December Research Bulletin

Research Bulletin

News from the Child Health Research Institute

December 2021

Children's 3D Printing Team Excited to Partner with CHRI Investigators

This month, we asked Gabe Linke, Children's Hospital & Medical Center's Advanced Imaging Outreach Program Coordinator, to explain how 3D printing is being used at Children's and how CHRI investigators might benefit from engaging with his office.

In what ways could your services and technology be of use to CHRI investigators?

We specialize in taking conceptual ideas and bringing them to reality. With the many technologies we have been blessed with, we are able to design and present ideas in multiple formats. We can present virtually in VR/AR formats or take concepts all the way to having printed prototypes for real-life use and testing. Often we are approached by physicians and medical staff who are looking to make an aspect of their practice better. These aspects span specific patient care concerns, hands-on training for new practices or new, more effective ways to educate outside of the traditional teaching methods.

In what ways have you worked with pediatric researchers already?

We have done a wide range of work with researchers ranging from rapid prototyping of new medical devices to designing 3D models for training on complex anatomy. One of our more novel projects has been in creating specialized phantoms for new imaging equipment.

In addition to creating hands and feet molds for grieving families through the 3D Legacy Prints Program, in what ways is 3D technology being used at Children’s?

Children’s 3D lab is focused on patient care applications. The majority of this work is centered on better visualization of medical imaging. We take images from CT, MRI, and in some cases, ultrasound and create 3D models to better understand complex anatomy. We use virtual and augmented reality as a digital platform and can take it a step further to 3D print anatomy so physicians can hold exact replicas of the patient anatomy in their hands. We can also print tissue-like material so surgeons can simulate cutting and suturing as well.

We can fuse 3D imaging from CT and MRI to assist in our Cardiac Cath lab to provide road maps for interventions.

Our open approach to sharing this technology has led us to many additional use cases. We have found incredible opportunities to impact training and education through 3D printing functional models for students and faculty. We feel strongly that having 3D printed models to practice on first, before having to perform a procedure on a patient, is a great advantage in both safety and technique.

The 3D Legacy Prints Program has created additional opportunities utilizing 3D scanning technology. We are starting a new program where we make personalized action figures for patients who battle chronic illness, Inspiring them to be brave and have hope during the difficult challenges they face.

It is hard to capture all the ways we use 3D at Children’s because we are constantly applying this technology in new ways to better our practices.

How can CHRI investigators begin the process of working with you and your team?

Reaching out to 3D@childrensomaha.org is the best way to start the process. We are working on a website for submissions and details on that should be available soon!

Is there anything that CHRI investigators should know in advance of reaching out to you and your team about the services and technology you provide?

We are excited to work with CHRI investigators and apply this technology to help improve healthcare as a whole!

CHRI Enrolls First Participants

in National Stress Study

This month, the Child Health Research Institute (CHRI) was the first in the nation to enroll children in phase 3 of The HERO “Health’s Early Roots and Origins” Study. The study will be run at clinics throughout the U.S. as part of the JPB Research Network on Toxic Stress. Ann Anderson-Berry, MD, PhD, professor Division of Neonatology is the principal investigator. This study is being lead by CHRI Research Nurse Coordinator, Betty Oberle

The aim of the JPB Research Network on Toxic Stress is to improve the outcomes of young children facing adversity by empowering pediatric clinicians, parents and other caregivers through a more robust metrics that make it possible to:

Enhance screening for individual differences in sensitivity to stress activation and behavioral measures that build resilience.
Strengthen the ability to make targeted referrals to well-matched services (when indicated), as well as convey credible reassurance for parents of children who are doing well.
Augment the capacity to measure variation in short-term intervention effects to inform ongoing, individualized management and sustainable payment for effective services.

CHRI is the only participating institution running this study in three separate clinic locations In order to collect data from rural children, the study is being implemented in Kearney, Neb. Sub-Investigator Angela Kratchovil Stava, MD, Operations Manager Travis Kirchner and the staff at the Kearney Children's Physician’s office were instrumental in establishing the study there. University of Nebraska Kearney students Jaci Dietz and Olivia Forrest have been employed as research assistants by CHRI to conduct on-site visits.

Installing a study in Kearney aids in establishing a CHRI presence and awareness in rural communities, which will aid in gaining participants in future studies. The speed and alacrity with which we establish studies builds our credibility nation-wide for involvement in ground-breaking studies in the future. We thank everyone for their efforts!

