Publications by authors named "Wenzhen Ge"

23 Publications

  • Page 1 of 1

Epidemiology of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in the United States and Western Europe: population-level projections for 2020-2025.

Leuk Lymphoma 2021 Sep 11:1-10. Epub 2021 Sep 11.

Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) treatments have been rapidly evolving for patients treated in later lines of therapy (LoT). Country-specific cancer registry data for the US and Western Europe (WE) were combined with physician survey results to project the incidence, prevalence, and number of DLBCL and FL patients eligible for and treated by LoT between 2020 and 2025. The total number of incidents and prevalent cases of DLBCL and FL is expected to increase between 2020 and 2025 in the US and WE. 56% and 53% of the third line plus (3L+) eligible DLBCL patients and 60% and 55% of eligible FL patients initiated treatment in the US and WE, respectively. Further research is warranted to understand the reasons behind the high proportion of treatment eligible patients who do not initiate treatment, and potential differences between countries, especially in the 3L + settings.
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http://dx.doi.org/10.1080/10428194.2021.1975188DOI Listing
September 2021

The association of triglyceride levels with the incidence of initial and recurrent acute pancreatitis.

Lipids Health Dis 2021 Jul 18;20(1):72. Epub 2021 Jul 18.

Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, One Gustav L. Levy Place, Hospital Box 1030, New York, NY, 10029, USA.

Background: This retrospective cohort study assessed the annualized incidence rate (IR) of acute pancreatitis (AP) in a nationally representative US adult population, as well as the variation in the risk of AP events across strata of triglyceride (TG) levels.

Methods: Data were obtained from IQVIA's US Ambulatory Electronic Medical Records (EMR) database linked with its LRxDx Open Claims database. Inclusion criteria included ≥1 serum TG value during the overlapping study period of the EMR and claims databases, ≥1 claim in the 12-month baseline period, and ≥ 1 claim in the 12 months post index. All TG measurements were assigned to the highest category reached: < 2.26, ≥2.26 to ≤5.65, > 5.65 to ≤9.94, > 9.94, and > 11.29 mmol/L (< 200, ≥200 to ≤500, > 500 to ≤880, > 880, and > 1000 mg/dL, respectively). The outcome of interest was AP, defined as a hospitalization event with AP as the principal diagnosis.

Results: In total, 7,119,195 patients met the inclusion/exclusion criteria, of whom 4158 (0.058%) had ≥1 AP events in the prior 12 months. Most patients (83%) had TGs < 2.26 mmol/L (< 200 mg/dL), while < 1% had TGs > 9.94 mmol/L (> 880 mg/dL). Overall, the IR of AP was low (0.08%; 95% confidence internal [CI], 0.08-0.08%), but increased with increasing TGs (0.08% in TGs < 2.26 mmol/L [< 200 mg/dL] to 1.21% in TGs > 11.29 mmol/L [> 1000 mg/dL]). In patients with a prior history of AP, the IR of AP increased dramatically; patients with ≥2 AP events at baseline had an IR of 29.98% (95% CI, 25.1-34.9%).

Conclusion: The risk of AP increases with increasing TG strata; however, the risk increases dramatically among patients with a recent history of AP.
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http://dx.doi.org/10.1186/s12944-021-01488-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286611PMC
July 2021

Ambient fine particulate matter air pollution and the risk of preterm birth: A multicenter birth cohort study in China.

Environ Pollut 2021 Oct 22;287:117629. Epub 2021 Jun 22.

Heart Center, Children's Hospital of Fudan University, National Center for Children's Health, Shanghai, China. Electronic address:

Preterm birth (PTB), defined as live birth before the 37th week of gestation, is believed to have profound impacts on the infant's health in later life. Air pollution has been suggested to be a potential risk factor of PTB, but the evidence was inconsistent. In this multicenter birth cohort study, we aimed to examine the association between fine particulate matter (PM) exposure during pregnancy and PTB in China. A total of 5976 live births were identified between Jan. 2009 and Feb. 2011 from 8 provinces in China. Residential exposures to PM were assigned based on satellite remote sensing estimates. Cox proportional hazards regressions were employed to explore the correlation for each trimester as well as the entire pregnancy. A total of 443 (7.4%) preterm births were observed. The average PM during pregnancy was 57.2 ± 8.8 μg/m. We found exposure to PM during the whole pregnancy (hazard ratio, HR = 1.262; 95% CI: 1.087-1.465) and in the first trimester (HR = 1.114; 95% CI: 1.007-1.232) was associated with higher risk of PTB. The associations of PM were stronger for subjects with older maternal or paternal age, lower maternal pre-pregnancy BMI, and lower family income. This study adds supports to the cumulating evidence linking PM exposure and elevated PTB risk. Measures of air pollution reduction are needed during pregnancy, especially at early stage of pregnancy to prevent adverse birth outcomes.
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http://dx.doi.org/10.1016/j.envpol.2021.117629DOI Listing
October 2021

Breast cancer risk factors and circulating anti-Müllerian hormone concentration in healthy premenopausal women.

J Clin Endocrinol Metab 2021 Jun 22. Epub 2021 Jun 22.

Department of Population Health, New York University School of Medicine, New York, NY.

Context: In a previous study we reported that anti-Müllerian hormone (AMH), a marker of ovarian reserve, is positively associated with breast cancer risk, consistent with other studies.

Objective: Assess whether risk factors for breast cancer are correlates of AMH concentration.

Design: Cross-sectional.

Participants: 3831 healthy premenopausal women (aged 21-57, 87% aged 35-49).

Setting: Ten cohort studies, general population.

