Research Bulletin
News from the Child Health Research Institute
September 2021
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PROSpect Trial Surpasses
100 Global Enrollees
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Sidharth Mahapatra, MD, PhD, associate professor, Division of Critical Care, and members of the Child Health Research Institute (CHRI) team recently celebrated the 100th enrollee into the PRone and OScillation Pediatric Clinical Trial (PROSpect). The PROSpect trial is an international, multi-center, randomized clinical trial funded by the National Heart, Lung and Blood Institute at the National Institutes of Health. Dr. Mahapatra is the primary investigator for Children’s Hospital & Medical Center, which is currently the leading study site worldwide in enrollment. Lucinda Kustka and Evan Roberts are the CHRI coordinators on this study.
The PROSpect trial is designed to gain understanding on how best to manage children with acute and severe respiratory failure. The ultimate goal of the study is to enroll 1,000 children and to sort them into four groups that combine one of two forms of mechanical ventilation and one of two forms of positioning for the child. The study team also hopes to learn more about a child’s quality of life and emotional health after they leave the Pediatric Intensive Care Unit (PICU).
To recognize this achievement, the PROSpect primary investigators sent 100 miniature bundt cakes to the PICU and research staff.
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CHRI Priorities & Activities:
Update from Ann Anderson Berry, MD, PhD
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In celebration of Research Administrators Day, September 25, I’d like to recognize the teams that support all of us in our research endeavors. Most of us in academic medicine would agree that provision of the highest quality of care begins with a skilled team of individuals who come together to achieve outcomes that are greater than the sum of their parts. Like patient care, research is also a team sport. Yet, it’s likely that as investigators we don’t know everyone who is on this team, working diligently behind the scenes, to ensure that our biomedical research moves forward smoothly and efficiently.
These individuals are working together in a wide variety of ways to create the systems that support your work, interfacing with UNMC and Children’s to ensure that your research is successful. A recent list of some of the items that your team has been working on shows exciting progress for CHRI, including advances to our opt-in for research consents at Children’s within the consent to treat; a data . . .
To read the rest of Dr. Anderson's letter, please click the link below.
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10-Year Longitudinal Study of
Sjögren-Larsson Syndrome
Concludes for Dr. William Rizzo
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William Rizzo, MD, professor, Division of Inherited Metabolic Diseases and the CHRI Scientific Director, recently concluded a 10-year, longitudinal study of Sjögren-Larsson syndrome (SLS). As part of the study, he saw patients from around the U.S. We talked to Dr. Rizzo about conclusions developed from the study and his feelings about it ending.
What were the most important findings that came out of the study?
SLS is an ultra-rare inherited disease with symptoms of ichthyosis (dry scaly skin), spasticity, intellectual disability and a distinctive retinopathy. Although about 200 SLS patients have been reported since the disease was first recognized 60 years ago, almost all have been cross-sectional case reports with no follow-up. We were able to investigate 20 SLS patients from around the country in our longitudinal study, which allowed us a unique opportunity to see the variation of symptoms and evolution of the disease. Some of the most important findings include:
· We found that most young patients under 6 years had normal intellect but developed worsening cognitive function over time, indicating progressive brain disease. Similarly, brain MRIs tended to be normal in young children, but white matter changes appeared later and progressed as they got older. These observations suggest a key age-dependent “window of opportunity” for potentially intervening with therapy.
· We found a unique lipid profile in SLS skin that is the basis for the ichthyosis and promises to be a useful biomarker for future clinical drug trials. The severity of the ichthyosis in the patients tended to get worse with age and correlated with severity of their intellectual disability.
· It had been known that the ophthalmologic disease is distinguished by macular degeneration with many small xanthoma-like deposits, so-called “glistening white dots.” Surprisingly, by comparing serial retinal photographs obtained over several years, we found that these dots are dynamic structures that can appear over time and even disappear, indicating the potential for reversal of some retinal abnormalities. Further, visual acuity is decreased in SLS, and the retina is thinner than normal, probably due to apoptotic cell death, but patients preserve their vision.
