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Melamine, its analogues, and aromatic amines (AAs) were commonly detected in a previous study of pregnant women in the Environmental influences on Child Health Outcomes (ECHO) Cohort. While these chemicals have identified toxicities, little is known about their influences on fetal development. We measured these chemicals in gestational urine samples in 3 ECHO cohort sites to assess associations with birth outcomes (n = 1,231). We estimated beta coefficients and 95% confidence intervals (CIs) using adjusted linear mixed models with continuous dilution-standardized concentrations (log 2 transformed and scaled by interquartile range, IQR) or binary indicators for detection. As secondary analyses, we repeated analyses using categorical outcomes. Forty-one of 45 analytes were detected in at least one sample, with > 95 % detection of melamine, cyanuric acid, ammelide, and aniline. Higher melamine concentration was associated with longer gestational age (β^ per IQR increase of log 2 -transformed: 0.082 [95 % CI: -0.012, 0.177]; 2nd vs 1st tertile: 0.173 [-0.048, 0.394]; 3rd vs 1st tertile: 0.186 [-0.035, 0.407]). Similarly in secondary analyses using categorical outcomes, an IQR increase in log 2 (melamine) was associated with 1.22 [0.99, 1.50] higher odds of post-term (>40 & ≤42 weeks) as compared to full-term (≥38 & ≤40 weeks). Several AAs were associated with birthweight and gestational length, with the direction of associations varying by AA. Some stronger associations were observed in females. Our findings suggest melamine and its analogs and AAs may influence gestational length and birthweight., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: By recent estimates, 40% of children worldwide are exposed to second-hand smoke (SHS), which has been associated with adverse health outcomes. While numerous studies have linked maternal smoking during pregnancy (MSDP) to widespread differences in child blood DNA methylation (DNAm), research specifically examining postnatal SHS exposure remains sparse. To address this gap, we conducted epigenome-wide meta-analyses to identify associations of postnatal SHS and child blood DNAm., Methods: Six cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium (total N = 2,695), with SHS data and child blood DNAm (aged 7-9 years) measured with the Illumina 450K array were included in the meta-analysis. Linear regression models adjusted for covariates were fitted to examine the association between the number of household smokers in postnatal life (0, 1, 2+) and child blood DNAm. Sensitivity models without adjusting for MSDP and restricted to mothers who did not smoke during pregnancy were evaluated., Results: Our analysis revealed significant associations (False Discovery Rate < 0.05) between household postnatal SHS exposure and DNAm at 11 CpGs in exposed children. Nine CpGs were mapped to genes (MYO1G, FAM184B, CTDSPL2, LTBP3, PDE10A, and FIBCD1), while 2 CpGs were located in open sea regions. Notably, all except 2 CpGs (mapped to FIBCD1 and CTDSPL2) have previously been linked to either personal smoking habits or in utero exposure to smoking. The models restricted to non-smoking mothers provided similar results. Importantly, several of these CpGs and their associated genes are implicated in conditions exacerbated by or directly linked to SHS., Conclusions: Our findings highlight the potential biological effects of SHS on blood DNAm. These findings support further research on epigenetic factors mediating deleterious effects of SHS on child health and call for public health policies aimed at reducing exposure, particularly in environments where children are present., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: The purpose of this analysis was to rapidly evaluate the potential costs, cost-effectiveness, and long-term effects of efforts by multisector community partnerships (MCPs) to improve chronic disease outcomes and advance health equity by addressing social determinants of health (SDOH)., Methods: In 2022, the evaluators partnered with 13 MCPs to collect data on start-up and ongoing costs for implementing SDOH interventions and on intervention reach and timing. In 2023, the team used the Prevention Impacts Simulation Model to estimate the longer-term impact of MCPs' efforts over 5-, 10-, and 20-year periods. The team also analyzed costs and cumulative 10- and 20-year cost-effectiveness of the MCPs' SDOH interventions., Results: Over 20 years, SDOH interventions implemented by the 13 MCPs can potentially prevent 970 premature deaths and avert $105 million in medical costs and $408 million in productivity losses. The 20-year cumulative results show potential net costs of $38,300 per quality-adjusted life-year gained from the healthcare sector perspective and indicate potentially reduced costs and improved health outcomes from the societal perspective., Conclusions: These findings can help inform and provide support for future investments in SDOH interventions. With a better understanding of costs needed to start up and implement SDOH interventions, funders, and MCPs can prepare for the resources required to do this work. Findings also suggest promising long-term impacts and potential cost-effectiveness for most MCP-implemented SDOH interventions., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Per- and polyfluoroalkyl substances (PFAS) are fluorinated chemicals linked to adverse pregnancy and birth outcomes. However, the underlying mechanisms, specifically their effects on maternal inflammatory processes, are not well characterized., Objective: We examined associations between prenatal PFAS exposure and repeated measures of inflammatory biomarkers, including C-reactive protein (CRP) and four cytokines [Interleukin-10 (IL-10), IL-1β, IL-6, and tumor necrosis factor-α (TNF-α)]., Methods: We analyzed data from 469 pregnant women in a nested case-control study of preterm birth at Brigham and Women's Hospital in Boston, Massachusetts (2006-2008). We measured nine PFAS in early pregnancy plasma samples (median gestation: 10 weeks), with inflammatory biomarkers measured at median gestations of 10, 18, 26, and 35 weeks. We used linear mixed models for repeated measures and multivariable regression for visit-specific analysis to examine associations between each PFAS and inflammation biomarker, adjusting for maternal demographics, pre-pregnancy BMI, and parity. We examined the effects of PFAS mixture using sum of all PFAS (∑PFAS) and quantile-based g-computation approaches., Results: We observed consistent inverse associations between most PFAS and cytokines, specifically IL-10, IL-6, and TNF-α, in both single pollutant and mixture analyses. For example, an interquartile range increase in perfluorooctanesulfonic acid was associated with -10.87 (95% CI: -19.75, -0.99), -13.91 (95% CI: -24.11, -2.34), and -8.63 (95% CI: -14.51, -2.35) percent change in IL-10, IL-6, and TNF-α levels, respectively. Fetal sex, maternal race, and visit-specific analyses showed associations between most PFAS and cytokines were generally stronger in mid-pregnancy and among women who delivered males or identified as African American., Conclusions: The observed suppression of both regulatory (IL-10) and pro-inflammatory (TNF-α) cytokines suggests that PFAS may alter maternal inflammatory processes or immune functions during pregnancy. Further research is needed to understand the effects of both legacy and newer PFAS on inflammatory pathways and their broader clinical implications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Per- and poly-fluoroalkyl substances (PFAS) are chemicals of concern-they are ubiquitous, persistent, with known and suspected health impacts. Well studied, primary sources of exposure to PFAS are drinking water and food. The presence of PFAS in human tissue of general populations suggests other important exposure sources/pathways. House dust measurements suggest widespread presence of PFAS in residences. Limited studies report paired analyses of PFAS occurrence in indoor media and PFAS concentrations in serum. While paired samples of house dust and blood serum are currently rare, the National Children's Study (NCS) contains paired samples, as well as sociodemographic information, from pregnant people that participated in the study. These archived NCS data and specimens for 104 participants collected between 2009 and 2014 were leveraged and analyzed for 16 commonly measured PFAS. We evaluated PFAS levels in the home, and the relationships between PFAS in dust and serum, and sociodemographic or housing variables. In addition, mechanistic exposure models, and then steady-state serum level models with simple parameters were used to estimate dust contributions of PFAS to serum. The geometric means for the most commonly found PFAS (full names in table 1) in serum were: 4.1 ng/mL for PFOS, 1.1 ng/mL for PFOA, 0.87 ng/mL for PFHxS, 0.16 ng/mL for PFDA. The geometric means of PFAS in dust were: 17 µg/kg for PFOS, 16 µg/kg for PFOA, 9.6 µg/kg for PFDS, 4.5 µg/kg for PFHpA, 4.4 µg/kg for PFNA, 3.9 µg/kg for PFHxS, 3.5 µg/kg for PFDA, 2.3 µg/kg for PFDoA, 2.1 µg/kg for PFUdA. PFOA was significantly correlated in serum and dust as was the sum of all PFAS detected in > 50 % of serum and dust. PFAS in serum was significantly associated with: Higher income, recent renovations, years lived in the home, and educational attainment. PFAS in dust was significantly associated with: Higher participant age, type of home, amount of carpet, educational attainment, higher income, recent renovation, and membership in the military. For some PFAS, 25 % of the overall exposure, on average, is from dust, but for others, 3-4 % is attributed to dust. We were able to identify important associations in PFAS exposure in the homes of pregnant people based on paired serum and dust samples. This built a clearer picture of which PFAS and at what quantities they exist in these homes, how they relate to each other, and how they are tied to sociodemographic and housing factors. Our results demonstrate that exposure to PFAS via house dust may contribute up to 25% of total exposure for adults, highlighting the importance of understanding what drives residential exposures., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

The current opioid epidemic is one of the most profound public health crises facing the United States. Despite that it has been under the spotlight for years, available treatments for opioid use disorder (OUD) and overdose are limited to opioid receptor ligands such as the agonist methadone and the overdose reversing drugs such as naloxone. Vaccines are emerging as an alternative strategy to combat OUD and prevent relapse and overdose. Most vaccine candidates consist of a conjugate structure containing the target opioid attached to an immunogenic carrier protein. However, conjugate vaccines have demonstrated some intrinsic shortfalls, such as fast degradation and poor recognition by immune cells. To overcome these challenges, we proposed a lipid-PLGA hybrid nanoparticle (hNP)-based vaccine against oxycodone (OXY), which is one of the most frequently misused opioid analgesics. The hNP-based OXY vaccine exhibited superior immunogenicity and pharmacokinetic efficacy in comparison to its conjugate vaccine counterpart. Specifically, the hNP-based OXY vaccine formulated with subunit keyhole limpet hemocyanin (sKLH) as the carrier protein and aluminum hydroxide (Alum) as the adjuvant (OXY-sKLH-hNP(Alum)) elicited the most potent OXY-specific antibody response in mice. The induced antibodies efficiently bound with OXY molecules in blood and suppressed their entry into the brain. In a following dose-response study, OXY-sKLH-hNP(Alum) equivalent to 60 μg of sKLH was determined to be the most promising OXY vaccine candidate moving forward. This study provides evidence that hybrid nanoparticle-based vaccines may be superior vaccine candidates than conjugate vaccines and will be beneficial in treating those suffering from OUD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Chenming Zhang, Marco Pravetoni reports financial support was provided by National Institutes of Health. Zhang, Walter, Hu, Pravetoni, and Hamid have filed patent #VTIP 23–084 pending to Virginia Tech. Other authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: The current literature lacks a clear evaluation of the effectiveness of Cognitive Behavioral Therapy for Insomnia (CBT-I) on acute insomnia. Our study aims to address this issue through a systematic review and meta-analysis of Randomized Controlled Trials (RCTs)., Method: We systematically searched PubMed, Embase, and Cochrane Library in April 2024 for RCTs comparing patients with clinically significant insomnia symptoms for less than 6 months (ie, acute insomnia) assigned to 1-6 weeks of CBT-I versus no CBT-I., Results: We included four RCTs comprising 327 patients with acute insomnia, of whom 162 (49.5 %) were randomized to CBT-I. CBT-I significantly reduced the Insomnia Severity Index score (MD -5.28; 95 % CI -6.01, -4.56; p < 0.00001; I 2  = 18 %), the incidence of chronic insomnia (MD 0.50; 95 % CI 0.35, 0.70; p < 0.0001; I 2  = 0 %), and the sleep latency (MD -11.04; 95 % CI -18.46, -3.61; p = 0.004; I 2  = 0 %)., Conclusion: These findings provide preliminary evidence that minimal CBT-I may be a feasible and effective preventive measure against chronic insomnia. However, future RCTs and effectiveness trials are necessary to validate, with greater statistical power, the hypothesis that CBT-I can prevent transition from acute to chronic insomnia, given the limited number of studies in our meta-analysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cytochromes P450 can metabolize endogenous fatty acids, such as arachidonic acid, to bioactive lipids such as epoxyeicosatrienoic acids (EETs) that have beneficial effects. EETs protect hearts against ischemic damage, heart failure or fibrosis; however, their effects are limited by hydrolysis to less active dihydroxy oxylipins by soluble epoxide hydrolase (sEH), encoded by the epoxide hydrolase 2 gene (EPHX2, EC 3.3.2.10). Pharmacological inhibition or genetic disruption of sEH/EPHX2 have been widely studied for their impact on cardiovascular diseases. Less well studied is the role of increased EPHX2 expression, which occurs in a substantial human population that carries the EPHX2 K55R polymorphism or after induction by inflammatory stimuli. Herein, we developed a mouse model with cardiomyocyte-selective expression of human EPHX2 (Myh6-EPHX2) that has significantly increased total EPHX2 expression and activity. Myh6-EPHX2 hearts exhibit strong, cardiomyocyte-selective expression of EPHX2. EPHX2 mRNA, protein, and epoxide hydrolysis measurements suggest that Myh6-EPHX2 hearts have 12-fold increase in epoxide hydrolase activity relative to wild type (WT) hearts. This increased activity significantly decreased epoxide:diol ratios in vivo. Isolated, perfused Myh6-EPHX2 hearts were not significantly different from WT hearts in basal parameters of cardiac function; however, compared to WT hearts, Myh6-EPHX2 hearts demonstrated reduced recovery of heart contractile function after ischemia and reperfusion (I/R). This impaired recovery after I/R correlated with reduced activation of PI3K/AKT and GSK3β signaling pathways in Myh6-EPHX2 hearts compared to WT hearts. In summary, the Myh6-EPHX2 mouse line represents a novel model of cardiomyocyte-selective overexpression of EPHX2 that has detrimental effects on cardiac function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Wildfires in western US forests increased over the last two decades, resulting in elevated solid and nutrient loadings to streams, and occasionally threatening drinking water supplies. We demonstrated that a linked LANDIS (LANDscape DIsturbance and Succession)-VELMA (Visualizing Ecosystem Land Management Assessments) modeling approach can simulate wildland fire effects on water quality using the 2002 Colorado Hayman Fire. Utilizing LANDIS-II's forest landscape model to simulate forest composition and VELMA's eco-hydrologic model to simulate pre- and post-fire water quantity and quality, the best calibration performance yielded a Nash-Sutcliffe Efficiency (NSE) of 0.621 during 2000-2006 (most optimal annual - 0.921) in comparison to North American Land Data Assimilation System (NLDAS) runoff. Pre-fire modeled runoff, nitrate, and surface water temperature (SWT) correlated with observations. Simulated post-fire runoff (229%) and SWT (20.6%) were elevated relative to pre-fire, with nitrate concentrations 34 times greater than the aquatic life threshold (0.01 mg N/L)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Poor sleep quality is a widespread concern. While the influence of particle exposure on sleep disturbances has received considerable attention, research exploring other dimensions of sleep quality and the chemical components of the particles remains limited. We employed a marginal structural model to explore the association of long-term exposure to PM 2.5 and its chemical components with poor sleep quality. The odds ratio (95 % CI) for poor sleep quality was 1.335 (1.292-1.378), 1.097 (1.080-1.113), 1.137 (1.100-1.174), 1.197 (1.156-1.240), and 1.124 (1.107-1.140) per IQR increase in the concentration of PM 2.5 , SO 4 2- , NO 3 - , NH 4 + , and BC, respectively. The score (and 95 % CI) of sleep latency, use of sleep medication, habitual sleep efficiency, subjective sleep quality, and daytime dysfunction were affected by PM 2.5 , with an increase of 0.059 (0.050-0.069), 0.054 (0.049-0.059), 0.011 (0.008-0.014), 0.011 (0.005-0.018), and 0.026 (0.018-0.034) per IQR increase in PM 2.5 concentrations, respectively. This study supports the association of long-term exposure to PM 2.5 and its chemical components with poor sleep quality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The potential for residential greenness to improve cardiovascular health through both physical and psychological mechanisms is well recognized. However, evidence from rapidly urbanizing developing countries and cohort-based causal inference approaches, remains limited. We aim to examine the effect of residential greenness and time to cardiovascular mortality in South China., Methods: We utilized data from a community-based population survey involving 748,209 participants at baseline from 2009 to 2015, followed up until 2020. Residential greenness exposure was assessed by the annual Normalized Difference Vegetation Index (NDVI) in the 500 m radius of each participant's residence. We used time-varying proportional hazard Cox models coupled with inverse probability weighting to fit marginal structural models and obtain hazard ratios (HRs) for cardiovascular disease (CVD) mortality after adjusting for confounders. Multiple effect modifiers on both additive and multiplicative scales were further explored., Results: A total of 15,139 CVD-related deaths were identified during a median of 7.9 years of follow-up. A protective effect was found between higher greenness exposure and reduced CVD mortality, with a 9.3 % lower rate of total CVD mortality (HR 0.907, 95 % CI 0.859-0.957) based on a 0.1 increase in annual average NDVI. Demographic (age, marital status) and lifestyle factors (smoking, drinking status) were found to modify the association between residential greenness and CVD mortality (all P interaction values < 0.05 or 95 %CI for RERI excluded the value 0). Notably, this effect was more pronounced among older adults, married, and individuals having healthier lifestyles, indicating a greater benefit from greenness for these subgroups., Conclusions: Our findings support a causal link between increased residential greenness exposure and a reduced risk of CVD mortality in South China with marked heterogenous effects, which has public health implications for cultivating greener urban environments to mitigate the impact of CVD within the context of rapid urbanization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Environmental phenols are endocrine disrupting chemicals hypothesized to affect early life development. Previous research examining the effects of phenols on fetal growth has focused primarily on associations with measures of size at delivery. Few have included ultrasound measures to examine growth across pregnancy., Objective: Investigate associations between prenatal exposure to phenols and ultrasound and delivery measures of fetal growth., Methods: Using the LIFECODES Fetal Growth Study (n = 900), a case-cohort including 248 small-for-gestational-age, 240 large-for-gestational age, and 412 appropriate-for-gestational-age births, we estimated prenatal exposure to 12 phenols using three urine samples collected during pregnancy (median 10, 24, and 35 weeks gestation). We abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-average phenol biomarker concentrations and repeated ultrasound measures of fetal growth using linear mixed effects models and associations with birthweight using linear regression models. We also used logistic regression models to estimate associations with having a small- or large-for-gestational birth., Results: We observed positive associations between 2,4-dichlorophenol, benzophenone-3, and triclosan (TCS) and multiple ultrasound measures of fetal growth. For example, TCS was associated with a 0.09 (95 % CI: 0.01, 0.18) higher estimated fetal weight z-score longitudinally across pregnancy. This effect size corresponds to a 21 g increase in estimated fetal weight at 30 weeks gestation. Associations with delivery measures of growth were attenuated, but TCS remained positively associated with birthweight z-scores (mean difference: 0.13, 95 % CI: 0.02, 0.25). Conversely, methylparaben was associated with higher odds of a small-for-gestational age birth (odds ratio: 1.45, 95 % CI: 1.06, 1.98)., Discussion: We observed associations between some biomarkers of phenol exposure and ultrasound measures of fetal growth, though associations at the time of delivery were attenuated. These findings are consistent with hypotheses that phenols have the potential to affect growth during the prenatal period., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Known as "forever chemicals", per- and polyfluoroalkyl substances (PFAS) are synthetic compounds used in consumer goods but pose significant public health concerns, including disruption of the thyroid system. As thyroid hormones (THs) are required for normal brain development, PFAS may also be developmental neurotoxicants. However, this is not well understood. Here we examine the endocrine and neurodevelopmental consequences of perfluorohexane sulfonate (PFHxS) exposure in pregnant, lactating, and developing rats, and compare its effects to an anti-thyroid pharmaceutical (propylthiouracil, PTU) that induces thyroid-mediated developmental neurotoxicity. We show that PFHxS dramatically reduces maternal serum thyroxine (T4), nearly equivalently to PTU (-55 and -51%, respectively). However, only PTU increases thyroid stimulating hormone. The lactational transfer of PFHxS is significant and reduces pup serum T4 across the postnatal period. Surprisingly, brain THs are only minimally decreased by PFHxS, whereas PTU drastically diminishes them. Evaluation of brain TH action by phenotyping, RNA-Sequencing, and quantification of radial glia cell morphology supports that PTU interrupts TH signaling while PFHxS has limited to no effect. These data show that PFHxS induces abnormal serum TH profiles; however, there were no indications of hypothyroidism in the postnatal brain. We suggest the stark differences between the neurodevelopmental effects of PFHxS and a typical antithyroid agent may be due to its interaction with TH distributing proteins like transthyretin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: The global coronavirus 2019 (COVID-19) pandemic began in early 2020, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In mid-2020 the CIAO (Modelling the Pathogenesis of COVID-19 Using the Adverse Outcome Pathway Framework) project was established, bringing together over 75 interdisciplinary scientists worldwide to collaboratively investigate the underlying biological mechanisms of COVID-19 and consolidate the data using the Adverse Outcome Pathway (AOP) Framework. Neurological symptoms such as anosmia and encephalitis have been frequently reported to be associated with infection with SARS-CoV-2., Objective: Within CIAO, a working group was formed to conduct a systematic scoping review of COVID-19 and its related neurological symptoms to determine which key events and modulating factors are most commonly reported and to identify knowledge gaps., Design: LitCOVID was used to retrieve 86,075 papers of which 10,244 contained relevant keywords. After title and abstract screening, 2,328 remained and their full texts were reviewed based on predefined inclusion and exclusion criteria. 991 studies fulfilled the inclusion criteria and were retrieved to conduct knowledge synthesis., Results: The majority of publications reported human observational studies. Early key events were less likely to be reported compared to middle and late key events/adverse outcomes. The majority of modulating factors described related to age or sex. Less recognised COVID-19 associated AO or neurological effects of COVID-19 were also identified including multiple sclerosis/demyelination, neurodegeneration/cognitive effects and peripheral neuronal effects., Conclusion: There were many methodological and reporting issues noted in the reviewed studies. In particular, publication abstracts would benefit from clearer reporting of the methods and endpoints used and the key findings, to ensure relevant papers are included when systematic reviews are conducted. The information extracted from the scoping review may be useful in understanding the mechanisms of neurological effects of COVID-19 and to further develop or support existing AOPs linking COVID-19 and its neurological key events and adverse outcomes. Further evaluation of the less recognised COVID-19 effects is needed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Ishita Virmani reports financial support was provided by a. RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic., (Copyright © 2024. Published by Elsevier B.V.)

