University Of Wisconsin-Madison Research Articles

Multi-institution single geometry plan complexity characteristics based on IROC phantoms.

Clinical intensity modulated radiation therapy plans have been described using various complexity metrics to help identify problematic radiotherapy plans. Most previous studies related to the quantification of plan complexity and their utility have relied on institution-specific plans which can be highly variable depending on the machines, planning techniques, delivery modalities, and measurement devices used. In this work, 1723 plans treating one of only four standardized geometries were simultaneously analyzed to investigate how radiation plan complexity metrics vary across four different sets of common objectives. To assess the treatment plan complexity characteristics of plans developed for Imaging and Radiation Oncology Core (IROC) phantoms. Specifically, to understand the variability in plan complexity between institutions for a common plan objective, and to evaluate how various complexity metrics differentiate relevant groups of plans. 1723 plans treating one of four standardized IROC phantom geometries representing four different anatomical sites of treatment were analyzed. For each plan, 22 MLC-descriptive plan complexity metrics were calculated, and principal component analysis (PCA) was applied to the 22 metrics in order to evaluate differences in plan complexity between groups. Across all metrics, pairwise comparisons of the IROC phantom data were made for the following classifications of the data: anatomical phantom treated, treatment planning system (TPS), and the combination of MLC model and treatment planning system. An objective k-means clustering algorithm was also applied to the data to determine if any meaningful distinctions could be made between different subgroups. The IROC phantom database was also compared to a clinical database from the University of Wisconsin-Madison (UW) which included plans treating the same four anatomical sites as the IROC phantoms using a TrueBeam™ STx and Pinnacle3 TPS. The IROC head and neck and spine plans were distinct from the prostate and lung plans based on comparison of the 22 metrics. All IROC phantom plan group complexity metric distributions were highly variable despite all plans being designed for identical geometries and plan objectives. The clusters determined by the k-means algorithm further supported that the IROC head and neck and spine plans involved similar amounts of complexity and were largely distinct from the prostate and lung plans, but no further distinctions could be made. Plan complexity in the head and neck and spine IROC phantom plans were similar to the complexity encountered in the UW clinical plans. There is substantial variability in plan complexity between institutions when planning for the same objective. For each IROC anatomical phantom treated, the magnitude of variability in plan complexity between institutions is similar to the variability in plan complexity encountered within a single institution database containing several hundred unique clinical plans treating corresponding anatomies in actual patients.

Evaluating the Effect of Extra-Cerebral Off-Target Binding in [F-18]MK6240 PET Scans in Early-Stage Alzheimer’s Disease

Abstract [F-18]MK6240 is a PET radioligand with favorable imaging characteristics for measuring tau aggregation in Alzheimer’s disease (AD). In this study we investigated the impact of extra-cerebral off-target binding (ECB) in the meninges and sinus present in [F-18]MK6240 PET scans on quantifying tau burden in preclinical AD. Based on large cohort data from 433 [F-18]MK6240 scans acquired at the University of Wisconsin-Madison, simulations were conducted to examine the range of effects of ECB by varying the ECB profile and input radiotracer concentration curves on areas of early tau accumulation in AD. The range and patterning of ECB in the imaging cohort had high variability between participants, however, 35% revealed moderate to high meningeal signal that could influence quantification. Partial volume effects, which can lead to measured PET signal from neighboring regions influencing signal in adjacent areas of interest, were examined in the simulated images. The simulations demonstrate that signal from the sinus increases the neighboring entorhinal cortex region (ERC) signal and activity detected from the meninges can similarly influence the inferior cerebellar grey matter reference region. ECB effects from the sinus were most prevalent in our cohort, and simulations with the average ECB profile had ERC uptake (SUV) 23% higher than simulations with no ECB. Spill-in effects from the sinus, which increases the medial and ventral temporal cortex SUVR, and spill-in from the meninges into the cerebellar reference region, which leads to a reduction in global SUVR, act in opposite directions, complicating the interpretation of the derived SUVR of [F-18]MK6240 images. These simulation results quantify the effects of ECB in [F-18]MK6240 scans and introduce correction factors to minimize bias of the SUVR measure.

