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We recruited women (primarily non-Hispanic White) from 14 rural, segregated counties in a Northeastern US state for an explanatory sequential study: 100 women (ages 50–65 years) completed a survey, and 16 women participated in focus groups. We sought to identify personal (e.g., healthcare mistrust) and environmental (e.g., travel time to healthcare providers) factors related to colorectal and cervical cancer screening. Quantitatively, 89% of participants were up-to-date for cervical screening, and 65% for colorectal screening. Factors interacted such that compounding barriers were associated with lower odds of screening (e.g., insurance status and healthcare mistrust: interaction p = .02 for cervical; interaction p = .05 for colorectal). Qualitatively, three themes emerged regarding barriers to screening: privacy concerns, logistical barriers, and lack of trust in adequacy of healthcare services. While cancer screening was common in rural, segregated counties, women who reported both environmental and personal barriers to screening had lower uptake. Future interventions to promote screening can target these barriers. Supplementary Information The online version contains supplementary material available at 10.1007/s13187-021-02069-0.

Summary Background & aims Consumption of rapid digesting sugars by children are under increased scrutiny because of their contribution to unhealthy weight gain. Previous studies in adults and children have suggested that altering the blend of carbohydrates (CHOs) consumed may cause shifts in substrate utilization. The purpose of this study was to examine the effects of consuming a slow digesting carbohydrate (SDC) and rapid digesting carbohydrate (RDC) on CHO and fat oxidation, glucose, and insulin responses at rest, during exercise, and post-exercise rest in pre-pubescent children. Methods A randomized, double-blind, crossover design was used. Nineteen pre-pubescent children (n = 10 boys, n = 9 girls, mean ± standard error, age = 9.84 ± 0.37-yrs) participated. Visits to the laboratory began with a 30-min measurement of resting metabolism followed by consumption of either an RDC or SDC drink. Postprandial resting metabolism was recorded for 60-min, immediately followed by 60-min of submaximal cycling exercise while metabolism was recorded, which was immediately followed by another 60-min recording of post-exercise metabolism. Total CHO and fat oxidation, endogenous and exogenous CHO oxidation, blood glucose, and insulin were assessed. Results Total CHO oxidation rate (g∙min−1) was greater after the RDC drink at 60 min (p = 0.032). Endogenous CHO oxidation rate (g∙min−1) was greater after the SDC drink at 15 min (p ≤ 0.010). Cumulative endogenous CHO oxidation (g) was greater after the SDC drink at 45 min (p = 0.009). Endogenous CHO oxidation accounted for a greater proportion of substrate oxidation after the first 60-min rest period (p = 0.028), while exogenous CHO oxidation accounted for a greater proportion of substrate oxidation for the RDC at all time points (p ≤ 0.019). Conclusions The present study provides novel data suggesting that an SDC promotes greater endogenous substrate utilization in pre-pubertal children, which may have beneficial health impacts on energy intake and carbohydrate regulation/metabolism during growth and development. Clinical trials registry number NCT03185884, clinicaltrials.gov

The purpose of this study was to compare measurements of muscle strength, size, and activation of the forearm flexors in pre- and post-pubescent males and females. Forty pre-pubescent (mean ± 95% confidence interval, age = 9.79 ± 0.35 years, n = 10 males, n = 10 females) and post-pubescent (age = 17.23 ± 0.58 years, n = 10 males, n = 10 females) youth participated. Subjects completed maximal voluntary isometric contractions (MVICs) of the forearm flexors, and submaximal isometric step muscle actions at 30, 50, and 70% of the peak MVIC. Percent voluntary activation (VA) was quantified during all isometric muscle actions. Forearm flexor (biceps brachii and brachialis) muscle cross-sectional area (CSA) was quantified from ultrasound images. MVIC strength was expressed in absolute terms and normalized to CSA. Post-pubertal males were 130% stronger, had 101% greater CSA, and 17% greater maximal VA than pre-pubertal males, while post-pubertal females were 72% stronger, had 54% greater CSA, and 23% greater maximal VA than pre-pubertal females. When MVIC strength was normalized to CSA, the post-pubertal males were still 15% stronger than the pre-pubertal males, while the post-pubertal females were only 12% stronger than the pre-pubertal females. The responses for VA across intensity reflected differences in muscle activation strategies between pre- and post-pubertal males and females. These results suggest that muscle size may account for a greater proportion of the growth and development-related differences in strength among males, while females may be more affected by changes in muscle activation. Regardless of sex, changes in muscle size and neuromuscular function influence strength increases during growth and development.

This study examined changes in vertical jump performance with progressively greater eccentric pre-loading in relation to growth and development in young female athletes. Twenty young female athletes ranging from 9 to 17 years old performed the following vertical jumps in random order: static jumps (SJs), counter-movement jumps (CMJs), and drop jumps (DJs) from drop heights of 20, 30, and 40 cm (DJ20, DJ30, and DJ40, respectively). Measurements included peak force (PF), peak rate of force development (RFD), peak power (PP), eccentric impulse (ECC), and concentric impulse (CON). Measurements of growth included age, maturity offset, height, body mass, fat-free mass, and thigh muscle cross-sectional area (CSA). PF increased from the SJ-DJ20 (P ≤ 0.009), then plateaued from DJ20-DJ40 (P = 1.000). RFD remained the same from SJ-CMJ (P = 1.000), increased from CMJ-DJ20 (P

Higher education notices the need to support minorities and students with dis/abilities and may have additional programs to support their student populations, but students with a history of foster care are largely invisible in higher education. Using prismatic phenomenology, this study seeks to create a platform for the voices of adults in higher education who experienced the intersection of foster placement, ethnic minority, and dis/ability as children. This chapter focuses on the life story of one young woman. The goal of identifying these formative childhood experiences is to better understand how to respond to the inequities experienced as well as develop equitable practices to support students, whether in the higher educational classroom, in the preservice teacher classroom, or in K-12 educational arena.

Written in dialogue form, the benefits and equality of Universal Design vs. Differentiated Design taking into account individual student needs will be explored while integrating literature, research, and both K-12 and higher education experiences. The danger of a singular lens is highlighted as well as the need for educators to be lifelong learners. Both Universal Design and differentiation theories will be tested against and/or aligned with disability studies, multicultural education, critical pedagogy, democratic education, LGBTQ voices, and educational leadership.

Objective: The purpose of this study was to determine the prevalence of poor iron status in young athletes throughout the stages of iron deficiency and assess sex differences with iron deficiency i...

