Childhood maltreatment and risk of endocrine diseases: an exploration of mediating pathways using sequential mediation analysis.

BACKGROUND: Adverse childhood experiences (ACEs), including childhood maltreatment, have been linked with increased risk of diabetes and obesity during adulthood. A comprehensive assessment on the associations between childhood maltreatment and all major endocrine diseases, as well as the relative importance of different proposed mechanistic pathways on these associations, is currently lacking. METHODS: Based on the UK Biobank, we constructed a cohort including 151,659 participants with self-reported data on childhood maltreatment who were 30 years of age or older on/after January 1, 1985. All participants were followed from the index date (i.e., January 1, 1985, or their 30th birthday, whichever came later) until the first diagnosis of any or specific (12 individual diagnoses and 9 subtypes) endocrine diseases, death, or the end of follow-up (December 31, 2019), whichever occurred first. We used Cox models to examine the association of childhood maltreatment, treated as continuous (i.e., the cumulative number of experienced childhood maltreatment), ordinal (i.e., 0, 1 and ≥ 2), or binary (< 2 and ≥ 2) variable, with any and specific endocrine diseases, adjusted for multiple covariates. We further examined the risk of having multiple endocrine diseases using Linear or Logistic Regression models. Then, sequential mediation analyses were performed to assess the contribution of four possible mechanisms (i.e., suboptimal socioeconomic status (SES), psychological adversities, unfavorable lifestyle, and biological alterations) on the observed associations. RESULTS: During an average follow-up of 30.8 years, 20,885 participants received a diagnosis of endocrine diseases. We observed an association between the cumulative number of experienced childhood maltreatment and increased risk of being diagnosed with any endocrine disease (adjusted hazard ratio (HR) = 1.10, 95% confidence interval 1.09-1.12). The HR was 1.26 (1.22-1.30) when comparing individuals ≥ 2 with those with < 2 experienced childhood maltreatment. We further noted the most pronounced associations for type 2 diabetes (1.40 (1.33-1.48)) and hypothalamic-pituitary-adrenal (HPA)-axis-related endocrine diseases (1.38 (1.17-1.62)), and the association was stronger for having multiple endocrine diseases, compared to having one (odds ratio (95% CI) = 1.24 (1.19-1.30), 1.35 (1.27-1.44), and 1.52 (1.52-1.53) for 1, 2, and ≥ 3, respectively). Sequential mediation analyses showed that the association between childhood maltreatment and endocrine diseases was consistently and most distinctly mediated by psychological adversities (15.38 ~ 44.97%), while unfavorable lifestyle (10.86 ~ 25.32%) was additionally noted for type 2 diabetes whereas suboptimal SES (14.42 ~ 39.33%) for HPA-axis-related endocrine diseases. CONCLUSIONS: Our study demonstrates that adverse psychological sequel of childhood maltreatment constitutes the main pathway to multiple endocrine diseases, particularly type 2 diabetes and HPA-axis-related endocrine diseases. Therefore, increased access to evidence-based mental health services may also be pivotal in reducing the risk of endocrine diseases among childhood maltreatment-exposed individuals.

Paeoniflorin protects NOD mice from T1D through regulating gut microbiota and TLR4 mediated myD88/TRIF pathway.

This study aimed to explore the effect of PF in regulating the progression of T1D through regulating gut microbiota and inhibiting TLR4-myD88/TRIF pathway. T1D mouse models were established and received PF treatment through intraperitoneal injection. The glucose, sugar tolerance, the incidence of T1D and H&E staining were detected to verify the effect of PF on T1D. Meanwhile, the changes of gut microbiota and the permeability of intestines in mice were also measured. On parallel, the number and function of immune cells were detected by Flow Cytometry. The expressions of ZO-1, ZO-2 and TLR4-myD88/TRIF pathway related proteins were detected by western blotting. Mice received PF treatment had decreased incidence of T1D and inflammatory infiltration in islet tissues compared with those received PBS treatment. In addition to that, PF treated mice had increased Sutterella species and decreased intestinal permeability, in which the decreased ratio of Th1/Th17 and increased Treg cells were also identified. The expression of TLR4-myD88/TRIF pathway was also suppressed in response to PF treatment. Moreover, further treatment with TLR4 agonist, LPS, could reverse the effect of PF on T1D mice. PF can suppress the TLR4 mediated myD88/TRIF pathway to change the distribution of gut microbiota, so as to protect NOD mice from T1D.