The US EPA's Toxicity Forecaster (ToxCast) is a suite of high-throughput in vitro assays to screen environmental toxicants and predict potential toxicity of uncharacterized chemicals. This work examines the relevance of ToxCast assay intended gene targets to putative molecular initiating events (MIEs) of neurotoxicants. This effort is needed as there is growing interest in the regulatory and scientific communities about developing new approach methodologies (NAMs) to screen large numbers of chemicals for neurotoxicity and developmental neurotoxicity. Assay gene function (GeneCards, NCBI-PUBMED) was used to categorize gene target neural relevance (1 = neural, 2 = neural development, 3 = general cellular process, 3 A = cellular process critical during neural development, 4 = unlikely significance). Of 481 unique gene targets, 80 = category 1 (16.6 %); 16 = category 2 (3.3 %); 303 = category 3 (63.0 %); 97 = category 3 A (20.2 %); 82 = category 4 (17.0 %). A representative list of neurotoxicants (548) was researched (ex. PUBMED, PubChem) for neurotoxicity associated MIEs/Key Events (KEs). MIEs were identified for 375 compounds, whereas only KEs for 173. ToxCast gene targets associated with MIEs were primarily neurotransmitter (ex. dopaminergic, GABA)receptors and ion channels (calcium, sodium, potassium). Conversely, numerous MIEs associated with neurotoxicity were absent. Oxidative stress (OS) mechanisms were 79.1 % of KEs. In summary, 40 % of ToxCast assay gene targets are relevant to neurotoxicity mechanisms. Additional receptor and ion channel subtypes and increased OS pathway coverage are identified for potential future assay inclusion to provide more complete coverage of neural and developmental neural targets in assessing neurotoxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Synthetic cannabinoid receptor agonists (SCRAs) remain one the largest classes of new psychoactive substances, and are increasingly associated with severe adverse effects and death compared to the phytocannabinoid Δ 9 -tetrahydrocannabinol (THC). In the attempt to circumvent the rapid emergence of novel SCRAs, several nations have implemented 'generic' legislations, or 'class-wide' bans based on common structural scaffolds. However, this has only encouraged the incorporation of new chemical entities, including distinct core and linker structures, for which there is a dearth of pharmacological data. The current study evaluated five emergent OXIZID SCRAs for affinity and functional activity at the cannabinoid CB 1 receptor (CB 1 ) in HEK 293 cells, as well as pharmacological equivalence with THC in drug discrimination in mice. All OXIZID compounds behaved as agonists in Gα i protein activation and β-arrestin 2 translocation assays, possessing low micromolar affinity at CB 1 . All ligands also substituted for THC in drug discrimination, where potencies broadly correlated with in vitro activity, with the methylcyclohexane analogue BZO-CHMOXIZID being the most potent. Notably, MDA-19 (BZO-HEXOXIZID) exhibited partial efficacy in vitro, generating an activity profile most similar to that of THC, and partial substitution in vivo. Overall, the examined OXIZIDs were comparatively less potent and efficacious than previous generations of SCRAs. Further toxicological data will elucidate whether the moderate cannabimimetic activity for this series of SCRAs will translate to severe adverse health effects as seen with previous generations of SCRAs., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate associations between perceived childhood neighborhood safety and sleep over the life course., Methods: Among a cohort of 1693 Black/African American women aged 23-35 years at enrollment (2010-2012), participants recalled neighborhood safety (safe vs. unsafe) when they were 5, 10, and 15 years old. Participants' mothers/caregivers and participants reported sleep-related health behaviors at age 5. We used ordinal logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for sleep-related health behaviors (i.e., rarely/never or sometimes vs. mostly/always going to bed by 8:00 p.m., bed in a quiet room, bed in a dimly lit or unlit room), separately. Adulthood sleep duration and insomnia symptoms were reported at enrollment and over three follow-up periods. We applied generalized estimating equations to log binomial regression models to estimate relative risks (RR) for adulthood sleep characteristics., Results and Conclusions: Four percent of participants reported an unsafe neighborhood at age 5 years, only, and 12% reported an unsafe neighborhood at all ages. Participants in perceived unsafe vs. safe neighborhoods at age 5 had higher odds of poor sleep-related health behaviors (e.g., rarely/never or sometimes going to bed in a quiet room: OR = 1.73 [1.27-2.35]). Participants in perceived unsafe vs. safe neighborhoods throughout childhood had higher risk of short sleep (RR = 1.10 [1.02-1.18]) and insomnia symptoms (RR = 1.07 [1.00-1.15]) during adulthood after adjustment for life course socioeconomic characteristics and adulthood health behaviors and characteristics. Perceived unsafe childhood neighborhood was associated with poorer sleep over the life course and may serve as an early intervention target., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lauren Hale reports a relationship with Harvard Medical School that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Lauren Hale reports a relationship with University of Miami that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Lauren Hale reports a relationship with Auburn University that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Lauren Hale reports a relationship with New York University that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Lauren Hale reports a relationship with Columbia University that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Lauren Hale reports a relationship with Princeton University Health Services that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Lauren Hale reports a relationship with National Sleep Foundation that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Lauren Hale reports a relationship with Idorsia Pharmaceuticals Ltd that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Lauren Hale ended her term as Editor-in-Chief of Sleep Health in 2020. Lauren Hale has not received any funding for work on this manuscript. The remaining authors report no conflicts of interest in this work., (Published by Elsevier B.V.)

