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Crisis in the NICU and the Medley with Midazolam
Nghi M. Nguyen, Jordan Hernandez, Adrian Flores, Jina Yi, Reeyan Bhakat, Neetha N. Vellichiramma, Chittibabu Guda, Sowmya V. Yelamanchili, and Gurudutt Pendyala
Epidemiologic studies of human patients have revealed a correlation between childhood exposure to general anesthetic and sedative agents and subsequent cognitive deficits. This association is supported by data from animal models, which shows that developmental exposure to both anesthetics and sedatives causes lasting impairments in learning. This study focused on midazolam (MDZ), a common benzodiazepine regularly used as a sedative agent on neonates in the Neonatal Intensive Care Unit (NICU). However, a knowledge gap that remains is how long-term exposure to MDZ during very early stages of life impacts synaptic alterations and neurobiological mechanisms. Elucidation of these mechanisms is of high clinical importance and may develop neuroprotective therapeutic strategies for optimizing outcomes for uniquely vulnerable NICU populations. Using a preclinical rodent model system, we mimicked a dose-escalation regimen from postnatal day 3 (P3) pups until P21 to comprehensively characterize how early-life exposure to MDZ impacts neurodevelopment outcomes at different tiers ─ phenotypic, molecular, behavioral, and high throughput- “omics” levels. Our data demonstrated that repetitive exposure to MDZ at an early age stunts neurodevelopment during the early stages of life disrupts the blood-brain barrier, and alters the synaptic components and neurochemistry, which may be indicative of behavioral deficits at later development. Additionally, our bioinformatics analysis from purified synaptosome identified enrichment of proteins associated with actin-binding and protein depolymerization process. One potential hit identified was alpha adducin (ADD1), belonging to the family of cytoskeleton proteins, upregulated in the MDZ group and whose expression was further validated by western blot. Our study has provided a comprehensive characterization of MDZ effects on development at multiple tiers yielding novel insights on how long-term exposure to MDZ impacts development. Notably, the identification of ADD1 as a potential target and further characterization of its downstream mechanisms can give additional insights into its role as a potential therapeutic for treating neurodevelopmental alterations associated with long-term MDZ use in neonates.
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Maternal and Cord β-Carotene levels and Their Association with Newborn Hearing Screen Results
O. Paetz, R. Slotkowski, A. Freeman, A. Hergenrader, S. Sweeney, K. Ali, N. Bender, R. Chaundary, M. VanOrmer, M. Thompson, M. Thoene, C. Hanson, and A. Anderson-Berry
Background. β-carotene is one of the few carotenoids that can be endogenously converted to vitamin A, a nutrient essential for inner ear development. While previous studies have identified a protective effect of carotenoids on hearing in adults, the impact of β-carotene on hearing outcomes in neonates is not well understood. The purpose of this study is to investigate the relationship between maternal β-carotene intake, maternal plasma, and umbilical cord plasma β-carotene levels and abnormal Newborn Hearing Screen (NHS) results.
Significance of Problem. The prenatal period is critical for auditory development; thus, effectors of auditory development may significantly impact long-term hearing ability. Because maternal nutrition is modifiable, an improved understanding of the relationship between β-carotene levels and hearing outcomes may be relevant for prenatal care recommendations.
Hypothesis. We hypothesize that higher levels of β-carotene will be associated with decreased risk of abnormal NHS results.
Experimental Design. An IRB-approved study enrolled mother-infant pairs (n=541) at the time of delivery. β-carotene plasma levels were analyzed with HPLC. Maternal intake of β-carotene over the past year was quantified using the validated Harvard Food Frequency Questionnaire. NHS results were obtained from the Electronic Medical Record. Statistical analysis was done using the Mann-Whitney U and logistic regression tests, with p<0.05 considered statistically significant.
Results. Of the 541 participants, 8.5% of infants had abnormal NHS results. Higher median maternal β-carotene intake was observed in infants who failed their NHS compared to those who passed (5924 vs. 4722 mcg/day, p=0.019). Higher median maternal plasma levels of both trans- (206 vs. 149 mcg/L, p=0.021) and cis-β-carotene (15.9 vs. 11.2 mcg/L, p=0.015) were observed in infants who failed their NHS. Higher median cord plasma trans β-carotene was observed in infants who failed their NHS (15.5 vs. 8.0 mcg/L, p=0.04). Associations between failed NHS and log-transformed β-carotene intake and serum levels remained in a logistic regression model after adjustment for NICU admission, race/ethnicity, smoking status, maternal age, corrected gestational age, infant sex, and log transformed maternal caloric intake.
Conclusion. The observed relationship between higher β-carotene levels and abnormal NHS was unexpected. While other studies suggest both deficient and excessive levels of vitamin A can impact inner ear development, β-carotene levels in our study were not exceptionally high. One possible explanation is that higher maternal β-carotene levels may be indicative of impaired transfer of β-carotene to the fetus. Further study is warranted to better understand the relationship between β-carotene and NHS results.
