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Tobacco smoking is a major known risk factor for lung cancer. While micronutrients, especially those involved in maintaining DNA integrity and regulating gene expression, may be protective, research on this association is limited. This report aimed to investigate associations of total folate, 5-methyltetrahydrofolate (5-mTHF) and vitamin B12 with incident risk of lung cancer, and whether the associations vary by smoking status. A nested case-control study with 490 incident lung cancer cases and 490 controls matched by age (±1 year), sex, residence, and center, drawn from a community-based prospective study in China, was conducted from 2016 to 2019. 5-mTHF accounted for the majority of total folate. Only 4.4% had detectable unmetabolized folic acid. Lung cancer cases had lower levels of 5-mTHF compared to controls. There was an inverse, nonlinear association between 5-mTHF and lung cancer, which persisted after adjustment for covariables (P for trend = .001). Compared to the lowest 5-mTHF quartile, those in higher quartiles had lower risks of lung cancer: second quartile OR = 0.65; 95% CI: 0.45-0.93; third quartile OR = 0.50; 95% CI: 0.34-0.74; fourth quartile OR = 0.56; 95% CI: 0.38-0.83. This inverse association was more pronounced among ever smokers; consistently, the highest risk of lung cancer (OR = 3.21, 95% CI: 1.97-5.24) was observed among ever smokers with low 5-mTHF levels compared to participants who never smoked and had higher 5-mTHF levels. Vitamin B12 was not associated with lung cancer risk. In this sample of Chinese adults without confounding by unmetabolized folic acid, higher levels of 5-mTHF were associated with lower risk of incident lung cancer.

Myopia is a major public health issue and occurs at young ages. Apart from its high prevalence, myopia results in high costs and irreversible blinding diseases. Accurate prediction of the risk of myopia onset is crucial for its precise prevention. We aimed to develop and validate an effective nomogram for predicting myopia onset in schoolchildren.School-based prospective cohort study.A total of 1073 schoolchildren were enrolled from November 2014 to May 2019 in China, and were divided into the training and validation cohorts. Myopia was defined as a spherical equivalent refraction (SER) ≤-0.5 diopters. Predictors of myopia were determined through the least absolute shrinkage and selection operator regression and multivariable Cox proportional hazard model based on the training cohort. The predictive performance of the nomogram was validated internally through time-dependent receiver operating characteristic (ROC) curves, calibration plot, decision curve analysis, and Kaplan-Meier curves.Independent predictors at baseline including gender, SER, axial length, corneal refractive power, and positive relative accommodation were included in the nomogram prediction model. This nomogram demonstrated excellent calibration, clinical net benefit, and discrimination, with all the area under the ROC curves (AUCs) between 0.74 and 0.86 in the training and validation cohorts. The Kaplan-Meier curves showed that 3 distinct risk groups stratified through X-tile analysis were well discriminated and robust among subgroups. The Harrell's C-index and net reclassification improvement demonstrated that the nomogram substantially improved compared with previous models. An online myopia risk calculator was generated for better individual prediction.The nomogram provides accurate and individual prediction of myopia onset in schoolchildren. External validation is needed to verify the generalizability of this nomogram.

Background. Cytokeratin 19 fragment 21-1 (CYFRA21-1) and carcinoembryonic antigen (CEA) are effective prognostic biomarkers for lung cancer. This study investigated the predictive effects of change rates of CYFRA21-1 and CEA before and after the first cycles of chemotherapy on advanced IIIb/IIIc or IV stage non-small-cell lung cancer (NSCLC) patients. Methods. Data of 103 NSCLC patients who received chemotherapy in Zhejiang Provincial People’s Hospital from February 2018 to November 2020 were retrospectively analyzed. All patients received platinum doublet chemotherapy for at least 2 cycles. CYFRA21-1 and CEA levels of patients were detected before and after the first chemotherapy cycle, respectively. After the second cycle, the efficacy was evaluated, and patients were divided into the disease control (DC) and progressive disease (PD) groups. The generalized linear model (GLM) and linear trend test assessed the relationship between change rates of CYFRA21-1 and CEA levels and chemotherapeutic efficacy before and after chemotherapy. Moreover, the receiver operating characteristic (ROC) curve determined the predictive value of change rates of CYFRA21-1 and CEA on chemotherapeutic efficacy. Results. After the second chemotherapeutic cycle, there were 92 patients in the DC group and 11 in the PD group. GLM and linear trend test both indicated that change rates of CYFRA21-1 and CEA were inversely correlated with chemotherapeutic efficacy for NSCLC. Change rates of CYFRA21-1 and CEA were used to predict area under the ROC curve of chemotherapeutic efficacy (0.87, 0.71-1.00), which is better than single index prediction of CYFRA21-1 (0.71, 0.49-0.94) or CEA change rate (0.85, 0.69-1.00) ( p < 0.001 ). Conclusion. Before and after chemotherapy of the first cycle for advanced NSCLC patients, combining serum CYFRA21-1 and CEA levels could increase sensitivity and specificity to predict the chemotherapeutic efficacy and guide the following therapy of advanced NSCLC patients.

