United States

Introduction: Tuberous Sclerosis Complex (TSC) is an autosomal dominant disease that affects nearly 2 million people worldwide. In most cases, mutations in either TSC2 (70%), or TSC1 (20%) induce the growth of benign tumors in multiple organ systems. Angiomyolipomas (AMLs) are benign tumors associated with TSC and are specific to the kidney. Importantly, approximately 40% of pediatric TSC patients will have cysts and/or AMLs by age 10. It is currently unclear why AMLs develop at different stages in life as the mechanisms of incomplete penetrance has yet to be elucidated. Importantly, metabolic changes occur in TSC cells, as evident by enhanced macropinocytosis, and changes to nucleic acid and lipid metabolism, which have been identified as potential therapeutic targets. Our goal is to understand the metabolic reprogramming in TSC, which may yield insights into the drivers of disease progression for clinical application. We hypothesize that AMLs in TSC patients show a distinct metabolic signature compared to those without AMLs. 
Methods: Utilizing the Tuberous Sclerosis Alliance Biosample Repository, we analyzed serum from 35 patients with TSC, confirmed by genetic testing. Concentrations of 276 metabolites were quantified in patients with AMLs (n = 18) and without AMLs (n = 17) using a LC/MS- based platform. We detected concentrations for 221 metabolites which were assessed using t-tests, and fold change (log2) analysis, to determine differentially abundant metabolites between TSC patients with or without AMLs. Statistical and pathway enrichment analyses were performed using MetaboAnalyst 6.0. Confirmatory t-tests were performed using PRISM.
Results: 21 metabolites had greater than 2-fold (log2) change in serum concentration in AML vs. non-AML patients (17 increased, 4 decreased). We discovered that the endogenous metabolites picolinic acid (1.239, p=0.009), and ribulose 5-phosphate (1.432, p=0.003) levels were strongly increased in AML vs. non-AML patients. Pathway enrichment analysis showed that methylhistidine metabolism, and homocysteine metabolism showed increased metabolite saturation in patients with AMLs, compared to those without AMLs.
Conclusions: Our data highlight the metabolic reprogramming that is characteristic of TSC and show that there are potential metabolic signatures intrinsic to TSC-associated AML tumorigenesis. Additional studies with larger patient cohorts may allow the development of prognostic indicators for formation of AMLs. 


AMA Research Challenge 2025 

Angiomyolipoma-associated Metabolic Reprogramming in TSC: Insights from Serum Metabolomics 

### Welcome to ACL 2023, the 61st Annual Meeting of the Association for Computational Linguistics! 
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ACL 2023

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Background
TCF7L2 is a transcription factor and critical effector of the Wnt/β-catenin pathway, with pleiotropic roles across human biology and disease. Intronic SNPs in TCF7L2 have been linked to increased risk for type 2 diabetes, colon cancer, schizophrenia, and autism spectrum disorder (ASD). In 2021, a case series of pediatric patients with mono-allelic predicted loss-of-function (pLOF) variants in TCF7L2 were described as having similar features, including developmental delays and variable myopia, autism, and ADHD, among other features. Defining the genetic and phenotypic spectrum and natural history of this patient population – herein referred to as TCF7L2-related neurodevelopmental disorder (TRND) – is urgently required.

Methods
We identified an international cohort of 76 patients with neurodevelopmental features and pLOF TCF7L2 variants from 2022-2024 using multiple recruitment strategies (GeneMatcher, DECIPHER, and clinician outreach following literature review and screening of public/private repositories). We phenotypically characterized these patients with a clinician-facing survey, extracting 81 enriched Human Phenotype Ontology (HPO) terms and 11 broader categories of phenotypic features. In parallel, we interrogated ~60,000 adult PennMedicine BioBank (PMBB) patients to identify a distinct group of 11 patients with pLOF TCF7L2 variants. 

