Exposure to Polyfluoroalkyl Chemicals and Cholesterol, Body Weight, and Insulin Resistance in the General U.S. Population

BACKGROUND. Polyfluoroalkyl chemicals (PFCs) are used commonly in commercial applications and are detected in humans and the environment worldwide. Concern has been raised that they may disrupt lipid and weight regulation. OBJECTIVES. We investigated the relationship between PFC serum concentrations and lipid and weight outcomes in a large publicly available data set. METHODS. We analyzed data from the 2003-2004 National Health and Nutrition Examination Survey (NHANES) for participants 12-80 years of age. Using linear regression to control for covariates, we studied the association between serum concentrations of perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorooctane sulfonic acid (PFOS), and perfluorohexane sulfonic acid (PFHxS) and measures of cholesterol, body size, and insulin resistance. RESULTS. We observed a positive association between concentrations of PFOS, PFOA, and PFNA and total and non-high-density cholesterol. We found the opposite for PFHxS. Those in the highest quartile of PFOS exposure had total cholesterol levels 13.4 mg/dL [95% confidence interval (CI), 3.8-23.0] higher than those in the lowest quartile. For PFOA, PFNA, and PFHxS, effect estimates were 9.8 (95% CI, -0.2 to 19.7), 13.9 (95% CI, 1.9-25.9), and -7.0 (95% CI, -13.2 to -0.8), respectively. A similar pattern emerged when exposures were modeled continuously. We saw little evidence of a consistent association with body size or insulin resistance. CONCLUSIONS. This exploratory cross-sectional study is consistent with other epidemiologic studies in finding a positive association between PFOS and PFOA and cholesterol, despite much lower exposures in NHANES. Results for PFNA and PFHxS are novel, emphasizing the need to study PFCs other than PFOS and PFOA.National Institute of Environmental Health Sciences (R21ES013724, T32ES014562

A New Spin on Research Translation: The Boston Consensus Conference on Human Biomonitoring

BACKGROUND. Translating research to make it more understandable and effective (research translation) has been declared a priority in environmental health but does not always include communication to the public or residents of communities affected by environmental hazards. Their unique perspectives are also commonly missing from discussions about science and technology policy. The consensus conference process, developed in Denmark, offers a way to address this gap. OBJECTIVES. The Boston Consensus Conference on Human Biomonitoring, held in Boston, Massachusetts, in the fall of 2006, was designed to educate and elicit input from 15 Boston-area residents on the scientifically complex topic of human biomonitoring for environmental chemicals. This lay panel considered the many ethical, legal, and scientific issues surrounding biomonitoring and prepared a report expressing their views. DISCUSSION. The lay panel's findings provide a distinct and important voice on the expanding use of biomonitoring. In some cases, such as a call for opt-in reporting of biomonitoring results to study participants, they mirror recommendations raised elsewhere. Other conclusions have not been heard previously, including the recommendation that an individual's results should be statutorily exempted from the medical record unless permission is granted, and the opportunity to use biomonitoring data to stimulate green chemistry. CONCLUSION. The consensus conference model addresses both aspects of a broader conception of research translation: engaging the public in scientific questions, and bringing their unique perspectives to bear on public health research, practice, and policy. In this specific application, a lay panel's recommendations on biomonitoring surveillance, communication, and ethics have practical implications for the conduct of biomonitoring studies and surveillance programs.National Institute of Environmental Health Sciences (R25 ES12084, P42ES007381

Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation.

Genomic sequence interpretation can miss clinically relevant missense variants for several reasons. Rare missense variants are numerous in the exome and difficult to prioritise. Affected genes may also not have existing disease association. To improve variant prioritisation, we leverage population exome data to identify intragenic missense-depleted regions (MDRs) genome-wide that may be important in disease. We then use missense depletion analyses to help prioritise undiagnosed disease exome variants. We demonstrate application of this strategy to identify a novel gene association for human brain malformation. We identified de novo missense variants that affect the GDP/GTP-binding site of ARF1 in three unrelated patients. Corresponding functional analysis suggests ARF1 GDP/GTP-activation is affected by the specific missense mutations associated with heterotopia. These findings expand the genetic pathway underpinning neurologic disease that classically includes FLNA. ARF1 along with ARFGEF2 add further evidence implicating ARF/GEFs in the brain. Using functional ontology, top MDR-containing genes were highly enriched for nucleotide-binding function, suggesting these may be candidates for human disease. Routine consideration of MDR in the interpretation of exome data for rare diseases may help identify strong genetic factors for many severe conditions, infertility/reduction in reproductive capability, and embryonic conditions contributing to preterm loss

