APOE ε4 allele modifies the associations of toxic metals and their mixture with cognitive impairment among older adults.

BACKGROUND: The evidence of interactive effect of the toxic metal (TM) mixture and apolipoprotein E (APOE) ε4 gene on cognitive impairment in older adults is scarce. We aimed to explore whether the associations of single TMs and their mixture with cognitive impairment depend on APOE ε4 in Chinese community-dwelling older people. METHODS: A total of 1148 older adults from a subset of the baseline survey of a cohort study were included. Blood arsenic (As), cadmium (Cd), lead (Pb), strontium (Sr), and vanadium (V) were detected by inductively coupled plasma mass spectrometry. APOE gene (rs429358, rs7412) polymorphisms were analyzed by the Polymerase Chain Reaction instrument. Mixed effects logistic regression was applied to estimate the relationships of single TMs and APOE genotype with cognitive impairment. Weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were performed to examine joint impacts of the TM mixture, as well as the interaction of the TM mixture with APOE ε4 genotype on cognitive impairment. RESULTS: Pb displayed a significant linear association with an increased odds of cognitive impairment after adjustment for covariates (Ptrend = 0.045). While APOE genotype did not show a significant correlation with cognitive impairment. WQS showed that the TM mixture was associated with an increased risk of cognitive impairment by 31.0% (OR=1.31, 95% CI: 0.92, 1.87) while no significance was found. BKMR exhibited a significant linear association between the TM mixture and cognitive impairment. Moreover, both WQS and BKMR indicated that Pb contributed the most to cognitive impairment within the mixture. Significant interactions of Pb or the TM mixture and APOE genotype on cognitive impairment were observed, contributing to 38.1% and 38.2% of total effects, respectively. CONCLUSIONS: APOE ε4 allele amplifies the associations of single Pb or the TM mixture with cognitive impairment. These findings may help to develop precision prevention.

Association of exposure to multiple heavy metals during pregnancy with the risk of gestational diabetes mellitus and insulin secretion phase after glucose stimulation.

BACKGROUND: Epidemiological evidence for the association between heavy metals exposure during pregnancy and gestational diabetes mellitus (GDM) is still inconsistent. Additionally, that is poorly understood about the potential cause behind the association, for instance, whether heavy metal exposure is related to the change of insulin secretion phase is unknown. OBJECTIVES: We aimed to explore the relationships of blood levels of arsenic (As), lead (Pb), thallium (Tl), nickel (Ni), cadmium (Cd), cobalt (Co), barium (Ba), chromium (Cr), mercury (Hg) and copper (Cu) during early pregnancy with the odds of GDM, either as an individual or a mixture, as well as the association of the metals with insulin secretion phase after glucose stimulation. METHODS: We performed a nested case-control study consisting of 302 pregnant women with GDM and 302 controls at the First Affiliated Hospital of Anhui Medical University in Hefei, China. Around the 12th week of pregnancy, blood samples of pregnant women were collected and levels of As, Pb, Tl, Ni, Cd, Co, Ba, Cr, Hg and Cu in blood were measured. An oral glucose tolerance test (OGTT) was done in each pregnant woman during the 24-28th week of pregnancy to diagnose GDM and C-peptide (CP) levels during OGTT were measured simultaneously. The four metals (As, Pb, Tl and Ni) with the highest effect on odds of GDM were selected for the subsequent analyses via the random forest model. Conditional logistic regression models were performed to analyze the relationships of blood As, Pb, Tl and Ni levels with the odds of GDM. The weighted quantile sum (WQS) regression and bayesian kernel machine regression (BKMR) were used to assess the joint effects of levels of As, Pb, Tl and Ni on the odds of GDM as well as to evaluate which metal level contributed most to the association. Latent profile analysis (LPA) was conducted to identify profiles of glycemic and C-peptide levels at different time points. Multiple linear regression models were employed to explore the relationships of metals with glycaemia-related indices (fasting blood glucose (FBG), 1-hour blood glucose (1h BG), 2-hour blood glucose (2h BG), fasting C-peptide (FCP), 1-hour C-peptide (1h CP), 2-hour C-peptide (2h CP), FCP/FBG, 1h CP/1h BG, 2h CP/2h BG, area under the curve of C-peptide (AUCP), area under the curve of glucose (AUCG), AUCP/AUCG and profiles of BGs and CPs, respectively. Mixed-effects models with repeated measures data were used to explore the relationship between As (the ultimately selected metal) level and glucose-stimulated insulin secretion phase. The mediation effects of AUCP and AUCG on the association of As exposure with odds of GDM were investigated using mediation models. RESULTS: The odds of GDM in pregnant women increased with every ln unit increase in blood As concentration (odds ratio (OR) = 1.46, 95% confidence interval (CI) = 1.04-2.05). The joint effects of As, Pb, Tl and Ni levels on the odds of GDM was statistically significant when blood levels of four metals were exceeded their 50th percentile, with As level being a major contributor. Blood As level was positively associated with AUCG and the category of glucose latent profile, the values of AUCG were much higher in GDM group than those in non-GDM group, which suggested that As exposure associated with the odds of GDM may be due to that As exposure was related to the impairment of glucose tolerance among pregnant women. The significant and positive relationships of As level with AUCP, CP latent profile category, 2h CP and 2h CP/2h BG were observed, respectively; and the values of 1h CP/1h BG and AUCP/AUCG were much lower in GDM group than those in non-GDM group, which suggested that As exposure may not relate to the impairment of insulin secretion (pancreatic ß-cell function) among pregnant women. The relationships between As level and 2h CP as well as 2h CP/2h BG were positive and significant; additionally, the values of 2h CP/2h BG in GDM group were comparable with those in non-GDM group; the peak value of CP occurred at 2h in GDM group, as well as the values of 2h CP/2h BG in high As exposure group were much higher than those in low As exposure group, which suggested that As exposure associated with the increased odds of GDM may be due to that As exposure was related to the change of insulin secretion phase (delayment of the peak of insulin secretion) among pregnant women. In addition, AUCP mediated 11% (p < 0.05) and AUCG mediated 43% (p < 0.05) of the association between As exposure and the odds of GDM. CONCLUSION: Our results suggested that joint exposure to As, Pb, Tl and Ni during early pregnancy was positively associated with the odds of GDM, As was a major contributor; and the association of environmental As exposure with the increased odds of GDM may be due to that As exposure was related to the impairment of glucose tolerance and change of insulin secretion phase after glucose stimulation (delayment of the peak of insulin secretion) among pregnant women.