Growth-blocking peptide (GBP), an insect cytokine, was first found in armyworm Mythimna separata. A functional analogue of GBP, stress-responsive peptide (SRP), was also identified in the same species. SRP gene expression has been demonstrated to be enhanced by GBP, indicating that both cytokines are organized within a hierarchical regulatory network. Although GBP1 (CG15917) and GBP2 (CG11395) have been identified in Drosophila melanogaster, immunological functions have only been characterized for GBP1. It is expected that the biological responses of two structurally similar peptides should be coordinated, but there is little information on this topic. Here, we demonstrate that GBP2 replicates the GBP1-mediated cellular immune response from Drosophila S2 cells. Moreover, the GBP2-induced response was silenced by pre-treatment with dsRNA targeting the GBP receptor gene, Mthl10. Furthermore, treatment of S2 cells with GBP2 enhanced GBP1 expression levels, but GBP1 did not affect GBP2 expression. GBP2 derived enhancement of GBP1 expression was not observed in the presence of GBP1, indicating that GBP2 is an upstream expressional regulator of a GBP1/GBP2 cytokine network. GBP2-induced enhancement of GBP1 expression was not observed in Mthl10 knockdown cells. Enhancement of GBP2 expression was observed in both Drosophila larvae and S2 cells under heat stress conditions; expressional enhancement of both GBP1 and GBP2 was eliminated in Mthl10 knockdown cells and larvae. Finally, Ca 2+ mobilization assay in GCaMP3-expressing S2 cells demonstrated that GBP2 mobilizes Ca 2+ upstream of Mthl10. Our finding revealed that Drosophila GBP1 and GBP2 control immune responses as well as their own expression levels through a hierarchical cytokine network, indicating that Drosophila GBP1/GBP2 system can be a simple model that is useful to investigate the detailed regulatory mechanism of related cytokine complexes., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Observational epidemiologic studies provide critical data for the evaluation of the potential effects of environmental, occupational and behavioural exposures on human health. Systematic reviews of these studies play a key role in informing policy and practice. Systematic reviews should incorporate assessments of the risk of bias in results of the included studies., Objective: To develop a new tool, Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS-E) to assess risk of bias in estimates from cohort studies of the causal effect of an exposure on an outcome., Methods and Results: ROBINS-E was developed by a large group of researchers from diverse research and public health disciplines through a series of working groups, in-person meetings and pilot testing phases. The tool aims to assess the risk of bias in a specific result (exposure effect estimate) from an individual observational study that examines the effect of an exposure on an outcome. A series of preliminary considerations informs the core ROBINS-E assessment, including details of the result being assessed and the causal effect being estimated. The assessment addresses bias within seven domains, through a series of 'signalling questions'. Domain-level judgements about risk of bias are derived from the answers to these questions, then combined to produce an overall risk of bias judgement for the result, together with judgements about the direction of bias., Conclusion: ROBINS-E provides a standardized framework for examining potential biases in results from cohort studies. Future work will produce variants of the tool for other epidemiologic study designs (e.g. case-control studies). We believe that ROBINS-E represents an important development in the integration of exposure assessment, evidence synthesis and causal inference., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Judy LaKind reports receipt of support for research on systematic reviews and assessments of review processes from NCASI, the American Petroleum Institute and the National Institute of Environmental Health Sciences and served on the GRADE panel for assessing the certainty of modeled evidence. Annette O’Connor reports funding from the US National Pork Board and the United Soybean Board that includes: consulting or advisory. Jelena Savović reports a relationship with JEMMDx Limited that includes: consulting or advisory. Jelena Savović reports a relationship with Core Models Limited that includes: teaching. Kate Tilling reports a relationship with CHDI Foundation that includes: consulting or advisory. Kate Tilling reports a relationship with UK MHRA that includes: paid expert testimony. Jos Verbeek reports a relationship with World Health Organization that includes: consulting or advisory. The remaining authors report no financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Parkinson's disease (PD) is the second most common neurodegenerative disorder, yet treatment options are limited. Clozapine (CLZ), an antipsychotic used for schizophrenia, has potential as a PD treatment. CLZ and its metabolite, Clozapine-N-Oxide (CNO), show neuroprotective effects on dopaminergic neurons, with mechanisms needing further investigation. This study aimed to confirm the neuroprotective effects of CLZ and CNO in a rotenone-induced mouse model and further explore the underlying mechanisms of CNO-afforded protection. Gait pattern and rotarod activity evaluations showed motor impairments in rotenone-exposed mice, with CLZ or CNO administration ameliorating behavioral deficits. Cell counts and biochemical analysis demonstrated CLZ and CNO's effectiveness in reducing rotenone-induced neurodegeneration of dopaminergic neurons in the nigrostriatal system in mice. Mechanistic investigations revealed that CNO suppressed rotenone-induced ferroptosis of dopaminergic neurons by rectifying iron imbalances, curtailing lipid peroxidation, and mitigating mitochondrial morphological changes. CNO also reversed autolysosome and ferritinophagic activation in rotenone-exposed mice. SH-SY5Y cell cultures validated these findings, indicating ferritinophage involvement, where CNO-afforded protection was diminished by ferritinophagy enhancers. Furthermore, knockdown of NCOA4, a crucial cargo receptor for ferritin degradation in ferritinophagy, hampered rotenone-induced ferroptosis and NCOA4 overexpression countered the anti-ferroptotic effects of CNO. Whereas, iron-chelating agents and ferroptosis enhancers had no effect on the anti-ferritinophagic effects of CNO in rotenone-treated cells. In summary, CNO shielded dopaminergic neurons in the rotenone-induced PD model by modulating NCOA4-mediated ferritinophagy, highlighting a potential therapeutic pathway for PD treatment. This research provided insights into the role of NCOA4 in ferroptosis and suggested new approaches for PD therapy., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Synthetic chemicals are increasingly being recognized for potential independent contributions to preterm birth (PTB) and low birth weight (LBW). Bisphenols, parabens, and triclosan are consumer product chemicals that act via similar mechanisms including estrogen, androgen, and thyroid disruption and oxidative stress. Multiple cohort studies have endeavored to examine effects on birth outcomes, and systematic reviews have been limited due to measurement of 1-2 spot samples during pregnancy and limited diversity of populations., Objective: To study the effects of prenatal phenols and parabens on birth size and gestational age (GA) in 3,619 mother-infant pairs from 11 cohorts in the NIH Environmental influences on Child Health Outcomes program., Results: While many associations were modest and statistically imprecise, a 1-unit increase in log 10 pregnancy averaged concentration of benzophenone-3 and methylparaben were associated with decreases in birthweight, birthweight adjusted for gestational age and SGA. Increases in the odds of being SGA were 29% (95% CI: 5%, 58%) and 32% (95% CI: 3%, 70%), respectively. Bisphenol S in third trimester was also associated with SGA (OR 1.52, 95% CI 1.08, 2.13). Associations of benzophenone-3 and methylparaben with PTB and LBW were null. In addition, a 1-unit increase in log 10 pregnancy averaged concentration of 2,4-dichlorophenol was associated with 43% lower (95% CI: -67%, -2%) odds of low birthweight; the direction of effect was the same for the highly correlated 2,5-dichlorophenol, but with a smaller magnitude (-29%, 95% CI: -53%, 8%)., Discussion: In a large and diverse sample generally representative of the United States, benzophenone-3 and methylparaben were associated with lower birthweight as well as birthweight adjusted for gestational age and higher odds of SGA, while 2,4-dichlorophenol. These associations with smaller size at birth are concerning in light of the known consequences of intrauterine growth restriction for multiple important health outcomes emerging later in life., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Communities across the world are facing extreme events, such as excessive heat, droughts, floods, and wildfires. In the presence of contaminated sites and waste management facilities, communities must consider the impacts of potential releases from these sites due to such events. Impacts of extreme events on sites and consequently on surrounding, often disadvantaged communities result from complex interactions between natural, physical, and social factors. A conceptual framework was developed to identify and provide a shared understanding of key vulnerabilities and pathways that transcend disciplines. A transparent and replicable method was developed to create mappable indicators that represent contaminated sites, waste facilities, contaminant transport via air and water, and population sensitivities. This method can be applied as a screening step to assist states and local communities in prioritizing targeted strategies and resources and determining where in-depth assessments are needed. These indicators can facilitate communication with a broad audience more easily than complex modeling approaches or aggregated indices. Case study results demonstrate the importance of considering indicators in conjunction with each other. The indicator method was developed together with U.S.-based partners, but can be adapted for other countries seeking to understand the potential impacts of extreme events on contaminated sites and communities.

Background: Personal care products (PCPs), a source of endocrine-disrupting chemical exposure, may be associated with the risk of hormone-sensitive cancers. Few studies have investigated associations for PCP use with the incidence of hormone-sensitive cancers or considered the joint effect of multiple correlated PCPs. We examined associations between frequently used, or "everyday", PCPs and incident cancers of the breast, ovary, and uterus with a fucus on the joint effect of multiple product exposure., Methods: Sister Study participants (n=49 899) self-reported frequency of use in the year before enrollment (2003-2009) for 41 PCPs. Using five-level frequency categories based on questionnaire options, hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the associations between multiple PCP use and incident breast, ovarian, and uterine cancer using quantile-based g-computation with Cox proportional hazards regression as the underlying model. Multiple PCP use was examined using groupings (beauty, hygiene, and skincare products) determined by both a priori knowledge and Spearman correlation coefficients for co-occurring product use. Associations between individual PCPs and the three cancers were also examined using Cox proportional hazards models coupling with Benjamini-Hochberg procedure for multiple comparisons., Results: Over an average of 11.6 years, 4 226 breast, 277 ovarian, and 403 uterine cancer cases were identified. Positive associations were observed between the hygiene mixture and ovarian cancer (HR=1.35, 95%CI=1.00, 1.83) and the beauty mixture with postmenopausal breast cancer (HR=1.08, 95%CI=1.01, 1.16). Additionally, we observed an inverse association between the skincare mixture and breast cancer (HR=0.91, 95%CI=0.83, 0.99). No significant associations were observed for individual products after corrected for multiple comparison., Conclusions: Findings from this multi-product, joint-effect approach contribute to the growing body of evidence for associations between PCPs and breast cancer and provides novel information on ovarian and uterine cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

