Causal Mediation Research Articles

Kidney function decline mediates the adverse effects of per- and poly-fluoroalkyl substances (PFAS) on uric acid levels and hyperuricemia risk

Previous studies indicated per- and poly-fluoroalkyl substances (PFAS) were related to uric acid and hyperuricemia risk, but evidence for the exposure-response (E-R) curves and combined effect of PFAS mixture is limited. Moreover, the potential mediation effect of kidney function was not assessed. Hence, we conducted a national cross-sectional study involving 13,979 US adults in NHANES 2003–2018 to examine the associations of serum PFAS with uric acid and hyperuricemia risk, and the mediation effects of kidney function. Generalized linear models and E-R curves showed positive associations of individual PFAS with uric acid and hyperuricemia risk, and nearly linear E-R curves indicated no safe threshold for PFAS. Weighted quantile sum regression found positive associations of PFAS mixture with uric acid and hyperuricemia risk, and PFOA was the dominant contributor to the adverse effect of PFAS on uric acid and hyperuricemia risk. Causal mediation analysis indicated significant mediation effects of kidney function decline in the associations of PFAS with uric acid and hyperuricemia risk, with the mediated proportion ranging from 19 % to 57 %. Our findings suggested that PFAS, especially PFOA, may cause increased uric acid and hyperuricemia risk increase even at low levels, and kidney function decline plays a crucial mediation effect.

Associations between symptoms of attention-deficit hyperactivity disorder, socioeconomic status and asthma in children

Socioeconomic status (SES) influences the risk of both physical diseases, such as asthma, and neurodevelopmental conditions, including attention-deficit/hyperactivity disorder (ADHD). Using Causal Mediation Analysis on French birth-cohort data, we found a causal pathway from SES to ADHD symptoms, in part mediated by asthma. An increase in family income at age 3 by one unit resulted in lower ADHD symptoms at age 5, by −0.37 [95% CI: −0.50, −0.24] SDQ-score-points, with additional −0.04 [95% CI: −0.08, −0.01] points reduction indirectly via asthma at age 3, both with statistical significance. Importantly, family income at age 3 exerted both direct and indirect (via asthma) negative effects on later ADHD symptoms with much higher magnitudes for the direct effect. Our findings underscore the importance of apprehending ADHD symptoms in the broader context of socioeconomic disparities, along with their comorbidities with asthma, potentially influencing public health interventions and clinical practice in managing ADHD.

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

ObjectiveExpanding 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. MethodsWe 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. ResultsOf 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. ConclusionsFindings 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.

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

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. 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. 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. Public health strategies should target improving social support and providing resilience-promoting interventions to help reduce mental disorders in vulnerable groups.

The Alcohol Harm Paradox in Periodontitis

Individuals of lower socioeconomic position (SEP) experience a greater rate of alcohol-related harms, yet they consume equal or lower amounts of alcohol than higher-SEP individuals. This phenomenon, called the “alcohol harm paradox” (AHP), gained attention recently, and different mechanisms have been proposed to explain it. Since both SEP and alcohol have been suggested to be associated with periodontitis risk, we conducted a secondary analysis using data from the National Health and Nutrition Examination Survey 2011 to 2012 and 2013 to 2014 cycles, aiming to examine 1) whether the association between alcohol consumption and periodontitis is modified by SEP and 2) the extent to which the effect of SEP inequalities on periodontitis is mediated by and/or interacts with alcohol consumption. We set educational attainment as the main SEP proxy and tested the poverty income ratio in subsequent sensitivity analyses. Effect measure modification analysis was employed, considering heavy drinking as exposure, and causal mediation analysis based on the potential outcome’s framework decomposed the effect of SEP on periodontitis in proportions attributable to mediation and interaction. Models were fitted using binary logistic regression and adjusted for sex, ethnicity, age, body mass index, smoking status, diabetes, binge drinking, and regular preventive dental visits. The analytical sample comprised 4,057 participants. After adjusting for covariates, less educated heavy drinkers presented 175% (odds ratio, 2.75; 95% confidence interval [CI], 2.04–3.72) higher odds of periodontitis than their counterparts, and super-additive associations were found (relative excess risk due to interaction: 1.35; 95% CI, 0.49–2.20). Additionally, −69.5% (95% CI, −122.1% to −16.8%) of the effects of education on periodontitis were attributable to interaction with heavy drinking, consistent with the AHP. No contribution was found for the mechanism of mediation. Heavy drinking disproportionately impacts the occurrence of periodontitis in lower-SEP individuals. Lower-SEP individuals seem to experience differential effects of heavy drinking on periodontitis.