Elevated levels of Zn, Cu and Co are associated with an increased risk of endometriosis: Results from a casecontrol study.

BACKGROUND: Endometriosis is a common gynecological disease that affects approximately 5 %∼10 % of reproductive-aged women. Zinc (Zn), selenium (Se), copper (Cu), cobalt (Co) and molybdenum (Mo) are essential trace elements and are very important for human health. However, studies on the relationship between mixtures of essential trace elements and the risk of endometriosis are limited and inconsistent. In particular, studies confirming the association via different sample types are limited. OBJECTIVE: This study aimed to investigate the associations between Zn, Se, Cu, Co and Mo concentrations in blood and follicular fluid (FF) and endometriosis risk in a Chinese population. METHODS: A total of 609 subjects undergoing in vitro fertilization (IVF) were recruited; 836 samples were analyzed, including 451 blood samples (234 controls and 217 cases) and 385 FF samples (203 controls and 182 cases). In addition, 227 subjects provided both blood and FF samples. Zn, Se, Cu, Co and Mo concentrations in blood and FF were quantified via inductively coupled plasma-mass spectrometry (ICP-MS). The associations between the levels of Zn, Se, Cu, Co and Mo and the risk of endometriosis were assessed using single-element models (logistic regression models), and the combined effect of the trace elements on endometriosis risk was assessed using multielement models (Bayesian kernel machine regression (BKMR) and weighted quantile sum (WQS) regression). RESULTS: Based on the single-element models, significant associations of Zn concentrations in blood (high-level vs. low-level group: aOR = 14.17, 95 % CI: 7.31, 27.50) and FF (first tertile vs. second tertile group: aOR = 0.34, 95 % CI: 0.16, 0.71; third tertile vs. second tertile group: aOR = 2.32, 95 % CI: 1.38, 3.91, respectively) and Co concentrations in blood (first tertile vs. second tertile group, aOR = 0.24, 95 % CI: 0.12, 0.48) and FF (third tertile vs. second tertile group: aOR = 3.87, 95 % CI: 2.19, 6.84) with endometriosis risk were found after adjustment for all confounders. In FF, Cu and Mo levels were significantly greater among the cases than among the controls, with a positive association with endometriosis risk (Cu (first tertile vs. second tertile group: aOR = 0.39, 95 % CI: 0.19, 0.81; third tertile vs. second tertile group: aOR = 2.73, 95 % CI: 1.61, 4.66, respectively) and Mo (high-level vs. low-level group: aOR = 14.93, 95 % CI: 7.16, 31.12)). However, similar associations between blood Cu and Mo levels and endometriosis risk were not found. In addition, the levels of these five essential trace element mixtures in blood and in FF were significantly and positively associated with endometriosis risk according to the BKMR analyses; the levels of Zn and Cu in blood and the levels of Mo in FF were significantly related to the risk of endometriosis, and the posterior inclusion probabilities (PIPs) were 1.00, 0.99 and 1.00 for Zn and Cu levels in blood and Mo levels in FF, respectively. Furthermore, Zn and Mo were the highest weighted elements in blood and FF, respectively, according to WQS analyses. CONCLUSION: The risk of endometriosis was associated with elevated levels of several essential trace elements (Zn, Cu and Co). Elevated levels of these elements may be involved in the pathomechanism of endometriosis. However, further studies with larger sample sizes will be necessary to confirm these associations.