There is a need to assess compounds reliably and quickly for neurotoxicity (NT) and developmental neurotoxicity (DNT). Adverse outcome pathways (AOPs) enable the mapping of molecular events to an apical endpoint in a chemical agnostic manner and have begun to be applied in NT and DNT testing frameworks. We assessed the status of NT/DNT AOPs in the AOP-Wiki (ca. 2/1/23; https://aopwiki.org/), to characterize the state of AOP development, identify strengths and knowledge gaps, elucidate areas for improvement, and describe areas for future focus. AOPs in the Wiki database were assessed for inclusion of NT/DNT molecular events and endpoints, AOP development and endorsement, as well as the linkages of key neurodevelopmental processes with in vitro new approach methods (NAMs). This review found that 41 AOPs have been proposed detailing NT/DNT, of which eight were endorsed by working parties in OECD. Further, this review determined that learning and memory is included as an adverse outcome in eight NT/DNT AOPS, often without distinction regarding the varying forms of learning and memory, regional specification, temporal dynamics, or acquisition mechanisms involved. There is also an overlap with key events (KEs) and in vitro NAMs, which synaptogenesis appeared as a common process. Overall, progress on NT/DNT AOPs could be expanded, adding in modes of action that are missing, improvement in defining apical endpoints, as well as utilizing NAMs further to develop AOPs and identify gaps in current knowledge., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Rationale: Pulmonary hypertension (PH) is a multifactorial disease with a poor prognosis and inadequate treatment options. We found two-fold higher expression of the orphan G-Protein Coupled Receptor 75 (GPR75) in leukocytes and pulmonary arterial smooth muscle cells from idiopathic PH patients and from lungs of C57BL/6 mice exposed to hypoxia. We therefore postulated that GPR75 signaling is critical to the pathogenesis of PH., Methods: To test this hypothesis, we exposed global (Gpr75 -/- ) and endothelial cell (EC) GPR75 knockout (EC-Gpr75 -/- ) mice and wild-type (control) mice to hypoxia (10% oxygen) or normal atmospheric oxygen for 5 weeks. We then recorded echocardiograms and performed right heart catheterizations., Results: Chronic hypoxia increased right ventricular systolic and diastolic pressures in wild-type mice but not Gpr75 -/- or EC-Gpr75 -/- mice. In situ hybridization and qPCR results revealed that Gpr75 expression was increased in the alveoli, airways and pulmonary arteries of mice exposed to hypoxia. In addition, levels of chemokine (CC motif) ligand 5 (CCL5), a low affinity ligand of GPR75, were increased in the lungs of wild-type, but not Gpr75 -/- , mice exposed to hypoxia, and CCL5 enhanced hypoxia-induced contraction of intra-lobar pulmonary arteries in a GPR75-dependent manner. Gpr75 knockout also increased pulmonary cAMP levels and decreased contraction of intra-lobar pulmonary arteries evoked by endothelin-1 or U46619 in cAMP-protein kinase A-dependent manner., Conclusion: These results suggest GPR75 has a significant role in the development of hypoxia-induced PH., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: DNA methylation-based measures of biological aging have been associated with air pollution and may link pollutant exposures to aging-related health outcomes. However, evidence is inconsistent and there is little information for Black women., Objective: We examined associations of ambient particulate matter <2.5 μm and <10 μm in diameter (PM 2.5 and PM 10 ) and nitrogen dioxide (NO 2 ) with DNA methylation, including epigenetic aging and individual CpG sites, and evaluated whether associations differ between Black and non-Hispanic White (NHW) women., Methods: Validated models were used to estimate annual average outdoor residential exposure to PM 2.5 , PM 10 , and NO 2 in a sample of self-identified Black (n=633) and NHW (n=3493) women residing in the contiguous US. We used sampling-weighted generalized linear regression to examine the effects of pollutants on six epigenetic aging measures (primary: DunedinPACE, GrimAgeAccel, and PhenoAgeAccel; secondary: Horvath intrinsic epigenetic age acceleration [EAA], Hannum extrinsic EAA, and skin & blood EAA) and epigenome-wide associations for individual CpG sites. Wald tests of nested models with and without interaction terms were used to examine effect measure modification by race/ethnicity., Results: Black participants had higher median air pollution exposure than NHW participants. GrimAgeAccel was associated with both PM 10 and NO 2 among Black participants, (Q4 versus Q1, PM 10 : β=1.09, 95% CI: 0.16-2.03; NO 2 : β=1.01, 95% CI 0.08-1.94) but not NHW participants (p-for-heterogeneity: PM 10 =0.10, NO 2 =0.20). In Black participants, we also observed a monotonic exposure-response relationship between NO 2 and DunedinPACE (Q4 versus Q1, NO 2 : β=0.029, 95% CI: 0.004-0.055; p-for-trend=0.03), which was not observed in NHW participants (p-for-heterogeneity=0.09). In the EWAS, pollutants were significantly associated with differential methylation at 19 CpG sites in Black women and one in NHW women., Conclusions: In a US-wide cohort study, our findings suggest that air pollution is associated with DNA methylation alterations consistent with higher epigenetic aging among Black, but not NHW, women., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Self-reported shingles was associated with history of high pesticide exposure events (HPEE) in licensed pesticide applicators aged >60 years in the Agricultural Health Study (AHS). In the current study, using AHS-linked Medicare claims data, we examined incident shingles in relation to pesticide-related illness and pesticide poisoning, as well as HPEE., Methods: We studied 22,753 licensed private pesticide applicators (97% white males, enrolled in the AHS 1993-97), aged ≥66 years with >12 consecutive months of Medicare fee-for-service hospital and outpatient coverage between 1999 and 2016. Incident shingles was identified based on having ≥1 shingles claim(s) after 12 months without claims. At AHS enrollment, participants were asked if they ever sought medical care or were hospitalized for pesticide-related illness, and a supplemental questionnaire (completed by 51%) asked about HPEE and poisoning. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression, adjusted for age, sex, race, state, and education., Results: Over 192,053 person-years (PY), 2396 applicators were diagnosed with shingles (10.5%; age-standardized rate, 13.6 cases per 1,000PY), with higher rates among those reporting hospitalization for pesticide-related illness, pesticide poisoning, and HPEE (23.2, 22.5, and 16.6 per 1,000PY, respectively). In adjusted models, shingles was associated with hospitalization for pesticide-related illness (HR 1.69; 1.18, 2.39), poisoning (1.49; 1.08, 1.46), and HPEE (1.23; 95% CI = 1.03, 1.46), especially HPEE plus medical care/poisoning (1.78; 1.30, 2.43)., Conclusion: These novel findings suggest that acute, high-level, and clinically impactful pesticide exposures may increase risk of shingles in subsequent years to decades following exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: Limited evidence suggests that antimony induces vascular inflammation and oxidative stress and may play a role in cardiovascular disease (CVD) risk. However, few studies have examined whether environmental antimony from sources other than tobacco smoking is related with CVD risk. The general population may be exposed through air, drinking water, and food that contains antimony from natural and anthropogenic sources, such as mining, coal combustion, and manufacturing., Objectives: To examine the association of urine antimony with incident acute myocardial infarction (AMI), heart failure, and stroke among people who never smoked tobacco., Methods: Between 1993 and 1997, the Danish Diet, Cancer and Health (DCH) cohort enrolled participants (ages 50-64 years), including n = 19,394 participants who reported never smoking at baseline. Among these never smokers, we identified incident cases of AMI (N = 809), heart failure (N = 958), and stroke (N = 534) using the Danish National Patient Registry. We also randomly selected a subcohort of 600 men and 600 women. We quantified urine antimony concentrations in samples provided at enrollment. We used modified Cox proportional hazards models to estimate adjusted hazard ratios (HR) for each incident CVD outcome in relation to urine antimony, statistically adjusted for creatinine. We used a separate prospective cohort, the San Luis Valley Diabetes Study (SLVDS), to replicate these results., Results: In the DCH cohort, urine antimony concentrations were positively associated with rates of AMI and heart failure (HR = 1.52; 95%CI = 1.12, 2.08 and HR = 1.58; 95% CI = 1.15, 2.18, respectively, comparing participants in the highest (>0.09 µg/L) with the lowest quartile (<0.02 µg/L) of antimony). In the SLVDS cohort, urinary antimony was positively associated with AMI, but not heart failure., Discussion: Among this sample of Danish people who never smoked, we found that low levels of urine antimony are associated with incident CVD. These results were partially confirmed in a smaller US cohort., Competing Interests: Declaration of Competing Interest Dr. Wellenius serves as a consultant to the Health Effects Institute (Boston, MA) and Google, LLC (Mountain View, CA). The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Personal care products (PCPs) contain many different compounds and are a source of exposure to endocrine disrupting chemicals (EDCs), including phthalates and phenols. Early-life exposure to EDCs commonly found in PCPs has been linked to earlier onset of puberty., Objective: To characterize the human and animal evidence on the association between puberty-related outcomes and exposure to PCPs and their chemical constituents and, if there is sufficient evidence, identify groups of chemicals and outcomes to support a systematic review for a class-based hazard or risk assessment., Methods: We followed the OHAT systematic review framework to characterize the human and animal evidence on the association between puberty-related health outcomes and exposure to PCPs and their chemical constituents., Results: Ninety-eight human and 299 animal studies that evaluated a total of 96 different chemicals were identified and mapped by key concepts including chemical class, data stream, and puberty-related health outcome. Among these studies, phthalates and phenols were the most well-studied chemical classes. Most of the phthalate and phenol studies examined secondary sex characteristics and changes in estradiol and testosterone levels. Studies evaluating PCP use and other chemical classes (e.g., parabens) had less data., Conclusions: This systematic evidence map identified and mapped the published research evaluating the association between exposure to PCPs and their chemical constituents and puberty-related health outcomes. The resulting interactive visualization allows researchers to make evidence-based decisions on the available research by enabling them to search, sort, and filter the literature base of puberty-related studies by key concepts. This map can be used by researchers and regulators to prioritize and target future research and funding to reduce uncertainties and address data gaps. It also provides information to inform a class-based hazard or risk assessment on the association between phthalate and phenol exposures and puberty-related health outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Organophosphate esters (OPEs), used as flame retardants and plasticizers, are chemicals of concern for maternal and infant health. Prior studies examining temporal trends and predictors of OPE exposure are primarily limited by small sample sizes., Objectives: Characterize temporal trends and predictors of OPE exposure biomarkers., Methods: We determined urinary concentrations of eight biomarkers of OPE exposure at three timepoints during pregnancy for participants in the LIFECODES Fetal Growth Study (n = 900), a nested case-cohort recruited between 2007 and 2018. We examined biomarker concentrations, their variability during pregnancy, and temporal trends over the study period. In addition, we identified sociodemographic and pregnancy characteristics associated with biomarker concentrations. Analyses were conducted using both the within-subject pregnancy geometric means and biomarker concentrations measured at individual study visits., Results: Five OPE biomarkers were detected in at least 60% of the study participants. Biomarkers were not strongly correlated with one another and intraclass correlation coefficients, measuring within-subject variability during pregnancy, ranged from 0.27 to 0.51. Biomarkers exhibited varying temporal trends across study years. For example, bis(1-chloro-2-propyl) phosphate (BCIPP) increased monotonically, whereas bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP), displayed non-monotonic trends with concentrations that peaked between 2011 and 2014. We observed associations between sociodemographic characteristics and OPE biomarkers. In general, concentrations of most OPE biomarkers were higher among participants from racial and ethnic minority populations, participants who were younger, had higher pre-pregnancy body mass index (BMI), and less than a college degree. We observed consistent results using either averaged or visit-specific biomarker concentrations., Significance: We observed widespread exposure to several OPEs and OPE biomarkers displayed varying temporal trends in pregnant people from 2007 to 2018. Concentrations of most OPE biomarkers