United States

Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency that is characterized by elevated serum IgE levels, recurrent sinopulmonary infections, and chronic eczema, among other symptoms. Though reports on patients with HIES exist, they primarily focus on the clinical features, diagnosis, and management of HIES without detailing surgical interventions.

Here, we present the surgical management of an extensive cellulitic infection that developed into skin necrosis in a HIES patient with a history of polysubstance abuse. The patient had a diagnosis of Job’s Syndrome, the autosomal dominant form of HIES. In this case, severe infection resulting from immunodeficiency led to cellulitis and full thickness tissue loss in the left upper limb. Due to the extent of infection and necrosis, multiple debridements and upper extremity reconstruction were necessary for limb preservation.

The 625 cm2 wound, which involved the left upper extremity and crossed the elbow joint, was managed with initial debridement followed by a period of local wound care to allow for clearance of infection. We then performed reconstruction in a staged fashion with dermal substitute (Integra) placement and split thickness skin grafting. In this case, we demonstrate that the extensive soft tissue infections that may be found in HIES patients can be successfully managed with skin grafting and dermal substitute.

AMA Research Challenge 2025 

The Surgical Management of Extensive Cellulitic Infection and Tissue Necrosis in Rare Immunodeficiency: Hyper-IgE Syndrome

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The neuropeptide hormone, endothelin (specially, ET-1) plays an important role in the invasiveness of breast cancer. High ET-1 levels are associated with decreased disease-specific survival. Very few studies highlight the differential expression of ET-1 and its receptors ETAR and ETBR among triple negative breast cancer (TNBC), non-TNBC, and normal phenotypes. The purpose of the present study was to find out whether the expression of ET-1, ETAR and ETBR is higher in TNBC cells versus non-TNBC and normal cells. An association between higher expression of ET-1 axis and promotion of aggressive TNBC phenotype could represent ET-1 axis as useful biomarkers of TNBC prognosis and potential therapeutic targets. Our hypothesis is that expression levels of ET-1 and its receptors might play an important role in the development and progression of TNBC cells as compared to non-TNBC and normal cells. We aimed to assess the possible prognostic and predictive values of ET-1, ETAR and ETBR by studying their mRNA expression and protein levels in TNBC and non-TNBC via formalin fixed paraffin embedded breast tissue from 4 subjects with TNBC and 4 normal subjects, representing non-TNBC. Western blot, immunofluorescent, and immunohistochemical analysis served to quantify the differential expression. Results from Western Blotting showed ET1 levels were 81.6% higher, ETAR levels were 35% higher, and ETBR levels were 30% higher in TNBC vs non-TNBC cell lines. Immunofluorescence revealed greater intensity of ETBR in all cell lines compared to ETAR, greater expression of ET-1 and ETBR in TNBC cell lines, HCC-1806 and MDA- 231, and greater expression of ETBR in the nucleus of all cell lines and of all proteins in MDA- 231. Immunohistochemistry visually depicted greater staining of ET1, ETAR, and ETBR and quantitatively showed approximately 20% higher ET1, 40% higher ETAR, and 20% higher ETBR positive cells in TNBC vs normal breast tissue. Due to the similar results obtained from Western blot analysis with cell lines and immunohistochemical analysis with breast tissue, our hypothesis that expression of ET-1 and its receptors is higher In TNBC than non- TNBC and control is validated and thus could guide subsequent investigations for targeted pharmaceuticals against these biomarkers in TNBC. 

Supported by MVTCP U54CA162069 and Fuji Oil Company, Osaka, Japan, and NIH MeTRC5U5AMD007593.

Differential Expression of Endothelial-1 (ET1) and its Receptors, Endothelin Receptor Type A (ETAR), and Endothelin Receptor Type B (ETBR) between Subjects with Normal, Triple Negative, and Non-Triple Negative Breast Cancer

Purpose:
KCC2, part of the SLC12 family of proteins, is a potassium-chloride cotransporter essential for neuronal function by regulating GABA signaling through chloride gradients. Recent studies suggest that downregulation of KCC2 may contribute to symptoms observed in opioid use disorder (OUD) which sees hyperpolarization of the postsynaptic cleft. While the idea of increasing chloride flux via KCC2 to stabilize the concentration gradient serves as a promising therapeutic target, few small-molecule agonists targeting KCC2 have been identified, and no definitive binding sites have been characterized. This study employs a machine-learning approach to build a model KCC2 protein, identify its possible active sites, and quantitatively characterize the intermolecular interactions with a library of ligands.

