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Occlusive disease of the iliac veins or major intrathoracic veins have traditionally been managed by conservative management or by major vascular reconstructive procedures. Over the past 15-20 years, these lesions have become amenable to management with venous stents. Lesions in the iliac venous system are typically due to thrombus secondary to deep vein thrombosis, and lesions in the superior vena cava are due to either malignant intrathoracic lesions, indwelling central venous catheters, pacemaker leads, or enlarged nodes due to granulomatous disease. The success rate for implantation is between 92% and 95% and associated implantation complications vary between 2% and 5%. Primary patency of iliac stents is 70-90% at three years. Venous stents have higher patency in the treatment of stenotic lesions compared to totally occlusive lesions. Primary patency of stents placed in the superior vena cava is also about 70-90% and generally lower in lesions due to malignancy likely related to life expectancy. Stents in the venous system are associated with few complications at the time of insertion and have excellent long-term patency.

AIM: To prospectively investigate the associations of urinary phthalate metabolite concentrations measured at four time points spanning pubertal development with semen parameters in Russian men. DESIGN: 516 boys were enrolled at ages 8-9 years (2003-2005) and followed annually. METHODS: Urine samples were collected annually and pooled into four exposure windows [prepuberty, early puberty, late puberty and sexual maturity] based on physician assessed Tanner genitalia stages and testicular volume. Fifteen phthalate metabolites were quantified using isotope dilution HPLC-MS/MS at Moscow State University. We calculated molar sums (∑) of di-2-ethylhexyl phthalate (DEHP), di-isononyl phthalate (DiNP), di-isodecyl phthalate (DiDP) and anti-androgenic phthalate (AAP) metabolites. At sexual maturity (ages 18-19 years), the men provided 1-2 semen samples for analysis. We estimated the associations of quintiles of urinary ∑phthalate metabolites as well as mono-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), and mono-benzyl phthalate (MBzP) at each pubertal window, with semen parameters by fitting generalized linear mixed models with random intercepts and adjusting for confounders. RESULTS: A total of 223 men who provided semen samples had phthalates measured at one or more pubertal windows. Higher urinary concentrations of ∑DiNP metabolites during late puberty were related to poorer semen quality (men with the highest quintile of urinary ∑DiNP had 30% lower sperm concentration, 32% lower count and 30% lower progressive motile count, compared to men in the lowest quintile). Also, young men with higher urinary concentrations of MiBP metabolites in early puberty tended to have poorer semen quality. No associations were observed for ∑DEHP metabolites, ∑DiDP metabolites, ∑AAP, MBzP or MnBP metabolites with semen quality parameters. CONCLUSIONS: ∑DiNP metabolites measured during late puberty and MiBP metabolites at early puberty were related to poorer semen quality, highlighting the importance of considering specific windows of exposure when investigating chemical exposures in relation to measures of reproductive health in men.

Although phthalate exposures have been associated with adverse effects on male reproductive health, few studies have explored longitudinal associations with male pubertal development.We examined the association of prepubertal urinary concentrations of phthalate metabolites with age at pubertal onset in a prospective cohort of Russian boys.At enrollment at ages 8-9 years, medical history, dietary, and demographic information was collected. At entry and annually, physical examinations and pubertal staging [Genitalia (G), Pubarche (P), and testicular volume (TV, in ml)] were conducted and spot urines were collected. Prepubertal urine samples (defined as either TV = 1, 2 and G = 1, 2 or TV = 3 and G = 1) were pooled for each boy and phthalate metabolite concentrations were quantified using isotope dilution LC-MS/MS at Moscow State University. We measured 15 metabolites including those from anti-androgenic parent phthalates (AAPs) such as di (2-ethylhexyl) (DEHP) and di-isononyl (DiNP) phthalates as well as monobenzyl (MBzP), mono-n-butyl (MnBP), and mono-isobutyl (MiBP) metabolites. We calculated the molar sums of DEHP (∑DEHP), DiNP (∑DiNP), and AAP (∑AAP) metabolites. Separate interval-censored models were used to assess associations of quartiles of prepubertal phthalate metabolites with each pubertal onset indicator, G2+, P2+ and TV 3 mL, adjusted for covariates and urine specific gravity.304 boys had 752 prepubertal urine samples (median 2, range: 1-6) for pooling. In adjusted models, higher urinary AAPs were consistently associated with later pubertal onset (P2) with mean shifts ranging from 8.4 to 14.2 months for the highest versus lowest quartiles. Significantly later onset for G2 and TV 3 mL was observed for higher versus lower quartiles of MiBP, MBzP, ∑DEHP and ∑DiNP.On average, boys with higher concentrations of prepubertal urinary AAPs had later pubertal onset by six months to over a year. The impact of AAPs on timing of male puberty may be attributable to disruption of androgen-dependent biological pathways.

The United States has quickly transitioned into one of the epicenters for the coronavirus pandemic. Limitations for rapid testing for the virus responsible for the pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the single most important barrier for early detection and prevention of future outbreaks. Combining innovative molecular biology techniques, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas nuclease systems and next generation sequencing (NGS) may prove to be an effective solution to establish a high-throughput diagnostic and genomic surveillance workflow for COVID-19 in the State of Delaware. Integrating key expertise across the medical institutions in Delaware, including ChristianaCare and Nemours/Alfred I. duPont Hospital for Children, is one potential solution for overcoming current barriers and driving a successful implementation of these techniques. © 2020, Delaware Academy of Medicine. All rights reserved.