Nanodrug-bacteria conjugates-mediated oncogenic collagen depletion enhances immune checkpoint blockade therapy against pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) cancer cells specifically produce abnormal oncogenic collagen to bind with integrin α3β1 receptor and activate the downstream focal adhesion kinase (FAK), protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) signaling pathway. Collectively, this promotes immunosuppression and tumor proliferation and restricts the response rate of clinical cancer immunotherapies. Here, by leveraging the hypoxia tropism and excellent motility of the probiotic Escherichia coli strain Nissle 1917 (ECN), we developed nanodrug-bacteria conjugates to penetrate the extracellular matrix (ECM) and shuttle the surface-conjugated protein cages composed of collagenases and anti-programmed death-ligand 1 (PD-L1) antibodies to PDAC tumor parenchyma. We found the oncogenic collagen expression in human pancreatic cancer patients and demonstrated its interaction with integrin α3β1. We proved that reactive oxygen species (ROS) in the microenvironment of PDAC triggered collagenase release to degrade oncogenic collagen and block integrin α3β1-FAK signaling pathway, thus overcoming the immunosuppression and synergizing with anti-PD-L1 immunotherapy. Collectively, our study highlights the significance of oncogenic collagen in PDAC immunotherapy, and consequently, we developed a therapeutic strategy that can deplete oncogenic collagen to synergize with immune checkpoint blockade for enhanced PDAC treatment efficacy. This work was supported by the University of Wisconsin Carbone Cancer Center Research Collaborative and Pancreas Cancer Research Task Force, UWCCC Transdisciplinary Cancer Immunology-Immunotherapy Pilot Project, and the start-up package from the University of Wisconsin-Madison (to Q.H.).

Outcomes and efficacy of magnetic resonance imaging-compatible sacral nerve stimulator for management of fecal incontinence: A multi-institutional study.

Fecal incontinence (FI) is an involuntary passage of fecal matter which can have a significant impact on a patient's quality of life. Many modalities of treatment exist for FI. Sacral nerve stimulation is a well-established treatment for FI. Given the increased need of magnetic resonance imaging (MRI) for diagnostics, the InterStim which was previously used in sacral nerve stimulation was limited by MRI incompatibility. Medtronic MRI-compatible InterStim was approved by the United States Food and Drug Administration in August 2020 and has been widely used. To evaluate the efficacy, outcomes and complications of the MRI-compatible InterStim. Data of patients who underwent MRI-compatible Medtronic InterStim placement at UPMC Williamsport, University of Minnesota, Advocate Lutheran General Hospital, and University of Wisconsin-Madison was pooled and analyzed. Patient demographics, clinical features, surgical techniques, complications, and outcomes were analyzed. Strengthening the Reporting of Observational studies in Epidemiology(STROBE) cross-sectional reporting guidelines were used. Seventy-three patients had the InterStim implanted. The mean age was 63.29 ± 12.2 years. Fifty-seven (78.1%) patients were females and forty-two (57.5%) patients had diabetes. In addition to incontinence, overlapping symptoms included diarrhea (23.3%), fecal urgency (58.9%), and urinary incontinence (28.8%). Fifteen (20.5%) patients underwent Peripheral Nerve Evaluation before proceeding to definite implant placement. Thirty-two (43.8%) patients underwent rechargeable InterStim placement. Three (4.1%) patients needed removal of the implant. Migration of the external lead connection was observed in 7 (9.6%) patients after the stage I procedure. The explanation for one patient was due to infection. Seven (9.6%) patients had other complications like nerve pain, hematoma, infection, lead fracture, and bleeding. The mean follow-up was 6.62 ± 3.5 mo. Sixty-eight (93.2%) patients reported significant improvement of symptoms on follow-up evaluation. This study shows promising results with significant symptom improvement, good efficacy and good patient outcomes with low complication rates while using MRI compatible InterStim for FI. Further long-term follow-up and future studies with a larger patient population is recommended.