· We recently found a unique metabolomic profile in SLS plasma that identifies abnormalities in unexpected biochemical pathways involving sphingosine, serotonin, bile acids and oxidative stress that may be important for understanding symptoms and developing new treatments. This metabolomic profile will also be useful for monitoring future therapeutic trials.
What was it like to work with the same study patients and families over 10 years? Will you still be able to work with some of them?
One of the joys of our research program has been developing long-term relationships with the SLS children and families, not just over the past 10 years, but much longer for some of them. Over the years, I’ve shared their meals, celebrations, milestones, achievements and illnesses. Through their own private Facebook page and blogs, many of the families have united to support each other and share their experiences. I expect to maintain contact with all of the families and hope to have many of them return for future studies.
Will you be able to continue some of the work you were doing in the study in new projects? And if so, will you be able to work with some of the families you were working with before?
We are still analyzing much of the data collected in this longitudinal study, and many of our findings have already raised questions that will be addressed in time. For example, what is the role of nutrition, oxidative stress, serotonin accumulation and deficient bile acids in SLS? We will need our SLS community to come back and help answer these questions.
Can you tell us about the R21 study you were awarded to examine the skin of Sjögren-Larsson syndrome patients via ultrasound?
The severity of all forms of ichthyosis is typically determined using a clinical scoring system. Although the outcome is validated, the scores are subjective and not particularly quantitative. While meeting on an unrelated topic with Ling Li, MD, PhD, RDMS, one of our CHRI ultrasonographers, we started brainstorming about the possible application of ultrasonography to this problem. Dr. Li was subsequently able to measure skin thickness and elastic properties in one SLS child before COVID-19 hit and shut down patient enrollment. Nevertheless, the results were spectacularly abnormal. Together with Zeljka Korade, DVM, PhD, professor in the division of Inherited Metabolic Diseases, we submitted a clinical trial preparedness grant for investigating the utility of ultrasound in future SLS trials. Patients will begin enrolling shortly. I expect that the ultrasound method will be applicable to all forms of ichthyosis.
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Paper Developed from Study Helped Define Sjögren-Larsson Syndrome
You don’t always need to do a sophisticated clinical trial to have an impact on pediatric medicine. Sometimes a lowly case report will suffice. As an example, we interviewed Dr. William Rizzo about a recent paper, “A Neurodegenerative Phenotype Associated with Sjögren-Larsson Syndrome,” that helped define this rare disease.
Who did you work with in studying this clinical case and developing the case report?
This work arose from our longitudinal natural history study of SLS, which recruited these rare patients from around the country and followed them for up to seven years. It required the efforts of a team, not the least being our clinical coordinator Sara Jones, whose development of a relationship with the families was critical for their continued participation. Terri Love, MD, assistant professor, department of Radiology, contributed imaging expertise, and Simone Warrack, DO, pediatrics resident, helped with the clinical description. Clinical support for EEG testing, ophthalmologic exams, neurocognitive testing and anesthesia has relied on additional key people at Children’s and the Munroe-Meyer Institute.
What are typical neurological symptoms in children with Sjögren-Larsson syndrome? How does this individual patient’s disease differ in this case?
Children and adults with SLS exhibit neurological symptoms of spastic diplegia and intellectual disability, which have always been considered as static symptoms. A particular SLS female patient developed a prolonged febrile Rotavirus infection at 2.5 years of age and immediately began losing neurologic skills, ultimately exhibiting a striking neurodegenerative course with severe loss of motor and cognitive function. She went from crawling, standing and self-feeding to being unable to sit independently, roll over or grasp objects. Her IQ decreased from 88 to 40. She is currently tube-fed and has a tracheostomy due to uncontrolled oral secretions. Serial MRIs showed progressive white matter disease that accompanied the clinical decline, whereas her EEGs over the subsequent three years never exhibited seizures.
Do you have any data or hypotheses about gene mutations that might underlie the unique disease form?
