Department of Pediatrics Works

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Pediatric assent for a study of antiretroviral therapy dosing for children in western Kenya: a case study in international research collaboration
(Regents of the University of California, 2009-03) Vreeman, Rachel C.; Nyandiko, Winstone M.; Meslin, Eric M.
Multinational collaborators in health research face particular ethical challenges when conducting studies involving vulnerable populations such as children. We use an example from our first attempt to implement pediatric assent in the context of a longstanding research and clinical partnership between Kenyan and American medical schools to highlight the ethical and procedural issues related to pediatric assent that must be considered for multinational, pediatric studies. We consider relevant domestic, professional, and international guidelines for assent in pediatric research subjects, and we discuss the particular ethical challenges related to pediatric assent in the Kenyan context. Finally, we propose a way forward for approaching pediatric assent within our collaborative research program in Kenya that may apply to other multinational research partnerships.
Contracting and Monitoring Relationships for Adolescents with Type 1 Diabetes: A Pilot Study
(2011-04) Carroll, Aaron E.; DiMeglio, Linda A.; Stein, Stephanie; Marrero, David G.
Background: Adolescents are developmentally in a period of transition—from children cared for by their parents to young adults capable of self-care, independent judgment, and self-directed problem solving. We wished to develop a behavioral contract for adolescent diabetes management that addresses some negotiable points of conflict within the parent–child relationship regarding self-monitoring and then assess its effectiveness in a pilot study as part of a novel cell phone–based glucose monitoring system. Methods: In the first phase of this study we used semistructured interview techniques to determine the major sources of diabetes-related conflict in the adolescent–parent relationship, to identify factors that could facilitate or inhibit control, and to determine reasonable goals and expectations. These data were then used to inform development of a behavioral contract that addressed the negotiable sources of conflict between parents and their adolescent. The second phase of this research was a 3-month pilot study to measure how a novel cell phone glucose monitoring system would support the contract and have an effect on glucose management, family conflict, and quality of life. Results: Interviews were conducted with 10 adolescent–caregiver pairs. The major theme of contention was nagging about diabetes management. Two additional themes emerged as points of negotiation for the behavioral contract: glucose testing and contact with the diabetes clinical team. Ten adolescent–parent pairs participated in the pilot test of the system and contract. There was a significant improvement in the Diabetes Self-Management Profile from 55.2 to 61.1 (P < 0.01). A significant reduction in hemoglobin A1c also occurred, from 8.1% at the start of the trial to 7.6% at 3 months (P < 0.04). Conclusions: This study confirms previous findings that mobile technologies do offer significant potential in improving the care of adolescents with type 1 diabetes. Moreover, behavioral contracts may be an important adjunct to reduce nagging and improve outcomes with behavioral changes.
The Perceived Impact of Disclosure of Pediatric HIV Status on Pediatric Antiretroviral Therapy Adherence, Child Well-Being, and Social Relationships in a Resource-Limited Setting
(2010-10) Vreeman, Rachel C.; Nyandiko, Winstone M.; Ayaya, Samwel O.; Walumbe, Eunice G.; Marrero, David G.; Inui, Thomas S.
In resource-limited settings, beliefs about disclosing a child’s HIV status and the subsequent impacts of disclosure have not been well studied. We sought to describe how parents and guardians of HIV-infected children view the impact of disclosing a child’s HIV status, particularly for children’s antiretroviral therapy (ART) adherence. A qualitative study was conducted using involving focus groups and interviews with parents and guardians of HIV-infected children receiving ART in western Kenya. Interviews covered multiple aspects of the experience of having children take medicines. Transcribed interview dialogues were coded for analysis. Data were collected from 120 parents and guardians caring for children 0–14 years (mean 6.8 years, standard deviation [SD] 6.4); 118 of 120 had not told the children they had HIV. Children’s caregivers (parents and guardians) described their views on disclosure to children and to others, including how this information-sharing impacted pediatric ART adherence, children’s well-being, and their social relationships. Caregivers believed that disclosure might have benefits such as improved ART adherence, especially for older children, and better engagement of a helping social network. They also feared, however, that disclosure might have both negative psychological effects for children and negative social effects for their families, including discrimination. In western Kenya, caregivers’ views on the risks and benefits to disclosing children’s HIV status emerged a key theme related to a family’s experience with HIV medications, even for families who had not disclosed the child’s status. Assessing caregivers’ views of disclosure is important to understanding and monitoring pediatric ART.
The HealthPia GlucoPack™ Diabetes Phone: A Usability Study
(2007-04) Carroll, Aaron E.; Marrero, David G.; Downs, Stephen M.
