Ella Adeline Nettnin

All Publications

• Health Literacy and Neurosurgical Outcomes: A Systematic Review and Framework for Action Guinle, M., Nettnin, E., Prolo, L. OXFORD UNIV PRESS INC. 2025: v194

  View details for DOI 10.1093/neuonc/noaf201.0767

  View details for Web of Science ID 001613298600028

• Macropinocytosis as a novel target for pediatric high grade glioma therapy Nguyen, T., Spees, K., Garcia, C., Arana, S., Du, P., Levin-Konigsberg, R., Vaughan-Jackson, A., Nettnin, E., Bassik, M., Prolo, L. OXFORD UNIV PRESS INC. 2025: v179-v180

  View details for DOI 10.1093/neuonc/noaf201.0709

  View details for Web of Science ID 001613298600026

• Disrupting BMAL1 enhances Temozolomide efficacy and abolishes circadian timing effects in pediatric high-grade gliomas Nettnin, E., Garcia, C., Sayed, F., Guinle, M., Gibson, E., Prolo, L. OXFORD UNIV PRESS INC. 2025: v340

  View details for DOI 10.1093/neuonc/noaf201.1340

  View details for Web of Science ID 001612035200038

• Role of health literacy in neurosurgical outcomes among pediatric and adult patients: a systematic review of international studies and call to action. Journal of neurosurgery. Pediatrics Barros Guinle, M. I., Nettnin, E. A., Prolo, L. M. 2025: 1-9

  Abstract

  Limited health literacy (HL) is associated with worse clinical outcomes across medical specialties. The association between limited HL and neurosurgical outcomes remains largely unknown. In this systematic review, the authors synthesized the existing literature on the association between limited patient and/or caregiver HL and neurosurgical outcomes.A systematic search was conducted in PubMed, Embase, CINAHL, and JBI EBP from inception to February 12, 2025, following PRISMA guidelines. Study quality was assessed using the Newcastle-Ottawa Scale. The study design, sample size, population of interest, neurosurgical diagnoses/procedures, HL assessment used, pertinent findings, and related demographic factors were collected.The search yielded 698 article titles and abstracts, of which 37 underwent full-text review and 6 met inclusion criteria for this systematic review. These 6 studies included 695 neurosurgical patients and/or caregivers and used various methods to assess HL. Neurosurgical outcomes were grouped into the following categories: 1) delivery and timing of neurosurgical care, 2) hospital admission and discharge, and 3) quality of life (QOL) and well-being. Study results were split evenly across these 3 categories, with 2 studies that explored the delivery and timing of neurosurgical care, 2 that examined hospital admission and discharge, and 2 that investigated QOL and well-being. Study designs included 2 prospective observational studies, 3 cross-sectional studies, and 1 qualitative study. Sample sizes ranged from 27 to 300 patients, including pediatric, adult, and mixed (pediatric and adult) populations, as well as caregivers of pediatric and adult patients. All 6 studies were conducted outside the United States. Limited HL was found to be associated with delays in neurosurgical care, increased rates of discharge against medical advice, decreased patient independence, and worse psychological well-being.This systematic review highlights the paucity of studies on neurosurgical outcomes among patients and/or caregivers with limited HL, while suggesting that limited HL is associated with worse neurosurgical outcomes. In addition, the lack of studies conducted in the US indicates a geographic gap in the literature. The authors provide a call to action and concrete steps to address the critical need for further research on HL to achieve more equitable neurosurgical care.

  View details for DOI 10.3171/2025.5.PEDS25172

  View details for PubMedID 41004858

• Circadian rhythms in pediatric high-grade gliomas may contribute to treatment efficacy. Scientific reports Nettnin, E. A., Garcia, C. A., Sayed, F. F., Schonfeld, E., Nguyen, T., Guinle, M. I., Petritsch, C. K., Gibson, E. M., Prolo, L. M. 2025; 15 (1): 32010

