestation were recruited from two Bangladesh clinics between 2008 and 2011. Neonate size metrics were measured at the time of delivery. Metals in cord blood were measured using inductively coupled plasma mass spectrometry. We employed multivariable linear regression and Bayesian kernel machine regression (BKMR) to estimate associations of individual metals and metal mixtures with birth size parameters.Results:Data from 1,088 participants was assessed. We found a significant negative association between metal mixture and birth length and head circumference when all metal concentrations were above the 60th and 55th percentiles, respectively, compared with the median. An interquartile range (IQR) increase in log Cd concentration {log[Cd (in micrograms per deciliter)] } was associated with a 0.13-standard deviation (SD) decrease in mean birth length (95% CI: , ) and a 0.17-SD decrease in mean head circumference (95% CI: , ), based on linear regression models adjusted for covariates and the other metals. An IQR increase in log Mn concentration {log[Mn (in micrograms per deciliter)] } was associated with a 0.07-SD decrease in mean birth weight (95% CI: , 0.002).Discussion:Metal mixtures in cord blood were associated with reduced birth size in Bangladeshi children. Results from linear regression models adjusted and the BKMR mixtures analyses suggest adverse effects of Cd and Mn, as individual metal exposures, on birth size outcomes. https://doi.org/10.1289/EHP7502

Effect of PM2.5 pollution on perinatal mortality in China

Using ArcGIS to analyze satellite derived PM2.5 estimates, this paper obtains the average concentration and maximum concentration of fine particulate matter (PM2.5) in China's 31 provinces from 2002 to 2015. We adopt fixed effects model and spatial Durbin model to investigate the association between PM2.5 and perinatal mortality rates. The results indicate that PM2.5 has a significantly positive association with perinatal mortality rates. A 1% increase of log-transformed average concentration and maximum concentrations of PM2.5 is associated with 1.76‰ and 2.31‰ increase of perinatal mortality rates, respectively. In spatial econometrics analysis, we find PM2.5 has significant spatial autocorrelation characteristics. The concentrations of log-transformed average and maximum PM2.5 increase 1% is associated with a 2.49% increase in a 2.49‰ and 2.19‰ increase of perinatal mortality rates, respectively. The potential mechanism is that air pollution has an impact on infant weight to impact perinatal mortality rates.

Pregnancy exposure to common-detect organophosphate esters and phthalates and maternal thyroid function

BackgroundContemporary human populations are exposed to elevated concentrations of organophosphate esters (OPEs) and phthalates. Some metabolites have been linked with altered thyroid function, however, inconsistencies exist across thyroid function biomarkers. Research on OPEs is sparse, particularly during pregnancy, when maintaining normal thyroid function is critical to maternal and fetal health.In this paper, we aimed to characterize relationships between OPEs and phthalates exposure and maternal thyroid function during pregnancy, using a cross-sectional investigation of pregnant women nested within the Norwegian Mother, Father, and Child Cohort (MoBa). MethodsWe included 473 pregnant women, who were euthyroid and provided bio-samples at 17 weeks' gestation (2004–2008). Four OPE and six phthalate metabolites were measured from urine; six thyroid function biomarkers were estimated from blood. Relationships between thyroid function biomarkers and log-transformed concentrations of OPE and phthalate metabolites were characterized using two approaches that both accounted for confounding by co-exposures: co-pollutant adjusted general linear model (GLM) and Bayesian Kernal Machine Regression (BKMR). ResultsWe restricted our analysis to common-detect OPE and phthalate metabolites (>94%): diphenyl phosphate (DPHP), di-n-butyl phosphate (DNBP), and all phthalate metabolites. In GLM, pregnant women with summed di-isononyl phthalate metabolites (∑DiNP) concentrations in the 75th percentile had a 0.37 ng/μg lower total triiodothyronine (TT3): total thyroxine (TT4) ratio (95% credible interval: [−0.59, −0.15]) as compared to those in the 25th percentile, possibly due to small but diverging influences on TT3 (−1.99 ng/dL [−4.52, 0.53]) and TT4 (0.13 μg/dL [−0.01, 0.26]). Similar trends were observed for DNBP and inverse associations were observed for DPHP, monoethyl phthalate, mono-isobutyl phthalate, and mono-n-butyl phthalate. Most associations observed in co-pollutants adjusted GLMs were attenuated towards the null in BKMR, except for the case of ∑DiNP and TT3:TT4 ratio (−0.48 [−0.96, 0.003]). ConclusionsMaternal thyroid function varied modestly with ∑DiNP, whereas results for DPHP varied by the type of statistical models.