Results: Adjusting for age and cohort, we observed positive associations of AMH with age at menarche (p<0.0001) and parity (p=0.0008), and an inverse association with hysterectomy/partial oophorectomy (p=0.0008). Compared to women of normal weight (BMI 18.5-24.9 kg/m 2, AMH was lower (relative geometric mean difference 27%, p<0.0001) among women who were obese (BMI>30). Current oral contraceptive use and current/former smoking were associated with lower AMH concentration than never use (40% and 12% lower, respectively, p<0.0001). We observed higher AMH concentrations among women who had had a benign breast biopsy (15% higher, p=0.03), a surrogate for benign breast disease, an association that has not been reported. In analyses stratified by age (<40/≥40), associations of AMH with BMI and oral contraceptives were similar in younger and older women, while associations with the other factors (menarche, parity, hysterectomy/partial oophorectomy, smoking, and benign breast biopsy) were limited to women ≥40 (p-interaction<0.05).

Conclusion: This is the largest study of AMH and breast cancer risk factors among women from the general population (not presenting with infertility), and suggests that most of the associations are limited to women over 40, who are approaching menopause and whose AMH concentration is declining.
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http://dx.doi.org/10.1210/clinem/dgab461DOI Listing
June 2021

Prenatal fine particulate matter exposure, placental DNA methylation changes, and fetal growth.

Environ Int 2021 02 17;147:106313. Epub 2020 Dec 17.

Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China (Fudan University), China; Key Laboratory of Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China. Electronic address:

This study was designed to examine the impact of prenatal fine particulate matter (PM) exposure on fetal growth and the underlying placental epigenetic mechanism in a cohort of Chinese women. Within the prospective Shanghai Mother-Child Pairs cohort (Shanghai MCPC), 329 women carrying singleton pregnancy with a due date in 2018 were recruited between 2017 and 2018. Maternal PM exposure levels were estimated using gestational exposure prediction model combining satellite-driven ambient concentrations and personal air sampling. Fetal growth characteristics were evaluated by prenatal ultrasound examinations and anthropometric measurements at birth. In a discovery phase, whole-genome DNA methylation analysis was performed using the Infinium 850 K array. In a validation phase, placental DNA methylation was measured using bisulfite pyrosequencing for five candidate genes that showed the most significant alterations and function relevance in our methylation array screen, including BID (BH3 interacting domain death agonist), FOXN3 (Forkhead box N3), FOXP1 (Forkhead box P1), IGF2 (Insulin-like growth factor 2) and HSD11B2 (Hydroxysteroid 11-beta dehydrogenase 2). Multivariate linear regression models were applied to examine the associations among PM exposure, fetal growth characteristics and DNA methylation on placental candidate genes. Sobel tests were used to evaluate the mediating role of DNA methylation in multivariable models. After excluding women who withdrew or failed to provide placenta, a total of 287 pregnant women with an average age of 30 entered the final analysis. Increased PM exposure was significantly associated with reduced biparietal diameter (BPD) (β: -0.136 mm, 95% CI: -0.228 to -0.043), head circumference (HC) (β: -0.462 mm, 95% CI: -0.782 to -0.142), femur length (FL) (β: -0.113 mm, 95% CI: -0.185 to -0.041) and abdominal circumference (AC) (β: -0.371 mm, 95% CI: -0.672 to -0.071) in the second trimester and birth length (β: -0.013 cm, 95% CI: -0.025 to -0.001). Prenatal PM exposure could lead to aberrant changes in DNA methylation profile of placenta genome, which were mainly enriched in reproductive development, energy metabolism and immune response. DNA methylation of IGF2 and BID showed significant associations with PM exposures during all exposure windows. In addition, BID methylation was negatively correlated with HC (β: -1.396 mm, 95% CI: -2.582 to -0.209) and BPD (β: -0.330 mm, 95% CI: -0.635 to -0.026) in the second trimester. Further mediation analysis indicated that BID methylation mediated about 30% of the effects of PM exposure on HC. These findings collectively suggested that prenatal PM exposure may cause adverse effects on fetal growth by modifying placental DNA methylation.
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http://dx.doi.org/10.1016/j.envint.2020.106313DOI Listing
February 2021

Associations of long-term exposure to ambient nitrogen dioxide with indicators of diabetes and dyslipidemia in China: A nationwide analysis.

Chemosphere 2021 Apr 24;269:128724. Epub 2020 Oct 24.

School of Public Health, Key Lab of Public Health Safety of the Ministry of Education and NHC Key Lab of Health Technology Assessment, Fudan University, Shanghai, 200032, China.

Background: The associations between ambient NO and diabetes and dyslipidemia have been controversial, and data is especially lacking in developing countries.

Objective: This study aimed to assess the associations of long-term exposure to NO with diabetes and dyslipidemia in China.

Methods: We conducted a cross-sectional study including 13,013 participants from the China Health and Retirement Longitudinal Study (CHRLS). The annual average concentrations of NO were estimated based on the residential addresses of participants. We applied logistic regression models to evaluate the associations of NO with diabetes and dyslipidemia, and linear regression models to assess the associations with blood biomarkers.

Results: A total of 1933 diabetes cases (14.85%) and 1935 (14.87%) dyslipidemia cases were identified. Significant associations were observed between NO and risk of diabetes and dyslipidemia independent of PM and O. For an interquartile range (IQR) increase in NO (12.39 μg/m), we observed a 13% [odds ratio (OR): 1.13; 95% confidence interval (CI): 1.01, 1.26] increased risk of diabetes, 1.48% (95%CI: 0.51%, 2.46%) increase in glucose, 0.74% (95%CI: 0.19%, 1.29%) increase in glycosylated hemoglobin (HbA1c), 17% (OR: 1.17; 95% CI: 1.05, 1.31) increased risk of dyslipidemia, 4.62% (95%CI: 2.49%, 6.79%) increase in triglyceride, and a decrease of 2.96% (95%CI: 2.13%, 3.79%) in high-density lipoprotein. The associations of NO with glucose disorders were stronger among smokers.

