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The post-transplant course of pediatric kidney transplant recipients is marked by a myriad of challenges, encompassing medical complications, recurrent hospitalizations, physical and dietary restrictions, and mental health concerns such as depression, anxiety, and post-traumatic stress disorder. Moreover, pediatric recipients are at risk of neurodevelopmental impairment, which may result in neurocognitive deficits and pose significant psychosocial obstacles. Addressing these multifaceted demands necessitates a multidisciplinary approach to pediatric kidney transplant care. However, the existing literature on the effective implementation of such a model remains scarce. This review examines the psychosocial and neurodevelopmental challenges faced by pediatric kidney transplant recipients and their families, discussing their impact on long-term transplant outcomes. Furthermore, it provides insights into risk assessment strategies and potential interventions within a multidisciplinary framework, aiming to enhance patient care and optimize post-transplant outcomes., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though the mechanism remained to be elucidated. Here we report trabectedin disrupts the intrinsic cellular antiviral response which increases viral transcript presence in the human tumor cells. We also extended our synergy findings to syngeneic murine sarcoma models, which are poorly susceptible to virus infection. In the absence of robust virus replication, we found trabectedin enhanced viroimmunotherapy efficacy by reducing infiltrating immunosuppressive CD4 T and myeloid cells and stimulating granzyme expression in infiltrating T and natural killer cells to cause immune-mediated tumor regressions. Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients., Competing Interests: L.B. is an employee of JJP Biologics. T.P.C. is a member of the Molecular Therapy editorial board and the editor-in-chief of Molecular Therapy Oncology. D.A.L. and P.R. are associate editors for Molecular Therapy Oncology., (© 2024 The Author(s).)

Purpose: Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. The purpose of this study is to identify metastasis-specific therapeutic vulnerabilities by delineating the cellular and molecular mechanisms underlying osteosarcoma lung metastatic niche formation., Experimental Design: Using single-cell transcriptomics (scRNA-seq), we characterized genome- and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multi-parameter immunofluorescence and spatial transcriptomics. Based on these findings, we evaluated the ability of nintedanib, a kinase inhibitor used to treat patients with pulmonary fibrosis, to impair metastasis progression in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models. Single-nucleus and spatial transcriptomics was used to perform molecular pharmacodynamic studies that define the effects of nintedanib on tumor and non-tumor cells within the metastatic microenvironment., Results: Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially differentiated epithelial intermediates and macrophages. Our data demonstrated that nintedanib prevented metastatic progression in multiple murine and human xenograft models by inhibiting osteosarcoma-induced fibrosis., Conclusions: Fibrosis represents a targetable vulnerability to block the progression of osteosarcoma lung metastasis. Our data support a model wherein interactions between osteosarcoma cells and epithelial cells create a pro-metastatic niche by inducing tumor deposition of extracellular matrix proteins such as fibronectin that is disrupted by the anti-fibrotic TKI nintedanib. Our data shed light on the non-cell autonomous effects of TKIs on metastasis and provide a roadmap for using single-cell and spatial transcriptomics to define the mechanism of action of TKI on metastases in animal models.

One of the greatest strengths of Drosophila genetics is its easily observable and selectable phenotypic markers. The mini-white marker has been widely used as a transgenic marker for Drosophila transgenesis. Flies carrying a mini-white construct can exhibit various eye colors ranging from pale orange to intense red, depending on the insertion site and gene dosage. Because the two copies of the mini-white marker show a stronger orange color, this is often used for selecting progenies carrying two transgenes together in a single chromosome after chromosomal recombination. However, some GAL4 lines available in the fly community originally have very strong red eyes. Without employing another marker, such as GFP, generating a recombinant chromosome with the strong red-eyed GAL4 and a desired UAS-transgene construct may be difficult. Therefore, we decided to change the red eyes of GAL4 lines to orange color. To change the eye color of the fly, we tested the CRISPR/Cas9 method with a guide RNA targeting the white gene with OK371-GAL4 and elav-GAL4. After a simple screening, we have successfully obtained multiple lines of orange-eyed OK371-GAL4 and elav-GAL4 that still maintain their original expression patterns. All of these simple experiments were performed by undergraduate students, allowing them to learn about a variety of different genetic experiments and genome editing while contributing to the fly research community by creating fruit fly lines that will be used in real-world research., (© 2024. The Author(s).)

Background: Anti-obesity medications (AOMs) are promising lifestyle modification (LSM) adjuncts for obesity treatment, and phentermine is commonly prescribed in paediatric weight management clinics. Determining 'real-world' AOM effectiveness and characteristics predicting response is important., Objectives: We sought to describe phentermine plus LSM effectiveness and identify baseline characteristics predicting response., Methods: This was a retrospective cohort study among youth seen in a US academic-based weight management clinic from 2012 to 2020. Baseline characteristics (e.g., body mass index (BMI), liver transaminases, eating-related behaviours) and outcomes (%BMI of 95th percentile (%BMIp95), BMI, %BMI change, weight) were determined through electronic health records and intake surveys., Results: Among 91 youth prescribed phentermine plus LSM over 8 years (mean %BMIp95 150%), %BMIp95 was statistically significantly reduced at 1.5, 3, 6 and 12 months (peak reduction 10.9 percentage points at 6 months; p < 0.001). Considering multiple comparisons, the presence of baseline elevated alanine aminotransferase was associated with statistically significant smaller 1.5-month %BMIp95 reductions (p = 0.001) and higher food responsiveness with smaller 3- (p = 0.001) and 6-month (p < 0.001) reductions., Conclusions: Phentermine plus LSM reduced %BMIp95 among youth in a weight management clinic, and baseline characteristics may help determine those more or less likely to respond. Prospective studies are needed to further characterize effectiveness and confirm response predictors., (© 2024 The Author(s). Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Importance: Adolescent severe obesity is usually not effectively treated with traditional lifestyle modification therapy. Meal replacement therapy (MRT) shows short-term efficacy for body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) reduction in adolescents, and financial incentives (FIs) may be an appropriate adjunct intervention to enhance long-term efficacy., Objective: To evaluate the effect of MRT plus FIs vs MRT alone on BMI, body fat, and cardiometabolic risk factors in adolescents with severe obesity., Design, Setting, and Participants: This was a randomized clinical trial of MRT plus FIs vs MRT alone at a large academic health center in the Midwest conducted from 2018 to 2022. Participants were adolescents (ages 13-17 y) with severe obesity (≥120% of the 95th BMI percentile based on sex and age or ≥35 BMI, whichever was lower) who were unaware of the FI component of the trial until they were randomized to MRT plus FIs or until the end of the trial. Study staff members collecting clinical measures were blinded to treatment condition. Data were analyzed from March 2022 to February 2024., Interventions: MRT included provision of preportioned, calorie-controlled meals (~1200 kcals/d). In the MRT plus FI group, incentives were provided based on reduction in body weight from baseline., Main Outcomes and Measures: The primary end point was mean BMI percentage change from randomization to 52 weeks. Secondary end points included total body fat and cardiometabolic risk factors: blood pressure, triglyceride to high-density lipoprotein ratio, heart rate variability, and arterial stiffness. Cost-effectiveness was additionally evaluated. Safety was assessed through monthly adverse event monitoring and frequent assessment of unhealthy weight-control behaviors., Results: Among 126 adolescents with severe obesity (73 female [57.9%]; mean [SD] age, 15.3 [1.2] years), 63 participants received MRT plus FIs and 63 participants received only MRT. At 52 weeks, the mean BMI reduction was greater by -5.9 percentage points (95% CI, -9.9 to -1.9 percentage points; P = .004) in the MRT plus FI compared with the MRT group. The MRT plus FI group had a greater reduction in mean total body fat mass by -4.8 kg (95% CI, -9.1 to -0.6 kg; P = .03) and was cost-effective (incremental cost-effectiveness ratio, $39 178 per quality-adjusted life year) compared with MRT alone. There were no significant differences in cardiometabolic risk factors or unhealthy weight-control behaviors between groups., Conclusions and Relevance: In this study, adding FIs to MRT resulted in greater reductions in BMI and total body fat in adolescents with severe obesity without increased unhealthy weight-control behaviors. FIs were cost-effective and possibly promoted adherence to health behaviors., Trial Registration: ClinicalTrials.gov Identifier: NCT03137433.

