An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.

Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an "intermediate" DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations.

The Buddy Benefit: Increasing the Effectiveness of an Employee-Targeted Weight-Loss Program.

It is well known that significant others (particularly romantic partners) can influence people's weight management efforts. However, what constitutes effective support-and from which type of individual (e.g., romantic partner, family member, friend)-is unclear. Thus, framed by confirmation theory, we assessed the effectiveness and types of communication of a weight-loss "buddy" through reports of 704 individuals enrolled in a 15-week synchronous online weight-loss program. Roughly 54% of participants chose buddies; and those who did lost more weight and waist inches than those who were involved in the program without buddy support. We also found that a combination of high accepting and high challenging messages from buddies was associated with the greatest decrease in body mass index (BMI) as well as the greatest reduction in waist size. Furthermore, the support by romantic partners paralleled support by other types of buddies. Having a supportive buddy who was not a romantic partner was just as effective as turning to a romantic partner for assistance. This study underscores the important role of a buddy in supporting weight-loss program involvement and encourages individuals to consider enlisting the help of a buddy, as opposed to losing weight alone, in order to maximize weight management effectiveness.

Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability.

Recently, the application of array-based comparative genomic hybridization (array CGH) has improved rates of detection of chromosomal imbalances in individuals with mental retardation and dysmorphic features. Here, we describe three individuals with learning disability and a heterozygous deletion at chromosome 17q21.3, detected in each case by array CGH. FISH analysis demonstrated that the deletions occurred as de novo events in each individual and were between 500 kb and 650 kb in size. A recently described 900-kb inversion that suppresses recombination between ancestral H1 and H2 haplotypes encompasses the deletion. We show that, in each trio, the parent of origin of the deleted chromosome 17 carries at least one H2 chromosome. This region of 17q21.3 shows complex genomic architecture with well-described low-copy repeats (LCRs). The orientation of LCRs flanking the deleted segment in inversion heterozygotes is likely to facilitate the generation of this microdeletion by means of non-allelic homologous recombination.

Randomized controlled trial targeting obesity-related behaviors: Better Together Healthy Caswell County.

INTRODUCTION: Collaborative and multilevel interventions to effectively address obesity-related behaviors among rural communities with health disparities can be challenging, and traditional research approaches may be unsuitable. The primary objective of our 15-week randomized controlled pilot study, which was guided by community-based participatory research (CBPR) principles, was to determine the effectiveness of providing twice-weekly access to group fitness classes, with and without weekly nutrition and physical activity education sessions, in Caswell County, North Carolina, a rural region devoid of medical and physical activity resources. METHODS: Participants were randomly divided into 2 groups: group 1 was offered fitness sessions and education in healthful eating and physical activity; group 2 was offered fitness sessions only. Outcome measures were assessed at baseline and immediately after the intervention. Standardized assessment procedures, validated measures, and tests for analysis of variance were used. RESULTS: Of 91 enrolled participants, most were African American (62%) or female (91%). Groups were not significantly different at baseline. Group 1 experienced significantly greater improvements in body mass index (F = 15.0, P < .001) and waist circumference (F = 7.0, P = .01), compared with group 2. Both groups significantly increased weekly minutes of moderate physical activity (F = 9.4, P < .003). Participants in group 1 also had significantly greater weight loss with higher attendance at the education (F = 14.7, P < .001) and fitness sessions (F = 18.5, P < .001). CONCLUSION: This study offers effective programmatic strategies that can reduce weight and increase physical activity and demonstrates feasibility for a larger scale CBPR obesity trial targeting underserved residents affected by health disparities. This study also signifies successful collaboration among community and academic partners engaged in a CBPR coalition.

Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2.

PURPOSE: To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. METHODS: The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. RESULTS: Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. CONCLUSION: Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay.

PURPOSE: The identification of variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing poses great challenges for the clinical management of variant carriers. The ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) variant classification framework, which incorporates multiple sources of evidence, has the potential to establish the clinical relevance of many VUS. We sought to classify the clinical relevance of 133 single-nucleotide substitution variants encoding missense variants in the DNA-binding domain (DBD) of BRCA2 by incorporating results from a validated functional assay into an ACMG/AMP-variant classification model from a hereditary cancer-testing laboratory. EXPERIMENTAL DESIGN: The 133 selected VUS were evaluated using a validated homology-directed double-strand DNA break repair (HDR) functional assay. Results were combined with clinical and genetic data from variant carriers in a rules-based variant classification model for BRCA2. RESULTS: Of 133 missense variants, 44 were designated as non-functional and 89 were designated as functional in the HDR assay. When combined with genetic and clinical information from a single diagnostic laboratory in an ACMG/AMP-variant classification framework, 66 variants previously classified by the diagnostic laboratory were correctly classified, and 62 of 67 VUS (92.5%) were reclassified as likely pathogenic (n = 22) or likely benign (n = 40). In total, 44 variants were classified as pathogenic/likely pathogenic, 84 as benign/likely benign, and 5 remained as VUS. CONCLUSIONS: Incorporation of HDR functional analysis into an ACMG/AMP framework model substantially improves BRCA2 VUS re-classification and provides an important tool for determining the clinical relevance of individual BRCA2 VUS.