Postoperative Intimal Hyperplasia: Review from My Research

AbstractPostoperative intimal hyperplasia is the major cause of the vein graft occlusion. It is very important to establish an animal model for the start of research. After my vascular surgery residency in Japan, I started my research work on postoperative intimal hyperplasia at the University of Wisconsin-Madison. My research showed that endothelial injury and monocyte infiltration is the key for postoperative intimal hyperplasia, which is very similar to Ross' pathogenesis of atherosclerosis as an inflammatory disease. Focusing on postoperative intimal hyperplasia as an inflammatory disease, especially on tumor necrosis factor-α, FR-167653 (tumor necrosis factor-α suppressive agent, inhibitor of p38 mitogen-activated protein kinase; Fujisawa Pharmaceutical Co., Ltd., Japan) is found to suppress postoperative intimal hyperplasia in a rat model by reducing serum monocyte chemoattractant protein-1 levels. However, FR-167653 is not commercially available today. Because endothelial injury is the first step of postoperative intimal hyperplasia, I investigated whether the free radical scavenger, edaravone (Radicut, Mitsubishi Tanabe Pharma Co., Japan), which alleviates the endothelial injury in vitro, can also suppress postoperative intimal hyperplasia. Moreover, the free radical scavenger edaravone (Radicut®, Mitsubishi Tanabe Pharma Co.) is also found to suppress postoperative intimal hyperplasia, by alleviating endothelial injury. In clinical settings, it is very important to detect postoperative intimal hyperplasia before its establishment. Hepatocyte growth factor is not only a hepatic growth factor but also a vascular endothelial growth factor. Recently, serum hepatocyte growth factor level was found to be a candidate biomarker for postoperative intimal hyperplasia in our rat model.

First person – Ashley Peterson

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping researchers promote themselves alongside their papers. Ashley Peterson is first author on ‘ Neutrophil motility is regulated by both cell intrinsic and endothelial cell ARPC1B’, published in JCS. Ashley conducted the research described in this article while a graduate research assistant (PhD student) in Anna Huttenlocher's lab at the University of Wisconsin-Madison, USA. She is currently searching for jobs in pharmaceutical/biotech industry. Her research interests are in using in vitro and microfluidics systems to model human disease for drug discovery and preclinical testing.

Serendipitous Sociologist: Transitions and Turning Points in My Journey

Serendipity, curiosity, and lived experience shaped my career as a social demographer and my interests in social policy. I transitioned from the humanities to sociology and demography as a graduate student the University of Texas at Austin, where I discovered my affinity for quantitative research. My interest in Latin American demography gave way to domestic concerns as new opportunities arose at each of the three institutions where I have had the privilege to work—the University of Wisconsin-Madison, the University of Chicago, and Princeton University. That all three institutions hosted vibrant demography and policy programs facilitated my research about the Hispanic population, family structure, urban poverty, college access, and myriad aspects of socioeconomic inequality and immigrant integration. Superb colleagues and talented graduate student collaborators deserve major credit for my career accomplishments. I attribute numerous opportunities to serve on philanthropic and corporate boards to the strength of weak ties. Expected final online publication date for the Annual Review of Sociology, Volume 50 is July 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The Nagoya Protocol and nitrogen-fixing maize: Close encounters between Indigenous Oaxacans and the men from Mars (Inc.)

In this article, we discuss the Nagoya Protocol and its implications for access and benefit-sharing (ABS) agreements related to genetic resources and biodiversity. We analyze a case study of the appropriation of olotón, a maize variety with an unusual nitrogen-fixing trait grown in many communities throughout Oaxaca and probably beyond that region. Samples of olotón were acquired by scientists affiliated with Mars, Inc., the University of California-Davis, and the University of Wisconsin-Madison. The article unpacks how the olotón ABS agreement with the single Oaxacan community of Totontepec became a topic of controversy despite its approval by the Mexican government under the auspices of the Nagoya Protocol. We pose the question: Is the olotón ABS agreement to be considered “fair and equitable” or could it be an example of the unjust appropriation of genetic resources known as “biopiracy”? To answer that question, we proceed to analyze the “procedural,” “distributive,” “commutative,” and “representational” forms of justice as they apply to the acquisition of olotón. The Nagoya Protocol was created in part to impede biopiracy by providing a framework for acquiring and using biodiversity in a “fair and equitable” way, but the Nagoya Protocol’s provisions are ambiguous and allow for confidentiality clauses that favor the acquisition of genetic materials in ways that we do not consider fair and equitable. We join other researchers and academics who cite the need for an improved approach for ethically accessing, using, and sharing genetic resources and knowledge.

Adaptive Intervention to Prevent Respiratory Illness in Cerebral Palsy: Protocol for a Feasibility Pilot Randomized Controlled Trial.

