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Cardiovascular diseases (CVDs) are the leading cause of death worldwide, which may be due to sedentary lifestyles with less physical activity and over nutrition as well as an increase in the aging population; however, the contribution of pollutants, environmental chemicals and nonessential metals to the increased and persistent CVDs needs more attention and investigation. Among environmental contaminant nonessential metals, antimony has been less addressed.Among environmental contaminant nonessential metals, several metals such as lead, arsenic, and cadmium have been associated with the increased risk of CVDs. Antimony has been less addressed, but its potential link to CVDs is being gradually recognized.Several epidemiological studies have revealed significant deleterious effects of antimony on the cardiovascular system in absence or presence of other nonessential metals. There has been less focus on whether antimony alone can contribute to the pathogenesis of CVDs and the proposed mechanisms of such possible effects. This review addresses this gap in knowledge by presenting the current available evidence that highlights the potential role of antimony in the pathogenesis of CVDs, most likely via antimony-mediated redox dyshomeostasis.More direct evidence from pre-clinical and mechanistic studies is urgently needed to evaluate the possible roles of antimony in mitochondrial dysfunction and epigenetic regulation in CVDs.

Figure S5,6. Effects of Nrf2 knockdown in different growth conditions

Figure S15. Relationship between KEAP1 mutant status and other genes in NSCLC

S1. Sequences of RNAi reagents S2. Data from siRNA screens S3. Genes decreased following Nrf2 KD and increased in KEAP1 mutant lung cancer cells S4. Data from CRISPR screens

Supplementary methods and figure legends

Figure S7,8. Effects of different compounds cell viability and genes included in CRISPR library

Mutations in KEAP1 and NFE2L2 (encoding the protein Nrf2) are prevalent in both adeno and squamous subtypes of non–small cell lung cancer, as well as additional tumor indications. The consequence of these mutations is stabilized Nrf2 and chronic induction of a battery of Nrf2 target genes. We show that knockdown of Nrf2 caused modest growth inhibition of cells growing in two-dimension, which was more pronounced in cell lines expressing mutant KEAP1. In contrast, Nrf2 knockdown caused almost complete regression of established KEAP1-mutant tumors in mice, with little effect on wild-type (WT) KEAP1 tumors. The strong dependency on Nrf2 could be recapitulated in certain anchorage-independent growth environments and was not prevented by excess extracellular glutathione. A CRISPR screen was used to investigate the mechanism(s) underlying this dependence. We identified alternative pathways critical for Nrf2-dependent growth in KEAP1-mutant cell lines, including the redox proteins thioredoxin and peroxiredoxin, as well as the growth factor receptors IGF1R and ERBB3. IGF1R inhibition was effective in KEAP1-mutant cells compared with WT, especially under conditions of anchorage-independent growth. These results point to addiction of KEAP1-mutant tumor cells to Nrf2 and suggest that inhibition of Nrf2 or discrete druggable Nrf2 target genes such as IGF1R could be an effective therapeutic strategy for disabling these tumors.Significance:This study identifies pathways activated by Nrf2 that are important for the proliferation and tumorigenicity of KEAP1-mutant non–small cell lung cancer.

Figure S1. Consequences of KEAP1 mutations on Nrf2 expression and ubiquitination Figure S2-4. Inducible knockdown of Nrf2 in KEAP1 mutant and WT cells and tumors

Figures S9-11. Effects of knocking down genes involved in oxidative stress

The human thymus is the site of T-cell maturation andninduction of central tolerance. Hematopoietic stem cell (HSC)-derived progenitors are recruited to the thymus from the fetal liver during early prenatal development and from bone marrow at later stages and postnatal life. The mechanism by which HSCs are recruited to the thymus is poorly understood in humans, though mouse models have indicated the critical role of thymic stromal cells (TSC). Here, we developed a 3D microfluidic assay based on human cells to model HSC extravasation across the endothelium into the extracellular matrix. We found that the presence of human TSC consisting of cultured thymic epithelial cells (TEC) and interstitial cells (TIC) increases the HSC extravasation rates by 3-fold. Strikingly, incorporating TEC or TIC alone is insufficient to perturb HSC extravasation rates. Furthermore, we identified complex gene expressions from interactions between endothelial cells, TEC and TIC modulates the HSCs extravasation. Our results suggest that comprehensive signaling from the complex thymic microenvironment is crucial for thymus seeding and that our system will allow manipulation of these signals with the potential to increase thymocyte migration in a therapeutic setting.