Multi-Trait Body Shape Phenotypes and Breast Cancer Risk in Postmenopausal Women: A Causal Mediation Analysis in the UK Biobank Cohort

Body shape phenotypes combining multiple anthropometric traits have been linked to postmenopausal breast cancer (BC). However, underlying biological pathways remain poorly understood. This study investigated to what extent the associations of body shapes with postmenopausal BC risk is mediated by biochemical markers. The study included 176,686 postmenopausal women from UK Biobank. Four body shape phenotypes were derived from principal component (PC) analysis of height, weight, body mass index, waist and hip circumferences, and waist-to-hip ratio (WHR). The four-way decomposition of the total effect was used to estimate mediation and interaction effects simultaneously as well as the mediated proportions. After 10.9 years median follow-up, 6,396 incident postmenopausal BC were diagnosed. There was strong evidence of positive associations between PC1 (general obesity) and PC2 (tall, low WHR), and BC risk. The association of PC1 with BC risk was positively mediated by testosterone and negatively by insulin-like growth factor-1 (IGF-1), with the overall proportion mediated (sum of the mediated interaction and pure indirect effect (PIE)) accounting for 11.4% (95% confidence intervals: 5.1 to 17.8%) and -12.2% (-20.5% to -4.0%) of the total effect, respectively. Small proportions of the association between PC2 and BC were mediated by IGF-1 (PIE: 2.8% (0.6 to 4.9%)), and sex hormone-binding globulin (SHBG) (PIE: -6.1% (-10.9% to -1.3%)). Our findings are consistent with differential pathways linking different body shapes with BC risk, with a suggestive mediation through testosterone and IGF-1 in the relationship of a generally obese body shape and BC risk, while IGF-1 and SHBG may mediate a tall/lean body shape-BC risk association.

Correction to: ‘Nonparametric efficient causal mediation with intermediate confounders’

Correction to: ‘Nonparametric efficient causal mediation with intermediate confounders’

Executive dysfunction as a possible mediator for the association between excessive screen time and problematic behaviors in preschoolers.

Excessive screen time in children is a growing concern for parents and healthcare providers worldwide because it frequently leads to behavioral problems. Although executive dysfunction is proposed to be one of the contributing factors to maladaptive behaviors, little is known about the link between screen time and behaviors. This study aimed to identify whether executive dysfunction contributes to the negative behaviors of children exposed to excessive screen time. A cross-sectional study was conducted on preschool-aged children from public and private schools in Chiang Mai, Thailand. The parents/guardians of each child completed the questionnaires regarding clinical characteristics and screen time use, the Behavior Rating Inventory for Executive Function-Preschool (BRIEF-P), and the Strengths and Difficulties Questionnaire (SDQ). Children with more than one hour of media exposure per day were considered to have excessive screen time. Multivariable Gaussian regression was analyzed to compare the BRIEF-P and SDQ scores between the excessive and appropriate screen time groups. Causal mediation analysis was performed to examine the effects of total screen time on increasing behavioral problems with executive functioning as a mediator. A total of 1,126 preschoolers were included in the analyses. After controlling for age, sex, socioeconomic status, and maternal education, the excessive screen time group had significantly higher BRIEF-P global executive composite score than the appropriate screen time group (mean difference of global executive composite score = 1.49, 95% CI [0.12, 2.86], and p = 0.033). Concurrently, there were significant differences in externalizing behavior subscales and SDQ total difficulties scores between the excessive and appropriate screen time groups (mean difference of total difficulties score = 0.90, 95% CI [0.29, 1.50], and p = 0.004). A significant average causal mediation effect (ACME) of screen time on behavioral problems mediated through executive functioning was β = 0.28, 95% CI [0.13-0.44], which was more than half of the total effect (54.9%, 95% CI [37.4-100%]). The current study suggests that the increase in behavioral issues in preschoolers might be partly explained by the direct effect of excessive screen time and the mediating effect of impaired executive functioning. Our results may raise concerns about the necessity to limit screen time and monitor for executive function deficits and behavioral problems in young children with high screen time.

