Exploring the relationship between urinary phthalate metabolites and Crohn's disease via oxidative stress, and the potential moderating role of gut microbiota: A conditional mediation model.

OBJECTIVE: Interactions between phthalic acid esters (PAEs) exposure and Crohn's disease (CD) were unknown. This study aims to examine the association between exposure to PAEs and CD activity and to explore the roles of oxidative stress and microbiota. METHODS: A cross-sectional study with 127 CD patients was conducted. The disease activity was evaluated based on symptoms (Harvey-Bradshaw index, HBI), endoscopy findings (Simple Endoscopic Score for CD, SES-CD), and computed tomography enterography (CTE-scores). Ten urinary PAEs metabolites (mPAEs), two urinary oxidative stress biomarkers, including 8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α), as well as 16S rRNA sequencing of stool samples were determined. Multiple linear regression models and Hayes's PROCESS macro for SPSS were used to evaluate the interplays between urinary PAEs metabolites, CD activities, oxidative stress, and microbiota diversity. RESULTS: There were positive associations between most mPAEs and HBI. Oxidative stress mediated 20.69-89.29% of the indirect associations between low molecular weight (LMW) mPAEs and HBI, while the majority of the high molecular weight (HMW) mPAEs were directly associated with HBI. In addition, microbiota diversity moderated the indirect associations of LMW mPAEs on HBI. CONCLUSIONS: PAEs exposure was related to CD activity, and the association could be mediated by oxidative stress and reversed or alleviated by rich gut microbiota.

Associations of urinary polycyclic aromatic hydrocarbon metabolites and blood pressure with the mediating role of cytokines: A panel study among children.

Little was known regarding the relations of polycyclic aromatic hydrocarbon (PAH) mixture with children's blood pressure (BP) and its potential mechanism. We conducted a panel study with up to 3 visits across 3 seasons in 2017-2018 among 103 children aged 4-13 years. Urinary PAH metabolites (OH-PAHs) were measured by gas chromatograph-tandem triple quadrupole mass spectrometer, and serum cytokines were detected by Bio-Rad 48-Plex Screening Panel. We employed linear mixed-effects models to assess the relations of each urinary OH-PAH with BP, least absolute shrinkage and selection operator (LASSO), and weighted quantile sum (WQS) regression to evaluate associations of OH-PAHs mixture with BP, and mediation analyses for the role of serum cytokines. We found the consistently positive associations of 1-hydroxynaphthalene and 9-hydroxyphenanthrene (9-OHPh) with systolic BP (SBP), 4-OHPh, and 9-OHPh with diastolic BP (DBP) and mean arterial pressure (MAP) in a dose-responsive manner. For instance, each 1-fold increment of 9-OHPh was related with increase of 0.92% (95% confidence interval (CI): 0.25%, 1.60%) in SBP, 1.32% (95%CI: 0.25%, 2.39%) in DBP, and 1.15% (95%CI: 0.40%, 1.88%) in MAP. Meanwhile, based on LASSO and WQS regression, OH-PAHs mixture was linked with increased DBP and MAP, to which 9-OHPh and 4-OHPh were the major contributors. Such relationships were modified by passive smoking status and 3-4 times stronger in passive smokers than non-passive smokers. A 1-fold increase in 9-OHPh was associated with an elevation of 3.51% in SBP among passive smokers while that of 0.55% in SBP among non-passive smokers. Furthermore, 4-OHPh and 9-OHPh were related to multiple cytokines elevation, of which platelet-derived growth factor (PDGF) mediated 9.99% and 12.57% in 4-OHPh-related DBP and MAP elevation, respectively. Accordingly, urinary OH-PAHs dominated by 9-OHPh and 4-OHPh were dose-responsively associated with elevated BP whereby a mechanism partly involving PDGF among children.

Co-exposure to priority-controlled metals mixture and blood pressure in Chinese children from two panel studies.

