Prognostic implications of thyroid hormones in acute aortic dissection: mediating roles of renal function and coagulation.

Background: Thyroid hormones significantly influence cardiovascular pathophysiology, yet their prognostic role in acute aortic dissection (AAD) remains inadequately explored. This study assesses the prognostic value of thyroid hormone levels in AAD, focusing on the mediating roles of renal function and coagulation. Methods: We included 964 AAD patients in this retrospective cohort study. Utilizing logistic regression, restricted cubic splines, and causal mediation analysis, we investigated the association between thyroid hormones and in-hospital mortality and major adverse cardiovascular events (MACEs). Results: In AAD patients overall, an increase of one standard deviation in FT4 levels was associated with a 31.9% increased risk of MACEs (OR 1.319; 95% CI 1.098-1.584) and a 36.1% increase in in-hospital mortality (OR 1.361; 95% CI 1.095-1.690). Conversely, a higher FT3/FT4 ratio was correlated with a 20.2% reduction in risk of MACEs (OR 0.798; 95% CI 0.637-0.999). This correlation was statistically significant predominantly in Type A AAD, while it did not hold statistical significance in Type B AAD. Key renal and coagulation biomarkers, including blood urea nitrogen, creatinine, cystatin C, prothrombin time ratio, prothrombin time, and prothrombin time international normalized ratio, were identified as significant mediators in the interplay between thyroid hormones and MACEs. The FT3/FT4 ratio exerted its prognostic influence primarily through the mediation of renal functions and coagulation, while FT4 levels predominantly impacted outcomes via a partial mediation effect on coagulation. Conclusion: FT4 levels and the FT3/FT4 ratio are crucial prognostic biomarkers in AAD patients. Renal function and coagulation mediate the association between the thyroid hormones and MACEs.

Delirium Mediated the Association Between a History of Falls and Short-Term Mortality Risk in Critically Ill Ischemic Stroke Patients.

Patients with ischemic stroke have an increased propensity to fall, resulting in significant physical and psychological distress. This study examined the association between falls in the 3 months prior to intensive care unit (ICU) admission and mortality within 28 days among 2950 adult ICU patients diagnosed with ischemic stroke from 2008 to 2019, focusing on the potential mediating role of delirium. The primary outcomes were short-term mortality (28, 60, and 90 days) and the risk of delirium. Each patient was followed for at least 1 year. Delirium was primarily assessed using the Confusion Assessment Method for the ICU and by reviewing nursing notes. Group differences between patients with and without a history of falls were compared using the Wilcoxon rank-sum test or the chi-squared test. Cox proportional risk or logistic regression models were used to explore the association between fall history and outcomes, and causal mediation analysis was performed. Results showed that patients with a recent fall history had a significantly increased risk of 28-day (hazard ratio [HR]: 1.62, 95% confidence interval [CI]: 1.35-1.94), 60-day (HR: 1.67, 95% CI: 1.42-1.98), and 90-day mortality (HR: 1.66, 95% CI: 1.41-1.95), as well as an increased risk of delirium (odds ratio: 2.00, 95% CI: 1.66-2.42). Delirium significantly mediated the association between fall history and 28-day mortality (total effect: HR: 1.77, 95% CI: 1.45-2.16; natural indirect effect: HR: 1.12, 95% CI: 1.05-1.21; proportion mediated: 24.6%). These findings suggest that ischemic stroke patients with a recent fall have an increased risk of short-term mortality, partly mediated by delirium. Strategies aimed at preventing delirium may potentially improve prognosis in this patient population.

Decomposition analysis to assess intervention strategies for reducing health-related exposure disparities in Michigan public drinking water systems.