Peritoneal dialysis in an end-stage renal disease patient with massive ascites and primary liver cancer.

End-stage renal disease (ESRD) coexisted with cirrhosis, ascites, and primary liver cancer represents an extraordinarily rare clinical condition that typically occurs in very late-stage decompensated cirrhosis and is associated with an extremely poor prognosis. We present a case of a 68-year-old male patient with ESRD who experienced various decompensated complications of liver cirrhosis, particularly massive ascites and hepatic space-occupying lesions. Peritoneal dialysis (PD) catheter insertion and continuous ambulatory peritoneal dialysis (CAPD) treatment were successfully performed. During meticulous follow-up, the patient survived for one year but ultimately succumbed to complications related to liver cancer. PD can serve as an efficacious therapeutic approach for such late-stage patients afflicted together with severe cirrhosis, massive ascites and primary liver cancer.

Gender associations between phthalate exposure and biomarkers of oxidative stress: A prospective cohort study.

Previous epidemiologic research has shown that phthalate exposure in pregnant women is related to adverse birth outcomes in a sex-specific manner. However, the biological mechanism of phthalate exposure that causes these birth outcomes remains poorly defined. In this research, we investigated the association between phthalate exposure and placental oxidative stress in a large population-based cohort study, aiming to initially explore the relationship between phthalate exposure and gene expression in placental oxidative stress in a sex-specific manner. Quantitative PCR was performed to measure the expression of placental inflammatory mRNAs (HO-1, HIF1α, and GRP78) in 2469 placentae. The multiple linear regression models were used to investigate the associations between mRNA and urinary phthalate monoesters. Phthalate metabolites monomethyl phthalate (MMP) and mono-n-butyl phthalate (MBP) were positively correlated with higher HIF1α expression in placentae of male fetuses (p < .05). Mono-benzyl phthalate (MBzP) increased the expression of HO-1, HIF1α, and GRP78 in placentae of male fetuses, and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) up-regulated the expression of HIF1α and GRP78. Additionally, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively correlated with HO-1, HIF1α, and GRP78 in placentae of female fetuses. Maternal phthalate exposure was associated with oxidative stress variations in placental tissues. The associations were closer in the placentas of male fetuses than in that of female ones. The placenta oxidative stress is worth further investigation as a potential mediator of maternal exposure-induced disease risk in children.

Association between prenatal metals exposure and blood pressure in 5-6 years children: A birth cohort study.

BACKGROUND: The trajectory of blood pressure (BP) from childhood to early middle age suggested that individuals with elevated BP in early childhood were more likely to be affected by cardiovascular disease in adulthood. Exposure to metals may affect BP in children, and pregnancy is a sensitive time for metal exposure. This study assessed the relationship between different stages of prenatal exposure to metals or metal mixtures and BP in children aged 5-6 years. METHODS: The study included 2535, 2680, 2534 mother-child pairs in three trimesters, from the Ma'anshan birth cohort study (MABC). We collected maternal blood samples during pregnancy and measured the serum levels of four metals (arsenic, selenium, cadmium, and mercury). BP was measured in children aged 5-6 years. A linear regression model and Bayesian kernel machine regression (BKMR) were used to explore associations between prenatal exposure to metals at different stages and multiple metal exposure with BP in children aged 5-6 years. RESULTS: Associations were observed between the arsenic in the third trimester and children's diastolic blood pressure (DBP) (ß = 0.88, 95% CI: 0.44, 1.33), systolic blood pressure (SBP) (ß = 0.72, 95% CI: 0.19, 1.24) and mean arterial pressure (MAP) (ß = 0.83, 95% CI: 0.42, 1.23), as well as between the mercury and children's DBP (ß = 0.65, 95% CI: 0.13, 1.16) and MAP (ß = 0.60, 95% CI: 0.14, 1.07). The BKMR analysis showed that multiple metals had a significant positive joint effect on children's DBP, SBP and MAP. A potential interaction between arsenic and mercury was observed (ß = -0.85, 95% CI: -1.62, -0.08). CONCLUSIONS: Exposure to arsenic and mercury during pregnancy was associated with altered BP in children. The third trimester may represent an important window of opportunity to reduce the effects of metal exposure on children's blood pressure and long-term health.

Genetic contribution of synapse-associated protein 97 to cerebellar functional connectivity changes in first-episode schizophrenia.