Background: Previous studies concerning the effect of plasma hemoglobin (HB) and other factors that may modify the risk of death in people living with HIV/AIDS (PLHIV) treated with antiretroviral therapy (ART) are limited. Results: Higher HB was independently linked to a lower death risk in PLHIV, with a decrease of 29% (13%, 43%) per standard deviation (SD) increment after adjusting for CD4, VL and other potential factors [hazard ratio (HR): 0.71, 95% confidence interval (CI): 0.57-0.87, P

Hypertension is a serious global health problem. Hypertensive retinopathy is generally considered to be a predictor of vascular disease elsewhere in the human body. In the past few decades, a variety of grading systems have been proposed for hypertensive retinopathy. However, these grading systems have some limitations. This study utilized optical coherence tomography angiography (OCTA) to investigate the morphological changes and macular retinal microvasculature in depth among 100 patients with hypertensive retinopathy and 66 healthy participants. Five main pathological changes were discovered in hypertensive retinopathy, as follows: focal capillary sparsity, scattered microangioma, focal macular arch ring defects, focal capillary disorder, and focal capillary nonperfusion at the levels of the superficial and deep vascular networks. In addition, we have found that the number of various pathological changes shows an increasing trend as hypertensive retinopathy progresses and may be related to renal damage. Finally, deep vessel density tended to decrease with progressive stages of hypertensive retinopathy and could be the best indicator to predict the risk of hypertensive retinopathy. Our study, therefore, proposes 3 stages of hypertensive retinopathy without macular edema according to the pathophysiology found by OCTA: stage 1 (only focal capillary sparsity), taking the place of KWB grade I; stage 2 (focal capillary sparsity and scattered microangioma), taking the place of KWB grade II; and stage 3 (focal capillary sparsity, scattered microangioma, focal capillary disorder, and nonperfusion), taking the place of KWB grade III. Hence, OCTA may be a potentially useful tool for evaluating the pathophysiology and staging of hypertensive retinopathy. Further longitudinal prospective studies are needed to confirm our findings.

Evidence on the association between phylloquinone status and cardiovascular diseases is scarce and conflicting. These inconsistencies may be due to differences in individual characteristics of the study populations, which may modify the association.This study aimed to evaluate the association between plasma phylloquinone and the risk of first total stroke and its subtypes, and to examine potential effect modifications by BMI in patients with hypertension.We performed a nested case-control study including 604 first stroke cases and 604 matched controls. The mean age was 62.2 y (range, 45 to 75). Lower BMI was defined as 25 kg/m2 and higher BMI was defined as ≥25 kg/m2. The risks of the first stroke were estimated by ORs and 95% CIs using conditional logistic regression. The primary outcome was total stroke or ischemic stroke.The relation between log-transformed phylloquinone concentration and stroke or ischemic stroke was modified by BMI. Higher phylloquinone concentrations were associated with lower stroke risk in those with a higher BMI. When plasma phylloquinone was assessed as tertiles, the adjusted ORs of first stroke and ischemic stroke for participants with a high BMI in tertile 2-3 were 0.70 (95% CI: 0.46, 1.08) and 0.57 (95% CI: 0.35, 0.92) compared with those in tertile 1, respectively. However, there was no significant association between plasma phylloquinone and risk of first total stroke or ischemic stroke for those with a lower BMI. Patients with a higher BMI and lower phylloquinone concentrations had the highest risk of ischemic stroke and showed a statistically significant difference compared with the reference group with a lower BMI and higher phylloquinone (OR = 1.80, 95% CI: 1.06, 3.10; P-interaction: 0.017).In Chinese patients with hypertension, there was an inverse association between baseline plasma phylloquinone and risk of first ischemic stroke among those with a higher BMI. This trial was registered at clinicaltrials.gov as NCT00794885.

Background Optimal ω-6/ω-3 polyunsaturated fatty acids ratio (PUFAR) is reported to exert protective effects against chronic diseases. However, data on PUFAR and diabetic retinopathy (DR) remains scarce. We aimed to thoroughly quantify whether and how PUFAR was related to DR as well as its role in DR detection. Methods This two-centre case-control study was conducted from August 2017 to June 2018 in China, participants were matched using a propensity score matching algorithm. We adopted multivariable logistic regression models and restricted cubic spline analyses to estimate the independent association of PUFAR with DR, adjusting for confounders identified using a directed acyclic graph. The value of PUFAR as a biomarker for DR identification was further evaluated by receiver operating characteristic analyses and Hosmer-Lemeshow tests. Findings An apparent negative relationship between PUFAR and DR was observed. Adjusted odds of DR decreased by 79% (OR: 0·21, 95% CI: 0·10–0·40) with an interquartile range increase in PUFAR. Similar results were also obtained in tertile analysis. As compared to those in the 1st tertile of PUFAR, the adjusted odds of DR decreased by 76% (OR: 0·24, 95% CI: 0·08–0·66) and 93% (OR: 0·07, 95% CI: 0·03–0·22) for subjects in the 2nd and 3rd tertiles, respectively. Good calibration and discrimination of the PUFAR associated predictive model were detected and PUFAR = 35 would be an ideal cut-off value for DR identification. Interpretation Our results suggest that serum PUAFR is inversely associated with DR. Although PUFAR-alteration is not observed amongst different stages of DR, it can serve as an ideal biomarker in distinguishing patients with DR from those without DR. Funding This study was funded by Natural Science Foundation of Zhejiang Province, Zhejiang Basic Public Welfare Research Project, the Major Project of the Eye Hospital of Wenzhou Medical University, and the Academician's Science and Technology Innovation Program in Zhejiang province. Part of this work was also funded by the National Nature Science Foundation of China, and Research Project for College Students in Wenzhou Medical University.