Methods:
An in-silico model of KCC2 was generated using published cryo-EM structural data from the RCSB Protein Data Bank. The protein surface was analyzed for potential active sites by evaluating parameters such as size, depth, hydrophobicity, and capacity for intermolecular interactions, including hydrogen bonding and Van der Waals forces. Ligand models for experimental agonists and FDA-approved negative controls were prepared, forming a small-molecule library. This library was screened against the identified binding sites using a rigid docking protocol. Ligand interactions were scored based on parameters including Van der Waals energy, Coulomb energy, hydrophobicity, and hydrogen bonding potential.

Results:
Surface analysis revealed nine potential active sites on KCC2 with SiteScores ranging from 0.895 to 0.979, indicating high reliability in distinguishing drug-binding regions. The highest-scoring site was located in the transmembrane domain encompassing SER896-PHE1090. Common key residue interactions among all agonist candidates involved HIE1051 (Pi-Pi stacking), ASN1086 (hydrogen bonding), and PHE1090 (Pi-Pi stacking). Agonist candidates averaged a more energetically favorable docking score of -4.5228, compared to -3.6087 seen with negative controls, supporting the increased specificity of these binding sites.

Conclusion:
While these findings are promising, it is noted that the docking scores for our library of ligand candidates are not as highly scored as other protein:ligand interactions (ibuprofen covalent binding to cyclooxygenase-2 results in a docking score of -10.3 using the same experimental parameters). Finally, we acknowledge the need for binding and functional assays need to be performed to validate on-target protein:ligand activity. Overall, these findings provide insights for the rational design of novel KCC2-targeted therapeutics, offering avenues for developing treatments optimized for increasing KCC2 activity, and consequently, symptoms associated with OUD.

Machine-Learning-Assisted KCC2 Protein Modeling and Small Molecule Drug Screening for the Rational Design of Therapeutics Against Opioid Use Disorder

Abstract Title
Age, Biological Sex, and Supine Blood Pressure
Background
Blood pressure is a prevalent modifiable risk factor for cardiovascular disease (CVD) and increases with age. Compared with traditional seated brachial blood pressure (BP), supine BP (brachial and aortic) has a greater association with CVD outcomes. However, the significance of biological sex on age-related supine BP is unknown. We hypothesize the relationship between age and supine BP will be sex specific.
Methods
A sample of 316 apparently healthy adults (165 Females, range: 20-84 years; 151 Males, range: 20-87 years) was used to assess the association of biological sex with supine BP. Data were analyzed using bivariate correlations between age and supine brachial and central (aortic) BP. Partial correlations were used to adjust for traditional risk factors (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], triglycerides, and blood glucose), body composition (body mass index [BMI], waist circumference), and vascular endpoints (augmentation index (AIx), AIx at heart rate 75, carotid-femoral pulse wave velocity (cfPWV)). Analysis of Variance (ANOVA) was used to compare group mean differences amongst young (18-44 yr), middle age (45-65 yr), and older (65+ yr) females and males.
Results
A positive correlation for age and supine brachial systolic BP (bSBP) and central SBP (cSBP) was identified in females (bSBP, r =.468; cSBP, r =.571, p<.05) and males (bSBP, r =.317; cSBP, r =.577, p<.05). Age remained correlated with supine bSBP and cSBP in females (bSBP, r =.166; cSBP, r =.174, p<.05), but not males (bSBP, r =.067; cSBP, r =.128, p>.05) after adjusting for traditional risk factors, body composition, and vascular endpoints. Supine bSBP of young females (117 ± 2 mmHg) was lower than middle-aged (125 ± 2 mmHg) and older (138 ± 2.8 mmHg) females (p<.05), and young males (126 ± 1 mmHg) was lower than older males (136 ± 2 mmHg, p<.05). Supine bSBP in young females was lower than in young males (p<.05), but not between older females and males (p>.05). A main effect of age (p<.05) was observed with supine cSBP.
Conclusion
Supine brachial and central BP are related to age in females independent of traditional CVD risk factors, but not males. Therefore, utilizing supine blood pressure may provide additional insight for CVD risk assessment in females.