This study will pilot-test an innovative just-in-time adaptive intervention to reduce severe respiratory illness among children with severe cerebral palsy (CP). Our intervention program, Respiratory Exacerbation-Plans for Action and Care Transitions (RE-PACT), delivers timely customized action planning and rapid clinical response when hospitalization risk is elevated. This study aims to establish RE-PACT's feasibility, acceptability, and fidelity in up to 90 children with severe CP. An additional aim is to preliminarily estimate RE-PACT's effect size. The study will recruit up to 90 caregivers of children with severe CP aged 0 to 17 years who are cared for by a respiratory specialist or are receiving daily respiratory treatments. Participants will be recruited from pediatric complex care programs at the University of Wisconsin-Madison (UW) and the University of California, Los Angeles (UCLA). Study participants will be randomly assigned to receive usual care through the complex care clinical program at UW or UCLA or the study intervention, RE-PACT. The intervention involves action planning, rapid clinical response to prevent and manage respiratory illness, and weekly SMS text messaging surveillance of caregiver confidence for their child to avoid hospitalization. RE-PACT will be run through 3 successively larger 6-month trial waves, allowing ongoing protocol refinement according to prespecified definitions of success for measures of feasibility, acceptability, and fidelity. The feasibility measures include recruitment and intervention time. The acceptability measures include recruitment and completion rates as well as intervention satisfaction. The fidelity measures include observed versus expected rates of intervention and data collection activities. The primary clinical outcome is a severe respiratory illness, defined as a respiratory diagnosis requiring hospitalization. The secondary clinical outcomes includehospital days and emergency department visits, systemic steroid courses, systemic antibiotic courses, and death from severe respiratory illness. The recruitment of the first wave began on April 27, 2022. To date, we have enrolled 30 (33%) out of 90 participants, as projected. The final wave of recruitment will end by October 31, 2023, and the final participant will complete the study by April 30, 2024. We will start analyzing the complete responses by April 30, 2024, and the publication of results is expected at the end of 2024. This pilot intervention, using adaptive just-in-time strategies, represents a novel approach to reducing the incidence of significant respiratory illness for children with severe CP. This protocol may be helpful to other researchers and health care providers caring for patients at high risk for acute severe illness exacerbations. ClinicalTrials.gov NCT05292365; https://clinicaltrials.gov/study/NCT05292365. DERR1-10.2196/49705.

Mindful Eco-Wellness: Steps Toward Personal and Planetary Health.

Rising greenhouse gas levels heat the earth's surface and alter climate patterns, posing unprecedented threats to planetary ecology and human health. At the same time, obesity, diabetes, and cardiovascular disease have reached epidemic proportions across the globe, caused in part by decreases in physical activity and by over-consumption of carbon-intensive foods. Thus, interventions that support active transportation (walking or cycling rather than driving) and healthier food choices (eating plant-based rather than meat-based diets) would yield health and sustainability "co-benefits." Emerging research suggests that mindfulness-based practices might be effective means toward these ends. At the University of Wisconsin-Madison, we have developed a mindfulness-based group program, Mindful Eco-Wellness: Steps Toward Healthier Living. Loosely based on the Mindfulness-Based Stress Reduction course, our curriculum teaches mindfulness practices in tandem with sustainability principles, following weekly themes of Air, Water, Food, Energy, Transportation, Consumption, Nature Experience, and Ethics. For example, the "Air" class offers participants practice in guided breath meditations while they learn about the benefits of clean air. The theme of "Food" is presented through mindful eating, accompanied by educational videos highlighting the consequences of food production and consumption. "Transportation" includes walking/movement meditations and highlights the health benefits of physical activity and detriments of fossil-fueled transportation. Pedagogical lessons on energy, ecological sustainability, and the ethics of planetary health are intertwined with mindful nature experience and metta (loving-kindness) meditation. Curricular materials, including teaching videos, are freely available online. Pilot testing in community settings (n = 30) and in group medical visits (n = 34) has demonstrated feasibility; pilot data suggests potential effectiveness. Rigorous evaluation and testing are needed.

An Epidemiologic Study of Bacterial Culture and Antibiotic Susceptibility Analyses in Captive Macaques and Marmosets at the Wisconsin National Primate Research Center.