Health care spending growth is expected to outpace that of the gross domestic product (GDP) during the coming decade, resulting in a health share of GDP that reaches 19.7 percent by 2032 (up from 17.3 percent in 2022). National health expenditures are projected to have grown 7.5 percent in 2023, when the COVID-19 public health emergency ended. This reflects broad increases in the use of health care, which is associated with an estimated 93.1 percent of the population being insured that year. In 2024, Medicaid enrollment is projected to decline significantly as states continue their eligibility redeterminations. Simultaneously, private health insurance enrollment is projected to increase because of the extension of enhanced subsidies for direct-purchase health insurance under the Inflation Reduction Act (IRA) of 2022, as well as a temporary special enrollment period for qualified people losing Medicaid coverage (after eligibility redeterminations). Over the course of 2024-26, the IRA expands Medicare's drug benefit generosity and implements drug price negotiations for beneficiaries; concurrently, the extended enhanced subsidies for direct-purchase health insurance expire in 2026. During 2027-32, personal health care price inflation and growth in the use of health care services and goods contribute to projected health spending that grows at a faster rate than the rest of the economy.

Introduction: Obesity affects approximately 20% of U.S. youth. Anti-obesity medications (AOMs) are promising lifestyle modification adjuncts for obesity treatment, and topiramate is commonly prescribed in pediatric weight management clinics. It is important to determine "real-world" effectiveness of AOMs and, given shifts towards personalized approaches, characteristics potentially predicting better or worse response. We therefore sought to describe clinical effectiveness from topiramate plus lifestyle modification, and to determine if baseline phenotypic characteristics are associated with better or worse response., Methods: We performed a retrospective cohort study (2012-2020) among youth (<18 years old) followed in a U.S. academic-based weight management clinic. Baseline characteristics (i.e., body mass index (BMI), liver function tests, eating-related behaviors) and outcomes (%BMI of 95 th percentile (%BMIp95), BMI, percent %BMI change, weight) were determined through review of electronic health records and clinic intake survey data., Results: Among 282 youth prescribed topiramate plus lifestyle modifications (mean baseline age 12.7 years, %BMIp95 144%), %BMIp95 and percent BMI change were statistically significantly reduced at each time point (1.5-, 3-, 6-, and 12-month %BMIp95 reductions: -2.2, -3.9, -6.6, and -9.3 percentage points, respectively; percent BMI reduction: -1.2%, -1.9%, -3.2%, and -3.4%, respectively; all p<0.01). Considering multiple comparisons, no baseline characteristics statistically significantly predicted response at any time point., Conclusions: We found that topiramate plus lifestyle modification reduced %BMIp95 and BMI among youth in a weight management clinical setting, and that no baseline characteristics evaluated were associated with response. These results should be considered preliminary given the observational nature of this study, and prospective studies are needed to further characterize clinical effectiveness and identify and confirm potential predictors of response., Competing Interests: EB and CF are or have been site principal investigators and co-investigators for Novo Nordisk. AK engages in unpaid consulting and educational activities for Boehringer Ingelheim, Novo Nordisk, Vivus, and Eli Lilly, and receives donated drug and placebo from Novo Nordisk and Vivus for National Institutes of Diabetes and Digestive and Kidney Diseases NIDDK-funded clinical trials. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bomberg, Clark, Rudser, Gross, Kelly and Fox.)

Introduction: Whilst glucagon-like peptide-1 receptor agonists (GLP1-RAs) are effective for treating adolescent obesity, weight loss maintenance (WLM; preventing weight regain) remains a challenge. Our goal was to investigate appetite/satiety hormones and eating behaviours that may predict WLM with exenatide (a GLP1-RA) versus placebo in adolescents with severe obesity., Methods: Adolescents who had ≥5% body mass index (BMI) reduction with meal replacement therapy were randomized to 52 weeks of once-weekly exenatide extended release or placebo. In this secondary analysis, eating behaviours and appetite/satiety regulation hormones post-meal replacement therapy (pre-randomization to exenatide or placebo) were evaluated as possible predictors of WLM. Percent change in BMI from randomization to 52 weeks served as the primary measure of WLM., Results: The analysis included 66 adolescents (mean age 16.0 years; 47% female). Lower leptin response to meal testing was associated with greater WLM in terms of BMI percent change in those receiving exenatide compared to placebo (p = 0.007) after adjusting for sex, age and BMI. There were no other significant predictors of WLM., Conclusions: Prior to exenatide, lower leptin response to meals was associated with improved WLM with exenatide compared to placebo. The mostly null findings of this study suggest that GLP1-RA treatment may produce similar WLM for adolescents with obesity regardless of age, BMI, sex and eating behaviours., (© 2024 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Obesity is a heterogeneous disease with variable treatment response. Identification of the unique constellation of contributors to obesity may allow for targeted interventions and improved outcomes., Objective: Identify empirically derived phenotypes of pediatric patients with obesity based on appetitive and psychological correlates of obesity., Methods: This cross-sectional study included patients aged 5-12 years who were treated in a weight management clinic and completed standard intake questionnaires including Child Eating Behavior Questionnaire (CEBQ), Vanderbilt ADHD Scale and Pediatric Symptom Checklist. Phenotypes were elicited using latent profile analysis of 12 indicators: eight CEBQ subscales, inattention, hyperactivity/impulsivity, internalizing and externalizing symptoms., Results: Parents/guardians of 384 patients (mean age 9.8 years, mean BMI 30.3 kg/m 2 ) completed the intake questionnaires. A 4-phenotype model best fits the data. Hedonic Impulsive phenotype (42.5%) exhibited high food enjoyment and hyperactivity/impulsivity. Inattentive Impulsive phenotype (27.4%) exhibited overall low food approach and high food avoid behaviours, and highest inattention. Hedonic Emotional phenotype (20.8%) scored the highest on food enjoyment, internalizing and externalizing symptoms. Picky Eating phenotype (9.3%) scored the lowest on food approach, inattention, hyperactivity/impulsivity, internalizing and externalizing symptoms., Conclusion: Appetitive traits and psychological symptoms appear to cluster in distinct patterns, giving rise to four unique phenotypic profiles, which, if replicated, may help inform the development of tailored treatment plans., (© 2024 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Severe obesity is a complex, chronic disease affecting nearly 9% of adolescents in the U.S. Although the current mainstay of treatment is lifestyle therapy, pediatric clinical practice guidelines recommend the addition of adjunct anti-obesity medication (AOM), such as phentermine and topiramate. However, guidance regarding when adjunct AOM should be started and how AOM should be used is unclear. Furthermore, an inherent limitation of current treatment guidelines is their "one-size-fits-all" approach, which does not account for the heterogeneous nature of obesity and high degree of patient variability in response to all interventions., Methods: This paper describes the study design and methods of a sequential multiple assignment randomized trial (SMART), "SMART Use of Medications for the Treatment of Adolescent Severe Obesity." The trial will examine 1) when to start AOM (specifically phentermine) in adolescents who are not responding to lifestyle therapy and 2) how to modify AOM when there is a sub-optimal response to the initial pharmacological intervention (specifically, for phentermine non-responders, is it better to add topiramate to phentermine or switch to topiramate monotherapy). Critically, participant characteristics that may differentially affect response to treatment will be assessed and evaluated as potential moderators of intervention efficacy., Conclusion: Data from this study will be used to inform the development of an adaptive intervention for the treatment of adolescent severe obesity that includes empirically-derived decision rules regarding when and how to use AOM. Future research will test this adaptive intervention against standard "one-size-fits-all" treatments., Competing Interests: Declaration of competing interest These authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: ACG, MS, DMV, NES, CTB, NJ. These authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: CKF receives research support from Novo Nordisk and Eli Lilly for serving as a site principal investigator. Compensation is paid directly to her institution. SJR receives research support from Novo Nordisk for serving as a site co-investigator. Compensation is paid directly to her institution. EMB is a site principal investigator and site co-investigator for Novo Nordisk. JRR receives donation of drug and placebo for a clinical trial from Boehringer Ingelheim. MOB receives research support in the form of donated study drug from Vivus Inc. ASK engages in unpaid consulting and educational activities for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Vivus; receives donated study product from Novo Nordisk and Vivus for National Institute of Diabetes and Digestive and Kidney Diseases-funded clinical trials. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: For patients with osteosarcoma, disease-related mortality most often results from lung metastasis-a phenomenon shared with many solid tumors. While established metastatic lesions behave aggressively, very few of the tumor cells that reach the lung will survive. By identifying mechanisms that facilitate survival of disseminated tumor cells, we can develop therapeutic strategies that prevent and treat metastasis., Methods: We analyzed single cell RNA-sequencing (scRNAseq) data from murine metastasis-bearing lungs to interrogate changes in both host and tumor cells during colonization. We used these data to elucidate pathways that become activated in cells that survive dissemination and identify candidate host-derived signals that drive activation. We validated these findings through live cell reporter systems, immunocytochemistry, and fluorescent immunohistochemistry. We then validated the functional relevance of key candidates using pharmacologic inhibition in models of metastatic osteosarcoma., Results: Expression patterns suggest that the MAPK pathway is significantly elevated in early and established metastases. MAPK activity correlates with expression of anti-apoptotic genes, especially MCL1. Niche cells produce growth factors that increase ERK phosphorylation and MCL1 expression in tumor cells. Both early and established metastases are vulnerable to MCL1 inhibition, but not MEK inhibition in vivo. Combining MCL1 inhibition with chemotherapy both prevented colonization and eliminated established metastases in murine models of osteosarcoma., Conclusion: Niche-derived growth factors drive MAPK activity and MCL1 expression in osteosarcoma, promoting metastatic colonization. Although later metastases produce less MCL1, they remain dependent on it. MCL1 is a promising target for clinical trials in both human and canine patients., (© 2023. The Author(s).)

