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Urinary Chemokine (C-C motif) ligand 14 (CCL14) is a biomarker associated with persistent severe acute kidney injury (AKI). There is limited data to support the implementation of this AKI biomarker to guide therapeutic actions. Sixteen AKI experts with clinical CCL14 experience participated in a Delphi-based method to reach consensus on when and how to potentially use CCL14. Consensus was defined as ≥ 80% agreement (participants answered with 'Yes', or three to four points on a five-point Likert Scale). Key consensus areas for CCL14 test implementation were: identifying challenges and mitigations, developing a comprehensive protocol and pairing it with a treatment plan, and defining the target population. The majority agreed that CCL14 results can help to prioritize AKI management decisions. CCL14 levels above the high cutoff (> 13 ng/mL) significantly changed the level of concern for modifying the AKI treatment plan (  < 0.001). The highest level of concern to modify the treatment plan was for discussions on renal replacement therapy (RRT) initiation for CCL14 levels > 13 ng/mL. The level of concern for discussion on RRT initiation between High and Low, and between Medium and Low CCL14 levels, showed significant differences. Real world urinary CCL14 use appears to provide improved care options to patients at risk for persistent severe AKI. Experts believe there is a role for CCL14 in AKI management and it may potentially reduce AKI-disease burden. There is, however, an urgent need for evidence on treatment decisions and adjustments based on CCL14 results.

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals widely detected in women of reproductive age. Prenatal PFAS exposure is associated with adverse health outcomes in children. We hypothesized that DNA methylation changes may result from prenatal PFAS exposure and may be linked to offspring cardio-metabolic phenotype. We estimated associations of prenatal PFAS with DNA methylation in umbilical cord blood. We evaluated associations of methylation at selected sites with neonatal cardio-metabolic indicators. Among 583 mother-infant pairs in a prospective cohort, five PFAS were quantified in maternal serum (median 27 wk of gestation). Umbilical cord blood DNA methylation was evaluated using the Illumina HumanMethylation450 array. Differentially methylated positions (DMPs) were evaluated at a false discovery rate and differentially methylated regions (DMRs) were identified using comb-p (Šidák-adjusted ). We estimated associations between methylation at candidate DMPs and DMR sites and the following outcomes: newborn weight, adiposity, and cord blood glucose, insulin, lipids, and leptin. Maternal serum PFAS concentrations were below the median for females in the U.S. general population. Moderate to high pairwise correlations were observed between PFAS concentrations ( ). Methylation at one DMP (cg18587484), annotated to the gene , was associated with perfluorooctanoate (PFOA) at . Comb-p detected between 4 and 15 DMRs for each PFAS. Associated genes, some common across multiple PFAS, were implicated in growth ( ), lipid homeostasis ( , , , ), inflammation and immune activity ( , ), among other functions. There was suggestive evidence that two PFAS-associated loci (cg09093485, cg09637273) were associated with cord blood triglycerides and birth weight, respectively ( ). DNA methylation in umbilical cord blood was associated with maternal serum PFAS concentrations during pregnancy, suggesting potential associations with offspring growth, metabolism, and immune function. Future research should explore whether DNA methylation changes mediate associations between prenatal PFAS exposures and child health outcomes. https://doi.org/10.1289/EHP6888.

BACKGROUND: Prenatal exposure to persistent organic pollutants (POPs) may contribute to the development of childhood obesity and metabolic disor-ders. However, little is known about whether the maternal nutritional status during pregnancy can modulate these associations.OBJECTIVES: The main objective was to characterize the joint associations and interactions between prenatal levels of POPs and nutrients on child-hood obesity.METHODS: We used data from to the Spanish INfancia y Medio Ambiente-Environment and Childhood (INMA) birth cohort, on POPs and nutritional biomarkers measured in maternal blood collected at the first trimester of pregnancy and child anthropometric measurements at 7 years of age. Six organochlorine compounds (OCs) [dichlorodiphenyldichloroethylene, hexachlorobenzene (HCB), 0-hexachlorocyclohexane (0-HCH) and polychlori-nated biphenyls 138, 153, 180] and four per-and polyfluoroalkyl substances (PFAS) were measured. Nutrients included vitamins (D, B12, and folate), polyunsaturated fatty acids (PUFAs), and dietary carotenoids. Two POPs-nutrients mixtures data sets were established: a) OCs, PFAS, vitamins, and carotenoids (n = 660), and b) OCs, PUFAs, and vitamins (n = 558). Joint associations of mixtures on obesity were characterized using Bayesian kernel machine regression (BKMR). Relative importance of biomarkers and two-way interactions were identified using gradient boosting machine, hierarchi-cal group lasso regularization, and BKMR. Interactions were further characterized using multivariate regression models in the multiplicative and addi-tive scale. RESULTS: Forty percent of children had overweight or obesity. We observed a positive overall joint association of both POPs-nutrients mixtures on overweight/obesity risk, with HCB and vitamin B12 the biomarkers contributing the most. Recurrent interactions were found between HCB and vita-min B12 across screening models. Relative risk for a natural log increase of HCB was 1.31 (95% CI: 1.11, 1.54, pInteraction = 0:02) in the tertile 2 of vitamin B12 and in the additive scale a relative excess risk due to interaction of 0.11 (95% CI: 0.02, 0.20) was found. Interaction between perfluorooc-tane sulfonate and 0-cryptoxanthin suggested a protective effect of the antioxidant on overweight/obesity risk.CONCLUSION: These results support that maternal nutritional status may modulate the effect of prenatal exposure to POPs on childhood overweight/ obesity. These findings may help to develop a biological hypothesis for future toxicological studies and to better interpret inconsistent findings in epi-demiological studies. https://doi.org/10.1289/EHP11258

Telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) variations are linked to age-related diseases and are associated with environmental exposure and nutritional status. Limited data, however, exist on the associations with mercury exposure, particularly early in life. We examined the association between prenatal mercury (Hg) exposure and TL and mtDNAcn in 1,145 Seychelles children, characterized by a fish-rich diet. Total mercury (THg) was determined in maternal hair at delivery and cord blood. TL and mtDNAcn were determined relative to a single-copy hemoglobin beta gene in the saliva of 7-y-old children. Linear regression models assessed associations between THg and relative TL (rTL) and relative mtDNAcn (rmtDNAcn) while controlling for maternal and cord serum polyunsaturated fatty acid (PUFA) status and sociodemographic factors. Interactions between THg and child sex, PUFA, and telomerase genotypes were evaluated for rTL and rmtDNAcn. Higher THg concentrations in maternal hair and cord blood were associated with longer rTL [ ; 95% confidence interval (CI): 0.002, 0.016 and ; 95% CI: 0.001, 0.003, respectively], irrespective of sex, PUFA, or telomerase genotypes. Maternal serum n-6 PUFA and n-6/n-3 ratio were associated with shorter [ ; 95% CI: , and ; 95% CI: , , respectively] and PUFA with longer ( ; 95% CI: 0.032, 0.65) rTL. Cord blood n-6 PUFA was associated with longer ( ; 95% CI: 0.050, 0.26) rTL. Further analyses revealed linoleic acid in maternal blood and arachidonic acid in cord blood as the main drivers of the n-6 PUFA associations. No associations were observed for THg and PUFA with rmtDNAcn. Our results indicate that prenatal THg exposure and PUFA status are associated with rTL later in childhood, although not consistently aligned with our initial hypothesis. Subsequent research is needed to confirm this finding, further evaluate the potential confounding of fish intake, and investigate the underlying molecular mechanisms to verify the use of rTL as a true biomarker of THg exposure. https://doi.org/10.1289/EHP14776.

Introduction . Disease recurrence in patients with the early hormone receptor‐positive (HR+), human epidermal growth factor receptor 2‐negative (HER2−) breast tumor subtype is particularly challenging to manage due to its complex and very heterogeneous biological nature. Namely, due to primary and secondary resistance, one‐quarter of patients with early‐stage disease will experience disease recurrence. This variability in the timing of recurrence highlights the need to better identify key biomarkers that could predict therapeutic outcomes and guide personalized treatment strategies for these patients. Mutations in the phosphatidylinositol 4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA) gene are highly prevalent (30–40%) in HR+/HER2− advanced breast cancer. They lead to activation of the PI3K/AKT/mTOR pathway, promoting cell growth, and proliferation, and are associated with poor prognosis in advanced breast cancer. Our aim was to examine the association between and impact of PIK3CA mutation status on disease‐free survival (DFS) in HR+/HER2− early breast cancer patients. Methods . This cohort study was multicentric and retrospective in nature and was conducted at five Croatian institutions from July 2020 to December 2021. The study included initially early and locally advanced operable HR+/HER2− breast cancer patients who were diagnosed with disease recurrence during adjuvant hormonal treatment or within the first six years of follow‐up. Results . A total of 186 patients were included, 40.9% of whom tested positive for the PIK3CA mutation. Primary and adjuvant treatment, particularly adjuvant endocrine treatment, were similar between the two groups. After adjustment for 14 relevant covariates, we found that patients with a positive PIK3CA status and the H1047 PIK3CA mutation had a significantly lower hazard of disease recurrence than patients with no PIK3CA mutation (HR 0.65; 95% CI 0.45; 0.95; p = 0.024; false discovery rate, FDR <10%). Conclusions . This study highlights the potential impact of PIK3CA mutations on disease recurrence during or following adjuvant endocrine therapy and potentially opens the door for further investigation of possibly more personalized treatment strategies.

