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Transitions into GME Program Leadership Roles in Neonatal-Perinatal Medicine: Opportunities for Improvement
Get PDFThis is an abstract from the Spotlight on Scholarship event in 2025
Advancing Drug Development through Translational DMPK and Model-Informed Pharmacokinetic Approaches
No full textThe integration of translational drug metabolism and pharmacokinetics (DMPK) with model-informed pharmacokinetic (PK) strategies is reshaping the landscape of modern drug development. A comprehensive understanding of in vitro and in vivo preclinical PK characteristics paves the way for the successful progression of drug candidates into clinical development. The first part of this dissertation focuses on the absorption, distribution, metabolism, and excretion (ADME) properties of JNJ-64619178 (JNJ) as a potential therapeutic for medulloblastoma. Overexpression of protein arginine methyltransferase 5 (PRMT5) is pivotal in MYC-driven primary medulloblastoma tumors, suggesting a potential therapeutic target for the treatment of medulloblastoma. JNJ is a potent inhibitor of PRMT5 and is currently under clinical trials, notably for non-Hodgkin lymphoma and lung cancer. In our study, we determined the potential of JNJ for treating Group 3 medulloblastoma. We developed a sensitive LC-MS/MS bioanalytical method to accurately quantify JNJ in the biological matrix. The developed method demonstrated appropriate sensitivity, selectivity, and robustness, meeting regulatory guideline requirements. Applying the validated method, we identified JNJ as having acceptable drug-like PK properties in terms of in vitro and in vivo studies. JNJ represented excellent stability in plasma and brain matrices, indicating resistance to enzymatic degradation. The metabolic stability result showed no significant phase I metabolism. Following IV dosing, the volume of distribution (Vd) was 1.16 L/kg, which is approximately 1.65 times of total body water in mice, indicating a considerable tissue distribution. The systemic clearance was slow, with a value of 0.23 L/h/kg. After oral dosing, the maximum plasma concentration (Cmax) reached was ~3.5 times higher than the IC50 of JNJ in the HD-MB cell line. JNJ was well-retained in the target brain environment after 24 hours with a mean concentration of 23.49 ng/g. However, as the achieved brain concentration was significantly below the in vitro IC50 value (1.7 µM or 821.71 ng/mL), alternate dosing strategies or improved drug delivery of an oral dosage form designed for medulloblastoma would be required.
Model-informed drug dosing approaches, including the incorporation of population pharmacokinetic (PopPK) and physiologically-based pharmacokinetic (PBPK) modeling, have become indispensable tools in translational clinical pharmacology to speed drug development. For an established drug, these approaches enhance therapeutic precision and clinical utility, explicitly in underserved populations such as pediatrics. In this context, by leveraging existing clinical and experimental data, we wanted to address knowledge gaps related to the variability of drug exposure across pediatric populations with obesity. We prospectively evaluated the PK variability of midazolam (CYP3A substrate) and its CYP3A-mediated major metabolite 1-hydroxy midazolam in obese children and adolescents using PopPK and subsequently a PBPK model. CYP3A metabolizes over 50 percent of marketed drugs, and substantial variability exists in functional activity, resulting in significant variability in drug effect when patients are given fixed doses of CYP3A metabolized drugs. We used midazolam as a probe drug to assess in vivo CYP3A activity in children with obesity. First, a PopPK model was developed for the drug and metabolite and validated with a nonlinear mixed-effects modeling approach (Phoenix NLME 8.3.5). In the final model, an increase in total body weight (TBW) was associated with a significant decrease in midazolam clearance via CYP3A metabolism. Midazolam clearance decreased 29.71 – 41.76 and 49.43 – 50.15 % in obese and morbidly obese patients, respectively, compared to normal weight individuals (p\u3c 0.05), with a fixed dosing of 2 mg. We observed a correlation between serum IL-6 and midazolam exposure; however, with limited samples and incomplete IL-6 data, body weight remained the predominant factor in PopPK analysis. Thus, with this result, we anticipated that a further investigation through a PBPK modeling strategy may help elucidate the likely multi-factorial underpinnings of altered PK in obesity and potentially identify tipping points for what burden of inflammatory cytokines may result in clinically relevant alterations in PK. Using literature published data and clinical samples, we developed whole-body PBPK models of midazolam and 1-hydroxy midazolam using GastroPlus™ (V9.9). Our developed model had good predictive performance, confirmed through mean fold error metrics and diagnostic goodness-of-fit plots. An inhibitory IL-6 PBPK model predicted that obesity-driven IL-6 elevation leads to up to 40% reduction in CYP3A4 activity and increased the systemic exposure of midazolam by up to 30% in obese populations. Overall, our findings provide a mechanistic basis for obesity-related changes in CYP3A mediated drug pharmacokinetics, emphasizing the need for development of dosing guidelines in this critical population
Symptom Clusters and their Association with Health-Related Quality of Life in Pediatric Cancer Survivors After Treatment Completion
No full textA critical area of cancer research, symptom management, has evolved from focusing on individual symptoms to recognizing the complexity of co-occurring symptoms, commonly referred to as symptom clusters. However, most studies on pediatric cancer symptom clusters have focused primarily on the treatment phase or long-term survivorship, overlooking the early post-treatment period. This dissertation examines the prevalence of multiple symptoms and symptom clusters in pediatric cancer survivors post-treatment; factors associated with the total number of symptoms and symptom clusters; and the association of the total number of symptoms and symptom clusters with health-related quality of life (HRQoL). We developed and tested a symptom cluster framework by adapting Tabudlo’s Theory of Symptom Cluster Management. Using a cross-sectional design, data were collected from 136 pediatric cancer survivors aged 10–25 who were within 8 years of treatment completion at Nebraska Medicine and Children’s Nebraska.
