Objective:To explore the robust relationship between insomnia and type 2 diabetes mellitus by two-sample Mendelian randomization analysis to overcome confounding factors and reverse causality in observational studies.Methods:We identified strong,independent single nucleotide polymorphisms(SNPs)of insomnia from the most up to date genome wide association studies(GWAS)within European ancestors and applied them as instrumental variable to GWAS of type 2 diabetes mellitus.After excluding SNPs that were significantly associated with smoking,physical activity,alcohol consumption,educational attainment,obesity,or type 2 diabetes mellitus,we assessed the impact of insomnia on type 2 diabetes mellitus using inverse variance weighting(IVW)method.Weighted median and MR-Egger regression analysis were also conducted to test the robustness of the association.We calculated the F statistic of the selected SNPs to test the applicability of instrumental variable and F statistic over than ten indicated that there was little possibility of bias of weak instrumental variables.We further examined the existence of pleiotropy by testing whether the intercept term in MR-Egger regression was significantly different from ze-ro.In addition,the leave-one-out method was used for sensitivity analysis to verify the stability and relia-bility of the results.Results:We selected 248 SNPs independently associated with insomnia at the genome-wide level(P＜5 ×10-8)as a preliminary candidate set of instrumental variables.After clum-ping based on the reference panel from 1000 Genome Project and removing the potential pleiotropic SNPs,a total of 167 SNPs associated with insomnia were included as final instrumental variables.The F statistic of this study was 39.74,which was in line with the relevance assumption of Mendelian randomi-zation.IVW method showed insomnia was associated with higher risk of type 2 diabetes mellitus that po-pulation with insomnia were 1.14 times more likely to develop type 2 diabetes mellitus than those without insomnia(95％CI:1.09-1.21,P＜0.001).The weighted median estimator(WME)method and MR-Egger regression showed similar causal effect of insomnia on type 2 diabetes mellitus.And MR-Egger re-gression also showed that the effect was less likely to be triggered by pleiotropy.Sensitivity analyses pro-duced directionally similar estimates.Conclusion:Insomnia is a risk factor of type 2 diabetes mellitus,which has positively effects on type 2 diabetes mellitus.Our study provides further rationale for indivi-duals at risk for diabetes to keep healthy lifestyle.

Objective:To assess the association between short-term ambient air pollution exposure and arterial stiffness and whether obesity modifies these associations.Methods:A cross-sectional study was conducted based on Fangshan family cohort in Beijing. The 24 hours average air pollutant levels on the day cohort participants took baseline survey were calculated as short-term air pollution. A generalized additive model (GAM) with Gaussian links was used to estimate changes in typical carotid artery intima-media thickness (CIMT), brachial-ankle pulse wave velocity (BAPWV), pulse pressure (PP) and ankle-branchial index (ABI) after short-term exposure to each air pollution (PM 2.5, PM 10, SO 2, NO 2, CO). The cross-product terms of each air pollution, body mass index (BMI), and waist-to-hip ratio were included in the GAM model to test the interaction. Further, they conducted a stratified analysis to test their effects on the relationship between short-term exposure to each air pollution and the arterial stiffness indicators. Results:A total of 4 211 individuals were included in the analysis. Individuals' age was (58.9±8.7) years, of which 2 268 (53.9%) were female. Several covariates, including sociodemographic factors, lifestyle behaviors, and history of drugs, were included in the analysis. The results of the GAM analysis showed that an increase in PM 2.5 ( β=2.912×10 -4, 95% CI: 1.424×10 -4-4.400×10 -4, P<0.001), CO ( β=0.027, 95% CI: 0.011-0.043, P<0.001), SO 2 ( β=2.070×10 -3, 95% CI: 7.060×10 -4-3.430×10 -3, P=0.003), and NO 2 ( β=3.650×10 -4, 95% CI: 2.340×10 -5-7.060×10 -4, P=0.036) were associated with an increase in CIMT, while an increase in PM 10 ( β=0.018, 95% CI: 0.002-0.033, P=0.028) was associated with an increase in PP in the study population. Besides, the waist-to-hip ratio had an effect-modification on the correlation of short-term exposure of PM 2.5 (interaction P=0.015), NO 2 (interaction P=0.008), and CO (interaction P=0.044) with CIMT, and the correlation between short-term exposure of PM 2.5 (interaction P=0.002), NO 2 (interaction P=0.010), CO (interaction P=0.029), PM 10 (interaction P<0.001) with PP. The significant association between CIMT, PP, and air pollution concentrations was more visible in people with lower waist-to-hip ratios. Conclusions:Short-term ambient air pollution exposure was associated with arterial stiffness indicators, and there was an effect modification of waist-to-hip ratio on these associations, and lower waist-to-hip ratios may enhance the association between air pollution exposure and indicators.