Metals may affect adversely cardiovascular system, but epidemiological evidence on the associations of priority-controlled metals including antimony (Sb), arsenic (As), cadmium, lead, and thallium with children's blood pressure (BP) was scarce and inconsistent. We conducted two panel studies with 3 surveys across 3 seasons among 144 and 142 children aged 4-12 years in Guangzhou and Weinan, respectively. During each seasonal survey, urine samples were collected for 4 consecutive days and BP was measured on the 4th day. We obtained 786 BP values and urinary metals measurements at least once within 4 days, while 773, 596, 612, and 754 urinary metals measurements were effective on the health examination day (Lag 0), and the 1st, 2nd, and 3rd day preceding BP measurement (Lag 1, lag 2 and lag 3), respectively. We used linear mixed-effect models, generalized estimating equations and multiple informant models to assess the associations of individual metal at each lag day and accumulated lag day (4 days averaged, lag 0-3) with BP and hypertension, and Bayesian Kernel Machine Regression to evaluate the relations of metals mixture at lag 0-3 and BP outcomes. We found Sb was positively and consistently related to systolic BP (SBP), mean arterial pressure (MAP), and odds of having hypertension within 4 days, which were the strongest at lag 0 and declined over time. And such relationships at lag 0-3 showed in a dose-response manner. Meanwhile, Sb was the only contributor to the relations of mixture with SBP, MAP, and odds of having hypertension. Also, synergistic interaction between Sb and As was significant. In addition, modification effect of passive smoking status on the association of Sb and SBP was more evident in passive smokers. Accordingly, urinary Sb was consistently and dose-responsively associated with increased BP and hypertension, of which Sb was the major contributor among children.

Practice, Knowledge, and Attitude of Health Care Providers regarding Cancer Pain Management: A National Survey.

Background: A lack of knowledge and inadequate practices of health care providers (HCPs) are the main obstacles to effective cancer pain management (CPM). The main objective of the study was to evaluate the CPM knowledge, CPM practice, and attitudes towards pharmacists' participation and advanced methods in CPM of physicians, nurses, and pharmacists in China. Methods: An open online survey was adopted using social media software (WeChat) as the platform to conduct a nationwide survey of HCPs involved in CPM in public medical institutions at all levels in China from March to June 2019. Results: A total of 1279 physicians, 2267 nurses, and 1466 pharmacists participated in the survey. Among the three types of professionals, nurses had the highest level of practical ability (61.63 ± 28.99) and best attitudes towards pharmacists' participation and advanced methods in CPM (72.05 ± 33.71) and physicians had the best mastery of CPM-related knowledge (69.60 ± 28.45), while pharmacists performed the worst in these three aspects (50.04 ± 26.69, 61.49 ± 28.95, and 62.07 ± 36.46, respectively). Only 19.69% of the hospitals had a pharmacist to tumor patient ratio ≥1 : 50. Hierarchical analysis showed that passing a good pain management (GPM) ward program and participating in advanced training had positive impacts on the scores of all three parts in the three professions (ptrend <0.05). Conclusions: HCPs' levels of practice, knowledge, and attitudes towards pharmacists and advanced methods of CPM were average in China; however, pharmacists had the worst performance, which demonstrates a need for further improvement. Furthermore, GPM ward programs and advanced trainings are helpful for improving CPM levels.

Heart rate variability mediates the association between polycyclic aromatic hydrocarbons exposure and atherosclerotic cardiovascular disease risk in coke oven workers.

Polycyclic aromatic hydrocarbons (PAHs) metabolites was related to heart rate variability (HRV) reduction and atherosclerotic cardiovascular disease (ASCVD), and ASCVD was also affected by HRV. However, the mediating role of HRV in the association between PAHs exposure and ASCVD risk was largely unknown. We aimed to investigate whether the relation of PAHs exposure with ASCVD risk was mediated by HRV among coke oven workers. A total of 1100 subjects with complete data were qualified in the current study. We measured 12 urinary PAHs metabolites by gas chromatography-mass spectrometry (GC-MS) and HRV indices by 3-channel digital Holter monitors. The associations between urinary PAHs metabolites, HRV indices, and ASCVD risk were explored using generalized linear models or multivariate logistic regression models. A mediation analysis was conducted to examine the role of HRV on the association between PAHs exposure and ASCVD risk. We found that urinary 1-hydroxynaphthalene (1-OHNa), 2-OHNa, and total PAH metabolites (ΣOH-PAH) were dose-responsive associated with increased risk of ASCVD. Compared with lowest quartile, the adjusted odds ratio (OR) for ASCVD risk in the highest quartile were 2.36 for 1-OHNa, 6.58 for 2-OHNa, and 1.60 for ΣOH-PAH (all Ptrend<0.05). In addition, significant dose-dependent relationships were found across 2-OHNa quartiles with decreasing HRV indices, which in turn, were positively associated with elevated risk of ASCVD (all Ptrend<0.05). Mediation analyses indicated that HRV mediate 2.7%-4.3% of the association between 2-OHNa exposure and higher ASCVD risk. Our data suggested that occupational exposure to PAHs may increase ASCVD risk, which was partially mediated by HRV.