Antimicrobial resistance (AMR) represents a growing public health threat that arises at the interface between animal, human, and environmental health. Although the pathways promoting the development of AMR are well characterized in human health settings, data within the veterinary medical world are less abundant, particularly from fields focusing on nontraditional species, such as nonhuman primates (NHPs). The purpose of this study was to describe trends in sample submission for bacterial culture, characterize patterns of microbial growth and any changes in AMR and susceptibility over time, and inform best practices for veterinary antimicrobial stewardship in a captively-housed, indoor NHP colony. Electronic health records from the Wisconsin National Primate Research Center were analyzed across a 10-y period using SAS Studio. There was an increasing pattern of sample submissions for culture and susceptibility analyses, with no corresponding increases in resistance to relevant antibiotics for potential zoonotic pathogens, such as Escherichia coli or Shigella species. Trends are suggestive of appropriate antimicrobial stewardship practices that were responsive to the medical needs of Wisconsin National Primate Research Center animals, as well as the needs of the larger research community at the University of Wisconsin-Madison. These findings can inform veterinary professionals working with NHPs and contribute to the growing body of literature surrounding AMR in nontraditional species.

Retrospective ratings of learning across pre-pandemic, emergency-remote, and post-pandemic instruction in an introductory biology laboratory

In 2019 a global pandemic forced biology teaching laboratories to move remotely. In this article we present data on student perceptions of laboratory instruction modality as experienced pre-, during, and post-pandemic. Our research took place at the University of Wisconsin-Madison in 2022. We designed a survey to evaluate students’ perception of key components of scientific critical thinking set as learning outcomes of the laboratory of an introductory biology course. Participants included students who took the course under the same teaching assistant. We surveyed four consecutive semesters in which teaching and learning environments were drastically altered: A) pre-pandemic in-person instruction Fall 2019, B) pandemic emergency-remote instruction Spring 2020, C) pandemic full-semester online instruction Fall 2020, and D) post-pandemic return to in-person instruction Spring 2021. We found differences in the response to four of the nine survey items. First, greater ratings were observed for D (post-pandemic in-person Spring 2021) relative to C (pandemic full-semester online Fall 2020) for the following three items: (a) developing research questions and hypotheses, (b) performing experiments and (c) level of engagement. Furthermore, the rating for the overall laboratory quality was greater for D (post-pandemic in-person Spring 2021) relative to A (pre-pandemic in-person Fall 2019). There were no differences in students’ perception for the following four items: presenting data, performing statistical analysis, discussion of results, and acquiring critical thinking skills. We concluded that students had a better appreciation for in-person laboratories after experiencing remote laboratory. In the future, student perceptions should be considered, along with their academic experiences, whenever laboratory teaching is done remotely.  

APA/APAGS Award for Distinguished Graduate Student in Professional Psychology: Sergio Domínguez Jr.

This award honors a graduate student who has demonstrated outstanding practice and application of psychology. "Sergio Domínguez Jr. is a PhD candidate in counseling psychology at the University of Wisconsin-Madison and a pre-doctoral intern in health service psychology at the University of Illinois Chicago Counseling Center. As a practitioner-scholar-advocate, their work focuses on facilitators and inhibitors to pleasure, particularly by using a racial-gender justice perspective as a vehicle toward achieving widespread freedom and liberation. Specifically, they are deeply invested in Black and Brown trans people's well-being, ethical and legal professional issues in psychology, and the transformative power of relationships in psychotherapy and in community-engaged psychological practice. Their connection to community and involvement in multilevel advocacy has enabled them to be a trusted collaborator for community-oriented individual, social, and systemic justice efforts. Sergio's dissertation involves a qualitative exploration of the ways trans people's gender euphoria defies systems of power that deprive all people from experiencing racialized gendered pleasure. After graduation, Sergio aspires to continue being a community-rooted psychological practitioner who intervenes individually, socially, and systemically to create pleasure-centric futures. While this award bears their name, this award was not earned by Sergio alone; instead, this award is shared with the many people who have done and will continue to do and support racial-gender justice advocacy." (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A Comprehensive Microscopy and Peripheral Blood Smear Curriculum for Hematology Fellows