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SAP30, a Novel Oncogenic Transcription Factor in High-Risk Neuroblastoma: Clinical Significance and Role in Tumor-Progression, Survival, and Drug Resistance
Anup Pathania, Philip Prathipati, Nagendra K. Chaturvedi, Subash Gupta, Don W. Coulter, and Kishore Challagundla
Neuroblastoma is the most common devastating extracranial solid malignancy in children, accounting for 15% of childhood cancer-related mortality. Despite an intense treatment regimen, approximately 50% of children treated for high-risk neuroblastoma have more aggressive tumor relapse with less than 20% five-year overall survival. Amplification of the oncogene MYCN is associated with a high risk of relapse. However, only 25% of high-risk neuroblastomas are MYCN-amplified, indicating that the rest are driven by factors other than MYCN. Therefore, it is essential to identify novel driver transcription factors but not passenger genes that improve prediction efficacy of therapy response and association with high-risk, progression, stage 4, and survival in neuroblastoma patients. We used three neuroblastoma patient datasets (n=1252 patients) and applied robust bioinformatic data mining tools such as Weighted Gene Co-expression Network Analysis (WGCNA), cisTarget, and Single-Cell Regulatory Network Inference and Clustering (SCENIC) to identify driver transcription factors (regulon) that associate with high-risk, progression, stage, and survival in neuroblastoma patients. Based on the regulon specificity score, we derived a 10-transcription factor signature and prioritized Sin3A Associated Protein 30 (SAP30), given its highest regulon specificity score, especially in high-risk and aggressive stage cohorts. Higher SAP30 expression was found in high-risk neuroblastoma patients and progression-specific patient-derived xenograft tumors than their respective controls. The advanced pharmacogenomic analysis and CRISPR-Cas9 screens indicated that SAP30 essentiality correlated with Cisplatin resistance and further validated in Cisplatin resistant patient-derived xenograft tumor-derived cell lines. SAP30 silencing inhibited cell proliferation, slowed growth and induced cell death in vitro, and reduced tumor burden and size in vivo. Overall, our results indicate that SAP30 is a better prognostic and Cisplatin resistant marker associated with high-risk, stage 4 progression, and poor survival in neuroblastoma patients.
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Case Report of Rare Mycobacterium Isolated from Mediastinal Abscess
Olivia Person, Andrew S. Huang Pacheco, Hana Niebur, Melissa Suh, and Kari Neemann
Introduction
Mycobacterium arupense, a member of the Mycobacterium terrae complex identified in 2016, rarely causes infections despite isolation from multiple environmental sources, including water, soil and fish tanks.1 Case reports have described tenosynovitis, osteomyelitis and disseminated infection in an immunocompromised host.1-3 Here we describe a case of M. arupense identified in a polymicrobial mediastinal abscess in a pediatric patient subsequently diagnosed with autosomal dominant hyper-IgE syndrome (AD-HIES).
Case Description
A 4-year-old female with a history of pneumonia, herpetic skin infection, orbital cellulitis, and eczema presented in respiratory distress with concern for pneumonia. Imaging revealed a posterior mediastinal abscess which was drained on Day 3. Blood cultures identified Streptococcus anginosus, and the abscess fluid grew Streptococcus anginosus, Streptococcus mitis/oralis and Candida albicans. An esophagram and esophagogastroduodenoscopy revealed an esophageal sinus opening and fistula draining into the mediastinal abscess. After surgical closure, the fistula recurred, and an esophageal wound vacuum assisted closure (VAC) was placed. On Day 25, the initial acid-fast bacillus (AFB) abscess culture became positive, and ethambutol, rifampin, azithromycin and amikacin were started. The AFB was identified as M. arupense, and treatment was modified to clarithromycin, rifabutin, and ethambutol. Her course was complicated by drug-induced neutropenia and transaminitis. She received in total 61 days of antifungal, 58 days of antibacterial, and 40 days of M. arupense coverage. Due to the atypical infection, immune evaluation was performed and demonstrated low Th17 lymphocytes. Genetic testing detected a heterozygous pathogenic missense variant in STAT3 (c.2141C>T) consistent with AD-HIES.
Discussion
This is the first case report of M. arupense isolated from a mediastinal abscess. Most M. arupense infections are secondary to direct inoculation injuries with resulting tenosynovitis and osteomyelitis.1,3 It is recognized as a possible respiratory tract colonizer, and therefore must meet clinical and microbiological criteria for diagnosis of NTM pulmonary disease.4,5 Limited susceptibility data has shown 97.5-100% of isolates susceptible to clarithromycin, ethambutol, and rifabutin. 3 Empiric therapy with these three drugs is recommended pending susceptibility data. Treatment duration data is limited but adequate source control is needed as shown here. Evaluation of inborn errors of immunity should be considered in atypical and severe infections, which led to the diagnosis of AD-HIES. AD-HIES due to dominant-negative mutations in STAT3 is characterized by elevated IgE, eczema, connective tissue and skeletal abnormalities, vascular malformations, and recurrent skin and pulmonary infections.6,7 Loss of STAT3 activation and Th17 response underlies our subject’s susceptibility to mycobacterial disease.8
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Exploring Nonlinearity in the Association Between Birth Defect Rates and Agrichemicals in Groundwater in an Agricultural State
Martha G. Rhoades, Debora L. Barnes-Josiah, Roy F. Spalding, Leslie M. Howard, Colleen E. Steele, and Cheryl L. Beseler
Background: Agricultural practices over the last 70 years have led to increased agrichemical contamination in some drinking water supplies. Studies report an elevated risk of birth defects associated with exposure to nitrate or atrazine, but little is known about effects of co-exposure. This ecological study evaluated the relationship between the concomitant presence of nitrate and atrazine in Nebraska drinking water supplies and risk for birth defects.
Methods: County birth data were combined with water chemistry data retrieved from a state-sponsored agrichemical contaminant database. Segmented linear regression was used to examine associations between percentage of wells with nitrate and atrazine (separately and as a mixture), and the risk of birth defects.
Results: When modeled for wells with nitrate-N concentrations > 2 mg/L, the slope of the first regression segment was positive, increasing to 58% positive wells. After 58% positivity, the slope showed a negative association with birth defect rates. Adding atrazine to the model moved the changepoints to a lower percentage of wells positive for these agrichemicals in the association to birth defect rates. Models consistently showed this pattern of association with and without other nitrosatable compounds present.