The use of next generation sequencing is critical for the surveillance of severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, transmission, as single base mutations have been identified with differences in infectivity. A total of 1,459 high quality samples were collected, sequenced, and analyzed in the state of Delaware, a location that offers a unique perspective on transmission given its proximity to large international airports on the east coast. Pangolin and Nextclade were used to classify these sequences into 16 unique clades and 88 lineages. A total of 411 samples belonging to the Alpha 20I/501Y.V1 (B.1.1.7) strain of concern were identified, as well as one sample belonging to Beta 20H/501.V2 (B.1.351), thirteen belonging to Epsilon 20C/S:452R (B.1.427/B.1.429), two belonging to Delta 20A/S:478K (B.1.617.2), and 15 belonging to Gamma 20J/501Y.V3 (p.1). A total of 2217 unique coding mutations were observed with an average of 17.7 coding mutations per genome. These data paired with continued sample collection and sequencing will give a deeper understanding of the spread of SARS-CoV-2 strains within Delaware and its surrounding areas.

Background: Higher blood lead levels (BLLs) have been linked to neurologic deficits and impaired growth, but few studies have evaluated their association with timing of sexual maturity or pubertal progression in boys. Methods: In a longitudinal cohort of Russian boys enrolled at age 8–9 and followed to adulthood, BLLs were measured at study entry, and pubertal staging (genitalia and pubic hair) and testicular volume (TV) measurements were obtained annually. We used interval-censored regression models to estimate differences between boys with higher BLL (≥5 μg/dL) and lower BLL in mean ages at sexual maturity (genitalia stage 5, pubic hair stage 5, or TV ≥ 20 mL) and duration of pubertal progression (onset to maturity), adjusting for potential confounders. Mediation analyses were conducted to quantify the percent of lead's effect attributable to its association with reduced somatic growth. Results: Among 481 evaluable boys, 28% had BLL ≥ 5 μg/dL. Adjusted mean ages at sexual maturity were 14.7 years for genitalia, 16.1 for pubic hair, and 13.9 for TV. In adjusted models, boys with BLLs ≥5 μg/dL had later maturity than those with lower levels by 4–5 months depending on pubertal indicator. In mediation analyses, height and body mass index at age 11 accounted for 40–71% of the shift in age at maturity for boys with higher compared to lower BLLs. Higher BLLs were not associated with pace of pubertal progression. Conclusions: Higher lead levels were associated with later attainment of sexual maturity in males, but not with the duration of pubertal progression. A high proportion of the delay in sexual maturity for boys with higher as compared to lower BLL was shown to be attributable to mediating effects of BLL on reduced growth. Keywords: Puberty, Growth, Sexual maturity, Blood lead, Endocrine disruptors, Interval-censoring, Mediation analysis, Pubertal progression

Background Dioxins, furans and polychlorinated biphenyls (PCBs) are endocrine disruptors with half-lives of months to years in humans. Peripubertal exposure to these chemicals may disrupt pubertal timing. Biomarker exposure metrics like the sum of non-dioxin-like PCBs in serum (∑NDL-PCBs) involve chemicals with different hypothetical effects. Empirical exposure metrics represent an alternative that requires no knowledge of biological mechanisms. Methods From 2003 to 2005, 516 Russian boys aged 8–9 residing near a plant that historically produced organochlorine pesticides were enrolled in the Russian Children’s Study. At enrollment, blood was collected for measurement of organochlorine chemicals by the Centers for Disease Control and Prevention (CDC). Variable cluster analysis was used to empirically group serum levels of 45 dioxins, furans and PCBs into eight cluster scores. These scores were compared to the sum of dioxin-like toxic equivalents (∑TEQs) and ∑NDL-PCBs using Spearman correlation coefficients. Results Clustering appeared to reflect number and position of chlorine atoms. Clusters 4, 7 and 1 contained, respectively, tri/tetra-, tetra/penta-, and hexa/hepta-chlorinated PCBs with chlorines at the 4,4′ positions. Clusters 2, 8 and 5 contained, respectively, tetra-to hexa-, hexa/hepta-, and hepta/octa-chlorinated PCBs with chlorines at the 2,2′ positions. ∑NDL-PCBs were highly correlated with 4,4′-chlorinated clusters 1 and 7 (Spearman’s ρ = 0.8) and less so with all other clusters (Spearman’s ρ = 0.4–0.5). Conclusions In this cohort of Russian boys, baseline serum dioxins, furans and PCBs seemed to cluster by chlorination pattern, possibly reflecting shared persistence, metabolism or source of exposure. The widely used measure ∑NDL-PCB seemed most representative of 4,4′-chlorinated PCBs.