Results
We identified 76 patients with truncating (n=10), out-of-frame indel (n=18), missense (n=33), splice site (n=10), in-frame indel (n=1), and CNV (n=4) variants in TCF7L2 meeting clinical and variant-specific criteria. Speech delay (95%), craniofacial dysmorphisms (73%), ophthalmologic conditions (65%), ASD (62%), and orthopedic abnormalities (53%) were most commonly observed, comprising the defining syndromic features of TRND. Ear morphology abnormalities (22%), hypertelorism (21%), down-slanted palpebral fissures (19%), and frontal bossing (16%) were the most frequent craniofacial features, co-occurring in a subset of patients. Phenotypic differences did not grossly cluster by variant type or genomic locus. Among PMBB patients, compared to an age/sex-matched PMBB control group, there was a nominal increased risk for type 2 diabetes with renal manifestations (nominal P=0.03), inviting neurodevelopmental follow-up to correlate with our cohort of pediatric patients and further functional investigation. 

Conclusion
We have assembled the most comprehensive characterization of the largest panel of patients to date with TRND, a new neurodevelopmental syndrome with hallmark speech, ophthalmologic, and orthopedic abnormalities. We launched a Simons Searchlight registry that is now accepting patients and the TRND Network, a coalition of TRND patients, researchers, physicians, and families. Alongside international patient recruitment, we plan to leverage this study tool to build a foundation for longitudinal investigation and generate clinical guidelines to improve patient care.

Characterization of the genetic and phenotypic spectrum of a new neurodevelopmental syndrome, TCF7L2-related neurodevelopmental disorder (TRND)

Abstract
Background: Postoperative cognitive dysfunction (POCD) is a frequent complication 
following brain tumor excision. Citicoline has neuroprotective properties, and selenium and 
zinc may enhance recovery after neurosurgical procedures.
Objective: This research aimed to assess the impacts of selenium and citicoline versus zinc and 
citicoline versus citicoline alone on cognitive recovery in postoperative brain tumor excision 
patients in the ICU, and to compare the safety and adverse impacts of these supplementation 
strategies.
Methods: This was a blind, prospective, randomized controlled study. Cases (n=144) 
undergoing brain tumor excision have been assigned to 1 of 3 groups: Selenium + Citicoline, 
Zinc + Citicoline, or Citicoline only. Cognitive function (MoCA scale), inflammatory markers 
(CRP, ESR), incidence of delirium, and ICU stay duration were assessed.
Results: Selenium supplementation with citicoline led to the most favorable cognitive 
outcomes and greater reductions in inflammatory markers. The selenium group also had the 
lowest incidence of delirium and the shortest ICU stays.
Conclusion: Selenium, followed by zinc, optimized postoperative cognitive recovery, reduced 
inflammation, and minimized delirium and ICU stay, suggesting that combining citicoline with 
antioxidants could enhance outcomes in patients undergoing brain tumor excision.
Keywords: Postoperative cognitive dysfunction, Brain tumor excision, Citicoline, Selenium, 
Zinc, Neuroprotection, Inflammation.


Effect of Selenium and Citicoline vs. Zinc and Citicoline vs. Citicoline Only on 
Postoperative Brain Tumor Excision Patients in the ICU