Children in rural settings are under-represented in clinical trials, potentially contributing to rural health disparities. We performed a scoping review describing available literature on barriers and facilitators impacting participation in pediatric clinical trials in rural and community-based (nonclinical) settings. Articles identified via PubMed, CINAHL, Embase, and Web of Science were independently double-screened at title/abstract and full-text levels to identify articles meeting eligibility criteria. Included articles reported on recruitment or retention activities for US-based pediatric clinical studies conducted in rural or community-based settings and were published in English through January 2021. Twenty-seven articles describing 31 studies met inclusion criteria. Most articles reported on at least one study conducted in an urban or suburban or unspecified community setting (n = 23 articles; 85%); fewer (n = 10; 37%) reported on studies that spanned urban and rural settings or were set in rural areas. More studies discussed recruitment facilitators (n = 25 studies; 81%) and barriers (n = 19; 61%) versus retention facilitators (n = 15; 48%) and barriers (n = 8; 26%). Descriptions of recruitment and retention barriers and facilitators were primarily experiential or subjective. Recruitment and retention facilitators were similar across settings and included contacts/reminders, community engagement, and relationship-building, consideration of participant logistics, and incentives. Inadequate staff and resources were commonly cited recruitment and retention barriers. Few studies have rigorously examined optimal ways to recruit and retain rural participants in pediatric clinical trials. To expand the evidence base, future studies examining recruitment and retention strategies should systematically assess and report rurality and objectively compare relative impact of different strategies.

Mutations in KEAP1 and NFE2L2 (encoding the protein Nrf2) are prevalent in both adeno and squamous subtypes of non–small cell lung cancer, as well as additional tumor indications. The consequence of these mutations is stabilized Nrf2 and chronic induction of a battery of Nrf2 target genes. We show that knockdown of Nrf2 caused modest growth inhibition of cells growing in two-dimension, which was more pronounced in cell lines expressing mutant KEAP1. In contrast, Nrf2 knockdown caused almost complete regression of established KEAP1-mutant tumors in mice, with little effect on wild-type (WT) KEAP1 tumors. The strong dependency on Nrf2 could be recapitulated in certain anchorage-independent growth environments and was not prevented by excess extracellular glutathione. A CRISPR screen was used to investigate the mechanism(s) underlying this dependence. We identified alternative pathways critical for Nrf2-dependent growth in KEAP1-mutant cell lines, including the redox proteins thioredoxin and peroxiredoxin, as well as the growth factor receptors IGF1R and ERBB3. IGF1R inhibition was effective in KEAP1-mutant cells compared with WT, especially under conditions of anchorage-independent growth. These results point to addiction of KEAP1-mutant tumor cells to Nrf2 and suggest that inhibition of Nrf2 or discrete druggable Nrf2 target genes such as IGF1R could be an effective therapeutic strategy for disabling these tumors. Significance: This study identifies pathways activated by Nrf2 that are important for the proliferation and tumorigenicity of KEAP1-mutant non–small cell lung cancer.

Context Use of continuous glucose monitoring (CGM) is increasing for insulin-requiring patients with diabetes. Although data on glycemic profiles of healthy, nondiabetic individuals exist for older sensors, assessment of glycemic metrics with new-generation CGM devices is lacking. Objective To establish reference sensor glucose ranges in healthy, nondiabetic individuals across different age groups using a current generation CGM sensor. Design Multicenter, prospective study. Setting Twelve centers within the T1D Exchange Clinic Network. Patients or Participants Nonpregnant, healthy, nondiabetic children and adults (age ≥6 years) with nonobese body mass index. Intervention Each participant wore a blinded Dexcom G6 CGM, with once-daily calibration, for up to 10 days. Main Outcome Measures CGM metrics of mean glucose, hyperglycemia, hypoglycemia, and glycemic variability. Results A total of 153 participants (age 7 to 80 years) were included in the analyses. Mean average glucose was 98 to 99 mg/dL (5.4 to 5.5 mmol/L) for all age groups except those over 60 years, in whom mean average glucose was 104 mg/dL (5.8 mmol/L). The median time between 70 to 140 mg/dL (3.9 to 7.8 mmol/L) was 96% (interquartile range, 93 to 98). Mean within-individual coefficient of variation was 17 ± 3%. Median time spent with glucose levels >140 mg/dL was 2.1% (30 min/d), and median time spent with glucose levels Conclusion By assessing across age groups in a healthy, nondiabetic population, normative sensor glucose data have been derived and will be useful as a benchmark for future research studies.