OBJECTIVE: Contamination in U.S. public drinking water systems (PWS) is estimated to cause millions of illnesses and billions of dollars in medical expenditures annually. Few prior studies have explored intervention strategies, including environmental enforcement, to reduce estimated health-related exposure disparities (exposure disparity) in PWS, which are driven partially by socioeconomic status (SES), racism, and PWS characteristics. METHOD: This study used a longitudinal measurement method to estimate the annual health-related exposure level (health level) of each PWS in Michigan, based on data from the Enforcement and Compliance Online (ECHO) and U.S. Census Bureau databases. Using a decomposition model with four strategies, we analyzed how eliminating disparities in SES, proportion minority, environmental enforcement, and PWS characteristics across communities would affect adjusted exposure disparities. RESULTS: This study found that adjusted race- and poverty-based exposure disparities have existed since the 1980s but might have decreased in the last one or two decades. PWS characteristics strongly impacted the crude and adjusted exposure disparity. Environmental enforcement, although less effective in minority-concentrated communities, reduced the adjusted race-based exposure disparity by 10%-20% in the 1980s, 8% in the 1990s, and 0.012% in the 2010s. Equalizing the poverty rate distribution reduced the adjusted race-based exposure disparity by 0.72% in the 1980s and 6.8% in the 2010s. However, equalizing racial and ethnic composition distribution increased the adjusted poverty-based exposure disparity in the 2000s. CONCLUSION: These findings indicate that economically disadvantaged or minority-concentrated communities in Michigan disproportionately suffer from poorer PWS quality. Enhanced environmental enforcement, increased household income, PWS investment, and other actions are needed to address these exposure disparities effectively.

Elevated maternal serum bile acids level, hypertensive disorders of pregnancy and adverse fetal outcomes: a cohort study of 117,789 pregnant women in China.

BACKGROUND: Elevated maternal serum total bile acids (sTBA) level during pregnancy was associated with adverse fetal outcomes. Women with elevated sTBA could complicate with hepatic dysfunction or vascular disorders (hypertensive disorders of pregnancy, HDP), which aggravated adverse fetal outcomes. However, the relationships among sTBA level, hepatic dysfunction, HDP and adverse fetal outcomes were still illusive. OBJECTIVE: We aimed to explore whether hepatic dysfunction or vascular disorders (HDP) mediated the associations between elevated sTBA level and adverse fetal outcomes. METHODS: A large retrospective cohort study encompassing 117,789 Chinese pregnant women with singleton delivery between Jan 2014 and Dec 2022 was conducted. Causal mediation analysis was applied to assess the mediating role of hepatic dysfunction (alanine transaminase > 40 U/L) or HDP in explaining the relationship between high maternal sTBA level (≥10 µmol/L) and adverse fetal outcomes, including low birth weight (LBW), small for gestational age (SGA), and preterm birth (PTB). RESULTS: sTBA level were positively associated with LBW (adjusted odds ratio (aOR) = 1.40; [95 % confidence interval (CI): 1.24-1.59]), SGA (aOR=1.31; [95 % CI: 1.18-1.46]), and PTB (aOR=1.27; [95 % CI: 1.15-1.41]), respectively. The estimated proportions of the total associations mediated by HDP were 47 % [95 % CI: 31 %-63 %] for LBW, 24 % [95 % CI: 13 %-35 %] for SGA, and 34 % [95 % CI: 19 %-49 %] for PTB, excepting the direct effects of high sTBA level. The contribution of hepatic dysfunction as a mediator was weaker on the association between high sTBA level on fetal outcomes, as the proportions mediated and 95 % CI were 16 % [4 %-29 %], 4 % [-6%-14 %], 32 % [15 %-50 %] for LBW, SGA, and PTB, respectively. Moreover, the mediating effect of hepatic dysfunction was nearly eliminated after excluding cases of HDP in the sensitivity analysis. CONCLUSIONS: The substantial mediating effects through HDP highlighted its significant role in adverse fetal outcomes associated with elevated sTBA level. The findings also provoked new insights into understanding the mechanism and developing clinical management strategies (i.e. vascular protection) for adverse fetal outcomes associated with elevated sTBA level.

Family concerns and relationship problems in anxious pregnant women and their associations with postnatal functional disability in Pakistan.