Establishing worksite wellness programs for North Carolina government employees, 2008.

BACKGROUND: State employee health plans sometimes provide worksite wellness programs to reduce the prevalence of chronic diseases among their members, but few offer the comprehensive range of interventions recommended by the Task Force on Community Preventive Services. COMMUNITY CONTEXT: North Carolina's State Health Plan for Teachers and State Employees provides health coverage for approximately 665,000 state employees, teachers, retirees, and dependents. Health claims indicate that the prevalence of having at least 1 chronic disease or of being obese is approximately 32% among state employees. METHODS: The State Health Plan created a partnership with North Carolina's Division of Public Health, Office of State Personnel, and other key state agencies to identify bureaucratic obstacles to providing worksite wellness programs for state employees and to develop a state policy to address them. The Division of Public Health established a model worksite program to guide development of the worksite wellness policy and pilot wellness interventions. OUTCOME: The state's first worksite wellness policy created an employee wellness infrastructure in state government and addressed administrative barriers to allow effective worksite wellness interventions. For example, the policy led to pilot implementation of a subsidized worksite weight management program. Positive results of the program helped generate legislative support to expand the weight management program throughout state government. INTERPRETATION: Strong interagency partnership is essential to guide worksite wellness policy and program development in state government. State health plans, public health agencies, and personnel agencies each play a role in that partnership.

Effects of a behavior-based weight management program delivered through a state cooperative extension and local public health department network, North Carolina, 2008-2009.

INTRODUCTION: Eat Smart, Move More, Weigh Less (ESMMWL) is an adult weight management program developed in response to North Carolina Obesity Plan recommendations to make weight management interventions accessible to underserved populations. ESMMWL was designed to be delivered through the North Carolina Cooperative Extension and North Carolina Division of Public Health. Program coursework included content on evidence-based eating and physical activity behaviors and incorporated mindful eating concepts. The objectives of this study were to describe participant changes in weight and behaviors and to document the effectiveness of the program. METHODS: In this prospective pilot study, courses were delivered and data collected from January 2008 through June 2009. Instructors provided feedback about implementation. For participants, height, weight, and waist circumference were measured at baseline and completion. Participants completed a questionnaire about changes in their eating and physical activity behaviors, changes in their confidence to engage in weight management behaviors, and their satisfaction with the course. RESULTS: Seventy-nine instructors delivered 101 ESMMWL courses in 48 North Carolina counties. Most of the 1,162 completers were white women. Approximately 83% reported moving toward or attaining their goal. The average weight loss was 8.4 lb. Approximately 92% reported an increase in confidence to eat healthfully, and 82% reported an increase in confidence to be physically active. Instructors made suggestions for program standardization. CONCLUSION: This study demonstrated the effectiveness, diffusion, and implementation of a theoretically based weight management program through a state extension and local public health department network. Study of the sustainability of changes in eating and physical activity behaviors is needed.

Mindfulness Approaches and Weight Loss, Weight Maintenance, and Weight Regain.

PURPOSE OF REVIEW: There is an urgent need for effective weight management techniques, as more than one third of US adults are overweight or obese. Recommendations for weight loss include a combination of reducing caloric intake, increasing physical activity, and behavior modification. Behavior modification includes mindful eating or eating with awareness. The purpose of this review was to summarize the literature and examine the impact of mindful eating on weight management. RECENT FINDINGS: The practice of mindful eating has been applied to the reduction of food cravings, portion control, body mass index, and body weight. Past reviews evaluating the relationship between mindfulness and weight management did not focus on change in mindful eating as the primary outcome or mindful eating as a measured variable. This review demonstrates strong support for inclusion of mindful eating as a component of weight management programs and may provide substantial benefit to the treatment of overweight and obesity.

The Move More Scholars Institute: a state model of the physical activity and public health practitioners course.

Physical activity has been identified as a public health priority. In response, training and professional development opportunities have been created to increase the capacity of public health practitioners to address this issue. Currently, training resources are primarily reaching national- and state-level professionals. Local-level physical activity and public health practitioners can also benefit from these resources. The Move More Scholars Institute, a 4-day training course for community-based physical activity practitioners in North Carolina, was developed for local practitioners. This article will describe the planning of, implementation of, and initial response to the Move More Scholars Institute.