Our previous study data suggested that the synapse-associated protein 97 (SAP97) rs3915512 polymorphism is significantly related to clinical performance in schizophrenia. The cerebellum exhibits abundant expression of SAP97, which is involved with negative symptoms, cognition and emotion in schizophrenia. As functional dysconnectivity with the cortical-subcortical-cerebellar circuitry has been widely shown in patients with schizophrenia, cortical-subcortical-cerebellar dysconnectivity can therefore be considered a possible intermediate phenotype that connects risk genes with schizophrenia. In this study, resting-state functional magnetic resonance imaging (fMRI) was applied to evaluate whether the SAP97 rs3915512 polymorphism changes cortical/subcortical-cerebellar resting-state functional connectivity (RSFC) in 104 Han Chinese subjects (52 first-episode schizophrenia (FES) patients and 52 matched healthy controls (HCs)). To examine RSFC between cortical/subcortical regions and the cerebellum, a ROI (region of interest)-wise functional connectivity analysis was conducted. The association between abnormal cortical/subcortical-cerebellar connectivity and clinical manifestation was further assessed in FES patients with different genotypes. The interactive effect of disease and genotype on RSFC was found between the frontal gyrus (rectus) and cerebellum. A positive correlation was suggested between RSFC in the cerebellum and the hostility scores in FES patients with the A allele, and no correlation was found in FES patients with the TT genotype. The current findings identified that SAP97 may be involved in the process of mental symptoms in FES patients via cerebellar connectivity depending on the rs3915512 polymorphism genotype.

Impact of climate factors and climate-gene interaction on systemic lupus erythematosus patients' response to glucocorticoids therapy.

BACKGROUND: Glucocorticoids (GCs) were the essential drugs for systemic lupus erythematosus (SLE). However, different patients differ substantially in their response to GCs treatment. Our current study aims at investigating whether climate variability and climate-gene interaction influence SLE patients' response to the therapy of GCs. METHODS: In total, 778 SLE patients received therapy of GCs for a study of 12-week follow-up. The efficacy of GCs treatment was evaluated using the Systemic Lupus Erythematosus Disease Activity Index. The climatic data were provided by China Meteorological Data Service Center. Additive and multiplicative interactions were examined. RESULTS: Compared with patients with autumn onset, the efficacy of GCs in patients with winter onset is relatively poor (ORadj = 1.805, 95%CIadj : 1.181-3.014, padj = 0.020). High mean relative humidity during treatment decreased the efficacy of GCs (ORadj = 1.033, 95%CIadj : 1.008-1.058, padj = 0.011), especially in female (ORadj = 1.039, 95%CIadj : 1.012-1.067, padj = 0.004). There was a significant interaction between sunshine during treatment and TRAP1 gene rs12597773 on GCs efficacy (Recessive model: AP = 0.770). No evidence of significant interaction was found between climate factors and the GR gene polymorphism on the improved GCs efficacy in the additive model. Multiplicative interaction was found between humidity in the month prior to treatment and GR gene rs4912905 on GCs efficacy (Dominant model: OR = 0.470, 95%CI: 0.244-0.905, p = 0.024). CONCLUSIONS: Our findings suggest that climate variability influences SLE patients' response to the therapy of GCs. Interactions between climate and TRAP1/GR gene polymorphisms were related to GCs efficacy. The results guide the individualized treatment of SLE patients.

The association between the essential metal mixture and fasting plasma glucose in Chinese community-dwelling elderly people.

BACKGROUND: Epidemiological studies about the effect of essential metal mixture on fasting plasma glucose (FPG) levels among elderly people are sparse. The object of this study was to examine the associations of single essential metals and essential metal mixture with FPG levels in Chinese community-dwelling elderly people. METHODS: The study recruited 2348 community-dwelling elderly people in total. Inductively coupled plasma-mass spectrometry was adopted to detect the levels of vanadium (V), selenium (Se), magnesium (Mg), cobalt (Co), calcium (Ca), and molybdenum (Mo) in urine. The relationships between single essential metals and essential metal mixture and FPG levels were evaluated by linear regression and Bayesian kernel machine regression (BKMR) models, respectively. RESULTS: In multiple-metal linear regression models, urine V and Mg were negatively related to the FPG levels (ß = - 0.016, 95 % CI: - 0.030 to - 0.003 for V; ß = - 0.021, 95 % CI: - 0.033 to - 0.009 for Mg), and urine Se was positively related to the FPG levels (ß = 0.024, 95 % CI: 0.014-0.034). In BKMR model, the significant relationships of Se and Mg with the FPG levels were also found. The essential metal mixture was negatively associated with FPG levels in a dose-response pattern, and Mg had the maximum posterior inclusion probability (PIP) value (PIP = 1.0000), followed by Se (PIP = 0.9968). Besides, Co showed a significant association with decreased FPG levels in older adults without hyperlipemia and in women. CONCLUSIONS: Both Mg and Se were associated with FPG levels, individually and as a mixture. The essential metal mixture displayed a linear dose-response relationship with reduced FPG levels, with Mg having the largest contribution to FPG levels, followed by Se. Further prospective investigations are necessary to validate these exploratory findings.

