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 genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS

The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking.To address this gap,we conducted a study aiming to investigate this association and identify relevant biomarkers.We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune microenvironment.Additionally,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7062 cases and 195745 controls)and European(24476 cases and 23073 controls)populations.We employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells.Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal tissues.Moreover,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90–0.97,P_(meta)=4.70×10^(-9)).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication.In conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.

Do credit constraints affect households'economic vulnerability?Empirical evidence from rural China

Poverty alleviation is still one of the major challenges in developing countries,especially in transitional economy like China.From the perspective of anti-poverty,this paper examines the impact of formal credit constraints(FCCs)and informal credit constraints(IFCCs)on economic vulnerability(EV)using the data from the China Household Income Project(CHIP)survey for 2013(CHIPs 2013)of rural households.The potential endogeneity problem of credit constraints(CCs)is addressed by applying the control function approach within an ordered probit model.The results show that both FCCs and IFCCs have a robust positive and significant impact on the EV of rural households and that the impact of FCCs is greater than that of IFCCs.To identify the potential mechanisms through which CCs affect EV,the seemingly unrelated regressions are used and the potential intercorrelation among these mechanisms is examined.We find that the impact of CCs on EV is partly mediated by health,trust,per capita financial assets and per capita income,whereby health and per capita income contribute to most of the total indirect effect.Thus,policies focus on supply-side and demand-side to improve credit accessibility could reduce rural households'EV,especially through its positive effect on health and per capita income.