Objective:To explore the effects of short-term particulate matter(PM)exposure and the melatonin receptor 1B(MTNR1B)gene on triglyceride-glucose(TyG)index utilizing data from Fang-shan Family-based Ischemic Stroke Study in China(FISSIC).Methods:Probands and their relatives from 9 rural areas in Fangshan District,Beijing,were included in the study.PM data were obtained from fixed monitoring stations of the National Air Pollution Monitoring System.TyG index was calculated by fasting triglyceride and glucose concentrations.The associations of short-term PM exposure and rs10830963 polymorphism of the MTNR1B gene with the TyG index were assessed using mixed linear models,in which covariates such as age,sex,and lifestyles were adjusted for.Gene-environment inter-action analysis was furtherly performed using the maximum likelihood methods to explore the potential effect modifier role of rs10830963 polymorphism in the association of PM with TyG index.Results:A total of 4 395 participants from 2 084 families were included in the study,and the mean age of the study participants was(58.98±8.68)years,with 53.90％females.The results of association analyses showed that for every 10 μg/m3 increase in PM2.5 concentration,TyG index increased by 0.017(95％CI:0.007-0.027),while for per 10 μg/m3 increment in PM1o,TyG index increased by 0.010(95％CI:0.003-0.017).And the associations all had lagged effects.In addition,there was a positive association between the rs10830963 polymorphism and the TyG index.For per increase in risk allele G,TyG index was elevated by 0.040(95％CI:0.004-0.076).The TyG index was 0.079(95％CI:0.005-0.152)higher in carriers of the GG genotype compared with carriers of the CC genotype.The inter-action of rs10830963 polymorphism with PM exposure had not been found to be statistically significant in the present study.Conclusion:Short-term exposure to PM2.5 and PM10 were associated with higher TyG index.The G allele of rs10830963 polymorphism in the MTNR1B gene was associated with the elevated TyG index.

Objective:To delve into the intricate relationship between common genetic variations across the entire genome and the risk of non-syndromic cleft lip with or without cleft palate(NSCL/P).Methods:Utilizing summary statistics data from genome-wide association studies(GW AS),a thorough investigation to evaluate the impact of common variations on the genome were undertook.This involved assessing single nucleotide polymorphism(SNP)heritability across the entire genome,as well as within specific genomic regions.To ensure the robustness of our analysis,stringent quality control measures were applied to the GWAS summary statistics data.Criteria for inclusion encompassed the absence of missing values,a minor allele frequency≥1％,P-values falling within the range of 0 to 1,and clear SNP strand orientation.SNP meeting these stringent criteria were then meticulously included in our analy-sis.The SNP heritability of NSCL/P was calculated using linkage disequilibrium score regression.Addi-tionally,hierarchical linkage disequilibrium score regression to partition SNP heritability within coding re-gions,promoters,introns,enhancers,and super enhancers were employed,and the enrichment levels within different genomic regions using LDSC(v1.0.1)software were further elucidated.Results:Our study drew upon GWAS summary statistics data obtained from 806 NSCL/P trios,comprising a total of 2 418 individuals from the Chinese population.Following rigorous quality control procedures,490 593 out of 492 993 SNP were deemed suitable for inclusion in SNP heritability calculations.The observed SNP heritability of NSCL/P was 0.55(95％CI:0.28-0.82).Adjusting for the elevated disease pre-valence within our sample,the SNP heritability scaled down to 0.37(95％CI:0.19-0.55)based on the prevalence observed in the general Chinese population.Notably,our enrichment analysis unveiled significant enrichment of SNP heritability within enhancer regions(15.70,P=0.04)and super enhan-cer regions(3.18,P=0.03).Conclusion:Our study sheds light on the intricate interplay between common genetic variations and the risk of NSCL/P in the Chinese population.By elucidating the SNP heritability landscape across different genomic regions,we contribute valuable insights into the genetic basis of NSCL/P.The significant enrichment of SNP heritability within enhancer and super enhancer re-gions underscores the potential role of these regulatory elements in shaping the genetic susceptibility to NSCL/P.This paves the way for further research aimed at uncovering novel genetic pathogenic factors un-derlying NSCL/P pathogenesis.