To compare measurements of muscle strength, size, and neuromuscular function among pre-adolescent and adolescent boys and girls with distinctly different strength capabilities. Fifteen boys (mean age ± confidence interval: 13.0 ± 1.0 years) and 13 girls (12.9 ± 1.1 years) were categorized as low strength (LS, n = 14) or high strength (HS, n = 14) based on isometric maximal voluntary contraction strength of the leg extensors. Height (HT), seated height, and weight (WT) determined maturity offset, while percent body fat and fat-free mass (FFM) were estimated from skinfold measurements. Quadriceps femoris muscle cross-sectional area (CSA) was assessed from ultrasound images. Isometric ramp contractions of the leg extensors were performed while surface electromyographic amplitude (EMGRMS) and mechanomyographic amplitude (MMGRMS) were recorded for the vastus lateralis (VL). Neuromuscular efficiency from the EMG and MMG signals (NMEEMG and NMEMMG, respectively) and log-transformed EMG and MMG vs. torque relationships were also used to examine neuromuscular responses. HS was 99–117% stronger, 2.3–2.8 years older, 14.0–15.7 cm taller, 20.9–22.3 kg heavier, 2.3–2.4 years more biologically mature, and exhibited 39–43% greater CSA than LS (p ≤ 0.001). HS exhibited 74–81% higher NMEEMG than LS (p ≤ 0.022), while HS girls exhibited the highest NMEMMG (p ≤ 0.045). Even after scaling for HT, WT, CSA, and FFM, strength was still 36–90% greater for HS than LS (p ≤ 0.031). The MMGRMS patterns in the LS group displayed more type I motor unit characteristics. Neuromuscular adaptations likely influence strength increases from pre-adolescence to adolescence, particularly when examining large, force-producing muscles and large strength differences explained by biological maturity, rather than simply age.

While challenges related to health care utilization among transgender individuals have been discussed, studies examining health services under Medicaid are limited. A retrospective review was performed on all patients who presented with Gender Dysphoria from 2013-2018 to one Medicaid managed program. Utilization rates of distinct services and interventions were analyzed. A total of 192 patients, with 787 encounters, were identified. Mean patient age was 15 years old. Mean number of encounters per patient was 4.1. The average number of distinct specialties seen was 1.4. Behavioral health (BH) services were most commonly utilized (50%). Endocrinology and surgical services were encountered less frequently. Medications were prescribed for 25% of patients; hormonal treatment was prescribed for 6.7%. This study highlights the deficiencies in services this population is receiving under one managed Medicaid program. While behavioral health services are widely employed, underutilization of medical and surgical consultations compromises patient awareness of available interventions.

It has been estimated that 10-15% of people with Robinow syndrome (RS) show delayed development, but no studies have formally assessed developmental domains. The objective of this study is to provide the first description of cognitive, adaptive, and psychological functioning in RS. Thirteen participants (10 males) aged 4-51 years were seen for neuropsychological screening. Eight had autosomal-dominant RS (DVL1, n = 5; WNT5A, n = 3), four had autosomal-recessive RS (NXN, n = 2; ROR2, n = 2), and one had a mutation on an RS candidate gene (GPC4). Participants completed measures of intellectual, fine-motor, adaptive, executive, and psychological functioning. Findings indicated generally average intellectual functioning and low-average visuomotor skills. Adaptive functioning was average in autosomal-recessive RS (RRS) but low average in autosomal-dominant RS (DRS). Parent-report indicated executive dysfunction and attention problems in 4/8 children, 3/4 of whom had a DVL1 variant; adult self-report did not indicate similar difficulties. Learning disabilities were also reported in 4/8 individuals with DRS, 3/4 of whom had a DVL1 variant. Peer problems were reported for a majority of participants, many of whom also reported emotional concerns. Altogether, the findings indicate average neurocognitive functioning in RRS. In contrast, DRS, especially DVL1 pathogenic alleles, may confer specific risk for neurodevelopmental disability.

OBJECTIVES: To examine differences in metabolic flexibility during submaximal aerobic exercise in sarcopenic (S) and non-sarcopenic (NS) older adults. METHODS: Twenty-two older adults (mean age ± SE = 77 ± 2) were categorized as NS (n = 11) and S (n = 11) based on grip strength and muscle mass. Participants completed an aerobic, steady-state 10-min walk on a treadmill at 50 – 60% of their estimated V̇O(2) max. Indirect calorimetry was assessed at baseline (fasted) and during the treadmill test to analyze respiratory quotient (RQ), carbohydrate (CHO) oxidation and fat oxidation, and % contributions of CHO and fat oxidation to energy expenditure (%CHO and %FAT, respectively). Two-way mixed factorial ANOVAS (time x group) and follow up t-tests were used to examine between group differences. RESULTS: At baseline, RQ was higher (0.76 ± 0.01 vs. 0.72 ± 0.01, p = 0.025) and fat oxidation was lower (0.08 ± 0.01 vs. 0.11 ± 0.01 g · min(−1), p = 0.003) in S than NS individuals. The S group had significantly greater %CHO versus %FAT from 6 – 10 min of exercise (p = 0.005–0.014), whereas NS individuals maintained an approximately equal distribution of %CHO and %FAT until 8 – 10 min (p = 0.034–0.047). RQ (0.90 ± 0.06 vs. 0.86 ± 0.01, p = 0.039) and %CHO (70% vs. 57%, p = 0.046) were greater in S compared to NS at 8 min of exercise. Fat oxidation was consistently higher in NS than S individuals from 4 - 10 of min exercise (p = 0.016–0.045). CONCLUSIONS: Since skeletal muscle utilizes a large amount of energy during exercise, metabolic flexibility is key to efficiently utilize both CHO and fat sources to generate energy to match metabolic demands. Our data reveals that NS individuals were able to rely on both fuel sources during submaximal exercise indicating metabolic flexibility. Typically, exercising at 50 – 60% V̇O(2) max utilizes 50% CHO and 50% fat contributions to energy expenditure, as observed in NS individuals. On the other hand, in S individuals, CHO composed a much larger proportion of total energy usage during exercise. These findings suggest that S individuals have low metabolic flexibility with higher dependence on CHO for energy during low-moderate aerobic activity. FUNDING SOURCES: This study was funded by Abbott Nutrition.