Background Epidemiologic literature on the relation of organochlorine pesticides (OCPs) with semen quality among adult men has been inconclusive, and no studies have prospectively explored the association between peripubertal serum OCPs and semen parameters in young men. Objective To evaluate prospective associations of peripubertal serum concentrations of hexachlorobenzene (HCB), β-hexachlorocylohexane (β-HCH), and p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE) with semen parameters among young Russian men. Methods This prospective cohort study included 152 young men who enrolled in the Russian Children’s Study (2003–2005) at age 8–9 years and were followed annually until young adulthood. HCB, β-HCH, and p,p′-DDE concentrations were measured at the CDC by mass spectrometry in serum collected at enrollment. Between 18 and 23 years, semen samples (n = 298) were provided for analysis of volume, concentration, and progressive motility; we also calculated total sperm count and total progressive motile count. Linear mixed models were used to examine the longitudinal associations of quartiles of serum HCB, β-HCH and p,p′-DDE with semen parameters, adjusting for total serum lipids, body mass index, smoking, abstinence time and baseline dietary macronutrient intake. Results Lipid-adjusted medians (IQR) for serum HCB, βHCH and p,p-DDE, respectively, were 150 ng/g lipid (102–243), 172 ng/g lipid (120–257) and 275 ng/g lipid (190–465). In adjusted models, we observed lower ejaculated volume with higher serum concentrations of HCB and βHCH, along with reduced progressive motility with higher concentrations of βHCH and p,p-DDE. Men in the highest quartile of serum HCB had a mean (95% Confidence Interval, CI) ejaculated volume of 2.25 mL (1.89, 2.60), as compared to those in the lowest quartile with a mean (95% CI) of 2.97 mL (2.46, 3.49) (p = 0.03). Also, men in the highest quartile of serum p,p-DDE had a mean (95% CI) progressive motility of 51.1% (48.6, 53.7), as compared to those in the lowest quartile with a mean (95% CI) of 55.1% (51.7, 58.5) (p = 0.07). Conclusion In this longitudinal Russian cohort study, peripubertal serum concentrations of selected OCPs were associated with lower ejaculated volume and progressive motility highlighting the importance of the peripubertal window when evaluating chemical exposures in relation to semen quality.

Protein arginine methyltransferase 5 (PRMT5) is the primary methyltransferase generating symmetric-dimethyl-arginine marks on histone and non-histone proteins. PRMT5 dysregulation is implicated in multiple oncogenic processes. Here, we report that PRMT5-mediated methylation of protein kinase B (AKT) is required for its subsequent phosphorylation at Thr308 and Ser473. Moreover, pharmacologic or genetic inhibition of PRMT5 abolishes AKT1 arginine 15 methylation, thereby preventing AKT1 translocation to the plasma membrane and subsequent recruitment of its upstream activating kinases PDK1 and mTOR2. We show that PRMT5/AKT signaling controls the expression of the epithelial-mesenchymal-transition transcription factors ZEB1, SNAIL, and TWIST1. PRMT5 inhibition significantly attenuates primary tumor growth and broadly blocks metastasis in multiple organs in xenograft tumor models of high-risk neuroblastoma. Collectively, our results suggest that PRMT5 inhibition augments anti-AKT or other downstream targeted therapeutics in high-risk metastatic cancers.

Protein arginine methyltransferase 5 (PRMT5) regulates a wide range of physiological processes, including cancer cell proliferation and metastasis, by generating symmetric di-methyl-arginine marks on histones and non-histone proteins. Here, we report that PRMT5 directly regulates epidermal growth factor receptor (EGFR) transcription to control EGF stimulated EGFR signaling. Furthermore, PRMT5 modulates protein kinase B (AKT) activation by methylation of AKT1 Arg 15, which is required for its subsequent phosphorylation at AKT1 Thr 308 and Ser 473. The PRMT5/EGFR/AKT axis converges to regulate transcription factors ZEB1, SNAIL, and TWIST1 to promote the epithelial-mesenchymal transition (EMT), in the manner that EGFR and AKT1 compensate each other to support tumor cell invasion and metastasis. Inhibiting PRMT5 methyltransferase activity with a small molecule inhibitor attenuated primary tumor growth and prevented hepatic metastasis in aggressive in vivo tumor models. Collectively, our results support the use of PRMT5 based therapies for metastatic cancer.

Racial equity is closely linked to principles of fairness and justice. It is distinct from the concept of racial equality. Community engaged strategies aimed at creating racial equity have generated effective ways to dismantle structural racism—the racialized policies and practices that have shaped economic and social institutions in the United States throughout its history. In crafting the Food & Fitness Initiative, the W.K. Kellogg Foundation made advancing racial equity a top priority. By doing so, it encouraged the community partnerships funded under the initiative to apply theories of expanding equity to real-world situations in order to reduce racial disparities in their neighborhoods. This article reviews the methods that were employed over the course of the initiative to support the partnerships with their efforts. It highlights three key components: (1) being intentional about maintaining a focus on racial equity, (2) concentrating on changing policies and systems, and (3) consistently incorporating meaningful and authentic community engagement into the work. The importance of making the concept of equity concrete and measurable is explored. Furthermore, the article discusses strategies that strengthened the capacity of the partnerships to navigate the policy-making process and to build leadership and shift power to community residents. The article concludes by detailing measures that could guide future efforts to make racial equity a priority and emphasizes that doing so is crucial given the rapid demographic shifts underway across the country.

Protein arginine methyltransferase 5 (PRMT5) regulates gene expression either transcriptionally by symmetric dimethylation of arginine residues on histones H4R3, H3R8, and H2AR3 or at the posttranslational level by methylation of nonhistone target proteins. Although emerging evidence suggests that PRMT5 functions as an oncogene, its role in metabolic diseases is not well-defined. We investigated the role of PRMT5 in promoting high-fat–induced hepatic steatosis. A high-fat diet up-regulated PRMT5 levels in the liver but not in other metabolically relevant tissues such as skeletal muscle or white and brown adipose tissue. This was associated with repression of master transcription regulators involved in mitochondrial biogenesis. In contrast, lentiviral short hairpin RNA–mediated reduction of PRMT5 significantly decreased phosphatidylinositol 3-kinase/AKT signaling in mouse AML12 liver cells. PRMT5 knockdown or knockout decreased basal AKT phosphorylation but boosted the expression of peroxisome proliferator–activated receptor α (PPARα) and PGC-1α with a concomitant increase in mitochondrial biogenesis. Moreover, by overexpressing an exogenous WT or enzyme-dead mutant PRMT5 or by inhibiting PRMT5 enzymatic activity with a small-molecule inhibitor, we demonstrated that the enzymatic activity of PRMT5 is required for regulation of PPARα and PGC-1α expression and mitochondrial biogenesis. Our results suggest that targeting PRMT5 may have therapeutic potential for the treatment of fatty liver.

