Research Bulletin
News from the Child Health Research Institute
May 2023
Dr. Gurudutt Pendyala above; Melody Nguyen inset below
Dr. Gurudutt Pendyala and Melody Nguyen Author Research Article
Published in Cells Journal
The journal Cells recently published an article authored by two CHRI members, Gurudutt Pendyala, PhD, Robert Lieberman Endowed Professor of Anesthesiology, and Melody Nguyen, graduate research associate in Genetics, Cell Biology & Anatomy. They kindly took time for a Q&A to highlight study findings in their article, “Identification of YWHAH as a Novel Brain-Derived Extracellular Vesicle Marker Post Long-Term Midazolam Exposure during Early Development.”
 
Your study focuses on midazolam (MDZ), a drug used often in NICU patients. What concerns about MDZ have been the motivation for this line of research?
 
Midazolam, a short-acting benzodiazepine, is extensively used as a sedative in the neonatal intensive care unit (NICU). While it has shown promise to induce sedation in neonates effectively, its long-term use has not been systematically evaluated. Earlier studies using preclinical model systems have majorly focused on the short-term or immediate effects, majorly with a single-dose or combined MDZ with other sedative agents. Given the knowledge gap on long-term repetitive use of MDZ and more so on brain development, it provided us the needed impetus to explore and better understand the potential risks and adverse effects associated with prolonged use of MDZ in NICU patients.
 
How do you mimic this condition in experiments with rodents?
 
Since MDZ induces strong sedation, we were very cautious in initiating our regimen at a low dose, equivalent to 1mg/kg, which induced only mild sedation. We gradually increased the dose over time until we reached the highest dose of 10mg/kg on day 6, which induced moderate sedation. We continued this regimen until the rodents were weaned at 21 days of age. By carefully controlling the dosage and duration of exposure, we aimed to replicate the conditions of long-term MDZ exposure in our experiments with rodents.
 
What had you learned before this study that suggested brain-derived extracellular vesicles (BDEVs) might be affected by long-term MDZ exposure?
 
In a previous study, we identified alterations in the synaptic proteome associated with long-term MDZ exposure, impacting neural plasticity and cytoskeletal architecture. Synapses are key points of communication between the different cells in the brain and play a critical role in proper brain function. Since MDZ use has been suggested to increase learning disturbances and cognitive impairment in children, in this study, we explored the role of key molecular regulators – brain-derived extracellular vesicles (BDEVs) contributing to such outcomes with long-term MDZ use during the early stages of life. BDEVs express a repertoire of cargo (proteins, DNA, RNA, lipids, etc.) that play important roles in inter/intracellular communication in several diseases. We hypothesized that BDEV protein cargo could be affected by long-term MDZ exposure and thus investigated their role as promising targets for studying and treating MDZ-induced neural impairments. Our findings have shown that the molecular cargo of BDEVs is indeed affected by long-term MDZ exposure.
 
When you analyzed “cargo” from BDEVs of treated and control rats, what were some of your key observations about molecular effects of MDZ?
 
One of our key observations was the identification of a potential protein marker YWHAH (or 14-3-3 eta), which was significantly downregulated in the BDEV of MDZ samples. This is important because the 14-3-3 protein family regulates many crucial cellular processes such as metabolism, protein trafficking, signal transduction, apoptosis, cell cycle regulation, stress responses, etc. Additionally, the 14-3-3 family is highly conserved and abundant in the brain, accounting for 1% soluble protein. Since 14-3-3 proteins are the most abundant in the brain and are frequently present in the cerebrospinal fluid of patients with neurodegenerative illnesses, alterations in their levels may exacerbate brain function. Interestingly, emerging evidence has implicated members of the 14-3-3 family to play a role in developing the nervous system, especially cortical development. Our finding on altered expression levels of a key member of this family and in the realm of neurodevelopment further strengthens the previous works. 
 
Where does this lead you in terms of future research?
 