Modeling-based prediction tools for preimplantation genetic testing of mitochondrial DNA diseases: estimating symptomatic thresholds, risk, and chance of success.

PURPOSE: Preimplantation genetic testing (PGT) has become a reliable tool for preventing the germline transmission of mitochondrial DNA (mtDNA) variants. However, procedures are not standardized across mtDNA variants. In this study, we aim to estimate symptomatic thresholds, risk, and chance of success for PGT for mtDNA pathogenic variant carriers. METHODS: We performed a systematic analysis of heteroplasmy data including 455 individuals from 187 familial pedigrees with the common m.3243A>G, m.8344A>G, or m.8993T>G pathogenic variants. We applied binary logistic regression for estimating symptomatic thresholds of heteroplasmy, simplified Sewell-Wright formula and Kimura equations for predicting the risk of disease transmission, and binomial distribution for predicting minimum oocyte numbers. RESULTS: We estimated the symptomatic thresholds of m.8993T>G and m.8344A>G as 29.86% and 16.15%, respectively. We could not determine a threshold for m.3243A>G. We established models for mothers harboring common and rare mtDNA pathogenic variants to predict the risk of disease transmission and the number of oocytes required to produce an embryo with sufficiently low variant load. In addition, we provide a table allowing the prediction of transmission risk and the minimum required oocytes for PGT patients with different variant levels. CONCLUSION: We have established models that can determine the symptomatic thresholds of common mtDNA pathogenic variants. We also constructed universal models applicable to nearly all mtDNA pathogenic variants which can predict risk and minimum numbers for PGT patients. These models have advanced our understanding of mtDNA disease pathogenesis and will enable more effective prevention of disease transmission using PGT.

Novel economical, accurate, sensitive, single-cell analytical method for mitochondrial DNA quantification in mtDNA mutation carriers.

PURPOSE: Although a variety of analytical methods have been developed to detect mitochondrial DNA (mtDNA) heteroplasmy, there are special requirements of mtDNA heteroplasmy quantification for women carrying mtDNA mutations receiving the preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PD) in clinic. These special requirements include various sample types, large sample number, long-term follow-up, and the need for detection of single-cell from biopsied embryos. Therefore, developing an economical, accurate, high-sensitive, and single-cell analytical method for mtDNA heteroplasmy is necessary. METHODS: In this study, we developed the Sanger sequencing combined droplet digital polymerase chain reaction (ddPCR) method for mtDNA quantification and compared the results to next-generation sequencing (NGS). A total of seventeen families with twelve mtDNA mutations were recruited in this study. RESULTS: The results showed that both Sanger sequencing and ddPCR could be used to analyze the mtDNA heteroplasmy in single-cell samples. There was no statistically significant difference in heteroplasmy levels in common samples with high heteroplasmy (≥ 5%), low heteroplasmy (< 5%), and single-cell samples, either between Sanger sequencing and NGS methods, or between ddPCR and NGS methods (P > 0.05). However, Sanger sequencing was unable to detect extremely low heteroplasmy accurately. But even in samples with extremely low heteroplasmy (0.40% and 0.92%), ddPCR was always able to quantify them. Compared to NGS, Sanger sequencing combined ddPCR analytical methods greatly reduced the cost of sequencing. CONCLUSIONS: In conclusion, this study successfully established an economical, accurate, sensitive, single-cell analytical method based on the Sanger sequencing combined ddPCR methods for mtDNA heteroplasmy quantification in a clinical setting.

Polymorphisms of mtDNA in the D-loop region moderate the associations of BMI with HOMA-IR and HOMA-ß among women with polycystic ovary syndrome: a cross-sectional study.