Purpose: 
Eyelid keloids may be associated with increased ocular morbidity, but this has not been previously investigated extensively. This study aimed to characterize outcomes of eyelid lacerations in patients with keloids.
Methods:
This retrospective cohort study used de-identified electronic records from the TriNetX database. Patients who sustained an eyelid laceration with a keloid diagnosis versus those without (matched controls) were identified. Charts were abstracted for eyelid surgical interventions, as well as follow-up duration. In addition, ocular complications within a three-year follow-up, if any, were recorded. Propensity matching was performed to control for age, sex, race, ethnicity, and laceration severity. Significance was defined as p<0.05 for the Odds Ratio (OR) with an adjusted hazard ratio (aHR) threshold of > 1.1or < 0.9.
Results:
After matching (n=6,099), patients with keloids had a lower likelihood of undergoing surgical repair of their eyelid laceration (35.8% vs. 50.5%; OR=0.546; p< 0.001) and a longer follow-up duration (729.8 ± 409.7 vs 553.1 ± 466.7 days). Additionally, patients with keloids who underwent an eyelid surgical intervention related to the laceration (n=2,817) had higher incidence of conjunctivitis (aHR=1.644 (1.314–2.055), keratitis (aHR=2.307 (1.792–2.971), eyelid infections (aHR=1.789 (1.292–2.478), diplopia (aHR=1.426 (1.044-1.946), eyelid retraction/blepharoptosis (aHR=2.100 (1.445–3.052), MGD (aHR=2.750 (1.922–3.936), and dry eye syndrome (aHR=2.363 (1.881–2.968).
Conclusion:
Patients with a history of keloids were less likely to undergo surgical repair following eyelid laceration compared to matched controls without keloids. Among patients who underwent repair, a keloid diagnosis was associated with increased postoperative ocular morbidity, including conjunctivitis, keratitis, infections, diplopia, eyelid malposition, Meibomian gland dysfunction, and dry eye syndrome, relative to non-keloid controls.


Outcomes of Eyelid Laceration in Patients with Keloids in a Large Database

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a significant public health problem, particularly in rural regions with health disparities, where it complicates infection management and consequentially increases morbidity and mortality. Adverse effects of pharmacotherapy and growing antibiotic resistance create a need for alternative treatment options. We investigated the potential of phytochemicals, antioxidants, antimicrobial peptides (AMPs), and Osteopathic Manipulative Therapy (OMT) as additional therapy for MRSA infections. These treatments have been shown to enhance the body's defense mechanisms against infection.

Objectives: We sought to investigate the potential of alternative treatments for MRSA infections, including phytochemicals, antioxidants, AMPs, and OMT.

Methods: A comprehensive literature review was conducted using Google Scholar and PubMed to identify studies on MRSA in Appalachia, antibiotic use, and alternative treatment approaches. Relevant data was extracted and synthesized to identify key trends and disparities.

Results: Phytochemicals possess antimicrobial properties that inhibit MRSA growth and biofilm formation, while antioxidants reduce oxidative stress and inflammation, enhancing immune response and tissue healing. AMPs target bacterial membranes by disrupting MRSA's defenses and minimize resistance development. The Multicenter Osteopathic Pneumonia Study (MOPSE) trial found that patients aged 50 and older who received standardized OMT protocol had reduced mortality, respiratory failure rates, length of hospital stay, and antibiotic use.

Conclusions: Alternative therapies such as phytochemicals, antioxidants, AMPs, and OMT show promise in treating MRSA by targeting MRSA's defense mechanisms while actively enhancing the body's immune response. Future research should include qualitative studies to investigate the specific factors contributing to MRSA's prevalence in Appalachia, focusing on the region’s social determinants of health (SDOH). Additionally, clinical trials should assess the efficacy of alternative therapies as adjunctive treatments for MRSA.

Potential of Adjunctive Treatment Approaches in Improving Methicillin-Resistant Staphylococcus Aureus (MRSA) Outcomes in the Appalachian Region

Background
Wearable devices such as biosensors and smartwatches have demonstrated clinical utility in arrhythmia detection in adult populations, but their integration into pediatric congenital heart disease (CHD) care remains limited. Despite advances in CHD management, challenges persist in the timely identification of arrhythmias in children. The use of wearables in pediatrics is constrained by research gaps, adherence issues, and complex data interpretation. Traditional tools like Holter monitors and event recorders face limitations in detecting intermittent arrhythmias and ensuring compliance. These devices cannot leverage artificial intelligence (AI) and machine learning (ML) to enhance ECG interpretation. This study analysis evaluates the potential of AI-augmented wearable biosensors to detect arrhythmias and early signs of decompensation more accurately and promptly than conventional methods, aiming to optimize outcomes in this vulnerable population.