Our future studies aim to further characterize the downstream mechanisms of YWHAH both in vitro and in vivo. This will allow us to better understand how MDZ exposure affects brain development at the molecular level. Ultimately, our goal is to develop YWHAH as a potential therapeutic to mitigate altered brain development with long-term MDZ exposure in neonates. 
Ann Anderson Berry, MD, PhD
Sarah Newman, DNP
CHRI Helps Identify Improved Care for
Opioid-Exposed Infants
The Child Health Research Institute is a site in the Eating, Sleeping and Consoling for Neonatal Opioid Withdrawal (ESC-NOW) study, a nationwide clinical trial funded by the National Institutes of Health.
 
CHRI Executive Director Ann Anderson Berry, MD, PhD, vice chair of research for the UNMC Department of Pediatrics and the Dr. John and Patti Sparks Chair of Pediatric Research at UNMC, serves as the primary investigator for the local study site. Sarah Newman, DNP, nurse practitioner with Nebraska Medicine, works on the study’s national writing team.
 
Omaha is one of 26 sites participating in the study, which found that the “Eat, Sleep, Console” care approach (ESC) is more effective than usual care approaches for opioid-exposed infants.
 
Researchers found the ESC approach substantially decreased the time until infants were medically ready for discharge. Newborns cared for with ESC were medically ready for discharge approximately 6.7 days earlier and were 63% less likely to receive drug therapy, compared to newborns cared for under the usual approach using traditional scoring and management methods. Safety outcomes at three months of age were similar between both groups. The study appears in the New England Journal of Medicine [nejm.org].
 
 
The IRB protocol number for the study is IRB#0934-19-CB. Click here to read the full story on UNMC Today. 
Wafaa N. Aldhafiri
Nusrat Ahmed
Wafaa N. Aldhafiri, MS, was recently awarded the Presidential Trainee Award and the Blue Ribbon by the American Society for Clinical Pharmacology and Therapeutics (ASCPT) for her abstract titled "Pharmacokinetics and Tissue Distribution of a Lipid-Based Extended-Release Nano-Formulation of MO-OH-Nap Tropolone to Enhance Pulmonary Delivery." Aldhafiri, a PhD student, works under the supervision of DJ Murry, PharmD, professor in the Department of Pharmacy Practice and Science, along with Yashpal Chhonker, PhD, research assistant professor, Department of Pharmacy Practice and Science, Dr. Ford, DO, associate professor, Division of Pediatric Hematology/Oncology, and Sarah Holstein, MD, PhD, professor, Department of Oncology & Hematology. Together, they are working on developing safer and more effective treatments for pulmonary metastatic osteosarcoma (OS) in children, which is the most common primary malignant bone tumor in children and adolescents.

Aldhafiri's research focuses on a novel lipid-based nanoparticle formulation of MO-OH-Nap Tropolone, a potent cytotoxic drug, to treat pulmonary metastatic osteosarcoma. The nanoparticle formulation showed a substantial increase in systemic exposure and pulmonary delivery of MO-OH-Nap. Aldhafiri expressed her excitement at the honor, stating that, "It is a great honor to have our work recognized by the ASCPT, the largest scientific and professional organization serving the disciplines of clinical pharmacology and translational medicine. This opportunity helped me contribute to the wider conversation on the future of pharmacology and clinical therapeutics and reflects the quality of education and research being conducted by the academic community at UNMC."

In addition to the Presidential Trainee Award, Aldhafiri also received the UNMC Dean of Graduate Studies Conference Attendance Award, which is funded by the Office of Graduate Studies.

Nusrat Ahmed, a PhD. student working in the field of Clinical Pharmacology under Dr. Murry, presented her research work “Contribution of inflammation and obesity to variability in midazolam pharmacokinetics in children” at the ASCPT- 2023 annual meeting. Ahmed was selected to receive a $500 Student/Trainee Grant for the ASCPT 2023 Annual Meeting.

The study Ahmed worked on aimed to develop and evaluate a population PK model of midazolam (MDZ) and its CYP3A-mediated major metabolite 1-hydroxy (1-OH) MDZ in obese children, which may guide appropriate dosing requirements in this population. The study represented the contribution of obesity on PK variabilities of midazolam in the pediatric population which is highly relevant and clinically important. The study team illustrated that midazolam clearance via CYP3A metabolism decreased substantially with increasing body weight, which can guide dosing recommendations in obese children and adolescents.