Direct, indirect and total bilirubin and risk of incident coronary heart disease in the Dongfeng-Tongji cohort.

BACKGROUND: Total bilirubin (TBIL) is known to be inversely associated with coronary heart disease (CHD) risk, however, whether this association is dose-response remains inconsistent and it is unclear which subtype of bilirubin is responsible for the potential protective effect. METHODS: We included 12,097 participants who were free of CHD, stroke, cancer and potential liver, biliary and renal diseases at baseline from September 2008 to June 2010 and were followed-up until October 2013. Cox proportional hazards models were used to assess the hazard ratios (HR) and 95% confidence interval (95% CI) of bilirubin with incident CHD risk. RESULTS: The adjusted HRs for incident CHD increased with increasing direct bilirubin (DBIL) (p for trend = .013). Participants within the highest quintile of DBIL had 30% higher risk of incident CHD compared to those in the lowest quintile (95% CI: 1.07, 1.58). In contrast, compared with subjects in the lowest quintile of TBIL, those in the third quintile had the lowest of 24% risk for CHD incidence (95% CI: 0.63, 0.92), which showed a U-shaped association (p for quadratic trend = .040). CONCLUSIONS: DBIL was associated with a dose-response increased risk for CHD incidence. However, a U-shaped association existed between TBIL, indirect bilirubin and incident CHD risk. Key messages Direct bilirubin is independently associated with incident coronary heart disease (CHD) in a dose-response manner. A similarly consistent U-shaped association was found between total bilirubin, indirect bilirubin and incident CHD. The potential protective effect of total bilirubin within the normal range on incident CHD should be mainly attributed to mild-to moderate elevated levels of indirect bilirubin.

Association of polycyclic aromatic hydrocarbons metabolites and risk of diabetes in coke oven workers.

Elevated polycyclic aromatic hydrocarbons (PAHs) metabolites have recently been linked to increased risk of diabetes in the general population, but little is known about the risk of diabetes due to high pollution levels of PAHs exposure. We aimed to examine whether occupational exposure to PAHs would be one of the important risk factors for diabetes in the coke oven workers. A total of 1472 coke oven workers with complete data were qualified for the present study. We measured 12 urinary monohydroxy polycyclic aromatic hydrocarbons (OH-PAHs) by gas chromatography-mass spectrometry (GC-MS). Multiple logistic regression was used to evaluate the associations between urinary OH-PAHs and risk of diabetes, with adjustment for the potential confounders. We found that elevated urinary 4-hydroxyphenanthrene (4-OHPh) was significantly associated, in a dose-dependent manner, with increased risk of diabetes (Ptrend = 0.003). Compared with individuals with 4-OHPh in the lowest quartile, the adjusted odds ratio (OR) of diabetes among those in the highest quartile was 2.80 (95% CI = 1.37-5.71). In stratified analysis, the association was more prominent in those who were smokers, overweight (BMI ≥24 kg/m2), with longer working years (≥20 years) and worked at coke oven settings. In addition, high levels of 4-OHPh combined with longer working years or overweight had a joint effect on the risk of diabetes. Our data suggested that elevated 4-OHPh was dose-responsive associated with increased risk of diabetes in the coke oven workers. The risk assessment of diabetes related to occupational PAHs exposure should take working years and BMI into consideration.

Dose-response relationship between serum uric acid levels and risk of incident coronary heart disease in the Dongfeng-Tongji Cohort.