The influence of childhood asthma on adult height: evidence from the UK Biobank.

BACKGROUND: To elucidate the influence of childhood asthma on adult height after consideration of genetic heterogeneity in height. METHODS: Based on the UK Biobank, we conducted a matched cohort study, including 13,602 European individuals with asthma diagnosed before 18 years old and 136,008 matched unexposed individuals without such an experience. Ascertainment of asthma was based on self-reported data (97.6%) or clinical diagnosis in healthcare registers (2.4%). We studied three height outcomes, including (1) the attained adult height (in centimeters), (2) the height deviation measured as the difference between a person's rank of genetically determined height (based on generated polygenetic risk score) and their rank of attained adult height in the study population (deviation in % of height order after standardization), and (3) the presence of height deficit comparing genetically determined and attained height (yes or no). We applied linear mixed-effect models to assess the associations of asthma diagnosed at different ages with attained adult height and height deviation, and conditional logistic regression models to estimate the associations of asthma with the risk of height deficit. RESULTS: 40.07% (59,944/149,610) of the study participants were born before 1950, and most of them were men (57.65%). After controlling for multiple covariates, childhood asthma was associated with shorter attained adult height, irrespective of age at asthma diagnosis. However, in the analysis of height deviation (deviation in %), we observed the greatest height deviation among individuals with asthma diagnosed before 4 years of age (- 2.57 [95% CI - 4.14 to - 1.00] and - 2.80 [95% CI - 4.06 to - 1.54] for the age of ≤ 2 and 3-4 years, respectively). The magnitude of height deviation in relation to asthma declined thereafter and became null after age 6. Similarly, there was a statistically significant height deficit in relation to an asthma diagnosis at ages ≤ 2 and 3-4 (odds ratios = 1.21, 95% CI 1.04 to 1.40, and 1.15, 95% CI 1.02 to 1.29) but not thereafter. The result pattern was similar when separately analyzing asthma with or without inhaled glucocorticoid (ICS) use, despite that the estimates were consistently stronger among asthma individuals who used ICS. CONCLUSIONS: Our results suggest a notable association of childhood asthma, primarily asthma diagnosed at an early age, with adult height, after consideration of genetic heterogeneity in height and use of ICS. This finding highlights the need for surveillance on the growth problems among children with asthma.

Genetic predispositions to psychiatric disorders and the risk of COVID-19.

BACKGROUND: Whether a genetic predisposition to psychiatric disorders is associated with coronavirus disease 2019 (COVID-19) is unknown. METHODS: Our analytic sample consisted of 287,123 white British participants in UK Biobank who were alive on 31 January 2020. We performed a genome-wide association study (GWAS) analysis for each psychiatric disorder (substance misuse, depression, anxiety, psychotic disorder, and stress-related disorders) in a randomly selected half of the study population ("base dataset"). For the other half ("target dataset"), the polygenic risk score (PRS) was calculated as a proxy of individuals' genetic predisposition to a given psychiatric phenotype using discovered genetic variants from the base dataset. Ascertainment of COVID-19 was based on the Public Health England dataset, inpatient hospital data, or death registers in UK Biobank. COVID-19 cases from hospitalization records or death records were considered "severe cases." The association between the PRS for psychiatric disorders and COVID-19 risk was examined using logistic regression. We also repeated PRS analyses based on publicly available GWAS summary statistics. RESULTS: A total of 143,562 participants (including 10,868 COVID-19 cases) were used for PRS analyses. A higher genetic predisposition to psychiatric disorders was associated with an increased risk of any COVID-19 and severe COVID-19. The adjusted odds ratio (OR) for any COVID-19 was 1.07 (95% confidence interval [CI] 1.02-1.13) and 1.06 (95% CI 1.01-1.11) among individuals with a high genetic risk (above the upper tertile of the PRS) for substance misuse and depression, respectively, compared with individuals with a low genetic risk (below the lower tertile). Slightly higher ORs were noted for severe COVID-19, and similar result patterns were obtained in analyses based on publicly available GWAS summary statistics. CONCLUSIONS: Our findings suggest a potential role of genetic factors in the observed phenotypic association between psychiatric disorders and COVID-19. Our data underscore the need for increased medical surveillance for this vulnerable population during the COVID-19 pandemic.

