United States

Glioblastoma (GBM) is an aggressive malignancy of glial cells that has a median survival rate of 15-20 months even in the face of current models of treatment. Despite extensive research efforts long-term survival remains low. Thus, there is a high unmet need to develop novel therapies, however, the current treatment approach through resection, radiation, and chemotherapy have remained unchanged in the last few years. A major hurdle in developing novel therapies is the extreme immunosuppression of the tumor microenvironment seen in GBM patients. A key environmental factor in driving this characteristic malignancy is hypoxia. GBMs often have necrotic regions with limited perfusion and poor oxygen delivery. Additionally, delivery of corticosteroids for glioblastoma patients is common, yet their impact on cell signaling has been unexplored. The aim of this study is to elucidate the role of chronic hypoxia and dexamethasone and their effect on GBM gene expression and phenotype. GBM cell lines are typically immortalized and exposed to ambient air (normoxia, 21% oxygen) compared to physiologic oxygen levels (physoxia, 5% oxygen) within the brain. We hypothesize that patient-derived GBM cell lines under chronic normoxia tensions demonstrate differences in gene expression signatures that alters cell growth and treatment responsiveness. Previous work has shown ERK signaling, a regulator of tumor survival and therapy resistance, is modulated by oxygen levels. ERK is activated by receptor tyrosine kinases and the PI3K/AKT pathway. Here, we further investigated GBM gene expression and phenotype using 2 patient-derived cell lines (GB10 and GB43) that were maintained under physoxia conditions and continued dexamethasone treatment for at least two passages. We found that both cell proliferation and migration decreased, with significantly reduced doubling times in GB10 and GB43 cell lines. Additionally, we examined markers of EMT using RT-qPCR that showed increased Slug and decreased IGFBP1 transcripts in GB43 cells maintained in physoxia. Western blotting of ERK, PDGFRβ, and AKT showed increased phosphorylation. Further, hypoxic conditions showed increased chemoresistance to temozolomide in GB10 cell lines. Finally, we explored the influence of hypoxia on inflammatory cytokine expression through RT-qPCR. Thus, we show that chronic exposure to physoxia and dexamethasone alters cell proliferation, migration, therapeutic resistance, immunological environment, and cell signaling.

AMA Research Challenge 2025 

Elucidating the effects of a low oxygen environment and dexamethasone on cell signaling in glioblastomas

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poster

Abstract Title: Sildenafil and Rapamycin potentiate chemo-immunotherapy-induced breast cancer cell killing while attenuating its cardiotoxicity

Background: Although Doxorubicin (DOX) and Trastuzumab (HER2 inhibitor) demonstrate synergistic effects on repressing breast cancer and enhancing patient survival, cardiotoxicity remains an undesirable consequence. Thus, cardioprotective drugs become necessary. Sildenafil (Sild) (an inhibitor of cGMP-specific phosphodiesterase 5) combined with DOX can increase the chemotherapeutic efficacy against prostate cancer, while attenuating DOX-induced cardiotoxicity. Rapamycin (Rapa) (an inhibitor of mammalian target of rapamycin, mTOR) also protects against myocardial ischemia/reperfusion injury. As mTOR signaling is overactivated in multiple cancers, including breast cancer, we examined the effects of combination therapy with Sild and Rapa on cardiotoxicity and cytotoxicity with DOX±HER2 inhibitor in human cardiomyocytes and HER2-positive breast cancer cells.

Methods: To determine the role of tumor-derived endogenous factors in causing cardiac injury after DOX+HER2 inhibitor treatment, we designed experiments using spheroid cultures of ErbB2/HER2 positive breast cancer cells (SKBR3) and human cardiomyocytes (AC-16). Spheroid cultures of SKBR3 were treated for 24 hours based on the following groups: (1) control (no treatment), (2) DOX (1 µM), (3) AG-825 (HER2 inhibitor, 5 µM), (4) DOX + AG-825, (5) DOX + AG-825 + Sild (10 µM) + Rapa (100 nM), (6) DOX + AG-825 + Sild, (7) DOX + AG-825 + Rapa, and (8) Sild + Rapa. After replacing treatment media with fresh media, SKBR3 cells were further incubated for 48 hours and medium was collected from each group. Then, AC-16 cells were treated with the medium from drug-treated SKBR3 spheroids for 48 hours. SKBR3 and AC-16 cell death were evaluated with Trypan blue staining and imaging. SKBR3 cell viability was assessed using MTS assay. Western Blots were conducted to evaluate protein expression profiles in AC-16 cells. 