Background: Measurement of intervention fidelity is an essential component of any scientifically sound intervention trial. However, few papers have proposed ways to integrate intervention fidelity data into the execution of these trials. Objective: The purpose of this article is to describe the intervention fidelity process used in a randomized controlled trial of a human patient simulator intervention and how these data were used to monitor drift and provide feedback to improve the consistency of both intervention and control delivery over time in a multisite education intervention for parents of children with newly diagnosed Type 1 diabetes. Methods: Intervention fidelity was measured for both the intervention and control condition by direct observation, self-report of interventionist delivery, and parent participant receipt of educational information. Intervention fidelity data were analyzed after 50%, 75%, and 100% of the participants had been recruited and compared by group (treatment and control) and research site. Results: The sample included 191 parents of young children newly diagnosed with Type 1 diabetes. Observations scores in both intervention and control groups indicated a high level of intervention fidelity. Treatment receipt was also high and did not differ by treatment group. The teaching session attendance rates by site and session were significantly different at Time Point 1 (50% enrollment); following study staff retraining and reinforcement, there were no significant differences at Time Point 3 (100% enrollment). Implications: Results demonstrate the importance of monitoring intervention fidelity in both the intervention and control condition over time and using these data to correct drift during the course of a multisite clinical trial.

Summary Background & aims Body mass index is a simple anthropometric measure (kg/m2) used as an indirect estimate of body fat in individuals, and in assessments of population health and comparisons between populations. Bioelectrical impedance analysis (BIA) is often used to provide additional information on body fat and fat-free mass, and has been used to generate body composition reference data in national health surveys. However, BIA measurements are known to be device-specific and there are few published studies comparing results from different BIA instruments. Therefore, we compared the performance of two BIA instruments in the Russian Children's Study (RCS) of male growth, pubertal development and maturation. Methods Paired BIA measurements were obtained using the Tanita BC-418MA (Tanita Corp., Tokyo, Japan) and ABC-01 ‘Medas’ (Medas Ltd, Moscow, Russia) BIA instruments. Cross-sectional data on 236 RCS subjects aged 18–22 years were used for the BIA comparison and the development of a conversion formula between measured resistances; follow-up data (n = 96) were used for validation of the conversion formula. Results Whole-body resistances were highly correlated (Spearman rho = 0.95), but fat mass (FM) estimates were significantly higher with the Medas than the Tanita device (median difference 3.3 kg, 95% CI: 2.9, 3.6 kg) with large limits of agreement (LoA) for the FM difference (−2.0, 8.6 kg). A conversion formula between the resistances (Res) was obtained: Medas Res = 0.882 × Tanita Res+26.2 (r2 = 0.91, SEE = 17.6 Ohm). After applying the conversion formula to Tanita data and application of the Medas assessment algorithm, the ‘converted’ Tanita FM estimates closely matched the Medas original estimates (median difference −0.1 kg, 95% CI: −0.3, 0.2 kg), with relatively small LoA for the FM difference (−2.3 to 2.1 kg), suggesting potential interchangeability of the ABC-01 ‘Medas’ and Tanita BC-418MA data at the group level. Conclusions Our results support the importance of cross-calibration of BIA instruments for population comparisons and proper data interpretation in clinical and epidemiological studies.

BACKGROUND: Childhood exposure to organochlorines has been associated with alterations in somatic growth. We evaluated the associations of peri-pubertal serum levels of dioxin-like compounds (DLCs) and nondioxin-like polychlorinated biphenyls (NDL-PCBs), with adolescent growth, body composition, and near adult height (NAH) in a longitudinal cohort study of Russian boys. METHODS: 473 8–9 year-old boys had serum DLCs and associated toxic equivalents (TEQs) and NDL-PCBs concentrations measured. Physical examinations were performed at enrollment between 2003–2005, and annually over 11 years to 2016; annual bio-electric impedance analysis (BIA) of body composition began in 2006. We used mixed effects models to evaluate associations of quartiles of serum chemical concentrations with longitudinal measurements through age 19 of body mass index (BMI-Z) and height (HT-Z) z-scores, annual height velocity (HV), and BIA-derived height-adjusted fat (FMi) and fat-free mass (FFMi) indexes. Potential modification by age of the associations of chemical exposures with growth was evaluated. NAH (defined as HV

Objective Parents who have a child newly diagnosed with type 1 diabetes (T1D) must quickly learn daily diabetes self-management. An RCT was conducted using human patient simulation (HPS) to enhance parents learning diabetes self-management with children with new-onset T1D. The purpose of this study was to describe parents’ perspectives of using HPS to augment diabetes education. Methods A qualitative descriptive design was used with open-ended in-depth interviews of parents (n = 49) post-intervention. Qualitative directed content analysis was used. Results The majority of parents were positive about learning with HPS. Although a few parents said the HPS was “hokey” or “creepy,” most reported the visual and hands-on learning was realistic and very beneficial. Seeing a seizure increased their fear although they would have panicked if they had not had that learning experience, and it helped build their diabetes self-management confidence. Recommendations included teaching others with the HPS (grandparents, siblings, babysitters, and school nurses). Conclusion HPS-enhanced education is an acceptable and viable option that was generally well-received by parents of children with new-onset T1D. Practice implications The technique should be studied with parents of children with other chronic illnesses to see if the benefits found in this study are applicable to other settings.