Urinary phthalate metabolite concentrations and hot flashes in women from an urban convenience sample of midlife women

ContextPhthalate exposure is associated with altered reproductive function, but little is known about associations of phthalate exposure with risk of hot flashes. ObjectiveTo investigate associations of urinary phthalate metabolite levels with four hot flash outcomes in midlife women. DesignA cross-sectional study of the first year of a prospective cohort of midlife women, the Midlife Women's Health Study (2006–2015), a convenience sample from an urban setting. Participants728 multi-racial/ethnic pre- and perimenopausal women aged 45–54 years. Outcome measuresWomen completed questionnaires about hot flash experience and provided 1–4 urine samples over four consecutive weeks that were pooled for analysis. Phthalate metabolites were assessed individually and as molar sums representative of common compounds (all phthalates: ƩPhthalates; DEHP: ƩDEHP), exposure sources (plastics: ƩPlastic; personal care products: ƩPCP), and modes of action (anti-androgenic: ƩAA). Covariate-adjusted logistic regression models were used to assess associations of continuous natural log-transformed phthalate metabolite concentrations with hot flash outcomes. Analyses were conducted to explore whether associations differed by menopause status, body mass index (BMI), race/ethnicity, and depressive symptoms. ResultsOverall, 45% of women reported a history of hot flashes. Compared to women who never experienced hot flashes, every two-fold increase in ƩPlastic was associated with 18% (OR: 1.18; 95%CI: 0.98, 1.43) and 38% (OR: 1.38; 95%CI: 1.11, 1.70) higher odds of experiencing hot flashes in the past 30 days and experiencing daily/weekly hot flashes, respectively. Some associations of phthalates with certain hot flash outcomes differed by menopause status, BMI, race/ethnicity, and depressive symptoms. ConclusionsThis study suggests that phthalates are associated with hot flash experience and may impact hot flash risk in women who are susceptible to experiencing hot flashes.

A predictive model of the impact of urbanization on bacterial loads in watersheds

Bacterial concentration is one of the most important aspects of water quality. Many regions in the world are affected by increasing urbanization and a potential increase in bacterial concentrations in waters. We used long-term data from 68 stations in eight watersheds in Eastern Thailand to quantify the temporal and geographical variation in total and fecal coliform bacteria. Descriptive statistics showed considerable seasonal, inter-annual, and geographical variation. In order to quantify this multi-level variation, we built a predictive model of bacterial loads. Using fixed- and mixed-effects regression models, we built a model including the effects of urbanization and other significant variables. The best model, fitted by restricted maximum likelihood, included the effects of season, year, urbanization as fixed effects, and of watershed and station as nested, random effects. Temporal variation was related to seasonal and annual variations. Spatial variation had a very significant impact on the bacterial concentrations. Urbanization was an important factor controlling concentrations of bacteria in rivers: we found that the proportion of urban area around a station had a statistically significant effect on log-transformed total coliform bacterial concentration with a slope equal to 1.3 (SE = 0.3), and on log-transformed fecal coliform bacterial concentration with a slope equal to 1.4 (SE = 0.3). Our model predicts that bacterial concentrations would be multiplied by 20 if land is transformed from non-urban to fully urban.

Exposure to Phenols, Phthalates, and Parabens and Development of Metabolic Syndrome Among Mexican Women in Midlife.