Methods
A comprehensive literature review was conducted using data from observational studies, randomized controlled trials, and pediatric cohorts. The primary outcome was the performance of wearable devices capable of ECG capture, photoplethysmography, or physiological pattern recognition integrated with AI or ML algorithms. Pediatric-focused studies were prioritized, though adult findings were considered when applicable to children. A secondary outcome assessed the incidence of postoperative arrhythmias in common CHDs and strategies for long-term rhythm surveillance.

Results
Commercial wearables, especially smartwatches, have shown promise in detecting atrial fibrillation (AF). In one study, smartwatch-detected AF achieved 96.2% sensitivity and 93.1% accuracy, with strong concordance with cardiologist interpretation. The Apple Heart Study (420,000 adults) reported that 0.5% received an irregular pulse notification; 34% of these were confirmed to have AF on follow-up ECG. Although Apple Watch ECG features are approved for users ≥22 years old, one pediatric-focused study found that 71% of new arrhythmias were detected using these devices, 29% of which were missed by traditional monitors. ML-enhanced AF detection further improved sensitivity to 100% and specificity to 96%. Tandon et al. demonstrated that AI can efficiently process complex datasets and detect early deviations from individual health baselines.

Conclusion
While limited, emerging data suggest AI-integrated wearables could transform arrhythmia detection in pediatric CHD. These technologies promise earlier identification, timely intervention, and better long-term outcomes. There is an urgent need for further research and funding to develop pediatric-specific, AI-driven wearable monitoring solutions.

Wearable Devices for Early Arrhythmia Detection: A Systematic Review ofLong-Term Clinical Outcomes

Abstract Title
Assessing the Burden of Agitation in Hospitalized Traumatic Brain Injury Patients with Comorbid Substance Use Disorders

Background
Traumatic brain injury (TBI) is a major cause of morbidity and prolonged hospitalization in the United States. While substance use disorders (SUD) frequently co-occur in this population, their role in shaping the incidence and severity of post-TBI agitation remains poorly understood. Prior research has seldom examined how premorbid SUD influences agitation-related outcomes or care needs. This study aims to fill this gap by characterizing the relationship between SUD, agitation, and clinical outcomes in hospitalized patients with acute TBI.

Methods
This single-center retrospective cohort study reviewed 650 consecutive TBI admissions at an academic Level I trauma center from March 2024 to March 2025. Patients hospitalized for at least three days were included (n=467). Agitation was defined by documented clinical observations, use of physical restraints, or administration of agitation-targeted medications. SUD was determined based on documented diagnoses within the preceding year, patient or collateral reports, toxicology results (excluding substances administered emergently), and referrals to addiction services. TBI severity was classified by the best Glasgow Coma Scale (GCS) score within 24 hours of admission. Patients were categorized into three groups: no agitation, agitation without SUD, and agitation with SUD. Primary endpoints included ICU and hospital length of stay, agitation duration, restraint utilization, and addiction-related consults.

Results
Among 467 patients meeting inclusion criteria, 52.2% demonstrated clinically significant agitation, exceeding previously reported estimates of 31.7%. SUD was identified in 40.7% of patients, most frequently involving alcohol (31.4%) and tobacco (12.2%), with 37.8% exhibiting polysubstance use. The mean ICU length of stay was significantly longer in patients with agitation compared to those without agitation (19.26 vs. 9.32 days; p<0.001). Although patients with both agitation and SUD experienced a longer mean duration of agitation (13.46 vs. 11.18 days; p=0.23) relative to those without SUD, this difference did not reach statistical significance. This interim analysis, representing 30% of planned enrollment, identified significant associations between agitation and increased ICU utilization, while differences in agitation duration by SUD status did not achieve significance.

Conclusion
These findings demonstrate a high prevalence of agitation and SUD among hospitalized TBI patients, emphasizing the need for systematic screening and targeted management strategies. Although premorbid SUD was linked to numerically longer agitation duration, this association was not statistically significant. Significant relationships were observed between agitation and greater ICU resource use and restraint application. Ongoing data collection will help determine whether integrated approaches addressing SUD and withdrawal can improve outcomes after TBI.


