SCRIP: Scholarly Research In Progress 2023 by GeisingerCollege

Volume 7 • November 2023

Scholarly Research In Progress

Table of contents 2

Quality Estimation of Protein Modeling Techniques in CASP_Commons (SARSCoV-2) Using a StructureBased Functional Prediction Approach: ResiRole

Erin M. Welby, Jasleen Kaur, Brooke A. Ostrander, and Sadana R. Padmanabhan

The Efficacy of Axillary Reverse Mapping for the Prevention of Lymphedema

Respiratory Failure in an Infant with Rapidly Evolving Cutaneous Lesions: Sweet Syndrome

Reducing the Incidence of Delirium in Hospitalized Patients

Carly Deter, Bryan D’Ostroph, Megan Dowd, Adriana Feliz, Jay Ganesh, and Ujwal Tuladhar

Hungry for More? An Assessment of Nutrition Education in Geisinger’s Total Health Curriculum

Hydrocodone Prescriptions in 2020 in the Medicare Part D Population

The Importance of Diabetic Screening in Individuals with Down Syndrome

Quality of Life Changes in Stroke Rehabilitation: A Comprehensive Review

Evaluating Leadership Education Assessment Tools within Medical School Program Objectives and Leadership Frameworks

Joey Harmon and Yevgeniy Busarov

Alexa N. Simonetti and Hattie M. Shrock

Katherine Musto, Mark Mandak, Oluwaseyi Olulana, Clement Rajakumar, and Michelle Corrnacchia

A Current Review of Neurological Effects of Cryptococcal Meningitis Infection in HIV-Positive Individuals Taylor C. Gammell, Sofia Victoria Sowden, Mohammad Daniyal Syed, and Ashley D. Tapia

Declines in Influenza Vaccination Coverage in White and Black, Non-Hispanic Children from 2012–2019 to 2019–2022 Abigail L. Corle

Predicting Tracheal Airway Size in Adolescent Patients Jia Ying Zheng, BS, Vincent M. Desiato, MD, Shweta S. Kumar, MD, Aileen Wertz, MD, and Evan B. Young, MD

Monitoring Hand Hygiene Adherence Through the Perception of the Hawthorne Effect: An Observational Study in Hospital Settings Miranda Chen, Mira Patel, Alexis Notarianni, and Miranda Rep

Open Transforaminal Lumbar Interbody Fusion Surgery and Minimally Invasive Transforaminal Lumbar Interbody Fusion Surgery: An Overview of Patient Demographics Adam Cole and Frank Vazquez

Risks and Benefits of LASIK Surgery Jonelle J. James, Tamara A. Katz, Abigail N. Bielecki, and Bryne N. Cunningham

Textbook Oncologic Outcomes Among Pancreatic Cancer Patients Who Receive Neoadjuvant Versus Adjuvant Therapy Kevin Zhao, Gregory Wu, Katie Frank, Rebecca Lynn Hoffman, and Joseph Alfred Blansfield

Alexis Notarianni, Mahdi Taye, Karla Feeley, Matthew Hamers, Sireesha Mamillapalli, Gabi N. Waite, and Sonia Lobo

Assessment of Achievement Motivation in Surgical Subspecialty Residents Irene Cho, Paul A. Covello, Joel Klena, Joseph Desantis, Matthew Meissner, and Rebecca L. Hoffman

Raymond A. Stemrich, Gabriel Brutico, Abhay Metgud, and Lindsay M. Dittman

Autoimmune Hemolytic Anemia Without Overt Signs of Hemolysis Jenna Rabadi, Raymond A. Stemrich, Queeneth Uwandu, and Habib Hamoud

Amanda E. Ruffino, Joshua D. Madera, Makayla M. Dearborn, and Jacqueline C. Oxenberg

Conflict of Interest Reporting in a Surgical Journal John P. McDonald, Ara Khoylyan, Kevin Lynch, and Brian J. Piper

Geoffrey J. Huang and William A. McLaughlin

Exercise-induced Neuroplasticity: A Therapeutic Strategy for Alzheimer’s Disease, Parkinson’s Disease, and Stroke Recovery

Deven Appel, Srivastava A. Kodavatiganti, Andrea DiMattia, and Ian McCoog

Evaluating the Use of Theatre to Decrease Depression and Anxiety Among Adolescents with Chronic Medical Conditions Maura M. Sheehan, Jennifer Agwagom, and Karen A. Ephlin

101 Increase in GHB Prescriptions and Their Cost for CHIP/ Medicaid and Medicare Part D Patients Josephine R. Barnhart, Sondra A. Vujovich, and Brian J. Piper

107 Therapeutic Advantages of Mirogabalin and Pregabalin Over Current Treatments for Chemotherapy-Induced Peripheral Neuropathy Shannon E. Harmon, Esther O. Maidoh, Emmanuel C. Megafu, and Elisabeth Point Du Jour

115 A Presentation of PRES with Rapid Cortical Enhancement Caused by Hypertension Secondary to Structural Renal Abnormalities Joshua Quach, Rachel Gifeisman, and Suman Kaza

118 Neurotoxic and Behavioral Effects of Prenatal Ketamine Exposure: A Literature Review Mariam Sy

121 A Cost Comparison of Two Commonly Used Techniques for Revision Total Knee Arthroplasty Carly Deter, Jessica Koshinski, Logan SanCraint, and James E. Murphy

123 2024 Summer Research Immersion Program 124 Medical Research Honors Program 125 Finding your way: Opportunities for student funding

A message from the editor-in-chief I am delighted to welcome you to the seventh edition of the Journal of Scholarly Research in Progress (SCRIP). It is an honor and a privilege to introduce you to this latest compilation of scholarly work, a testament to the dedication and passion of our talented students at Geisinger College of Health Sciences. In this edition, we continue to emphasize the crucial role that scholarship plays in the development of our future medical professionals. The ability to communicate effectively through the written word is not just a skill, but a cornerstone of academic and professional success. I believe that nurturing these skills in our students empowers them not only to convey their research findings with clarity and accuracy, but also to advocate for their patients and engage with the broader medical community effectively. Additionally, as we navigate the ever-evolving landscape of scholarship, we cannot ignore the transformative influence of artificial intelligence (AI). AI has revolutionized research, aiding in data analysis, literature reviews, and even assisting in the writing and editing process. This year’s SCRIP cover is an artistic rendition of the themes covered in the manuscript by Huang and McLaughlin. It was created via an AI image-generation software called MidJourney and seeks to capture the intricacies of comparing protein structures at the atomic level. While AI can accelerate certain aspects of research, it underscores the importance of human intellect, creativity, and ethical judgement in the research process. I would like to extend my appreciation to the dedicated students who have contributed their research, the mentors who have guided them, our reviewers, and members of our marketing, communications, and design team who play a pivotal role in SCRIP’s final production. It is my hope that this journal, with its focus on student research, embodies the spirit of inquiry and scholarly excellence that aligns with Geisinger College of Health Sciences strategic plan to transform health through research, inspiration, value, and education. Suggestions from our contributors and readers to further develop and/or improve the journal are more than welcome; if you would like to share your thoughts, please email me at slobo1@geisinger.edu. Sincerely,

Sonia Lobo, PhD Editor-in-Chief

Student editors Carolyn Young, MD Class of 2026 Christopher Manko, MD Class of 2025 Niraj Vyas, MD Class of 2024 Jaclyn Podd, MD Class of 2024 Saishravan Shyamsundar, MD Class of 2023 Marketing, Communications, and Design Jessica L. Martin, Managing Editor Geisinger Marketing & Communications Heather M. Davis, MFA Director, Marketing & Communications Shannon Lesniak Graphic Designer Acknowledgments SCRIP would not be possible without the contributions of faculty and student volunteers committed to the review and assessment of submitted articles. Their feedback provides student authors with an opportunity to strengthen their writing and to respond to critiques. We gratefully acknowledge the following faculty members for their support in providing peer review. Mark White, MD, MPH Tierney Lyons, MLS Christian Carbe, PhD Michelle Schmude, EdD, MBA Youngjin Cho, PhD Elizabeth Kuchinski, MPH Michael Sulzinski, PhD Amanda Caleb, PhD Igor Danelisen, MD, MSc, PhD, MBA John A. Arnott, PhD Brian Piper, PhD Jennifer Boardman, PhD Cyamatare Felix Rwabukwisi, MD, MPH Youssef Soliman, MD, PhD William McLaughlin, PhD Kimberly Miller, PharmD Renee Frank, MD Saishravan Shyamsundar, MD Lakshmi IIango Thomas Buerkert Marina Hierl Nitya Deshmukh Ara Khoylyan Matthew Dzeda Jonathan Kerr Office of Research & Scholarship MSB, Suite 2024, 2nd Floor West 570-504-9662 Sonia Lobo, PhD, RYT Associate Dean for Research & Scholarship Professor of Biochemistry

Volume 7 • November 2023

Scholarly Research In Progress

On the cover: This is an artistic rendition of the themes covered in the manuscript by Huang and McLaughlin on page 2. The image was created via an AI image-generation software called MidJourney and seeks to capture the intricacies of comparing protein structures at the atomic level. All rights to the images created by users are owned by the users themselves. go.geisinger.edu/midjourney

Michele Lemoncelli Program Coordinator, Research & Scholarship Tracey Pratt, MPH Manager, Research Education Resources Laura E. Mayeski MT(ASCP), MHA Manager, Research Compliance

Scholarly Research In Progress • Vol. 7, November 2023

Quality Estimation of Protein Modeling Techniques in CASP_Commons (SARSCoV-2) Using a Structure-Based Functional Prediction Approach: ResiRole Geoffrey J. Huang1† and William A. McLaughlin1 Geisinger Commonwealth School of Medicine, Scranton, PA 18509 Doctor of Medicine Program Correspondence: ghuang@som.geisinger.edu

1 †

Abstract Model quality estimation is essential to the field of protein structure prediction through computational methods. Our technique, ResiRole, rates model quality principally based on preservation of the structural characteristics of protein functional sites between the model and the target. ResiRole is a method that uses basic statistical techniques to allow for an unbiased, quantitative measure of structure model quality by implementing a machine learning program called FEATURE. CASP is a biannual protein modeling competition where various research teams in the field of protein structure prediction compete against each other to produce three-dimensional (3D) models of protein structure given only the primary sequence. In this study, we applied ResiRole to the protein structure models available through CASP_Commons related to the SARS-CoV-2 proteome. A statistical analysis was conducted by calculating the difference in the cumulative probabilities for each functional prediction model (SeqFEATURE model) with the corresponding cumulative probability of the same functional site prediction model in the target protein to generate a “difference” score. We then globally averaged the difference scores obtained for each structure prediction technique, using the value obtained as a metric to rank the accuracy of these techniques. On a limited dataset, we showed that average difference score (ADS) correlates well with existing methods of protein quality assessment used for CASP. We also showed that ADS is sensitive enough to detect quality differences between the primary and secondary structure prediction attempts by each structure prediction technique submitted to CASP_Commons. A similar study is currently being conducted on CASP15 (2022) to provide a larger dataset to achieve more generalizable results.

Introduction Protein structure prediction by computational methods requires accurate means to assess the quality of modeled protein structures. Using techniques such as X-ray crystallography, which can solve protein structures up to as high as 1.5 Å resolutions, many quality estimation techniques that use the experimentally determined protein structure to benchmark modeling accuracy have been developed. A non-exhaustive list of common methods of protein quality estimation currently used include root-mean-square deviation (14), template modeling score (15), global distance test total score (GDT-TS) (17), contact area difference score (16), Local Distance Difference Test (LDDT) (13), and SphereGrinder (5). Many of these techniques rely on a 3D superposition of the modeled structure and the reference structure, which is also called the “target” or “experimentally determined”

structure. Simplified, subsequent calculation of a distance difference between backbone atoms (i.e., α-carbons) or sidechain atoms is often used as a proxy for measuring protein structure model quality. Other techniques, such as ResiRole (10), approach quality estimation of protein models from a different perspective. ResiRole approaches quality estimation from the perspective of preserving protein function using a program called FEATURE [see Altman et al. (2)], which is a program that uses data with information containing hydrogen bonding patterns, ionic bonding interactions, hydrophobicity, and other variables to determine the probability of existence of a functional motif, such as a calcium binding site, in the given protein. ResiRole differs from such conventional techniques by incorporating a structure-based functional prediction approach, where model quality is judged based on the tendency of a model to preserve their functional motifs compared to the target protein. Other quality estimation techniques, such as QMEANDisCo (9), measure model quality without requiring knowledge of the experimental structure, but we do not discuss their impact here. In the biannual CASP experiment, the experimental structures and quality analysis of these proteins are not given to the researchers until after all submissions have been received to ensure the fidelity of the competition. There is also a comparable weekly competition that ResiRole has already been applied to where the accuracy of protein models is evaluated via the Continuous Automated Model EvaluatiOn (CAMEO) project (7). Here we conduct a study of the comparison of the quality of protein modeling techniques used in CASP Commons to build SARS-CoV-2 protein models using ResiRole, analyzing only the proteins whose experimental structures are currently available through the Protein Data Bank (PDB). Only two of the seven released whole protein targets had solved experimental structures, and we limited our analysis to these two proteins. These two proteins are the ORF3a ion channel and the ORF8 accessory protein, possibly involved in immune evasion (1). In the biannual CASP experiment, the experimental structures and quality analyses of the proteins are not given to the researchers until after all submissions have been received to ensure the fidelity of the competition. Five modeling attempts are allotted for each team participating in CASP per protein structure. There is also a comparable weekly competition that ResiRole has already been applied to where the accuracy of protein models is evaluated via the Continuous Automated Model EvaluatiOn (CAMEO) project (7). In this study, we conducted a comparison of the quality of protein modeling techniques that were used in CASP_Commons (3), which was an extension of the CASP14 experiment. The target sequences of CASP_Commons are all from the SARS-CoV-2 proteome.

Quality Estimation of Protein Modeling Techniques in CASP_Commons (SARSCoV-2)

We used the ResiRole method to analyze only the protein targets whose experimental structures are currently available in the Protein Data Bank (PDB) (12). At the time of our study, only two of the seven released whole protein targets had solved experimental structures, and we limited our analysis to these two proteins as test cases. These two proteins are the ORF3a ion channel and the ORF8 accessory protein, which is a protein possibly involved in immune evasion (1). As part of the ResiRole method, the FEATURE program was used to extract and analyze hydrogen bonding patterns, ionic bonding interactions, hydrophobicity, and other variables to determine the probability of existence of a functional motif, such as a calcium binding site, in the given protein. FEATURE uses machine learning techniques trained on known protein data sets to create submodels that capture spherical microenvironments around selected atoms in a protein to predict the presence or absence of various functional site motifs. Using FEATURE, ResiRole differs from conventional techniques by incorporating a structure-based functional site prediction approach, where model quality is judged based on the tendency of a model to preserve the structural characteristics of the predicted functional sites in the models compared to the reference structures. Other quality estimation techniques, such as QMEANDisCo (9), measure model quality without requiring knowledge of the experimental (reference) structure, but we do not discuss their roles in quality estimation here.

Methods

and standard deviation of the raw FEATURE scores for each functional prediction model. Assuming that these scores are normally distributed, we converted our FEATURE raw scores to Z-scores. Only those functional site predictions that had a Z-score greater than the Z-scores corresponding to specificity levels of at least 90% for the SeqFEATURE models for the reference structures were included based on the receiver operating characteristic curve analysis by Toth et al. (10). Using Z-scores, we calculated a measure of cumulative probability for the existence of a particular functional site in both the modeled protein structure and the experimentally determined protein structure. The difference between those cumulative probabilities was then averaged across all functional prediction models of to achieve an ADS, which we used as a measure of the quality of the corresponding protein structure prediction technique. We used Open-PBS, an open-source job scheduler to manage the large volume of script-runs needed to perform our data analysis. CASP publicly provides quality estimation and assessment results on their website (https://predictioncenter. org/) for the solved SARS-CoV-2 protein targets which we obtained to compare ResiRole with other established methods of protein structure quality estimation.

Results An empirical demonstration of the value of our functional site prediction-based protein quality estimation technique was conducted using the protein visualization software Chimera (6). By identifying an atom selected by a SeqFEATURE model with a relatively high difference score, we can visualize the structural differences between a model and the reference structure by superposing the model and reference structure. In the image produced, we zoomed in around the atom or residue of interest. Figure 1 illustrates the result of such a demonstration. Here we identified a region corresponding to a relatively large difference score. In the illustration, we then see a difference in both 3D and hydrogen bond structure illustrating ResiRole’s ability to identify and properly rank areas of structural mismatch.

Many of the scripts and programs used in this study were designed using the CentOS or Rocky Linux operating system, and they were implemented to run on CAMEO data [see Toth et al. (10)]. Modifications and additions to the programs were made for the purposes of restructuring the code to account for different input data from CASP. Data containing information about each protein model and their corresponding experimental structure first needed to be downloaded from the CASP public website and sorted into a library of directories using Python. Then, we ran the FEATURE program on all the 3D coordinate files. The FEATURE program works by first deciphering atoms of interest for a particular functional site prediction model. FEATURE then outputs a raw score based on how likely a spherical microenvironment around the atom of interest describes a particular SeqFEATURE functional site (11). FEATURE selects atoms and constructs their functional site prediction models using data from Figure 1. The figure depicts a ribbon-style superposition by RMSD of AlphaFold’s protein structure model established sequence-based (brown) onto the experimentally determined structure of chain A of SARS-CoV-2 ORF3a (blue) (PDB ID: functional motif mapping 6XDC). The figure focuses on a 20-residue range around GLU 194 (purple) in both structures. The blue lines initiatives such as PROSITE indicate paths containing hydrogen bonds. GLU 194 was identified by ResiRole to have a high magnitude (8). Using an expansive library difference score (83.73%) by FEATURE functional prediction model BETA AMYLASE 2.5.GLU.OE2. Note of data, covering an extensive the absence of the helical motif in the target structure that is present only in the model. Molecular graphics portion of the PDB, Toth et and analyses performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, al. (10) calculated the mean and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311 (6).

Quality Estimation of Protein Modeling Techniques in CASP_Commons (SARSCoV-2)

To show the relationship between ResiRole and other already established methods of protein quality estimation, we analyzed the trend between ADS and LDDT. LDDT is a widely used measure of protein model quality that is a superposition-free score that evaluates local distance differences of all atoms in a model, including validation of stereochemical plausibility, with respect to a reference structure (4). Figure 2 demonstrates that ADS has a significant correlation with LDDT, with AlphaFold ranking best from the perspective of ADS. A similar analysis and result were obtained when comparing ADS and GDT-TS, but not shown here. Because the CASP experiment allows for the submission of multiple protein structure prediction attempts, we performed an analysis comparing the quality of models submitted in each group’s first attempt with each group’s corresponding second attempt. Under the assumption that groups submitted their best models for their first attempt, we demonstrate both ADS and LDDT averages are consistent with this trend. Notably, a t-test conducted at α=.05 between mean average difference score (MEADS) of groups’ attempt 1 and attempt 2 submissions show a statistically significant difference, shown in Figure 3A. However, the same test does not show a statistically significant difference in the mean LDDT (MLDDT) scores of groups’ attempt 1 and attempt 2 submissions, shown in Figure 3B. If our original assumption is valid, we may infer that ADS performed better than LDDT in discerning the relative intentional quality of protein models between each group’s attempt 1 vs. attempt 2 submissions made to CASP_Commons. That is, if we assume the structure prediction group intended the model for attempt one to be of higher accuracy than model submitted for attempt 2, ADS could detect that quality difference. ADS can thereby inform CASP modeling groups about the degree to which their accuracy differed or was improved for their first attempt model compared to their second attempt model.

Discussion There is a need in the field of protein quality estimation to generate techniques that evaluate the quality of protein models based on metrics that are representative of protein similarity. Such techniques need not be purely distance dependent. A comparison of the efficacy of ResiRole with that of traditional protein quality estimation methods would be useful to guide the development of improved protein modeling techniques, especially since many protein modeling groups modify their programs to optimize quality estimation scores. The QR code provided in Figure 4 provides a link to our website showcasing ResiRole’s application to CAMEO. To further establish the validity of our technique in assessing protein model quality, we are currently conducting an extensive application of ResiRole to CASP15 data. CASP15 data contains experimental information from the most up-to-date modeling techniques as applied to a large variety of proteins found in nature. This larger set of data will allow us to test and rank the estimated accuracies of various protein structure prediction techniques more rigorously. Additionally, we will perform an outlier analysis and a headto-head comparison between modeling groups regarding the accuracies of their techniques using ResiRole.

Conclusion We intend to help identify the most accurate modeling techniques, as well as apply our methods to evaluate existing forms of protein quality estimation. Properly ranking the accuracy of each structure prediction technique will inform studies that require knowledge of which models of protein targets are the most reliable and accurate. These models could then be used in applications that include structure-based drug design as the structure model with the highest estimated accuracy would be identified for the research team.

Figure 4. QR code accessing the ResiRole website: https://protein.som.geisinger. edu/ResiRole

Figure 2. Average Difference Score vs. Local Distance Difference Test (LDDT). The figure depicts a scatter plot of the average difference scores across all SeqFEATURE models compared to the average LDDT scores for all protein structure model submission attempts. Each point corresponds to a unique protein prediction group (not all group names shown). The average difference score is calculated as |Probmodel − Probtarget|. Note the descending values of the x-axis, with a lower ADS corresponding to a better model. Three group names which likely represent outliers to the relationship are shown. *The p-value of the F-statistic for the linear regression was calculated to be 2.30441 * 10−8, despite the shown value of R2.

Quality Estimation of Protein Modeling Techniques in CASP_Commons (SARSCoV-2)

Figure 3. (A) Attempt 1 vs. Attempt 2 Model Quality by Mean Average Distance Score (MEADS). The graph in (A) depicts a comparison between MEADS across all attempt 1 models vs. all attempt 2 models across all modeling groups for both SARS- CoV-2 protein targets addressed in the study. (B) Attempt 1 vs. Attempt 2 Model Quality by Mean Local Distance Difference Test (MLDDT). The graph in (B) depicts a comparison between mean local distance difference test (MLDDT) scores across all attempt 1 models vs. all attempt 2 models across all modeling groups for both SARS-CoV-2 protein targets. Only groups that submitted at least 2 modeling attempts for each SARS-CoV-2 protein target were considered for calculating MLDDT. Error bars show one standard deviation around the mean. Standard deviation for the MEADS was calculated from ADS data, and it does not show the high variance of individual difference scores that occur as a result of the nature of the FEATURE program (10). *The p-values shown are calculated from a two-tailed paired t- Test at α = .05.

Acknowledgments We thank Thomas K. Parry for preparing an updated pipeline of the data analyses scripts as applied to CAMEO data which enabled the project to use the current computing environment. This research was funded in part by the National Institute of General Medical Sciences, grant number 5U01GM093324-02.

Mariani V, Biasini M, Barbato A, Schwede T. lddt: a local superposition-free score for comparing protein structures and models using distance difference tests, Bioinformatics, 29 (2013), pp. 2722–2728.

Olechnovič K, Monastyrskyy V, Kryshtafovych A, Venclovas Č. Comparative analysis of methods for evaluation of protein models against native structures, Bioinformatics, 35 (2018), pp. 937–944.

Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. Ucsf chimera—a visualization system for exploratory research and analysis, Journal of Computational Chemistry, 25 (2004), pp. 1605– 1612.

Robin X, Haas J, Gumienny R, Smolinski A, Tauriello G, Schwede T. Continuous automated model evaluation (cameo)—perspectives on the future of fully automated evaluation of structure prediction methods, Proteins: Structure, Function, and Bioinformatics, 89 (2021), pp. 1977–1986.

Sigrist CJA, Cerutti L, de Castro E, Langendijk-Genevaux PS, Bulliard V, Bairoch A, Hulo N. PROSITE, a protein domain database for functional characterization and annotation, Nucleic Acids Research, 38 (2009), pp. D161– D166.

References 1.

Flower TG, Buffalo CZ, Hooy RM, Allaire M, Ren X, Hurley JH. Structure of sars-cov-2 orf8, a rapidly evolving immune evasion protein, Proceedings of the National Academy of Sciences, 118 (2021), p. e2021785118.

Halperin I, Glazer DS, Wu S, Altman RB. The feature framework for protein function annotation: modeling new functions, improving performance, and extending to novel applications, BMC Genomics, 9 (2008), pp. 1–14.

Kryshtafovych A, Moult J, Billings WM, Della Corte D, Fidelis K, Kwon S, Olechnovič K, Seok C, Venclovas Č, Won J, et al., Modeling sars-cov-2 proteins in the casp-commons experiment, Proteins: Structure, Function, and Bioinformatics, 89 (2021), pp. 1987–1996.

Quality Estimation of Protein Modeling Techniques in CASP_Commons (SARSCoV-2)

Studer G, Rempfer C, Waterhouse AM, Gumienny R, Haas J, Schwede T. QMEANDisCo—distance constraints applied on model quality estimation, Bioinformatics, 36 (2019), pp. 1765–1771.

10. Toth JM, DePietro PJ, Haas J, McLaughlin WA, Resirole: residue-level functional site predictions to gauge the accuracies of protein structure prediction techniques, Bioinformatics, 37 (2021), pp. 351–359. 11. Wu S, Liang MP, Altman RB, The seqfeature library of 3d functional site models: comparison to existing methods and applications to protein function annotation, Genome Biology, 9 (2008), pp. 1–19. 12. Berman HM, et al. The protein data bank. Nucleic Acids Research 28.1 (2000): 235-242. 13. Mariani V, et al. LDDT: a local superposition-free score for comparing protein structures and models using distance difference tests. Bioinformatics 29.21 (2013): 2722-2728. 14. Carugo O, Pongor S. A normalized root-mean-square distance for comparing protein three-dimensional structures. Protein Science. 2001 Jul;10(7):1470-3. 15. Zhang Y, Skolnick J. Scoring function for automated assessment of protein structure template quality. Proteins: Structure, Function, and Bioinformatics. 2004 Dec 1;57(4):702-10. 16. Olechnovič K, Kulberkytė E, Venclovas Č. CAD-score: a new contact area difference-based function for evaluation of protein structural models. Proteins: Structure, Function, and Bioinformatics. 2013 Jan;81(1):149-62. 17. Zemla A. LGA: a method for finding 3D similarities in protein structures. Nucleic Acids Research. 2003 Jul 1;31(13):3370-4

Scholarly Research In Progress • Vol. 7, November 2023

The Efficacy of Axillary Reverse Mapping for the Prevention of Lymphedema Amanda E. Ruffino1†‡, Joshua D. Madera1†‡, Makayla M. Dearborn1†‡, and Jacqueline C. Oxenberg² ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 ²Department of General Surgery, Geisinger Wyoming Valley Medical Center, Wilkes-Barre, PA 18711 † Doctor of Medicine Program ‡ Authors contributed equally Correspondence: amandaruffino@gmail.com

Abstract Background: Lymphedema (LE) is the most notable complication of axillary surgery. The axillary reverse mapping (ARM) technique was created to decrease LE. This study aims to evaluate a single surgeon’s experience with ARM in patients undergoing sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) for breast cancer. Methods: We retrospectively analyzed 139 patients who underwent SLNB or ALND. Tumor characteristics and treatments received were evaluated. Surgical intervention and the use of ARM were compared to assess LE rates. A subgroup analysis was also performed of patients who underwent neoadjuvant chemotherapy (NAC). Results: LE was initially reported in 7.1% (n=10) of patients; 3.3% (n=4) with SLNB and 35% (n=6) with ALND. At initial follow-up, LE was reported 16.4% more often in patients who underwent ALND with no ARM, and 38.8% more often in patients who underwent ALND plus ARM. An increased risk of LE was found in patients treated with ALND (OR = 16.0, p < 0.001). All patients who underwent ARM were 12.75% more likely to develop LE if they received NAC (p < 0.05). Patients in the ALND group who also received NAC were more likely to undergo ARM as compared with patients in the SLNB group (p < 0.01). Conclusion: Our study found that ARM failed to decrease the incidence of LE. Until better surgical outcomes are shown for the prevention of LE using ARM, other approaches should be utilized. Future iterations might include larger prospective studies to better evaluate ARM.

Introduction Lymphedema (LE) continues to be an unfortunate comorbidity following axillary surgery for breast cancer and can significantly affect patients’ quality of life. While decades of research have endorsed deescalating the extent of axillary surgery, axillary sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) remain the standards of care for breast cancer (1–3). However, both procedures share a common notable complication of LE. The prevalence of LE ranges from 16.5–24.6% following ALND, and 3.7–7.5% following SLNB (4). Striving to reduce morbidity and improve patient outcomes, axillary reverse mapping (ARM) was introduced in 2007 as a promising technique to better discern arm lymphatics from the breast (5). Once the arm nodes were visualized and identified, preserving them helped prevent most LE (5–6). A systematic review by Ahmed et al. reported

LE rates ranging from 0–6% during ARM-assisted SLNB and 5.9–24% during ARM-assisted ALND (7). Realizing its benefit, this technique has been employed by many surgeons’ treating breast cancer, as well as scrutinized further. While several studies have already assessed the efficacy, oncologic safety, and LE outcomes regarding ARM (4, 7–11), it has been less studied in patients with locally advanced breast cancer who underwent neoadjuvant chemotherapy (NAC) (12–13). Its role in preventing LE has also not been well investigated. This is an important outcome to highlight as it will elucidate patients who are more likely to benefit from ARM. Therefore, this study aims to evaluate a single surgeon’s experience with ARM in patients undergoing either SLNB or ALND for breast cancer. We hypothesized that using ARM would decrease the rate of LE by allowing preservation or identification for the repair of lymphatics, even in the setting of NAC. However, our study findings showed that LE rates did not improve with the use of ARM.

Methods Appropriate IRB approval was obtained from the Geisinger Institutional Review Board and the study was determined to be exempt. A retrospective chart review was conducted for a single institution and a single surgeon for patients with nonmetastatic breast cancer undergoing either SLNB or ALND from December 2018 to October 2021. Patients were included if they had stages 0–3 breast cancer and were excluded if they underwent surgery for non-breast cancers, had distant metastatic disease or did not undergo axillary surgery. Patient and tumor characteristics obtained included age at diagnosis, tumor type, tumor grade, clinical stage, pathologic stage, and hormone receptor status. Treatment characteristics evaluated included chemotherapy, radiation, type of breast surgery (mastectomy vs. breast conservation), type of axillary surgery (SLNB vs ALND), number of nodes removed, and number of nodes found with metastatic disease. Final definitive surgical procedure was utilized if multiple surgeries were performed. Sentinel node biopsy was defined by complete excision of nodes identified by periareolar injection of intraoperative lymphatic mapping via the use of technetiumlabeled sulfur colloid or lymphazurin blue. Axillary lymph node dissection was defined as dissection of axillary levels 1 and 2 lymph node basins with level 3 taken if clinically suspicious. Patients undergoing bilateral procedures were included and each side was analyzed separately given each axilla had its own individual risk.

The Efficacy of Axillary Reverse Mapping for the Prevention of Lymphedema

Intraoperative factors that were evaluated include the use of ARM, if ARM lymphatics were seen, if ARM lymphatics had crossover with either the sentinel node or axillary dissection nodes and if repair of the arm lymphatics was performed. ARM was performed via injection of 4–5 mL lymphazurin blue subcutaneously in the upper inner arm medial intramuscular groove for localization of the lymphatics draining the arm (14). ARM was only utilized if adequate uptake was found with the utilization of technetium-labeled sulfur colloid if SLNB was being performed. When ARM was utilized, blue nodes were still removed if they were mapped to be the sentinel nodes or in the area of axillary dissection and were labeled as crossover nodes. In the case of ALND after NAC, lymphazurin blue was not injected for ARM until adequate axillary sampling (at least the clipped node and/or 3 nodes sampled) were able to be performed. Repair of lymphatics was performed by reapproximation with interrupted 4-0 vicryl if possible (5–6). LE was measured during the first postoperative visit (defined as LE initially reported) and at the last follow-up visit (defined as patients’ last recorded office visit in their chart). While bioimpedance spectroscopy and arm circumference measurements were attempted for all patients as screening modalities for lymphedema, these were unable to be utilized uniformly for lymphedema screening, given the time period during COVID-19. Therefore, any lymphedema diagnosis was recorded (subclinical and clinical) but lymphedema at the time of the last follow-up included only patients with clinically significant (Stage 2 per ISL criteria) LE requiring interventions (compression sleeves, physical therapy, etc.) (15). Patients referred to physical therapy early were also recorded as some did undergo early interventions with compression sleeves. The date of the last follow-up and disease status were also recorded. A subset analysis was performed for patients who underwent ARM and those who underwent NAC. Descriptive statistics relating to patient, tumor, treatment, and surgery characteristics were calculated and presented. A combination of Wilcoxon rank sum tests, Fisher’s exact tests, and Pearson’s Chi-squared tests were used to test for associations between variables. Logistic regression models were created for the binary outcomes of lymphedema at initial followup and lymphedema at most recent follow-up using a variety of predictor variables. The backward selection procedure using Bayesian information criterion (BIC) was applied to identify simpler models from the full models. Results from these models were presented as odds ratios (ORs) and 95% confidence intervals (95% Cis). All p-values were two-tailed, and p < 0.05 was considered statistically significant. Analyses were performed using R Version 4.0.5.

Results A total of 140 breast/axillary surgeries were included in 139 patients (one had bilateral breast cancer). The median age of diagnosis for patients was 62.8 years old (IQR: 52-73 years old). The most common breast tumor type was invasive carcinoma of no special type (n=87) with 62.1%. Tumor characteristics including grade, clinical stage, and pathologic stage can be seen in Table 1. Sixteen patients (11.4%) had estrogen receptor negative (ER negative)/human epidermal growth factor receptor 2 (HER2) negative disease, 6 (4.3%) had ER negative/

Table 1. Patient and tumor characteristics of the study sample by use of ARM.

HER2 positive disease, 98 (70.0%) had ER positive/HER2 positive disease and 9 (6.4%) had ER positive/HER2 positive disease. Eleven patients had ductal carcinoma in situ (DCIS) with 9 ER+ and 2 ER-. NAC was the treatment for 15.7% of patients (n=22) and 12.1% (n=17) received adjuvant chemotherapy. Most (77.1%) patients received radiation therapy (n=108), while 22.9% of patients were not treated with radiation (n=32). 62.1% of patients

The Efficacy of Axillary Reverse Mapping for the Prevention of Lymphedema

Table 3. Intraoperative lymphatic findings with ARM for SLNB and ALND

Table 2. Patient and surgery characteristics of the study population by use of ARM

received breast conservation therapy (n=87) while 37.9% of patients received mastectomy alone (n=53). Most (87.9%, n=123) patients underwent SLNB, while 12.1% (n=17) patients underwent ALND. A median of 2 nodes were examined (range 1–28) with a median of 0 nodes positive (range 0–11). Patients were stratified based on the use of ARM (n = 80, 57.1%) vs. no ARM (n=60, 42.9%). Results of surgery characteristics and treatment differences can be seen in Table 2. No significant differences between the ARM and no ARM group were seen for surgery characteristics or types of treatment. Intraoperative lymphatic findings with ARM can be seen in Table 3. Of the 80 patients who received ARM, arm lymphatics were identified in 40.0% of patients (n=32). Overlap between arm lymphatics and sentinel or axillary dissection nodes was observed in 23.8% of the 80 patients (n=19). LE was initially reported in 7.1% (n=10) of all patients; 3.3% (n=4) with SLNB and 35.3% (n=6) with ALND. However, at a median follow-up of 15.7 months (range 8-20.3 months), only 4.3% (n=6) of all patients, 1.6% (n=2) with SLNB and 23.5% (n=4) with ALND, still had clinical signs of lymphedema or were still being treated (utilizing compression sleeves or seeing physical therapy). Median follow-up time was longer for the patients who did not undergo ARM (median 19.7 months (IQR 11.8-28.1) vs. 16.5 months (IQR 12.1-22.9), p = 0.041). No significant difference in lymphedema in the ARM vs. no ARM group was found (Table 4). Stratification by type of surgery revealed that patients who underwent ALND had a higher risk of experiencing LE as

Table 4. LE rates in ARM versus no ARM at initial and last follow-up

compared with SLNB at both initial and final follow-up visits. At the initial follow-up visit, LE was reported 16.4% more often in patients who underwent ALND with no ARM, and 38.8% more often in patients who underwent ALND plus ARM as compared to SLNB. Similarly, at the final follow-up visit, patients who underwent ALND plus ARM experienced LE 31.9% more often. In contrast, LE was reported 1.6% less often at the final follow-up visit in patients who underwent ALND with no ARM compared to the SLNB group. The logistic regression model for LE at initial follow-up with the eight predictors such as age at diagnosis, use of NAC, use of radiation, type of surgery, type of breast surgery, ARM used, number of regional lymph nodes examined, and number of regional lymph nodes positive did not reveal any significant explanatory variables associated with the development of LE (Figure 1, top). However, in a simpler model selected using backward selection with BIC, type of surgery (SLNB vs. ALND) was identified as a significant predictor with ALND patients having 15.95 times the odds (95% CI: 3.99-71.17) of presenting with lymphedema at initial follow-up than SLNB patients (Figure 1, bottom). In the logistic regression model for LE at most recent

The Efficacy of Axillary Reverse Mapping for the Prevention of Lymphedema

follow-up with the eight aforementioned predictors and LE reported at initial follow-up, only LE reported at initial follow-up was significantly associated with the outcome (Figure 2, top). Using the same backward selection procedure, LE reported at initial follow-up remained as the only significant covariate, with patients originally presenting with LE having 127 times the odds (95% CI: 16.74-2697.68) of presenting with LE at most recent follow-up than patients not originally presenting with lymphedema (Figure 2, bottom).

Examination of additional factors in all patients who underwent ARM revealed a 12.75% increase in the likelihood of LE development in those who received NAC as compared with those who did not (p < 0.05). Similarly, the presence of positive nodes in patients who underwent ARM led to the development of LE 30.2% more often than in patients with negative nodes (p < 0.05). However, no significant differences in LE rates were identified based on the use of radiation therapy or surgery type (mastectomy vs. breast conservation) patients received (p > 0.05). However, of those with LE who underwent ARM, 71.4% (n=5) had crossover nodes resected. Of patients with LE at last follow-up, 100% (n=5) had ARM lymphatics seen and had crossover nodes resected. Subgroup analysis of patients undergoing NAC can be seen in Table 5. The number of nodes removed ranged from 1 to 28 nodes (median of 5 nodes) with a median of 0 nodes positive (range 0–6). Rates of LE were similar between all patients who received NAC, regardless of the use of ARM or type of mastectomy (p > 0.05). However, patients in the ALND group who also received NAC were more likely to undergo ARM as compared with patients in the SLNB group (p < 0.01). This same trend was observed for the number of nodes examined and the number of positive nodes, such that patients who received NAC had increased ARM usage (p < 0.01).

Figure 1. Effects of demographics, clinical, and surgery characteristics on lymphedema at initial follow-up. Full model results (top) and simple model results (bottom) are shown as odds ratios and 95% confidence intervals (CIs).

Figure 2. Effects of demographics, clinical, and surgery characteristics on lymphedema at most recent follow-up. Full model results (top) and simple model results (bottom) are shown as odds ratios and 95% confidence intervals (CIs). 10

Discussion Our study showed that using ARM failed to decrease LE rates. While our findings are consistent with a systematic review published by Bakri et al., other studies have contradicted this (4, 7–8, 10). The muddled evidence has created a need for more conclusive studies, especially in the setting of advanced breast cancer. A study by Tummel et al. found objective lymphedema rates to be 6.9% in ALND and 1.2% in SLNB in patients whose arm nodes were successfully identified and preserved.10 Our overall LE rate with ARM was 7.1%, with 3.3% after SLNB and 35% after ALND. Moreover, evaluating the rate of LE following ARM in the setting of NAC or locally advanced breast cancer needed to be further assessed as varying evidence currently exists or has not been explored in this context (11, 16). Our subgroup analysis of all patients who received NAC revealed that patients who underwent ALND had increased rates of ARM usage. However, we found no significant differences in LE rates at follow-up visits when assessing all patients who received NAC. This suggests that

The Efficacy of Axillary Reverse Mapping for the Prevention of Lymphedema

Conclusion Until we can show better surgical outcomes for the prevention of LE using ARM, other approaches including radiation therapy as well as utilizing NAC to downstage locally advanced axillary disease should be utilized. However, larger prospective studies are needed to evaluate ARM as well as standardization and more widespread training for formal lymphatic repairs before the preservation of arm nodes can consistently reduce the incidence of LE in patients.

Disclosures The study authors reported no conflicts of interest.

References

Table 5. NAC subset analysis of patient and surgery characteristics, intraoperative lymphatic findings, and lymphedema rates stratified by the use of ARM

patients with locally advanced breast cancer, requiring NAC or more extensive axillary dissections, may not have benefited from ARM. Since a large percentage of patients with LE were found to have crossover nodes, this may support that ARM may predict who is at risk for LE, but also questions the efficacy of lymphatic repair. Prior studies have demonstrated that immediate lymphatic repair, known as lymphatic microsurgical preventive healing approach (LYMPHA), during axillary surgery is a promising and safe approach for preventing LE in a high-risk patient population (17–18). However, a more novel surgical technique has been created, known as Simplified-LYMPHA (S-LYMPHA), which repairs lymphatics without utilizing a microscope (19). Utilizing these surgical techniques in the immediate and/or delayed setting can be better explored to reduce the clinical significance and morbidity of LE. Limitations of this study include its small retrospective nature. Additionally, other factors such as body mass index (BMI) that can increase the risk for lymphedema were not included. Further, S-LYMPHA was not an adopted surgical approach to repair lymphatics and primary lymphatic repair was performed with simple reapproximation with a 4-0 vicryl.

Krag DN, Anderson SJ, Julian TB, Brown AM, Harlow SP, Ashikaga T, Weaver DL, Miller BJ, Jalovec LM, Frazier TG, Noyes RD. Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: Results from the NSABP B-32 randomised phase III trial. Lancet Oncol. 2007 Oct 1;8(10):881-8.

Lucci A, McCall LM, Beitsch PD, Whitworth PW, Reintgen DS, Blumencranz BW, Leitch AM, Saha S, Hunt KK, Giuliano AE. Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol. 2007 Aug 20;25(24):3657-63.

Donker M, van Tienhoven G, Straver ME, Meijnen P, van de Velde CJ, Mansel RE, Cataliotti L, Westenberg AH, Klinkenbijl JH, Orzalesi L, Bouma WH. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): A randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol. 2014 Nov 1;15(12):1303-10.

Bakri NA, Kwasnicki RM, Khan N, Ghandour O, Lee A, Grant Y, Dawidziuk A, Darzi A, Ashrafian H, Leff DR. Impact of axillary lymph node dissection and sentinel lymph node biopsy on upper limb morbidity in breast cancer patients: A systematic review and meta-analysis. Ann Surg. 2023 Apr 1;277(4):572-80.

Thompson M, Korourian S, Henry-Tillman R, Adkins L, Mumford S, Westbrook KC, Klimberg VS. Axillary reverse mapping (ARM): A new concept to identify and enhance lymphatic preservation. Ann Surg Oncol. 2007 Jun;14(6):1890-95.

Boneti C, Korourian S, Bland K, Cox K, Adkins LL, HenryTillman RS, Klimberg VS. Axillary reverse mapping: mapping and preserving arm lymphatics may be important in preventing lymphedema during sentinel lymph node biopsy. J Am Coll Surg. 2008 May 1;206(5):1038-42.

Ahmed M, Rubio IT, Kovacs T, Klimberg VS, Douek M. Systematic review of axillary reverse mapping in breast cancer. Br J Surg. 2016 Feb;103(3):170-8.

The Efficacy of Axillary Reverse Mapping for the Prevention of Lymphedema

Han C, Yang B, Zuo WS, Zheng G, Yang L, Zheng MZ. The feasibility and oncological safety of axillary reverse mapping in patients with breast cancer: A systematic review and meta-analysis of prospective studies. PLoS One. 2016 Feb 26;11(2):e0150285.

Bedrosian I, Babiera GV, Mittendorf EA, Kuerer HM, Pantoja L, Hunt KK, Krishnamurthy S, Meric-Bernstam F. A phase I study to assess the feasibility and oncologic safety of axillary reverse mapping in breast cancer patients. CA Cancer J Clin. 2010 Jun 1;116(11):2543-8.

10. Tummel E, Ochoa D, Korourian S, Betzold R, Adkins L, McCarthy M, Hung S, Kalkwarf K, Gallagher K, Lee JY, Klimberg VS. Does axillary reverse mapping prevent lymphedema after lymphadenectomy? Ann Surg. 2017 May 1;265(5):987-92. 11. Khandelwal R, Poovamma CU, Shilpy C, Prema M, Anthony P. Axillary reverse mapping: Is it feasible in locally advanced breast cancer patients?. Breast Dis. 2014 Jan 1;34(4):1515. 12. Yoon KH, Lim SM, Koo B, Kim JY, Park HS, Park S, Kim SI, Park BW, Cho YU. Conserving the lymphatics from the arm using fluorescence imaging in patients with breast cancer at high risk of postoperative lymphedema: A pilot study. Gland Surg. 2020 Jun;9(3):629. 13. Liu S, Wang N, Gao P, Liu P, Yang H, Xie F, Wang S, Liu M, Wang S. Using the axillary reverse mapping technique to screen breast cancer patients with a high risk of lymphedema. World J Surg Oncol. 2020 Dec;18(1):1-8. 14. Boneti C, Korourian S, Diaz Z, Santiago C, Mumford S, Adkins L, Klimberg VS. Scientific impact award: Axillary reverse mapping (ARM) to identify and protect lymphatics draining the arm during axillary lymphadenectomy. Am J Surg. 2009 Oct 1;198(4):482-7. 15. Executive Committee of the International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2020 Consensus document of the international society of lymphology. Lymphology. 2020;53(1):3-19. PMID: 32521126. 16. Gobardhan PD, Wijsman JH, van Dalen T, Klompenhouwer EG, van der Schelling GP, Los J, Voogd AC, Luiten EJ. ARM: Axillary reverse mapping–the need for selection of patients. Eur J Surg Oncol. 2012 Aug 1;38(8):657-61. 17. Johnson AR, Fleishman A, Granoff MD, Shillue K, Houlihan MJ, Sharma R, Kansal KJ, Teller P, James TA, Lee BT, Singhal D. Evaluating the impact of immediate lymphatic reconstruction for the surgical prevention of lymphedema. Plast Recon Surg. 2021 Mar 1;147(3): 373e-81e. 18. Lipman K, Luan A, Stone K, Wapnir I, Karin M, Nguyen D. Lymphatic microsurgical preventive healing approach (LYMPHA) for lymphedema prevention after axillary lymph node dissection—A single institution experience and feasibility of technique. J Clin Med. 2022 Jan;11(1):92. 19. Ozmen T, Lazaro M, Zhou Y, Vinyard A, Avisar E. Evaluation of simplified lymphatic microsurgical preventing healing approach (S-Lympha) for the prevention of breast cancer– related clinical lymphedema after axillary lymph node dissection. Ann Surg. 2019 Dec 1;270(6):1156-60. 12

Scholarly Research In Progress • Vol. 7, November 2023

Respiratory Failure in an Infant with Rapidly Evolving Cutaneous Lesions: Sweet Syndrome Raymond A. Stemrich1†, Gabriel Brutico1†, Abhay Metgud1†, and Lindsay M. Dittman1,2 ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 ²Geisinger Medical Center, Danville, PA 17822 † Doctor of Medicine Program Correspondence: rstemrich1@gmail.com

Abstract Acute febrile neutrophilic dermatosis, or Sweet syndrome, is an uncommon condition in adults and is especially rare in the pediatric population. Its low prevalence and variable clinical presentation in adult and pediatric patients often lead to delayed diagnosis and potential complications. This report presents a 10-week-old male with no significant history delivered via C-section after an uncomplicated pregnancy who developed persistent oral lesions. The lesions began to evolve rapidly, starting as small vesicles and becoming large, indurated, fluid-filled pustules spreading to the face, trunk, and extremities. Initial evaluation did not reveal a clear diagnosis and the patient decompensated quickly. Once intubated and in the PICU, a skin biopsy revealed neutrophilic infiltrates consistent with Sweet syndrome. After a prolonged admission and steroid therapy, the skin lesions improved, and the patient recovered to baseline. Although Sweet syndrome is rare with a wide variation in clinical presentations and disease course, it should be considered as a differential diagnosis for any patient presenting with rapidly evolving cutaneous lesions, especially in the absence of a clear etiology. A prominent feature of the condition is resolution with corticosteroid treatment and many patients improve following initiation of the therapy.

Introduction Acute febrile neutrophilic dermatosis, or Sweet syndrome (SS), is an uncommon condition that impacts both adult and pediatric patients. It is exceedingly rare in infants and children, with only a small number of cases reported in the literature (1, 2). The criteria for diagnosing Sweet syndrome are based on findings seen in the adult population, which are then extrapolated to the pediatric cases. Although useful for generation of differential diagnoses, there is significant variation between the adult and pediatric forms of the condition (1–3). New research suggests that the pediatric category should be further stratified into neonatal, infantile, and juvenile forms to account for the variable presentations seen in that patient cohort (3). The case below describes one clinical presentation of SS in a pediatric patient, highlighting an unexpected and severe respiratory complication.

Two weeks prior to his admission, the patient saw his pediatrician for vesicular lesions in his mouth and he was diagnosed with an unspecified viral illness. He was prescribed amoxicillin for a concurrent otitis media, which improved, but the oral lesions persisted and prompted an emergency department visit. He was diagnosed with hand, foot, and mouth disease. The rash worsened after discharge, spreading to his face, neck, and extremities, prompting the family to return to the emergency department. He also developed a low-grade fever (100.6°F) during this time. Per the family, the rash started as pinpoint “pimples” that rapidly grew and evolved into larger, firm lesions with yellow coloration. The initial lesions in his mouth were improving; however, the rash on his body continued to worsen. His mother reported that he appeared to be in discomfort during bottle and breast feedings and would only take about one ounce at a feeding as a result. On examination, his vitals were within normal limits. He had vesicular lesions on the soft palate. He had small vesicular and pustular lesions along the right upper eyelid, and lesions on his neck, face, hands, and lower extremities ranging from small vesicles or pustules to indurated, nodular, and umbilicated lesions, with the largest roughly 1.5 cm in size (Figure 1). Some of the lesions had surrounding erythema. The soles, palms, and diaper area were spared, and there was no noted desquamation. Initial laboratory findings included an elevated leukocyte count (18.8 K/uL) with an increased absolute neutrophil count (9.29 K/uL), and an elevated CRP (46 mg/L). The respiratory viral panel and early cultures were negative. Differential diagnoses were broad, including herpes simplex virus and bullous impetigo. Peripheral blood cultures and herpes simplex virus PCR were obtained from surfaces and serum. He was subsequently started on cefazolin, vancomycin, and acyclovir.

Case Presentation The patient is a 10-week-old male born at 40 weeks gestation via C-section for arrest of dilation. The pregnancy was uncomplicated with no maternal history of infections or significant medical conditions. He had neonatal hyperbilirubinemia, but he did not require phototherapy. Gastroesophageal reflux was the only issue noted after discharge and he received his 2-month vaccinations at approximately 6 weeks of age.

Figure 1. Vesicular/pustular lesions found on face, ankle, and hand. Mature lesions were firm and indurated with surrounding erythema. 13

Respiratory Failure in an Infant with Rapidly Evolving Cutaneous Lesions: Sweet Syndrome

Less than 12 hours after admission, the patient developed respiratory failure with rapid decompensation. He had tachycardia with heart rates >200 beats per minute and increased work of breathing as evidenced by intercostal and subcostal retractions and oxygen saturations as low as 70%. The patient had persistent hypoxia despite escalations in respiratory support from high-flow nasal cannula to CPAP and eventually BIPAP. His chest X-ray showed evidence of tracheal narrowing with bilateral apical atelectasis, but no parenchymal infiltrates. He was intubated without issue and transferred to the pediatric intensive care unit. A respiratory viral panel was completed and was negative. There the patient was noted to have severe anemia (hemoglobin 5 g/dL) and received a transfusion of packed red blood cells. His endotracheal tube was noted to have been plugged with a significant amount of blood. Laryngoscopy was performed, and there was no evidence of laryngeal lesions causing obstruction. A bronchoscopy was not performed. Laboratory testing did not reveal any etiology for the anemia, although a thorough evaluation was not conducted. The working theory was blood loss secondary to endotracheal tube placement; however, the procedure was completed without issue.

Within the pediatric population, the syndrome is associated with paraneoplastic disease (15–25% of cases), post-infectious entity (22–45%), or is labeled idiopathic without any recognized association (21–42%). In patients less than 3 months of age, immunodeficiencies, autoimmune diseases, and chronic conditions (i.e., neonatal lupus and metabolic disorders) can be associated with Sweet syndrome. In patients older than 3 months, association with infectious etiologies, such as viral illnesses, may be more likely (1–4). Pediatric Sweet syndrome is diagnosed using the same criteria as the adult population (Table1); however, the criteria do not always apply in the pediatric age group and clinical presentations vary widely (3). This case reports on an infant who initially presented with oral lesions, which are typically a rare clinical finding in the pediatric form of the syndrome. Mucosal involvement is reported in only about 5% of patients. Mucosal involvement has been associated with underlying hematologic malignancy in the adult population; however, no such association has been shown in the pediatric population (2, 3).

Major Criteria The patient was in the PICU for 5 days, was extubated after 4 days, and then 1. Abrupt onset of typical cutaneous lesions admitted to the pediatric unit for an 2. Predominantly neutrophilic infiltration of the dermis on biopsy additional 18 days. During this time, a skin biopsy was performed, which Minor Criteria revealed dermal papillary edema and 1. Preceded by associated infections, vaccinations, malignancies, inflammatory dense neutrophilic infiltrates, consistent disorders, drug exposures, or pregnancy with neutrophilic dermatosis. The 2. Presence of fever and consitutional signs and symptoms histopathology results and clinical picture 3. Leukocytosis, elevated ESR, positive CRP were consistent with Sweet syndrome. The patient was started on prednisolone 4. Significant response to systematic corticosteroids 1mg/kg BID with rapid subsequent ESR= Erythryocyte sedimentation rate CRP= C-Reactive Protein improvement in skin lesions. Once the *Must include both Major Criteria and at least 2 Minor Criteria pending cultures resulted as negative, all antibiotics and antiviral medications were discontinued. A peripheral blood smear, Table 1. Criteria to diagnosis Sweet syndrome* (Adapted from McClanahan et al., and full body MRI, dihydrorhodamine assay, Uihlein et al.) primary immunodeficiency panel, and autoimmune evaluation (including ANA, SS-A, SS-B, and U1-RNP) were ordered. This patient rapidly decompensated and developed respiratory The additional testing was negative, with the failure requiring intubation and mechanical ventilation. primary immunodeficiency panel indicating two Although the condition is often associated with a preceding variants of unknown significance. respiratory infection, true pulmonary Sweet syndrome has been reported in approximately 5% of pediatric cases with After 23 days of admission, the patient returned to his chest radiographs showing pulmonary infiltrates and perhaps baseline and was discharged home with close follow-up with visualization of lesions in the respiratory tract (3). Respiratory dermatology and endocrinology. His final diagnoses included symptoms typically present later in the disease, but can present classic (idiopathic) Sweet syndrome and iatrogenic adrenal both prior to and concurrent with the cutaneous lesions (3, 5). insufficiency secondary to lengthy steroid treatment. To date, In this patient, no signs of infiltrates were seen on chest X-ray systemic corticosteroids have continued to control disease and laryngoscopy did not reveal lesions in the upper respiratory activity and the patient has not developed any additional tract, but bronchoscopy was not done to evaluate the lower skin lesions. respiratory tract. The temporal relationship between the worsening of the patient’s skin lesions and the development of Discussion respiratory decompensation without any identifiable etiologies Sweet syndrome is a rare condition in the pediatric population, indicate that they were likely part of the same process. accounting for just around 5% of all occurrences, with male Regardless of age, the treatment, management, and surveillance patients less than 3 years of age more commonly impacted, of Sweet syndrome is similar. One hallmark of the condition is its in contrast to the female predominance in the adult form (2).

Respiratory Failure in an Infant with Rapidly Evolving Cutaneous Lesions: Sweet Syndrome

response to systemic corticosteroids, which typically resolves the cutaneous lesions rapidly after a tapered treatment. Management includes evaluation for associated malignancies, immunodeficiencies, autoimmune conditions, and inflammatory processes, especially in the pediatric population (1–3). Pediatric patients should also undergo cardiac evaluation, as complications may be silent but progress to fatal complications (1, 3). Finally, close monitoring by dermatology for exacerbation of cutaneous lesions are essential. This is particularly important in pediatric patients who have the greatest risk of recurrence and may develop refractory disease. A course of corticosteroids is the treatment of choice for flares of cutaneous lesions; however, to minimize the long-term effects of chronic steroid use, steroid-sparing therapies such as potassium iodide have proven effective (1–4).

Conclusion This case report highlights the variability in clinical presentation and course of Sweet syndrome, especially in the pediatric population. It is often not considered as a possible diagnosis due to the low prevalence of this condition in children. Delayed recognition may lead to significant complications. Although cases of pulmonary Sweet syndrome are noted in the literature, it is exceedingly rare, and often defaults as a diagnosis of exclusion without clear evidence of lesions in the airways. Nonetheless, it should be acknowledged as a potential complication and the care team should be prepared to manage an acute decompensation.

Disclosures The authors declare that there is no conflict of interest regarding the publication of this article.

References 1.

Nelson CA, Stephen S, Ashchyan HJ, James WD, Micheletti RG, Rosenbach M. Neutrophilic dermatoses: Pathogenesis, Sweet syndrome, neutrophilic eccrine hidradenitis, and Behcet disease. J Am Acad Dermatol. 2018;79(6):987– 1006.

Uihlein LC, Brandling-Bennett HA, Lio PA, Liang MG. Sweet Syndrome in Children. Pediatr Dermatol. 2012;29(1):38–44.

McClanahan D, Funk T, Small A. Sweet Syndrome in the Pediatric Population. Dermatol Clin. 2022;40:179–90.

Cohen PR. Sweet’s syndrome – a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007 Jul 26;2:34.

Arakaki R, Shofner JD, Kroshinsky D. An infant with pulmonary-cutaneous Sweet syndrome. J Pediatr. 2012;161(5):959–61.

Scholarly Research In Progress • Vol. 7, November 2023

Reducing the Incidence of Delirium in Hospitalized Patients Carly Deter1†‡, Bryan D’Ostroph1†‡, Megan Dowd1†‡, Adriana Feliz1‡, Jay Ganesh1†‡, and Ujwal Tuladhar2‡ ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 ²Geisinger Community Medical Center, Scranton, PA 18510 † Doctor of Medicine Program ‡ Authors contributed equally Correspondence: cdeter@som.geisinger.edu

Abstract Delirium is a condition characterized by attention, consciousness, and cognition alterations, affecting focus, attention shifting, and sustaining abilities. It is prevalent in older inpatients, with reports indicating 50–70% of patients age ≥65 years experience delirium. Complications range from falls and extended hospital stays to increased mortality and cognitive decline progression. Risk factors include underlying dementia, age ≥65, immobility, sensory impairment, and highrisk medication use. Sleep disturbance is a significant cause in hospitalized patients. Current strategies involve optimizing sleep, providing familiar objects, orientation, and promoting wakefulness. Delirium measurement is challenging; the Confusion Assessment Method (CAM) is commonly used. A study found 80% of high-risk patients at a community medical center developed delirium in the prior 3 months. The aim of the study was to reduce the incidence of acute delirium on the floors of this center by 10% over 3 months. Seventy-three patients at high-risk for delirium (based on age ≥65 and/or underlying dementia) were admitted between December 2022 and February 2023 and included in the study. Those with a pre-existing diagnosis of delirium were excluded. A CAM screen order was placed for these patients every 8 hours, and positive results triggered the implementation of a sleep protocol. The charts were reviewed to assess the impact of the sleep protocol on reducing delirium incidence, considering CAM screen results, sleep protocol utilization, and the occurrence of delirium. The data were analyzed based on CAM screen results, sleep protocol utilization, and the development of delirium. Patients were categorized into groups based on their CAM screen results positive, negative, or no record of CAM screening during hospitalization. Sixty-one of the 73 patients underwent CAM screening, while the remaining 12 patients had no record of a CAM result. Seven patients received a positive CAM screen, but the implementation of the sleep protocol varied among these patients. All 4 patients who had a positive CAM screening but did not receive a sleep protocol developed delirium. In contrast, out of the 54 patients with a negative CAM screen, only 6 developed delirium. The initiation of a sleep protocol for CAM-negative patients did not appear to affect the incidence of delirium development. The utilization of early CAM screenings and subsequent implementation of the sleep protocol demonstrated a reduction in delirium incidence among our study's patient population.

Introduction Delirium is a complex condition that profoundly affects attention, consciousness, and cognition, leading to impaired focus, attention shifting, and sustained attention. Its clinical

presentation encompasses a spectrum of symptoms, ranging from heightened psychomotor activity and behavioral disturbances to a state of reduced activity and disruptions in sleep patterns (1). Among older patients, age 65 years and above, who are hospitalized, delirium emerges as a highly prevalent issue, with reports indicating that approximately 50– 70% of them are affected by this condition (2). Delirium brings forth a multitude of complications, including increased risks of falls, prolonged hospital stays, elevated mortality rates within one year, and accelerated cognitive decline (2). Various factors contribute to the development of delirium, including underlying dementia, advanced age, immobility, sensory impairments, and the usage of high-risk medications such as benzodiazepines, sedatives, anticholinergics, and opiates (3). Sleep disturbance plays a significant role in the etiology of delirium among hospitalized patients, although the causes of delirium are diverse and multifaceted (2). Current strategies for managing delirium focus on optimizing sleep duration by minimizing interruptions, providing familiar objects and orientation cues such as hearing aids and glasses, and promoting wakefulness during the day through appropriate lighting and engaging activities. Nevertheless, the measurement of delirium remains complex due to the involvement of various contributing factors, making it challenging to ascertain its presence accurately. To address this, the Confusion Assessment Method (CAM) screening tool is commonly employed to identify patients with delirium during their hospitalization. A recent study conducted at a community medical center shed light on the prevalence of delirium within a 3-month period. Among a high-risk population, a staggering 80% of patients developed delirium, underscoring the urgency and significance of addressing this condition effectively.

Methods The study protocol has been approved and overseen by the Institutional Review Board (2022-0863) and was conducted in accordance with relevant guidelines and regulations of the IRB, including the Helsinki Declaration. During the period from December 2022 to February 2023, we conducted a study involving patients who were admitted to the medical-surgical floors at a community medical center and identified as high risk for delirium based on their age being greater than 65 and/or having underlying dementia. A total of 73 patients fitting the criteria for being "high-risk for delirium" were included in the study. Patients who already had an initial diagnosis of delirium prior to admission were excluded from the study to ensure a focused analysis.

Reducing the Incidence of Delirium in Hospitalized Patients

As part of the study protocol, a CAM screen order was implemented for these high-risk patients for screenings to be conducted every 8 hours and documented in the electronic medical record. If a patient received a positive CAM screen result, a sleep protocol order would then be issued for that individual. To assess the impact of the sleep protocol on delirium incidence, we thoroughly reviewed the patients' medical charts, examined the results of the CAM screenings and assessed whether a sleep protocol was initiated in response. Furthermore, the charts were assessed for any mention of delirium by a doctor or any formal diagnosis of delirium, utilizing specific search terms. For the purpose of analysis, the collected data was categorized into different groups: CAM positive (Yes or No), Sleep protocol (Yes or No), and the development of delirium (Yes or No). These groupings allowed for a comprehensive examination of the relationships between CAM screening results, sleep protocol utilization, and the occurrence of delirium within the patient population under study.