Dr. Timothy Nelson and Cara Tomaso Co-author Article on Preschool Sleep Problems and Classroom Engagement

Timothy Nelson, PhD, professor of psychology and associate director of the Rural Drug Addiction Research (RDAR) Center at the University of Nebraska-Lincoln, and Cara Tomaso, senior graduate student in the Nelson lab, are co-authors of a new article in Early Childhood Research Quarterly, “Associations between preschool sleep problems and observed dimensions of elementary classroom engagement.”¹ Dr. Nelson is a CHRI member. Ms. Tomaso kindly took time to respond to this Q&A.

Leading up to your study, how much was known about the impact of preschoolers’ sleep quality upon future performance in school? What was your team trying to learn?

Any parent can tell you that dealing with an overtired preschooler is no fun. Most of the time, though, the consequences of a bad night’s sleep or a missed nap are short-term and relatively easy to manage. However, as many as 1 in 5 preschoolers experience chronic sleep problems. Sleep is really important for young children’s brain development, so problems falling or staying asleep may have a long-term impact on children’s behavior and their ability to focus and perform well in school. Yet, most research on pediatric sleep problems focuses on late childhood and adolescence, and data collection over multiple time points is uncommon.

Our team was interested in understanding the long-term relationship between preschool sleep problems and the kinds of classroom behaviors that support learning. We focused on behaviors during first grade because this year often sets the tone for future school success in that children have to navigate greater academic and behavioral demands.

For the children participating in the study, how did you assess the presence of sleep problems and eventually measure their classroom engagement?

When their children were in preschool, parents completed surveys measuring different aspects of their home life and their children’s behavior, including sleep problems. The most unique part of our study was that a few years later, we were able to directly observe children’s behaviors in their classrooms. Trained research assistants went to the students’ schools, and they recorded how often children were getting ready to learn (e.g., getting out supplies or looking at the teacher), were actively engaged in the lesson (e.g., reading or asking a question) or were distracted or disengaged (e.g., interrupting a classmate or talking over the teacher).

What were the most noteworthy results to emerge from your analysis?

As we expected, children whose parents noted more sleep problems in preschool were less engaged in lessons and more disruptive or off-task during the first grade. One surprising result was that this pattern didn’t change depending on the financial security of children’s families; that is, the strength of the relationship between sleep problems and future classroom behaviors was the same regardless of family income. However, lower family income was generally associated with less classroom engagement and more disruptive behaviors, which is consistent with other research showing that children whose families have fewer financial resources tend to struggle more in school.

Based on these discoveries, it seems logical that correcting sleep problems early in life could enhance kids’ success in school. What might such an intervention look like?

The beauty of sleep interventions for preschoolers and young children is that they don’t need to be complicated to be effective. The first hurdle is assessing for sleep problems early on. After ruling out medical concerns that may be impacting sleep, pediatricians can provide resources and refer families to psychologists or therapists who have experience with behavioral interventions. These clinicians can assess the child’s evening routine and look for environmental factors that may make it challenging for a child to get to sleep. They can also teach parents how to handle bedtime resistance and make a plan for reinforcing sleep-promoting behaviors. Finally, it is always a good idea to assess for other psychological problems, like anxiety or ADHD, that may be affecting a child’s sleep. Ideally, treatment would address sleep problems in the context of any other challenges that a child is facing, including the early onset of mental health problems.

¹ Tomaso CC, James T, Nelson JM, Espy KA, Nelson TD. Associations Between Preschool Sleep Problems and Observed Dimensions of Elementary Classroom Engagement. Early Child Res Q. 2021 4th Quarter;57:251-259.

Dr. Soonjo Hwang Publishes Article on Neural Responses to Fluoxetine in Youths

Soonjo Hwang, MD, associate professor in the UNMC department of Psychiatry, is the lead author of a recent publication in the Journal of Child and Adolescent Psychopharmacology.¹ The paper is titled, “Neural Responses to Fluoxetine in Youths with Disruptive Behavior and Trauma Exposure: A Pilot Study.” Dr. Hwang provides context and key conclusions in the following Q&A.

Q: Who were your collaborators in this study?

The study was conducted and completed by international collaboration. UnSun Chung, MD, PhD, endowed associate professor in Child and Adolescent Psychiatry, and Yong Min Chang, PhD, professor in the Department of Molecular Medicine at Kyungpook National University Hospital, conducted the clinical trial, neuroimaging (functional MRI) and patient assessment/aftercare. James Blair, PhD, director of the Center for Neurobehavioral Research at Boys Town National Research Hospital, and I provided data analyses and manuscript preparation/publication. Ellen Leibenluft, MD, senior investigator and chief of the Section on Mood Dysregulation and Neuroscience at the National Institute of Mental Health, participated as a scientific adviser.

The patient population enrolled in your study were youth with disruptive behavior disorders and a history of trauma exposure. What prompted your team to evaluate a serotonergic agent (fluoxetine) as a treatment for this condition?