There is no genotype-phenotype correlation in SLS. Our SLS patient has a missense mutation, which might be expected to be “milder” than some others, but even complete deletion of the SLS gene does not lead to more severe disease. Nothing in our patient’s prior medical history would have predicted this unusual neurologic deterioration. We can speculate that her neurologic course was triggered by severe oxidative stress from her prolonged febrile GI infection, perhaps alterations in her intestinal microbiome, secondary metabolic changes or the involvement of other unknown modifier genes.
How could these findings affect the approach to clinical care for patients with suspected or diagnosed SLS?
This unusual case illustrates the value of a single SLS patient for defining the spectrum of this disease. We were able to review more than 200 published SLS patient cases and identified several other neurodegenerative patients with uncontrolled seizures in the literature, though none as dramatic as our patient. We have no way to predict which child is at increased risk for a neurodegenerative phenotype. Nevertheless, we now recommend that physicians aggressively treat febrile illnesses and seizures in SLS patients. Unfortunately, we also need to counsel SLS families that a neurodegenerative course is a rare complication of this disease.
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CHRI Grant Calendar Tool Updated |
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During the past summer, Jackie Ostronic, CHRI project manager, and Matt Sandbulte, PhD, CHRI grant/scientific writer, redesigned the CHRI Grant Calendar Tool. The tool is now built in Excel, easier to search and organizes each opportunity by seven category headings. Over 150 grants are listed and linked within the tool, which can be accessed on this page. Users are encouraged to filter by topic, funding institute and type of award to make the database more useful to individual needs. We welcome your feedback regarding the update. Email comments to chri@unmc.edu.
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A Screenshot of Five of the Seven Grant Calendar Heading Categories |
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UNMC Core Facility Profile:
Movement Analysis Research Core
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David Kingston, PhD, director of the Movement Analysis Research Core (MOVAN) and assistant professor in the Department of Biomechanics at the University of Nebraska Omaha, provided answers to our questions about MOVAN and how CHRI investigators can engage with its offerings.
What services can the Movement Analysis Research Core provide to CHRI investigators?
MOVAN provides access to state-of-the-art equipment and highly skilled personnel to enhance biomechanics and analytical research into human movement in the Department of Biomechanics, NU system and the state of Nebraska. These tools and expertise function to treat and prevent motor-related disorders, improve our understanding of injury and neurological control mechanisms and support the significant research activities of investigators. Services to investigators include experimental design, validation of cutting-edge approaches and data collection, processing and interpretation. The general behavioral and movement analysis categories include 3D motion capture, neuroimaging, electromyography, energetics, assistive devices, modeling and simulation, balance and posture, robotics and virtual reality environments.
If an investigator wants to learn more about the Movement Analysis Research Core in connection with research projects, what is a good way of getting needed information?
What are the first steps toward engaging the services of the Movement Analysis Research Core?
Initiating work with MOVAN follows a five-step process:
2. Communication from the Core will take place to gain a more complete understanding of your needs.
3. The Core will send a quote for the work. A mutual non-disclosure agreement or service agreement may need to be completed.
4. Clients provide the Core with data or other items required to complete the work.
5. Work commences.
What are some common questions you get about MOVAN, and what are the answers to those questions?
Common questions are:
Q: Can MOVAN complete all of the necessary IRB documentation on my behalf?
A: Yes. We will estimate this cost as appropriate and include any IRB-mandated fees related to external companies if needed.
Q: Can MOVAN build a custom test apparatus for my study?
Q: What are the hourly fees?
A: Internal customer rates (those within the NU system) are $143/hour. External customer rates are $206/hour.
What is the main thing you hope readers take away from your profile in the CHRI Research Bulletin about the Center for Movement Analysis Research Core?
MOVAN is happy to coordinate tours of our facilities and showcase what is possible with UNO Biomechanics. The Biomechanics Research Building includes a complement of 16 faculty members in the area cardiovascular, clinical, prosthetics, exoskeleton and applied research. We are open to collaboration!
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Meet a Fellow CHRI Member |
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Aleisha Nabower, MD, is an assistant professor, Division of Hospital Medicine.
What is your current primary area of research?
My research primarily focuses on clinical studies regarding the management of inpatient pediatric conditions, primarily infectious disease-related, as well as the variability in care across institutions.