Identification of circular RNA BTBD7_hsa_circ_0000563 as a novel biomarker for coronary artery disease and the functional discovery of BTBD7_hsa_circ_0000563 based on peripheral blood mononuclear cells: a case control study.

BACKGROUND: BTBD7_hsa_circ_0000563 is a novel circRNA and contains conserved binding sites with RNA-binding proteins. However, BTBD7_hsa_circ_0000563 has not been fully studied in coronary artery disease (CAD). We aimed to clarify the diagnostic value and the possible functional role of BTBD7_hsa_circ_0000563 in CAD. METHODS: A total of 276 human peripheral blood mononuclear cell (PBMC) samples were employed. The circularization of BTBD7_hsa_circ_0000563 was verified via Sanger sequencing. The expression level of BTBD7_hsa_circ_0000563 in CAD samples and control individuals was analysed via qRT-PCR. The diagnostic potential of BTBD7_hsa_circ_0000563 was evaluated using Spearman's analysis, univariate and multivariable logistic regression analysis, and receiver-operator characteristic (ROC) curve analysis. ChIRP-MS was performed to directly explore the proteins bound to BTBD7_hsa_circ_0000563. Bioinformatic analysis was conducted to investigate the possible functions and interactions of proteins bound to BTBD7_hsa_circ_0000563. RESULTS: In the present study, BTBD7_hsa_circ_0000563 was verified as a circular RNA in the PBMCs of CAD patients. The expression level of BTBD7_hsa_circ_0000563 in the CAD group was significantly lower than that in the control group. The area under the ROC curve was 0.690. ChIRP-MS found seven proteins that were directly bound to BTBD7_hsa_circ_0000563. Bioinformatic analysis of these seven proteins showed that the mitophagy and DNA repair pathways were enriched. These proteins interacted with each other to a certain extent. CONCLUSION: BTBD7_hsa_circ_0000563 may be a novel biomarker for the diagnosis of CAD and may influence the initiation and progression of CAD. These studies may reveal new possibilities for the diagnosis and treatment of CAD.

Development and validation of polygenic risk scores for prediction of breast cancer and breast cancer subtypes in Chinese women.

BACKGROUND: Studies investigating breast cancer polygenic risk score (PRS) in Chinese women are scarce. The objectives of this study were to develop and validate PRSs that could be used to stratify risk for overall and subtype-specific breast cancer in Chinese women, and to evaluate the performance of a newly proposed Artificial Neural Network (ANN) based approach for PRS construction. METHODS: The PRSs were constructed using the dataset from a genome-wide association study (GWAS) and validated in an independent case-control study. Three approaches, including repeated logistic regression (RLR), logistic ridge regression (LRR) and ANN based approach, were used to build the PRSs for overall and subtype-specific breast cancer based on 24 selected single nucleotide polymorphisms (SNPs). Predictive performance and calibration of the PRSs were evaluated unadjusted and adjusted for Gail-2 model 5-year risk or classical breast cancer risk factors. RESULTS: The primary PRSANN and PRSLRR both showed modest predictive ability for overall breast cancer (odds ratio per interquartile range increase of the PRS in controls [IQ-OR] 1.76 vs 1.58; area under the receiver operator characteristic curve [AUC] 0.601 vs 0.598) and remained to be predictive after adjustment. Although estrogen receptor negative (ER-) breast cancer was poorly predicted by the primary PRSs, the ER- PRSs trained solely on ER- breast cancer cases saw a substantial improvement in predictions of ER- breast cancer. CONCLUSIONS: The 24 SNPs based PRSs can provide additional risk information to help breast cancer risk stratification in the general population of China. The newly proposed ANN approach for PRS construction has potential to replace the traditional approaches, but more studies are needed to validate and investigate its performance.

Disease trajectories and mortality among individuals diagnosed with depression: a community-based cohort study in UK Biobank.