OBJECTIVE: Expanding on existing research suggesting that strategies to reduce prenatal anxiety can decrease functional disability (e.g., difficulties in performing everyday activities and social participation), we examined if this effect varied by type of anxiety-producing problem (i.e., having family concerns and relationship problems versus other problems) reported during pregnancy. Further, we explored if perceived social support mediated this relationship. METHODS: We used longitudinal data on 310 anxious Pakistani women who received any psychosocial intervention sessions as part of a program that was based on Cognitive Behavioral Therapy. The Psychological Outcome Profiles (PSYCHLOPS) was used to assess whether women had 'family concerns and relationship problems' or 'other problems.' The WHO Disability Assessment Schedule 2.0 assessed functional disability at six-weeks after delivery. Lack of support was measured using a 12-item Multi-dimensional Scale of Perceived Social Support. We employed linear regression to examine associations between types of problems reported during pregnancy and postnatal functional disability. Causal mediation analysis was used to assess whether postnatal social support mediated this relationship. RESULTS: Of anxious pregnant women, 34% reported family concerns or relationship problems as primary problems in pregnancy. They were more likely to report higher functional disability at six-weeks after delivery than women who reported other problems (adjusted B = 2.40, 95% CI: 0.83-3.97). Lack of overall social support (Estimateindirect = 0.69, 95% CI: 0.04-1.38) and lack of support from friends (Estimateindirect = 0.62, 95% CI: 0.01-1.29) significantly mediated the relationship. CONCLUSIONS: Findings suggest that complementing pre- and post-natal care with support programs and services that address family concerns and relationship problems, as well as enhancing social support is important to functional disability.

Causal mediation analysis with mediator values below an assay limit.

Causal indirect and direct effects provide an interpretable method for decomposing the total effect of an exposure on an outcome into the indirect effect through a mediator and the direct effect through all other pathways. A natural choice for a mediator in a randomized clinical trial is the treatment's targeted biomarker. However, when the mediator is a biomarker, values can be subject to an assay lower limit. The mediator is affected by the treatment and is a putative cause of the outcome, so the assay lower limit presents a compounded problem in mediation analysis. We propose two approaches to estimate indirect and direct effects with a mediator subject to an assay limit: (1) extrapolation and (2) numerical optimization and integration of the observed likelihood. Since these estimation methods solely rely on the so-called Mediation Formula, they apply to most approaches to causal mediation analysis: natural, separable, and organic indirect, and direct effects. A simulation study compares the two estimation approaches to imputing with half the assay limit. Using HIV interruption study data from the AIDS Clinical Trials Group described in Li et al 2016, AIDS; Lok and Bosch 2021, Epidemiology, we illustrate our methods by estimating the organic/pure indirect effect of a hypothetical HIV curative treatment on viral suppression mediated by two HIV persistence measures: cell-associated HIV-RNA and single-copy plasma HIV-RNA.

Association between endocrine-disrupting chemical mixtures and non-alcoholic fatty liver disease with metabolic syndrome as a mediator among adults: A population-based study in Korea.

Endocrine-disrupting chemicals (EDCs) may play a role in non-alcoholic fatty liver disease (NAFLD); however, studies on the combined effects of EDC mixtures on NAFLD development are limited. Here, we explored the association between exposure to EDC mixtures and NAFLD and investigated the potential mediating role of metabolic syndrome (MetS). We included participants from the Korean National Environmental Health Survey Cycle 4 (2018-2020) and quantified the urinary concentrations of various EDCs-eight phthalate metabolites, three phenols, one antibacterial compound, four parabens, four polycyclic aromatic hydrocarbons, and one pyrethroid pesticide metabolite-as well as serum concentrations of five perfluorinated compounds (PFCs). NAFLD was defined as a hepatic steatosis index (HSI) ≥36 or a fatty liver index (FLI) ≥60. Weighted quantile sum (WQS) regression was employed to evaluate the associations between EDC mixtures and the risk of MetS or NAFLD. Causal mediation analysis was conducted to explore the potential mediating effect of MetS on the association between mixtures of EDCs and NAFLD risk. All estimates were adjusted for age, sex, educational level, physical activity, smoking status, involuntary smoking, and drinking habits. A total of 2942 adults were included in the analysis. Moderate-to-high positive correlations were identified between phthalate metabolites and PFCs. Higher WQS scores were associated with an elevated risk of MetS and NAFLD. The sex-stratified WQS regression model showed that the interactions between the WQS index and sex were significant for MetS and NAFLD. According to the causal mediation analysis, both the direct and indirect effects of EDC mixtures on NAFLD, with MetS as a mediator, were significant in females. Collectively, these findings highlight the need for interventions that could address both EDC mixture exposure and metabolic status to effectively reduce the risks associated with NAFLD and its related complications.