Conclusions: Our study indicated long-term exposure to NO might contribute to the development of diabetes and dyslipidemia, and the associations were potentially independent of O and PM.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904633PMC
April 2021

Ambient fine particulate matter induced the elevation of blood pressure through ACE2/Ang(1-7) pathway: The evidence from urine metabolites.

Ecotoxicol Environ Saf 2020 Oct 21;203:111044. Epub 2020 Jul 21.

Department of Environmental Health, School of Public Health and the Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, China; Children's Hospital of Fudan University, National Center for Children's Health, Shanghai, China. Electronic address:

Background: Exposure to ambient fine particulate matter (PM) is associated with various adverse health outcomes. Although several mechanisms have been proposed including oxidative stress and inflammatory responses, the exact mechanism is still unknown. Few studies have investigated the mechanism linking PM and blood pressure (BP). In this study, we measured urinary metabolites and BP -related renin-angiotensin-aldosterone system (RAAS) to investigate the associations between ambient PM exposure and BP in healthy C57BL/6 mice.

Methods: The C57BL/6 mice were exposed to ambient concentrated PM or filtered air (FA) for 16 weeks. Systolic BP and diastolic BP were measured by noninvasive BP system. The urine metabolites were quantified using the untargeted metabolomics approach. The expression of RAAS-related proteins angiotensin-converting enzyme (ACE)2, angiotensin (Ang) II, Ang (1-7) and aldosterone (ALD) were measured using Western blot and ELISA kits.

Results: The metabolomics analysis demonstrated that PM exposure induced significant changes of some metabolites in urine, including stress hormones, amino acids, fatty acids, and lipids. Furthermore, there was an elevation of BP, increase of serous Ang II and ALD, along with the decrease of ACE2 and Ang (1-7) in kidney in the PM-exposed mice compared with FA-exposed mice.

Conclusions: The results demonstrated that PM exposure-induced BP elevation might be associated with RAAS activation. Meanwhile, PM exposure-induced changes of stress hormone and lipid metabolism might mediate the activation of RAAS. The results suggested that the systemic stress hormone and lipid metabolism was associated with the development of hypertension.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111044DOI Listing
October 2020

Necessity of personal sampling for exposure assessment on specific constituents of PM: Results of a panel study in Shanghai, China.

Environ Int 2020 08 17;141:105786. Epub 2020 May 17.

School of Public Health, Key Lab of Public Health Safety of the Ministry of Education and NHC Key Laboratory of Health Technology Assessment, Fudan University, Shanghai, China; Key Laboratory of Reproduction Regulation of National Population and Family Planning Commission, Shanghai Institute of Planned Research, Institute of Reproduction and Development, Fudan University, Shanghai, China. Electronic address:

Many epidemiological studies have evaluated the health risks of ambient fine particulate matter (PM). However, few studies have investigated the potential exposure misclassification caused by using ambient PM concentrations as proxy for individual exposure to PM in regions with high-level of air pollution. This study aimed to compare the differences between personal and ambient PM constituent concentrations, and to predict the personal exposure of sixteen PM constituents. We collected 141 72-h personal exposure filter samples from a panel of 36 healthy non-smoking college students in Shanghai, China. We then used the liner mixed effects models to predict personal constituent-specific exposure using ambient observations and several possible influencing factors including time-activity patterns, temporal variables, and meteorological conditions. The final model of each component was further evaluated by determination coefficient (R) and root mean square error (RMSE) from leave-one-out-cross-validation (LOOCV). We observed ambient concentrations were higher than personal concentrations for all PM components except for Mn, Fe, Ca, and V. Especially, ambient NH, As, and NO concentrations were 3.65, 5.65 and 7.33-fold higher than their corresponding personal concentrations, respectively. The ambient level was the strongest predictor of their corresponding personal PM components with the highest marginal R (R: 0.081 ~ 0.901), meteorological conditions (R: 0.000 ~ 0.357), time-activity pattern (R: 0.000 ~ 0.083) and temporal indicators (R: 0.031 ~ 0.562) were also important predictors. Our final models predicted at least 50% of the variance of all personal PM constituents and even over 90% for K, Pb, and SO. LOOCV analysis showed that R and RMSE ranged from 0.251 to 0.907 and 0.000 to 0.092 μg/m, respectively. Our results showed that ambient concentration of most PM constituents along with time-activity patterns, temporal variables, and meteorological conditions, could adequately predict personal exposure concentration. Prediction models of individual PM constituent may help to improve the accuracy of exposure measurement in future epidemiological studies.
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http://dx.doi.org/10.1016/j.envint.2020.105786DOI Listing
August 2020

Lactational exposure of polybrominated diphenyl ethers and its association with infant developmental measurements.

J Hazard Mater 2020 04 8;388:122031. Epub 2020 Jan 8.

Key Laboratory of Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China. Electronic address:

This study was designed to assess the effect of lactational polybrominated diphenyl ether (PBDE) exposure on early physical development of both healthy and fetal growth restriction (FGR) infants. Z scores of head circumference-for-age (ZHC), length-for-age (ZLEN), weight-for-age (ZWEI) and weight-for-length (ZWFL) were calculated according to the WHO Child Growth Standards. FGR infants had a higher PBDE exposure level and faster growth speed from 42 days to 6 months compared with healthy infants. Exposure of lower brominated BDEs (BDE28∼154) and the sum of 18 BDE congeners (BDE28∼209) negatively associated with ZHC [mean difference estimate (95 % CI): -0.71 (-1.22, -0.22) and -0.81 (-1.31, -0.33)] in FGR boys. Both BDE153 and BDE196 exposure had a significant correlation with ZLEN of boys in FGR group [mean difference estimate (95 % CI): -0.28 (-0.48, -0.07) and -0.52 (-0.91, -0.14)]. Each 10 ng/g lipid increase in the concentrations of BDE154 were respectively associated with 0.16 increase in ZWEI among boys in healthy group. No significant association was found in girls. Lactational PBDE exposure had effects on the early growth of both FGR and healthy infants. The encouragement of breastfeeding should therefore be considered in conjunction with PBDE contamination levels.
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http://dx.doi.org/10.1016/j.jhazmat.2020.122031DOI Listing
April 2020

Clinical and Molecular Prevalence of Lipodystrophy in an Unascertained Large Clinical Care Cohort.