Results: DOX+AG-825 significantly increased SKBR3 cell death compared to DOX or AG-825 alone. Sild and Rapa combined significantly augmented the cytotoxic effects of DOX+AG825 on SKBR3 cells compared to individual drug treatments by intensifying DOX+AG-825-induced cell death. The media from DOX+AG825-treated SKBR3 spheroids induced AC-16 death, which was mitigated by DOX+AG825+Sild+Rapa-treated SKBR3 spheroid medium. Western Blots revealed DOX±AG-825 increased cleaved PARP levels, which was suppressed with Sild+Rapa co-treatment, indicating protection against DOX+AG-825-induced cardiomyocyte apoptosis. DOX+AG-825+Sild+Rapa reduced phospho-mTOR and phospho-S6, which represents inhibition of mTOR, specifically mTORC1 activity. Phospho-AKT was increased following DOX+AG-825+Sild+Rapa co-treatment, indicating mTORC2 complex activation and protection against DOX+AG-825 toxicities. 

Conclusion: Through modulating mTOR-signaling, combination treatment with DOX+AG-825+Sild+Rapa enhanced chemoimmunotherapy-induced breast cancer cell killing while protecting cardiac cells compared to DOX±AG-825 treatment.

Sildenafil and Rapamycin potentiate chemo-immunotherapy-induced breast
cancer cell killing while attenuating its cardiotoxicity

Background 
Type 1 diabetes (T1D) is an autoimmune condition that affects 1 in 400 U.S. kids and teens, causing their bodies to no longer produce insulin and requiring lifelong insulin replacement therapy with injections or pumps to manage their blood sugar. Omnipod5 launched in 2022 as the first tubeless automated insulin delivery system. This pump integrates with the Dexcom G7 continuous glucose monitor and can be managed via a smartphone to adjust insulin delivery and manage glucose levels automatically. While Omnipod 5 has significantly improved glucose control, there are only modest A1c improvements for many patients. Our goal was to understand the drivers of glucose control based on measurable clinical, behavioral, or technological data. We investigated the relationship between insulin settings, patient behavior, and pump performance to identify the factors that influence time in range (TIR) (70-180 mg/dL). 
Methods 
All patients with T1D using the Omnipod 5 system at the Baylor College of Medicine pediatric endocrinology clinic in San Antonio were considered for this IRB-approved quality-improvement study. Approximately 400 patients were evaluated, and 59 were selected for inclusion in the 
study (22 males, 37 females, ages 4 to 19.4 years, mean 11.2 years). No specific exclusion criteria were applied. Data were obtained from the Glooko data management system. A multiple linear regression model was run with carb entries per day (1 to 6.8, mean 3) and percent time in automated mode (10% to 100%, mean 83%) against percent time in range (16% to 92%, mean 52%). 
Results 
For each additional carb entry per day, the TIR increases by 4.06% (p = 0.00094). For each additional 1% of time spent in automated mode, the TIR increases by 0.37% (p = 6.29e-06). Similarly, a 10% increase in time spent in automated mode is roughly equivalent to the impact of an additional carb entry (3.7% vs 4.06%). Both predictors are statistically significant and are positively associated with the TIR. The R-squared value was 0.5244. 
Conclusion 
Patients using Omnipod 5 may increase TIR and ultimately lower their blood glucose readings by increasing the amount of time in automated mode and increasing the number of carb entries per day, which justifies future interventional studies.

Improving Outcomes in Pediatric Type 1 Diabetes with Omnipod 5

Background: Worse surgical outcomes are related to increasing patient age, particularly in the emergency setting. Appendicitis is one of the most common conditions requiring emergency general surgery (EGS) in the United States. We aimed to characterize and investigate the impact of comorbidities on outcomes in younger and older patients with acute appendicitis to inform post-operative care and follow-up. 