  Abstract

  Pediatric high-grade gliomas (pHGG) are highly invasive with poor survival outcomes. Timing of Temozolomide administration has been shown to affect survival of adult patients with glioblastoma. We investigated whether pHGGs express circadian genes rhythmically and whether underlying rhythms affect Temozolomide sensitivity. Circadian gene expression in pediatric gliomas was analyzed using PedcBioPortal. Immunoblotting was used to assess protein levels in patient-derived pHGG lines and in high- and low- grade (pLGG) glioma specimens. Rhythmic gene expression in pHGG lines was measured via qPCR, and Temozolomide efficacy was tested during peak versus trough Bmal1 expression. Patient data revealed significantly different mRNA expression in multiple circadian genes between pHGGs and pLGGs, including higher Bmal1 expression in pHGG specimens and lower Rev-Erbα expression. Significantly higher BMAL1 and CLOCK protein levels and lower REV-ERBα were present in pHGG versus pLGG tissue specimens. Our three pHGG lines displayed rhythmic Bmal1 and Rev-Erbα expression post-synchronization. We found significantly decreased proliferation when Temozolomide was applied during trough versus peak Bmal1 expression. The positive arm of the circadian clock appears upregulated in pHGGs compared to pLGGs. Pediatric HGGs rhythmically express circadian genes and exhibit differential Temozolomide sensitivity based on timing of administration.

  View details for DOI 10.1038/s41598-025-17461-9

  View details for PubMedID 40887493

  View details for PubMedCentralID 6395056

• Health care utilization among Medicare beneficiaries with newly diagnosed back pain. North American Spine Society journal Barros Guinle, M. I., Johnstone, T., Ruiz Colón, G. D., Weng, Y., Nettnin, E. A., Ratliff, J. K. 2024; 20: 100565

  Abstract

  Low back pain (LBP) is the most common medical cause of disability among adults 65 or older. No previous study has characterized health care costs and treatment patterns of LBP among Medicare beneficiaries.This retrospective cohort study quantifies health care utilization costs among Medicare beneficiaries with newly diagnosed LBP, compares costs between patients managed operatively and nonoperatively, identifies costs associated with treatment guideline nonadherence, and characterizes opioid prescribing patterns. Patients were queried via ICD codes from a 20% random sample of Medicare claims records. Patients with concomitant or previous "red flag" diagnoses, neurological deficits, or diagnoses that could cause nondegenerative LBP were excluded. Total costs of care in the year of diagnosis were calculated and stratified by operative versus nonoperative management. To assess for guideline adherence, utilization and costs of different services were tabulated. Opioid prescription patterns were characterized by quantity, cost, duration, and medication type.About 1,269,896 patients were identified; 23,919 (1.8%) underwent surgery. These accounted for 7% of the cohort's total cost ($514 million total, $21,496 per person). Patients treated nonoperatively accounted for over $7 billion in costs ($5,880 per person; p<.001). Within the nonoperative cohort, 626,896 (50.3%) patients were nonadherent to current guidelines for conservative management of LBP. Guideline nonadherence increased total annual costs by $4,012 per person ($7,873 for nonadherent vs. $3,861 for adherent patients, p<.001). About 460,867 opioid prescriptions were filled for 303,796 unique patients (23.9%) within 30 days of LBP diagnosis. Within the nonsurgical cohort, patients nonadherent to imaging guidelines were more likely to have an opioid prescription within this window than adherent patients (26.5% vs. 21.2%; p<.001).Nonoperative management of LBP is associated with significantly lower costs per patient. Early imaging and opioid prescription are significant drivers of excess cost. Adherence to proposed treatment guidelines can save over $2.8 billion in total health care costs.

  View details for DOI 10.1016/j.xnsj.2024.100565

  View details for PubMedID 39670143

  View details for PubMedCentralID PMC11636345

• THE ROLE OF MAP4K4 IN TUMOR CELL INVASION OBSERVED IN A 3D IN VITRO MODEL OF PEDIATRIC GLIOBLASTOMA Garcia, C., Nettnin, E., Arana, S., Nguyen, T., Guinle, M., Wilson, C., Petritsch, C. K., Bassik, M. C., Prolo, L. M. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.0226

  View details for Web of Science ID 001362572400036

• PEDIATRIC GLIOMAS EXPRESS CIRCADIAN GENES AND DEMONSTRATE CIRCADIAN REGULATION OF TEMOZOLOMIDE SENSITIVITY Nettnin, E. A., Garcia, C. A., Schonfeld, E., Mehl, L. C., Guinle, M., Petritsch, C. K., Gibson, E. M., Prolo, L. M. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.0157