Association of natriuretic peptides and receptor activity with cardio-metabolic health at middle age.

Natriuretic peptides (NP) have multiple actions benefitting cardiovascular and metabolic health. Although many of these are mediated by Guanylyl Cyclase (GC) receptors NPR1 and NPR2, their role and relative importance in vivo is unclear. The intracellular mediator of NPR1 and NPR2, cGMP, circulates in plasma and can be used to examine relationships between receptor activity and tissue responses targeted by NPs. Plasma cGMP was measured in 348 participants previously recruited in a multidisciplinary community study (CHALICE) at age 50 years at a single centre. Associations between bio-active NPs and bio-inactive aminoterminal products with cGMP, and of cGMP with tissue response, were analysed using linear regression. Mediation of associations by NPs was assessed by Causal Mediation Analysis (CMA). ANP's contribution to cGMP far exceed those of other NPs. Modelling across three components (demographics, NPs and cardiovascular function) shows that ANP and CNP are independent and positive predictors of cGMP. Counter intuitively, findings from CMA imply that in specific tissues, NPR1 responds more to BNP stimulation than ANP. Collectively these findings align with longer tissue half-life of BNP, and direct further therapeutic interventions towards extending tissue activity of ANP and CNP.

Importance of circulating leptin and adiponectin in the causal pathways between obesity and the development of colorectal cancer in Japanese men.

BACKGROUND: The mechanistic associations between obesity and risk of colorectal cancer (CRC) remain unclear. Here, using body mass index (BMI) as an obesity indicator, we decomposed the total effects of obesity on the risk of CRC into: (1) direct effects, which are possibly mediated by unmeasured or currently unknown factors; (2) indirect effects mediated by circulating leptin and adiponectin; and (3) indirect effects that are not mediated by circulating leptin and adiponectin but by hyperinsulinemia and chronic inflammation (assessed via circulating connecting peptide and C-reactive protein, respectively). METHODS: We adopted a causal mediation framework, using data from a large prospective cohort study of 44,271 Japanese men. RESULTS: BMI was not associated with the risk of CRC due to direct and indirect effects that were not mediated by circulating leptin and adiponectin. By contrast, individuals with BMIs of 25.0-27.4 kg/m2 (risk ratio, 1.29; 95% confidence interval, 0.98-1.69) and ≥27.5 kg/m2 (risk ratio, 1.28; 95% confidence interval, 0.98-1.68) had a higher risk of CRC due to indirect effects of circulating leptin and adiponectin. CONCLUSIONS: Our mediation analyses suggest that the association between BMI and CRC risk may be largely mediated by a pathway involving circulating leptin and adiponectin.

Social Support, Resilience, and Mental Health Among Three High-Risk Groups in Hong Kong: A Mediation Analysis.