Background: Evidence suggests exposure to endocrine-disrupting chemicals (EDCs) can influence Metabolic Syndrome (MetS) risk in adults, but it is unclear if EDCs impact women during midlife. We examined if EDCs measured in adult women were predictive of MetS and its components 9 years later.Methods: We measured urinary phthalate metabolites, phenols, and parabens collected in 2008 among 73 females from the ELEMENT study. MetS and its components (Abdominal Obesity, Hypertriglyceridemia, Cholesterolemia, Hypertension, and Hyperglycemia) were assessed in 2017. We regressed log-transformed EDC concentrations on MetS and MetS components using logistic regression, adjusting for age and physical activity.Results: At follow-up, the mean (SD) age was 46.6 (6.3) years; the prevalence of MetS was 34.3%. Sum of dibutyl phthalate metabolites (ΣDBP), monobenzyl phthalate (MBzP), and monoethyl phthalate (MEP) were associated with an increased odds of hypertriglyceridemia. 2,5-dichlorophenol (2,5 DCP) and 2,4-dichlorophenol (2,4 DCP) were associated with increased odds of hypertriglyceridemia. The odds of hypertension were 4.18 (95% CI: 0.98, 17.7, p < 0.10) and 3.77 (95% CI: 0.76, 18.62, p < 0.10) times higher for every IQR increase in MCOP and propyl paraben, respectively. The odds of hyperglycemia were 0.46 (95% CI: 0.18, 1.17 p < 0.10) times lower for every IQR increase in the sum of di-2-ethylhexyl phthalate metabolites (ΣDEHP), and the odds of abdominal obesity were 0.70 (95% CI: 0.40, 1.21, p < 0.10) lower for every IQR increase in the concentration of triclosan.Conclusion: We found EDCs measured in 2008 were marginally predictive of hypertriglyceridemia and hypertension 9 years later. Results suggest that lower exposure to certain toxicants was related to lower markers of metabolic risk among midlife women.

Analysis and assessment of heavy metal contamination in the vicinity of Lake Atamanskoe (Rostov region, Russia) using multivariate statistical methods.

Assessment of spatial patterns of potentially toxic metals is one of the most urgent tasks in soil chemistry. In this study, descriptive statistics and three methods of multivariate statistical analysis, such as the hierarchical cluster analysis (HCA), correlation analysis, and conditional inference tree (CIT), were used to identify patterns and potential sources of heavy metals (Co, Ni, Cu, Cr, Pb, MnO, and Zn). The investigation was carried out on 81 sample points, using 20 testing parameters. A strong positive correlation found among Ni, Cu, Zn, and HCA results has confirmed the common origin of the elements from waste discharge. Hierarchical CA divided the 81 test sites into 5 classes based on the soil quality and HMs contamination similarity. Regression trees for Cr, Pb, Zn, and Cu were verified by the splitting factor including HMs content and soil chemistry factors. The CIT has revealed that the elements (Cr, Pb, Zn, and Cu) concentration values are split at the first level by some other metal, indicating common anthropogenic impact resulting from industrial waste discharges. The factors at the next hierarchical level of splitting, in addition to the HMs, include compounds belonging to soil chemistry variables (SiO2, Al2O3, and K2O). The CIT nonlinear regression model is in good agreement with the data: R2 values for log-transformed concentrations of Cr, Pb, Zn, and Cu are equal to 0.775; 0.774; 0.775; 0.804, respectively.

Individual exposure to urban air pollution and its correlation with placental angiogenic markers in the first trimester of pregnancy, in São Paulo, Brazil.

Pollution of the atmosphere is known that may lead to adverse obstetric outcomes, including fetal growth restriction, gestational hypertension, and preeclampsia. Such disorders are correlated with imbalances in angiogenic factors, which may also be involved in the pathological mechanism as the pollutants impact placental and maternal physiology. In the first trimester of gestation, this study assessed the outcomes of personal maternal short period exposure to air pollution on soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PLGF) of pregnant women blood concentrations. This was a cross-sectional study, held in the city of São Paulo, Brazil, and conducted with low-risk pregnant women, who carried personal passive nitrogen dioxide (NO2) and ozone (O3) monitors for about a few days preceding the ultrasound evaluation, and on this day, the venous blood sample was collected to measure the angiogenic factors sFlt1 and PLGF and their ratio (sFlt1/PLGF) by enzyme-linked immunosorbent assay (ELISA). By means of multiple regression models, the effect of the studied pollutants on the log-transformed concentrations of the angiogenic factors was evaluated. One hundred thirty-one patients were included. The log of the sFlt1/PLGF ratio increased with rising NO2 levels (p = 0.021 and beta = 0.206), and the log of the PLGF concentration showed a negative correlation with NO2 (p = 0.008 and beta = - 0.234). NO2, an indicator of the levels of primary air pollutants, presented significant positive correlation with an increased sFlt1/PLGF ratio and diminished PLGF levels, which may reflect an antiangiogenic state generated by air pollution exposure.

