Is detection of enteropathogens and human or animal faecal markers in the environment associated with subsequent child enteric infections and growth: an individual participant data meta-analysis.

BACKGROUND: Quantifying contributions of environmental faecal contamination to child diarrhoea and growth faltering can illuminate causal mechanisms behind modest health benefits in recent water, sanitation, and hygiene (WASH) trials. We aimed to assess associations between environmental detection of enteropathogens and human or animal microbial source tracking markers (MSTM) and subsequent child health outcomes. METHODS: In this individual participant data meta-analysis we searched we searched PubMed, Embase, CAB Direct Global Health, Agricultural and Environmental Science Database, Web of Science, and Scopus for WASH intervention studies with a prospective design and concurrent control that measured enteropathogens or MSTM in environmental samples, or both, and subsequently measured enteric infections, diarrhoea, or height-for-age Z-scores (HAZ) in children younger than 5 years. We excluded studies that only measured faecal indicator bacteria. The initial search was done on Jan 19, 2021, and updated on March 22, 2023. One reviewer (AM) screened abstracts, and two independent reviewers (AM and RT) examined the full texts of short-listed articles. All included studies include at least one author that also contributed as an author to the present Article. Our primary outcomes were the 7-day prevalence of caregiver-reported diarrhoea and HAZ in children. For specific enteropathogens in the environment, primary outcomes also included subsequent child infection with the same pathogen ascertained by stool testing. We estimated associations using covariate-adjusted regressions and pooled estimates across studies. FINDINGS: Data from nine published reports from five interventions studies, which included 8603 children (4302 girls and 4301 boys), were included in the meta-analysis. Environmental pathogen detection was associated with increased infection prevalence with the same pathogen and lower HAZ (ΔHAZ -0·09 [95% CI -0·17 to -0·01]) but not diarrhoea (prevalence ratio 1·22 [95% CI 0·95 to 1·58]), except during wet seasons. Detection of MSTM was not associated with diarrhoea (no pooled estimate) or HAZ (ΔHAZ -0·01 [-0·13 to 0·11] for human markers and ΔHAZ -0·02 [-0·24 to 0·21] for animal markers). Soil, children's hands, and stored drinking water were major transmission pathways. INTERPRETATION: Our findings support a causal chain from pathogens in the environment to infection to growth faltering, indicating that the lack of WASH intervention effects on child growth might stem from insufficient reductions in environmental pathogen prevalence. Studies measuring enteropathogens in the environment should subsequently measure the same pathogens in stool to further examine theories of change between WASH, faecal contamination, and health. Given that environmental pathogen detection was predictive of infection, programmes targeting specific pathogens (eg, vaccinations and elimination efforts) can environmentally monitor the pathogens of interest for population-level surveillance instead of collecting individual biospecimens. FUNDING: The Bill & Melinda Gates Foundation and the UK Foreign and Commonwealth Development Office.

Cross-sectional and prospective associations of early childhood circulating metals with early and mid-childhood cognition in the Project Viva cohort.

BACKGROUND: Relatively little is known about the immediate and prospective neurodevelopmental impacts of joint exposure to multiple metals (i.e., metal mixtures) in early childhood. OBJECTIVES: To estimate associations of early childhood (∼3 years of age) blood metal concentrations with cognitive test scores at early and mid-childhood (∼8 years of age). METHODS: We studied children from the Project Viva cohort. We measured erythrocyte concentrations of seven essential (Co, Cu, Mg, Mn, Mo, Se, and Zn) and eight non-essential metals (As, Ba, Cd, Cs, Hg, Pb, Sn, and Sr) in early childhood blood samples. Trained research assistants administered cognitive tests assessing vocabulary, visual-motor ability, memory, and general intelligence (standard deviations: ∼10 points), in early and mid-childhood. We employed multivariable linear regression to examine associations of individual metals with test scores adjusting for confounders, other concurrently measured metals, and first-trimester maternal blood metals. We also estimated joint associations and explored interaction between metals in mixture analyses. RESULTS: We analyzed 349 children (median whole blood Pb ∼1 µg/dL). In cross-sectional analyses, each doubling of Pb was associated with lower visual-motor function (mean difference: -2.43 points, 95% confidence interval (CI): -4.01, -0.86) and receptive vocabulary, i.e., words understood (-1.45 points, 95% CI: -3.26, 0.36). Associations of Pb with mid-childhood cognition were weaker and less precise by comparison. Mg was positively associated with cognition in cross-sectional but not prospective analyses, and cross-sectional associations were attenuated in a sensitivity analysis removing adjustment for concurrent metals. We did not observe joint associations nor interactions. DISCUSSION: In this cohort with low blood Pb levels, increased blood Pb was robustly associated with lower cognitive ability in cross-sectional analyses, even after adjustment for prenatal Pb exposure, and regardless of adjustment for metal co-exposures. However, associations with mid-childhood cognition were attenuated and imprecise, suggesting some buffering of Pb neurotoxicity in early life. WHAT THIS STUDY ADDS: Relatively few studies have comprehensively separated the effects of neurotoxic metals such as lead (Pb) from pre- and postnatal co-occurring metals, nor examined persistence of associations across childhood. In a cohort of middle-class children, we found higher early childhood (∼3 y) blood Pb was associated with lower scores on cognitive tests, independent of other metals and prenatal blood Pb. However, early childhood Pb was only weakly associated with cognition in mid-childhood (∼8 y). Our results suggest the effects of low-level Pb exposure may attenuate over time in some populations, implying the presence of factors that may buffer Pb neurotoxicity in early life.