Objectives: To compare the prevalence of anxiety/depression, resilience, and social support among nurses, foreign domestic helpers (FDHs), and residents living in subdivided units (SDUs), and to examine their associations in these high-risk groups in Hong Kong during Omicron waves. Methods: We recruited 1,014 nurses, 621 FDHs, and 651 SDU residents from December 2021 to May 2022 in this cross-sectional survey. The depression, anxiety, social support, and resilience levels were measured by the validated scales. The multivariate binary logistic regression and causal mediation analysis were applied to examine the associations. Results: We observed a prevalence of 17.7% in anxiety and 21.6% in depression which were the highest in SDU residents, followed by FDHs, and lowest in nurses. Social support was associated with increased resilience levels and decreased risks of anxiety/depression. The association of social support with mental disorders was partly mediated by resilience, accounting for 30.9% and 20.9% of the total effect of social support on anxiety and depression, respectively. Conclusion: Public health strategies should target improving social support and providing resilience-promoting interventions to help reduce mental disorders in vulnerable groups.

H4K20me3, H3K4me2 and H3K9me2 mediate the effect of ER on prognosis in breast cancer.

Previous studies have indicated that histone methylations act as mediators in the relationship between oestrogen receptor (ER) and breast cancer prognosis, yet the mediating role has never been assessed. Therefore, we investigated seven histone methylations (H3K4me2, H3K4me3, H3K9me1, H3K9me2, H3K9me3, H3K27me3 and H4K20me3) to determine whether they mediate the prognostic impact of ER on breast cancer. Tissue microarrays were constructed from 1045 primary invasive breast tumours, and the expressions of histone methylations were examined by immunohistochemistry. Multifactorial logistic regression was used to analyse the associations between ER and histone methylations. Cox proportional hazard model was performed to assess the relationship between histone methylations and breast cancer prognosis. The mediation effects of histone methylations were evaluated by model-based causal mediation analysis. High expressions of H3K9me1, H3K9me2, H3K4me2, H3K27me3, H4K20me3 were associated with ER positivity, while high expression of H3K9me3 was associated ER negativity. Higher H3K9me2, H3K4me2 and H4K20me3 levels were associated with better prognosis. The association between ER and breast cancer prognosis was most strongly mediated by H4K20me3 (29.07% for OS; 22.42% for PFS), followed by H3K4me2 (11.5% for OS; 10.82% for PFS) and least by H3K9me2 (9.35% for OS; 7.34% for PFS). H4K20me3, H3K4me2 and H3K9me2 mediated the relationship between ER and breast cancer prognosis, which would help to further elucidate the impact of ER on breast cancer prognosis from an epigenetic perspective and provide new ideas for breast cancer treatment.

Hypertensive disorders of pregnancy, neonatal outcomes and offspring developmental delay in Japan: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

INTRODUCTION: Developmental delay at an early age indicates the probability of continued problems after school age. Hypertensive disorders of pregnancy (HDP) are associated with developmental delays in offspring, with inconsistent outcomes. Neonatal outcomes vary according to HDP exposure and are relevant to development in later years. Here we aimed to clarify the relationship between HDP and developmental delay in offspring and whether neonatal outcomes mediate this association. MATERIAL AND METHODS: We used data from 5934 mother-child pairs from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study, a prospective cohort study conducted in Japan between July 2013 and March 2017. The Ages and Stages Questionnaires, third edition, at 24 and 42 months of age, measured developmental delay in five areas. We performed multivariate quasi-Poisson regression and causal mediation analysis by neonatal outcomes. RESULTS: At 24 months of age, compared to offspring born from normotensive mothers, offspring born from HDP-affected mothers were more likely to experience developmental delay (risk ratio [RR] 1.29, 95% confidence interval [CI]: 1.09-1.52) in the areas of communication (RR 1.21, 95% CI: 1.00-1.45) and personal-social (RR 1.15, 95% CI: 1.03-1.28). This association was mediated by neonatal outcomes: preterm birth, neonatal asphyxia, NICU admission, and neonatal small head circumference. No association was observed between HDP and developmental delay at 42 months of age. CONCLUSIONS: Exposure to HDP during fetal life is associated with offspring developmental delay. This association is partly mediated by neonatal outcomes.

Exposure to household secondhand tobacco smoke and the odds of developing atopic dermatitis among adolescents: A causal mediation analysis.