Practical causal mediation analysis: extending nonparametric estimators to accommodate multiple mediators and multiple intermediate confounders.

Mediation analysis is appealing for its ability to improve understanding of the mechanistic drivers of causal effects, but real-world data complexities challenge its successful implementation, including (i) the existence of post-exposure variables that also affect mediators and outcomes (thus, confounding the mediator-outcome relationship), that may also be (ii) multivariate, and (iii) the existence of multivariate mediators. All three challenges are present in the mediation analysis we consider here, where our goal is to estimate the indirect effects of receiving a Section 8 housing voucher as a young child on the risk of developing a psychiatric mood disorder in adolescence that operate through mediators related to neighborhood poverty, the school environment, and instability of the neighborhood and school environments, considered together and separately. Interventional direct and indirect effects (IDE/IIE) accommodate post-exposure variables that confound the mediator-outcome relationship, but currently, no readily implementable nonparametric estimator for IDE/IIE exists that allows for both multivariate mediators and multivariate post-exposure intermediate confounders. The absence of such an IDE/IIE estimator that can easily accommodate both multivariate mediators and post-exposure confounders represents a significant limitation for real-world analyses, because when considering each mediator subgroup separately, the remaining mediator subgroups (or a subset of them) become post-exposure intermediate confounders. We address this gap by extending a recently developed nonparametric estimator for the IDE/IIE to allow for easy incorporation of multivariate mediators and multivariate post-exposure confounders simultaneously. We apply the proposed estimation approach to our analysis, including walking through a strategy to account for other, possibly co-occurring intermediate variables when considering each mediator subgroup separately.

Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis.

To investigate sex-related differences in amyotrophic lateral sclerosis (ALS) prognosis and their contributing factors. Our primary cohort was the Piemonte and Aosta Register for ALS (PARALS); the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) and the Answer ALS databases were used for validation. Survival analyses were conducted accounting for age and onset site. The roles of forced vital capacity and weight decline were explored through a causal mediation analysis. Survival and disease progression rates were also evaluated after propensity score matching. The PARALS cohort included 1,890 individuals (44.8% women). Men showed shorter survival when stratified by onset site (spinal onset HR 1.20, 95% CI 1.00-1.44, p = 0.0439; bulbar onset HR 1.36, 95% CI 1.09-1.70, p = 0.006917), although women had a steeper functional decline (+0.10 ALSFRS-R points/month, 95% CI 0.07-0.15, p < 0.00001) regardless of onset site. Instead, men showed worse respiratory decline (-4.2 forced vital capacity%/month, 95% CI -6.3 to -2.2, p < 0.0001) and faster weight loss (-0.15 kg/month, 95% CI -0.25 to -0.05, p = 0.0030). Causal mediation analysis showed that respiratory function and weight loss were pivotal in sex-related survival differences. Analysis of patients from PRO-ACT (n = 1,394, 40.9% women) and Answer ALS (n = 849, 37.2% women) confirmed these trends. The shorter survival in men is linked to worse respiratory function and weight loss rather than a faster disease progression. These findings emphasize the importance of considering sex-specific factors in understanding ALS pathophysiology and designing tailored therapeutic strategies. ANN NEUROL 2024;96:159-169.