ObjectiveThe aim of this study was to describe the association of individual-level characteristics (sex, race/ethnicity, birth weight, maternal education) with child BMI within each US Census region and variation in child BMI by region.MethodsThis study used pooled data from 25 prospective cohort studies. Region of residence (Northeast, Midwest, South, West) was based on residential zip codes. Age- and sex-specific BMI z scores were the outcome.ResultsThe final sample included 14,313 children with 85,428 BMI measurements, 49% female and 51% non-Hispanic White. Males had a lower average BMI z score compared with females in the Midwest (β=-0.12, 95% CI: -0.19 to -0.05) and West (β=-0.12, 95% CI: -0.20 to -0.04). Compared with non-Hispanic White children, BMI z score was generally higher among children who were Hispanic and Black but not across all regions. Compared with the Northeast, average BMI z score was significantly higher in the Midwest (β=0.09, 95% CI: 0.05 to 0.14) and lower in the South (β=-0.12, 95% CI: -0.16 to -0.08) and West (β=-0.14, 95% CI: -0.19 to -0.09) after adjustment for age, sex, race/ethnicity, and birth weight.ConclusionsRegion of residence was associated with child BMI z scores, even after adjustment for sociodemographic characteristics. Understanding regional influences can inform targeted efforts to mitigate BMI-related disparities among children.

We provide guidance for conducting clinical trials with Indigenous children in the United States. We drew on extant literature and our experience to describe 3 best practices for the ethical and effective conduct of clinical trials with Indigenous children. Case examples of pediatric research conducted with American Indian, Alaska Native, and Native Hawaiian communities are provided to illustrate these practices. Ethical and effective clinical trials with Indigenous children require early and sustained community engagement, building capacity for Indigenous research, and supporting community oversight and ownership of research. Effective engagement requires equity, trust, shared interests, and mutual benefit among partners over time. Capacity building should prioritize developing Indigenous researchers. Supporting community oversight and ownership of research means that investigators should plan for data-sharing agreements, return or destruction of data, and multiple regulatory approvals. Indigenous children must be included in clinical trials to reduce health disparities and improve health outcomes in these pediatric populations. Establishment of the Environmental Influences on Child Health Outcomes Institutional Development Award States Pediatric Clinical Trials Network (ECHO ISPCTN) in 2016 creates a unique and timely opportunity to increase Indigenous children’s participation in state-of-the-art clinical trials.

Significance Evolutionary innovations change how organisms interact with their environments. Trait modularization is thought to facilitate evolutionary innovation, while integration constrains diversification patterns. Cranial asymmetry in flatfishes was an innovation that allowed them to colonize, and dominate benthic aquatic habitats. In this study, we quantify rates of skull shape evolution, and integration across 102 species of flatfishes and their relatives and test for the effect of integration on rates of morphological diversification. We find that cranial asymmetry evolution was a rapid, integrated process. We additionally find that flatfishes are significantly more evolutionarily integrated than their relatives. These results suggest that trait integration plays a key role in the evolution of innovation by allowing traits to mount synchronous responses to selective pressures., Evolutionary innovations are scattered throughout the tree of life, and have allowed the organisms that possess them to occupy novel adaptive zones. While the impacts of these innovations are well documented, much less is known about how these innovations arise in the first place. Patterns of covariation among traits across macroevolutionary time can offer insights into the generation of innovation. However, to date, there is no consensus on the role that trait covariation plays in this process. The evolution of cranial asymmetry in flatfishes (Pleuronectiformes) from within Carangaria was a rapid evolutionary innovation that preceded the colonization of benthic aquatic habitats by this clade, and resulted in one of the most bizarre body plans observed among extant vertebrates. Here, we use three-dimensional geometric morphometrics and a phylogenetic comparative toolkit to reconstruct the evolution of skull shape in carangarians, and quantify patterns of integration and modularity across the skull. We find that the evolution of asymmetry in flatfishes was a rapid process, resulting in the colonization of novel trait space, that was aided by strong integration that coordinated shape changes across the skull. Our findings suggest that integration plays a major role in the evolution of innovation by synchronizing responses to selective pressures across the organism.

OBJECTIVE This study evaluated the effects of continuous glucose monitoring (CGM) combined with family behavioral intervention (CGM+FBI) and CGM alone (Standard-CGM) on glycemic outcomes and parental quality of life compared with blood glucose monitoring (BGM) in children ages 2 to RESEARCH DESIGN AND METHODS This was a multicenter (N = 14), 6-month, randomized controlled trial including 143 youth 2 to RESULTS Approximately 90% of participants in the CGM groups used CGM ≥6 days/week at 6 months. Between-group TIR comparisons showed no significant changes: CGM+FBI vs. BGM 3.2% (95% CI −0.5, 7.0), Standard-CGM vs. BGM 0.5% (−2.6 to 3.6), CGM+FBI vs. Standard-CGM 2.7% (−0.6, 6.1). Mean time with glucose level CONCLUSIONS CGM used consistently over a 6-month period in young children with type 1 diabetes did not improve TIR but did significantly reduce time in hypoglycemia. The FBI benefited parental well-being.