Diabetes 2020 02 13;69(2):249-258. Epub 2019 Dec 13.

Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc., Tarrytown, NY.

Lipodystrophies are a group of disorders characterized by absence or loss of adipose tissue and abnormal fat distribution, commonly accompanied by metabolic dysregulation. Although considered rare disorders, their prevalence in the general population is not well understood. We aimed to evaluate the clinical and genetic prevalence of lipodystrophy disorders in a large clinical care cohort. We interrogated the electronic health record (EHR) information of >1.3 million adults from the Geisinger Health System for lipodystrophy diagnostic codes. We estimate a clinical prevalence of disease of 1 in 20,000 individuals. We performed genetic analyses in individuals with available genomic data to identify variants associated with inherited lipodystrophies and examined their EHR for comorbidities associated with lipodystrophy. We identified 16 individuals carrying the p.R482Q pathogenic variant in LMNA associated with Dunnigan familial partial lipodystrophy. Four had a clinical diagnosis of lipodystrophy, whereas the remaining had no documented clinical diagnosis despite having accompanying metabolic abnormalities. We observed a lipodystrophy-associated variant carrier frequency of 1 in 3,082 individuals in our cohort with substantial burden of metabolic dysregulation. We estimate a genetic prevalence of disease of ∼1 in 7,000 in the general population. Partial lipodystrophy is an underdiagnosed condition. and its prevalence, as defined molecularly, is higher than previously reported. Genetically guided stratification of patients with common metabolic disorders, like diabetes and dyslipidemia, is an important step toward precision medicine.
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http://dx.doi.org/10.2337/db19-0447DOI Listing
February 2020

Associations between in utero exposure to polybrominated diphenyl ethers, pathophysiological state of fetal growth and placental DNA methylation changes.

Environ Int 2019 12 23;133(Pt B):105255. Epub 2019 Oct 23.

Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China (Fudan University), China; Key Laboratory of Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China. Electronic address:

Background: Polybrominated diphenyl ethers (PBDEs) are environmental chemicals with harmful effects on pregnancy, but their effects on adverse developmental outcomes are not fully understood. The placental DNA methylation is strongly influenced by prenatal environmental factors and has been linked to fetal growth.

Objective: To evaluate the association between in utero PBDEs exposure, placental DNA methylation changes (growth regulatory genes), and pathophysiology of fetal growth (birth outcomes, fetal growth retardation) in a population-based pregnancy cohort study.

Methods: This was a nested case-control study within the prospective Wenzhou Birth Cohort including 130 fetal growth retardation (FGR) cases and 130 healthy controls and their mothers recruited from June 2016 to June 2017. FGR was diagnosed based on the comprehensive evaluation of ultrasound results at 24, 28, and 32 weeks of gestation. Neonatal birth measurements were obtained from medical records. Gestational exposure to 19 PBDEs, including 13 lower BDE congeners (BDE-17-190) and 6 higher brominated BDE congeners (BDE-196-209), were determined by gas chromatography tandem mass spectrometry in the umbilical cord blood. Placental DNA methylation changes of one repetitive element (LINE1) and two candidate genes (HSD11B2, IGF2) were characterized by quantitative polymerase chain reaction-pyrosequencing. Multiple linear regression and logistic regression models were used to examine the associations among PBDEs exposure, fetal growth indicators, and DMR (differential methylation region) methylation fractions. Sobel tests were conducted to assess DNA methylation as a mediator in multivariate models.

Results: After excluding women who withdrew from the study or were lost to follow-up or failed to provide placenta or umbilical cord blood, 249 mother-newborn pairs (124 FGR cases, 125 controls) were included in the final analysis. Elevated BDE-206 (OR: 1.569, 95% CIs: 1.053-2.338), BDE-17-190 (OR: 2.860, 95% CIs: 1.233-6.634), BDE-196-209 (OR: 1.688, 95% CIs: 1.024-2.783) and ∑PBDEs (OR: 2.387, 95% CIs: 1.220-4.668) concentrations were associated with increased risk of FGR in newborns. FGR birth was also associated with increased DNA methylation of HSD11B2 (OR: 1.145, 95% CIs: 1.032-1.270) and decreased DNA methylation of IGF2 (OR: 0.892, 95% CIs: 0.845-0.941). In addition, BDE-17-190 showed significant associations with DNA methylation of HSD11B2 and IGF2 (β: 1.127, 95% CIs: 0.069-2.186; β: -3.452, 95% CIs: -5.512-1.392), indicating placental DNA methylation changes of HSD11B2 and IGF2 were related to both lower BDE congeners exposure and fetal growth. Further mediation analyses showed that IGF2 methylation mediated about 40% of the effects of BDE-17-190 in umbilical cord blood on neonatal FGR.

Conclusion: We report an inverse association between in utero exposures to PBDEs and fetal growth and provide evidence supporting epigenetic gene plasticity in these associations. Changes in placental DNA methylation might be part of the underlying biological pathway between prenatal PBDEs exposure and adverse fetal growth.
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http://dx.doi.org/10.1016/j.envint.2019.105255DOI Listing
December 2019

Impact of short-term exposure to fine particulate matter air pollution on urinary metabolome: A randomized, double-blind, crossover trial.

Environ Int 2019 09 11;130:104878. Epub 2019 Jun 11.

School of Public Health, Key Lab of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China; Key Laboratory of Reproduction Regulation of National Population and Family Planning Commission, Shanghai Institute of Planned Parenthood Research, Institute of Reproduction and Development, Fudan University, Shanghai 200032, China. Electronic address:

Background: Metabolomics is a novel tool to explore the biological mechanisms of the health effects of fine particulate matter (PM) air pollution. Very few studies have examined the urinary metabolomic changes associated with PM exposure.