Urinary phthalate metabolites and alternatives and serum sex steroid hormones among pre- and postmenopausal women from NHANES, 2013–16

BackgroundExposure to phthalates is ubiquitous across the United States. While phthalates have anti-androgenic effects in men, there is little research on their potential impacts on sex hormone concentrations in women and that also take into account menopausal status. MethodsCross-sectional data on urinary phthalate metabolites, serum sex hormones, and relevant covariates were obtained from the National Health and Nutrition Examination Survey 2013–14 and 2015–16. Women over the age of 20 who were not pregnant or breastfeeding and had not undergone oophorectomy were included (n = 698 premenopausal, n = 557 postmenopausal). Weighted multivariable linear and Tobit regression models stratified by menopausal status were fit with natural log-transformed phthalate concentrations and sex hormone outcomes adjusting for relevant covariates. ResultsPhthalate metabolites were associated with differences in sex hormone concentrations among postmenopausal women only. Di-2-ethylhexyl phthalate (DEHP) was associated with lower serum estradiol and bioavailable testosterone concentrations. Specifically, a doubling of DEHP concentrations was associated with 5.9% (95% Confidence Interval (CI): 0.2%, 11.3%) lower estradiol and 6.2% (95% CI: 0.0%, 12.1%) lower bioavailable testosterone concentrations. In contrast, 1,2-cyclohexane dicarboxylic acid di-isononyl ester (DINCH) was associated with higher free testosterone, bioavailable testosterone, and free androgen index. Finally, di-2-ethylhexyl terephthalate (DEHTP) was associated with a higher testosterone-to-estradiol ratio. None of these results retained statistical significance when adjusted for multiple comparisons. ConclusionsDEHP, DINCH, and DEHTP were associated with differences in serum sex hormone concentrations among postmenopausal women, highlighting the need for further research into the safety of these chemicals.

Sphingolipids and physical function in the Atherosclerosis Risk in Communities (ARIC) study

Long-chain sphingomyelins (SMs) may play an important role in the stability of myelin sheath underlying physical function. The objective of this study was to examine the cross-sectional and longitudinal associations of long-chain SMs [SM (41:1), SM (41:2), SM (43:1)] and ceramides [Cer (41:1) and Cer (43:1)] with physical function in the Atherosclerosis Risk in Communities (ARIC) study. Plasma concentrations of SM (41:1), SM (41:2), SM (43:1), Cer (41:1) and Cer (43:1) were measured in 389 ARIC participants in 2011–13. Physical function was assessed by grip strength, Short Physical Performance Battery (SPPB), 4-m walking speed at both 2011–13 and 2016–17, and the modified Rosow-Breslau questionnaire in 2016–2017. Multivariable linear and logistic regression analyses were performed, controlling for demographic and clinical confounders. In cross-sectional analyses, plasma concentrations of SM 41:1 were positively associated with SPPB score (β-coefficients [95% confidence internal]: 0.33 [0.02, 0.63] per 1 standard deviation [SD] increase in log-transformed concentration, p value 0.04), 4-m walking speed (0.042 m/s [0.01, 0.07], p value 0.003), and negatively with self-reported disability (odds ratio = 0.73 [0.65, 0.82], p value < 0.0001). Plasma concentrations of the five metabolites examined were not significantly associated with longitudinal changes in physical function or incidence of poor mobility. In older adults, plasma concentrations of long-chain SM 41:1 were cross-sectionally positively associated with physical function.

Associations between maternal socioeconomic, psychosocial and seasonal factors, infant characteristics and human milk cortisol concentrations.