Assessing the Burden of Agitation in Hospitalized TBI Patients with Comorbid Substance Use Disorders

Sixteen of the world’s fifty known species of box jellyfish are associated
with Irukandji syndrome, which causes a multitude of delayed reactionary and
potentially life-threatening symptoms. The primary species that release the potent
fast acting Irukandji-causing venoms are the Carukia barnesi jellyfish, of the
Carybdea genus. These box jellyfish are native to Australian waters where most
of the Irukandji syndrome cases occur. However, cases of Irukandji-like
syndrome have been reported worldwide after envenomations by Carybdea
jellyfish. Herein we report a probable new case of Irukandji-like syndrome in the
US Florida Keys, a region where Carybdea jellyfish have not been recorded.
While it is unclear which exact jellyfish is the causal organism, the clustering
incidents in the Florida Keys suggest a possible new box jellyfish or a member of
the Carybdied genus are causing Irukandji-like syndrome in the area.

Probable Case of Irukandji-Like Syndrome in the United States Florida Keys

• Alpha-Gal Syndrome (AGS) is a delayed-onset IgE-mediated food allergy caused by an immune response to galactose-alpha-1,3-galactose (alpha-gal), a carbohydrate found in most mammals (e.g., pork, beef, rabbit, lamb, venison) but absent in humans. AGS is linked to bites from the lone star tick (Amblyomma americanum) in the U.S., which triggers sensitivity to alpha-gal.
• Unlike typical food allergies, AGS reactions occur 2–6 hours after consuming red meat or 4-legged mammalian derived products. Symptoms range from hives, itching, and GI distress to severe anaphylaxis.
• Alpha-gal in some medications necessitates careful prescribing to prevent allergic reactions, underscoring the need for thorough assessment and increased provider awareness.
• The CDC identified 110,000+ suspected cases (2010–2022), though the true number may be higher due to underdiagnosis and there are many healthcare providers who may not be familiar with the emerging disease1 . This study examines atrial fibrillation management in an AGS patient, highlighting allergic sensitivity to dofetilide and alternative treatment strategies.

Challenges in Managing Atrial Fibrillation in a Patient with Alpha-Gal Syndrome: A Case of Allergic Sensitivity to Dofetilide


Background
Dual epidural catheters (DEC) were originally described in 1949 to alleviate labor pain (1). Although uncommon, the technique has been successfully used for complex surgical procedures including spine deformity surgery, esophagectomy, and abdominal perineal resections (2,3,4). DECs have not been shown to significantly increase adverse events and have been associated with a 50% reduction in the rate of major post-operative complications, including anastomotic leaks, pulmonary complications, atrial fibrillation, and sepsis (3). We present a patient who received DEC for a two-stage removal of a coccygeal tumor.
Case Presentation
A 62-year-old 60kg female with a history of sacral chondrosarcoma s/p multiple intralesional resections presented for a 2-stage surgical removal. The first procedure was an anterior discectomy of the lumbar sacral spine. The pain service placed a T8-T9 epidural and started an infusion of bupivacaine 0.075% with hydromorphone 2mcg/cc at 5cc/hr. Patient reported 0/10 post op pain. On POD 2, she underwent stage 2 (posterior approach) of her tumor resection, and the surgeon placed a Lumbar epidural. The lumbar epidural infusion started at the post-op at 3cc/hr of the same epidural solution while the thoracic epidural was continued at 3cc/hr. Notably, the first epidural was continued intraoperatively at a rate of 3cc/hr during the second stage. After her second procedure, the patient again reported 0-3/10 pain for the next 5 days with both epidurals in place. Hemodynamics remained stable throughout, and the patient quickly met postoperative milestones. Multimodal agents added to her pain regimen included acetaminophen 500 mg q6h IV, gabapentin 300mg BID, and methocarbamol 500mg q8h IV. For breakthrough pain, her regimen included epidural boluses of 3cc q3h, oxycodone 5mg q4h prn and hydromorphone 0.25mg q4h PRN. She seldom required any PRN medications. Both catheters were removed on POD 5 from the second surgery.