Findings revealed that approximately 80% of participants experienced multiple symptoms, with four distinct symptom clusters identified: fatigue, mood disturbance, gastrointestinal, and neurologic-autonomic. Factors associated with the total number of symptoms were participants’ state of residence, treatment modality, diagnosis, father’s education level, and median household income. Also, higher symptom numbers were negatively associated with HRQoL. Sociodemographic factors (sex, cohabitation status, education level, and race/ethnicity); clinical factors (diagnosis and treatment modality combinations); and parental factors (mother’s education) were associated with symptom clusters. Additionally, symptom clusters were negatively associated with HRQoL, reinforcing their impact on long-term survivorship outcomes. This association was further validated by our developed and tested conceptual framework of symptom clusters that incorporated clinical factors, survivors’ sociodemographic characteristics, parental sociodemographics, and HRQoL. Empirical testing confirmed the relevance and applicability of this model in pediatric cancer survivorship research.
The findings emphasize that the total number of symptoms and symptom clusters vary across sociodemographic groups, clinical characteristics, and parental contexts, highlighting the heterogeneity of survivorship experiences. These differences point to the inadequacy of uniform symptom management approaches and reinforce the need for personalized strategies that account for individual risk profiles, contextual factors, and developmental needs. Tailored interventions that are grounded in symptom cluster science and responsive to the survivor’s unique circumstances are essential for improving HRQoL and long-term outcomes in pediatric cancer survivors
Effects of Treatment Integrity Level and Error Type on Dro Efficacy: A Parametric and Comparative Analysis
No full textDifferential reinforcement of other behavior (DRO) is a strategy commonly used in applied contexts to address challenging behavior but can be difficult to implement with high treatment integrity. Previous research has shown that DRO may be robust despite marginal errors of commission, but the impact of differing degrees of errors and different error types during DRO is still unclear. The purpose of the current study was to conduct a parametric evaluation of treatment integrity level (100%, 80%, 60%, 40%, 20%) in DRO when implemented with combined errors (Experiment 1) and to directly compare error types (commission errors, omission errors, combined errors; Experiment 2) in a human-operant arrangement using a multiple treatments reversal design. Rate of target responding was evaluated across baseline, DRO with 100% treatment integrity, and DRO with reduced treatment integrity. Results of Experiment 1 indicate that DRO may be robust with as little as 60% treatment integrity when implemented with combined errors. Results of Experiment 2 suggest that combined errors are most detrimental, and omission errors are slightly more detrimental than commission errors. These findings will inform future evaluations of treatment integrity errors in DRO and may contribute to a better understanding of how to arrange effective DRO interventions in applied contexts
ASDAT: Evaluating Autism Symptom Severity
Get PDFThis study aims to develop and validate the Autism Spectrum Disorder Assessment Tool (ASDAT), a user-friendly, objective tool for assessing the severity of ASD symptoms and informing treatment planning. Currently, there are no tools that both evaluate ASD severity across DSM-5 criteria and guide treatment dosage recommendations. The ASDAT will address this gap by providing a standardized measure that aids diagnosticians and practitioners in determining appropriate care and treatment levels. Children aged 16 months to 14 years who are receiving diagnostic services at MMI’s Autism Diagnostic Clinic, along with their caregivers, will be recruited for this study. While the children are the primary recipients of the diagnostic services, their caregivers will participate by completing four surveys via REDCap about their child: one collecting demographic and medical information, one assessing the child’s communication and social interaction, one evaluating restricted and repetitive behaviors, and one providing feedback on the survey’s acceptability. Caregivers will complete these surveys only once, during their child\u27s diagnostic appointment. Additionally, providers who are both part of the ADC clinic and the research team will complete two questionnaires: a demographics questionnaire about themselves and a survey about the child participant for whom they are providing diagnostic services. The ASDAT will be tested for diagnostic sensitivity and specificity, and its acceptability and feasibility will be evaluated through completion rates and time. This study will provide insights into the ASDAT’s ability to diagnose ASD and guide treatment decisions, with the goal of creating a standardized, objective tool for clinicians, diagnosticians, and managed care providers.https://digitalcommons.unmc.edu/surp2025/1006/thumbnail.jp
Retrospective Chart Review of the Acute Care Psychosocial Evaluation Process for Females Diagnosed with Breast Cancer
No full textBackground: A breast cancer diagnosis can significantly impact an individual’s quality of life. This retrospective chart review explored the occupational therapy evaluation process with female patients in an inpatient acute care hospital with a breast cancer diagnosis.