Background: As childhood obesity prevalence increases, determining which patients respond to anti-obesity medications would strengthen personalized approaches to obesity treatment. In the SCALE Teens trial among pubertal adolescents with obesity (NCT02918279), liraglutide 3.0 mg (or maximum tolerated dose) significantly reduced body mass index (BMI) standard deviation score on average versus placebo. That said, liraglutide effects on BMI reduction varied greatly among adolescents, similar to adults., Objectives: To identify post hoc characteristics predictive of achieving ≥5% and ≥10% BMI reductions at 56 weeks with liraglutide versus placebo in adolescents from the SCALE Teens trial., Methods: Logistic regression analysis was performed in 251 adolescents treated with liraglutide (n = 125) or placebo (n = 126) for 56 weeks. Baseline characteristics (selected a priori) included sex, race, ethnicity, age, Tanner (pubertal) stage, glycemic status (hyperglycemia [type 2 diabetes/prediabetes] vs. normoglycemia), obesity category (Class II/III vs. I), severity of depression symptoms (Patient Health Questionnaire-9), and weight variability (weight fluctuations over time). The effects of early responder status (≥4% BMI reduction at week 16) on week 56 response were assessed using descriptive statistics., Results: Baseline characteristics did not affect achievement of ≥5% and ≥10% BMI reductions at week 56 in adolescents treated with liraglutide. Further, there was no association between weight variability and BMI reduction. Early liraglutide responders appeared to have greater BMI and body weight reductions at week 56 compared with early non-responders., Conclusions: This secondary analysis suggests that adolescents with obesity may experience significant BMI reductions after 56 weeks of liraglutide treatment, regardless of their sex, race, ethnicity, age, pubertal stage, glycemic status, obesity category, severity of depression symptoms, or weight variability. Early response may predict greater week 56 response., (© 2023 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Tumors are complex tissues containing collections of phenotypically diverse malignant and nonmalignant cells. We know little of the mechanisms that govern heterogeneity of tumor cells nor of the role heterogeneity plays in overcoming stresses, such as adaptation to different microenvironments. Osteosarcoma is an ideal model for studying these mechanisms-it exhibits widespread inter- and intra-tumoral heterogeneity, predictable patterns of metastasis, and a lack of clear targetable driver mutations. Understanding the processes that facilitate adaptation to primary and metastatic microenvironments could inform the development of therapeutic targeting strategies., Results: We investigated single-cell RNA-sequencing profiles of 47,977 cells obtained from cell line and patient-derived xenograft models as cells adapted to growth within primary bone and metastatic lung environments. Tumor cells maintained phenotypic heterogeneity as they responded to the selective pressures imposed during bone and lung colonization. Heterogenous subsets of cells defined by distinct transcriptional profiles were maintained within bone- and lung-colonizing tumors, despite high-level selection. One prominent heterogenous feature involving glucose metabolism was clearly validated using immunofluorescence staining. Finally, using concurrent lineage tracing and single-cell transcriptomics, we found that lung colonization enriches for multiple clones with distinct transcriptional profiles that are preserved across cellular generations., Conclusions: Response to environmental stressors occurs through complex and dynamic phenotypic adaptations. Heterogeneity is maintained, even in conditions that enforce clonal selection. These findings likely reflect the influences of developmental processes promoting diversification of tumor cell subpopulations, which are retained, even in the face of selective pressures., (© 2023. The Author(s).)