Results and Discussion The patients included in the study were categorized into different groups based on their CAM screen results those with at least one positive CAM screen (10%), those with at least one negative CAM screen and without any positive CAM screens (74%), and those with no record of CAM screening during their hospital stay (16%) (Table 1). Among the 61 patients who underwent CAM screening, the results of the CAM screens, the initiation of the sleep protocol, and the development of delirium were documented. Out of the 61 patients who received screening as ordered, 7 had a positive CAM screen, but the initiation of the sleep protocol occurred in only 3 patients (Figure 1). Two out of these 3 patients developed delirium (67%). All 4 patients who had a

Table 1. Rate of CAM screen recording, development of delirium, and sleep protocol

Figure 1. Outcomes in patients with positive CAM screening

positive CAM screening but did not receive a sleep protocol order developed delirium (100%). This resulted in a total of 6 out of 7 patients in the CAM positive group developing delirium (86%). Among the 54 patients with a negative CAM screen result during admission, only 6 of them developed delirium (Figure 2). In the group who received sleep protocol, 25% developed delirium. In the group who did not receive sleep protocol, 6% developed delirium. Overall, the rates of delirium in patients who had a positive CAM screen (87%) far exceeded the rates of delirium in patients who screened negative on all CAM results (11%). It appears that the initiation of the sleep protocol for patients with a positive CAM screen affected the incidence of delirium development. These findings shed light on the potential association between CAM screen results, the implementation of the sleep protocol, and the occurrence of delirium among the study participants. Further analysis is necessary to fully understand the implications and establish any causal relationships.

Conclusion In conclusion, our study provides evidence that the utilization of early CAM screenings and subsequent initiation of the sleep protocol effectively reduced the incidence of delirium in our patient population. This reduction in delirium incidence can be attributed to various factors, including changes in pharmacy management for delirium, the presence of additional delirium workgroups, and the potential increase in awareness of delirium among hospital staff. Given the substantial risks of mortality and cognitive decline associated with delirium, it is crucial to prioritize the early use of CAM screenings in high-risk patients. However, it is important to identify and address possible barriers to administering the CAM screening, as 16% of the patients in our study did not receive the screening. Inconsistencies in the pattern of the initiation of sleep protocol should also be addressed. Sleep protocol in this study was intended to be initiated only in the setting of a positive CAM screen, but the pattern of its use was not consistent with this protocol, showing that there may be a lack of uniformity in understanding it’s use. Moving forward, it is recommended to continue improving education on CAM screenings and sleep protocol among patient care providers. Additionally, gaining insights into the difficulties

Figure 2. Outcomes in patients with negative CAM screening 17

Reducing the Incidence of Delirium in Hospitalized Patients

encountered during CAM screenings administration and implementing measures to overcome these challenges will help prevent any lapses in survey administration. In summary, our findings were limited by sample size but provide a foundation for future work on discovering the potential for reducing delirium within high-risk patient populations. By further enhancing screening practices and addressing potential obstacles, we can continue to make strides in mitigating the impact of delirium on patient outcomes.

References

Echeverría M de LR, Schoo C, Paul M. (2022). Delirium. StatPearls. from https://www.ncbi.nlm.nih.gov/books/ NBK470399/

Farasat S, Dorsch JJ, Pearce AK, Moore AA, Martin JL, Malhotra A, Kamdar BB. Sleep and Delirium in Older Adults. Curr Sleep Med Rep. 2020;6(3):136-148.

Ahmed S, Leurent B, Sampson EL. Risk factors for incident delirium among older people in acute hospital medical units: a systematic review and meta-analysis. Ageing. 2014 May;43(3):326-33.

Scholarly Research In Progress • Vol. 7, November 2023

Hungry for More? An Assessment of Nutrition Education in Geisinger’s Total Health Curriculum Alexis Notarianni1†‡, Mahdi Taye1†‡, Karla Feeley1†‡, Matthew Hamers1†‡, Sireesha Mamillapalli¹, Gabi N. Waite¹, and Sonia Lobo¹ ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 † Doctor of Medicine Program ‡ Authors contributed equally Correspondence: anotarianni@som.geisinger.edu

Abstract Background: A national survey of nutrition education in United States medical schools indicates that most fall short of providing students with adequate training, thus impacting their ability as future physicians to provide nutritional counseling. The National Academy of Sciences recommends a minimum of 25 hours of nutrition instruction throughout medical school, and the American Society of Clinical Nutrition suggests 37 to 44 hours. In this study, we sought to assess and quantify nutrition education content in Geisinger Commonwealth School of Medicine’s (GCSOM) Total Health Curriculum to establish if recommended minimum instruction hours are being met. Methods: Using recommended undergraduate medical education nutrition competencies, we established 73 nutrition search terms and assessed the four-year Total Health Curriculum for nutrition content. Using these search terms, we reviewed 4,374 learning objectives (LOs) to generate a curricular map and quantify nutrition-related course content using time estimates of required reading assignments and prerecorded lecture materials. In total, 188 LOs met search criteria and were included in the study. Results: During the 2021–2023 academic years, roughly 14 hours of didactic instruction were focused on nutrition. The Integrated Science Course, which includes Case-Based Learning, and the Physician and Patient-Centered Care course accounted for 10.25 hours and 10 minutes of dedicated nutrition education time in the preclinical phase, respectively. In the clinical phase, the pediatric clerkship accounted for 3 hours. These results do not account for informal nutrition instruction gained through independent learning, extracurricular activities, or clinical interactions. Conclusion: The 14 hours spent on nutrition education at GCSOM fall short of national recommendations with nutrition instruction predominating in the preclinical phase and centered on the basic sciences. Additionally, nutrition content is not longitudinal, with gaps between formal preclinical and clinical instruction and a lack of focus on chronic disease prevention. These shortcomings are not unique to GCSOM’s medical curriculum and warrant deeper qualitative investigation to identify barriers.

Introduction The influence of diet on common causes of death, including heart disease, cancer, stroke, and diabetes, is significant in the United States (U.S.). In fact, poor dietary choices are the strongest risk factors for death and disability in the U.S., having

an even greater negative impact on health than tobacco use (1). According to the World Health Organization, over 80% of current chronic disease burden is attributable to dietary and lifestyle factors (2), with the economic costs of this burden rising steadily. Maintenance of a healthy lifestyle pattern that includes healthy eating and weight loss, can substantially reduce cancer risk (3), coronary heart disease mortality (4), and risk of Type 2 diabetes (5) and should be prioritized for chronic disease prevention. Despite the significant influence of diet on health, limited curriculum time is devoted to the teaching of nutrition in medical schools worldwide (6–7); thus, it is not surprising that most medical practitioners report lacking competence and confidence at providing accurate and effective nutrition counseling to their patients (8). In the U.S., a national survey of nutrition education in medical schools indicated that only 27% of medical schools met the minimum hours set by the National Academy of Sciences in 2010; in 2004, 38% of schools did so (9). Current recommendations for nutrition instruction in medical school come from the 1985 National Academy of Sciences report, which recommends 25 hours of nutrition instruction as a minimum (10), and the 1989 American Society of Clinical Nutrition, which suggests 37 to 44 hours (11). Regardless of the source, most medical schools fall short of meeting the recommendations for providing students with adequate training, thus impacting their ability as future physicians to provide nutritional counseling. To effectively treat and prevent chronic conditions like diabetes, cancer, obesity, and cardiovascular disease, physicians must be able to recognize and treat the underlying nutritional root causes. Geisinger Commonwealth School of Medicine’s (GCSOM) Total Health Curriculum aims to train compassionate physicians who provide individualized patient care and promote health in the communities they serve. Equipping students with adequate nutrition knowledge advances these curricular goals. In this study, we sought to characterize and quantify nutrition education content in GCSOM’s undergraduate medical curriculum and determine if nationally recommended minimum instruction hours are being met.

Methods GCSOM’s Total Health Curriculum (Figure 1) is a four-year, three-phase curriculum including a 15-month first phase, Principles of Medical Science and Practice, a 12-month second phase, Core Clinical Immersion, and a 16-month third phase, Career Differentiation and Exploration. The first phase includes three semesters and is organized into integrated, system-based

Hungry for More? An Assessment of Nutrition Education in Geisinger’s Total Health Curriculum

blocks that feature learning through the Clinical Presentation Model. This preclinical phase contains no lectures and has only two parallel courses—the Integrated Science Courses (ISC-I, II, and III and Case-Based Learning [CBL]) and the Physician and Patient Centered Care Course (PPCC I, II, and III)—that integrate all science and clinical content together. Phases 2 and 3 comprise the core clinical clerkship experiences and electives that develop advanced clinical skills and training to suit individual interests and career goals. Additionally, the curriculum emphasizes six themes, including Social Justice and Health Equity, Health System Citizenship, Primary Care, Personal and Professional Development, Community Immersion, and Population Health. Using nutrition competencies recommended by Adams et al. and the National Board of Medical Examiners (i.e., USMLE Content Outline) for undergraduate medical education as a benchmark (9), we established 73 search terms for nutrition or related topics and reviewed nutrition content throughout the Total Health Curriculum in the context of disease and wellness in both preclinical and clinical phases. Learning objectives (LOs) for each course were reviewed using these search terms, and the course content was reviewed to generate a curriculum map and to assess the number of hours dedicated to teaching

each nutrition topic. In total, we reviewed 4,374 learning objectives—3,564 from the Integrated Science Course (ISC-I, ISC-II, and ISC-III), 638 from the Physician and Patient Centered Care Course (PPCC-I, PPCC-II, and PPCC-III), 70 from the themes in the preclinical phase, and 102 from clerkships and electives in the clinical phases. Nutrition-related course content identified from the LOs was assigned a time value in minutes using time management resources provided to students, including time estimates of reading assignments, time-stamped lecture transcripts, and pre-recorded lecture materials (Table 1). In total, 188 learning objectives across 45 lectures contained a key search term and were included in the study. For CBL, we reviewed questions from each case using established search terms to identify nutrition-focused content. For quantification purposes, the total CBL session time was divided by the number of questions to yield an average time estimate for each nutrition-related question. Because the clinical phase predominantly involves clerkship rotations and electives, we only included content with LOs pertaining to nutrition.

Results

During the 2021–2023 academic years, roughly 14 hours of didactic instruction were focused on nutrition. The dedicated nutrition content was plotted as a layered pie chart revealing the estimates for each course during the preclinical and clinical phases of the curriculum. All the LOs that met the search criteria with a given time value were assigned a content area identified from Adams et al. For quantification purposes, the times for all the LOs that fell within a particular content area were pooled to estimate total time for five-content areas in each course. Figure 1. Overview of Geisinger Commonwealth School of Medicine’s Total Health Additionally, the time estimate described Curriculum. The Total Health Curriculum is a four-year, three-phase curriculum including as overlap contained the LOs that included a 15-month first phase, Principles of Medical Science and Practice, a 12-month second multiple content areas. These total time phase, Core Clinical Immersion, and a 16-month third phase, Career Differentiation and Exploration. The first phase is an active learning-based, integrated curriculum that uses the estimates were plotted against each course clinical presentation model, within system-based blocks. This phase contains no lectures as shown in Figure 2. and has only two parallel courses—the Integrated Science Courses (ISC-I, II, and III and Case Based Learning) and the Physician and Patient Centered Care (PPCC-I, II, and III) course—that integrate all science and clinical content together over three semesters. Phase 2 contains a Transition to Clerkship/Orientation session, five clerkship blocks, bridge weeks, a capstone experience, and components of the required Career Pathway Program. Phase 3 includes required core clinical rotations, expanded elective exploration opportunities, and a formal Transition to Residency component.

Table 1. Sample Analysis with Content Areas and Time Estimates Assigned. The table includes a sample analysis of nutrition-related course content identified from the LOs and assigned a time value in minutes using time management resources provided to students, including time estimates of reading assignments, time-stamped lecture transcripts, and prerecorded lecture materials.

The number of hours dedicated to teaching nutrition in the preclinical phase (Phase 1) was 10.42 hours and in the clinical phase (Phases 2 and 3), 3.58 hours. The major contributing courses included ISC-I, ISC-II, and ISC-III, which accounted for 9.67 hours of dedicated nutrition education time in the preclinical phase and the pediatric clerkship for 3.58 hours in the clinical phase. Additionally, 0.17 hours of dedicated nutrition instruction occurred in the PPCC longitudinal course and 0.58 hours within CBL sessions. These results may be an underestimate of the total learning time spent on nutrition, as it does not account for informal instruction gained through independent learning, extracurricular activities, optional assignments and lectures, or clinical interactions with preceptors and patients. Notably, a formal elective in culinary medicine with a medical

Hungry for More? An Assessment of Nutrition Education in Geisinger’s Total Health Curriculum

to 40 years, there has been minimal advancement in addressing the issue of insufficient nutrition education in medical schools (13), despite the consensus among experts that nutrition plays a central role in maintaining a healthy lifestyle and managing patients effectively (14) and the frequently voiced opinion that clinically relevant nutrition education should be embedded in medical school, residency, and fellowship curricula (15).

Figure 2. Percentage of Nutrition Content by Phase, Course, and Content Area as Described by Adams et al (9). During the 2021–2023 academic years, roughly 14 hours of didactic instruction were focused on nutrition. The Integrated Science Course, (ISC-I, II and III) which includes Case-Based Learning (CBL) and the Physician and Patient-Centered Care Course (PPCC-I, II and III), accounted for 9.67, 0.58 and 0.17 hours of dedicated nutrition education time in the preclinical phase, respectively. In the clinical phase, the pediatric clerkship accounted for 3.58 hours. Foundational aspects of nutrition science and disease treatment take precedence over other nutritional competencies covered in pre-clinical and clinical (clerkship) phases respectively.

nutrition component is offered to students in the clinical phase of the curriculum, and as part of the health system science interprofessional selective, students can participate in the Fresh Food Farmacy option, which incorporates nutrition as part of the diabetic care. Since 2021, one student has participated in the culinary medicine elective, and 27 students in the Fresh Food Farmacy option.

Discussion A careful review of the Total Health Curriculum indicates that the 14 hours allocated for nutrition education at GCSOM does not meet recommended minimum targets set by the National Academy of Sciences in 1985 (25 hours) (10) or the American Society of Clinical Nutrition (37–44 hours) (11). Notably, this deficiency is not exclusive to our medical curriculum, as it extends to other medical schools as well. Surveys conducted between 2000 and 2021, 2004, and 2008–2009 indicate that 68%, 63%, and 73% of U.S. medical schools, respectively, did not meet these standards (9). Moreover, a systematic review on nutrition in medical education reveals that the absence of nutrition education in medical schools persists even a decade later (12). This suggests that very little progress has been made in incorporating adequate nutrition education into medical curricula. It is disheartening to observe that over the span of 30

The question then arises: what could explain this lack of progress? Firstly, nutrition education throughout the clinical years of medical schools is predominantly embedded within the hidden curriculum (16). For instance, during rounds in the clerkships, attending physicians may casually discuss the nutritional requirements of a patient with colon cancer while walking in the hallway. Students might gain insights into best practices for a team approach when they observe a family physician effectively collaborating with a dietitian for patient management. Additionally, students may participate in a research study aimed at enhancing the nutritional information provided in pamphlets given to patients whose body mass index falls outside the healthy weight range. These valuable learning instances, which are not explicitly included in the LOs, emphasize that nutrition is treated as an incidental aspect of medical training. Consequently, the extent to which supervisors integrate nutrition into patient care can vary significantly, creating an inconsistent experience for the learner. Moreover, nutrition education cannot be captured in curricular maps, which are necessary to create meaningful longitudinal links between preclinical and clinical instruction. Secondly, many medical schools have opted to condense their preclinical learning curriculum, often by six or even 12 months, giving preference to “high-yield” learning material (17). Unfortunately, there persists a perception that nutrition content is considered "low yield," with limited testing or easily answerable questions in licensing exams (18). Consequently, dedicated activities focused on nutrition learning have been eliminated in favor of topics like the mechanisms of gastrointestinal nutrient absorption or the blood cell indices of vitamin deficiency anemia. The emphasis on learning of perceived high-yield medical material extends into the clinical years of education, where differential diagnosis and disease-based management take priority over learning about food as medicine. Moreover, nutrition is often viewed as inherent knowledge that can be left to nutritionists or other specialists to handle if necessary (16). At GCSOM, we have recently partnered with a health care system that is committed to transitioning toward a culture of value-based care. This model involves providers being reimbursed based on their patients' health outcomes, which in turn opens opportunities for the inclusion of reimbursement for lifestyle counseling, including nutrition. As a result, nutrition education now holds a prominent position in the realm of high-yield knowledge. As we look towards the future, our work will entail conducting qualitative assessments with key stakeholders within Geisinger. This assessment will aim to identify perceived gaps and competencies in the delivery of nutrition education and solicit proposals for improvement and interventions. Our goal is to actively contribute to a cultural shift that recognizes nutrition as a clinical tool of equal importance to surgical procedures like bypass surgery in healing patients.

Hungry for More? An Assessment of Nutrition Education in Geisinger’s Total Health Curriculum

Conclusion Based on our review of the Total Health Curriculum, the 14 hours spent on nutrition education at GCSOM falls short of current national recommendations of a 25-hour minimum established by the National Academy of Sciences. Formal nutrition instruction predominates in the preclinical phase of the curriculum and is centered around the basic sciences, lacking a focus on chronic disease prevention. These shortcomings are not unique to GCSOM’s medical curriculum and have become a national issue resulting in congressional resolutions calling on medical education programs to place a higher emphasis on nutritional education. Indeed, studies show that nutrition education increases knowledge and confidence in dietary counseling both in medical students (19) and in residents (20); thus, cultivating the skill and competence of physicians to recognize and appropriately tackle nutritionrelated challenges in their patients should be a priority.

Adams, KM. Kohlmeier, RD, Zeisel SH. Nutrition Education in U.S. Medical Schools: Latest Update of a National Survey. Acad. Med. 2010;85:1537-1542.

10. National Research Council Committee on Nutrition in Medical Education. Nutrition Education in U.S. Medical Schools. Washington, DC; National Academy Press; 1985. 11. Weinsier RI, Boker JR, Brooks CM, et al. Priorities for Nutrition Content in a Medical School Curriculum: A National Consensus of Medical Educators. Am J Clin Nutr. 1989;50:707-712. 12. Crowley J, Ball L, Hiddink GJ. Nutrition in medical education: a systematic review. Lancet Planet Health. 2019; 3:e379-389.

Acknowledgments

13. Mogre V, Stevens FC, Aryee PA, Amalba A, Scherpbier AJJA. Why nutrition education is inadequate in the medical curriculum: a qualitative study of student’s perspectives on barriers and strategies. BMC Medical Education 2018;26, DOI: 10.1186/s12909-018-1130-5.

The authors would like to acknowledge Emily Groff for her early contributions to this project, Tierney Lyons for her assistance with the literature search, and the Department of Medical Education at GCSOM for their funding support.

14. Who J, FOAE Consultation. Diet, nutrition, and the prevention of chronic diseases. Report of a joint WHO/ FAO expert consultation (WHO Technical Report Series, 916).

Disclosures The study authors reported no conflicts of interest.

References 1.

Murray CJ, Atkinson C, Bhalla K, et al. The state of U.S. health, 1990-2010: burden of diseases, injuries, and risk factors. JAMA. 2013;310:591-608.

World Health Organization. Global health risks: mortality and burden of disease attributable to selected major risks. Geneva; 2009.

Song M, Giovannucci E. Preventable incidence and mortality of carcinoma associated with lifestyle factors among white adults in the United States. JAMA Oncol. 2016;2:1154-1161.

Glenn AJ, Viguiliouk E, Seider M, et al. Relation of vegetarian dietary patterns with major cardiovascular outcomes: A systematic review and meta-analysis of prospective cohort studies. Front Nutr. 2019 Jun 13;6:80.

Qian F, Liu G, Hu FB, et al. Association between plant-based dietary patterns and risk of type 2 diabetes. JAMA Intern Med. 2019;179(10):1335-1344.

DiMaria-Ghalili R, Edwards M, Friedman G, et al. Capacity building in nutrition science: revisiting the curricula for medical professionals. Ann NY Acad Sci. 2013;1306:21-40.

Fitzpatrick L, Sayegh M, Ray S. Nutrition in the University of Cambridge medical curriculum—student perspectives. FASEB J. 2015;29:LB411.

Aggarwal M, Devries S, Freeman AM, et al. The Deficit of Nutritional Education of Physicians. The American Journal of Medicine. 2018;131:339-345.

15. Devries S, Willett W, Bonow RO. Nutrition education in medical school, residency training, and practice. JAMA 2019; 321(14), 1351-1352, DOI: 10.1001/ jama.2019.1581. 16. Martin S, Sturgiss E, Douglas K, Ball L. Hidden curriculum within nutrition education in medical school. BMJ Nutrition Prevention & Health 2020; doi:10.1136/ bmjnph-2019-000059. 17. Chatterjee N. Infusing the interdisciplinary into medical/ health sciences education: vitamins or vaccines? Medical Education Online 2009. DOI: 10/3402/meo.v7i4541. 18. Patel S, Taylor K, Berlin KL, Geig RW, Danek R, Waite GN. Nutrition education in U.S. medical schools: an assessment of nutrition content in USMLE STEP preparation materials. J Curr and Teaching 2015; 4(1), 108-113. 19. Schlair S, Hanley K, Gillespie C, et al. How medical students’ behaviors and attitudes affect the impact of a brief curriculum on nutrition counseling. J Nutr Educ Behav. 2012;44:653-7. 20. Vetter ML, Herring SJ, Sood M, et al. What do resident physicians know about nutrition? An evaluation of attitudes, self-perceived proficiency knowledge. J Am Coll Nur. 2009;49:1841-50.

Scholarly Research In Progress • Vol. 7, November 2023

Hydrocodone Prescriptions in 2020 in the Medicare Part D Population Alexa N. Simonetti1*‡ and Hattie M. Shrock1*‡ ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 *Master of Biomedical Sciences Program ‡ Authors Contributed Equally Correspondence: asimonetti@som.geisinger.edu

Abstract Hydrocodone is an opioid commonly prescribed to Medicare patients for pain management. In the past decade, opioid use has increased for pain management and recreational purposes, contributing to a nationwide misuse issue. Given the current opioid epidemic, an evaluation of the Medicare Part D data from the Centers of Medicare and Medicaid was conducted to determine what provider specialty was responsible for the highest percentage of hydrocodone prescriptions in 2020. The data was filtered to include all hydrocodone prescriptions, consisting of just hydrocodone and combination products. Family medicine was the highest prescriber of hydrocodone (24.85%) and total opioids (22.42%). The second highest was internal medicine, with (17.05%) of hydrocodone prescriptions and (17.47%) of total opioid prescriptions. In conclusion, protocols for opioid stewardship can be implemented to the top prescribing specialties with the intention of decreasing hydrocodone and overall opioid prescriptions.

Introduction Medicare is a government-associated health insurance program (1). The populations that are eligible to apply for Medicare include people 65 years of age or older and those with a disability, end stage renal disease, or Lou Gehrig’s disease (1, 2). There are four different parts of Medicare: Part A, B, C, and D (2). Medicare Part D involves prescription drug coverage and has been suggested to be responsible for the increase in overall prescriptions utilized by the geriatric population by lowering their personal costs (3). Opioids are used as analgesics, antitussives, antidiarrheals, and pain management medications (4, 5). In recent years, opioids have emerged as a popular drug for recreational use due to their sedative effects that make people feel relaxed and “high” (6). Between 2012 and 2018, opioid misuse has increased from 10 to 24 per 1,000 individuals within the Medicare population. The continuation of prescriptions that fall under part D has raised some concern, specifically the increase in reports of chronic pain along with increasing suicide rates among the older adult population is suspected to be correlated to the misuse of prescription opioids (7, 8). Hydrocodone is a semi-synthetic opioid that is prescribed for pain management. The drug is a mu-receptor agonist. Upon saturation of mu-opioid receptors, hydrocodone can also activate delta and kappa opioid receptors (9). By attaching to these receptors, opioids block normal pain signals sent throughout the body and release large amounts of dopamine (4). This dopamine release activates the reward pathway in the nucleus accumbens may accelerate user misuse of the drug.

Habitual misuse of hydrocodone can result in slowed breathing, which can then cause hypoxia when too little oxygen reaches the brain (4). Hypoxia can lead to detrimental effects including permanent brain damage, coma, or death (4). The U.S. Drug Enforcement Administration reclassified hydrocodone from Schedule III to Schedule II under the Controlled Substances Act in 2014. This change called for stricter policies on prescribing hydrocodone products due to their high potential for misuse (10). Given the concern for opioid prevalence in the Medicare Part D population, previous studies focused on analyzing the top specialties who prescribed these Schedule II drugs as well as the general pattern of opioid distribution. Between 2007 and 2011, opioid distribution increased in volume leading to prolonged usage among the Medicare population (11). In 2013, family medicine, internal medicine, nurse practitioners and physician assistants were found to dominate overall opioid prescriptions (12). In 2015, a cross-sectional analysis showed that nurse practitioners and physician assistants were still prescribing a high volume of opioids (13). The trends in these investigations show little progress in reducing opioid prescriptions between the years of 2007 and 2015. Little research exists that evaluates more recent hydrocodone prescription patterns. The purpose of this investigation was to compare various specialties for their hydrocodone and opioid claims in 2020.

Methods Data was examined from the Centers for Medicare and Medicaid Services (14) database, specifically the Medicare Part D Prescribers 2020 data set and the Medicare Part D Prescribers by Provider and Drug 2020 data (14). The Medicare Part D Prescribers by Provider and Drug 2020 was filtered through USAN Generic Names to only include data regarding hydrocodone prescriptions. In order to obtain data regarding all prescriptions containing hydrocodone, combination productions were included in the data. This was done by setting the filter to act on the generic name of the drugs and include all drugs that contained hydrocodone. The top combination products included mixtures of hydrocodone with acetaminophen and ibuprofen. The prescribers included in this data set each had a valid National Prescriber Identifier (NPI) and had been included within Medicare Part D Prescription Drug Events (PDE) which were reported via Part D plan sponsors during the 2020 calendar year. The data extracted from each set included the prescriber type (physicians (MD/DO), dentists (DMD/ DDS), nurse practitioners (NP), and physician assistants (PA)), prescriber NPI, prescriber state, and total claims number. No data was excluded. Procedures were exempt by the Geisinger IRB.

Hydrocodone Prescriptions in 2020 in the Medicare Part D Population

The data was used to calculate the provider types that prescribed the highest percentage of opioids of all 2020 Medicare Part D prescribers, 2020 opioid prescriptions, and provider type percentages of hydrocodone prescriptions. Some of the drugs in the overall opioid data included fentanyl citrate, acetaminophen with codeine, codeine, morphine sulfate, buprenorphine, and tapentadol HCL (15). These drugs were chosen using the complete Medicare enrollment database, CMS Chronic Condition Data Warehouse (CCW). The following calculations were performed for each provider type to find: the percentage of hydrocodone claims (sum of hydrocodone claims per provider Table 1. Hydrocodone (H) claims and total opioid (O) claims by provider type, along with type/total sum of hydrocodone claims), percentages of H/O claims by provider type, and H/Total O claims in Medicare Part D in percentage of total opioid prescriptions 2020. (PM&R: Physical Medicine & Rehabilitation) under Medicare Part D (sum of opioid prescriptions per provider type/sum of total opioid prescriptions by all providers), Discussion hydrocodone percentage of opioid claims (sum of hydrocodone The report found that family medicine prescribed the highest claims per provider type/sum of opioid claims per provider percentage of both opioids and hydrocodone to the Medicare type), and hydrocodone percentage of total opioid claims Part D population compared to any other specialty. Among the (hydrocodone claims by provider type/total opioid claims Medicare Part D population, opioid medication usage poses under Medicare part D). These calculations were repeated a risk for falls, unexpected drug interactions, or accidental to determine the provider type that prescribed the highest overdose (16). Short-term effects of opioid use include pain percentage of hydrocodone. relief and euphoria dissociation. However, short-term usage among any population may turn into long-term usage. The latter Results has the potential to cause drowsiness, confusion, nausea, and There were 51,918,067 total opioid claims in 2020 where constipation. These concerns and potential adverse effects 20,760,192 of the claims were for hydrocodone. Hydrocodone introduce the importance for looking into why family medicine accounted for 39.99% of all opioid claims. This data were has the highest prescription rates for hydrocodone and opioids then used to explore which provider type was responsible in general. One plausible reason family medicine prescribers for the highest percentage of hydrocodone prescriptions and make up most of the opioid/hydrocodone claims could be how that compared to their opioid prescription percentages. that individuals seek out their primary care/family medicine Family medicine providers were the top prescribers of physician more than any other specialty (16). Pain, the common both hydrocodone and opioids. Table 1 shows that family cold, and acute bronchitis were the main complaints made by medicine providers reported 5,159,671 hydrocodone claims patients who were prescribed hydrocodone by their family which accounted for 24.85% of all hydrocodone claims, and medicine physician (17–19). In 2016, there were roughly 50 11,641,178 opioid claims which were responsible for 22.42% million individuals in the US experiencing chronic pain (20). of all opioid claims. Of their 11,641,178 opioid claims, 44.32% Opioids have had popular use for chronic pain management. were for hydrocodone. One-tenth (9.94%) of all opioid claims However, not all common cold cases require hydrocodone. The reported in 2020 were for hydrocodone by family medicine CDC reports that individuals tend to have 2–3 colds per year, providers. and that this number is even higher in children (19). That poses the question of why are providers exposing their patients to a Along with family medicine, the other leaders in hydrocodone drug with such high abuse potential to treat a condition as mild and opioid Medicare Part D prescriptions in 2020 included as a common cold, potentially 2–3 times per year? Ultimately, internal medicine, nurse practitioners, physician assistants, it was concluded family medicine may appear as the top pain management, anesthesiology, physical medicine and prescriber due to the frequency and popularity of visits to this rehabilitation (PM&R), orthopaedic surgery, emergency provider. medicine, and dentists. The corresponding calculations for total hydrocodone and opioid claims and percentages for each provider type can be found in Table 1. Figure 1 provides a visual representation of the total opioid and hydrocodone claims made by the top ten providers. Figure 2 showcases the percentages of hydrocodone and opioid claims made by each of the top ten providers.

Furthermore, internal medicine contributed a large portion of hydrocodone and opioid claims. On a broader scale, internal medicine treats a wide variety of cases similarly to primary care physicians. However, they see mainly adults (21). This narrowing of the population in which internists treat may account for the difference in total claims from family medicine.

Hydrocodone Prescriptions in 2020 in the Medicare Part D Population

population as well as the increased suicide rates have potential to cause higher rates of misuse (8). Considering this information, evaluating the prescription rate of hydrocodone is important to identify who is prescribing these drugs with a high abuse potential. Telemedicine is another component to consider in regard to its contributions to the opioid epidemic. Following the COVID-19 pandemic, the rates of virtual provider visits have increased. The DEA implemented a policy granting the ability to prescribe Schedule II drugs without evaluating the individual in person (23). The already vulnerable population is now enabled to Figure 1. 2020 Top 10 Prescriber Specialties of Hydrocodone Compared to Total Opioid obtain a script for hydrocodone without Prescriptions by Medicare Part D Claims. This figure gives a visual comparison of the total ever leaving their home. The current hydrocodone claims made by each provider type compared to their total number of opioid study used data from 2020, therefore we claims in 2020. (PM&R: Physical Medicine & Rehabilitation) may see an inflated dataset compared to years preceding the COVID-19 pandemic. Future studies may focus on comparing these data between multiple years, both before and after the pandemic. Future studies should note a limitation that may exist with the current Medicare Part D Population due to their lack of utilization of technology, but as years progress, the next generation of older adults may be more accustomed to technology and may utilize telemedicine to acquire drugs.

Figure 2. 2020 Prescriber Percentages by Provider Type: Hydrocodone vs Total Opioid Claims in Medicare Part D. (PM&R: Physical Medicine & Rehabilitation)

Other providers worth mentioning include nurse practitioners (NPs) and physician assistants (PAs). Both are licensed to prescribe, administer, and distribute Schedule II drugs in most states. The volume of this profession is continuing to grow and slowly alleviating the physician shortage (22). Both NPs and PAs have been found to prescribe at rates similar to licensed physicians, however they have been shown to provide a greater number of outliers who prescribed higher frequencies and dosages of opioids (13). The findings of this analysis are similar to and extend upon the previous reports using the 2013 and 2015 data (12, 13). The similarity in patterns should raise concern since the same specialties are still dominating opioid prescriptions. Drawing awareness and implementing regulatory measures to these specialties could result in a downward trend of all opioid and hydrocodone prescriptions. The vulnerability of the Medicare population creates a concern for misuse. Reports of increasing chronic pain in the aging

Another potential contributor to the opioid epidemic in the United States is opioid specific direct to physician promotional payments. A study was conducted to evaluate the association between opioid promotion to physicians and their opioid prescribing rates under Medicare Part D between 2014 and 2016. It was found that physicians who received promotional payment prescribed significantly more doses of opioids (24). They also evaluated the payment patterns of specific opioids and found that physicians who received hydrocodone related payments prescribed about 5161 additional daily doses of hydrocodone (24). Hydrocodone and oxycodone displayed the largest association of increased prescribing rates by physicians who received promotional payment from the drug manufacturers (24). Given this study found significant increases in the rates of opioid prescriptions due to promotional payments, the structure and ethicalness of these promotional programs should be reevaluated at an institutional level. By ceasing these promotional/payment programs, physicians will be less encouraged to prescribe these drugs due to the lack of financial compensation that currently accompanies them. Awareness of the patterns of prescribing among all, including doctors and other provider types, is crucial, especially in the Medicare Part D population as it may ignite the process of lowering and refining these numbers. A few policy implementations have begun with the intent to regulate and lower these rates. The Department of Health in Rhode Island implemented the screening brief intervention and referral treatment (SBIRT) using the opioid risk scale to compile an assessment of an individual's potential for misuse. Additionally, they advise making a treatment plan that is specific to each individual patient by taking into consideration their SBIRT, and mental and physical health (25, 26). Although these may

Hydrocodone Prescriptions in 2020 in the Medicare Part D Population

seem like great measures to regulate the access to Schedule II drugs, reports have been made about the inconsistency of these policies from state to state (27). As the present study confirms with the CMS data, there is still a lot of work to be done. The authors would like to note several limitations of this study and propose future directions of potential research. First, a limitation pertaining to the data was the reporting of claims by NPs and PAs. Data were supplied for these providers as their own entity, while other individual PAs and NPs were included in other provider type categories such as family medicine and internal medicine. (14, 15). Second, this study did not evaluate polypharmacy. When administered alone, opioids produce dose-dependent sedative effects. Their effect can be enhanced by combining them with other sedatives (6). Therefore, future studies should be conducted to investigate the effects of hydrocodone when taken with other opioids or sedative drugs. This study did not filter for specific combination products (i.e., with acetaminophen or ibuprofen), as any drug consisting of hydrocodone was included in the data. The above data were pulled from 2020 (i.e., the most recent available). This may draw an unrealistic picture for the present year considering the impact of the COVID-19 pandemic. It may be beneficial to do an analysis on prescription rates every five years to evaluate the progress of opioid and hydrocodone prescription reductions. Finally, analysis of claims does not allow for determination of what portion of hydrocodone prescriptions were appropriate for individual patients. Further studies with electronic medical records are needed.

Conclusion Family medicine was the top prescriber of hydrocodone to Medicare Part D patients, followed by internal medicine, nurse practitioners, physician assistants, pain management, anesthesiology, PM&R, orthopaedic surgery, emergency medicine, and dentists. This information will allow for the implementation of proper regulations and policies to aid in the reduction of hydrocodone distribution to the Medicare Part D population.

Acknowledgments The authors of this paper would like to extend their gratitude and appreciation to Brian Piper, PhD, for his guidance and advising, in addition to Amanda Ruffino and Josh Madera on their assistance with data collection and organization.

Disclosures The authors have no disclosures.

References 1.

Medicare. What’s Medicare? [Internet]. Baltimore, MD: Centers for Medicare and Medicaid Services; 2023 [cited 2023 March 20]. Available from: https://www.medicare. gov/what-medicare-covers/your-medicare-coveragechoices/whats-medicare

HHS. Who’s eligible for Medicare? [Internet]. Washington, DC: US Department of Health and Human Services; 2023 [cited 2023 March 20]. Available from: https://www.hhs. gov/answers/medicare-and-medicaid/who-is-eligible-formedicare/index.html

Lichtenberg FR, Sun SX. The impact of Medicare Part D on prescription drug use by the elderly. Health Aff. 2007;26(6):1735-44.

NIDA. What are prescription opioids? [Internet]. Baltimore, MD: National Institute on Drug Abuse;2021. Available from: https://nida.nih.gov/publications/drugfacts/prescriptionopioids. (Accessed 2023).

Schumacher MA, Basbaum AI, Naidu RK. "Basic and Clinical Pharmacology: Opioid Agonists & Antagonists." Basic & Clinical Pharmacology, 15e Eds. Bertram G. Katzung, and Todd W. Vanderah. McGraw Hill, 2021, https://accessmedicine.mhmedical.com/content. aspx?bookid=2988&sectionid=250599194.

KuKanich B, Wiese AJ. Opioids. Vet Anaesth Analg. 2015;29:207-26.

Kuo YF, Baillargeon J, Raji MA. Overdose deaths from nonprescribed prescription opioids, heroin, and other synthetic opioids in Medicare beneficiaries. J Subst Abuse Treat. 2021;124:108282.

West NA, Severtson SG, Green JL, Dart RC. Trends in abuse and misuse of prescription opioids among older adults. Drug Alcohol Depend. 2015;149:117-21.

Cofano S, Yellon R. Hydrocodone [Internet]. Treasure Island, FL: StatPearls; 2021. Available from: https://www. ncbi.nlm.nih.gov

10. Jones CM, Lurie PG, Throckmorton DC. Effect of US Drug Enforcement Administration’s rescheduling of hydrocodone combination analgesic products on opioid analgesic prescribing. JAMA Intern Med. 2016;176(3):399402. 11. Kuo YF, Raji MA, Chen NW, Hasan H, Goodwin JS. Trends in opioid prescriptions among Part D Medicare recipients from 2007 to 2012. Am J Med. 2016;129(2):221-21. 12. Chen JH, Humphreys K, Shah NH, Lembke A. Distribution of opioids by different types of Medicare prescribers. JAMA intern med. 2016 Feb 1;176(2):259-61. 13. Lozada MJ, Raji MA, Goodwin JS, Kuo YF. Opioid prescribing by primary care providers: a cross-sectional analysis of nurse practitioner, physician assistant, and physician prescribing patterns. J Gen Intern Med. 2020;35:2584-92. 14. CMS. Medicare Part D Prescribers- By Provider and Drug. Baltimore, MD: Centers for Medicare and Medicaid Services; 2020. Available from: https://data.cms.gov. (Accessed 2023). 15. CMS. Medicare Part D Prescribers. Baltimore, MD: Centers for Medicare and Medicaid Services; 2020 . Available from:https://data.cms.gov (Accessed 2023).

Hydrocodone Prescriptions in 2020 in the Medicare Part D Population

16. Pan K, Blankley AI, Hughes PJ. An examination of opioid prescription for Medicare Part D patients among family practice prescribers. Fam Pract. 2019;36(4):467-72. 17. Bhamb B, Brown D, Hariharan J, Anderson J, Balousek S, Fleming MF. Survey of select practice behaviors by primary care physicians on the use of opioids for chronic pain. Curr Med Res Opin. 2006;22(9):1859-65. 18. Albert RH. Diagnosis and treatment of acute bronchitis. Am Fam Physician. 2010;82(11):1345-50. 19. CDC. Common colds: protect yourself and others. Atlanta, GA: CDC;2021. Available from: https://www.cdc.gov (accessed 2023). 20. Dahlhamer J, Lucas J, Zelaya C, Nahin R, Mackey S, DeBar L, et al. Prevalence of chronic pain and high-impact chronic pain among adults - United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67:1001–1006. 21. Beaumont. Choosing Between a Family Medicine Doctor and an Internal Medicine Doctor [Internet]. Dearborn, MI: Beaumont Health; 2023 Available from: https://www. beaumont.org/health-wellness/blogs/choosing-between-afamily-medicine-doctor-and-an-internal-medicine-doctor (accessed 2023). 22. Zhang P, Patel P. Practitioners and prescriptive authority. StatPearls; 2022. Available from: https://www.ncbi.nlm.nih. gov. 23. Oyler DR, Slavova S, Freeman PR, Huang Z, Talbert J, Walsh SL, et al. Broadband internet subscription rates and opioid prescribing via telemedicine during the COVID-19 pandemic. J Rural Health. 2022;38(4):900-7. 24. Nguyen TD, Bradford WD, Simon KI. Pharmaceutical payments to physicians may increase prescribing for opioids. Addiction. 2019;114(6):1051-9. 25. State of Rhode Island Department of Health. Safe Opioid Prescribing. Providence, RI: Department of Health;2023 Available from: https://health.ri.gov/healthcare/medicine/ about/safeopioidprescribing/. (Accessed 2023). 26. Passik SD, Kirsh KL. The interface between pain and drug abuse and the evolution of strategies to optimize pain management while minimizing drug abuse. Exp Clin Psychopharmacol. 2008;16(5):400. 27. Jukiewicz DA, Alhofaian A, Thompson Z, Gary FA. Reviewing opioid use, monitoring, and legislature: Nursing perspectives. Int J Nurs Sci. 2017;4(4):430-6.

Scholarly Research In Progress • Vol. 7, November 2023

The Importance of Diabetic Screening in Individuals with Down Syndrome Katherine Musto1†‡, Mark Mandak1†‡, Oluwaseyi Olulana1†‡, Clement Rajakumar1†‡, and Michelle Corrnacchia2‡ ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 ²Geisinger Medical Center, Danville, PA 17821 † Doctor of Medicine Program ‡ Authors contributed equally Correspondence: kmusto01@som.geisinger.edu

Abstract This study was conducted to increase diabetic screenings of patients with Down Syndrome (DS) at the Geisinger Medical Center Internal Medicine Comprehensive Care Clinic in Danville, Pa., using the Global Down Syndrome Foundation Guidelines. A retrospective chart review was conducted from March 1, 2022, through Aug. 31, 2022, to assess prediabetic and diabetic screenings performed on patients with DS. An electronic medical record smart phrase prompting the physician to screen patients was implemented and a prospective chart review was conducted from Sept. 1, 2022, through March 1, 2023. Screening for prediabetes and diabetes increased by 76.5% in adults with DS by March 2023 using the Global DS Guidelines. Future steps for this project will target (include, encompass, engage) multiple Geisinger clinics that treat patients with DS to increase sample size and corroborate our results.

Introduction Trisomy 21, also known as Down Syndrome (DS), is the most frequent chromosomal abnormality (aneuploidy). This condition is due to the presence of an extra complete or segment of chromosome 21 caused by a nondisjunction event in embryonic cells prior to conception. It is estimated each year there are about 5,000 neonates born with this chromosomal abnormality, this being about 1 in every 691 births in the United States (1). In the last 30 years the frequency of the condition has increased by 30% and seems to be rising with increased frequency of advanced maternal age pregnancies. Clinical features associated with DS include disturbance of brain development and MSK/ craniofacial abnormalities such as brachycephaly, thinning of the calvarium, small rudimentary nasal bones, and epicanthal folds. These individuals are also at an increased risk of congenital heart disease, gastrointestinal abnormalities, musculoskeletal issues, spine disorders, and endocrine disorders. With age these patients are classically at risk of development of early onset dementia sharing many commonalities with Alzheimer's disease. Some studies suggest there is an up to 70% incidence of Alzheimer’s dementia in patients with DS by the age of 50 (2). These patients are also at an increased risk of developing hyperglycemia through the pancreatic beta-cell dysfunctional process seen with Type 1 diabetes (T1D) and insulin resistance seen with Type 2 diabetes (T2D). There are few areas of research that illustrate the impact and pathophysiology of diabetes in individuals with DS. Several animal models studies have demonstrated increased

inflammatory markers of autoimmunity in this population. This and the increased pancreatic B-cell dysfunction found in this population suggests an impaired auto-immune metabolic/ inflammatory process of basal insulin deficiency. Insulin resistance in DS has been associated with a gene found in the extra chromosome, RCAN1, regulating hepatic glucose production and expression of gluconeogenic genes (2). Individuals with DS have up to four times the incidence of diabetes as compared to the general population, with younger age of onset and a higher incidence of obesity. The effects of hyperglycemia and lack of insulin can have numerous deleterious outcomes. These outcomes may include retinopathy, neuropathy, nephropathy, and increased risk of vascular ischemic events. Recent studies have also investigated the role of insulin in neuronal activity and synaptic plasticity leading to a higher risk of developing age-related cognitive decline and neurodegenerative diseases. These studies suggest cognitive decline seen with DS is accelerated by insulin deficiency/ resistance (2). These risks pose a great need for preventive care in people with DS, including earlier screening and detection of diabetes, which can greatly influence their health outcomes (3). The current guideline for diabetic screening is made by the Global DS Foundation. These guidelines established in 2021 suggest BMI monitoring for individuals with DS should be done annually, and these results will dictate the frequency of screening in the population, either using HbA1c or a fasting blood glucose test. In addition to BMI, the patient age will be used to assess when to begin screening (4). The need for screening of prediabetes and diabetes in individuals with DS is proving to be a field requiring further investigation. Research has shown that there are molecular mechanisms linking DS to both Type 1 and Type 2 diabetes (5). The prevalence of these conditions and prediabetes among people with DS is 3–5% for ages 16–30 and 5.5% for ages greater than 30. The effectiveness of the current screening protocol is poor on the national level. Missed diagnoses of diabetes or prediabetes in patients can increase the risk for retinopathies, neuropathies, nephropathies, and cardiovascular damage. While this guideline and others exist, there is more work that must be done to gain strong evidence that can help clinicians in their practice of care for the population of individuals with DS. Organizations including the American Academy of Family Physicians (AAFP) have published articles emphasizing the need for screening recommendations for diabetes in people with DS.

The Importance of Diabetic Screening in Individuals with Down Syndrome

Currently, there is no protocol or emphasis regarding the screening for prediabetes and diabetes in patients with DS at Geisinger. Development and implementation of a tool to aid Geisinger physicians in the diagnosis of prediabetes and diabetes in these individuals will not only enhance the care we are providing our patients, but also minimize the disease burden within these individuals that may be more susceptible to T1D or T2D. Our aim was to improve the diagnosis of prediabetes and diabetes in adults with DS at Geisinger Medical Center (GMC) Internal Medicine Comprehensive Care Clinic by 50% by March 2023 by using the Global DS Guidelines.

Methods A project aim was developed and defined: “To improve the diagnosis of prediabetes and diabetes in adults with DS at the GMC Internal Medicine Comprehensive Care Clinic (by 50%) by March 2023 utilizing the Global Medical Care Guidelines for Adults with DS.” An electronic health record SMART phrase, “Diabetes: asymptomatic adults screen at 30 yo and if obesity, screen at 21 yo,” was then implemented into each comprehensive care visit in patients with DS of 18 years or older starting on Sept. 1, 2022. A retrospective chart review which focused on screenings before utilization of the more recent Global DS Guidelines and SMART phrase was performed between March 1, 2022, and August 31, 2022, recording age, gender, hemoglobin A1c, and BMI. This was subsequently followed by a prospective review performed between Sept. 1, 2022, and March 1, 2023. Results including patients who were screened for prediabetes and diabetes pre- and postintervention, as well as identification of prediabetic or diabetic status according to HbA1C was recorded (Normal Range <5.7%, Prediabetic 5.7% - 6.4%, Diabetic 6.5%+). The study was piloted at the Department of General Internal Medicine at GMC in Danville, Pa.

Results and Discussion Prior to implementation of the Epic SMART phrase intervention, only 3 of 17 patients who qualified for screening (17.6%) were properly screened for diabetes and prediabetes (Figure 1). After intervention was implemented into each comprehensive care visit, 16 out of 17 qualifying patients (94.1%) were screened (Figure 2). Therefore, screening for prediabetes and diabetes increased by 76.5% in adults with DS by March 2023 using the Global DS Foundation Guidelines. The 3 patients (of the total possible 17) who were screened during the retrospective chart review prior to intervention were determined to be prediabetic (Figure 3). However, of the 14 remaining individuals who did not receive diabetes screening during their comprehensive care visit prior to intervention (March 1, 2022 – Aug. 31, 2022), 100% of these patients who had appointments during the prospective chart review period (Sept. 1, 2022 – March 31, 2023) were properly screened (Figure 4). 21.4% of these individuals who were not screened during the pre-intervention period but were properly screened post-intervention were found to be prediabetic. Of the 16 patients who were screened during the prospective chart review, 5 were found to be prediabetic and 11 were determined to have HbA1C levels within the normal range.

Figure 1. Bar graph representing HbA1c screening performed in qualifying patients with DS at GMC Internal Medicine Comprehensive Care Clinic from March 1, 2022, to Aug. 31, 2022, prior to intervention. 17.6% of qualifying patients were screened.

Figure 2. Bar graph representing HbA1C screening performed in qualifying patients with DS at GMC Internal Medicine Comprehensive Care Clinic from Sept. 1, 2022, to March 1, 2023, post intervention. 94.1% of qualifying patients were screened.

Figure 3. Bar graph representing prediabetes and diabetes status of patients with DS at GMC Internal Medicine Comprehensive Care Clinic who were screened from March 1, 2022 to Aug. 31, 2022. Prior to intervention, only 3 members of a possible 17 in this patient population were screened.

The Importance of Diabetic Screening in Individuals with Down Syndrome

Figure 4. Bar graph representing prediabetes and diabetes status of patients with DS at GMC Internal Medicine Comprehensive Care Clinic who were screened from Sept. 1, 2022 to March 31, 2022. Post intervention, 16 members of a possible 17 in this patient population were screened.

Conclusion While we believe this study can provide insight into appropriate management plans for metabolic diseases such as diabetes mellitus in patients with DS, there were some important limitations to this study that influence the quality of the interpretation of the data, such as the small sample size due to piloting this study at only one clinic within the larger Geisinger system. In the future, it will be important to institute this intervention in clinics within the system to increase the patient population and ultimately the number of patients screened. The study can further be expanded to more clinics across multiple systems in order to increase the confidence in our hypothesis. The increased detection for prediabetes in patients with a DS diagnosis will leave room for early detection of metabolic disease which will improve both quality of life for these patients and overall cost of care associated with complications that can be endured secondary to late detection and treatment.

Disclosures The authors have nothing to disclose.

References 1.

Moreau M, Benhaddou S, Dard R, et al. Metabolic diseases and down syndrome: How are they linked together? Biomedicines. 2021;9(2).

Dierssen M, Fructuoso M, Martínez de Lagrán M, Perluigi M, Barone E. Down syndrome is a metabolic disease: Altered insulin signaling mediates peripheral and brain dysfunctions. Frontiers in neuroscience. 2020;14:670.

Bunt CW, Bunt SK. Role of the family physician in the care of children with down syndrome. American family physician. 2014;90(12):851-858.

Global Guidelines Diabetes Toolkit [Internet]. Global Down Syndrome Foundation; [cited 2023 Jun 2]. Available from: https://www.globaldownsyndrome.org/wp-content/ uploads/2021/06/2021-GLOBAL-Guideline-DiabetesToolkit.pdf

Tsou AY, Bulova P, Capone G, et al. Medical care of adults with Down syndrome: A clinical guideline. JAMA: the journal of the American Medical Association. 2020;324(15):1543-1556.

Ptomey LT, Oreskovic NM, Hendrix JA, Nichols D, Agiovlasitis S. Weight management recommendations for youth with down syndrome: Expert recommendations. Front Pediatric. 2023;10.

Golden SH, Brown A, Cauley JA, et al. Health disparities in endocrine disorders: Biological, clinical, and nonclinical factors—An endocrine society scientific statement. The Journal of Clinical Endocrinology and Metabolism. 2012;97(9):E1579-E1639.

Mazurek D, Wyka J. Down syndrome – genetic and nutritional aspects of accompanying disorders. Rocz Panstw Zakl Hig. 2015;66(3):189.

Scholarly Research In Progress • Vol. 7, November 2023

A Current Review of Neurological Effects of Cryptococcal Meningitis Infection in HIV-Positive Individuals Taylor C. Gammell1*, Sofia Victoria Sowden1*, Mohammad Daniyal Syed1*, and Ashley D. Tapia1* ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 *Master of Biomedical Sciences Program Correspondence: msyed@som.geisinger.edu

Abstract Cryptococcal meningitis (CM) is one of the most common fungal opportunistic infections affecting HIV-positive individuals. Viral infection is caused by exposure to ubiquitous encapsulated yeast Cryptococcus neoformans through the inhalation of basidiospores or yeast cells. Potential sources of infection include soil or avian droppings. The disease is characterized by a low CD4 T cell count, high intracranial pressure, and other neurological clinical symptoms including headache, sensitivity to light, stiff neck, and altered mental status. Most notably, it affects the lungs and central nervous system of immunocompromised HIV-positive individuals, which can lead to a variety of neurological manifestations and be the defining event of an AIDS diagnosis. HIV-positive CM is most prevalent in areas such as sub-Saharan Africa due to limited resources so investigations into antifungal treatments such as antiretroviral therapy demonstrate a lack of effect. New point-of-care screening methods such as a lateral flow cryptococcal antigen assay must be explored to counteract this effect. Aggressive management may also be utilized as a more invasive approach to control increased intracranial pressure, which is one of the main causes of neurological symptoms associated with cryptococcal meningitis. A lack of timely treatment and monitoring of intracranial pressure accounts for much of the morbidity and mortality associated with this disease. This narrative review utilized various sources and databases of peer-reviewed articles that were most up-to-date and relevant about evaluating the current findings of neurocognitive effects of cryptococcal meningitis infection in HIV-positive individuals, along with advancements in clinical management and drug therapy.

Introduction HIV, human immunodeficiency virus, is a transmissible viral infection that damages the body's immune system and weakens its ability to fight infection and disease (1). By targeting CD4 T cells, a type of lymphocyte integral in immune response coordination, HIV infection increases an individual’s susceptibility to opportunistic infections, such as fungal cryptococcal meningitis (CM) and bacterial infections (2). Bloodwork determining an individual’s CD4 T cell count is a key metric in HIV disease progression evaluation and can play a central role in a host of clinical decisions such as when to initiate antiretroviral therapy (ART) (2). CD4 T cell count monitoring is also central in assessing an HIV-positive individual’s risk for opportunistic infection and can aid in infection diagnostics, identifying which prophylactic(s) should be administered and treatment onset (2,3). The normal range of CD4 count is from 500 to 1,500 cells/cubic millimeter of blood (4). If the number of CD4 cells in a person's blood falls below 200 cells/cubic

millimeter of blood, their immunity is weakened and can lead to acquired immunodeficiency syndrome (AIDS) (4). The immune system is severely damaged in AIDS and is susceptible to fatal infections or cancer (5). It is estimated that in 2021, 38.4 million people are living with HIV worldwide and 650,000 people died of HIV-related illnesses (4). CM is a type of meningitis that often affects people who have HIV and is one of the most prevalent opportunistic infections that can occur in people with AIDS (6). HIV-associated CM is a significant complication in HIV-positive individuals and is an AIDS defining illness especially in environments with limited resources, and accounts for up to 15% of overall HIV-related deaths (7). There are approximately 152,000 cases of CM that occur among people with HIV/AIDS worldwide each year, resulting in an estimated 112,000 deaths (7). Outcomes can be poor, with the most significant burden of the disease in subSaharan Africa and Southeast Asia (8). Despite the observed overall decrease in CM incidence over the years, improvement in the health and mortality of individuals with this infection should remain a necessary public health goal to aid in decreasing the global disease burden. Disease presentation of CM is usually acute, with a gradual increase in fever, malaise, and headache (9). These symptoms can sometimes be associated with neck stiffness, photophobia, vomiting, confusion, and a decreased level of consciousness (9). Clinical symptoms evolve as the infection progresses, eventually including nausea, photophobia, visual obscurations, diplopia, meningismus, and encephalopathy (10). These symptoms could be a sign of increased intracranial pressure (ICP), and a neurologic examination can be performed to assess signs of papilledema, defined as bilateral optic disc swelling induced by intracranial hypertension and additional cranial neuropathies (10). CM is most commonly caused by the ubiquitous encapsulated yeast Cryptococcus neoformans (10). Exposure occurs through inhalation of the basidiospores or yeast cells from soil or avian droppings (11). C. neoformans can establish an innate immune response within the lungs through phagocytes like macrophages or cause pulmonary disease (12). Following inhalation, the cell wall components of cryptococcal cells are recognized by receptors in the immune system, which triggers the innate immune response (13). This response includes the phagocytosis of alveolar macrophages and the formation of granulomas (12). The mode of infection is characterized as the “Trojan horse” approach, which involves C. neoformans hiding inside white blood cells, such as macrophages, monocytes, and neutrophils (14). These cells act as a reservoir for C. neoformans, shielding the fungus from the body’s immune system, which can help promote latent infection or persistent chronic inflammation (14,

Neurological Effects of Cryptococcal Meningitis Infection in HIV-Positive Individuals

15). The latent infection can then be distributed to the CNS, cross the blood-brain barrier (BBB), and infect the meninges, leading to cryptococcal meningitis as seen in Figure 1 (11). Limited research has been conducted on the neural mechanism of how this fungus survives in the brain once it crosses the BBB. Several studies have explored how C. neoformans can survive in a nutrient-poor environment in the CNS and brain (16). These studies suggest that this organism adapts to host-specific signals and can modify immune responses while spreading into the CNS (16). Additional study has shown that C. neoformans forms melanin via substrates, including diphenolic compounds such as epinephrine, dihydroxyphenylalanine (DOPA), and norepinephrine (17). The enhanced accessibility of these neurotransmitters in neural tissue has been suggested as a potential explanation for the neurotrophic properties of C. neoformans (16). There has been a reduction in the estimated total global burden of HIV-associated CM since 2014, likely due to antiretroviral therapy (ART) expansion and improved screening programs (7). However, much remains unknown regarding CM's longterm neurocognitive and neurological effects in HIV. Analysis suggests that neuroradiological data is limited to case reports and small case studies from developed countries (18). Studies so far show that neuroradiological lesions related to CM include dilated perivascular spaces, pseudocysts, cryptococcosis, basal meningitis, and hydrocephalus (19). Seizures were also common among patients with HIV-associated cryptococcal meningitis and were associated with decreased neurocognitive function and survival (20). Still, further research needs to be completed in countries where the disease burden remains high, primarily those in the sub-Saharan African region that experience the effects of limited resources and suboptimal health care. Although substantial research is currently focused on an increased understanding of disease pathogenesis, there is a lack of emphasis placed on the understanding of mechanisms underlying disease development in the brain. This narrative review evaluates the neurological effects of cryptococcal meningitis infection in HIV-positive individuals, advancements in clinical management, point of care, and novel drug therapy regimens.

Methods A literature search was performed and utilized various sources and databases while evaluating the neurocognitive effects of cryptococcal meningitis, including PubMed and Google Scholar. No date range or journal exclusion was applied; however, priority was assigned to manuscripts published in or after 2010. The following key terms were used to find relevant articles: “cryptococcal meningitis,” “cryptococcal meningoencephalitis,” “HIV-associated meningitis,” “opportunistic infections,” “fungal infections,” or “cryptococcus neoformans” in combination with “neurological effect,” “neurocognitive effect,” “antiretroviral,” “therapy,” or “treatment,” and “therapeutic lumbar puncture meningitis,” or “cryptococcal meningitis neuroimmunology” or “clinical considerations for cryptococcal meningitis” or “shunting in cryptococcal meningitis” or “ICP in meningitis” or “clinical standards for ICP.” These papers were peer-reviewed and were among the most up-to-date and relevant articles pertaining to these queries. The mechanism of Cryptococcus neoformans figure was created using a website called BioRender.

Discussion Relationship Between Cryptococcal Meningitis and HIV Opportunistic Infections Opportunistic infections (OIs) can become pathogenic when the functioning of the body’s immune system is suboptimal (21). The four main types of OIs are bacterial, parasitic, fungal, and viral. When these pathogens take advantage of the weakened immune system, they can harm one’s health by causing unusually severe diseases. Since these microbes typically inhabit environments other than human hosts, once they enter a human body, the transmission depends on human-to-human contact to continue the spread (22). Transmission can occur through various mechanisms, including airborne, aerosol, respiratory droplets, vector-borne, fecal-oral, and direct or indirect contact. OIs are considerably associated with morbidity and mortality and can arise from an altered microbiota, a breached epithelium, and, most notably, an already weakened immunity (23).

Figure 1. Summary of Cryptococcus neoformans mechanism of infection. Common sources of C. neoformans are soil and avian excreta. The portal of entry is through the inhalation of spores into the lungs. In an immunocompetent individual, the innate response uses cells like macrophages to phagocytose this pathogen and secretes pro-inflammatory mediators to eliminate the infection. In contrast, in an immunocompromised individual, like an HIV-infected individual, the immune system cannot fight off the infection, thus leading to pulmonary disease or a latent infection that will be reactivated later. The infection then spreads to the CNS, crosses the blood-brain barrier, and leads to cryptococcal meningitis. This figure was created using biorender.com.

Neurological Effects of Cryptococcal Meningitis Infection in HIV-Positive Individuals

Human Immunodeficiency Virus Human immunodeficiency virus (HIV) is an infection characterized by a viral attack on the body’s immune system (24). There are two versions of HIV: HIV-1, which is more often associated with OIs, and HIV-2, which is less common. HIV-1 is a single-stranded, positive sense ribonucleic acid (RNA) virus that infects a host’s genome by transcribing viral RNA into deoxyribonucleic acid (DNA) and replicating it (25). The three main stages of HIV are the acute primary infection stage, the asymptomatic or latent stage, and the symptomatic chronic illness stage. The progression of the disease between each stage varies from person to person. The clinical manifestations of the acute infection stage can last between 3 and 25 days and may include general symptoms such as fever, fatigue, weight loss, headaches, myalgias, vomiting, and diarrhea (26). HIV can affect the body’s systems, such as cardiac, ocular, gastrointestinal, and neurologic systems. Cryptococcal Meningitis and HIV OIs are often present in the third stage of HIV infection, as a positive individual is at a higher risk and is more susceptible to complications due to their immune system (7, 27). In the majority of cases, the presence of more than 20 OIs is also seen as the AIDS-defining event of a patient living with HIV. Although the number of OIs in HIV patients has decreased in developed countries, they remain a source of hospitalization and death in these areas despite improvements. More importantly, a reduction in OI incidence has not been established in resource-limited regions, such as in sub-Saharan Africa, where communities struggle with late diagnoses and poor access to treatments (7, 28). The predominant type of OI seen in HIV patients, especially in more advanced cases or during the third stage, are CNS OIs, as a favorable environment is created by the combination of a high HIV load and diminishing immunity (25). The most common CNS fungal infection in HIV individuals is CM, which can prove fatal within three months of the disease onset (26, 29, 30). Both computerized tomography (CT) and magnetic resonance imaging (MRI) brain scans can aid in evaluating cryptococcomas, meningeal inflammation, vasculitis, and ventricular compression (31). To diagnose cryptococcal meningoencephalitis definitively, a cerebrospinal fluid (CSF) sample must be obtained via lumbar puncture (LP) and examined for signs of infection. A patient’s opening CSF pressure should also be measured as raised intracranial pressure is common and may necessitate therapeutic CSF drainage management (9). CSF culture remains the gold standard for CM diagnosis; however, definitive results may take one to two weeks, and often, patients' analyses demonstrate normal CSF levels (7, 29). Two novel diagnostic methods that may be used are India ink microscopy, a more efficient test, and cryptococcal antigen testing (CrAg), which is highly specific and more sensitive than the CSF culture, with the ability to detect CM in the blood weeks to months before the onset of symptoms (18, 28, 29). Additional diagnostic features may include clinical presentation of symptoms, temporal evolution, and both CSF and radiographic findings, along with a CD4+ cell count of lower than 200 cells per microliter (25, 30). Universal symptoms may include headache, nausea, fever, discomfort, and seizures, and these acute signs may present concurrently for up to three weeks (29, 30, 32). Vision-related complications include diplopia, papilledema, photophobia, and reduced visual acuity.