Please share information on a current research project.
I am currently leading a multi-site collaborative that is studying how a multiplex cerebrospinal fluid polymerase chain reaction panel (Biofire FilmArray) has impacted the management of pediatric meningitis and encephalitis. Specifically, we are evaluating its effects on length of stay and time on antimicrobials, as well as clinical outcomes. Additionally, we are examining discordant results on the panel when compared to the gold standard of CSF culture.
What has been the primary benefit of CHRI membership?
CHRI membership has been crucial in supporting several of my projects through their grant program. Additionally, it has served as a network to find collaborators to work with.
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Joyce Solheim, PhD, is a professor in the Eppley Institute and a professor (Courtesy) in the Pathology & Microbiology Department and the Biochemistry & Molecular Biology Department. She is the Director of the Cancer Research Doctoral and MS Programs and the Fred & Pamela Buffett Cancer Center Associate Director for Training & Education.
What is your current primary area of research?
Research in our laboratory is devoted to comprehending the mechanisms of effective anti-cancer immune responses and to developing new approaches to cancer treatment, particularly ones that employ immunological strategies.
Please share information on a current research project.
Neuroblastoma is a cancer that typically affects children, and neuroblastoma patients in the high-risk category have a five-year survival rate of less than 50 percent, so better treatments are greatly needed. Investigation of cancer-induced suppression of immunity in the neuroblastoma tumor microenvironment, and development of means to counteract that immunosuppression, is expected to lead to better outcomes for the pediatric patients who suffer from this terrible disease. In one of our current research projects that is based on many findings by our laboratory about a protein called amyloid precursor-like protein 2 (APLP2), we are analyzing the extent to which the pro-tumor effects of macrophages are facilitated by APLP2. We are testing whether immune responses against neuroblastoma cells can be improved by inhibiting the enzymatic processing of APLP2.
What has been the primary benefit of CHRI membership?
CHRI membership has many benefits, and my favorite is the opportunity for multidisciplinary interactions involving investigators in areas of laboratory, clinical and public health research that are related to pediatric health care.
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Thank you Drs. Nabower and Solheim 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. |
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PRO Education Committee Tip of the Month:
Research Involving Children
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Research Involving Children
Taken from UNMC IRB Policies and Procedures:
- In the state of Nebraska, the age of majority is defined as, “all persons under nineteen years of age are declared to be minors, but in case any person marries under the age of nineteen years, his or her minority ends.”
- If the subject is Native American living on federal tribal lands, regardless of the state law, federal law has set the age of majority at age 18.
- If the research is conducted in another state under the oversight of the UNMC IRB, the age of majority is set by that state.
Assent
- Verbal assent for ages 7-12 – the Child Information Sheet is used to explain the study to the child in a language understandable for this age group.
- Written assent for ages 13-18, – the Youth Information Sheet is now the “Invitation and Summary” on the parental consent form and should be used to explain the study to the youth.
- Unless assent has been waived, children who do not provide assent, or who actively dissent, may not be enrolled in the research.
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Training Opportunity for Community-Engaged Clinical and Translational Research |
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The Great Plains IDeA Clinical and Translational Research Network (GP IDeA-CTR) is debuting its first Community-Engaged Clinical and Translational Research (CTR) Institute. The 2021 Community-Engaged CTR Institute is an intensive program providing training opportunities for scientists, community members, clinicians and other stakeholders interested in participatory research.
The institute will cover topics related to initiating and sustaining partnerships, creating research questions that are innovative and locally impactful and facilitating culturally competent engagement between research and community audiences. Leaders from the GP IDeA CTR will lead many of the sessions.
Based on community feedback, the institute will occur over four consecutive Thursdays: October 14, 21, 28, and November 4. Sessions will be comprised of didactic, interactive and working opportunities to apply learning objectives and principles.
Click here to register for the institute. Click here for the calendar of events
For more information, please view the website. For questions and additional information, please contact Emily Frankel by email or call 402-836-9283.