Background Early detection through screening can reduce colorectal cancer (CRC) mortality, but approximately 33% of adults aged 50–75 are not getting screened as recommended. Many interventions to increase CRC screening have been tested, but clinical and community organizations may be challenged in identifying the optimum programs and program materials to increase screening and ultimately reduce CRC mortality. Methods We conducted a scoping review to characterize existing, US-based interventions to improve CRC screening and to identify gaps in the literature. We used t-tests and correlations to analyze the relationship between project features and intervention effect sizes. Results The overall effect sizes were + 16% for changes in screening by any modality. The average effect sizes were greater for projects with more components, used patient navigation, and provided free/low-cost testing. Conclusion Interventions varied greatly in terms of follow-up time, test modality, and data sources. Organizations seeking to implement a program aimed at increasing CRC screening should consider both intervention components and relevant program materials.

Background The purpose of this study was to examine relationships among biomarkers of iron status, athletic performance, growth and development, and dietary intakes in pre-adolescent and adolescent male and female athletes. Methods Two-hundred and forty-nine male (n = 179) (mean ± standard deviation for age = 12.0 ± 2.1 years, height = 156.3 ± 13.9 cm, and weight = 49.1 ± 16.5 kg) and female (n = 70) (12.0 ± 2.2 years, 152.4 ± 12.3 cm, 45.3 ± 14.5 kg) athletes volunteered for capillary blood sample, anthropometric, athletic performance, and dietary intake assessments. Outcomes included maturity offset from peak height velocity, percent body fat, estimated muscle cross-sectional areas, vertical jump height (VJ), broad jump distance (BJ), pro-agility time (PA), L-cone time, 20-yard dash time (20YD), power push up (PPU) force, dietary intakes, and ferritin, soluble transferrin receptor (sTfR), and hemoglobin (Hb) concentrations. Results Athletic performance was consistently correlated with Hb in males (r = .237–.375, p 0.05). After partialing out age and height, VJ, PA, LC, and 20YD remained correlated with Hb in males (|r Hb,y.Age| = .208–.322, p = 0.001–0.041; |r Hb,y.Height| = .211–.321, p = 0.001–0.038). After partialing out iron intake, PA and LC remained correlated with sTfR in females (|r sTfR,y.ironintake| = .516–.569, p = 0.014–0.028). Conclusions Iron status biomarkers demonstrated sex-specific relationships with anaerobic exercise performance in youth athletes, which may be more dependent on maturity status and dietary intake than age. Moderate relationships between sTfR and athletic performance in adolescent female athletes emphasizes the importance of iron intake in this demographic.

Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence-based guidelines due to the lack of data for this rare condition.

Most children with hypothalamic hamartoma (HH) manifest symptoms of epilepsy and associated cognitive deficits and behavioral difficulties as well as central precocious puberty (CPP). However, there is little to no research examining behavioral difficulties in children with HH without epilepsy, nor is there research examining treatments to address the behavioral difficulties of patients with HH without epilepsy. In the current case report, the authors implemented a validated parent management training program [the Brief Behavioral Intervention (BBI)], to treat symptoms of ADHD and disruptive behavior in a 6-year-old female patient with HH and CPP. The family participated in six BBI sessions over a period of 8 weeks. Parent behavioral ratings suggested significant reductions of symptoms of ADHD and disruptive behaviors to the normal range. The current case report demonstrates the effectiveness of the BBI program in the treatment of behavioral difficulties in a patient with HH and CPP. Further, the present study explores behavioral manifestations rarely explored in patients with HH without epilepsy.

* Abbreviation: DSD — : disorder of sexual development The birth of a child with a disorder of sexual development (DSD) is challenging from multiple perspectives, particularly that of sex assignment. Patients, parents, and health care professionals who care for patients with DSDs understand that the physical, biochemical, and mental characteristics of these patients better fit a model of fluidity. Yet, sex continues to be predominantly binary, and the decision that families make early on often has medical, social, and legal implications. Until recently, all US birth certificates listed either male or female sex. However, in December 2016, the state of New York issued the nation’s first intersex birth certificate to a 55-year-old individual who was born with a DSD consisting of male chromosomes, female external genitalia, and mixed internal genitalia.1 This legal landmark challenges the traditional legal framework of the binary division of sex. Therefore, we are taking this opportunity to discuss the fluidity of sex assignment and how this unprecedented event may provide an opportunity to improve the care of patients with a DSD. Multiple terms and classification systems have been used to describe patients with DSDs. The classification systems were initially based on anatomy and were modified over time as the chromosomal basis of sex, gonadal characteristics, and sexual differentiation were better understood. However, the subclassifications had the qualifiers of male or female, implying the sex to be assigned.2 It was not until 2006 that the Pediatric Endocrine Society and the European Society of Paediatric Endocrinology revised the nomenclature into a classification system … Address correspondence to Lefkothea Karaviti, MD, PhD, Baylor College of Medicine, Section of Endocrinology and Diabetes, Department of Pediatrics, 6701 Fannin St, Ste. D.1060.01, Houston, TX 77030. E-mail: lpkaravi{at}texaschildrens.org

Objective The aim of this study was to develop and validate a psychosocial screening tool to predict risk for poor glycemic control in children with type 1 diabetes. Methods Participants seen for psychological screening were 196 children aged 3–18 yr at diabetes diagnosis. A psychosocial risk index was developed to predict poor glycemic control [mean hemoglobin A1c (HbA1c) ≥ 9.5%; 80 mmol/mol] 1–4 yr post diagnosis. Cutoff scores were derived for multiple levels of risk from receiver operating characteristic (ROC) curves and likelihood ratios (LRs). Discrimination and calibration were examined in the sample, and validated in 1000 bootstrap samples. Ability to predict diabetes-related emergency-room (ER) visits and diabetic ketoacidosis (DKA) was also tested. Results The risk index accounted for 16.2% of variance in mean HbA1c, discriminated between children with and without poor glycemic control [area under the receiver operating characteristic curve (AUC) = 0.814, 0.713–0.915; p < 0.001], ER visits (AUC = 0.655, 0.561–0.748; p = 0.001), and DKA(AUC = 0.709, 0.588–0.830; p = 0.001), and was well-calibrated. Every one-point increase in score was associated with an absolute increase in risk for poor glycemic control of approximately10% (LRs = 1.7, 3.2, 5.8, and 9.3). Sensitivity and specificity were 0.68 (0.43–0.86) and 0.79 (0.72–0.84) for detecting patients at moderate risk, and 0.53 (0.29–0.75) and 0.91 (0.85–0.95) for detecting high-risk patients. The index performed equally well in validation samples. Conclusions This paper presents the first psychosocial risk index for poor glycemic control in children newly diagnosed with type 1 diabetes. It is brief, easily administered, and provides a single score that translates directly into an estimate of risk that can help guide routine diabetes care.