A key neurologically-based manifestation that arises in CM infection is hydrocephalus in combination with increased intracranial pressure that may bring rise to encephalopathic symptoms such as memory loss, altered behavior, lethargy, and personality changes (25, 29). Other neurological indications include cryptococcomas or mass lesions and accumulation of cysts in Virchow Robin (VR) spaces, which are the spaces that surround blood vessels of the brain and cranial nerves (25, 32). Neurological findings included detections of basal meningeal enhancement, hydrocephalus, cerebral infarcts, cryptococcomas, and pseudocysts or VR space dilatation. One study compared two groups of HIV-positive patients with CM, where one group was classified as young adults (≤40 years), and the other group was classified as older adults (>40 years) (33). The study found that older patients initially experienced headaches, fevers, seizures, visual disturbances, and hearing impairment. It also determined that younger patients presented with a higher incidence of headaches as the primary manifestation, which may be due to increased ICP found in the young adult group. An additional study analyzed brain lesions from radiological brain images of HIV-positive patients with CM, utilizing both CT and MRI imaging (35). Radiological findings at baseline found upon CT interpretation included pseudocysts, hydrocephalus, edema, intracerebral masses, dilated VR spaces, and radiological meningitis, while radiological findings at baseline upon MRI interpretation were intracerebral masses, pseudocyst, dilated VR spaces, meningitis, perilesional edema, as well as nodules or masses in the frontal and occipital lobes, parietal gyri, basal ganglia, and the corpus callosum (35). Although MRI imaging proved more accurate in determining brain lesions, both scans showed abnormal brain imaging that could be linked to poor prognosis and increased fatality from the time of diagnosis of CM. Cryptococcal Meningitis in HIV-Positive Children The vast majority of research executed regarding CM in HIVpositive individuals has solely included adult patients, therefore, little is known concerning infected patients who are under the age of 18. The previously cited study concerned with the clinical characteristics of CM in a younger demographic found that younger patients had a higher incidence of headaches due to higher intracranial pressure and a better clinical outcome at discharge and after a year of follow-up (33). However, even in this study, young adults were classified as patients who were 40 years or younger. Another study followed 19 patients in the age range of 4.8–10.8 years, and they presented with basic clinical symptoms of fever, headaches, nausea, abdominal pain, dyspnea, and seizures (35). The primary neurologic sign described in this age group was meningeal irritation that included pleocytosis and increased CSF protein levels, with no focal neurologic signs being recorded. A third study investigated children under the age of 16, and the main neurologic abnormalities found were hypodensities, hydrocephalus, calcifications, masses, an increase in meningeal enhancement, and cerebral hemorrhages (36). Nevertheless, this same study described the low frequency of CM in HIVpositive children, citing that there were less than 1,000 cases of CM in children discussed in worldwide literature as of 2012. The reason for this occurrence remains unknown, but a potential explanation may be that children have antibodies against Cryptococcus species that were gained from exposure to 33

Neurological Effects of Cryptococcal Meningitis Infection in HIV-Positive Individuals

fungus and infections during their childhood. Overall, research focused on HIV-positive pediatric populations infected with CM is minimal, and despite low incidence, can serve as a source for further investigations in the future. Antifungal Treatment Evidence supports poor outcomes regarding the long-term effects of antifungal treatment, attributing them to late presentation, lack of access to medications, and monitoring (37, 38). Furthermore, a lack of adherence and retention, which are common in HIV care, is causing a lack of decrease in CM incidence despite the availability of antiretroviral therapy (ART). Nonetheless, detection technique advancements have improved outcomes by providing the option of earlier screening, diagnosis, and treatment (38). Research focused on improving ART has demonstrated impressive feats and continues to update medication regimens and monitor availability to allow better access for patients in low-resource areas. Currently, the combination of Amphotericin B and flucytosine is the regimen of choice, having shown a higher survival advantage over Amphotericin alone, in conjunction with faster clearance of infection (38). However, the 14-day regimen of amphotericin B poses challenges for low-resource clinics due to prevalent adverse effects such as renal impairment, hypokalemia, hypomagnesemia, and anemia (39). The Center for Global Health in the United Kingdom has continued to make strides with regard to treatment standards, finding comparable results with high doses of fluconazole and flucytosine with one week of amphotericin B. This new regimen would be more readily available and safer to use in areas with limited resources while also being associated with low mortality (40). Other medications have shown reputable results, as previous studies have explored that an additional dose of sertraline can increase early fungicidal activity and show a decrease in relapse (41). The most current research showcases a new medication called Viamet 1129 (VT-1129), which has shown promising efficacy in CM murine models with plans for further studies and clinical trials (42). In considering the ART regimen associated with the best outcomes, it is essential to appreciate other symptoms that could be detrimental if not closely monitored. Increased intracranial pressure and raised levels of CSF are associated with additional manifestations and worse outcomes (38). Immune reconstitution inflammatory syndrome (IRIS) is a newly recognized complication after initiating ART therapy. The manifestations of CM-associated IRIS include a paradoxical worsening of CNS symptoms and the unmasking of disease in organs not previously recognized to be affected (38). Improved CSF value monitoring can reduce high mortality rates, thus permitting earlier antifungal treatment and reduction of poor outcomes (43). Changes to Point-of-Care When considering point of care in resource-limited settings, regimens that require a shorter hospital stay and are better tolerated need to be considered. A phase III trial was completed exploring the use of high-dose liposomal amphotericin B (AmBisome), showing comparable results to the standard ART regimens (37). Having shorter regimens will allow the patients to have more flexibility in their care, therefore increasing adherence to treatment and improving subsequent responses 34

and outcomes. The Infectious Disease Institute of Makerere University in Kampala, Uganda, has endorsed community engagement as having positive effects on trial referrals, drug adherence, and reduction of missed visits (43). Reiterating the importance of more manageable treatments in tandem with strong community support. In recent years, simple lateral flow assays (LFA) for CrAg have been developed. These are inexpensive and provide rapid results when performed on CSF, serum, or urine. The immunoassay (IMMY) lateral flow test has a high sensitivity for detecting Cryptococcus in CSF of HIV-infected patients and has become the foundation of diagnosis in screen-and-treat programs (44). LFA is a test that uses two different types of antibodies to identify cryptococcal infections (44). It is very sensitive and can identify both C. neoformans and C. gattii species complexes (13). The IMMY CrAg LFA is also a lowcost, rapid, easy-to-use test, which is an advantage for limited resource environments (13). Role of Invasive Therapeutics Raised Intracranial Pressure Management Despite mortality of individuals with concurrent human immunodeficiency virus and cryptococcal meningitis infection being as high as 78% one year post-CM diagnosis, people living with HIV/AIDS (PLWH) who survive C. neoformans infection are at increased risk for suffering from lifelong sequelae, including long-term morbidity primarily due to both cognitive, visual, and auditory impairments (45, 46). The role of ancillary therapies in effectively addressing raised ICP caused by CM and adequately controlling neurological and sensorineural sequelae is a vital consideration when discussing the management of CM in PLWH. More invasive interventions should be considered, given the lack of efficacy exhibited by potentially harmful medical treatments traditionally administered in cases of idiopathic ICP such as acetazolamide (47, 48). Furthermore, the overarching goal of additional invasive interventions is to diminish disability and increase the overall quality of life for PLWH who have survived CM infection. Therapeutic Lumbar Punctures An association between increased fungal burden at baseline and increased baseline CSF opening pressure (CSFOP) has been established in HIV-associated cryptococcal meningitis, and aggressive management of increased intracranial pressure (IICP) is the current standard to improve morbidity and mortality in CM infection (49, 50). Baseline CSF opening pressure obtained via LP should be rapidly obtained in all patients with confirmed or suspected CM infection unless the patient presents with altered mental status (46). Indications of altered mental status upon presentation would necessitate further investigation via neuroimaging, thus superseding a baseline LP, however, CSFOP measurements should remain a priority in all positive or possible CM cases (46). CSFOP measurements are sensitive to sex, age, and body mass index differences. Still, the current standard range in clinical practice ICP measured by LP in adults in a typical clinical setting should now be regarded as 6 to 25 cmH2O. (51, 52). A general population means of about 18 cmH2O should be considered when studying IICP in the context of HIV-CM concurrent infection (52, 53).

Neurological Effects of Cryptococcal Meningitis Infection in HIV-Positive Individuals

Performing therapeutic LP to drain CSF to achieve CSP closing pressure of less than 20 cmH2O is a treatment option to supplement medication management (46). This intervention can be carried out daily until the desired measurement has been achieved and CSF pressure has normalized, and recent clinical findings have determined a 69% relative survival protection rate due to repeat therapeutic LP (46). While the number of LPs received by patients is highly variable, scheduling two therapeutic LPs during the first week of antifungal treatment is strongly suggested, alongside an additional LP two weeks post-diagnosis, may be instrumental in symptom management and reduction of neurological sequelae (54). The effects of raised ICF can be acute and present within the first two weeks, although results may not be present until week 10 in some individuals. These findings suggest that formulating an updated standardized therapeutic LP schedule, which also considers suboptimal treatment environments, would improve patient outcomes (54). The implementation of a standardized LP treatment plan for patients who meet the criteria would address this specific treatment goal and would support effective longterm management (54). Ventriculostomy and Ventriculoperitoneal Shunt Performance of a ventriculostomy, temporary placement of a catheter to divert CSF build-up to an external collection system, or surgical placement of a ventriculoperitoneal shunt (VPS) are two additional invasive strategies utilized for acute and longterm management of increased ICP in CM patients (47, 55). VPS placement averts CSF build-up from the lateral ventricles to the peritoneum via a pressure valve (56). Historically, the increased risk of infection in HIV-positive individuals with CM has dissuaded surgeons from ventriculostomy and VPS placement, but recent investigations, including retrospective cohort studies, have sought to determine the long-term benefits of VPS in ICP management despite the assumed increased risk of infection. VSP placement is applicable as a secondary treatment for patients who have had a significant amount of CSF removed via LP but need sustained intervention to remain neurologically asymptomatic without interfering with antifungal treatment (57, 59). Although surgical complications can pose a threat to an individual with HIV-CM, various studies have succeeded in delineating a relationship between the use of VPS and improved survival rates (47, 57, 60, 61). Such studies have demonstrated that surgical infection due to VPS placement is uncommon and generally should not be a significant factor dissuading clinicians from neurosurgical intervention in this context (47, 57, 60, 61). Additionally, a related study performed in rural Central Africa examined the safety of LP in resource-limited settings, and determined that when a LP is performed in accordance with local clinical standards, the procedure only resulted in moderate, non-life threatening, adverse events (62). Incidence and mortality remain significant issues with HIV-CM concurrent infection; nevertheless, it has been demonstrated that in under-resourced circumstances, particularly in the absence of neuroimaging, LPs are not solely significant contributors in CM diagnosis, but also can provide a safe route of intervention (62). Increased utilization of the invasive interventions discussed can potentially improve overall outcomes, especially in cases of substantially increased CSFOP, while accounting for patient age and the severity of fungal infection (61).

Conclusion Cryptococcal meningitis continues to be the most common form of meningitis in HIV-positive adult individuals globally and the most impactful fungal infection affecting HIV-positive individuals. This is due to the damaging and potentially lifelong neurological and neurocognitive effects that can affect the CNS through lesions, hydrocephalus, increased cranial pressure, and more, along with visual and auditory complications against already susceptible people. Newer point-of-care methods like cryptococcal antigen lateral flow assays are being explored outside of ART. These methods are faster and easier to administer, which can help to combat the high mortality rate of the disease. This will be particularly true in areas with limited resources like sub-Saharan Africa and Southeast Asia, where CM remains at an all-time high, so the screening and diagnostic processes can be lessened to reach the treatment phase more rapidly. Increased intracranial pressure remains a problem in CM that, in many cases, needs to be addressed with more intrusive strategies to help improve patients’ overall quality of life. These include therapeutic LPs, ventriculostomies, and ventriculoperitoneal shunt placement that work to relieve the intracranial pressure and possibly diminish the risk of long-term sequelae associated with excess CSP and IICP. However, the need to establish the longevity of the functionality of these interventions remains and there is a substantial need to further explore to understand potential complications, especially among HIV-positive individuals of all ages. Along with the limitation of research on performing a ventriculostomy and ventriculoperitoneal shunts, further research is needed on the acute and long-term effects of CM on HIV-positive pediatric populations because only a handful of findings are available and current surrounding the potential consequences and complications faced by this age group.

References 1.

Simon V, Ho DD, Abdool KQ. HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet. 2006;368(9534):489-504.

Ford N, Chiller T. CD4 cell count: A critical tool in the human immunodeficiency virus response. Clin Infect Dis. 2022;74(8):1360-1361.

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach. World Health Organization; 2016. 4, Available from: https://www. ncbi.nlm.nih.gov/books/NBK374316/

HIV/AIDS [Internet] World Health Organization. World Health Organization; c2023 [cited2023Mar2]. Available from: https://www.who.int/health-topics/hiv-aids.

Spec A, Powderly WG. Cryptococcal meningitis in AIDS. Handb Clin Neurol. St. Louis, MO: Elsevier; 2018;152:13950.

Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM, et al. Global burden of disease of HIVassociated cryptococcal meningitis: An updated analysis. Lancet Infect Dis. 2017;17(8):873-81.

Neurological Effects of Cryptococcal Meningitis Infection in HIV-Positive Individuals

Rajasingham R, Govender NP, Jordan A, Loyse A, Shroufi A, Denning DW, et al. The global burden of HIV-associated cryptococcal infection in adults in 2020: A modeling analysis. Lancet Infect Dis. 2022;22(12):1748-55.

22. Gnat S, Lagowski D, Nowakiewicz A, Dylag M. A global view on fungal infections in humans and animals: Infections caused by dimorphic fungi and dermatophytoses. J Appl Microbiol. 2021;131(6):2688-704.

Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009;23(4):525-30.

23. Sedghizadeh PP, Mahabady S, Allen CM. Opportunistic oral infections. Dent Clin North Am. 2017;61(2):389-400.

Ngan NTT, Flower B, Day JN. Treatment of cryptococcal meningitis: How have we got here and where are we going? Drugs. 2022;82(12):1237-49.

24. Shenoy N, Ramapuram JT, Shenoy A, Ahmed J, Srikant N. Incidence of opportunistic infections among HIV-positive adults on highly active antiretroviral therapy in a teaching hospital, India: Prospective study. J Int Assoc Provid AIDS Care. 2017;16(3):309-11.

10. Saylor D. Neurologic complications of human immunodeficiency virus infection. Continuum (Minneap Minn). 2018;24(5):1397-1421.

25. Tan IL, Smith BR, von Geldern G, Mateen FJ, McArthur JC. HIV-associated opportunistic infections of the CNS. Lancet Neurol. 2012;11(7):605-17.

11. Onyishi CU, May RC. Human immune polymorphisms associated with the risk of cryptococcal disease. Immunology. 2022;165(2):143-57.

26. Moylett EH, Shearer WT. HIV: Clinical manifestations. J Allergy Clin Immunol. 2002;110(1):3-16.

12. May RC, Stone NR, Wiesner DL, Bicanic T, Nielsen K. Cryptococcus: From environmental saprophyte to global pathogen. Nat Rev Microbiol. 2016;14(2):106-17. 13. Wake RM, Jarvis JN, Harrison TS, Govender NP. Brief Report: Point of care cryptococcal antigen screening: Pipetting finger-prick blood improves performance of immuno mycologics lateral flow assay. J Acquir Immune Defic Syndr. 2018;78(5):574-8.

27. Buchacz K, Lau B, Jing Y, Bosch R, Abraham AG, Gill MJ, et al. Incidence of AIDS-defining opportunistic infections in a multicohort analysis of HIV-infected persons in the United States and Canada, 2000-2010. J Infect Dis. 2016;214(6):862-72. 28. Limper AH, Adenis A, Le T, Harrison TS. Fungal infections in HIV/AIDS. Lancet Infect Dis. 2017;17(11):334-43. 29. Albarillo F, O'Keefe P. Opportunistic neurologic infections in patients with acquired immunodeficiency syndrome (AIDS). Curr Neurol Neurosci Rep. 2016;16(1):1-3.

14. Mohamed SH, Nyazika TK, Ssebambulidde K, Lionakis MS, Meya DB, Drummond RA. Fungal CNS infections in Africa: The neuroimmunology of cryptococcal meningitis. Front Immunol. 2022;13.

30. Sharma SR, Hussain M, Habung H. Neurological manifestations of HIV-AIDS at a tertiary care institute in North Eastern India. Neurol India. 2017;65(1):64-8.

15. Garcia HD, Janbon G, Dromer F. Epidemiological evidence for dormant Cryptococcus neoformans infection. J Clin Microbiol. 1999;37(10):3204-9.

31. Bramantono B, Danial A, Hadi U. A case of an AIDS patient with Cryptococcus neoformans infection. Pan Afr Med J. 2020;36:88.

16. Esher SK, Zaragoza O, Alspaugh JA. Cryptococcal pathogenic mechanisms: A dangerous trip from the environment to the brain. Mem Inst Oswaldo Cruz. 2018;113(7):180057.

32. Guiloff RJ, Tan SV. Central nervous system opportunistic infections in HIV disease: Clinical aspects. Baillieres Clin Neurol. 1992;1(1):103-54.

17. Williamson PR, Wakamatsu K, Ito S. Melanin biosynthesis in Cryptococcus neoformans. J Bacteriol. 1998;180(6):1570-2. 18. Rajasingham R, Wake RM, Beyene T, Katende A, Letang E, Boulware DR. Cryptococcal meningitis diagnostics and screening in the era of point-of-care laboratory testing. J Clin Microbiol. 2019;57(1)1238-18. 19. Loyse A, Moodley A, Rich P, Molloy SF, Bicanic T, Bishop L, et al. Neurological, visual, and MRI brain scan findings in 87 South African patients with HIV-associated cryptococcal meningoencephalitis. J Infect. 2015;70(6):668-75. 20. Pastick KA, Bangdiwala AS, Abassi M, Flynn AG, Morawski BM, Musubire AK, et al. Seizures in human immunodeficiency virus-associated cryptococcal meningitis: Predictors and outcomes. Open Forum Infect Dis. 2019;6(11):ofz478. 21. Riccardi N, Rotulo GA, Castagnola E. Definition of opportunistic infections in immunocompromised children on the basis of etiologies and clinical features: A summary for practical purposes. Curr Pediatr Rev. 2019;15(4):197-206.

33. Huang YJ, Tsai WC, Lien CY, Lee JJ, Lu CH, Chang WN. The clinical features and therapeutic outcomes of young adults with cryptococcal meningitis. Acta Neurol Taiwan. 2021;30(1):11-20. 34. Charlier C, Dromer F, Leveque C, Chartier L, Cordoliani YS, Fontanet A, et al. Cryptococcal neuroradiological lesions correlate with severity during cryptococcal meningoencephalitis in HIV-positive patients in the HAART era. PLoS One. 2008;3(4):e1950. 35. Likasitwattanakul S, Poneprasert B, Sirisanthana V. Cryptococcosis in HIV-infected children. Southeast Asian J Trop Med Public Health. 2004;35(4):935-9. 36. Lizarazo J, Escandon P, Agudelo CI, Castaneda E. Cryptococcosis in Colombian children and literature review. Mem Inst Oswaldo Cruz. 2014;109(6):797-804. 37. Jarvis JN, Lawrence DS, Meya DB, Kagimu E, Kasibante J, Mpoza E, et al. Single-dose liposomal amphotericin B treatment for cryptococcal meningitis. N Engl J Med. 2022;386(12):1109-20.

Neurological Effects of Cryptococcal Meningitis Infection in HIV-Positive Individuals

38. Williamson PR, Jarvis JN, Panackal AA, Fisher MC, Molloy SF, Loyse A, et al. Cryptococcal meningitis: Epidemiology, immunology, diagnosis and therapy. Nat Rev Neurol. 2017;13(1):13-24. 39. Molefi M, Chofle AA, Molloy SF, Kalluvya S, Changalucha JM, Cainelli F, et al. AMBITION-cm: Intermittent high dose AmBisome on a high dose fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa: Study protocol for a randomized controlled trial. Trials. 2015;16:276. 40. Kanyama C, Molloy SF, Chan AK, Lupiya D, Chawinga C, Adams J, et al. One-year mortality outcomes from the advancing cryptococcal meningitis treatment for Africa trial of cryptococcal meningitis treatment in Malawi. Clin Infect Dis. 2020;70(3):521-4. 41. Rhein J, Morawski BM, Hullsiek KH, Nabeta HW, Kiggundu R, Tugume L, et al. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: An open-label dose-ranging study. Lancet Infect Dis. 2016;16(7):809-18. 42. Wiederhold NP, Xu X, Wang A, Najvar LK, Garvey EP, Ottinger EA, et al. In vivo efficacy of VT-1129 against experimental cryptococcal meningitis with the use of a loading dose-maintenance dose administration strategy. Antimicrob Agents Chemother. 2018;62(11)1315-18. 43. Bahr NC, Skipper CP, Huppler HK, Ssebambulidde K, Morawski BM, Engen NW, et al. Recurrence of symptoms following cryptococcal meningitis: Characterizing a diagnostic conundrum with multiple etiologies. Clin Infect Dis. 2022;ciac853. 44. Vijayan T, Chiller T, Klausner JD. Sensitivity and specificity of a new cryptococcal antigen lateral flow assay in serum and cerebrospinal fluid. MLO Med Lab Obs. 2013;45(3):16-20. 45. Pasquier E, Kunda J, De Beaudrap P, Loyse A, Temfack E, Molloy SF, et al. Long-term mortality and disability in cryptococcal meningitis: A systematic literature review. Clin Infect Dis. 2018;66(7):1122-32. 46. Gushiken AC, Saharia KK, Baddley JW. Cryptococcosis. Infect Dis Clin North Am. 2021;35(2):493-514. 47. Chai Z, Shou Y, Mungur R, Gong J, Zheng P, Zheng J. Analysis of the efficacy and related factors of ventriculoperitoneal shunt for AIDS with cryptococcal meningitis. Front Surg. 2022;9:942506. 48. Espino BP, Morgan ML, Foroozan R, Lee AG. Neuroophthalmic presentations and treatment of cryptococcal meningitis-related increased intracranial pressure. Can J Ophthalmol. 2014;49(5):473-7.

51. Lencean SM, Ciurea AV. Intracranial hypertension: Classification and patterns of evolution. J Med Life. 2008;1(2):101-7. 52. Lee SC, Lueck CJ. Cerebrospinal fluid pressure in adults. J Neuroophthalmol. 2014;34(3):278-83. 53. Bø SH, Lundqvist C. Cerebrospinal fluid opening pressure in clinical practice - A prospective study. J Neurol. 2020;267(12):3696-701. 54. Kagimu E, Engen N, Ssebambulidde K, Kasibante J, Kiiza TK, Mpoza E, et al. Therapeutic lumbar punctures in human immunodeficiency virus-associated cryptococcal meningitis: Should opening pressure direct management? Open Forum Infect Dis. 2022;9(9):ofac416. 55. Munakomi S, J MD. Ventriculostomy. StatPearls, Treasure Island (FL): StatPearls Pub, 2022. 56. Fowler JB, De JO, Mesfin FB. Ventriculoperitoneal shunt. StatePearls, Treasure Island (FL): StatPearls Pub, 2022. 57. Liu L, Zhang R, Tang Y, Lu H. The use of ventriculoperitoneal shunts for uncontrollable intracranial hypertension in patients with HIV-associated cryptococcal meningitis with or without hydrocephalus. Biosci Trends. 2014;8(6):327-32. 58. Wen J, Yin R, Chang J, Chen Y, Dong X, Cao W, et al. Shortterm and long-term outcomes in patients with cryptococcal meningitis after ventriculoperitoneal shunt placement. Front Neurol. 2022;13:773374. 59. Zhao J, Liu J, Zhang Z, Li J, Xiao G, Liao X, et al. Treatment of cryptococcal meningitis by use of shunting and review in literature. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2016; 41(5):541-7. 60. Xu XL, Zhao T, Huang YQ, Lu YQ, He XJ, Wu YS, et al. Therapeutic lumbar puncture and lumbar drainage: Which is more effective for the management of intracranial hypertension in HIV patients with cryptococcal meningitis? Results of a prospective non-randomized interventional study in China. Curr Med Res Opin. 2022;38(5):803-10. 61. Baddley JW, Thompson GR 3rd, Riley KO, Moore MK, Moser SA, Pappas PG. Factors associated with ventriculoperitoneal shunt placement in patients with cryptococcal meningitis. Open Forum Infect Dis. 2019; 20;6(6):ofz241. 62. Mukendi D, Kalo JL, Kayembe T, Lutumba P, Barbé B, Gillet P, et al. Where there is no brain imaging: Safety and diagnostic value of lumbar puncture in patients with neurological disorders in a rural hospital of Central Africa. J Neurol Sci. 2018;393:72-79.

49. Bicanic T, Brouwer AE, Meintjes G, Rebe K, Limmathurotsakul D, Chierakul W, et al. Relationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures. AIDS. 2009;23(6):701-6. 50. Rolfes MA, Hullsiek KH, Rhein J, Nabeta HW, Taseera K, Schutz C, et al. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis. 2014;59(11):1607-14.

Scholarly Research In Progress • Vol. 7, November 2023

Declines in Influenza Vaccination Coverage in White and Black, Non-Hispanic Children from 2012–2019 to 2019–2022 Abigail L. Corle1* ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 *Master of Biomedical Sciences Program Correspondence: acorle@som.geisinger.edu

Abstract Declines in routine influenza vaccination rates have become a cause for concern as influenza vaccine coverage rates have declined among Black non-Hispanic children compared to an increase in coverage among White non-Hispanic children ages 6 months to 17 years old. Influenza season years analyzed were 2012–2022 using data provided by the US Center for Disease Control’s FluVaxView database. Data for this database are sourced from the National Immunization Survey–Flu and the Behavioral Risk Factor Surveillance System survey. White, non-Hispanic children saw an increase in vaccination coverage from 55.8% to 60.3%, whereas Black non-Hispanic children decreased from 58.2% to 52.9% coverage. Chi-squared tests with Yates correlation were performed to find statistical significance. Vaccination coverage rate changes for both demographics were found to be statistically significant at p < 0.00001. 70% influenza vaccination coverage rate remains the goal for the U.S. Department of Health’s Healthy People 2030 initiative for all demographics and may be achieved by utilizing interventional tools such as motivational interviewing, provider-patient dialogue, community-based vaccination clinics, or home visits. Evidence-based interventional provider-patient dialogue has had success in increasing vaccination rates among other vaccines. Continued research into the cause of influenza vaccination rate decline among vulnerable and medically underserved populations is needed to best implement vaccinebased interventions.

Introduction The influenza vaccine is a routine vaccine that has increased in importance in a post-COVID-19 world. During the COVID-19 pandemic, numerous campaigns were held to increase vaccination coverage for the influenza vaccine. Despite this, low vaccination rates of 52.9% coverage have been observed for Black non-Hispanic children in the 2019–2022 influenza seasons (1). The aforementioned low vaccination rate value is a substantial decrease from the 58.2% on average in the 2012– 2019 influenza seasons (1). Concern has been expressed for an influenza rebound following the COVID-19 pandemic that may lead to difficulties in controlling future influenza seasons (2). It is known that Black communities face a problem of health inequity, where vaccinations may be hindered by lack of transportation or information, geographic segregation, or cost as compared to White communities (3). Between 2012–2019 and 2019–2022, influenza vaccination rates rose among White non-Hispanic children, beginning at 55.8% and ending at 60.3% (1). Despite the many workforce hardships caused by COVID-19, it is known that the low vaccination rates were not caused by a lack of influenza vaccine supply (4).

Children ages 6 months to 17 years currently account for the largest amount of outpatient visits regarding respiratory illnesses. Additionally, influenza-related pediatric deaths have reached a 3-year high of 152 as of the week of May 19, 2023 (5). More research is required if this rate of influenza vaccine coverage has decreased enough to warrant additional actions (such as actively promoting vaccines) among the providers that care for Black non-Hispanic children. This data analysis was performed in order to investigate the significance of the low influenza vaccination rates among Black non-Hispanic children as compared to White non-Hispanic children.

Methods Datasets provided by the Centers for Disease Control and Prevention’s flu vaccine coverage database, FluVaxView, were analyzed. FluVaxView provides yearly data regarding percentage coverage of influenza vaccination in both children and adults based upon specific age, sex, race/ethnicity, geographical location (within the United States), and place of vaccination. FluVaxView compiles its data from National Immunization Survey–Flu (NIS-Flu) and Behavioral Risk Factor Surveillance System (BRFSS) surveys. BRFSS conducts its surveys largely through in-person interviews, whereas the NIS-Flu collects its data via state inpatient databases created by the Healthcare Cost and Utilization Project (1, 4). The exposure of interest is the impact of the COVID-19 pandemic. Using the “Percentage Vaccinated” variable, the CDC FluVaxView database’s change in influenza vaccination coverage percentage in the target populations of White and Black non-Hispanic children ages 6 months to 17 years old was analyzed and averaged based upon the ranges of 2012–2019 and 2019– 2022. The study was determined to be “Not Human Subject Research” by the IRB. Variation was utilized as a form of descriptive analysis to detect any major loss or gain in percentage vaccination coverage within the target population of both White and Black non-Hispanic children ages 6 months to 17 years old and depicted using a line series graph. All calculations were performed and compiled using Microsoft Excel 2023. Data was further analyzed using a chi-squared test without Yates correction and used to calculate the p-value. Chi-squared values will be determined using percentages of vaccination coverage given by FluVaxView.

Results Influenza vaccination coverage percentage among Black non-Hispanic children showed a decrease during 2019–2022 influenza seasons (58.2%) compared to pre-pandemic influenza seasons of 2012–2019 (52.9%) in Figure 1; vaccination coverage for White non-Hispanic children largely increased

Declines in Influenza Vaccination Coverage in White and Black, Non-Hispanic Children

Figure 1. Comparison of percentage influenza vaccine coverage in White and Black, non-Hispanic children ages 6 months to 17 years between 2012–2019 and 2019–2022.

from 55.8% to 60.3% as shown in Figure 1. Table 1 shows the sample size and percentage vaccinated for each influenza season by year for both demographics. The Black non-Hispanic chi-squared test in Table 2 showed a p-value X² (1, N = 137467) = 117.97, p < 0.00001. The White non-Hispanic chi-squared test in Table 3 also showed an identical, p value X² (1, N = 795636) = 2337.9, p < 0.00001.

Discussion A noticeable decrease in influenza vaccination rates was present among Black non-Hispanic children following the advent of the COVID-19 pandemic in 2020 compared to their pre-pandemic levels in the 2012–2019 influenza seasons. The final vaccination coverage value is far below the U.S. Department of Health’s Healthy People 2030 initiative’s desired target of 70% coverage by 2030 among all populations to better protect communities (6). The percentage coverage among White non-Hispanic children is also below this threshold; however, there is a greatly positive trend toward the goal. The positive increase in influenza vaccination rates among White nonHispanic children during 2019–2022

Year

White, Non-Hispanic Children

Black, Non-Hispanic Children

Percentage Vaccinated

2012-2013

53.8

61,350

56.7

10,414

2013-2014

55.2

75,934

57.2

12,934

2014-2015

74,683

58.3

13,368

2015-2016

55.3

73,660

60.9

13,717

2016-2017

54.3

100,341

59.3

14,196

2017-2018

55.6

69,289

55.3

11,919

2018-2019

60.5

80,684

59.5

13,171

2019-2020

63.1

88,926

57.9

14,517

2020-2021

60.4

82,087

49.1

15,105

2021-2022

57.4

88,682

51.6

18,126

Table 1. Compiled sample sizes and percentages of influenza vaccinated for White and Black non-Hispanic children for each influenza season from 2012–2019 and 2019–2022.

Vaccinated

Unvaccinated

p-value

Pre-Pandemic (2012-2019)

52216

37503

< 0.00001

Pandemic (2019-2022)

25259

22489

Table 2. Results calculated comparing the sample sized of Black non-Hispanic children ages 6 months to 17 years. Data is stratified by influenza vaccination status and influenza season years.

Declines in Influenza Vaccination Coverage in White and Black, Non-Hispanic Children

community-based vaccination clinics and home visits may provide an accessible Pre-Pandemic 299055 236886 < 0.00001 avenue for those with limited medical care (2012-2019) availability. More individualized medicine may also prove effective if communityPandemic 156596 103099 based education is already in place. (2019-2022) Evidence-based provider-patient dialogue Table 3. Results calculated comparing the sample sized of White non-Hispanic children ages 6 is an effective tool utilized to increase months to 17 years. Data is stratified by influenza vaccination status and influenza season years. vaccination coverage. Improving and combining individual-centered care and community-based education approaches is influenza seasons was unforeseen due to primary medical recommended to reach underserved communities and increase service utilization sharply declining during the COVID-19 vaccination rates. If an increase in healthcare accessibility pandemic (7). By partnering with community-based resources, occurs and evidence-based education is utilized, an increase in influenza vaccinations may be more attainable for Black noninfluenza vaccinations may result. Hispanic communities that experience health inequities that Vaccinated

Unvaccinated

may be absent among White communities (8). With mobile health care becoming more common, home visits for vaccination are a method that could increase vaccination coverage if medical clinics are inaccessible (9). Due the significance of the found p values, it is important to consider more personalized medicine to raise the vaccination rates among both demographics toward the desired target of 70% coverage. Motivational interviewing may be an effective patient-centered tool to convince patients of the benefits of vaccines and to dispel any myths the patient may believe regarding vaccines. Motivational interviewing entails creating an empathy-based partnership between the patient and the provider to foster a healthy learning environment for the patient to learn about vaccines without being judged or scrutinized (10). This style of provider-patient communication has been effective for other vaccines such as many neonatal vaccines, with vaccination coverage increasing as much as 15% across 3, 5, and 7 months of age (11). This study was subject to limitations due to data retrieval and stratification methods. The CDC FluVaxView tool does not include datasets stratified by both race/ethnicity and age; thus, supplemental estimates were utilized in calculations. Secondly, the CDC states that response rates for surveys conducted via NIS-Flu and BRFSS may be skewed due to both NIS-Flu and BRFSS excluding some households without a telephone (12). Lastly, recall bias may be present among the parents surveyed regarding their child’s influenza vaccination status (13). Future research regarding this topic should reference additional survey programs such as the National Health Interview Survey.

Conclusion A decrease in vaccinations among all demographics has been cause for concern in the current medical climate. Health inequities among Black non-Hispanic children have been increasingly prevalent due to the COVID-19 pandemic, leading to decreased average influenza vaccination coverage as compared to White non-Hispanic children. Inaccessibility to clinics and distrust in modern medicine have contributed to this decrease, showing the importance of community-based healthcare and medical education for those in communities experiencing health inequities to reverse the decrease in influenza vaccination coverage. Increased attention toward

p-value

Acknowledgments The author would like to express her deepest gratitude to Dr. Brian Piper for his feedback, guidance, and tutelage in the creation of this manuscript. Furthermore, the author would acknowledge the assistance of the VaxView team with the U.S. CDC for their assistance in acquiring the proper data sets.

Disclosures The author declares that she has no financial or pertinent conflicts of interest to share regarding the topics described in the paper.

References 1.

Flu vaccination coverage, United States, 2020–21 influenza season [Internet]. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention; 2021 [cited 2022Sep8]. Available from: https:// www.cdc.gov/flu/fluvaxview/coverage-2021estimates.htm

Lee SS, Viboud C, Petersen E. Understanding the rebound of influenza in the post covid-19 pandemic period holds important clues for epidemiology and Control. International Journal of Infectious Diseases [Internet]. 2022Aug3 [cited 2023Mar17];122:1002–4.

Brown IM, Khan A, Slocum J, Campbell LF, Lacey JR, Landry AM. Covid-19 disparities and the Black Community: A Health Equity–informed rapid response is needed. American Journal of Public Health [Internet]. 2020 [cited 2023Mar17];110(9):1350–1.

Early, low estimates for flu vaccination coverage in some groups raise concerns at CDC [Internet]. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention; 2021 [cited 2022Sep8]. Available from: https://www.cdc.gov/flu/spotlights/2021-2022/ early-vacccoverage.htm

Weekly U.S. Influenza Surveillance Report [Internet]. Centers for Disease Control and Prevention; 2023 [cited 2023 May 23]. Available from: https://www.cdc.gov/flu/ weekly/index.htm#PedMortality

Declines in Influenza Vaccination Coverage in White and Black, Non-Hispanic Children

Increase the proportion of people who get the flu vaccine every year - IID 09 [Internet]. Healthy People 2030. United States Department of Health and Human Services; [cited 2023Mar17]. Available from: https://health.gov/ healthypeople/objectives-and-data/browse-objectives/ vaccination/increase-proportion-people-who-get-fluvaccine-every-year-iid-09

Whaley CM, Pera MF, Cantor J, Chang J, Velasco J, Hagg HK, et al. Changes in health services use among commercially insured US populations during the covid-19 pandemic. JAMA Network Open [Internet]. 2020 Nov 5 [cited 2023 Jun 22];3(11).

Suryadevara M, Bonville CA, Ferraioli F, Domachowske JB. Community-centered education improves vaccination rates in children from low-income households. PEDIATRICS [Internet]. 2013Aug8 [cited 2023Mar17];132(2):319–25.

Brugha RF, Kevany JP. Maximizing immunization coverage through home visits: a controlled trial in an urban area of Ghana. Bull World Health Organ [Internet]. 1996 [cited 2023Mar17];74(5):517–24.

10. Zolezzi M, Paravattil B, El-Gaili T. Using motivational interviewing techniques to inform decision-making for covid-19 vaccination. International Journal of Clinical Pharmacy [Internet]. 2021 [cited 2023Mar17];43(6):1728–34. 11. Gagneur A, Lemaître T, Gosselin V, Farrands A, Carrier N, Petit G, et al. A postpartum vaccination promotion intervention using motivational interviewing techniques improves short-term vaccine coverage: Promovac study. BMC Public Health [Internet]. 2018 [cited 2023Mar17];18(1). 12. Flu vaccination coverage, United States, 2021–22 influenza season [Internet]. Centers for Disease Control and Prevention; 2022 [cited 2023 Jun 22]. 13. Brown C, Clayton-Boswell H, Chaves SS, Prill MM, Iwane MK, Szilagyi PG, et al. Validity of Parental Report of influenza vaccination in young children seeking medical care. Vaccine [Internet]. 2011 Oct 19 [cited 2023 Jun 22];29(51):9488–92.

Scholarly Research In Progress • Vol. 7, November 2023

Predicting Tracheal Airway Size in Adolescent Patients Jia Ying Zheng, BS1†, Vincent M. Desiato, MD², Shweta S. Kumar, MD², Aileen Wertz, MD², and Evan B. Young, MD² ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 ²Geisinger Medical Center, Danville, PA 17822 † Doctor of Medicine Program Correspondence: jzheng@som.geisinger.edu

Abstract Background: The relationship between tracheal airway size and BMI has not been investigated in the adolescent population. Currently in pediatric patients, tracheal tube size is selected according to patient age. We aimed to determine if there is a relationship between patient characteristics including age, height, weight, and body mass index (BMI) and tracheal airway dimensions in adolescent patients. Methods: Retrospective case series of patients aged 13 to 18 years old who underwent head and neck computed tomography (CT) at our institution from Jan. 1, 2009, to Dec. 31, 2019. Measurements were taken at the level of cricoid (subglottis) and narrowest anterior-posterior (A-P) diameter of the trachea. AP diameter, lateral diameter, and cross-sectional airway area were measured. Data analysis was done using bivariate analysis followed by linear regression to determine patient characteristics independently associated with tracheal airway size. Results: 156 neck CTs were eligible. Height and age were significantly associated with tracheal airway dimensions for both female and male patients (F: p < 0.001; M: p < 0.02). Weight and BMI were not associated with tracheal airway size (F: p > 0.1; M: p > 0.1). Linear regression modeling for both genders has a positive association with height at all airway levels, including at the narrowest A-P diameter and narrowest lateral diameter, which was always at the subglottis. Conclusion: Our results show estimating endotracheal tube size should consider height and patient's age, but not weight or BMI.

Introduction Estimating tracheal airway size for endotracheal tube (ETT) placement is challenging. A too-narrow tube provides inadequate airflow and ventilation (1). Using a larger-thannecessary tube is associated with increased morbidity due to laryngeal and tracheal trauma (2). Complications can include sore throat, hoarseness, vocal cord injury, acute laryngeal injury, granulomas, and laryngotracheal stenosis (3, 4). In adult populations, there are conflicting methods and no widely accepted guidelines for determining ETT size. Health staff often rely on clinical judgment (5, 6). A retrospective study found that larger endotracheal or tracheostomy tubes are often used in patients with a higher BMI, but that increases in body mass are not associated with increased tracheal size in adult patients; in fact, often the opposite is true (7). Currently, in pediatric patients, tracheal tube size is selected according to patient age (Cole formula: ID [inner diameter] = 4 + age/4 for uncuffed tube; Motoyama formula: ID = 3.5 + 4/ age for cuffed tube in children aged 2 or more years; Khine

formula: ID = 3.0 + 4/age for cuffed tube in children under 2 years of age) (8). Pediatric patients not only have a diverse range of body dimensions, but selection may be influenced by factors such as patient gender and body habitus. Studies have investigated the viability of using other methods besides the traditional age-based formulas to predict ETT size. In limited studies, ultrasonography was used to measure the subglottic upper airway (9) and, in another, diameter measurements of the epiphysis of the radius (10) were found to be correlated with ETT size. The relationship between tracheal airway size and BMI has not been investigated in the adolescent population. The adolescent population contains a diverse range of body dimensions. There is an additional challenge in that pediatric age-based formulas may not be accurate, and yet adult guidelines do not apply either. Multiple intubation attempts lead to greater risk of injury. A study found that the cross-sectional size of the trachea was 25% (218± 44 vs. 163±24 mm², P<0.01) larger in males vs. females among ages 13–17 years (11). In this project, we aimed to determine the relationship between patient characteristics including age, height, weight, and BMI and tracheal airway dimensions in the population of adolescent patients.

Methods This is a retrospective case series of patients aged 13 to 18 years old who underwent head and neck computed tomography (CT) at our institution from Jan. 1, 2009, to Dec. 31, 2019. Exclusion criteria were history of craniofacial or musculoskeletal abnormalities, tracheotomy/airway surgery prior to CT, head and neck malignancy, premature birth (<34 weeks) Variables gathered were age, gender, height, weight, and BMI. A single investigator collected measurement data using dedicated medical imaging software Aquarius TeraRecon version 4.4.14.P1 (52), which provides a 3D reconstruction of the airway. Measurements were taken at the level of cricoid which is synonymous with subglottis/narrowest lateral measurement (1–2 cm below glottis using visual exam and confirmation with TeraRecon) and narrowest anterior-posterior (A-P) diameter of the trachea. These measurements included A-P diameter, lateral diameter, and cross-sectional airway area. Data analysis was performed using Graphpad Prism. Bivariate analysis followed by linear regression was used to determine patient characteristics independently associated with airway size. Measurements of airway size that were included in data analysis included narrowest A-P and lateral diameter, as well as A-P and lateral cross-sectional area. Comparison across gender was accomplished using independent t test. This study received IRB approval (#2020-1090).

Predicting Tracheal Airway Size in Adolescent Patients

Results In this investigation,156 patients were included in which 73 (47%) were female. Three hundred twenty-five CT scans were initially identified as performed during the study period on patients in the proposed age range. There were 169 patients who were excluded due to history of craniofacial or musculoskeletal abnormalities, tracheotomy/airway surgery prior to CT or MRI, head and neck malignancy, premature birth (<34 weeks), and repeated CTs (in which the earliest CT in date range was used). The BMI range for males was 17.5 to 47.9 and was 15.8 to 43.1 for females. See Table 1 for demographic information and clinical characteristics.

AP (Trachea)

Entire Sample (n=156)

Female (n=73)

Male (n=83)

P value

Age (Y)

16.41 (1.68)

16.34 (1.73)

16.5 (1.65)

0.6522

BMI (kg m-2)

25.67 (6.74)

25.17 (5.87)

26.1 (7.46)

0.3875

AP (mm)

12.9 (2.45)

13.23 (2.61)

12.6 (2.28)

0.1085

Lateral (mm)

8.89 (1.55)

8.76 (1.6)

9.0 (1.47)

0.3577

AP Cross Sectional Area (mm2)

151.55 (46.75)

152.9 (52.91)

150.3 (42.99)

0.7343

Cricoid Cross Sectional Area (mm2)

112.4 (35.08)

108.2 (35.87)

116.2 (34.14)

0.2322

Table 1. Descriptive statistics for entire sample and stratified by gender, data obtained from CT head and neck done at Geisinger Commonwealth Medical Center from Jan. 1, 2009, to Dec. 31, 2019. Values are the mean (SD). P-values are for independent t-test result between male and female. BMI, body mass index; AP, anteroposterior measurement at narrowest point in trachea; lateral, lateral measurement at cricoid.

Lateral (Cricoid)

Airway Area (Trachea)

Airway Area (Cricoid)

Male

Female

Table 2. Bivariate Analysis. All airway lateral measurements in mm and area in mm². ** Statistically significant correlations. Data obtained from CT head and neck done at Geisinger Medical Center from Jan. 1, 2009, to Dec. 31, 2019.

Predicting Tracheal Airway Size in Adolescent Patients

The narrowest A-P diameter was found to always be the trachea. Narrowest lateral diameter was always at subglottis, synonymous with cricoid. These measurements were included in data analysis. Height and age were found to be correlated with CT A-P/lateral diameters and A-P/lateral cross-sectional airway area, as shown in Table 2. Height and age were significantly associated with tracheal airway dimensions for both female and male patients (F: p=2.17E-08, p=0.0001; M: p=6.675E-09, p=0.01626). Weight and BMI were not found to be significant predictors (F: p=1186, p=0.1739; M: p=0.1090, p=0.4687). Linear regression modelling (Figure 1) showed significant associations for females with height and age on both tracheal A-P and cricoid lateral diameters and A-P and cricoid crosssectional airway area. Age was a significant predictor of airway dimensions, including narrowest A-P (p= 0.0001), A-P crosssectional area (p=0.0008), cricoid lateral (p=0.0021), and cricoid cross-sectional area (p= 0.0160). Females also demonstrated

Narrowest AP Measurement (Trachea)

Narrowest Lateral Measurement (Cricoid)

an increased cricoid cross-sectional area with increased weight, but this relationship is not consistent with BMI trends or repeated in other airway measurements or in males. Although BMI and weight did not show statistical significance, Figure 2 shows the trend for smaller airway size when plotted against BMI. The male patient with a BMI of 17.5 had an A-P tracheal airway measurement of 14.6 mm and a subglottis of 9.8 mm. The male patient with a BMI of 47.9 had an A-P tracheal airway measurement of 9.8 mm and a subglottis of 8.67 mm in comparison. There was no statistically significant difference in height vs airway size between sexes (Table 1). There appears to be a larger A-P diameter measurement in females compared with males, but this was not shown to be significant (P= 0.1085). However, males had larger lateral diameter compared to females. Again, this was not found to be significant (P=0.3577).

Discussion The most important finding of this investigation is that height was most strongly positively correlated with cricoid area and narrowest tracheal area. An important secondary finding was weight and BMI were not associated with airway size, which differed from previous findings in adults that suggested they do (7). Current studies support that boys and girls have similar dimensions of the airways from birth until approximately age 14 (11). After this age, there is a difference between sexes, with significantly larger tracheal dimensions being found in boys than in girls (11). This difference is likely because of puberty (9), when growth of the central airways continues in boys and starts to decline in girls. Our results did not show a significant difference between sexes, and we did not further analyze the different in growth after age 14 but age itself was a predictor of airway size in both sexes. Age was a significant predictor of A-P and airway area, cricoid and airway area in female patients. Age was also a significant predictor in male patients, but only for cricoid and A-P airway area (Table 2). Another report showed that patients with elevated BMI may have smaller tracheal sizes in various dimensions than normal or low weight patients (12). However, the categorization for adolescent BMI is different from categorization for adults and

AP Cross Sectional Area (mm2)

Figure 1. Linear regression modelling of cross-sectional area and diameter at the narrowest AP and lateral airway measurements. Figures on the left show effect of age and on the right shows effect of height. None are significantly different between sexes. 44

Figure 2. BMI vs AP Cross-Sectional Area. Not statistically significant but suggests trend of smaller airway measurements with increasing BMI. Male: slope=-0.4643 R²=0.0065, p=0.4688; Female: slope= -0.9919, R²=0.01516 and p=0.3029.

Predicting Tracheal Airway Size in Adolescent Patients

varies by age percentile and gender (13), so this should be a consideration. It would be of interest to see how this study can be applied to a more diverse patient population. One hundred thirty-nine patients (89%) in this study were White, which may affect the applicability of this information in practice. Of the estimated 4,424 pediatric tracheostomies that occurred in 2012, 51% were ≤3 years old, and 62% were male. Nearly half (48%) were White, followed by Black (21%), Hispanic (20%), and Asian (3%) (14). There are preliminary studies suggesting that among pediatric Chinese populations, endotracheal tube size should be smaller (15), but this has not been extensively studied. A study with a population that includes patients of various heights, weights, body mass indexes, and ethnicities may be beneficial and more applicable to other adolescent populations.

Coordes A, Rademacher G, Knopke S. Selection and placement of oral ventilation tubes based on tracheal morphometry. Laryngoscope. 2011;121(6):1225-1230.

CBA Cao A, MD Rereddy S, Mirza N MD, (2021) Commentary on current practices in endotracheal tube size selection for adults. J Anesth Clin Res. 12:985.

D'Anza B, Knight J, Greene JS. Does body mass index predict tracheal airway size? Laryngoscope. 2015;125(5):1093-1097.

King BR, Baker MD, Braitman LE, Seidl-Friedman J, Schreiner MS. Endotracheal tube selection in children: a comparison of four methods. Ann Emerg Med. 1993;22(3):530-534.

Shibasaki M, Nakajima Y, Ishii S, Shimizu F, Shime N, Sessler DI. Prediction of pediatric endotracheal tube size by ultrasonography. Anesthesiology. 2010 Oct;113(4):819-24.

A limitation of this study is that it was a retrospective chart review of a limited population. CT images obtained were not all conducted with the same protocol or have the same image quality. There are cross-section changes during breathing which could potentially affect airway dimensions. Another limitation of this study is the inability to completely exclude the potential of some degree of underlying pathologic airway disease that could lead to airway changes, despite adherence to the exclusion criteria.

10. Kim HY, Cheon JH, Baek SH, Kim KH, Kim TK. Prediction of endotracheal tube size for pediatric patients from the epiphysis diameter of radius. Korean J Anesthesiol. 2017;70(1):52-57.

Conclusion

12. Fenley H, Voorman M, Dove JT, Greene JS. Predicting pediatric tracheal airway size from anthropomorphic measurements. Int J Pediatr Otorhinolaryngol. 2020;134:110020.

Our results show estimating endotracheal or tracheostomy tube size should consider height and the patient's age. We may also consider in the future whether race and gender have any effect. A study with a population that includes patients of various heights, weights, body mass indexes, and ethnicities may be beneficial and more generalizable to other pediatric/ adolescent populations.

Acknowledgments Joseph Scott Greene, MD (Geisinger): Critically reviewed the study proposal.

Disclosures

11. Ripoll, Juan G. Sex differences in paediatric airway anatomy. Experimental Physiology. 105,4 (2020): 721-731.

13. Randestad A, Lindholm CE, Fabian P. Dimensions of the cricoid cartilage and the trachea. Laryngoscope. 2000;110(11):1957-1961. 14. Sakai M, Kou YF, Shah GB, Johnson RF. Tracheostomy demographics and outcomes among pediatric patients ages 18 years or younger-United States 2012. Laryngoscope. 2019;129(7):1706-1711. 15. Chan WH, Sung CW, Chang HCH, Ko PCI, Huang EPC. (2020) Measurement of subglottic diameter and distance to pre-epiglottic space among Chinese adults. PLOS ONE 15(7): e0236364.

The authors have nothing to disclose.

References 1.

Ahmed RA, Boyer TJ. Endotracheal Tube. [Updated 2021 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https:// www.ncbi.nlm.nih.gov/books/NBK539747/

Hillel AT, Karatayli-Ozgursoy S, Samad I. Predictors of posterior glottic stenosis: a multi-institutional case-control study. Ann Otol Rhinol Laryngol. 2016;125(3):257-263.

Gomes Cordeiro AM, Fernandes JC, Troster EJ. Possible risk factors associated with moderate or severe airway injuries in children who underwent endotracheal intubation. Pediatr Crit Care Med. 2004;5(4):364-368.

Pluijms, W.A., van Mook, W.N., Wittekamp, B.H. Postextubation laryngeal edema and stridor resulting in respiratory failure in critically ill adult patients: updated review. Crit Care 19, 295 (2015). 45

Scholarly Research In Progress • Vol. 7, November 2023

Monitoring Hand Hygiene Adherence Through the Perception of the Hawthorne Effect: An Observational Study in Hospital Settings Miranda Chen1†‡, Mira Patel1†‡, Alexis Notarianni1†‡, and Miranda Rep1†‡ ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 † Doctor of Medicine Program ‡ Authors contributed equally Correspondence: mchen03@som.geisinger.edu

Abstract Standardized hand hygiene protocols are crucial in reducing the incidence of hospital-acquired infections. However, compliance rates among healthcare workers remain suboptimal, necessitating strategies to improve adherence. The Hawthorne effect, wherein individuals modify their behavior due to awareness of being observed, presents challenges in accurately monitoring hand hygiene practices. The quality improvement project described in this study aimed to increase hand hygiene adherence by leveraging the Hawthorne effect, by increasing staff awareness of being observed over two months. Three of seven hospital units participated, and hand hygiene compliance was assessed using direct observations and indirect estimates by product usage. The two measures demonstrated contrary trends over time in compliance rates. Estimations by product usage showed a 20% increase in compliance at the end of the two months, while direct observations did not show any significant change. With these preliminary findings, we cannot yet conclude that this quality improvement project led to increased hand hygiene adherence.

Introduction Standardized hand hygiene protocols are essential in healthcare settings to mitigate the risk of healthcare-associated infections (1). Despite routine infection control training, healthcare workers exhibit suboptimal compliance rates, with some institutions finding hand sanitization occurring in only approximately half of the appropriate instances (1). The most commonly used method of measurement of hand hygiene compliance rates is direct observation, in which human auditors monitor the hand hygiene compliance of healthcare workers as they go about their regular duties. This method of measurement is often complicated by different biases, including the Hawthorne effect. The Hawthorne effect refers to the tendency of individuals to modify their behavior due to the awareness of being observed. Since human observation influences its subjects, electronic tracking of hand hygiene product use has also been introduced. This may seem like a superior measuring system at first glance. However, unlike human observers, automated counts are not easily adaptable in evolving clinical contexts. For example, tracking product use without concomitantly tracking room entries does not account for bundled care, which minimizes the number of entries into a patient room by combining multiple tasks in one patient encounter. While human observers understand that this decreases the number of handwashing

opportunities, tracking product use alone would yield an artificially low estimate of compliance. It has been shown that the Hawthorne effect transiently increases hand hygiene compliance rates, as healthcare workers tend to follow hand hygiene protocols more closely if they believe they are being monitored (2). Understanding this trend, some healthcare systems have utilized the Hawthorne effect to their advantage by strategically deploying trained auditors to improve compliance rates (3). In the quality improvement project described in this study, we sought to leverage the Hawthorne effect to improve hand hygiene adherence at the Geisinger Lewistown Hospital (GLH) by announcing increased monitoring of staff hand hygiene practices on participating units during the two-month study period. We describe the first cycle of this new quality improvement project. This project may be repeated or revised by subsequent student cohorts.

Methods Three units at Geisinger Lewistown Hospital (GLH) were selected for implementation: Med Surg (Unit 3B), Telemetry (Unit 4B), and Onco Med Surg (Unit 5A). Posters announcing a "new hand hygiene initiative" were placed in staff-only areas, accompanied by printed reminders about best practices. The posters implied that GLH would monitor hand hygiene practices more closely for the months of December 2022 and January 2023. This message was reinforced during morning huddles every day on participating units. Only nurse leaders and a small number of support staff were privy to the project design. Two measures of hand hygiene compliance were collected, yielding separate data sets over the study period. The first measure was direct human observation, reported by select staff members. No new personnel were recruited for this study because the hospital was already monitoring hand hygiene this way. Staff observers were required to record a minimum of 20 observations per month of hand hygiene opportunities for their assigned units; if this was not met, the data was excluded. Designated staff observers were instructed to record every hand hygiene opportunity that occurred in their field of vision in 5- or 10-minute sessions to minimize selection bias when recording observations. Due to staff scheduling, this data was primarily collected during the day shift on weekdays. The second measure was a series of indirect estimates based on automated refill counts of hand sanitizer dispensers, or “product counts.” One refill of an electronic dispenser corresponded to approximately 200 dispenses; therefore, dispenses were counted in increments of 200. The hospital had pre-calculated

Monitoring Hand Hygiene Adherence Through the Perception of the Hawthorne Effect

Table 1. Compliance rates reported by staff observers on their respective units for the months of November 2022 through February 2023. Figure 1. Handwashing compliance reported by staff observers on the three units where increased observation was announced. There was no significant change in compliance rates combined across units. Red – 3B, green – 4B, blue – 5A.

Table 2. Estimated compliance by unit by month based on patientdays, approximate number of hand sanitizer dispenses, and expected number of hand sanitizer dispenses. Pooled monthly totals are included as used in the subsequent statistical analysis.

estimates of how many dispenser refills would be needed on each unit to meet 100% compliance, adjusted for patientdays and tailored to individual units (Table 1). Using these calculations, compliance was estimated by comparing actual product counts against expected product counts. Because this was an indirect measure, we reasoned that analyzing change over time would yield more useful information than the absolute values of individual estimates. We also predicted that since this measure would theoretically not be influenced by the Hawthorne effect, the product count-derived estimates would be lower than observer-reported compliance rates. Data was exported for all hospital units, including nonparticipating units (6B, OB, ICU, and ED) and was compiled to span the announced observation period and at least one month prior. Compliance rates on participating units were plotted by month and trends over time were compared between the two measures. For statistical analysis, data from participating units was pooled for maximum sample size. The two-sample z-test was used to calculate a 95% confidence interval (CI) for changes in compliance between the months prior to the announcements and the end of the study period.

Results Data that were available for export and analysis are shown in Tables 1 and 2. The number of direct human observations

Figure 2. Estimated handwashing compliance on the three participating units, calculated by product count (i.e., hand sanitizer dispenser refills) from October 2022 to January 2023. Estimated compliance, combined across units, was 20% higher in January than in November. Red – 3B, green – 4B, blue – 5A.

submitted by staff each month was not included in the data exports, so monthly observations could not be pooled across units. For statistical testing, they were combined into unweighted averages with a conservative assumption of 20 observations per data point. The two measures of hand hygiene compliance, direct observations vs. product counts, exhibited divergent compliance rates in both absolute values and trends over time (Figures 1 and 2). Staff-observed compliance reached a maximum of 100% while product count estimates never surpassed 80%. In December 2022, overall compliance peaked in observer reports but reached its lowest point according to product counts. Analyzing product counts alone revealed a statistically significant increase of approximately 20% (95% CI: 9.6% – 31%) in combined handwashing rates for the three units from November 2022 to January 2023. Notably, product counts from all hospital units showed an increase in the same time period: combined product counts from the non-participating units increased from 68% to 84% (95% CI: 4.9% – 27%). Data from October 2022 were incomplete and not used for analysis. 47

Monitoring Hand Hygiene Adherence Through the Perception of the Hawthorne Effect

There was no significant change in hand hygiene compliance reported by staff observers from November to January.

Discussion In this study, the inconsistencies between direct observations and product count data once again highlight the challenges of measuring compliance accurately. The Hawthorne effect was known to be a likely culprit in elevating staff-observed compliance rates compared to the automated product counts. Other human biases may have also contributed to differences between the data sets, such as subjective pressures on staff observers to make their home units appear more adherent. The statistically significant increase in handwashing based on product counts is consistent with our hypothesis that announcing increased monitoring could influence hand hygiene practices in the hospital; However, we hesitate to attribute this increase to the announcements and posters because of the vast inconsistencies between the two measures of compliance used. There are at least three potential explanations for the significant increase found in the product count data. First, the morning huddles, where staff were verbally reminded about the handwashing initiative, involved staff members who worked on multiple units. This may have spread the awareness of “being watched” to non-participating hospital units. Second, confounders such as floor-specific hand hygiene initiatives and seasonal patterns may have boosted compliance during the study period. Finally, the refill-counting system itself was new, going live the same month that this project began collecting data. While no specific problems were noted, it is possible that the product counts were less reliable in the first few months of rollout. Having baseline data across longer time periods, ideally years, would give better context to these preliminary findings. Our hope is that this quality improvement project will be continued by subsequent student cohorts. This first cycle will serve as a baseline for further study. Another potential contributor to differences between observerreported compliance and the estimates by product count is the practice of bundled care, as mentioned previously. It would be helpful to investigate whether bundled care is practiced more often during certain times of year, such as around holidays when staffing is lighter. These seasonal patterns would influence the hand hygiene compliance estimates from the product count system. Extensions of this preliminary study may include anonymous interviews with staff observers to explore observer bias. A qualitative study of staff members’ attitudes and beliefs about their hand hygiene habits would also be worthwhile. Insight into these areas will allow hospitals to target more specific human thoughts and behaviors to improve hand hygiene practices.

Conclusion In this quality improvement project, we aimed to leverage the Hawthorne effect to increase hand hygiene adherence by announcing increased monitoring of staff behavior in three hospital units. The direct and indirect measures of compliance used in this study demonstrated contrary trends in compliance rates. Staff compliance based on direct observations did not significantly change from the beginning to the end of the study period. While the product count analysis indicated a statistically 48

significant increase in adjusted hand sanitizer use, we hesitate to attribute the improvement to the project announcements. Further iterations of this study design are needed to support this assertion.

Acknowledgments The authors would like to thank Kathleen Depra, RN, regional director of quality & patient safety at Geisinger Lewistown Hospital, for her guidance and immense support throughout the development and execution of this project.

Disclosures We have no financial conflicts of interest to disclose.

References 1.

Makhni S, Umscheid CA, Soo J, et al. Hand Hygiene Compliance Rate During the COVID-19 Pandemic. JAMA Intern Med. 2021;181(7):1006–1008.

Srigley JA, Furness CD, Baker GR, Gardam M. Quantification of the Hawthorne effect in hand hygiene compliance monitoring using an electronic monitoring system: a retrospective cohort study. BMJ Qual Saf. 2014;23(12):974-980.

McDonald EG, Smyth E, Smyth L, Lee TC. Hand hygiene "hall monitors": Leveraging the Hawthorne effect. Am J Infect Control. 2018;46(6):706-707.

Scholarly Research In Progress • Vol. 7, November 2023

Open Transforaminal Lumbar Interbody Fusion Surgery and Minimally Invasive Transforaminal Lumbar Interbody Fusion Surgery: An Overview of Patient Demographics Adam Cole1† and Frank Vazquez1† ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 † Doctor of Medicine Program Correspondence: acole@som.geisinger.edu

Abstract Lumbar fusion procedures are indicated for patients with spinal instability with disabling symptoms and radiographic evidence of increased segmental spinal motion that have not responded to conservative treatments (1). This study examines patient demographics of individuals who underwent transforaminal lumber interbody fusion surgery from a hospital system in northeastern Pennsylvania to analyze the patient populations for two surgical techniques. A total of 36 patients who underwent transforaminal lumbar interbody fusion surgery were randomly selected from November 2019 through January 2023. One half of the patients underwent a minimally invasive transforaminal lumbar interbody fusion (MITLIF) surgery, while the other half underwent open transforaminal lumbar interbody fusion (TLIF) surgery. The analysis provides a general overview of patient demographics for each surgical approach and offers demographic information to be used in future studies to perform statistical assessments to examine patient indications for each approach.

