Influence of preterm birth on the association between gestational diabetes mellitus and childhood developmental vulnerability:a causal mediation analysis

Background Epidemiological studies examining the direct and indirect effects of gestational diabetes mellitus(GDM)on offspring early childhood developmental vulnerability are lacking.Therefore,the aims of this study were to estimate the direct and indirect effects of GDM(through preterm birth)on early childhood developmental vulnerability.Methods We conducted a retrospective population-based cohort study on the association between gestational diabetes mellitus and early childhood developmental vulnerability in children born in Western Australia(WA)using maternal,infant and birth records from the Midwives Notification,Hospitalizations,Developmental Anomalies,and the Australian Early Development Census(AEDC)databases.We used two aggregated outcome measures:developmentally vulnerable on at least one AEDC domain(DV1)and developmentally vulnerable on at least two AEDC domains(DV2).Causal mediation analysis was applied to estimate the natural direct(NDE),indirect(NIE),and total(TE)effects as relative risks(RR).Results In the whole cohort(n=64,356),approximately 22%were classified as DV1 and 11%as DV2 on AEDC domains.Estimates of the natural direct effect suggested that children exposed to GDM were more likely to be classified as DV1(RR=1.20,95%CI:1.10-1.31)and DV2(RR=1.34,95%CI:1.19-1.50)after adjusting for potential confounders.About 6%and 4%of the effect of GDM on early childhood developmental vulnerability was mediated by preterm birth for DV1 and DV2,respectively.Conclusion Children exposed to gestational diabetes mellitus were more likely to be developmentally vulnerable in one or more AEDC domains.The biological mechanism for these associations is not well explained by mediation through preterm birth.

Causal association of obesity-related anthropometric traits with myopia and the mediating role of educational attainment:a Mendelian randomization study

AIM:To study the causal relationship between obesityrelated anthropometric traits and myopia and the mediating role of educational attainment(EA).METHODS:Univariable Mendelian randomization(UVMR)was performed to evaluate the causal association between body mass index(BMI),height,waist-hip ratio(WHR,adjusted for BMI),and mean spherical equivalent(MSE).BMI was divided into fat and fat-free mass and included in multivariable Mendelian randomization(MVMR)to explore the roles of different BMI components in the causal relationship between BMI and MSE.A mediation analysis based on two-step Mendelian randomization(MR)was carried out.Specifically,UVMR was conducted to estimate the causal effect of BMI on EA.The direct effect of EA on MSE was estimated from MVMR.The mediation effect of EA in the BMI-EA-MSE model was calculated by the product of coefficients method.Expression quantitative trait loci(eQTL)-MR,reverse MR,and Linkage Disequilibrium Score Regression(LDSC)were performed to assess the robustness.RESULTS:Genetically predicted higher BMI had a positive total effect on MSE(βIVW=0.26 D,95%CI=0.14 to 0.37 D,P<0.001),whereas there was no significant association between height,WHR,and MSE.Fat mass was found to play a significant role in the effect of body mass on MSE(βIVW=0.50 D,95%CI=0.21 to 0.78 D,P=0.001),but there was no significant association between fat-free mass and MSE.The causal effect of BMI on EA was-0.14(95%CI=-0.16 to-0.11,P<0.001),and the direct effect of EA on MSE was-0.63 D(95%CI=-0.81 to-0.44 D,P<0.001).The mediating effect of EA in the BMI-EA-MSE model was 0.09 D(95%CI=0.06 to 0.12 D),with a mediation proportion of 33%(95%CI=22.1%to 44.6%).No reverse causal associations were detected except for BMI on EA.The results of eQTL-MR and LDSC were consistent with each MR analysis.CONCLUSION:Genetically predicted higher BMI decreases the degree of myopia with a 33%mediation proportion by EA,and fat mass provides a dominant protective role in body mass-myopia.As a supplement to previous observational studies,it provides strong evidence for the relationship between anthropometric traits and refractive errors and offers a theoretical basis for future measures to prevent and control myopia.