Methods: A retrospective chart review of the EGS registry was conducted for patients with acute appendicitis between 03/01/2023 and 08/31/2024 at three hospitals (one academic, two community) within our institution. Patients were stratified based on age: Younger (<65 years) and Older (≥65 years). The primary outcome was 90-day complication (e.g., SSI, C. difficile). Secondary outcomes included operative approach, readmission, mortality, and disposition. Multivariable logistic regression was performed to determine predictors of 90-day complication after adjusting for age, perforation, Charlson Comorbidity Index (CCI), and hospital. 

Results: 529 acute appendicitis patients were included, 81.3% (n=430) were <65 years, and 18.7% (n=99) were ≥65 years. Older adults experienced higher 90-day complication (19.2% vs 5.8%, p<0.001), readmission (28.3% vs 9.5%, p<0.001), mortality rates (5.1% vs 0.5%, p=0.002), and were significantly more likely to present with perforation (53.5% vs 18.4%, p<0.001). Older patients more frequently experienced systemic complications (e.g., C. difficile, sepsis), while younger patients more often had surgical-site complications. Older patients tended to be readmitted for cardiovascular or infectious reasons, whereas younger patients were readmitted for intraabdominal abscesses. On multivariable logistic regression, perforation independently predicted 90-day complication (aOR 4.85, 95% CI 2.41–9.74) and 90-day readmission (aOR 2.42, 95% CI 1.36–4.30). CCI was associated with increased odds of 90-day readmission (aOR 1.37, 95% CI 1.13–1.66) and 90-day ED visits (aOR 1.21, 95% CI 1.02–1.44). Age group was not associated with 90-day complication, or 90-day readmission to the hospital or ED. Outcomes were consistent across hospital sites.

Conclusion: Although older adults with acute appendicitis experience higher unadjusted rates of 90-day complication and 90-day readmission, age was not an independent predictor of these outcomes; rather, perforation and CCI were the primary predictors of adverse outcomes. This highlights the need for risk stratification and targeted postoperative management strategies, particularly among older EGS patients presenting with perforated appendicitis or significant medical comorbidities.

The Predominant Role of Perforation and Comorbidity Over Chronologic Age in Acute Appendicitis

Background: Current NCCN guidelines recommend right hemicolectomy (RHC) for appendiceal neuroendocrine tumors (aNETs) > 2.0 cm and observation for < 1.0 cm, but the management of tumors 1.0 – 2.0 cm remains controversial. Our goal was to compare long-term survival and recurrence for patients undergoing RHC versus appendectomy (APY) for 1.0 – 2.0 cm aNETs.

Methods: Patients with pathologically confirmed 1.0 – 2.0 cm aNETs treated at three Mayo Clinic sites from 1972-2024 were included. Primary outcomes were tumor recurrence and all-cause mortality post-resection. Associations with lymph node (LN) metastasis were calculated for patients with LN involvement.

Results: Sixty-five patients with 1.0 – 2.0 cm aNETs were identified, of whom 30 (46.2%) underwent APY alone, 34 (52.3%) underwent RHC, and one (1.5%) underwent ileocecectomy. The cohort was predominantly female (71%) and white (94%), with a median age at diagnosis of 39 years. Among patients with lymph nodes examined, the rate of nodal positivity for 1.0 – 2.0 cm tumors was 15.2%. Tumor size >1.5 cm vs ≤1.5 cm, T3/T4 stage, nor lymphovascular invasion were associated with node positivity. There was no significant difference in all-cause mortality between patients undergoing APY versus RHC. Node positivity was not associated with worse long-term survival. No recurrences were identified during a median follow up of 6.25 years (IQR 2.44 – 12.63).

Conclusion: In patients with 1.0 – 2.0 cm aNETs, RHC after APY did not confer a survival advantage. No recurrence was seen in patients undergoing APY only, and node positivity was not associated with worse survival. APY alone may be sufficient surgical treatment in this patient population.