Background: Type I diabetes is a common chronic disease of childhood. Both the growing influence of peers and the shifting away from parental influence have been implicated as prime elements contributing to poor glycemic outcomes in adolescents. Mobile technology that can be directed towards providing self-management support and modifying potentially negative child parent interaction holds promise to improve control in adolescents with diabetes. Methods: HealthPia, Inc. (Palisades Park, NJ) has developed a prototype system, the HealthPia GlucoPack™ Diabetes Monitoring System, which integrates a small blood glucose monitoring device into the battery pack of a cell phone. A pilot study used mixed quantitative and qualitative methods to evaluate user satisfaction with the integrated system, including the potential of the device to transmit self-monitoring data to a website for review and analysis by clinicians, parents, and patients. Results: Adolescents in our study liked the integration of the two technologies and agreed that the glucometer was easy to use and that the tool was useful in the management of their diabetes. Conclusions: Future work will focus on the utilization of the diabetes phone as a component of a care delivery system for adolescents with diabetes, including involvement of the health care team and enhancement of the web services that support the use of the phone.
Using a cell phone-based glucose monitoring system for adolescent diabetes management
(2011-01) Carroll, Aaron E.; DiMeglio, Linda A.; Stein, Stephanie; Marrero, David G.
INTRODUCTION: Mobile technology may be useful in addressing several issues in adolescent diabetes management. PURPOSE: To assess the feasibility and acceptability of a cell phone glucose monitoring system for adolescents with type 1 diabetes and their parents. METHODS: The authors recruited patients with type 1 diabetes who had been diagnosed for at least 1 year. Each adolescent used the system for 6 months, filling out surveys every 3 months to measure their usability and satisfaction with the cell phone glucose monitoring system, as well as how use of the system might affect quality of family functioning and diabetes management. RESULTS: Adolescents reported positive feelings about the technology and the service, even though a concerning number of them had significant technical issues that affected continued use of the device. Nearly all thought that the clinic involvement in monitoring testing behavior was quite acceptable. The use of the Glucophone™ did not, however, significantly change the quality of life of the adolescents, their level of conflict with their parents, their reported self-management of diabetes, or their average glycemic control within the short time frame of the study. CONCLUSIONS: As a feasibility study of the technology, this work was successful in demonstrating that cell phone glucose monitoring technology can be used in an adolescent population to track and assist in self-monitoring behavior. The authors speculate that explicitly attempting to change behavior, perhaps with the use of behavioral contracts, would enhance the technology's ability to improve outcomes.
Giving patients granular control of personal health information: Using an ethics “Points to Consider” to inform informatics system designers
(http://dx.doi.org/10.1016/j.ijmedinf.2013.08.010, 2013-12) Meslin, Eric M.; Alpert, Sheri A.; Carroll, Aaron E.; Odell, Jere D.; Tierney, William M.; Schwartz, Peter H.
OBJECTIVE: There are benefits and risks of giving patients more granular control of their personal health information in electronic health record (EHR) systems. When designing EHR systems and policies, informaticists and system developers must balance these benefits and risks. Ethical considerations should be an explicit part of this balancing. Our objective was to develop a structured ethics framework to accomplish this. METHODS: We reviewed existing literature on the ethical and policy issues, developed an ethics framework called a "Points to Consider" (P2C) document, and convened a national expert panel to review and critique the P2C. RESULTS: We developed the P2C to aid informaticists designing an advanced query tool for an electronic health record (EHR) system in Indianapolis. The P2C consists of six questions ("Points") that frame important ethical issues, apply accepted principles of bioethics and Fair Information Practices, comment on how questions might be answered, and address implications for patient care. DISCUSSION: The P2C is intended to clarify what is at stake when designers try to accommodate potentially competing ethical commitments and logistical realities. The P2C was developed to guide informaticists who were designing a query tool in an existing EHR that would permit patient granular control. While consideration of ethical issues is coming to the forefront of medical informatics design and development practices, more reflection is needed to facilitate optimal collaboration between designers and ethicists. This report contributes to that discussion.
Adolescent Health-Risk Behavior and Community Disorder
(2013-11) Wiehe, Sarah E.; Kwan, Mei-Po; Wilson, Jeffrey S.; Fortenberry, J. Dennis
Background Various forms of community disorder are associated with health outcomes but little is known about how dynamic context where an adolescent spends time relates to her health-related behaviors. Objective Assess whether exposure to contexts associated with crime (as a marker of community disorder) correlates with self-reported health-related behaviors among adolescent girls. Methods Girls (N = 52), aged 14–17, were recruited from a single geographic urban area and monitored for 1 week using a GPS-enabled cell phone. Adolescents completed an audio computer-assisted self-administered interview survey on substance use (cigarette, alcohol, or marijuana use) and sexual intercourse in the last 30 days. In addition to recorded home and school address, phones transmitted location data every 5 minutes (path points). Using ArcGIS, we defined community disorder as aggregated point-level Unified Crime Report data within a 200-meter Euclidian buffer from home, school and each path point. Using Stata, we analyzed how exposures to areas of higher crime prevalence differed among girls who reported each behavior or not. Results Participants lived and spent time in areas with variable crime prevalence within 200 meters of their home, school and path points. Significant differences in exposure occurred based on home location among girls who reported any substance use or not (p 0.04) and sexual intercourse or not (p 0.01). Differences in exposure by school and path points were only significant among girls reporting any substance use or not (p 0.03 and 0.02, respectively). Exposure also varied by school/non-school day as well as time of day. Conclusions Adolescent travel patterns are not random. Furthermore, the crime context where an adolescent spends time relates to her health-related behavior. These data may guide policy relating to crime control and inform time- and space-specific interventions to improve adolescent health.