Introduction Transforaminal lumbar interbody fusion (MITLIF) surgery was first described in 1982 by Harms and Rollinger (2). The procedure is used for stabilization and treatment of degenerative lumbar diseases such as spinal stenosis, degenerative disks, spondylolisthesis, or degenerative scoliosis (3). Its conception resulted from an attempt to limit the amount of neural retraction required to decrease potential nerve root injury, dural tears, and epidural fibrosis (3), while also trying to improve bone fusion due to increased laminar surface area for new bone to grow (1). The difficulty of the TLIF surgery is that it requires significant muscle dissection and retraction (2). As a result, the procedure is associated with lengthy hospital stays and significant costs (4) and is reported to be associated with a higher complication rate (5). The minimally invasive transforaminal lumbar interbody fusion (MITLIF) was therefore developed to minimize iatrogenic soft tissue trauma and improve overall patient outcomes (2). MITLIF attempts to achieve this through leaving the smallest operative footprint possible, using a unilateral approach when necessary to attain bilateral decompression, and achieve indirect neural decompression (5). Understanding patient demographics is important for establishing indications for each approach. By collecting demographic information, future studies will be able to determine statistically important patient characteristics for

selecting one approach over the other, ensuring that patients undergo lumbar fusion surgery using the correct surgical approach.

Methods A list of orthopaedic spinal surgeries performed at various Geisinger hospitals from November 2019 to January 2023 was obtained. Patients were then randomly selected from the list. Surgeries which included the neurological surgery department were excluded. Only patients who self-reported all the demographic variables examined in this analysis were included. Variables examined included height, weight, age, sex, race, and number of care partners. In total, 36 patients were selected. One half of the patients underwent TLIF surgery, while the other half underwent MITLIF surgery.

Results Height, weight, race, and number of care partners were selfreported by the patients. Body mass index (BMI) was then calculated using the patient-reported height and weight. Age and sex were recorded from the patients’ electronic health records. Mean height, mean weight, mean BMI, mean age, number of males and females, and the race of the patients for each surgical approach are shown in Table 1. Median values for age, height, weight, and BMI are also shown in Table 1. No statistical analysis was conducted to compare the two patient populations.

Discussion This analysis offers a general overview of patient demographics for each type of surgical approach. Aggregating demographic information for patients undergoing each type of surgery will provide data for future statistical analyses about who are the best surgical candidates for each type of procedure. On average, patients for both TLIF and MITLIF surgeries tended to be older than 55 years old (58.3 and 56.2 years old, respectively), overweight or obese (32.8 kg/m2 and 27.8 kg/ m2, respectively (note, a BMI of 25–29.9 kg/m2 is considered overweight, and a BMI >30 kg/m2 is considered obese (6)), and White (94% White for both surgeries). Additionally, most patients for both TLIF and MITLIF procedures were female (61% and 67%, respectively). In each patient group, 15 out of 18 individuals reported having at least one care partner. The major limitation of this study was the lack of statistics performed. Without statistical analyses, significant similarities

Open and Minimally Invasive Transforaminal Lumbar Interbody Fusion Surgery

Table 1. Demographic Characteristics of Selected Patients Who Underwent Transforaminal Lumbar Interbody Fusion or Minimally Invasive Transforaminal Lumbar Interbody Fusion Procedures.

or differences cannot be determined. Additionally, this analysis is limited by the number of patients examined. Increasing the total patient number would provide a more accurate assessment of demographics for each group. Future studies should examine a larger population size and statistically compare the patient populations and determine whether significant similarities or differences exist between the two groups to determine selection criteria for the two surgical approaches.

Conclusion The analysis performed on this patient population was intended to compile demographic information about the populations of each surgical technique. Patient characteristics were collected from medical health records, in addition to the characteristics self-reported by the patients. While the goal of this analysis is to provide an overview of patient demographics for the different surgical approaches, statistical analysis of demographic data is crucial to improving healthcare. Compiling the demographic data is necessary for future studies to perform statistical analyses about the different surgical techniques.

References 1.

Sakeb P N, Ahsan K. Comparison of the early results of transforaminal lumbar interbody fusion and posterior lumbar interbody fusion in symptomatic lumbar instability. Ind J of Ortho. 2013;47(3):255–63. doi:10.4103/00195413.111484

Hammad A, Wirries A, Ardeshiri A, Nikiforov O, Geiger F. Open versus minimally invasive TLIF: Literature review and meta-analysis. J Ortho Surg and Research. 2019;14(1). doi:10.1186/s13018-019-1266-y

Mobbs RJ, Phan K, Malham G, Seex K, Rao PJ. Lumbar interbody fusion: techniques, indications and comparison of interbody fusion options including PLIF, TLIF, MI-TLIF, OLIF/ATP, LLIF and ALIF. J Spine Surg. 2015 Dec;1(1):2-18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039869/. doi: 10.3978/j.issn.2414-469X.2015.10.05

Foley KT, Holly LT, Schwender JD. Minimally Invasive Lumbar Fusion. Spine. 2003;28(supplement). doi:10.1097/01.brs.0000076895.52418.5e

Lener S, Wipplinger C, Hernandez RN, Hussain I, Kirnaz S, Navarro-Ramirez R, et al. Defining the mis-TLIF: A systematic review of techniques and technologies used by surgeons worldwide. Global Spine J. 2020;10(2). doi:10.1177/2192568219882346

Assessing your weight [Internet]. Centers for Disease Control and Prevention; 2022 [cited 2023 Jun 2]. Available from: https://www.cdc.gov/healthyweight/assessing/index. html

Scholarly Research In Progress • Vol. 7, November 2023

Risks and Benefits of LASIK Surgery Jonelle J. James1‡, Tamara A. Katz1‡, Abigail N. Bielecki1‡, and Bryne N. Cunningham1‡ ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 ‡ Authors contributed equally Correspondence: jjames01@som.geisinger.edu

Abstract Millions of individuals around the world suffer from refractive error in the eyes and, as a result, poor vision. Laser-assisted in situ keratomileusis (LASIK) is a procedure characterized by the correction of optical dysfunction for those who desire higher visual acuity. There are several pros and cons to undergoing the treatment, and selected candidates should carefully consider how the procedure may affect their quality of life, alternatives to LASIK, and potential risks of receiving the surgery. Studies indicate that this procedure may have positive effects on mental well-being and high overall satisfaction ratings following the surgery due to mostly optimal results. Meanwhile, alternatives to LASIK treatment may offer benefits to certain individuals, including faster healing time, harm reduction, and an option for those who cannot receive LASIK. Following treatment, some patients may experience flap abnormalities, gas bubble formation, rupture of the ocular vessels, disrupted vision, chronic dry eye, and corneal pain. Although rare, these possibilities are important to consider before undergoing LASIK. The purpose of this review is to provide an in-depth summary of each factor to highlight the benefits and risks that certain individuals may experience following surgery. Additionally, we will discuss clinical trials surrounding the healing process and control for postoperative pain following the vision correction procedure.

that we see. Blurry vision is caused by the light rays bouncing into the wrong parts of the eye and not focusing on the retina (3). Before undergoing LASIK surgery, it is important to have a complete eye examination from the patient’s optometrist, who will then refer them to the ophthalmologist for surgery in most states in the United States (4). Only 10 states allow optometrists to perform laser surgery if certified by the Board of Optometry (5). Laser surgeries such as argon laser

Introduction Laser-assisted in situ keratomileusis (LASIK) is a surgical procedure to correct various visual refractive errors. LASIK is typically an ophthalmic surgical procedure that was patented by Gholam Peyman, MD, in 1989. The surgery quickly became popular on account of its quick recovery time, reduced postsurgical adverse effects, and ideal circumstances or efficacy for surgery (1). LASIK is used to treat myopia, hyperopia, and astigmatisms by changing the physical shape of the cornea and stroma, in turn improving visual acuity (2). The surgery allows the doctor to alter the refractive power in the patient’s cornea (1). Nearly 50% of individuals are estimated to suffer from such visual deficits, while close to 16 million LASIK procedures have been performed since the surgery’s inception into ophthalmic practice (2). A refractive error occurs in the patient’s eye when the light coming into the eye does not bend light correctly. Clear vision results from the proper flow of light into the retina. The light will first enter the surface of the eye, which then proceeds through the cornea and lens, and lastly, reflects onto the retina (Figure 1). In order to see clearly, when light enters the eye, it proceeds through the cornea through the lens in the before until the reflected light arrives at the retina. Once the light rays reach the retina, the light is transformed into the signals sent to the brain, which become the different shapes, lines, and in turn, objects

Figure 1. Anatomy of the Human Eye. The human eye is separated into three compartments: the eye's surface, the front of the eye, and the back of the eye. The eye's surface consists of a membrane known as the conjunctiva (64). The tear film coats the outer surface of the eye to maintain lubrication and consists of three layers: mucous (most inner layer), watery (middle layer), and oil (outer layer) (64). The conjunctiva generates the mucous layer, while glands surrounding the eye orbit supply tears to the watery and oil layer (not illustrated) (64). Light passes into the eye through the cornea. Posterior to the cornea is the anterior chamber, which constantly produces aqueous humor, which regulates the eye's pressure. Following the anterior chamber is the pupil, surrounded by the iris, the portion of the eye that contains color. Behind the pupil and iris is the lens, whose primary function is to focus the light that enters the eye (64). The cavity containing the vitreous humor separates the lens and the tissue of the back of the eye, known as the retina. The retina contains photoreceptors that transmit visual signals to the brain in response to light (64). Lastly, the macula of the retina mainly functions in detailed and central vision, and the peripheral retina allows for our peripheral vision. Image from Vecteezy.com (65) 51

Risks and Benefits of LASIK Surgery

trabeculoplasty (ALT), selective laser trabeculoplasty (SLT), and laser peripheral iridotomy (LPI) treat glaucoma. YAG laser capsulotomy treats complications post-cataract surgery, and photorefractive keratectomy (PRK) treats abnormal vision due to eye refractive errors (5). Alaska and Oklahoma allow optometrists to perform all five types of laser surgery (5). Colorado, Indiana, Kentucky, Louisiana, Wyoming, and Virginia cover four, excluding PRK (5). Arkansas allows optometrists access to YAG, ALT, and SLT surgeries (5). Mississippi only allows for the YAG capsulotomy cataract surgery (5). It is also necessary to have a medical examination by the patient’s primary care physician. Typical candidates for LASIK surgery are those with myopia, hyperopia, or astigmatism, but there are other irregularities that doctors may look for before the surgery (Figure 2). They will test for irregular astigmatism, forme fruste keratoconus, and keratoconus to determine whether the surgery will lead to unforeseeable complications. An essential attribute to have before surgery to be a good candidate would be on a stable prescription for at least 1 year staying within 0.5 diopters of the previous refraction (4). Prescriptions are measured in the unit diopters, which is the refractive power equal to the reciprocal, in meters, of the focal length. According to a study conducted in Cleveland, a surgeon had specific criteria for LASIK surgery candidates, which are similar requirements for other practices (6). A patient with myopia should have less than or equal to 10.5 diopters, hyperopia should have less than or equal to 4.50 diopters, and astigmatism should be less than or equal to 6.00 diopters (4). The other measurable requirement of surgery is the corneal thickness consisting of more than 480 μm, measured using ultrasonic pachymetry. It is also important to not have any signs of abnormalities in the cornea that would suggest keratoconus or corneal diseases, or other ocular pathology. Those who are pregnant should not have this surgery (6). If cataracts were detected during the exam using a slit lamp, the patient would not be suitable for LASIK surgery (7). According to the American Academy of Ophthalmology, keratoconus is the thinning of the cornea and bulging outward, which, as mentioned before, can make the light rays not land correctly on the cornea. The cause of keratoconus is still unknown but is likely genetic and can be connected to excessive eye rubbing, allergies, and connective tissue diseases. Two genetic diseases are known to cause keratoconus: EhlersDanlos syndrome and Marfan syndrome (3). In LASIK treatment, a specialized laser or microkeratome is used to create a corneal flap which is then displaced to change the stromal structure beneath before the flap is repositioned (8) (Figure 3). For individuals with near-sightedness (myopia), the surgery consists of decreasing the overall curvature of the cornea, which would reduce the eye's refractive power (1). High myopia can be a greater risk for post-LASIK ectasia and reduced vision quality (4). In patients who suffer from farsightedness (hyperopia), the corneal surface is flattened, increasing refractive power. This corrective

surgery offers promising results to those who have suffered visual complications throughout their lifetime. However, it is important to note several risks (and benefits) associated with the LASIK procedure (1). This review will examine the risks, benefits, alternatives, and studies of LASIK eye surgery.

Methods A review of the literature was conducted using selected sources through the PubMed database and Google advanced search and keywords, phrases, and terms such as “LASIK,” “Alternatives to LASIK eye surgery,” “Benefits of LASIK,” and “Risks of LASIK.”

Figure 2. Common Visual Abnormalities Treated with LASIK. Patients with visual abnormalities such as myopia, hyperopia, and astigmatism can undergo LASIK surgery to improve vision by altering the eye’s refractive power. Myopia, also known as near-sightedness, occurs when light cannot focus on the retina (1). LASIK would decrease the cornea's curvature for patients with myopia to reduce the eye’s refractive power (1). Patients who suffer from farsightedness experience hyperopia due to a flattened cornea surface, thus increasing the eye's refractive power and causing blurry vision of nearby objects (1). Reshaping the cornea during the LASIK procedure can correct the pathway in which light travels through the eye (1). Astigmatism occurs due to an abnormal curvature of the cornea and lens in the eye, light refraction error, and causing blurry vision at varying distances. Image from Vecteezy.com (66).

Figure 3. Overview of LASIK Surgery. Before surgery, numbing medication is administered to the eye, and surgical instruments are used to hold the eyelids open. A suction ring is placed on the eye prior to cutting the hinged corneal flap (1). Microkeratome or femtosecond laser pulses reshape the cornea (1). Small amounts of cornea tissue are removed by photoablation based on the patient's indication (1). The corneal flap is then sealed and repositioned to the original position. Postsurgical care can include but is not limited to artificial tear drops, antibiotics, and steroidal eye drops (1).

Risks and Benefits of LASIK Surgery

The articles and journals selected were published during 2023 and the past 30 years. The team evaluated the articles, journals, and authors to ensure appropriate quality and standards. All patients, regardless of age, race, and gender, were included in this paper to expand on the variety and accuracy of LASIK surgery. The team used all the resources to build a list of advantages and disadvantages for any person who has had LASIK or is considering having LASIK completed and the available alternatives to the surgery. The criteria for articles that were selected to be included in this review were those that were peer-reviewed, didn’t have any disclosures that are a conflict of interest, and included significant data from the research. Single-patient case studies were excluded from this review. Overall, the literature included needed to be from reputable journals known to have accurate information on this topic.

Discussion Effects of Lasik Procedure on Mental Health and Quality of Life Individuals who suffer from visual impairment are likely to also suffer from mental disturbances, such as both depression and anxiety, which may lead to significant influences on quality of life and well-being (9). It appears that as visual acuity declines, symptoms of depression worsen, suggesting a clear association (9). Unfortunately, feelings of depression can exacerbate vision loss by affecting personal choices, such as engaging in dangerous behavior (e.g., smoking and drug use) (9). Certain antidepressant medications can promote abnormal neurotransmitter functioning, decreasing visual processing (9). Additionally, it seems that anxiety, including obsessivecompulsive disorder, paranoia, and post-traumatic stress disorder, plays a small role in visual impairment (9). This may be attributed to the feelings of distress surrounding thoughts of living life with a disability (9). Patterns of anxiety are typically seen in adults and children affected by visual disturbances (9). Both depression and anxiety may also lead to diminished social interaction and affect an individual’s ability to perform daily tasks (9). These factors are detrimental to the lives of millions worldwide; mental health and quality of life are just a few components that highlight the significance of visual impairment (9). The LASIK procedure can positively impact the lives and wellbeing of those with visual impairments that can be corrected by surgical intervention (10). A recent study was conducted to explore the association between LASIK and mental healthrelated quality of life and the factors that may lead to improved well-being (10). This team of researchers found that refractive surgery had the potential to alleviate psychological disturbances and improve physical ability in the first month following the surgery (10). Factors such as self-esteem, lower stress levels, and confidence were dramatically enhanced (10–25%) (10). Interestingly, the improvements in quality of life may be seen on the first day after the procedure; however, the highest level of quality of life comes later in the recovery period. (10). Unfortunately, these improvements appear to dissipate at the 6-month mark following surgery, suggesting that effects may be temporary, or at least diminish over time (11). Individuals who suffered from complications following surgery, such as double

vision or a visual halo, were found to present lower on the quality of health scale, signifying a relationship between quality of life status and mental wellness (11). Researchers also noted that there may be a relationship between the axial length of the eyes prior to surgery and mental health following the procedure (11). This could indicate a connection between the severity of myopia and mental health (11). In another recent study performed in 2020, a team of investigators found that when measured before the LASIK procedure, individuals with longer axial lengths were more likely to experience myopic regression following the surgery (12). This finding further supports the likelihood that those with longer axons in the eye may be subjected to worsening mental health after LASIK (12). Satisfaction in LASIK Surgery Patients Many individuals will choose to receive the LASIK procedure after several years of depending on eyeglasses and contact lenses for visual acuity. These corrective tools can be an annoyance, and contact lenses are known to cause a multitude of infections, such as Acanthamoeba keratitis, Pseudomonas aeruginosa, and multiple strains of Staphylococcus (13,14). Individuals may consider refractive surgery, which is an option for those who suffer from myopia, hyperopia, or astigmatism, as the procedure is typically safe and effective (15). According to a previous study that aimed to define the advantages of LASIK, this procedure is common for a reason (16). The process is predictable, has a short recovery period, involves low discomfort, and enhances visual acuity (16). These are just a few reasons individuals are likely to choose LASIK over other refractive surgery intervention options (16). An early study sought to define the level of satisfaction in LASIK surgery patients in an attempt to form an association between the procedure and higher visual ability (15). After evaluating a group of 150 patients who had undergone refractive surgery, researchers concluded that 93% of the subjects were satisfied with the overall experience (15). From a more global standpoint, 98.5% of people feel that their initial objectives of better eyesight were achieved following the LASIK procedure, and quality of life was boosted in about 93% of individuals (17). Aside from the abundance of successful surgeries, the most notable complaint among participants appeared to be lower night vision and dry eye (15). The LASIK procedure increases feelings of satisfaction in patients by decreasing refractive error, correcting contrast visual acuity, and enhancing psychological wellness (18). Recovery and Healing Period Following LASIK Procedure LASIK is almost an instantaneous fix to poor eyesight and is a desirable option due to the short recovery period that follows (19). Patients are typically capable of carrying out their day-today activities within just one to two days. Within three to six months, they will notice a significant improvement in sight (19). Patients can expect to feel some pain or discomfort following their procedure, as LASIK surgery is still invasive and can be traumatic on the nerves of the cornea (20). It is recommended that patients take certain medications following the procedure to alleviate any secondary injury, such as anti-inflammatory drugs and tear supplements (20). Another factor that must be considered in the healing process is the ability of the eye to regenerate nerves. A prior study measured both the number

Risks and Benefits of LASIK Surgery

and density of nerves in the eye following the LASIK procedure (21). When researchers evaluated participants a month following their surgery, more than 90% of subbasal nerves and their density were decreased in the eye (21). Interestingly, two years following the procedure, measurements of nerve density in the cornea presented similarly to pre-surgery (21). However, after three years, nerve density significantly decreased in subjects (21). Stromal nerves appear to recover slowly but not to the same extent as pre-surgery (21). In an early study conducted to evaluate the clinical results following LASIK to treat myopia and myopic astigmatism, researchers found that out of 138 patients, the mean epithelial healing time was estimated to be within three to seven days (22). About 86% of patients presented with clear corneas, and contrast sensitivity was either unchanged or had improved in subjects throughout the healing process (22).

Flap abnormalities risks such as flap displacements can occur postoperatively. A study of 81,238 eyes calculated flap displacement incidence in individuals who underwent LASIK surgery to correct hyperopia, myopia, or mixed astigmatism (27). Flap displacement is very rare, occurring in 10 of the 81,238 eyes (0.012%), and occurs shortly after surgery, with all displacements occurring within 48 hours of surgery, defined as early flap displacement (ERD) (27). Of the 10 eyes, 7 underwent microkeratome LASIK, concluding that the odds of ERD are 10.53 times higher with this type of surgery (27).

Children and LASIK Surgery

Rainbow glare is caused by a grating pattern on the back of the LASIK flap resulting in the diffraction of light producing a glare (30). In a consecutive case series study, two groups of 129 patients each underwent FS-LASIK (29). The initial group received FS-LASIK with a femtosecond laser with altered flap cut settings, including a decrease in spot and line separation and pulse energy (29). Compared to the group who received FSLASIK at the original laser setting, the group with a laser with decreased flap cut settings experienced significantly lower rates of rainbow glare at 1.57% compared to 13.73% (29). Rainbow glare, on average, appeared within the first three months post-LASIK, according to findings of a survey administered to post-operative patients who underwent FS-LASIK with a pulse setting at 60Hz and a spot and line separation of eight micrometers (28). The incidence of rainbow glare using these settings resulted in a 2.32% decrease from a previous study that used an older femtosecond laser model (28).

When typical means of corrective treatment were not helpful in children, LASIK surgery has been used to reduce amblyopia. For this surgery, anesthesia is used for children, and parents must be fully educated on all possible risks. Children are usually still in their developmental stage when they are young, and this surgery will help reduce asymmetry in the eye. Long-term glasses and contact wear can inhibit emmetropization (a process that occurs in childhood, which balances both axial length and focal power of the eye to reduce refractive error during growth) due to the removal of the retinal blur from the lens because the stimulus causes the myopic movement toward emmetropization (23). Emmetropization is having no refractive error and achieving 20/20 vision or the best vision the optometrist can get a patient that is not blurry. Risks of LASIK LASIK risks can be categorized as intraoperative and postoperative complications. Compared to postoperative complications, intraoperative complications are rare, with lower incidence rates (24). Patients are more likely to report postoperative complications at various time points after surgery. Postoperative complications can be described as either earlyonset or late-onset (24). A poor keratectomy can result in an aftereffect of flap abnormalities; the incidence of abnormal flap creations ranges from 0.3% to 5% (25). Abnormal flaps can be defined as those that are irregularly shaped, short, thin, torn, or incomplete (25). A severe flap-shape abnormality is the buttonholed flap. The reported occurrence of this abnormality is between 0.04% and 2.6% (25, 26). The buttonhole-shaped flap can occur when the microkeratome blade exits and enters the epithelium midincision (25). A suitable LASIK flap creation grants for a hinge on either side of the cornea (25). Although rare, the entire LASIK flap can become completely displaced from the cornea creating a free cap (25). Various risk factors can contribute to flap abnormalities and are typically screened for preoperatively. Risk factors for flap abnormalities can include corneal scarring, steep corneal curvature, loss of suction during the procedure, power level changes of the microkeratome motor, blade imperfections of the microkeratome, flat corneas, deep orbits, and poorly placed suction rings (25). Intraoperative abnormal flap creation pauses or aborts the LASIK procedure (25).

LASIK flaps created by femtosecond lasers are less likely to undergo the aforementioned complications (25). Complications such as rainbow glare and intraoperative gas bubble formation are more common intraoperative risks in femtosecond laser-assisted LASIK (FS-LASIK) compared to mechanical microkeratome LASIK (28, 29).

Gas bubble formation during LASIK is typically not a risk of great concern as bubbles form to create a level of separation in tissue near the lamellar fibers for flap creation (25). These bubbles are known as cavitation bubbles, made up of water and carbon dioxide, which will disappear with the rising of the flap (25). When the cavitation bubbles move into the subepithelium, anterior or posterior stroma and anterior chamber risks such as vertical gas breakthrough and opaque bubble layer formation can arise (31). In a consecutive chart review of 2,886 eyes that had undergone FS-LASIK, four eyes (i.e., four patients) were identified where a gas bubble formation occurred in the anterior chamber, reporting an incidence of 0.14% (31). Since gas bubbles of this nature cannot be resolved by flap lifting, it is of concern that the bubble could affect visual acuity, flap formation, and pupillary tracking (25). The rare incidence of gas bubble formation showed no significant postoperative consequence (31). All four cases of anterior chamber gas bubbles identified had no adverse changes to corrected and uncorrected visual acuity examinations (31). Intraoperative bleeding of perilimbal vessels of the cornea is a specific LASIK complication (32). This bleeding occurs when a microkeratome blade or a femtosecond laser comes in contact with these vessels (25). At a single ophthalmology practice, 20 cases of intraoperative bleeding were identified in LASIK procedures treating myopia (32). When cases of bleeding were compared to 20 normal LASIK procedures, bleeding caused a

Risks and Benefits of LASIK Surgery

higher frequency of interface haze, a higher risk of developing post-LASIK keratitis, and significant visual regression (32). The cause of regression following corneal perilimbal vessel bleeding may be attributed to a wound healing response causing more corneal remodeling in the eye versus a patient that experiences no bleeding (32). The goal of LASIK is improving vision, but adverse visual changes, retreatment, and visual regression are of concern postoperatively (33). Retreatment rates of LASIK were reported to be 8.2% to 17.5% (33). A prospective study assessed the effectiveness of LASIK retreatment on 157 eyes with primary under-correction and visual regression (33). Almost threequarters (73%) of the eyes underwent LASIK retreatment for regression, and 27% of the eyes underwent LASIK retreatment for under-correction (33). Before LASIK retreatment, all eyes had a level of residual myopia, and 10.8% of eyes had an irregular flap requiring a recut (33). In most eyes, visual regression was reported within the first six months but can be started up to two years post the initial LASIK procedure (33). Of the 157, 68.8% had a significant improvement in uncorrected vision, noting the success of LASIK retreatment (33). While the efficacy of LASIK retreatment is promising, the cause of visual regressions in patients still needs to be determined (33). Despite retreatment, some patients will have to undergo multiple retreatments in the future (33). Distorted night vision is reported after LASIK procedures, specifically halo phenomena, which can be described as visual disturbances where someone sees halos or clouded circles around lights at night (34). The halo phenomenon is caused by corneal surface aberrations secondary to the LASIK procedure (34). In addition to halos, visual disturbances such as glare and diplopia are also related to high-order aberration caused by FS-LASIK procedures (35). FS-LASIK causes a change of highorder aberrations on the anterior corneal surface, significantly impacting visual acuity (35). Aberrations are produced due to abnormal corneal flaps and greater ablation depths (35). While vision disturbances after LASIK are common, the occurrence of vision loss from a LASIK procedure is rare at about 0.66% from 2003 through 2019 (36). Corneal ectasia is a rare risk involving the weakening and thinning of the cornea and the development of astigmatism resulting in visual changes, with an estimated 0.2%–0.9% incidence rate (37, 38). Post-LASIK corneal ectasia is caused by the weakening of the cornea bed during flap creation, excess ablation, or postoperative eye rubbing (37). Risk factors for corneal ectasia include high preoperative myopia, low residual stroma beds, and keratoconus (39). The onset of corneal ectasia varies significantly from one week to many years postoperatively; late-onset cases are caused by a gradual progression of corneal weakness, with symptoms going unnoticed for a while (25, 37). The epithelium layer of the cornea is subject to damage during flap formation of LASIK procedures, risk of epithelial ingrowth at the flap edge, loosening of the epithelial layer, and thickening of the epithelium layer can occur (40, 41). Epithelial ingrowth is described as a tongue-like or peninsula protrusion from the flap edge (40). Significant cornea epithelial ingrowth occurs more in cases of LASIK retreatment requiring flap re-lifting three or more years after the initial LASIK procedure (42). Higher grades of corneal epithelial ingrowth require immediate treatment

and negatively impact visual acuity (40, 42). The incidence of epithelial loosening is rare and can be treated effectively with post-operative eye lubrication and bandage contact lenses (43). When corneal epithelial thickness (CET) is analyzed between post-LASIK eyes compared to healthy eye groups, CET is higher one year later in LASIK-treated groups than in eyes that never underwent LASIK (41). Over 90% of the time, immediately following the LASIK procedures, a case of dry eye is observed (25). Dry eye symptoms ranged from acute to chronic conditions (25). A retrospective analysis of 88 eyes reported adverse effects of tear film stability, noting a continual decrease in fluorescein breakup time post-LASIK (44). While LASIK did not affect meibomian gland function, it did cause a decrease in tear volume, with a significant reduction reported at two weeks, one month, and three months postoperative (44). Chronic dry eye disease is very treatable, but it poses a risk of negatively affecting the refractive outcomes of LASIK patients and creating corneal surface sensitivities (44). Patients requiring punctual plug treatment were likelier to experience refractive regression (44). Neuropathic corneal pain (NCP) is frequently accompanied by chronic dry disease; a 26-year retrospective case series concluded the prevalence of NCP was estimated to be 1 in 900 cases (45). Risk factors of NCP included pre-existing neuropsychiatric disorders, pain syndromes, autoimmune disease, and hypothyroidism (45). Treatment of NCP included dry eye treatment, pain, and anti-inflammatory medication, alleviating most NCP symptoms (45). The pathology of NCP is not well understood, but early detection and multifactorial treatments allow for adequate management of NCP (45). Alternatives to LASIK Eye Surgery LASIK is the most common procedure for refractive surgery. The alternatives are photorefractive keratectomy (PRK), EpiLASIK, laser subepithelial keratomileusis (LASEK), and small incision lenticule extraction (SMILE). LASEK combines elements from both LASIK and PRK, which loosens the epithelial adhesion of the corneal stroma, where the epithelial is moved away from the treatment area. The ablation of the subepithelial stroma is performed before the loose epithelial is returned to the original position. Compared to LASIK or PRK, some advantages are reducing the flap, haze risk, and reduced visual recovery (46). Bandage lenses are typically used as bandages to keep the epithelial flap mentioned above in the proper position after surgery (47). The bandages can help relieve any irritation or reactions from the surgery (47). These bandages are typically only worn after surgery for a few days, causing no to little damage to the endothelium (47). Hydrogel soft contact lenses have previously been used as bandages due to the handling, comfort, and short adaptations of only three to five days (47). A study compared the types of contact lenses, such as silicon hydrogel and soft contact lenses, used as bandages after surgery (47). The two different types of silicon hydrogel are Galyfilcon A and Balaficon A (47). Results determined that different factors should be considered when choosing the best bandages, such as comfort, deposit resistance, and high oxygen transmission (47). By comparing the ocular response and grading subjective feelings, two different types of silicon hydrogel lenses had an average rating of performance 55

Risks and Benefits of LASIK Surgery

(47). The silicon hydrogel lenses do not cause hypoxia, which is a complication to any damage to the corneal epithelium (47). Blurry vision and pain can be caused by deposit formation, which can be remedied by eye drops (47). PRK has a complete removal of the outermost corneal epithelium all the way to the Bowman’s layer. It then ablates the stroma, which then redesigns the corneal surface. This is a great option for those patients with myopia of 12 diopters, hyperopia to 5 diopters, or astigmatism of 6 diopters or lower. This is not a treatment for those patients with diseases such as cataracts, glaucoma, dry eye, allergies, or blepharitis. Post-surgery uses topical anesthetics to lower pain with no adverse effects. Steroids are used for the first few months but do have a high risk of ocular hypertension (48). Small incision lenticule extraction (SMILE) is where a dissector passes through a small 2- to 3-millimeter incision that separates the lenticular surfaces, which allows the lenticule to be extracted. Unlike LASIK, this procedure does not create a flap; instead, the small incision allows the surgery to reduce trauma to the subbasal nerve plexus (49, 50). This treatment was approved by the Food and Drug Administration in 2016. This surgery is typically used for patients with mild dry eyes (50). The benefits to SMILE are the use of only one laser, reducing dry eye symptoms, and better biochemical corneal stability (51). Epi-LASIK is a surface ablation photorefractive surgery that uses the Centurion EpiEdge epikeratome. This device separates the corneal epithelium from the stroma, which can then be repositioned after the operation of the cornea. Some differences from other surgeries are the cornea is not required to be cleaned with alcohol, and the surgery is mechanical. This surgery is an option for patients with low myopic vision and require protective contact lenses after surgery. LASIK has a shorter recovery time, and patients report less postoperative pain than Epi-LASIK (52). Clinical Trials Many clinical trials have been conducted on the postoperative pain and side effects of LASIK surgery. The use of therapeutic lenses as bandages to aid in the healing process of LASIK has been studied (53). Bandage lenses have been used for a myriad of corneal treatments and are often constructed from the same material as regular corrective contact lenses, known as senofilcon or focofilcon due to their low friction and subsequent decreased mechanical stress on a damaged cornea (54). The trial randomly assigned each patient with two different-sized bandage lenses, an 8.4-mm in one eye and an 8.8-mm base curve in the other (53). This study revealed that tightly fitted lenses allowed for the stability of the epithelial flap created by the LASIK treatment and an increased rate of healing time with a decrease in postoperative pain after the 2-hour mark (53). A separate study from 2019 fitted patients with a similar bandage lens in only one eye, with the opposite eye used as a control, for use only overnight and aimed to determine again the effects of lenses on the epithelial flap healing process (55). Researchers generated self-reported scores for symptoms, including pain and photophobia, as well as physical examination of the flap margins. This investigation also showed statistically significant lower levels of patient discomfort in the treatment group as well as an elevated healing response indicated by observed narrower and smoother margins and lower reflectivity (55). 56

Other clinical trials looked at the use of topical analgesics for the treatment of postoperative pain. The first trial utilized a 2% lidocaine gel as a topical anesthetic for use during LASIK operations as well as postoperative pain control. In this doubleblind, randomized clinical trial, patients underwent bilateral LASIK procedures, with patients receiving lidocaine gel in both eyes or carbomer gel as a placebo and then a verbal scoring of pain throughout the procedure at various steps as well as intervals postoperatively (56). It was determined that the 2% lidocaine addition to the 0.5% proparacaine solution already in use significantly decreased pain both intra- and postoperatively, as well as increased patient compliance throughout the treatment as scored by the physician, which was hypothesized to also increase surgical safety (56). A separate investigation looking at topical treatment for pain focused on the use of diclofenac sodium, which is more commonly known as artificial tears and is a common ophthalmic NSAID (57), and patients were evaluated at five time points over the course of 24 hours following surgery. The maximum benefit was noted at four hours post-procedure, and only a single dose was sufficient to reduce the need for oral pain medication (58). Dexamethasone inserts were the topic of a separate clinical trial used for the control of pain and postoperative symptoms and were compared to currently used topical prednisolone acetate. Dexamethasone inserts are an extended-release treatment to be placed intracanalicular and can be used for up to 30 days before requiring removal, as opposed to the topical administration of prednisolone administered four times daily at a tapered dosage (59). Results showed an 80% preference toward the dexamethasone insert for control of inflammation, and both received similar levels of dry eye and corneal staining postoperatively. This preference was thought to be due to the decreased need for self-administration of postoperative medications (59). Investigators in a separate trial went so far as to say that this decreased reliance on patient cooperation and adherence to the tapered dosage of prednisolone administration could potentially lead to better surgical outcomes when using the dexamethasone insert (60). A retrospective investigation which concluded in 2021, found that these methods are often used in combination to treat pain and prevent postoperative complications. Researchers looked at 18 individual cases seen by the same physician over the course of 26 years and noted that there was no single common treatment to reduce symptoms in those who developed dry eye syndrome and corneal pain (52). However, many individuals were able to achieve relief through combinatory therapy, often including topical and oral analgesics and anti-inflammatory medications, bandage lenses, and artificial tears (52). In some instances, multiple publications note the use of gabapentin or tricyclic antidepressants was also used in this multimodal treatment approach to alleviate the negative effects of LASIK treatment, such as corneal nerve pain (52, 61, 62). Additional modalities for the reduction in symptoms post-surgery, including those listed above, as well as the potential for standard cooling therapy for a reduction in inflammation and notes that the inflammatory response control is vital in the reduction of these negative side effects (57).

Risks and Benefits of LASIK Surgery

Conclusion Laser vision correction is a growing field and one that has proven to be both an effective and safe method of visual improvement for the past 27 years. Several technological advancements have been made since its emergence, and the process is now quick, involves minimal pain, and entails a quick recovery (63). However, as with all minimally invasive procedures, there are risks associated with the outcome; intraoperative risks include but are not limited to flap abnormalities, flap displacement, vertical gas breakthrough, opaque bubble layer formation, and intraoperative bleeding (25, 49, 32). Common postoperative risks are adverse visual changes, vision acuity regression, and dry eye disease (33, 44). Rare postoperative risks such as high-grade epithelial ingrowth corneal ectasia require immediate medical intervention (37, 40). In many cases, candidates who are not suitable for the LASIK procedure have access to alternative methods of vision correction. Some of these options include (but are not limited to) LASEK, PRK, SMILE, and Epi-LASIK (45). As for clinical trial research, many current studies aim to compare LASIK to alternative treatments and therapies; however, several still look at postoperative treatment for pain and other negative symptoms, as well as methods to increase healing and recovery. Several topical drugs already exist or are in clinical trials for approval for use during surgery or recovery, including lidocaine and diclofenac sodium (56, 58). Extendedrelease dexamethasone inserts show promising effects due to their anti-inflammatory components as well as reduced reliance on patients’ adherence to self-administered medication schedules (59, 60). Additionally, the use of bandage lenses shows promise as a means of protection and added stability for the epithelial flap during the healing process and has led to an elevated healing response (53, 55). The most current literature supports the recommendation for a combinatorial approach when treating post-LASIK effects and notes that no one-sizefits-all approach has been found to be routinely effective (52).

Acknowledgments We would like to sincerely thank Brian J. Piper, PhD, and Gabrielle Verbeke-O’Boyle for assisting us with this process and editing our initial drafts. Additionally, we would like to express our gratitude toward Amy Houck and the Geisinger library staff for their continuous support.

Disclosures We have no conflicts of interest to disclose.

References 1.

Moshirfar M, Bennett P, Ronquillo Y. Laser in situ keratomileusis. StatPearls Publishing; 2022 [updated 2022 Jul: cited 2023 Mar] Available from: https://www.ncbi.nlm. nih.gov/books/NBK555970/ Bandeira F, Yusoff NZ, Yam GH-F, Mehta JS. Corneal reinnervation following refractive surgery treatments. Neural Regen Res. 2019;14(4):557–65. Boyd K. LASIK - Laser eye surgery. Am. J. Ophthalmol. 2022 [cited 2023 Mar] Available from: https://www.aao.org/eyehealth/treatments/lasik

Huang D, Feldman BH, Reddy V, Saad A, Shafer B. Lasik for myopia and astigmatism: Safety and efficacy. Am. J. Ophthalmol. 2010 [updated 2023 Jan; cited 2023 Mar]. Available from: https://eyewiki.aao.org/LASIK_for_Myopia_ and_Astigmatism:_Safety_and_Efficacy

Goldberg L, Nguyen Q, Geller M. Optometry scope of practice in the United States. Eyes On Eyecare; 2022. Available from: https://eyesoneyecare.com/resources/ optometry-scope-of-practice-united-states/

Torricelli AA, Bechara SJ, Wilson SE. Screening of refractive surgery candidates for LASIK and PRK. Cornea. 2014;33(10):1051-5.

Hashmani S, Hashmani N, Kumar S, Kumar S, Dhomeja V, Razak S,et al.Reasons for refusing laser-assisted in situ keratomileusis in a Pakistani population. Cureus. 2017; 25;9(6).

Wilkinson JH, Cozine EW, Kahn AR. Refractive eye surgery: Helping patients make informed decisions about LASIK. Am Fam Physician. 2017;95(10):637–44.

Demmin DL, Silverstein SM. Visual impairment and mental health: Unmet needs and treatment options. Clin Ophthalmol. 2020:4229-51.

10. Klokova OA, Sakhnov SN, Geydenrikh MS, Damashauskas RO. Quality of life after refractive surgery: ReLEx SMILE vs Femto-LASIK. Clin Ophthalmol. 2019;13:561. 11. Tounaka-Fujii K, Yuki K, Negishi K, Toda I, Abe T, Kouyama K, et al. Effects of laser in situ keratomileusis on mental health-related quality of life. Clin Ophthalmol. 2016:185964. 12. Gab-Alla AA. Is the axial length a risk factor for post-LASIK myopic regression?. Graefes Arch Clin Exp Ophthalmol. 2021;259:777-86. 13. Radford CF, Bacon AS, Dart JK, Minassian DC. Risk factors for acanthamoeba keratitis in contact lens users: A casecontrol study. BMJ. 1995;310(6994):1567-70. 14. Ahuja M. Contact lens wear and microbial keratitis. J Indian Med Assoc. 2002;100(11):664-6. 15. Patel DB, Patel AM, Shah MA, Vyas AK, Shah S. Functional outcome and patient satisfaction following LASIK surgery. Indian J Clin Exp Ophthalmol. 2018;4(4):473-7. 16. Doroodgar F, Sedaghat M, Niazi S, Niazi F, Rezazadeh A, Sanginabadi A. LASIK, SMILE and PRK: Advantages and indications. Int Eye Sci. 2019:1643-51. 17. Bamashmus MA, Hubaish K, Alawad M, Alakhlee H. Functional outcome and patient satisfaction after laser in situ keratomileusis for correction of myopia and myopic astigmatism. Middle East Afr J Ophthalmol. 2015;22(1):108. 18. Lazon de La Jara P, Erickson D, Erickson P, Stapleton F. Visual and non-visual factors associated with patient satisfaction and quality of life in LASIK. Eye (Lond). 2011;25(9):1194-201. 19. LASIK Recovery Time: What to expect after LASIK? J. Refract. Surg 2016. [updated 2022 Jun; cited 2023 Mar] Available from:https://americanrefractivesurgerycouncil. org/what-to-expect-with-lasik-recovery/

Risks and Benefits of LASIK Surgery

20. Toda I. Dry eye after LASIK. Invest Ophthalmol Vis Sci. 2018;59(14):DES109-15. 21. Calvillo MP, McLaren JW, Hodge DO, Bourne WM. Corneal reinnervation after LASIK: Prospective 3-year longitudinal study. Invest Ophthalmol Vis Sci. 2004;45(11):3991-6. 22. Katsanevaki VJ, Kalyvianaki MI, Kavroulaki DS, Pallikaris IG. One-year clinical results after epi-LASIK for myopia. Ophthalmology. 2007;114(6):1111-7. 23. O’Keefe M, Nolan L. LASIK surgery in children. Br J Ophthalmol. 2004;88(1):19-21. 24. Sahay P, Bafna RK, Reddy JC, Vajpayee RB, Sharma N. Complications of laser-assisted in situ keratomileusis. Indian J. Ophthalmol. 2021;69(7):1658. 25. Stephen MT, Farley ND, Tomasko KR, Amin SR. Intraoperative LASIK complications. Int Ophthalmol Clin. 2016;56(2):47-57. 26. Carrillo C, Chayet AS, Dougherty PJ, Montes M, Magallanes R, Najman J, et al. Incidence of complications during flap creation in LASIK using the NIDEK MK2000 microkeratome in 26,600 cases. J Refract Surg. 2005;21(5):655-657. 27. Clare G, Moore TC, Grills C, Leccisotti A, Moore JE, Schallhorn S. Early flap displacement after LASIK. Ophthalmology 2011;118(9):1760-5 28. Bamba S, Rocha KM, Ramos-Esteban JC, Krueger RR. Incidence of rainbow glare after laser in situ keratomileusis flap creation with a 60 kHz femtosecond laser. J Cataract Refract Surg. 2009;35(6):1082-6. 29. Zhang Y, Chen YG. High incidence of rainbow glare after femtosecond laser assisted-LASIK using the upgraded FS200 femtosecond laser. BMC Ophthalmol. 2018;18:1-6. 30. Gatinel D, Saad A, Guilbert E, Rouger H. Unilateral rainbow glare after uncomplicated femto-LASIK using the FS-200 femtosecond laser. J Refract Surg. 2013;29(7):498-501. 31. Rush SW, Cofoid P, Rush RB. Incidence and outcomes of anterior chamber gas bubble during femtosecond flap creation for laser-assisted in situ keratomileusis. J Ophthalmol. 2015;2015:1-4 32. Vajpayee RB, Balasubramanya R, Rani A, Sharma N, Titiyal JS, Pandey RM. Visual performance after interface hemorrhage during laser in situ keratomileusis. Br J Ophthalmol. 2003;87(6):717-9. 33. Lyle WA, Jin GJ. Retreatment after initial laser in situ keratomileusis. J Cataract Refract Surg. 2000;26(5):650-9 34. Villa C, Gutierrez R, Jimenez JR, Gonzalez-Meijome JM. Night vision disturbances after successful LASIK surgery. Br J Ophthalmol. 2007;91(8):1031-7. 35. Feng Z, Wang Q, Du C, Yang F, Li X. High-order aberration changes after femtosecond LASIK surgery in patients with high myopia. Ann Palliat Med. 2021;10(7):7689-96. 36. Wu YT, Ho A, Naduvilath T, Lim C, Carnt N, Keay LJ, et al. The risk of vision loss in contact lens wear and following LASIK. Ophthalmic Physiol Opt. 2020;40(2):241-8.

37. Said A, Hamade IH, Tabbara KF. Late onset corneal ectasia after LASIK surgery. Saudi J Ophthalmol. 2011;25(3):22530. 38. Bohac M, Koncarevic M, Pasalic A, Biscevic A, Merlak M, Gabric N, et al. Incidence and clinical characteristics of post LASIK ectasia: A review of over 30,000 LASIK cases. Semin Ophthalmol. 2018;33(7-8):869-877. 39. Randleman JB, Russell B, Ward MA, Thompson KP, Stulting RD. Risk factors and prognosis for corneal ectasia after LASIK. Ophthalmology. 2003;110(2):267-75. 40. Sridhar MS, Rao SK, Vajpayee RB, Aasuri MK, Hannush S, Sinha R. Complications of laser-in-situ-keratomileusis. Indian J. Ophthalmol. 2002;50(4):265-82. 41. Díaz-Bernal J, García-Basterra I, Mora-Castilla J, Guerrero AM. Corneal epithelial thickness one year after myopic LASIK surgery, measured by anterior segment optical coherence tomography combined with Placido disk. Arch Soc Esp Oftalmol (Engl Ed). 2020;95(11):544-549 42. Caster AI, Friess DW, Schwendeman FJ. Incidence of epithelial ingrowth in primary and retreatment laser in situ keratomileusis. J Cataract Refract Surg. 2010;36(1):97-101. 43. Oruçoğlu F, Kenduşim M, Ayoglu B, Toksu B, Goker S. Incidence and management of epithelial loosening after LASIK. Int Ophthalmol. 2012;32(3):225-8 44. Albietz JM, Lenton LM, McLennan SG. Effect of laser in situ keratomileusis for hyperopia on tear film and ocular surface. J Refract Surg. 2002;18(2):113-23 45. Moshirfar M, Bhavsar UM, Durnford KM, McCabe SE, Ronquillo YC, Lewis AL, et al. Neuropathic corneal pain following LASIK surgery: A retrospective case series. Ophthalmol Ther. 2021;10(3):677-68 46. Taneri S, Zieske JD, Azar DT. Evolution, techniques, clinical outcomes, and pathophysiology of LASEK: Review of the literature. Surv Ophthalmol. 2004;49(6):576-602. 47. Qu XM, Dai JH, Jiang ZY, Qian YF. Clinic study on silicone hydrogel contact lenses used as bandage contact lenses after LASEK surgery. Int J Ophthalmol. 2011;4(3):314. 48. Somani SN, Majid Moshirfar, Patel BC. Photorefractive keratectomy (PRK) [Internet]. StatPearls Publishing; 2019 [updated 2022 Jun; cited 2023 Mar] . Available from: https://www.ncbi.nlm.nih.gov/books/NBK549887/ 49. Reinstein DZ, Archer TJ, Gobbe M. Small incision lenticule extraction (SMILE) history, fundamentals of a new refractive surgery technique and clinical outcomes. Eye Vis (Lond). 2014;1:3 50. Moshirfar M, Birdsong OC, Ronquillo Y, Tanner J. Smallincision lenticule extraction. Advances in Ophthalmology and Optometry. Indian J Ophthalmol. 2018;3(1):279-301. 51. Doane JF, Cauble JE, Rickstrew JJ, Tuckfield JQ. Small incision lenticule extraction SMILE–The future of refractive surgery is here. MO med. 2018;115(1):82. 52. Pallikaris IG, Kalyvianaki MI, Katsanevaki VJ, Ginis HS. Epi-LASIK: Preliminary clinical results of an alternative surface ablation procedure. J Cataract Refract Surg. 2005;31(5):879-85.

Risks and Benefits of LASIK Surgery

53. Kim J-S, Na K-S, Joo C-K. Base curves of therapeutic lenses and their effects on post epi-LASIK vision and pain: A prospective randomized clinical trial. Jpn J Ophthalmol. 2009;53(4):368–73. 54. Shafran T, Gleason W, Osborn Lorenz K, SzczotkaFlynn LB. Application of Senofilcon a contact lenses for therapeutic bandage lens indications. Eye Contact Lens. 2013;39(5):315–23. 55. Zhao L-Q, Li L-M, Liu J, Li P. Bandage contact lens application reduces fibrotic wound healing of flap margins after FS-LASIK: A prospective randomized clinical trial. J Ophthalmol. 2019;2019. 56. Lam DSC, Law RWK, Ng ASY, Lam PTH, Jhanji V, Lee VYW, et al. Randomized double-masked controlled trial comparing pain scores with and without the use of supplementary 2% lidocaine gel in LASIK. Am J Ophthalmol. 2012;153-4. 57. Benatti CA, Afshari NA. Postoperative pain after laser refractive surgery. Int Ophthalmol Clin. 2016;56(2):83–100. 58. Parker J, Tandon A, Shtein RM, Soong KH, Cooney TN, Musch DC, et al. Management of pain with diclofenac after femtosecond-assisted laser in situ keratomileusis. J Cataract Refract Surg. 2011;37(3):569–73. 59. Greenwood MD, Gorham RA, Boever KR. A randomized fellow-eye clinical trial to evaluate patient preference for dexamethasone intracanalicular insert or topical prednisolone acetate for control of postoperative symptoms following bilateral femtosecond laser in site keratomileusis (lasik). Clin Ophthalmol. 2020;14:2223–8. 60. Lee A, Blair HA. Dexamethasone intracanalicular insert: A review in treating post-surgical ocular pain and inflammation. Drugs. 2020;80(11):1101–8. 61. Michael R, Jeffers JV, Messenger W, Aref AA. Gabapentin for presumed neuropathic ocular pain. Am J Ophthalmol Case Rep. 2020;19. 62. Dieckmann G, Goyal S, Hamrah P. Neuropathic corneal pain. Ophthalmology. 2017;124(11). 63. Joffe SN. The 25th anniversary of laser vision correction in the United States. Clin Ophthalmol. 2021:1163-72. 64. Willoughby CE, Ponzin D, Ferrari S, Lobo A, Landau K, Omidi Y. Anatomy and physiology of the human eye: effects of mucopolysaccharidoses disease on structure and function–a review. J Clin Exp Ophthalmol. 2010;38:2-11. 65. Human Eye Anatomy Image Vector. Vecteezy. Accessed July 2023. https://www.vecteezy.com/vectorart/1271085-human-eye-anatomy 66. Human Eye Vision Disorder Image Vector. Vecteezy. Accessed July 2023. https://www.vecteezy.com/vectorart/4932284-vision-disorders-concept-of-eyes-defectnormal-vision-hyperopia-myopia-astigmatism-anatomyeyeball-vector

Scholarly Research In Progress • Vol. 7, November 2023

Exercise-induced Neuroplasticity: A Therapeutic Strategy for Alzheimer’s Disease, Parkinson’s Disease, and Stroke Recovery Erin M. Welby1*‡, Jasleen Kaur1*‡, Brooke A. Ostrander1*‡, and Sadana R. Padmanabhan1*‡ ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 *Master of Biomedical Sciences Program ‡ Authors contributed equally Correspondence: erinmwelby@gmail.com

Abstract Neurodegenerative disorders include multiple disease types characterized by a progressive loss of function or death of cells, leading to varying symptoms such as decreased coordination, cognition, or sensation. The development of neurodegenerative diseases has been linked to the natural process of aging. Neuroplasticity is the brain’s ability to modify the connectivity of its neurons throughout an individual’s life. This is an especially important topic of research for those impacted by neurological diseases that depend upon mechanisms of neuroplasticity for recovery. Current research is focused on aging, its effects on neuroplasticity, and treatments aimed to promote neuroplasticity. Neurotrophins, such as BDNF, IGF-1, and VEGF, are present with physical exercise and are recognized as influencing and enabling neuroplasticity. Therefore, physical exercise is being explored as both a cognitive repair technique after stroke and a neuroprotective mechanism for Parkinson’s disease and Alzheimer’s disease. Furthermore, various exercise types have been shown to produce different neuroplastic outcomes. The purpose of this literature review was to examine current information regarding the potential role of physical exercise-induced neuroplasticity in stroke rehabilitation, as well as in the treatment and prevention of Parkinson’s disease and Alzheimer’s disease.

Introduction

promising rehabilitation method to improve brain function following stroke (11–14). The idea of PE having a major impact on preventing a significant decline in cognition has been a topic of much research (4). Not only does PE help manage weight, strengthen the body, and assist in combating illness, it positively impacts the brain’s ability to rearrange and restore itself (15, 16). There remains uncertainty in the scientific community regarding the specific biochemical mechanism behind the relationship between neuroplasticity and PE. It is important to further investigate the mechanism responsible for this relationship to understand how to utilize it clinically in the treatment of neurodegenerative disorders and neurological damage (15). The hippocampus is linked to spatial memory, consolidation, and a high degree of plasticity (1). Therefore, many investigations have focused on this area when exploring the effects of exercise-induced neuroplasticity (1, 3, 17). Although the PEinduced neuroplasticity biological process remains primarily undetermined, it is believed that neurotrophins produced during and after exercise facilitate neuroplasticity through neurogenesis, angiogenesis, and synaptogenesis, in addition to increasing cerebral blood flow (3, 16, 18–20). Neurogenesis (when new neurons in the brain are formed) improves spatial learning, memory, and cognition (1, 21). Angiogenesis, when new blood vessels are formed, is vital in neurorepair and takes place following PE (1).

Several different neurotrophins are consistently identified in Neuroplasticity is the central nervous system’s ability to mediating, regulating, and otherwise impacting neuroplasticity adapt or recover following injury, aging, or other impactful (Table 1). Brain-derived neurotrophic factor (BDNF) is an occurrences by reorganizing its structure, connections, and important modulator of plasticity and increases cell survival functions throughout life (1, 2). More specifically, it involves with respect to learning and memory (1, 3, 19, 22). Exercise neurogenesis, reorganization of neural networks, and synaptogenesis to persevere and prosper after or through acute and long-term transformative events (1, 2). Intrinsically, aging generates neuroplasticity, as it induces decreased cognition and memory, in addition to genome, oxidative, and DNA damage, consequently increasing the susceptibility to developing neurodegenerative diseases (3–5). Recent experimentation has focused on the potential neurobiological paths associated with aging, ways to improve preservation, the human experience with this, and the subsequent neurodegenerative diseases and disorders (1,4). Physical exercise (PE) may be a neuroprotective mechanism for Table 1. Select Neurotrophins and Their Effect in Neuroplasticity. A list of selected Parkinson’s disease (PD) and Alzheimer’s neurotrophins, their known function in the mechanism underlying neuroplasticity, and the disease (AD) (6–10). PE may also be a effect that exercise has on their expression in the human body. 60

Exercise-induced Neuroplasticity

increases BDNF transport and production (1, 3). Lactate, essential for the brain’s metabolism, has been associated with greater BDNF levels and may play a role in exercise neurobenefits (19, 23, 24). Insulin-like growth factor 1 (IGF-1), a hormone involved in many functions including neurogenesis, is suggested to be another mediator of neuroplasticity, and seems to support cognitive function (1, 15, 22). Previous research has identified increased IGF-1 post-exercise, particularly in resistance training (1). Several other growth factors, such as vascular endothelial growth factor (VEGF), appear to contribute to neurogenesis and cognitive improvement as well (1, 25, 26). Protein kinase C (PKC), known for mediating inflammation and immunity in various ways and is part of differentiation, survival, and development, has also shown better memory and learning with direct involvement (3, 15). N-methyl-D-aspartate (NMDA) receptors are a glutamate receptor family integral for learning, memory, and excitation (1, 3). Higher expression of some NMDA receptors has been reported after exercise, with the possibility of more remarkable plasticity at glutamatergic synapses (1, 27). Presently, it has been shown that there are differences in the effect on neuroplasticity among exercise types. One study determined that the longer duration of exercise produced elevated BDNF (20), while another determined that highintensity interval training (HIIT) did the same as continuous exercise (23). Aerobic exercise regulates cellular redox homeostasis, improves memory, cognition, and learning, and increases synaptic plasticity and corticospinal excitability (22, 23, 28). Aerobic and strength training both have exhibited neuroplasticity and facilitated better memory (15). However, more research is needed focusing on strength and resistance training regarding its relation to exercise-induced neuroplasticity specifically (1, 3). This review aims to determine if, based on all available research, PE can be an effective treatment in neurological damage caused by AD, PD, and stroke.

Methods A thorough literature search was conducted utilizing databases including Google Scholar and PubMed. A combination of search terms including aging, stroke, exercise, aerobic exercise, Parkinson’s disease, and Alzheimer’s disease were utilized to select sources. We only examined relevant articles published within the past 25 years, with a specific focus on exploring exercise as a therapeutic strategy for the treatment of neurological degeneration specifically due to stroke, AD, and PD. In order to ensure the reliability of included studies, we selected articles that were published in peer-reviewed journals and sourced from reputable databases.

Discussion Benefits of Exercise for Stroke Recovery Stroke is one neurological disease that remains a major concern and a prominent area of investigation, and the role of PE as a therapeutic tool for stroke has continued to spark great interest. It is a leading cause of death and long-term disability in the United States (U.S.) (29). Every year, over 795,000 people have a stroke, with the most common type of stroke being ischemic (29). In this type of stroke, blood flow to cerebral tissue is substantially reduced causing a time-sensitive cascade

of events (30). First, there is a loss of tissue function because of disturbances in normal electrical and membrane functioning (30). These disturbances can eventually lead to reactive oxygen species (ROS) generation, and eventually, cell lysis and neuronal death (30). The excessive production of ROS has been linked to severe functional deficits by causing oxidative stress and, consequently, neuronal damage (31). Moreover, the loss of these neurons is one of the most direct causes of neuronal injuries observed after stroke (32). Thus, neuronal regeneration and neuronal protection are key areas worth investigating to prevent cerebral functional deficits (33). PE is believed to help with post-stroke recovery by increasing the expression of proteins involved with neuroplasticity and serving as a neuroprotective mechanism against neuronal damage (13). A recent study investigated the ways in which rehabilitation exercises improved neurological function in rats that had undergone middle cerebral artery occlusion (MCAO). The results indicated that treadmill exercise 24 hours after MCAO increased the expression of VEGF (34). The increased VEGF expression by endothelial cells was linked to promoting neurological functioning by stimulating angiogenesis and reducing apoptosis (25, 26). In another report, the neuroprotective effects of PE in rats following an ischemic stroke were analyzed, and similar effects were observed (35). However, compared to the previous study mentioned (34), this investigation revealed a different molecular pathway and mechanism for neuroprotection (35). Post-stroke treadmill exercise increased oxaloacetate, as well as decreased glucose and phosphoenolpyruvic acid (PEP) in rats (35). During ischemic injury, the switch to gluconeogenesis due to impaired mitochondrial oxidative phosphorylation, leads to excess PEP and lactic acidosis activity, contributing to ROS production and cell death (35–37). Therefore, the researchers suggested that the process of gluconeogenesis in these rats was suppressed because of the PE, and consequently, helped protect against neuronal death (38). Moreover, a type of exercise known as skilled reaching training (SRT) had positive effects on the cognitive function of transient MCAO rats (39). Specifically, it upregulated BDNF and stimulated gray and white matter plasticity (39, 40). Furthermore, antisense BDNF oligonucleotide was injected into the contralateral lateral ventricle of rats after ischemic stroke to determine the role of this molecule in improving cognitive performance. The blocked production of BDNF mRNA due to the injected oligonucleotide resulted in the ineffectiveness of the rehabilitation on the recovery (41). Thus, this study further emphasized the importance of increased BDNF in synaptic plasticity resulting from PE therapy post-stroke. PE may serve as an important non-invasive therapeutic tool for ischemic stroke by modulating synaptic plasticity. Benefits of Exercise in the Treatment of Parkinson’s Disease PD is the second-most common neurodegenerative disorder diagnosed in North America, currently affecting about 1 million Americans (42). A new study has shown that PD has an incidence rate of nearly 90,000 diagnoses each year, which is about 50% higher than current estimates (43). PD incidence increases with age of 65 or older and is higher in males at all ages (43). Incidence of PD is higher in certain geographical

Exercise-induced Neuroplasticity

regions, including the “Rust Belt,” southern California, southeastern Texas, central Pennsylvania, and Florida (43). PD has an annual economic burden of $52 billion in the U.S. (44). Pathologically, PD is characterized by the loss of nigrostriatal dopaminergic innervation, but neurodegeneration seen in the disease is not limited to just these neurons (45). PD has a very widespread pathology, so reliable diagnostic tests are not available yet (45). Diagnosis is based on clinical symptom presentation (45). Diagnosis requires the presence of two clinical features: resting tremor, bradykinesia, rigidity, and/ or postural instability (45). These criteria can only diagnose probable PD (45). True diagnosis requires histopathology testing to identify alpha-synuclein-containing Lewy bodies (45). The pathogenesis of PD involves alpha-synuclein misfolding and aggregation (46), mitochondrial dysfunction (47), and dysfunctional protein clearance (45). Treatment of PD includes increasing levels of dopamine in the brain (48). The current first-line treatment for the motor symptoms of PD is levodopa (48). Levodopa (or L-dopa) is a dopamine precursor (49). L-dopa is usually used in combination with carbidopa, which inhibits aromatic-L-amino-acid decarboxylase, the enzyme responsible for the breakdown of dopamine (49). These drugs both work to increase the levels of dopamine in the synapses (49). This treatment does not modify the course of neurodegeneration, but it is very effective at treating the motor symptoms of the disease (49). Drugs like carbidopa-levodopa extended-release capsules, also called IPX066, have been shown to have an increased efficacy and improved patient compliance (50). Although these treatments can manage the symptoms of PD, there is currently no cure for this debilitating disease. In a recent study that evaluated 114 countries from 1994-2019, it was estimated that there were 1,064,753 deaths due to PD globally (51). Throughout this period, the mortality rate in both men and women increased substantially (51). Overall, PD is the second-most prevalent neurodegenerative disease in the U.S. for which there is no current cure. Current treatment methods need improvement to reduce PD-related morbidity and mortality. There is widespread evidence of the beneficial effects of aerobic exercise on inducing neuroplasticity and improving cognition (52–57). Specifically, it has been shown that exercise reduces atrophy in the motor systems of aging individuals and induces neuroplasticity, which preserves motor function and promotes the relearning of motor skills (53). PE has been linked to improved motor function which includes increased gait speed, balance, and coordination (53). Due to these results, the effects of aerobic exercise have recently been studied in PD to determine if this could be an effective addition to current treatment options. The substantia nigra, the main area affected by PD-related neurodegeneration, can produce new neurons throughout adulthood (58). Due to this, and the ability of exercise to induce neuroplasticity, it has been thought that exercise may improve the symptoms of and possibly protect from the progression of PD. More recent studies have shown that exercise induces alterations in dopaminergic and glutamatergic neurotransmission, which diminishes the cortically driven hyperexcitability present in the basal ganglia of PD patients (27). Studies of PD-specific goal-based motor training and aerobic exercise have shown the potential to 62

improve the cognitive and autonomic components of motor control in mild to moderate PD (10). More research is needed to fully understand the circuitry involved in exercise-induced neuroplasticity and how it can improve motor function in PD patients before it is recommended as a therapeutic intervention. Furthermore, additional study is warranted to evaluate the ideal amounts of exercise in order to mitigate injury and maximize the impact of its use. Benefits of Exercise in the Treatment of Alzheimer’s Disease The clinical impact of PE extends beyond neuroplasticity to benefit patients diagnosed with dementia and, specifically, AD. This disease is characterized by cognitive decline, memory loss, and disorientation and affects a large percentage of the world population, specifically individuals 65 years of age and older (59, 60). Based on the World Alzheimer Report, as of 2016, 47 million people across the world live with dementia, and nearly 70% of them are eventually diagnosed with Alzheimer’s (7). Due to the irreversibility of AD and the absence of successful pharmacological treatments, the number of patients with AD is continuing to increase and is projected to be four times higher by 2050 (7, 61). This disease explicitly affects the more complex parts of the brain connected to memory, such as the hippocampus and neocortex (61). At the cellular level, patients with AD present with an increased level of amyloid plaques, composed of Aß peptides and neurofibrillary tangles, which are connected to the deterioration of cognitive functions (7, 59, 61). Simultaneously, a low count of BDNF also accounts for the neurocognitive decline of patients with dementia (62). Along with these pathophysiological features that characterize Alzheimer’s, risk factors that contribute to worsening and expedited symptoms of this disorder include diabetes, hypertension, obesity, and a sedentary lifestyle (8, 60, 63, 64). Engaging in PE has been shown to reduce a patient’s risk of AD by 45% by impacting the individual at a behavioral, cellular, and molecular level by enhancing blood flow, improving brain plasticity, and conserving brain tissue (7, 9). In a 2011 metaanalysis, patients with dementia scored higher on cognitive tests following 6 to 12 months of exercise versus a sedentary lifestyle. Moreover, the patients that took part in PE had improved spatial memory and larger hippocampus volumes (8). This is parallel to the neurotrophic hypothesis, which emphasizes that improved cognition is tied to the increase in growth factors and neurotrophins induced by PE (59). In a follow-up investigation in 2020, high levels of Aß in rats were reversed by physical and cognitive exercise, which further reversed damages done to the hippocampus brought on by neurotoxicity (65). PE also increased BDNF levels which can further slow the progression of AD symptoms and reduce the risk of developing Alzheimer’s in healthy older individuals (61). While other forms of treatment to slow down the development of Alzheimer’s are being studied, such as the impact of a healthy diet with low fat intake and drugs, PE is the most promising. Is has been shown to slow the spread and low-cost intervention to treating and lowering the risk of patients with AD (62, 66, 67). In a 2022 study, the benefits of a Mediterranean diet combined with PE resulted in higher BDNF levels compared to a Western diet and a sedentary lifestyle (62). Nonpharmacological interventions such as PE are thought to have a better success rate in slowing AD compared to pharmaceutical

Exercise-induced Neuroplasticity

drug treatments (68). For example, it is hypothesized that NSAIDs can reduce the risk of AD due to the anti-inflammatory component; however, there is limited research to prove this to be as successful as PE (69). Similarly, intranasal insulin, omega-3 fatty acids, and vitamin B12 are being studied. These are also more costly than maintaining a healthy diet and PE (63, 70). Moreover, even with the medications that are currently available, the growth of AD as a leading cause of morbidity in the U.S. and the lack of clinical trials, with a current 0.4% success rate, points toward the need for a better understanding of the progression of this disease (69, 71, 72). Since pharmaceutical treatments for AD are expensive to develop and test, the success of PE as a preventative measure points to its benefits as a cheaper alternative while searching to find a cure (7–9).