Imposters among us: globular cluster kinematics and the halo mass of ultra-diffuse galaxies in clusters

The velocity dispersion of globular clusters (GCs) around ultra-diffuse galaxies (UDGs) in the Virgo cluster spans a wide range, including cases where GC kinematics suggest haloes as massive as (or even more massive than) that of the Milky Way around these faint dwarfs. We analyse the catalogues of GCs derived in post-processing from the TNG50 cosmological simulation to study the GC system kinematics and abundance of simulated UDGs in galaxy groups and clusters. UDGs in this simulation reside exclusively in dwarf-mass haloes with M200 ≲ 1011.2 M⊙. When considering only GCs gravitationally bound to simulated UDGs, we find GCs properties that overlap well with several observational measurements for UDGs. In particular, no bias towards overly massive haloes is inferred from the study of bound GCs, confirming that GCs are good tracers of UDG halo mass. However, we find that contamination by intracluster GCs may, in some cases, substantially increase velocity dispersion estimates when performing projected mock observations of our sample. We caution that targets with less than 10 GC tracers are particularly prone to severe uncertainties. Measuring the stellar kinematics of the host galaxy should help confirm the unusually massive haloes suggested by GC kinematics around some UDGs

Rapid assessment of psychological and epidemiological correlates of COVID-19 concern, financial strain, and health-related behavior change in a large online sample

16 pagesCOVID-19 emerged in November 2019 leading to a global pandemic that has not only resulted in widespread medical complications and loss of life, but has also impacted global economies and transformed daily life. The current rapid response study in a convenience online sample quickly recruited 2,065 participants across the United States, Canada, and Europe in late March and early April 2020. Cross-sectional findings indicated elevated anxiety and depressive symptoms compared to historical norms, which were positively associated with COVID-19 concern more strongly than epidemiological data signifying risk (e.g., world and country confirmed cases). Employment loss was positively associated with greater depressive symptoms and COVID-19 concern, and depressive symptoms and COVID-19 concern were significantly associated with more stringent self-quarantine behavior. The rapid collection of data during the early phase of this pandemic is limited by under-representation of non-White and middle age and older adults. Nevertheless, these findings have implications for interventions to slow the spread of COVID-19 infection.This research was supported by funding from Ann Swindells Endowment to the University of Oregon. The funding sources had no role in the study design, data collection and analysis, or submission process

Rapid assessment of psychological and epidemiological correlates of COVID-19 concern, financial strain, and health-related behavior change in a large online sample

16 pagesCOVID-19 emerged in November 2019 leading to a global pandemic that has not only resulted in widespread medical complications and loss of life, but has also impacted global economies and transformed daily life. The current rapid response study in a convenience online sample quickly recruited 2,065 participants across the United States, Canada, and Europe in late March and early April 2020. Cross-sectional findings indicated elevated anxiety and depressive symptoms compared to historical norms, which were positively associated with COVID-19 concern more strongly than epidemiological data signifying risk (e.g., world and country confirmed cases). Employment loss was positively associated with greater depressive symptoms and COVID-19 concern, and depressive symptoms and COVID-19 concern were significantly associated with more stringent self-quarantine behavior. The rapid collection of data during the early phase of this pandemic is limited by under-representation of non-White and middle age and older adults. Nevertheless, these findings have implications for interventions to slow the spread of COVID-19 infection.This research was supported by funding from Ann Swindells Endowment to the University of Oregon. The funding sources had no role in the study design, data collection and analysis, or submission process

Confirmatory factor analysis of the Child Feeding Questionnaire among low-income African American families of preschool children

This study examined the factor structure for three of the Child Feeding Questionnaire (CFQ) subscales, a widely used measure of parental feeding practices, among 296 low-income parents of African American preschool children. Confirmatory factor analysis showed an overall poor fit among CFQ subscales; Restriction, Pressure to Eat, and Concern about Child Weight, (χ2, (df = 87 = 300.249, CFI = 1.00, NNFI = 1.07, RMSEA = .091). Additionally, Cronbach’s Alpha coefficients for 2 of the three subscales were below acceptable recommendations (Restriction = 0.69; Pressure to Eat = 0.58). These results suggest further psychometric clarification is needed to understand commonly reported feeding practice constructs among low-income African American mothers of preschool aged children

Confirmatory factor analysis of the Child Feeding Questionnaire among low-income African American families of preschool children