IntroductionDespite advances in diabetic retinopathy (DR) medications, early identification is vitally important for DR administration and remains a major challenge. This study aims to develop a novel system of multidimensional network biomarkers (MDNBs) based on a widely targeted metabolomics approach to detect DR among patients with type 2 diabetes mellitus (T2DM) efficiently.Research design and methodsIn this propensity score matching-based case-control study, we used ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry system for serum metabolites assessment of 69 pairs of patients with T2DM with DR (cases) and without DR (controls). Comprehensive analysis, including principal component analysis, orthogonal partial least squares discriminant analysis, generalized linear regression models and a 1000-times permutation test on metabolomics characteristics were conducted to detect candidate MDNBs depending on the discovery set. Receiver operating characteristic analysis was applied for the validation of capability and feasibility of MDNBs based on a separate validation set.ResultsWe detected 613 features (318 in positive and 295 in negative ESI modes) in which 63 metabolites were highly relevant to the presence of DR. A panel of MDNBs containing linoleic acid, nicotinuric acid, ornithine and phenylacetylglutamine was determined based on the discovery set. Depending on the separate validation set, the area under the curve (95% CI), sensitivity and specificity of this MDNBs system were 0.92 (0.84 to 1.0), 96% and 78%, respectively.ConclusionsThis study demonstrates that metabolomics-based MDNBs are associated with the presence of DR and capable of distinguishing DR from T2DM efficiently. Our data also provide new insights into the mechanisms of DR and the potential value for new treatment targets development. Additional studies are needed to confirm our findings.

Associations between vitamin D and stroke remain inconsistent. One major risk factor for stroke is high blood glucose, but the role it plays in this association is not well studied.We aimed to evaluate the individual association between plasma 25-hydroxyvitamin D [25(OH)D] and risk of first stroke stratified by fasting blood glucose (FBG), and the joint associations between plasma 25(OH)D, glycemic status, and first stroke in hypertensive adults.This study was a nested, case-control design utilizing data from the China Stroke Primary Prevention Trial (CSPPT). This analysis included 591 first stroke cases (of which 475 were ischemic stroke, 114 were hemorrhagic stroke, and 2 were uncertain type) and 591 matched controls. The age range of the study population was 45-75 y. The normal FBG (NFG) group had FBG 5.6 mmol/L, and the impaired FBG (IFG) group had FBG ≥5.6 mmol/L and 7.0 mmol/L. Diabetes was defined as participants with FBG ≥7 mmol/L or who were receiving treatment with hypoglycemic agents. ORs (95% CIs) were calculated using unconditional logistic regression models.Multivariable adjusted models revealed an inverse association between quartiles of 25(OH)D and risk of first stroke among participants with NFG, but the opposite trend was observed for those with IFG or diabetes. The largest ORs (2) were observed among patients with diabetes, compared with the reference group of NFG and high 25(OH)D. Those with NFG and low 25(OH)D (OR = 1.73, 95% CI: 1.22 to 2.44) or those with IFG and high 25(OH)D (OR = 1.74, 95% CI: 1.14 to 2.67) both had a higher risk of total stroke. There was a significant interaction between 25(OH)D and a combined group of IFG and diabetes (P = 0.001). Similar results were observed for ischemic stroke.In a hypertensive population, the relation between plasma 25(OH)D and risk of first stroke was significantly modified by FBG. This trial was registered at https://www.clinicaltrials.gov as NCT00794885.

Oxidative DNA damage pathogenically links to some major diseases. This study aimed to comprehensively assess the association between serum total cholesterol (TC) and oxidative DNA damage based on propensity score matching (PSM) method. A total of 407 participants chronically exposed to arsenic via drinking water from China were enrolled. Oxidative DNA damage was determined with urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG). Serum TC was classified into favourable TC (FTC, TC5.18 mmol/L) and unfavourable TC (NFTC, TC ≥5.18 mmol/L) categories. Multivariable generalised linear regression model was applied to examine the association. Of 407 participants, 125 pairs with FTC and NFTC subjects were matched using PSM. Urinary 8-OHdG/creatinine levels in NFTC were significantly higher than those in FTC category (

l-cysteine (l-Cys) plays an important role in many physiological processes. The previously reported methodologies for l-Cys detection have many drawbacks, and thus the development of specific/sensitive approaches is crucial for its direct/quick assay in food matrices. Herein, silicon quantum dots (SiQDs) and glutathione-stabilized copper nanoclusters (CuNCs) were successfully synthesized and integrated as a ratiometric fluorescent probe for assay l-Cys assay in milks. The fluorescence of SiQDs was quenched by CuNCs through fluorescence resonance energy-transfer process. Upon addition of l-Cys, the 440-nm fluorescence of SiQDs changed insignificantly, while the 650-nm fluorescence of CuNCs decreased significantly. Ratiometric fluorescence signal was linear in the l-Cys concentration range of 0.25 μM to 2.5 mM with a detection limit of 75 nM and visual color changes from red to blue. The probe can realize rapid and portable detection without the participation of intermediate ions, and has good selectivity and accuracy for l-cysteine in milk samples.

Objective Early identification of diabetic retinopathy (DR) is key to prioritizing therapy and preventing permanent blindness. This study aims to propose a machine learning model for DR early diagnosis using metabolomics and clinical indicators. Methods From 2017 to 2018, 950 participants were enrolled from two affiliated hospitals of Wenzhou Medical University and Anhui Medical University. A total of 69 matched blocks including healthy volunteers, type 2 diabetes, and DR patients were obtained from a propensity score matching-based metabolomics study. UPLC-ESI-MS/MS system was utilized for serum metabolic fingerprint data. CART decision trees (DT) were used to identify the potential biomarkers. Finally, the nomogram model was developed using the multivariable conditional logistic regression models. The calibration curve, Hosmer–Lemeshow test, receiver operating characteristic curve, and decision curve analysis were applied to evaluate the performance of this predictive model. Results The mean age of enrolled subjects was 56.7 years with a standard deviation of 9.2, and 61.4% were males. Based on the DT model, 2-pyrrolidone completely separated healthy controls from diabetic patients, and thiamine triphosphate (ThTP) might be a principal metabolite for DR detection. The developed nomogram model (including diabetes duration, systolic blood pressure and ThTP) shows an excellent quality of classification, with AUCs (95% CI) of 0.99 (0.97–1.00) and 0.99 (0.95–1.00) in training and testing sets, respectively. Furthermore, the predictive model also has a reasonable degree of calibration. Conclusions The nomogram presents an accurate and favorable prediction for DR detection. Further research with larger study populations is needed to confirm our findings.