References

Conclusion Neurodegenerative diseases remain a persistent issue in healthcare since they are often challenging to treat due to the brain’s complex circuitry. Thus, therapies that help prevent the onset and progression of these diseases continue to draw attention in neurology. PE is one noninvasive therapy that can serve to reduce the burden of these diseases by inducing neuroplasticity in the hippocampus, an area of the brain linked to exhibiting high instances of plasticity and memory consolidation (1). Particularly, neurotrophins produced during and after exercise improve cognitive function by supporting cell growth, proliferation, and the processes of neurogenesis and angiogenesis (1, 3, 16, 18–21, 73). Numerous studies have found elevated BDNF, VEGF, and IGF-1 after exercise (1, 20, 34, 39–41, 61, 62). The upregulation of these molecules is associated with increased cognitive functioning in experiments involving rat models with different diseases, such as ischemic stroke, AD, and PD (10, 34, 39–41, 61, 62). Aerobic exercise, particularly, improves memory and cognition via neuroplasticity (74). PE positively influences neuroplasticity, neurorepair, and rehabilitation of Alzheimer’s disease, Parkinson’s disease, and stroke (28). Due to the costly nature of studies centered around human participants and the availability of current research, there are limitations on the ability to conduct research on human subjects with neurodegenerative diseases such as AD and PD (1, 15, 66). Future studies should explore different exercise protocols for comparison, including more resistance studies or varying intensity, and more human and animal studies for a more generalized interpretation (1, 11, 15, 19). Multiple studies have discussed the idea of utilizing pharmaceuticals to administer the beneficial exerkines, especially considering some individuals experiencing the effects of aging, AD, PD, and stroke may be unable to complete PE (20, 23).

Acknowledgments We would like to thank Iris Johnson for technical support and Gabrielle Verbeke O’Boyle, MBS, and Brian Piper, PhD, for feedback and editing.

Disclosures The authors have no relevant disclosures.

Cassilhas RC, Tufik S, de Mello MT. Physical exercise, neuroplasticity, spatial learning and memory. Cell Mol Life Sci. 2016;73:975-83.

Gulyaeva NV. Molecular mechanisms of neuroplasticity: An expanding universe. Biochemistry (Mosc). 2017;82:237-42.

Vilela TC, Muller AP, Damiani AP, Macan TP, da Silva S, Canteiro PB, et al. Strength and aerobic exercises improve spatial memory in aging rats through stimulating distinct neuroplasticity mechanisms. Mol Neurobiol. 2017;54(10):7928-37.

Gutchess A. Plasticity of the aging brain: New directions in cognitive neuroscience. Science. 2014;346(6209):579-82.

Anderson ND. Cognitive neuroscience of aging. J Gerontol B Psychol Sci Soc Sci. 2019;74(7):1083-5.

Johansson H, Hagströmer M, Grooten WJ, Franzén E. Exercise-induced neuroplasticity in Parkinson’s disease: A metasynthesis of the literature. Neural Plast. 2020.

Lin TW, Tsai SF, Kuo YM. Physical exercise enhances neuroplasticity and delays Alzheimer’s disease. Brain Plast. 2018;4(1):95-110.

Ahlskog JE, Geda YE, Graff-Radford NR, Petersen RC. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc. 2011;86(9):876-84.

Huuha AM, Norevik CS, Moreira JB, Kobro-Flatmoen A, Scrimgeour N, Kivipelto M, et al. Can exercise training teach us how to treat Alzheimer’s disease? Ageing Res Rev. 2022;75:101559.

10. Petzinger GM, Fisher BE, McEwen S, Beeler JA, Walsh JP, Jakowec MW. Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson’s disease. Lancet Neurol. 2013;12(7):716-26. 11. Penna LG, Pinheiro JP, Ramalho SH, Ribeiro CF. Effects of aerobic physical exercise on neuroplasticity after stroke: Systematic review. Arq Neuropsiquiatr. 2021;79:832-43. 12. Crozier J, Roig M, Eng JJ, MacKay-Lyons M, Fung J, Ploughman M, et al. High-intensity interval training after stroke: An opportunity to promote functional recovery, cardiovascular health, and neuroplasticity. Neurorehabil Neural Repair. 2018;32(6-7):543-56. 13. Nie J, Yang X. Modulation of synaptic plasticity by exercise training as a basis for ischemic stroke rehabilitation. Cell Mol Neurobiol. 2017;37(1):5-16. 14. Xing Y, Bai Y. A review of exercise-induced neuroplasticity in ischemic stroke: Pathology and mechanisms. Mol Neurobiol. 2020;57(10):4218-31. 15. Liang J, Wang H, Zeng Y, Qu Y, Liu Q, Zhao F, et. al. Physical exercise promotes brain remodeling by regulating epigenetics, neuroplasticity and neurotrophins. Rev Neurosci. 2021;32(6):615-29. 16. Gourgouvelis J, Yielder P, Murphy B. Exercise promotes neuroplasticity in both healthy and depressed brains: An fMRI pilot study. Neural Plast. 2017;2017:8305287.

Exercise-induced Neuroplasticity

17. Nauer RK, Dunne MF, Stern CE, Storer TW, Schon K. Improving fitness increases dentate gyrus/CA3 volume in the hippocampal head and enhances memory in young adults. Hippocampus. 2020;30(5):488-504.

31. Hu X, Wu D, He X, Zhao H, He Z, Lin J, et al. CircGSK3ß promotes metastasis in esophageal squamous cell carcinoma by augmenting ß-catenin signaling. Mol Cancer. 2019;18:160

18. Halliday MR, Abeydeera D, Lundquist AJ, Petzinger GM, Jakowec MW. Intensive treadmill exercise increases expression of hypoxia-inducible factor 1α and its downstream transcript targets: A potential role in neuroplasticity. Neuroreport. 2019;30(9):619-27.

32. Chen YC, Ma NX, Pei ZF, Wu Z, Do-Monte FH, Keefe S, et al. A neuroD1 AAV-based gene therapy for functional brain repair after ischemic injury through in vivo astrocyte-toneuron conversion. Mol Ther. 2020;28:217–234.

19. Müller P, Duderstadt Y, Lessmann V, Müller NG. Lactate and BDNF: Key mediators of exercise induced neuroplasticity?. J Clin Med. 2020;9(4):1136. 20. Vints WA, Levin O, Fujiyama H, Verbunt J, Masiulis N. Exerkines and long-term synaptic potentiation: Mechanisms of exercise-induced neuroplasticity. Front neuroendocrinol. 2022;66:100993. 21. Li C, Liu T, Li R, Zhou C. Effects of exercise on proactive interference in memory: Potential neuroplasticity and neurochemical mechanisms. Psychopharmacology (Berl). 2020;237:1917-29. 22. El-Sayes J, Turco CV, Skelly LE, Nicolini C, Fahnestock M, Gibala MJ, et al. The effects of biological sex and ovarian hormones on exercise-induced neuroplasticity. Neuroscience. 2019;410:29-40. 23. Huang Z, Zhang Y, Zhou R, Yang L, Pan H. Lactate as potential mediators for exercise-induced positive effects on neuroplasticity and cerebrovascular plasticity. Front Physiol. 2021;12:1006. 24. Sungjun L, Yonghyun C, Eunseo J, Jongjun P, Jiwon K, Masayoshi T, et al. Physiological significance of elevated levels of lactate by exercise training in the brain and body. J Biosci Bioeng. 2023;135:167-175 25. Oshikawa M, Okada K, Kaneko N, Sawamoto K, Ajioka I. Affinity-immobilization of VEGF on laminin porous sponge enhances angiogenesis in the ischemic brain. Adv Healthc Mater. 2017;6:1700183 26. Hatakeyama M, Ninomiya I, Kanazawa M. Angiogenesis and neuronal remodeling after ischemic stroke. Neural Regen Res. 2020;15:16–19. 27. Petzinger GM, Fisher BE, Van Leeuwen JE, Vukovic M, Akopian G, Meshul CK, et al. Enhancing neuroplasticity in the basal ganglia: The role of exercise in Parkinson's disease. Mov Disord. 2010;1(1):S141-5. 28. Mu L, Cai J, Gu B, Yu L, Li C, Liu QS, et al. Treadmill exercise prevents decline in spatial learning and memory in 3× Tg-AD mice through enhancement of structural synaptic plasticity of the hippocampus and prefrontal cortex. Cells. 2022;11(2):244. 29. Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, et al. Heart disease and stroke statistics- 2022 update: A report from the American Heart Association. Circ Journal. 2022;145(8):e153-e639. 30. Feske SK. Ischemic stroke. Am J Med. 2021;134(12):14571464.

33. Zhao Y, Zhang X, Chen X, Wei Y. Neuronal injuries in cerebral infarction and ischemic stroke: From mechanisms to treatment. Int J Mol Med. 2022; 49(2):15. 34. Geng H, Li M, Tang J, Lv Q, Li R, Wang L. Early rehabilitation exercise after stroke improves neurological recovery through enhancing angiogenesis in patients and cerebral ischemia rat model. Int J Mole Sci. 2022;23(18):10508. 35. Geng X, Li F, Yip J, Peng C, Elmadhoun O, Shen J, et al. Neuroprotection by chlorpromazine and promethazine in severe transient and permanent ischemic stroke. Mol Neurobio. 2017;54(10):8140–8150. 36. Rabinowitz JD, Enerback S. Lactate: The ugly duckling of energy metabolism. Nat Metab. 2020;2(7):566–571. 37. Wu KC, Cheng KS, Wang YW, Chen YF, Wong KL, Su TH, et al. Perturbation of Akt signaling, mitochondrial potential, and ADP/ATP ratio in acidosis-challenged rat cortical astrocytes. J Cell Biochem Suppl. 2017;118(5):1108–1117. 38. Li F, Geng X, Ilagan R, Bai S, Chen Y, Ding Y. Exercise postconditioning reduces ischemic injury via suppression of cerebral gluconeogenesis in rats. Brain Behav. 2023;13(1):e2805. 39. Yong MS, Hwangobo K. Skilled reach training influences brain recovery following intracerebral hemorrhage in rats. J Phys Ther Sci. 2014;26:405–407. 40. Li C, Sun R, Chen J, Hong J, Sun J, Zeng Y, et al. Different training patterns at recovery stage improve cognitive function in ischemic stroke rats through regulation of the axonal growth inhibitor pathway. Behav Brain Res. 2022;421:113730. 41. Ploughman M, Windle V, MacLellan CL, White N, Doré JJ, Corbett D. Brain-derived neurotrophic factor contributes to recovery of skilled reaching after focal ischemia in rats. J Stroke. 2009;40(4):1490-5. 42. Kalia LV, Lang AE. Parkinson’s disease. Lancet. 2015;386(9996):896–912. 43. Willis AW, Roberts E, Beck JC, Fiske B, Ross W, Savica R, et al. Incidence of Parkinson disease in North America. NPJ Parkinsons Dis. 2022;8(1):170. 44. Yang W, Hamilton JL, Kopil C, Beck JC, Tanner CM, Albin RL, et al. Current and projected future economic burden of Parkinson's disease in the U.S. NPJ Parkinsons Dis. 2020;6:15. 45. Kouli A, Torsney KM, Kuan WL. Parkinson’s disease: Etiology, neuropathology, and pathogenesis. Exon Publications. 2018:3-26.

Exercise-induced Neuroplasticity

46. Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, et al. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol. 1998;152(4):879–84.

60. Bernardo TC, Marques-Aleixo I, Beleza J, Oliveira PJ, Ascensao A, Magalhaes J. Physical exercise and brain mitochondrial fitness: The possible role against Alzheimer's disease. Brain Pathol. 2016;26(5):648-63.

47. Moon HE, Paek SH. Mitochondrial dysfunction in Parkinson’s disease. Exp Neurobiol. 2015;24(2):103–16.

61. De la Rosa A, Olaso-Gonzalez G, Arc-Chagnaud C, Millan F, Salvador-Pascual A, García-Lucerga C, et al. Physical exercise in the prevention and treatment of Alzheimer's disease. J Sport Health Sci. 2020;9(5):394-404.

48. NIA. Parkinson's disease: Causes, symptoms, and treatments [Internet]. Bethesda, MD; NIH;2022. https:// www.nia.nih.gov/health/parkinsons-disease 49. Siegel A, Sapru HN. Essential neuroscience. Lippincott Williams & Wilkins; 2006. 50. Müller T, Möhr JD. Efficacy of carbidopa-levodopa extended-release capsules (IPX066) in the treatment of Parkinson disease. Expert Opin Pharmacother. 2018;19(18):2063-71. 51. Lampropoulos IC, Malli F, Sinani O, Gourgoulianis KI, Xiromerisiou G. Worldwide trends in mortality related to Parkinson's disease in the period of 1994–2019: Analysis of vital registration data from the WHO Mortality Database. Front Neurol. 2022;13. 52. Hötting K, Röder B. Beneficial effects of physical exercise on neuroplasticity and cognition. Neurosci Biobehav Rev. 2013;37:2243-2257. 53. Nicolini C, Fahnestock M, Gibala MJ, Nelson AJ. Understanding the neurophysiological and molecular mechanisms of exercise-induced neuroplasticity in cortical and descending motor pathways: Where do we stand? Neuroscience. 2021;457:259-282. 54. El-Sayes J, Harasym D, Turco CV, Locke MB, Nelson AJ. Exercise-induced neuroplasticity: A mechanistic model and prospects for promoting plasticity. Neuroscientist. 2019;25(1):65-85. 55. Rogge A-K, Röder B, Zech A, Hötting K. Exercise-induced neuroplasticity: Balance training increases cortical thickness in visual and vestibular cortical regions. Neuroimage. 2018;179:471-9. 56. Vilela TC, Muller AP, Damiani AP, Macan TP, da Silva S, Canteiro PB, et al. Strength and aerobic exercises improve spatial memory in aging rats through stimulating distinct neuroplasticity mechanisms. Mol Neurobiol. 2017;54(10):7928-37. 57. Kuhne LA, Ksiezarczyk AM, Braumann KM, Reer R, Jacobs T, Röder B, et al. Cardiovascular exercise, learning, memory, and cytokines: Results of a ten-week randomized controlled training study in young adults. Biol Psychol. 2022;176:1-14. 58. Steiner B, Winter C, Hosman K, et al. Enriched environment induces cellular plasticity in the adult substantia nigra and improves motor behavior function in the 6-OHDA rat model of Parkinson's disease. Exp Neurol. 2006;199(2):291300. 59. Llorens-Martín M. Exercising new neurons to vanquish Alzheimer disease. Brain Plast. 2018;4(1):111-26.

62. Xue B, Waseem SM, Zhu Z, Alshahrani MA, Nazam N, Anjum F, et al. Brain-derived neurotrophic factor: A connecting link between nutrition, lifestyle, and Alzheimer’s disease. Front Neurosci. 2022;16:925991. 63. Pronk NP. Neuroplasticity and the role of exercise and diet on cognition. Am J Clin Nutr. 2021;113(6):1392-3. 64. Foster PP, Rosenblatt KP, Kuljiš RO. Exercise-induced cognitive plasticity, implications for mild cognitive impairment and Alzheimer’s disease. Front Neurol. 2011;2:28. 65. Dare LR, Garcia A, Soares CB, Lopes L, Neves BH, Dias DV, et al. The reversal of memory deficits in an Alzheimer’s disease model using physical and cognitive exercise. Front Behav Neurosci. 2020;14:152 66. Voss MW, Vivar C, Kramer AF, van Praag H. Bridging animal and human models of exercise-induced brain plasticity. Trends Cogn Sci. 2013;17(10):525-44. 67. Raefsky SM, Mattson MP. Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance. Free Radic Biol Med. 2017;102:203-16. 68. Tan ZX, Dong F, Wu LY, Feng YS, Zhang F. The beneficial role of exercise on treating Alzheimer’s disease by inhibiting ß-amyloid peptide. Mol Neurobiol. 2021;58(11):5890-906. 69. Kelly AM. Exercise-induced modulation of neuroinflammation in models of Alzheimer’s disease. Brain Plast. 2018;4(1):81-94. 70. Esiri MM, Chance SA. Cognitive reserve, cortical plasticity and resistance to Alzheimer's disease. Alzheimers Res Ther. 2012;4(2):1-8 71. Bhattacharjee S, Patanwala AE, Lo-Ciganic WH, Malone DC, Lee JK, Knapp SM, et al. Alzheimer's disease medication and risk of all-cause mortality and all-cause hospitalization: A retrospective cohort study. Alzheimers Dement (NY). 2019;5:294-302. 72. Casey DA, Antimisiaris D, O’Brien J. Drugs for Alzheimer’s disease: Are they effective?. PT. 2010;35(4):208. 73. de Sousa Fernandes MS, Ordônio TF, Santos GC, Santos LE, Calazans CT, Gomes DA, et al. Effects of physical exercise on neuroplasticity and brain function: A systematic review in human and animal studies. Neural Plast. 2020;2020. 74. Penna LG, Pinheiro JP, Ramalho SH, Ribeiro CF. Effects of aerobic physical exercise on neuroplasticity after stroke: Systematic review. Arq Neuropsiquiatr. 2021;79:832-43.

Scholarly Research In Progress • Vol. 7, November 2023

Conflict of Interest Reporting in a Surgical Journal John P. McDonald1†, Ara Khoylyan1†, Kevin Lynch1†, and Brian J. Piper1,2 ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 ²Center for Pharmacy Innovation and Outcomes, Danville, PA 17821 † Doctor of Medicine Program Correspondence: jmcdonald01@som.geisinger.edu

Abstract Background: Leading journals have developed stringent conflict of interest (COI) guidelines to ensure proper disclosure of financial connections. With the goal of achieving transparency and accuracy in reporting such disclosures, the Centers for Medicare and Medicaid Services (CMS) Open Payments database publishes the data of financial transactions between drug and medical device companies and health care providers. This study investigated if authors in Annals of Surgery with the highest compensations according to CMS Open Payments followed disclosure requirements as stipulated by the journal. In addition, different specialties were analyzed. Methods: This is a cross-sectional study including primary research articles published in Annals of Surgery between 2017 and 2020. First and last authors of original articles were screened in the Open Payments database for financial relationships, and contributions between 2017 and 2020 were recorded. The authors with contributions above $50,000 within the timeframe were further investigated for whether the disclosure requirements were met by comparing the COI statement in the article to the data available on Open Payments. Those with a mismatch were classified as discordant. A Fisher's exact test was conducted to evaluate the association between specialties and concordant reporting. Results: The total payment amount received by all authors (N = 374) was $9.46 million, with a median payment amount of $706.29 (IQR = $6,378.65) and a range of $1.13 million. Of the 31 authors with contributions greater than $50,000, 16 (52%) were found to be discordant. There was no difference in rates of discordance when comparing general surgery, other surgical specialties, and nonsurgical specialties. Conclusion: More than half of the authors in Annals of Surgery did not adequately disclose financial conflicts of interest. Journals may need to reconsider disclosure policies to ensure transparency in surgical research.

Introduction In 1984, the New England Journal of Medicine began requiring authors to disclose financial conflict of interests (COIs) (1). Subsequently, academic journals have developed additional protocols for authors to properly disclose financial ties. The International Committee of Medical Journal Editors (ICMJE) has set guidelines for authors to disclose any potential direct or indirect COI related to the publication or a COI that could be perceived as relevant by readers. This includes any COI within the three years before publication (2). In surgical fields, substantial financial ties exist between physicians and device manufacturers because of the use of surgical devices. The relationship between commercial

manufacturers and physicians provides a symbiotic opportunity for innovation, although care must be taken to alleviate concerns of influence on research outcomes and patient care. One study looking at the recommendations of robotic surgery found that authors with undisclosed COIs were more than 20% more likely to recommend robotic surgery than those without (3). A recent 2015 study showed only 8 out of 64 (12%) of general and abdominal surgery journals did not require COI disclosure (4), but further work has shown difficulties in adhering to COI disclosure requirements required by most journals. In a study specifically investigating COIs in transcarotid artery revascularization, results showed at least one author in 58 out of 79 studies (73%) received an undisclosed payment (5). Similar findings were shown in studies investigating the COIs of cardiothoracic surgeons (6), surgeons publishing in spinal journals (7), and the top-earning physicians compensated by vascular device companies (8). Of note, three of those studies found those with higher median payments were more likely to accurately disclose COIs than those who did not, which may demonstrate a disconnect in the understanding of what type of payments should be disclosed. While such studies have identified disparities in reporting conflict of interest within specific surgical specialties or with certain surgical devices, our study aims to build upon findings by investigating the broader field of surgery and identifying differences among the subsets. With the passing of the Sunshine Act, the Centers for Medicare & Medicaid Services (CMS) Open Payments program was established to enhance transparency and provide the public with information about financial relationships between health care providers and pharmaceutical companies, medical device manufacturers, and other entities in the healthcare industry. The CMS Open Payments program requires applicable manufacturers to report payments made to physicians. This includes a wide range of financial transactions such as consulting fees, research grants, travel reimbursements, and even certain ownership or investment interests (9). This data can act as a supplement to the disclosure statements made by authors. Scientific journals play a crucial role in the dissemination of scholarly research and, thereby, should bear the important responsibility of propagating COI disclosure requirements, though third parties such as CMS Open Payments have seemed to engulf this role. This study investigates if authors in Annals of Surgery with the highest compensations according to Open Payments followed disclosure requirements as stipulated by the journal. In addition, we performed an analysis of the differences that may exist in disclosure among gender, specialty, or degree. Our study contributes to the body of literature on the rates of accurate disclosure in a leading journal. Annals of Surgery is a surgical journal with high impact, providing a large sample of authors in various surgical specialties that allows a broad inquiry into

Conflict of Interest Reporting in a Surgical Journal

disclosure concordance in surgical specialties. Our findings, therefore, can further guide investigation into subspecialties.

Methods This was a cross-sectional study including primary research articles published in Annals of Surgery between 2017 and 2020. Annals of Surgery was selected because of its high impact factor (13.787). Articles were included if they were original research articles, and the authors were U.S.-based physicians (N = 272). The first and last authors were screened in the CMS Open Payments database and general contributions between 2017 and 2020 were recorded. We identified 374 unique authors for analysis. Only general contributions were recorded, which included consulting fees, food and beverage, travel and lodging, honoraria, or speaker fees. Contributions classified as research, ownership, patents, and investment were excluded. Authors with total contributions >$50,000 within the period were investigated for concordance between COI statements and Open Payment contributions (N = 31). Authors were classified as concordant if their COI declaration statement in the journal article matched their Open Payments data. Authors were considered discordant if they lacked or misrepresented a COI declaration statement in the journal article while, according to Open Payments, having ties to companies that manufacture surgical devices or pharmaceuticals relevant to the study. A twosample unequal variance t-test was performed for identifying difference in median pay between male and female authors. A Fisher's exact test was conducted to evaluate the association between specialties and concordant reporting. Procedures were deemed exempt by the IRB of Geisinger.

Discussion More than half of the authors included in the study failed to adequately disclose COIs. There was no statistically significant difference in rates of discordance between specialties. While it is beyond the scope of this paper to determine why the majority of authors were found to be discordant, research has suggested confusion surrounding when COIs are relevant to disclose. In the language of International Committee of Medical Journal Editors, guidelines exist for authors to disclose any potential direct or indirect COI related to the publication or a COI that could be perceived as relevant by readers (2). This element of perception may explain the difference between self-reported COI and the data available on Open Payments. Future refinements to the clarity of the definition of a COI may be useful in the future to encompass financial relationships that may be tangentially related to the publication on hand. This may aid in helping physicians identify the interplay of their financial relationships and their research. In addition, some of the payments included on Open Payments include contributions

Results The total payment amount received by all authors (N = 374) was $9.46 million, with a median payment amount of $706.29 (IQR = $6,378.65) and a range of $1.13 million. Over two-thirds (71.4%) of the total authors were male (N = 267) and they amassed 85.2% ($8.06 million) of total payments, with a mean of $30,174.01 per author (SD = $108,865.05). Though male authors received a much greater proportion of the total amount, there was no statistically significant difference found between the mean payment of male and female authors (p = 0.08).

Figure 1. Concordant vs. discordant authors publishing in the Annals of Surgery. There were 31 authors with compensation greater than $50,000. Of those, 15 were concordant with the COI requirements of the journal while 16 were discordant.

Authors who received payments related to their research and appropriately disclosed this status were considered concordant and those who did not disclose their payments were considered discordant. Over half (52%, 16) of authors were identified as discordant with COI disclosure requirements, while 15 authors (48%) were concordant (Figure 1). Of the 15 authors found to be concordant, 6 disclosed COIs within their article despite evidence suggesting that they did not explicitly need to do so. After classifying the authors as general surgery, other surgical specialty, and nonsurgical specialty, comparisons were made in discordance rates between specialties. As shown in Figure 2, seven of 13 authors in the field of general surgery, 6 of 12 authors in other surgical specialties, and 3 of 6 authors in nonsurgical specialties were found to be discordant. There were no significant differences observed in rate of discordance between general surgeons and other surgical subspecialties (p = 1.0), general surgeons and non-surgeons (p = .516), or other surgical subspecialists and non-surgeons (p = 1.0).

Figure 2. Concordant vs. discordant authors publishing in the Annals of Surgery by Specialty. There was no statistically significant difference between rates of discordance between general surgery and other surgical subspecialty (p = 1), general surgery and nonsurgical specialty (p = .516), or other surgical subspecialty and nonsurgical specialty (p = 1) after a Fisher Exact test.

Conflict of Interest Reporting in a Surgical Journal

that could be seen as lower-value relationships like food, traveling, and lodging, which may be perceived as something that could not lead to research bias (7).

Probst P, Hüttner FJ, Klaiber U, Diener MK, Büchler MW, Knebel P. Thirty years of disclosure of conflict of interest in surgery journals. Surgery. 2015;157(4):627-633.

Industry investment plays a crucial role in advancing medical research by providing essential resources, expertise, and funding. However, it is equally essential to recognize the potential influence of financial ties on research outcomes. Clear disclosure mechanisms enable stakeholders to assess the validity and potential biases associated with research findings, leading to a more comprehensive understanding of the benefits and risks of medical interventions. Standardization of COI statements can help alleviate some of the confusion surrounding COI disclosure. Medical journals can continue to take steps to increase the strength of their disclosure requirements, including establishing precise disclosure guidelines, verifying disclosure statements, and streamlining the process among various journals and professional societies.

Moon T, Bahadur A, Aalberg J, Jonczyk M, Chen L, Margenthaler JA, et al. Assessment of conflicts of interest in the transcarotid artery revascularization literature. J Surg Res. 2023 Jun 28;291:133-138.

Karamchandani MM, Tian T, Hall R, Nickel I, Aalberg J, Lassaletta AD, et al. Discrepancies in financial conflicts of interest in robotic cardiothoracic surgery studies. Ann Thorac Surg. 2023; S0003-4975(23)00573-8.

Tisherman RT, Wawrose RA, Chen J, Donaldson WF, Lee JY, Shaw JD. Undisclosed conflict of interest is prevalent in spine literature. Spine (Phila Pa 1976). 2020 Nov 1;45(21):1524-9.

Al-Khouja F, Nyam A, Sheehan B, Sullivan B, Kabutey NK, Stamos MJ, Pigazzi A, Jafari MD. Conflict of interest disclosure among the highest earning physicians receiving compensation from vascular device companies. Am Surg. 2022 Oct;88(10):2538-2543.

CMS Open Payments. Updated June 30, 2023. Accessed July 20, 2023. Available from: https://www.cms.gov/ openpayments

Conclusion We believe robust disclosure policies can ensure transparency, maintain scientific integrity, and uphold the trust of readership and the wider medical community. Although our study included an only moderately sized sample (N = 374), future studies should work to expand the scope to include authors in other high impact surgical journals, such as JAMA Surgery. Investigating if the lack of COI statements lead to pro-industry results in surgical journals is an important next step. Lastly, standardized disclosure policies may be an important tool to increase the rates of COI disclosure, and research surrounding the reception and demand of such a concept may lead to important breakthroughs in the future.

Acknowledgments Thanks to the Biomedical Research Club for their support.

Disclosures BJP’s osteoarthritis research was supported from 2019 to 2021 by Pfizer and Eli Lilly. Current research is supported by the Health Resources Services Administration and the Pennsylvania Academic Clinical Research Center. The other authors report no relevant disclosures.

References 1.

Relman AS. Dealing with conflicts of interest. N Engl J Med. 1984 May 3;310(18):1182-3.

International Committee of Medical Journal Editors Recommendations for the conduct, reporting, editing, and publication of scholarly work in medical journals: author responsibilities—conflicts of interest. Updated May 2023. Accessed July 20, 2023. Available from: http://www.icmje. org/recommendations

Patel SV, Yu D, Elsolh B, Goldacre BM, Nash GM. Assessment of conflicts of interest in robotic surgical studies: Validating author's declarations with the Open Payments database. Ann Surg. 2018;268(1):86-92. doi:10.1097/SLA.0000000000002420.

10. Chen S, Roberts AL, Zhao K, Burke AC, Ritter JE, Musto KM, Piper BJ. Conflict of interest disclosure accuracy among physician authors of cancer research journals. Scholarly Research in Progress. 2021 Nov 5;89-91.

Scholarly Research In Progress • Vol. 7, November 2023

Autoimmune Hemolytic Anemia Without Overt Signs of Hemolysis Jenna Rabadi¹, Raymond A. Stemrich2†, Queeneth Uwandu¹, and Habib Hamoud¹ ¹Geisinger Wyoming Valley Medical Center, Wilkes-Barre, PA 18711 ²Geisinger Commonwealth School of Medicine, Scranton, PA 18509 † Doctor of Medicine Program Correspondence: rstemrich1@gmail.com

Abstract

Case Presentation

Autoimmune hemolytic anemia (AIHA) is a common cause of acquired hemolysis where the immune system targets antigens found on the body’s red blood cells. This eventually leads to the activation of the complement system, manifesting the clinical signs of anemia. A methodical approach is required to assess anemia including laboratory studies and, in some cases, imaging. However, the studies vary in clinical sensitivity and specificity, especially in AIHA. Patient is a 35-year-old morbidly obese female with a past medical history significant for Roux-en-Y gastric bypass, hepatic steatosis, alcohol use disorder, and Guillain-Barré syndrome who presented to the Emergency Department for altered mental status, dyspnea, and a productive cough. She was found to have normocytic anemia with a hemoglobin level of 3.5 g/dL. Previous immunological panels were negative at an outpatient appointment less than two months prior to the admission. During her admission, the standard anemia evaluation did not suggest hemolysis or reveal the underlying cause of the anemia, which proved to be refractory to transfusions. Repeat immunological testing provided evidence of autoimmune hemolytic anemia, which was further supported by the patient’s response to empiric steroid therapy. Determining the etiology underlying anemia presents a challenge requiring a systematic approach. AIHA presents with evidence of hemolysis and a positive direct antiglobulin test (DAT); however, it is often a diagnosis of exclusion necessitating a complete workup. It is important to recognize that DAT is not completely sensitive or specific. Additionally, AIHA may be DAT-negative or acquired after previously negative immunologic evaluations. These are important considerations in refractory anemia in which all other causes of anemia have been thoroughly evaluated.

Patient is a 35-year-old morbidly obese female with a past medical history significant for Roux-en-Y gastric bypass, hepatic steatosis, alcohol use disorder, and Guillain-Barré syndrome. Of note, she was diagnosed with iron deficiency anemia after her bariatric surgery in 2018 and was started on folate and iron supplementation with a new hemoglobin baseline around 11 g/dL. Her hemoglobin remained stable until two months before her admission. During that time, she underwent an anemia evaluation including iron studies, blood smears, and an immunologic assessment with DAT, antinuclear antibody (ANA) test, and C-reactive protein, all of which were consistent with her baseline or negative.

Introduction Autoimmune hemolytic anemia (AIHA) is a common cause of acquired hemolysis in which a patient’s immune system targets antigens found on the body’s red blood cells destroying the cell. This immune response eventually leads to the activation of the complement system, manifesting the clinical signs of anemia including pallor, fatigue, tachycardia, and tachypnea (1). Those patients with evidence of anemia should undergo a stepwise evaluation to assess hemolysis with both clinical evaluation and laboratory studies. Laboratory studies including complete blood count (CBC), haptoglobin, lactate dehydrogenase (LDH), and peripheral smear yield evidence of hemolysis; however, some of the studies vary in clinical sensitivity or specificity, especially in AIHA. The case detailed below presents a 35-year-old female who presented with signs of anemia but no significant indicators of hemolysis.

The patient presented to the Emergency Department for altered mental status, dyspnea, and a productive cough. Upon initial evaluation, she was found to have normocytic anemia with a hemoglobin level of 3.5 g/dL. She received 6 units of packed red blood cells (PRBC) over the next 12 hours, improving her hemoglobin to 5.4 g/dL. Another unit of PRBC and platelets was transfused, increasing her hemoglobin to 7.0 g/dL, at which time she was hemodynamically stable. Concurrently, the patient was diagnosed with septic shock secondary to E. coli urinary tract infection and pneumonia, requiring initiation of vasopressor support with norepinephrine, IV ceftriaxone, and Intensive Care Unit (ICU) admission. Her septic status improved, but she developed anasarca and her anemia remained refractory even after an additional 3 units of transfused PRBCs. She was subsequently transferred to the Progressive Care Unit (PCU) for continued close monitoring. While in the PCU, she continued to have frequent drops in her hemoglobin prompting evaluation (Figure 1). Her iron studies remained suggestive of anemia of chronic disease with a total iron-binding capacity of 79 ug/dL and transferrin saturation of 15%, but she also had mild reticulocytosis (122.6 K/uL). Additionally, her urinalysis contained urobilinogen, but no bilirubin. Throughout her admission, she was jaundiced with an elevated total (7.5–11.9 mg/dL) and direct (4.4–7.2 mg/dL) bilirubin; however, she had a known history of hepatic steatosis and was found to have transaminitis with an elevated gammaglutamyl transferase (118 U/L) on admission. Her haptoglobin and lactate dehydrogenase remained within normal limits. She received an upper endoscopy, excluding gastric ulcerations. She was given another 2 units of PRBC, improving her hemoglobin, but its level did not remain stable. Subsequent CT and tagged red blood cell scans did not show any evidence of extravascular bleeding. Previous outpatient antibody testing demonstrated that she was direct and indirect Coombs negative; however, on repeat testing during the admission, she tested positive for direct Coombs with immunoglobulin and C3. A peripheral blood 69

Autoimmune Hemolytic Anemia Without Overt Signs of Hemolysis

Figure 1. Trend of patient’s hemoglobin (g/dL) during the 11-day admission. Red letters indicate points at which packed red blood cell (PRBC) units were transfused. a.= 4 units PRBC transfused; b.= 2 units PRBC transfused; c.= 1 unit PRBC transfused.

anemia with pallor, fatigue, tachycardia, dyspnea, and potentially jaundice. In these patients, the laboratory assessments are essential to discerning the type and cause of the anemia. These tests are especially important in cases where the patient remains refractory to transfusions with continued decreases in hemoglobin, as a source of the bleeding needs to be controlled. Tests such as a CBC, reticulocyte count, blood smear, and LDH yield certain results expected in AIHA, a hemolytic anemia. This patient is unique in that she did not demonstrate the typical laboratory findings expected in patients with AIHA (Table 1). For instance, she had direct Table 1. Laboratory values throughout the patient's 14-day admission. Repeat labs within a hyperbilirubinemia with normal haptoglobin 24-hour period are listed in chronological order. and LDH levels. For learning purposes, an elevated indirect hyperbilirubinemia, decreased haptoglobin levels, and increased smear demonstrated macrocytic (MCV 107.3 fL) red cells with LDH levels are typical (1, 2). LDH is found intracellularly, typical granular platelets, no white cell atypia, and no evidence therefore, when RBCs rupture, we expect LDH to be released of dysplasia or malignancy. into the bloodstream. Haptoglobin typically binds free Due to the presence of antibodies and anemia refractory to hemoglobin after rupture of RBCs. There were no spherocytes transfusions (13 total units) with no overt signs of hemolysis, or red blood cell fragments present on the patient’s peripheral hematology was consulted for additional recommendations. blood smear, another common finding of AIHA. Being that the Transfusions were held until the patient became symptomatic, patient did not have these findings, it is difficult to say that and a prednisone taper was started. She remained anemic, but she was in a true state of hemolytic anemia (3, 4). Further her hemoglobin did not decrease to the threshold necessitating complicating the diagnosis was her previously diagnosed transfusion or to the level of becoming symptomatic. Since hepatic steatosis, which can lead to elevated LDH and discharge from the hospital, the patient remains anemic reduced haptoglobin (1). (average hemoglobin 8 g/dL) and follows closely with Admittedly, a repeat antibody test was not conducted at the hematology outpatient for continued treatment of suspected time of admission given her outpatient assessment, which warm autoimmune hemolytic anemia. was negative for any abnormality. Imaging and endoscopic evaluations were the next steps to identify the source of Discussion bleeding. These were also negative, which necessitated repeat Autoimmune hemolytic anemia is a rare condition with a antibody testing. The direct Coombs test or direct antiglobulin heterogeneous clinical presentation leading to diagnostic test (DAT) is the most sensitive and specific test in diagnosing challenges. The symptomatology is similar to other cases of AIHA, especially when distinguishing warm, cold, and mixed 70

Autoimmune Hemolytic Anemia Without Overt Signs of Hemolysis

forms (3–5). Although considered the gold standard laboratory test, DAT is not completely sensitive or specific so alternative causes of anemia should be investigated (3). DAT detects the presence of IgG or C3d complement, but monoclonal antibodies specific for IgM, IgA, and complement C3c can be utilized to broaden the results (2). In 5–10% of cases, AIHA is DATnegative, further complicating diagnosis and delaying treatment. After other causes are ruled out, diagnosis is established based on response to empiric treatment with steroids, which is an effective treatment for any classification of acquired AIHA (3).

Conclusion The multitude of potential etiologies underlying anemia present a diagnostic challenge for any clinical team, requiring a methodical approach including physical exam, laboratory assessments, and imaging. Typically, autoimmune hemolytic anemia presents with evidence of hemolysis and a positive DAT; however, it is often a diagnosis of exclusion necessitating a complete hematological workup. In some cases, as in this patient, signs of hemolysis beyond a low hemoglobin may not be evident, completing the clinical presentation. Although DAT is the gold standard test for AIHA, it is important to recognize that the test is not completely sensitive or specific. Additionally, AIHA may be DAT-negative in a small cohort of patients and patients may acquire AIHA despite previously negative immunologic evaluations. These considerations are especially essential in cases refractory to transfusions in which all other causes of anemia have been thoroughly evaluated.

Disclosures The authors declare there is no conflict of interest regarding this article's publication.

References 1.

Hill A, Hill QA. Autoimmune hemolytic anemia. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):382–9.

Jäger U, Barcellini W, Broome CM, Gertz MA, Hill A, Hill QA, et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting. Blood Reviews. 2020 May;41:100648.

Fatizzo B, Giannotta JA, Serpenti F, Barcellina W. Difficult cases of autoimmune hemolytic anemia: a challenge for the internal medicine specialist. J Clin Med. 2020;9(12).

Barcellini W, Fattizzo B. Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia. Disease Markers. 2015;2015:1–7.

Hill QA, Hill A, Berentsen S. Defining autoimmune hemolytic anemia: a systematic review of the terminology used for diagnosis and treatment. Blood Advances. 2019 Jun 25;3(12):1897–906.

Scholarly Research In Progress • Vol. 7, November 2023

Assessment of Achievement Motivation in Surgical Subspecialty Residents Irene Cho1†, Paul A. Covello³, Joel Klena4, Joseph Desantis5, Matthew Meissner6, and Rebecca L. Hoffman² ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 ²Department of General Surgery, Geisinger Medical Center, Danville, PA 17822 ³Department of Oral Medicine and Maxillofacial Surgery, Geisinger Medical Center, Danville, PA 17822 4 Department of Orthopaedic Surgery, Geisinger Medical Center, Danville, PA 17822 5 Department of Plastic Surgery, Geisinger Medical Center, Danville, PA 17822 6 Department of Urology, Geisinger Medical Center, Danville, PA 17822 † Doctor of Medicine Program Correspondence: icho@som.geisinger.edu

Abstract Background: Goal orientation (GO) theory is used to describe motivational disposition in learners. Three main GO profiles are Mastery (MG), or motivation guided by learning for the sake of content/skill mastery; Performance-Approach (PAP), motivation guided by demonstrating competence compared to others; and Performance-Avoid (PAV), where learners are motivated toward competence by avoiding the appearance of incompetence. Positive correlations between MG and feedback-seeking behavior/job performance/well-being, and negative correlations between PAV and burnout/anxiety/cognitive load have been shown repeatedly in non-medical learners, and more recently, in general surgery (GS) residents but never in surgical subspecialty (SS) residents. The aim of this study was to measure the frequency of GO feelings in SS residents and compare them to that of GS residents from the same hospital system. Methods: SS residents (orthopaedics, plastics, urology, obstetrics/gynecology, and oral/maxillofacial surgery) participated in a cross-sectional study measuring GO using the Goal Orientation in Surgical Trainees scale, a 10-item survey that measures the 3 domains using a 5-point Likert scale (1=never,3=weekly,5=daily). Mean scale scores were calculated overall, as well as by gender and training level (intern vs chief). T-tests were used to compare study participants to GS residents who previously took the survey. Results: Seventy-six percent of SS residents participated (44/58). The mean age was 30.3 years and 34% (n=15) were female. Mean overall SS scores were 3.7 for MG, 3.5 for PAP, 3.5 for PAV, showing significant differences only between programs in MG (orthopaedics vs plastics, 4.1 vs 2.7, p=0.01). SS orthopaedic residents scored significantly higher on MG than GS residents overall (4.1 vs 3.7, p=0.04). There were no significant differences seen in SS and GS intern GO profiles. SS chief residents showed significantly higher PAV (3.8 vs 2.5, p=0.0001) and PAP (3.6 vs 2.6, p=0.04) mean scores than GS chiefs. Conclusion: Examining GO in SS and GS in the same hospital allowed for improved understanding of the specialty-specific cultural influences on motivational learning. Overall, SS residents endorsed mastery feelings occurring between 2 and 4 times per week, with higher MG scores driven by orthopaedics. In both SS and GS, MG scores remained high throughout residency. The differential mastery scores between orthopedics

and GS may help guide a learning opportunity between specialties. Furthermore, the increased frequency of more maladaptive PAV feelings in SS chiefs identifies an area of for intervention to nurture more adaptive dispositions throughout resident training.

Introduction The theories of goal orientation and growth mindset were both conceptualized by Carol Dweck more than three decades ago and are recently being explored in the field of surgery (1–4). Expanding on previous non-medical research showing the impact that positive internal states have on learner performance, a 2020 study with surgical residents across multiple subspecialties showed near unanimous agreement among residents that excellence in the operating room was mediated by certain mindsets (5). These mindsets were found to be influenced by an individual’s innate disposition, as well as by the actions and comments of the faculty. Mindset and achievement motivation (goal orientation) are intimately related to one another. In general, mindset theory relates to a person’s beliefs about their ability, and goal orientation (GO) theory describes the subconscious reasoning for the effort behind their learning. In the latter theory, motivation is broken into three constructs: Mastery (MG), when an individual is driven by innate desire to become competent in a skillset, and two performance orientations, where individuals are driven by the desire to impress or avoid disappointing others: Performance-Approach (PAP) and Performance-Avoid (PAV). In PAP, individuals view themselves as competent and are driven by their desire to display ability amongst their peers. In PAV, individuals are driven by their desire to avoid showing their lack of ability to peers (6). Between the two, PAV is regarded to be a more maladaptive approach to learning. In an academic setting, students that set MG goals showed a higher preference for challenge and academic risk-taking whereas, students that set performance goals showed higher correlations with negative impacts on learning and achievement (7, 8). Previous work by our group has identified a relationship between higher levels of PAV GO and emotional exhaustion, as well as perceived stress in the general surgery resident population (9). In addition, we have also shown some differences in GO by gender and training level in the same study population

Assessment of Achievement Motivation in Surgical Subspecialty Residents

(10). By expanding this to surgical subspecialty residents, the aim of this study was to better understand the distribution of goal orientations among surgical subspecialty residents under one large health system.

Methods

orthopaedics were combined and compared with the latter group. For the purposes of comparing GO by training levels, a chief was defined as most senior level trainee within each program and an intern was defined as a resident in their first year of training. Chi square or Fisher’s exact test, and Student’s T-tests were performed as appropriate to evaluate for differences between groups and scores.

Study Population All 58 residents in 5 surgical subspecialties (orthopaedic surgery, plastic surgery, urology, obstetrics/gynecology, and oral/maxillofacial surgery) at one large academic medical center were invited to participate in a cross-sectional study to measure GO over the course of 3 months (January–April 2022). All participating residents were on clinical rotations. Residents on research electives or professional development time during the study period were excluded. Demographic information collected included the resident’s identifying gender, post-graduate year (PGY) level, age, and surgical specialty.

Results A total of 44 surgical subspecialty (SS) residents (RR=75.9%) completed the survey. Among the surgical subspecialties, orthopaedics (n=20) and plastics (n=4) had a 100% resident participation, followed by oral maxillofacial (n=9, 90%), urology (n=6, 75%), and obstetrics/gynecology (n=5, 31%). More than half of participants (n=27, 64.3%) identified as male (Table 1). The mean age of participants was 30.3 years (SD 2.7). Each subspecialty had at least one intern represented except obstetrics/gynecology.

Program leaders of the five surgical subspecialties distributed The mean scale scores by domain were: 3.5 (SD 0.8) for a survey link for the Goal Orientation in Surgical Trainees scale PAV, 3.5 (SD 1.0) for PAP, and 3.7 (SD 0.9) for MG (Table 2). (GO-ST), a 10-item validated instrument which measures the frequency of feelings over the previous month in the three domains of GO on a Total Cohort Orthopaedic All Other p-value Likert scale (one=never, to a maximum of Surgery Subspecialties five=daily) (10). The questions on GO-ST Total Residents 44 20 (45.5%) 24 (54.5%) ask residents to reflect on their most recent month of training. The assessment was Age (mean, SD) 30.3 (2.7) 30.2 (2.2) 30.4 (3.2) 0.74 designed to understand trainee learning Male Gender (n, %) 27 (64.3%) 17 (85.0%) 10 (45.5%) 0.008 processes with their patient and healthcare Training Level (n, %) 0.60 team interactions in and out of the operation room, such as: How often have you thought Intern 8 (47.1%) 4 (50.0%) 4 (44.4%) about getting through the day without making Chief 9 (52.9%) 4 (50.0%) 5 (55.6%) a mistake regarding patient care? How often GO Domain (mean, SD) have you thought about how you were perceived by your attending/program director Performance Avoid 3.5 (0.84) 3.7 (0.86) 3.4 (0.81) 0.21 compared to your peers? Responses measured Performance 3.5 (0.98) 3.5 (1.03) 3.5 (0.96) 1.0 the frequency of feelings that a resident Approach expressed for each goal orientation domain, Mastery 3.7 (0.87) 4.1 (0.71) 3.4 (0.89) 0.01 where higher scores correlated to more Abbreviations: SD, standard deviation; GO, Goal Orientation frequent expression of that orientation. Approval was granted by the Institutional Review Board prior to recruitment of participants and informed consent was obtained through participation of the survey. Participation was voluntary and data was collected, anonymized, and managed using REDCap electronic data capture tools hosted at Geisinger Medical Center (11,12). Statistical Analysis Surveys were considered complete and eligible for analysis when all questions were completed. Descriptive statistics for the study demographics were performed. Mean scores were calculated for each question and by each GO domain for the entire population and by specialty. Due to the discrepancy in sizes of surgical subspecialty programs and their participants, for the sake of anonymity, all specialties except

Table 1. Demographics of the study population by SS group

Male Gender

Female Gender

Total Residents*

Age (mean, SD)

30.5 (2.6)

30.3 (3.0)

Training Level (mean, SD)

p-value

0.81 0.62

Intern

6 (54.5)

2 (33.3)

Chief

5 (45.5)

2 (33.3)

Performance Avoid

3.5 (0.79)

3.6 (0.98)

0.52

Performance Approach

3.2 (1.02)

3.9 (0.78)

0.03

Mastery

3.8 (0.85)

3.5 (0.89)

0.28

GO Domain (mean, SD)

*: 2 participants did not identify their gender in the survey Abbreviations: SD, standard deviation; GO, Goal Orientation Table 2. Demographics of study participants by gender

Assessment of Achievement Motivation in Surgical Subspecialty Residents

Question

Total Cohort

Orthopaedic Surgery

All Other Subspecialties

p-value

1. How often have you thought about making it through the day without making a mistake regarding patient care? (PAV)

3.8 (1.2)

4.2 (1.0)

3.5 (1.2)

0.07

2. How often have you thought about how you were perceived by your attendings/program director compard to your peers? (PAP)

4.0 (1.1)

4.0 (1.7)

4.1 (1.1)

0.81

3. How often have you thought about how a patient interaction would help you to be more prepared for independent practice? (MG)

3.9 (1.1)

4.3 (0.9)

3.6 (1.2)

0.04*

4. How often have you thought about wanting to appear more competent or skilled compared to your peers? (PAP)

3.8 (1.2)

3.7 (1.1)

4.0 (1.2)

0.39

5. How often have you worried about being perceived as incompetent? (PAV)

3.7 (1.2)

3.9 (1.2)

3.5 (1.1)

0.32

6. Think about some operative cases you have done lately. How often have you felt more relieved after leaving a case because you avoided harsh criticism rather than satisfied with the learning experience? (PAV)

2.6 (1.2)

2.7 (1.2)

0.86

7. How often have you worried about how a negative patient interaction would make you look to your senior residents/attendings? (PAV)

2.7 (1.2)

2.9 (1.3)

2.5 (1.1)

0.28

8. How often have you worked harder because you wanted to avoid making a mistake or looking incompetent? (PAV)

4.0 (1.1)

4.2 (1.2)

3.8 (1.1)

0.30

9. How often did you seek feedback because you knew it would be constructive for learning? (MG)

3.5 (1.0)

3.9 (0.9)

3.3 (1.0)

0.05

10. How often did you seek feedback because you were interested in impoving a skill set? (MG)

3.7 (1.0)

4.1 (0.8)

3.4 (1.0)

0.01

Abbreviations: SS, surgical subspecialties; Ortho, Orthopaedic surgery residents; PAV, performance avoid; PAP, performance approach; MG, Mastery *: Colored cells highlight significant values, which are all of the mastery questions. Table 3. Mean scores of goal orientation in surgical trainees scale in the total cohort, orthopaedic residents, and other surgical subspecialty residents

Intern

Chief

p-value

Total Residents*

Age (mean, SD)

27.8 (1.3)

33.2 (3.0)

0.0003

Male Gender (n, %)

6 (75.0)

5 (55.6)

0.62

Performance Avoid

3.6 (0.94)

3.8 (0.51)

0.62

Performance Approach

3.1 (1.2)

3.6 (0.92)

0.35

Mastery

3.6 (0.65)

3.6 (1.0)

1.0

Abbreviations: SD, standard deviation; GO, Goal Orientation

By gender, female SS residents scored significantly higher on the PAP scale than males (3.8 vs 3.2, p=0.04). There were no significant differences in PAV or MG expression between genders. Both mean MG, PAV and PAP scores for SS interns were not significantly different from SS chiefs, but both chief PAV (3.8 vs 3.6, p=0.62) and PAP scores (3.6 vs 3.1, p=0.35) were slightly higher than that of interns (Table 4).

Table 4. Comparisons by training level

Discussion

GO Domain (mean, SD)

Orthopaedics had significantly higher MG expression that the other SS groups (4.1 vs. 3.4, p=0.01). The two most commonly endorsed sentiments identified on the GO-ST in all SS residents were worry about how one appears to their program director/attendings compared to peers (performance-approach, mean 4.0±1.1) and working harder to avoid looking incompetent (performance-avoid, mean 4.0±1.1). SS residents overall least commonly endorsed greater relief for leaving a case and avoiding criticism than satisfaction in learning (mean 2.6±1.2). The only significant differences between orthopaedic residents and other SS by individual question were in each of the mastery questions (Table 3), where

the orthopaedic residents score significantly higher. While not significantly different, orthopaedic residents also scored higher on each of the PAV questions except question 6, referring to relief versus satisfaction after leaving a case.

In this first study of GO in SS trainees, we have shown that there are some differences between specialties, the implications of which may be useful to guide future studies and interventions. Overall, MG expression remained high in all SS residents, averaging 2-4 times per week, followed closely by PAP and PAV expressions. Orthopaedic residents showed the highest resident participation, and their results predominantly drove this trend, with MG dominance disappearing with removal of their data from the cohort. The other surgical subspecialties showed overall highest preference for PAP, followed closely by MG and PAV. Orthopaedic surgery remains within the top five most competitive residencies to match into, and applicants must

Assessment of Achievement Motivation in Surgical Subspecialty Residents

prove their competitiveness through distinguished scores and extracurricular involvement (13). GO studies in non-medical and medical learners have shown that learners with preference for MG had higher levels of autonomous motivation with increased utilization of metacognitive studying strategies (14, 15). While it is possible that the MG preference seen in orthopaedic residents reflects the innate mindsets or extraneous motivational qualities that applicants develop to succeed in a highly competitive field, more studies are needed to further validate this finding. What is evident from this study is that this group of orthopaedic residents think about feedback and are motivated by learning for future patient care, but also care frequently about avoiding the appearance of incompetence, albeit not quite as often. This sets up an interesting situation in motivational learning in which residents recognize the necessity of mastery but do not acquire the inefficiencies bred by a performance-avoid mindset (16). Another important factor that must be considered, is that when subspecialty residents train in silos of their own without intermingling, they foster their own unique cultural environments. This may perpetuate subspecialty stereotypes and can obscure the unique strengths and abilities of each program. The changes in GO profile dominance seen with and without the inclusion of the orthopaedic cohort demonstrates a small but significant difference amongst surgical subspecialties. GO is a measurement of subconscious motivations, and by applying this to a larger sample size of SS residents, future studies may also be able to capture the subtler specialty-specific cultural differences that affect resident learning. With recent surgical residency attrition rates increased to as high as 18% overall and 25% in female residents, another area of interest for our study was comparison of GO by gender profile (17). SS female residents showed significantly higher preference for PAP expression compared to their male counterparts. While there were no significant differences seen in MG and PAV expression, female residents had an overall higher average PAV expression and an overall lower average MG expression. These results are comparable to results from a previous study conducted with general surgery residents, where females also showed lower MG scores and significantly higher PAV scores (10). This continuous preference for performance orientations is an area of that requires further understanding in medical learners. Previous studies with non-medical learners have shown that performance-based learners have external loci of control and more likely to consider their performance in the context of others (18). The long-term implications and potential causes of this preference must be explored in future studies with female surgical residents. Lastly, mean performance profiles were insignificantly increased in chiefs versus interns. Due to gain of experience and skill, we expected that SS chiefs would show less performance-based dispositions, but their scores remained similar if not greater in value to the interns. As a resident advances into a chief title, they gain more responsibility in the operation room and hold a higher obligation to ensuring adequate patient care. These increased workplace expectations may explain the sustained pressure to perform. On the other hand, previous studies have demonstrated that when learners already have requisite ability to perform a task effectively, MG expression is no longer necessary to hone in on these acquired skillsets

(3). For residents reaching the end of their training, continued application and improvement in the form of performance profiles can be a reflection of their continued mastery of a skillset. The increase in PAV expression that was seen in chief residents, however, is an area of concern. A previous study with general surgeons showed chief residents with significant decreases in PAV score expression with increased training level (10). There is a clear correlation with PAV and workplace burnout, and a significant increase of PAV seen in chief residents is an area for future educational intervention that may not be limited to institution of study (19). One of the limitations in this study was that the assessment was only applied to residents under one hospital system, which limits generalizability. Results may have been biased by the educational curriculum specific to Geisinger Medical Center (2022). In addition, attitudes and experiences were limited to the most recent training month. Lastly, SS grouping for statistical analysis and reporting of GO to preserve anonymity limited our ability to comment on specific differences by surgical specialty.

Conclusions This cross-sectional study was the first to measure frequency of GO in SS residents in an effort to understand whether previously described trends in general surgery were also applicable to other specialties. There was a strong overall preference for MG expression largely driven by the orthopaedic resident cohort, and a rise in PAV feelings in chief residents. Understanding GO across specialties may allow for future studies which can aim to better understanding of how a program culture perpetuates or cultivates adaptive (or maladaptive) goal orientation dispositions.

Disclosures None of the authors have disclosure(s). No funding was used for this project.

References 1.

Dweck CS. Motivational processes affecting learning. American Psychologist. 1986;41(10):1040-1048.

Bandura M, Dweck CS. The relationship of conceptions of intelligence and achievement goals to achievement-related cognition, affect and behavior. Unpublished manuscript, Harvard University. 1985.

Gardner AK, Diesen DL, Hogg D, Huerta S. The impact of goal setting and goal orientation on performance during a clerkship surgical skills training program. Am

Hoffman RL, Hudak-Rosander C, Datta J, Morris JB, Kelz RR. Goal orientation in surgical residents: a study of the motivation behind learning. J Surg Res. 2014;190(2):451-456.

Babchenko O, Scott K, Jung S, et al. Resident Perspectives on Effective Surgical Training: Incivility, Confidence, and Mindset. J Surg Educ. 2020;77(5):1088-1096.

Brophy J. Goal Theorists Should Move on From Performance Goals. Educational Psychologist. 2005;40(3):167-176.

Assessment of Achievement Motivation in Surgical Subspecialty Residents

Schunk DH, Meece JL. Student perceptions in the classroom. Hillsdale, N.J.: L. Erlbaum; 1992.

Dupeyrat C, Mariné C. Implicit theories of intelligence, goal orientation, cognitive engagement, and achievement: A test of Dweck’s model with returning to school adults. Contemporary Educational Psychology. 2005;30:43-59.

Fatunmbi A, Woelfel I, Young K, et al. A new angle on surgical resident wellness: exploring the correlation between emotional exhaustion, stress and performanceavoid goal orientation learning behaviors. Global Surgical Education - Journal of the Association for Surgical Education. 2022;2(1):5.

10. Balanoff C, Fatunmbi A, Aarons C, et al. Relationship Between Gender, Training Level and Goal Orientation Achievement Motivation: Implications for Learners and Faculty. J Surg Educ. 2022;79(6):e38-e47. 11. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—A metadata-driven methodology and workflow process for providing translational research informatics support. Journal of Biomedical Informatics. 2009;42(2):377-381. 12. Harris PA, Taylor R, Minor BL, et al. The REDCap consortium: Building an international community of software platform partners. Journal of Biomedical Informatics. 2019;95:103208. 13. Nasser JS, Artino AR, Jr., Kind T, Duan X, Mihalic AP, Chretien K. Matching into competitive surgical residencies: predictors of success. Med Educ Online. 2023;28(1):2189558. 14. Sobral DT. What kind of motivation drives medical students' learning quests? Medical Education. 2004;38(9):950-957. 15. Archer J. Achievement Goals as a Measure of Motivation in University Students. Contemporary Educational Psychology. 1994;19(4):430-446. 16. Ross S, Pirraglia C, Aquilina AM, Zulla R. Effective competency-based medical education requires learning environments that promote a mastery goal orientation: A narrative review. Med Teach. 2022;44(5):527-534. 17. Khoushhal Z, Hussain MA, Greco E, et al. Prevalence and Causes of Attrition Among Surgical Residents: A Systematic Review and Meta-analysis. JAMA Surg. 2017;152(3):265-272. 18. Kusurkar R, ten Cate O. AM last page: Education is not filling a bucket, but lighting a fire: self-determination theory and motivation in medical students. Acad Med. 2013;88(6):904. 19. Licht BG, Dweck CS. Determinants of academic achievement: The interaction of children's achievement orientations with skill area. Developmental Psychology. 1984;20(4):628-636.