Patients with depression are at increased risk for a range of comorbid diseases, with, however, unclear explanations. In this large community-based cohort study of the UK Biobank, 24,130 patients diagnosed with depression were compared to 120,366 matched individuals without such a diagnosis. Follow-up was conducted from 6 months after the index date until death or the end of 2019, for the occurrence of 470 medical conditions and 16 specific causes of death. The median age at the time of the depression diagnosis was 62.0 years, and most of the patients were female (63.63%). During a median follow-up of 4.94 years, 129 medical conditions were found to be significantly associated with a prior diagnosis of depression, based on adjusted Cox regression models. Using disease trajectory network analysis to visualize the magnitude of disease-disease associations and the temporal order of the associated medical conditions, we identified three main affected disease clusters after depression (i.e., cardiometabolic diseases, chronic inflammatory diseases, and diseases related to tobacco abuse), which were further linked to a wider range of other conditions. In addition, we also identified three depression-mortality trajectories leading to death due to cardiovascular disease, respiratory system disease and malignant neoplasm. In conclusion, an inpatient diagnosis of depression in later life is associated with three distinct network-based clusters of medical conditions, indicating alterations in the cardiometabolic system, chronic status of inflammation, and tobacco abuse as key pathways to a wide range of other conditions downstream. If replicated, these pathways may constitute promising targets for the health promotion among depression patients.

COVID-19 related outcomes among individuals with neurodegenerative diseases: a cohort analysis in the UK biobank.

BACKGROUND: An increased susceptibility to COVID-19 has been suggested for individuals with neurodegenerative diseases, but data are scarce from longitudinal studies. METHODS: In this community-based cohort study, we included 96,275 participants of the UK Biobank who had available SARS-CoV-2 test results in Public Health England. Of these, 2617 had a clinical diagnosis of neurodegenerative diseases in the UK Biobank inpatient hospital data before the outbreak of COVID-19 (defined as January 31st, 2020), while the remaining participants constituted the reference group. We then followed both groups from January 31st, 2020 to June 14th, 2021 for ascertainment of COVID-19 outcomes, including any COVID-19, inpatient care for COVID-19, and COVID-19 related death. Logistic regression was applied to estimate the association between neurogenerative disease and risks of COVID-19 outcomes, adjusted for multiple confounders and somatic comorbidities. RESULTS: We observed an elevated risk of COVID-19 outcomes among individuals with a neurodegenerative disease compared with the reference group, corresponding to a fully adjusted odds ratio of 2.47 (95%CI 2.25-2.71) for any COVID-19, 2.18 (95%CI 1.94-2.45) for inpatient COVID-19, and 3.67 (95%CI 3.11-4.34) for COVID-19 related death. Among individuals with a positive test result for SARS-CoV-2, individuals with neurodegenerative diseases had also a higher risk of COVID-19 related death than others (fully adjusted odds ratio 2.08; 95%CI 1.71-2.53). CONCLUSION: Among UK Biobank participants who received at least one test for SARS-CoV-2, a pre-existing diagnosis of neurodegenerative disease was associated with a subsequently increased risk of COVID-19, especially COVID-19 related death.

Characteristics of circular RNAs expression of peripheral blood mononuclear cells in humans with coronary artery disease.

Circular RNAs (circRNAs) function as promising biomarkers and therapeutic targets for coronary artery disease due to their high stability, covalently closed structure, and potential gene regulation. We aimed to identify the expression profile and role of circular RNAs (circRNAs) in coronary artery disease (CAD). We performed RNA sequence analysis of circRNAs in peripheral blood mononuclear cells of five patients with CAD and five controls. Bioinformatics analyses were adopted to explore biological functions of differentially expressed circRNAs. The miRanda and TargetScan tools were used to predict the microRNA (miRNA)-targeting interactions and to construct a triple network of differentially expressed gene-circRNA-miRNA-mRNA. In total, 13,160 downregulated and 12,905 upregulated circRNAs were identified in CAD. A gene ontology annotation analysis showed that genes in the network were involved in organelle organization, cell cycle, mitotic cycle, and cellular metabolic process. Parental genes of the 10 dysregulated circRNAs were involved in metabolism and protein modification, and these circRNAs might regulate gene expression associated with CAD via miRNA sponges. As potential competing endogenous RNAs (ceRNAs), dysregulated circRNAs may be involved in the pathogenesis of CAD, which provides new insights into the diagnosis and prognosis of coronary artery disease.

COVID-19 and risk of subsequent life-threatening secondary infections: a matched cohort study in UK Biobank.