Liquid chromatography tandem mass spectrometry (LC-MS/MS) has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules,due to its rapid method development and high accuracy.In this study,we established a new LC-MS/MS method for the determination of the anti-sclerostin monoclonal antibody (SHR-1222) in cynomolgus monkey serum,and compared it to a previous electrochemiluminescence method.The antibody was quantified by detecting the surrogate peptide obtained by trypsin digestion.The surrogate peptide was carefully selected by investigating its uniqueness,stability and MS response.The quantitative range of the pro-posed method was 2.00-500 μg/mL,and this verified method was successfully applied to the tox-icokinetic assessment of SHR-1222 in cynomolgus monkey serum.It was found that the concentrations of SHR-1222 in cynomolgus monkeys displayed an excellent agreement between the LC-MS/MS and electrochemiluminescence methods (ratios of drug exposure,0.8-1.0).Notably,two monkeys in the 60 mg/kg dose group had abnormal profiles with a low detection value of SHR-1222 in their individual sample.Combining the high-level anti-drug antibodies (ADAs) in these samples and the consistent quantitative results of the two methods,we found that the decreased concentration of SHR-1222 was due to the accelerated clearance mediated by ADAs rather than the interference of ADAs to the detection platform.Taken together,we successfully developed an accurate,efficient and cost-effective LC-MS/MS method for the quantification of SHR-1222 in serum samples,which could serve as a powerful tool to improve the preclinical development of antibody drugs.

Objective:To evaluate the systemic absorption and safety of multiple doses of topical tazarotene/betamethasone dipropionate cream in healthy subjects and patients with psoriasis.Methods:From September 2008 to April 2009, 12 healthy subjects collected from Hospital for Skin Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College were randomly and equally divided into tazarotene 0.15%/betamethasone dipropionate 0.15% cream group and tazarotene 0.2%/betamethasone dipropionate 0.2% cream group; these subjects were instructed to apply 0.03 g of the test drug per day on each of the 4 body sites, including the flexor aspects of bilateral forearms, waist and back, for 7 consecutive days, and venous blood samples were obtained before, and 1, 3, 5 and 7 days after the start of drug application. From October 2010 to August 2011, 60 patients with non-cephalic psoriasis collected from the Hospital for Skin Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College were randomly divided into 3 groups at a ratio of 3∶1∶1, i.e., tazarotene 0.05%/betamethasone dipropionate 0.05% cream group ( n = 36) and tazarotene 0.05% gel group ( n = 12) topically treated with a cream vehicle in the morning and the test drug at night, and betamethasone dipropionate 0.05% cream group ( n = 12) topically treated with the test drug twice a day (once in the morning and again in the evening) ; the treatment lasted 6 consecutive weeks, and venous blood samples were collected before, and 2, 4 and 6 weeks after drug application. Liquid chromatography-tandem mass spectrometry was performed to determine the concentrations of tazarotenic acid and betamethasone in plasma. During the trial, adverse events in the subjects were recorded, routine blood and urine examinations were carried out, and liver and kidney function were evaluated before and after treatment. Results:The plasma concentrations of tazarotenic acid and betamethasone in the 12 healthy subjects were below the lower limit of quantitation (0.04 μg/L) after 1-, 3-, 5- and 7-day treatment. After the consecutive treatment, tazarotenic acid and betamethasone were detected in 2 (5.56%) and 4 (11.11%) patients respectively at week 2, 4 or 6 in the tazarotene 0.05%/betamethasone dipropionate 0.05% cream group, and the highest plasma concentrations of tazarotenic acid and betamethasone were 0.112 and 0.201 μg/L respectively; in the betamethasone dipropionate 0.05% cream group, betamethasone was detected in 2 of 12 patients, and the highest plasma concentration of betamethasone was 0.112 μg/L. No test drug-related systemic adverse reactions or laboratory abnormalities were observed in any of the healthy subjects or patients.Conclusion:Multiple doses of topical tazarotene/betamethasone dipropionate cream has advantages of little systemic absorption, no long-term accumulation and good systemic safety.

Objective: To explore the relationship between glycemic control and visceral adiposity index (VAI) among type 2 diabetes mellitus (T2DM) patients.Methods: A community-based epidemiological field study for patients with T2DM aged ≥ 40 years was conducted in China.Every participant underwent physical examinations, biochemical tests of fasting glucose, glycosylated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and so on, and a questionnaire, including anthropometric characteristics, lifestyle, disease history, family history, and medication use.Those participants with HbA1c ≥7.0% were classified as the poorly controlled in our analysis of relationship between glycemic control and VAI.Anthropometric characteristics, lifestyle, and biochemical indexes of the participants were compared among the groups of different VAI levels.Logistic models were applied in multiple analysis adjusting for possible confounders.Results: A total of 1 607 patients with T2DM were recruited in our analysis with a mean age of (59.4±8.1) years and an average T2DM duration of (7.0±6.4) years.Among them, 78.3% were on hypoglycemic therapy.The cutoff points of quartiles of VAI were calculated for the males and females, respectively.According to the ascending order of the quartiles of VAI, the participants were divided into four groups, i.e.Q1, Q2, Q3, and Q4.The poor glycemic control rate for these groups were 60.6%, 65.7%, 70.1%, and 71.0%, respectively (Trend χ2=12.20, P<0.001).After adjustment for age, gender, systolic blood pressure (SBP), diastolic blood pressure (DBP), LDL-C, smoking, cardio-cerebral vascular disease (CVD) history, hypoglycemic therapy, T2DM duration, and family history of diabetes, the Logistic regression models showed that the glycemic control rate was significantly associated with VAI levels among the patients with T2DM.Compared with the participants in group Q1, the ORs of poor glycemic control for those in groups Q2, Q3, and Q4 were 1.239 (95%CI 0.918 to 1.672), 1.513 (95%CI 1.117 to 2.050), and 1.535 (95%CI 1.128to 2.088), respectively (trend P=0.003).With each quartile increase in VAI, the OR of poor glycemic control was 1.162 (95%CI 1.054 to 1.282).Conclusion: The glycemic control among the patients with T2DM is significantly associated with VAI.High level of VAI is an indicator of poor glycemic control.