Glucocorticoids are one component of human milk (HM) potentially affecting offspring development. Previous studies have identified various maternal, obstetric and socioeconomic characteristics that are associated with HM cortisol concentration but the literature is still scarce concerning these determinants in human populations. We aimed to identify which factors are linked with HM cortisol concentration at 2months postpartum. We analyzed data from 340 lactating Finnish mothers using ordinary least squares regression with log-transformed HM cortisol concentration as the dependent variable. Potential predictors included obstetric and maternal factors (maternal age, parity status, delivery mode, gestational age, pre-pregnancy obesity, and smoking in pregnancy), socioeconomic status (education and socioeconomic class), subjective economic well-being, maternal psychosocial factors (postpartum depression and anxiety symptoms), infant sex and age, and HM sample characteristics (time of the day and season of the year at sample collection). The strongest and most robust predictors were season of the year of sample collection and parity status. HM cortisol concentration was significantly higher for primiparas than multiparas. HM samples collected in summer showed significantly higher cortisol concentrations than those collected in winter, spring or autumn. The findings suggest that parity and season of the year at sample collection may be important factors to control for when examining HM cortisol. The strongest and most robust associations were related to maternal and sample characteristics and not to socioeconomic and psychosocial distress. This may be related to the fact that the study was conducted in a low-risk population.

Elevated Growth Differentiation Factor-15 Is a Biomarker of Sarcopenia in Older Adults

Growth differentiation factor 15 (GDF-15) is associated with disease progression, mitochondrial dysfunction and mortality. Elevated GDF-15 level was recently reported to be associated with poorer physical performance in healthy community-dwelling adults. However, the relationship between serum GDF-15 concentration and sarcopenia in community-dwelling older adults has not been well characterized. We analyzed 929 participants (mean age 75.9±8.9 years, 48.0% men) from the Korean Frailty and Aging Cohort Study who underwent assessment of serum GDF-15 concentration and sarcopenia. Participants with an estimated glomerular filtration rate <60 ml/min/1.73 m2 were excluded from this analysis. Sarcopenia status was determined as per the Asian Working Group for Sarcopenia (AWGS) 2019 guidelines. As per the AWGS 2019 algorithm, 154 (16.6%) participants in the study population were classified as having sarcopenia. Median serum GDF-15 concentration was elevated in the sarcopenic group vs. the non-sarcopenic group (920 vs. 793 pg/ml, p<0.001). In the multivariate analysis adjusted for potential confounders, the highest GDF-15 tertile (≥1245 pg/ml) was associated with a higher risk of sarcopenia vs. the lowest tertile (<885 pg/ml) (odds ratio [OR] = 1.95, 95% confidence interval [CI] 1.15–3.31). This association remained unchanged (OR = 1.90, 95% CI 1.14–3.23) after further adjustment for potential biomarkers (myostatin, dehydroepiandrosterone, and insulin-like growth factor-1). The OR per unit increase in log-transformed GDF-15 concentration was 3.59 (95% CI 1.21–10.70). To conclude, our results suggest that higher circulating GDF-15 concentration was independently associated with a greater risk of sarcopenia in community-dwelling older adults. Serum GDF-15 concentration can be a promising biomarker for sarcopenia

Effect of CYP3A5*3 genotypes on lumefantrine plasma concentrations among malaria-HIV-infected women.

Aim: We aimed to assess the effect of a functional polymorphism of CYP3A5 on lumefantrine pharmacokinetics. Patients & methods: Sixty-nine women diagnosed with malaria received standard doses of artemether-lumefantrine. Concentration-time data for lumefantrine and genotyping data were obtained for each participant. Pharmacokinetic-genotype associative relationships were assessed using linear regressions, Mann-Whitney U-test or Kruskal-Wallis statistics. Results: Average age and weight (standard deviation) of the patients were 33(6.8) years and 59.5(11.6) kg, respectively. CYP3A5*3genotypeassociated with the log-transformed maximum concentration with the median (interquartile range) values of 8279 (6516-13,420) and 6331 (4093-8631) ng/ml (p = 0.032) among the carriers and noncarriers of CYP3A5*3, respectively. Besides, the NR1I3 c.152-1089T>C genotypes had an associative trend with the lumefantrine area under the curve (AUC0-96h) and clearance. Conclusion:CYP3A5*3 genetic variant is associated with a high maximum plasma concentration of lumefantrine. This warrants further investigations on the association between CYP3A5*3 gene variants, lumefantrine pharmacokinetics and electrophysiological effect.