Background Diagnosing primary progressive aphasia (PPA) is challenging. It requires establishing language impairment as predominant and classifying the PPA variant based on speech and language features. Neuroimaging and biomarker assessments are recommended for greater diagnostic accuracy. However, difficulties in diagnosis are common, particularly in low‐ and middle‐income countries (LMICs), where socio‐economic variables exacerbate these challenges. This work presents the PPA diagnostic roadmap developed at Fleni (Argentina) to address these barriers. Method The PPA diagnostic roadmap combines extensive clinical experience with insights from existing literature, integrating clinical, neuropsychological, neuroimaging, and biomarker data to identify and classify PPA variants. Based on the diagnostic criteria by Gorno‐Tempini et al. (2011), the framework has been adapted to the local population to streamline diagnostic processes and reduce delays in resource‐limited settings. Result Patients undergo an initial assessment by a neurologist, including a neurological‐physical examination and extended anamnesis (Stage 1, see Figure 1). During the same visit, Stage 2 tests are ordered. These include laboratory tests (e.g., blood count, thyroid profile, vitamin B12), a cognitive 3T MRI protocol with resting‐state, and a standard neuropsychological assessment (MoCA, UDS‐3, and socioemotional and functional scales). Stage 2 results enable the neurologist to establish a baseline PPA diagnosis, identifying primary progressive language impairment and obtaining imaging‐based confirmation. Determining the specific PPA variant, however, requires a language‐specific assessment (Stage 3). The PPA protocol at Fleni evaluates key aspects of language and speech to determine the patient's linguistic profile. It includes the MLSE, Token Test, Boston Naming Test, Pyramids and Pharaohs Test, FTLD‐module of UDS‐3, and a speech protocol. Additionally, FDG‐PET, amyloid‐PET biomarkers, and/or genetic counseling and testing are requested (Stage 4). Conclusion Stages 1 and 2 of the diagnostic roadmap constitute possible scenarios considering the region's capabilities. Laboratory tests and MRI are viable, and the standard neuropsychological assessment includes readily available tests in Spanish. However, Stages 3 and, especially, Stage 4 are currently achievable only in specific socio‐economic contexts due to limiting factors (e.g., limited access to language specialists, high costs of specialized studies, lack of healthcare coverage). This roadmap serves as a framework to guide professionals in the region and optimize the diagnostic process.

Cannabis is the most frequently used illicit drug among pregnant women, but data describing the effects of prenatal cannabis exposure and concurrent nicotine and cannabis exposures on neonatal growth are inconsistent. Testing of meconium, the first neonatal feces, offers objective evidence of prenatal cannabis exposure, but the relative ability of meconium testing and maternal self-report to identify affected neonates remains unclear. Eighty-six pregnant women provided detailed self-reports of daily cannabis and tobacco consumption throughout pregnancy. Cannabinoids and tobacco biomarkers were identified in oral fluid samples collected each trimester and quantified in meconium at birth. Cannabis-using women were significantly more likely to also consume tobacco, and smoked similar numbers of cigarettes as non-cannabis-using tobacco smokers. As pregnancy progressed, fewer women smoked cannabis and those who continued to use cannabis reported smoking a smaller number of cannabis joints, but positive maternal oral fluid tests cast doubt on the veracity of some maternal self-reports. More neonates were identified as cannabis exposed by maternal self-report than meconium analysis, because many women quit cannabis use after the first or second trimester; meconium was more likely to be positive if cannabis use continued into the third trimester. Cannabis exposure was associated with decreased birth weight, reduced length, and smaller head circumference, even after data were controlled for tobacco coexposure. Prenatal cannabis exposure was associated with fetal growth reduction. Meconium testing primarily identifies prenatal cannabis exposure occurring in the third trimester of gestation.