Ahmed's work on obesity in children, a national health issue, aims to be provide data that ensures safe dosing for pediatric patients.
Pharmacy Grad Students Receive
American Society for Clinical Pharmacology
and Therapeutics Awards
CHRI Priorities & Activities:
Update from Executive Director Ann Anderson Berry, MD, PhD
Research is certainly a team endeavor, and Clinical Research Coordinators Day on May 20 is a great opportunity to reflect on the expertise that supports our work in CHRI. Our CHRI coordinator team is also part of the Pediatric Research Office (PRO) and is one of the CORE services that CHRI has for child health investigators. Currently the team supports nearly 300 studies and engages with researchers on the Children’s, UNMC and Nebraska Medicine campuses as well as in general pediatrics offices in Omaha, Lincoln and Kearney.
 
Our coordinator team functions as a group with teams of subspecialists. For example, hematology/oncology work is done primarily by a small group of coordinators, but they can cross train to support studies from other divisions to prevent a gap in coverage for patient enrollment, regulatory questions or if a serious adverse event were to need to be reported. This system also allows for investigators to only pay for the time that a highly trained coordinator works on their particular study instead of being responsible for the full-time salary of an individual.
 
The coordinators who work in CHRI have a wide variety of skill sets and backgrounds including nursing, nutrition, science degrees and phlebotomy. Having a wide range of abilities among the team members allows us to support a wide variety of studies. Many of our coordinators have been working for the PRO since before CHRI existed, but we have recently hired a number of new individuals to support your work. As these individuals are one of our most sought-after resources, this month I encourage all of you to reach out and thank the people who support your research.
 
We also are dependent on so many other individuals to get our research accomplished. This included our CHRI administrative staff, pre and post award grants support, finance team, the individuals at the IRB, Sponsored Programs Administration and our basic science staff. The graduate students, lab technicians, post-doctoral researchers, members of the cores, scientific writers, IT support, statisticians, project managers and so many others make the work we do happen. Please take a moment to express your gratitude to all of those who support you! Science is a great team sport!
 
Finally, congratulations to everyone presenting your work at the CHRI Pediatric Research Forum this month! It’s a great opportunity to connect with others in our field and to reflect on the great work we are doing here at CHRI, UNMC and Children’s.
 
Ann
Meet a Fellow CHRI Member
 
Laura Phipps, PhD, EdS, BCBA, is an assistant professor in the Pediatric Feeding Department at UNMC's Munroe-Meyer Institute.
 
What is your current primary area of research?
 
I am trained in applied behavior analysis and school psychology. I completed my doctoral training and post-doctoral fellowship in the Pediatric Feeding Department at UNMC. My areas of expertise are autism and pediatric feeding disorders, single-case research design, behavior modification and applied behavior analysis.
 
Broadly, my research interest is in evaluating ways to improve the intensive treatment experience for individuals. My current focus is on determining how to assess, monitor and identify child distress during pediatric feeding treatment and recognize ways to modify treatment such that it remains effective but is also comfortable for the child and their family.
 
Please share information on a current research project. 
 
One of the current research projects I am working on aims to assess physiological arousal and emotional valence for children with pediatric feeding disorders during behavior-analytic treatment. Researchers recorded child indices of happiness and unhappiness, measured physiological responses (e.g., heart rate variability) using a wrist-worn biosensor and utilized a new data collection system used to allow practitioners to record observable behaviors and physiological responses concurrently during treatment.
 
Are you looking for a particular type of researcher to collaborate with?
 
Of course, collaborating with other health professionals is a passion of mine! I am particularly interested in working with pediatric dentistry because of the overlap with pediatric feeding disorders. I am also interested in projects that are looking into how to prevent post-intensive care syndrome following critical care.
Member Awards:
CHRI Members Drs. Sarah Holstein and Siddappa Byrareddy Receive Honors
Congratulations goes to CHRI Member, Sarah Holstein, MD, PhD, professor, Division of Oncology & Hematology! Dr. Holstein received the Outstanding Mentor of Junior Faculty Award during the annual faculty meeting. Read Dr. Holstein's UNMC Today profile here.