INTRODUCTION: Exposure to household secondhand tobacco smoke (SHS) among adolescents has been shown to be associated with atopic dermatitis, and affects disproportionality females. However, the mechanisms underlying this link are uncertain. This study sought to identify modifiable factors that mediate the relationship between household SHS exposure and atopic dermatitis among adolescents. METHODS: During October 2015, a cross-sectional study was conducted using the ISAAC questionnaire for data collection from adolescents enrolled in nine high schools of Hawalli - one of the six governorates of Kuwait. Data were collected on sociodemographic characteristics, self-reported tobacco smoking among adolescents, household SHS exposure (≥1 smokers at home vs none), self-reported asthma and atopic dermatitis. For causal mediation analysis an inverse odds-weighting approach was used. RESULTS: Of 746 participants, 74.8% were Kuwaiti, 50.1% were female, 12.4% were regular daily smokers and 54.1% had household SHS exposure, which was more common among Kuwaiti (79.6%) than non-Kuwaiti (20.4%) adolescents. The prevalences of self-reported asthma and atopic dermatitis were 20.6% and 14.9%, respectively. After adjusting for the pre-exposure covariates (i.e. sex and nativity), household SHS exposure had a significant (p=0.043) total effect, non-significant (p=0.133) natural direct effect, and marginally insignificant (p=0.058) natural indirect effect, which were jointly mediated by asthma status and adolescent's self-reported smoking status, with a proportion of mediated risk to atopic dermatitis of 29.6%. CONCLUSIONS: Asthma and self-tobacco smoking among adolescents not only directly affected but also mediated household SHS exposure effect on atopic dermatitis risk. Voluntarily adopting a smoke-free home rule may minimize household SHS exposure, reduce the odds of developing asthma, and deter the initiation of tobacco smoking among adolescents. Such an effort will likely mitigate the atopic dermatitis risk among adolescents in this and other similar settings. If implemented, future studies may contemplate evaluating the impact of such intervention.

Larger hypothalamic subfield volumes in patients with chronic insomnia disorder and relationships to levels of corticotropin-releasing hormone.

The hypothalamus is a well-established core structure in the sleep-wake cycle. While previous studies have not consistently found whole hypothalamus volume changes in chronic insomnia disorder (CID), differences may exist at the smaller substructural level of the hypothalamic nuclei. The study aimed to investigate the differences in total and subfield hypothalamic volumes, between CID patients and healthy controls (HCs) in vivo, through an advanced deep learning-based automated segmentation tool. A total of 150 patients with CID and 155 demographically matched HCs underwent T1-weighted structural magnetic resonance scanning. We utilized FreeSurfer v7.2 for automated segmentation of the hypothalamus and its five nuclei. Additionally, correlation and causal mediation analyses were performed to investigate the association between hypothalamic volume changes, insomnia symptom severity, and hypothalamus-pituitary-adrenal (HPA) axis-related blood biomarkers. CID patients exhibited larger volumes in the right anterior inferior, left anterior superior, and left posterior subunits of the hypothalamus compared to HCs. Moreover, we observed a positive association between blood corticotropin-releasing hormone (CRH) levels and insomnia severity, with anterior inferior hypothalamus (a-iHyp) hypertrophy mediating this relationship. In conclusion, we found significant volume increases in several hypothalamic subfield regions in CID patients, highlighting the central role of the HPA axis in the pathophysiology of insomnia.

The role of breastfeeding support in racial/ethnic disparities in breastfeeding practices.