Right Hemicolectomy vs. Appendectomy for 1.0 – 2.0 cm Appendiceal Neuroendocrine Tumors: A Mult-Center Cohort Experience

ABSTRACT
Background: Femoral stem design is critical in cementless primary total hip arthroplasty (THA). Porous-coated and grit-blasted femoral stems are commonly utilized, but their relative performance in terms of revision rates and complications remains unclear. This systematic review aims to evaluate revision rates and reasons for failure between porous-coated and grit-blasted femoral stems to inform surgical decision-making.

Methods: A systematic search of peer-reviewed studies published through October 17, 2024, was conducted using PubMed, Embase, and Cochrane databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines focusing on porous-coated and grit-blasted femoral stems and primary cementless THA. Outcomes of interest included revision rates and reasons for revisions, such as periprosthetic fractures, stem loosening, dislocation, and infection.

Results: Twelve studies encompassing 1987 patients were included in this systematic review. The aggregated data indicates that porous-coated femoral stems exhibited revision rates as low as 1.5% (10/650 hips) compared to grit-blasted femoral stems with revision rates of approximately 9.2% (123/1,337 hips). In addition, studies focusing on porous-coated implants consistently reported significant improvements in functional outcomes, with Harris Hip Scores (HHS) improvements ranging from 16 to 47.6 points and postoperative HHS values reaching up to 96.1.

Conclusion: The findings of this systematic review support the clinical advantage of porous-coated femoral stems over grit-blasted stems in primary cementless THA. The lower revision and significant functional improvements seen through gains in the HHS suggest that anatomic design features of porous-coated stems enhance stress transfer, reduce stress shielding, and promote superior osseointegration.


Revision rates of porous-coated versus grit-blasted femoral stems in cementless Total Hip Arthroplasty: A Systematic Review

Background: Mechanical complications after total shoulder arthroplasty (TSA) are a major cause of morbidity. Computed-tomography (CT) Hounsfield units (HUs) estimate bone-mineral density (BMD), but their predictive value for TSA mechanical complications is unknown. This study assessed whether glenoid HUs (gHUs) can be used to predict mechanical complication risk.
Methods: In this retrospective cohort study at a single tertiary academic center (January 2011–April 2024), preoperative CT scans from 250 TSAs in 233 patients were independently reviewed by a senior orthopaedic resident, a fellowship-trained shoulder and elbow surgeon, and a musculoskeletal radiologist to measure gHUs. Mechanical complications included periprosthetic or intraoperative fractures and aseptic implant loosening or dissociation were identified and stratified by gHU. Infection and dislocation were excluded. Inter-rater reliability was assessed with the intraclass correlation coefficient (ICC). Receiver operating characteristic (ROC) analysis identified optimal gHU thresholds. Risk-group comparisons used chi-square tests and multivariable logistic regression adjusting for age, sex, body mass index (BMI), and arthroplasty type.
Results: Among 250 TSAs in 233 patients, ICC for gHU measurement was 0.90 (95% CI 0.87–0.92). ROC analysis yielded a cut-off of 177 HU (AUC 0.59; sensitivity 39%; specificity 81%). Mechanical complications occurred in 29% of cases with gHU < 177 versus 13% with gHU ≥ 177 (p = 0.008; adjusted p = 0.02). Patients with gHU < 110 had the highest risk (57% vs 14%; p < 0.001; adjusted p = 0.002).
Conclusions: Preoperative gHU measurements can help to predict increased risk of mechanical complications after TSA. A gHU threshold of 177 HU identifies patients at elevated risk, while gHU < 110 marks the highest-risk group. CT-derived HU may be helpful in guiding preoperative risk stratification, surgical decision making, and surgical planning.


Low Glenoid Hounsfield Units Predicts High Risk of Mechanical Complications After Total Shoulder Arthroplasty

Title:
Evaluating Large Language Models for Pneumothorax Detection on Chest X-rays

Background:
The rapid advancement of large language models (LLMs), such as GPT-4o and Gemini 2.5 Pro, has prompted their exploration for medical image analysis tasks. Chest X-ray interpretation, particularly pneumothorax detection, remains a crucial diagnostic challenge. Accurate and timely detection significantly impacts patient outcomes. This study evaluates the diagnostic performance of two prominent LLMs, GPT-4o and Gemini, in detecting pneumothorax on frontal chest X-rays.