Siddappa Byrareddy, PhD, professor and vice chair of research in the UNMC Department of Pharmacology and Experimental Neurosciences, received the Joseph Wybran Award from the Society on Neuroimmune Pharmacology in March.

Dr. Byrareddy received the award during the organization’s annual conference in Delhi, India.

The Wybran Award, the highest honor bestowed by the society, is given to an individual who has made extraordinary scientific contributions that have resulted in the preservation and expansion of the field of neuroimmune pharmacology. Read more here.

Congratulations Dr. Byrareddy!
Children’s Virtual Library and Current Users Moving from RefWorks to Zotero by June 30, 2023
The RefWorks (legacy version) citation management software will no longer be available after June 30, 2023. Anyone at Children’s Hospital that uses RefWorks accounts will need to move their account contents to a new Zotero account. Instructions on transferring records from Legacy RefWorks to Zotero are on this McGoogan Library Research Guide: https://unmc.libguides.com/zotero.  
 
Zotero is a powerful and comprehensive citation management software. It is open-source and free to use. It enables users to organize, store and cite research records quickly and efficiently. It encourages collaboration with co-authors through shared group folders.
Individual and group training sessions are available in-person or virtually with the Children’s Hospital liaison librarian, Teri Hartman. Submit your request through librarian@childrensomaha.org.
Speaker Proposals Sought for Nebraska Brain Injury Conference
The Brain Injury Alliance of Nebraska is beginning preparations for our annual Nebraska Brain Injury Conference held in March 2024. They are inviting any interested members of The Child Health Research Institute to submit speaker proposals. Speaker proposal submissions are due July 12, 2023. Click here for more information.
UNeMed is calling for entries into its second Back-o-the-Napkin contest.
The deadline for entries is July 1, and the contest is open to all faculty, students and staff who have ideas for innovative medical devices.

The top three innovations will win additional support with a professionally engineered and designed prototype. The prototype stage is a common hazard for inventors because prototypes can be costly and time-consuming to create. Yet they are essential for attracting additional support and financing for further development.

Click here or more information.
Drs. Lynda K. Harris and Dong Wang to Present Research at May CHRI Seminar Series
Join CHRI for this month’s Seminar Series on May 19 at noon over Zoom. Lynda K. Harris, PhD, associate professor, Department of Obstetrics and Gynecology, will present on "Strategies for Targeted Manipulation of Uteroplacental Function in Pregnancy." Dong Wang, PhD, professor, Department of Pharmaceutical Sciences, will deliver his presentation "Reimagine Cortisol - the Development of Tissue-specific Glucocorticoids."
In-Person June Seminar Series Event

CHRI will host a unique in-person Seminar Series event on June 16 featuring Bethany Hansen, PhD, BCBA-D, associate director of the Department of Pediatric Feeding and an assistant professor at the University of Nebraska Medical Center’s Munroe-Meyer Institute. Dr. Hansen will be presenting on, "A Replication and Extension of Comparisons of Trial-based and Extended Functional Analyses of Inappropriate Mealtime Behavior." The second presentation will feature representatives from the IDeA-CTR speaking on “Great Plains IDeA-CTR Resources for Investigators.” The IDeA-CTR representatives will be available for questions and in-person interactions after the presentation. Plan to join us in the Glow Auditorium or via Zoom!
Save the Date
2023 Thriving Children, Families and Communities Conference 
Plan now to connect with peers, meet leaders from across the state and help children, families and businesses throughout your local community thrive! The sixth annual Thriving Children, Families and Communities Conference will take place Tuesday, Sept. 19, in Kearney, Neb. 
 
This in-person conference will bring together community leaders and elected officials from business, education, economic development, childcare, government, health care, higher education, philanthropy and more to focus on quality early childhood education and its connection to economic development and community vitality.
 