Osteosarcoma is an aggressive malignancy characterized by high genomic complexity. Identification of few recurrent mutations in protein coding genes suggests that somatic copy-number aberrations (SCNA) are the genetic drivers of disease. Models around genomic instability conflict-it is unclear whether osteosarcomas result from pervasive ongoing clonal evolution with continuous optimization of the fitness landscape or an early catastrophic event followed by stable maintenance of an abnormal genome. We address this question by investigating SCNAs in >12,000 tumor cells obtained from human osteosarcomas using single-cell DNA sequencing, with a degree of precision and accuracy not possible when inferring single-cell states using bulk sequencing. Using the CHISEL algorithm, we inferred allele- and haplotype-specific SCNAs from this whole-genome single-cell DNA sequencing data. Surprisingly, despite extensive structural complexity, these tumors exhibit a high degree of cell-cell homogeneity with little subclonal diversification. Longitudinal analysis of patient samples obtained at distant therapeutic timepoints (diagnosis, relapse) demonstrated remarkable conservation of SCNA profiles over tumor evolution. Phylogenetic analysis suggests that the majority of SCNAs were acquired early in the oncogenic process, with relatively few structure-altering events arising in response to therapy or during adaptation to growth in metastatic tissues. These data further support the emerging hypothesis that early catastrophic events, rather than sustained genomic instability, give rise to structural complexity, which is then preserved over long periods of tumor developmental time., Significance: Chromosomally complex tumors are often described as genomically unstable. However, determining whether complexity arises from remote time-limited events that give rise to structural alterations or a progressive accumulation of structural events in persistently unstable tumors has implications for diagnosis, biomarker assessment, mechanisms of treatment resistance, and represents a conceptual advance in our understanding of intratumoral heterogeneity and tumor evolution., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Background: Meal replacement therapy (MRT) is a structured treatment that is effective for short-term weight reduction in adolescents with severe obesity. However, like other interventions, MRT response is variable., Objective: The goal of the current study was to characterize the experience of adolescents with severe obesity participating in MRT., Methods: Seventeen adolescents with severe obesity participated in semi-structured, individual interviews about their experience participating in MRT. The authors used a biopsychosocial model as the theoretical framework and data was analysed using Interpretive Phenomenological Analysis. A biopsychosocial model views an individual's health as a blend of biological characteristics, behavioural factors, and social conditions., Results: Results showed that adolescents with severe obesity described three biopsychosocial factors that were central to their experience with MRT: (1) scheduling and planning, (2) social support and pressure, and (3) intrapersonal factors. Specifically, adolescents with severe obesity identified that planning ahead, social support, and intrapersonal changes (e.g. self-confidence) can promote engagement in MRT. On the other hand, unplanned schedule changes, social pressures, and different intrapersonal factors (e.g., taste preference) can make engagement challenging., Conclusions: Adolescents provided information on factors that supported or hindered their engagement in MRT, and themes were consistent with prior literature on health behaviour change. Overall, adolescents would recommend MRT to other teenagers who carry extra weight. Future research can use the rich information provided by adolescents with severe obesity to enhance and individualize treatment options., (© 2022 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Desmoplastic small round cell tumor (DSRCT) is a rare pediatric sarcoma with poor overall survival. This tumor is absolutely dependent on the continued expression and activity of its defining molecular lesion, the EWS-WT1 transcription factor. Unfortunately, the therapeutic targeting of transcription factors is challenging, and there is a critical need to identify compounds that inhibit EWS-WT1. Here we show that the compound lurbinectedin inhibits EWS-WT1 by redistributing the protein within the nucleus to the nucleolus. This nucleolar redistribution interferes with the activity of EWS-WT1 to reverse the expression of over 70% of the transcriptome. In addition, the compound blocks the expression of the EWS-WT1 fusion protein to inhibit cell proliferation at the lowest GI50 ever reported for this compound in any cell type. The effects occur at concentrations that are easily achievable in the clinic and translate to the in vivo setting to cause tumor regressions in multiple mice in a xenograft and PDX model of DSRCT. Importantly, this mechanism of nucleolar redistribution is also seen with wild-type EWSR1 and the related fusion protein EWS-FLI1. This provides evidence for a "class effect" for the more than 18 tumors driven by EWSR1 fusion proteins. More importantly, the data establish lurbinectedin as a promising clinical candidate for DSRCT., (©2022 American Association for Cancer Research.)

Background: There are limited data comparing the relative associations of various BMI metrics with adiposity and cardiometabolic risk factors in youth., Objective: Examine correlations of 7 different BMI metrics with adiposity, cardiometabolic risk factors, and biomarkers (i.e. blood pressure, waist circumference, cholesterol, leptin, insulin, high molecular weight adiponectin, high-sensitivity c-reactive protein (hsCRP))., Methods: This was a cross-sectional analysis of youth in all BMI categories. BMI metrics: BMI z-score (BMIz), extended BMIz (ext.BMIz), BMI percentile (BMIp), percent of the BMI 95th percentile (%BMI p95 ), percent of the BMI median (%BMI p50 ), triponderal mass index (TMI), and BMI (BMI). Correlations between these BMI metrics and adiposity, visceral adiposity, cardiometabolic risk factors and biomarkers were summarized using Pearson's correlations., Results: Data from 371 children and adolescents ages 8-21 years old were included in our analysis: 52% were female; 20.2% with Class I obesity, 20.5% with Class II, and 14.3% with Class III obesity. BMIp consistently demonstrated lower correlations with adiposity, risk factors, and biomarkers (r = 0.190-0.768) than other BMI metrics. The %BMI p95 and %BMI p50 were marginally more strongly correlated with measures of adiposity as compared to other BMI metrics. The ext.BMIz did not meaningfully outperform BMIz., Conclusion: Out of all the BMI metrics evaluated, %BMI p95 and %BMI p50 were the most strongly correlated with measures of adiposity. %BMI p95 has the benefit of being used currently to define obesity and severe obesity in both clinical and research settings. BMIp consistently had the lowest correlations. Future research should evaluate the longitudinal stability of various BMI metrics and their relative associations with medium to long-term changes in adiposity and cardiometabolic outcomes in the context of intervention trials., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Neonatal Intensive Care Unit (NICU) Follow-Up programs vary in the duration for which they monitor child development and neurocognitive outcomes. This study explores the early predictive value of a widely used developmental measure for intellectual functioning during early childhood to better inform whether there is value added in continued monitoring., Methods: Participants were 209 children who had at least two assessments between the ages of 1 and 6 years old as part of NICU Follow-Up clinic. The Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) was administered when children were 1 and 2 years old and the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) was administered when children were 3 years and older., Results: The Bayley-III at 1 year of age was a significant predictor of Bayley-III performance at age 2. Similarly, Bayley-III at ages 1 year and 2 years were significant predictors of WPPSI-IV performance. Strength of prediction was moderate with the majority of variance unexplained. Exploratory analyses examining whether early developmental abilities as assessed on the Bayley-III could identify patients at risk for poorer WPPSI-IV performance indicated appropriate specificity but inadequate sensitivity., Conclusions: This study supports ongoing assessment of children who were born with perinatal complications into at least early childhood. Assessing development only during the infant and toddler years did not sufficiently identify children who went on to have lower cognitive functioning in preschool and the early school years., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Studies examining the association between hedonic hunger, that is, having frequent thoughts about food in the absence of an energy deficit, and obesity in youth show mixed results. This may be due to the confounding effect of binge eating, which has been associated with both hedonic hunger and obesity. The purpose of this study was to determine the extent to which hedonic hunger is associated with obesity independent of binge eating in youth. Methods: Data for this cross-sectional study were collected from youth enrolled in a larger study of cardiovascular disease and obesity. Linear regression models were used to assess the association between hedonic hunger measured by Power of Food Scale (PFS) and binge eating measured by Eating Disorder Examination-Questionnaire, on percent of the 95th BMI percentile (BMIp95). Results: Among 269 participants (mean age 12.8 years), 16.4% endorsed binge eating. PFS was positively associated with BMIp95 with a difference in percent of BMIp95 of 5.9% [95% confidence interval (1.5-10.3), p  = 0.009]. However, when binge eating was added to the model, the relationship between PFS and BMIp95 was no longer significant. Conclusion: Hedonic hunger, above and beyond binge eating, may not be associated with BMI. Future research should examine whether screening for and targeting binge eating rather than hedonic hunger in weight management care may have more impact on obesity outcomes. Clinical Trial Registration number: NCT01508598.

Background: The Child and Adult Eating Behavior Questionnaires (CEBQ, AEBQ) are established measures of eating behaviors. However, no similar measure is available for adolescents. Prior research has validated the AEBQ in adult samples, and one study has explored using the measure with adolescents. However, no studies to date have examined the validity of the AEBQ in adolescent clinical populations. Furthermore, no studies have examined associations between the AEBQ and indicators of health status in adolescents., Methods: A total of 280 adolescents (12-17 years old, 60% female) seen in a pediatric weight management clinic completed the AEBQ at intake. Confirmatory factor analysis (CFA) was conducted with AEBQ items to evaluate the model fit of one-, two-, seven-, and eight-factor structures. Intercorrelations between scale scores from AEBQ Food Approach and Food Avoidance domains were calculated. Associations of AEBQ scales with body mass index (BMI) and binge-eating behaviors were examined using Spearman Rho correlations and independent t-tests., Results: CFAs revealed that the best fitting model was a seven-factor structure excluding the Hunger scale, although overall model fit was only marginally acceptable (X 2  = 980.94, CFI = 0.925, TLI = 0.915, RMSEA = 0.074). Intercorrelation analyses indicated that all Food Approach scales were significantly associated with one another (r = 0.243-0.654); Food Avoidance scales were inconsistently correlated (r = 0.034-0.439). No AEBQ scales were correlated with BMI (r = -0.101-0.082). Stronger links were found with binge eating; higher frequency binge-related behaviors were associated with higher Food Approach scores., Conclusions: The seven-factor structure of AEBQ demonstrates a marginally acceptable fit for treatment-seeking adolescents with obesity. The Food Approach scales demonstrated more convergent validity than the Food Avoidance scales. The Food Approach scales also exhibited some clinical utility for identifying patients with increased risk for binge eating, which is a common target for behavioral intervention. Implications for maximizing the AEBQ's potential for assessing eating behaviors in adolescents with obesity are discussed.