Background: Optimal ω-6/ω-3 polyunsaturated fatty acids ratio (PUFAR) is reported to exert protective effects against chronic diseases. However, data on PUFAR and diabetic retinopathy (DR) are scarce. We aimed to thoroughly quantify how PUFAR was associated with DR as well as its role in DR detection. Methods: This is a two-center case-control study, patients were matched using a propensity score algorithm. Multivariable logistic regression models and restricted cubic spline analyses were used to examine the association of PUFAR with DR after adjusting for confounders, which were screened by directed acyclic graph. Performance of the predictive ability to identify DR with PUFAR was assessed by receiver operating characteristic (ROC) analysis and Hosmer-Lemeshow test. Findings: An apparent negative relationship between PUFAR and DR was observed. Adjusted likelihood of DR decreased by 79% (OR:0.21, 95% CI:0.10-0.40) with per interquartile range of PUFAR elevation. Similar results were also obtained in tertile analysis. As compared to those in the 1st tertile of PUFAR, the adjusted odds of DR decreased by 76% (OR:0.24, 95% CI:0.08-0.66) and 93% (OR:0.07, 95% CI:0.03-0.22) for subjects in the 2nd and 3rd tertiles, respectively. Good calibration and discrimination of the predictive model were detected and consistent in both training and testing sets, and PUFAR=35 would be an ideal cut-off value for DR identification. Interpretation: Our present study shows that serum PUAFR was inversely associated with DR and could serve as an ideal biomarker in distinguishing DR from type 2 diabetes. Funding: This study was funded by Natural Science Foundation of Zhejiang Province, Zhejiang Basic Public Welfare Research Project, the Major Project of the Eye Hospital of Wenzhou Medical University and the academician’s science, and technology innovation program in Zhejiang province. Part of this work was also funded by the National Nature Science Foundation of China and Science and Research Funding Project for College Students in Wenzhou Medical University. Declaration of Interest: We declare no conflicts of interests. Ethical Approval: The protocol had been carefully reviewed and approved by the Ethic committee of the Eye hospital of Wenzhou medical university before the study (Number: KYK [2017] 46).

Objectives Youngsters who are overweight or obese (YOO) have become an important global health concern. Some micronutrients may be modifiable influential factors. This study aimed to investigate the individual and joint association of whole-blood magnesium (WBMg) and total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), or high-density lipoprotein cholesterol (HDL-C) in YOO. Methods This is a propensity score matching-based case-control study. YOO was defined depending on age- and sex-specific body mass index z-score, calculated with SAS macros (%group_standard and %WHO2007) from the World Health Organization website. WBMg, blood lipids, and covariates were carefully measured by trained technicians using a whole-blood, five-element, basic analyzer and atomic absorption spectrometer or automatic biochemical analyzer. Locally weighted scattered plot smoothing and multivariable conditional logistic regression models were applied to estimate the associations of WBMg and blood lipids in YOO. Results WBMg was positively associated with YOO. The adjusted likelihood of YOO significantly increased by 21% (odds ratio: 1.21; 95% confidence interval [CI], 1.10–1.33) with per-interquartile range elevation of WBMg. Compared with the 1st quartile, adjusted odds ratios among youngsters in the 2nd, 3rd, and 4th quartiles of WBMg were 1.11 (95% CI, 0.92–1.35), 1.29 (95% CI, 1.06–1.57), and 1.47 (95% CI, 1.18–1.83), respectively. Furthermore, the relationship between WBMg and YOO was moderated by lipid profiles. Compared with those having lower ( Conclusions WBMg was an independent risk factor of YOO, and the associations were stronger among those with unhealthy blood lipids. Our findings can help to guide clinical and public health policies on the relevance of magnesium nutritional status.

Diabetic retinopathy (DR), the most common microvascular complication of diabetes and leading cause of visual impairment in adults worldwide, is suggested to be linked to abnormal lipid metabolism. The present study aims to comprehensively investigate the relationship between n-6 polyunsaturated fatty acids (PUFAs) and DR. This was a propensity score matching based case–control study, including 69 pairs of DR patients and type 2 diabetic patients without DR with mean age of 56.7 ± 9.2 years. Five n-6 PUFAs were determined by UPLC-ESI-MS/MS system. Principle component regression (PCR) and multiple conditional logistic regression models were used to investigate the association of DR risk with n-6 PUFAs depending on independent training and testing sets, respectively. According to locally weighted regression model, we observed obvious negative correlation between levels of five n-6 PUFAs (linoleic acid, γ-linolenic acid, eicosadienoic acid, dihomo-γ-linolenic acid and arachidonicacid) and DR. Based on multiple PCR model, we also observed significant negative association between the five n-6 PUFAs and DR with adjusted OR (95% CI) as 0.62 (0.43,0.87). When being evaluated depending on the testing set, the association was still existed, and PCR model had excellent classification performance, in which area under the curve (AUC) was 0.88 (95% CI: 0.78, 0.99). In addition, the model also had valid calibration with a non-significant Hosmer–Lemeshow Chi-square of 9.44 (P = 0.307) in the testing set. n-6 PUFAs were inversely associated with the presence of DR, and the principle component could be potential indicator in distinguishing DR from other T2D patients.