Background: Dioxins, furans, and polychlorinated biphenyls (PCBs), dioxin-like and non-dioxin-like, have been linked to alterations in puberty. Objectives: We examined the association of peripubertal serum levels of these compounds [and their toxic equivalents (TEQs)] with pubertal onset and maturity among Russian boys enrolled at ages 8–9 years and followed prospectively through ages 17–18 years. Methods: At enrollment, 473 boys had serum dioxin-like compounds and PCBs measured. At the baseline visit and annually until age 17–18 years, a physician performed pubertal staging [genitalia (G), pubarche (P), and testicular volume (TV)]. Three hundred fifteen subjects completed the follow-up visit at 17–18 years of age. Pubertal onset was defined as TV > 3 mL, G2, or P2. Sexual maturity was defined as TV ≥ 20 mL, G5, or P5. Multivariable interval-censored models were used to evaluate associations of lipid-standardized concentrations with pubertal timing. Results: Medians (interquartile ranges) of the sum of dioxin-like compounds, TEQs, and non-dioxin-like PCBs were 362 pg/g lipid (279–495), 21.1 pg TEQ/g lipid (14.4–33.2), and 250 ng/g lipid (164–395), respectively. In adjusted models, the highest compared to lowest TEQ quartile was associated with later pubertal onset [TV = 11.6 months (95% CI: 3.8, 19.4); G2 = 10.1 months (95% CI: 1.4, 18.8)] and sexual maturity [TV = 11.6 months (95% CI: 5.7, 17.6); G5 = 9.7 months (95% CI: 3.1, 16.2)]. However, the highest compared to the lowest quartile of non-dioxin-like PCBs, when co-adjusted by TEQs, was associated with earlier pubertal onset [TV = –8.3 months (95% CI:–16.2, –0.3)] and sexual maturity [TV = –6.3 months (95% CI:–12.2, –0.3); G5 = –7.2 months (95% CI:–13.8, –0.6)]; the non-dioxin-like PCB associations were only significant when adjusted for TEQs. TEQs and PCBs were not significantly associated with pubic hair development. Conclusions: Our results suggest that TEQs may delay, while non-dioxin-like PCBs advance, the timing of male puberty. Citation: Burns JS, Lee MM, Williams PL, Korrick SA, Sergeyev O, Lam T, Revich B, Hauser R. 2016. Associations of peripubertal serum dioxin and polychlorinated biphenyl concentrations with pubertal timing among Russian boys. Environ Health Perspect 124:1801–1807; http://dx.doi.org/10.1289/EHP154

Introduction: Inorganic arsenic (iAs) has been associated with type 2 diabetes in adults, but there are few studies in children. We assessed the associations of peripubertal urinary iAs concentrati...

This chapter reviews normal variant short stature, comprised of both familial short stature (FSS) and constitutional delay of growth and puberty (CDGP), as well as idiopathic short stature (ISS). FSS and CDGP are physiologic variants of short stature without an organic cause. Although ISS is not a “normal variant” of short stature, as with FSS and CDGP it does not have an underlying pathological etiology. A child with short stature requires a comprehensive history and physical examination and consideration for diagnostic studies prior to establishing these non-pathological causes of short stature. Once a diagnosis of either a normal variant short stature or ISS is established, then ongoing monitoring of auxologic parameters throughout childhood and adolescence is indicated. The Food and Drug Administration’s approval of growth hormone for ISS triggered considerable debate within the medical community in terms of costs, benefits, and the ethics of treating children with growth hormone for this form of non-pathological short stature. The treatment of normal variant short stature and ISS should be individualized for each child.

Background: In animal studies, organochlorine pesticide (OCP) exposure alters pubertal development; however, epidemiological data are limited and inconsistent. Objective: To evaluate the associations of serum OCP concentrations [hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), and p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE)] with male pubertal onset. Methods: In Chapaevsk, Russia, a town environmentally contaminated with OCPs, 350 8–9 year old boys with measured OCPs were enrolled during 2003–2005 and were followed annually for eight years. We evaluated three measures of pubertal onset: testicular volume (TV) > 3 mL in either testis, or stage 2 or greater for genitalia (G2+), or pubic hair (P2+). We used multivariable interval-censored models to evaluate associations of OCPs (quartiles) with physician-assessed pubertal onset. Results: In adjusted models, boys with higher HCB concentrations had later mean ages of TV > 3 mL and P2+ (but not G2+). Mean age at attaining TV > 3 mL was delayed 3.6 (95% CI: −2.6, 9.7), 7.9 (95% CI: 1.7, 14.0), and 4.7 months (95% CI: −1.4, 10.9) for HCB Q2, Q3, and Q4, respectively, compared to Q1 (trend p: 0.06). Boys with higher HCB concentrations reached P2+ 0.1 months earlier (95% CI: −5.8, 5.6) for Q2, 4.7 months later (95% CI: −1.0, 10.3) for Q3 and 4.6 months later (95% CI: −1.1, 10.3) for Q4 compared to Q1 (trend p: 0.04). There were no associations of serum β-HCH and p,p′-DDE concentrations with age of pubertal onset. Conclusion: Higher prepubertal serum HCB concentrations were associated with later age of gonadarche and pubarche. Keywords: β-HCH, HCB, Organochlorine pesticides, Male puberty, p,p′-DDE

Purpose of review The current review summarizes recent epidemiologic data demonstrating the effects of endocrine disrupting compounds (EDCs) on the timing of puberty and highlights the complexity of understanding the interplay of environmental and genetic factors on pubertal timing. Recent findings In girls, there have been mixed results, with some exposures being associated with earlier timing of puberty, and some with later puberty. In boys, prepubertal exposures to nondioxin-like polychlorinated biphenyls accelerate puberty, whereas levels of insecticides, dioxin-like compounds, organochlorine pesticides, and lead delay puberty. Summary The effects of EDCs on pubertal timing are sexually dimorphic, compound specific, and varies according to the window of exposure. These studies confirm that low-level exposures to a mix of environmental compounds may mask the effects of individual compounds and complicate our ability to translate data from animal studies to human health and to fully understand the clinical implications of environmental epidemiology studies.