Scholarly Research In Progress • Vol. 7, November 2023

Textbook Oncologic Outcomes Among Pancreatic Cancer Patients Who Receive Neoadjuvant Versus Adjuvant Therapy Kevin Zhao†1, Gregory Wu², Katie Frank², Rebecca Lynn Hoffman², and Joseph Alfred Blansfield² ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 ²Geisinger Medical Center, Danville, PA 17822 † Doctor of Medicine Program Correspondence: kzhao@som.geisinger.edu

Abstract Background: Textbook oncologic outcome (TOO) is a quality measure defined by the receipt of an idealized baseline level of care in cancer patients undergoing curative surgical resection. The patient achieves TOO if they receive a surgery in which adequate lymph nodes (LN) are resected, negative surgical margins are achieved, the postoperative stay does not exceed expected length, there are no unplanned hospital readmissions, and adjunct guideline concordant chemotherapy with or without radiation is delivered. Each requirement has been shown to individually improve survival. While literature has shown TOO to be associated with improved survival in patients with pancreatic cancer, it is achieved at low rates in this population. Additionally, the lack of clinical practice guidelines for the medical management of pancreatic cancer in the setting of multimodal therapy complicates the consistent achievement of TOO. The aim of this study was to compare TOO attainment among patients who received neoadjuvant therapy and those who received adjuvant therapy for pancreatic cancer. Methods: Patients who underwent neoadjuvant or adjuvant therapy and surgical resection for pancreatic cancer between 2014 and 2018 were identified using the National Cancer Database (NCDB). The four requirements used to define TOO were: 12 or more lymph nodes examined, R0 resection, nonlength-of-stay (LOS) outlier (>16 days), and no 30-day hospital readmission. Univariate analysis was used to identify factors associated with TOO. Cox proportional hazards was used to identify factors associated with survival. Results: A total of 12,510 patients were included. Over half (51.0%) were male (n=6,383), 85.4% were Caucasian (n=10,689), and 53.6% were treated at an academic facility (n=6,708). Most patients received adjuvant therapy at 76% (n=9,498) and just over half of all patients (50.4%, n=6,306) achieved TOO. Patients who received neoadjuvant therapy had a significantly higher rate of achieving TOO than those who received adjuvant therapy (59% vs 48%, p<0.001). Each of the four requirements for TOO were independently associated with receipt of neoadjuvant therapy. Positive lymph nodes were observed more often in patients who received adjuvant therapy (67% vs 55%, p<0.001). On COX analysis, survival was not significantly increased in patients who had TOO, although R0 resection (p<0.001) and non-LOS outlier (p<0.001) were both associated with improved survival. Conclusion: Despite the inconclusive survival benefits of TOO, receipt of neoadjuvant therapy was associated with TOO attainment in pancreatic cancer patients. The shorter LOS and lower readmission rates may represent a considerable net positive perioperative outcome for patients. For these

reasons, we recommend neoadjuvant therapy in the multimodal approach to curative pancreatic cancer therapy.

Introduction While a multimodal approach of surgery and chemotherapy is the only curative approach to pancreatic cancer, variable patient outcomes indicate the need for a high-quality care measure (1). Textbook oncologic outcomes (TOO) is an aggregate quality metric composed of no unplanned readmissions, non-prolonged postoperative stay, negative margin status, adequate lymph node yield, and receipt of guideline concordant chemotherapy (2, 3). Each measure independently offers an essential glimpse into patient care and is associated with improved oncologic outcomes (4–11). As a composite, TOO retains much of the generalizability of its constituent metrics and is applicable to different malignancies. It also adds the benefit of scope, with medical management, surgery, and perioperative performance concisely integrated. Lastly, TOO has been shown to improve survival in patients undergoing surgery for pancreatic cancer and be associated with other markers of quality, including surgical volume (3, 12–14). Despite these positive associations, this patient population qualifies for TOO at low rates. Aquina et al. compared TOO rates among pancreas, rectal, gastric, and colon cancer, with the lowest rate in pancreatic cancer at 25.0%, compared to the next lowest at 31.8% in gastric cancer (12). Kulshrestha et al. and Sweigert et al. also identified low rates in patients specifically undergoing pancreaticoduodenectomy at 21.5% and 16.8%, respectively (3, 14). Sweigert et al. also compared TOO in patients undergoing open and minimally invasive pancreatectomy, but rates were still low in both groups at 23.5% and 24.7%, respectively (13). A possible explanation for this finding may be found within the measures that compose TOO. Qualification for receipt of chemotherapy depends on recommendations afforded by the National Comprehensive Cancer Network (NCCN) (15). However, chemotherapy sequencing recommendations for pancreatic cancer remain a subject of debate (10, 16–18). Survival outcomes have been observed in receipt of neoadjuvant and adjuvant therapy, yet the relationship between sequence and textbook outcomes is still underdeveloped. Thus, receipt of guideline concordant chemotherapy is a potential source of resistance to TOO achievement in this patient population. Sweigert et al. utilized adjuvant therapy within 12 weeks of surgery as TOO criteria, while Aquina et al. included patients who received neoadjuvant and adjuvant treatment (3, 12, 14). In both circumstances however, receipt of chemotherapy was the criteria achieved at the lowest rate at 48.2–49.3% and 65.4%, respectively. 77

Neoadjuvant Versus Adjuvant Therapy in Pancreatic Cancer Patients

Improving the achievement of desired patient outcomes is the goal and controlling for variables most likely to limit the attainment of a composite measure may be the first step. This study aimed to compare TOO rates in pancreatic cancer patients who receive neoadjuvant and adjuvant therapy. The secondary objectives were to identify other factors associated with TOO and to characterize any survival benefits TOO might afford.

Methods Study Design This retrospective cohort study utilized the National Cancer Database (NCDB), a joint project between the Commission on Cancer (CoC) of the American College of Surgeons (ACS) and the American Cancer Society. The database consists of information from approximately 1,500 CoC-accredited hospitals. It includes treatment, demographics, tumor traits, and outcome data from more than 70% of newly diagnosed cancer patients in the United States. Data used in this examination were de-identified, and IRB approval was exempted. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed or the conclusions drawn from these data by the investigator. Facility-type designations were based on those listed by the National Cancer Database (19). Rural-Urban Commuting Area Codes (RUCA) codes classify census tracts or zip codes as urban or rural based on census data from the 2010 decennial census and the 20062010 American Community Survey (21). Patients with invasive primary pancreas cancers diagnosed between 2014 and 2018 and underwent chemotherapy and surgery with a documented treatment sequence were included in the analysis. Metastatic disease, missing endpoint data, and cancers of non-pancreas histology or site were reasons for exclusion. Patients with missing TOO component data were also excluded. Patients qualified for TOO if they met the four non-controlled criteria: no readmissions within 30 days of surgery, a nonoutlier postoperative length of stay (LOS), tumor resection with microscopically negative (R0) margins, and American Joint Committee on Cancer (AJCC) compliant lymph node resection. According to the AJCC, 12 or more lymph nodes were considered a compliant resection at the time of surgery (2010-2015, AJCC 7th) [20]. Outlier LOS were based on Tukey’s interquartile range (Q3 + 1.5 × IQR) as applied by Aquina et al (12). All patients in the study population were concordant with guideline recommendations for chemotherapy since the inclusion criteria were for patients who had undergone neoadjuvant or adjuvant chemotherapy with surgery. Statistical Analysis Demographic information was categorized by frequency using univariate analysis. Chi-square and Wilcoxon rank sum tests were used to compare neoadjuvant and adjuvant treatment groups. Factors associated with receipt of TOO were identified using logistic regression analysis. An odds ratio greater than one indicated an increased likelihood of TOO achievement. Survival analysis was used to estimate point survival and confidence intervals for each group while log-rank tests were used to 78

assess the null hypothesis that there was no difference in survival probability between the two treatment groups. Overall survival (OS) was defined as the number of months between treatment initiation and the date of death from any cause. Cox proportional hazards was used to identify the effect of potential factors on survival probability. A hazards ratio greater than one indicated an improved likelihood of survival. Statistical analysis was conducted using R Version 4.0.5 (R Core Team, 2021). Results were considered statistically significant if the p≤0.05.

Results Demographics This report identified 12,510 patients who met inclusion criteria from the original 498,987 in the NCDB file (Table 1). The mean age was 65.8 ± 9.5 years, and approximately half were male (n=6,383; 51.0%). The sample was predominantly White (n=10,689; 85.4%) and located in metropolitan areas, assigned codes 1–3 under the RUCA schema (n=10,740, 85.9%) (21). Most patients were covered by government insurance (n=7,374; 58.9%) and were treated at academic or research programs (n=6,708; 53.6%). The most common procedure was Whipple (n=8,928; 71.4%), followed by distal pancreatectomy (n=2,056; 16.4%), and total pancreatectomy (n=1,408; 11.3%). Only a quarter of the sample received neoadjuvant therapy (n=3,012; 24.1%). While demographic features between the neoadjuvant and adjuvant therapy groups were similar, tumor characteristics varied between the treatment groups. Higher rates of distal pancreatectomies were achieved in the adjuvant therapy group compared to the neoadjuvant therapy group (17.9% vs. 12.0%; p < 0.001). Whipple procedures were more common in the neoadjuvant therapy group (75.2% vs. 70.2%; p < 0.001). Patients who received adjuvant therapy had higher rates of all documented histologic grades, while those who received neoadjuvant had higher rates of a histologically ungraded or undocumented tumor (p < 0.001). A higher proportion of patients who received adjuvant therapy were pathologically staged as 2A or 2B (86.5% vs. 77.3%; p < 0.001) compared to the neoadjuvant therapy group, in which patients were staged 1A or 1B more frequently (22.6% vs. 13.5%; p < 0.001). Lastly, positive lymph node rates (67.4% vs. 55.3%; p < 0.001) and median lymph node ratio (0.09 vs. 0.04; p < 0.001) were higher in patients who received adjuvant therapy. Virtually half of all patients qualified for all four TOO criteria (n=6,306; 50.4%). Individually, 91.6% had no unplanned readmission within 30 days of surgery (n=11,453), 89.8% had a non-outlier LOS (n=11,230), 80.8% had R0 margins (n=10,111), and 74.3% had ≥12 lymph nodes examined (n=9,290). There was a significant difference in all TOO metrics between patients who received neoadjuvant and adjuvant chemotherapy. A higher proportion of patients who received neoadjuvant therapy had no unplanned 30-day readmission (93.0% vs. 91.1%; p = 0.001), a non-outlier LOS (91.4% vs. 89.2%; p < 0.001), and negative surgical margins (83.0% vs. 80.1%; p < 0.001) compared to those who received adjuvant therapy. The component measure achieved at the lowest rate in both groups was adequate lymph node yield (81.3% vs. 72.0%; p < 0.001). Overall, patients who received neoadjuvant therapy qualified for TOO significantly more frequently than patients who received adjuvant therapy (58.4% vs. 47.9%; p < 0.001).

Neoadjuvant Versus Adjuvant Therapy in Pancreatic Cancer Patients

Table 1. Demographics. 1Wilcoxon rank sum test; Pearson's Chi-squared test, IQR: Interquartile range, SD: Standard deviation, TOO: textbook oncologic outcome, RUCA: Rural-urban commuting area code, NOS: Not otherwise specified, LOS: Length-of-stay 79

Neoadjuvant Versus Adjuvant Therapy in Pancreatic Cancer Patients

Figure 1. Forest plot of factors associated with overall survival in pancreatic cancer patients. A hazards ratio of less than one is associated with decreased likelihood of survival and a ratio greater than one is associated with increased likelihood of survival. Data from the National Cancer Database includes patients who received treatment between 2014 and 2018. RUCA: Rural-urban commuting area code, LNY: Lymph node yield, LOS: Length-of-stay, TOO: Textbook oncologic outcomes

Survival Cox analysis identified several factors associated with survival. All factors analyzed for survival are listed in (Figure 1). In this analysis, TOO was not significantly associated with survival (HR, 0.965; 95% CI, 0.875–1.065). Individually, both non-outlier LOS (HR, 0.880; 95% CI, 0.804–0.964) and negative microscopic margins (HR, 0.638; 95% CI, 0.586–0.693) were associated with improved survival regardless of treatment. Worse survival was predicted by an older age of diagnosis (HR, 1.010; 95% CI, 1.007–1.014), treatment at a non-academic/non-research facility (HR, 1.107; 95% CI, 1.053–1.164), residence in a non-metropolitan area (HR, 1.122; 95% CI, 1.047–1.204), a higher comorbidity burden (HR, 1.214; 95% CI, 1.153–1.278), receipt of neoadjuvant chemotherapy (HR, 1.092; 95% CI, 1.023–1.166), and a higher lymph node ratio (LNR) (HR, 1.089; 95% CI, 1.072–1.106). Other factors associated with improved survival were a more recent year of diagnosis (HR, 0.972; 95% CI, 0.966–0.977) and having private insurance or managed care coverage (HR, 0.906; 95% CI, 0.852–0.964). Factors Associated with TOO As expected of a composite measure, TOO was multifactorial (Figure 2). Multivariate analysis revealed neoadjuvant therapy 80

to be the strongest predictor of TOO qualification of all variables analyzed in this study (OR, 1.297; 95% CI, 1.175– 1.433). Earlier diagnosis (OR, 1.100; 95% CI, 1.089–1.111), female gender (OR, 1.129; 95% CI, 1.042–1.224), and having private insurance or managed care coverage (OR,1.144; 95% CI, 1.036–1.263) were all additionally shown to be associated with qualifying for TOO. Factors associated with not receiving TOO included: non-White or unknown race (OR, 0.874; 95% CI, 0.779–0.982), treatment at a non-academic/non-research facility (OR, 0.712; 95% CI, 0.656–0.772), histologically nongraded disease (OR, 0.840; 95% CI, 0.760–0.929), and distal pancreatectomy (OR, 0.804; 95% CI, 0.720–0.897).

Discussion To our knowledge, this was the first investigation to compare the achievement of textbook outcomes in pancreatic cancer patients with different treatment sequences. This study demonstrates that pancreatic cancer patients who receive neoadjuvant therapy are more likely to qualify for TOO than those who receive adjuvant therapy. Neoadjuvant therapytreated patients were also more likely to achieve the individual component measures of no 30-day unplanned readmission, non-LOS outlier, negative surgical margins, and adequate lymph

Neoadjuvant Versus Adjuvant Therapy in Pancreatic Cancer Patients

Figure 2. Forest plot of factors associated with Textbook Oncologic Outcomes in pancreatic cancer patients. An odds ratio less than one is associated with a decreased likelihood of achieving TOO and an OR greater than one is associated with increased odds of achieving TOO. Data from the National Cancer Database includes patients who received treatment between 2014 and 2018. RUCA: Rural-urban commuting area code

node yield. While this report did not find a significant correlation between TOO and survival, patients with a non-LOS outlier and negative microscopic margins following surgery demonstrated improved survival compared to those without. Quality improvement efforts in care have improved the experiences of innumerable patients (22). The increased reliance of the healthcare industry on care guidelines has been driven by the increased use of quality metrics for decades (23). Composite measures have particularly been utilized in quality assessment for their ability to summarize multiple statistics and convey the information in a more digestible format for physicians, patients, and payers alike (24). Patients have also shown a preference for surgery-specific, quality-of-care information when evaluating a hospital’s performance (25) and summarized but comprehensive evidence rather than detailed or individual measures when contemplating this information (26). TOO is definitionally a single quality metric that delivers a condensed report in a binary, “all-or-nothing” format (27). Whether a patient is weighing facilities for potential treatment, or a stakeholder is assessing a hospital’s interventional efficacy, TOO offers critical insight into the achievement of specific, ideal patient outcomes. The role of neoadjuvant therapy in pancreatic cancer is still not well-defined. Without addressing specific regimens, multiple options and modalities have been shown in prior literature to share positive associations with survival (28–30). As our study did not find a survival association between neoadjuvant therapy and TOO, the primary benefit of this modality may exist in its effects on other measures of patient outcome. Margin status and lymph node resection may be assessed as pathologic

responses to chemotherapy treatment before surgery. Some studies have shown no or questionable effects of neoadjuvant therapy in resectable disease, but improvement in resectability of borderline resectable or locally advanced disease through tumor shrinkage and control of micrometastases (31–33). Merkow et al. found neoadjuvant therapy decreased the likelihood of margin involvement in pancreatic cancer patients undergoing surgery (34). In this study, higher rates of adequate lymph node resection, lower positive lymph nodes, and lower LNRs among patients treated with neoadjuvant therapy may represent a favorable postoperative profile and one of the benefits of neoadjuvant therapy. The relationship between lymph node yield and oncologic outcomes is well established (4, 5, 35–37). The number of positive lymph nodes and the lymph node ratio are also powerful prognostic indicators (38–40). Given the pronounced disparity in adequate lymph node resection and negative surgical margin rates compared to that of other TOO metrics, future exploration of factors that influence their achievement in the context of textbook outcomes may be warranted.

Avoidance of 30-day readmission and LOS outlier was accomplished in the overwhelming majority of patients in this study regardless of therapy sequence. Readmission and prolonged LOS have both been linked to worse prognoses and increased costs in pancreatic cancer patients (9, 41). In these studies, procedure-related complications were the most common reason for readmission within 30 days of surgery, but the reasons for and frequency of readmission changed beyond this period. Studies in textbook outcomes that have utilized Medicare data offer an extended 90-day observation. Readmission rates dropped as low as 71.9% and 67.5% in minor and major pancreatic operations, respectively (27). Readmission rates are likely higher, and the 30-day window captured by NCDB is insufficient to assess the actual frequency of clinically significant readmits. However, extending the discussion of ideal patient outcomes to include a more accurate assessment of true readmissions calls for an alternate data pool to be employed. Limitations This study has several limitations. The retrospective and observational nature of this research limits its level of evidence. Additionally, the data sourced for this project through the NCDB offers good insight into patient demographics and surgical outcomes but lacks the granularity to capture comorbidity, operative, and complication details that undoubtedly influence immediate and long-term patient wellbeing. The focus of this investigation was also directed toward the facility level. Surgeon-specific features such as experience and patient-provider management decisions are important

Neoadjuvant Versus Adjuvant Therapy in Pancreatic Cancer Patients

factors in discussions on outcomes but are excluded due to the availability of such information. Facilities not captured by the NCDB and not accredited by the CoC make up a substantial proportion of the healthcare system. Patients at these facilities comprise roughly 30% of newly diagnosed malignancies. Accreditation status has shown some evidence to play a role in patient satisfaction and quality of care (42–44). Thus, this study’s findings may not be applicable to patients receiving care at non-accredited facilities.

Conclusion In conclusion, TOO rates were higher in pancreatic cancer patients who received neoadjuvant therapy compared to those who received adjuvant therapy. While TOO was not significantly associated with survival in this study, its component measures of margin status and post-operative stay were independently so. Furthermore, the lower readmission rates and LOS outliers seen in the neoadjuvant therapy group may additionally contribute to a considerable net positive outcome. We recommend receipt of neoadjuvant therapy for pancreatic cancer patients who require surgical management for their disease.

Disclosures The authors declare no conflicts of interest. The research did not receive any funding from agencies in the public, commercial, or not-for-profit sectors. All authors made substantial contributions to either the concept and/or design of this study. KF collected and analyzed the data for the present study. KZ, GW, KF, RH, and JB all interpreted the data and drafted and/ or edited the manuscript. KZ, GW, KF, RH, and JB reviewed the manuscript for errors and provided feedback for changes. All authors approved this version of the manuscript and agreed to be accountable for all aspects of the article.

References 1.

Bilimoria KY, Bentrem DJ, Lillemoe KD, Talamonti MS, Ko CY, Pancreatic Cancer Quality Indicator Development Expert Panel AC of S. Assessment of pancreatic cancer care in the United States based on formally developed quality indicators. J Natl Cancer Inst. 2009/06/09 ed. 2009 Jun 16;101(12):848–59.

Warschkow R, Widmann B, Beutner U, Marti L, Steffen T, Schiesser M, et al. The more the better—lower rate of stage migration and better survival in patients with retrieval of 20 or more regional lymph nodes in pancreatic cancer. Pancreas. 2017 May;46(5):648–57.

Tummers WS, Groen JV, Sibinga Mulder BG, FarinaSarasqueta A, Morreau J, Putter H, et al. Impact of resection margin status on recurrence and survival in pancreatic cancer surgery. Br J Surg. 2019/03/18 ed. 2019 Jul;106(8):1055–65.

Kaltenmeier C, Nassour I, Hoehn RS, Khan S, Althans A, Geller DA, et al. Impact of resection margin status in patients with pancreatic cancer: a national cohort study. J Gastrointest Surg. 2020/12/02 ed. 2021 Sep;25(9):2307–16.

Strobel O, Neoptolemos J, Jäger D, Büchler MW. Optimizing the outcomes of pancreatic cancer surgery. Nature reviews. Clinical oncology. 2018 Oct 19;16(1):11–26.

Niedergethmann, M, Farag Soliman, M, & Post, S. Postoperative complications of pancreatic cancer surgery. Minerva Surg. 2004;59(2), 175–183.

10. Ansari D, Gustafsson A, Andersson R. Update on the management of pancreatic cancer: surgery is not enough. World J Gastroenterol. 2015 Mar 21;21(11):3157–65. 11. Deplanque G, Demartines N. Pancreatic cancer: are more chemotherapy and surgery needed? The Lancet. 2017 Mar;389(10073):985–6. 12. Aquina CT, Hamad A, Becerra AZ, Cloyd JM, Tsung A, Pawlik TM, et al. Is textbook oncologic outcome a valid hospital-quality metric after high-risk surgical oncology procedures? Ann Surg Oncol. 2021 Aug 15;28(13):8028–45. 13. Sweigert PJ, Wang X, Eguia E, Baker MS, Kulshrestha S, Tsilimigras DI, et al. Does minimally invasive pancreaticoduodenectomy increase the chance of a textbook oncologic outcome? Surgery. 2021 Sep;170(3):880–8. 14. Kulshrestha S, Sweigert PJ, Tonelli C, Bunn C, Luchette FA, Abdelsattar ZM, et al. Textbook oncologic outcome in pancreaticoduodenectomy: Do regionalization efforts make sense? J Surg Oncol. 2021/10/07 ed. 2022 Mar;125(3):414–24.

Kolfschoten NE, Kievit J, Gooiker GA, van Leersum NJ, Snijders HS, Eddes EH, et al. Focusing on desired outcomes of care after colon cancer resections; hospital variations in ‘textbook outcome.’ Eur J Surg Oncol. 2013 Feb;39(2):156– 63.

Sweigert PJ, Eguia E, Baker MS, Paredes AZ, Tsilimigras DI, Dillhoff M, et al. Assessment of textbook oncologic outcomes following pancreaticoduodenectomy for pancreatic adenocarcinoma. J Surg Oncol. 2020 May;121(6):936–44.

16. van Dam JL, Janssen QP, Besselink MG, Homs MYV, van Santvoort HC, van Tienhoven G, et al. Neoadjuvant therapy or upfront surgery for resectable and borderline resectable pancreatic cancer: A meta-analysis of randomised controlled trials. Eur J Cancer. 2022 Jan;160:140–9.

Schwarz RE, Smith DD. Extent of lymph node retrieval and pancreatic cancer survival: information from a large US population database. Ann Surg Oncol. 2006 Sep;13(9):1189–200.

17. Lee YS, Lee JC, Yang SY, Kim J, Hwang JH. Neoadjuvant therapy versus upfront surgery in resectable pancreatic cancer according to intention-to-treat and per-protocol analysis: A systematic review and meta-analysis. Sci Rep. 2019 Oct 30;9(1):15662–15662.

15. The National Comprehensive Cancer Network (NCCN) has announced updates to the NCCN clinical practice guidelines in oncology. PharmacoEconomics. 2008 May;552(1):3–3.

Neoadjuvant Versus Adjuvant Therapy in Pancreatic Cancer Patients

18. Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. The Lancet. 2020 Jun;395(10242):2008–20. 19. About cancer program categories. J Am Coll Surg; 2023 Feb 15. Available from: http://www.facs.org/quality-programs/ cancer/coc/accreditation/categories 20. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010 Feb 24;17(6):1471–4. 21. Rural-urban commuting area codes. USDA ERS. 2023 Feb 25. Available from https://www.ers.usda.gov/dataproducts/rural-urban-commuting-area-codes/ 22. Cantiello J, Kitsantas P, Moncada S, Abdul S. The evolution of quality improvement in healthcare: Patient-centered care and health information technology applications. J Hosp Adm. 2016 Jan 5;5(2):62. 23. Nigam A. Changing health care quality paradigms: The rise of clinical guidelines and quality measures in American medicine. Soc Sci Med. 2012 Dec;75(11):1933–7. 24. Dimick, C. Quality Check: An overview of quality measures and their uses. J AHIMA, 2010;81(9), 34–38. 25. Marang-van de Mheen PJ, Dijs-Elsinga J, Otten W, Versluijs M, Smeets HJ, Vree R, et al. The relative importance of quality of care information when choosing a hospital for surgical treatment. Med Decis Making. 2010 Dec 3;31(6):816–27. 26. Dijs-Elsinga J, Otten W, Versluijs MM, Smeets HJ, Kievit J, Vree R, et al. Choosing a hospital for surgery: the importance of information on quality of care. Med Decis Making. 2010 Jan 28;30(5):544–55. 27. Merath K, Chen Q, Bagante F, Beal E, Akgul O, Dillhoff M, et al. Textbook outcomes among Medicare patients undergoing hepatopancreatic surgery. Ann Surg. 2018 Nov 29;271(6):1116–23. 28. Maeda S, Unno M, Yu J. Adjuvant and neoadjuvant therapy for pancreatic cancer. Pancreatology. 2019 Jul 23;2(3):100–6. 29. Shridhar R, Takahashi C, Huston J, Meredith KL. Neoadjuvant therapy and pancreatic cancer: a national cancer database analysis. J Gastrointest Oncol. 2019 Aug;10(4):663–73. 30. Lo W, Zureikat A. Neoadjuvant therapy in pancreatic cancer: a review and update on recent trials. Curr Opin Gastroenterol. 2022 Jul 15;38(5):521–31. 31. Barugola G, Partelli S, Crippa S, Capelli P, D’Onofrio M, Pederzoli P, et al. Outcomes after resection of locally advanced or borderline resectable pancreatic cancer after neoadjuvant therapy. Am J Surg. 2012 Feb;203(2):132–9. 32. Gugenheim J, Crovetto A, Petrucciani N. Neoadjuvant therapy for pancreatic cancer. Updates Surg. 2021/10/09 ed. 2022 Feb;74(1):35–42.

34. Merkow RP, Bilimoria KY, Bentrem DJ, Pitt HA, Winchester DP, Posner MC, et al. National assessment of margin status as a quality indicator after pancreatic cancer surgery. Ann Surg Oncol. 2013 Dec 13;21(4):1067–74. 35. Zhao K, Fatunmbi A, Wang S, Young K, Hoffman RL, Blansfield JA. Lymph node yield as a measure of pancreatic cancer surgery quality. Surg Prac Sci. 2022 Sep;10:100103. 36. Vuarnesson H, Lupinacci RM, Semoun O, Svrcek M, Julié C, Balladur P, et al. Number of examined lymph nodes and nodal status assessment in pancreaticoduodenectomy for pancreatic adenocarcinoma. Eur J Surg Oncol. 2013 Oct;39(10):1116–21. 37. Tol JAMG, Gouma DJ, Bassi C, Dervenis C, Montorsi M, Adham M, et al. Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: A consensus statement by the International Study Group on Pancreatic Surgery (ISGPS). Surgery. 2014 Sep;156(3):591–600. 38. House MG, Gönen M, Jarnagin WR, D’Angelica M, DeMatteo RP, Fong Y, et al. Prognostic significance of pathologic nodal status in patients with resected pancreatic cancer. J Gastrointest Surg. 2007 Sep 4;11(11):1549–55. 39. Riediger H, Keck T, Wellner U, zur Hausen A, Adam U, Hopt UT, et al. The lymph node ratio is the strongest prognostic factor after resection of pancreatic cancer. J Gastrointest Surg. 2009 May 6;13(7):1337–44. 40. Roland CL, Yang AD, Katz MHG, Chatterjee D, Wang H, Lin H, et al. Neoadjuvant therapy is associated with a reduced lymph node ratio in patients with potentially resectable pancreatic cancer. Ann Surg Oncol. 2014/10/29 ed. 2015 Apr;22(4):1168–75. 41. Yermilov I, Bentrem D, Sekeris E, Jain S, Maggard ma, Ko CY, et al. Readmissions following pancreaticoduodenectomy for pancreas cancer: a population-based appraisal. Ann Surg Oncol. 2008 Nov 11;16(3):554–61. 42. Knutson AC, McNamara EJ, McKellar DP, Kaufman CS, Winchester DP. The role of the American College of Surgeons’ cancer program accreditation in influencing oncologic outcomes. J Surg Oncol. 2014 Jul 8;110(5):611–5. 43. Merkow RP, Chung JW, Paruch JL, Bentrem DJ, Bilimoria KY. Relationship between cancer center accreditation and performance on publicly reported quality measures. Ann Surg. 2014 Jun;259(6):1091–7. 44. Schroeder MC, Gao X, Lizarraga I, Kahl AR, Charlton ME. The impact of commission on cancer accreditation status, hospital rurality and hospital size on quality measure performance rates. Ann Surg Oncol. 2022 Jan 23;29(4):2527–36.

33. Oba A, Ho F, Bao QR, Al-Musawi MH, Schulick RD, Del Chiaro M. Neoadjuvant treatment in pancreatic cancer. Front Oncol. 2020 Feb 28;10:245–245.

Scholarly Research In Progress • Vol. 7, November 2023

Quality of Life Changes in Stroke Rehabilitation: A Comprehensive Review Joey Harmon1† and Yevgeniy Busarov1† ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 † Doctor of Medicine Program Correspondence: jharmon@som.geisinger.edu

Abstract Stroke is a leading cause of long-term disability and significantly affects the quality of life of individuals. Rehabilitation plays a crucial role in promoting functional recovery and enhancing the well-being of stroke survivors. Understanding the changes in quality of life during the rehabilitation process is essential for optimizing stroke care and developing interventions that address patients' multidimensional needs. This review paper aims to explore the changes in quality of life among stroke patients undergoing rehabilitation by analyzing relevant studies. The reviewed studies encompass various aspects of stroke rehabilitation and employ diverse methodologies to evaluate quality of life changes. The findings highlight the positive impact of rehabilitation interventions on functional outcomes and certain domains of quality of life. However, challenges in sustaining long-term improvements and addressing psychosocial factors are evident. The importance of home-based rehabilitation programs, early rehabilitation, comprehensive discharge planning, and addressing sexuality issues in stroke care is emphasized. The synthesis of existing evidence aims to enhance the understanding of factors influencing patient outcomes and inform the development of evidence-based interventions to optimize the overall well-being and quality of life for stroke survivors.

al. emphasizes the use of stroke-specific quality of life (SS-QoL) measures as accurate and helpful tools for evaluating the QoL of the post-stroke population (9). Early rehabilitation Barthel index (ERBI) described by Rollnik is another effective measure of the effectiveness of early intervention (10). Overall, there are a variety of ways to follow patients through the course of their recovery. The reviewed studies encompass various aspects of stroke rehabilitation and employ diverse methodologies to evaluate quality of life changes. The focus areas include home-based rehabilitation programs, early neurological rehabilitation, inpatient stroke rehabilitation, and the effects of rehabilitation on disability and functional outcomes. By considering a range of perspectives and approaches, we aim to capture the multifaceted nature of quality of life in stroke rehabilitation; further, by synthesizing the existing evidence on quality-of-life changes in stroke rehabilitation, this review aims to contribute to the understanding of the factors that influence patient outcomes and inform the development of evidence-based interventions. Ultimately, the goal is to enhance the overall wellbeing and quality of life for stroke survivors and optimize their rehabilitation journey.

Methods

Introduction

Literature Search Strategy

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) identified stroke to be the second cause of mortality worldwide, and a third cause of mortality and morbidity combined (7). Rehabilitation plays a crucial role in promoting functional recovery and enhancing the overall well-being of stroke survivors. Understanding the changes in quality of life that occur during the rehabilitation process is essential for optimizing stroke care and developing interventions that address the multidimensional needs of patients.

A systematic search of electronic databases was conducted to identify relevant studies for inclusion in this review. The following databases were searched: PubMed, MEDLINE, Embase, and Google Scholar. The search terms included variations and combinations of keywords such as "stroke," "rehabilitation," "quality of life," "home-based rehabilitation," "inpatient rehabilitation," and "long-term outcomes." The search was limited to studies published in English between 2000 and 2023 to ensure the inclusion of recent research. Additionally, reference lists of the selected articles were manually reviewed to identify any additional relevant studies.

This review paper aims to explore the changes in quality of life among stroke patients undergoing rehabilitation, drawing upon a comprehensive analysis of relevant studies. By synthesizing the findings from multiple investigations, we seek to provide an understanding of the impact of stroke rehabilitation on quality of life outcomes. Assessing the changes in a patient's quality of life (QoL) following a stroke can be a complex task. However, there are various questionnaires and assessment tools available to aid clinicians in navigating the post-stroke recovery process. QoL assessment holds significant importance in medical research across different health-related domains. One systematic review conducted by Haraldstad et al. acknowledges the significance of QoL in medical research, but also highlights the challenges of establishing a unified concept of QoL within the research community (8). Another study by Lin et 84

Study Selection Criteria The studies included in this review met the following criteria: (1) focused on stroke rehabilitation and its impact on qualityof-life outcomes, (2) employed quantitative or mixed-methods research designs, (3) included stroke patients as the study population, (4) reported relevant outcomes related to quality of life, functional status, or disability, and (5) were published in peer-reviewed journals. QoL Assessment Tools A variety of methods were employed by the researchers to assess the QoL of the patient population under investigation.

Quality of Life Changes in Stroke Rehabilitation: A Comprehensive Review

Rasmussen et al. utilized several tools, including a modified Rankin Scale, modified Barthel-100 Index, Motor Assessment Scale, CT-50 Cognitive Test, EuroQol-5D, body mass index, and treatment-associated economy (4). Similarly, Lim et al. employed a 10-meter walk test, a figure of 8 walk test, a four-square step test, and a 36-item short-form survey to monitor the improvement of post-stroke patients (1). In the study conducted by Hopman and Verner, the Health-Related Quality of Life (HRQOL) was utilized to evaluate the QoL of the subjects (3). Specifically, they used the mean value of the Medical Outcomes Study 36-item Short Form (SF-36). Seidel et al. used Barthel Index (ERBI), the modified Rankin Scale (mRS) and a 12-item quality of life survey (SF-12) (2). McLaughlin et al. utilized surveys to assess communication barriers between patients and providers (5). Figure 1 describes the steps taken in obtaining sources for this study.

The results of the reviewed studies provide valuable insights into the changes in quality of life among stroke patients undergoing rehabilitation. Study 1: Lim et al. (2020). Home-based rehabilitation programs on postural balance, walking, and quality of life in patients with stroke: A single-blind, randomized controlled trial.

Eligibility

Screening

Identification

This study demonstrated that home-based rehabilitation programs had a significant positive impact on postural balance, walking ability, and overall quality of life compared to the control group. The home rehabilitation and control groups, 10-meter walk test, figure 8 walk test and four square step test showed significant improvement (p<0.05) with both home-based rehabilitation and clinic-based exercises, which was identified as standard care. However, when the figure 8 walking test was assessed, findings demonstrated a significant difference between the home rehabilitation group and the control group. Specifically, there was a median improvement score value of -6.74 on the home rehabilitation group compared to a -2.00 change in the control group, making this statistically significant

Inclusion

Study 2: Seidel et al. (2019). Quality of life and disability after severe stroke and early neurological rehabilitation. This study investigated the long-term effects of severe stroke and early neurological rehabilitation on quality of life and disability. Using median improvement in ERBI scores, the findings revealed significant improvement in functional outcomes up to 12 months after discharge from early rehabilitation (p<0.001). However, based on SF-12 survey results, there were no significant differences in quality of life over time (p>0.32), indicating a potential disparity between functional recovery and overall well-being in these patients. Study 3: Hopman and Verner (2003). Quality of life during and after inpatient stroke rehabilitation.

Results

492 records identified through PubMed database

(p<0.05). This indicates that providing rehabilitation services in the home setting can lead to substantial improvements in these important functional domains.

327 records identified through Google Scholar database

104 records identified through MEDLINE database

This study found that during inpatient stroke rehabilitation, there were substantial improvements in health-related quality of life (HRQOL) across five domains based on SF-36 results. However, after discharge, significant declines were observed in certain HRQOL domains. Statistically significant positive changes following admission to discharge were noted in physical functioning (p<0.001), mental health (p<0.01), social functioning (p<0.01), bodily pain (p<0.05), and general health perception (p<0.05). Additionally, the physical functioning scores remained similar to the previous time frame, and the role physical domain, defined as “limitations in physical role activities because of physical health problems,” showed some improvement at the 6-month follow-up mark. However, in the same time period, negative trends were noticed in emotional (p<0.001), mental health (p<0.001), social functioning (p<0.05), bodily pain (p<0.001), and general health perceptions (p<0.001). After discharge, only one domain maintained statistical significance, despite three domains showing continued improvement without statistical significance. This suggests the need for ongoing support and community services to sustain and enhance longterm quality of life for stroke survivors.

74 records identified through Embase database

261 records after the removal of duplicates

261 records screened

241 records removed after review of title and abstract

20 full text records assessed for eligibility

11 records removed full text review: lack of numerical data, differing focus

9 records included in study

Figure 1. Study Selection Flow Diagram and Rule Out Criteria

Study 4: Rasmussen et al. (2015). Stroke rehabilitation at home before and after discharge reduced disability and improved quality of life: a randomised controlled trial. This study investigated the effects of home-based rehabilitation on disability and quality of life in stroke patients. The results demonstrated that home-based rehabilitation, in addition to standard care, significantly reduced disability and improved overall quality of life compared to standard care alone. Specifically, patients that underwent home-based rehabilitation demonstrated improved modified Rankin Scale scores (p<0.05) and improved quality of life scores (p<0.05). This underscores the importance of providing comprehensive and integrated care that extends beyond the traditional boundaries of health care

Quality of Life Changes in Stroke Rehabilitation: A Comprehensive Review

settings. Interestingly, the number of minutes spent during home-based rehabilitation was associated with improved mRS and quality of life scores (p<0.01). Costs were also found to be lower than the total costs of standard treatment. This highlights the potential benefits of incorporating home-based rehabilitation programs as a cost-effective alternative to enhance outcomes and quality of life in stroke patients.

Characteristic

Inpatient Rehabilitiation

Outpatient Rehabilitation

Setting

Specialized facility or hospital

Outpatient clinic or home

Intensity of Care

Intensive, 24/7 care

Varies based on needs and availability

Support and Assistance

Immediate access to healthcare professionals and support staff

Relies more on family caregivers and community-based support systems

Transition to

Transition from hospital to home/

Rehabilitation takes place in

Community community may pose challenges familiar environment, facilitating The collective findings of these studies continuity of care indicate that rehabilitation interventions, whether provided at home or during Considerations Severe stroke, complex medical Milder stroke, good home needs, limited home support, support, benefit from therapy in inpatient care, have a positive impact on need for intense therapy familiar environment various aspects of quality of life in stroke patients. Home-based rehabilitation Table 1. Characteristic Comparison in Inpatient vs. Outpatient Rehabilitation programs specifically showed significant improvements in postural balance, walking ability, and overall quality of life. However, Discussion the studies also highlight the challenges in maintaining longThe findings from the reviewed studies provide valuable term improvements in quality of life, emphasizing the need for insights into the changes in quality of life among stroke patients ongoing support and addressing psychosocial and emotional undergoing rehabilitation. The results consistently highlight factors in stroke rehabilitation. the positive impact of rehabilitation interventions on various It is worth noting that the pilot study by McLaughlin and Cregan aspects of quality of life. However, they also shed light on the sheds light on the neglected issue of sexuality in stroke care challenges and areas that require further attention to ensure (5). The experiences of health and social care professionals sustained improvements in overall well-being. revealed a lack of training in addressing sexuality issues during Home-based rehabilitation programs emerged as a promising stroke rehabilitation. Health care workers involved in stroke approach in Study 1, demonstrating significant improvements in patient care were administered a survey that had three main postural balance, walking ability, and overall quality of life similar domains: “experience, involvement, and future vision.” The to current standard of care. These findings do suggest, however, “experience” section was focused on experience addressing that providing rehabilitation services in the home setting sexual issues before their employment as post-stroke offers unique advantages, such as increased convenience, caregivers. Out of 13 participants, 10 indicated a lack of prior personalized care, and a familiar environment, which contribute experience in addressing sexual issues, and 12 did not receive to enhanced outcomes in stroke patients. Incorporating hometraining specifically addressing sexual issues. “Involvement” based rehabilitation programs as part of the standard care focused on the experience of encountering such questions pathway could be a cost-effective strategy to improve functional while working in stroke rehabilitation. According to the survey outcomes and overall quality of life. results, 9 out of 13 participants had encountered sexualityThe importance of early rehabilitation is emphasized in Study related questions while on shift, and 11 out of 13 found the 2, where severe stroke patients experienced significant lack of training to be a major shortcoming in addressing these functional recovery up to 12 months after discharge from early questions. Lastly, the participants agreed on the importance of neurological rehabilitation. However, the lack of significant training that specifically addresses sexual issues in post-stroke improvements in quality of life over time highlights the need patients. Moreover, they suggested that a workshop led by an to address the psychosocial and emotional aspects of stroke independent psychosexual expert would be the best modality. recovery. Rehabilitation efforts should not solely focus on This indicates the importance of incorporating comprehensive functional gains, but should also encompass strategies to sexual health care into stroke rehabilitation programs to enhance overall well-being and satisfaction with life. Ongoing enhance the overall quality of life for stroke patients. support and interventions targeted at addressing long-term As seen in Table 1, the results indicate that while rehabilitation quality of life issues are crucial to ensure comprehensive stroke interventions can lead to significant improvements in functional rehabilitation. outcomes and certain domains of quality of life, sustained Study 3 reveals a pattern of initial improvements in healthenhancements in overall quality of life require ongoing support, related quality of life during inpatient stroke rehabilitation, community services, and the integration of psychosocial and followed by declines in certain domains after discharge. These emotional aspects of care. Addressing sexuality issues and findings underscore the need for continuity of care and support providing comprehensive sexual health care should be a priority beyond the inpatient setting. The transition from inpatient to ensure holistic and improved quality of life outcomes for to community-based rehabilitation should be accompanied stroke survivors. by comprehensive discharge planning, ensuring that stroke

Quality of Life Changes in Stroke Rehabilitation: A Comprehensive Review

survivors have access to community services and support that address their ongoing needs. This may involve facilitating access to physical therapy, occupational therapy, psychological support, and social engagement programs to sustain and enhance the gains achieved during inpatient rehabilitation. Building upon the insights from the previous studies, Study 4 demonstrates the significant benefits of incorporating home-based rehabilitation as an adjunct to standard care. The findings reveal that home-based rehabilitation not only reduces disability but also improves overall quality of life compared to standard care alone. This underscores the importance of providing comprehensive and integrated care that extends beyond the traditional boundaries of health care settings. By bringing rehabilitation services directly to the home environment, stroke patients can experience increased autonomy, greater participation in daily activities, and improved well-being, ultimately enhancing their quality of life. Table 2 offers a summary of the findings from all papers utilized in this study. It is crucial to acknowledge the neglected issue of sexuality in stroke care highlighted by McLaughlin and Cregan (5). The lack of training and awareness among health care professionals in addressing sexuality issues during stroke rehabilitation is a significant barrier to holistic care. Integrating comprehensive sexual health care into stroke rehabilitation programs is vital to promote a positive self-image, enhance relationships, and improve overall quality of life for stroke survivors.

Conclusion The findings from the reviewed studies underscore the importance of rehabilitation interventions in improving quality

of life among stroke patients. Home-based rehabilitation programs, early rehabilitation, and comprehensive discharge planning are crucial components in achieving sustained improvements in functional outcomes and overall well-being. Additionally, addressing psychosocial factors, including sexuality issues, and providing ongoing support are vital to ensure a holistic approach to stroke rehabilitation. Future research should focus on developing and evaluating comprehensive rehabilitation models that encompass physical, functional, psychosocial, and sexual health aspects to optimize quality of life outcomes for stroke survivors. Limitations Despite the valuable insights provided by the reviewed studies, there are several limitations that should be acknowledged. Firstly, the small sample sizes and the specific settings in which the studies were conducted may limit the generalizability of the findings. Larger-scale studies involving diverse populations are needed to confirm the results and determine their applicability to broader stroke rehabilitation contexts. Secondly, most of the reviewed studies relied on self-report measures to assess quality of life, which are subject to potential bias and subjective interpretation. Future studies could incorporate objective measures and include assessments from multiple perspectives, such as caregiver reports, to provide a more comprehensive understanding of the impact of rehabilitation on quality of life. Furthermore, the duration of follow-up in some studies was relatively short, ranging from a few months to one year. Longer-term follow-up is necessary to examine the sustainability of the observed improvements in quality of life and to capture any potential changes or challenges that may arise over time.

Outcome

Inpatient Rehabilitiation

Outpatient Rehabilitation

Future Studies

Functional Improvement

Significant gains during rehabilitation period

Focuses on maintaining and improving functional abilities

Quality of Life Improvement

May show initial improvements, potential declines after discharge

Sustained progerss over longer duration of rehabilitation

To further advance the understanding of quality-of-life changes in stroke patients undergoing rehabilitation, future studies could consider the following directions:

Long-Term Sustainability

Challenges in maintaining gains after transitioning to community setting

Emphasizes continuity of care and support for sustained outcomes

Access to Support Services

Immediate access to multidisciplinary team and 24/7 care

May require greater reliance on family caregivers and community support systems

Transition and Adaptation

Transition from controlled hspital environment to home/ community setting

Facilitates smoother transition as rehabilitation takes place in familiar environment

Patient Independence

May require more support and assitance due to intensive care setting

Promotes patient independence and self-management skills

Cost Effectiveness

Generally higher cost due to intensive care and 24/7 staffing

Potentially more cost-effective due to reduced hospitalization and flexible scheduling

Severity of Stroke

Suitable for severe stroke cases with complex medical needs

Suitable for milder stroke cases with good home support

Table 2. Comparison of Outcomes in Inpatient vs. Outpatient Rehabilitation

Long-term follow-up: Conducting studies with extended follow-up periods, such as two or more years, to investigate the long-term impact of rehabilitation on quality-of-life outcomes. This would provide insights into the durability of the observed improvements and the potential for late-stage changes in quality of life. Intervention Optimization Conducting studies that focus on optimizing rehabilitation interventions to address specific domains of quality of life, such as psychosocial wellbeing, sexual health, and community reintegration. These studies could explore innovative approaches, such as technology-assisted interventions or group-based rehabilitation programs, to enhance the effectiveness and efficiency of stroke rehabilitation. 87

Quality of Life Changes in Stroke Rehabilitation: A Comprehensive Review

Health Equity Considerations Investigating the impact of rehabilitation interventions on quality-of-life outcomes among diverse populations, including those from different socioeconomic backgrounds, racial and ethnic groups, and geographical locations. Understanding the potential disparities in access to and outcomes of stroke rehabilitation can inform strategies to promote equitable delivery of care and improve quality of life for all stroke survivors. Addressing these limitations and pursuing these future research directions would contribute to a more comprehensive understanding of the factors influencing quality of life changes in stroke rehabilitation and facilitate the development of evidence-based interventions that optimize patient outcomes and overall well-being.

Acknowledgments The authors would like to thank Dr. Amina Khan and Dr. Wail Alsalfi for their review and recommendations.

Disclosures The authors have no conflicting interest to disclose.

References 1.

Lim JH, Lee HS, Song CS. Home-based rehabilitation programs on postural balance, walking, and quality of life in patients with stroke: A single-blind, randomized controlled trial. Medicine (Baltimore). 2021 Sep 3;100(35):e27154.

Seidel G, Röttinger A, Lorenzen J, Kücken D, Majewski A, Klose K, Terborg C, Klass I, Wohlmuth P, Zukunft E, Debacher U. Lebensqualität und Behinderung nach schwerem Schlaganfall und neurologischer Frührehabilitation [Quality of life and disability after severe stroke and early neurological rehabilitation]. Nervenarzt. 2019 Oct;90(10):1031-1036. German.

Hopman WM, Verner J. Quality of life during and after inpatient stroke rehabilitation. Stroke. 2003 Mar;34(3):801-5.

Rasmussen RS, Østergaard A, Kjær P, Skerris A, Skou C, Christoffersen J, Seest LS, Poulsen MB, Rønholt F, Overgaard K. Stroke rehabilitation at home before and after discharge reduced disability and improved quality of life: a randomised controlled trial. Clin Rehabil. 2016 Mar;30(3):225-36.

McLaughlin J, Cregan A. Sexuality in Stroke Care: A Neglected Quality of Life Issue in Stroke Rehabilitation? A Pilot Study. Sex Disabil. 2005;23(4):213-226.

Madden S, Hopman WM, Bagg S, Verner J, O'Callaghan CJ. Functional status and health-related quality of life during inpatient stroke rehabilitation. Am J Phys Med Rehabil. 2006 Oct;85(10):831-8.

GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021 Oct;20(10):795-820.

Haraldstad K, Wahl A, Andenæs R, Andersen JR, Andersen MH, Beisland E, Borge CR, Engebretsen E, Eisemann M, Halvorsrud L, Hanssen TA, Haugstvedt A, Haugland T, Johansen VA, Larsen MH, Løvereide L, Løyland B, Kvarme LG, Moons P, Norekvål TM, LIVSFORSK network. A systematic review of quality of life research in medicine and health sciences. Qual Life Res. 2019 Oct;28(10):26412650.

Lin KC, Fu T, Wu CY, Hsieh CJ. Assessing the strokespecific quality of life for outcome measurement in stroke rehabilitation: minimal detectable change and clinically important difference. Health Qual Life Outcomes. 2011 Jan 11;9:5.

10. Rollnik JD. The early rehabilitation Barthel Index (ERBI). Die Rehabilitation. 2011;50(6):408-411. German.

Scholarly Research In Progress • Vol. 7, November 2023

Evaluating Leadership Education Assessment Tools within Medical School Program Objectives and Leadership Frameworks Deven Appel1†, Srivastava A. Kodavatiganti1*, Andrea DiMattia1, and Ian McCoog1 ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 † Doctor of Medicine Program *Master of Biomedical Sciences Program Correspondence: dappel@som.geisinger.edu

Abstract

Introduction

Effective leadership skills need better incorporation in medical training to promote the efficacy of healthcare teams. Leadership training is not historically embraced as a critical element of team-based care for medical professionals. For most aspiring physicians, leadership ability grows early in their careers and increases with their responsibility, but reaching this level of individual leadership is a complex endeavor. Medical professionals need time to progressively understand, reflect upon, and practice the ability to lead effectively. For these reasons, there is a large benefit to introducing and incorporating leadership principles into the undergraduate medical training curriculum. In addition, medical education institutions must have a framework by which they can assess their progress in incorporating the domains and concepts of leadership into their curriculum. Through this study, we aim to synthesize an evidence-based, medical school-specific framework that assesses holistic leadership models and the objectives, competencies, and assessment methods used by Geisinger Commonwealth School of Medicine (GCSOM) to better perceive relative strengths and gaps in embedding leadership within the curriculum.

Medical leadership is a required competency for all physicians (1). A hallmark of good patient care is well-coordinated care. Good medical leadership allows clinical teams to deliver highquality healthcare (1). Medical trainees are typically introduced into leadership roles early in their careers. Most residents lead a group of junior residents and medical students (2). This responsibility continues to grow over the career of a physician; as a result, leadership training should be emphasized during medical training (1). Recognizing the critical role leadership plays in medical practice and delivery, the current lack of leadership-specific education among other technical skills may limit the success of future medical trainees (1, 2).

A literature search was conducted using key terms related to leadership studies. Main themes, gaps, and analytic frameworks were summarized. The six GCSOM program objectives and the corresponding competencies for each objective were used in conjunction with high-yield findings to supply an example and comparison of related terms in leadership domains. The Medical Leadership Competency Framework (MLCF), Emotional Quotient Inventory (EQ-i), and the Five Factor Model (OCEAN) were evaluated for each model’s ability to be an assessment tool to gauge the incorporation of the leadership domains into the curriculum of GCSOM. In comparing the five leadership domains of the MLCF, GCSOM’s objectives and competencies did not explicitly mention the principles and concepts referenced in the MLCF but maintained themes. While a good framework for students to reflect on personality traits affecting individual growth, the OCEAN model was not valid for institutional assessment of leadership. The EQ-i assessment provided a satisfactory framework for leadership evaluation in comparison to GCSOM’s program objectives and competencies. While the literature captures the disparities and overall necessity to include leadership in medical school curricula, there is still a gap in providing a standard assessment to evaluate institutional progress. By evaluating assessment tools used by GCSOM in leadership education, the school, and other medical schools can improve leadership training to better develop a generation of leadership-oriented physicians.

During a time when burnout is a concern, progressive leadership training may assist in building resilience and providing physicians with a framework for self-reflection and improvement (3). Various leadership frameworks have been developed to support the self-evaluation of physicians and trainees alike. The Medical Leadership Competency Framework (MLCF) is a tool that categorizes five domains of leadership, and each domain is broken down into four to five competencies that a medical trainee can assess themselves against (4, 5). Daniel Goleman, a key figure in emotional intelligence research, references the power of emotional intelligence in leadership success (6, 7). The Emotional Quotient Inventory (EQ-i) is a 133-statement assessment that takes approximately 20 minutes to complete and evaluates emotional intelligence. Five domains each contain 3 competencies for a total of 15 elements, as described in Figure 1. The Five-Factor Model (OCEAN) looks at Openness, Conscientiousness, Extroversion, Agreeableness, and Neuroticism (8). These traits are assessed with different tools, including the Trait Self-Descriptive Inventory in 1992 by Tupes and Christal, as well as more modern approaches using 15–25 item surveys. Concepts such as emotional intelligence, cultural sensitivity, and professionalism training have slowly crept into medical curricula nationwide (9, 10). However, it can become unclear how to compare a trainee’s individual leadership development alongside institutional progress due to inconsistent objectives between the frameworks. Overall, these frameworks help to compile the various principles that can guide a student doctor to be a good leader in healthcare (9). Each framework emphasizes different components of leadership, providing multiple perspectives. In addition, there is no standardized leadership development curriculum for medical educational institutions (4). This makes it difficult to evaluate the extent to which institutions have incorporated and progressed medical leadership into training (4). Therefore, some schools such as the University of Massachusetts have developed optional leadership modules 89

Evaluating Leadership Education Assessment Tools

Results After matching MLCF framework competencies to GCSOM program objectives and corresponding competencies within them, each MLCF domain did match with at least one GCSOM objective (Figure 2). Most domains incorporated several objectives, with many including multiple competencies within that objective. Major associations have been noted in Figure 3. Of note, MLCF competencies like "Acting with Integrity," "Managing Resources," and "Ensuring Patient Safety" touched upon five of the six GCSOM objectives each, excluding “Critical Thinking” for the first and “Professional Identity” for the latter two. These are individually supported by several GCSOM competencies. One example includes the fourth competency of GCSOM objective “Health System Science,” outlined as “Engage in identifying medical errors and implementing potential systems solutions,” paired with the MLCF competency “Ensuring Patient Safety” under the MLCF domain “Improving Services.”

Figure 1. Emotional Intelligence wheel showcasing the 5 domains and 15 competencies used within the EQ-i assessment (Copyright © 2011 Multi-Health Systems Inc. All rights reserved. Based on the original BarOn EQ-i authored by Reuven Bar-On, copyright 1997).

with feedback to enhance leadership domain integration (4). Other than this approach, utilizing direct assessment tools with current curriculum offerings can show if there is need for a separate program in the first place, and what steps may help to further leadership training efforts.

Methods

With the EQ-i comparison, multiple factors within the assessment matched GCSOM objectives, including direct matches between each of the given EQ-i domains. These include matches like “Self-Perception” with “Professional Identity,” “Decision Making” with “Critical Thinking,” and “Interpersonal” with “Patients, Families, and Communities.” Of note, the GCSOM objectives “Clinical Skills” and “Knowledge for Practice” had weaker ties to EQ-i competencies than the other four objectives. When reconsidering the OCEAN model as an assessment tool, the use was found to be largely limited to military and business personnel. Traits like “Neuroticism” did not explicitly match into MLCF domains but did match single competencies for several GCSOM objectives. Regarding leadership, multiple studies cited traits like “Agreeableness” as both a positive and negative predictor, limiting some use as an accurate tool for institutional leadership assessment.

A literature review was conducted using the PubMed database. Discussion The terms “medical,” “leadership,” and “curriculum” were used As anticipated by the likes of Daniel Goleman and other to produce 3,977 articles between 2014 and 2023. After researchers in the emotional intelligence space, there was which, we used the terms “framework” and “training” to further significant overlap in domains of emotional intelligence with filter our results. We assessed the peer-reviewed articles for those of leadership. Specific competencies within GCSOM's leadership frameworks that can be used for assessment. As students of Geisinger Commonwealth School of Medicine (GCSOM) and the School of Graduate Education, GCSOM Geisinger Objective "Professional Identity," Competency 2: was determined to be a feasible medical Engage in lifelong personal and professional development education institution to compare these and socialzation into the medical community of practice. frameworks against. The EQ-i, developed MLCF Domain MLCF Competency MLCF Criteria by The Emotional Intelligence Training Company from a model by Reuven Bar-On, A. Demonstrating 3. Continuing Personal 1) Actively seek opportunities and has already been used by GSCOM in order Personal Qualities Development challenges for personal learning and to collect data on emotional intelligence development for medical students. Each framework was 2) Acknowledge mistakes and treat first compared to the GCSOM six program them as learning opportunities objectives followed by the respective 3) Participate in continuing competencies within each objective professional development activities to determine if there was a relevant 4) Change their behaviour in the relationship and incorporation of leadership light of feedback and reflection principles. Several tables were generated noting relevant passages between domains Figure 2. Example of entry made for the GCSOM objective “Professional Identity” paired and competencies. with relevant MLCF domains.

Evaluating Leadership Education Assessment Tools

Figure 3. Mental map of key connections (see supplemental data for full connections) between the MLCF domains, Geisinger Commonwealth objectives, and the Emotional Quotient Inventory (EQ-i) domains.

list of objectives touched upon each leadership and emotional intelligence domain, though some areas had weaker associations or limited connection. It could be useful to weigh the scaling of the EQ-i against GCSOM objectives to measure which objectives are being reinforced the most at GCSOM. With such overlap overall, the EQ-i makes for a compelling choice to model both GCSOM objectives, as well as MLCF domains. GCSOM itself currently offers eight EQ-i trained faculty coaches to optionally review results individually with students for 1-hour sessions. A broad overview session is offered as well, though with limited direct reference to leadership. Despite using the EQ-i assessment, only the Workplace and Coaching reports have been disseminated to students. The Leadership Report, which includes categories in Authenticity, Coaching, Insight, and Innovation, could be useful as a more streamlined way to assess leadership for students within this assessment. As seen from the theme analysis, these leadership qualities could also be pulled out from the assessment using the Coaching and Workplace reports as well.

Conclusion The EQ-i does show adequate standing as a leadership assessment tool based on its correlation to traditional leadership frameworks and matching with GCSOM’s own objectives and competencies. Although the assessment is already performed at the school, there could be improvements made with the execution in order to better measure leadership. The Leadership Report offered by EQ-i could be disseminated to students and coaches to more clearly reflect on this trait.

In addition, coaching sessions could be incorporated into the curriculum rather than offered as an optional session to encourage participation and ensure reflection is taken regarding these traits. If measurement of longitudinal progression is beneficial, hosting the assessment early in the medical school timeline and then again before matriculation to residency would be an appropriate option. This could allow for counseling of students to recognize their strengths and develop their weaknesses as desired. While it was shown that GCSOM’s objectives and competencies matched with leadership criteria in multiple forms, consideration could be made to more explicitly call out these leadership domains. GCSOM currently fits curriculum themes within the Society, Systems, and Humanities in Medicine framework, and explicitly implementing leadership sessions into the preclinical curriculum may provide more easily perceptible changes with tools like the EQ-i. It would also be advantageous to continue monitoring the usefulness of the EQ-i as a leadership tool and compare methodologies with other medical schools as leadership instruction within medical education continues to gain traction.

Acknowledgments We thank Dr. Amanda Caleb for contributions to developing the project scope and reviewing current GCSOM assessment tools.

Disclosures None

Evaluating Leadership Education Assessment Tools

References 1.

Warren OJ, Carnall R. Medical leadership: why it's important, what is required, and how we develop it. Postgrad Med J. 2011 [cited 2023 Mar 24];87(1023):27-32.

Rotenstein LS, Sadun R, Jena AB. Why doctors need leadership training. Harvard Business Review [Internet]. 2018 Oct 17 [cited 2023 Apr 16]; Leadership Development:[about 2p.]. Available from: https://hbr. org/2018/10/why-doctors-need- leadership-training.

Wright B, Richmond MJ. Training medical students to manage difficult circumstances – a curriculum for resilience and resourcefulness? BMC Med Educ. 2019 [cited 2023 Mar 24];19(1):280.

Richard K, Noujaim M, Thorndyke LE, Fischer MA. Preparing medical students to be physician leaders: a leadership training program for students designed and led by students. MedEdPORTAL. 2019 [cited 2023 May 18];15:10863.

Academy of Medical Royal Colleges. Medical leadership curriculum [Internet]. Coventry (GB): NHS institute for Innovation and Improvement; 2009 [cited 2023 May 18]. 45 p. Available from: https://www.leadershipacademy. nhs.uk/wp-content/ uploads/2012/12/NHSLeadershipLeadership-Framework-Medical-Leadership-Curriculum. pdf.

Goleman, D. Primal leadership: realizing the power of emotional intelligence. Boston:Harvard Business School Press, 2002. 249 p.

Cavaness K, Picchioni A, Fleshman JW. Linking Emotional Intelligence to Successful Health Care Leadership: The Big Five Model of Personality. Clin Colon Rectal Surg. 2020 [cited 2023 April 16];33(4):195-203.

O'Keefe DF, Kelloway EK, Francis R. Introducing the ocean.20: a 20-item five-factor personality measure based on the trait self-descriptive inventory. Mil Psychol [Internet]. 2012 [cited 2023 Mar 24]; 24(5): 433–60.

Keijser WA, Handgraaf HJM, Isfordink LM, et al. Development of a national medical leadership competency framework: the Dutch approach. BMC Med Educ. 2019 [cited 2023 Mar 24];19(1):441.

10. Quince T, Abbas M, Murugesu S, et al. Leadership and management in the undergraduate medical curriculum: a qualitative study of students' attitudes and opinions at one UK medical school. BMJ Open. 2014 [cited 2023 May 18]; 4(6).

Scholarly Research In Progress • Vol. 7, November 2023

Evaluating the Use of Theatre to Decrease Depression and Anxiety Among Adolescents with Chronic Medical Conditions Maura M. Sheehan1†, Jennifer Agwagom1†, and Karen A. Ephlin1,2 ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 ²Geisinger Pediatrics, Hanover, PA 17331 † Doctor of Medicine Program Correspondence: msheehan@som.geisinger.edu

Abstract

Introduction

Background: Adolescents with chronic medical conditions have higher rates of anxiety and depression than their peers, possibly due to maladaptive coping strategies. We have developed a roleplay intervention based on Integrative Community Therapy that uses improvisational theatre to teach healthy coping strategies to adolescents with chronic medical conditions. To assess the appropriateness of this intervention for this population, we conducted a pre-intervention assessment of participants’ quality of life and knowledge and utilization of coping strategies.

Adolescents with chronic medical conditions (CMCs) are more likely to develop anxiety and depression than their peers without CMCs (1, 2). Research has shown that children with CMCs are more likely to have depressive symptoms as early as age 11 and to be diagnosed with anxiety by age 16. The number of depressive and anxious symptoms also increases with the number of CMC diagnoses in each patient (1). This increased risk may be due to maladaptive coping strategies (3). Additional risk factors for anxiety and depression in adolescents with CMCs are low self-esteem, peer problems, and emotional expression and regulation difficulties (4). This increased risk for anxiety and depression necessitates the development of a unique intervention strategy to help adolescents with CMCs.