PURPOSE: Polycystic ovary syndrome (PCOS) is one of the leading causes of infertility in women of childbearing age, and many patients with PCOS have obesity and insulin resistance (IR). Although obesity is related to an increased risk of IR, in clinical practice, PCOS patients exhibit different effects on improving insulin sensitivity after weight loss. Therefore, in the present study, we aimed to examine the moderating effect of polymorphisms of mtDNA in the D-loop region on the associations of body mass index (BMI) with the homeostasis model assessment of insulin resistance index (HOMA-IR) and pancreatic ß cell function index (HOMA-ß) among women with PCOS. METHODS: Based on a cross-sectional study, women with PCOS were recruited from the Reproductive Center of the First Affiliated Hospital of Anhui Medical University from 2015 to 2018. A total of 520 women who were diagnosed with PCOS based on the revised 2003 Rotterdam criteria were included in the study. Peripheral blood was collected from these patients, followed by DNA extraction, PCR amplification, and sequencing at baseline. HOMA-IR and HOMA-ß were calculated according to blood glucose-related indices. Moderating effect models were performed with BMI as an independent variable, polymorphisms of mtDNA in the D-loop region as moderators, and ln (HOMA-IR) and ln (HOMA-ß) as dependent variables. To verify the stability of moderating effect, sensitivity analysis was performed with the quantitative insulin sensitivity check index (QUICKI), fasting plasma glucose/fasting insulin (G/I), and fasting insulin as dependent variables. RESULTS: BMI was positively associated with ln (HOMA-IR) and ln (HOMA-ß) (ß = 0.090, p < 0.001; ß = 0.059, p < 0.001, respectively), and the relationship between BMI and ln (HOMA-IR) or ln (HOMA-ß) was moderated by the polymorphisms of mtDNA in the D-loop region. Compared with the respective wild-type, the variant -type of m.16217 T > C enhanced the association between BMI and HOMA-IR, while the variant-type of m.16316 A > G weakened the association. On the other hand, the variant-type of m.16316 A > G and m.16203 A > G weakened the association between BMI and HOMA-ß, respectively. The results of QUICKI and fasting insulin as dependent variables were generally consistent with HOMA-IR, and the results of G/I as dependent variables were generally consistent with HOMA-ß. CONCLUSION: Polymorphisms of mtDNA in the D-loop region moderate the associations of BMI with HOMA-IR and HOMA-ß among women with PCOS.

Resilience of infertile families undergoing in vitro fertilization: An application of the double ABC-X model.

BACKGROUND: Family resilience plays a crucial role in protecting the mental health and family stability of infertile patients. However, information associated with infertile families resilience is scarce. The double ABC-X model provides a roadmap for this, helps organize knowledge, and lays the foundation for knowledge development. AIMS: To describe the current situation of family resilience of infertile women, and to test the predictive theoretical model of family resilience based on infertility stigma, individual resilience, coping style, and posttraumatic growth. DESIGN: A cross-sectional study. METHODS: A convenience sample of 372 infertile women undergoing in vitro fertilization were recruited between April and August 2020. The Chinese-Family Resilience Assessment Scale, Infertility Stigma Scale, Simplified Coping Style Questionnaire, Chinese version of Connor-Davidson Resilience Scale, and Chinese version of Post Traumatic Growth Inventory were used to measure family resilience, infertility stigma, individual resilience, coping style, and posttraumatic growth. Structural equation models were used to analyze the relationship among these variables. RESULTS: The results showed that family resilience was related to infertility stigma, positive coping, and individual resilience. Moreover, the path analysis indicated that positive coping and individual resilience mediated the effects of infertility stigma on family resilience. CONCLUSIONS: A high level of stigma among infertile women should be identified. Interventions for targeting positive coping and individual resilience might ultimately increase their family resilience.

The effect of phthalates exposure during pregnancy on asthma in infants aged 0 to 36 months: a birth cohort study.

This cohort study sought to investigate the effects of phthalates exposure during pregnancy on offspring asthma and its association with placental stress and inflammatory factor mRNA expression levels. A total of 3474 pregnant women from the China Ma'anshan birth cohort participated in this study. Seven phthalate metabolites were detected in urine samples during pregnancy by solid phase extraction-high-performance liquid chromatography tandem mass spectrometry. Placenta stress and inflammation mRNA expression were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). Early pregnancy may be the critical period when phthalates exposure increases the risk of asthma in infants and young children, and there is a certain gender difference in the risk of asthma in infants and young children. Moreover, through the placenta stress and inflammatory factor associated with infant asthma found anti-inflammatory factor of interleukin-10 (IL-10) mRNA expression will reduce the risk of 36-month-old male infant asthma. The expression of interleukin-4(IL-4) and macrophage (M2) biomarker cluster of differentiation 206(CD206) mRNA reduced the risk of asthma in 18-month-old female infants. Placental stress and inflammatory response were analyzed using mediating effects. Tumor necrosis factor-α (TNFα) showed a complete mediating effect between mono-benzyl phthalate (MBzP) exposure in early pregnancy and asthma in 12-month-old males, and IL-10 also showed a complete mediating effect between mono-n-butyl phthalate (MBP) exposure in early and late pregnancy and asthma in 36-month-old males. In summary, exposure to phthalates during pregnancy may contribute to the development of asthma in infants, which may be associated with placental stress and inflammation.

Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function.