Use of continuous glucose monitors (CGM) is associated with lower HbA1c, with the best effect seen for those using the sensor at least 6 of 7 days. Prior studies have shown youth with type 1 diabetes to have poor adherence to CGM use. We aim to evaluate CGM adherence during typical use in our patients with type 1 diabetes. In this retrospective chart review, the medical records for all patients treated with type 1 diabetes mellitus at the University of Louisville Physicians Pediatric Endocrinology outpatient clinic who initiated CGM use between 2017-2019 were reviewed to determine CGM utilization. CGM use data for patients, ages 2-18 years, was extracted from downloads performed at each clinic visit. Data available for review was 14 or 30 days, determined by receiver type. During the 2-year study period, CGM was initiated for 253 youth mean age 12 years (SD 3.78). Patients were followed for a mean of 13.4 months (SD 6.7), encompassing 784 follow-up visits (3.1 visits per patient, SD 1.94). Within this time, 64 patients (25%) discontinued use, with a mean of 4.7 months of use (SD 5.4), including 24 patients (9.5%) who received the device and never used it. Of the 190 who initiated CGM use, only 142 (56%) reported current CGM use at each follow-up visit during the study period. Continuous use was associated with younger age at initiation of CGM (p=0.001), shorter duration of diabetes (p=0.005), lower HbA1c (p For youth initiating CGM use during a 2-year period, we found a low rate of adherence to CGM use. However, the majority of those with consistent use wore the sensor at least 6 of 7 days, as recommended for effective use. Factors associated with continuous use included earlier implementation and prior professional CGM trial. Disclosure E.L. Montgomery: None. K.S. Jawad: None. S. Eubanks: None. K.A. Wintergerst: None. H.M. Rush: None. S. Watson: None.

Education Diplomacy engages the business sector with educators, policymakers, and government agencies by building consensus on policy, practice, and lifelong outcomes and taps into business people's natural skills and influence. The Education Diplomat is an important role for all stakeholders to make a lasting difference in the lives of children, and thereby society at large.

Adolescents with diabetes are at increased risk for depression and anxiety, which when untreated negatively affects diabetes control. During a 6-month period, the Patient Health Questionnaire for Depression and Anxiety (PHQ-4) screening tool was utilized. Those with a positive screen then completed the Patient Health Questionnaire for Adolescents (PHQ-A) and the Generalized Anxiety Disorder 7-item (GAD-7) scale. In this article, we report on the correlations in outcomes between the PHQ-4 and the PHQ-A and GAD-7 and its clinical utility for determining the need for standard versus acute behavioral health care. Over 6 months, 77 patients aged 10 to 18 years screened positive on the PHQ-4. Thirty-two patients had positive screening with the PHQ-A and/or the GAD-7. Thoughts of self-harm were reported by 13 (40%), with 1 experiencing current/active symptoms. The PHQ-4 as a screening tool was able to identify adolescents with symptoms of depression and/or anxiety who would benefit from further evaluation by a behavioral health provider.

For someone managing type 1 diabetes, understanding their body's glucose response to physical activity could aid in effectively addressing nocturnal hypoglycemia. The purpose of this investigation was to examine the acute temporal associations between blood glucose and measures of moderate-vigorous physical activity (MVPA) through an accelerometer. Ten adolescent athletes with type 1 diabetes wore an accelerometer and continuous glucose monitor (CGM) consecutively for a minimum of 2 weeks. Physical activity was analyzed according to intensity indicating time spent in light, moderate, and vigorous intensities. Hypoglycemic episodes were defined as two successive CGM readings70 mg/dL, at 5-min intervals, with an episode ending with at least two CGM readings70 mg/dL. Incidence of nocturnal hypoglycemia occurred during 29% of the nights measured with an average duration of 52.33 ± 41.04 min. When combining total minutes of moderate and vigorous intensities a significant difference was observed between combined MVPA and number of nocturnal hypoglycemic episodes (62.92 min vs. 49 episodes