varied according to sociodemographic factors, suggesting higher burdens of exposure among participants with higher pre-pregnancy BMI, those belonging to racial and ethnic minority populations, and lower educational attainment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: Little is known about inhaled flavored cannabis use. This study aimed to investigate the prevalence and patterns of flavored cannabis use and cannabis-tobacco co-use., Methods: This study surveyed adult past 30-day cannabis users in U.S. states and districts that have legalized cannabis for nonmedical/adult use (n=9) (November 2018; n=2,978). By product/behavior (any cannabis, cannabis extract vaporizers, mixed cannabis-nicotine vaporizers, blunts, chasing), the association between flavored (versus non-flavored) use and sociodemographic characteristics, cannabis use disorder symptoms, and tobacco use was estimated using weighted multivariable logistic regression in January 2022., Results: Almost half of adult cannabis users reported using at least one flavored cannabis product (46.5%). Flavored cannabis use was more likely among respondents who were female (AOR=1.2, CI=1.0, 1.4), were Black (ref: White; AOR=2.2, CI=1.5, 3.1), were Hispanic/Latino/a/x (ref: White; AOR=1.6, CI=1.2, 1.9), had cannabis use disorder symptoms (AOR=2.0, CI=1.6, 2.4), or were currently using tobacco (AOR=2.4, CI=2.1, 2.9). Use was less likely among middle-aged/older adults (ref: ages 21-34 vs 35-49 years; AOR=0.6, CI=0.5, 0.7)., Conclusions: Observed differences in flavored cannabis use are concerning if flavors raise appeal or dependence. Integrating flavored cannabis and tobacco research and practice is warranted., (Copyright © 2023 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Olfactory impairment and Parkinson's disease (PD) may share common genetic and environmental risk factors. This study investigates the association of a PD polygenic risk score (PRS) with olfaction, and whether the associations are modified by environmental exposures of PM 2.5 , NO 2 , or smoking., Methods: This analysis included 3358 women (aged 50-80) from the Sister Study with genetic data and results from the Brief Smell Identification Test (B-SIT) administered in 2018-2019. PD PRS was calculated using 90 single nucleotide polymorphisms. Olfactory impairment was defined with different B-SIT cutoffs, and PD diagnosis was adjudicated via expert review. We report odds ratios (ORs) and 95% confidence intervals (CIs) from multivariable logistic regression., Results: As expected, PD PRS was strongly associated with the odds of having PD (OR highest vs. lowest quartile = 3.79 (1.64, 8.73)). The highest PRS quartile was also associated with olfactory impairment, with OR ranging from 1.24 (0.98, 1.56) for a B-SIT cutoff of 9 to 1.42 (1.04, 1.92) for a cutoff of 6. For individual B-SIT items, the highest PRS quartile was generally associated with lower odds of correctly identifying the odorant, albeit only statistically significant for pineapple (0.72 (0.56, 0.94), soap (0.76 (0.58, 0.99)) and rose (0.70 (0.54, 0.92)). The association of PD PRS with olfactory impairment was not modified by airborne environmental exposures or smoking., Conclusion: These preliminary data suggest that high PD genetic susceptibility is associated with olfactory impairment in middle-aged and older women., Competing Interests: Declaration of competing interest Dr. Pinto is on the speaker's bureau for Sanofi and Regeneron; he also serves as a site investigator for these two companies. He has served on an advisory board for Connect Biopharma. Other authors declare no conflict of interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Multi-attribute methods employing mass spectrometry are applied throughout the biopharmaceutical industry for product and process characterization purposes but are not yet widely accepted as a method for batch release and stability testing under the good manufacturing practice (GMP) regime, due to limited experience and level of comfort with the technical, compliance and regulatory aspects of its implementation at quality control (QC) laboratories. This article is the second part of a two-tiered publication aiming at providing guidance for implementation of the multi-attribute method by peptide mapping liquid chromatography mass spectrometry (MAM) in a QC laboratory. The first part [1] focuses on technical considerations, while this second part provides considerations related to GMP compliance and regulatory aspects. This publication has been prepared by a group of industry experts representing 14 globally acting major biotechnology companies under the umbrella of the European Federation of Pharmaceutical Industries and Associations (EFPIA) Manufacturing & Quality Expert Group (MQEG)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Social determinants are structures and conditions in the biological, physical, built, and social environments that affect health, social and physical functioning, health risk, quality of life, and health outcomes. The adoption of recommended, standard measurement protocols for social determinants of health will advance the science of minority health and health disparities research and provide standard social determinants of health protocols for inclusion in all studies with human participants., Methods: A PhenX (consensus measures for Phenotypes and eXposures) Working Group of social determinants of health experts was convened from October 2018 to May 2020 and followed a well-established consensus process to identify and recommend social determinants of health measurement protocols. The PhenX Toolkit contains data collection protocols suitable for inclusion in a wide range of research studies. The recommended social determinants of health protocols were shared with the broader scientific community to invite review and feedback before being added to the Toolkit., Results: Nineteen social determinants of health protocols were released in the PhenX Toolkit (https://www.phenxtoolkit.org) in May 2020 to provide measures at the individual and structural levels for built and natural environments, structural racism, economic resources, employment status, occupational health and safety, education, environmental exposures, food environment, health and health care, and sociocultural community context., Conclusions: Promoting the adoption of well-established social determinants of health protocols can enable consistent data collection and facilitate comparing and combining studies, with the potential to increase their scientific impact., (Published by Elsevier Inc.)

Background and Aim: Epidemiological studies conducted mostly in low- and middle-income countries have found a positive association between household combustion of wood and lung cancer. However, most studies have been retrospective, and few have been conducted in the United States where indoor wood-burning usage patterns differ. We examined the association of exposure to indoor wood smoke from fireplaces and stoves with incident lung cancer in a U.S.-wide cohort of women., Methods: We included 50,226 women without prior lung cancer participating in the U.S.-based prospective Sister Study. At enrollment (2003-2009), women reported frequency of use of wood-burning stoves and/or fireplaces in their longest-lived adult residence. Cox regression was used to estimate adjusted hazard ratios (HR adj ) and 95 % confidence intervals (CI) for the association between indoor wood-burning fireplace/stove use and incident lung cancer. Lung cancer was self-reported and confirmed with medical records., Results: During an average 11.3 years of follow-up, 347 medically confirmed lung cancer cases accrued. Overall, 62.3 % of the study population reported the presence of an indoor wood-burning fireplace/stove at their longest-lived adult residence and 20.6 % reported annual usage of ≥30 days/year. Compared to those without a wood-burning fireplace/stove, women who used their wood-burning fireplace/stove ≥30 days/year had an elevated rate of lung cancer (HR adj  = 1.68; 95 % CI = 1.27, 2.20). In never smokers, positive associations were seen for use 1-29 days/year (HR adj  = 1.64; 95 % CI = 0.87, 3.10) and ≥30 days/year (HR adj  = 1.99; 95 % CI = 1.02, 3.89). Associations were also elevated across all income groups, in Northeastern, Western or Midwestern U.S. regions, and among those who lived in urban or rural/small town settings., Conclusions: Our prospective analysis of a cohort of U.S. women found that increasing frequency of wood-burning indoor fireplace/stove usage was associated with incident lung cancer, even among never smokers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Many United States (US) cities are experiencing urban heat islands (UHIs) and climate change-driven temperature increases. Extreme heat increases cardiovascular disease (CVD) risk, yet little is known about how this association varies with UHI intensity (UHII) within and between cities. We aimed to identify the urban populations most at-risk of and burdened by heat-related CVD morbidity in UHI-affected areas compared to unaffected areas. ZIP code-level daily counts of CVD hospitalizations among Medicare enrollees, aged 65-114, were obtained for 120 US metropolitan statistical areas (MSAs) between 2000 and 2017. Mean ambient temperature exposure was estimated by interpolating daily weather station observations. ZIP codes were classified as low and high UHII using the first and fourth quartiles of an existing surface UHII metric, weighted to each have 25% of all CVD hospitalizations. MSA-specific associations between ambient temperature and CVD hospitalization were estimated using quasi-Poisson regression with distributed lag non-linear models and pooled via multivariate meta-analyses. Across the US, extreme heat (MSA-specific 99th percentile, on average 28.6 °C) increased the risk of CVD hospitalization by 1.5% (95% CI: 0.4%, 2.6%), with considerable variation among MSAs. Extreme heat-related CVD hospitalization risk in high UHII areas (2.4% [95% CI: 0.4%, 4.3%]) exceeded that in low UHII areas (1.0% [95% CI: -0.8%, 2.8%]), with upwards of a 10% difference in some MSAs. During the 18-year study period, there were an estimated 37,028 (95% CI: 35,741, 37,988) heat-attributable CVD admissions. High UHII areas accounted for 35% of the total heat-related CVD burden, while low UHII areas accounted for 4%. High UHII disproportionately impacted already heat-vulnerable populations; females, individuals aged 75-114, and those with chronic conditions living in high UHII areas experienced the largest heat-related CVD impacts. Overall, extreme heat increased cardiovascular morbidity risk and burden in older urban populations, with UHIs exacerbating these impacts among those with existing vulnerabilities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Exposure science is evolving from its traditional "after the fact" and "one chemical at a time" approach to forecasting chemical exposures rapidly enough to keep pace with the constantly expanding landscape of chemicals and exposures. In this article, we provide an overview of the approaches, accomplishments, and plans for advancing computational exposure science within the U.S. Environmental Protection Agency's Office of Research and Development (EPA/ORD). First, to characterize the universe of chemicals in commerce and the environment, a carefully curated, web-accessible chemical resource has been created. This DSSTox database unambiguously identifies >1.2 million unique substances reflecting potential environmental and human exposures and includes computationally accessible links to each compound's corresponding data resources. Next, EPA is developing, applying, and evaluating predictive exposure models. These models increasingly rely on data, computational tools like quantitative structure activity relationship (QSAR) models, and machine learning/artificial intelligence to provide timely and efficient prediction of chemical exposure (and associated uncertainty) for thousands of chemicals at a time. Integral to this modeling effort, EPA is developing data resources across the exposure continuum that includes application of high-resolution mass spectrometry (HRMS) non-targeted analysis (NTA) methods providing measurement capability at scale with the number of chemicals in commerce. These research efforts are integrated and well-tailored to support population exposure assessment to prioritize chemicals for exposure as a critical input to risk management. In addition, the exposure forecasts will allow a wide variety of stakeholders to explore sustainable initiatives like green chemistry to achieve economic, social, and environmental prosperity and protection of future generations., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: On behalf of my coauthors and I, I hereby declare that we have no competing financial or personal relationship conflicts of interest that would bias the research presented in our article “Cutting-Edge Computational Chemical Exposure Research at the U.S. Environmental Protection Agency.”, (Copyright © 2023. Published by Elsevier Ltd.)