Background and Objectives. Diabetic kidney disease is a leading cause of chronic kidney disease and end-stage renal disease across the world. Early identification of DKD is vitally important for the effective prevention and control of it. However, the available indicators are doubtful in the early diagnosis of DKD. This study is aimed at determining novel sensitive and specific biomarkers to distinguish DKD from their counterparts effectively based on the widely targeted metabolomics approach. Materials and Method. This case-control study involved 44 T2DM patients. Among them, 24 participants with DKD were defined as the cases and another 20 without DKD were defined as the controls. The ultraperformance liquid chromatography-electrospray ionization-tandem mass spectrometry system was applied for the assessment of the serum metabolic profiles. Comprehensive analysis of metabolomics characteristics was conducted to detect the candidate metabolic biomarkers and assess their capability and feasibility. Result. A total of 11 differential metabolites, including Hexadecanoic Acid (C16:0), Linolelaidic Acid (C18:2N6T), Linoleic Acid (C18:2N6C), Trans-4-Hydroxy-L-Proline, 6-Aminocaproic Acid, L-Dihydroorotic Acid, 6-Methylmercaptopurine, Piperidine, Azoxystrobin Acid, Lysopc 20:4, and Cuminaldehyde, were determined as the potential biomarkers for the DKD early identification, based on the multivariable generalized linear regression model and receiver operating characteristic analysis. Conclusion. Serum metabolites might act as sensitive and specific biomarkers for DKD early detection. Further longitudinal studies are needed to confirm our findings.

Background: Since the outbreak in Wuhan China in December 2019, novel coronavirus pneumonia (COVID-19) has spread rapidly throughout the whole nation Besides W

ObjectivesHis bundle pacing (HBP) can potentially correct left bundle branch block (LBBB). We aimed to assess the efficacy of HBP to correct LBBB and long-term clinical outcomes with HBP in patients with heart failure (HF).MethodsThis is an observational study of patients with HF with typical LBBB who were indicated for pacing therapy and were consecutively enrolled from one centre. Permanent HBP leads were implanted if the LBBB correction threshold was ResultsIn 74 enrolled patients (69.6±9.2 years and 43 men), LBBB correction was acutely achieved in 72 (97.3%) patients, and 56 (75.7%) patients received permanent HBP (pHBP) while 18 patients did not receive permanent HBP (non-permanent HBP), due to no LBBB correction (n=2), high LBBB correction thresholds (n=10) and fixation failure (n=6). The median follow-up period of pHBP was 37.1 (range 15.0–48.7) months. Thirty patients with pHBP had completed 3-year follow-up, with LVEF increased from baseline 32.4±8.9% to 55.9±10.7% (p0.05).ConclusionspHBP improved LVEF, LVESV and NYHA Class in patients with HF with typical LBBB.

Preterm birth (PTB) contributes significantly to infant mortality and morbidity with lifelong impact. Few robust genetic factors of PTB have been identified. Such ‘missing heritability' may be partly due to gene × environment interactions (G × E), which is largely unexplored. Here we conduct genome-wide G × E analyses of PTB in 1,733 African-American women (698 mothers of PTB; 1,035 of term birth) from the Boston Birth Cohort. We show that maternal COL24A1 variants have a significant genome-wide interaction with maternal pre-pregnancy overweight/obesity on PTB risk, with rs11161721 (PG × E=1.8 × 10−8; empirical PG × E=1.2 × 10−8) as the top hit. This interaction is replicated in African-American mothers (PG × E=0.01) from an independent cohort and in meta-analysis (PG × E=3.6 × 10−9), but is not replicated in Caucasians. In adipose tissue, rs11161721 is significantly associated with altered COL24A1 expression. Our findings may provide new insight into the aetiology of PTB and improve our ability to predict and prevent PTB., Preterm birth (PTB) has high prevalence and PTB infants have greater risk for mortality. Here, Hong and colleagues perform a genome-wide gene × environment interaction analysis and find that maternal COL24A1 variants have a significant interaction with maternal pre-pregnancy obesity in increasing PTB risk.

ObjectivesWe investigated the association of specific serum amino acids (AAs) with the odds of arsenic-induced skin lesions (AISL) and their ability to distinguish patients with AISL from people chronically exposed to arsenic.DesignCase–control study.SettingThree arsenic-exposed villages in Wuyuan County, Hetao Plain, Inner Mongolia, China were evaluated.ParticipantsAmong the 450 residents aged 18–79 years, who were chronically exposed to arsenic via drinking water, 56 were diagnosed as having AISL (defined as cases). Another 56 participants without AISL, matched by gender and age (±1 year) from the same population, were examined as controls.Main outcome measures and methodsAA levels were determined by ultra-high-performance liquid chromatography–quadrupole time-of-flight mass spectrometry-based metabolomics analysis. Potential confounding variables were identified via a standardised questionnaire and clinical examination. Multivariable conditional logistic regression model and receiver operating characteristic curve analyses were performed to investigate the relationship between specific AAs and AISL.ResultsTryptophan and phenylalanine levels were negatively associated with AISL (pConclusionsSpecific AAs may be linked to AISL and play important roles in early AISL identification.Trial Registration numberNCT02235948.