Design and implementation of a nutrition and physical activity curriculum for child care settings.

BACKGROUND: Childhood overweight continues to increase in the United States. Children should begin establishing healthy eating and physical activity behaviors at a young age. CONTEXT: Many children spend a large part of their day in child care settings, whether in preschools or home day care settings. Child care providers in these settings have an opportunity to establish and reinforce habits that promote good health. However, the providers need training and creative educational materials to teach children about healthy eating and physical activity. Color Me Healthy is an educational program focusing on nutrition and physical activity that was developed for children aged 4 and 5 years by three of the authors (C.D., C.T., and L.P.). METHODS: In 2001 and 2002, the program was implemented in 47 North Carolina counties and the North Carolina Cherokee reservation. In December 2001, we used an information-dissemination model called Train the Trainer during a session to teach county teams comprising local public health professionals and cooperative extension employees how to teach child care providers in their communities to use the curriculum. The child care providers were then trained between March and August 2002. Follow-up evaluation forms were given to trained child care providers 8 weeks after the training. CONSEQUENCES: Of the providers who completed the evaluations (n = 486), 92.0% indicated that using the Color Me Healthy curriculum increased the physical activity of their students, and 91.8% indicated that it increased the children's knowledge about movement. In addition, 93.0% of providers also indicated that using Color Me Healthy had increased the children's knowledge about healthy eating. INTERPRETATION: Child care providers need educational materials on healthy eating and physical activity and should be trained to use them. The Train the Trainer model is an effective way to teach public health professionals to train child care providers on the Color Me Healthy curriculum materials about healthy eating and physical activity.

Using synchronous distance education to deliver a weight loss intervention: A randomized trial.

OBJECTIVE: To implement a randomized trial to evaluate the effectiveness of a weight loss program delivered using synchronous distance education compared with a wait-list control group with 6-month follow-up. METHODS: Adults with a body mass index (BMI) ≥25 were randomized to the intervention (n = 42) or wait-list control group (n = 38). The intervention group participated in a synchronous, online, 15-week weight loss program; weight loss was the primary outcome. Secondary measures included height, BMI, and confidence in ability to be physically active and eat healthy. Assessments occurred at three and four time points in the intervention and control group, respectively. RESULTS: Participants who completed the program lost significantly more weight (1.8 kg) than those in the wait-list control group (0.25 kg) at week 15 [F(1,61) = 6.19, P = 0.02] and had a greater reduction in BMI (0.71 vs. 0.14 kg/m(2) ), [F(1,61) = 7.45, P = 0.01]. There were no significant differences between the intervention and the wait-list control groups for change in confidence in ability to be physically active or eat healthy. Weight loss was maintained at 6 months. CONCLUSIONS: Use of synchronous distance education is a promising approach for weight loss. The results of this study will help to inform future research that employs Web-based interventions.

IL-15 regulation in human endometrial stromal cells.

A greater knowledge of IL-5 regulation within human endometrium is important in understanding key reproductive events and uterine Natural Killer cell function. In the present study, expression of IL-15 mRNA was shown to be up-regulated by both PGE(2) and IFN-gamma in cultures of human endometrial stromal cells (ESC). Release of IL-15 protein was also shown to be under the control of PGE(2) and IFN-gamma using an enzyme-linked immunosorbent assay for IL-15. In addition, 8-Bromo cAMP was able to increase IL-15 release from ESCs (P < 0.005) implying the actions of PGE(2) may be via this second messenger. Addition of a progestin appeared to enhance these effects. Real-time quantitative PCR has demonstrated an up-regulation in IL-15 mRNA expression in the late secretory phase of the menstrual cycle (P < 0.005) and a progressive rise in IFN-gamma expression throughout the secretory phase and into first trimester decidua. These results suggest that IL-15 regulation in the human endometrium is complex and that hormonal control may be indirect.

Using synchronous distance-education technology to deliver a weight management intervention.

OBJECTIVE: To compare the effectiveness of online delivery of a weight management program using synchronous (real-time), distance-education technology to in-person delivery. METHODS: Synchronous, distance-education technology was used to conduct weekly sessions for participants with a live instructor. Program effectiveness was indicated by changes in weight, body mass index (BMI), waist circumference, and confidence in ability to eat healthy and be physically active. RESULTS: Online class participants (n = 398) had significantly greater reductions in BMI, weight, and waist circumference than in-person class participants (n = 1,313). Physical activity confidence increased more for in-person than online class participants. There was no difference for healthy eating confidence. CONCLUSIONS AND IMPLICATIONS: This project demonstrates the feasibility of using synchronous distance-education technology to deliver a weight management program. Synchronous online delivery could be employed with no loss to improvements in BMI, weight, and waist circumference.