Methods: Participants were recruited from pediatric subspecialty offices, electronic medical records, and local high schools and middle schools. Pre-intervention variables were measured using both quantitative and qualitative methods. Participants were screened for major depressive disorder and generalized anxiety disorder using the Revised Children’s Anxiety Depression Scale. Quality of life was assessed by the Pediatric Quality of Life Inventory. Knowledge and utilization of coping strategies were assessed using the KidCOPE questionnaire. Qualitative interviews were also conducted and coded using modified grounded theory. Results: This pilot study consists of 3 participants between the ages of 15 and 17. No participant had a clinically significant score for either major depressive disorder or generalized anxiety disorder. On the Pediatric Quality of Life Inventory, emotional and school functioning were the most significantly affected categories, with median scores of 45/100 and 50/100 respectively. On the KidCOPE checklist, 2 out of the 3 participants scored less than 1, meaning they endorsed using more negative coping strategies than positive ones. In qualitative interviews, most participants endorsed significant emotional and functional effects of their illnesses on their everyday lives, corresponding with the domains indicated in the Pediatric Quality of Life Inventory. When presented with standard scenarios, most participants were more likely to use positive problem-based coping strategies when standing up for a friend to another peer. Additionally, participants were more likely to use maladaptive, avoidant behaviors when confronted with an authority figure. Conclusion: This intervention is inexpensive and easy to administer. It uses improvisational theatre to teach healthy coping strategies to adolescents with chronic medical conditions. The pre-intervention assessment of participants in this pilot study indicates that this population is ideal for this intervention given the impact of their medical conditions on their everyday lives and their lack of utilization of positive coping strategies.

The format of the intervention described here is based on integrative community therapy (ICT). ICT is a unique form of therapy that was developed to “integrate the knowledges developed by community members through their lived experiences” (5). Due to the peer interaction and sharing of local knowledge inherent in this type of practice, it is ideal for working with adolescents. Adolescent patients with CMCs value peer support as a fundamental aspect of their care (6). The most important aspect of peer support groups and mentoring relationships is having the opportunity to voice concerns and get advice (7, 8). Interventions with a peer support aspect have been shown to decrease anxiety and depression (9). Adolescents with CMCs clearly have a lot of local knowledge to share about disease management, and this knowledge has been shown to benefit others, making ICT an ideal format. ICT has also been shown to improve empowerment (10), which has in turn been shown to decrease anxiety, depression, perceived stress, and to improve disease outcomes (11). The intervention described here also incorporates role-play. Whereas in traditional ICT, participants describe difficult situations they are struggling with, in this intervention, situations are discussed using role-play to increase anonymity. This is particularly important with this age group to increase openness and avoid embarrassment. Role-play interventions have been shown to have beneficial social emotional effects in both adults and children. In adults, role-play interventions increase people’s abilities to recognize and express emotions (12, 13), increase insightfulness (14), and decrease aggressive behavior (15). In children, such interventions increase prosocial behavior (16–18), decrease aggression (16), and reduce depression (19). Although there is good evidence for the use of role-play interventions, there are several gaps in the way they are typically studied. These interventions are often not based on

Evaluating the Use of Theatre to Decrease Depression and Anxiety Among Adolescents with Chronic Medical Conditions

any underlying psychological framework, making them difficult to replicate or adapt to a new population. They can lack fidelity, as there are multiple facilitators with various levels of training. These studies are also limited by small sample size, lack of statistical analysis, and lack of a control group. Additionally, many studies for role-play interventions do not utilize mixed methods evaluation with quantitative and qualitative components. Most interventions of this type are studied in homogenous populations of patients with the same condition.

was done to be responsive to the needs of the community while preventing a large developmental gap between participants. Other requirements were to be able and willing to participate in improvisational theatre in spoken English, and to be able to understand and answer standard questionnaires used for evaluation in English. No exclusion criteria were defined. Participants were recruited from subspecialty offices, from electronic medical records, and from local high schools and middle schools.

This study addresses many of these gaps. This intervention is based on ICT, an existing therapeutic technique that has been studied, allowing for replication and adaptation to other patient populations. Fidelity will be ensured by a facilitator guide and training that have been specifically developed for this intervention. We plan to implement this intervention alongside a control group, using improvisation as usual. We will also be utilizing mixed methods evaluation with both quantitative and qualitative measures. Finally, this study is unique because it will follow a heterogenous population of adolescents with different CMCs.

Participants for this study were recruited from pediatric subspecialty offices in the Scranton and Wilkes-Barre areas using a poster hung in clinical areas and waiting rooms (Figure 1). The poster invited participants to fill out a RedCap survey indicating their interest in the program and requesting their contact information. A medical student also sat in the waiting room of pediatric subspecialty clinics and invited patients to fill out the survey while they were waiting. Electronic medical records were also used to recruit patients. Patient ages and contact information were obtained from

In this intervention, role-play is used with an ICT framework to facilitate the transfer of peer-to-peer knowledge regarding emotional regulation and navigation of difficult social situations. The goal is that this will prevent anxiety and depression and increase disease-related quality of life by increasing knowledge and utilization of different coping strategies and increasing empathy. Here, we describe this intervention and the pre-intervention assessment undergone by participants in the pilot study. We have conducted a pre-intervention assessment of quality of life and knowledge and utilization of coping strategies with 3 adolescents with CMCs, and we concluded that this is an appropriate target population for this intervention.

Methods This is a program pilot study with Geisinger Commonwealth School of Medicine and the Geisinger clinical enterprise. The institutional review board at Geisinger reviewed and approved this study (protocol number: 2022-0322). This study was conducted in accordance with institutional review board guidelines and the Helsinki Declaration. Recruitment Inclusion in this study required that patients self-identify as having a CMC, which we defined as an ongoing medical issue that affects the patient’s everyday life. Participants between the ages of 5 and 17 were recruited, but the intervention is planned to be completed with the age group from which the first 3 people responded that were aged within 3 years of each other. This 94

Figure 1. Recruitment Poster. This poster was used to recruit participants from pediatric subspecialty offices, high schools, and middle schools.

Evaluating the Use of Theatre to Decrease Depression and Anxiety Among Adolescents with Chronic Medical Conditions

electronic medical records for patients that attended a Geisinger outpatient clinic within 50 miles of Scranton, Pa., prior to June 1, 2022, who were between the ages of 5 and 17, lived within 50 miles of Scranton, Pa., and had English listed as their primary language. Patients were not contacted if they did not have an acute or chronic problem listed in their problem list. Emails advertising the study were sent to both patient and parent/guardian emails listed in electronic medical record.

an analysis of those scenes according to a standardized scene analysis guide (Figure 2). The analysis is considered stage five. The guide also provides an opportunity for participants to share their local knowledge if they have gone through a similar experience as one of the characters.

Lastly, posters were given to officials at local high schools and middle schools, including principals, assistant principals, counselors, nurses, and performing arts instructors to hang in student areas to elicit interest.

Stage Six: Closing Ritual: At least 10 minutes at the end of the group is reserved for a closing, and it is done the same way every time. One possible closing is “Wow, Pluses, and Deltas,” in which participants share one thing that they learned or an insight they had (wow), what people did well either regarding acting or analyzing scenes (pluses), and what the group or individuals could improve for next time (deltas).

Intervention

Evaluation

This intervention consists of ten 90-minute sessions held once per week. The intension is to have two arms, one consisting of the intervention and one consisting of improvisation as usual, to account for the beneficial effects of participation in the arts. The inclusion of a control arm has been limited by lack of participants.

Participants will complete an evaluation assessment at the beginning of the intervention, immediately following the intervention, then 6 months and 12 months after the intervention. Each evaluation utilizes both quantitative and qualitative methods.

The structure of sessions within this intervention is based on the structure of ICT sessions. This structure, developed by Adalberto Barreto, MD, PhD (5), consists of five stages: Welcoming and Warming Up, Selecting a Theme, Contextualizing the Theme – Linking Suffering, Sharing of Local Knowledge, and Closing Ritual. We have adapted these stages to incorporate the element of role-play. This allows adolescents at a tender stage to have a layer of anonymity when sharing local knowledge. Instead of analyzing and providing advice for a situation that they have been in, we analyze and provide advice for a fictional scene, which elicits the same feeling as a situation that they have been in. The stages for this intervention are described in detail below. Stage One: Welcoming and Warming Up: Participants are welcomed as they come into the room. There is some form of formal welcome when the entire group gathers, such as everyone sharing a piece of good news from their day. Warming up consists of doing 1 to 2 improvisation warmups and 1 to 2 short-form games. Stage Two: Selecting a Theme and Stage Three: Contextualizing the Theme – Linking Suffering: Stages two and three are performed together. Participants share either a specific story or they share a feeling that they’ve been experiencing lately. In ICT, the theme for the session is described as “the pebble in your shoe.” Themes for this intervention should be somehow related to living with a CMC or symptoms that participants experience. As themes are suggested, if they are a story, the facilitator translates them into a universal feeling so that they are more widely applicable to all the participants. The group then votes on the theme that resonates with the most members and most members would like to explore. Stage Four: Intervention Scenes and Stage Five: Sharing Local Knowledge: Stage four is specific to this intervention and does not occur in traditional ICT. Instead of analyzing one specific person’s story, as is done in ICT, groups of about 4–5 people create an improvisation scene based on the chosen theme. The groups are given 5–10 minutes to discuss and prepare their scenes before performing them. Group leaders then facilitate

Quantitative Measures Participants are assessed for major depressive disorder and generalized anxiety disorder using the Revised Children’s Anxiety Depression Scale (RCADS). This is a validated selfreport tool consisting of 47 scaled items, which can be scored according to unique subscales for specific disorders (20). The Pediatric Quality of Life Inventory (PedsQL) is being used to assess patients’ disease-related quality of life. This validated self-report tool consists of 23 items covering the domains of physical, emotional, social, and school functioning (21). Median measures of this tool are reported due to the nonparametric distribution of the results because of the low number of participants. Knowledge and utilization of coping strategies are being evaluated using the KidCOPE checklist. Although this is not a validated questionnaire, it has been a widely used research instrument since its development in 1988. The instrument asks respondents to consider a difficult situation they had to cope with and reflect on how often they utilized each of 10 coping strategies, assigning a possible score of 0–3, and how effective each one was, assigning a possible score of 0–4 (22). The KidCOPE score is reported as the sum of the frequency of utilization of each strategy multiplied by its effectiveness, resulting in a maximum possible score of 120. We also report the ratio of positive to negative coping strategies used, which was calculated by summing the frequency of utilization of each positive coping strategy divided by the sum of the frequency of utilization of each negative coping strategy. Additional Instruments During the pre-intervention assessment, participants were also asked to fill out the Pediatric Adverse Childhood Events (ACE) and Related Life Events Screener (PEARLS) (23), a demographics form, and the Ask Suicide-Screening questions (24). ACE scores and demographic information were collected to assess for confounding effects, and the Ask Suicide-Screening questions were asked after qualitative interview to assess safety since sensitive topics were discussed, such as chronic disease, quality of life, and bullying.

Evaluating the Use of Theatre to Decrease Depression and Anxiety Among Adolescents with Chronic Medical Conditions

Figure 2. Facilitator Scene Analysis Guide. These questions are used by the facilitator to lead a discussion of the intervention scenes to analyze coping strategies and share local knowledge.

Evaluating the Use of Theatre to Decrease Depression and Anxiety Among Adolescents with Chronic Medical Conditions

Social dynamic

Interview question

Qualitative Measures

Peer-to-peer interaction antagonistic toward the patient

You are standing outside on the playground and someone in your class comes up to you and says your shoes are ugly. What are your thoughts about this situation? What do you do?

Peer-to-peer interaction antagonistic toward the particpant's friend

You are getting your coat after class and you're standing next to your best friend. Someone comes over and accuses your friend of stealing their favorite pencil case out of their desk. What are your thoughts about this situation? What would you do?

Semi-structured qualitative interviews were conducted and coded using modified grounded technique. Interviews were conducted one-on-one with a study team member via Zoom or phone, and they were transcribed verbatim. Two study team members generated the codebook from the data and coded the interviews. Disagreements in coding were discussed, and the codebook was modified in an iterative process until all coding was unanimous.

Interaction with an authority figure

You are sitting at your desk quietly doing work and you drop your pencil. You get up to get it, and your teacher yells at you for getting up while people are supposed to be quietly working. What are your thoughts and what do you do?

Table 1. Interview Guide Standard Scenarios. This table describes standard scenarios with various social dynamics described in participant interviews to elicit coping strategies participants would use in scenarios that will remain consistent between participants and over time.

Interview topics included the participants’ feelings about the intervention, their CMC journey and quality of life, and some specific scenarios and how the participant would cope with them. The specific scenarios involved a peer-to-peer interaction antagonistic toward the participant, a peer-to-peer interaction antagonistic toward the participant’s friend, and an interaction with an authority figure (Table 1). Whereas for the KidCOPE instrument, the participant thought of a stressor they recently experienced, the purpose of these questions was to ascertain what coping strategies the participant would use in standard scenarios with various social dynamics that would be consistent between participants and over time.

Results Recruitment

Number of Survey Respondents from Each Age Group

A total of 12 unique responses were collected from the RedCap participant interest survey. The average age of respondents was 11, with most being from the 15–17 age group (Figure 3). The majority of respondents were either lost to follow-up, not interested in the intervention, or did not have a CMC. Of the 12 respondents, 3 were interested in and available to participate in the program, met the inclusion criteria, and were aged within 3 years of each other. Pre-intervention assessments were completed with these 3 participants, and the results are discussed below. Summary Statistics

Figure 3. Number of Survey Respondents from Each Age Group. This figure shows the frequency of the ages recorded in each survey response. The responses are aggregated in groups of ages within 3 years of each other because that is who would be eligible to complete the program together, and individual responses are not reported for privacy.

Domain

Median Score

Physical

84.38

Emotional

Social

School

Table 2. Results of the Pediatric Quality of Life Inventory. This table shows the median scores of the 3 participants recruited for the pilot study on the Pediatric Quality of Life Inventory. A higher score indicates a better quality of life.

All 3 participants are female, age 15–17. Two suffer from CMCs involving mental health, while one has a condition involving physical health. The median age at CMC onset was 11 years of age, and the median length of time living with the condition is 7 years. Pre-Intervention Quantitative Findings RCADS scores were not clinically significant for generalized anxiety disorder or major depressive disorder. Scores were recorded for comparison post-intervention. The PedsQL revealed moderate amounts of dysfunction in the emotional and school functioning domains, while physical and social functioning were less affected (Table 2). This corresponds with the qualitative interview findings, discussed below. The participant with a CMC affecting physical health did endorse a worse quality of life in the physical health category, perhaps unsurprisingly, but for privacy, individual results are not reported here. The median score on the KidCOPE checklist was 34. Although the maximum possible score of this measure is 120, it is not a realistic score because the instrument includes both positive and negative comping strategies. If all positive coping strategies 97

Evaluating the Use of Theatre to Decrease Depression and Anxiety Among Adolescents with Chronic Medical Conditions

Coping strategy

List item

Emotional regulation

Tried to calm myself by talking to myself, praying, taking a walk or just trying to relax

Problem-solving

I thought of ways to solve the problem; talked to others to get more facts and information about the problem and/or tried to actually solve the problem.

Table 3. KidCOPE Checklist Items Being Specifically Evaluated. This table shows list items on the KidCOPE Checklist that this intervention is specifically targeting for increased utilization. Please note that on the instrument itself, only the list items are shown, not what coping strategy they indicate.

assessed were endorsed with the maximum possible frequency and effectiveness, and no negative coping strategies were endorsed, the score would be 40. We will be evaluating for an increase in this overall score after the intervention. To provide a score that more accurately reflects positive and negative coping strategies used, we assessed the ratio of positive to negative coping strategies endorsed. Two out of the 3 participants had a score less than 1, indicating that they use negative coping strategies more often than positive ones. All 3 participants endorsed using emotional regulation and problem-solving coping strategies (Table 3) infrequently, with no one endorsing a 0 (not at all) or 3 (almost all the time) for frequency on either of these list items. Increasing use of these specific strategies is one of the goals of this intervention. Pre-Intervention Qualitative Findings Participants expressed excitement for the activities of the intervention as they pertained to doing theatre, some connecting the intervention to previous positive experiences they had doing theatre in the past. In addition to excitement for the activities of the intervention, participants anticipated unintended benefits of the intervention, such as practice with public speaking and making friends. When asked about their CMCs, participants described knowing about the condition long before they were able to obtain a formal diagnosis. Participants used phrases like, “As far back as I can remember...” or “I’ve always felt...” This led to complex feelings when a diagnosis was obtained. As one participant described, “At first I would say it was definitely a big relief, but it was also like pretty scary because we had never heard of it...” Participants described ways in which their conditions affect their everyday lives both emotionally, by affecting their emotional outlook, and functionally, by affecting their ability to live life the way they want to. From an emotional aspect, one participant said, “I feel really alone, like I’m the only person in the world who has it even though I know that other people have it.” Functionally, participants made comments like, “It’s, like, hard to leave the house sometimes.” These themes correspond to the PedsQL results, in which the most affected domains across the board were emotional and school functioning (Table 2). Although participants discussed ways in which their conditions affect their everyday lives, typically negatively, an unexpected theme that emerged was strengths that participants feel they have in navigating their conditions. Participants described 98

strengths such as participating in school-based programs, having the right medications, and having a good medical team. One participant said, “And so it took almost 5 years to really find a good medical team, so I would say in that point of view I am in the best, like, team and, like, treatment-wise as I have been.” We assessed participants’ baseline knowledge of coping strategies at the start of the intervention both explicitly, by asking what coping strategies they were aware of, and implicitly, by presenting participants with scenarios and asking what they would do in those situations. Coping strategies were grouped by study team members as problem-based (attempting to address the source of stress), emotion-based (attempting to adapt to the source of stress), or avoidant (attempting to ignore the source of stress) (3). When asked explicitly about coping strategies, participants only named emotion-based strategies and did not name any problem-based strategies. When asked implicitly, they named more problem-based strategies, but did not recognize them as “coping strategies.” The most frequently named emotionbased coping strategy when asked explicitly was breathing techniques. One participant also endorsed using music and art for emotional regulation. When asked about coping strategies implicitly, participants exclusively endorsed problem-based or avoidant coping strategies. In addition to identifying what participants would do, we tried to elicit their thought process. Themes identified in the scenarios portion of the interview are described in Table 4. Interview Code

Description

Utilization of coping strategies

Naming coping strategies or avoidant behaviors that participants have used or would use during conflict

Emotion-based

Participant describes coping strategies they have used or would use to regulate their emotions and that do not actively try to control the stressor (they do not have to identify the coping strategy or even be aware that it is a strategy)

Problem-based

Participant describes coping strategies they have used or would use to actively try to control the stressor (they do not have to identify the coping strategy or even be aware that it is a strategy)

Avoidant

Participant describes a time that they either have or would avoid a stressor so they wouldn't have to cope with it

Awareness of other people's perspectives vs. Internalization

Any awareness or lack thereof that participants have of other people having different perspectives from them

Internalization of other people's opinions

Any time a participant allows another person's opinion to affect their opinion of themselves, or their emotional well-being

Recognition of the Any time a participant recognizes that separateness of other someone has a different opinion than them, people's opinions but does not allow that to affect them Table 4. Interview Themes Identified in Standard Scenarios. This table describes themes that were identified in participant responses to the standard scenarios described in Table 1.

Evaluating the Use of Theatre to Decrease Depression and Anxiety Among Adolescents with Chronic Medical Conditions

For the first peer-to-peer interaction scenario (Table 1), most participants internalized the comments made by their peer and allowed it to affect their emotional well-being. Although participants were able to identify problem-based coping strategies that they could use in that situation, such as confronting the peer or telling a teacher, most stated that they would not take this action or would take action to escape the situation but that it would continue to affect them after leaving. In the second peer-to-peer interaction (Table 1), all participants were able to recognize that the antagonist had a different opinion from them without allowing it to affect their opinions or emotional well-being. All participants endorsed that they would employ a problem-based coping strategy, stating that they would listen to both sides of the story and try to act as a mediator. In the interaction with an authority figure (Table 1), participants endorsed avoidant coping behaviors and internalizing thoughts. Participants stated that even though they realized the teacher was wrong to yell at them, they would not feel comfortable challenging an authority figure. The interaction would also affect their emotional well-being after it was over.

Discussion These results demonstrate that adolescents with CMCs is an appropriate target population for this intervention, given the effect of their condition on their emotional and school functioning, their use of mostly negative coping strategies, their internalization of others’ opinions, and their use of avoidant coping behaviors. The intervention is well-received by this population, who anticipate both intended and unintended benefits. Quantitative analysis with RCADS revealed that these participants did not suffer from generalized anxiety disorder or major depressive disorder. If participants’ scores were compared to those without CMCs, it’s possible their individual scores may have been higher, but none reached a clinically diagnosable threshold. These scores also do not account for any current treatment for anxiety and depression being undertaken by participants, if any exists. Literature on the increased risk of anxiety and depression in those with CMCs faults maladaptive coping strategies, so we are hopeful that this intervention will decrease subclinical scores of depression and anxiety symptoms and/or prevent an increase in scores to a clinically significant level post-intervention. Based on the PedsQL, quality of life was most severely affected in the emotional and school functioning domains. This makes sense, as 2 out of the 3 participants had disorders affecting their mental health. However, all participants had moderate distress in emotional functioning, demonstrating that even conditions affecting physical health affect emotional functioning. Additionally, all participants showed moderate distress in school functioning. During the interview, it was revealed that both mental health conditions and physical health conditions had functional effects on quality of life, preventing participants from doing activities they wanted to do. This supports the assertion in the literature that emotion-based coping techniques are most effective in adolescents with CMCs. Problem-based coping strategies may not be effective or appropriate in the face of a condition that cannot be changed, however, effective emotional

regulation is important to deal with these challenges (3). Therefore, post-intervention, we hope to see an increase in the emotional quality of life of participants. It is also possible that we may see an increase in school functioning quality of life since mental health issues affect that domain in some participants, and it may be directly improved. Alternatively, if participants want to do some activities, perhaps this intervention will give them confidence for self-advocacy so that they can participate in activities in an alternative way or with accommodations. Knowledge and utilization of coping strategies were limited in this population pre-intervention. The KidCOPE scores revealed that participants endorsed using more negative coping strategies than positive ones, and although they all endorsed using the individual list items for emotional regulation and problem-solving techniques, no one endorsed them with the maximum frequency or efficacy. Paired with the qualitative interview responses, it seems that participants are not explicitly aware of a large variety of coping strategies that span both the emotion-based and problem-based domains. Even when they are aware of them, they may not have the self-efficacy to employ them in difficult situations. During the qualitative interview, participants showed a pattern of internalizing other people’s opinions of them by both peers and authority figures. Participants made comments such as, “I’d probably get really anxious,” suggesting that they would undergo a fight-or-flight response that may prevent higherlevel cognitive analysis of the situation and analysis of options for action in the moment. This led to the use of avoidant coping behaviors in most of these situations. Interestingly, when participants were standing up for a friend to a peer, this fight-orflight response did not seem to be present, and all participants were able to recognize that the antagonist in those situations had a different opinion from them without allowing it to affect them. This allowed all participants to employ a problem-based, rather than an avoidant coping behavior in this scenario. Our goal is to increase emotional regulation in participants, allowing them to analyze all options for action in all situations, and act on the best option. This study describes an inexpensive intervention, that can be employed with limited time and resources, and has the potential to increase effective knowledge and utilization of coping strategies among adolescents with CMCs. The ultimate goal is to decrease development of anxiety and depression in this population. This study employs both quantitative and qualitative evaluation techniques, a standardized intervention protocol, and a long follow-up period. Weaknesses of this study are the small sample size and lack of a control group. We hope that based on the enjoyment of participants in this pilot study, information about this program may spread, and enough participants for a control group will be available in the future. This pilot study will serve as proof of concept for the anticipated effects of this intervention. Adolescents with CMCs are an appropriate audience to teach effective coping strategies with a role-play intervention based on ICT with an added element of role-play. Future research will hopefully demonstrate that this teaching is effective and prevents anxiety and depression in this population.

Evaluating the Use of Theatre to Decrease Depression and Anxiety Among Adolescents with Chronic Medical Conditions

Acknowledgments Special thanks to Justine Andrews, LPC, NCC, Erin Joyce, MA, and Brittney Tunilo, LPC, who were very helpful in the design of this research and in providing advice along the way.

Disclosures The authors of this work have no conflicts of interest to disclose. This research was generously supported by a Student Research Award and funds from the Summer Research Immersion Program from the Office of Research and Scholarship at Geisinger Commonwealth School of Medicine.

References

11. Weigensberg MJ, Vigen C, Sequeira P, Spruijt-Metz D, Juarez M, Florindez D, et al. Diabetes Empowerment Council: Integrative Pilot Intervention for Transitioning Young Adults With Type 1 Diabetes. Glob Adv Health Med. 2018;7:2164956118761808. 12. Feniger-Schaal R, Orkibi H. Integrative systematic review of drama therapy intervention research. Psychology of Aesthetics, Creativity, and the Arts. 2020;14(1):68-80. 13. Doomen L. The effectiveness of schema focused drama therapy for cluster C personality disorders: An exploratory study. The Arts in Psychotherapy. 2018;61:66-76. 14. Feniger-Schaal R, Koren-Karie N. Using Drama Therapy to Enhance Maternal Insightfulness and Reduce Children's Behavior Problems. Front Psychol. 2020;11:586630.

Jones LC, Mrug S, Elliott MN, Toomey SL, Tortolero S, Schuster MA. Chronic Physical Health Conditions and Emotional Problems From Early Adolescence Through Midadolescence. Acad Pediatr. 2017;17(6):649-55.

Cobham VE, Hickling A, Kimball H, Thomas HJ, Scott JG, Middeldorp CM. Systematic Review: Anxiety in Children and Adolescents With Chronic Medical Conditions. J Am Acad Child Adolesc Psychiatry. 2020;59(5):595-618.

Compas BE, Jaser SS, Dunn MJ, Rodriguez EM. Coping with chronic illness in childhood and adolescence. Annu Rev Clin Psychol. 2012;8:455-80.

Lacomba-Trejo L, Valero-Moreno S, Montoya-Castilla I, Perez-Marin M. Psychosocial Factors and Chronic Illness as Predictors for Anxiety and Depression in Adolescence. Front Psychol. 2020;11:568941.

Barreto A, Grandesso M. Community therapy: A participatory response to psychic misery. The International Journal of Narrative Therapy and Community Work. 2010;4:9.

19. Butler L, Miezitis S, Friedman R, E. C. The effect of two school-based intervention programs on depressive symptoms in preadolescents. American Educational Research Journal. 1980;17(Spring):111-9.

Bomba F, Herrmann-Garitz C, Schmidt J, Schmidt S, Thyen U. An assessment of the experiences and needs of adolescents with chronic conditions in transitional care: a qualitative study to develop a patient education programme. Health Soc Care Community. 2017;25(2):652-66.

20. Chorpito BF, Yim L, Moffitt C, Umemoto LA, Francis SE. Assessment of symptoms of DSM-IV anxiety and depression in children: A revised child anxiety and depression scale. Behaviour Research and Therapy. 2000;38:835-55.

Kohut AS, Stinson J, Forgeron P, van Wyk M, Harris L, Luca S. A qualitative content analysis of peer mentoring video calls in adolescents with chronic illness. J Health Psychol. 2018;23(6):788-99.

21. Varni J, Seid M, Kurtin P. PedsQL 4.0: Reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care. 2001;39(8):800-12.

Stinson J, Ahola Kohut S, Forgeron P, Amaria K, Bell M, Kaufman M, et al. The iPeer2Peer Program: a pilot randomized controlled trial in adolescents with Juvenile Idiopathic Arthritis. Pediatr Rheumatol Online J. 2016;14(1):48.

22. Spirito A, Stark LJ, Williams C. Development of a Brief Coping Checklist for Use with Pediatric Populations. Journal of Pediatric Psychology. 1988;13(4):555-74.

Mohamadpour F, Nurallah, Mohamadi. Effectiveness of Online Compassion-Focused Group Therapy on Depression, Anxiety and Chronic Fatigue Severity of Multiple Sclerosis in Female Patients. International Journal of Applied Behavioral Sciences. 2021;8(2):46-56.

10. Miranda NA, Berardinelli LM, Saboia VM, Brito ID, Santos RD. Interdisciplinary care praxis in groups of people living with fibromyalgia. Rev Bras Enferm. 2016;69(6):1115-23.

100

15. Blacker J, Watson A, Beech AR. A combined drama-based and CBT approach to working with self-reported anger aggression. Crim Behav Ment Health. 2008;18(2):129-37. 16. Kõiv K, Kaudne L. Impact of Integrated Arts Therapy: An Intervention Program for Young Female Offenders in Correctional Institution. Psychology. 2015;06(01):1-9. 17. Joronen K, Hakamies A, Astedt-Kurki P. Children's experiences of a drama programme in social and emotional learning. Scand J Caring Sci. 2011;25(4):671-8. 18. Daykin N, Orme J, Evans D, Salmon D, McEachran M, Brain S. The impact of participation in performing arts on adolescent health and behaviour: a systematic review of the literature. J Health Psychol. 2008;13(2):251-64.

23. Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med. 1998;14(4):245-58. 24. Aguinaldo LD, Sullivant S, Lanzillo EC, Ross A, He JP, Bradley-Ewing A, et al. Validation of the ask suicidescreening questions (ASQ) with youth in outpatient specialty and primary care clinics. Gen Hosp Psychiatry. 2021;68:52-8.

Scholarly Research In Progress • Vol. 7, November 2023

Increase in GHB Prescriptions and Their Cost for CHIP/ Medicaid and Medicare Part D Patients Josephine R. Barnhart¹*‡, Sondra A. Vujovich¹*‡, and Brian J. Piper1,2 ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 ²Center for Pharmacy Innovation and Outcomes, Geisinger, Danville, PA 17821 *Master of Biomedical Science Program ‡ Authors contributed equally Correspondence: JBarnhart3@som.geisinger.edu

Abstract Background: The purpose of this study was to describe the temporal pattern of gamma-hydroxybutyrate (GHB) distribution and cost nationally and between states for CHIP/Medicaid and Medicare Part D patients. Methods: GHB prescriptions were extracted by brand name, from the State Utilization Data Tool from medicaid.gov and the Medicare part D Prescribers by Provider and Drug Dataset from cms.gov. GHB prescriptions were separated by state, corrected for population, and analyzed. States outside a 95% confidence interval were considered statistically significant. GHB cost analyses were performed between 2017 and 2020. GHB prescribers were observed for Medicare Part D enrollees in 2019. Results: There was a steady increase in the cost of GHB prescriptions with an overall 40% cost increase from 2017 to 2020 for CHIP/Medicaid enrollees. Maryland prescribed fourfold more GHB than the next-highest state. Specialists other than somnologists were found to prescribe the highest number of GHB prescriptions to Medicare Part D enrollees.

including, prescriber and patient enrollment, education, and documentation, monitoring drug usage and dispensing, and pharmacists’ certification on the drug (5). There was a 23.6–29.1% increase in recreational GHB/gamma butyrolactone drug consumption during the COVID-19 pandemic (6). GHB users had the highest increase in drug usage (6). These observations were due to GHB being one of the least expensive and easiest to obtain despite pandemic shutdowns (6). This investigation examined the change in usage of GHB among Medicaid and Medicare patients to provide insight as to what GHB is being prescribed for and who is prescribing the drug. We also examined state level differences in prescribing which was previously completed for other drugs (7–9). Therefore, we believe our study will help support that there was an increase in prescribed number of GHB to CHIP/Medicaid patients and Medicare patients during 2017–2019 and after 2020. It was also hypothesized that there was an overall increase in cost during this time as well.

Conclusion: A significant difference in the number of GHB prescriptions per state and per person was observed. Further research is necessary to understand how the COVID-19 pandemic may have affected these findings including the origins of the pronounced state-level disparities.

Introduction Gamma-hydroxybutyrate (GHB) is the sodium salt of gamma-hydroxybutyric acid, a naturally occurring neurotransmitter in the brain (1). GHB (Xyrem) is FDAapproved for excessive daytime sleepiness due to narcolepsy and cataplexy, which denotes a sudden loss of muscle tone while awake (2). Despite GHB’s use for daytime sleepiness (3), it is known to be prescribed off label for alcohol withdrawal along with maintaining abstinence of cravings for alcohol for approximately 9–12 months (4). Due to the potential risk of misuse, the Xyrem U.S. Risk Evaluation and Mitigation Program was put in place. This program incorporates strict guidelines

Figure 1. GHB prescriptions per Medicaid enrollee in 2019 year. Twenty states not displayed due to no (<11) prescriptions: AK, AR, HI, ID, IN, KS, MA, MD, MS, MT, ND, NH, NM, NV, OK, SD, TX, VT, WV, and WY. *p < .05 vs state mean.

101

Increase in GHB Prescriptions and Their Cost for CHIP/Medicaid and Medicare Part D Patients

Figure 2. GHB prescriptions per Medicare Part D Enrollee in 2019 (*p < .05 versus state mean).

Methods Databases Data was extracted from the Medicaid State Utilization and the Medicare Part D Prescribers and Drug claims databases. Medicaid.gov provided breakdowns of the amount and cost of drugs being prescribed to Children's Health Insurance Program (CHIP)/Medicaid enrollees (10). The drug breakdowns were also able to be extracted for each state within the U.S. (10). Additional information provided by medicaid.gov included total cost analysis of the overall Medicaid spending budget (10). Data. cms.gov provided the same breakdown of the amount and cost of drugs being prescribed to the Medicare Part D enrollees (11). The Medicare prescription database provided the total number of drugs being prescribed during 2019 (the most recent year when the analyses were completed) and what type of medical provider was prescribing the drug (12). Data from the District of Columbia was incorporated into the Maryland data to keep both databases consistent. Procedures were approved by the IRB of Geisinger. 102

Procedures Medicaid.gov provided the following variables: number of GHB prescriptions per year, number of prescriptions per state, cost of GHB prescriptions each year, and the total amount of Medicaid spending allocated to GHB prescriptions each year. In-depth cost analysis of GHB prescriptions for CHIP/Medicaid was compared between the entirety of each year from 2017 through 2020. Data.cms.gov provided the following variables: number of GHB prescriptions per year, number of GHB prescriptions per state, and type of GHB prescription prescriber. GHB CHIP/ Medicaid and Medicare Part D prescriber data was obtained for 2019. The number of prescriptions/enrollee/state of GHB prescriptions were analyzed and corrected based on the number of CHIP/Medicaid or Medicare Part D enrollees. The data collected for CHIP/Medicaid and Medicare Part D programs were from 2019. Data for CHIP/Medicaid and Medicare Part D were suppressed from states who reported less than 11 GHB prescriptions per quarter as per the CMS

Increase in GHB Prescriptions and Their Cost for CHIP/Medicaid and Medicare Part D Patients

Figure 3. Scatterplot comparing GHB prescriptions per 100,000 patients between CHIP/Medicaid and Medicare Part D enrollees.

2.2

2.0

Percent Change

Year Figure 4. The total change in GHB prescription cost for Medicaid enrollees across a four-year period (2017–2018, 2018–2019, 2019–2020).

1.6

1.4 20

0 02

9 -2

19 20

-2 18 20

-2

1.8

All analyzed data was examined through tables, bar graphs, and heatmaps constructed from Microsoft® Excel version 2022 for Windows, GraphPad Prism, and JMP statistical software. The data was analyzed based on calculated standard deviation values. A significance value of α=.05 was used to determine significance of data. Statistically significant states were identified as states with prescribing rates that fell outside the 95% confidence interval (beyond 1.96 standard deviations). Percent differences in cost of GHB prescriptions across the years 2017– 2018, 2018–2019, and 2019–2020 were reported. States with GHB data suppressed due to low prescribing were counted as a “0” for analyses.

Dollar Amount (millions)

Data Analysis

confidentiality policy, and therefore omitted from figures. GHB usage, central tendencies, and total number of GHB prescriptions among CHIP/Medicaid and Medicare Part D enrollees were examined.

Year Figure 5. The percent calculated of total Medicaid spending dedicated to GHB prescriptions across the pre-pandemic (2017–2019) and pandemic years (2020). 103

Increase in GHB Prescriptions and Their Cost for CHIP/Medicaid and Medicare Part D Patients

Figure 6. Heat maps of the US visualizing the comparison in density of GHB prescriptions distributed across each state per 100,000 patients enrolled in Medicaid and Medicare in 2019.

Figure 7. Heat maps of the U.S. visualizing the comparison in density of total number of GHB prescriptions per state between CHIP/Medicaid and Medicare Part D. The total number of GHB prescriptions were distributed during the 2019 year.

Results

total number of GHB prescriptions prescribed, with OH (11 prescribers) GA/MI/MO/NC/RI (12 prescribers), and VT (13 prescribers) having the least amount of GHB prescribers. Figure 5 provides the visual representation of the data highlighted in Table 2. All GHB prescribers make up a total of 0.02% of all Medicare Part D prescribers within the U.S. (12).

The highest prescription rate was in the state of CT with OH falling short by only a few GHB prescriptions for CHIP/Medicaid (Figure 1). Both states (OH and CT) were also found to be above one standard deviation for the CHIP/Medicaid program (Figure 1). The highest prescription density for Medicare Part D was MD (Figure 2). Maryland as an outlier was also the only state above one standard deviation for Medicare Part D. Figure 3 provides a visual representation for prescription density per 100,000 patients between CHIP/Medicaid and Medicare Part D programs via scatterplot. Data for CHIP/Medicaid and Medicare Part D were suppressed from states who reported less than 11 GHB prescriptions per quarter as per the CMS confidentiality policy. The number of GHB prescriptions fluctuated in years prior to and during the pandemic. Table 2 arranged the total number of GHB prescriber types for Medicare Part D enrollees based on GHB prescriptions for 2019. Providers included family practice, non-doctor, other specialties, and sleep medicine, respectively. Among the highest grand total of prescribers, the highest prescriber types came from “other specialties” in FL (1,481 prescribers), TX (1,072 prescribers), and CA (919 prescribers) (Table 2). These numbers could be correlated to the higher populations found in these states. The lowest grand total of prescribers was denoted to the following states: AR (36 prescribers), WY (13 prescribers), ME (52 prescribers). Prescribers in family practice had the lowest

104

Figure 4 shows the total difference in GHB prescription cost across each year from 2017 to 2020. Both Figures 3 and 4 show a steady increase between each year listed. Figure 5 represents the percent change of Medicaid spending of GHB prescriptions as it relates to each year starting from 2017 through 2020. Figure 6 heatmaps show the density of GHB prescriptions distributed across each state per 100,000 patients who were enrolled in CHIP/Medicaid and Medicare Part D in the year of 2019. Figure 7 heatmaps show a comparison in density of the total number of GHB prescriptions per state between CHIP/ Medicaid and Medicare Part D in 2019.

Discussion The hypothesis was that the use of GHB as a medication approved for narcolepsy would increase each year between 2017 and 2020. It was also projected that costs would rise overall during this time. This analysis supports the hypothesis that there was an increase in the use and prescription of GHB. The total spending on GHB prescriptions by CHIP/Medicaid increased as well (Figure 4). Between 2017 and 2019, there

Increase in GHB Prescriptions and Their Cost for CHIP/Medicaid and Medicare Part D Patients

Total Number of GHB Prescriptions 2019 States

Grand Total

Total Number of GHB Prescriptions 2019

Medicare Part D CHIP/Medicaid State Grand Total

16498

7265

States

Prescriber Type family practice

nondoctor

other specialty

Sleep Medicine

Grand Total

460

1508

13180

1335

16483

23763

Table 1. GHB prescriptions in Medicaid and Medicare in 2019.

was an annual increase of 0.18 %, with a 0.21% increase during the pandemic year (Figure 5). These findings are consistent with prior data indicating that drug use increased during the pandemic (13). This study also identified pronounced state-level differences. The Medicare Part D program provided an extensive amount of data when compared to the CHIP/Medicaid program. Only two states participating in Medicare Part D did not report the number of GHB prescriptions given out during the 2019 year, in comparison to the 19 states who did not report (i.e., values suppressed due to being < 11 can be treated as 0) for CHIP/ Medicaid. If additional data was not suppressed for being a part of the “Preferred Drug List” for the CHIP/Medicaid program, more significant findings could have been observed given the difference in number of enrollees between both programs (62,010,391 Medicare Part D enrollees vs. 70,948,221 CHIP/Medicaid enrollees). More similarities in density of GHB prescription per 100,000 patients could have also been identified. Data not provided, however, did not meet the CMS confidentiality policy as mentioned earlier. A notable finding from Table 2 was the fact that somnologists were the third-lowest GHB prescribers in Medicare Part D patients, with cardiologists ranking first. Rather than being used solely as a narcolepsy drug, GHB has been found to be used in cardiology as a long-term sedative without depression of cardio-circulatory or respiratory measures, kidney and other

Grand Total

Table 2. GHB prescriptions for all states was extracted from the Medicare Provider and Drug dataset on data.cms.gov. The total number of prescriptions for Medicare Part D enrollees were arranged based on the type of provider (family practice, advanced practice provider, other specialty, and sleep medicine). The bottom row depicts the total number of prescriptions given from each type of medical provider.

functions (14). The mean age for bypass patients undergoing heart surgery is 68.5 years (15), a demographic that correlates to Medicare Part D enrollees’ outpatient prescription drug benefits program (16). An important implication to consider for this study and future research is the issue of drug misuse. Despite this study covering GHB prescriptions that were prescribed by a medical provider, there is still concern about the prescriptions being inappropriately used by patients, as well as being inappropriately diverted to GHB drug misusers for nonmedical purposes.

105

Increase in GHB Prescriptions and Their Cost for CHIP/Medicaid and Medicare Part D Patients

There are also several limitations to consider. These findings, while applicable for Medicaid and Medicare patients which account for over one-third of the U.S. population, further study among those with private insurance should be completed. As narcolepsy is an uncommon disorder (19–56/100,000 people), additional study with electronic medical records may be necessary to determine what percent of prescriptions were for off-label indications (17).

Conclusion In conclusion, this study found a significant difference in the number of GHB prescriptions given to CHIP/Medicaid patients versus Medicare Part D patients during the 2019 year. Cost analysis concluded a steady rise in the total cost of both GHB prescriptions and CHIP/Medicaid program spending dedicated to GHB prescriptions prior to and during the pandemic years. Additional research could include analysis of the 2021 postpandemic year to include differences in GHB prescriptions and costs in quarterly plots as restrictions began to be lifted. This research along with future related research could allow for greater insight into how the COVID-19 pandemic has impacted GHB drug usage among CHIP/Medicaid and Medicare Part B patients.

Acknowledgments We would like to thank Elizabeth Kuchinski, MPH, and Jonique Depina, MBS, for their consistent support and guidance throughout this research project, as well as Bhawana Chhetri for her contributions to data analyses. A special thanks to Dr. White for his insights.

Disclosures Brian J. Piper, PhD, was part of an osteoarthritis research team from 2019 to 2021, funded by Pfizer and Eli Lily. The other authors have no disclosures.

References

Strunc MJ, Black J, Lillaney P, Profant J, Mills S, Bujanover S, et al. The Xyrem® (sodium oxybate) risk evaluation and mitigation strategy (REMS) Program in the USA: Results from 2016 to 2017. Drugs Real World Outcomes. 2021; 8(1):15–28.

Bendau A, Viohl L, Petzold MB, Helbig J, Reiche S, Marek R, et al. No party, no drugs? Use of stimulants, dissociative drugs, and GHB/GBL during the early COVID-19 pandemic. Int J Drug Policy. 2022; 102(103582):103582.

Harrison LR, Arnet RE, Ramos AS, Chinga PA, Anthony TR, Boyle JM, McCall KL, Nichols SD, Piper BJ. Pronounced declines in Meperidine in the US: Is the end imminent? Pharmacy (Basel). 2022 Nov 20;10(6):154.

Aguilar AG, Beauregard BA, Conroy CP, Khatiwoda YT, Horsford SME, Nichols SD, Piper BJ. Pronounced regional variation in esketamine and ketamine prescribing to US Medicaid patients. J Psychoactive Drugs. 2023 March 1;1-7.

Madera JD, Ruffino AE, Feliz A, McCall KL, Davis CS, Piper BJ. Declines and pronounced state disparities in prescription opioid distribution in the United States. Declines and pronounced state disparities in prescription opioid distribution in the United States. MedRxiv. 2022:2021.12.02.21266660.

10. National Medicaid & Chip Program Information. Medicaid. https://www.medicaid.gov/medicaid/national-medicaidchip-program-information/i ndex.html 11. Centers for Medicare & Medicaid Services. Medicare. https://data.cms.gov/provider-summary-by-type-ofservice/medicare-part-d-prescribers/medicare-part-dprescribers-by-provider-and-drug 12. More physicians no longer seeing medicare patients. Health Leadership Committee. https://www.hlc.org/ news/more-physicians-no-longer-seeing-medicarepatients/#:~:text=While%20685%2C000%20doctors%20 take%20Medicare%20patients%2C%20their%20 frustration%20factor%20has%20grown

Carter LP, Pardi D, Gorsline J, Griffiths RR. Illicit gammahydroxybutyrate (GHB) and pharmaceutical sodium oxybate (Xyrem): Differences in characteristics and misuse. Drug Alcohol Depend. 2009; 104(1–2):1–10.

13. Taylor S, Paluszek MM, Rachor GS, McKay D, Asmundson GJG. Substance use and abuse, COVID-19-related distress, and disregard for social distancing: A network analysis. Addict Behav. 2021; 114:106754.

Xyrem (sodium oxybate) Information [Internet]. U.S. Food & Drug Administration; 2017 January [cited 2023 April 24]. Available from: https://www.fda.gov/drugs/postmarketdrug-safety-information-patients-and-providers/xyremsodium-oxybate-information

14. Corkery JM, Loi B, Claridge H, Goodair C, Corazza O, Elliott S, et al. Gamma hydroxybutyrate (GHB), gamma butyrolactone (GBL) and 1,4-butanediol (1,4-BD; BDO): A literature review with a focus on UK fatalities related to non-medical use. Neurosci Biobehav Rev. 2015;53:52–78.

Boscolo-Berto R, Viel G, Montagnese S, Raduazzo DI, Ferrara SD, Dauvilliers Y. Narcolepsy and effectiveness of gamma-hydroxybutyrate (GHB): A systematic review and meta-analysis of randomized controlled trials. Sleep Med Rev. 2012; 16(5):431–43.

15. Acinapura AJ, Jacobowitz IJ, Kramer MD, Adkins MS, Zisbrod Z, Cunningham JN Jr. Demographic changes in coronary artery bypass surgery and its effect on mortality and morbidity. Eur J Cardiothorac Surg. 1990;4(4):175–81.

Leone MA, Vigna-Taglianti F, Avanzi G, Brambilla R, Faggiano F. Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses. Cochrane Database Syst Rev. 2010; (2):CD006266.

16. Cubanski J and Damico A. Key facts about Medicare Part D enrollment, premiums, and cost sharing in 2021. KFF. https://www.kff.org/medicare/issue-brief/key-facts-aboutmedicare-part-d-enrollment-premiums-and-cost-sharingin-2021/ 17. Hale L, Guan S, Emanuele E. Epidemiology of narcolepsy. ln: Goswami M, Thorpy M, Pandi-Perumal S. Narcolepsy. Springer, Cham; 2016. p. 37-43.

106

Scholarly Research In Progress • Vol. 7, November 2023

Therapeutic Advantages of Mirogabalin and Pregabalin Over Current Treatments for Chemotherapy-Induced Peripheral Neuropathy Shannon E. Harmon1*‡, Esther O. Maidoh1*‡, Emmanuel C. Megafu1*‡, and Elisabeth Point Du Jour1*‡ ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 *Master of Biomedical Sciences Program ‡ Authors contributed equally Correspondence: emaidoh@som.geisinger.edu

Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a side effect of chemotherapy among cancer patients. In 2020, the cancer incidence in the United States was over 1.8 million. As cancer remains one of the prominent causes of death in the U.S., the incidence of CIPN poses concerning issues in cancer patients. Understanding the CIPN-induced neurodegeneration that occurs in cancer patients allows for treatments to be developed to reduce neuropathic pain. Compounds such as gabapentin, magnesium and calcium, vitamin B12, and goshajinkigan, have been used to treat CIPN; however, these drugs have displayed little to no effectiveness. Duloxetine is an effective treatment, but new drugs such as mirogabalin and pregabalin have also been evaluated for efficacy in cancer patients with CIPN. This literature review was conducted using two databases, Google Scholar and PubMed, to summarize the history, pharmacokinetics, pharmacodynamics, and effect of pregabalin, mirogabalin, and current treatments used in cancer and diabetic patients with peripheral neuropathy. Studies of pregabalin and mirogabalin on CIPN patients demonstrate their effectiveness in decreasing neuropathic pain; however, mirogabalin had a higher rate of improvement for neuropathic pain than pregabalin.

Introduction Peripheral neuropathy (PN) is a category of neurodegeneration that occurs as a result of nerve damage within the peripheral nervous system (1). The peripheral nervous system is comprised of nerves that branch outside the brain and spinal cord. These nerves control the motor and sensory divisions while contributing to the critical functions of the autonomic and somatic nervous systems (2). In the United States, the total percentage of existing cases of PN in adults age 40 and older without diabetes is 11.8%, with prevalence being higher in older adults with diabetes (28.4%) (3). Patients suffering from PN generally present with symptoms that are subclassified as "neuropathic pain." Such symptoms include but are not limited to severe pain (hyperalgesia and allodynia), numbness, tingling in the hands or feet, and burning sensations (paresthesia) (4). Many factors contribute to PN. The most common type is diabetic PN. As indicated in its name, diabetic peripheral neuropathy (DPN) is a diabetes-induced type of nerve damage in the hands and feet resulting from higher-than-normal blood glucose and triglyceride levels (5). Recent epidemiologic research has revealed that DPN prevalence was 34% in a community study of approximately 15,000 diabetic patients

from varying ethnic backgrounds (6). Despite the prevalence of DPN, nondiabetic forms of PN also exist. Since cancer remains one of the prominent causes of death in the U.S., both the prevalence and incidence of PN pose concerning issues in cancer patients (7–9). Specifically, patients who have received chemotherapy as a general treatment for various cancers have developed a more specific type of PN known as chemotherapyinduced peripheral neuropathy (CIPN) (10–12). CIPN is peripheral neuropathy in cancer patients that occurs as an adverse effect of chemotherapy. Concerning cancer-related deaths, pancreatic cancer (PC) is the fourth most common cause (13). The U.S. cancer incidence was over 1.8 million in 2020 (14). PC has one of the lowest survival rates, at 9% (13). One of the reasons for the low rate is because PC presents itself later in patients when the tumor has reached an advanced stage, which makes it challenging to resect. Therefore, only 15–20% of patients can undergo surgical interventions (13). Surgical interventions are determined based on a high-resolution CT scan of the PC to analyze the stage. A study examining patients with PC revealed more prolonged survival after receiving chemoradiotherapy (13). As cancer mortality and incidence continue to increase worldwide, further research has been conducted to observe the effects of current cancer treatments, such as chemotherapy (13). The development of CIPN is a limiting factor in chemotherapy. Chemotherapeutic drugs affect normal cells by damaging the nervous system's structure, thus creating adverse effects such as CIPN (15). An example of this is evident in taxane-induced peripheral neuropathy (TIPN) cases (16). Taxanes are a class of chemotherapeutic drugs used to treat metastatic breast cancer and have been linked to multiple TIPN cases (16). Provided that chemo drugs are neurotoxic agents, finding the proper treatment for CIPN becomes imperative (16). Following the studies of PC patients, multiple treatment mechanisms have been utilized to treat CIPN. Such treatments include duloxetine, acupuncture, opioids, anti-seizure medications, and many more (17). Novel methods have considered using mirogabalin and pregabalin (18). However, since cancer types are not limited to PC, it becomes essential to assess the effectiveness of both drugs and apply these implications in future treatments of CIPN. This paper focuses on reviewing and exploring the efficacy of mirogabalin and pregabalin as potential alternative treatments to prevent and reduce the progression of CIPN in cancer patients. The pharmacology, response, and efficacy assessment of pregabalin and mirogabalin in CIPN will be further discussed.

107

Therapeutic Advantages of Mirogabalin and Pregabalin for CIPN

Methods A literature review of mirogabalin and pregabalin as potential treatments for CIPN in cancer patients was conducted using PubMed and Google Scholar. The following key terms were used: “chemotherapy-induced peripheral neuropathy,” “taxaneinduced peripheral neuropathy,” “peripheral neuropathy,” “mirogabalin,” and “pregabalin.” The literature review included articles published between 2002 and 2023, except for one published in 1997. Meta-analyses, reviews, clinical trials, randomized controlled trials, and systematic reviews were included in this literature review. The chemical structures were derived from the ChemSpider software (19-20).

Discussion Current Treatments for CIPN Several previously identified substances have been used to attempt to treat the effects of CIPN. Some such substances include duloxetine, gabapentin, magnesium and calcium, vitamin B12, and goshajinkigan. Goshajinkigan is an herbal medicine from Japan commonly used to relieve general pain (21). Due to these therapeutic properties, a systematic review of five trials examined whether goshajinkigan effectively alleviated CIPN symptoms. Among these trials, it was found that while goshajinkigan was tolerated well, it was ineffective at preventing the effects of CIPN (21). Additionally, this herb was ineffective in reducing the risk of CIPN (22). Interestingly, though goshajinkigan did not prevent CIPN, it has been found effective at preventing acute PN induced by oxaliplatin (OXA) in rats (23). Magnesium and calcium have also been proposed as CIPN treatments. The rationale behind this is that both molecules are involved with neuron excitability and the contraction of muscles (24). A longitudinal study was conducted regarding lifestyles and nutrition among 196 patients with colorectal cancer (CRC) (24). OXA is a cytotoxic chemotherapy used for treating CRC (25). CIPN is a common side effect of OXA in this subset of cancer patients (25). Magnesium consumption in the diet was associated with a lower prevalence of CIPN among CRC patients (prevalence ratio = 0.53) and higher magnesium intake during (ß = -1.08) and after (ß = -0.93) OXA chemotherapy treatments were associated with lower severity of symptoms caused by CIPN (24). Due to magnesium’s role in the neuromuscular system, magnesium was found to be an effective treatment, whereas surprisingly, calcium was ineffective (24). Due to the high demand for vitamin B12 in the nervous tissue, vitamin B12 deficiencies have been attributed to neuropathy manifestations (26). Therefore, the administration of vitamin B12 for CIPN treatment has been explored. Data from a clinical survey of oncology specialists was collected regarding the administration of certain pharmacotherapies, such as vitamin B12, for treating CIPN symptoms such as numbness and pain. Vitamin B12 was ineffective for CIPN, but some clinicians propose its use as placebo to alleviate symptoms due to its limited adverse effects (27). Rather than taking a pharmacological approach, some investigators have found benefits in classic exercise for treating CIPN. A secondary analysis of a randomized controlled trial investigated how fatigue symptoms in breast cancer patients who received neurotoxic chemotherapy responded to exercise

108

(28). The exercise regimen consisted of a progressive walking prescription for six weeks, followed by a therapeutic resistant band prescription that was individually tailored to each patient (28). The findings suggested that exercise effectively reduced the severity and prevalence of CIPN in cancer patients (28). Additional results have determined how sensorimotor and other resistance training has reduced the perceived sensory symptoms in the feet of cancer patients with CIPN (29). Various investigations about gabapentin for CIPN have shown contradictory results. Gabapentin’s use as an anti-neuropathic is associated with many adverse effects, such as lethargy, dizziness, and convulsions (30). In an effort to avoid some of these side effects, studies have been done using a topical administration of gabapentin and found therapeutic effects without those side effects (30). While many currently proposed treatments for CIPN have shown little to no effectiveness, duloxetine is a drug that has demonstrated the opposite (31). Duloxetine belongs to the serotonin and norepinephrine reuptake inhibitors class of drugs (32). Its therapeutic use in treating neuropathies is by activating serotonergic and noradrenergic neurons in the spinal pain pathway (32). Duloxetine as a treatment for CIPN and DPN has been studied extensively and has been recommended as a first-line treatment for DPN (33). In 2022, researchers wanted to investigate tapentadol’s efficacy as an analgesic for CIPN management (34). Tapentadol is a μ-opioid receptor agonist as well as a norepinephrine reuptake inhibitor (34). Due to its action as an opioid analgesic, tapentadol was cultivated for chronic pain management and thought to be beneficial for treating PN (34). To analyze tapentadol’s impact on CIPN, a randomized, double-blind trial was conducted where patients either received tapentadol alone, or tapentadol plus duloxetine, as duloxetine is a common current treatment supported by the American Society of Clinical Oncology (34-35). Based on this comparison, it was found that tapentadol alone was an effective analgesic and improved the quality of life for CIPN patients (34). Patients Treated with Pregabalin and Mirogabalin According to a retrospective report published in 2021 in Japan, 163 patients diagnosed with PC who were administered either gemcitabine plus nab-paclitaxel (GnP) or a combination of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) as their chemotherapy regimens, were enrolled in a study testing the effectiveness of mirogabalin and pregabalin in treating those who developed CIPN (18). While FOLFIRINOX and GnP are successful treatments for PC, CIPN is often a side effect of these chemotherapy regimens. Comparisons were made between pretreatment severity scores and then again at two, four, and six weeks after treatment (18). In the mirogabalin-treated group, significant improvements in CIPN grade were shown at two, four, and six weeks compared to the pretreatment grade with P<0.01 (18). In the pregabalin group, significant improvements in CIPN grade were shown at two, four, and six weeks compared to the pretreatment grade with P<0.05 (18). At two weeks (84.6% vs. 33.3%), four weeks, and six weeks (92.3% vs. 33.3%), mirogabalin showed significantly higher rates of improvement in CIPN than the pregabalin group with P<0.01 (18). This study concluded that mirogabalin generated a higher rate of CIPN improvement than pregabalin in patients treated with GnP and FOLFIRINOX,

Therapeutic Advantages of Mirogabalin and Pregabalin for CIPN

although both drugs had therapeutic improvement effects (18). Due to this being a retrospective study, having a small sample size, and varying treatment doses, further investigation into the effectiveness of mirogabalin and pregabalin would be informative for future CIPN patients (18). While pregabalin and mirogabalin have been found effective treatments for PC patients, many other cancer patients also develop CIPN. A report involving lung cancer patients who have developed neuropathic pain looked at the efficacy of duloxetine and pregabalin as potential therapies (36). Positive and negative symptoms associated with neuropathic pain were evaluated before and after treatment, and pregabalin showed statistically significant reductions (P<0.001) in pain symptoms in these lung cancer patients. However, the results may not reveal clinical significance due to the relatively moderate sample size (N=42) (36). Paclitaxel is a type of chemotherapy and is known to have the common side effect of paclitaxel-induced peripheral neuropathy (PIPN). The vast majority (97%) of all urological and gynecological cancer patients have developed PIPN (37). Although pregabalin is often prescribed as a treatment for PIPN in patients with breast and gynecologic cancers, even more research is needed to test its effectiveness (38). Mirogabalin has been found effective in alleviating symptoms in patients suffering from postherpetic neuralgia and diabetic peripheral neuropathic pain (39). Due to its success in treating DPN, in Japan, mirogabalin became covered by insurance to treat CIPN (18). As previously discussed, due to the neurotoxic identity of chemotherapeutic drugs, CIPN represents a common disabling effect. Chemotherapeutic drugs exert their neurotoxic effects through myelinopathy, neuronopathy, and axonopathy (40). Additionally, multifactorial mechanisms such as oxidative stress, increased apoptosis, calcium imbalance, and immunologic neuropathy are among the many associated pathophysiologies (40). Patients receiving chemotherapy bear a high risk of CIPN chronicity and impairments in their quality of life (41–44). Considering the severity and progression of CIPN symptoms, the pursued use of chemotherapy in cancer treatment may negatively affect patient prognosis (42, 44–45). Limited CIPN treatment options exist. Current targeted therapies mainly focus their pharmacokinetic dispositions on reducing and preventing further symptoms in affected patients (46). However, despite the limited treatment options, many efforts have been made to assess the efficacy of three main drugs: duloxetine, pregabalin, and mirogabalin (47–52). The pharmacokinetics and pharmacodynamics of pregabalin and mirogabalin in CIPN will be further discussed. Response to Pregabalin: Pharmacokinetics/ Pharmacodynamics Pregabalin, depicted in Figure 1, has been approved by the FDA since 2004 for use in the United States (19, 53). Like mirogabalin, pregabalin is a gabapentinoid primarily used in treating neuropathic pain associated with DPN, spinal cord injuries, various forms of neuralgia, and multiple forms of PN (55). Pregabalin is referred to as an analog of the neurotransmitter gamma-aminobutyric acid (GABA) due to its structural similarity. Although its pharmacological profile resembles gabapentin, neither compound binds to GABAA or GABAB receptors (55–57). After oral administration, like

mirogabalin, pregabalin functions as a ligand that selectively binds to the α2δ subunit of presynaptic voltage-gated calcium channels (VGCCs), with high affinity (56). The analgesic effects of pregabalin are attributed to the decreased neuronal calcium influx and lessened release of excitatory neurotransmitters induced by depolarization (57). In healthy fasting patients without renal impairments, rapid absorption is typically observed after administration, with average maximum plasma concentrations achieved within 0.5–1.5 hours (58). Steady-state concentrations are achieved within two days. The bioavailability of pregabalin is greater than or equal to 90%, and its volume of distribution is 42.1 L (57–58). Renally excreted in the urine, pregabalin is mainly 98% eliminated as an unchanged drug, with an elimination half-life of approximately 6 hours (55–58). Though pregabalin is well-tolerated in treating neuropathic pain, some patients have reported dose-dependent adverse symptomatic events. Adverse effects include weight gain, drowsiness, dizziness, edema, xerostomia, ataxia, euphoria, and hyperhidrosis (59). Response to Mirogabalin: Pharmacokinetics/ Pharmacodynamics Mirogabalin besylate (mirogabalin), shown in Figure 2, was manufactured in Japan and gained its first marketing approval in 2019 after phase 3 clinical trials were completed (20, 54). FDA considerations for approval are still undergoing as U.S.

OH O

NH 2

Figure 1. Pregabalin chemical structure (19). Pregabalin Molecular Formula: C8H17NO2, PubChem CID: 5486971, IUPAC Name: (3R)-3(Aminomethyl)-5-methylhexanoic acid (53).