Purpose of Review: This review describes clinical management of early-onset severe obesity, defined here as severe obesity in children ≤ 5 years old. It summarizes current information regarding (1) assessment, specifically growth, genetics, cardiometabolic risk, health behaviors, developmental considerations, and psychosocial factors, and (2) treatment, focusing on lifestyle modification including parent training and a brief summary of pharmacotherapy., Recent Findings: Prevalence of severe obesity in young children has remained stable yet most of these children will become adults with obesity. Interventions that address multiple health domains, such as eating habits, physical activity, and parenting skills, are necessary for addressing early-onset severe obesity. Research into pharmacotherapy remains limited but may provide future strategies for management. Early-onset severe obesity significantly influences children's long-term health and management should focus on intervention to promote BMI reduction. Further research into effective strategies is necessary to address the needs of this high-risk population.

Purpose of Review: The purpose of this review was to investigate and synthesize psychosocial outcomes from pharmacotherapy experimental trials for weight loss among adolescents with obesity., Recent Findings: There is a paucity of research regarding pharmacological interventions for adolescents with obesity. These studies have typically reported reductions in weight, and side effects have been inconsistently described. Overall, medication seems to be a safe and effective obesity treatment modality for adolescents with obesity. Six articles were included in this review. Studies varied in medication type, medication dosing, lifestyle components, psychosocial measures, measurement intervals, and psychosocial outcomes. All studies found a reduction in weight and/or BMI. Studies were often underpowered to detect differences in psychosocial variables, which were always considered secondary or exploratory outcomes. Future research should include psychosocial outcomes as a primary endpoint of pharmacological interventions for adolescent obesity. Ultimately, the treatment of the complex disease of obesity deserves to be assessed through multiple health domains extending beyond weight reduction.

Tie2-expressing monocytes/macrophages (TEMs) are a distinct subset of proangiogenic monocytes selectively recruited to tumors in breast cancer. Because of the hypoxic nature of solid tumors, we investigated if oxygen, via hypoxia-inducible transcription factors HIF-1α and HIF-2α, regulates TEM function in the hypoxic tumor microenvironment. We orthotopically implanted PyMT breast tumor cells into the mammary fat pads of syngeneic LysMcre, HIF-1α fl/fl /LysMcre, or HIF-2α fl/fl /LysMcre mice and evaluated the tumor TEM population. There was no difference in the percentage of tumor macrophages among the mouse groups. In contrast, HIF-1α fl/fl /LysMcre mice had a significantly smaller percentage of tumor TEMs compared with control and HIF-2α fl/fl /LysMcre mice. Proangiogenic TEMs in macrophage HIF-2α-deficient tumors presented significantly more CD31 + microvessel density but exacerbated hypoxia and tissue necrosis. Reduced numbers of proangiogenic TEMs in macrophage HIF-1α-deficient tumors presented significantly less microvessel density but tumor vessels that were more functional as lectin injection revealed more perfusion, and functional electron paramagnetic resonance analysis revealed more oxygen in those tumors. Macrophage HIF-1α-deficient tumors also responded significantly to chemotherapy. These data introduce a previously undescribed and counterintuitive prohypoxia role for proangiogenic TEMs in breast cancer which is, in part, suppressed by HIF-2α., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Lack of food preparation knowledge, time to prepare meals and concerns about fruit and vegetable spoilage before consumption are the potential barriers to home cooking. These barriers may be addressed by meal kits (bundles of recipes and ingredients). We described home cooking barriers and evaluated acceptability of meal kits, using semi-structured focus groups with caregivers and adolescent patients of an outpatient paediatric weight management clinic. One meal kit per family, containing non-perishable food, a $20 gift card to a grocery store and recipes designed by clinic dietician for two meals, were given at clinic appointments. Two in-person semi-structured focus groups were conducted within 2 weeks of meal kit receipt. Four adolescent participants (75% female; 12.7 ± 0.9 years) and eight caregivers (88% female) participated in the focus groups. Four barriers to home cooking were identified: (a) healthy food cost, (b) preparation time, (c) food preparation knowledge and (d) picky eaters. Participants felt the meal kits addressed the time and lack of food preparation knowledge barriers to home cooking. A clinical meal kit programme was acceptable to a treatment-seeking adolescent population with obesity and their caregivers., (© 2020 World Obesity Federation.)

Psychological stressors have been implicated in the progression of various tumor types. We investigated a role for stress in tumor immune cell chemotaxis in the B16F10 mouse model of malignant melanoma. We exposed female mice to 6-hour periods of restraint stress (RST) for 7 days, then implanted B16F10 malignant melanoma tumor cells and continued the RST paradigm for 14 additional days. We determined serum corticosterone and liver catecholamine concentrations in these mice. To evaluate the tumor microenvironment, we performed IHC and examined cytokine expression profiles using ELISA-based analysis of tumor homogenates. We found that tumors in mice subjected to RST grew significantly slower, had reduced tumor C-C motif ligand 2 (CCL2), and contained fewer F4/80-positive macrophages than tumors from unstressed mice. We observed a concomitant increase in norepinephrine among the RST mice. An in vitro assay confirmed that norepinephrine downregulates CCL2 production in both mouse and human macrophages, and that pretreatment with the pan-β-adrenergic receptor inhibitor nadolol rescues this activity. Furthermore, RST had no effect on tumor growth in transgenic CCL2-deficient mice. This study suggests that stress reduces malignant melanoma by reducing recruitment of tumor-promoting macrophages by CCL2., (©2020 American Association for Cancer Research.)

Background: In adults, poor sleep quality is associated with increased obesogenic eating behaviours; less is known about this relationship in youth. The objectives of this study were to assess the strength of association between fatigue-related quality of life (QoL) and eating behaviours among youth and to describe the associations in participants with percent body fat (%BF) above and below the 90th percentile for sex and age., Methods: Caregiver-reported measures of fatigue (Pediatric QoL Multidimensional Fatigue Scale) and eating behaviours (Child Eating Behaviour Questionnaire) were obtained from participants aged 8-17 years. %BF was measured by iDXA and grouped by sex- and age-specific percentiles. Multiple linear regression adjusting for age, sex and race/ethnicity was used., Results: Of the 352 participants (49% male), 44.6% had %BF >90th percentile. General, sleep/rest and cognitive fatigue QoL was inversely associated with food approach behaviours: food responsiveness, enjoyment of food, emotional overeating and desire to drink. For participants with %BF >90th percentile, higher general fatigue QoL was associated with higher satiety responsiveness (0.13; 95% confidence interval [CI 0.03, 0.24]). For participants with %BF ≤90th percentile, higher general fatigue QoL was associated with less satiety responsiveness (-0.16; 95% CI [-0.31, -0.01])., Conclusion: Less fatigue symptoms were associated with less behaviours associated with food approach among paediatric participants. For participants with %BF >90th percentile, less symptoms of general fatigues corresponded with more satiety. Though causation has yet to be established, youth with elevated %BF should be screened for fatigue symptoms and offered counselling on sleep hygiene or a sleep medicine referral to help mitigate weight gain., Competing Interests: Dr Kelly receives research support (drug/placebo) from Astra Zeneca Pharmaceuticals and serves as a consultant for Novo Nordisk, WW and Vivus Pharmaceuticals but does not accept personal or professional income for these activities. Dr Oberle receives research support from Vivus Pharmaceuticals. No other competing financial interests exist., (© 2020 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Ewing sarcoma (EWS) is the second most common and aggressive type of metastatic bone tumor in adolescents and young adults. There is unmet medical need to develop and test novel pharmacological targets and novel therapies to treat EWS. Here, we found that EWS expresses high levels of a p53 isoform, delta133p53. We further determined that aberrant expression of delta133p53 induced HGF secretion resulting in tumor growth and metastasis. Thereafter, we evaluated targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in preclinical studies. Surprisingly, we found that targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in combination with GD2-specific, CAR-reengineered T-cell therapy synergistically inhibited primary tumor growth and establishment of metastatic disease in preclinical models. Furthermore, our data suggested that AMG102 treatment alone might increase leukocyte infiltration including efficient CAR-T access into tumor mass and thereby improves its antitumor activity. Together, our findings warrant the development of novel CAR-T-cell therapies that incorporate HGF receptor neutralizing antibody to improve therapeutic potency, not only in EWS but also in tumors with aberrant activation of the HGF/c-MET pathway., (© 2019 UICC.)