This study examined the factor structure for three of the Child Feeding Questionnaire (CFQ) subscales, a widely used measure of parental feeding practices, among 296 low-income parents of African American preschool children. Confirmatory factor analysis showed an overall poor fit among CFQ subscales; Restriction, Pressure to Eat, and Concern about Child Weight, (χ2, (df = 87 = 300.249, CFI = 1.00, NNFI = 1.07, RMSEA = .091). Additionally, Cronbach’s Alpha coefficients for 2 of the three subscales were below acceptable recommendations (Restriction = 0.69; Pressure to Eat = 0.58). These results suggest further psychometric clarification is needed to understand commonly reported feeding practice constructs among low-income African American mothers of preschool aged children

Primary myoblasts from intrauterine growth-restricted fetal sheep exhibit intrinsic dysfunction of proliferation and differentiation that coincides with enrichment of inflammatory cytokine signaling pathways

Intrauterine growth restriction (IUGR) is linked to lifelong reductions in muscle mass due to intrinsic functional deficits in myoblasts, but the mechanisms underlying these deficits are not known. Our objective was to determine if the deficits were associated with changes in inflammatory and adrenergic regulation of IUGR myoblasts, as was previously observed in IUGR muscle. Primary myoblasts were isolated from IUGR fetal sheep produced by hyperthermia-induced placental insufficiency (PI-IUGR; n = 9) and their controls (n = 9) and from IUGR fetal sheep produced by maternofetal inflammation (MI-IUGR; n = 6) and their controls (n = 7). Proliferation rates were less (P \u3c 0.05) for PI-IUGR myoblasts than their controls and were not affected by incubation with IL-6, TNF-α, norepinephrine, or insulin. IκB kinase inhibition reduced (P \u3c 0.05) proliferation of control myoblasts modestly in basal media but substantially in TNF-α-added media and reduced (P \u3c 0.05) PI-IUGR myoblast proliferation substantially in basal and TNF-α-added media. Proliferation was greater (P \u3c 0.05) for MI-IUGR myoblasts than their controls and was not affected by incubation with TNF-α. Insulin increased (P \u3c 0.05) proliferation in both MI-IUGR and control myoblasts. After 72-h differentiation, fewer (P \u3c 0.05) PI-IUGR myoblasts were myogenin+ than controls in basal and IL-6 added media but not TNF-α-added media. Fewer (P \u3c 0.05) PI-IUGR myoblasts were desmin+ than controls in basal media only. Incubation with norepinephrine did not affect myogenin+ or desmin+ percentages, but insulin increased (P \u3c 0.05) both markers in control and PI-IUGR myoblasts. After 96-h differentiation, fewer (P \u3c 0.05) MI-IUGR myoblasts were myogenin+ and desmin+ than controls regardless of media, although TNF-α reduced (P \u3c 0.05) desmin+ myoblasts for both groups. Differentiated PI-IUGR myoblasts had greater (P \u3c 0.05) TNFR1, ULK2, and TNF-α-stimulated TLR4 gene expression, and PI-IUGR semitendinosus muscle had greater (P \u3c 0.05) TNFR1 and IL6 gene expression, greater (P \u3c 0.05) c-Fos protein, and less (P \u3c 0.05) IκBα protein. Differentiated MI-IUGR myoblasts had greater (P \u3c 0.05) TNFR1 and IL6R gene expression, tended to have greater (P = 0.07) ULK2 gene expression, and had greater (P \u3c 0.05) β-catenin protein and TNF-α-stimulated phosphorylation of NFκB. We conclude that these enriched components of TNF-α/TNFR1/NFκB and other inflammatory pathways in IUGR myoblasts contribute to their dysfunction and help explain impaired muscle growth in the IUGR fetus. Lay Summary-- Myoblasts are stems cells whose functional capacity can limit muscle growth. However, stressful intrauterine conditions cause these cells to be intrinsically dysfunctional. This restricts muscle growth capacity, leading to intrauterine growth restriction (IUGR) of the fetus, low birth weight, and less muscle mass after birth. Consequently, meat yield is reduced in IUGR-born food animals and glucose homeostasis is impaired in IUGR-born humans, which contributes to metabolic dysfunction. Intrinsic dysfunction of IUGR myoblasts has been previously observed, but the fetal programming changes (i.e., permanent changes in the development of cellular mechanisms that explains different functional outcomes) have not been identified. This study shows that one mechanism is the enhancement of signaling pathways for TNF-α and other inflammatory cytokines. These cytokines have roles in stress responses and regulation of muscle growth. Programmed enhancement of these pathways means that IUGR myoblasts are more responsive to even normal amounts of circulating cytokines. Unfortunately, the primary response of myoblasts to cytokines is slower differentiation (i.e., cellular transformation necessary for muscle growth). Programmed enhancement of this response directly impedes myoblast-dependent muscle growth, and the deficit is lifelong. However, identifying this mechanism is a fundamental step for developing strategies to improve muscle growth in low birth weight offspring