Historically, soil ingestion rate estimates were based on trace element-based mass balance (MB) study results. These were used in assessing exposures and health risks for children residing in Superfund or chemically contaminated communities. However, soil and dust can have considerable differences with respect to their sources, chemical, physical, and toxicological characteristics. Unfortunately, the MB approach is incapable of disentangling dust ingestion rates from soil ingestion rates. Alternative methods, such as activity pattern and biokinetic modeling techniques, have also been used to predict soil and dust ingestion rates. The results from these studies differed from those obtained from the MB studies. This research evaluated the MB methodology and formulated a physical model which characterized the environmental and behavioral determinants of soil and dust ingestion exposures by children. This new approach explicitly separates outdoor soil exposures from the indoor tracked-in soil portion of the dust and total dust exposures by utilizing information from five key MB studies along with new information derived from the SHEDS-Soil/Dust time-activity pattern-based modeling runs. Application of this new hybrid methodology showed that the predicted mean soil ingestion rates are 30%-70% less than the "total soil" ingestion rates obtained from the selected MB studies. In contrast, most of the predicted dust ingestion rate estimates were typically greater than the predicted soil ingestion rates. Moreover, the predicted total soil plus dust ingestion rates were found to be mostly higher (by ≤ 60%) than the MB-based "total soil" ingestion rates. Except for one study these results were higher than the results produced by the stand-alone SHEDS-Soil/Dust model runs. Across the MB studies analyzed, predicted outdoor soil ingestion rate contributions to "total soil" ingestion rates varied between 29% and 70% while the tracked-in soil portion of the indoor dust ingestion rates varied between 30% and 71%., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility., Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry., Design, Setting, and Participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry., Outcome Measurements and Statistical Analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness., Results and Limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10 -4 )., Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry., Patient Summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Multi-attribute methods employing mass spectrometry are applied throughout the biopharmaceutical industry for product and process characterization purposes but are not yet widely accepted as a method for batch release and stability testing under good manufacturing practice (GMP) due to limited experience and level of comfort with the technical, compliance and regulatory aspects of its implementation at quality control (QC) laboratories. Here, current literature related to the development and application of the multi-attribute method by peptide mapping liquid chromatography mass spectrometry (MAM) is compiled with the aim of providing guidance for the implementation of MAM in a QC laboratory. This article, focusing on technical considerations, is the first part of a two-tiered publication, whereby the second part will focus on GMP compliance and regulatory aspects. This publication has been prepared by a group of industry experts representing 14 globally acting major biotechnology companies under the umbrella of the European Federation of Pharmaceutical Industries and Associations (EFPIA) Manufacturing & Quality Expert Group (MQEG)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology., Objective: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data., Design, Setting, and Participants: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis., Outcome Measurements and Statistical Analyses: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking., Results and Limitations: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p < 5 × 10 -8 ) to 24. The 4p16.3 (FGFR3/TACC3) locus was associated with a stronger risk for women than for men (p-interaction = 0.002). Bladder cancer risk was increased by interactions between smoking status and genetic variants at 8p22 (NAT2; multiplicative p value for interaction [p M-I ] = 0.004), 8q21.13 (PAG1; p M-I  = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; p M-I  = 0.02). The PRS based on the 24 independent GWAS markers (odds ratio per standard deviation increase 1.49, 95% confidence interval 1.44-1.53), which also showed comparable results in two prospective cohorts (UK Biobank, PLCO trial), revealed an approximately fourfold difference in the lifetime risk of bladder cancer according to the PRS (e.g., 1st vs 10th decile) for both smokers and nonsmokers., Conclusions: We report novel loci associated with risk of bladder cancer that provide clues to its biological underpinnings. Using 24 independent markers, we constructed a PRS to stratify lifetime risk. The PRS combined with smoking history, and other established risk factors, has the potential to inform future screening efforts for bladder cancer., Patient Summary: We identified new genetic markers that provide biological insights into the genetic causes of bladder cancer. These genetic risk factors combined with lifestyle risk factors, such as smoking, may inform future preventive and screening strategies for bladder cancer., (Published by Elsevier B.V.)

Background: Air pollution exposure is associated with cardiovascular morbidity and mortality. Although exposure to air pollution early in life may represent a critical window for development of cardiovascular disease risk factors, few studies have examined associations of long-term air pollution exposure with markers of cardiovascular and metabolic health in young adults., Objectives: By combining health data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) with air pollution data from the Fused Air Quality Surface using Downscaling (FAQSD) archive, we: (1) calculated multi-year estimates of exposure to ozone (O 3 ) and particulate matter with an aerodynamic diameter ≤ 2.5 µm (PM 2.5 ) for Add Health participants; and (2) estimated associations between air pollution exposures and multiple markers of cardiometabolic health., Methods: Add Health is a nationally representative longitudinal cohort study of over 20,000 adolescents aged 12-19 in the United States (US) in 1994-95 (Wave I). Participants have been followed through adolescence and into adulthood with five in-home interviews. Estimated daily concentrations of O 3 and PM 2.5 at census tracts were obtained from the FAQSD archive and used to generate tract-level annual averages of O 3 and PM 2.5 concentrations. We estimated associations between average O 3 and PM 2.5 exposures from 2002 to 2007 and markers of cardiometabolic health measured at Wave IV (2008-09), including hypertension, hyperlipidemia, body mass index (BMI), diabetes, C-reactive protein, and metabolic syndrome., Results: The final sample size was 11,259 individual participants. The average age of participants at Wave IV was 28.4 years (range: 24-34 years). In models adjusting for age, race/ethnicity, and sex, long-term O 3 exposure (2002-07) was associated with elevated odds of hypertension, with an odds ratio (OR) of 1.015 (95% confidence interval [CI]: 1.011, 1.029); obesity (1.022 [1.004, 1.040]); diabetes (1.032 [1.009,1.054]); and metabolic syndrome (1.028 [1.014, 1.041]); PM 2.5 exposure (2002-07) was associated with elevated odds of hypertension (1.022 [1.001, 1.045])., Conclusion: Findings suggest that long-term ambient air pollution exposure, particularly O 3 exposure, is associated with cardiometabolic health in early adulthood., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Azo dyes are used in textiles and leather clothing. Human exposure can occur from wearing textiles containing azo dyes. Since the body's enzymes and microbiome can cleave azo dyes, potentially resulting in mutagenic or carcinogenic metabolites, there is also an indirect health concern on the parent compounds. While several hazardous azo dyes are banned, many more are still in use that have not been evaluated systematically for potential health concerns. This systematic evidence map (SEM) aims to compile and categorize the available toxicological evidence on the potential human health risks of a set of 30 market-relevant azo dyes., Methods: Peer-reviewed and gray literature was searched and over 20,000 studies were identified. These were filtered using Sciome Workbench for Interactive computer-Facilitated Text-mining (SWIFT) Review software with evidence stream tags (human, animal, in vitro) yielding 12,800 unique records. SWIFT Active (a machine-learning software) further facilitated title/abstract screening. DistillerSR software was used for additional title/abstract, full-text screening, and data extraction., Results: 187 studies were identified that met populations, exposures, comparators, and outcomes (PECO) criteria. From this pool, 54 human, 78 animal, and 61 genotoxicity studies were extracted into a literature inventory. Toxicological evidence was abundant for three azo dyes (also used as food additives) and sparse for five of the remaining 27 compounds. Complementary search in ECHA's REACH database for summaries of unpublished study reports revealed evidence for all 30 dyes. The question arose of how this information can be fed into an SEM process. Proper identification of prioritized dyes from various databases (including U.S. EPA's CompTox Chemicals Dashboard) turned out to be a challenge. Evidence compiled by this SEM project can be evaluated for subsequent use in problem formulation efforts to inform potential regulatory needs and prepare for a more efficient and targeted evaluation in the future for human health assessments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Pulmonary hypertension (PH) is associated with pulmonary vasoconstriction and endothelial dysfunction leading to impaired nitric oxide (NO) and prostacyclin (PGI 2 ) pathways. Metformin, the first line treatment for type 2 diabetes and AMP-activated protein kinase (AMPK) activator, has been recently highlighted as a potential PH treatment. AMPK activation has been reported to improve endothelial function by enhancing endothelial NO synthase (eNOS) activity and to have relaxant effects in blood vessels. In this study, we examined the effect of metformin treatment on PH as well as on NO and PGI 2 pathways in monocrotaline (MCT)-injected rats with established PH. Moreover, we investigated the anti-contractile effects of AMPK activators on endothelium-denuded human pulmonary arteries (HPA) from Non-PH and Group 3 PH patients (due to lung diseases and/or hypoxia). Furthermore, we explored the interaction between treprostinil and the AMPK/eNOS pathway. Our results showed that metformin protected against PH progression in MCT rats where it reduced the mean pulmonary artery pressure, pulmonary vascular remodeling and right ventricular hypertrophy and fibrosis compared to vehicle-treated MCT rats. The protective effects on rat lungs were mediated in part by increasing eNOS activity and protein kinase G-1 expression but not through the PGI 2 pathway. In addition, incubation with AMPK activators reduced the phenylephrine-induced contraction of endothelium-denuded HPA from Non-PH and PH patients. Finally, treprostinil also augmented eNOS activity in HPA smooth muscle cells. In conclusion, we found that AMPK activation can enhance the NO pathway, attenuate vasoconstriction by direct effects on smooth muscles, and reverse established MCT-induced PH in rats., Competing Interests: Declaration of competing interest Over the last three years, Christophe Guignabert reports grants from Acceleron and Janssen and grants and personal fees from Merck and ShouTi, outside of this submitted work. Xavier Norel has received educational research grants from United Therapeutics. Adam M. Silverstein is employee of United Therapeutics. The other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Strong evidence indicates critical roles of NADPH oxidase (a key superoxide-producing enzyme complex during inflammation) in activated microglia for mediating neuroinflammation and neurodegeneration. However, little is known about roles of neuronal NADPH oxidase in neurodegenerative diseases. This study aimed to investigate expression patterns, regulatory mechanisms and pathological roles of neuronal NADPH oxidase in inflammation-associated neurodegeneration. The results showed persistent upregulation of NOX2 (gp91 phox ; the catalytic subunit of NADPH oxidase) in both microglia and neurons in a chronic mouse model of Parkinson's disease (PD) with intraperitoneal LPS injection and