Background: Peripheral blood smear (PBS) analysis is an essential skill for the practicing hematologist and allows for the timely diagnosis of a variety of hematologic disorders. In most cases, PBS analysis can be performed faster than advanced laboratory tests, allowing for the prompt treatment of life-threatening diseases, such as acute promyelocytic leukemia and thrombotic microangiopathies. For these reasons, the Accreditation Council for Graduate Medical Education requires that hematology fellows achieve competency in PBS interpretation in order to graduate. However, most hematology training programs lack a structured PBS curriculum and formalized method of skills assessment. Consensus recommendations were recently developed by a multi-institutional focus group as to the ideal structure and components of PBS curricula within hematology training programs (Chase et al., Blood Advances, 2023). Herein, we report our initial experience implementing a longitudinal PBS curriculum for hematology fellows based on these consensus guidelines and demonstrate the effectiveness of this curriculum using a novel assessment tool. Methods: We developed a longitudinal PBS curriculum for hematology fellows at the University of Wisconsin-Madison. The curriculum included an introductory course for first-year fellows on the use of a microscope, slide handling, and PBS review using a hands-on and collaborative approach (Figure 1A). The introductory course included five two-hour sessions spanning the first two months of fellowship. The first three sessions were led by a faculty member and senior fellow and included training on how to use the microscope as well as identification of normal blood cell morphology and blood cell morphologies and hematologic diagnoses deemed high-priority by consensus recommendations using a slide library. For the final two sessions, the fellows were provided with a set of unknowns and asked to work as a group to identify the pathologic findings and underlying diagnosis. The introductory course was supplemented with ongoing experience and education on PBS interpretation through hematology consult, ward, and clinic rotations throughout fellowship under the direction of hematology faculty skilled in PBS analysis. A novel assessment tool was distributed to participants before and after the introductory course in order to assess the effectiveness of the curriculum. The assessment tool was a ten-question image-based questionnaire in which fellows were prompted to identify high-priority morphologies or hematologic diagnoses after being provided with a clinical vignette and associated PBS for review. Results: To date, four hematology fellows have participated in the PBS curriculum. Prior to the introductory course, no participants expressed feeling very or extremely confident in analyzing and interpreting PBS. After the introductory course, 25% of participants expressed feeling very confident in analyzing and interpreting PBS, whereas the remaining 75% felt somewhat confident. 75% of participants strongly agreed that the course improved their ability to use a microscope, and 100% of participants strongly agreed that the course improved their ability to analyze and interpret PBS. Participation in the course led to improved ability of participants to identify high-priority blood cell morphologies and diagnoses as determined by the assessment tool (Figure 1B, 8.25/10 pre-course compared to 9/10 post-course). Conclusions: Our longitudinal PBS curriculum was perceived positively by hematology fellows and led to improved confidence and independence in using a microscope and PBS interpretation. Additionally, participation in the introductory course improved identification of high-priority PBS morphologic abnormalities and hematologic diagnoses. Our curriculum and assessment tool serve as proof of concept that can now be improved upon and potentially adopted on a larger scale to promote competency in PBS interpretation among hematology trainees.

Prevalence and Spectrum of Autoimmune Diseases Among Patients with Telomere Biology Disorder