Mark your calendar now and watch for registration opening coming soon!
CHRI DEI Research Journal Club
Meeting May 18, Noon
The CHRI DEI Research Journal Club will meet on Thursday, May 18, at noon to discuss the article, Systemic and Structural Racism: Definitions, Examples, Health Damages and Approaches to Dismantling [files.constantcontact.com]. We will be discussing the full article over Zoom.
 
The article is linked above. Below is the article abstract. If you require Zoom information, please email Kelly Erickson.
 
Braveman, P. A., et al. (2022). "Systemic and Structural Racism: Definitions, Examples, Health Damages, and Approaches to Dismantling." Health Affairs 41 (2): 9.
               
Racism is not always conscious, explicit, or readily visible—often it is systemic and structural. Systemic and structural racism are forms of racism that are pervasively and deeply embedded in systems, laws, written or unwritten policies, and entrenched practices and beliefs that produce, condone, and perpetuate widespread unfair treatment and oppression of people of color, with adverse health consequences. Examples include residential segregation, unfair lending practices and other barriers to home ownership and accumulating wealth, schools’ dependence on local property taxes, environmental injustice, biased policing and sentencing of men and boys of color, and voter suppression policies. This article defines systemic and structural racism, using examples; explains how they damage health through many causal pathways; and suggests approaches to dismantling them. Because systemic and structural racism permeate all sectors and areas, addressing them will require mutually reinforcing actions in multiple sectors and places; acknowledging their existence is a crucial first step.
Disseminating Discoveries -
April Publications
CHRI members listed as authors in publications:
Kristen Fishler, MS, CGC
Department of Genetic Medicine, Munroe-Meyer Institute

  • Seizures in trisomy 18: Prevalence, description, and treatment. Jaspersen SL, Bruns DA, Candee MS, Battaglia A, Carey JC, Fishler KP*. American Journal of Medical Genetics, Part A. 2023;191(4):1026-37.

Regina Idoate, PhD
Department of Health Promotion

Martina Clark, PhD
Department of Internal Medicine

  • Barriers and opportunities for promoting health professions careers among African American students in the Midwest. King KM, Tchouankam T, Shope R, Idoate R*, Clarke M, Su D, Johansson P. Journal of the National Medical Association. 2023;115(2):101-18.
Timothy D. Nelson, PhD
Department of Psychology, UNL

  • Preschool Executive Control, Temperament, and Adolescent Dietary Behaviors. Kidwell KM, James TD, Brock RL, Lazarus Yaroch A, Hill JL, Mize Nelson J, Alex Mason W, Andrews Espy K, Nelson TD*. Annals of behavioral medicine : a publication of the Society of Behavioral Medicine. 2023;57(3):260-8.

Zeb Timmons, MD
Division of Emergency Medicine, Department of Pediatrics/Children’s

  • Management of pediatric ureterolithiasis in the emergency room: A single institution review and new management pathway. Nelson R, Stamm J, Timmons Z*, Grimsby GM. Journal of Pediatric Urology. 2023;19(2):177.e1-.e6.
Funding Opportunities:
  • Standard R21 terms: up to $275,000 direct costs over 2 years
  • Twice-a-year application cycles have deadlines in May and Oct.
  • Participating Institutes: NICHD and NCATS
 
  • Standard R03 terms: up to $100,000 direct costs over 2 years
  • Twice-a-year application cycles have deadlines in May and Oct.
  • Participating Institutes: NICHD and NCATS
 
TeamConnor Childhood Cancer Foundation
  • Grants range from $20,000 to $100,000 per year; and up to $1,000,000+ will be issued based on annual fundraising
  • TCCF will consider renewal grants
  • Current Deadline is Aug. 11, 2023
 
Society of Pediatric Psychology
Targeted Research Grants
  • Deadline: Oct. 1
  • Award up to two grants in the amount of $20,000 each, for one year
Child Health Research Institute
986847 Nebraska Medical Center
Omaha, NE 68198-6847
402-559-4032 or 402-955-7907