Abstract 15168: Circulating Cell-free DNA Correlates With Markers of Disease Severity in the Rat Sugen/hypoxia Model of Pulmonary Arterial Hypertension

Introduction: Cell-free DNA (cfDNA) is released into circulation following tissue injury and cell turnover. In cancer and allograft rejection, cfDNA serves as a valuable biomarker for monitoring disease severity, progression, and response to therapy. The goal of the current study is to determine the temporal relationship between plasma cfDNA and disease severity in a PAH rodent model. Methods: Blood collection was performed weekly (weeks 4-11) in both sugen/hypoxia PAH rats (n=12) and age-matched, normoxia controls (n=12). cfDNA was isolated from plasma and concentration was determined by qRT-PCR. Cardiac MRI, cardiac catheterization and necropsy were performed at the end of study. Log-transformed concentrations of cfDNA were compared using linear mixed models. Pearson correlation coefficients were calculated to identify associations between rates of change in cfDNA and measures of disease severity. Results: Plasma cfDNA concentrations were significantly higher in PAH rats beginning at week 5 and continuing through week 10 (P &lt; 0.05 for the comparison at each week; Figure 1). From weeks 4 to 11, there was an overall trend toward increasing cfDNA concentration over time in PAH rats (P = 0.07), whereas concentrations in control rats remained unchanged (P = 0.52). In PAH rats, the rate of change in log-transformed cfDNA concentration correlated inversely with RVEF (r = -0.80, P = 0.003), stroke volume index (r = -0.67, P = 0.02), and positively with total pulmonary resistance index (r = 0.62, P = 0.04). There were non-significant trends between the rate of change in cfDNA concentration and LV end-diastolic volume index (r = -0.54, P = 0.09), and Fulton index (r = 0.55, P = 0.08). Conclusions: Plasma cfDNA is elevated in the rat sugen/hypoxia PAH model and significantly correlated with markers of disease severity. Circulating cfDNA may reflect ongoing pulmonary vascular injury and remodeling, RV strain or both and thus may serve as a novel biomarker of PAH disease progression.

Abstract 14550: Sex Differences on Time-dependent Changes in Brain-type Natriuretic Peptide Among Patients With Hypertrophic Cardiomyopathy

Introduction: Sex differences in biomarkers such as brain-type natriuretic peptide (BNP) have not been fully elucidated among patients with hypertrophic cardiomyopathy (HCM). Hypothesis: Sex affects transition of BNP concentration among patients with HCM. Methods: This retrospective cohort study analyzed clinical personal record of HCM, a national database of Japanese Ministry of Health, Labor and Welfare, between 2009 and 2014. This record annually collected HCM patient data. Patients with HCM who were assessed with BNP concentration both at baseline and 2-year follow-up were included. Patients were excluded if they received ventricular assist device or heart transplantation during follow-up period. Outcomes were assessed according to sex. The primary endpoint was BNP concentration at 2-year follow-up. The log-transformed BNP concentration at 2-year was analyzed by analysis of covariance adjusted for baseline characteristics including baseline BNP. The cubic spline analysis of BNP concentration at 2-year for sex by BNP concentration was performed. Results: Out of 3,570 patients enrolled in the clinical personal record of HCM, 611 patients were included in the present analysis. Mean age was 60.4 years and female and male were 254 (41.6%) and 357 (58.4%), respectively. Left ventricular (LV) ejection fraction was higher in female (64.7 ± 14.5 vs. 61.4 ± 16.0%, P =.012), LV diastolic diameter (43.4 ± 7.8 vs. 48.0 ± 8.0 mm, P &lt;.001), LV systolic diameter (27.3 ± 8.9 vs. 31.2 ± 9.0 mm, P &lt;.001), posterior wall thickness (11.2 ± 3.0 vs. 11.9 ± 3.8 mm, P =.011), and left atrial diameter (41.8 ± 8.8 vs. 45.8 ± 10.1 mm, P &lt;.001) were smaller in female. Baseline BNP concentration was higher in female (320.3 [159.0-583.1] vs. 182.8 [86.1-363.9], P &amp;lt;.001). Female sex was associated with higher log-transformed BNP at 2-year in both complete case analysis (coefficient 0.31; 95% confidence interval [CI] 0.13-0.48; P &lt;.001) and multiple imputation analysis (coefficient 0.63: 95% CI 0.44-0.82; P &lt;.001). Cubic spline analysis showed that female sex was associated with higher BNP concentration at 2-year irrespective of baseline BNP concentration. Conclusions: Female sex was associated with higher BNP levels at 2-year follow-up compared with male sex in HCM.