Background His bundle pacing (HBP) has been shown to correct left bundle branch block (LBBB), however it often requires high pacing output and the success rate is variable. Objective To assess the feasibility and safety of left bundle branch area pacing (LBBAP) in patients with LBBB. Methods From Apr 2014 to Aug 2018, patients with LBBB from multicenters indicated for CRT or pacing therapy were included. LBBAP was performed by advancing the MDT 3830 lead deep into the septum about 1 cm distal to the His bundle region (Figure 1F). Pacing characteristics, success rate, threshold and R-wave amplitude were assessed. Results A total of 94 patients aged 68.3±10.7 y with the native QRS duration of 167.2±17.2 ms were included. In 92 patients, LBBAP was successfully achieved and demonstrated RBBB pattern during unipolar tip pacing (UTP), with the paced QRS duration of 116.4±12.6ms (Figure 1C). Fusion of LBBAP and native conduction via the RBB eliminated RBBB and resulted in an average QRS duration of 103.2±10.1 ms (Figure 1D). LBB potential could be recorded from the LBB lead during correction of LBBB by HBP in 21 patients who used two leads method (His lead and LBB lead, Figure 1B). Output dependent selective and non-selective LBBAP were demonstrated in 48 patients (Figure 1C, D). The LBB capture threshold by UTP was 0.53±0.18V/0.5ms at acute and 0.62±0.17V/0.5ms at 6 months and 0.65±0.2V/0.5ms at 1 year. The R-wave amplitude were 11.4±5.2mV, 12.4±5.8mV and 12.0±5.8mV at acute, 6 month and 1 year. During follow-up, only one patient had an increase in LBB capture threshold to 2.5V/0.5ms at 3 months and there were no other complications such as dislodgment, infections, embolism or stroke associated with the implantation. Conclusion Permanent LBBAP is feasible and safe in patients with LBBB.

Background: Accurate forecast of the death risk is crucial to the administration of people living with HIV/AIDS (PLHIV). We aimed to establish and validate an effective prognosis nomogram in PLHIV receiving antiretroviral therapy (ART). Methods: All the data were obtained from 2006 to 2018 in the Wenzhou area from China AIDS prevention and control information system. Factors included in the nomogram were determined by univariate and multiple Cox proportional hazard analysis based on the training set. The receiver operating characteristic (ROC) and calibration curves were used to assess its predictive accuracy and discriminative ability. Its clinical utility was also evaluated using decision curve analysis (DCA), X-tile analysis and Kaplan-Meier curve, respectively in an independent validation set. Findings: Independent prognostic factors including haemoglobin, viral load and CD4+ T-cell count were determined and contained in the nomogram. Good agreement between the prediction by nomogram and actual observation could be detected in the calibration curve for mortality, especially in the first year. In the training cohort, AUC (95% CI) and C-index (95% CI) were 0.93 (0.90, 0.96) and 0.90 (0.85, 0.96), respectively. In the validation set, the nomogram still revealed excellent discriminations [AUC (95% CI): 0.95 (0.91, 1.00)] and good calibration [C-index (95% CI): 0.92 (0.82–1.00)]. Moreover, DCA also demonstrated that the nomogram was clinical beneficial. Additionally, participants could be classified into three distinct (low, middle and high) risk groups by the nomogram. Interpretation: The nomogram presents accurate and favourable prognostic prediction for PLHIV who underwent ART. Funding: This work was supported by Zhejiang Basic Public Welfare Research Project (LGF19H260011), Wenzhou Basic Public Welfare Research Project (Y20180201), the Initial Scientific Research Fund (KYQD170301), the Major Project of the Eye Hospital Wenzhou the Major Project of the Eye Hospital Wenzhou Medical University (YNZD201602). Part of this work was also funded by National Natural Science Foundation of China (81670777) and Science and Technology Innovation Activity Plan and New Talents Plan for College Students in Zhejiang Province (2019R413073). The funders had no roles in study design, data collection, data analysis, interpretation and writing of the report. Keywords: PLHIV, Nomogram, Prognosis, HIV/AIDS-related mortality, DCA

Background: Prenatal exposure to ambient PM2.5, (i.e., fine particulate matter, aerodynamic diameter ≤ 2.5 μm) has been associated with preterm birth and low birth weight. The association between prenatal PM2.5 exposure and intrauterine inflammation (IUI), an important risk factor for preterm birth and neurodevelopmental outcomes, has not been evaluated. Objectives: We aimed to investigate the association between maternal exposure to PM2.5 and IUI in the Boston Birth Cohort, a predominantly urban low-income minority population. Methods: This analysis included 5,059 mother–infant pairs in the Boston Birth Cohort. IUI was assessed based on intrapartum fever and placenta pathology. PM2.5 exposure was assigned using data from the U.S. EPA’s Air Quality System. Odds ratios (OR) and 95% confidence intervals (CI) quantified the association of maternal PM2.5 exposure during preconception and various periods of pregnancy with IUI. Results: Comparing the highest with the lowest PM2.5 exposure quartiles, the multi-adjusted association with IUI was significant for all exposure periods considered, including 3 months before conception (OR = 1.52; 95% CI: 1.22, 1.89), first trimester (OR = 1.93; 95% CI: 1.55, 2.40), second trimester (OR = 1.67; 95% CI: 1.35, 2.08), third trimester (OR = 1.53; 95% CI: 1.24, 1.90), and whole pregnancy (OR = 1.92; 95% CI: 1.55, 2.37). Conclusions: Despite relatively low exposures, our results suggest a monotonic positive relationship between PM2.5 exposure during preconception and pregnancy and IUI. IUI may be a sensitive biomarker for assessing early biological effect of PM2.5 exposure on the developing fetus. Citation: Nachman RM, Mao G, Zhang X, Hong X, Chen Z, Soria CS, He H, Wang G, Caruso D, Pearson C, Biswal S, Zuckerman B, Wills-Karp M, Wang X. 2016. Intrauterine inflammation and maternal exposure to ambient PM2.5 during preconception and specific periods of pregnancy: the Boston Birth Cohort. Environ Health Perspect 124:1608–1615; http://dx.doi.org/10.1289/EHP243