BACKGROUND: With the increasing number of people infected with and recovered from coronavirus disease 2019 (COVID-19), the extent of major health consequences of COVID-19 is unclear, including risks of severe secondary infections. METHODS: Based on 445,845 UK Biobank participants registered in England, we conducted a matched cohort study where 5151 individuals with a positive test result or hospitalized with a diagnosis of COVID-19 were included in the exposed group. We then randomly selected up to 10 matched individuals without COVID-19 diagnosis for each exposed individual (n = 51,402). The life-threatening secondary infections were defined as diagnoses of severe secondary infections with high mortality rates (i.e., sepsis, endocarditis, and central nervous system infections) from the UK Biobank inpatient hospital data, or deaths from these infections from mortality data. The follow-up period was limited to 3 months after the initial COVID-19 diagnosis. Using a similar study design, we additionally constructed a matched cohort where exposed individuals were diagnosed with seasonal influenza from either inpatient hospital or primary care data between 2010 and 2019 (6169 exposed and 61,555 unexposed individuals). After controlling for multiple confounders, Cox models were used to estimate hazard ratios (HRs) of life-threatening secondary infections after COVID-19 or seasonal influenza. RESULTS: In the matched cohort for COVID-19, 50.22% of participants were male, and the median age at the index date was 66 years. During a median follow-up of 12.71 weeks, the incidence rate of life-threatening secondary infections was 2.23 (123/55.15) and 0.25 (151/600.55) per 1000 person-weeks for all patients with COVID-19 and their matched individuals, respectively, which corresponded to a fully adjusted HR of 8.19 (95% confidence interval [CI] 6.33-10.59). The corresponding HR of life-threatening secondary infections among all patients with seasonal influenza diagnosis was 4.50, 95% CI 3.34-6.08 (p for difference < 0.01). Also, elevated HRs were observed among hospitalized individuals for life-threatening secondary infections following hospital discharge, both in the COVID-19 (HR = 6.28 [95% CI 4.05-9.75]) and seasonal influenza (6.01 [95% CI 3.53-10.26], p for difference = 0.902) cohorts. CONCLUSION: COVID-19 patients have increased subsequent risks of life-threatening secondary infections, to an equal extent or beyond risk elevations observed for patients with seasonal influenza.

[Population-based Study of the Effects of Adiponectin, Leptin and Soluble Leptin Receptor on Risks for Breast Cancer].

OBJECTIVE: To explore the individual or combined effects of adiponectin, leptin, and soluble leptin receptor (sOB-R) on risks for premenopausal and postmenopausal breast cancer, and to provide evidence for revealing the molecular mechanism between obesity and breast cancer. METHODS: 469 newly-diagnosed breast cancer cases were sequentially recruited for the study and 469 age-frequency-matched healthy women were enrolled as the controls over the same period of time. The participant baseline information was collected with questionnaires, and plasmic levels of adiponectin, leptin and sOB-R were checked with ELISA. Multivariate unconditional logistic regression was conducted and the analyses were further stratified according to waist-to-hip ratio (WHR) and body mass index (BMI) to explore the effect of the indicators on the risks for premenopausal and postmenopausal breast cancer. RESULTS: A total of 480 premenopausal and 458 postmenopausal women were included in the study. Among the premenopausal subjects, 249 were breast cancer patients and 231 were controls. The median BMI was 22.9 kg/m 2and 23.2 kg /m 2, respectively, and the median WHR was 0.80 and 0.83, respectively. Among the postmenopausal subjects, 220 were breast cancer patients and 238 were controls. The median BMI was 23.4 kg/m 2 and 23.7 kg/m 2, respectively, and the median WHR was 0.82 and 0.86, respectively. Multivariate logistic regression analysis showed that before and after model adjustment, the increase in sOB-R and adiponectin levels was correlated to reduced risks of premenopausal and postmenopausal breast cancer ( P<0.05), while the increase in the leptin/sOB-R ratio (also known as free leptin index, FLI) and leptin/adiponectin (L/A) ratio was only correlated to increased risks of postmenopausal breast cancer. After further stratification by WHR and BMI, the association between adiponectin, FLI and postmenopausal breast cancer remained statistically significant in all subgroups. Among subjects with normal-BMI central obesity (18.5 kg/m 2≤BMI<24 kg/m 2 & WHR≥0.85) , higher L/A ratio was associated with an increased risk of postmenopausal breast cancer. No clear association between leptin and premenopausal and risks for postmenopausal breast cancer was found in the study. CONCLUSION: Postmenopausal women with decreased levels of sOB-R and adiponectin, and increased FLI and L/A, and premenopausal women with decreased levels of sOB-R and adiponectin were found to be at high risks for breast cancer.