Age, Biologic Sex, and Supine Blood Pressure

Background
Cholangiocarcinoma, a rare but deadly cancer of the bile ducts, has a low incidence in the US, 1.26 cases per 100,000 annually. Often diagnosed at an advanced stage, the median survival of 6 to 7 months may improve with early detection by screening. Our collaborators, van Haag, et al. applied machine learning to UK Biobank data to design a risk assessment score. This “TOP5” model utilizes the 5 most associated factors of cholangiocarcinoma (age, elevated GGT, complications of cirrhosis, cholangitis, and bile duct obstruction) to identify at-risk individuals and improve prognosis. We aimed to utilize TriNetX, an ultra-large scale clinical database, to externally verify this screening tool and evaluate its predictive value.

Methods
TriNetX contains electronic health records from over 150 million de-identified patients. Using GGT values and ICD codes for TOP5 criteria (incorporating age into subsequent analysis), we created three cohorts of interest: a “healthy” population of patients with no identified risk factors for cholangiocarcinoma; an “at-risk” population with at least one general risk factor, but none of the TOP5; and a cohort with one general risk factor plus two of the TOP5 criteria, an elevated GGT lab value plus another, named “GGT +1” cohort. Patients with pancreatic cancer were excluded due to errors in diagnostic overlap with cholangiocarcinoma. Propensity score matching was utilized to reduce the influence of other identified covariates: demographics, BMI, diabetes, etc. Cholangiocarcinoma (ICD: C22.1, C24) must have occurred at least 1 year after the index event, to exclude non-detected cancer at enrollment.

Results
In females, 200 outcomes occurred among ~73,000 “GGT +1” patients, 37 in ~75,000 “at risk,” and ≤10 in ~75,000 “healthy.” In males, 312 outcomes were observed in ~74,000 “GGT +1,” 66 in ~77,000 “at risk,” and ≤10 in ~80,000 “healthy.”
Compared to the “healthy” cohort, “GGT +1” hazard ratios (HR) were 77.1 (95% CI: 24.7-241.2) for females and 95.1 (35.5-255.1) for males. Compared to the “at risk” group, “GGT+1” HRs were 7.6 (5.3-10.7) for females and 6.5 (5.0-8.5) for males.

Conclusion
The GGT +1 group demonstrated a higher incidence of cholangiocarcinoma compared to at-risk and healthy populations. Analyses revealed strong associations, evidenced by high hazard ratios, suggesting the predictive utility of the TOP5 model as a screening tool. Future directions include applying the model to prospectively collected data to further validate predictive performance. This study, limited by reliance on ICD-based data, may prove unreliable from incorrect charting.

Cholangiocarcinoma Risk in a Real-World Population: Validation of a TOP5 Model Derivative

Background: Group A Streptococcal (GAS) pharyngitis is a common cause of sore throat, but complications like post-streptococcal reactive arthritis (PSRA) are less frequently recognized, particularly in adults with atypical presentations. PSRA typically presents with early-onset, nonmigratory joint pain and limited response to NSAIDs. This case highlights an atypical presentation of PSRA in a young adult, emphasizing the difficulty in diagnosing this condition.

Case Presentation: A 28-year-old female who presented with a sore throat, non-pruritic rash, dysuria, and acute left ankle pain that impaired weight-bearing. Initial rapid strep and mononucleosis tests were negative, and she was prescribed cephalexin. The following day, she returned with worsening joint pain and persistent dysuria; a repeat rapid strep test was positive, and treatment was switched to amoxicillin-clavulanate and topical NSAIDs. Laboratory results revealed elevated inflammatory markers (ESR 51 mm/hr, CRP 36 mg/L), normal ASO titer, low MCH/MCHC, mildly elevated TSH, and negative autoimmune and STI panels. Follow-up bloodwork six weeks later showed resolution of TSH without intervention, new-onset normocytic anemia, and vitamin D insufficiency.