This patient population often poses significant challenges for treatment, due to a lack of evidence-based treatment options. Clinical presentation is often complicated, since they are regarded as “bad kids doing bad things” due to anger outbursts, emotional dysregulation and aggressive behavior. However, there is significant correlation of their behavioral and emotional symptoms with past history of trauma exposure (such as neglect and abuse). We do know that past trauma history is often related to development of Post-Traumatic Stress Disorder (PTSD), which involves significant impairment in the serotonergic system and responds to serotonergic agent such as fluoxetine.

Thus, we decided to run the clinical trial of fluoxetine, although these children did not present typical symptoms of PTSD, but, rather, disruptive behavioral and emotional symptoms. We also wanted to probe the actual neural changes by implementing neuroimaging modality (fMRI) in addition to assessing symptom changes after treatment.

Along with clinical assessments of behavioral symptoms, before and after eight weeks of treatment, you used fMRI to capture neural responses of specific brain regions. What did you discover about the impact of fluoxetine on behavior and neural activity in these individuals?

We found that fluoxetine treatment indeed improved emotional and behavioral symptoms in this population, including irritability (emotional dysregulation), aggressive behavior and trauma-related symptoms after fluoxetine treatment. In addition, the key neural areas related to symptom manifestation (including amygdala and ventro-medial prefrontal cortex) showed significant correction of their impaired functioning after treatment. Not only that, the degree of changes in the symptom profile significantly correlated with the degree of neural changes. Thus, we were able to show that, indeed, these children respond to the treatment geared towards trauma-exposure, and the improvement is driven by the neural changes in the core brain areas.

According to the article’s title this was a pilot study. Where do you expect it to lead next, in terms of the research path or application in the clinic?

Clinically speaking, the article shows that it would be critical to assess trauma exposure history in this population. These children are often prescribed medications (for example, medications for treatment of Attention-Deficit Hyperactivity Disorder) and experience worsening of symptoms. Thus, careful history-taking of trauma exposure history is very important. As for future research, we would like to conduct a large clinical trial with true double-blind randomization design. Long-term follow-up of these children with various treatment options is very necessary, too.

¹ Hwang S, Chung U, Chang Y, Kim E, Suk JW, Meffert H, Kratochvil C, Leibenluft E, Blair J. Neural Responses to Fluoxetine in Youths with Disruptive Behavior and Trauma Exposure: A Pilot Study. J Child Adolesc Psychopharmacol. 2021 Oct;31(8):562-571.

CHRI Priorities & Activities:

Update from Executive Director Ann Anderson Berry, MD, PhD

December brings with it so many opportunities for both celebration and reflection, and at the Child Health Research Institute (CHRI), we are doing both in equal measures. What a fantastic year it has been for our investigators and our staff. We have much to celebrate as the rewards for hard work are evident in our impact and output.

As we celebrate, we also reflect on the continued and enduring nature of the pandemic, and its impact on our work and lives. While we have been productive, we also remain separated and socially distanced, often working from home or alone in our labs. We have experienced firsthand the December 2020 release of the COVID-19 vaccines, administered them to our colleagues, family and friends and enrolled the children in our community in a CHRI-sponsored research study designed to ensure vaccine safety for children aged 6 months to 11 years. What an honor to be involved in so many parts of this progress fighting the pandemic. Despite our best efforts, many of us have been ill, quarantined or lost loved ones to the pandemic. The losses from this pandemic are profound in large and small ways, for the young and the old.

Through all of this, CHRI has grown in numbers, in scope, in talent and in the research we perform. In 2021, we have had record-breaking numbers of subjects enrolled at our two campuses; we continue to see great CHRI internal grant submissions; and our area of emphasis mini-summits have produced numerous collaborations. We are proud to have contributed to the COVID-19 vaccine for children, numerous other COVID-19 studies and all of our lab-based and clinical trials that mean so much to children and families in Omaha and across the world.

As I look ahead to 2022, there is, as usual, uncertainty. We don’t know the next turn that the pandemic will take, which of our studies will be funded and if our hypothesis will be supported by our next data analysis. I am, however, certain of several things, and those bring me great excitement. First, I know that our science will continue to produce remarkable and impactful results for children everywhere. Second, I know CHRI, our staff and our members, will continue to rise to every occasion. We have the skills, the talent and the drive to shape our future, no matter what it holds in store for us.

I wish you all the very best of this holiday season and a remarkable, happy and successful 2022.