Conclusions: The results support an effect of nitrate and nitrosatable compounds on fetal development and suggest the relationship may be nonlinear. Exposure to nitrate and nitrosatable compounds as a mixture may have separate biological effects on reproductive outcomes when compared to the single compounds.
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Slurred, Blurred, and a Hard-to-Find Word: Acute Progressive Neurologic Changes in a Pediatric Patient
Lauren Ridgway, Amelia Sneve, Andrew Nguyen, and Aleisha Nabower
Background: Acute disseminated encephalomyelitis (ADEM) is typically a viral sequelae, with a 1-3% mortality rate. ADEM has been described as a consequence of acute SARS-CoV-2 infection. This case report describes a child diagnosed with ADEM in the setting of acute SARS-CoV-2 infection with the clinical course complicated by co-infection with Human herpesvirus 6 (HHV-6). HHV-6 positivity in the CSF is often considered an incidental finding, but it has been shown to cause encephalopathy, seizures, and demyelinating disease. This case is unique in that the dual infection with SARS-CoV-2 and HHV-6 may have contributed to the development of ADEM, poor clinical outcome, and resistance to treatment in this case.
Case Presentation: A 9 y.o. male with ADHD presented with 12 hours of acute onset left-sided weakness, blurred vision with left-sided vision loss, expressive aphasia, and ataxia. Head CT was negative at an outside ED prior to transfer. On exam, he was responsive to commands and agitated with waxing and waning consciousness. Exam significant for decreased left peripheral and blurry vision, expressive aphasia, slurred speech, and decreased left grip strength, although full strength testing was limited. Patellar reflexes 3+ but symmetric, Babinski down, and no clonus. Evaluation was pertinent for positive respiratory panel for SARS-CoV-2. CSF was without pleocytosis, elevated protein, and positive for HHV6. Serum studies positive for GAD65 Ab. MRI brain and spine with T2 hyperintensities showing extensive punctate white matter lesions throughout the cerebral hemispheres, midbrain, and cerebellum, enhancing signal abnormality throughout the spinal cord, and dominant lesions in the frontal lobes, to be correlated with vasculitis or demyelinating disorders. Normal MRA/MRV head. The patient received high dose IV steroids followed by IVIG due to lack of response. He was started on IV Ganciclovir, Remdesivir, Cefepime, and Vancomycin. He developed status epilepticus (SE) resistant to multiple anti-epileptic drugs and diabetes insipidus (DI), progressing to cerebral edema and herniation, neurogenic shock, and brain death.
Discussion: The combination of encephalopathy, recent viral illness, acute neurological changes, and multi-white matter lesions in the brain and spine supported a diagnosis of ADEM due to SARS-CoV-2 versus HHV- 6. One study reported that seizures occurred in 11% of children with ADEM. SE is a serious complication of ADEM and likely contributed to the development of cerebral edema, resulting DI, and the patient’s poor outcome. It is uncertain at this time if co-viral illnesses played a role in this patient’s rapid decline.
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Feasibility and Application of Early Enteral Feeding Initiation in Extremely Low Birth Weight Infants
Lauren Ridgway, Melissa K. Thoene, and Ann Anderson-Berry
Background: Extremely low birth weight (ELBW) infants (< 1000g) have specialized nutritional needs to promote best outcomes, so identifying optimal nutrition therapies is critical. Previous studies indicate that late initiation of enteral feeds (>3 days) is associated with increased inflammation and adverse neonatal outcomes. Delayed breastfeeding after the first hour of life in term infants has also been associated with increased mortality. In consideration of these factors and the heterogeneity that exists between enteral feeding initiation in an ELBW population, there is a lack of studies examining the hour of life in which enteral feeds are initiated in ELBW infants. This study evaluates the feasibility of early initiation of enteral feeds in ELBW infants and describes the impact on time to reach full enteral feeds.
Methods: A retrospective chart review was conducted including ELBW infants born from June 2016 to July 2019 in a level III NICU. Infants with congenital or genetic anomalies or who transferred or deceased prior to 30 days of life were excluded. Feeding categories were defined as early (< 12 hours of life), moderate (12-24 hours), or late (>24 hours). The number of days to reach full enteral feeds was also analyzed, as defined by receiving a volume > 145 mL/kg/day of human milk 24 kcal/oz feedings using human milk fortifier and a protein modular.
Results: 44 ELBW infants were included. The median time of enteral feeding initiation was 12.4 hours of life (min 4.1 hours, max 178.4 hours). Enteral feeds were started in the early category for 19 infants (43%), moderate for 19 infants (43%), and late for 6 infants (14%). The median time to reach full enteral feeds was 9.5 days of life within the cohort. The median time to reach full enteral feeds was 9 days for infants in the early category, 10 days for moderate, and 14 days for the late category.
Conclusions: These results indicate the feasibility of initiating enteral feeds within the first 12 hours of life in the ELBW infant population. Earlier start of enteral feedings—even by hours of life—results in a reduction in the number of days to reach full enteral feeds. These results may be considered in the development of feeding protocols and early enteral nutrition initiation in the ELBW infant population. More studies are needed to assess the impact of early initiation of enteral feeds on neonatal outcomes like growth and morbidities.
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Racial Disparities in Caesarean Delivery Among Nulliparous Women that Delivered at Term: Cross-Sectional Decomposition Analysis of Nebraska Birth Records
Rebecca Slotkowski, C. Hanson, K. Samson, A. Anderson Berry, and D. Su
Background: Access to medically indicated caesarean sections is an essential strategy for reducing maternal and infant mortality rates worldwide. However, overuse of medically unnecessary caesarean sections is associated with excess maternal-child morbidity. Previous studies suggest higher rates of caesarean section among women who identify as racial/ethnic minorities.