Urinary metals and adipokines in midlife women: The Study of Women's Health Across the nation (SWAN)

BackgroundInformation on the associations between metal exposures and adipokines in human populations is limited and results are inconsistent. We evaluated the associations between metals and adipokines. MethodsUrinary concentrations of 15 metals (arsenic, barium, cadmium, cobalt, cesium, copper, mercury, manganese, molybdenum, nickel, lead, antimony, tin, thallium, and zinc) were measured in 1999–2000 among 1228 women of the Study of Women's Health Across the Nation Multi-Pollutant Study. Serum adipokines including high molecular weight (HMW)-adiponectin, leptin, and soluble leptin receptor (sOB-R) were measured at the follow-up visit (2002–2003). Linear regression models with adaptive elastic-net (AENET) were fit to identify metals associated with adipokines and to compute estimated percent changes in adipokines for one standard deviation increase in log-transformed urinary metal concentrations. ResultsAfter adjustment for confounders, urinary molybdenum was associated with a 5.54% higher level (95% CI: 1.36%, 9.90%), whereas cadmium was associated with a 4.53% lower level (95% CI: −8.17%, −0.76%) of HMW-adiponectin. Urinary molybdenum was also associated with a 5.95% lower leptin level (95% CI: −10.15%, −1.56%) and a 2.98% (95% CI: 0.69%, 5.32%) higher sOB-R level. Urinary cesium and lead were associated with a 3.58% (95% CI: −6.06%, −1.03%) and a 2.53% (95% CI: −4.80%, −0.21%) lower level of sOB-R, respectively. ConclusionsOur findings suggest that molybdenum was associated with favorable profiles of HMW-adiponectin, leptin, and sOB-R. Exposures to cadmium, cesium, and lead were associated with adverse adipokine profiles.

246P Impact of genetically predicted elevated concentrations of C-reactive protein on ovarian cancer risk: A Mendelian randomization study

C-reactive protein (CRP) is the inflammation-responsible protein and a significant rise of the plasma concentration of CRP is pervasive in the progress of ovarian cancer. However, there are few studies that comprehensively evaluate the correlation between CRP concentrations and ovarian cancer and the causal effect remains unknown. With a Mendelian randomization (MR) approach, we were able to investigate the causal relationship between genetically predicted CRP levels and ovarian cancer risk. Utilizing 32 CRP-related single nucleotide polymorphisms as instrumental variables identified by the latest genome-wide association studies, we investigated the correlation between genetically predicted CRP and ovarian cancer risk using summary statistics from the Ovarian Cancer Association Consortium (25,509 cases and 40,941 controls). The Inverse variance weighted (IVW) method was applied to estimate the causality between genetically elevated CRP concentrations and ovarian cancer risk. To further evaluate the pleiotropy, the weighted median and the MR-Egger regression method were implemented. Subgroup analyses according to different histotypes of ovarian cancer were also conducted. An inverse association was observed between genetically predicted one-unit increase in the log-transformed CRP concentrations and ovarian cancer (OR = 0.93, 95%CI = 0.87-1.00 p = 0.047). When results were examined by histotypes, an inverse association was observed between genetically predicted one-unit increase in the log-transformed CRP concentrations and endometrioid ovarian cancer (OR = 0.80, 95%CI = 0.70-0.91 p = 0.001), low-grade serous ovarian cancer (OR = 0.70, 95%CI = 0.58-0.86 p = 0.001) and serous ovarian cancer (OR = 0.84, 95%CI = 0.74-0.96 p = 0.012). Additionally, the results demonstrated the absence of the horizontal pleiotropy. MR findings provide evidence for a causal relationship between genetically predicted one-unit increase in the log-transformed CRP concentrations and reduced ovarian cancer risk, overall and among specific histotypes. Further studies are warranted to investigate the underlying mechanism.