Association of education with cholelithiasis and mediating effects of cardiometabolic factors:A Mendelian randomization study

BACKGROUND Education,cognition,and intelligence are associated with cholelithiasis occurrence,yet which one has a prominent effect on cholelithiasis and which cardiometabolic risk factors mediate the causal relationship remain unelucidated.AIM To explore the causal associations between education,cognition,and intelligence and cholelithiasis,and the cardiometabolic risk factors that mediate the associations.METHODS Applying genome-wide association study summary statistics of primarily European individuals,we utilized two-sample multivariable Mendelian randomization to estimate the independent effects of education,intelligence,and cognition on cholelithiasis and cholecystitis(FinnGen study,37041 and 11632 patients,respectively;n=486484 participants)and performed two-step Mendelian randomization to evaluate 21 potential mediators and their mediating effects on the relationships between each exposure and cholelithiasis.RESULTS Inverse variance weighted Mendelian randomization results from the FinnGen consortium showed that genetically higher education,cognition,or intelligence were not independently associated with cholelithiasis and cholecystitis;when adjusted for cholelithiasis,higher education still presented an inverse effect on cholecystitis[odds ratio:0.292(95%CI:0.171-0.501)],which could not be induced by cognition or intelligence.Five out of 21 cardiometabolic risk factors were perceived as mediators of the association between education and cholelithiasis,including body mass index(20.84%),body fat percentage(40.3%),waist circumference(44.4%),waist-to-hip ratio(32.9%),and time spent watching television(41.6%),while time spent watching television was also a mediator from cognition(20.4%)and intelligence to cholelithiasis(28.4%).All results were robust to sensitivity analyses.CONCLUSION Education,cognition,and intelligence all play crucial roles in the development of cholelithiasis,and several cardiometabolic mediators have been identified for prevention of cholelithiasis due to defects in each exposure.

Interoception mediates the association between social support and sociability in patients with major depressive disorder

BACKGROUND Interoception dysfunction has an important impact on the onset and development of major depressive disorder(MDD).Social support serves as a protective factor against MDD,and sociability also plays a significant role in this condition.These interconnected constructs-social support and sociability-play pivotal roles in MDD.However,no research on the mechanisms underlying the associations be-tween social support and sociability,particularly the potential role of interocep-tion,have been reported.ception,social support,and sociability,respectively.A mediation analysis model for the eight dimensions of intero-ception(noticing,not distracting,not worrying,attention regulation,emotional awareness,self-regulation,body listening,and trust),social support,and sociability were established to evaluate the mediating effects.RESULTS A partial correlation analysis of eight dimensions of the MAIA-2,SSRS,and TSBI scores,with demographic data as control variables,revealed pairwise correlations between the SSRS score and both the MAIA-2 score and TSBI score.In the major depression(MD)group,the SSRS score had a positive direct effect on the TSBI score,while the scores for body listening,emotional awareness,self-regulation,and trust in the MAIA-2C had indirect effects on the TSBI score.In the HC group,the SSRS score had a positive direct effect on the TSBI score,and the scores for attention regulation,emotional awareness,self-regulation,and trust in the MAIA-2C had indirect effects on the TSBI score.The proportion of mediators in the MD group was lower than that in the HC group.CONCLUSION Interoceptive awareness is a mediating factor in the association between social support and sociability in both HCs and depressed patients.Training in interoceptive awareness might not only help improve emotional regulation in depressed patients but also enhance their social skills and support networks.

Intraoperative Blood Pressure Lability Acts as a Key Mediator in the Impacts of Goal-Directed Fluid Therapy on Postoperative Complications in Patients Undergoing Major Spine Surgery

Objective Although goal-directed fluid therapy(GDFT)has been proven to be effective in reducing the incidence of postoperative complications,the underlying mechanisms remain unknown.The aim of this study was to examine the mediating role of intraoperative hemodynamic lability in the association between GDFT and the incidence of postoperative complications.We further tested the role of this mediation effect using mean arterial pressure,a hemodynamic indicator.Methods This secondary analysis used the dataset of a completed nonrandomized controlled study to investigate the effect of GDFT on the incidence of postoperative complications in patients undergoing posterior spine arthrodesis.We used a simple mediation model to test whether there was a mediation effect of average real variability between the association of GDFT and postoperative complications.We conducted mediation analysis using the mediation package in R(version 3.1.2),based on 5,000 bootstrapped samples,adjusting for covariates.Results Among the 300 patients in the study,40%(120/300)developed postoperative complications within 30 days.GDFT was associated with fewer 30-day postoperative complications after adjustment for confounders(odds ratio:0.460,95%CI:0.278,0.761;P=0.003).The total effect of GDFT on postoperative complications was-0.18(95%CI:-0.28,-0.07;P<0.01).The average causal mediation effect was-0.08(95%CI:-0.15,-0.04;P<0.01).The average direct effect was-0.09(95%CI:-0.20,0.03;P=0.17).The proportion mediated was 49.9%(95%CI:18.3%,140.0%).Conclusions The intraoperative blood pressure lability mediates the relationship between GDFT and the incidence of postoperative complications.Future research is needed to clarify whether actively reducing intraoperative blood pressure lability can prevent postoperative complications.