Long-term excess body fat in adulthood and the risk of pre- and postmenopausal breast cancer in Chinese women.

PURPOSE: This study aimed to investigate the association between long-term excess body fat and breast cancer risk by studying adult weight gain together with the subsequent weight fluctuations. METHODS: Weight gain measure in three different time periods in adulthood of 1500 participants was collected in a case-control study of Western China. Logistic regression models were used to estimate odds ratios and 95% CIs. RESULTS: The increased risk of postmenopausal BC was associated with adult weight gain at 5 years and at 10 years before enrollment (OR 1.24, 95% CI 1.03-1.49 per 5 kg increase; OR 1.40, 95% CI 1.14-1.70 per 5 kg increase) but was not associated with adult weight gain at enrollment (OR 0.97, 95% CI 0.81-1.16 per 5 kg increase). Only a positive association was observed in premenopausal women who had gained > 5.0 kg at 10 years before enrollment (OR 1.61, 95% CI 1.10-2.35). Women who had gained > 5.0 kg at 10 years before enrollment and continued to gain during the subsequent 5 years had the highest postmenopausal BC risk (OR 3.34, 95% CI 1.58-7.08). CONCLUSION: Adult weight gain at 5 years and 10 years before enrollment are more closely associated with postmenopausal BC risk than adult weight gain at enrollment in Western China. Controlling body weight as early as possible throughout adulthood to keep weight gain not more than 5.0 kg is particularly necessary for Chinese women.

The effectiveness of quarantine of Wuhan city against the Corona Virus Disease 2019 (COVID-19): A well-mixed SEIR model analysis.

A novel coronavirus pneumonia, first identified in Wuhan City and referred to as COVID-19 by the World Health Organization, has been quickly spreading to other cities and countries. To control the epidemic, the Chinese government mandated a quarantine of the Wuhan city on January 23, 2020. To explore the effectiveness of the quarantine of the Wuhan city against this epidemic, transmission dynamics of COVID-19 have been estimated. A well-mixed "susceptible exposed infectious recovered" (SEIR) compartmental model was employed to describe the dynamics of the COVID-19 epidemic based on epidemiological characteristics of individuals, clinical progression of COVID-19, and quarantine intervention measures of the authority. Considering infected individuals as contagious during the latency period, the well-mixed SEIR model fitting results based on the assumed contact rate of latent individuals are within 6-18, which represented the possible impact of quarantine and isolation interventions on disease infections, whereas other parameter were suppose as unchanged under the current intervention. The present study shows that, by reducing the contact rate of latent individuals, interventions such as quarantine and isolation can effectively reduce the potential peak number of COVID-19 infections and delay the time of peak infection.

Echocardiographic Changes in Newly Diagnosed Type 2 Diabetes Mellitus Patients with and without Hypertension.

BACKGROUND Whether type 2 diabetes mellitus (T2DM) is independently associated with structural heart abnormalities is controversial because of confounders associated with T2DM. This study aimed to investigate echocardiographic features in patients with newly diagnosed T2DM, exploring changes in cardiac structure and function. MATERIAL AND METHODS This was a retrospective study of new T2DM cases treated at the Second People's Hospital Affiliated to Nanjing Medical University (Changzhou) in 2014-2016. In all, 128 T2DM cases were included (62 hypertensive and 66 non-hypertensive individuals). Controls were selected among individuals who underwent examination at the same department/period. Interventricular septal thickness (IVST), left ventricular end-diastolic diameter (LVEDD), posterior left ventricular wall thickness (PWTD), left ventricle mass (LVM), end-diastolic thickness of left ventricular posterior wall (Dd), aortic root diameter, left atrial diameter (LAd), left atrial diameter fraction-shortening values, and left ventricular ejection fraction (LVEF) were determined routinely. RESULTS IVST, LVEDD, PWTD, Dd, LAd, and left atrial diameter fraction-shortening values were larger in patients with T2DM (all P<0.05 vs. controls). LVM was higher in T2DM patients (median, 57.12 vs. 54.77 g, P=0.001). There were no differences in aortic root diameter and EF (both P>0.05). Multivariable analysis showed that IVST (OR=1.33, 95% CI: 1.01-1.76, P=0.04), LAd (OR=1.16, 95% CI: 1.07-1.25, P<0.001), TGs (OR=1.34, 95% CI: 1.09-1.63, P=0.005), and HDL (OR=1.46, 95% CI: 1.02-2.08, P=0.04) were independently associated with hypertension in patients with T2DM. CONCLUSIONS Patients with newly diagnosed T2DM already display structural heart abnormalities. LAd and IVST are independently associated with hypertension in these patients, probably contributing to increased cardiovascular risk.