NH 2 OH O Figure 2. Mirogabalin chemical structure (20). Mirogabalin Molecular Formula: C12H19NO2, PubChem CID: 59509752, IUPAC Name: [(1R,5S,6S)-6-(Aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl] acetic acid (54). 109

Therapeutic Advantages of Mirogabalin and Pregabalin for CIPN

researchers continue to assess the applications of the drug’s mechanisms of action in different types of PN pain (60). As a category of gabapentinoids, mirogabalin functions to provide analgesia by lessening dorsal horn sensitivity (61–62). Upon oral administration, mirogabalin serves as a ligand that selectively binds to the α2δ-1 and α2δ-2 subunits of VGCCs (60–62). In an investigation examining the activity of human VGCCs in vitro, upon exposure to mirogabalin, it was discovered that mirogabalin binding differed for both subunits. For the α2δ-1 subunit, the dissociation half-life of mirogabalin was approximately 11.1 hours, compared to 2.4 hours for the α2δ-2 subunit (62). Due to its longer dissociation half-life in the α2δ-1 subunit, mirogabalin is considered to have a more potent effect, with a greater affinity for that subunit, thus producing a longer duration (62–63). As per the pharmacokinetics of mirogabalin, the drug is absorbed rapidly, and renal elimination occurs at a maximum of 72% through urine. Dosage measurements are determined based on renal function, with renal-impaired patients receiving lower doses. Mirogabalin volume of distribution ranges from 64 L to 88 L, with steady-state plasma concentrations achieved three days after initial administration (61, 63). Patients who have received mirogabalin to treat PN pain have reported moderate adverse effects. Adverse effects include dizziness, drowsiness, and headaches (61, 63-64). Applications of Pregabalin and Mirogabalin in Cancer Patients Many symptoms are associated with CIPN, most of which start in the fingers and toes and then progress to the body. Several symptoms related to this condition were reported, including tingling or pins-and-needles sensations, pain, burning, numbness, temperature sensitivity, and difficulty with fine motor skills, such as writing and picking up small items (65). These symptoms have been analyzed using pregabalin and mirogabalin in cancer patients to further observe how these treatments would work for CIPN in cancer patients. In chemotherapy, CIPN is one of the most common adverse effects caused by OXA and paclitaxel (39). OXA is a drug given to cancer patients through chemotherapy. It has been reported that patients with colorectal cancer develop acute and chronic pain related to oxaliplatin-induced peripheral neuropathy (66). OXA-related neuropathies have different pathophysiological bases, both acute and chronic. Several causes lead to neuropathic pain, including central sensitization of nociceptive neurons, causing the somatosensory system to have increased sensitivity, namely hyperalgesia and allodynia (66). Physiological sensations of pain are due to peripheral stimuli of enough intensity to trigger or threaten the activation of nociceptive pathways that result in acute nociceptive pain in patients (67). Peripheral sensitization represents the function of the nociceptor, which occurs from an injury that releases inflammatory mediators (68). Nociceptors are crucial in restoring the body’s overall function; they are the peripheral pathway to nociceptive pain. This contributes to the hypersensitivity pain experienced in patients (68). In a double-blind, randomized, placebo-controlled trial, neuropathic pain was measured daily in cancer patients via the 100-mm visual analogue scale, with 0 mm indicating no pain and 100 mm indicating unbearable pain, and averaged over seven days (69). Pregabalin significantly decreased neuropathic pain in

110

cancer patients from 7.77 mm to 2.5 mm on the visual analogue scale compared to the placebo group, which decreased from 7.47 mm to 3.4 mm (69). On the fourth visit, 100% of the patients from the placebo group required rescue morphine dosage compared to 16.7% of patients in the pregabalin group (69). Pregabalin provided a decrease in neuropathic pain in patients with cancer. After the administration of OXA, patients treated with 150 mg/day pregabalin for two to six weeks displayed neuropathy improvements (66). This further highlights the function of pregabalin used to control neuropathic pain (17). As a result of pregabalin's improvement in neuropathic pain, morphine dosages can be significantly reduced in combination therapy. Pregabalin is the recommended first choice in the Neuropathic Pain Special Interest Group Guidelines (70). Pregabalin was also used as a treatment for breast cancer patients with TIPN. Research shows that TIPN has a negative impact on the quality of life in patients with breast cancer (51). After the completion of chemotherapy, patients could suffer from neuropathic pain and paresthesia, obstructing the daily activities of the patients. This may affect their mental health leading to anxiety, depression, and cognitive impairment (52). The quality of life and the overall well-being of patients were impacted for those who needed breast cancer surgery. Acute postoperative pain after breast cancer surgery must be managed (71). In breast cancer patients who received pregabalin postoperatively, there was a decrease in tramadol consumption in the pregabalin group of 92.86 mg in comparison to the placebo group with a consumption of 162.50 mg (P=0.029) (71). Additionally, in patients with pronociceptive pain who underwent surgery, administration of pregabalin perioperatively reduced analgesic consumption by 16% (71). A selective α2δ ligand, mirogabalin, was approved to treat peripheralπ neuropathic pain in Japan (72). In a study to determine the symptomatic grade changes before and after mirogabalin for patients who underwent chemotherapy for breast cancer, five mg of mirogabalin was administered twice daily, yielding stable symptoms for about six weeks; thus, the dosage was increased to 22.5 mg per day (73). The effect of mirogabalin decreased the numerical rating scale for numbness from 5/10 to 3/10 and pain from 8/10 to 5/10, further confirming the positive impact mirogabalin has on neuropathy (73). The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Chemotherapy-Induced Peripheral Neuropathy assesses the sensory neuropathy, autonomic neuropathy, and motor function of CIPN patients. The efficacy of patients introduced with mirogabalin controls the worsening of CIPN and improved sensory neuropathy (74). Mirogabalin did not further progress CIPN in patients with PC. As a result, it has been demonstrated to be a suitable treatment for patients with sensory neuropathy, including tingling and numbness symptoms (74). The cumulative toxicity of mirogabalin may not be a hindrance because it slows down the progression of CIPN and significantly improves sensory neuropathy. Dosing and titration should be carefully monitored due to the high rate of adverse events (74). Overall, the mirogabalin and pregabalin groups displayed significant progress upon treatment compared to the pretreatment grade (18). However, the rate of improvement was higher in the mirogabalin group.

Therapeutic Advantages of Mirogabalin and Pregabalin for CIPN

Applications of Pregabalin and Mirogabalin in DPN and Adverse Effects Pregabalin has been shown to be very effective when treating patients with neuropathic pain, most notably diabetic neuropathy (75). One of the advantages of using pregabalin as a treatment option for DPN is its tolerability. A recent study investigated the dosage for individuals taking pregabalin to manage diabetic neuropathy and concluded that patients exhibited several signs of improvement (76). The dosage ranged from 150 mg/kg to 600 mg/kg and was taken between 4 weeks and 14 weeks. The results indicated that taking 600 mg of pregabalin daily significantly reduced the average pain score by more than 50% (77). Pain relief typically occurred in the first two weeks of treatment for DPN and was sustained throughout the study. When comparing the different doses of pregabalin (daily doses of 150 mg/kg, 300 mg/kg, and 600 mg/ kg), there was a positive correlation between the dosage and the rate of pain reduction (78, 55). Using pregabalin to treat DPN also comes with mild to moderate side effects, including dizziness, edema, weight gain, fatigue, epigastric pain, and motor incoordination (77).

In terms of limitations, the primary limitation of this literature review that could be addressed with future research was the inclusion of some outdated articles. With our methodology, we included articles published between 2002 and 2023, except for one published in 1997. Although current and future research focuses on novel treatments of CIPN, these older articles were included in this review to provide foundational insight into the past treatments of CIPN. While there has been some discovery of effective treatments for CIPN, much more information can be gained by conducting further analyses. Administering future investigations of the effectiveness of pregabalin, mirogabalin, and any other potential new drugs, such as venlafaxine, would be beneficial with much larger sample sizes to obtain stronger statistical and clinical significance. Duloxetine has been used as a first-line treatment for CIPN. Both duloxetine and venlafaxine are serotonin and norepinephrine reuptake inhibitors that have been recognized to be effective in treating CIPN (87). Consequently, applying the use of these drugs to treat the side effects of CIPN in other cancers, such as breast and colorectal cancers, and diabetic neuropathy patients will increase the discoveries of pharmacotherapies for CIPN.

Mirogabalin was intended to treat pain associated with fibromyalgia and neuropathic pain (80). Patients who were generally administered mirogabalin either once or twice daily, with a dosage range between 5 and 30 mg, produced average daily pain scores that were significantly reduced when compared to patients who were given a placebo (81). An investigation was conducted to compare the effects of mirogabalin that were administered to patients with DPN (15 mg/day, 20 mg/day, and 30 mg/day) and determined that mirogabalin provided greater pain relief than pregabalin (82). Patients who initially took pregabalin to treat DPN and eventually switched to mirogabalin reported improved sleep (52). Patients who discontinued their mirogabalin treatment experienced a lower incidence of somnolence and a higher incidence of edema and dizziness, resulting in the cessation of that treatment (84–86). Overall, mirogabalin is an alternative treatment for DPN due to its comparable effectiveness to pregabalin (79).

Acknowledgments

Conclusion The incidence of cancer was over 1.8 million in 2020 in the U.S. CIPN is peripheral neuropathy in cancer patients that occurs as an adverse effect of chemotherapy. Since 30–40% of patients treated with neurotoxic chemotherapy develop CIPN, CIPN needs to be assessed to discover and develop therapies (43). While many potential substances have been attempted to treat CIPN symptoms, few have significantly impacted symptom severity and prevalence in cancer patients. Though duloxetine has been previously shown to be an effective treatment, pregabalin and now mirogabalin have shown greater efficacy at treating CIPN in retrospective studies. Provided that mirogabalin was a preliminary treatment for DPN and has now been concluded to be more efficacious than pregabalin for treating CIPN, the potential for new drug discoveries as well as repurposing current drugs as therapies for CIPN is of critical importance for improving the quality of life of these cancer patients. Mirogabalin demonstrated more significant pain relief and rate of improvement in comparison to pregabalin in patients with peripheral neuropathy.

We express our gratitude to our professor, Brian J. Piper, PhD, and teaching assistant Gabrielle M. Verbeke-O'Boyle for their guidance and support.

Disclosures The authors have no relevant disclosures.

References 1.

DiAntonio A. Axon degeneration: Mechanistic insights lead to therapeutic opportunities for the prevention and treatment of peripheral neuropathy. Pain. 2019;160(1):1722.

Sternini C. Organization of the peripheral nervous system: Autonomic and sensory ganglia. J Investig Dermatol Symp Proc. 1997;2(1):1-7.

Hicks CW, Wang D, Windham BG, Matsushita K, Selvin E. Prevalence of peripheral neuropathy defined by monofilament insensitivity in middle-aged and older adults in two US cohorts. Sci Rep. 2021;11(1):19159.

Reichling DB, Levine JD. Pain and death: Neurodegenerative disease mechanisms in the nociceptor. Ann Neurol. 2011;69(1):13-21.Izenberg A, Perkins BA, Bril V. Diabetic neuropathies. Semin Neurol. 2015;35(4):424– 430.

Iqbal Z, Azmi S, Yadav R, Ferdousi M, Kumar M, Cuthbertson DJ, et al. Diabetic peripheral neuropathy: Epidemiology, diagnosis, and pharmacotherapy. Clin Ther. 2018;40(6):828-849.

Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33.

111

Therapeutic Advantages of Mirogabalin and Pregabalin for CIPN

Selvy M, Kerckhove N, Pereira B, Barreau F, Nguyen D, Busserolles J, et al. Prevalence of chemotherapy-induced peripheral neuropathy in multiple myeloma patients and its impact on quality of life: A single center cross-sectional study. Front Pharmacol. 2021;12:637593.

22. Mizuno K, Kono T, Suzuki Y, Miyaji C, Omiya Y, Miyano K, et al. Goshajinkigan, a traditional Japanese medicine, prevents oxaliplatin-induced acute peripheral neuropathy by suppressing functional alteration of TRP channels in rat. J Pharmacol Sci. 2014;125(1):91-98.

Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, et al. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain. 2014;155(12):2461-2470.

23. Wesselink E, Winkels RM, Van Baar H, Geijsen AJ, Van Zutphen M, Van Halteren HK, et al. Dietary intake of magnesium or calcium and chemotherapy-induced peripheral neuropathy in colorectal cancer patients. Nutrients. 2018;10(4):398.

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

24. Kang L, Tian Y, Xu S, Chen H. Oxaliplatin-induced peripheral neuropathy: Clinical features, mechanisms, prevention and treatment. J Neurol. 2021;268(9):3269-3282.

10. Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol. 2002;249(1):9-17. 11. Gordon-Williams R, Farquhar-Smith P. Recent advances in understanding chemotherapy-induced peripheral neuropathy. F1000Res. 2020;9:F1000. 12. Fogel EL, Shahda S, Sandrasegaran K, DeWitt J, Easler JJ, Agarwal DM, et al. A multidisciplinary approach to pancreas cancer in 2016: A review. Am J Gastroenterol. 2017;112:537-554. 13. Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145-64. 14. Zajączkowska R, Kocot-Kępska M, Leppert W, Wrzosek A, Mika J, Wordliczek J. Mechanisms of chemotherapyinduced peripheral neuropathy. Int J Mol Sci. 2019;20(6):1451. 15. Rivera E, Cianfrocca M. Overview of neuropathy associated with taxanes for the treatment of metastatic breast cancer. Cancer Chemother Pharmacol. 2015;75(4):659-70. 16. Zhang S. Chemotherapy-induced peripheral neuropathy and rehabilitation: A review. Semin Oncol. 2021;48(3):193207. 17. Sugimoto M, Takagi T, Suzuki R, Konno N, Asama H, Sato Y, et al. Mirogabalin vs pregabalin for chemotherapy-induced peripheral neuropathy in pancreatic cancer patients. BMC Cancer. 2021;21(1):1319. 18. CSID:3902475, http://www.chemspider.com/ChemicalStructure.3902475.html (accessed 22:28, May 10, 2023) 19. CSID:32701007, http://www.chemspider.com/ChemicalStructure.32701007.html (accessed 23:05, May 10, 2023) 20. Kuriyama A, Endo K. Goshajinkigan for prevention of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Support Care Cancer. 2018;26(4):1051-1059. 21. Hoshino N, Ganeko R, Hida K, Sakai Y. Goshajinkigan for reducing chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Int J Clin Oncol. 2018;23(3):434-442.

112

25. Pavlov CS, Damulin IV, Shulpekova YO, Andreev EA. Neurological disorders in vitamin B12 deficiency. Ter Arkh. 2019;91(4):122-129. 26. Hirayama Y, Yoshida Y, Mori M, Tamura K. Effects of the publication of clinical guidelines for the management of chemotherapy-induced peripheral neuropathy on the administration preferences of oncology specialists: Japanese association of supportive care in cancer. Jpn J Clin Oncol. 2020;50(8):897-902. 27. Kleckner IR, Kamen C, Gewandter JS, Mohile NA, Heckler CE, Culakova E, et al. Effects of exercise during chemotherapy on chemotherapy-induced peripheral neuropathy: A multicenter, randomized controlled trial. Support Care Cancer. 2018;26(4):1019-1028. 28. Müller J, Weiler M, Schneeweiss A, Haag GM, Steindorf K, Wick W, et al. Preventive effect of sensorimotor exercise and resistance training on chemotherapy-induced peripheral neuropathy: A randomised-controlled trial. Br J Cancer. 2021;125(7):955-965. 29. Shahid M, Subhan F, Ahmad N, Sewell RDE. Efficacy of a topical gabapentin gel in a cisplatin paradigm of chemotherapy-induced peripheral neuropathy. BMC Pharmacol Toxicol. 2019;20(1):51. 30. Sugimoto M, Takagi T, Suzuki R, Konno N, Asama H, Sato Y, et al. Drug treatment for chemotherapy-induced peripheral neuropathy in patients with pancreatic cancer. Fukushima J Med Sci. 2022;68(1):1-0. 31. Dhaliwal JS, Spurling BC, Molla M. Duloxetine. StatPearls. 2023. 32. Battaglini E, Park SB, Barnes EH, Goldstein D. A double blind, placebo controlled, phase II randomised cross-over trial investigating the use of duloxetine for the treatment of chemotherapy-induced peripheral neuropathy. Contemp Clin Trials. 2018;70:135-138. 33. Sansone P, Giaccari LG, Aurilio C, Coppolino F, Passavanti MB, Pota V, et al. Comparative efficacy of tapentadol versus tapentadol plus duloxetine in patients with chemotherapyinduced peripheral neuropathy (CIPN): A randomized noninferiority clinical trial. Cancers (Basel). 2022;14(16):4002.

Therapeutic Advantages of Mirogabalin and Pregabalin for CIPN

34. Hou S, Huh B, Kim HK, Kim KH, Abdi S. Treatment of chemotherapy-induced peripheral neuropathy: Systematic review and recommendations. Pain Physician. 2018;21(6):571-592. 35. Gül ŞK, Tepetam H, Gül HL. Duloxetine and pregabalin in neuropathic pain of lung cancer patients. Brain Behav. 2020;10(3):e01527. 36. Klein I, Lehmann HC. Pathomechanisms of paclitaxelinduced peripheral neuropathy. Toxics. 2021;9(10):229. 37. Hiramoto S, Asano H, Miyamoto T, Takegami M, Kawabata A. Risk factors and pharmacotherapy for chemotherapyinduced peripheral neuropathy in paclitaxel-treated female cancer survivors: A retrospective study in Japan. PLoS One. 2021;16(12):e0261473. 38. Kim JY, Abdi S, Huh B, Kim KH. Mirogabalin: Could it be the next generation gabapentin or pregabalin? Korean J Pain. 2021;34(1):4-18. 39. Miltenburg NC, Boogerd W. Chemotherapy-induced neuropathy: A comprehensive survey. Cancer Treat Rev. 2014;40(7):872–882. 40. Maihöfner C, Diel I, Tesch H, Quandel T, Baron R. Chemotherapy-induced peripheral neuropathy (CIPN): Current therapies and topical treatment option with high-concentration capsaicin. Support Care Cancer. 2021;29(8):4223-4238. 41. Boyette-Davis JA, Hou S, Abdi S, Dougherty PM. An updated understanding of the mechanisms involved in chemotherapy-induced neuropathy. Pain Manag. 2018;8(5):363–375. 42. Staff NP, Grisold A, Grisold W, Windebank AJ. Chemotherapy-induced peripheral neuropathy: A current review. Ann Neurol. 2017;81(6):772–781. 43. Starobova H, Vetter I. Pathophysiology of chemotherapyinduced peripheral neuropathy. Front Mol Neurosci. 2017;10:174. 44. Gießen-Jung C, von Baumgarten L. Chemotherapieinduzierte periphere neuropathie [Peripheral neuropathy as a side effect of chemotherapy and targeted therapy]. Dtsch Med Wochenschr. 2018;113(13):970–978. 45. Jordan B, Jahn F, Sauer S, Jordan K. Prevention and management of chemotherapy-induced polyneuropathy. Breast Care (Basel). 2019;14(2):79-84. 46. Mezzanotte JN, Grimm M, Shinde NV, Nolan T, WorthenChaudhari L, Williams NO, et al. Updates in the treatment of chemotherapy-induced peripheral neuropathy. Curr Treat Options Oncol. 2022;23(1):29-42. 47. Staurengo-Ferrari L, Bonet IJM, Araldi D, Green PG, Levine JD. Neuroendocrine stress axis-dependence of duloxetine analgesia (anti-hyperalgesia) in chemotherapy-induced peripheral neuropathy. J Neurosci. 2022;42(3):405-415. 48. Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: A randomized clinical trial. JAMA. 2013;309(13):1359-67.

49. Avan R, Janbabaei G, Hendouei N, Alipour A, Borhani S, Tabrizi N, et al. The effect of pregabalin and duloxetine treatment on quality of life of breast cancer patients with taxane-induced sensory neuropathy: A randomized clinical trial. J Res Med Sci. 2018;23:52. 50. Salehifar E, Janbabaei G, Hendouei N, Alipour A, Tabrizi N, Avan R. Comparison of the efficacy and safety of pregabalin and duloxetine in taxane-induced sensory neuropathy: A randomized controlled trial. Clin Drug Investig. 2020;40(3):249-257. 51. Baba M, Matsui N, Kuroha M, Wasaki Y, Ohwada S. Mirogabalin for the treatment of diabetic peripheral neuropathic pain: A randomized, double-blind, placebocontrolled phase III study in Asian patients. J Diabetes Investig. 2019;10(5):1299-1306. 52. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004-. PubChem Compound Summary for CID 5486971, Pregabalin. 53. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004-. PubChem Compound Summary for CID 59509752, Mirogabalin. 54. Frampton JE, Scott LJ. Pregabalin: In the treatment of painful diabetic peripheral neuropathy. Drugs. 2004;64(24):2813-20. 55. Cross AL, Viswanath O, Sherman AL. Pregabalin [Internet]. Treasure Island, FL: StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470341/ 56. Tassone DM, Boyce E, Guyer J, Nuzum D. Pregabalin: A novel gamma-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders. Clin Ther. 2007;29(1):26-48. 57. Chew ML, Alvey CW, Plotka A, Pitman VW, Alebic-Kolbah T, Scavone JM, et al. Pregabalin controlled-release pharmacokinetics in healthy volunteers: Analysis of four multiple-dose randomized clinical pharmacology studies. Clin Drug Investig. 2014;34(9):627-37. 58. Onakpoya IJ, Thomas ET, Lee JJ, Goldacre B, Heneghan CJ. Benefits and harms of pregabalin in the management of neuropathic pain: A rapid review and meta-analysis of randomized clinical trials. BMJ Open. 2019;9(1):e023600. 59. Kim JY, Abdi S, Huh B, Kim KH. Mirogabalin: Could it be the next generation gabapentin or pregabalin? Korean J Pain. 2021;34(1):4-18. 60. Deeks ED. Mirogabalin: First global approval. Drugs. 2019;79(4):463-468. 61. Tetsunaga T, Tetsunaga T, Nishida K, Misawa H, Takigawa T, Yamane K, et al. Short-term outcomes of mirogabalin in patients with peripheral neuropathic pain: A retrospective study. J Orthop Surg Res. 2020;15(1):191. 62. Nair A. Mirogabalin, a selective gabapentinoid for managing neuropathic pain - A curtain raiser. J Anaesthesiol Clin Pharmacol. 2022;38(4):691-692.

113

Therapeutic Advantages of Mirogabalin and Pregabalin for CIPN

63. Jansen M, Warrington S, Dishy V, Ohwada S, Johnson L, Brown K, et al. A randomized, placebo-controlled, doubleblind study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and repeated doses of mirogabalin in healthy Asian volunteers. Clin Pharmacol Drug Dev. 2018;7(6):661-669.

75. Pachman DR, Barton DL, Watson JC, Loprinzi CL. Chemotherapy-induced peripheral neuropathy: Prevention and treatment. Clin Pharmacol Ther. 2011;90(3):377-87.

64. Brown TJ, Sedhom R, Gupta A. Chemotherapy-induced peripheral neuropathy. JAMA Oncol. 2019;5(5):750.

77. Richter RW, Portenoy R, Sharma U, Lamoreaux L, Bockbrader H, Knapp LE. Relief of painful diabetic peripheral neuropathy with pregabalin: A randomized, placebo-controlled trial. J Pain. 2005;6(4):253-260.

65. De Andrade DC, Jacobsen Teixeira M, Galhardoni R, Ferreira KSL, Braz Mileno P, Scisci N, et al. Pregabalin for the prevention of oxaliplatin-induced painful neuropathy: A randomized, double-blind trial. Oncologist. 2017;22(10):1154-e105. 66. Latremoliere A, Woolf CJ. Central sensitization: A generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895-926. 67. Woolf CJ, Ma Q. Nociceptors--Noxious stimulus detectors. Neuron. 2007;55(3):353-64. 68. Mishra S, Bhatnagar S, Goyal GN, Rana SP, Upadhya SP. A comparative efficacy of amitriptyline, gabapentin, and pregabalin in neuropathic cancer pain: A prospective randomized double-blind placebo-controlled study. Am J Hosp Palliat Care. 2012;29(3):177-82. 69. Dworkin RH, O'Connor AB, Audette J, Baron R, Gourlay GK, Haanpää ML, et al. Recommendations for the pharmacological management of neuropathic pain: An overview and literature update. Mayo Clin Proc. 2010;85(3 Suppl):S3-14. 70. Rai AS, Khan JS, Dhaliwal J, Busse JW, Choi S, Devereaux PJ, et al. Preoperative pregabalin or gabapentin for acute and chronic postoperative pain among patients undergoing breast cancer surgery: A systematic review and meta-analysis of randomized controlled trials. JPRAS. 2017;70(10):1317-28. 71. Kato J, Matsui N, Kakehi Y, Murayama E, Ohwada S, Sugihara M. Mirogabalin for the management of postherpetic neuralgia: A randomized, double-blind, placebo-controlled phase 3 study in Asian patients. Pain. 2019;160(5):1175–85. 72. Saito Y, Takekuma Y, Oshino T, Sugawara M. Combination of mirogabalin and duloxetine attenuates peripheral neuropathy by eribulin: A novel case report. Case Rep Oncol. 2022;15(2):606-610. 73. Takasaki Y, Fujisawa T, Ushio M, Takahashi S, Yamagata W, Suzuki A, et al. Effect of mirogabalin on chemotherapyinduced peripheral neuropathy caused by gemcitabine plus nab-paclitaxel therapy in pancreatic cancer patients: A pilot study. J Vasc Surg. 2022;1(1):36-42. 74. Freynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebocontrolled trial of flexible-and fixed-dose regimens. Pain. 2005;115(3):254-63.

114

76. Verma V, Singh N, Singh Jaggi A. Pregabalin in neuropathic pain: Evidences and possible mechanisms. Curr Neuropharmacol. 2014;12(1):44-56.

78. Freeman R, Durso-Decruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: Findings from seven randomized, controlled trials across a range of doses. Diabetes Care. 2008;31(7):1448-1454. 79. Merante D, Rosenstock J, Sharma U, Feins K, Hsu C, Vinik A. Efficacy of mirogabalin (DS-5565) on patient-reported pain and sleep interference in patients with diabetic neuropathic pain: Secondary outcomes of a phase II proofof-concept study. Pain Med. 2017;18(11):2198-2207. 80. Yokoyama T, Arakawa N, Domon Y, Matsuda F, Inoue T, Kitano Y, et al. Pharmacological, pharmacokinetics and safety profiles of DS-5565, a novel α2δ ligand. Neurol Sci. 2013;333:e535. 81. Vinik A, Rosenstock J, Sharma U, Feins K, Hsu C, Merante D. Efficacy and safety of mirogabalin (DS-5565) for the treatment of diabetic peripheral neuropathic pain: A randomized, double-blind, placebo - And active comparator-controlled, adaptive proof-of-concept phase 2 study. Diabetes Care. 2014;37(12):3253-3261. 82. Tetsunaga T, Tetsunaga T, Nishida K, Misawa H, Takigawa T, Yamane K, et al. Short-term outcomes of mirogabalin in patients with peripheral neuropathic pain: A retrospective study. J Orthop Surg Res. 2020;15(1):191. 83. Baba M, Matsui N, Kuroha M, Wasaki Y, Ohwada S. Longterm safety and efficacy of mirogabalin in Asian patients with diabetic peripheral neuropathic pain. J Diabetes Investig. 2020;11(3):693-698. 84. Alyoubi RA, Alshareef AA, Aldughaither SM, Aljaroudi AM, Alabdulwahed A, Alduraibi FM, et al. Efficacy and safety of mirogabalin treatment in patients with diabetic peripheral neuropathic pain: A systematic review and metaanalysis of randomised controlled trials. Int J Clin Pract. 2021;75(5):e13744. 85. Javed S, Alam U, Malik RA. Mirogabalin and emerging therapies for diabetic neuropathy. J Pain Res. 2018;11:1559-1566. 86. Aziz MT, Good BL, Lowe DK. Serotonin-norepinephrine reuptake inhibitors for the management of chemotherapyinduced peripheral neuropathy. Ann Pharmacother. 2014;48(5):626-32.

Scholarly Research In Progress • Vol. 7, November 2023

A Presentation of PRES with Rapid Cortical Enhancement Caused by Hypertension Secondary to Structural Renal Abnormalities Joshua Quach1†, Rachel Gifeisman1†, and Suman Kaza² ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 ²Geisinger Wyoming Valley Medical Center, Department of Neurology, Wilkes-Barre, PA 18711 † Doctor of Medicine Program Correspondence: rgifeisman@som.geisinger.edu

Abstract Posterior reversible encephalopathy syndrome (PRES) typically presents with acute onset headaches, seizures, altered mental status, and visual disturbances. Common etiologies include uncontrolled hypertension, preeclampsia, and vasculitis. While the above constellation of features is usually seen, PRES is a diagnosis of exclusion corroborated by magnetic resonance imaging (MRI) of the head, and atypical manifestations are known to occur. There is a paucity of PRES cases with clinical findings of ophthalmalgia and serial MRI findings of rapidly developing and resolving cortical enhancement. In this report we present a case where the presenting symptoms were subacute onset headache, papilledema, visual field loss, and ophthalmalgia. Unusual MRI findings included the rapid development of cortical and leptomeningeal enhancements found on MRI 10 days after a prior MRI showed no specific findings. Further investigation demonstrated anomalous renal artery anatomy with a concomitant right renal artery stenosis.

Introduction

diagnosis included ophthalmalgia, papilledema, and anomalous renal anatomy with concomitant right renal artery stenosis as key findings on clinical investigation.

Case Presentation J.D. is a 19-year-old female with a history of anxiety who presented to the Emergency Department (ED) with two weeks of progressive headaches and bilateral visual changes. One week prior the patient saw outpatient ophthalmology, where fundoscopic exam revealed papilledema and MRI (Figure 1A) was unremarkable. A diagnosis of pseudotumor cerebri was made and a 7-day course of prednisone and acetazolamide was started with mild improvement. In the ED the patient complained of bilateral eye pain, nausea, and vomiting. Patient denied sexual activity or travel and noted episodic rashes extending from her face to her clavicle. Physical exam revealed right central vision loss and left peripheral vision loss. Vital signs were a temperature of 100.4° F, blood pressure 190/130, pulse 80, and respiratory rate 16. Complete blood count revealed leukocytosis, thrombocytosis, and erythrocytosis. Comprehensive metabolic panel showed hypokalemia and erythrocyte sedimentation rate and c-reactive protein were normal. Repeat MRI revealed multiple enhancing flair hyperintense lesions with leptomeningeal and cortical enhancements and multiple enhancements in the posteromedial occipital and left anterior frontal convexities (Figure 1B). Tests for syphilis, gonorrhea, bartonella, tuberculosis, HIV, Lyme disease, COVID, and a respiratory virus panel were negative. Urinalysis showed mild ketonuria. Because her hypertension classified the patient’s condition as a hypertensive emergency

PRES is a clinical syndrome associated with a broad spectrum of clinical features, including seizures, headaches, focal neurological deficits, encephalopathy, and visual disturbances. The most common findings are seizures in over 70% of cases of PRES, hypertension present in 60% of cases, headache in 50% of cases, and encephalopathy in 28% of cases. Less commonly, PRES is noted to present with visual disturbances in roughly 20% of presentations. PRES is more prevalent in females, accounting for 63.5% of documented cases (1). The mean age of onset for PRES is 45 years old. However, a wide range of ages can be affected and there is literature documenting cases in patients ranging from age 4 through 90. The diagnosis of PRES is typically made with T2 or FLAIR MRI studies showing focal regions of symmetric hyperintensities with occipito-parietal involvement in 98% of cases. Special care must be taken to exclude other diagnoses such as vasculitis, infection, white matter disease, and autoimmune pathologies (2). There are few recorded PRES cases where patients have presented with visual disturbances without changes in mental status, focal neurologic deficits, or seizures Figure 1. A comparison of T1 Sagittal FLAIR post-contrast MRIs of the brain taken (A) and rapid development and resolution of 10 days prior to patient presentation, (B) on presentation to the ED, and (C) on hospital cortical enhancements on MRI. In this case day 3. Notice the diffuse hyper-intense lesions with periventricular and leptomeningeal discussion we present a patient whose PRES involvement with resolution of enhancements on MRI conducted on hospital day 3.

115

PRES with Rapid Cortical Enhancement

with concurrent neurological symptoms, the patient was admitted. Overnight the patient’s systolic blood pressure peaked at over 200 and was unresponsive to 5 mg nicardipine drip. The patient required a four-drug antihypertensive regimen of amlodipine 10 mg, lisinopril 10 mg, and hydralazine 25 mg daily in addition to the 5 mg nicardipine drip to maintain systolic blood pressure less than 140. Day 2 blood tests for anti-neutrophilic cytoplasmic antibodies, anticardiolipin antibodies, anti-nuclear antibodies, antiaquaporin 4 glycoprotein, and anti-myelin oligodendrocyte glycoprotein were negative, as were lumbar punctures for glucose, leukocytes, and oligoclonal bands. Abdominal computed tomography (CT) without contrast initially showed what was thought to be a potentially infarcted hypoattenuating left kidney (Figure 2A), however CT angiography showed right renal artery stenosis (RAS) with bilateral renal artery accessory poles. A diagnosis of RAS and PRES was made and the hypoattenuation of the left kidney in comparison to the right was understood to be due to delayed clearance of prior contrast administrations. The upper portion of the right kidney appeared bright due to right renal artery stenosis limiting blood flow and thus delaying clearance, while the lower lobe of the right kidney remained dark due to preserved blood flow via anomalous renal vasculature (Figure 2B). MRI of the brain conducted in hospital on day 3 showed resolution of contrast enhancement seen in previous MRI (Figure 1C). The patient was discharged on hospital day 3 with a course of prednisone and follow up appointments with nephrology and vascular surgery for renal angioplasty were scheduled.

cases with emergent hypertension of unknown cause and neurological findings. A pertinent feature in this case was the findings of accessory renal arteries and renal artery stenosis, a remarkable finding in this otherwise healthy, young female patient with no prior contributing history. Physiologically, the previously undiagnosed renal artery abnormalities explained this patient’s emergent hypertension, hypokalemia, and poor response to blood pressure medications on admission. The blood pressure changes in this patient were likely chronic, eventually leading to her papilledema, intracranial hypertension, and the development of PRES. Workup in this case was initially conducted to surveil for etiologies that could lead to contrast enhancement such as central autoimmune demyelination, Neuromyelitis Optica, SLE, vasculitis, idiopathic intracranial hypertension, and stroke. It included CBC, CRP, glucose level, B12 level, ANA, RF APA, lupus anticoagulant, serum ACE, UA, ANCA, Mantoux test, quantINTERFERON, infectious disease panel, HIV serology, mycoplasma serology, NMO, MOG antibodies, lumbar puncture, and MRI in addition to history and physical examination. In this case, the driver of hypertension was found on abdominal CTA to be right renal artery stenosis, despite non-contrast CT of abdomen giving the appearance of left renal ischemic changes. Renal artery stenosis is believed to cause 1–10% of cases of hypertension in the United States, with unilateral involvement in 53–80% of cases, typically affecting older male patients above 45 years old due to atherosclerotic changes (3).

Following diagnosis of PRES, treatment focuses on resolving the underlying cause, most commonly hypertension, iatrogenic causes, eclampsia, and systemic factors (4). After the patient was stabilized, follow-up with vascular surgery was necessary for placement of a renal artery stent to normalize blood pressures. The patient was followed up closely by vascular surgery and nephrology. Pathophysiology behind PRES is thought to be related to alterations in cerebrovascular autoregulation leading to subsequent vasogenic edema. Autoimmune etiologies and concomitant vasculitides such as thrombotic thrombocytopenic purpura, primary sclerosing cholangitis, Figure 2. A) Non-contrast CT of the abdomen revealing swelling and hypo-attenuation in rheumatoid arthritis, polyarteritis nodosa, the left kidney and right lower pole of the right kidney, originally suspicious for infarctions, and systemic lupus erythematous are eventually determined to be due to delayed clearance of contrast from prior imaging notable associations. PRES also has a strong studies by right kidney, secondary to right renal artery stenosis and right accessory renal association with preeclampsia, with up to arteries. Hypo-attenuated regions (circled in red) later understood to be areas with healthy renal function supplied by accessory renal vasculature while vasculature supplying hyper50% of patients subsequently developing attenuated regions is stenosed. B) CTA of the abdomen demonstrating two accessory right PRES during the peripartum period. renal arteries (circled in black) extending into the right kidney’s lower pole, with main right middle renal artery demonstrating high-grade stenosis (circled in blue). Compare to intact left renal artery on the other side.

Discussion This case was an atypical PRES presentation with headache, hypertension secondary to RAS and accessory renal arteries bilaterally, visual changes, and papilledema without AMS or seizures — two notable exclusions for PRES. While PRES commonly presents with seizures and altered mental status changes, clinicians should elevate their suspicion of PRES in 116

Other relevant points in this case were the acute development of hyperintensities on MRI over a 10-day period, with the prior diagnosis of papilledema masking the recognition of the patient’s hypertension being secondary to vascular abnormalities. While pseudotumor cerebri traditionally presents as a headache and bilateral visual symptoms worse in the morning in a female patient with elevated BMI, some surveillance should be conducted to rule out other causes of intracranial hypertension4. Key considerations to rule out include malignancy, vascular abnormalities, overproduction

PRES with Rapid Cortical Enhancement

or under-resorption of CSF, and etiologies causing acute and chronic hypertension (5). A workup of this patient’s elevated blood pressures could have led to prompt diagnosis and treatment.

Conclusion In summary, PRES is a diagnosis of exclusion supported with MRI findings that requires workup for etiologies driving vasogenic changes. Treatment focuses on resolving underlying causes. In this case rare presenting features were accessory renal artery poles, right renal artery stenosis, and symptoms of ophthalmalgia with multifocal hyperintensities found on MRI presenting in a young patient with no prior medical history. Workup for PRES is broad, including assessment for hypertensive, vascular, autoimmune, inflammatory, pregnancyrelated, and iatrogenic causes.

Disclosures The authors have nothing to disclose.

References 1.

Buchhanolla P, Bir S, Angelette A, Lewis A, Kandregula S, Guthikonda B, et al. Determination of Prevalence of Posterior Reversible Encephalopathy Syndrome (PRES) and Its Association with Cerebral Infarction, and Outcome in the Nationwide Inpatient Sample, 2016–2018 (P1610.002). Neurology [Internet]. 2022 May 3 [cited 2023 Jun 19];98(18 Supplement). Available from: https://n. neurology.org/content/98/18_Supplement/3555

Zelaya JE, Al-Khoury L. Posterior Reversible Encephalopathy Syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Jun 19]. Available from: http://www.ncbi.nlm.nih.gov/ books/NBK554492/

Bokhari MR, Bokhari SRA. Renal Artery Stenosis. [Updated 2022 Sep 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https:// www.ncbi.nlm.nih.gov/books/NBK430718/.

Rigi M, Almarzouqi SJ, Morgan ML, Lee AG. Papilledema: epidemiology, etiology, and clinical management. Eye Brain. 2015;7:47–57.

Triplett JD, Kutlubaev MA, Kermode AG, Hardy T. Posterior reversible encephalopathy syndrome (PRES): diagnosis and management. Pract Neurol. 2022 Jun;22(3):183–9.

117

Scholarly Research In Progress • Vol. 7, November 2023

Neurotoxic and Behavioral Effects of Prenatal Ketamine Exposure: A Literature Review Mariam Sy1* ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 *Master of Biomedical Sciences Program Correspondence: msy1@geisinger.edu

Abstract Prenatal exposure to ketamine, a widely used anesthetic and analgesic, poses risks to the developing fetus due to its ability to cross the blood-brain and placental barriers. This literature review examines the effects of prenatal ketamine on offspring neurodevelopment and behavior. Animal studies indicate that ketamine exposure during pregnancy leads to increased apoptosis, neuronal death, and altered dendritic growth in the prefrontal cortex. These neurotoxic effects are associated with affective disorders, cognitive impairments, and anxiety-like behaviors in adulthood. Prenatal ketamine exposure is also linked to schizophrenia-like behaviors, including cognitive deficits, social withdrawal, and aggressive behaviors. However, postnatal use of ketamine shows antidepressant benefits and can attenuate stress-induced neuronal changes. Dexmedetomidine (DEX), an alternative sedative/anxiolytic agent, has shown promise in mitigating the neurotoxic effects of ketamine. DEX administration along with ketamine reduces apoptosis and neuronal degeneration, particularly in the frontal cortex. DEX also exhibits neuroprotective effects when combined with other anesthetics, such as propofol. Further research is needed to explore the precise mechanisms and longterm consequences of prenatal ketamine exposure, as well as to optimize the use of DEX as a neuroprotective agent.

Introduction Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist widely used for its anesthetic and analgesic properties, has a history of abuse as a recreational drug due to its psychotropic effects (1). More recently, ketamine has also been utilized as an antidepressant. It is known that ketamine can cross the blood-brain and the blood-placenta barrier. Indirect administration of ketamine to a fetus involves the transfer of the drug through the maternal-fetal barrier/placenta or given to a baby through breast milk. One minute 37 seconds after intravenous injection of ketamine to the mother, ketamine levels in newborn cord blood reaches the same levels as the mother's venous blood (1). As seen in lactating mice, phencyclidine, which is pharmacologically similar to ketamine, readily crosses into breast milk, increasing concentrations to levels 10-fold higher than in plasma (1). This rapid entry of ketamine into fetal/neonatal circulation alters neurodevelopment due to its accumulation in the brain. The presence of ketamine in the developing brain can lead to increased apoptosis and necrosis in neuronal cells, decreased proliferation of neural stem cells, increased reactive oxygen species, increased cell death of immature GABAergic interneurons, and decreased dendritic growth (1).

118

Mothers often suffer from postpartum depression (PPD) as a complication of cesarean section. When given intravenously during surgery, S-ketamine can help prevent PPD despite its neurotoxic effects (2). For example, s-ketamine given through patient-controlled intravenous analgesia (PCIA) reduced PPD within 14 days and relieved pain within 48 hours after cesarean delivery without increasing the adverse effects compared to the control group (2).

Methods A review of the literature was conducted pertaining to the use of ketamine prenatally and its effects on offspring. References were obtained from PubMed, Google Scholar, and Geisinger Libraries with publication years ranging from 2012 to 2022. Keywords screened for in the database search included: prenatal ketamine, ketamine, ketamine misuse, dexmedetomidine, schizophrenia. The research did not include any exclusion criteria.

Discussion Ketamine-Induced Neurotoxicity The prefrontal cortex (PFC) is important for emotional and cognitive processes. Prenatal ketamine use harms development as it contributes to offspring suffering from affective disorders and cognitive impairments. Based on animal models, exposure of fetal rats to ketamine results in cell apoptosis and neuronal death. There is more dendritic branching in PFC neurons due to prenatal ketamine exposure when compared to the control (3). Increased neuronal cell death is evident in the frontal cortex of newborn mice after prenatal exposure to ketamine compared to the parietal cortex (4). Cortical layers II-IV are especially impacted by the loss of Gad67-GFP interneurons, along with a significant reduction in their dendritic spine density (5). Ketamine and Behavior Embryonic and infant exposure to ketamine harms the developing brain, and behavioral changes accompany this ketamine-induced neurotoxicity. Through the use of an open field test and an elevated plus maze, it was determined that mice prenatally exposed to ketamine did not show any effects during puberty. However, they later portrayed anxiety-like behaviors during adulthood (6). Using cFos to map neuronal activity, it was discovered that there was abnormal activity in the bed nucleus of the stria terminalis (6). Once this abnormal activity was silenced, the anxiety-like behavior induced by ketamine was reduced, leading to the conclusion that prenatal exposure to ketamine was the cause of the abnormal activity (6).

Neurotoxic and Behavioral Effects of Prenatal Ketamine Exposure: A Literature Review

MAOA-LPR is a gene that regulates monoaminergic neurotransmission (7). Animals prenatally exposed to ketamine expressed the sensitivity MAOA-LPR genotype especially following first and second-trimester exposures (7). Ketamine administration in the first trimester correlated the sensitivity genotype with inhibited behaviors, such as less emotional expression in responsiveness observations and less contact with novel objects (7). Exposure in the second trimester showed a positive correlation between ketamine dosage and activity level seen in responsiveness observations (7). Postnatal ketamine, in combination with the low activity variant of monoamine oxidase A (MAOA), led to poor performance on a visual memory test (8). Disturbances to the prenatal immune system can contribute to the pathophysiology of neuropsychiatric disorders. Maternal immune activation (MIA) increases oxidative stress and metalloproteinase expression in the fetal brain and amniotic fluid (9). Injection with ketamine on postnatal day 54 after MIA was induced led to memory impairment and deficits, in addition to observed behavioral deficits in adult rats (9). However, administration of (R)-ketamine twice weekly for four weeks in juvenile and adolescent offspring of maternal rats who experienced MIA blocked the development of cognitive defects and decreased dendritic spine density in the medial prefrontal cortex (mPFC) (10). Despite its negative behavioral changes, there is an antidepressant benefit to the postnatal use of ketamine. A rat prenatal stress model of depression showed that mGluR5 is associated with depression-like behaviors and is increased in rats exposed to prenatal stress (11). However, ketamine can attenuate the stress-induced increase of mGluR5 (11). Ketamine and Schizophrenia Schizophrenia is a mental disorder characterized by cognitive impairments pertaining to attention, working memory, verbal learning, processing speed, and executive functioning (12). Exposure to prenatal ketamine has been strongly linked with schizophrenia-like behaviors in animal models (13). There is disinhibition and hyperactive behavior in pubertal rats exposed to ketamine, followed by cognitive impairments, social withdrawal, anxiety, depression, and aggressive-like behaviors in adulthood (13). Transplantation of mesenchymal stem cells into rodents who experienced a schizophrenic decrease in hippocampal neurogenesis due to ketamine exposure led to an improvement in social novelty and prepulse inhibition as well as behavioral improvement, increased hippocampal neurogenesis, and increased gene expression (14).

When comparing the effects of ketamine and DEX on the primary sensory and limbic brain regions, ketamine causes significant cell degradation and apoptosis in the limbic regions and insignificant changes in the primary sensory brain areas. In contrast, DEX produces opposite results (18). It causes significant cell degradation and apoptosis in the primary sensory brain regions and insignificant changes in the limbic regions (18). General anesthetics can cause developmental neurotoxicity, such as neuronal cell death, long-term memory deficits, and learning abnormalities (19). It has been discovered that while ketamine causes apoptosis and impaired brain function in the developing brain, DEX can attenuate these effects when administered with ketamine (20). As a result, Ketamine and DEX have been increasingly used in combination for pediatric patients (20). Propofol is another anesthetic widely used in pediatric patients; however, previous studies have indicated that it can also induce apoptosis and damage cognitive and memory functions (21). Similar to its effects when administered with ketamine, DEX attenuates the effect of propofol-induced neurotoxicity on hippocampal neurons (21).

Conclusion Ketamine is widely used as an analgesic, anesthetic, and antidepressant. Due to its hydrophilic and lipophilic properties, it can cross the blood-brain barrier as well as the placental barrier, making ketamine detrimental to developing fetuses. Ketamine is known to induce neurotoxicity and behavioral deficits following prenatal exposure. Prenatal ketamine administration is linked to apoptosis, neuronal death, anxietylike behaviors, and schizophrenia-like behaviors. Ketamine, like other anesthetics, has been proven to promote neurotoxicity; however, DEX can attenuate the effects of ketamine when used in conjunction. DEX also reduces the neurotoxic effects of propofol. This decrease in neurotoxicity due to DEX may lead to a new age of anesthetic and antidepressant practices.

Acknowledgments I would like to thank Brian Piper, PhD, for his guidance and feedback.

References 1.

Cheung HM, Yew DTW. Effects of perinatal exposure to ketamine on the developing brain. Front Neurosci. 2019; 13:138.

Han Y, Li P, Miao M, Tao Y, Kang X, Zhang J. S-ketamine as an adjuvant in patient-controlled intravenous analgesia for preventing postpartum depression: A randomized controlled trial. BMC Anesthesiol. 2022; 22(1).

Zhao T, Li C, Wei W, Zhang H, Ma D, Song X, et al. Prenatal ketamine exposure causes abnormal development of prefrontal cortex in rat. Sci Rep. 2016; 6:26865.

Najm M, Mubarak H, Jarullah H. Nissl stain expression in the frontal and parietal cortices of the newborn mice after prenatal exposure to ketamine. Iraqi Journal of Medical Sciences. 2018; 16(3):268–278.

Is Dexmedetomidine an Alternative to Ketamine? Dexmedetomidine (DEX) is an a2-adrenoreceptor agonist with sedative, anxiolytic, and analgesic effects (15) that has a mechanism of action different from ketamine. Ketamine exposure leads to apoptosis and degeneration in the frontal cortex; however, DEX exposure causes no or minimal neuroapoptotic and neurodegenerative lesions in the frontal cortex at low doses (16). Although DEX is a neuroprotectant in clinical doses, high doses result in neuroapoptosis (17). Its current dosing schedules in humans yield plasma levels below the concentrations required to induce neurotoxicity (17).

119

Neurotoxic and Behavioral Effects of Prenatal Ketamine Exposure: A Literature Review

Aligny C, Roux C, Dourmap N, Ramdani Y, Do-Rego JC, Jégou S, et al. Ketamine alters cortical integration of GABAergic interneurons and induces long-term sexdependent impairments in transgenic Gad67-GFP mice. Cell Death Dis. 2014; 5(7):e1311.

18. Pancaro C, Segal BS, Sikes RW, Almeer Z, Schumann R, Azocar RJ, et al. Dexmedetomidine and ketamine show distinct patterns of cell degeneration and apoptosis in the developing rat neonatal brain. J Matern Fetal Neonatal Med. 2016; 29(23):3827-33.

Sun J, Lin J, Feng X, Lu Z, Liu T, Lin L, et al. Prenatal exposure to ketamine leads to anxiety-like behaviors and dysfunction in bed nucleus of stria terminalis. Int J Neuropsychopharmacol. 2020; 23(3):181-191.

19. Bosnjak ZJ, Logan S, Liu Y, Bai X. Recent insights into molecular mechanisms of propofol-induced developmental neurotoxicity: Implications for the protective strategies. Anesth Analg. 2016; 123(5):1286-1296.

Capitanio JP. Knowledge of biobehavioral organization can facilitate better science: A review of the biobehavioral assessment program at the California national primate research center. Animals (Basel). 2021; 11(8):2445.

20. Duan X, Li Y, Zhou C, Huang L, Dong Z. Dexmedetomidine provides neuroprotection: Impact on ketamine-induced neuroapoptosis in the developing rat brain. Acta Anaesthesiol Scand. 2014; 58(9):1121-6.

Herrington JA, Del Rosso L, Capitanio JP. Behavioral effects of postnatal ketamine exposure in rhesus macaque infants are dependent on MAOA-LPR genotype. Dev Psychobiol. 2019; 61(4): 605–614.

21. Wei Y, Hu J, Liang Y, Zhong Y, He D, Qin Y, et al. Dexmedetomidine pretreatment attenuates propofol induced neurotoxicity in neuronal cultures from the rat hippocampus. Mol Med Rep. 2016; 14(4):3413-20.

Simões LR, Sangiogo G, Tashiro MH, Generoso JS, Faller CJ, Dominguini D, et al. Maternal immune activation induced by lipopolysaccharide triggers immune response in pregnant mother and fetus, and induces behavioral impairment in adult rats. J Psychiatr Res. 2018; 100:71-83.

10. Tan Y, Fujita Y, Pu Y, Chang L, Qu Y, Wang X, et al. Repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages prevents schizophrenia-relevant phenotypes in adult offspring after maternal immune activation: A role of TrkB signaling. Eur Arch Psychiatry Clin Neurosci. 2022. 11. Wang Y, He W, Zhang H, Yao Z, Che F, Cao Y, et al. mGluR5 mediates ketamine antidepressant response in susceptible rats exposed to prenatal stress. J Affect Disord. 2020; 272:398-408. 12. Chen C, Yang Y, Ye X, Jin Y, Cai Z, Zheng J. Impact of aerobic exercise on cognitive function in patients with schizophrenia during daily nursing: A protocol for systematic review and meta-analysis. Medicine (Baltimore). 2021; 100(1):e23876. 13. Coronel-Oliveros CM, Pacheco-Calderón R. Prenatal exposure to ketamine in rats: Implications on animal models of schizophrenia. Dev Psychobiol. 2018; 60(1):30-42. 14. Gobshtis N, Tfilin M, Fraifeld VE. Transplantation of mesenchymal stem cells causes long-term alleviation of schizophrenia-like behaviour coupled with increased neurogenesis. Mol Psychiatry. 2019; 26:4448–4463. 15. Wei Q, Chen J, Xiao F, Tu Y, Zhong Y, Xie Y. High-dose dexmedetomidine promotes apoptosis in fetal rat hippocampal neurons. Drug Des Devel Ther. 2021; 15:24332444. 16. Koo E, Oshodi T. Comparative neurotoxic effects of dexmedetomidine and ketamine in prenatal monkey brains. Anesth Analg. 2012 ;144(5):S402. 17. Liu JR, Yuki K, Baek C, Han XH, Soriano SG. Dexmedetomidine-induced neuroapoptosis is dependent on its cumulative dose. Anesth Analg. 2016; 123(4):1008-17.

120

Scholarly Research In Progress • Vol. 7, November 2023

A Cost Comparison of Two Commonly Used Techniques for Revision Total Knee Arthroplasty Carly Deter1†, Jessica Koshinski1†, Logan SanCraint¹, and James E. Murphy1,2 ¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 ²Geisinger Musculoskeletal Institute, Wilkes-Barre, PA 18702 † Doctor of Medicine Program Correspondence: cdeter@som.geisinger.edu

Abstract Most total knee revision implants use intramedullary stems and fall into one of two categories: all-cemented or hybrid fixation (combination of articular surface cementing and stem diaphyseal press fit). We hypothesized that while both techniques will provide rigid fixation, the costs associated with each technique will be different. Total knee revisions done from 2019 to 2021 in a large health system were identified by CPT code. Single component exchange, megaprosthesis and revision for periprosthetic fracture were excluded due to effect on costs. Revisions done for infection were excluded in first stage and included for the second stage. The cohort was divided into two groups: all-cemented and hybrid fixation. A Mann-Whitney test and analysis was then performed on total cost, cement cost, and use of a cone or sleeve. Sixty-seven patients were enrolled in the hybrid group and 129 in the all-cemented group. The hybrid group median cost was $25,463. Offset connectors median cost was $6,066 when used and were used 52.24% of the time. Metaphyseal cones or sleeves were used 46.27% of the time and median cost of $6,054. The cemented group median cost was $22,984 and offset connectors were used only 1.55% of the time with a median cost of $1,591. Metaphyseal cones were used 45.74% and had a median cost of $5,522. Statistical analysis revealed no significant difference between the two groups in median total cost ($25,463 vs $22,984, p=0.22). Cement costs were significantly higher in all-cemented group ($565.0 vs $333.7, p<0.0001). Total costs for revisions using cones were significantly higher ($28,138 vs $19,404, p<0.0001). Hybrid technique costs are more expensive by $2,479 than an all-cemented technique, but not to statistical significance. Offset connectors were used 52% of the time in hybrid technique and only 2% in all-cemented technique. Cement costs are higher by $231 in the all-cemented group. There is a statistically significant increase in cost by $8,734 when cones or sleeves are used. Special attention should be given to the usage of offset connectors, cones, and sleeves when performing revision total knee arthroplasty.

Introduction Based on recent National Inpatient Sample, rates of primary TKA in the United States in 2025, 2030, and 2040 are projected to reach (in thousands) 652, 850 and 1429 respectively (1). These numbers represent 110%, 182%, and 401% increases in annual primary TKAs (1). With an increase in primary total knee surgery will come an increase in revision surgery. Increasing incidence requires data to support clinical decisions about which implant and fixation type best suits each revision TKA. Costs associated with surgery have generally focused on primary total knee arthroplasty. In revision surgery, there

can be a varying amount of bone loss which may require different implant options to provide rigid bony fixation. These implants include different style femoral and tibial components, metaphyseal cones and sleeves, intramedullary stems, and offset connectors which can connect the femoral prosthesis to the stem. Most techniques fall into two general categories which are used to address the varying amount of bone loss: allcemented or hybrid fixation (which is a combination of articular surface cementing and stem diaphyseal press fit). We evaluated the costs associated with each technique and compared the two groups using modern pricing structures in a major health system. With an increase in revision surgery predicted at 182% over the next 9 years, this cost data will be critical to surgeons making educated decisions during surgery (2). We hypothesized that while both techniques will provide the rigid internal fixation necessary for revision surgery, the costs associated with each implant will be different (3).

Methods This study utilized a retrospective design and chart review. All total knee revisions done from 2019 to 2021 in a large multifacility health system were identified by CPT code, 27247. Any single component exchange, megaprosthesis, and revision done for periprosthetic fracture were excluded due to their influence on cost. A fellowship-trained adult reconstructive surgeon evaluated the radiographs to ensure an intramedullary stem was used. Any revision done for the purpose of first stage in a single-stage infection revision was excluded because they receive different implants than the ones being studied, while the second stage reimplantation of a two-stage infection revision was included because it requires the same implants as other indications for revision. Only the implant cost itself was included in the analysis. The cohort was then divided into two groups: all-cemented and hybrid fixation. The database of costs was analyzed using Microsoft PowerBi, where each component of the final implant was recorded. A Mann-Whitney test was performed on total cost and cement cost for both groups. A subgroup analysis compared the groups that used a cone or sleeve from those revisions which did not use a cone or sleeve.

Results A total of 67 patients in the hybrid group and 129 patients in the cemented group were included in the final analysis. The median implant cost for the hybrid group was $25,463, with the majority of the costs coming from the femoral component build, with a median cost of $11,472 and accounting for 45.3% of the overall price of the implant (Table 1). Offset connectors had a median price of $6,066 when used and were used 52.24% of the time. Metaphyseal cones and sleeves were used 46.27% of the 121

A Cost Comparison of Two Commonly Used Techniques for Revision Total Knee Arthroplasty

time and had a median cost of $6,054, accounting for 28.3% of the total price when used (Table 1). The cemented group median cost was $22,984 with most of the costs coming from the femoral component build which had a median cost of $11,342 and accounted for 47.8% of the overall price (Table 1). Offset connectors were used only 1.55% of the time in the all-cemented group. Metaphyseal cones were used 45.74% of the time and had a median cost of $5,522 when used (Table 1). The statistical analysis revealed no significant difference between the two groups in median total cost ($22,984 vs $25,463, p=0.22) (Figure 1). Cement costs were significantly higher in all-cemented groups ($565.0 vs $333.7, p<0.0001). The total costs for revision surgery using cones were significantly higher than costs without cones ($28,138 vs $19,404) (Figure 2). Revision Component

Hybrid Median Cost

% Usage

Cemented Median Cost

% Usage

Discussion Both hybrid and all-cemented techniques provide stable implant fixation in the setting of bone loss during revision total knee arthroplasty but have different costs. The median hybrid technique costs are more expensive by $2,479 than an all-cemented revision TKA, but not enough to show statistical significance. This conclusion is based on using offset connectors approximately half the time and usage over that number could increase total cost more. The femoral component build is the most expensive part of the total implant and accounts for nearly half the total cost. Surgeons can note that both techniques provide a statistically similar cost to the health care payor. Using cement in the all-cemented technique, while proving to be more expensive statistically, only increased the cost by $231 and should not be considered a detriment to usage. There is a statistically significant increase in cost when cones or sleeves are used by $8,734 on either hybrid or all-cemented fixation, demonstrating that they can be a powerful driver of total cost.

Conclusion As the rates of TKA revisions rise and economic conditions deteriorate around the world, special attention should be given to the total cost of the implant, including usage of offset connectors, cones, and sleeves when determining which technique to use during revision total knee arthroplasty. Table 1. Total costs of hybrid and cemented components

Acknowledgments With gratitude to Idorenyin F. Udoeyo for assistance with statistical analysis.

References

Figure 1. Median costs of hybrid and all-cemented fixation

Figure 2. The use of cones significantly increases cost of rTKA

122

Singh JA, Yu S, Chen L, Cleveland JD. Rates of Total Joint Replacement in the United States: Future Projections to 2020-2040 Using the National Inpatient Sample. The Journal of Rheumatology. 2019;46(9):1134-1140.

Rassir R, Nolte PA, van der Lugt JCT, Nelissen RGHH, Sierevelt IN, Verra WC. No differences in costeffectiveness and short-term functional outcomes between cemented and uncemented total knee arthroplasty. BMC Musculoskeletal Disorders. 2020;21(1).

Schwartz, A, Farley K, Guild G, Bradbury, T. Projections and Epidemiology of Revision Hip and Knee Arthroplasty in the United States to 2030. J Arthroplasty. 2020 Jun;35(6S):S79-S85.

Scholarly Research In Progress • Vol. 7, November 2023

2024 Summer Research Immersion Program Each summer the Geisinger Commonwealth School of Medicine Summer Research Immersion Program (SRIP) brings together first year medical students for an opportunity to gain research experience in basic science, clinical science, public/ community health, behavioral health, or medical education under the guidance of a research mentor. The summer research experience includes a $2,500 educational stipend. At the end of the program, students present their research in a poster session. In addition to research, SRIP students participate in a variety of complementary enrichment activities:

• Provide research opportunities that span the translational continuum from laboratory based biomedical studies to clinical and public health research conducted with community partners • Engage students in peer learning and networking • Enhance students’ skills in oral and written scholarship

Program dates:

•

GCSOM and Geisinger faculty research seminars

SRIP 2024 will be an eight-week program held June 3 – July 26, 2024.

•

GCSOM Grand Rounds and clinical seminars at our hospital partners

Program deadlines:

•

Special events or conferences related to your research topic

Application release date: Dec. 1, 2023 Application submission deadline: Feb. 2, 2024

•

Clinical exposure

•

Scientific writing & communication workshops

SRIP program goals: • Provide students with an immersive research experience under a mentor’s guidance • Enhance students’ knowledge of the scope and types of research relevant to improving health in the region, nationally, and globally

For more information, contact: Sonia Lobo, PhD SRIP Program Administrator Associate Dean for Research & Scholarship slobo1@geisinger.edu Elizabeth Kuchinski, MPH SRIP Director eckuchinski@geisinger.edu

123

Through the MRHP, you will:

Medical Research Honors Program Current first-year medical students are eligible to join the Medical Research Honors Program (MRHP). With a mentor’s guidance, you will drive this long-term, thesis focused research experience. By completing the requirements while remaining in good academic standing, you’ll graduate with an honors distinction.

Through the MRHP, you will: • Advance fundamental scientific knowledge • Stand apart in competitive residency application fields • Refine scholarly communication • Gain a mindset of continual growth and learning To complete this 4-year program, you must submit a research project proposal, write a thesis, and deliver an oral defense. You will also write abstracts, present posters, and publish findings while building towards your thesis defense. Your research experience is guided by a research mentor, a thesis advisory committee, and the program director. We encourage you to participate in the Summer Research Immersion Program as well.

Application packet must include: • MRHP application form • Letter of support from research mentor • CV • Acknowledgment of mentor’s expectations • Project proposal: project title, specific aims, hypothesis, background, preliminary data (if available)

Be a mentor If you would be willing to have a medical student work with you on a long-term, thesis driven research project, email us at mrhp@geisinger.edu or scan the QR code. Be sure to indicate your willingness to commit time, facilities, and resources to a student as needed throughout the program.

Application deadline:

Questions about the MRHP program or mentoring?

Wednesday, April 24, 2024

Contact: Sonia Lobo, PhD Associate Dean for Research and Scholarship slobo1@geisinger.edu Tracey Platt, MPH Program Manager tpratt@geisinger.edu

124

Scholarly Research In Progress • Vol. 6, November 2022

Finding your way: Opportunities for student funding You can find assistance in searching for funding opportunities specifically designed for students at the Office of Research and Scholarship. Funding opportunities may include support for fellowships, internships, research, programming, and collaboration. The Office of Research and Scholarship can help you locate and qualify funding opportunities as well as assist in application review. So please call or stop by early in the proposal development process so that we can work with you to meet your deadline.

Geisinger Clinical Research Fund (CRF) Students working under the supervision of a Geisinger clinical mentor may be eligible for support through the CRF. Funds may be used to cover services through the Geisinger research cores or relevant software costs. In addition, funds may be used to support student professional development like publication costs or travel to present at a national conference.

than 6 months and conclude by December 1, 2024. The maximum award for each project is $2000. Funds cannot be requested for stipends, tuition, travel, or wages for the student or faculty mentor. Indirect costs to the sponsoring institution are not allowed. SRAs are intended to foster student scholarship and lead to a tangible deliverable such as an abstract for submission to a regional/national meeting or a manuscript for publication in SCRIP and/or a peer-reviewed journal. SRA applications will be due May 1, 2024, at 11:59 p.m. ET. Contact Tracey Pratt, MPH, or studentresearch@geisinger.edu if you are interested in applying.

Contact information:

GCSOM Student Research Awards (SRAs) The Office of Research and Scholarship is pleased to announce the availability of funds for the 2023 academic year to support student research projects in the areas of basic or clinical science, public/community health, behavioral health, and medical education research. The proposed project must be under the supervision of a faculty mentor and be endorsed by the Office of Research and Scholarship. The proposed project period must be no longer

Tracey Pratt, MPH Manager of Research Education Resources Office of Research and Scholarship Phone: 570-558-3955 Internal extension: 5335 Email: tpratt@geisinger.edu

125

525 Pine St. Scranton, PA 18509

570-504-7000 geisinger.edu/gcsom studentresearch@geisinger.edu

From left: Samuel K. Wyman, Christina L. Shaffern, and Ara Khoylyan received Excellence in Research Awards for their outstanding abstract submissions at the 2023 Summer Research Symposium.

1023210-10/23-HD/SL