Significance of Problem: Despite national efforts to prioritize the reduction of medically unnecessary caesarean sections, caesareans rates in the United States have remained stable over the last decade. Women who identify as racial or ethnic minorities experience disproportionally higher rates of caesarean, even when controlling for demographic, behavioral, medical, and institutional level factors. However, detailed analysis of factors contributing to racial/ethnic disparities in caesarean section rates remains largely unexplored. Identifying these factors and assessing their relative importance is critical for the development of interventions specifically tailored to reduce racial and ethnic disparities in caesarean use.
Question: The objective of this study was to understand underlying social and demographic factors that contribute to differences in caesarean rates across racial and ethnic groups.
Experimental Design: Data was collected from 2005-2014 Nebraska birth records on singleton births occurring on or after 37 weeks gestation (n=87,908). Risk ratios (RR) and 95% confidence intervals (CI) for caesarean were calculated for different racial and ethnic categories. Fairlie decomposition technique was utilized to quantify the contribution of individual variables to the observed differences in caesarean.
Results: In the adjusted analysis, relative to non-Hispanic (NH) White race, both Asian-NH (RR 1.21, 95% CI 1.14, 1.28) and Black-NH races (RR 1.13, 95% CI 1.08, 1.19) were associated with a significantly higher risk for caesarean. The decomposition analysis showed that among the variables assessed, maternal age, education, and pre-pregnancy BMI contributed the most to the observed differences in caesarean rates across racial/ethnic groups.
Conclusion: This analysis quantified the effect of social and demographic factors on racial differences in caesarean delivery, which may guide public health interventions aimed towards reducing racial disparities in caesarean rates. Interventions targeted towards modifying maternal characteristics, such as reducing pre-pregnancy BMI or increasing maternal education, may narrow the gap in caesarean rates across racial and ethnic groups. Future studies should determine the contribution of physician characteristics, hospital characteristics, and structural determinants of health towards racial disparities in caesarean rates.
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Hypertensive Disorders of Pregnancy are Associated with Differences in Maternal Serum Concentrations of Arachidonic Acid Metabolites
Rebecca Slotkowski, M. Van Ormer, M. Thompson, T. Nordgren, M. Thoene, E. Lyden, M. Mukherjee, A. Yuil-Valdes, A. Ulu, S. Nataragan, T. Hahka, A. Akbar, C. Hanson, and A. Anderson Berry
Background: Hypertensive disorders of pregnancy (HDP), including gestational hypertension, chronic hypertension, and preeclampsia, are a significant cause of maternal morbidity and mortality in the United States. Dysregulation of inflammation is thought to play a role in the development of HDP. Maternal diet has the potential to alter the risk of HDP by modulating inflammation. Arachidonic acid (AA) is a dietary polyunsaturated fatty acid which can be metabolized into both pro- and anti-inflammatory bioactive metabolites.
Significance of Problem: HDP places women and their infants at risk for potentially severe pregnancy complications including placental abruption, embolism, end-organ failure, or death. Few treatments are currently available for HDP.
Question: The objective of this study was to describe how maternal AA metabolites serum concentrations are associated with diagnosis of HDP.
Experimental Design: Serum was collected from 121 pregnant women admitted to the labor and delivery unit at Nebraska Medical Center. Women were divided into normotensive or hypertensive groups based on definitions from the American College of Obstetricians and Gynecologists (ACOG). Concentrations of AA metabolites were measured using liquid chromatography-mass spectrometry. Descriptive statistics were generated, and Mann-Whitney U tests were used to compare metabolite concentrations between groups.
Results: Women with HDP had significant higher serum concentrations of PGF2α (p=0.02) and 15-HETE (p=0.04), two metabolites with known inflammatory and vasoconstrictive properties. Women with HDP had significantly lower serum concentrations of 8(9)-DiHET (p=0.04), 11(12)-DiHET (p=0.04), and 14(15)-DiHET (p=0.001), which are all associated with vasodilation. Unexpectantly, hypertensive mothers also had lower serum concentrations of 5-HETE (p=0.02), which is associated with vasoconstriction.
Conclusion: Overall, our study reveals that mothers diagnosed with HDP had significantly higher serum concentrations of vasoconstrictive AA metabolites and significantly lower serum concentrations of vasodilating AA metabolites compared to normotensive mothers. Future directions include analyzing differences in maternal metabolite profile separately for mothers with chronic hypertension, gestational hypertension, and preeclampsia compared to normotensive mothers. Results from these analyses will guide nutritional recommendations for women at risk of developing HDP.
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Thematic Analysis of Third-Year Medical Student Reflections on Social Determinants of Health During Their Pediatric Clerkship: Emergent Themes and Topic Interconnectedness
Paul Witt, Michelle Howell Smith, Shirley F. Delair, Nathan Gollehon, Sharon R. Stoolman, and Jason Burrows
Background. Social determinants of health (SDOH), as defined by the World Health Organization, are the “non-medical factors that influence health outcomes… the conditions in which people are born, grow, work, live, and age, and the wider set of forces and systems shaping the conditions of daily life.” Studies have estimated that SDOH account for 30-55% of health outcomes. Understanding the impact of SDOH can be integrated into medical education in different formats, here we explore student reflections.
Methods. In the 2021-2022 academic year, third-year medical students at a midwestern medical school submitted discussion board reflections on their experiences with SDOH during their 8-week pediatric clerkship. We analyzed de-identified posts to look for emergent themes that showcase the experiences and perceptions of medical students as they care for patients and learn about the socio-environmental factors in the community. Initial coding was built on a preliminary codebook drafted based on the medical school’s SDOH curriculum. Utilizing a grounded theory approach, we added new codes as novel topics and themes emerged. We then examined the relationships between the codes and SDOH categories outlined in the US Department of Health and Human Services Healthy People 2030 objectives.