BACKGROUND: Persistent racial/ethnic disparities in breastfeeding practices in the United States are well documented but the underlying causes remain unclear. While racial/ethnic disparities are often intertwined with socioeconomic disparities in breastfeeding, studies suggest that lack of breastfeeding support from family, health care organizations and workplaces may contribute to racial/ethnic disparities in breastfeeding rates. No studies have investigated the extent to which racial/ethnic disparities in breastfeeding practices can be explained by breastfeeding support. METHODS: We used survey data from participants of a federal nutrition assistance program in Los Angeles County, the most populous county in the United States, to examine causal mechanisms underlying racial/ethnic disparities in breastfeeding in five groups: Spanish-speaking Latina, English-speaking Latina, Non-Hispanic White (NHW), Non-Hispanic Black (NHB) and Non-Hispanic Asian (NHA). Applying causal mediation analysis, this study estimated the proportion of racial/ethnic differences in breastfeeding ('any' breastfeeding, i.e., partial or exclusive) rates at 6 months that could be explained by differential access to breastfeeding support from family, birth hospitals and workplaces. RESULTS: NHB and English-speaking Latina mothers were less likely, and Spanish-speaking Latina mothers more likely to breastfeed through 6 months than NHW mothers. Lack of breastfeeding support from family, hospitals and workplaces accounted for approximately 68% of the difference in any breastfeeding rates at 6 months between NHW and NHB mothers and 36% of the difference between NHW and English-speaking Latina mothers. CONCLUSION: These findings highlight the importance of improving support from family, hospitals and workplaces for breastfeeding mothers to reduce racial/ethnic disparities in breastfeeding.

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.

Chewing difficulties mediated association between edentulism and depressive symptoms among middle aged and older population.

BACKGROUND: Depression is a major health condition among the aging population. Previous studies indicated that edentulism was a risk factor for depression. The link between edentulism and depression has not been fully clarified. OBJECTIVES: This study aimed to estimate whether chewing difficulties play a mediating role in the association between edentulism and depression among middle-aged and older populations with national cross-sectional data. METHODS: Data were obtained from the latest fourth wave of the China Health and Retirement Longitudinal Study (CHARLS). The outcome variable was set as depression, which was measured by the Center for Epidemiologic Studies Depression Scale (CES-D-10). Independent and mediated variables were separately set as self-assessed edentulism and chewing difficulties. The nearest neighbour propensity score matching (PSM) method was used to construct a matching group to balance the basic characteristics of individuals with and without edentulism with minimised bias in the estimation. Causal mediation analysis was performed to estimate the degree of contribution of chewing difficulties to the association between edentulism and depression. Several sensitivity analyses were performed to evaluate the robustness of the primary result. RESULTS: A total of 15 853 individuals remained for analysis. After PSM, 809 individuals with edentulism and 2628 without edentulism remained for analysis. Among the matched individuals, the mean age was 66.3 ± 9.2 years, 58.5% were female, 78.8% lived in rural areas, 23.5% had edentulism, 51.1% had depressive symptoms, and 50.1% had chewing difficulties. Logistic regression results showed that a higher incidence of edentulism was associated with a higher rate of depression (OR: 1.39, 95% CI: 1.19-1.63) in the matching group. Causal mediation analysis results indicated that the average mediation effect of chewing difficulties on the association between edentulism and depression was 0.010 (95% CI: 0.005-0.015), and the average direct effect was 0.072 (95% CI: 0.036-0.11). The mediation proportion of chewing difficulties was 11.7% (95% CI: 0.079-0.21). CONCLUSION: A higher prevalence of edentulism was associated with a higher rate of depression among middle-aged and elderly populations. Chewing difficulties moderately mediated the association between edentulism and depression. Fundamental oral function should not be neglected to improve mental health among the aging population.

Elevated homocysteine levels may moderate and mediate the association between HIV and cognitive impairment among middle-aged and older adults in an underserved population in Baltimore, Maryland.