Introduction Telomeres are the protective ends of linear chromosomes that prevent DNA degradation with each replication. Premature attrition or dysfunction of telomeres due to an inherited defect in a telomere maintenance gene results in a spectrum of phenotypes collectively known as telomere biology disorders (TBD). To date, 18 genes have been implicated in TBD. Disease phenotypes are variable including bone marrow failure, immunodeficiency, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, nail dystrophy, and premature graying of hair. Short telomeres have been observed in patients with autoimmune disorders (AID) and have been shown to increase the risk of AID. Furthermore, TBD have been associated with T cell dysfunction and exhaustion, mechanisms which may predispose to autoimmune phenotypes. Given the potential relationship between short telomeres and immune dysregulation, we hypothesize that the prevalence of AID may be increased in patients with a diagnosis of TBD. The aim of this study is to describe the prevalence and spectrum of AID in a cohort of patients with TBD. Methods Health record data were reviewed for 34 adult patients with confirmed TBD treated at the University of Wisconsin-Madison. A TBD diagnosis was established for patients who had a compatible clinical history plus either critically short lymphocyte telomere lengths (<1 st percentile for age as measured by FlowFISH) or one or more pathogenic/likely pathogenic variant(s) in a gene known to cause TBD. Demographics, rheumatologic history, serologies, and family history were collected. AID were included if diagnoses were made by a rheumatologist or other appropriate specialist with clinical features, physical exam findings, and/or serologies meeting diagnostic criteria per subspecialty guidelines. Results Eight of 34 patients (23.5%) with TBD had a concomitant diagnosis of a primary autoimmune condition. Specific AID included inflammatory bowel disease, Graves' disease, Hashimoto's thyroiditis, rheumatoid arthritis, scleroderma, and Sjogren's syndrome (Table 1). Two patients had autoimmune cytopenias, including steroid-responsive immune thrombocytopenic purpura and pure red cell aplasia (PRCA). Patient 8 was diagnosed with PRCA mixed with spur cell anemia prior to transplant, and bone marrow biopsy showed pure erythroid hypoplasia without evidence of malignancy. He responded to treatment with steroids and immunosuppression. Of the eight patients with a primary autoimmune condition, two had pathogenic/like pathogenic variants, two had rare variants of uncertain significance, and four had no detectable variants in a telomere associated gene. Twenty-three patients (67.6%) had a first- or second-degree relative with an autoimmune disorder. Conclusions An AID, as defined by strict diagnostic criteria per subspecialty guidelines, was present in 23.5% of patients with TBD defined by conservative diagnostic criteria. The spectrum of AID was diverse, including two patients with autoimmune hematologic disorders, and the majority had a family history of various AID. Thus, TBD may be associated with an increased prevalence of AID, though confirmation in a larger cohort of genetically defined TBD patients is needed. In the absence of a causative genetic lesion, diagnosis of a TBD based on critically short telomeres in those with multisystem autoimmune disorders with features that overlap TBD phenotypes can be challenging. Screening for AID as part of routine TBD comprehensive assessments as well as offering germline genetic testing for individuals with primary autoimmune disease with a compatible TBD phenotypes and studies to determine the mechanistic relationship between telomere length and autoimmunity are warranted.

Abstract 14555: Early Predictors That Identify Patients With Significant Left Main and Three-Vessel Coronary Artery Disease in Non-ST Elevation Acute Coronary Syndrome: Validating the MADISON Score

Introduction: In patients with non-ST elevation acute coronary syndrome (NSTE-ACS), identifying those with a high probability of having high-risk disease such as left main (LM) or three-vessel disease (3VD) could influence decisions to preload with P2Y12 inhibitors and timing of coronary angiography. The MADISON score was developed to predict LM/3VD on coronary angiography in patients with NSTE-ACS. In this study, we validated the MADISON score using data from an external cohort. Methods: The MADISON score was first developed using a retrospective cohort of 1700 patients presenting with NSTE-ACS at the University of Wisconsin-Madison (UW) (2011-2018). Those with prior CABG, cardiac arrest/shock, and bleeding on initial presentation were excluded from the analysis. Multivariable estimates were employed and model performance was assessed using receiver operating characteristic curve analysis. The score was then validated using a retrospective Houston Methodist Hospital (HMH) cohort of 622 patients (2019-2022). Results: The MADISON score variables and their adjusted odds ratios (95% CI) are presented in Figure 1A. Risk categories and corresponding LM/3VD probabilities are presented in Figure 1B. In the UW cohort, the area under the curve (AUC) was 0.68 (0.65-0.71) (Figure 2A). Interestingly, the AUC was also 0.68 (0.64-0.72) in the HMH validation cohort (Figure 2B). Conclusions: The MADISON score performed well and similarly between 2 large, independent cohorts in predicting patients most likely to have LM/3VD. The MADISON score is a simple and practical tool to guide decisions. Prospective validation of the score is planned to evaluate its impact on clinical outcomes.

Unified topological inference for brain networks in temporal lobe epilepsy using the Wasserstein distance

Persistent homology offers a powerful tool for extracting hidden topological signals from brain networks. It captures the evolution of topological structures across multiple scales, known as filtrations, thereby revealing topological features that persist over these scales. These features are summarized in persistence diagrams, and their dissimilarity is quantified using the Wasserstein distance. However, the Wasserstein distance does not follow a known distribution, posing challenges for the application of existing parametric statistical models. To tackle this issue, we introduce a unified topological inference framework centered on the Wasserstein distance. Our approach has no explicit model and distributional assumptions. The inference is performed in a completely data driven fashion. We apply this method to resting-state functional magnetic resonance images (rs-fMRI) of temporal lobe epilepsy patients collected from two different sites: the University of Wisconsin-Madison and the Medical College of Wisconsin. Importantly, our topological method is robust to variations due to sex and image acquisition, obviating the need to account for these variables as nuisance covariates. We successfully localize the brain regions that contribute the most to topological differences. A MATLAB package used for all analyses in this study is available at https://github.com/laplcebeltrami/PH-STAT.