Evaluating the moderated-mediation effects of switchingcosts in the link between social capital and NPD performance

In this study,we explore the causes and performance outcomes of switching costs in the context of new product development(NPD)from both the supplier and customer perspectives,and discuss the role that switching costs play as moderators and mediators in the relationship between social capital and NPD performance.Based on data from 214 Chinese manufacturers,we employ the structural equation model to test our conceptual model and hypotheses.The results indicate that relationship quality and customer involvement positively and negatively affect switching costs,respectively,and that switching costs negatively affect NPD performance.Switching costs mediate and moderate the relationship between social capital and NPD performance.Furthermore,switching costs significantly and positively moderate the relationship between relationship quality and NPD performance.On the other hand,switching costs insignificantly and negatively moderate the relationship between customer involvement and NPD performance.The theoretical and managerial implications of the findings are discussed.

The effects of managerial ability on firm performance and the mediating role of capital structure:evidence from Taiwan

This study utilizes mediation analysis and bootstrapping to analyze the mediating effect of capital structure on the association between managerial ability and firm performance.The dataset consists of 6384 firm-year observations from the Taiwan Residents electronics industry during 2005–2018.Our results indicate that(1)low(high)levels of debt are likely observed in firms with CEOs with high(low)ability,(2)managerial ability positively affects firm performance,and(3)capital structure mediates the positive relationship between managerial ability and firm performance.Overall,the findings may have limited generalizability due to the specific sample characteristics and provide convincing support for the importance of capital structure as a mediator in the managerial ability-firm performance nexus.Specifically,this study highlights the need for examining the effect of managerial ability on firm performance through a mediator.

The mediatory role of water quality on the association between extreme precipitation events and infectious diarrhea in the Yangtze River Basin,China

Extreme precipitation is exacerbating the burden of infectious diarrhea in the context of climate change,it is necessary to identify the critical and easy-to-intervene intermediate factors for public health strategies.Water quality may be the most important mediator,while relevant empirical evidence is limited.This study aimed to examine the role of water quality in the process of infectious diarrhea caused by extreme precipitation.Weekly infectious diarrhea cases,meteorological factors and water quality data in Yangtze River Basin in China between October 29,2007 to February 19,2017 were obtained.Two-stage statistical models were used to estimate city-specific extreme precipitation,water quality and infectious diarrhea relationships that were pooled to derive regional estimates.A causal mediation analysis was used to assess the mediation effect of water quality.In Yangtze River Basin,extreme precipitation events had a significant impact on infectious diarrhea(Incidence Rate Ratios[IRR]:1.027,95%Confidence Interval[CI]:1.013~1.041).After extreme precipitation events,the dissolved oxygen(DO)in surface water decreased(-0.123 mg/L,95%CI:-0.159 mg/L~-0.086 mg/L),while the un-ionized ammonia(NH(3)-N)increased(0.004 mg/L,95%CI:0.001 mg/L~0.006 mg/L).The combined overall effect of DO and NH(3)-N on infectious diarrhea showed that both low and high concentrations were associated with an increased risk of infectious diarrhea.The causal mediation analysis showed that the mediation proportion of the two water quality indexes(DO and NH(3)-N)is 70.54%(P<0.001).To reduce the health effects of extreme precipitation,in contrast to current population-oriented health strategies,those that take into account more direct and easy-to-intervene water quality indicators should be encouraged by future policies.

Relationships between blood chromium exposure and liver injury:Exploring the mediating role of systemic inflammation in a chromate-exposed population

Hexavalent chromium and its compounds are prevalent pollutants,especially in the work environment,pose a significant risk for multisystem toxicity and cancers.While it is known that chromium accumulation in the liver can cause damage,the dose-response relationship between blood chromium(Cr)and liver injury,as well as the possible potential toxic mechanisms involved,remains poorly understood.To address this,we conducted a follow-up study of 590 visits from 305 participants to investigate the associations of blood Cr with biomarkers for liver injury,including serum alanine aminotransferase(ALT),aspartate aminotransferase(AST),total bilirubin(TBIL),and direct bilirubin(DBIL),and to evaluate the mediating effects of systemic inflammation.Platelet(PLT)and the platelet-to-lymphocyte ratio(PLR)were utilized as biomarkers of systemic inflammation.In the linear mixed-effects analyses,each 1-unit increase in blood Cr level was associated with estimated effect percentage increases of 0.82%(0.11%,1.53%)in TBIL,1.67%(0.06%,3.28%)in DBIL,0.73%(0.04%,1.43%)in ALT and 2.08%(0.29%,3.87%)in AST,respectively.Furthermore,PLT mediated 10.04%,11.35%,and 10.77%increases in TBIL,DBIL,and ALT levels induced by chromate,respectively.In addition,PLR mediated 8.26%and 15.58%of the association between blood Cr and TBIL or ALT.These findings shed light on the mechanisms underlying blood Cr-induced liver injury,which is partly due to worsening systemic inflammation.