Background: In the antiretroviral therapy (ART) era, HIV-associated neurocognitive disorders (HAND) remain a considerable challenge for people with HIV, yet not all such disorders can be attributed to HIV alone. This study aimed to: (1) identify factors influencing neurocognitive impairment (NCI) utilizing the NIH Toolbox Cognition Battery (NIHTB-CB) as per the revised research criteria for HAND; (2) ascertain the moderating role of high homocysteine levels in the association between NCI and HIV; and (3) assess the mediating effect of elevated homocysteine levels on this association.Methods: We analyzed data from 788 adults (≥45 years) participating in a study on HIV-related comorbidities in underserved Baltimore communities, using NIHTB-CB to gauge neurocognitive performance. Special attention was given to results from the Dimensional Change Card Sort (DCCS) test within the executive function domain during causal mediation analysis.Results: Overall, HIV was not associated with NCI presence. However, HIV was associated with NCI among individuals with homocysteine >14 µmol/L. Furthermore, HIV was both directly and indirectly associated with NCI in DCCS test scores. Notably, the mediating role of elevated homocysteine in DCCS scores was only observable among individuals who had never used cocaine or had used it for ≤ 10 years, suggesting that extended cocaine use may have a substantial influence on cognitive performance.Conclusions: The findings from this study suggest elevated homocysteine levels may moderate and mediate the association between HIV and neurocognitive impairment.

Multiply robust estimation of natural indirect effects with multiple ordered mediators.

Multiple mediation analysis is a powerful methodology to assess causal effects in the presence of multiple mediators. Several methodologies, such as G-computation and inverse-probability-weighting, have been widely used to draw inferences about natural indirect effects (NIEs). However, a limitation of these methods is their potential for model misspecification. Although powerful semiparametric methods with high robustness and consistency have been developed for inferring average causal effects and for analyzing the effects of a single mediator, a comparably robust method for multiple mediation analysis is still lacking. Therefore, this theoretical study proposes a method of using multiply robust estimators of NIEs in the presence of multiple ordered mediators. We show that the proposed estimators not only enjoy the multiply robustness to model misspecification, they are also consistent and asymptotically normal under regular conditions. We also performed simulations for empirical comparisons of the finite-sample properties between our multiply robust estimators and existing methods. In an illustrative example, a dataset for liver disease patients in Taiwan is used to examine the mediating roles of liver damage and liver cancer in the pathway from hepatitis B/C virus infection to mortality. The model is implemented in the open-source R package "MedMR."

Nasopharyngeal Viral Load Is the Major Driver of Incident Antibody Immune Response to SARS-CoV-2 Infection.

Background: Virologic determinants of seroconversion to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were defined in a post hoc analysis of prospectively studied vaccine- and infection-naïve individuals at high risk for coronavirus disease 2019 (COVID-19). Methods: This phase 3 COVID-19 prevention trial (NCT04452318) with casirivimab and imdevimab was conducted in July 2020-February 2021, before widespread vaccine availability. Placebo-treated participants who were uninfected (SARS-CoV-2 quantitative reverse transcription polymerase chain reaction [RT-qPCR] negative) and seronegative were assessed weekly for 28 days (efficacy assessment period [EAP]) for COVID-19 symptoms and SARS-CoV-2 infection by RT-qPCR of nasopharyngeal swab samples and for serostatus by antinucleocapsid immunoglobulin (Ig) G. Regression-based modeling, including causal mediation analysis, estimated the effects of viral load on seroconversion. Results: Of 157/1069 (14.7%) uninfected and seronegative (for antispike IgG, antispike IgA, and antinucleocapsid IgG) participants who became infected during the EAP, 105 (65%) seroconverted. The mean (SD) maximum viral load of seroconverters was 7.23 (1.68) log10 copies/mL vs 4.8 (2.2) log10 copies/mL in those who remained seronegative; viral loads of ∼6.0 log10 copies/mL better predicted seroconversion. The mean of the maximum viral load was 7.11 log10 copies/mL in symptomatic participants vs 5.58 log10 copies/mL in asymptomatic participants. The mean duration of detectable viral load was longer in seroconverted vs seronegative participants: 3.24 vs 1.63 weeks. Conclusions: Maximum SARS-CoV-2 viral load is a major driver of seroconversion and symptomatic COVID-19, with high viral loads (∼6.0 log10 copies/mL) better predicting seroconversion. Serology underestimates infection rates, incidence, and prevalence of SARS-CoV-2 infection.