Introduction Disruptive behavior problems are the most common referral reason to behavioral health professionals among preschool-age children. Parent management training (PMT) is the primary intervention for the treatment of disruptive behaviors, but current programs have high attrition rates in part due to their length. The Brief Behavioral Intervention (BBI) is a manualized parent management training PMT designed specifically to have fewer sessions in order to limit attrition associated with attending a long series of sessions and for easy implementation in hospital clinics and outpatient settings. Methods BBI consists of five core sessions, each focused on a specific behavioral management skill. These sessions occur on a weekly basis and last from 45 minutes to 1 hour per session, with one booster session after the first 2 weeks if needed. Thus, the intervention lasts from 5–7 weeks. The BBI manual is intended to be used by experienced professionals as a self-teaching guide or by faculty for teaching graduate and medical students interventions for children with disruptive behaviors. Results To date, we have trained seven faculty members, 14 postdoctoral fellows, 44 predoctoral interns, and 19 predoctoral practicum students using this manual. Many of those students use the BBI manual in their daily work. Over the years, we have received positive quantitative and qualitative feedback from the learners. Discussion The creation of this manual, coupled with supervised implementation, has resulted in a new generation of therapists trained in evidence-based strategies within a model brief enough to maintain patient participation and easy to export to myriad settings.

Dysregulation of the mitogen activated protein kinase (MAPK) pathway in Costello syndrome (CS) may contribute to increased risk for autism-spectrum disorder (ASD). We examined prevalence of ASD symptoms in 14 individuals (six females) age 1–18 years with molecularly confirmed CS. Caregivers completed the Modified Checklist for Autism in Toddlers (M-CHAT) for ages 0–4 years (n = 7), and the Social Communication Questionnaire (SCQ) for ages 4 and older (n = 7). Age was associated with meeting ASD criteria: 5/7 (71.4%) younger children met the ASD cut-off on the MCHAT, compared to 0/7 older children on the SCQ. The following medical and developmental factors were strongly associated with ASD criteria on the M-CHAT: having a gastrostomy tube at time of assessment, not eating solid food, not walking, and not being toilet trained. Two children who met stricter ASD criteria had significantly lower adaptive functioning and were physically much more impaired. Among older participants, SCQ subscale scores in communication, socialization, and repetitive behavior domains were comparable to the typically-developing normative sample. ASD symptoms were highly elevated in younger CS individuals. Older children did not differ from typically developing samples in prevalence of ASD symptoms. CS individuals may appear to fall on the autism spectrum in early childhood due to severe feeding and orthopedic problems that improve by age four, suggesting many of these children may eventually emerge out of an ASD presentation.

As natural resource management agencies and conservation organizations seek guidance on responding to climate change, myriad potential actions and strategies have been proposed for increasing the long-term viability of some attributes of natural systems. Managers need practical tools for selecting among these actions and strategies to develop a tailored management approach for specific targets at a given location. We developed and present one such tool, the participatory Adaptation for Conservation Targets (ACT) framework, which considers the effects of climate change in the development of management actions for particular species, ecosystems and ecological functions. Our framework is based on the premise that effective adaptation of management to climate change can rely on local knowledge of an ecosystem and does not necessarily require detailed projections of climate change or its effects. We illustrate the ACT framework by applying it to an ecological function in the Greater Yellowstone Ecosystem (Montana, Wyoming, and Idaho, USA)--water flows in the upper Yellowstone River. We suggest that the ACT framework is a practical tool for initiating adaptation planning, and for generating and communicating specific management interventions given an increasingly altered, yet uncertain, climate.

The primary aims of this exploratory study were to determine the rate of occurrence of acute stress disorder (ASD) in children newly diagnosed with Type 1 diabetes and their parents, to examine relationships with demographic and psychosocial factors, and to examine the relationships between ASD symptom clusters and early adherence behavior (clinic attendance). The sample consisted of 102 parents of children ages 0-17 years and 40 youth ages 11-17 who were evaluated within three days of diabetes diagnosis. Eighteen percent of parents and 17% of youth reported subthreshold symptoms of ASD. Acute stress symptoms and demographic variables predicted clinic attendance, with a differential pattern evident in the responses of youth and their parents. These findings reinforce the importance of screening symptoms of ASD in youth with newly diagnosed diabetes and their parents to assist in identifying families who may be in need of additional support.

OBJECTIVE Psychosocial screening has been recommended for pediatric patients with newly diagnosed type 1 diabetes and their families. Our objective was to assess a psychosocial screening protocol in its feasibility, acceptability to families, and ability to predict early emerging complications, nonadherent family behavior, and use of preventive psychology services. RESEARCH DESIGN AND METHODS A total of 125 patients and their caregivers were asked to participate in a standardized screening interview after admission at a large urban children’s hospital with a new diagnosis of type 1 diabetes. Medical records were reviewed for subsequent diabetes-related emergency department (ED) admissions, missed diabetes clinic appointments, and psychology follow-up within 9 months of diagnosis. RESULTS Of 125 families, 121 (96.8%) agreed to participate in the screening, and a subsample of 30 surveyed caregivers indicated high levels of satisfaction. Risk factors at diagnosis predicted subsequent ED admissions with a sensitivity of 100% and a specificity of 98.6%. Children from single-parent households with a history of behavior problems were nearly six times more likely to be seen in the ED after diagnosis. Missed appointments were likeliest among African Americans, 65% of whom missed at least one diabetes-related appointment. Psychology services for preventive intervention were underutilized, despite the high acceptability of the psychosocial screening. CONCLUSIONS Psychosocial screening of newly diagnosed patients with type 1 diabetes is feasible, acceptable to families, and able to identify families at risk for early emerging complications and nonadherence. Challenges remain with regards to reimbursement and fostering follow-up for preventive care.

Nonadherence to different aspects of the diabetes regimen is common. Problems early in the course of illness predict later difficulties with nonadherence; conversely, good management early on protects against later complications. Screening for early risk factors at the time of diabetes diagnosis is therefore critical for promoting the health of children with type 1 diabetes. The purpose of this paper is to review and synthesize the recent empirical literature on early risk factors for nonadherence in type 1 diabetes, with a focus on three specific adherence behaviors: insulin administration, blood glucose monitoring, and clinic attendance. Risk factors are considered within several broad categories: sociodemographic barriers that limit access to care; child and parent factors that affect adherence both directly and indirectly via their impact on the development of family teamwork; and family interactions with their health-care providers. We integrate the different findings into a "simple model" that can be used to develop efficient screening protocols that can in turn guide efforts at preventive intervention.