p21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics
(2009-03) Allen, Jayme D; Jaffer, Zahara M; Park, Su-Jung; Burgin, Sarah; Hofmann, Clemens; Sells, Mary A; Chen, Shi; Derr-Yellin, Ethel; Michels, Elizabeth G; McDaniel, Andrew; Bessler, Waylan K; Ingram, David A; Atkinson, Simon J; Travers, Jeffrey B; Chemoff, Jonathan; Clapp, D Wade
Mast cells are key participants in allergic diseases via activation of high-affinity IgE receptors (FcϵRI) resulting in release of proinflammatory mediators. The biochemical pathways linking IgE activation to calcium influx and cytoskeletal changes required for intracellular granule release are incompletely understood. We demonstrate, genetically, that Pak1 is required for this process. In a passive cutaneous anaphylaxis experiment, Wsh/Wsh mast cell–deficient mice locally reconstituted with Pak1−/− bone marrow–derived mast cells (BMMCs) experienced strikingly decreased allergen-induced vascular permeability compared with controls. Consistent with the in vivo phenotype, Pak1−/− BMMCs exhibited a reduction in FcϵRI-induced degranulation. Further, Pak1−/− BMMCs demonstrated diminished calcium mobilization and altered depolymerization of cortical filamentous actin (F-actin) in response to FcϵRI stimulation. These data implicate Pak1 as an essential molecular target for modulating acute mast cell responses that contribute to allergic diseases.
A Fluorescently Tagged C-Terminal Fragment of p47phox Detects NADPH Oxidase Dynamics during Phagocytosis
(2009-03) Li, Xing Jun; Tian, Wei; Stull, Natalie D; Grinstein, Sergio; Atkinson, Simon J; Dinauer, Mary C
The assembly of cytosolic p47phox and p67phox with flavocytochrome b558 at the membrane is crucial for activating the leukocyte NADPH oxidase that generates superoxide for microbial killing. p47phox and p67phox are linked via a high-affinity, tail-to-tail interaction involving a proline-rich region (PRR) and a C-terminal SH3 domain (SH3b), respectively, in their C-termini. This interaction mediates p67phox translocation in neutrophils, but is not required for oxidase activity in model systems. Here we examined phagocytosis-induced NADPH oxidase assembly, showing the sequential recruitment of YFP-tagged p67phox to the phagosomal cup, and, after phagosome internalization, a probe for PI(3)P followed by a YFP-tagged fragment derived from the p47phox PRR. This fragment was recruited in a flavocytochrome b558-dependent, p67phox-specific, and PI(3)P-independent manner. These findings indicate that p47PRR fragment probes the status of the p67phox SH3b domain and suggest that the p47phox/p67phox tail-to-tail interaction is disrupted after oxidase assembly such that the p67phox-SH3b domain becomes accessible. Superoxide generation was sustained within phagosomes, indicating that this change does not correlate with loss of enzyme activity. This study defines a sequence of events during phagocytosis-induced NADPH oxidase assembly and provides experimental evidence that intermolecular interactions within this complex are dynamic and modulated after assembly on phagosomes.
Dishevelled-associated activator of morphogenesis 1 (Daam1) is required for heart morphogenesis
(2011-01) Li, Deqiang; Hallett, Mark A.; Zhu, Wuqiang; Rubart, Michael; Liu, Ying; Yang, Zhenyun; Chen, Hanying; Haneline, Laura S.; Chan, Rebecca J.; Schwartz, Robert J.; Field, Loren J.; Atkinson, Simon J.; Shou, Weinian
Dishevelled-associated activator of morphogenesis 1 (Daam1), a member of the formin protein family, plays an important role in regulating the actin cytoskeleton via mediation of linear actin assembly. Previous functional studies of Daam1 in lower species suggest its essential role in Drosophila trachea formation and Xenopus gastrulation. However, its in vivo physiological function in mammalian systems is largely unknown. We have generated Daam1-deficient mice via gene-trap technology and found that Daam1 is highly expressed in developing murine organs, including the heart. Daam1-deficient mice exhibit embryonic and neonatal lethality and suffer multiple cardiac defects, including ventricular noncompaction, double outlet right ventricles and ventricular septal defects. In vivo genetic rescue experiments further confirm that the lethality of Daam1-deficient mice results from the inherent cardiac abnormalities. In-depth analyses have revealed that Daam1 is important for regulating filamentous actin assembly and organization, and consequently for cytoskeletal function in cardiomyocytes, which contributes to proper heart morphogenesis. Daam1 is also found to be important for proper cytoskeletal architecture and functionalities in embryonic fibroblasts. Biochemical analyses indicate that Daam1 does not regulate cytoskeletal organization through RhoA, Rac1 or Cdc42. Our study highlights a crucial role for Daam1 in regulating the actin cytoskeleton and tissue morphogenesis.

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