Objective: This study aimed to determine whether children and adolescents demonstrate, similarly to adults, a threshold of total percent body fat (%BF) above which the slope of visceral adipose tissue (VAT) rises., Methods: This cross-sectional study included 557 youth, aged 8 to 18 years, with a wide range of BMI values. Dual-energy x-ray absorptiometry was used to determine body composition (including VAT), and fasting blood was collected for measurement of lipids, glucose, insulin, and biomarkers. Segmented linear regression analysis identified the threshold for %BF unadjusted and adjusted for Tanner stage. Linear regression with robust variance estimation compared associations of risk factors and thresholds., Results: Thresholds of %BF were identified by sex (males = 33%, females = 38%), age (< 12 years = 34%; ≥ 12 years = 30%), and race (White/non-Hispanic = 31%; all other races/Hispanic = 38%) above which the slope of VAT was significantly steeper (all P < 0 .001). The percentage of total body fat stored as VAT was higher above versus below these thresholds (all P < 0.001). Above threshold, but not below it, VAT was associated with triglycerides/high-density lipoprotein ratio, insulin, adiponectin, and blood pressure., Conclusions: The thresholds should be confirmed in longitudinal studies, and they may be useful in identifying youth at increased cardiometabolic risk in need of close clinical monitoring and/or intensive intervention to reduce excess adiposity., (© 2019 The Obesity Society.)

Purpose of Review: This review describes (1) the clinical assessment of pediatric patients with severe obesity, including a summary of salient biological, psychological, and social factors that may be contributing to the patient's obesity and (2) the current state of treatment strategies for pediatric severe obesity, including lifestyle modification therapy, pharmacotherapy, and metabolic and bariatric surgery., Recent Findings: Lifestyle modification therapy alone is insufficient for achieving clinically significant BMI reduction for most youth with severe obesity and metabolic and bariatric surgery, though effective and durable, is not a scalable treatment strategy. Pharmacological agents in the pipeline may 1 day fill this gap in treatment. Treatment of severe pediatric obesity requires a chronic care management approach utilizing multidisciplinary teams of health care providers and multi-pronged therapies.

Pediatric obesity is a serious public health concern affecting almost 16% of two- to five-year-olds. Prior research has not sufficiently addressed how various factors combine to contribute to the heterogeneous condition of obesity. The goal of this study was to assess multiple individual factors to determine how they collectively contribute to weight status in young children, as this information could lead to tailored interventions. This was a cross-sectional, population-based study of three- to five-year-olds. Child height and weight were measured. Parents completed a demographic survey and validated questionnaires regarding these child characteristics: internalizing and externalizing behaviors, sleep problems, executive functions, and food approach and food avoid behaviors. Data for 154 participants (mean age: 4.4 ± 0.8 years; mean body mass index- z : .28 ± 1.0; 50% male) were analyzed using linear and logistic regression and a stepwise regression procedure. In the stepwise selection procedure for the binary outcome of obese/overweight versus normal weight, food avoid ( p = .151), food approach ( p = .017), and the White demographic variable ( p = .117) were identified as important predictors. In conclusion, when considering various cognitive, emotional, and behavioral factors, only food approach and food avoid eating behaviors predicted weight status in young children, suggesting prevention and intervention efforts should specifically address these aspects in young children.

It remains largely unknown as to why some individuals experience substantial weight loss with obesity interventions, while others receiving these same interventions do not. Person-specific characteristics likely play a significant role in this heterogeneity in treatment response. The practice of precision medicine accounts for an individual's genes, environment, and lifestyle when deciding upon treatment type and intensity in order to optimize benefit and minimize risk. In this review, we first discuss biopsychosocial determinants of obesity, as understanding the complexity of this disease is necessary for appreciating how difficult it is to develop individualized treatment plans. Next, we present literature on person-specific characteristics associated with, and predictive of, weight loss response to various obesity treatments including lifestyle modification, pharmacotherapy, metabolic and bariatric surgery, and medical devices. Finally, we discuss important gaps in our understanding of the causes of obesity in relation to the suboptimal treatment outcomes in certain patients, and offer solutions that may lead to the development of more effective and targeted obesity therapies., Competing Interests: Conflict of interest statement: J.R.R. received research support in the form of drug/placebo from Boehringer Ingelheim. C.K.F. received research support from Novo Nordisk. S.D.S. received grant funding from Astra Zeneca Pharmaceuticals. A.S.K. received research support (drug/placebo) from Astra Zeneca Pharmaceuticals and served as a consultant for Novo Nordisk, WW, and Vivus Pharmaceuticals but did not accept personal or professional income for these activities. The other authors have no disclosures.

Background: Food insecurity may trigger eating behaviors that contribute to pediatric obesity. The aim of this study is to identify eating behaviors among a pediatric population with obesity and household food insecurity. Methods: A cross-sectional study analyzed Child Eating Behavior Questionnaire (CEBQ) and household food insecurity screener responses, and BMI measurements from pediatric participants with obesity (BMI ≥95th percentile) from a weight management clinic between 2013 and 2017. Multivariate linear regression was performed to evaluate associations between CEBQ eating domains [Food Responsiveness, Emotional Overeating, Enjoyment of Food, Desire to Drink (DD), Satiety Responsiveness, Slowness in Eating, Emotional Undereating (EUE), and Food Fussiness] and household food insecurity, adjusting for age, sex, race/ethnicity, SNAP participation, and BMI percentile. A sub-group analysis was performed on participants from food insecure (FI) households to evaluate the associations between SNAP participation and eating domains. Results: Eight hundred twenty-two participants were included in the final analysis. Participants from FI households had significantly higher BMI percentiles even after adjustment for age, sex, race/ethnicity, and SNAP status ( p  = 0.000). Household food insecurity was associated with increased DD beverages ( p  = 0.000). Among participants from FI households, SNAP participation was significantly positively associated with the EUE ( p  = 0.009). Conclusions: Youth from FI households have higher BMIs even among a population with obesity. DD is positively associated with household food insecurity and may contribute to obesity in this population. Results suggest that providers treating pediatric patients with obesity should consider regularly screening for household food insecurity and associated eating behaviors as part of their medical management of obesity.