Objective To explore the relationship between type 2 diabetes mellitus(T2DM)and serum stromal cell derived factor-1(SDF-1)levels. Methods A community-based epidemiological field study for T2DM patients and non-T2DM subjects was conducted in Beijing,China. Every subject underwent physical examinations, biochemical tests of stromal cell derived factor 1 and so on,and completed a standardized questionnaire. A total of 756 subjects were recruited in our analysis ,including 267 T2DM patients and 489 non-T2DM subjects ,T2DM patients were further divided into 81 simple T2DM patients and 186 macrovascular complication patients on the basis of the status of macrovascular complication. The correlation between serum SDF-1 levels and T2DM was analyzed. Results Compared with non-T2DM group,the level of SDF-1 in T2DM group was higher(P=0.019). The level of SDF-1 in simple T2DM group was also higher than macrovascular complication group(P=0.044). In the multi-ple linear regression analysis,after adjustment for age,gender,smoking,drinking,dyslipidemia,hypertension and BMI,SDF-1 level in simple T2DM group was higher than macrovascular complication group(P = 0.049), still. Conclusions Simple T2DM patients had a higher serum SDF-1 level than T2DM patients with macrovascular complications as well as those who did not suffer T2DM,suggesting that the stromal cell derived factor-1 may play a certain role in the development of T2DM and macrovascular complications.

Objective:To compare the suicidality risk in major depressive disorder (MDD)patients with and without anxious characteristics,and analyze the risk factors of suicidality in MDD patients. Methods:This was a secondary analysis of the data from the Diagnostic Assessment Service for people with Bipolar Disorders in China (DASP),which was initiated by the Chinese Society of Psychiatry (CSP),from September 1,2010 to February 28, 201 1. Based on the anxious module and suicide module of Mini International Neuropsychiatric Interview (M. I. N. I),1 172 MDD patients were classified as suffering from anxious MDD (n=728,62. 1%)and non-anxious MDD(n=444,37. 9%). Logistic regression was employed to examine the risk factors of suicidality in MDD pa-tients. Results:Among the anxious MDD patients,331 (45. 5%)of them had suicidality risk. And 54(12. 2%)of non-anxious MDD patients had suicidality risk. Compare to the non-anxious group,the anxious MDD patients had significantly higher suicidality risk (P<0. 00 1 ). Logistic regression analysis showed that more frequent depressive episodes (OR=2. 07 ),depressive episodes with psychotic symptoms (OR=2. 0 1 ),comorbid with anxious charac-teristics (OR=3. 18)or melancholic characteristics (OR=2. 90)were associated with suicidality risk in patients with MDD. Conclusion:It indicates that the anxious MDD patients may have higher suicidality risk than non-anx-ious MDD patients,and more frequent depressive episodes,depressive episodes with psychotic symptoms,comorbid with anxious characteristics or melancholic characteristics may be risk factors of suicidality in patients with MDD.

This study aims to develop a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of ivabradine and N-demethylivabradine in human plasma, and investigate effects of stable isotope labeled (SIL) internal standard (IS) on ivabradine. The analytes and IS were extracted from plasma by protein precipitation with acetonitrile, and chromatographied on a Capcell PAK C18 (100 mm x 4.6 mm, 5 μm) column using a mobile phase of methanol and 5 mmol x L(-1) ammonium acetate. Multiple reaction monitoring with electrospray ionization (ESI) was used in the positive mode for mass spectrometric detection. The effect of ivabradine isotope peak [M+H+3] + on IS and the effect of SIL IS purity on ivabradine were evaluated. An appropriate concentration of SIL IS was chosen to permit method selectivity and linearity of the assay over the required range. The standard curves were demonstrated to be linear in the range of 0.100 to 60.0 ng x mL(-1) for ivabradine, and 0.050 0 to 20.0 ng x mL(-1) for N-demethylivabradine. The intra and inter day precision and accuracy were within the acceptable limits for all concentrations. Besides, the interaction between IS and ivabradine did not impact the determination of analytes. This method was successfully applied to a pharmacokinetic study of hydrogen sulfate ivabradine sustained release tablets on Chinese healthy volunteers.