Chronic arsenic exposure via drinking water has become a worldwide public health concern. In humans, inorganic arsenic (iAs) is metabolized to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) mainly mediated by arsenic (+3 oxidation state) methyltransferase (As3MT). We reported recently that N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) was involved in arsenic metabolism, and examined its interactive effect with As3MT on arsenic metabolism in vitro. To further evaluate the interactive effect of N6AMT1 and As3MT on arsenic biomethylation in humans, we conducted a human population-based study including 289 subjects living in rural villages in Inner Mongolia, China, and assessed their urinary arsenic metabolites profiles in relation to genetic polymorphisms and haplotypes of N6AMT1 and As3MT. Five N6AMT1 single nucleotide polymorphisms (SNPs; rs1003671, rs7282257, rs2065266, rs2738966, rs2248501) and the N6AMT1 haplotype 2_GGCCAT were significantly associated with the percentage of iAs (% iAs) in urine (e.g., for rs7282257, mean was 9.62% for TT, 6.73% for AA). Rs1003671 was also in a significant relationship with urinary MMA and DMA (the mean of %MMA was 24.95% for GA, 31.69% for GG; the mean of % DMA was 69.21% for GA, 59.82% for GG). The combined effect of N6AMT1 haplotype 2_GGCCAT and As3MT haplotype 2_GCAC showed consistence with the additive significance of each haplotype on % iAs: the mean was 5.47% and 9.36% for carriers with both and null haplotypes, respectively. Overall, we showed that N6AMT1 genetic polymorphisms were associated with arsenic biomethylation in the Chinese population, and its interaction with As3MT was observed in specific haplotype combinations.

Early detection of the health lesions induced by chronic arsenic exposure (HLICAE) are crucial to prevent permanent arsenic-induced damage. If HLICAE can be identified in time, appropriate preventive and therapeutic measures may be provided without various avoidable lesions. The present study aims to assess the probability of HLICAE early recognition with metabolomics. Applying a case-control study, 94 participants with HLICAE (cases) and other 94 subjects without HLICAE (controls) were matched with gender and age (±1 year), coming from a previous chronic arsenic exposure cohort. Serum metabolomic profiles were assessed by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) and analyzed with univariate and multivariate statistics. A total of 210 and 364 features were detected in positive and negative ion modes (ESI+/ESI-), respectively. The altered metabolic pathways included lipid and amino acid metabolisms. 28 metabolomics-based biomarkers were significantly associated with HLICAE and provided areas under the curve (AUC, 95% confidence interval) of 0.898 (0.836, 0.960) and 0.908 (0.855, 0.960) in the discovery phase, 78.6% and 86.4% of positive predictive values in the validation phase, in distinguishing HLICAE from controls in ESI+/ESI-, respectively. This study provides novel insights on mechanisms of health effects probably induced by chronic arsenic exposure, and these biomarkers may be applied in HLICAE early detection.

Depressive and anxiety symptoms are frequently observed in breast cancer survivors. To date, few randomized controlled trials have been conducted on the efficacy of cognitive behavioural therapy (CBT) for depressive and anxiety symptoms in Chinese population. This study aims to verify the efficacy of CBT in Chinese breast cancer survivors. Women (n = 392) with breast cancer were randomly assigned to 3 groups: CBT (n = 98), self-care management (SCM, n = 98), and usual care (UC, n = 196) using the proportion 1:1:2. Women in the CBT and SCM groups received a series of nine sessions for 12 weeks, while women in the UC group received their usual medical care only. Depressive and anxiety symptoms were assessed using the Hamilton Depression Rating Scale (HAMD) and the Hamilton Anxiety Scale (HAMA) score at baseline, 2, 4, 8, 12, 16, and 24 weeks. A significant intergroup difference was found in the HAMD and HAMA scores. Women in the CBT group showed significantly less depressive and anxiety symptoms compared with women in the SCM and UC groups over time. In conclusion, this study supports the efficacy of CBT for depressive and anxiety symptoms in Chinese breast cancer survivors.

As a nonmutagenic human carcinogen, arsenic (As)'s carcinogenic activity is likely the result of epigenetic changes, particularly alterations in DNA methylation. While increasing studies indicate a potentially important role for timing of As exposure on DNA methylation patterns and the subsequent differential risks for As toxicity and carcinogenesis, there is a lack of research that tackles these critical questions, particularly in human based populations. Here we reported a family-based study including three generations, in which each generation living in the same household had a distinctive timing of As exposure: in adulthood, in utero and during early childhood, and in germlines exposure for grandparents, parents, and grandchildren, respectively. We generated genome-wide DNA methylation data for 18 As-exposed families, nine control families, as well as 18 arsenical skin lesion patients. Our analysis showed that As exposure may leave detectable DNA methylation changes even though exposure occurred decades ago, and the most significant changes of global DNA methylation were observed among patients afflicted with arsenical skin lesions. As exposure across generations shared common differentially methylated DNA loci and regions (744 DML and 15 DMRs) despite the distinctive exposure timing in each generation. Importantly, based on these DML, clustering analysis grouped skin lesion patients together with grandparents in exposed families in the same cluster, separated from grandparents in control families. Further analysis identified a number of DML and several molecular pathways that were significantly distinguished between controls, exposed populations, as well as skin lesion patients. Finally, our exploratory analysis suggested that some of these DML altered by As exposure, may have the potential to be inherited affecting not only those directly exposed but also later generations. Together, our results suggest that common DML and/or DMRs associated with an increased risk for disease development could be identified regardless of when exposure to As occurred during their life span, and thus may be able to serve as biomarkers for identifying individuals at risk for As-induced skin lesions and possible cancers.