Background The association of exposure to endocrine disrupting chemicals in the peripubertal period with subsequent sperm DNA methylation is unknown. Objective We examined the association of peripubertal serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations with whole-genome bisulfite sequencing (WGBS) of sperm collected in young adulthood. Methods The Russian Children’s Study is a prospective cohort of 516 boys who were enrolled at 8–9 years of age and provided semen samples at 18–19 years of age. WGBS of sperm was conducted to identify differentially methylated regions (DMR) between highest (n = 4) and lowest (n = 4) peripubertal TCDD groups. Results We found 52 DMRs that distinguished lowest and highest peripubertal serum TCDD concentrations. One of the top scoring networks, “Cellular Assembly and Organization, Cellular Function and Maintenance, Carbohydrate Metabolism”, identified estrogen receptor alpha as its central regulator. Conclusion Findings from our limited sample size suggest that peripubertal environmental exposures are associated with sperm DNA methylation in young adults.

Background: Childhood blood lead levels (BLL) have been associated with growth impairment. Objectives: We assessed associations of peripubertal BLL with adolescent growth and near adult height in a longitudinal cohort of Russian boys. Methods: 481 boys were enrolled at ages 8–9years and followed annually to age 18. At enrollment, BLL was measured, and height, weight, and pubertal staging were obtained annually during 10years of follow-up. Mixed effects models were used to assess the associations of BLL with longitudinal age-adjusted World Health Organization Z-scores for height (HT-Z) and body mass index (BMI-Z), and annual height velocity (HV). Interactions between boys' age and BLL on growth outcomes were evaluated. Results: The median (range) BLL was 3.0 (0.5–31.0) μg/dL. At age 18years, 79% of boys had achieved near adult height (HV

Organochlorine pesticides (OCPs) have been linked to adult metabolic disorders; however, few studies have examined these associations in childhood. We prospectively evaluated the associations of baseline serum OCPs (hexachlorobenzene, β-hexachlorocyclohexane, and p,p'-dichlorodiphenyldichloroethylene) in Russian boys with subsequent repeated measurements of serum glucose, insulin, lipids, leptin, and calculated homeostatic model assessment of insulin resistance (IR). During 2003-2005, we enrolled 499 boys aged 8-9 years in a prospective cohort; 318 had baseline serum OCPs and serum biomarkers measured at ages 10-13 years. Multivariable generalized estimating equation and mediation regression models were used to examine associations and direct and indirect (via body mass index (BMI) (weight (kg)/height (m)(2))) effects of prepubertal OCP tertiles and quintiles with biomarkers. In multivariable models, higher p,p'-dichlorodiphenyldichloroethylene (quintile 5 vs. quintile 1) was associated with lower leptin, with relative mean decreases of 61.8% (95% confidence interval: 48.4%, 71.7%) in models unadjusted for BMI and 22.2% (95% confidence interval: 7.1%, 34.9%) in models adjusted for BMI; the direct effect of p,p'-dichlorodiphenyldichloroethylene on leptin accounted for 27% of the total effect. IR prevalence was 6.6% at ages 12-13 years. Higher hexachlorobenzene (tertile 3 vs. tertile 1) was associated with higher odds of IR in models adjusted for BMI (odds ratio = 4.37, 95% confidence interval: 1.44, 13.28). These results suggest that childhood OCPs may be associated with IR and lower leptin.

Purpose The purpose of this exploratory focus group study was to describe the perspectives of teens and their parents about self-management knowledge, behaviors (including division of labor associated with T1D management), and resources used to manage T1D. The overall goal is to use this information to develop a teen–family transition clinic. Methods The self and family management behaviors framework undergirded the separate teen–parent focus groups that were conducted concurrently. Note-based qualitative content analysis was used, resulting in several important messages. Results From the teens’ perspective there was variation in interest in learning more about T1D and management. Those teens who had been diagnosed at a very young age reported not knowing anything else but diabetes, while those diagnosed later developmentally embraced the active learning process. Diabetes camp and peer group support were not seen as beneficial. All the teens were interested in “helping others” with diabetes. Parents shared the common struggle with transition of self-management, with variation in parenting styles. A small group of parents reported their “job” as a parent was to make sure their child was self-sufficient in self-management, but felt pressure from the health care providers (HCPs) to physically do the care, defeating the purpose. Parents and teens reported wanting HCPs to be less focused on “numbers” (blood glucose levels) and more on the whole person. Scheduling appointment changes and long waiting times were reported as problematic by all participants. Conclusions Teen and parent perspectives are critical in designing future well-received adolescent–family transition clinics. Development from the ground up with family recommendations may contribute to high-quality health outcomes.