Discussion
Overall, our patient tolerated the procedure and successfully transitioned to oral multimodals. The DEC technique has been reported to decrease opioid requirements and dependence on mechanical ventilation, which is increasingly important for today’s aging and sicker population. It allows for limited opioid use and its side effects such as respiratory depression, delirium, and ileus. The use of neuraxial can promote early recovery of bowel function, shortened hospital length of stay, decreased risk of perioperative complications such as immunosuppression and opioid induced endocrinopathy (4). While the DEC approach is promising, risks must be balanced with the benefit of the patients. Kinking, knotting, or looping of the catheter can cause it to break off and be left within the patient as seen in rare cases (5). However, complications of DEC are the same as single epidural catheters, and include infection, hematoma, and abscesses (6).



Dual Epidural Catheters for effective pain management after sacral coccygeal tumor removal

Abstract Title: 
Double jeopardy: A case of anomalous RCA arising from left coronary sinus with inter-arterial course complicated by significant advanced atherosclerotic disease

Background:
Coronary artery anomalies are developmental variations with an estimated incidence of 1-5.6%. While often benign, certain anomalies can lead to significant ischemic events, arrhythmias, and sudden cardiac death. The anomalous origin of a right coronary artery (RCA) from the left coronary sinus with an inter-arterial course between the aorta and pulmonary artery is a high-risk "malignant" variant. This case highlights the diagnostic and management complexities when this 
congenital anomaly is compounded by advanced acquired atherosclerotic disease

Case presentation:
A 64-year-old female with a history of hypertension, diabetes, and endstage renal disease on peritoneal dialysis presented with acute hypoxic respiratory failure, hypertensive emergency, and elevated troponins. Her hospital course was complicated by atrial fibrillation and a suspected subacute stroke. Initial electrocardiograms showed a left ventricular hypertrophy with strain 
pattern, later evolving to deep T-wave inversions. A left heart catheterization was performed for ongoing chest pain, revealing an 80% heavily calcified proximal left anterior descending artery lesion, which was treated with shockwave atherectomy and a drug-eluting stent. The RCA could not be engaged. A subsequent coronary computed tomography angiography (CTA) identified an anomalous RCA originating from the left coronary sinus. The vessel had a high-risk inter-arterial course between the aortic and pulmonary artery roots and demonstrated extensive, long-segment, 
calcified atherosclerotic plaque causing possible severe obstructive luminal narrowing. 

Discussion:
This case represents a "double jeopardy" scenario, where a high-risk congenital anomaly is superimposed with severe acquired coronary artery disease. The inter-arterial course of the RCA creates a risk for dynamic, exertional compression between the great vessels, while the fixed, calcified atherosclerotic plaque independently obstructs blood flow. This combination dramatically elevates the risk for myocardial infarction and sudden cardiac death, as even minor dynamic 
compression can become hemodynamically critical in the presence of a pre-existing stenosis. 
Determining functional significance of such lesions becomes pivotal. While surgical revascularization with coronary artery bypass grafting (CABG) is the definitive treatment to address both the dynamic and fixed obstructions when significant, patient had symptomatically improved. For further risk stratification, outpatient Stress test and Ambulatory monitoring were pursued which were negative for inducible ischemia and ventricular arrhythmias. The decision was then made to pursue aggressive medical management. This case underscores the importance of advanced imaging like coronary CTA in diagnosing complex coronary anatomy and highlights the challenges in managing patients with combined congenital and advanced acquired cardiovascular pathologies. We anticipate newer technologies like CT FFR might prove beneficial in such cases as they may provide crucial functional context to anatomical abnormalities, enabling a more comprehensive diagnostic assessment.


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Characterization of the genetic and phenotypic spectrum of a new neurodevelopmental syndrome, TCF7L2-related neurodevelopmental disorder (TRND)

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