Happy holidays,

Ann

UNMC Core Facility Profile:

The Genomics Core Facility

The UNMC Genomics Core facility is a comprehensively equipped facility that serves the regional research community. A wide variety of RNA/DNA samples are processed in the core for a number of different applications including RNA sequencing (traditional and single cell), exome, genomic resequencing, metagenomics, methylation and ChIP sequencing. James Eudy, PhD, director of the Genomics Core Facility, generously responded to our questions regarding the ways in which CHRI investigators can engage with the facility.

In what way can engagement with the Genomics Core Facility benefit CHRI investigators?

Researchers benefit by having access to cutting edge technology including Next Generation DNA sequencing (NGS) as well as access to scientific expertise related to how to employ this technology. NGS is used for a whole variety of assays related to biomedical research to include RNAseq to measure gene transcription, metagenomics to investigate microbial contributions to health and exome and whole genome sequencing to identify mutations associated with inherited and acquired disease. It has become one of the primary means by which biomedical researchers gain insight into their research projects under study.

If an investigator wants to learn more about the Genomics Core Facility in connection with research projects, what is a good way of getting needed information?

Set up an appointment to communicate with the director of the Genomics Core. Email communication is the best way.

What are some common questions about the Genomics Core Facility and what are the answers to those questions?

How do I set up my experiments to measure RNA transcription, profile bacterial communities in my specimens, identify mutations in childhood cancer samples, etc.? NOTE: The answer is way too complicated to go into in an email, so one-on-one discussions are needed and available.

What is the main thing you hope readers take away from your profile in the CHRI Research Bulletin about Genomics Core Facility?

The UNMC Genomics Core has the most cutting-edge genomics instrumentation available to researchers, is very well-versed in the technological applications associated with them and is well-staffed. Our team is happy to help these researchers with their projects, and we look forward to hearing from them.

Meet a Fellow CHRI Member

Russell Hopp, DO, professor of Pediatric Allergy at UNMC and Allergy Director at Children’s Hospital & Medical Center.

What is your current primary area of research?

My areas of research are asthma, small airway asthma, eosinophilic esophagitis and food allergy.

Please share information on a current research project.

I am starting to collect data on small airway asthma.

What has been the primary benefit of CHRI membership?

The primary benefit is the opportunity for interaction with peers.

Ryan Koehler, MD, is an assistant professor in the Department of Orthopaedic Surgery. He is a Pediatric Orthopaedic and Sports Medicine Surgeon at Children’s Hospital & Medical Center.

What is your current primary area of research?

I have several areas of interest within pediatric orthopaedics, including sports medicine, spine and trauma. On the sports medicine side of things, I’m interested in improving outcomes in common pediatric sports surgeries like ACL reconstructions and shoulder stabilization procedures. I also see pediatric spine conditions and have an interest in newer methods of surgically treating scoliosis without fusion of the spine.

Please share information on a current research project.

I am part of a collaborative multi-center pediatric orthopaedic trauma study group called CORTICES that is looking at enhancing care for common pediatric orthopaedic injuries encountered in the emergency setting. This group has also been looking at the wide range of care that patients receive across the country when presenting to the emergency room with a musculoskeletal infection. We are currently looking at ways to improve care for patients with acute osteomyelitis and septic joints.

What has been the primary benefit of CHRI membership?

Having the CHRI resources available to help get projects underway as a new faculty member has been a very valuable part of membership so far in my practice. I also like having the chance to see what other investigators are doing around the institution.

Thank you Drs. Hopp and Koehler for your time and responses. At this time, we are randomly selecting the members to be profiled, but if you would like to be featured, please email chri@unmc.edu.

PRO Education Committee Tip of the Month:

Research Subject Compensation

Compensation for research subjects may be acceptable if:

The possibility of coercion or undue influence is minimized.
The compensation is considered a reasonable incentive either for participation in the research and/or reimbursement for study-related travel and other expenses.
It is not presented to the potential subject as a benefit in either the process of consent, or the potential benefits section of the consent form.
Is not tied to the degree of risk or discomfort associated with the study.

Since the risks associated with “minimal risk” research do not exceed those of daily life or routine physical or psychological examination, compensation is not an inducement to offset risk. Therefore, there is no restriction on compensation for minimal risk research.

Compensation for research which involves greater than minimal risk should be based on a reasonable hourly wage for time spent in preparation for, participation in and recovery from, research interventions. A reasonable hourly rate is $20.00 per hour.

The terms of the compensation must be completely disclosed in the IRB application and in the informed consent process and on the Informed Consent Form.

For studies where compensation is likely to total more than $600, the consent form must include a statement that an IRS form 1099 will be issued if the total compensation from participation in research reaches $600 in any given year and the subject must agree to provide his/her social security number.

Taken from UNMC IRB Policies and Procedures