Genetic studies of autism spectrum disorder (ASD) have revealed multigene variations that converge on synaptic dysfunction. DOCK4, a gene at 7q31.1 that encodes the Rac1 guanine nucleotide exchange factor Dock4, has been identified as a risk gene for ASD and other neuropsychiatric disorders. However, whether and how Dock4 disruption leads to ASD features through a synaptic mechanism remain unexplored. We generated and characterized a line of Dock4 knockout (KO) mice, which intriguingly displayed a series of ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, and perturbed object and spatial learning. Mice with conditional deletion of Dock4 in hippocampal CA1 recapitulated social preference deficit in KO mice. Examination in CA1 pyramidal neurons revealed that excitatory synaptic transmission was drastically attenuated in KO mice, accompanied by decreased spine density and synaptic content of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)- and NMDA (N-methyl-D-aspartate)-type glutamate receptors. Moreover, Dock4 deficiency markedly reduced Rac1 activity in the hippocampus, which resulted in downregulation of global protein synthesis and diminished expression of AMPA and NMDA receptor subunits. Notably, Rac1 replenishment in the hippocampal CA1 of Dock4 KO mice restored excitatory synaptic transmission and corrected impaired social deficits in these mice, and pharmacological activation of NMDA receptors also restored social novelty preference in Dock4 KO mice. Together, our findings uncover a previously unrecognized Dock4-Rac1-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and social behavior.

Exposure to multiple toxic metals and the risk of early embryonic arrest among women undergoing assisted reproductive techniques.

BACKGROUND: Early embryonic arrest is a great challenge for in vitro fertilization. Whether exposure to toxic metals is associated with an increased risk of early embryonic arrest warrants investigation. OBJECTIVES: Here, we conducted a case-control study in infertile women to estimate the associations between blood barium (Ba), arsenic (As), mercury (Hg), and lead (Pb) exposure levels and the risk of early embryonic arrest. METHODS: Ba, As, Hg, and Pb exposure levels in fasting blood collected from 74 infertile women (123 cycles) with early embryonic arrest and 157 infertile women (180 cycles) without early embryonic arrest were measured by ICP-MS. Bayesian kernel machine regression (BKMR) was used to assess the association of exposure level of toxic metals mixture with the risk of early embryonic arrest as well as to evaluate which metal playing a leading role in the association, and then generalized estimating equations (GEEs) were used to evaluate the relationship between the selected harmful metal and the risk of early embryonic arrest. Finally, the potential causes of early embryonic arrest originating from the harmful metal exposure were explored. RESULTS: Blood Ba levels were significantly higher in the case group than that in the control group (p = 0.009) rather than As, Pb and Hg. Results from BKMR showed that exposure to toxic metals mixture increased the risk of early embryonic arrest, with Ba playing a leading role (PIP = 0.9612). GEE analysis showed that high Ba exposure level was related with the increased risk of early embryonic arrest (p < 0.05) and it impacted on the oogenesis significantly. CONCLUSIONS: Our study found that exposure to toxic metals mixture was associated with the increased risk of early embryonic arrest, and Ba contributed most to the increased risk. Higher Ba exposure in whole blood corresponds to a higher risk of early embryonic arrest and impacted on the oogenesis significantly.

Prior nasal delivery of antagomiR-122 prevents radiation-induced brain injury.

Radiation-induced brain injury is a major adverse event in head and neck tumor treatment, influencing the quality of life for the more than 50% of patients who undergo radiation therapy and experience long-term survival. However, no effective treatments are available for these patients, and preventative drugs and effective drug-delivery methods must be developed. Based on our results, miR-122-5p was upregulated in the mouse radiation-induced brain injury (RBI) model and patients with nasopharyngeal carcinoma (NPC) who received radiation therapy. Intranasal administration of a single antagomiR-122-5p dose before irradiation effectively alleviated radiation-induced cognitive impairment, neuronal injury, and neuroinflammation in the mouse RBI model. Results further indicated that miR-122-5p inhibition in microglia reduced the levels of proinflammatory cytokines and enhanced the phagocytic function to protect against radiation-induced neuronal injury in cell models. Further, we profiled transcriptome data and verified that Tensin 1 (TNS1) may be the target of miR-122-5p in RBI. In summary, our results reveal a distinct role for miR-122-5p in regulating neuroinflammation in RBI, indicating that a non-invasive strategy for intranasal miR-122-5p administration may be an attractive therapeutic target in RBI, providing new insights for clinical trials. Further systematic safety assessment, optimization of drug administration, and clarity of mechanism will accelerate the process into clinical practice.

Community engagement on-site rapid test for chlamydia and gonorrhea among men who have sex with men: a pioneering study in Guangzhou, China.

