Effects Of Antiphospholipid Antibodies On Trophoblast-Mediated Angiogenesis And Vascular Remodeling

EFFECTS OF ANTIPHOSPHOLIPID ANTIBODIES ON TROPHOBLAST-MEDIATED ANGIOGENESIS AND VASCULAR REMODELING Tamara Y. Carroll, Melissa Mulla and Vikki M. Abrahams. Section of Reproductive Immunology, Department of Obstetrics and Gynecology, Yale University, School of Medicine, New Haven, CT. Women with antiphospholipid antibody syndrome (APS) are at increased risk for miscarriage and preeclampsia, which are associated with diminished trophoblast invasion and limited spiral artery transformation. Antiphospholipid antibodies (aPL) specifically target the placenta by binding trophoblast beta2glycoprotein I (&beta2GPI). Thus, we determined whether aPLs alter trophoblast angiogenic factor production, endothelial tube formation, and trophoblast-endothelial cell interactions, and evaluated the effect of low molecular weight heparin (LMWH) on these responses. Human first trimester trophoblast produced significantly more VEGF, PlGF and sEng following exposure to aPL. This occurred independently of TLR4 and in both MyD88-dependent and independent manners. LMWH was unable to reverse the effects of the aPL on trophoblast VEGF and sEng production, and enhanced PlGF secretion. Strikingly, sFlt-1 secretion in the untreated and aPL-treated cells was increased in the presence of LMWH. However, aPL did not alter endothelial tube formation or trophoblast-endothelial cell interactions, nor did LMWH have an impact. In conclusion, this study demonstrates that aPL modulate the normal production of trophoblast angiogenic factors, that LMWH cannot reverse this effect, and LMWH may even enhance it. However, this altered angiogenic factor profile may not directly impact trophoblast-endothelial interactions/remodeling, suggesting that other mechanisms may be involved

Center for Pediatric Obesity and Diabetes Prevention Research

poster abstractBackground To facilitate both research and treatment of obesity in youth who are at especially high risk for diabetes, we have created the Center for Pediatric Obesity and Diabetes Prevention Research. The mission of the center is to advance the health of vulnerable populations through obesity and diabetes prevention research focusing on mechanisms of progression from obesity to type 2 diabetes, defining best practices for obesity/diabetes prevention among youth, and cost-effective translation of the research to the community. Specific Aims 1. To promote the clinical investigation of pathophysiologic mechanisms, diagnosis, and primary prevention of type 2 diabetes among vulnerable youth 2. Foster collaboration and facilitate interdisciplinary research between investigators interested in childhood obesity and diabetes prevention 3. Participate in community-based diabetes prevention research Key Ongoing Collaborative Research Projects Youth Diabetes Prevention Clinic (YDPC) – Patient-Centered Outcomes Project This program is designed to evaluate and assess the needs of adolescents (ages 10 – 21) who have evidence of prediabetes. Our goal is to successfully intervene in the trajectory toward the development of diabetes, and to promote healthy weight-control and improved well-being through an individualized treatment plan. Not only has this allowed us to address a significant unmet clinical need, but also to advance pediatric obesity patient-centered outcomes research and comparative effectiveness research in adolescent obesity / diabetes prevention. Dietary Intervention for Glucose Intolerance in Teens (DIG-IT Study) The objective of this study is to determine the impact on glycemic control, in adolescents who have prediabetes, of an individually-tailored wellness coaching strategy used to modify lifestyle habits. Additionally, the study aims to identify lifestyle factors that drive glycemic control, independent of changes in weight. We are conducting this study in in the Youth Diabetes Prevention Clinic via a collaboration with Dr. Gletsu-Miller (Purdue University). ENCOURAGE Healthy Families Study This is a randomized trial evaluating the comparative effectiveness and costs of an adaptation of the Diabetes Prevention Program (DPP) directed at mothers and their children. The intervention is a group based lifestyle program which we developed and implemented in partnership with the YMCA. We are comparing the ENCOURAGE intervention targeted to 1) mothers who have had gestational diabetes or prediabetes, and 2) mothers who have had GDM or prediabetes along with their school-aged children

Codesigned Shared Decision-Making Diabetes Management Plan Tool for Adolescents With Type 1 Diabetes Mellitus and Their Parents: Prototype Development and Pilot Test