Background: Although anti-retroviral therapy (ART) and CD4 counts before ART (CD4CBA) link to death risk of timely diagnosed HIV/AIDS patients, the role of ART and its joint effects with CD4CBA on late diagnosed HIV/AIDS participants (LDPs) remain unclear. Methods: Based on data extracted from the AIDS Prevention and Control Information System, multiple cox proportion hazardous regression models were applied to assess effects of ART and CD4CBA on the death risk of LDPs. Findings: Among 607 LDPs, the overall mortality (95% CI) for participants receiving ART was 13·48 (8·95, 18·01) per 10000 person-month and significantly lower than that of controls [468·46 (328·46, 608·46), P =120 cells/μl (median) had the lowest risk of death [AHR: 0·03; 95% CI: 0·02, 0·06; P

Background: Although previous studies suggest that exposure to traffic-related pollution during childhood increases the risk of childhood overweight or obesity (COWO), the role of early life exposu...

Background Complement Factor I ( CFI ) and the CD46 complement regulator ( CD46 ) play an important role in the complement activation pathways, which is known to affect the development of uveitis. The present study was performed to investigate the association of the CFI and CD46 genes with acute anterior uveitis (AAU). Methods A total of 600 subjects (300 patients with AAU and 300 healthy controls) were recruited for this case-control study. Six CFI single nucleotide polymorphisms (SNP) (rs7356506, rs10029485, rs11726949, rs12512308, rs7438961, rs998538) and four CD46 SNPs (rs12138764, rs2466571, rs2796278, rs7545126) were genotyped using Sequenom MassARRAY technology. Allele and genotype frequencies were compared between patients and controls using the χ 2 test. Analyses were stratified for gender, human leukocyte antigen (HLA)-B27, and ankylosing spondylitis status. Results Rs7356506 in the CFI gene was found to be protective against AAU. There was a significant increase in the frequency of the A allele (p=0.003, pc=0.03, OR=0.684, CI 0.534 to 0.876) and AA homozygosity (p=0.004, pc=0.04, OR=0.624, CI 0.452 to 0.862) in AAU patients as compared to controls. Stratified analysis, according to gender and HLA-B27 status for AAU, also revealed the association with CFI -rs7356506. None of the tested SNPs of CD46 were associated with AAU. Conclusions This study has revealed a significant association between AAU and CFI -rs7356506, suggesting that CFI is involved in the pathogenesis of AAU, and that its influence on AAU may differ depending on gender and HLA-B27 status.

Supplemental Digital Content is available in the text, Serum cytokeratin 19 fragment (CYFRA21-1) has been found to be a useful prognostic marker in lung cancer. Previous studies have revealed that change in CYFRA21-1 synchronously predicted therapeutic effectiveness in advanced nonsmall cell lung cancer (NSCLC) after the second cycle of chemotherapy. The objective of this study was to investigate the early predictive value of percentage change in serum CYFRA21-1 from pretreatment to completion of the first cycle of chemotherapy for chemotherapeutic effectiveness in advanced NSCLC patients. Ninety-seven advanced NSCLC patients with elevated serum CYFRA21-1 level (≥3.8 μg/L), who received 2 platinum-containing drugs, were included in this retrospective study. Serum CYFRA21-1 had been assayed before and after the first cycle of chemotherapy. To evaluate the effectiveness of chemotherapy, patients were allocated to disease control (DC) and progressive disease groups. The percentage changes of serum CYFRA21-1 concentration before and after first-cycle chemotherapy that occurred in each group were evaluated for their ability to predict achievement of radiologic DC, that is, to predict therapeutic effectiveness. The percentage change of serum CYFRA21-1 and the prevalence of ≥5% weight loss were higher in patients with progressive disease than in those with DC. The differences in other clinical and pathological variables including age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, cigarette smoking, histological type, gross type, clinical stage, and chemotherapy regimens of the 2 groups were not significant. Both multiple generalized linear model analysis and linear trend tests indicated that the percentage change of serum CYFRA21-1 concentration was independently and negatively linked to the effectiveness of chemotherapy for NSCLC (P

Objectives: To investigate the independent and joint associations of hyperhomocysteinemia and hypertension with incident stroke and stroke death in Chinese adults. Methods: About 39,165 rural Chinese adults aged 35 years or older who had no history of stroke at the baseline study were prospectively followed to determine major cardiovascular events, with an average follow-up of 6.2 years. Using a nested case–control design, this report includes 179 incident stroke cases (121 stroke deaths) and 179 controls without vascular events from the original cohort matched by age, sex, community, and length of plasma storage. Baseline plasma total homocysteine (tHcy) measurements were obtained for all subjects. Logistic regression analysis was performed to investigate the independent and joint associations between H-type hypertension, defined as subjects with concomitant hypertension and elevated homocysteine (≥10 μmol/L), and risk of incident stroke and stroke death, after adjusting for important covariates. Results: We analyzed each risk factor independently and jointly. For analysis, homocysteine was divided into three groups: low (tHcy Conclusions: This study provides strong evidence that hyperhomocysteinemia and hypertension are two independent, modifiable risk factors, which act additively to increase the risk of incident stroke and stroke death. The results strongly suggest that H-type hypertension is a major risk factor for vascular disease and mortality, and those with H-type hypertension may particularly benefit from homocysteine-lowering therapy along with anti-hypertension therapy in Chinese populations.

Previous studies suggest that chronic stress may induce immune system malfunction and a broad range of adverse health outcomes; however, the underlying pathways for this relationship are unclear. Our study aimed to elucidate this question by examining the relationship between parental cardiovascular risk factors including systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), and waist-to-hip ratio (WHR) and maternal psychological stress score (MPSS) relative to the severity of the child's food allergy (FA) and number of affected children. SBP, DBP, BMI, and WHR were measured and calculated at the time of recruitment by trained nurses. MPSS was obtained based on self-report questionnaires covering lifestyle adjustments, perceived chronic stress, and quality of life. General linear models examined whether caregiver chronic stress was associated with FA. For mothers with children under age 5 years, SBP, DBP and number of affected children had strong and graded relationships with severity of the child's FA. MPSS was also significantly and positively associated with child FA severity (P