Objective: This study aimed to examine whether 1-month BMI improvement is predictive of superior 6- and 12-month BMI changes in a national sample of youth in pediatric weight management treatment., Methods: Participants were 4- to 18-year-olds from the Pediatric Obesity Weight Evaluation Registry, a prospective study collecting data from 31 pediatric weight management programs across the United States. Response at 1 month was defined as ≥ 3% BMI reduction; success at 6 and 12 months was defined as ≥ 5% BMI reduction from baseline. Analyses used linear and logistic regression with robust variance estimation., Results: Primary analyses were completed with 687 participants (mean age 12.2 years). One-month responders demonstrated significant improvements in BMI compared with nonresponders at 6 months (BMI, -2.05 vs. 0.05; %BMI, -5.81 vs. 0.23; P < 0.001 for all) and 12 months (BMI, -1.87 vs. 0.30; %BMI, -5.04 vs. 1.06; P < 0.001 for all). The odds of success for 1-month responders were 9.64 (95% CI: 5.85-15.87; P < 0.001) times that of nonresponders at 6 months and 5.24 (95% CI: 2.49-11.02; P < 0.001) times that of nonresponders at 12 months., Conclusions: In treatment-seeking youth with obesity, early BMI reduction was significantly associated with greater long-term BMI reduction. Nonresponders may benefit from early treatment redirection or intensification., (© 2019 The Obesity Society.)

Objective: To investigate the relationship between adverse childhood experiences (ACEs) and weight status among adolescents., Study Design: Data were drawn from the Minnesota Student Survey, a large (n = 105 759), statewide, anonymous survey of public school students in eighth, ninth, and eleventh grades. Self-reported height and weight were used to calculate body mass index. Multinomial logistic regression was used to examine associations between self-reported ACEs and weight status, controlling for key sociodemographic characteristics., Results: ACEs were positively associated with weight status; adolescents with more ACEs were more likely to have overweight, obesity, and severe obesity than adolescents with no ACEs. Adolescents who reported an ACE were 1.2, 1.4, and 1.5 times as likely to have overweight, obesity, and severe obesity, respectively, compared with their peers with no ACEs. There was no relationship between ACEs and underweight., Conclusions: The results of this large sample of adolescents with anonymous data support the hypothesis that ACEs and obesity are strongly associated. The directionality of this relationship needs to be understood. Moreover, these findings suggest that child health professionals may need to screen for ACEs as an important aspect of clinical weight management., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Osteosarcoma (OS), a malignant tumor of bone, kills through aggressive metastatic spread almost exclusively to the lung. Mechanisms driving this tropism for lung tissue remain unknown, though likely invoke specific interactions between tumor cells and other cells within the lung metastatic niche. Aberrant overexpression of ΔNp63 in OS cells directly drives production of IL-6 and CXCL8. All these factors were expressed at higher levels in OS lung metastases than in matched primary tumors from the same patients. Expression in cell lines correlated strongly with lung colonization efficiency in murine xenograft models. Lentivirus-mediated expression endowed poorly metastatic OS cells with increased metastatic capacity. Disruption of IL-6 and CXCL8 signaling using genetic or pharmaceutical inhibitors had minimal effects on tumor cell proliferation in vitro or in vivo, but combination treatment inhibited metastasis across multiple models of metastatic OS. Strong interactions occurred between OS cells and both primary bronchial epithelial cells and bronchial smooth muscle cells that drove feed-forward amplification of IL-6 and CXCL8 production. These results identify IL-6 and CXCL8 as primary mediators of OS lung tropism and suggest pleiotropic, redundant mechanisms by which they might effect metastasis. Combination therapy studies demonstrate proof of concept for targeting these tumor-lung interactions to affect metastatic disease.

Objective: To evaluate the relationships of depression and anxiety symptoms with cardiovascular disease (CVD) risk factors and measures of vascular health in youth., Study Design: Participants (n = 202) were 8- to 18-year-olds from a cross-sectional study evaluating cardiovascular health across a wide range of body mass index values (normal weight to severe obesity). CVD risk measurement included blood pressure, fasting lipids, glucose, insulin, carotid artery intima-media thickness, compliance and distensibility, brachial artery flow-mediated dilation, carotid-radial artery pulse wave velocity, body fat percentage, and a metabolic syndrome cluster score. Anxiety and depression symptoms were self-reported on the Screen for Child Anxiety Related Disorders and Center for Epidemiological Studies Depression Scale for Children. Two sets of adjustment variables were used in evaluation of differences between those with and without anxiety or depression symptomatology for the CVD risk factor and vascular outcomes. The first set included adjustment for Tanner stage, sex, and race; the second was additionally adjusted for percent body fat., Results: Anxiety was not significantly associated with CVD risk factors or vascular health in either model. Depression was associated with high-density lipoprotein cholesterol, triglycerides, and metabolic syndrome cluster score; these relationships were attenuated when accounting for percent body fat., Conclusions: When accounting for body fat, we found no clear relationship of self-reported depression or anxiety symptoms with CVD risk factors or vascular health in youth., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The American Heart Association set 2020 Strategic Impact Goals that defined cardiovascular risk factors to be included in the concept of ideal cardiovascular health (ICH). The prevalence of ICH among differing levels of adiposity in youth, especially severe obesity, is uncertain., Methods and Results: The cross-sectional study measured ICH metrics in 300 children and adolescents stratified by adiposity: normal weight, overweight/obese, and severely obese. ICH incorporates 7 behavioral and health metrics, and was characterized as poor, intermediate, or ideal. Individual ICH metrics were transformed into standardized sample z -scores; a summary ICH sample z -score was also calculated. Multivariable linear regression models were used to estimate differences in ICH sample z -scores by adiposity status. Of the 300 participants, 113 were classified as having normal weight, 87 as having overweight/obesity, and 100 as having severe obesity (mean age 12.8 years, SD 2.7; 48% female). No participants met the criteria for ICH; 80% of those classified as having normal weight, 81% of those with overweight/obesity, and all of those with severe obesity were in poor cardiovascular health. After multivariable adjustment, those with overweight/obesity (sample z -score: -1.35; 95% confidence interval, -2.3, -1.1) and severe obesity (sample z -score: -1.45; 95% confidence interval, -2.9, -0.92) had lower overall ICH sample z -scores compared with participants with normal weight. Results were similar for individual ICH metrics., Conclusions: Poor cardiovascular health was highly prevalent in youth; ICH sample z -scores increased across levels of adiposity. Youth with obesity, particularly those with severe obesity, remain a rich target for primary prevention efforts., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01508598., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Although obesity affects approximately one in five youths, only a fraction is treated in pediatric weight management clinics. Characteristics distinguishing youth with obesity who seek weight management treatment from those who do not are largely unknown. Yet identification of specific health characteristics which differentiate treatment-seeking from non-treatment seeking youth with obesity may shed light on underlying motivations for pursuing treatment., Objectives: Compare the cardiometabolic profiles of an obesity treatment-seeking sample of youth to a population-based sample of youth with obesity, while controlling for body mass index (BMI)., Methods: This cross-sectional study included participants, ages 12-17 years, with obesity from the Pediatric Obesity and Weight Evaluation Registry (POWER) and National Health and Nutrition Examination Survey, representing the treatment-seeking and population samples, respectively. Mean differences were calculated for systolic and diastolic blood pressure percentiles, total cholesterol, low-density and high-density lipoprotein-cholesterol, triglycerides, fasting glucose, glycated hemoglobin and alanine aminotransferase, while adjusting for age, sex, race/ethnicity, insurance status, and multiple of the 95th BMI percentile., Results: The POWER and National Health and Nutrition Examination Survey cohorts included 1,823 and 617 participants, respectively. The POWER cohort had higher systolic blood pressure percentile (mean difference 17.4, 95% confidence interval [14.6, 20.1], p < 0.001), diastolic blood pressure percentile (21.8 [19, 24.5], p < 0.001), triglycerides (42.3 [28, 56.5], p < 0.001) and alanine aminotransferase (7.5 [5.1, 9.8], p < 0.001) and lower fasting glucose (-6.9 [-8.2, -5.6], p < 0.001) and high-density lipoprotein-cholesterol (-2.3 [-3.8, -0.9], p < 0.002). There were no differences in total cholesterol or low-density lipoprotein-cholesterol or clinical differences in glycated hemoglobin., Conclusion: For a given BMI, obesity treatment-seeking youth are more adversely affected by cardiometabolic risk factors than the general population of youth with obesity. This suggests that treatment-seeking youth may represent a distinct group that is at particularly high risk for the development of future cardiometabolic disease.