Objective: To assess the alternation in urine metabolomics in response to short-term PM exposure.

Methods: We conducted a randomized, double-blind, crossover trial of 9-day real or sham indoor air purification among 45 healthy college students in Shanghai, China. Urine samples were collected immediately at the end of each intervention stage and were analyzed for metabolomics using ultrahigh performance liquid chromatography-mass spectrometry. Orthogonal partial least square-discriminant analysis and linear mixed effect models were used to examine metabolomic changes between interventional scenarios and their associations with continuous PM exposure.

Results: The time-weighted average personal PM exposure in the real-purified scenario was 50% lower than in the sham-purified air scenario (28.3 μg/m VS 56.9 μg/m). A total of 40 differentiated urinary metabolites at a false discovery rate <0.05 were identified for the effects of both intervention and continuous PM exposure, including 16 lipids, 5 purine metabolites, 2 neurotransmitters, and 3 coenzymes.

Conclusions: This real-world randomized crossover trial demonstrated that short-term PM exposure could result in significant changes in urinary metabolomic profile, which may further lead to perturbation in energy metabolism, oxidative stress and inflammation.
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http://dx.doi.org/10.1016/j.envint.2019.05.072DOI Listing
September 2019

Personal exposure to PM constituents associated with gestational blood pressure and endothelial dysfunction.

Environ Pollut 2019 Jul 11;250:346-356. Epub 2019 Apr 11.

Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China (Fudan University), China; Key Laboratory of Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai, 200032, China. Electronic address:

Ambient fine particulate matter (PM) pollution has been implicated in the development of hypertensive disorders of pregnancy. However, evidence on the effects of PM-derived chemical constituents on gestational blood pressure (BP) is limited, and the potential mechanisms underlying the association remain unclear. In this study, we repeated three consecutive 72-h personal air sampling and BP measurements in 215 pregnant women for 590 visits during pregnancy. Individual PM exposure level was assessed by gravimetric method and 28 PM chemical constituents were analyzed by ED-XRF method. Plasma biomarkers of endothelial function and inflammation were measured using multiplexed immunoassays. Robust multiple linear regression models were used to estimate the associations among personal PM exposure and chemical constituents, BP changes (compared with pre-pregnancy BP) and plasma biomarkers. Mediation analyses were performed to evaluate underlying potential pathways. Result showed that exposure to PM was significantly associated with increases in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) in the early second trimester. Meanwhile, elevated concentration of lead (Pb) constituent in PM was significant associated with increases in DBP and MAP after adjusting for PM total mass. PM and Pb constituent also presented positive associations with plasma biomarkers of endothelial function (ET-1, E-selectin, ICAM-1) and inflammation (IL-1β, IL-6, TNFα) significantly. After multiple adjustment, elevated ET-1 and IL-6 were significantly correlated with increased gestational BP, and respectively mediated 1.24%-25.06% and 7.01%-10.69% of the increased BP due to PM and Pb constituent exposure. In conclusion, our results suggested that personal exposure to PM and Pb constituent were significantly associated with increased BP during pregnancy, and the early second trimester might be the sensitive window of PM exposure. The endothelial dysfunction and elevated inflammation partially mediated the effect of PM and Pb constituent on BP during pregnancy.
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http://dx.doi.org/10.1016/j.envpol.2019.04.024DOI Listing
July 2019

Breast cancer risk prediction in women aged 35-50 years: impact of including sex hormone concentrations in the Gail model.

Breast Cancer Res 2019 03 19;21(1):42. Epub 2019 Mar 19.

Department of Population Health, New York University School of Medicine, 650 First Avenue, New York, NY, 10016, USA.

Background: Models that accurately predict risk of breast cancer are needed to help younger women make decisions about when to begin screening. Premenopausal concentrations of circulating anti-Müllerian hormone (AMH), a biomarker of ovarian reserve, and testosterone have been positively associated with breast cancer risk in prospective studies. We assessed whether adding AMH and/or testosterone to the Gail model improves its prediction performance for women aged 35-50.

Methods: In a nested case-control study including ten prospective cohorts (1762 invasive cases/1890 matched controls) with pre-diagnostic serum/plasma samples, we estimated relative risks (RR) for the biomarkers and Gail risk factors using conditional logistic regression and random-effects meta-analysis. Absolute risk models were developed using these RR estimates, attributable risk fractions calculated using the distributions of the risk factors in the cases from the consortium, and population-based incidence and mortality rates. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory accuracy of the models with and without biomarkers.

Results: The AUC for invasive breast cancer including only the Gail risk factor variables was 55.3 (95% CI 53.4, 57.1). The AUC increased moderately with the addition of AMH (AUC 57.6, 95% CI 55.7, 59.5), testosterone (AUC 56.2, 95% CI 54.4, 58.1), or both (AUC 58.1, 95% CI 56.2, 59.9). The largest AUC improvement (4.0) was among women without a family history of breast cancer.

Conclusions: AMH and testosterone moderately increase the discriminatory accuracy of the Gail model among women aged 35-50. We observed the largest AUC increase for women without a family history of breast cancer, the group that would benefit most from improved risk prediction because early screening is already recommended for women with a family history.
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http://dx.doi.org/10.1186/s13058-019-1126-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425605PMC
March 2019

Phthalate exposure and childhood overweight and obesity: Urinary metabolomic evidence.

Environ Int 2018 12 9;121(Pt 1):159-168. Epub 2018 Sep 9.