Clinical and molecular analyses of Costello syndrome are proceeding at a rapid pace, including the delineation of the adult phenotype. We designed a two-part survey in order to describe the quality of life (QoL) of older individuals with Costello syndrome. The survey consisted of the Costello syndrome quality of life (CSQoL): Caregiver Questionnaire, to obtain objective information such as skills, activities, and medical issues from caregivers; and the CSQoL:Self-Questionnaire assessing subjective information including self-esteem, life satisfaction, and interpersonal relations from affected individuals. Thirteen of 18 (72%) individuals with Costello syndrome (age 16-34 years, mean 22 years) and caregiver pairs responded. The data were analyzed to study day-to-day life, and to determine potential impediments on QoL for older individuals with Costello syndrome. The CSQoL:Caregiver total scores were significantly lower than the CSQoL:Self total scores as demonstrated by the Wilcoxon Signed Ranks Test (P < 0.008). The CSQoL:Caregiver total scores appear negatively correlated with total number of medical issues (r = -0.549; P = 0.065). No association was found between the CSQoL:Self scores and total number of medical issues (r = -0.107; P = 0.769). Four impediments to QoL for individuals with Costello syndrome were identified: relationships outside of their immediate circle of family and friends, lack of independence, male gender, and the presence of major medical issues. This information may be useful to the families and health care professionals of adults with Costello syndrome. As a measurable characteristic, QoL may have utility as a metric in future therapeutic trials.

Periodontal diseases have long been postulated to contribute to systemic diseases and, likewise, it has been proposed that periodontal disease treatment may ameliorate certain systemic diseases. Short-chain fatty acids (SCFA) are major secondary metabolites produced by oral anaerobic bacteria and, among the SCFAs, butyric acid (BA) in high amounts contribute to periodontal disease development. Periodontal disease level-butyric acid (PDL-BA) is found among patients suffering from periodontal disease and has previously shown to induce oxidative stress, whereas, oxidative stress is correlated to endoplasmic reticulum (ER) stress. This would imply that PDL-BA may likewise stimulate ER stress, however, this was never elucidated. A better understanding of the correlation between PDL-BA and systemic ER stress stimulation could shed light on the possible systemic effects of PDL-BA-related periodontal diseases. Here, PDL-BA was injected into the gingival mucosa and the systemic blood obtained from the rat jugular was collected at 0, 15, 60, and 180 min post-injection. Collected blood samples were purified and only the blood cytosol was used throughout this study. Subsequently, we measured blood cytosolic GADD153, Ca2+, representative apoptotic and inflammatory caspases, and NF-κB amounts. We found that PDL-BA presence increased blood cytosolic GADD153 and Ca2+ amounts. Moreover, we observed that blood cytosolic caspases and NF-κB were activated only at 60 and 180 min post-injection in the rat gingival mucosa. This suggests that PDL-BA administered through the gingival mucosa may influence the systemic blood via ER stress stimulation and, moreover, prolonged PDL-BA retention in the gingival mucosa may play a significant role in ER stress-related caspase and NF-κB activation. In a periodontal disease scenario, we propose that PDL-BA-related ER stress stimulation leading to the simultaneous activation of apoptosis and inflammation may contribute to periodontal disease pathogenesis.

Gingival crevice (GC) increases with age allowing periodontopathic bacteria and its products to enter. We hypothesize that by mimicking this event we can utilize the GC as a potential vaccination route. Here, we used 20 wk-old (young) and 77 wk-old (old) Sprague-Dawley rats. Initially, we elucidated the difference between oral-administration and oral-supplementation in both young and old rats and, subsequently, we determined the optimal component concentration for xanthan gel-encapsulation. Next, through molecular docking, we simulated xanthan gel-encapsulation of a representative antigen (for this study we used influenza H5N1 hemagglutinin) in order to verify that target epitopes were not blocked. Lastly, we compared the antibody titer among gingival-vaccinated rats (old and young) and, likewise, we evaluated the antibody titer produced via the gingival route as compared to other vaccination routes (intradermal, oral, sublingual). Rat blood serum was collected for further downstream analyses. Throughout the study, we were able to establish the following conditions: higher target components enter old rats via oral-supplementation; 100 μg mL(-1) is the optimal component concentration for xanthan gel-encapsulation; and xanthan gel-encapsulation leaves antibody epitopes exposed. More importantly, we observed that gingival-vaccinated old rats have higher antibody titer as compared to young rats and, likewise, we found that antibody titer elicited via gingival vaccination is comparable to other mucosal vaccination routes. Thus, we propose that the GC has the potential to serve as a non-invasive vaccination route.

In this chapter we describe an innovative system designed to promote adherence, prevent nonadherence, and provide interventions for nonadherence based on level and type of risk. While there are many discrete interventions focused on adherence being implemented at institutions across the country, they tend to be highly focused in terms of method and target population. The model sketched out here provides a different approach, focused on improving the overall system in which treatment takes place, rather than placing the entire burden of treatment adherence on the patient (or patient and parent) alone. The system utilizes a web-based hub and incorporates universal screening for risk for nonadherence at disease diagnosis; triage to targeted interventions; and ongoing surveillance for newly emerging adherence problems or psychosocial concerns. In the model, interventions are based on level and type of assessed risk or need. At the Universal level (low risk patients), we provide examples of preventive educational materials and tools that can be given to patients and parents. At the Targeted (moderate risk) level, we delineate using outreach supports as efficient ways to mitigate risk by keeping at-risk patients and families connected to, and helping them navigate, the healthcare system. For children assessed to be at the Clinical (highest risk) level, we provide guidelines for referral for individualized intervention. We end the chapter with a summary of the key factors and guiding principles for developing an effective system-based approach to adherence.

Nonadherence is believed to be the single greatest cause of treatment failure, resulting in substantial morbidity and mortality, much of which could have been avoided. In this chapter we review the scope of the problem of nonadherence, and discuss definitional issues including the distinctions between disease and illness; compliance, adherence, and nonadherence; and intentional and unintentional nonadherence. The multi-factorial nature of nonadherence is highlighted. Barriers inherent in the current healthcare system are then reviewed with an eye toward identifying areas where more improvement could be made.

Only in recent years has a large enough body of research on adherence-promoting interventions been amassed so that systematic reviews and meta-analyses of their impact can reliably be evaluated. Overall, these reviews indicate that interventions tend to result in modest improvements in adherence to treatment recommendations and medications, with effect sizes typically in the small to medium range across various chronic condition populations and intervention types. Positive effects on health outcomes have also been reported. This chapter reviews the literature on interventions for pediatric nonadherence, paying special attention to recent innovations that have the potential to expand interventions’ reach and effectiveness.