Background/objectives: Bariatric surgery produces robust weight loss, however, factors associated with long-term weight-loss maintenance among adolescents undergoing Roux-en-Y gastric bypass surgery are unknown., Subjects/methods: Fifty adolescents (mean±s.d. age and body mass index (BMI)=17.1±1.7 years and 59±11 kg m -2 ) underwent Roux-en-Y gastric bypass surgery, had follow-up visits at 1 year and at a visit between 5 and 12 years following surgery (Follow-up of Adolescent Bariatric Surgery at 5 Plus years (FABS-5+) visit; mean±s.d. 8.1±1.6 years). A non-surgical comparison group (n=30; mean±s.d. age and BMI=15.3±1.7 years and BMI=52±8 kg m -2 ) was recruited to compare weight trajectories over time. Questionnaires (health-related and eating behaviors, health responsibility, impact of weight on quality of life (QOL), international physical activity questionnaire and dietary habits via surgery guidelines) were administered at the FABS-5+ visit. Post hoc, participants were split into two groups: long-term weight-loss maintainers (n=23; baseline BMI=58.2 kg m -2 ; 1-year BMI=35.8 kg m -2 ; FABS-5+ BMI=34.9 kg m -2 ) and re-gainers (n=27; baseline BMI=59.8 kg m -2 ; 1-year BMI=36.8 kg m -2 ; FABS-5+ BMI=48.0 kg m -2 ) to compare factors which might contribute to differences. Data were analyzed using generalized estimating equations adjusted for age, sex, baseline BMI, baseline diabetes status and length of follow-up., Results: The BMI of the surgical group declined from baseline to 1 year (-38.5±6.9%), which, despite some regain, was largely maintained until FABS-5+ (-29.6±13.9% change). The BMI of the comparison group increased from baseline to the FABS-5+ visit (+10.3±20.6%). When the surgical group was split into maintainers and re-gainers, no differences in weight-related and eating behaviors, health responsibility, physical activity/inactivity, or dietary habits were observed between groups. However, at FABS-5+, maintainers had greater overall QOL scores than re-gainers (87.5±10.5 vs 65.4±20.2, P<0.001) and in each QOL sub-domain (P<0.01 all)., Conclusions: Long-term weight outcomes for those who underwent weight-loss surgery were superior to those who did not undergo surgical treatment. While no behavioral factors were identified as predictors of success in long-term weight-loss maintenance, greater QOL was strongly associated with maintenance of weight loss among adolescents who underwent Roux-en-Y gastric bypass surgery surgery.

Objective: To assess the safety and efficacy of short-term meal replacement therapy followed by topiramate for body mass index (BMI) reduction in adolescents with severe obesity., Methods: Adolescents (ages 12-18 years) with severe obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m 2 ) were recruited for this double-blind, randomized, placebo-controlled trial. Participants completed 4 weeks of meal replacement therapy followed by randomization (1:1) to either 24 weeks of topiramate 75 mg/day or placebo. Mean changes were compared between groups., Results: Thirty adolescents (mean age 15.2 ± 1.7 years, mean BMI 40.3 ± 4.6 kg/m 2 ) completed the meal replacement phase and were randomized; 21 completed the study. The difference in mean percent change in BMI between the topiramate and placebo groups was not significant (-1.9%; 95% CI: -5.2% to +1.5%; P = 0.291). Significant improvements in visceral fat and very-low-density lipoprotein cholesterol were observed in the topiramate compared with the placebo group. There were no concerning changes in neurocognitive function or bone health., Conclusions: In this pilot study, 4 weeks of meal replacement therapy followed by 24 weeks of low-dose topiramate compared with meal replacement therapy alone did not result in significant BMI reduction for adolescents with severe obesity., (© 2016 The Obesity Society.)

The purposes of this study were to characterize the impact of depression and anxiety on the severity of obesity among youth seeking weight management treatment and to determine the extent to which emotional eating mediates the relationship between depression and/or anxiety and degree of obesity. This cross-sectional, retrospective chart review of 102 adolescent patients from a weight management clinic analyzed demographics, body mass index, depression (Patient Health Questionnaire-9), and anxiety (Generalized Anxiety Disorder Scale-7) screens and the Child Eating Behavior Questionnaire, Emotional Over-Eating subscale. After adjusting for demographics and emotional eating, the odds of having severe obesity versus obesity were 3.5 times higher for patients with depression compared with those without (odds ratio [OR] = 3.5; 95% CI = 1.1, 11.3; P = .038) and nearly 5 times higher for those with anxiety (OR = 4.9; CI = 1.2, 20.9; P = .030). Emotional eating, however, was not a mediator between depression/anxiety and degree of adiposity., (© The Author(s) 2015.)

Purpose: The objective of this study was to investigate the soft tissue response and periimplant crevicular fluid (PICF) content around platform-switched (PS) and platform-matched (PM) implants during early healing., Materials and Methods: Nonsmokers treatment planned to receive a single implant in 2 quadrants were recruited. Two-stage implant placement protocol with 1 PM and 1 PS implant was implemented. Periimplant probing depths (PDs), modified sulcus bleeding index, and plaque indices were recorded, and PICF was collected at 1, 2, 4, and 6 weeks after abutment connection., Results: PD readings were higher at week 1 than at week 6 for both groups (P = 0.0005). PD was statistically deeper in PM than in PS at week 1 (P = 0.03). There was a time-dependent decrease in total PICF volume for both groups. This decrease was statistically significant for PS (P = 0.0005), with no differences between the 2 groups at any time (P > 0.05). The decrease observed in both PM and PS for PICF interleukin 6 and macrophage inflammatory protein-1β, and in PS for tumor necrosis factor-α (TNF-α) was statistically significant (P ≤ 0.03). TNF-α was statistically higher in PS than in PM at week 1 (P = 0.005)., Conclusion: Within the limits of this study, it seems that periimplant soft tissue response around PM and PS implants is mostly similar during the early healing period.

Introduction: Our objectives were to (a) identify rates of food insecurity among patients seen in a pediatric weight management clinic and (b) test a pilot intervention to address food insecurity in the identified patients., Methods: All new patients seen in the clinic were screened for food insecurity and Supplemental Nutrition Assistance Program (SNAP) benefit status. Families with food insecurity and no SNAP benefits were asked if they wanted SNAP enrollment assistance from a partnering food bank. Those agreeing to assistance were connected to the food bank., Results: A total of 116 new patients were evaluated in the clinic during the intervention; 28 (24%) endorsed food insecurity, and 40 (34%) were eligible for SNAP enrollment assistance. Three (8%) of the eligible patients completed the SNAP enrollment process., Discussion: Food insecurity in this pediatric weight management clinic was common. However, even when given direct access to SNAP enrollment assistance, only a small minority of patients matriculated into this program., (Copyright © 2016 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.)

Despite the increasing number of medications recently approved to treat obesity among adults, few agents have been formally evaluated in children or adolescents for this indication. Moreover, there is a paucity of guidance in the literature addressing best practices with regard to pediatric obesity pharmacotherapy clinical trial design, and only general recommendations have been offered by regulatory agencies on this topic. The purposes of this article are to (1) offer a background of the current state of the field of pediatric obesity medicine, (2) provide a brief review of the literature summarizing pediatric obesity pharmacotherapy clinical trials, and (3) highlight and discuss some of the unique aspects that should be considered when designing and conducting high-quality clinical trials evaluating the safety and efficacy of obesity medications in children and adolescents. Suggestions are offered in the areas of target population and eligibility criteria, clinical trial end-point selection, trial duration, implementation of lifestyle modification therapy and recruitment and retention of participants. Efforts should be made to design and conduct trials appropriately to ensure that high-quality evidence is generated on the safety and efficacy of various medications used to treat pediatric obesity.