Background: The burden of T1D includes multiple visits to an endocrinologist each year, often requiring significant travel. Youth with T1D are especially impacted as pediatric endocrinologists are primarily concentrated at academic centers in urban areas. Objectives: To assess the impact of distance to the diabetes treatment center on diabetes outcome measures. And to determine if the prevalence of technology use for the management of diabetes differs among youth with T1D living in urban versus rural communities. Methods: Retrospective data was collected for youth ≤ 18 years of age, with a diagnosis of T1D for ≥ 6 months, seen at the Wendy Novak Diabetes Care Center. GIS mapping was used to analyze outcome measures by distance to the treatment center. Rural-Urban Commuting Area (RUCA) Codes were assigned to identify those living in metropolitan (RUCA 1-3), micropolitan (RUCA 4-6), and rural communities (RUCA 7-10). Results: Inclusion criteria were met by 823 youth. Of these, 710 (86.3%) were white. Current CGM use was identified for 288 (35%), and pump use by 385 (46.8%). The mean distance traveled to the center was 18 miles (S.D. 8.8-52.2). Those traveling farther distances attended fewer clinic visits (p=0.0033). Those using a CGM or an insulin pump had more visits per year (p < 0.0001 and p=0.01, respectively). Among white youth, those traveling Conclusions: Those with a greater burden of travel to receive specialty care attended fewer visits and were less likely to use CGM technology that has important benefits in improving blood glucose management and safety for those living with T1DM. This will be important to consider when developing strategies to improve access and support for this technology. Disclosure S. Watson: None. K.S. Jawad: None. M.A. Rodriguez Luna: None. K.A. Wintergerst: None. Funding Jaeb Center for Health Research

Purpose: To determine associations between physical activity (PA) and sport participation on HbA1c levels in children with type 1 diabetes (T1D). Method: Pediatric patients with T1D were invited to complete a PA and sport participation survey. Data were linked to their medical records for demographic characteristics, diabetes treatment and monitoring plans, and HbA1c levels. Results: Participants consisted of 71 females and 81 males, were 13 ± 3 years old with an average HbA1c level of 8.75 ± 1.81. Children accumulating 60 min of activity 3 days or more a week had significantly lower HbA1c compared to those who accumulated less than 3 days (p &lt, 0.01) of 60 min of activity. However, there was no significant difference in HbA1c values based on sport participation groups. A multiple linear regression model indicated that PA, race, age, duration of diagnosis, and CGM use all significantly predicted HbA1c (p &lt, 0.05). Conclusion: This study demonstrated the significant relationship between daily PA and HbA1c. Those in this sample presented with lower HbA1c values even if accumulating less than the recommended number of days of activity. Further, it was shown that sport participation alone may not be adequate enough to impact HbA1c in a similar manner.

Background/Objective The impact of family composition on glycemic control in children with type 1 diabetes remains unclear. We sought to evaluate the relationship between health insurance coverage, family composition, and insulin management, and assess their impact on glycemic control in a pediatric type 1 diabetes population. Methods A retrospective chart review was completed for patients seen in the Pediatric Endocrinology Clinic at the University of Louisville in 2012. Results The analysis included 729 patients with type 1 diabetes; 268 (37%) had public insurance while 461(63%) had private insurance. Compared with publicly insured patients, privately insured patients had higher rates of intensive insulin management with multiple daily injections (MDI) plans or pump devices (88 vs. 83.2%, p = 0.066) and lower HbA1c levels [8.57 vs. 9.39% (70 vs. 79 mmol/mol), p

Objective Obesity, particularly child obesity, is one of the most common public health problems in the world and raises the risk of end-stage renal disease. Zinc (Zn) is essential for multiple organs in terms of normal structure and function; however, effects of Zn deficiency or supplementation among young individuals with obesity have not been well studied. Methods Weaned mice were fed high-fat diets (HFD) with varied contents of Zn (Zn deficient, adequate, and supplemented) for 3 or 6 months. This study examined associations between renal pathogenesis and dietary Zn levels, specifically assessing inflammatory pathways by utilizing P38 MAPK inhibitor SB203580. Results HFD feeding induced typical syndromes of obesity-related renal disorders, which worsened by Zn marginal deficiency. The progression of obesity-related renal disorders was delayed by Zn supplementation. HFD induced renal inflammation, reflected by increased P38 MAPK phosphorylation along with increases of inflammatory cytokines MCP-1, IL-1β, IL-6, and TNF-α. P38 MAPK inhibition prevented renal pathological changes in mice fed with HFD and HFD/Zn deficiency. Conclusions P38 MAPK mediated the renal inflammatory responses, which played a central role in the pathogenesis of HFD-induced renal disorders. Zn could delay the progression of obesity-related kidney disease by down-regulating P38 MAPK-mediated inflammation.

Mutant KRAS represents one of the most frequently observed oncogenes in NSCLC, yet no therapies are approved for tumors that express activated KRAS variants. While there is strong rationale for the use of MEK inhibitors to treat tumors with activated RAS/MAPK signaling, these have proven ineffective clinically. We therefore implemented a CRISPR screening approach to identify novel agents to sensitize KRAS mutant NSCLC cells to MEK inhibitor treatment. This approach identified multiple components of the canonical RAS/MAPK pathway consistent with previous studies. In addition, we identified MAPK7 as a novel, strong hit and validated this finding using multiple orthogonal approaches including knockdown and pharmacological inhibition. We show that MAPK7 inhibition attenuates the re-activation of MAPK signaling occurring following long-term MEK inhibition, thereby illustrating that MAPK7 mediates pathway reactivation in the face of MEK inhibition. Finally, genetic knockdown of MAPK7 combined with the MEK inhibitor cobimetinib in a mutant KRAS NSCLC xenograft model to mediate improved tumor growth inhibition. These data highlight that MAPK7 represents a promising target for combination treatment with MEK inhibition in KRAS mutant NSCLC.