Screening provides the foundation for all subsequent clinical decision making. Moreover, it makes possible a preventive approach, which we argue is critical to improving the health and well-being of children. This chapter discusses the rationale for screening, lays out a blueprint for developing a psychosocial screening program, and describes our experience in implementing a screening program in a busy pediatric hospital. We focus primarily on children and youth with type 1 diabetes, as this has been an active area of our research. The chapter also links to tools clinicians can use to screen their patients, and provides guidance in their use specifically written for professionals who lack training in psychology. A version of Kazak’s Pediatric Psychosocial Preventive Health Model is presented as a guide for clinical decision-making.

In this final chapter, we summarize the ten most important take-home points from this volume on pediatric adherence in the context of the following main ideas. (1) Successful adherence depends on developing healthcare partnerships between patients, families, and providers, and that nonadherence often results from the breakdown of teamwork between any (or all) of the partners. (2) A focus on self-management instead of teamwork is likely to be self-defeating. Promoting patient independence too early risks a dangerous decline in illness management and control. In contrast, supporting patient autonomy (i.e., volitional behavior) can foster development without having to withdraw whatever assistance the youth may need. (3) Communication is the key to developing successful partnerships, which will usually be characterized by having shared goals and (ideally) a shared model of illness. We end this chapter—and the book—by highlighting the added value of partnerships for reducing the management burden chronic illness places on children.

The impact of diabetes on the developing brain is well-accepted. Effects on neurocognitive functioning are moderate but have larger functional implications, especially when considered through a developmental lens. Pathophysiological factors such as severe hypoglycemia and chronic hyperglycemia can alter developmental trajectories in early childhood and perhaps at later periods. In this paper, we selectively review neurocognitive outcomes in pediatric diabetes (largely type 1), integrating recent research from developmental neuroscience and neuroimaging. We examine the effects of diabetes at different stages and place findings within a neurodevelopmental diathesis/stress framework. Early-onset diabetes is associated with specific effects on memory and more global cognitive late-effects, but less is known about cognitive outcomes of diabetes in later childhood and in adolescence, a time of increased neurobehavioral vulnerability that has received relatively limited empirical attention. Studies are also needed to better elucidate risk and protective factors that may moderate neurodevelopmental outcomes in youth with diabetes.

OBJECTIVE To determine whether impairments in neurocognitive functioning are detectable at type 1 diabetes diagnosis and associated with subsequent glycemic control. RESEARCH DESIGN AND METHODS Children/adolescents (N = 147) aged 5–18 years completed neuropsychological testing during their inpatient hospitalization for new-onset type 1 diabetes. Test scores were compared with normative data using one-sample Student t tests. Children with onset before 8 years of age were compared with children aged 9–18 years using ANOVA, and associations between neurocognitive performance at diagnosis and glycemic control 1 year postdiagnosis were examined using regression analyses. RESULTS Children with type 1 diabetes performed significantly below expectations on most neurocognitive measures (P values 1 SD), visuomotor integration (0.7 SD), and phonemic fluency (0.8 SD). High incidence of impairment (scores less than second percentile) was evident on all tasks except digit span. Dominant-hand psychomotor speed was significantly associated with poor glycemic control (A1C ≥9.5% [80 mmol/mol]; P = 0.032) 1 year postdiagnosis, controlling for race/ethnicity, sex, and reading ability. Impaired psychomotor speed was associated with a 0.77% increase in mean A1C (8.4 mmol/mol). CONCLUSIONS Deficits were evident in neurocognitive functioning within days of diabetes diagnosis that were associated with diabetes outcomes over 1 year postdiagnosis. Impairment was most apparent in psychomotor speed, consistent with research implicating damage to posterior white matter tracts and associated gray matter regions in type 1 diabetes. Psychomotor impairment may be an early marker for a broader neurobehavioral vulnerability that has implications for long-term diabetes management.

This training toolkit is an outgrowth of a training program we developed to teach clinicians to conduct psychosocial risk screenings of children and adolescents newly diagnosed with Type 1 diabetes, one of the most common (and challenging) chronic illnesses in childhood. When we began the screening program in 2007, we focused on training psychology graduate students enrolled in our predoctoral internship. Since then, interest in psychosocial screening has grown among other medical clinics in our hospital, and it became apparent that the need could not be met by Psychology interns alone. Indeed, as recently noted by Cameron and Northam (2012), psychology resources are a scarce commodity in many medical settings. We therefore designed this toolkit to provide healthcare professionals and learners from many different backgrounds (e.g., Medicine, Nursing, and Social Work, as well as Psychology) with the training and tools necessary to conduct psychosocial screenings competently and effectively in a pediatric setting. The toolkit is a comprehensive resource that can be used as a self-teaching resource for experienced professionals, or for training faculty to use to teach graduate and medical students. Included in the toolkit are 1) a Clinician Training Manual, with all of the necessary materials and tools to complete screenings as well as a self-assessment tool, and 2) a Supervisor's Guide that includes a detailed training curriculum and a standardized Checkout Rating procedure for evaluating learners' readiness to conduct screenings independently. Also included are the semi-structured interview forms used to conduct screenings, and guides to triage and intervention. Our hope is that dissemination of these materials will help psychosocial screening become more widely adopted as the standard of care for all children and youth diagnosed with Type 1 diabetes. Over the past six years, we have trained over twenty predoctoral interns and three postdoctoral fellows in clinical psychology. The training procedures were formalized into this toolkit over the past year, which was then piloted with four Psychology interns, one nurse practitioner, and two social workers. In addition, three Psychology postdoctoral fellows have been trained as instructors/ supervisors using these materials. Feedback was solicited from seven of these participants. All of the participants (100%) felt that all four learning objectives were met. Feedback was also collected on open-ended questions. In terms of the most valuable things learned from the training program, participants reported learning or gaining: “about the potential risk factors that might interfere with treatment adherence.” “about the medical and psychosocial issues related to diabetes and the factors that influence adherence.” “to incorporate MI [motivational interviewing] strategies to gain more accurate information on diabetes management.” “about the psychosocial factors that impact a family with a child with diabetes [which] was important since this is such a prevalent medical condition.” “a range of family responses to new diagnosis … and how to triage.” Participants also reported having gained the following from the program: “exposure to working in the inpatient setting, practice in modifying my clinical approach to match the family's response to the diagnosis and coping style and became more competent at educating the families about diabetes from a psychosocial perspective.” “a greater understanding of ‘miscarried helping’ and the interaction cycle between parents and children with diabetes.” The supervisors who used the submitted materials provided the following feedback: “The overall experience of training interns in conducting brief, evidence-based screens was very helpful. Supervising someone in conducting a brief screen helped me to refine my own clinical skills and to highlight the important aspects of the screening process. Further, I feel that having the supervision experience with these screens is generalizeable and I would be able to participate in other screening development processes.” “Supervision and teaching are a large part of my training goals and this experience fulfilled those needs.” Respondents provided the following feedback on the program materials: “I think they were helpful.” “I found the materials to be very helpful.” “The forms were helpful because they provided specific markers of skills to observe and rate. The teaching tools are great!” “The rating form is lengthy and perhaps with time if some portions of the form are deemed not as necessary as others, the length could be reduced.”