Results. Ninety-seven student discussion posts were analyzed. Our preliminary results demonstrate the two most common themes, social support and communication, together represented approximately 50% of all student responses. With the addition of the next two most frequently discussed topics, healthcare access and diet/nutrition, this set of themes comprises over 75% of student responses. Student responses also demonstrated the interconnectedness of SDOH categories through frequent overlap of categories during coding and analysis.
Conclusion. Our study demonstrates the most common SDOH themes students identified during the pediatric clerkship involve social support, communication, access to care, and diet/nutrition. We found a multifactorial, connected nature of those themes as they impact patient health. This study validates the need for explicit education on SDOH topics during medical school so that future physicians are well-equipped to intervene or accommodate these factors throughout their careers. Future directions include comparing our results to preexisting social and educational frameworks and future cohort comparisons as curriculum evolves.
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Therapeutic Potential of Suvorexant on Intergenerational Maternal Oxycodone Exposure
Jina Yi, Sneh Koul, Gurudutt Pendyala, and Sowmya V. Yelamanchili
Background:
Maternal opioid misuse is a rising public health concern. Our lab previously published findings that in-utero oxycodone exposure (IUO) has detrimental impacts that persist to the F2 generation, including abnormal genetic expression, increased anxiety, and a difference in phenotypic measurements. The estimated cost of hospital admissions for infants suffering from Neonatal Abstinence Syndrome was $316 million in 2012 and is still rising. This figure does not take into account long-term costs, nor does it consider lasting effects on the F2 generation. Thus, it is critical to find a way to mitigate the negative impacts of IUO.
Suvorexant (suvo) is a dual hypocretin receptor antagonist that is FDA-approved for the treatment of insomnia. The hypocretin system is involved in the regulation of the sleep/wake cycle, feeding behavior, and notably, addiction. Our previous findings showed that Hcrtr1 is upregulated in both F1 and F2 IUO offspring. This project will test the therapeutic potential of suvorexant to attenuate the impacts of IUO.
Hypothesis: The administration of suvorexant on F1 animals that have been subjected to IUO will result in the alleviation of developmental impairments in the F2 generation.
Methods:
Female Sprague Dawley rats in the F0 generation were orally gavaged with 15mg/kg oxycodone or equal volumes of saline. Dosing was maintained from mating until weaning at post-natal day 21 (P21). F1 animals were given ascending doses of suvorexant (3mg/kg P3-P6, 10mg/kg P7-P10, 30mg/kg P11-P21) or an equal volume of DMSO through subcutaneous injection. At P60, 2 females from each condition were mated with naïve breeders. Phenotypic measurements of the F2 generation including weight, head size circumference, and body length were taken at P3 and P14. At P21, 6-8 animals were sacrificed, and organs were collected. Social preference/novelty tests were conducted at P28 and P45. The next phase of this study will consist of molecular assays, imaging, and further behavior testing including an oxycodone self-administration study.
Results:
Our preliminary results showed that F2 IUO-Suvo animals exhibited significant differences in body weight, body length, and head size circumference at P7 and P14 compared to the control. Furthermore, in the social preference test, the IUO-Suvo animals had significantly more entries into both the toy and naïve chambers at P45, as well as significantly more contacts with both the toy and naïve animal at P28.
Conclusions: Administering suvorexant in the F1 generation may mitigate physical and behavioral deficits in the F2 generation caused by intergenerational IUO.
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Unsolicited Advice
Kara Arnold
This piece was written with the phrases that have been said to me or to other female colleagues throughout my year of clinical rotations. Although women in medicine have come a long way, I want this to illustrate the pain that is still inflicted towards female professionals through words like these.
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Eternal
Nicholas Braukmann
This original orchestral composition paints the story of a father and his emotional journey from the moment his baby girl is born through her early childhood to the diagnosis of an abrupt and serious disease.
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Novel Mouse Model for Analysis of Macrophage Function in Neuroblastoma
Gabrielle L. Brumfield, Shelby M. Knoche, Alaina C. Larson, Brittany Poelaert, Benjamin T. Goetz, Poomy Pandey, Don W. Coulter, and Joyce C. Solheim
Background: Neuroblastoma is the third most common childhood cancer and accounts for 12% of cancer-associated deaths in children under the age of 15. Patients with high risk neuroblastoma have a poor 5-year survival rate of less than 50%. Neuroblastoma tumors treated with the histone deacetylase inhibitor (HDACi) vorinostat have increased infiltration of macrophages with upregulated immune cell-surface receptors. Neuroblastoma cells release VEGF and M-CSF, which may alter intratumoral macrophage populations. VEGF has also been implicated in alteration of amyloid precursor protein family processing. Our lab demonstrated that amyloid precursor protein 2 (APLP2), a member of the amyloid precursor protein family, plays an important role in the migration of tumor cells. APLP2 is known to be expressed by macrophages, but no studies have previously examined macrophage functions that are impacted by APLP2 in the context of neuroblastoma disease and its treatment by HDACi drugs.
Significance of Problem: Because of the high morbidity and mortality associated with neuroblastoma, studies such as this one that are designed to comprehend the interaction of immunity and treatment in neuroblastoma are clinically significant. The results from this study are also expected to expand our comprehension of macrophage function and regulation, and thus will be of broad value in the immunology and oncology fields.