High adherence to the French dietary guidelines decreases type 2 diabetes risk in females through pathways of obesity markers: Evidence from the E3N-EPIC prospective cohort study

Obesity and type 2 diabetes (T2D) have been associated with low adherence to the 2017 French food-based dietary guidelines, as assessed by the Programme National Nutrition Santé - guidelines score 2 (PNNS-GS2). Whether the association between T2D and PNNS-GS2 is direct or mediated by obesity has been little investigated. The study included 71,450 women from the E3N-EPIC cohort, mean age of 52.9 y (SD 6.7). The simplified PNNS-GS2 was derived via food history questionnaire. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of T2D. Causal mediation analyses were used to decompose the total effect of sPNNS-GS2 on T2D into a direct effect and indirect effect mediated by body mass index (BMI) or the waist-hip ratio (WHR). During a mean follow-up of 19 y, 3679 incident T2D cases were identified and validated. There was a linear association between adherence to sPNNS-GS2 and T2D (P-nonlinearity = 0.92). In the fully adjusted model, each 1-SD increase in the sPNNS-GS2 was associated with a lower T2D risk [HR (95% CI), 0.92 (0.89, 0.95)]. The overall associations were mainly explained by sPNNS-GS2-associated excess weight, with BMI and WHR mediating 52% and 58% of the associations, respectively. Higher adherence to French food-based dietary guidelines was associated with a lower risk of T2D in women, and a significant portion of this effect could be attributed to excess weight measured by BMI or WHR. This finding helps better understand the mechanisms underlying the diet-T2D association.

Sleepiness in retired male boxers: daytime sleepiness and its relationship with impulsiveness and depression symptomatology in retired professional male boxers

Background Boxing exposes fighters to head impacts and potential traumatic brain injury (TBI). Though research has explored the neuropsychiatric consequences of contact sports, there is limited research into Excessive Daytime Sleepiness (EDS) and its relationship to other outcomes, such as impulsiveness and depression. Therefore, this study aimed to describe EDS in retired boxers using the Epworth Sleepiness Scale (ESS) and to examine how boxing and sleepiness relate to impulsiveness and depression symptomatology. Methods 86 male retired professional boxers from the Professional Fighters Brain Health Study (PFBHS) met the inclusion criteria. Adjusted multivariable models analyzed relationships between professional boxing bouts, EDS (ESS), impulsiveness (Barratt Impulsiveness Scale Version 11 (BIS-11)), and/or depression (Patient Health Questionnaire-9 (PHQ-9)). A causal mediation analysis was performed to assess whether boxing bouts and ESS scores predicted BIS-11 and PHQ-9 scores. Results Mean age was ∼51 years, fighters averaged ∼36 professional bouts, and ESS mean(SD) was 7.5(5.3). ESS scores were significantly associated with raw BIS-11 (Beta = 1.26, 95%CI = 0.77–1.75, p < 0.001) and ordinal PHQ-9 (OR = 1.20, 95%CI = 1.11–1.31, p < 0.001) scores in adjusted models, and the significant relationship between boxing bouts and BIS-11/PHQ-9 was mediated by ESS. Conclusions EDS in retired male professional boxers may be strongly associated with other neuropsychiatric sequelae of TBI (impulsiveness and depression). Sleepiness; sleep; boxing; contact sports; impulsiveness; impulsivity; depression; Epworth sleepiness scale box

Total Tau Protein Mediates the Association of Ischemic Cerebrovascular Disease with Cognitive Decline

Background: Patients with transient ischemic attack (TIA) or ischemic stroke demonstrate an increased risk of cognitive dysfunction. Accumulating evidence indicates that ischemic cerebrovascular disease (ICVD) may interact with the amyloid/tau/neurodegeneration (AT[N]) biomarkers to promote dementia. However, the precise pathological mechanisms remain to be fully characterized. Objective: To elucidate the interrelationships among ICVD, ATN biomarkers in cerebrospinal fluid (CSF), and cognition. Methods: A total of 2524 participants were recruited from the CABLE study. ICVD referred to TIA/ischemic stroke. Cognitive performance was assessed by China Modified Mini-Mental State Examination (CM-MMSE) and Montreal Cognitive Assessment-b (MoCA-b). Multivariate linear regression analyses were performed to evaluate the associations of ICVD with CSF ATN biomarkers and cognition. Causal mediation analyses were used to identify whether the association was mediated by ATN biomarkers. Results: ICVD was associated with higher total-tau (t-tau) (p = 2.828×10–2) and poorer cognition (CM-MMSE: p = 1.539×10–5, MoCA-b: p = 4.552×10–6). Additionally, no discernible correlation surfaced between ICVD and amyloid-β (Aβ) 42 (p = 6.910×10–1) or phosphorylated tau (p-tau) (p = 4.324×10–1). The influence of ICVD on cognitive function was partially mediated by CSF t-tau (CM-MMSE: proportion: 2.74%, MoCA-b: proportion: 2.51%). Subgroup analyses revealed the influences of t-tau were especially evident in male (CM-MMSE: proportion: 5.45%, MoCA-b: proportion: 5.38%) and mid-life group (CM-MMSE: proportion: 9.83%, MoCA-b: proportion: 5.31%). Conclusions: These results delineated t-tau as a potential mediator for the influence of ICVD on cognition. Targeting brain ischemia and alleviating neuronal injury induced by ischemia may be a promising approach for preventing cognitive decline.