Effects of PM_(2.5)and Its Components on Disease Severity in Patients with Schizophrenia and the Mediating Role of Thyroid Hormones

Studies have indicated the different effects of PM_(2.5)components on human health.However,specific components that influence the severity of disease in schizophrenia patients and their underlying mechanisms remain unclear.Therefore,a repeated measures study for schizophrenia was constructed based on Anhui Mental Health Center.We collected information,including demographics and thyroid hormones(TH)levels,on repeat admissions of schizophrenia patients during 2017−2020,assessing their illness severity by positive and negative symptom scales(PANSS).Concentrations from the nearest component monitoring station in the 3 months before admission were assigned as the participant’s exposure level.We assessed the effects of PM_(2.5)components individually and in combination on schizophrenia and explored the mediating role of THs.Results indicated that benzo[a]pyrene,sulfate,nitrate,chloride,ammonia,cadmium,chromium,lead,selenium,and thallium exposure were associated with increased PANSS scores,with more significant results observed in males.Mixed exposure to PM_(2.5)components was found to be associated with increased PANSS scores and decreased free triiodothyronine(FT3).Mediation analysis suggested that the reduction in FT3 might mediate the association between the PM_(2.5)components and PANSS scores.The findings emphasize the impacts of PM_(2.5)components on schizophrenia and the potential value of focusing on changes in THs.

Associations of diet with infectious diseases in UK Biobank

The current study used multivariable logistic regression analysis to investigate associations between the intake frequencies of 13 food groups(or four diet groups)and infectious diseases.The analysis included 487849 participants from the UK Biobank,with 75209 participants diagnosed with infectious diseases.Participants reporting the highest intake frequency of processed meat(odds ratio[OR]=1.0964,95%confidence interval[CI]:1.0622–1.1318)and red meat(OR=1.0895,95%CI:1.0563–1.1239)had a higher risk of infectious diseases,compared with those with the lowest intake frequency.Consuming fish 2.0–2.9 times(OR=0.8221,95%CI:0.7955–0.8496),cheese≥5.0 times(OR=0.8822,95%CI:0.8559–0.9092),fruit 3.0–3.9 servings(OR=0.8867,95%CI:0.8661–0.9078),and vegetables 2.0–2.9 servings(OR=0.9372,95%CI:0.9189–0.9559)per week were associated with a lower risk of infection.Low meat-eaters(OR=0.9404,95%CI:0.9243–0.9567),fish-eaters(OR=0.8391,95%CI:0.7887–0.8919),and vegetarians(OR=0.9154,95%CI:0.8561–0.9778)had a lower risk of infectious diseases,compared with regular meat-eaters.The mediation analysis revealed that glycosylated hemoglobin,white blood cell count,and body mass index served as the mediators in the associations between diet and infectious diseases.The current study indicates that the intake frequency of food groups is a risk factor for infectious diseases,and fish-eaters have a lower risk of infection.

Inflammation as a Mediator of Microbiome Dysbiosis-Associated DNA Methylation Changes in Gastric Premalignant Lesions

Evidence for the influence of chronic inflammation induced by microbial dysbiosis on aberrant DNA methylation supports a plausible connexion between disordered microbiota and precancerous lesions of gastric cancer(PLGC).Here,a comprehensive study including multi-omics data was performed to estimate the relationships amongst the gastric microbiome,inflammatory proteins and DNA methylation alterations and their roles in PLGC development.The results demonstrated that gastric dysbacteriosis increased the risk of PLGC and DNA methylation alterations in related tumour suppressor genes.Seven inflammatory biomarkers were identified for antrum and corpus tissues,respectively,amongst which the expression levels of several biomarkers were significantly correlated with the microbial dysbiosis index(MDI)and methylation status of specific tumour suppressor genes.Notably,mediation analysis revealed that microbial dysbiosis partially contributed to DNA methylation changes in the stomach via the inflammatory cytokines C-C motif chemokine 20(CCL20)and tumour necrosis factor receptor superfamily member 9(TNFRSF9).Overall,these results may provide new insights into the mechanisms that might link the gastric microbiome to PLGC.