BackgroundIt is not known if dysglycemia and sleep-disordered breathing are linked in adolescents, as in adults.ObjectiveTo perform a pilot study evaluating measures of sleep-disordered breathing across the spectrum of glucose tolerance in obese adolescents. We hypothesized that dysglycemia would be associated with sleep-disordered breathing.Participants/methodsThis was a prospective, cross-sectional clinical pilot study that included 57 adolescents [body mass index (BMI) 38.9 ± 8.4 kg/m2] aged 12–18 years (14.5 ± 1.6) with normal glucose tolerance (NGT), or dysglycemia [impaired glucose tolerance (IGT) or type 2 diabetes (T2D)].MeasuresAnthropometrics, overnight polysomnogram, and oral glucose tolerance tests were performed. Participant characteristics and outcome measures were compared by glucose tolerance status. Correlational analyses were conducted to assess the associations between variables of interest.ResultsParticipants with dysglycemia (n = 21) were not different from those with NGT (n = 36) for BMI, waist circumference, body fat, or sleep characteristics. Nocturnal oxygen desaturation was associated with higher BMI (r = −0.334, p = 0.012). The apnea–hypopnea index (AHI) was not associated with physical and metabolic parameters. Although participants with dysglycemia tended to have higher AHIs (median 3.2, 2.2, and 1.6 events/h for T2D, IGT, and NGT, respectively), there was not a linear relationship between measures of glycemia and AHI.ConclusionFurther study with a larger proportion of youth with prediabetes and T2D is necessary to determine whether evaluation for sleep-disordered breathing is uniformly warranted.

Objective To examine relationships among blood pressure (BP), adiposity, and sleep quality with the use of overnight polysomnography in obese adolescents. Study design Overnight polysomnogram and morning BP measurements were performed in obese (body mass index [BMI] >95th percentile) nondiabetic adolescents (eligible age range 12-18 years, n=49). Subjects were stratified into 2 groups, one with normal BP, and one with elevated BP, and demographic and clinical characteristics were compared between the groups. Multiple linear regression analysis was used to assess the effects of sleep quality on BP. Results Participants (n = 27) had a normal morning BP, and 22 (44.9%) had elevated morning BP. There were no differences in age ( P = .53), sex ( P = .44), race ( P = .58), or BMI ( P = .56) between the 2 BP groups. The group with elevated BP spent shorter percentages of time in rapid eye movement (REM; P = .006) and slow-wave sleep (SWS; P = .024). Multiple linear regression analysis showed that a lower percentage of both REM and SWS was associated with increased morning BP after we adjusted for pubertal stage, sex, race, and BMI. Conclusion Lack of deeper stages of sleep, REM sleep, and SWS is associated with greater morning BP in obese adolescents, independent of BMI. Poor sleep quality should be considered in the work-up of obese youth with hypertension. Intervention studies are needed to evaluate whether improving the quality of sleep will decrease BP elevation.

Background Pediatric studies examining the association between obstructive sleep apnea (OSA) and insulin sensitivity/cardiometabolic risk are limited and conflicting.

An assessment of the hirudinifauna of Washington State is presented. In total, 11 distinct leech species were found representing two new records for the state and two new species of the genus Placobdella, both described herein. Placobdella kwetlumye, n. sp., and Placobdella sophieae, n. sp., both collected in Squires Lake, Whatcom County, are morphologically similar to P. burresonae and P. pediculata respectively, but exhibit morphological features that readily separate them from congeners. In addition to the descriptions of the new species, here we provide a brief summary of the morphological traits possessed by each species found.

The impact of family composition on glycemic control in children with type 1 diabetes remains unclear. We sought to evaluate the relationship between health insurance coverage, family composition, and insulin management, and assess their impact on glycemic control in a pediatric type 1 diabetes population.A retrospective chart review was completed for patients seen in the Pediatric Endocrinology Clinic at the University of Louisville in 2012.The analysis included 729 patients with type 1 diabetes; 268 (37%) had public insurance while 461(63%) had private insurance. Compared with publicly insured patients, privately insured patients had higher rates of intensive insulin management with multiple daily injections (MDI) plans or pump devices (88 vs. 83.2%, p = 0.066) and lower HbA1c levels [8.57 vs. 9.39% (70 vs. 79 mmol/mol), p 0.001]. Of the 729 patients, 243 were in single-adult homes (33%). Single-adult homes had higher HbA1c levels than two-adult homes, [9.3 vs. 8.6% (78 vs. 70 mmol/mol), p 0.001]. Among publicly insured, there was no difference in HbA1c levels for single-adult vs. two-adult homes [9.4 (79 mmol/mol), p = 0.868]. For privately insured, patients in single-adult homes had higher HbA1c levels than peers in two-adult homes [9.2 vs. 8.4% (77 vs. 68), p 0.001].Insurance type and family composition have significant associative effects on glycemic control and insulin management that may be mitigated by insulin pump therapy. Identifying and addressing factors such as availability of resources, family education, and adult support and supervision, may help improve glycemic control in high-risk pediatric diabetes patients.