  View details for Web of Science ID 001362582300007

• CDC42BPA::BRAF represents a novel fusion in desmoplastic infantile ganglioglioma/desmoplastic infantile astrocytoma. Neuro-oncology advances Barros Guinle, M. I., Nirschl, J. J., Xing, Y. L., Nettnin, E. A., Arana, S., Feng, Z. P., Nasajpour, E., Pronina, A., Garcia, C. A., Grant, G. A., Vogel, H., Yeom, K. W., Prolo, L. M., Petritsch, C. K. 2024; 6 (1): vdae050

  View details for DOI 10.1093/noajnl/vdae050

  View details for PubMedID 38741773

  View details for PubMedCentralID PMC11089409

• Review: therapeutic approaches for circadian modulation of the glioma microenvironment. Frontiers in oncology Nettnin, E. A., Nguyen, T., Arana, S., Barros Guinle, M. I., Garcia, C. A., Gibson, E. M., Prolo, L. M. 2023; 13: 1295030

  Abstract

  High-grade gliomas are malignant brain tumors that are characteristically hard to treat because of their nature; they grow quickly and invasively through the brain tissue and develop chemoradiation resistance in adults. There is also a distinct lack of targeted treatment options in the pediatric population for this tumor type to date. Several approaches to overcome therapeutic resistance have been explored, including targeted therapy to growth pathways (ie. EGFR and VEGF inhibitors), epigenetic modulators, and immunotherapies such as Chimeric Antigen Receptor T-cell and vaccine therapies. One new promising approach relies on the timing of chemotherapy administration based on intrinsic circadian rhythms. Recent work in glioblastoma has demonstrated temporal variations in chemosensitivity and, thus, improved survival based on treatment time of day. This may be due to intrinsic rhythms of the glioma cells, permeability of the blood brain barrier to chemotherapy agents, the tumor immune microenvironment, or another unknown mechanism. We review the literature to discuss chronotherapeutic approaches to high-grade glioma treatment, circadian regulation of the immune system and tumor microenvironment in gliomas. We further discuss how these two areas may be combined to temporally regulate and/or improve the effectiveness of immunotherapies.

  View details for DOI 10.3389/fonc.2023.1295030

  View details for PubMedID 38173841

  View details for PubMedCentralID PMC10762863

• Review: therapeutic approaches for circadian modulation of the glioma microenvironment Fronteirs in Oncology Nettnin, E. A., Nguyen, T., Arana, S., Barros Guinle, M., Garcia, C. A., Gibson, E. M., Prolo, L. M. 2023: 1295030

  Abstract

  High-grade gliomas are malignant brain tumors that are characteristically hard to treat because of their nature; they grow quickly and invasively through the brain tissue and develop chemoradiation resistance in adults. There is also a distinct lack of targeted treatment options in the pediatric population for this tumor type to date. Several approaches to overcome therapeutic resistance have been explored, including targeted therapy to growth pathways (ie. EGFR and VEGF inhibitors), epigenetic modulators, and immunotherapies such as Chimeric Antigen Receptor T-cell and vaccine therapies. One new promising approach relies on the timing of chemotherapy administration based on intrinsic circadian rhythms. Recent work in glioblastoma has demonstrated temporal variations in chemosensitivity and, thus, improved survival based on treatment time of day. This may be due to intrinsic rhythms of the glioma cells, permeability of the blood brain barrier to chemotherapy agents, the tumor immune microenvironment, or another unknown mechanism. We review the literature to discuss chronotherapeutic approaches to high-grade glioma treatment, circadian regulation of the immune system and tumor microenvironment in gliomas. We further discuss how these two areas may be combined to temporally regulate and/or improve the effectiveness of immunotherapies.

  View details for DOI 10.3389/fonc.2023.1295030

  View details for PubMedCentralID PMC10762863

• Mobility and self-care outcomes in patients with a bariatric comorbidity during inpatient rehabilitation PM&R Bines, K., Strehlow, E., Gray, E., Nettnin, E., Stoff, L., Rafferty, M. R. 2024; 16 (5): 426-433