Association between circular RNA expression content and severity of coronary atherosclerosis in human coronary artery.

BACKGROUND: Circular RNAs (circRNAs) may act as biomarkers of coronary artery disease (CAD). However, the relationship between expression characteristics of circRNAs and coronary atherosclerosis has not been fully explored. The aim of this study was to determine and characterize the circRNAs from human coronary artery. METHODS: The coronary artery segments were obtained from an 81-year-old male patient with sudden death of myocardial infarction at autopsy. The coronary stenosis and atherosclerosis were evaluated by hematoxylin and eosin (H&E) staining, and the circRNAs expression profile was characterized by RNA sequencing (RNA-seq). The differentially expressed circRNAs were validated by qRT-PCR. RESULTS: The analysis of H&E staining indicated that coronary atherosclerosis grade and extent in the LM was more serious than that in other coronary arteries. Twenty-seven circRNAs were selected for expression validation in coronary artery. CircRNAs corresponding cyclization sites of 3 circRNAs (hsa_circ_0016868, hsa_circ_0001364, hsa_circ_0006731) have been verified by Sanger sequencing. CONCLUSION: The 3 circRNAs are suggested to play a pathological role underlying the coronary arteries atherosclerosis and may serve as a valuable resource as diagnostic or therapeutic targets against CAD.

Induced Abortion, Birth Control Methods, and Breast Cancer Risk: A Case-Control Study in China.

BACKGROUND: The association between induced abortion and birth control methods (including oral contraceptives and intrauterine devices) and breast cancer may vary among countries, due to the different usage and frequency of birth control methods and induced abortion among countries. A better understanding of this association may help in determining safer birth control methods for Chinese women. METHODS: A case-control study was conducted with a total of 794 cases and 805 controls. Standardized questionnaires were used to collect information on demographic characteristics, exposure to induced abortion, birth control methods, and other risk factors for breast cancer. Multivariate logistic regression was conducted to explore the association between birth control methods and breast cancer. RESULTS: Multivariate logistic regression analyses showed that having a history of medical abortions, ≥3 surgical abortions, or both medical and surgical abortions was associated with an increased risk of breast cancer in post-menopausal women (odds ratio [OR] 2.48; 95% confidence interval [CI], 1.14-5.40). Pre-menopausal women who had used intra-uterine devices (IUDs) for more than 20 years tended to have a lower breast cancer risk than other age-matched pre-menopausal women (OR 0.41; 95% CI, 0.25-0.68). Both pre-menopausal and post-menopausal women who had <20 years exposure to IUDs and those who had used two or more birth control methods (with the exception of women who used IUDs for more than 20 years) tended to have much higher breast cancer risk. CONCLUSION: The relationship between induced abortion and birth control methods and breast cancer was complex, though being exposed to induced abortion and two or more birth control methods in one's lifetime appeared to be risk factors for breast cancer in Chinese women.

STAT3-mediated epigenetic silencing of FOXP3 in LADA T cells is regulated through HDAC5 and DNMT1.

In LADA patients, Tregs are reduced and FOXP3 is downregulated in CD4+ T cells, but the etiology remains unclear. Our study included in 20 LADA patients and 20 healthy control patients. qRT-PCR results showed that STAT3, HDAC3, HDAC5, SIRT1, DNMT1 and DNMT3b mRNAs were significantly upregulated in LADA CD4+ T cells than controls, while FOXP3 mRNA significantly decreased. p-STAT3, STAT3, DNMT1 and DNMT3b expressions were increased demonstrated by western blot. ChIP-PCR suggested that p-STAT3 binds to the Foxp3 promoter, meanwhile, histone H3 acetylation at K9 and K14 of FOXP3 promoter were significantly lower than controls. Luciferase reporter assay showed that ectopic STAT3 expression significantly reduced FOXP3 promoter activities. The Foxp3 promoter was significantly hypermethylated in LADA than controls. LADA patients showed stronger binding of p-STAT3, HDAC5 and DNMT1 than controls using CHIP. These findings reveal a crucial role of STAT3 in regulating the epigenetic status of T cells in LADA.