Gonadotropin-releasing hormone analogs (GnRHa) are standard of care for the treatment of central precocious puberty (CPP). GnRHa have also been prescribed in other clinical settings with the hope of increasing adult stature, although evidence to support this practice is lacking. The degree to which GnRHa are being prescribed for indications other than CPP in routine clinical care has not been described. We sought to systematically examine GnRHa prescribing practices among the pediatric endocrinologists at our academic medical center.We reviewed medical records of children treated with GnRHa during a 6-year interval. Variables analyzed included gender, age at start of treatment, indication for therapy, and use of growth hormone as adjunctive treatment. Nonparametric analyses were utilized to compare treatment characteristics of those with CPP versus those without.A total of 260 patients (82% female) aged 8.06 ± 2.68 years were identified. Of these, 191 (73.5%) were treated for CPP, whereas 69 (26.5%) were treated for normally timed puberty in the context of idiopathic short stature/poor predicted height (n = 37), growth hormone deficiency (n = 17), congenital adrenal hyperplasia (n = 10), primary hypothyroidism (n = 4), and developmental delay (n = 1). Of the 161 girls with CPP, GnRHa therapy was initiated at ≥8 years of age in 62 (39%).Whereas most patients were treated for CPP, ~27% were treated for other indications. Of girls with CPP, 39% were treated at an age when benefit in terms of height is unlikely. This highlights the need for rigorous studies of GnRHa use for indications beyond CPP.

This publication includes a series of short essays that offer interesting, alternative, exciting, sobering, unusual, out-of-the box perspectives, observations, or reflections at the intersection of news, digital media, and youth - broadly defined. The contributions in this publication reflect the diversity of ideas and perspectives that form the core and spirit of the Berkman community. Some of the essays are closely connected to specific research and publications conducted by the Youth and Media team (www.youthandmedia.org) at the Berkman Center for Internet & Society at Harvard University, others reflect more generally on personal observations and/or opinions, or highlight and discuss insights and learnings from other studies or concrete projects.

Orally administered selegiline hydrochloride is a selective monoamine oxidase type B inhibitor at the recommended regimen of 10 mg/day, but it loses selectivity at higher doses. In bypassing first-pass metabolism, a 24-hour application of transdermally administered selegiline (7.8 mg/24 hr) yields fifty times greater systemic exposure than is provided by single oral doses. The current study was designed to demonstrate that, similar to the oral regimen, transdermally administered selegiline is devoid of the pressor effects associated with tyramine and classic monoamine oxidase type A inhibitors. A single-blind, staggered, parallel-group study of pressor response to tyramine during a single 24-hour application of one-quarter, one-half, or one selegiline transdermal system relative to baseline (drug-free) response to tyramine was conducted in three groups, each with five healthy male volunteers. The end point of pressor response was declared if a participant's systolic blood pressure rose by > 30 mmHg, heart rate decreased by > 25 bpm with an associated > 20-mmHg rise in systolic blood pressure, or a clinically significant change was observed in the electrocardiogram. Doses up to 600 mg were administered during the baseline phase and up to 200 mg during the active-treatment phase. Participants received escalating tyramine doses every 4 hours until the maximum or threshold dose was achieved. Doses up to 200 mg were tolerated without apparent increase in sensitivity in participants receiving one-quarter, one-half, or one selegiline transdermal system. All participants completed the trial, and no significant adverse events were reported. Monoamine oxidase type B inhibition was complete (100%) by 12 hours after initial application in all treatment groups while plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) after 24-hour application were unaffected relative to baseline. These results suggest that systemic selegiline levels may not predict the propensity for a hypertensive crisis associated with presumed nonselective doses and that the avoidance of peripheral monoamine oxidase type A inhibition in the gut via the selegiline transdermal system may provide a safe vehicle for administering selegiline at plasma levels beyond that which can be safely obtained after oral administration. These findings will need to be confirmed in a long-term dose setting.