Methods: This descriptive retrospective chart review analyzed 134 occupational therapy evaluations of female patients with breast cancer admitted to a southeastern US academic medical center. Data were extracted and categorized using the Occupational Therapy Practice Framework.
Results: The most frequently administered assessments were non-standardized and the AM-PAC 6-Clicks. Documented short-term goals primarily focused on self-care (56.6%), gross motor skills (24.7%), and instrumental activities of daily living (10.8%). Few goals addressed psychosocial needs, despite documentation of psychosocial factors impacting occupational performance in 37.1% of the charts.
Discussion: The findings highlight a potential gap in addressing psychosocial needs within acute care occupational therapy for breast cancer patients. Time constraints, the emphasis on medical stability, and the historical separation of mental and physical health care may contribute to this gap.
Conclusion: Occupational therapists must adopt a more holistic approach that integrates psychosocial assessment and intervention to comprehensively support the well-being of individuals with breast cancer.
Knowledge Translation Takeaway: This study advocates for incorporating the evaluation of psychosocial functioning into acute care occupational therapy practice to facilitate early identification of psychosocial needs and inform interventions that support patient engagement in meaningful occupations
Creating a Safe Space: Engaging Graduate Nursing Students in Meaningful Discourse About Racism
No full textINTRODUCTION: Providing education for graduate nursing students about implicit bias, covert/overt racism in the United States has become challenging due to state and federal policies. Yet, national accrediting bodies require these concepts in doctoral level nursing curricula. While these concepts may be viewed as divisive, faculty can facilitate meaningful discourse by fostering an authentic and safe learning environment.
METHODS: This article describes a curricular revision and our approach of integrating these concepts into a doctoral level ethics course using Mezirow\u27s Transformative Learning Theory and Kitchenham\u27s evolution of Mezirow\u27s theory with instrumental learning, dialogic/discourse learning, and self-reflection.
RESULTS: Students evaluations revealed their enhanced awareness of implicit bias and racism and its toll on minoritized populations.