Key Lab of Health Technology Assessment, National Health Commission of the People's Republic of China (Fudan University), China; Key Laboratory of Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China. Electronic address:

Objective: Metabolomics may unravel global metabolic changes in response to environmental exposures and identify important biological pathways involved in the pathophysiology of childhood obesity. Phthalate has been considered an obesogen and contributing to overweight and obesity in children. The purpose of this study is to evaluate changes in urine metabolites in response to the environmental phthalate exposure among overweight or obese children, and to investigate the metabolic mechanisms involved in the obesogenic effect of phthalate on children at puberty.

Methods: Within the national Puberty Timing and Health Effects in Chinese Children (PTHEC) study, 69 overweight/obese children and 80 normal weight children were selected into the current study according to their puberty timing and WGOC (The Working Group for obesity in China) references. Urinary concentrations of six phthalate monoesters (MMP, MEP, MnBP, MEHP, MEOHP and MEHHP) were measured using API 2000 electrospray triple quadrupole mass spectrometer (ESIMS/MS). Metabolomic profiling of spot urine was performed using gas chromatography-mass spectrometry. Differentially expressed urinary metabolites associated with phthalate monoesters exposure were examined using orthogonal partial least square-discriminant analysis and multiple linear regression models. In addition, the candidate metabolites were regressed to obesity indices with multiple linear regression models and logistic regression models in all subjects.

Results: Compared with normal weight children, higher levels of MnBP were detected in urinary samples of children with overweight and obesity. After adjusting for confounders including chronological age, gender, puberty onset, daily energy intake and physical activity and socio-economic level, positive association remained between urinary MnBP concentration and childhood overweight/obesity [OR = 1.586, 95% CI:1.043,2.412]. We observed elevated MnBP concentration was significantly correlated with increased levels of monostearin, 1-monopalmitin, stearic acid, itaconic acid, glycerol 3-phosphate, 5-methoxytryptamine, kyotorphin, 1-methylhydantoin, d-alanyl-d-alanine, pyrrole-2-carboxylic acid, 3,4-Dihydroxyphenylglycol, and butyraldehyde. Meanwhile, increased MnBP concentration was also significantly correlated with decreased levels of lactate, glucose 6-phosphate, d-fructose 6-phosphate, palmitic acid, 4-acetamidobutyric acid, l-glutamic acid, n-acetyl-l-phenylalanine, iminodiacetic acid, hydroxyproline, pipecolinic acid, l-ornithine, n-acetyl-l-glutamic acid, guanosine, cytosin, and (s)-mandelic acid in the normal weight subjects. The observations indicated that MnBP exposure was related to global urine metabolic abnormalities characterized by disrupting arginine and proline metabolism and increasing oxidative stress and fatty acid reesterification. Among the metabolic markers related to MnBP exposure, 1-methylhydantoin, pyrrole-2-carboxylic acid and monostearin were found to be positively correlated with obesity indices, while hydroxyproline, l-ornithine, and lactate were negatively associated with overweight/obesity in children.

Conclusions: Our results suggested that the disrupted arginine and proline metabolism associated with phthalate exposure might contribute to the development of overweight and obesity in school-age children, providing insights into the pathophysiological changes and molecular mechanisms involved in childhood obesity.
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http://dx.doi.org/10.1016/j.envint.2018.09.001DOI Listing
December 2018

Circulating anti-Müllerian hormone and breast cancer risk: A study in ten prospective cohorts.

Int J Cancer 2018 06 8;142(11):2215-2226. Epub 2018 Feb 8.

Department of Population Health, New York University School of Medicine, New York, NY.

A strong positive association has been observed between circulating anti-Müllerian hormone (AMH), a biomarker of ovarian reserve, and breast cancer risk in three prospective studies. Confirming this association is important because of the paucity of biomarkers of breast cancer risk in premenopausal women. We conducted a consortium study including ten prospective cohorts that had collected blood from premenopausal women. A nested case-control design was implemented within each cohort. A total of 2,835 invasive (80%) and in situ (20%) breast cancer cases were individually matched to controls (n = 3,122) on age at blood donation. AMH was measured using a high sensitivity enzyme-linked immunoabsorbent assay. Conditional logistic regression was applied to the aggregated dataset. There was a statistically significant trend of increasing breast cancer risk with increasing AMH concentration (p across quartiles <0.0001) after adjusting for breast cancer risk factors. The odds ratio (OR) for breast cancer in the top vs. bottom quartile of AMH was 1.60 (95% CI = 1.31-1.94). Though the test for interaction was not statistically significant (p  = 0.15), the trend was statistically significant only for tumors positive for both estrogen receptor (ER) and progesterone receptor (PR): ER+/PR+: OR  = 1.96, 95% CI = 1.46-2.64, p <0.0001; ER+/PR-: OR  = 0.82, 95% CI = 0.40-1.68, p  = 0.51; ER-/PR+: OR  = 3.23, 95% CI = 0.48-21.9, p  = 0.26; ER-/PR-: OR  = 1.15, 95% CI = 0.63-2.09, p  = 0.60. The association was observed for both pre- (OR = 1.35, 95% CI = 1.05-1.73) and post-menopausal (OR  = 1.61, 95% CI = 1.03-2.53) breast cancer (p  = 0.34). In this large consortium study, we confirmed that AMH is associated with breast cancer risk, with a 60% increase in risk for women in the top vs. bottom quartile of AMH.
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http://dx.doi.org/10.1002/ijc.31249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922424PMC
June 2018

Genetic Polymorphisms in Vitamin D Metabolism and Signaling Genes and Risk of Breast Cancer: A Nested Case-Control Study.

PLoS One 2015 21;10(10):e0140478. Epub 2015 Oct 21.

Department of Population Health, New York University School of Medicine, New York, New York, United States of America; New York University Cancer Institute, New York University School of Medicine, New York, New York, United States of America.

Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH)D concentration in GWAS were also associated with plasma 25(OH)D in our study (p-trend <0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH)D with breast cancer risk, do not support an association between vitamin D and breast cancer risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140478PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619526PMC
June 2016

Genotyping of Single Nucleotide Polymorphisms in DNA Isolated from Serum Using Sequenom MassARRAY Technology.