Discussion: This case illustrates an atypical manifestation of PSRA in an adult: afebrile, initially false-negative for GAS, and presenting with monoarticular arthritis and dysuria in the absence of urinary infection. The diagnostic course was further complicated by the normal ASO titer and the evolving lab profile. This report underscores the limitations of current diagnostic tools such as RADTs and ASO in identifying streptococcal complications in non-classic cases. Clinical judgment, repeat testing, and ongoing assessment played a critical role in this patient’s care. This case underscores the limitations of current diagnostic tools and highlights the need for improved diagnostic strategies and follow-up in adult patients with evolving symptoms and initial negative testing.


A Diagnostic Challenge: Atypical Streptococcal Infection with Monoarticular Arthritis and Dysuria

Background
Iododerma is a rare cutaneous condition that results from exposure to high levels of iodine, often from imaging contrast, medications like amiodarone, or topical antiseptics. Its nonspecific clinical presentation and histological resemblance to infectious conditions make for a challenging diagnosis.

Case Presentation
A 64-year-old female with multiple chronic conditions, including stage 4 CKD, atrial fibrillation, and HFpEF, was admitted for right lower lobe pneumonia and underwent contrast-enhanced CT imaging. She subsequently developed multiple painful, non-pruritic, purpuric skin lesions, initially appearing on her left arm and later spreading to both upper extremities over 4 days. She was transferred to SLU for rheumatology and dermatology evaluation due to concern for vasculitis. Physical exam revealed purpuric skin lesions, erosions, crusting, and scattered bruising on both forearms and the right posterior arm. Based on this presentation, the initial differentials included several neutrophilic dermatoses, such as Sweet’s syndrome and EED, vasculitis, and deep fungal or atypical mycobacterial infections. The workup included a shave biopsy of lesions from the right posterior upper arm and punch biopsies of lesions from bilateral anterior forearms. Skin biopsies revealed ulceration, necrosis, acanthosis, and dense dermal neutrophilic infiltrates with vacuole-like structures resembling Cryptococcus. However, GMS, tissue Gram, and Fite stains all returned negative. An iodine level was also obtained and returned significantly elevated at 10,074.4 micrograms per liter. In the context of her recent contrast exposure and histological findings, her elevated iodine levels supported the diagnosis of iododerma. The patient was treated with a 30-day course of oral prednisone. There has been no recurrence of the skin lesions after discontinuation of the prednisone.

Discussion
Iododerma can present a diagnostic challenge due to its rarity and histopathological features resembling Cryptococcoid-like structures pointing towards infectious dermatoses. In this case, the clinical picture and histology initially suggested a fungal infection, but negative stains and a history of recent iodine exposure helped guide the diagnostic process towards iododerma. Ultimately, iododerma is a diagnosis of exclusion that requires careful integration of clinical history, histopathological examinations, and other lab testing. Early corticosteroid treatment is the recommended treatment and can lead to favorable outcomes.

Iododerma Mimicking Cryptococcoid Neutrophilic Dermatosis

Background
Corona mortis (CM), meaning “crown of death,” is a vascular anatomical variation involving an anastomosis between the obturator artery and either the external iliac or inferior epigastric artery. This variation, present in a significant portion of individuals, is located near the superior pubic ramus, placing it at risk during pelvic or abdominal surgeries and trauma cases. Historical anatomical studies have documented CM as a key vascular hazard, given its propensity for severe hemorrhage if injured. This case highlights the implications of CM injury, emphasizing preoperative planning, intraoperative vigilance, and understanding of vascular variations among surgeons and radiologists.
Case Presentation
A 42-year-old male with end-stage cirrhosis presented to the emergency department with acute right lower quadrant abdominal pain and hypotension, two weeks post-robotic assisted bilateral inguinal and umbilical hernia repair. He was transferred from an outside hospital after imaging revealed intra-abdominal bleeding.
Upon arrival at the outside facility, the patient exhibited hypotension (90/58 mm Hg), tachycardia (128 bpm), and labs revealed a hemoglobin of 11.1 g/dL and hematocrit of 31.4%. Initial stabilization involved transfusion with 7 units of packed red blood cells before transfer.
Interventional radiology was consulted, and angiography identified bleeding from a right-sided CM variant arising from the inferior epigastric artery. Coil embolization was performed.
Following embolization, the patient was admitted to the ICU. His condition deteriorated, with worsening hemodynamic instability requiring intubation and pressor support. Despite consultations with general surgery and nephrology and aggressive resuscitative efforts, the patient ultimately experienced a pulseless electrical activity arrest. At the family’s request, further resuscitative measures were withheld.
Discussion
This anatomical variation poses a heightened risk for cirrhotic patients who are prone to coagulopathy and impaired hemostasis, complicating surgical outcomes and increasing the risk of severe hemorrhage, as demonstrated in our patient post-hernia repair. Preoperative imaging with CT angiography can help identify CM, aiding in surgical planning to minimize intraoperative risks. Surgeons should exercise caution with retractors and dissection near the superior pubic ramus, and in the event of an unexpected CM injury, direct pressure, hemostatic agents, or embolization may be necessary.
This case illustrates the critical need for heightened awareness of anatomical variations, particularly when operating on high-risk patients. Key takeaways include the value of preoperative imaging, cautious dissection near the pubic rami, and an interdisciplinary approach. Awareness of CM, combined with prompt identification and management, can prevent fatal outcomes.