BACKGROUND: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections are prevalent among men who have sex with men (MSM) in China. However, compared to syphilis and HIV, the testing rate for chlamydia and gonorrhea remains low. The purpose of this pilot study was to evaluate the feasibility for conducting rapid nucleic acid test for chlamydia and gonorrhea in MSM community-based organizations (CBO). METHOD: We recruited our participants through an MSM CBO where free HV and syphilis testing were routinely provided. We collected data including social-demographic background, sexual history, chlamydia and gonorrhea testing history, and reasons for accepting this on-site rapid testing. Urine and/or anorectal swab samples were collected and tested for chlamydia and gonorrhea on-site and the testing results were delivered in about 1.5 h. Positive cases received on-site free treatment. RESULTS: From August 2020 to October 2020, 634 MSM visited the CBO for syphilis and HIV testing and 158 (158/634, 24.9%) accepted the on-site chlamydia and gonorrhea rapid test, 135 were finally enrolled. The positive rate fo chlamydia was 16.3% (22/135) and 3.0% (4/135) for gonorrhea, respectively. Only 19.3% participants had previously undergone chlamydia and gonorrhea testing and 68.9% (93/135) participants reported that they had heard of gonorrhea, 47.4% (64/135) had heard of chlamydia. The main reason for testing was "free for charge" (66.2%), followed by "convenient, 'shorter waiting time" (45.2%) and "had high-risk sexual behavior recently" (16.3%). CONCLUSIONS: This pilot study showed that the chlamydia and gonorrhea infection rate remains high among MSM, while the testing rate was low. On-site rapid testing is feasible and potentially preferred by MSM.

The associations of serum metals concentrations with the intermediate and pregnancy outcomes in women undergoing in vitro fertilization (IVF).

BACKGROUND: Toxic and essential trace elements are reported to have impact on female fertility. However, studies on the potential synergistic or antagonistic effects of metal mixtures on IVF outcomes remain limited. OBJECTIVE: To evaluate whether serum concentrations of metals, individually and as mixtures, are associated with pregnancy outcomes in women undergoing IVF. METHODS: In a prospective birth cohort study about IVF from the First Affiliated Hospital of Anhui Medical University (n = 1184), we measured the concentrations of serum metals by ICP-MS according to a previously established method. Oocyte/embryo development indicators and follow-up results were also collected. The individual and joint effects of metals were estimated using logistic regressions and Bayesian kernel machine regressions (BKMR). RESULTS: At embryonic stage, we found negative associations between the serum lead (Pb) (ß = -0.14, 95%CI: -0.32, -0.04) and cadmium (Cd) (ß = -0.24, 95%CI: -0.39, -0.09) concentrations and the high-quality embryos rate; and positive associations between the serum cobalt (Co) (ß = 0.18, 95%CI: 0.05, 0.31) and selenium (Se) (ß = 0.17, 95%CI: 0.06, 0.41) concentrations and the MII rate. Regarding to the pregnancy outcomes, the serum Pb was negatively related with successful implantation (OR=0.85, 95%CI: 0.77, 0.94) and clinical pregnancy (OR=0.95, 95%CI: 0.91, 0.99); and positively associated with spontaneous abortion (OR=1.39, 95% CI: 1.02, 1.91). The BKMR analysis showed linear or parabolic associations between the metal mixtures and pregnancy outcomes, with Pb showing the highest posterior inclusion probabilities. CONCLUSIONS: The toxic (Pb, Cd) and essential (Co, Se) metals could be incorporated as simultaneous predictors of IVF outcomes including potential antagonistic effects, in which Pb exhibits major contributions.

The perceptions of sexuality and sexually transmitted diseases (STDs) among adolescent STD patients: A qualitative study.

PURPOSE: To explore the causes and outcomes of sexually transmitted diseases (STDs) in the adolescent STD patients (ASPs) in relation to their access to and interpretation of sexual and STD knowledge, their attitudes towards premarital sex, and their feelings and thoughts after getting STDs. METHODS: A qualitative study was conducted to interview 16 ASPs (12 males, 4 females) using convenience sampling. One-on-one, semi-structured, and confidential interviews were conducted in an outpatient clinic room at a dermatology hospital in Guangzhou, China. Data were analysed via thematic analysis with NVivo 12 software. RESULTS: Four main themes were derived from the data: sex education before getting STDs, cognition of the definition of STDs and their transmission, attitude towards premarital sex, and impact of infection with STDs. Most of the participants had very limited information about sexuality from their families or schools, lacked STD knowledge, and considered premarital sex as normal or common. Infection with STDs had a negative influence on all the participants, especially on female participants, as they felt ashamed and some even did not want to get married in the future. CONCLUSION: Limited sex education, lack of sexual knowledge, and an open attitude towards premarital sex led to STDs among adolescents. This study highlights the importance of providing effective sex education. In addition, specific and targeted health guidance and suggestions should be provided to ASPs to help them deal with STDs and the life experience with STDs objectively and correctly.