Experimental Design and Results: We have treated neuroblastoma tumor cells in vitro with M344, an HDACi with structural similarity to vorinostat, and showed that M344 decreases neuroblastoma cell growth. In addition, we have generated mice that lack APLP2 expression in cells expressing the Csf-1 receptor (a protein characteristically expressed by macrophages and dendritic cells). We discovered that following polarization, macrophages collected from the bone marrow of these mice have an altered distribution of M1 and M2 sub-populations, which are macrophage sub-populations known to differ in their migratory capabilities. Furthermore, we have shown that M1 and M2 subpopulations of bone marrow-derived macrophages from normal mice differ in their expression of APLP2. Thus, APLP2 is influential in macrophage biology, and we have created a novel mouse model for defining its specific contributions in mice treated with HDACi that influence macrophage biology.
Conclusions: Based on the data that we have acquired, we are well positioned to fully explore both the impact of HDACi drugs on macrophage/dendritic cell populations in a syngeneic neuroblastoma mouse model, and to define the role of APLP2 in the function of these cell populations in the context of neuroblastoma.
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Power Training Improves the Sensorimotor Cortical Oscillations in Youth with Cerebral Palsy
Morgan Busboom, Anna Reelfs, Mike Trevarrow, Brad Corr, Heidi Reelfs, Sarah Baker, Hannah Bergwell, Tony W. Wilson, and Max J. Kurz
Background: Our magnetoencephalographic (MEG) brain imaging studies have shown that youth with cerebral palsy (CP) demonstrate altered sensorimotor beta (18-24Hz) cortical oscillations when controlling their leg motor actions and these anomalous cortical oscillations are linked with the extent of their mobility impairments. Current therapeutic trends for improving mobility have shifted from strength training to high-velocity power training, which has shown improvements in isokinetic strength, power production and mobility of youth with CP. However, no studies have assessed whether these clinically relevant improvements are linked with changes in the sensorimotor cortical oscillations. The objective of this study was to utilize MEG brain imaging to examine the potential changes in sensorimotor cortical oscillations following power training.
Methods: Youth with CP (N=11; Age=15.9 ±1.1yrs; GMFCS I-III) and neurotypical controls (NT) (N=16; Age=14.6 ±0.8yrs) were recruited to participate in this study. The youth with CP underwent 24 high-velocity leg press power training sessions that were performed on a Total Gym® sled. Pre-Post bilateral leg press 1-repetition maximum (1RM) and peak power production were used to assess the muscular performance changes. The 1-minute walk was used to assess mobility changes. During MEG recordings, participants used their right leg to complete a goal-directed isometric target-matching task. Advanced beamforming methods were subsequently used to image the strength of the sensorimotor beta oscillatory power. The NTs only underwent the baseline MEG assessment.
Results: Youth with CP increased their 1RM (Pre=158.3 ±24.7kg, Post=247.5 ±41.5kg, p<0.01), and peak power production (Pre=509.9 ±64.7W, Post=677.1 ±113.3W, p=0.04). Participants with CP also improved their 1-minute walk (Pre=77.4 ±9.2m, Post=80.8 ±8.4m, p = 0.02). The beta sensorimotor cortical oscillations in the leg region were stronger in the youth with CP prior to training compared with the NTs (CP=-25.9±1.8%; NT=-17.2±3.6%, p=0.04). However, the youth with CP had a reduction in the strength of the beta oscillations after undergoing the power training (pre=-25.9 ±1.8%, post=-14.8 ±3.6%, p=0.02), and the strength of the oscillations was not significantly different from the NTs after training (p=0.68). Lastly, the peak power production after training was tightly linked with the strength of the post-therapy sensorimotor cortical oscillations (r=0.79, p=0.03).
Conclusion: Power training appears to improve the neural generators that control the leg motor actions, and these neuroplastic changes partly contribute to improvements in the peak power production of youth with CP. Potentially, power training might provide the key therapeutic ingredients for complementary muscular and neurological plastic change.
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The Secret
Aaron Clem
I wrote this poem about my experience in the NICU taking care of babies with total anomalous pulmonary venous return (TAPVR).
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Truncus - the Odyssey
Aaron Clem
I’ve been tempted to write a drum part with the heart beat as the foundation for a long time. I had the idea to tell the story of a newborn with congenital heart disease through the stages of pre-operative life, cardiac surgery, and post-op ICU care. I chose Truncus Arteriosus as the specific lesion because of the rapid neonatal course and the rich sonic landscape it provides. To “spice” things up a bit, I incorporated all sorts of physical exam findings and arrhythmias into the piece (and took a few percussive liberties to make it easier on the ears).
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Early Systolic Dysfunction and Impact of Gene Mutation Severity in Marfan Syndrome
Aaron Clem, Lois J. Starr, David Danford, Mary Craft, Ling Li, Jason Christensen, and Anji Yetman
Background
Marfan syndrome is caused by a mutation in the fibrillin-1 gene that manifests with a variety of features including aortic root dilation. Recent research has identified a primary cardiomyopathy in patients with Marfan syndrome, hypothesized to be due to the presence of abnormal fibrillin-1 in the myocardium. Controversy over the nature and significance of this cardiomyopathy remains. Echocardiographic measurement of the first-phase of ejection (defined as the beginning of systole to peak aortic valve flow) may be more sensitive to systolic dysfunction and provide useful clinical information. The purpose of this study is to:
- Assess systolic dysfunction in patients with Marfan syndrome
- Describe first-phase fractional area change (FAC1) in patients with Marfan syndrome and determine how it varies between Marfan syndrome patients and a control group
- Verify there is a difference in propensity for cardiomyopathy in mild vs severe gene mutation Marfan syndrome patients not secondary to increased aortic stiffness
Methods
Patients were identified from a pre-existing list of patients with Marfan syndrome maintained by the Children's Hospital and Medical Center and University of Nebraska Medical Center. All relevant medical records were reviewed. Echocardiographic parameters will include left ventricular (LV) ejection fraction, LV FAC1, LV end-diastolic volume, global longitudinal strain, aortic root diameter, and aortic stiffness. Patients were excluded if they have more than mild aortic insufficiency or mitral valve regurgitation. Neonatal Marfan syndrome patients and patients with other significant congenital heart disease will also be excluded. Statistical analysis of the data will be performed including basic statistical tests, univariate regression, and multivariate regression to compare data from each group. P values will be calculated and a p value < 0.05 will be considered statistically significant.