BACKGROUND: In prospective studies, relationship of serum uric acid (SUA) with risk of coronary heart disease (CHD) incidence is inconsistent. We evaluated the association of SUA with incident CHD and the potential modifying effect of major CHD risk factors related to SUA among a middle aged and elderly Chinese population. METHODS: We included 16, 063 participants who were free of CHD, stroke, cancer and renal diseases at baseline from Sep. 2008 to June 2010, and were followed until Oct. 2013. Cox proportional hazard model was used to estimate the hazard ratios (HR) and 95% confidence interval (95% CI) of CHD incidence in relation to SUA. RESULTS: The adjusted HR for incident CHD increased gradually with the increasing SUA levels (P for linear trend=0.005), and the HR across sex-specific SUA quartile was 1.26 (95% CI: 1.09, 1.47), 1.13 (95% CI: 0.97, 1.31), 1.23 (95% CI: 1.06, 1.43) and 1.00 (reference; P for trend=0.014), respectively. In particular, the association was more evident in individuals with normal-weight and those without hypertension or metabolic syndrome (all P for interactions<0. 05). CONCLUSIONS: These findings suggested that higher SUA levels were independently associated with a dose-response increased risk of CHD incidence.

Sleep Duration and Midday Napping with 5-Year Incidence and Reversion of Metabolic Syndrome in Middle-Aged and Older Chinese.

STUDY OBJECTIVES: Prospective evidence on the association of sleep duration and midday napping with metabolic syndrome (MetS) is limited. We aimed to examine the associations of sleep duration and midday napping with risk of incidence and reversion of MetS and its components among a middle-aged and older Chinese population. METHODS: We included 14,399 subjects from the Dongfeng-Tongji (DFTJ) Cohort Study (2008-2013) who were free of coronary heart disease, stroke, and cancer at baseline. Baseline data were obtained by questionnaires and health examinations. Odds ratios (ORs) and 95% confidence interval (CI) were derived from multivariate logistic regression models. RESULTS: After controlling for potential covariates, longer sleep duration (≥ 9 h) was associated with a higher risk of MetS incidence (OR, 1.29; 95% CI, 1.08-1.55) and lower reversion of MetS (OR, 0.80; 95% CI, 0.66-0.96) compared with sleep duration of 7 to < 8 h; whereas shorter sleep duration (< 6 h) was not related to incidence or reversion of MetS. For midday napping, subjects with longer napping (≥ 90 min) was also associated with a higher risk of MetS incidence and a lower risk of MetS reversion compared with those with napping of 1 to < 30 min (OR, 1.48; 95% CI, 1.05-2.10 and OR, 0.70; 95% CI, 0.52-0.94, respectively). Significance for incidence or reversion of certain MetS components remained in shorter and longer sleepers but disappeared across napping categories. CONCLUSIONS: Both longer sleep duration and longer midday napping were potential risk factors for MetS incidence, and concurrently exert adverse effects on MetS reversion.

Green tea consumption is associated with reduced incident CHD and improved CHD-related biomarkers in the Dongfeng-Tongji cohort.

Prospective studies on the association of green tea with risk of coronary heart disease (CHD) incidence were scarce. This study examined whether green tea can reduce CHD incidence and have a beneficial effect on CHD-related risk markers in middle-aged and older Chinese population. We included 19,471 participants who were free of CHD, stroke or cancer at baseline from September 2008 to June 2010, and were followed until October 2013. Cox proportional hazard models were used to examine the hazard ratios (HR) of CHD incidence in relation to green tea consumption. Linear regression models were used to evaluate the effect of green tea on 5-year changes of CHD-related biomarkers. Compared with non-green tea consumers, the multivariable-adjusted HR for CHD was 0.89 (95% CI, 0.81-0.98) in green tea consumers. Particularly, the reduced risk of CHD incidence with green tea consumption was more evident among participants who were male, more than 60 years old, overweight, or with diabetes mellitus. In addition, green tea consumption improved multiple CHD-related risk markers including total cholesterol, HDL-cholesterol, triglycerides, mean platelet volume, and uric acid. In conclusion, green tea consumption was associated with a reduced risk of CHD incidence in the middle-aged and older Chinese populations, and the association might be partly due to altered CHD-related biomarkers.