Development of a movement and state plan for obesity prevention, Eat Smart, Move More North Carolina.

This report outlines the evolution of the Eat Smart, Move More North Carolina movement and publications in support of the movement, including North Carolina's Plan to Address Obesity: Healthy Weight and Healthy Communities, 2013-2020. This evidence-based plan guides the efforts of many organizations as they work to fulfill the mission of Eat Smart, Move More North Carolina: to reverse the rising tide of obesity and chronic disease among North Carolinians by helping them to eat smart, move more, and achieve a healthy weight.

Delivering a behavior-change weight management program to teachers and state employees in North Carolina.

PURPOSE: To ascertain the effectiveness of a behavior-change weight management program offered to teachers and state employees in North Carolina (NC). DESIGN: Fifteen-week weight management program with premeasures and postmeasures. SETTING: State agencies and public K-12 schools in five NC counties. SUBJECTS: A total of 2574 NC state employees enrolled in 141 classes. INTERVENTION: Eat Smart, Move More, Weigh Less (ESMMWL) is a 15-week weight management program delivered by trained instructors. Lessons inform, empower, and motivate participants to live mindfully as they make choices about eating and physical activity. MEASURES: Height, weight, body mass index (BMI), waist circumference, blood pressure, confidence in ability to eat healthy and be physically active, changes in eating, and physical activity behaviors. ANALYSIS: Descriptive statistics, t-tests, χ(2) tests, and analyses of variance. RESULTS: Data are reported for 1341 participants in ESMMWL who completed the program, submitted an evaluation, and had not participated in the program in the past; 89% were female and mean age was 48.8 years. Average BMI and waist circumference decreased significantly. Confidence in eating healthfully and being physically active increased significantly. The percentage of participants with a BMI < 30 kg/m(2) increased from 40% to 45% and those with a normal blood pressure increased from 23% to 32.5%. Participants reported being more mindful of what and how much they ate (92%), being more mindful of how much daily physical activity they got (88%), and eating fewer calories (87.3%). CONCLUSION: This project demonstrated the feasibility of implementing a behavior change-based weight management program at the worksite to achieve positive outcomes related to weight, blood pressure, healthy eating, and physical activity behaviors. Programs such as this have the potential to provide health care cost savings.

Increasing fruit and vegetable consumption among preschoolers: evaluation of color me healthy.

OBJECTIVE: Determine whether Color Me Healthy (CMH), an interactive nutrition and physical activity program for preschool children, increases fruit and vegetable consumption. DESIGN: Intervention study. Data were collected at baseline, 1 week post-intervention, and 3 months post-intervention. SETTING: Child care centers. PARTICIPANTS: Preschool children (n = 263) in 17 child care centers. INTERVENTION: Child care centers were randomly assigned to 1 of 2 conditions; children (n = 165) in 10 centers received the CMH curriculum, and children (n = 98) in 7 centers acted as comparisons and did not receive the curriculum. MAIN OUTCOME MEASURES: Process and outcome evaluation. Consumption of fruit and vegetable snacks. ANALYSIS: Data were analyzed using repeated-measures analysis of variance and hierarchical linear modeling. RESULTS: Children who received CMH significantly increased their consumption of fruit snacks by approximately 20.8% and vegetable snacks by approximately 33.1% between baseline assessment and the assessment conducted 3 months after the completion of the CMH program. Hierarchical linear modeling determined that group assignment (ie, CMH or control) was the only significant predictor of fruit and vegetable consumption. CONCLUSIONS AND IMPLICATIONS: Findings suggest that CMH may be used in child care settings for developing healthful eating habits.

Familial 3q29 microdeletion syndrome providing further evidence of involvement of the 3q29 region in bipolar disorder.

The 3q29 microdeletion syndrome is caused by a recurrent 1.6 Mb deletion of the 3q subtelomeric region. Though sometimes visible on routine microscopy, the deletion is detected more reliably using subtelomeric fluorescence in-situ hybridization (FISH) or molecular karyotyping. The clinical features associated with a 3q29 microdeletion are variable and include developmental delay, autistic features, skeletal abnormalities and dysmorphic facial features with a relatively long face, long nose with a high bridge and broad tip, short philtrum and large ears. Orofacial clefting, cardiac defects, ocular anomalies and genitourinary malformations have been reported occasionally. We report a three generation family where four individuals were confirmed to have a 3q29 microdeletion and compare their clinical features to those of previously reported patients. This family shows that the learning difficulties associated with a 3q29 deletion may be relatively mild. The history of a severe depressive disorder commencing in adulthood in the affected grandmother also supports previous studies linking the 3q29 region to bipolar disorder and links with the observation of Digilio et al. (2009) who also reported a history of depression in an adult woman with a similar deletion.