Results
At the time of writing, 126 patients with Marfan syndrome have been identified. 44 were excluded based on significant mitral or aortic valve disease, prior cardiovascular surgery, or poor echocardiographic image quality. Of the 82 patients not excluded, genetic testing results are available for 59 and are being categorized to allow for statistical analysis. Echocardiographic measurements are underway.
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Evaluation of brain cholesterol metabolism after neonatal hypoxic-ischemic brain injury
Amanda Dave, Luke Allen, Zeljka Korade, and Eric Peeples
Introduction
Neonatal hypoxic-ischemic brain injury (HIBI), resulting from impaired cerebral blood flow and oxygen delivery to the brain, affects at least 1.5 per 1,000 live births each year in the United States. Altered levels of cholesterol and cholesterol metabolites have been identified in brain tissue and in serum after adult brain injury such as traumatic brain injury and stroke. We hypothesized that there would be temporal and brain region-specific alterations in cholesterol and sterol precursors after neonatal HIBI.
Methods
Postnatal day 9 CD1 mouse pups were anesthetized with isoflurane and randomized to HIBI induced by carotid artery ligation or controls receiving sham surgery consisting of dissection without ligation (n=24/group). Pups were allowed to recover after surgery and then placed in a hypoxia chamber at 8% oxygen for HIBI or 21% for controls for 30 minutes. Each group was further divided into three sub-groups (n=8/group) for blood and brain tissue collection at 30 minutes, 24 hours, or 72 hours after injury. Brain tissue was dissected into four regions: cortex, cerebellum, striatum/thalamus, and hippocampus. For each region, protein was quantified by BCA assay, interleukin-6 (IL-6) levels were measured by ELISA as a marker of injury severity, and liquid chromatography mass spectrometry was performed to evaluate for the following sterols: cholesterol, desmosterol, 7-dehydrocholesterol, 8-dehydrocholesterol, and lanosterol. Levels were compared between HIBI and control groups at each time point and neuroanatomical region. Additionally, the four samples in each group demonstrating the most severe injury, as defined by IL-6 levels, were stratified as “severe injury”. Differences were analyzed with a two-sided Mann-Whitney test.
Results
When assessing the entire cohort, no statistically significant differences were seen between HIBI and controls with respect to temporal or regional differences for any of the sterols measured. In animals with severe HIBI, however, cholesterol, 7-dehydrocholesterol, 8-dehydrocholesterol, and desmosterol were higher in the cortex at 24 hours after injury compared to controls. Additionally, desmosterol was also elevated in the cerebellum but decreased in the striatum 24 hours after injury in the severely injured animals.
Conclusion
Severe neonatal encephalopathy appears to be associated with alterations in cortical brain sterol levels, peaking around 24 hours after injury. Further defining the aberrations in brain metabolism in infants with HIBI could provide opportunities for not only diagnostic biomarkers but also the development of targeted therapies.
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Femoral and Tibial Indications for Initial and Reoperation Surgeries with Fassier-Duval Intramedullary Rods for Children with Osteogenesis Imperfecta
Adriano DellaPolla, Kaeli Samson, Tinotenda Sekeramayi, Arianna Dalamaggas, Megan Gillespie, Vincent Eaton, Elizabeth Strudthoff, and Maegen Wallace
Background: Osteogenesis imperfecta (OI) is a genetic connective tissue disorder affecting quantity and integrity of collagen type I, which is integral for the strength of osseus tissue. OI has a heterogenous molecular inheritance pattern – divided into four major subgroups (I-IV). Defects in collagen protein products lead to poor development of skeletal structures and increased fracture rates. Children with OI suffer from multiple fractures and bone deformities often requiring surgical intervention with osteotomies and intramedullary telescoping rods, most often with Fassier-Duval (FD) rods. Our study–updated cohort from 2018 paper Azzam et al.–looked at the relationship between initial and reoperation indications for femur and tibia FD rodding surgeries based on age, bone, and OI type.
Methods: Retrospective chart review of initial surgeries included 197 bones (femurs and tibias) from 58 patients. Reoperations included 140 bones from 45 patients. Variables included age at first operation (0-24, 24.1-48, 48.1+ months), time to reoperation, operation indications, bone, and OI type. Spearman correlations were used separately for each bone-type to assess associations between age at first surgery and total number of surgeries. To assess dichotomous outcomes (i.e. specific indication), generalized estimating equations were utilized and adjusted for bone-type and side. Hazard ratios and associated 95% confidence intervals were derived from frailty survival models for the time to first reoperation outcome. Kaplan-Meier curves were generated to display time to reoperation, stratified by age at first operation and bone-type. Data was collected from 2003-2018. Analyses were performed using SAS software v9.4.
Results: There was a statistically significant correlation between age at first surgery and indication (bowing and fracture) for initial (p<0.0001, p=0.01) and reoperation surgeries (p=0.004, p=0.03), respectively. All bones, except left tibias, showed significant negative correlation between age at first surgery and total number of surgeries. Both older age at first surgery groups (24.1-48, 48.1+ months) had significantly lower risks of needing reoperation relative to the 0-24 months group (p=0.0003, p=0.0004). Descriptive analyses suggest median survival of FD rods in OI type III was decreased relative to type IV, XV or unknown when initial surgery was between 0-24 months.