Methods:
Two thousand chest X-rays, evenly split into cases with and without pneumothorax, were evaluated using standardized prompts tailored for each LLM. The GPT-4o and Gemini 2.5 Pro models classified images based on predefined radiological criteria, including visible pleural lines, deep sulcus signs, lung translucency asymmetry, and signs of lung collapse. Confusion matrices were generated, and performance metrics such as accuracy, precision, recall, and F1-score were calculated to compare model efficacy.

Results:
The GPT model achieved an overall accuracy of 64%, with precision, recall, and F1-score for pneumothorax detection at 66%, 57%, and 61%, respectively. Conversely, the Gemini model exhibited a lower overall accuracy of 62% but demonstrated higher sensitivity (recall) at 88% for pneumothorax detection. However, its precision was notably lower at 55%, yielding an F1-score of 68%. GPT's balanced performance contrasts with Gemini's tendency toward high sensitivity at the expense of precision.

Conclusion:
Both GPT-4o and Gemini LLMs demonstrate potential in pneumothorax detection on chest X-rays but exhibit distinct strengths and weaknesses. GPT-4o provides balanced performance across metrics, suitable for general screening purposes. Gemini’s high sensitivity makes it advantageous for initial screening scenarios, despite a higher false-positive rate. These findings suggest tailored use-cases for each model depending on clinical priorities, highlighting the need for continued refinement of LLMs for medical imaging applications.

Evaluating Large Language Models for Pneumothorax Detection on Chest X-Rays

Background
Urinary tract infections (UTIs) are among the most common bacterial infections, causing pain and emotional distress for millions of patients each year. While Escherichia coli is the leading cause, Actinotignum schaalii is an emerging but underdiagnosed pathogen, especially in older adults and those with urologic conditions. This Gram-positive, facultatively anaerobic bacillus requires CO₂ and prolonged incubation to grow. These conditions are not met by routine urine cultures, leading to frequent underdetection, sterile pyuria, and progression to urosepsis. Molecular studies show a higher prevalence: one study detected A. schaalii in 16% of urine samples overall and up to 22% in patients over age 60. Despite its clinical relevance, taxonomy within the Actinotignum genus remains unclear. Notably, the distinction between A. schaalii and A. timonense has not been fully resolved. This study uses genomic and phenotypic tools to clarify species boundaries and enhance diagnostic accuracy.

Methods
Whole-genome sequence analysis was performed on 50 clinical isolates identified as A. schaalii, A. timonense, A. urinale, or A. sanguinis. Phylogenomic analysis was based on 560 conserved core genes, and average nucleotide identity (ANI) was calculated. Biochemical phenotyping was done using the Analytical Profile Index 50 Carbohydrate Fermentation (API 50 CH) assay. Comparative genomics was used to develop a multiplex PCR assay targeting specific rearrangements. The assay was benchmarked against matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF MS).

Results
A. schaalii and A. timonense exhibited overlapping phylogenetic clades with ANI values exceeding the species-level threshold (>95%). PERMANOVA testing of API 50 CH profiles revealed significant metabolic differentiation (p < 0.001, R² = 0.32). A stable chromosomal rearrangement was identified, enabling the design of a multiplex PCR assay, which outperformed MALDI-ToF MS in classifying several misidentified isolates.

Conclusion
While the phylogenetics of A. timonense and A. schaalii are similar, differences exist in their metabolic profiles and chromosomal structures. Their metabolic profiles differ significantly, but species designation only explains a modest portion of the variation. Based on these findings, we demonstrate that A. timonense is closely related to A. schaalii, with potential for similar pathogenicity. Reclassifying A. timonense as a subspecies of A. schaalii and incorporating our new PCR assay enhances accurate identification, diagnosis, and targeted treatment of urinary tract infections, particularly in vulnerable populations.