Migrant farmworkers are one of the most health care-impoverished populations in the United States. Mobility, hazardous occupations, cultural diversity, and low socioeconomic status place migrants, and particularly migrant children, at high risk for inadequate health care and preventable health problems. This article presents a synthesis of the existing research on migrant demographics, major health risks, and geographic, financial, and cultural barriers to health care access. Innovative nursing strategies to enhance access and improve the health of migrant children are explored. These include the use of lay community outreach workers, the creation of alternative health care delivery models, and the development of information tracking systems.

With government attention now directed to graduate medical education, it is imperative that nursing leaders clearly articulate how Medicare dollars can best be directed to meet current nursing workforce goals.

Objectives To determine the magnitude and distribution of US Medicare funding for nursing education and to assess the extent to which Medicare funding contributes to meeting national health care workforce priorities. Data sources Medicare Hospital Cost Report Information System, American Hospital Association Annual Survey of Hospitals, and National League for Nursing national surveys of schools of nursing. Data analysis Using hospital identifiers, data from three data sets were merged and analyzed to estimate percentage distributions of Medicare funding according to types of educational programs, hospital characteristics, and student enrollment. Results Fifteen percent of direct Medicare graduate medical education funding goes to hospitals for the training of nurses and paramedical personnel. Totaling approximately $174 million in 1991, 71% of these funds went to hospitals for nursing education costs. Most of the nation's teaching hospitals (289 of 381 Council of Teaching Hospitals member hospitals) and nurse education programs (1112 of 1484) do not qualify under existing policies for Medicare nursing education reimbursement. Sixty-six percent of Medicare nurse training funds, totaling $114 million in 1991, went to 145 hospitals operating diploma nursing programs; these programs produce less than 10% of nurse graduates. Three states (Pennsylvania, New Jersey, and Ohio) received nearly one half (48%) of the $114 million for diploma nursing education. Conclusions Medicare is the largest single source of federal support for nursing education. Yet, the majority of Medicare nursing education funding goes to hospitals affiliated with an increasingly smaller, idiosyncratic subset of nurse training programs. Unlike graduate medical education, Medicare supports primarily preprofessional education in nursing. Graduate education, including the preparation of nurse practitioners, does not generally qualify for reimbursement. Medicare reimbursement for nursing education must be retargeted.

Background Heme oxygenase-1 (HO-1) is a HEME regulator and plays a role in ameliorating HIV-1 infection. In particular, HO-1 inhibits Tat-dependent activation of HIV-1 LTR promoter inhibiting viral gene expression. This suggests that increasing HO-1 activity in HIV-infected cells can reverse Tat action which may contribute to AIDS prevention. However, the correlation between HO-1 and HIV-1 Tat has not been fully elucidated. In order to fully understand how increasing HO-1 activity reverses Tat action and result into the prevention of HIV infection, the mechanism behind the correlation between HIV-1 Tat and HO-1 should first be established.

Background Chronic neuroinflammation is an important component of Alzheimer’s disease and could contribute to neuronal dysfunction, injury and loss that lead to disease progression. Multiple clinical studies implicate tumor necrosis factor-α as an inflammatory mediator of neurodegeneration in patients with Alzheimer’s because of elevated levels of this cytokine in the cerebrospinal fluid, hippocampus and cortex. Current Alzheimer’s disease interventions are symptomatic treatments with limited efficacy that do not address etiology. Thus, a critical need exists for novel treatments directed towards modifying the pathophysiology and progression. Methods To investigate the effect of early immune modulation on neuroinflammation and cognitive outcome, we treated triple transgenic Alzheimer’s disease mice (harboring PS1M146V, APPSwe, and tauP301L transgenes) with the small molecule tumor necrosis factor-α inhibitors, 3,6′-dithiothalidomide and thalidomide, beginning at four months of age. At this young age, mice do not exhibit plaque or tau pathology but do show mild intraneuronal amyloid beta protein staining and a robust increase in tumor necrosis factor-α. After 10 weeks of treatment, cognitive performance was assessed using radial arm maze and neuroinflammation was assessed using biochemical, stereological and flow cytometric endpoints. Results 3,6′-dithiothalidomide reduced tumor necrosis factor-α mRNA and protein levels in the brain and improved working memory performance and the ratio of resting to reactive microglia in the hippocampus of triple transgenic mice. In comparison to non-transgenic controls, triple transgenic Alzheimer’s disease mice had increased total numbers of infiltrating peripheral monomyelocytic/granulocytic leukocytes with enhanced intracytoplasmic tumor necrosis factor-α, which was reduced after treatment with 3,6′-dithiothalidomide. Conclusions These results suggest that modulation of tumor necrosis factor-α with small molecule inhibitors is safe and effective with potential for the long-term prevention and treatment of Alzheimer’s disease.

Children born with disorders of sexual differentiation (DSD) pose numerous challenges for the parents, family, and treating physicians. The pediatrician is usually the first medical contact for newborns with DSD or for toddlers and children who present with DSD at a later time. Several years ago, we formed a Gender Medicine Team (GMT) at Baylor College of Medicine and Texas Children’s Hospital (TCH) to explore and evaluate the most appropriate management strategies, which had long been a matter of concern and contention. Subsequently, the GMT, composed of experts in the fields of endocrinology, ethics, genetics, gynecology, psychology, pediatric surgery, and urology, formed a Task Force to evaluate the information available from our own experiences and from reviews of the literature. Utilizing the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system to assess the evidence and recommendations, the Task Force developed a consensus statement for clinical management of DSD and for making appropriate sex assignments.