DISCUSSION: With the ever-increasing diversity in the United States, our intentional approach for addressing implicit bias, covert/overt racism provided a platform for students to enhance their transcultural nursing skills by learning to appreciate differing worldviews and experiences
Investigate the Role of TGFβ3 in Regulating IRF6 and ΔNp63 in Periderm Desquamation
No full textIntroduction: Failure in palatal fusion during palate development results in cleft palate, one of the most common birth defects in the US. During the final phases of palatogenesis, the palatal periderm (a protective cell layer that prevents premature fusion and adhesion with oral epithelium) must be removed, also known as desquamation. This process is a prerequisite for establishing the midline seam in the fused palate. Previous studies have shown that transforming growth factor-β3 (TGFβ3) plays an irreplaceable role in palate development in mice. Our previously published mechanistic models outline the role of TGFβ3 and its downstream signaling cascade involving proteins (e.g. Irf6 and dNp63) in periderm desquamation. Our previously published data have shown a regulatory feedback loop between ΔNp63 and Irf6 in differentiating oral/palatal epithelial cells that is potentially dependent on functional TGFβ3 signal. Our goal in this research is to explore how TGFβ3 fits into regulating Irf6 and ΔNp63 in periderm desquamation, hence, we ask the question, “How can TGFβ3 -/- palatal fusion defects be corrected through the timely induction of periderm desquamation?”. Objectives: In this aim, we investigate mechanisms by which TGFβ3 -/- cleft palate can be rescued in vivo by modulating ΔNp63 and Irf6 genes in triple transgenic TGFβ3, IRF6, and ΔNp63 mouse model systems. As per our published and preliminary data introducing a novel role for TGFβ3 in periderm desquamation, we will test the hypothesis that the timely removal of the 4 periderm or the key peridermal regulator ΔNp63 in Tgfb3-/- mice will rescue the defective palatal shelf adhesion seen in Tgfb3 null mutants. Our hypothesis is that the timely removal of the periderm or the key peridermal regulator ΔNp63 and Irf6 in Tgfb3-/- mice will rescue the defective palatal shelf adhesion seen in Tgfb3 null mutants. Results: Using Cre-loxp murine transgenic experimental models and innovative imaging of newborn palate to document the dynamic cellular changes that are controlled by TGFβ signaling during palatogenesis, such as micro-CT, palatal size’s shape and volume measurements, Hematoxylin-Eosin (H/E) and Safranin O staining. Our results demonstrate that while induction of ΔNp63 in Tgfb3-/- mice rescued cleft palate in 40% of mice, and as expected, induction of IRF6 in Tgfb3-/- mice did not rescue palatal cleft. This unique observation agrees with our hypothesis that TGFβ3 and ΔNp63 play crucial roles in periderm morphogenesis and desquamation. However, while IRF6 is necessary for palatal fusion, it is not dependent on functional TGFβ3 signaling. And we propose that IRF6 has its independent pathways in palate development. Conclusion: Using both in vitro model and in vivo genetic models in newborn palates to analyze their structural, functional, and biochemical properties places us in an advantageous position to be able to interpret the regulatory feedback loop among TGFβ3-ΔNp63-Irf6 signaling in greater detail, to improve our understanding of how the cells process vast information. And thus, our study presents a new paradigm with significant conceptual advances in understanding the detailed mechanisms, by which periderm desquamation takes place in the pathogenesis of cleft palate. The hierarchical order TGFβ3, Irf6, and ΔNp63 is critical in the development of approaches to prevent cleft palate as well as in the development of therapeutic strategies
Interventions to Improve Community Mobility in Autistic People: A Systematized Review
No full textImportance: Community mobility (CM) enables access to locations outside the home, allowing participation in work, leisure, and social environments. Autistic adults have reported less access to public transportation and driving than the general population (Wilson et al., 2021), impacting their community participation, life satisfaction, and likelihood of employment and further education (Egilson et al., 2016, Song et al., 2022, Wilson et al., 2021). Occupational therapists can support autistic people by providing interventions to increase CM.
Objective: To evaluate the effectiveness of interventions to improve CM in autistic people.
Methods: We collaborated with a medical librarian to conduct a systematic review through three databases: PubMed, Scopus, and CINAHL. 247 articles were reviewed for inclusion. We included articles if they were published between 2015 and 2025, written in English, quantitative, and included autistic people as the population, occupational therapy interventions, and CM as the outcome. 48 articles were retrieved for full-text review and 15 met inclusion criteria.
Results: Three themes emerged: driving and community mobility education, driving simulators, and virtual reality. Two Level 1B and four Level 3B studies provide moderate strength of evidence supporting driving and CM education programs to improve driving and CM skills. Four Level 3B studies provided moderate strength of evidence supporting driving simulator interventions to improve simulated driving performance. One Level 2A, two level 3B, and one level 4 studies provided low strength of evidence supporting virtual reality or video games to improve CM skills.
Conclusion: Occupational therapists may consider implementing group or individual education sessions and driving simulator interventions on a routine basis. Virtual reality interventions may be considered on a case-by-case basis.
Impact Statement: This review provides updated information on evidence-based practices to improve community mobility in autistic people.
Learning Objective 1:
What interventions should be used routinely to improve community mobility in autistic people?
Learning Objective 2:
In this body of evidence, what are the most common measures of community mobility?
Research Area: Translational Research
Research Type: Qualitative
Primary Topic Category: Developmental Disabilities
Secondary Topic Category: Driving & Community Mobility
Level of Material: Introductory
Level Rational: This literature is aimed to be read by general practitioners who have no previous knowledge of this subject matter. The focus is to provide introductory information to whomever reads the article.https://digitalcommons.unmc.edu/cahp_ot_sysrev/1027/thumbnail.jp