Background: Few studies have evaluated predictors of childhood exposure to organochlorine pesticides (OCPs), a class of lipophilic persistent chemicals. Objectives: Our goal was to identify predictors of serum OCP concentrations—hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), and p,p-dichlorodiphenyldichloroethylene (p,p´-DDE)—among boys in Chapaevsk, Russia. Methods: Between 2003 and 2005, 499 boys 8–9 years of age were recruited in a prospective cohort. The initial study visit included a physical examination; blood collection; health, lifestyle, and food-frequency questionnaires; and determination of residential distance from a local factory complex that produced HCB and β-HCH. Fasting serum samples were analyzed for OCPs at the U.S. Centers for Disease Control and Prevention. General linear regression models were used to identify predictors of the boys’ serum HCB, β-HCH, and p,p´-DDE concentrations. Results: Among 355 boys with OCP measurements, median serum HCB, β-HCH, and p,p´-DDE concentrations were 158, 167, and 284 ng/g lipid, respectively. Lower body mass index, longer breastfeeding duration, and local dairy consumption were associated with higher concentrations of OCPs. Boys who lived < 2 km from the factory complex had 64% (95% CI: 37, 96) and 57% (95% CI: 32, 87) higher mean HCB and β-HCH concentrations, respectively, than boys who lived ≥ 5 km away. Living > 3 years in Chapaevsk predicted higher β-HCH concentrations, and having parents who lacked a high school education predicted higher p,p´-DDE concentrations. Conclusions: Among this cohort of prepubertal Russian boys, predictors of serum OCPs included consumption of local dairy products, longer local residence, and residential proximity to the local factory complex. Citation: Lam T, Williams PL, Burns JS, Sergeyev O, Korrick SA, Lee MM, Birnbaum LS, Revich B, Altshul LM, Patterson DG Jr, Turner WE, Hauser R. 2013. Predictors of serum chlorinated pesticide concentrations among prepubertal Russian boys. Environ Health Perspect 121:1372–1377; http://dx.doi.org/10.1289/ehp.1306480

Background: Childhood lead exposure has been associated with growth delay. However, the association between blood lead levels (BLLs) and insulin-like growth factor 1 (IGF-1) has not been characterized in a large cohort with low-level lead exposure. Methods: We recruited 394 boys 8–9 years of age from an industrial Russian town in 2003–2005 and followed them annually thereafter. We used linear regression models to estimate the association of baseline BLLs with serum IGF-1 concentration at two follow-up visits (ages 10–11 and 12–13 years), adjusting for demographic and socioeconomic covariates. Results: At study entry, median BLL was 3 μg/dL (range, < 0.5–31 μg/dL), most boys (86%) were prepubertal, and mean ± SD height and BMI z-scores were 0.14 ± 1.0 and –0.2 ± 1.3, respectively. After adjustment for covariates, the mean follow-up IGF-1 concentration was 29.2 ng/mL lower (95% CI: –43.8, –14.5) for boys with high versus low BLL (≥ 5 μg/dL or < 5 μg/dL); this difference persisted after further adjustment for pubertal status. The association of BLL with IGF-1 was stronger for mid-pubertal than prepubertal boys (p = 0.04). Relative to boys with BLLs < 2 μg/dL, adjusted mean IGF-1 concentrations decreased by 12.8 ng/mL (95% CI: –29.9, 4.4) for boys with BLLs of 3–4 μg/dL; 34.5 ng/mL (95% CI: –53.1, –16.0) for BLLs 5–9 μg/dL; and 60.4 ng/mL (95% CI: –90.9, –29.9) for BLLs ≥ 10 μg/dL. Conclusions: In peripubertal boys with low-level lead exposure, higher BLLs were associated with lower serum IGF-1. Inhibition of the hypothalamic–pituitary–growth axis may be one possible pathway by which lead exposure leads to growth delay.

The purpose of this study is to determine whether parental knowledge of the continuous subcutaneous insulin infusion (CSII) device affects glycemic control as measured by hemoglobin A1c (A1C) level.Parents of children with type 1 diabetes mellitus (T1DM) using CSII completed a 14-item questionnaire. Questions 1-10 were knowledge-based questions that required the parent to extract specific information from their child's CSII device. Questions 11-14 asked parents to provide a self-assessment of their CSII knowledge.Twenty-two parents of youth with T1DM participated in the study. Ten of the youth were in the Low-A1C group (A1C8%), and the other 12 were in the High-A1C group (A1C≥8%). Parents of youth in the Low-A1C group scored statistically better on the 10-item performance survey than parents of youth in the High-A1C group. Most of the parents of children in the Low-A1C group responded that they knew their child's insulin pump "very well" and that their pump knowledge had "increased" since their child started on the insulin pump.Our findings reveal that youth with T1DM whose parents are more knowledgeable about pump functions have optimal glycemic control as evidenced by A1C. These findings underscore the importance of ongoing pump training for both pediatric patients and their parents.

Organochlorine chemicals and lead are environmental exposures that have endocrine disrupting properties (EDCs) which interfere with many aspects of hormone action. Childhood and adolescence are windows of susceptibility for adverse health effects of EDCs. Our ongoing study, the Russian Children’s Study (RCS), is one of the few longitudinal studies investigating the impact of EDCs on growth and puberty in boys. It is conducted in the historically contaminated city of Chapaevsk, in the Samara region. The study focuses on evaluating the associations of persistent organochlorine chemicals and lead with growth and pubertal timing. At enrollment in 2003–2005, we collected blood from 516 boys at ages 8–9 years to measure dioxins, furans, polychlorinated biphenyls (PCBs), chlorinated pesticides and lead. At enrollment and at annual visits through the ages of 18–19 years, a physician performed physical examinations that included pubertal staging and testicular volume measurements. We review the history of Chapaevsk as a research site and summarize published RCS data on the association of peripubertal serum concentrations of organochlorines and blood lead levels with growth, pubertal onset and sexual maturity. Overall, we found that persistent organochlorines and lead negatively affected growth during puberty. Our results also suggest that total toxic equivalents (TEQs), dioxin-like compounds, organochlorine pesticides and lead may delay, while nondioxin-like-PCBs may advance, the timing of male puberty. These findings promoted remediation programs in Chapaevsk, with improvement in health indicators, resulting in Chapaevsk being designated a member of the World Health Organization (WHO) network “Healthy Cities” in 2015.