PLoS One 2015 14;10(8):e0135943. Epub 2015 Aug 14.

Department of Population Health, New York University School of Medicine, New York, New York, United States of America; NYU Cancer Institute, New York University Langone Medical Center, New York, New York, United States of America.

Background: Large epidemiologic studies have the potential to make valuable contributions to the assessment of gene-environment interactions because they prospectively collected detailed exposure data. Some of these studies, however, have only serum or plasma samples as a low quantity source of DNA.

Methods: We examined whether DNA isolated from serum can be used to reliably and accurately genotype single nucleotide polymorphisms (SNPs) using Sequenom multiplex SNP genotyping technology. We genotyped 81 SNPs using samples from 158 participants in the NYU Women's Health Study. Each participant had DNA from serum and at least one paired DNA sample isolated from a high quality source of DNA, i.e. clots and/or cell precipitates, for comparison.

Results: We observed that 60 of the 81 SNPs (74%) had high call frequencies (≥95%) using DNA from serum, only slightly lower than the 85% of SNPs with high call frequencies in DNA from clots or cell precipitates. Of the 57 SNPs with high call frequencies for serum, clot, and cell precipitate DNA, 54 (95%) had highly concordant (>98%) genotype calls across all three sample types. High purity was not a critical factor to successful genotyping.

Conclusions: Our results suggest that this multiplex SNP genotyping method can be used reliably on DNA from serum in large-scale epidemiologic studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135943PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537187PMC
May 2016

A prospective study of arm circumference and risk of death in Bangladesh.

Int J Epidemiol 2014 Aug 7;43(4):1187-96. Epub 2014 Apr 7.

Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA, Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York City, USA, Leon H Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, USA, Columbia University Arsenic Research Project, Dhaka, Bangladesh, Departments of Health Studies, Medicine and Human Genetics and Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA and Department of Biostatistics, Mailman School of Public Health, Columbia University, New York City, USA

Background: Epidemiological studies have observed protective effects of mid-upper arm circumference (MUAC) against all-cause mortality mostly in Western populations. However, evidence on cause-specific mortality is limited.

Methods: The sample included 19 575 adults from a population-based cohort study in rural Bangladesh, who were followed up for an average of 7.9 years for mortality. Cox proportional hazards regression was used to evaluate the effect of MUAC, as well as the joint effect of body mass index (BMI) and MUAC, on the risk of death from any cause, cancer and cardiovascular disease (CVD).

Results: During 154 664 person-years of follow-up, 744 deaths including 312 deaths due to CVD and 125 deaths due to cancer were observed. There was a linear inverse relationship of MUAC with total and CVD mortality. Each 1-cm increase in MUAC was associated a reduced risk of death from any cause [hazard ratio (HR) = 0.85; 95% confidence interval (C), 0.81-0.89) and CVD (HR = 0.87; 95% CI, 0.80-0.94), after controlling for potential confounders. No apparent relationship between MUAC and the risk of death from cancer was observed. Among individuals with a low BMI (<18.5 kg/m(2)), a MUAC less than 24 cm was associated with increased risk for all-cause (HR = 1.81; 95% CI, 1.52-2.17) and CVD mortality (HR = 1.45; 95% CI, 1.11-1.91).

Conclusions: MUAC may play a critical role on all-cause and CVD mortality in lean Asians.
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http://dx.doi.org/10.1093/ije/dyu082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121562PMC
August 2014

Association between arsenic exposure from drinking water and hematuria: results from the Health Effects of Arsenic Longitudinal Study.

Toxicol Appl Pharmacol 2014 Apr 28;276(1):21-7. Epub 2014 Jan 28.

Department of Health Studies, The University of Chicago, Chicago, IL, USA; Department of Medicine, The University of Chicago, Chicago, IL, USA; Department of Human Genetics, The University of Chicago, Chicago, IL, USA; Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA. Electronic address:

Arsenic (As) exposure has been associated with both urologic malignancy and renal dysfunction; however, its association with hematuria is unknown. We evaluated the association between drinking water As exposure and hematuria in 7843 men enrolled in the Health Effects of Arsenic Longitudinal Study (HEALS). Cross-sectional analysis of baseline data was conducted with As exposure assessed in both well water and urinary As measurements, while hematuria was measured using urine dipstick. Prospective analyses with Cox proportional regression models were based on urinary As and dipstick measurements obtained biannually since baseline up to six years. At baseline, urinary As was significantly related to prevalence of hematuria (P-trend<0.01), with increasing quintiles of exposure corresponding with respective prevalence odds ratios of 1.00 (reference), 1.29 (95% CI: 1.04-1.59), 1.41 (95% CI: 1.15-1.74), 1.46 (95% CI: 1.19-1.79), and 1.56 (95% CI: 1.27-1.91). Compared to those with relatively little absolute urinary As change during follow-up (-10.40 to 41.17 μg/l), hazard ratios for hematuria were 0.99 (95% CI: 0.80-1.22) and 0.80 (95% CI: 0.65-0.99) for those whose urinary As decreased by >47.49 μg/l and 10.87 to 47.49 μg/l since last visit, respectively, and 1.17 (95% CI: 0.94-1.45) and 1.36 (95% CI: 1.10-1.66) for those with between-visit increases of 10.40 to 41.17 μg/l and >41.17 μg/l, respectively. These data indicate a positive association of As exposure with both prevalence and incidence of dipstick hematuria. This exposure effect appears modifiable by relatively short-term changes in drinking water As.
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http://dx.doi.org/10.1016/j.taap.2014.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959280PMC
April 2014

Association between body mass index and cardiovascular disease mortality in east Asians and south Asians: pooled analysis of prospective data from the Asia Cohort Consortium.

BMJ 2013 Oct 1;347:f5446. Epub 2013 Oct 1.

Department of Population Health, New York University School of Medicine, New York, NY, USA.