Background: Adolescents with type 1 diabetes mellitus have difficulty achieving optimal glycemic control, partly due to competing priorities that interfere with diabetes self-care. Often, significant diabetes-related family conflict occurs, and adolescents’ thoughts and feelings about diabetes management may be disregarded. Patient-centered diabetes outcomes may be better when adolescents feel engaged in the decision-making process. Objective: The objective of our study was to codesign a clinic intervention using shared decision making for addressing diabetes self-care with an adolescent patient and parent advisory board. Methods: The patient and parent advisory board consisted of 6 adolescents (teens) between the ages 12 and 18 years with type 1 diabetes mellitus and their parents recruited through our institution’s Pediatric Diabetes Program. Teens and parents provided informed consent and participated in 1 or both of 2 patient and parent advisory board sessions, lasting 3 to 4 hours each. Session 1 topics were (1) patient-centered outcomes related to quality of life, parent-teen shared diabetes management, and shared family experiences; and (2) implementation and acceptability of a patient-centered diabetes care plan intervention where shared decision making was used. We analyzed audio recordings, notes, and other materials to identify and extract ideas relevant to the development of a patient-centered diabetes management plan. These data were visually coded into similar themes. We used the information to develop a prototype for a diabetes management plan tool that we pilot tested during session 2. Results: Session 1 identified 6 principal patient-centered quality-of-life measurement domains: stress, fear and worry, mealtime struggles, assumptions and judgments, feeling abnormal, and conflict. We determined 2 objectives to be principally important for a diabetes management plan intervention: (1) focusing the intervention on diabetes distress and conflict resolution strategies, and (2) working toward a verbalized common goal. In session 2, we created the diabetes management plan tool according to these findings and will use it in a clinical trial with the aim of assisting with patient-centered goal setting. Conclusions: Patients with type 1 diabetes mellitus can be effectively engaged and involved in patient-centered research design. Teens with type 1 diabetes mellitus prioritize reducing family conflict and fitting into their social milieu over health outcomes at this time in their lives. It is important to acknowledge this when designing interventions to improve health outcomes in teens with type 1 diabetes mellitus

Pediatric decision support using adapted Arden Syntax

BACKGROUND: Pediatric guidelines based care is often overlooked because of the constraints of a typical office visit and the sheer number of guidelines that may exist for a patient's visit. In response to this problem, in 2004 we developed a pediatric computer based clinical decision support system using Arden Syntax medical logic modules (MLM). METHODS: The Child Health Improvement through Computer Automation system (CHICA) screens patient families in the waiting room and alerts the physician in the exam room. Here we describe adaptation of Arden Syntax to support production and consumption of patient specific tailored documents for every clinical encounter in CHICA and describe the experiments that demonstrate the effectiveness of this system. RESULTS: As of this writing CHICA has served over 44,000 patients at 7 pediatric clinics in our healthcare system in the last decade and its MLMs have been fired 6182,700 times in "produce" and 5334,021 times in "consume" mode. It has run continuously for over 10 years and has been used by 755 physicians, residents, fellows, nurse practitioners, nurses and clinical staff. There are 429 MLMs implemented in CHICA, using the Arden Syntax standard. Studies of CHICA's effectiveness include several published randomized controlled trials. CONCLUSIONS: Our results show that the Arden Syntax standard provided us with an effective way to represent pediatric guidelines for use in routine care. We only required minor modifications to the standard to support our clinical workflow. Additionally, Arden Syntax implementation in CHICA facilitated the study of many pediatric guidelines in real clinical environments

The Effect of Body Mass Index on Blood Pressure Varies by Race among Children

poster abstractThe effect of adiposity on blood pressure (BP) intensifies as children become obese, and black children tend to have greater body mass index (BMI) and higher BP than age-matched white children. But few studies have compared the magnitude of the effect of BMI on BP in obese black and white children. We used a novel analytic technique to examine the influence of age and BMI on BP in children seen at a hospital-based obesity clinic. The study sample included 821 overweight and obese children (age and sex adjusted BMI% ranged from 87% to 100%; 306 males, 515 females, 362 blacks, and 459 whites). The mean age of the study subjects was 11.72 ± 3.48 years, the mean BMI was 36.22 ± 8.51 kg/m2, and the mean systolic and diastolic BP were 109.36 ± 16.10 and 69.99 ± 10.48 mmHg, respectively. In comparison, blacks and whites were similar in age (11.89 vs 11.58; p=0.197); while black patients had higher BMI (37.32 vs 35.34 kg/m2; p=0.0010), and higher systolic BP% than whites (58.71 vs 50.72 mmHg; p=0.00062). Semiparametric regression models showed that while age and BMI were significantly associated with systolic BP% in both race groups, black children had significantly higher BP% values as compared with white children of the same age and BMI (Fig 1 (a) and (b)). Although BP% values have taken into account the effect of age, there continued to be a significant effect of age on BP% in black children. In conclusion, among children referred for treatment of obesity, black children are at a significantly greater risk for having elevated BP as compared with their white peers of similar age and severity of obesity. Further research is needed to better understand this population-specific intensification of the adiposity effect on BP in obese black children