Background: Exposures to endocrine-disrupting chemicals during critical phases of testicular development may be related to poorer semen parameters. However, few studies have assessed the association between childhood organochlorine (OC) exposure and adult semen parameters. Objective: We examined whether peripubertal serum OC concentrations are associated with semen parameters among young Russian men. Methods: From 2003 through 2005, 516 boys were enrolled at age 8–9 years and followed for up to 10 years. Serum OCs were measured in the enrollment samples using high-resolution mass spectrometry. At 18–19 years, 133 young men provided 1 or 2 semen samples (256 samples) collected approximately 1 week apart, which were analyzed for volume, sperm concentration, and motility. Unadjusted and adjusted linear mixed models were used to examine the associations of quartiles of lipid-standardized concentrations of dioxins [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated dibenzo-p-dioxins (PCDDs)], furans, polychlorinated biphenyls (PCBs), and corresponding toxic equivalents (TEQs) with semen parameters. Results: The median (range) for TCDD was 2.9 (0.4–12.1) pg/g lipid and PCDD TEQ was 8.7 (1.0–36.0) pg TEQ/g lipid. Higher quartiles of TCDD and PCDD TEQs were associated with lower sperm concentration, total sperm count, and total motile sperm count (p-trends ≤ 0.05). The highest quartile of peripubertal serum TCDD concentrations was associated with a decrease (95% CI) of 40% (18, 66%), 29% (3, 64%), and 30% (2, 70%) in sperm concentration, total sperm count, and total motile sperm count, respectively, compared with the lowest quartile. Similar associations were observed for serum PCDD TEQs with semen parameters. Serum PCBs, furans, and total TEQs were not associated with semen parameters. Conclusion: Higher peripubertal serum TCDD concentrations and PCDD TEQs were associated with poorer semen parameters. Citation: Mínguez-Alarcón L, Sergeyev O, Burns JS, Williams PL, Lee MM, Korrick SA, Smigulina L, Revich B, Hauser R. 2017. A longitudinal study of peripubertal serum organochlorine concentrations and semen parameters in young men: the Russian Children’s Study. Environ Health Perspect 125:460–466; http://dx.doi.org/10.1289/EHP25

To improve health in the twenty-first century, to promote both access to and quality of health care services and delivery, and to address significant health disparities, legal and policy approaches, specifically those focused on civil rights, could be used more intentionally and strategically. This review describes how civil rights laws, and their implementation and enforcement, help to encourage health in the United States, and it provides examples for peers around the world. The review uses a broad lens to define health for both classes of individuals and their communities—places where people live, learn, work, and play. Suggestions are offered for improving health and equity broadly, especially within societal groups and marginalized populations. These recommendations include multisectorial approaches that focus on the social determinants of health.

Background: Few studies have investigated reproductive health effects of contemporary agricultural pesticides in boys. Objectives: To determine the association between pesticide exposure and reproductive health of boys. Methods: We conducted a cross-sectional study in rural South Africa of boys living on and off farms. The study included a questionnaire (demographics, general and reproductive health, phyto-estrogen intake, residential history, pesticide exposures, exposures during pregnancy); and a physical examination that included sexual maturity development ratings; testicular volume; height, weight, body mass index; and sex hormone concentrations. Results: Among the 269 boys recruited into the study, 177 (65.8%) were categorized as farm (high pesticide exposures) and 98 (34.2%) as non-farm residents (lower pesticide exposures). Median ages of the two groups were 11.3 vs 12.0 years, respectively (p

Background: Exposure to dioxins has been associated with delayed pubertal onset in both epidemiologic and animal studies. Whether genetic polymorphisms may modify this association is currently unknown. Identifying such genes could provide insight into mechanistic pathways. This is one of the first studies to assess genetic susceptibility to dioxins. Objectives: We evaluated whether common polymorphisms in genes affecting either molecular responses to dioxin exposure or pubertal onset influence the association between peripubertal serum dioxin concentration and male pubertal onset. Methods: In this prospective cohort of Russian adolescent boys (n = 392), we assessed gene–environment interactions for 337 tagging single-nucleotide polymorphisms (SNPs) from 46 candidate genes and two intergenic regions. Dioxins were measured in the boys’ serum at age 8–9 years. Pubertal onset was based on testicular volume and on genitalia staging. Statistical approaches for controlling for multiple testing were used, both with and without prescreening for marginal genetic associations. Results: After accounting for multiple testing, two tag SNPs in the glucocorticoid receptor (GR/NR3C1) gene and one in the estrogen receptor-α (ESR1) gene were significant (q < 0.2) modifiers of the association between peripubertal serum dioxin concentration and male pubertal onset defined by genitalia staging, although not by testicular volume. The results were sensitive to whether multiple comparison adjustment was applied to all gene–environment tests or only to those with marginal genetic associations. Conclusions: Common genetic polymorphisms in the glucocorticoid receptor and estrogen receptor-α genes may modify the association between peripubertal serum dioxin concentration and pubertal onset. Further studies are warranted to confirm these findings.