There is a known association between adiposity and hypertension (HTN). However, whether and to what extent body mass index (BMI) predicts adult HTN has not been well examined longitudinally. In this study, we attempt to quantify the effects of childhood overweight and obesity on adult HTN in a prospective cohort. The original cohort was established in 1986, and consisted of 1117 healthy children (47% male), recruited from schools in Indianapolis, Indiana (mean age 12.1; SD 5.7 years). During the course of follow-up, blood pressure, height, and weight were measured semiannually with a mean of 8.4 visits per child (SD 7.2). BMI was calculated from recorded height and weight; weight status was determined by age and sex-adjusted BMI percentile values (BMI%). Subjects were classified as normal weight, overweight (BMI% ≥ 85% and < 95%), or obese (BMI% ≥ 95%) based on either their mean BMI % or maximum BMI % during childhood. Evaluation based on mean childhood BMI % revealed that 765 (68%) were normal weight, 176 (16%) were overweight, and 176 (16%) were obese. The mean age of the subjects as of 2013 was 33.4 years (SD 3.9). From the cohort, we identified 119 adult cases of HTN through active follow up and medical chart review. In those with normal weight as children, 6% were hypertensive as adults. The rate of HTN was higher for those classified as overweight or obese as children (14% and 26% respectively, p = In conclusion, the degree of adiposity in childhood significantly impacts the risk for HTN in adulthood. Childhood obesity is associated with a quadrupled risk of adult HTN. This has significant implications for early prevention of childhood obesity and public health.

Intestinal microbial dysbiosis contributes to the dysmetabolism of luminal factors, including steroid hormones (sterones) that affect the development of chronic gastrointestinal inflammation and the incidence of sterone-responsive cancers of the breast, prostate, and colon. Little is known, however, about the role of specific host sterone nucleoreceptors, including estrogen receptor β (ERβ), in microbiota maintenance. Herein, we test the hypothesis that ERβ status affects microbiota composition and determine if such compositionally distinct microbiota respond differently to changes in diet complexity that favor Proteobacteria enrichment. To this end, conventionally raised female ERβ +/+ and ERβ −/− C57BL/6J mice (mean age of 27 weeks) were initially reared on 8604, a complex diet containing estrogenic isoflavones, and then fed AIN-76, an isoflavone-free semisynthetic diet, for 2 weeks. 16S rRNA gene surveys revealed that the fecal microbiota of 8604-fed mice and AIN-76-fed mice differed, as expected. The relative diversity of Proteobacteria , especially the Alphaproteobacteria and Gammaproteobacteria , increased significantly following the transition to AIN-76. Distinct patterns for beneficial Lactobacillales were exclusive to and highly abundant among 8604-fed mice, whereas several Proteobacteria were exclusive to AIN-76-fed mice. Interestingly, representative orders of the phyla Proteobacteria , Bacteroidetes , and Firmicutes , including the Lactobacillales , also differed as a function of murine ERβ status. Overall, these interactions suggest that sterone nucleoreceptor status and diet complexity may play important roles in microbiota maintenance. Furthermore, we envision that this model for gastrointestinal dysbiosis may be used to identify novel probiotics, prebiotics, nutritional strategies, and pharmaceuticals for the prevention and resolution of Proteobacteria -rich dysbiosis.

Primary adrenal insufficiency (AI) in children usually presents with non-specific symptoms such as fatigue, nausea, vomiting, and anorexia. Here, we report an unusual case of a 15 year old girl who presented with acute mental status change and was ultimately diagnosed with AI due to autoimmune polyglandular syndrome type II (APS2). Central nervous system imaging revealed a cerebral infarction. To our knowledge, the constellation of APS2, stroke and acute mental status change has not been previously reported. We review the literature with regard to the presentation of AI as well as the association between vasculitis and APS2.

Purpose of review To provide up-to-date information on outcomes and adverse events associated with the use of recombinant human growth hormone (rhGH). We will focus on patients with Prader Willi Syndrome and Idiopathic Short Stature. We will also discuss recent reports on long-term adverse events from the European database. Recent findings Prader Willi Syndrome is associated with hypogonadism, which does not appear to be affected by treatment with rhGH. However, there is new evidence that treatment may improve cognition. For patients with Idiopathic Short Stature, the gain in near adult height with treatment with rhGH appears to be 3-4 cm. Although a recent analysis of this group shows that certain patient characteristics may help identify those most likely to have a good response to treatment. Additionally, the safety and appropriateness of growth hormone treatments in Europe study released preliminary data from patients treated in two separate locations that showed conflicting information on risk of mortality from treatment with rhGH. Summary Although we will continue to receive new information regarding the safety and effects of treatment with rhGH, it is important to discuss the risks and benefits with our patients. Additionally, it is incumbent on us to help guide the treatment to those most likely to benefit.