Genome-Wide Analysis of DNA Methylation and Cigarette Smoking in a Chinese Population.

BACKGROUND: Smoking is a risk factor for many human diseases. DNA methylation has been related to smoking, but genome-wide methylation data for smoking in Chinese populations is limited. OBJECTIVES: We aimed to investigate epigenome-wide methylation in relation to smoking in a Chinese population. METHODS: We measured the methylation levels at > 485,000 CpG sites (CpGs) in DNA from leukocytes using a methylation array and conducted a genome-wide meta-analysis of DNA methylation and smoking in a total of 596 Chinese participants. We further evaluated the associations of smoking-related CpGs with internal polycyclic aromatic hydrocarbon (PAH) biomarkers and their correlations with the expression of corresponding genes. RESULTS: We identified 318 CpGs whose methylation levels were associated with smoking at a genome-wide significance level (false discovery rate < 0.05), among which 161 CpGs annotated to 123 genes were not associated with smoking in recent studies of Europeans and African Americans. Of these smoking-related CpGs, methylation levels at 80 CpGs showed significant correlations with the expression of corresponding genes (including RUNX3, IL6R, PTAFR, ANKRD11, CEP135 and CDH23), and methylation at 15 CpGs was significantly associated with urinary 2-hydroxynaphthalene, the most representative internal monohydroxy-PAH biomarker for smoking. CONCLUSION: We identified DNA methylation markers associated with smoking in a Chinese population, including some markers that were also correlated with gene expression. Exposure to naphthalene, a byproduct of tobacco smoke, may contribute to smoking-related methylation. CITATION: Zhu X, Li J, Deng S, Yu K, Liu X, Deng Q, Sun H, Zhang X, He M, Guo H, Chen W, Yuan J, Zhang B, Kuang D, He X, Bai Y, Han X, Liu B, Li X, Yang L, Jiang H, Zhang Y, Hu J, Cheng L, Luo X, Mei W, Zhou Z, Sun S, Zhang L, Liu C, Guo Y, Zhang Z, Hu FB, Liang L, Wu T. 2016. Genome-wide analysis of DNA methylation and cigarette smoking in Chinese. Environ Health Perspect 124:966-973; http://dx.doi.org/10.1289/ehp.1509834.

Association of plasma IL-6 and Hsp70 with HRV at different levels of PAHs metabolites.

BACKGROUND: Exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with reduced heart rate variability (HRV), a strong predictor of cardiovascular diseases, but the mechanism is not well understood. OBJECTIVES: We hypothesized that PAHs might induce systemic inflammation and stress response, contributing to altered cardiac autonomic function. METHODS: HRV indices were measured using a 3-channel digital Holter monitor in 800 coke oven workers. Plasma levels of interleukin-6 (IL-6) and heat shock protein 70 (Hsp70) were determined using ELISA. Twelve urinary PAHs metabolites (OH-PAHs) were measured by gas chromatography-mass spectrometry. RESULTS: We found that significant dose-dependent relationships between four urinary OH-PAHs and IL-6 (all Ptrend<0.05); and an increase in quartiles of IL-6 was significantly associated with a decrease in total power (TP) and low frequency (LF) (Ptrend = 0.014 and 0.006, respectively). In particular, elevated IL-6 was associated in a dose-dependent manner with decreased TP and LF in the high-PAHs metabolites groups (all Ptrend<0.05), but not in the low-PAHs metabolites groups. No significant association between Hsp70 and HRV in total population was found after multivariate adjustment. However, increased Hsp70 was significantly associated with elevated standard deviation of NN intervals (SDNN), TP and LF in the low-PAHs metabolites groups (all Ptrend<0.05). We also observed that both IL-6 and Hsp70 significantly interacted with multiple PAHs metabolites in relation to HRV. CONCLUSIONS: In coke oven workers, increased IL-6 was associated with a dose-response decreased HRV in the high-PAHs metabolites groups, whereas increase of Hsp70 can result in significant dose-related increase in HRV in the low-PAHs metabolites groups.