Infant Feeding Practices and Metal Concentrations in Children's Blood.

This cohort study assesses the association between 4 infant feeding practices and concentrations of 8 nonessential and 7 essential metals in red blood cells.

Mixtures of Metals and Micronutrients in Early Pregnancy and Cognition in Early and Mid-Childhood: Findings from the Project Viva Cohort.

BACKGROUND: The developing fetal brain is sensitive to many environmental exposures. However, the independent and joint effects of prenatal exposure to metals and micronutrients on child cognition are not well understood. OBJECTIVES: Our aim was to evaluate associations of first-trimester (∼10 wk) maternal erythrocyte concentrations of mixtures of nonessential and essential metals and micronutrients with early (∼3 y) and mid-childhood (∼8 y) cognitive test scores in Project Viva, a prebirth cohort in Boston, Massachusetts, USA. METHODS: We measured concentrations of five essential metals (Cu, Mg, Mn, Se, Zn) and two micronutrients (vitamin B12 and folate), together termed the "nutrient mixture," as well as six nonessential metals (As, Ba, Cd, Cs, Hg, Pb), together termed the "neurotoxic mixture," in first-trimester (∼10 wk) maternal erythrocytes (metals) or plasma (micronutrients). We assessed visual-motor function and receptive vocabulary in early childhood (∼3 y), and visual-motor function, visual memory, and fluid and crystallized intelligence in mid-childhood (∼8 y). We employed adjusted quantile g-computation and linear regression to estimate mixture and individual component associations, respectively. RESULTS: Analyses included 900 mother-child pairs (74% college graduates; 52% male children). In mixture analyses, a quartile increase in the nutrient mixture was associated with a mean difference in early childhood receptive vocabulary score of 1.58 points [95% confidence interval (CI): 0.06, 3.10], driven by Zn and Se. A quartile increase in the neurotoxic mixture was associated with a mean difference in mid-childhood visual-motor score of -3.01 points (95% CI: -5.55, -0.47), driven by Ba and Cs. Linear regressions supported quantile g-computation findings for mixture component contributions. DISCUSSION: Maternal circulating concentrations of several essential (Zn and Se) and nonessential (Ba and Cs) metals were associated with some domains of child cognition. In this folate-replete cohort, first-trimester circulating concentrations of known neurotoxic metals, such as Pb, were not associated with child cognition. https://doi.org/10.1289/EHP12016.

Effects of water, sanitation, and hygiene interventions on detection of enteropathogens and host-specific faecal markers in the environment: a systematic review and individual participant data meta-analysis.