Platelet bioenergetic profiling uncovers a metabolic pattern of high dependency on mitochondrial fatty acid oxidation in type 2 diabetic patients who developed in-stent restenosis

Although platelet bioenergetic dysfunction is evident early in the pathogenesis of diabetic macrovascular complications, the bioenergetic characteristics in type 2 diabetic patients who developed coronary in-stent restenosis (ISR) and their effects on platelet function remain unclear. Here, we performed platelet bioenergetic profiling to characterize the bioenergetic alterations in 28 type 2 diabetic patients with ISR compared with 28 type 2 diabetic patients without ISR (non-ISR) and 28 healthy individuals. Generally, platelets from type 2 diabetic patients with ISR exhibited a specific bioenergetic alteration characterized by high dependency on fatty acid (FA) oxidation, which subsequently induced complex III deficiency, causing decreased mitochondrial respiration, increased mitochondrial oxidant production, and low efficiency of mitochondrial ATP generation. This pattern of bioenergetic dysfunction showed close relationships with both α-granule and dense granule secretion as measured by surface P-selectin expression, ATP release, and profiles of granule cargo proteins in platelet releasates. Importantly, ex vivo reproduction of high dependency on FA oxidation by exposing non-ISR platelets to its agonist mimicked the bioenergetic dysfunction observed in ISR platelets and enhanced platelet secretion, whereas pharmaceutical inhibition of FA oxidation normalized the respiratory and redox states of ISR platelets and diminished platelet secretion. Further, causal mediation analyses identified a strong association between high dependency on FA oxidation and increased angiographical severity of ISR, which was significantly mediated by the status of platelet secretion. Our findings, for the first time, uncover a pattern of bioenergetic dysfunction in ISR and enhance current understanding of the mechanistic link of high dependency on FA oxidation to platelet abnormalities in the context of diabetes.

50 Why are Black and Mexican American children more vulnerable than White children to upper respiratory viral infection?

OBJECTIVES/GOALS: There is an excess risk of upper respiratory infection (URI) among Black and Mexican-American children in the US. Factors that underpin these disparities are largely unknown. We evaluated the extent to which socioeconomic status (SES), serum cotinine, obesity, and household size explained the association between race/ethnicity and URI. METHODS/STUDY POPULATION: We studied children, 6-17 years of age, who identified as Black, Mexican-American, or White in the National Health and Nutritional Examination Survey (2007-2012). URI was defined as a self-reported cough, cold, phlegm, runny nose, or other respiratory illness (excluding hay fever and allergies) in the past 7 days. The proportion of the association between race/ethnicity and URI explained by SES, serum cotinine, obesity, and household size was estimated as the average causal mediation effect (i.e., the indirect effect of race/ethnicity via the mediator) divided by the total effect of race/ethnicity. The average causal mediation effect was derived from survey weighted logistic regression models adjusted for age and sex. RESULTS/ANTICIPATED RESULTS: Black children were nearly 40% and Mexican American children were ~60% more likely to report a URI than those who identified as White (OR, 1.37; 95% CI, 1.06-1.77 and OR, 1.61; 95% CI, 1.21-2.13, respectively). Lower SES explained ~25% of the association between Black and Mexican American identity and URI (percent mediated 24.7; 95% CI, 23.0-26.6 and 26.1; 95% CI, 24.2-28.2, respectively). Obesity explained ~7% of the association between Black and Mexican-American identity and URI (percent mediated, 7.6; 95% CI, 7.3-8.0 and percent mediated, 6.7; 95% CI, 6.4-6.9, respectively). Nicotine exposure explained 8% of the association between Black identity and URI (percent mediated, 7.9; 95% CI, 5.6-10.1). DISCUSSION/SIGNIFICANCE: Lower SES explained a quarter of the association between race/ethnicity and URI. Low SES is a broad concept that may work through different mechanisms to lead to disparities in URI by race/ethnicity. Future research is needed to better understand these mechanisms and to identify modifiable aspects that can serve as targets for intervention.