Life-threatening Hemorrhage Due to Corona Mortis Injury: A Case Report

Background: Lung cancer screening with LDCT can lead to early detection and reduced lung cancer mortality. Sadly, uptake remains suboptimal with an estimated 5% of those eligible receiving LDCT. Cancer survivors require surveillance and preventive care but may face barriers to recommended screenings. Evidence also suggests survivors have higher lung cancer rates after LDCT than those without a cancer history, magnifying its benefit. This study examines smoking status and whether or not LDCT screening were discussed based on survivorship status.

Methods: Data from the nationally representative Health Information National Trends Survey 2022 were used to assess discussions of LDCT, comparing those with a prior cancer diagnosis (survivors) and those w/o cancer. Sample was limited to prior or current smokers aged 50-80 (pack year history not available); lung cancer survivors were excluded given expected surveillance with diagnostic CT scans. Demographics included age, race/ethnicity, gender, education, income, employment, and sexual orientation. Univariate analyses and logistic regression focused on predictors of LDCT discussion.

Results: Overall, 3,585 with current or prior smoking history were included of which 560 (15.6%) were cancer survivors. Survivors were older (median 69 vs. 65), less likely employed (26.2% vs. 40.4%), more commonly White (89.8% vs. 84.4%), and less often Black race (23.1% vs. 27.3%) (p < 0.05 for all) than those w/o a cancer history.

Among the cohort, 59 (10.5%) survivors vs. 346 (11.4%) non-survivors are current smokers (p=0.54). Actively smoking survivors were younger than survivors who had quit smoking (median age 63 vs. 68, p= 0.04).

More cancer survivors reported having a LDCT discussion with their provider in the last year than those w/o a cancer history (10.5% vs. 4.8%, p<0.001). Logistic regression confirmed this association, survivors were less likely to have not had a LDCT discussion (OR = 0.43, 95% CI [0.32, 0.59], p < 0.001). Further evaluation limited to survivors showed no significant differences in reported LDCT discussion by age, gender, race, ethnicity, sexual orientation, income, education, or current smoking status.

Conclusion: In this national study, cancer survivors with a smoking history report low rates of discussion of LDCT, despite one in ten being active smokers. While more common in survivors, only a tenth of eligible survivors and one in twenty without cancer are having this important screening discussion. Future interventions should focus on standardizing provider communication, improving survivorship care, and ensuring equitable LDCT screenings among all eligible individuals.


Low-Dose CT (LDCT) Discussions for Cancer Survivors with a Smoking History

Background

Large language models (LLMs) are transforming medicine in general and ophthalmology in particular. Many patients deviate from medical advice due to misunderstandings, leading to adverse effects on visual outcomes. Patient educational materials (PEMs) typically require a high level of language understanding, posing comprehension challenges for marginalized populations. Given the average American reads at a 6th grade level, a potential application of LLM technology includes explaining diagnoses and customizing care plans to patients’ comprehension level. The purpose of this study is to review the literature for LLM-generated ophthalmologic PEMs to determine type and frequency of LLMs used, topics most frequently addressed, metrics used to evaluate PEMs, and success of LLMs in generating and simplifying text.