Improving Identification of Actinotignum schaalii: An Overlooked Cause of Urinary Tract Infections

Abstract Title
Equipping Medical Students for Street Medicine: Perspectives, Preparedness, and Educational Needs

Background
Homelessness remains a significant public health crisis, affecting over 650,000 individuals across the United States on any given night. People experiencing homelessness (PEH) face disproportionate burdens of chronic disease, mental illness, and early mortality, yet encounter persistent barriers to care. Street medicine (SM) programs aim to close these gaps by delivering healthcare directly to unsheltered individuals. With growing affiliation to academic institutions, medical students are increasingly engaged in SM initiatives. While student attitudes toward homelessness have been studied, few investigations have examined the perspectives, motivations, and perceived preparedness of medical student SM volunteers. This study aimed to assess these domains following a structured SM orientation at a large urban Midwestern institution. 

Methods
Following a street medicine (SM) orientation, medical students completed a post-session survey assessing their level of agreement with statements related to homelessness, healthcare access, and their role in caring for people experiencing homelessness (PEH). Items included, “Homeless people are victims of circumstance” and “Social justice is an important part of health care,” rated on a Likert scale from Strongly Disagree to Strongly Agree. Additional items asked students to identify their top motivations for participating in SM and to indicate which trainings would help them feel most confident in outreach. Quantitative data were analyzed descriptively. Thematic categories were also developed to align with key survey domains to identify common patterns in student perspectives.

Results
Survey responses (n=32) revealed strong alignment with social justice values. All students agreed that PEH deserve access to healthcare; 97% rejected the notion that homelessness is a personal choice, and 78% viewed homelessness as rooted in systemic factors. Students were primarily motivated by the opportunity to build individual connections (75%) and address healthcare system shortcomings (72%). While 97% reported comfort working in diverse, team-based care settings, only 59% felt prepared to care for patients with serious mental illness, highlighting a training gap. Students prioritized wound care (81%), patient interview skills training (81%), trauma-informed care (59%), and hearing from individuals with lived experiences (63%) as key areas for further education. 

Conclusion
Medical students engaged in SM demonstrate strong ethical commitment and a desire to serve marginalized populations. However, gaps in mental health preparedness and practical clinical skills persist. Structured orientations incorporating skill-building, trauma-informed care, and lived experience perspectives can enhance student readiness. Integrating SM into medical education may strengthen the physician workforce’s capacity to deliver equitable care to underserved populations. 


Equipping Medical Students for Street Medicine: Perspectives, Preparedness, and Educational Needs

Background
Antisepsis prior to intravitreal injection is most commonly achieved via povidone-iodine (PI), the gold-standard; however, patients often report eye irritation. Chlorhexidine (CHX) is emerging as a potential alternative due to comparable endophthalmitis rates and less patient-reported discomfort. Limited data exist on the in vitro efficacy and corneal tissue response to PI and CHX. This study aims to compare the antimicrobial efficacy of CHX and PI against patient- derived endophthalmitis isolates as well as evaluate the corneal tissue viability after exposure to PI and CHX in an in vitro model.
Methods
The inhibition zone (mm) of PI (5%, 10%) and CHX (0.05%, 0.1%) was assessed using a well diffusion assay against eight ocular isolates (S. epidermidis, MRSA, E. coli, P. aeruginosa). The same concentrations of PI and CHX were applied to a healthy or infected (S. epidermidis) tissue model of corneal epithelial cells and cell viability was assessed with MTT assay.
Results
PI had greater inhibition for S. epidermidis and MRSA, but less for P. aeruginosa (48, 38, 19 mm), as compared to CHX (35, 29, 23 mm). Inhibition of E. coli was similar for both PI and CHX. In healthy corneal tissue model, 5% and 10% PI had less tissue viability (17%, 11%) as compared to 0.05% and 0.1% CHX (71%, 41%). Infected tissue at all concentrations of PI had less cell viability (17%, 9%) than CHX (100%, 93%).
Conclusion
While inhibition was organism dependent for both antiseptics, CHX preserved higher tissue viability than PI in both infected and noninfected models. CHX shows promise as an alternative for ocular antisepsis against endophthalmitis isolates.

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Sildenafil and Rapamycin potentiate chemo-immunotherapy-induced breast cancer cell killing while attenuating its cardiotoxicity

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