BACKGROUND: Water, sanitation, and hygiene (WASH) improvements are promoted to reduce diarrhoea in low-income countries. However, trials from the past 5 years have found mixed effects of household-level and community-level WASH interventions on child health. Measuring pathogens and host-specific faecal markers in the environment can help investigate causal pathways between WASH and health by quantifying whether and by how much interventions reduce environmental exposure to enteric pathogens and faecal contamination from human and different animal sources. We aimed to assess the effects of WASH interventions on enteropathogens and microbial source tracking (MST) markers in environmental samples. METHODS: We did a systematic review and individual participant data meta-analysis, which included searches from Jan 1, 2000, to Jan 5, 2023, from PubMed, Embase, CAB Direct Global Health, Agricultural and Environmental Science Database, Web of Science, and Scopus, of prospective studies with water, sanitation, or hygiene interventions and concurrent control group that measured pathogens or MST markers in environmental samples and measured child anthropometry, diarrhoea, or pathogen-specific infections. We used covariate-adjusted regression models with robust standard errors to estimate study-specific intervention effects and pooled effect estimates across studies using random-effects models. FINDINGS: Few trials have measured the effect of sanitation interventions on pathogens and MST markers in the environment and they mostly focused on onsite sanitation. We extracted individual participant data on nine environmental assessments from five eligible trials. Environmental sampling included drinking water, hand rinses, soil, and flies. Interventions were consistently associated with reduced pathogen detection in the environment but effect estimates in most individual studies could not be distinguished from chance. Pooled across studies, we found a small reduction in the prevalence of any pathogen in any sample type (pooled prevalence ratio [PR] 0·94 [95% CI 0·90-0·99]). Interventions had no effect on the prevalence of MST markers from humans (pooled PR 1·00 [95% CI 0·88-1·13]) or animals (pooled PR 1·00 [95% CI 0·97-1·03]). INTERPRETATION: The small effect of these sanitation interventions on pathogen detection and absence of effects on human or animal faecal markers are consistent with the small or null health effects previously reported in these trials. Our findings suggest that the basic sanitation interventions implemented in these studies did not contain human waste and did not adequately reduce exposure to enteropathogens in the environment. FUNDING: Bill and Melinda Gates Foundation and the UK Foreign and Commonwealth Development Office.

Responses to Wildfire and Prescribed Fire Smoke: A Survey of a Medically Vulnerable Adult Population in the Wildland-Urban Interface, Mariposa County, California.

California plans to substantially increase the use of prescribed fire to reduce risk of catastrophic wildfires. Although for a beneficial purpose, prescribed fire smoke may still pose a health concern, especially among sensitive populations. We sought to understand community health experience, adaptive capacity, and attitudes regarding wildland and prescribed fire smoke to inform public health guidance. We conducted a cross-sectional survey of medically vulnerable persons in a rural, high fire risk county (N = 106, 76% > 65 years) regarding wildfire and prescribed smoke health effects; health protective actions; information needs; and support for fire management policies. Qualitative comments were reviewed for context and emerging themes. More than half (58%) of participants reported health impacts from wildfire smoke; 26% experienced impacts from prescribed fire smoke. Participants expressed strong support for prescribed fire, although also concerns about safety and smoke. Respondents reported taking actions to reduce smoke exposure (average 5 actions taken per person), but many (47%) lacked confidence that they could successfully protect their health. Persons who were satisfied with the information received tended to be more confident in their ability to protect their health compared to those who were not satisfied (61% vs. 35%). More information was desired on many topics, including notifications about prescribed fire, health protection and exposure reduction. As California expands use of prescribed fire, the need for effective health protective communication regarding smoke is increasingly vital. We recommend seeking solutions that strengthen community resilience and address equity for vulnerable populations.

Wildfires and the Changing Landscape of Air Pollution-related Health Burden in California.

Rationale: Wildfires are a growing source of pollution including particulate matter ⩽2.5 µm in aerodynamic diameter (PM2.5), but associated trends in health burden are not well characterized. Objectives: We investigated trends and disparities in PM2.5-related cardiorespiratory health burden (asthma, chronic obstructive pulmonary disease, and all-cause respiratory and cardiovascular emergency department [ED] visits and hospital admissions) for all days and wildfire smoke-affected days across California from 2008 to 2016. Methods: Using residential Zone Improvement Plan code and daily PM2.5 exposures, we estimated overall and subgroup-specific (age, gender, race and ethnicity) associations with cardiorespiratory outcomes. Health burden trends and disparities were evaluated on the basis of relative risk, attributable number, and attributable fraction by demographic and geographic factors and over time. Measurements and Main Results: PM2.5-attributed burden steadily decreased, whereas the fraction attributed to wildfire smoke varied by fire season intensity, constituting up to 15% of the annual PM2.5-burden. The highest relative risk and PM2.5-attributed burden (92 per 100,000 people) was observed for respiratory ED visits, accounting for 2.2% of the respiratory annual burden. Disparities in overall morbidity in the oldest age, Black, and "other" race groups were also reflected in PM2.5-attributed burden, whereas Asian populations had the highest risk rate in respiratory outcomes and thus the largest fraction of the total burden attributed to the exposure. In contrast, high wildfire PM2.5-attributed burden rates in rural, central, and northern California populations occurred because of differential exposure. Conclusions: In California, wildfires' impact on air quality offset the public health gains achieved through reductions in nonsmoke PM2.5. Disproportionate effects could be attributed to differences in subpopulation susceptibility, relative risk, and differential exposure.

Exposures to FD&C synthetic color additives from over-the-counter medications and vitamins in United States children and pregnant women.