Rationale and Design of a Comparative Effectiveness Trial to Prevent Type 2 Diabetes in Mothers and Children: The ENCOURAGE Healthy Families Study

The number of youth with type 2 diabetes (T2D) is expected to quadruple over 4 decades. Gestational diabetes mellitus (GDM) is also increasing and is linked with development of T2D in women, and greater risk for T2D in adolescents exposed to GDM. Despite the increasing prevalence of T2D, approaches to prevent diabetes in high-risk youth and families are rare. To address this, we are conducting the Encourage Health Families Study (ENCOURAGE). This is a randomized trial evaluating the comparative effectiveness and costs of an adaptation of the Diabetes Prevention Program (DPP) directed at mothers who had GDM or prediabetes and their children. The intervention is a group-based lifestyle program which we developed and implemented in partnership with the YMCA. We are comparing the ENCOURAGE intervention targeted to 1) mothers who have had GDM or prediabetes, and 2) mothers who have had GDM or prediabetes along with their school-aged children. This manuscript provides 1) the rationale for a targeted approach to preventing T2D and the interventions, 2) description of the translation of the DPP curriculum, and 3) the study design and methodology. The primary aims are to determine if participation leads to 1) weight loss in high-risk mothers, and 2) youth having healthier weights and lifestyle habits. We will also evaluate costs associated with each approach. These data are essential to build a translation model of T2D prevention that is both realistic and feasible to address this growing problem in both youth and adults

The effect of body mass index on blood pressure varies by race among obese children

Objective: Previous studies have shown that the effect of adiposity on blood pressure (BP) intensifies as children become increasingly obese. Black children tend to have greater body mass index (BMI) and higher BP than age-matched white children. It is unclear whether the BP effects of BMI are race-specific among black and white children, and data on obese Hispanic children are sparse. We compared the BP effect of BMI in obese white, black, and Hispanic children. Methods: We examined the medical records of children enrolled in a pediatric obesity clinic. Height, weight, BP, and fasting insulin were assessed as part of routine clinical care. The concurrent effects of age and BMI on BP percentile values were examined using semiparametric regression, which allows the accommodation of nonlinear effects. Results: The study included 873 children (338 male; 354 black, 447 white, 72 Hispanic; 11.7±3.5 years, BMI 36.2±8.5 kg/m2). While BMI Z-scores were similar among the groups, systolic BP (SBP) was higher in black children and Hispanic children (white: 107 mm Hg; black: 112 mm Hg; Hispanic: 112 mm Hg; p=0.0001). Age, sex, and height-adjusted SBP percentiles were significantly different among the three groups (white: 50; black: 59; Hispanic: 59; p=0.0006). In children of the same age, BP was higher at any given BMI in black children and Hispanic children. Conclusions: Among children referred for treatment of obesity, black children and Hispanic children are at a greater risk for having elevated BP when compared to white children of similar age and BMI

Depressive symptoms are associated with fasting insulin resistance in obese youth

BACKGROUND: In adults, depressive symptoms are positively associated with insulin resistance. OBJECTIVE: To determine whether an association exists between depressive symptoms and markers of insulin resistance in youth. METHODS: This study used a retrospective review of data from an obesity clinic. We evaluated the association between depressive symptoms (Children's Depression Inventory, CDI) and fasting insulin and homeostatic model assessment-insulin resistance (HOMA-IR) in obese youth (n = 207, age 10-18 years). Individuals with lower vs. higher CDI T-scores (<65 vs. ≥65) were compared; this cut-point is accepted as indicating the possibility of clinical depression. Multiple linear regression was used to evaluate relationships between CDI T-scores and insulin resistance. RESULTS: Fasting insulin and HOMA-IR values were 40% higher in patients with higher CDI T-scores (P = 0.04). After accounting for gender, race, age and body mass index, CDI T-score remained associated with HOMA-IR, although the strength of the association was small (b = 0.007, P = 0.049). CONCLUSIONS: Relationships between depressive symptoms and insulin resistance should be considered when evaluating obese youth