  Abstract

  First, we describe the characteristics and functional outcomes of obese and bariatric patients in an inpatient rehabilitation facility (IRF). Second, we assessed differences in functional outcomes for bariatric, obese, and standard weight body mass index (BMI) groups. Third, we explored whether these characteristics differ between time periods and diagnostic groups.A retrospective study comparing electronic medical record data collected in 2016 and 2018, using a repeated cross-sectional cohort design.IRF.Individuals ≥18 years of age diagnosed with brain injury, medical complexity, general neurology, orthopedic, spinal cord injury (SCI), and stroke. Participants grouped as standard (BMI <30 kg/m2), obese (BMI 30-39 kg/m2), and bariatric (BMI ≥40 kg/m2) weights. (N = 2015 in 2016, N = 2768 in 2018.) INTERVENTIONS: Patients received standard inpatient rehabilitation. In 2018, clinicians had access to new weight-appropriate equipment.Discharge destination; length of stay (LOS) by BMI group and medical diagnoses; item-specific functional independence measure (FIM) change scores.Sixty-four percent to 67% of all BMI groups achieved a home discharge. The bariatric BMI group had a longer LOS (21 days) than the standard or obese groups. There was a significant interaction in a linear regression analysis between diagnosis and LOS, where LOS was longer in medically complex patients with bariatric BMI (19.3 days compared to 16.1 days) but shorter in bariatric patients with SCI (20.6 days) compared to standard weight patients (26.2 days). In 2018, the bariatric BMI group had greater average FIM change scores for bathing, lower body dressing, toilet transfers, and bed transfers.Patient BMI is associated with LOS in the IRF, although affected by diagnosis. Patients with higher BMIs can make changes in specific individual motor FIM items. For patients with bariatric BMIs, FIM change scores were higher in 2018, possibly due to the use of equipment and facilities designed for higher weight capacities.

  View details for DOI 10.1002/pmrj.13079

  View details for Web of Science ID 001110550400001

  View details for PubMedID 37817058

• CDC42BPA::BRAF REPRESENTS A NOVEL FUSION IN DESMOPLASTIC INFANTILE GLIOMA Guinle, M., Nettnin, E. A., Nasajpour, E., Nirschl, J., Garcia, C. A., Vogel, H., Yeom, K., Prolo, L., Petritsch, C. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245400685

• Activity Monitoring in Parkinson Disease: A Qualitative Study of Implementation Determinants Fowler King, B., Macdonald, J., Stoff, L., Nettnin, E., Jayaraman, A., Goldman, J. G., Rafferty, M. LIPPINCOTT WILLIAMS & WILKINS. 2023: 189-199

  Abstract

  There is interest in incorporating digital health technology in routine practice. We integrate multiple stakeholder perspectives to describe implementation determinants (barriers and facilitators) regarding digital health technology use to facilitate exercise behavior change for people with Parkinson disease in outpatient physical therapy.The purposeful sample included people with Parkinson disease (n = 13), outpatient physical therapists (n = 12), and advanced technology stakeholders including researchers and reimbursement specialists (n = 13). Semistructured interviews were used to elicit implementation determinants related to using digital health technology for activity monitoring and exercise behavior change. Deductive codes based on the Consolidated Framework for Implementation Research were used to describe implementation determinants.Key implementation determinants were similar across stakeholder groups. Essential characteristics of digital health technology included design quality and packaging, adaptability, complexity, and cost. Implementation of digital health technology by physical therapists and people with Parkinson disease was influenced by their knowledge, attitudes, and varied confidence levels in using digital health technology. Inner setting organizational determinants included available resources and access to knowledge/information. Process determinants included device interoperability with medical record systems and workflow integration. Outer setting barriers included lack of external policies, regulations, and collaboration with device companies.Future implementation interventions should address key determinants, including required processes for how and when physical therapists instruct people with Parkinson disease on digital health technology, organizational readiness, workflow integration, and characteristics of physical therapists and people with Parkinson disease who may have ingrained beliefs regarding their ability and willingness to use digital health technology. Although site-specific barriers should be addressed, digital health technology knowledge translation tools tailored to individuals with varied confidence levels may be generalizable across clinics.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content available at: http://links.lww.com/JNPT/A436 ).