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Disseminating Discoveries:
August Publications
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Take a minute to check out the wide range of research published by CHRI members in August. |
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2022 Innovation Grant
Alex’s Lemonade Stand Foundation for Childhood Cancer
Letter of Intent due: November 15, 2021
Max amount: $250k over 2 years
Grant for Infrastructure/Registry Research in pediatric neurology
Pediatric Epilepsy Research Foundation
Letter of Intent due: November 8, 2021
Max amount: $300k over 3 years
William Weston Career Development Award
Pediatric Dermatology Research Alliance
Application due: December 2, 2021
Max amount: $40k for 1 year
For more funding opportunities, please review the CHRI grant calendar available here.
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Upcoming Events:
Diversity Supplement Seminar October 7, 4-5 pm
The National Institute of Health has developed a mechanism to support diversity candidates interested in or developing their research career, including undergraduates, graduate students and faculty, by providing a supplement mechanism on top of funded grants, either at the time of initial submission or after funding award notice has occurred. Learn more about who is eligible for this funding mechanism and strategies from faculty who have been successful in submitting or receiving these supplements.
The panel includes:
- David Dzewaltowski, College of Public Health
- Regina Idoate, College of Public Health
- Paul Trippier, College of Pharmacy
- Todd Wyatt, College of Medicine/College of Public Health
Join from a PC, Mac, iPad, iPhone or Android device:
Please click this URL to join.
Passcode: 549477
Time will be allotted for questions from attendees.
CHRI Seminar Series - Friday, October 15, Noon
Sathish Kumar Natarajan, PhD - Palmitoleate Protects against Zika Virus-Induced Endoplasmic Reticulum Stress and Apoptosis
Sheridan Jost, MD - Pediatric Hospital Medicine Triage Curriculum
CHRI Bone Health Mini Research Summit
The Child Health Research Institute invites you to attend the Bone Health Mini Summit on November 18, convened by the CHRI Genetics, Development, Exposures & Injuries Area of Emphasis (AOE).
The mini summit, led by Matthew Halanski, MD, associate professor and Chief of Pediatric Orthopaedic Surgery; Eric Peeples, MD associate professor, Division of Neonatology and Bill Rizzo, professor, Division of Inherited Metabolic Diseases and CHRI Scientific Director, welcomes attendees to join us to share projects, discover new resources and make valuable connections for future collaborative opportunities that improve child health.
The AOE has selected bone-related health and disorders as its theme for this year’s summit. While not an exclusive list of potential topics, trainees, investigators and supporting research and clinical personnel who are performing or are interested in the research topics below may benefit from participating in the virtual summit.
- Developmental biology, embryology and limb development
- Osteoblasts, osteocytes, and osteoclasts
- Bone dysplasias, genetic disorders and inherited disorders of metabolism affecting bone
- Collagen diseases
- Osteomyelitis, neonatal sepsis, MRSA musculoskeletal infections
- Bone metabolism
- Endocrinology and the skeleton
- Vitamin D, calcium, phosphorous
- Maternal fetal interactions in the developing skeleton
- Bone deformities and bone growth
- Primary malignancies of bone
- Biomechanics of bone
- Bone fracture, healing and remodeling
- Osteoimmunology
- Periosteum, cartilage and bone
- Orthopaedic implants and 3D scaffolds
- BMPs, FGFs, CNP, signaling
- Animal models
- Imaging of the skeletal system
- 3D modeling of osseus structure
- Bioengineered Scaffolds
- Novel therapeutic delivery systems
Please fill out the brief pre-registration form if you would like to receive a calendar hold and be on our list to receive the latest updates about the event as the agenda is finalized.
Two types of registration will be available:
- Participating investigator for those who plan to prepare and present a brief summary of their work and engage in active discussion to spark collaboration and resource sharing
- Active listener for those in research supportive roles or from other areas of research who would like to listen to the investigators and mini summit presentations
We look forward to seeing you at the mini summit. For questions or concerns, please reach out to chri@unmc.edu.
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Child Health Research Institute
986847 Nebraska Medical Center
Omaha, NE 68198-6847
402-559-4032 or 402-955-7907
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