Conclusion: Bowing and fractures are the most common causes for initial and reoperation surgeries in children with OI. Patients in older age groups at first surgery need fewer reoperation surgeries. Median survival probabilities of FD rods increased when age at first surgery was after 48.1+ months. OI type may impact median survival of FD rods.
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Evaluation of Pseudomonas aeruginosa Eradication Protocol in Pediatric Patients with Cystic Fibrosis: A Retrospective Medical Chart Review
Adam DeVries, Heather Thomas, and Diane Acquazzino
Background
Pseudomonas aeruginosa (Pa) is a leading cause of lung infection in patients with cystic fibrosis (CF), increasing morbidity and mortality. Despite this, there is no standardized treatment among the medical community for Pa eradication in patients with CF. The Nebraska Regional Cystic Fibrosis Center at Children’s Hospital and Medical Center (CHMC) in Omaha, Nebraska has a Pa eradication protocol. This study aims to increase Pa eradication for children with CF by investigating the effectiveness and adherence to the current Pa eradication protocol.
Methods
This study is a retrospective medical chart review of 1–21-year-olds with CF receiving care at CHMC. Medical records for each patient were screened for Pa culture results and Pa treatments. Primary endpoints were the degree of protocol adherence, eradication success, and subsequent colonization following CHMC’s Pa eradication protocol. The current protocol starts patients on step one with inhaled tobramycin for 28 days and oral ciprofloxacin for 14 days following a positive Pa culture. If still positive after that time, they are started on step two with 10-14 days of intravenous antibiotics. If sustained positivity following IV antibiotics, they progress to step three with six months of alternating monthly inhaled tobramycin, colistin, or aztreonam. If positivity after step three, they are considered colonized. If they have a negative sputum culture following any step, Pa is considered eradicated, they continue quarterly monitoring, and restart the protocol following another positive Pa result.
Results
Of the 184 CHMC’s CF patients, 172 patients were used for the study (8 excluded for age and 4 for inadequate medical records). For those included, the protocol was fully followed correctly for 70.3% (N=121) of patients. When step one of the protocol was followed, 151/206 (73.3%) of treatments had Pa eradication compared to 36/61 (59.0%) of patients with non-protocol treatment (OR 0.52, 95% CI 0.29-0.95, P=0.03). However, there was no statistically significant difference in eradication when comparing steps two and three to non-protocol treatments. When the complete protocol was followed, 12/121 (9.9%) of patients became chronically colonized with Pa compared to 27/51 (52.9%) of patients who did not follow protocol guidelines (OR 0.099, 95% CI 0.04-0.22, P-value= <0.0001).
Discussion
Adherence to the CHMC’s current protocol is associated with increased Pa eradication levels when used at step one and decreased colonization cases. Early initiation of treatment using this protocol is vital to improving morbidity and mortality associated with Pa infections in cystic fibrosis children.
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Daily Learning
Megan Gibbons
Pencil drawing and embroidery. The piece is representing the physiological changes happening daily in our brains. Health care is a field where learning happens daily, which is especially evident as a medical student.
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December 18
Lauren Gillespie
December 18th, 2020 Memorial Park Omaha, Nebraska. This picture was taken December 18th in Memorial Park. I treated myself to a delightful walk that evening after finishing my neurology shelf and first semester of M3 year.
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life as medical student on rotation
Amanda Goodwin
A reflection of the stress and wonder surrounding M3 year
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Fit for Life: Educating About a Healthy Lifestyle in Omaha Elementary Schools
Emilee Greager, Mary Conklin, Jordan Nustad, Tyler Bendrick, Haley Bremer, Tavishi Chopra, Jane Driano, Connor Eggleston, Lily Foley, Jeffrey Kepple, Ryan Leuty, Taylor Mattice, Alison Mause, Elizabeth Mause, Molly Olsen, Breanne Parets, Heerali Patel, Thomas Pennington, Miranda Prints, Eva Schaible, Christopher Toivonen, Grace Vitek, Claire Willman, Allen Zheng, and Kody Moffatt
Background: The prevalence of childhood obesity is increasing across the country. Health education at a young age is critical for children to establish healthy habits. The Fit for Life program is put together by Creighton medical students to inspire elementary students to lead a healthy lifestyle. The curriculum integrates physical exercise, real organ demonstrations, emotional wellness exercises, and nutritious meal building to model and encourage healthy habits.
Methods: Over four weeks, medical students taught the 4th and 5th graders of two Omaha schools over live video while they followed along with hands-on activities. Before and after the program, students’ height and weight were measured to calculate BMI, and the students completed pre- and post-program quizzes. Paired t-tests were performed to analyze differences in student BMIs and quiz scores. Pre-program quiz scores of students who completed two consecutive years were compared using paired t-tests.
Results: Student BMIs before and after the program showed no significant changes (p = 0.479, n = 45) however, quiz scores significantly improved after the program (p < 0.001, n = 44). Self-reported survey responses after the program demonstrate increased motivation for a healthy lifestyle as well as improved understanding of the importance of sleep, exercise, reduced screen time, and healthy eating. Those who completed the program for two consecutive years had significantly higher pre-program quiz scores the second year (p < 0.05, n = 18).
Conclusion: Our study found a significant increase in pre- and post-program assessment scores which suggest improvement in student perspective and knowledge of healthy habits. Similarly, students who completed the program for two consecutive years demonstrated an increase in pre-program quiz scores suggesting retention of health knowledge. While there was no significant difference in pre- and post-program BMIs, results may be limited by the duration of the study, given that changes in weight are often insubstantial in the short-term.
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