Mobile phone applications and self-management of diabetes: A systematic review with meta-analysis, meta-regression of 21 randomized trials and GRADE.

We conducted a systematic review with meta-analysis of randomized controlled trials that evaluated the effect of diabetes mobile phone applications. A total of 1550 participants from 21 studies were included. For type 1 diabetes, a significant 0.49% reduction in HbA1c was seen (95% CI, 0.04-0.94; I2 = 84%), with unexplained heterogeneity and a low GRADE of evidence. For type 2 diabetes, using diabetes apps was associated with a mean reduction of 0.57% (95% CI, 0.32-0.82; I2 = 77%). The results had severe heterogeneity that was explained by the frequency of HCP feedback. In studies with no HCP feedback, low frequency and high frequency HCP feedback, the mean reduction is 0.24% (95% CI, 0.02-0.49; I2 = 0%), 0.33% (95% CI, 0.07-0.59; I2 = 47%) and 1.12% (95% CI, 0.91-1.32; I2 = 0%), respectively, with a high GRADE of evidence. There is evidence that diabetes apps improve glycaemic control in type 1 diabetes patients. A reduction of 0.57% in HbA1c was found in type 2 diabetes patients. However, HCP functionality is important to achieve clinical effectiveness. Future studies are needed to explore the cost-effectiveness of diabetes apps and the optimal intensity of HCP feedback.

Cigarette Smoke Extract Changes Expression of Endothelial Nitric Oxide Synthase (eNOS) and p16(INK4a) and is Related to Endothelial Progenitor Cell Dysfunction.

BACKGROUND Endothelial dysfunction is an important pathophysiologic feature in many smoke-related diseases. Endothelial progenitor cells (EPCs) are the precursors of endothelial cells and play a fundamental role in the maintenance of endothelial integrity and function. Endothelial nitric oxide synthase (eNOS) is the dominant NOS isoform in the vasculature and plays a central role in the maintenance of endothelial homeostasis. p16(INK4a) is a cyclin-dependent kinase inhibitor and could be regarded as a major dominant senescence gene. The present study aimed to determine whether the expression of eNOS and p16(INK4a) in EPCs is related to EPCs function and the possible epigenetic mechanism, if any. MATERIAL AND METHODS We investigated EPCs capacity for proliferation, adhesion, and secretion, and the expression of eNOS and p16(INK4a) in EPCs which were altered by cigarette smoke extract (CSE) in vitro. Furthermore, Decitabine (Dec), an agent of demethylation, was used to examine whether it could alter the changes induced by CSE. RESULTS The present study demonstrated that EPCs altered by CSE in vitro displayed decreased capacities of proliferation, adhesion, and secretion, which was accompanied by decreased eNOS expression and increased p16(INK4a) expression in EPCs. Furthermore, Dec could alleviate the changes in the expression of eNOS and p16(INK4a), and protect against the EPCs dysfunction caused by CSE. CONCLUSIONS The decreased eNOS expression and increased p16(INK4a) expression was associated with dysfunction of EPCs caused by CSE. The mechanism of methylation, one of the most common epigenetic mechanism, may be involved in the EPCs dysfunction caused by CSE.

Comparative study between macrolide regulatory proteins MphR(A) and MphR(E) in ligand identification and DNA binding based on the rapid in vitro detection system.

The macrolide regulatory protein MphR(A) has been widely studied and used in various aspects such as metabolism monitoring, exogenous gene expression, and in vivo and in vitro macrolide antibiotic screening. Another macrolide regulatory protein, MphR(E), has rarely been reported. In this study, in vitro ELISA-type systems were established for MphR(A) and MphR(E) to study their correlation. The reactivity of 14 macrolide antibiotics and pseudo-macrolide antibiotics was tested in the systems. The results indicated that the ligand identification spectra of MphR(A) and MphR(E) were basically consistent. The binding characteristics of MphR(A) and MphR(E) with three corresponding promoter DNA sequences were preliminarily studied. According to the ELISA-type analysis results, MphR(A) and MphR(E) have consistent DNA binding properties, which bind to A-DNA/B-DNA more easily than to C-DNA. This study has confirmed that MphR(E) can bind to the promoter DNA sequences mrx(E) and mph(E) in plasmid pRSB111, and different DNAs can affect the sensitivity of the in vitro detection systems.