Comparison of chest radiograph and lung ultrasound in children with acute respiratory failure.

Chest x-ray (CXR) is the standard imaging used to evaluate children in acute respiratory distress and failure. Our objective was to compare the lung-imaging techniques of CXR and lung ultrasound (LUS) in the evaluation of children with acute respiratory failure (ARF) to quantify agreement and to determine which technique identified a higher frequency of pulmonary abnormalities. This was a secondary analysis of a prospective observational study evaluating the sensitivity and specificity of LUS in children with ARF from 12/2018 to 02/2020 completed at the University of Wisconsin-Madison (USA). Children > 37.0weeks corrected gestational age and ≤ 18years of age admitted to the PICU with ARF were evaluated with LUS. We compared CXR and LUS completed within 6h of each other. Kappa statistics (k) adjusted for maximum attainable agreement (k/kmax) were used to quantify agreement between imaging techniques and descriptive statistics were used to describe the frequency of abnormalities. Eighty-eight children had LUS completed, 32 with concomitant imaging completed within 6h are included. There was fair agreement between LUS and CXR derived diagnoses with 58% agreement (k/kmax = 0.36). Evaluation of imaging patterns included: normal, 57% agreement (k = 0.032); interstitial pattern, 47% agreement (k = 0.003); and consolidation, 65% agreement (k = 0.29). CXR identified more imaging abnormalities than LUS. There is fair agreement between CXR and LUS-derived diagnoses in children with ARF. Given this, clinicians should consider the benefits and limitations of specific imaging modalities when evaluating children with ARF. Additional studies are necessary to further define the role of LUS in pediatric ARF given the small sample size of our study.

MRI radiomics for hamstring strain injury identification and return to sport classification: a pilot study.

To determine if MRI-based radiomics from hamstring muscles are related to injury and if the features could be used to perform a time to return to sport (RTS) classification. We hypothesize that radiomics from hamstring muscles, especially T2-weighted and diffusion tensor imaging-based features, are related to injury and can be used for RTS classification. MRI data from 32 athletes at the University of Wisconsin-Madison that sustained a hamstring strain injury were collected. Diffusion tensor imaging and T1- and T2-weighted images were processed, and diffusion maps were calculated. Radiomics features were extracted from the four hamstring muscles in each limb and for each MRI modality, individually. Feature selection was performed and multiple support vector classifiers were cross-validated to differentiate between involved and uninvolved limbs and perform binary (≤ or > 25days) and multiclass (< 14 vs. 14-42 vs. > 42days) classification of RTS. The combination of radiomics features from all diffusion tensor imaging and T2-weighted images provided the most accurate differentiation between involved and uninvolved limbs (AUC ≈ 0.84 ± 0.16). For the binary RTS classification, the combination of all extracted radiomics offered the most accurate classification (AUC ≈ 0.95 ± 0.15). While for the multiclass RTS classification, the combination of features from all the diffusion tensor imaging maps provided the most accurate classification (weighted one vs. rest AUC ≈ 0.81 ± 0.16). This pilot study demonstrated that radiomics features from hamstring muscles are related to injury and have the potential to predict RTS.

Using Linear and ARIMA Model to Exanimate and Forecast the Grade Inflation Phenomenon in the University of Wisconsin-Madison

Nowadays, in US universities, A stands for average, B stands for below average, and C stands for choose another major, but B used to be appreciated, and A used to be attainable only to those that are either hardworking or talented, or both. To investigate the ongoing increase of average GPA since decades ago of US universities, this paper utilizes linear and ARIMA model to forecast future average GPA of the University of Wisconsin-Madison. This paper then successfully examines the existence of grade inflation in the University of Wisconsin-Madison and concludes that at least in the near future of 5 years, the average GPA will continue to grow. After considering results of former researchers, this paper provides three possible solutions to mitigate grade inflation: an increase in exam difficulty, a revised SETs system, and a fixed distribution of grades. Hopefully this paper will contribute to stop grades from losing its value and university transforming from the place to learn to the place to get a degree.