  View details for DOI 10.1097/NPT.0000000000000451

  View details for Web of Science ID 001069616800002

  View details for PubMedID 37306418

• Associations between exercise classes and self-reported exercise by people with Parkinson's disease at Parkinson's foundation centers of excellence CLINICAL PARKINSONISM & RELATED DISORDERS Nettnin, E., Burrows, S., Miao, G., Wu, S. S., Simon, D. K., Rafferty, M. R., Parkinson's Fdn Quality 2022; 6: 100137

  Abstract

  Despite evidence of the benefits of exercise, people with Parkinson's disease (PD) often exercise less than recommended. We sought to identify exercise class-related factors associated with the amount of exercise in PD communities.We used Parkinson's Outcome Project (POP) data from 3146 people with PD at 19 participating Centers of Excellence (COEs). POP data included self-reported moderate-vigorous exercise (MVE) hours, light physical activity (PA) hours, demographic and disease severity variables. We also collected information about weekly exercise class availability, intensity, cost, and distance from class location to the COE. We examined differences between COE-based and community-based exercise classes using the Akritas test for paired and unpaired samples. We tested associations between class characteristics and exercise hours based on a two-part model: logistic regression on whether a participant does MVE or light PA and linear regression for log-transformed time of exercise.Community-based exercise classes had a significantly higher weekly availability than COE-based classes (class hours per week: 47.5 ± 25.6 vs 6.5 ± 8.6, p < 0.001), a higher percentage of vigorous-intensity classes (24.2 ± 17.8 vs 11 ± 14.7, p < 0.001), and a broader geographic distribution (miles to COE: 12.8 ± 4.6 vs 6.2 ± 5.7, p < 0.001). Greater weekly hours of availability, intensity, and distance to COE were associated with increased MVE and light PA hours among participants who exercised (p < 0.01). Of these, higher weekly class availability explained the most variability in reported exercise hours.Parkinson's COEs may be able to increase exercise by facilitating a high weekly availability of exercise classes with higher intensity levels and broader geographical distribution.

  View details for DOI 10.1016/j.prdoa.2022.100137

  View details for Web of Science ID 001133960900019

  View details for PubMedID 35252834

  View details for PubMedCentralID PMC8892167

• Dorsal clock neurons in <i>Drosophila</i> sculpt locomotor outputs but are dispensable for circadian activity rhythms ISCIENCE Nettnin, E. A., Sallese, T. R., Nasseri, A., Saurabh, S., Cavanaugh, D. J. 2021; 24 (9): 103001

  Abstract

  The circadian system is comprised three components: a network of core clock cells in the brain that keeps time, input pathways that entrain clock cells to the environment, and output pathways that use this information to ensure appropriate timing of physiological and behavioral processes throughout the day. Core clock cells can be divided into molecularly distinct populations that likely make unique functional contributions. Here we clarify the role of the dorsal neuron 1 (DN1) population of clock neurons in the transmission of circadian information by the Drosophila core clock network. Using an intersectional genetic approach that allowed us to selectively and comprehensively target DN1 cells, we show that suppressing DN1 neuronal activity alters the magnitude of daily activity and sleep without affecting overt rhythmicity. This suggests that DN1 cells are dispensable for both the generation of circadian information and the propagation of this information across output circuits.

  View details for DOI 10.1016/j.isci.2021.103001

  View details for Web of Science ID 000698069100066

  View details for PubMedID 34505011

  View details for PubMedCentralID PMC8413890

• Frameworks for Parkinson's Disease Rehabilitation Addressing When, What, and How CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS Rafferty, M. R., Nettnin, E., Goldman, J. G., MacDonald, J. 2021; 21 (3): 12

  Abstract

  This review summarizes the evidence on rehabilitation for people with Parkinson's disease, including when to refer, what rehabilitation professionals should address, and how to deliver rehabilitation care.Clinical practice guidelines support physical therapy, occupational therapy, and speech-language pathology for Parkinson's disease. However, integrating guidelines into practice may be difficult. Implementation studies take into account patient and clinician perspectives. Synthesizing guidelines with implementation research can improve local delivery. There is moderate to strong evidence supporting physical therapy, occupational therapy, and speech-language pathology soon after diagnosis and in response to functional deficits. We propose a framework of three pathways for rehabilitation care: (1) consultative proactive rehabilitation soon after diagnosis for assessment, treatment of early deficits, and promotion meaningful activities; (2) restorative rehabilitation to promote functional improvements; and (3) skilled maintenance rehabilitation for long-term monitoring of exercise, meaningful activities, safety, contractures, skin integrity, positioning, swallowing, and communication.

  View details for DOI 10.1007/s11910-021-01096-0

  View details for Web of Science ID 000620091200001

  View details for PubMedID 33615420

  View details for PubMedCentralID PMC8215896