BACKGROUND: Food and Drug Administration (FDA) Food Drug and Cosmetic (FD&C) synthetic color additives (SCAs) have been associated with attentional and behavioral problems in children. Efforts to quantify exposure have focused on foods, while the contribution of medications and supplements remains unknown. OBJECTIVE: To estimate exposures to SCAs in children (2-16 years) and pregnant women from intake of common over-the-counter (OTC) medications and vitamins. METHODS: We estimated single-day exposure (mg/kg/day) to FD&C SCAs based on measurements of 25 different products and recommended dosages on product labels. Exposures were compared to SCA exposure estimates from food we previously developed and acceptable daily intakes (ADIs) established by FDA and the World Health Organization. RESULTS: The highest exposure was found for FD&C Red No. 40 in a children's cold/cough/allergy syrup. A child aged 12-16 years consuming the maximum daily dosage would have an exposure of 0.221 mg/kg/day, which is twice this age group's typical exposure to this additive from food. No estimated exposures exceeded the ADIs. SIGNIFICANCE: Some children's OTC medications and vitamins may cause daily SCA exposures comparable to those from foods. OTC medications and vitamins should be considered in efforts to quantify population exposure to FD&C SCAs. IMPACT: Exposure to synthetic color additives (SCAs) from foods has been associated with behavioral problems in children. Exposures from over-the-counter (OTC) medications and vitamins remain unquantified despite widespread use. We estimated exposures in children and pregnant women for 25 different OTC medication and vitamin products sold in the United States. While exposures were below acceptable daily intakes (ADIs) established by the US Food and Drug Administration and the World Health Organization, some were comparable to typical daily exposures from foods. This work critically informs future SCA exposure assessments and provides valuable information for parents concerned about the health effects of SCAs.

Dietary Exposure to United States Food and Drug Administration-Approved Synthetic Food Colors in Children, Pregnant Women, and Women of Childbearing Age Living in the United States.

The Food and Drug Administration (FDA) regulates artificial food colors (AFCs) in the United States. Exposure to AFCs has raised concerns about adverse behavioral effects in children. We quantified AFC exposure in women of childbearing age, pregnant women, and children and compared them to FDA and World Health Organization acceptable daily intakes (ADIs). We estimated the "typical" and "high" single-day and two-day average dietary exposure to each AFC (mg/kg/day) based on laboratory measurements and food consumption data from the 2015−2016 National Health and Nutrition Examination Survey (NHANES). We also examined whether AFC intake differed by income, education, and ethnicity. Exposure tended to be higher in children and the highest AFC exposure was found for Red No. 40. Children's mean and 95th percentile FD&C Red No. 3 estimated intakes exceeded the ADIs in some instances. Juice drinks, soft drinks, icings, and ice cream cones were major foods contributing to children's (<16 years old) AFC exposure. AFC intake was higher in participants with lower incomes and education and of African American ethnicity. The findings indicate widespread AFC exposure including in very young children. Research is needed on the sociodemographic determinants of exposure and AFC toxicokinetics to better describe the absorption and organ-specific exposure.

CFTR gene variants, air pollution, and childhood asthma in a California Medicaid population.

Carriers of the cystic fibrosis transmembrane conductance regulator (CFTR) gene ("carriers") have been found to have an increased risk of persistent asthma. However, it is unclear at what level of CFTR function this risk exists and whether it is modified by asthmogens, such as air pollution. We conducted a retrospective cohort study of children born in California between July 2007 and December 2013, linking CFTR genotype data from the California newborn screening program to Medicaid claims records through March 17, 2020 to identify asthma cases, and to air pollution data from CalEnviroScreen 3.0 to identify levels of particulate matter with diameter 2.5 microns or smaller (PM2.5 ). Log-binomial regression models for asthma risk were fitted, adjusting for race/ethnicity and sex. Compared to population controls, carriers had higher risk of asthma (adjusted risk ratio (aRR) = 1.29, 95% confidence interval (CI): 0.98, 1.69; p < 0.1). Other non-CF-causing variants on the second allele did not appear to further increase risk. Genotypes with the greatest asthma risk were F508del with an intron 10 T7 or (TG)11T5 in trans (aRR=1.52, 95% CI: 1.10, 2.12). This association was higher among children living in areas at or above (aRR = 1.80) versus below (aRR = 1.37) the current national air quality standard for PM2.5 , though this difference was not statistically significant (pinteraction > 0.2). These results suggest carriers with CFTR functional levels between 25% and 45% of wildtype are at increased risk of asthma. Knowledge of CFTR genotype in asthmatics may be important to open new CFTR-related treatment options for these patients.