Gestational lead (Pb) exposure can adversely affect offspring health through multiple mechanisms, including epigenomic alterations via DNA methylation (5mC) and hydroxymethylation (5hmC), an intermediate in oxidative demethylation. Most current methods do not distinguish between 5mC and 5hmC, limiting insights into their individual roles. Our study sought to identify the association of trimester-specific (T1, T2, T3) prenatal Pb exposure with 5mC and 5hmC levels at multiple cytosine-phosphate-guanine sites within gene regions previously associated with prenatal Pb ( , , , in whole blood leukocytes of children ages 11-18 years of age. Participants from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohorts were selected ( ) for pyrosequencing analysis following oxidative or standard sodium bisulfite treatment. This workflow directly quantifies total methylation ( ) and 5mC only; 5hmC is estimated by subtraction. Participants were 51% male, and mean maternal blood lead levels (BLL) were in Trimester 1 (T1), in Trimester 2 (T2), and in Trimester 3 (T3). In addition, 5hmC levels were calculated for ( , ), (G/C: ; GG: ), ( ), and ( ). Furthermore, 5mC levels were measured in ( ), (heterozygotes: ; GG homozygotes: ), ( ), and ( ). Several significant associations between BLLs and 5mC/5hmC were identified: T1 BLLs with 5mC in ( , ) and 5hmC in ( , ); T2 BLLs with 5mC in ( , ) and 5hmC in ( , ); and T3 BLLs with 5mC in ( , ) and ( , ) and 5hmC in ( , ). 5mC was negatively correlated with gene expression (Pearson , ), whereas 5hmC was positively correlated ( , ). These findings suggest there is variable 5hmC in human whole blood and that prenatal Pb exposure is associated with gene-specific 5mC and 5hmC levels at adolescence, providing evidence to consider 5hmC as a regulatory mechanism that is responsive to environmental exposures. https://doi.org/10.1289/EHP8507.

Mercury is a global pollutant, and prenatal exposure is associated with adverse health effects. To date, no studies have evaluated the association between prenatal mercury exposure and DNA hydroxymethylation, an epigenetic modification important for tissue differentiation and embryonic development. We sought to evaluate the association between prenatal mercury exposure and offspring global DNA methylation and hydroxymethylation at birth and test for persistence of the association in childhood. Within Project Viva, a U.S. prebirth cohort, we examined associations of maternal second trimester red blood cell mercury (RBC-Hg) concentrations with global 5-hydroxymethylcytosine (%-5hmC) and 5-methylcytosine (%-5mC) DNA content in blood collected at birth ( =306), early childhood ( =68; 2.9 to 4.9 y), and midchildhood ( =260; 6.7 to 10.5 y). Median prenatal RBC-Hg concentration was 3.23μg/g [interquartile range (IQR)=3.29]. At birth, median cord blood %-5mC, %-5hmC, and their ratio were 4.95%, 0.22%, and 24.37, respectively. The mean adjusted difference [95% confidence interval (CI)] of blood %-5hmC for a doubling in prenatal RBC-Hg concentration was -0.013% (-0.029, 0.002), -0.031% (-0.056, -0.006), and 0.005% (-0.007, 0.018) at birth, early, and midchildhood, respectively. The corresponding relative adjusted change in the genomic ratio of %-5mC to %-5hmC for a doubling in prenatal RBC-Hg concentration was 4.70% (0.04, 9.58), 22.42% (7.73, 39.11), and 0.73% (-4.18, 5.88) at birth, early, and midchildhood, respectively. No associations were present between prenatal maternal RBC-Hg and %-5mC at any time point. Prenatal mercury exposure was associated with lower %-5hmC genomic content and a corresponding increase in the ratio of %-5mC to %-5hmC in cord blood. This association was persistent in early but not midchildhood blood. Our results demonstrate the potential malleability of epigenetic modifications associated with mercury exposure . https://doi.org/10.1289/EHP1467.

Barker and colleagues' studies on the developmental origins of health and disease demonstrated that fetal undernutrition can lead to poor cardiovascular and metabolic health decades later. Prenatal environmental exposures are also linked to fetal growth restriction and adverse childhood cardiometabolic outcomes; however, few studies have characterized the long-term effects of prenatal exposure to per- and polyfluoroalkyl substances (PFAS). In this issue of Environmental Health Perspectives, Zhang et al. assess relationships between concentrations of six PFAS and their mixture measured during early pregnancy and multiple measures of body composition in late adolescence (age: 16-20 years old) in the Project Viva cohort.2 The authors found that higher concentrations of PFAS, particularly perfluorooctane sulfonate (PFOS), and the PFAS mixture were associated with greater body mass index (BMI), risk of obesity, and accelerated growth in the first 20 years of life. Consistent with the Barker hypothesis, a prior study from the same cohort found that prenatal PFOS concentrations were associated with lower birth weight.