Persistent DNA Methylation Changes across the First Year of Life and Prenatal Exposure in a Canadian Prospective Birth Study.

Evidence suggests that prenatal air pollution exposure alters DNA methylation (DNAm), which could go on to affect long-term health. It remains unclear whether DNAm alterations present at birth persist through early life. Identifying persistent DNAm changes would provide greater insight into the molecular mechanisms contributing to the association of prenatal air pollution exposure with atopic diseases. This study investigated DNAm differences associated with prenatal nitrogen dioxide () exposure (a surrogate measure of traffic-related air pollution) at birth and 1 y of age and examined their role in atopic disease. We focused on regions showing persistent DNAm differences from birth to 1 y of age and regions uniquely associated with postnatal exposure. Microarrays measured DNAm at birth and at 1 y of age for an atopy-enriched subset of Canadian Health Infant Longitudinal Development (CHILD) study participants. Individual and regional DNAm differences associated with prenatal () were identified, and their persistence at age 1 y were investigated using linear mixed effects models (). Postnatal-specific DNAm differences () were isolated, and their association with in the first year of life was examined. Causal mediation investigated whether DNAm differences mediated associations between and age 1 y atopy or wheeze. Analyses were repeated using biological sex-stratified data. At birth (), 18 regions of DNAm were associated with , with several annotated to HOX genes. Some of these regions were specifically identified in males (), but not females (). The effect of prenatal across CpGs within altered regions persisted at 1 y of age. No significant mediation effects were identified. Sex-stratified analyses identified postnatal-specific DNAm alterations. Regional cord blood DNAm differences associated with prenatal persisted through at least the first year of life in CHILD participants. Some differences may represent sex-specific alterations, but replication in larger cohorts is needed. The early postnatal period remained a sensitive window to DNAm perturbations. https://doi.org/10.1289/EHP13034.

423 Impact of predialysis renal care on the US incident home dialysis use, a causal mediation analysis

423 Impact of predialysis renal care on the US incident home dialysis use, a causal mediation analysis

Human milk oligosaccharide composition following supplementation with folic acid vs (6S)-5-methyltetrahydrofolic acid during pregnancy and mediation by human milk folate forms.

Supplementation with folic acid versus (6S)-5-methyltetrahydrofolic acid (5-MTHF) results in different folate forms in human milk, with folic acid increasing unmetabolized folic acid (UMFA) at the expense of reduced folate forms. It is unknown whether folate forms present in human milk have further effects on human milk composition, such as human milk oligosaccharide (HMO) concentrations. We randomized 60 pregnant women in Canada to 0.6 mg/day folic acid or (6S)-5-MTHF. Human milk folate forms (LC-MS/MS) and nineteen HMOs (HPLC) were quantified at 1 week postpartum. Linear regression and causal mediation analysis were used to evaluate the effect of folate supplementation on HMO concentrations, and possible mediation by concentrations of UMFA and reduced folate forms in human milk (controlling for secretor status and parity). HMO concentrations were not different between groups, with no evidence of mediation by reduced folate forms; however, increased UMFA was associated with reduced concentrations of total HMOs and 3'-sialyllactose.

Arsenic Exposure-Related Hypertension in Bangladesh and Reduced Circulating Nitric Oxide Bioavailability.