The role of ATXR6 expression in modulating genome stability and transposable element repression in Arabidopsis.

ARABIDOPSIS TRITHORAX-RELATED PROTEIN 5 (ATXR5) AND ATXR6 are required for the deposition of H3K27me1 and for maintaining genomic stability in Arabidopsis Reduction of ATXR5/6 activity results in activation of DNA damage response genes, along with tissue-specific derepression of transposable elements (TEs), chromocenter decompaction, and genomic instability characterized by accumulation of excess DNA from heterochromatin. How loss of ATXR5/6 and H3K27me1 leads to these phenotypes remains unclear. Here we provide extensive characterization of the atxr5/6 hypomorphic mutant by comprehensively examining gene expression and epigenetic changes in the mutant. We found that the tissue-specific phenotypes of TE derepression and excessive DNA in this atxr5/6 mutant correlated with residual ATXR6 expression from the hypomorphic ATXR6 allele. However, up-regulation of DNA damage genes occurred regardless of ATXR6 levels and thus appears to be a separable process. We also isolated an atxr6-null allele which showed that ATXR5 and ATXR6 are required for female germline development. Finally, we characterize three previously reported suppressors of the hypomorphic atxr5/6 mutant and show that these rescue atxr5/6 via distinct mechanisms, two of which involve increasing H3K27me1 levels.

Effectiveness of Abbott BinaxNOW Rapid Antigen Test for Detection of SARS-CoV-2 Infections in Outbreak among Horse Racetrack Workers, California, USA.

The Abbott BinaxNOW rapid antigen test is cheaper and faster than real-time reverse transcription PCR (rRT-PCR) for detecting severe acute respiratory syndrome coronavirus 2. We compared BinaxNOW with rRT-PCR in 769 paired specimens from 342 persons during a coronavirus disease outbreak among horse racetrack workers in California, USA. We found positive percent agreement was 43.3% (95% CI 34.6%-52.4%), negative percent agreement 100% (95% CI 99.4%-100%), positive predictive value 100% (95% CI 93.5%-100%), and negative predictive value 89.9% (95% CI 87.5%-92.0%). Among 127 rRT-PCR-positive specimens, the 55 with paired BinaxNOW-positive results had a lower mean cycle threshold than the 72 with paired BinaxNOW-negative results (17.8 vs. 28.5; p<0.001). Of 100 specimens with cycle threshold <30, a total of 51 resulted in positive virus isolation; 45 (88.2%) of those were BinaxNOW-positive. Our comparison supports immediate isolation for BinaxNOW-positive persons and confirmatory testing for negative persons.

Examining the relationship between ambient carbon monoxide, nitrogen dioxide, and mental health-related emergency department visits in California, USA.

Growing evidence suggests air pollutants may harm the central nervous system, potentially impacting mental health. However, such impacts of air pollutants on mental health and the sub-populations most affected remain poorly understood, especially in California. We examined the relationship between short-term ambient carbon monoxide (CO), nitrogen dioxide (NO2), and mental health-related emergency department (ED) visits in California from 2005 to 2013. Daily mean concentrations of the pollutants were acquired from the U.S. Environmental Protection Agency Air Quality System Data Mart ground monitoring data. Moving averages of pollutant concentrations were linked to counts of ED visits obtained from the California Office of Statewide Health Planning and Development. Seven mental health outcomes, defined by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, were studied: all mental disorders, bipolar disorder, depression, schizophrenia, substance abuse, homicide/inflicted injury, and suicide/self-harm. Monitor-level associations were estimated with quasi-Poisson regression models and combined using random-effects meta-analysis. CO and NO2 were found to be positively associated with ED visits due to homicide/inflicted injury, with the warm season (May-October) driving the CO association. An interquartile range (IQR) (0.28 ppm) increase in two-day average CO during the warm season was associated with a 3.13% (95% confidence interval (CI): 1.43, 4.84) elevation in risk of an ED visit due to homicide/inflicted injury (n = 122,749 ED visits). An IQR (10.79 ppb) increase in two-day average NO2 was associated with a 2.60% (95% CI: 1.17, 4.05) elevation in risk of an ED visit due to homicide/inflicted injury (n = 206,919 ED visits). Subgroup analyses indicated children, Hispanics, and males were particularly vulnerable. Except for an inverse relationship between NO2 and substance abuse, neither pollutant was robustly associated with visits due to other mental health morbidities. Our results suggest short-term elevations in CO and NO2 may promote violent behavior. Further investigation in other populations and ranges of air pollution exposure is warranted.