Objective: To evaluate the association between body mass index and mortality from overall cardiovascular disease and specific subtypes of cardiovascular disease in east and south Asians.

Design: Pooled analyses of 20 prospective cohorts in Asia, including data from 835,082 east Asians and 289,815 south Asians. Cohorts were identified through a systematic search of the literature in early 2008, followed by a survey that was sent to each cohort to assess data availability.

Setting: General populations in east Asia (China, Taiwan, Singapore, Japan, and Korea) and south Asia (India and Bangladesh).

Participants: 1,124,897 men and women (mean age 53.4 years at baseline).

Main Outcome Measures: Risk of death from overall cardiovascular disease, coronary heart disease, stroke, and (in east Asians only) stroke subtypes.

Results: 49,184 cardiovascular deaths (40,791 in east Asians and 8393 in south Asians) were identified during a mean follow-up of 9.7 years. East Asians with a body mass index of 25 or above had a raised risk of death from overall cardiovascular disease, compared with the reference range of body mass index (values 22.5-24.9; hazard ratio 1.09 (95% confidence interval 1.03 to 1.15), 1.27 (1.20 to 1.35), 1.59 (1.43 to 1.76), 1.74 (1.47 to 2.06), and 1.97 (1.44 to 2.71) for body mass index ranges 25.0-27.4, 27.5-29.9, 30.0-32.4, 32.5-34.9, and 35.0-50.0, respectively). This association was similar for risk of death from coronary heart disease and ischaemic stroke; for haemorrhagic stroke, the risk of death was higher at body mass index values of 27.5 and above. Elevated risk of death from cardiovascular disease was also observed at lower categories of body mass index (hazard ratio 1.19 (95% confidence interval 1.02 to 1.39) and 2.16 (1.37 to 3.40) for body mass index ranges 15.0-17.4 and <15.0, respectively), compared with the reference range. In south Asians, the association between body mass index and mortality from cardiovascular disease was less pronounced than that in east Asians. South Asians had an increased risk of death observed for coronary heart disease only in individuals with a body mass index greater than 35 (hazard ratio 1.90, 95% confidence interval 1.15 to 3.12).

Conclusions: Body mass index shows a U shaped association with death from overall cardiovascular disease among east Asians: increased risk of death from cardiovascular disease is observed at lower and higher ranges of body mass index. A high body mass index is a risk factor for mortality from overall cardiovascular disease and for specific diseases, including coronary heart disease, ischaemic stroke, and haemorrhagic stroke in east Asians. Higher body mass index is a weak risk factor for mortality from cardiovascular disease in south Asians.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788174PMC
http://dx.doi.org/10.1136/bmj.f5446DOI Listing
October 2013

Association between anthropometric measures of obesity and subclinical atherosclerosis in Bangladesh.

Atherosclerosis 2014 Jan 19;232(1):234-41. Epub 2013 Nov 19.

Department of Environmental Medicine, New York University School of Medicine, New York, NY, USA. Electronic address:

Background: Anthropometric measures such as waist-hip-ratio (WHR), waist-height-ratio (WHtR), waist circumference, Mid-upper arm circumference (MUAC), and upper thigh circumference, have been linked to the risk of cardiovascular disease (CVD). However, their relationships with subclinical atherosclerosis are unclear. Studies in normal-weight populations, especially in Asian countries where leanness is prevalent, are lacking.

Methods: We conducted a cross-sectional study to assess the associations of WHR, WHtR, waist circumference, hip circumference, body mass index (BMI), MUAC and upper thigh circumference with carotid intima-media thickness (cIMT) among 562 middle-aged participants free of CVD in rural Bangladesh.

Results: After adjusting for age and sex, WHR and waist circumference but not BMI showed a positive significant association with cIMT. In multivariate analysis, each standard deviation (SD) increase of WHR (0.08) or WHtR (0.07) was associated with an 8.96 μm (95% CI, 1.12-16.81) or 11.45 μm (95%CI, 0.86-22.04) difference in cIMT, respectively, after controlling for age, sex, BMI, smoking status, education level, and systolic blood pressure (SBP). The associations of WHR and WHtR with cIMT were independent of the influence of other anthropometric measures. The associations of other anthropometric measures and cIMT were not apparent.

Conclusions: In our relatively lean, healthy Asian population, WHR and WHtR appear to be better predictors of early atherosclerosis than other common surrogates of adiposity.
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http://dx.doi.org/10.1016/j.atherosclerosis.2013.11.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888510PMC
January 2014

Daily visibility and hospital admission in Shanghai, China.

Biomed Environ Sci 2011 Apr;24(2):117-21

Fudan University, Shanghai 200032, China.

Objective: The study is to investigate the associations between visibility, major air pollutants and daily counts of hospital admission in Shanghai, China.

Methods: Daily data on hospital admission, visibility, and air pollution during 2005-2008 were obtained from the Shanghai Insurance Bureau (SHIB), Shanghai Meteorological Bureau, and Shanghai Environmental Monitoring Center, respectively. The generalized additive model (GAM) with penalized splines was used to examine the associations between daily visibility and hospital admission.

Results: Among various pollutants, PM(2.5) showed strongest correlation with visibility. Decreased visibility was significantly associated with increased risk of hospital admission in Shanghai. An inter-quartile range decrease in the 2-day (L01) moving average of visibility corresponded to 3.66% (95%CI: 1.02%, 6.31%), 4.06% (95%CI: 0.84%, 7.27%), and 4.32% (95%CI: 1.67%, 6.97%) increase of total, cardiovascular, and respiratory hospitalizations, respectively.

Conclusion: Our analyses provide the first piece of evidence in China, demonstrating that decreased visibility has an effect on hospital admission, and this finding strengthens the rationale for further limiting air pollution levels in Shanghai.
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http://dx.doi.org/10.3967/0895-3988.2011.02.005DOI Listing
April 2011
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