The lung tumor microenvironment consists of tumor cells, stroma, blood vessels, immune infiltrates and the extracellular matrix. Genetic alterations in oncogenes and tumor suppressor genes or epigenetic changes in the tumor that modulate tumor growth and invasion into the surrounding tissue orchestrate the persistence of inflammatory infiltrates. These cellular infiltrates modulate tumor development and progression. The infiltrates vary by size and composition in diverse tumor types and at different stages of tumor development. The lung tumor programs the cellular infiltrates and dysregulates inflammation to sustain tumor growth, progression and hypo responsiveness of the tumor. Characterization of the complex interactions among the infiltrates and lung cancer will aid in defining their role in tumor progression. This understanding will be important for the development of novel anticancer therapies. Although this is not a trivial undertaking, the information garnered will take us a step closer to personalized medicine. If we know an individual’s lung tumor inflammatory infiltrates, we will be able to predict the risk of tumor progression and then give specific treatment to reprogram the tumor microenvironment to control the disease.

Lung cancer is the most common cause of cancer mortality worldwide for both men and women, causing approximately 1.2 million deaths per year. With the existing therapeutic efforts, the long-term survival for lung cancer patients remains low with only 15% surviving for 5 years following diagnosis. Therefore, new therapeutic strategies are needed. One such approach is the development of immune therapy for lung cancer. Immune approaches for lung cancer remain attractive because although surgery, chemotherapy and radiotherapy alone or in combination have response rates in all histological types of lung cancer, relapse is frequent. Immunologic targeting of lung cancer has the potential for nontoxic and specific therapy. Strategies that harness the immune system to react against tumors can be integrated with existing forms of therapy for optimal responses toward this devastating disease.

Costello syndrome is characterized by severe failure-to-thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto-oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype-phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p.G13C and individuals with p.G12S. The individuals with p.G13C had many typical findings including polyhydramnios, failure-to-thrive, HCM, macrocephaly with posterior fossa crowding, and developmental delay. Subjectively, their facial features were less coarse. Statistically significant differences included the absence of multifocal atrial tachycardia (P-value = 0.033), ulnar deviation of the wrist (P < 0.001) and papillomata (P = 0.003), and fewer neurosurgical procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height below -2 SD) without use of growth hormone (P < 0.001). The noteworthy absence of malignant tumors did not reach statistical significance. Novel ectodermal findings were noted in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, different from the tight curls typical for most Costello syndrome individuals. Unusually long eye lashes requiring trimming are a novel finding we termed dolichocilia. These distinctive ectodermal findings suggest a cell type specific effect of this particular mutation. Additional patients are needed to validate these findings.

Epidemiological data indicate that nearly 20% of preschool aged children have significant behavioral problems. Parents typically consult their child’s primary care provider, who frequently refers to child psychologists for treatment regarding these difficulties. Psychologists skilled in providing effective services for young children are in short supply, limiting accessibility, and parents often are reluctant to follow up with a mental health specialist, suggesting low acceptability. The Behavior Consultation Clinic is a structured clinic for preschool children designed to address these issues of effectiveness, accessibility and acceptability. A retrospective review of 550 patients seen over a 5-year period found that half were seen for one therapy session. Review of the remaining patients found that slightly more than half showed improvement (32% successful discharge with improvement, 24% premature discharge with improvement) with a typical range of two to seven half-hour sessions, about a quarter did not improve, and the remaining patients were referred to a higher level of service. These data indicate that a structured, brief clinic that focuses on the needs of preschool children utilizing evidence-based approaches can be effective, acceptable, and accessible. The Behavior Consultation Clinic also serves as a training clinic for psychology interns and pediatric medical residents.

Costello syndrome is a rare congenital disorder typically characterized by severe failure-to-thrive, cardiac abnormalities including tachyarrhythmia and hypertrophic cardiomyopathy, distinctive facial features, a predisposition to papillomata and malignant tumors, neurologic abnormalities, developmental delay, and mental retardation. Its underlying cause is de novo germline mutations in the oncogene HRAS. Almost all Costello syndrome mutations affect one of the glycine residues in position 12 or 13 of the protein product. More than 80% of patients with Costello syndrome share the same underlying mutation, resulting in a G12S amino acid change. We report on two patients with novel HRAS mutations affecting amino acids 58 (T58I) and 146 (A146V), respectively. Despite facial features that appear less coarse than those typically seen in Costello patients, both patients show many of the physical and developmental problems characteristic for Costello syndrome. These novel HRAS mutations may be less common than the frequently reported G12S change, or patients with these changes may be undiagnosed due to their less coarse facial features. In addition to the findings previously known to occur in Costello syndrome, one of our patients had hypertrophic pyloric stenosis. This led us to review the medical histories on a cohort of proven HRAS mutation positive Costello syndrome patients, and we found a statistically significantly (P

Costello syndrome encompasses pre- and postnatal medical problems including polyhydramnios, failure to thrive, cardiac complications, and an increased risk for solid tumors. Hypotonia and developmental delay are typical in infancy, and mental retardation can be diagnosed in older patients. Previous studies on the cognitive development in Costello syndrome relied on clinically diagnosed cases. The recent discovery of heterozygous HRAS mutations allows for molecular confirmation of the clinical diagnoses. We report here on cognitive abilities and adaptive behavior in the first cohort of patients with molecularly confirmed diagnoses. Further, this is the first longitudinal assessment of cognitive function in this patient population. Sixteen patients with identified HRAS mutations were tested, and 14 completed the Leiter International Performance Scale-Revised. The mean Full-Scale IQ score of 57 (range 30-87) was within the range of mild Mental Retardation. Analysis of test component subsets showed a relative strength in Fluid Reasoning with a mean score of 69 (range 48-98), in the mild range of Mental Retardation. Longitudinal analysis was performed for 12 patients by comparison of data obtained at the first evaluation (T1) to results obtained 2 years later (T2). In these patients intellectual and language abilities remained stable, and no deterioration was seen. We have thus shown that Costello syndrome is a static condition regarding intellectual and language abilities. The Leiter-R Memory Screen indicated functioning in the mildly delayed range for the majority of patients. Adaptive behavior was evaluated using the Vineland tool, and longitudinal data comparison for adaptive behavior showed improvements in Daily Living Skills, Communication, and the Adaptive Behavior Composite. However, these results must be interpreted cautiously as the measuring tool was updated from T1 to T2. Receptive language skills were measured with the Peabody Picture Vocabulary Test-III, showing a mean receptive vocabulary standard score of 65 (SD 15) in the Extremely Low range. Expressive language skills, as measured by the Expressive Vocabulary Test (EVT), scored a mean of 51 (SD 14), in the Extremely Low range. However, half of the subjects obtained the lowest possible score on the EVT, demonstrating that this is not the ideal tool for use in this patient population.