Hypertension is a major cause of death worldwide. Although arsenic exposure has been associated with the risk of hypertension, this association appears nonuniform due to inconsistent results from studies conducted in different populations. Moreover, hypertension is a complex condition with multiple underlying mechanisms and factors. One factor is impaired production and bioavailability of vascular nitric oxide (NO). However, the implications of the effects of arsenic exposure on circulating NO and its association with hypertension in humans are largely unknown. We investigated the dose-response relationship between arsenic exposure and hypertension with vascular NO levels as a potential mediator of arsenic-related hypertension in individuals exposed to a broad range of arsenic. A total of 828 participants were recruited from low- and high-arsenic exposure areas in Bangladesh. Participants' drinking water, hair, and nail arsenic concentrations were measured by inductively coupled plasma mass spectroscopy. Hypertension was defined as a systolic blood pressure (SBP) value of and a diastolic (DBP) value of . Serum NO levels reflected by total serum nitrite concentrations were measured by immunoassay. A formal causal mediation analysis was used to assess NO as a mediator of the association between arsenic level and hypertension. Increasing concentrations of arsenic measured in drinking water, hair, and nails were associated with the increasing levels of SBP and DBP. The odds of hypertension were dose-dependently increased by arsenic even in participants exposed to relatively low to moderate levels () of water arsenic [odds ratios (ORs) and 95% confidence intervals (CIs): 2.87 (95% CI: 1.28, 6.44), 2.67 (95% CI: 1.27, 5.60), and 5.04 (95% CI: 2.71, 9.35) for the , , and groups, respectively]. Causal mediation analysis showed a significant mediating effect of NO on arsenic-related SBP, DBP, and hypertension. Increasing exposure to arsenic was associated with increasing odds of hypertension. The association was mediated through the reduction of vascular NO bioavailability, suggesting that impaired NO bioavailability was a plausible underlying mechanism of arsenic-induced hypertension in this Bangladeshi population. https://doi.org/10.1289/EHP13018.

Acute kidney injury in hospitalized patients with nonmalignant pleural effusions: a retrospective cohort study

BackgroundNonmalignant pleural effusion (NMPE) is common and remains a definite health care problem. Pleural effusion was supposed to be a risk factor for acute kidney injury (AKI). Incidence of AKI in NMPE patients and whether there is correlation between the size of effusions and AKI is unknown.ObjectiveTo assess the incidence of AKI in NMPE inpatients and its association with effusion size. Study design and methodWe conducted a retrospective cohort study of inpatients admitted to the Chinese PLA General Hospital with pleural effusion from 2018-2021. All patients with pleural effusions confirmed by chest radiography (CT or X-ray) were included, excluding patients with diagnosis of malignancy, chronic dialysis, end-stage renal disease (ESRD), community-acquired AKI, hospital-acquired AKI before chest radiography, and fewer than two serum creatinine tests during hospitalization. Multivariate logistic regression and LASSO logistic regression models were used to identify risk factors associated with AKI. Subgroup analyses and interaction tests for effusion volume were performed adjusted for the variables selected by LASSO. Causal mediation analysis was used to estimate the mediating effect of heart failure, pneumonia, and eGFR < 60 ml/min/1.73m2 on AKI through effusion volume. ResultsNMPE was present in 7.8% of internal medicine inpatients. Of the 3047 patients included, 360 (11.8%) developed AKI during hospitalization. After adjustment by covariates selected by LASSO, moderate and large effusions increased the risk of AKI compared with small effusions (moderate: OR 1.47, 95%CI 1.11-1.94 p = 0.006; large: OR 1.86, 95%CI 1.05-3.20 p = 0.028). No significant modification effect was observed among age, gender, diabetes, bilateral effusions, and eGFR. Volume of effusions mediated 6.8% (p = 0.005), 4.0% (p = 0.046) and 4.6% (p < 0.001) of the effect of heart failure, pneumonia and low eGFR on the development of AKI respectively. ConclusionThe incidence of AKI is high among NMPE patients. Moderate and large effusion volume is independently associated with AKI compared to small size. The effusion size acts as a mediator in heart failure, pneumonia, and eGFR.