Methods

A literature review was conducted on PubMed using the search term “ChatGPT and Ophthalmology Educational Material,” resulting in 36 articles. 10 were excluded due to no generation of PEMs (n=4), non-ophthalmologic topic (n=3), prognostic/diagnostic use of AI (n=2), and no use of AI/LLMs (n=1). 26 articles were used in the final analysis. 

Results

The most frequently used LLMS were Chat-GPT 3.5 (65%, n=17) followed by Google Bard/Gemini (62%, n=16) and Chat-GPT 4.0 (50%, n=13). The most frequently used metrics to analyze PEMs were readability (100%, n=26) followed by grade level (88%, n=23) and accuracy (54%, n=14). The most frequently covered topics were pediatric ophthalmology/strabismus (27%, n=7) followed by cornea/external disease (19%, n=5). Studies consistently found PEMs generated by LLMS, especially Chat-GPT 3.5 and 4.0, were longer and more difficult to read requiring a university degree. Most LLM-generated PEMs were of high quality, understandability, and accuracy. Furthermore, Chat-GPT 3.5 responses were more accurate than other LLMs.

Several studies showed that when prompted to rewrite PEMs at a lower reading level, Chat-GPT 3.5 and 4.0 were most successful in simplifying text, reducing average grade level to middle or high-school without sacrificing quality, understandability or accuracy, and comprehensiveness. One article found Chat-GPT 3.5 was more efficacious in simplifying Spanish PEMs compared to English PEMs.

Conclusion

ChatGPT is the most used LLM among studies and represents a viable information source for eye health. By using specific prompts requesting easier-to-understand health information, LLMs have the potential to both create and modify already-existing content for patients with varying health literacy, thereby improving readability while maintaining quality and accuracy. Finally, physicians can overcome limitations of AI by proofreading LLM outputs to ensure they are evidence-based and accurate before administering to patients.


Large Language Model-Generated Ophthalmologic Patient Educational Materials: A Literature Review

Background 
The anatomy course is a core part of medical education; however, studies have shown that anatomy exams significantly raise stress levels. Mentorship programs have been proven effective in enhancing students’ well-being and performance; however, there is limited research on the impact of anatomy mentorship on medical and physician assistant (PA) students. The main goal of this study is to assess the effect of the Anatomy Student Mentorship Program (ASMP) on academic performance and well-being of PA students. 

Methods 
The ASMP offered guided anatomy review sessions led by upperclassmen for PA students at Creighton University’s Phoenix campus. Forty-six students who took the course from 2024 to 2025 were invited to an anonymous Qualtrics survey evaluating their well-being and lab performance. In addition, students/mentor participation hours were recorded by each anatomy session, de-identified, and linked to two anatomy exam scores (MSK and all systems). The association between ASMP participation and quantitative academic performance were assessed using Pearson’s correlation coefficient in SPSS. The study was approved by the institutional IRB. 

Results 
Overall, 72% (33 students) participated in ASMP. There was no significant correlation between ASMP participation hours and exam performance for each exam (p>0.05) or between previous anatomy lab experience and exam performance (p>0.05). However, there is a positive Pearson correlation between the performance of first and second exam (0.471, P=0.001). There is also a positive correlation between participation of ASMP for the first and second exam (0.402, p=0.006). Overall, the total number of ASMP participation hours among all students decreased from the first to second exam (118.5 to 44 hours) and the class average scores decreased by 8.22%. The survey response rate was 15% (7 students) with 100% ASMP participation. All respondents reported that ASMP improved their ability to recognize, identify, and find different structures. Only 42.9% said ASMP reduced stress, but all reported increased confidence. The top benefits were reinforcing anatomy knowledge and receiving personal support, while 85.7% cited time constraints as the main barrier. Overall satisfaction was 94.2%. 

Conclusion 
There was no direct correlation between ASMP participation and exam on an individual level, but greater use of ASMP with the first exam led to higher class average compared to the second exam. Overall, ASMP increased students’ confidence and comfort in the anatomy lab. Despite limitation in response rate, ASMP is shown to enhance learning experiences and should continue as a resource to support interprofessional medical education.

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Differential Expression of Endothelial-1 (ET1) and its Receptors, Endothelin Receptor Type A (ETAR), and Endothelin Receptor Type B (ETBR) between Subjects with Normal, Triple Negative, and Non-Triple Negative Breast Cancer

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