LPS-treated midbrain neuron-glia cultures (a cellular model of PD). Notably, NOX2 was found for the first time to exhibit a progressive and persistent upregulation in neurons during chronic neuroinflammation. While primary neurons and N27 neuronal cells displayed basal expression of NOX1, NOX2 and NOX4, significant upregulation only occurred in NOX2 but not NOX1 or NOX4 under inflammatory conditions. Persistent NOX2 upregulation was associated with functional outcomes of oxidative stress including increased ROS production and lipid peroxidation. Neuronal NOX2 activation displayed membrane translocation of cytosolic p47 phox subunit and was inhibited by apocynin and diphenyleneiodonium chloride (two widely-used NADPH oxidase inhibitors). Importantly, neuronal ROS production, mitochondrial dysfunction and degeneration induced by inflammatory mediators in microglia-derived conditional medium were blocked by pharmacological inhibition of neuronal NOX2. Furthermore, specific deletion of neuronal NOX2 prevented LPS-elicited dopaminergic neurodegeneration in neuron-microglia co-cultures separately grown in the transwell system. The attenuation of inflammation-elicited upregulation of NOX2 in neuron-enriched and neuron-glia cultures by ROS scavenger N-acetylcysteine indicated a positive feedback mechanism between excessive ROS production and NOX2 upregulation. Collectively, our findings uncovered crucial contribution of neuronal NOX2 upregulation and activation to chronic neuroinflammation and inflammation-related neurodegeneration. This study reinforced the importance of developing NADPH oxidase-targeting therapeutics for neurodegenerative diseases., Competing Interests: Declaration of competing interest We state ‘Declarations of interest: none’ in the title page and have a Section “Competing interests” and statement “The authors declare that they have no competing interests” in the manuscript., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The role of vaccine hesitancy on influenza vaccination is not clearly understood. Low influenza vaccination coverage in U.S. adults suggests that a multitude of factors may be responsible for under-vaccination or non-vaccination including vaccine hesitancy. Understanding the role of influenza vaccination hesitancy is important for targeted messaging and intervention to increase influenza vaccine confidence and uptake. The objective of this study was to quantify the prevalence of adult influenza vaccination hesitancy (IVH) and examine association of IVH beliefs with sociodemographic factors and early-season influenza vaccination., Methods: A four-question validated IVH module was included in the 2018 National Internet Flu Survey. Weighted proportions and multivariable logistic regression models were used to identify correlates of IVH beliefs., Results: Overall, 36.9% of adults were hesitant to receive an influenza vaccination; 18.6% expressed concerns about vaccination side effects; 14.8% personally knew someone with serious side effects; and 35.6% reported that their healthcare provider was not the most trusted source of information about influenza vaccinations. Influenza vaccination ranged from 15.3 to 45.2 percentage points lower among adults self-reporting any of the four IVH beliefs. Being female, age 18-49 years, non-Hispanic Black, having high school or lower education, being employed, and not having primary care medical home were associated with hesitancy., Conclusions: Among the four IVH beliefs studied, being hesitant to receiving influenza vaccination followed by mistrust of healthcare providers were identified as the most influential hesitancy beliefs. Two in five adults in the United States were hesitant to receive an influenza vaccination, and hesitancy was negatively associated with vaccination. This information may assist with targeted interventions, personalized to the individual, to reduce hesitancy and thus improve influenza vaccination acceptance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Exposure to many phthalates and phenols is declining as replacements are introduced. There is little information on temporal trends or predictors of exposure to these newer compounds, such as phthalate replacements, especially among pregnant populations., Objective: Examine temporal trends and predictors of exposure to phthalates, phthalate replacements, and phenols using single- and multi-pollutant approaches., Methods: We analyzed data from 900 singleton pregnancies in the LIFECODES Fetal Growth Study, a nested case-cohort with recruitment from 2007 to 2018. We measured and averaged concentrations of 12 phthalate metabolites, four phthalate replacement metabolites, and 12 phenols in urine at three timepoints during pregnancy. We visualized and analyzed temporal trends and predictors of biomarker concentrations. To examine chemical mixtures, we derived clusters of individuals with shared exposure profiles using a finite mixture model and examined temporal trends and predictors of cluster assignment., Results: Exposure to phthalates and most phenols declined across the study period, while exposure to phthalate replacements (i.e., di(isononyl) cyclohexane-1,2-dicarboxylic acid, diisononyl ester [DINCH] and di-2-ethylhexyl terephthalate [DEHTP]) and bisphenol S (BPS) increased. For example, the sum of DEHTP biomarkers increased multiple orders of magnitude, with an average concentration of 0.92 ng/mL from 2007 to 2008 and 61.9 ng/mL in 2017-2018. Biomarkers of most chemical exposures varied across sociodemographic characteristics, with the highest concentrations observed in non-Hispanic Black or Hispanic participants relative to non-Hispanic White participants. We identified five clusters with shared exposure profiles and observed temporal trends in cluster membership. For example, at the end of the study period, a cluster characterized by high exposure to phthalate replacements was the most prevalent., Significance: In a large and well-characterized pregnancy cohort, we observed exposure to phthalate replacements and BPS increased over time while exposure to phthalates and other phenols decreased. Our results highlight the changing nature of exposure to consumer product chemical mixtures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Monoclonal antibodies (mAbs) are one of the fastest-growing classes of drugs and have been approved to treat several diseases, including cancers and autoimmune disorders. Preclinical pharmacokinetics studies are performed to determine the therapeutically meaningful dosages and efficacy of candidate drugs. These studies are typically performed in non-human primates; however, using primates is costly and raises ethical considerations. As a result, rodent models that better mimic human-like pharmacokinetics have been generated and remain an area of active investigation. Pharmacokinetic characteristics of a candidate drug, such as half-life, are partly controlled by antibody binding to the human neonatal receptor hFCRN. Due to the abnormally high binding of human antibodies to mouse FCRN, traditional laboratory rodents do not accurately model the pharmacokinetics of human mAbs. In response, humanized rodents expressing hFCRN have been generated. However, these models generally use large inserts randomly integrated into the mouse genome. Here, we report the production and characterization of a CRISPR/Cas9-mediated hFCRN transgenic mouse termed SYNB-hFCRN. Using CRISPR/Cas9-assisted gene targeting, we prepared a strain with a simultaneous knockout of mFcrn and insertion of a hFCRN mini-gene under the control of the endogenous mouse promoter. These mice are healthy and express hFCRN in the appropriate tissues and immune cell subtypes. Pharmacokinetic evaluation of human IgG and adalimumab (Humira®) demonstrate hFCRN-mediated protection. These newly generated SYNB-hFCRN mice provide another valuable animal model for use in preclinical pharmacokinetics studies during early drug development., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kurt Jarnagin reports financial support was provided by Bristol Myers Squibb Co. David R. Webb reports a relationship with Synbal, Inc. that includes: employment and equity or stocks. Kurt Jarnagin reports a relationship with Synbal, Inc. that includes: employment and equity or stocks. Shannon Xu reports a relationship with Synbal, Inc. that includes: employment and equity or stocks. Don van Fossan reports a relationship with Synbal Inc. that includes: employment and equity or stocks. Kristen Read reports a relationship with Synbal Inc. that includes: employment and equity or stocks. Dale O. Cowley reports a relationship with Transviragen, Inc. that includes: employment and equity or stocks. Oscar Alvarez reports a relationship with Synbal, Inc. that includes: employment and equity or stocks. Christopher M. Conner reports a relationship with Synbal, Inc. that includes: employment and equity or stocks., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Epidemiologic studies of serum per- and polyfluoroalkyl substances (PFAS) and antibody response to vaccines have suggested an adverse association, but the consistency and magnitude of this association remain unclear., Objective: The goal of this systematic review was to determine the size of the association between a doubling in perfluoroalkyl substances (PFAS) serum concentration and difference in log e antibody concentration following a vaccine, with a focus on five PFAS: perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA)., Data Source: We conducted online searches of PubMed and Web of Science through May 17, 2022 and identified 14 eligible reports published from 2012 to 2022., Study Eligibility Criteria, Participants, and Interventions: We included studies conducted in humans, including mother-child pairs, which examined serum PFAS concentration in relation to serum concentration of antibody to a specific antigen following a vaccine., Study Appraisal and Synthesis Methods: We used the risk of bias assessment for non-randomized studies of exposure and certainty assessment method proposed by Morgan et al. (2019). Using a multilevel meta-regression model, we quantitatively synthesized the data., Results: The 14 reports represented 13 unique groups of subjects; the frequency of studies of a given antibody was Tetanus (n = 7); followed by Diphtheria (6); Measles (4); Rubella (3); Haemophilus influenzae type b and Influenza A H1N1 (2 each); and Hepatitis A, Hepatitis B, Influenza A H2N3, Influenza B, and Mumps (1 each). There were approximately 4,830 unique participants included in the analyses across the 14 reports. The models of coefficients between antibody concentration and the five principal PFAS showed homogeneity of associations across antibody types for each principal PFAS. In the models with all antibodies treated as one type, evidence of effect modification by life stage was present for PFOA and PFOS, and for consistency, all associations were evaluated for all ages and for children. The summary associations (coefficients for difference in log e [antibody concentration] per doubling of serum PFAS) with 95% confidence intervals that excluded zero ("statistical support"), and certainty of evidence ratings were as follows: for PFOA and all antibodies treated as one type in all ages, -0.06 (-0.10, -0.01; moderate) and in children, -0.10 (-0.16, -0.03; moderate); for Diphtheria in children, -0.12 (-0.23, -0.00; high); for Rubella in all ages, -0.09 (-0.17, -0.01; moderate), and for Tetanus in children, -0.12 (-0.24, -0.00; moderate). For PFOS the summary associations were, for all antibodies treated as one type in all ages, -0.06 (-0.11, -0.01; moderate) and in children, -0.10 (-0.18, -0.03; moderate); for Rubella in all ages, -0.09 (-0.15, -0.03; high) and in children, -0.12 (-0.20, -0.04; high). For PFHxS the summary associations were, for all antibodies treated as one type in all ages, -0.03 (-0.06, -0.00; moderate) and in children, -0.05 (-0.09, -0.00; low); and for Rubella in children, -0.07 (-0.11, -0.02; high). Summary associations for PFNA and PFDA did not have statistical support, but all PFAS studied tended to have an inverse association with antibody concentrations., Limitations and Conclusions: Epidemiologic data on immunosuppression and five principal PFAS suggest an association, with support across antibodies against multiple types of antigens. Data on Diphtheria, Rubella, and Tetanus were more supportive of an association than for other antibodies, and support was greater for associations with PFOA, PFOS, and PFHxS, than for PFNA or PFDA. The data on any specific antibody were scarce. Confounding factors that might account for the relation were not identified. Nearly all studies evaluated were judged to have a low or moderate risk of bias., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)