United States

Background: Aerobic exercise induces a range of complex molecular adaptations in skeletal muscle. However, a complete understanding of the specific transcriptional changes following exercise warrants further research. Methods: This study aimed to identify gene expression patterns following acute aerobic exercise by analyzing Gene Expression Omnibus (GEO) datasets. We performed a comparative analysis of transcriptional profiles of related genes in two independent studies, focusing on both established and novel genes involved in muscle physiology. Results: Our analysis revealed ten consistently upregulated and eight downregulated genes across both datasets. The upregulated genes were predominantly associated with mitochondrial function and cellular respiration, including MDH1, ATP5MC1, ATP5IB, and ATP5F1A. Conversely, downregulated genes such as YTHDC1, CDK5RAP2, and PALS2 were implicated in vascular structure and cellular organization. Importantly, our findings also revealed novel exercise-responsive genes not previously characterized in this context. Among these, MRPL41 and VEGF were significantly upregulated and are associated with p53-mediated apoptotic signaling and fatty acid metabolism, respectively. Novel downregulated genes included LIMCH1, CMYA5, and FOXJ3, which are putatively involved in cytoskeletal dynamics and muscle fiber type specification. Conclusions: These findings enhance our understanding of the transcriptional landscape of skeletal muscle following acute aerobic exercise and identify novel molecular targets for further investigation in the fields of exercise physiology and metabolic health.

2025 AMA Research Challenge – Member Premier Access

Transcriptional Signatures of Aerobic Exercise-Induced Muscle Adaptations in Healthy Young Humans

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Background: Neonates with severe forms of congenital heart disease (CHD) such as hypoplastic left heart syndrome (HLHS) are at increased risk of delayed brain development and brain injury. Disorders of the placenta have been linked to brain abnormalities in this population, but mechanisms by which the placenta increases this risk are unknown. We hypothesize that placental pathologies impact the development of cerebral autoregulation (CAR), leading to higher risk of brain injury and delayed brain development. Placental vascular malperfusion lesions may be most likely to exert deleterious effects on cerebral hemodynamics. The purpose of this study was to compare the percentage of time spent with impaired CAR during the early postnatal period in neonates with HLHS and healthy placenta versus those with histopathologic lesions of the placenta. 

Methodology: In this single center observational cohort study, we analyzed time synchronized vital sign data in neonates with HLHS born at ≥35 weeks' gestation. CAR was determined in the early postnatal and pre-operative time period using the temporal relationship between mean arterial blood pressure (MAP) and regional cerebral oxygen saturation (rSO₂). To assess intact versus impaired CAR, we used a rolling calculation of the Cerebral Oximetry Index (COx), a dynamic correlation in which values >0.3 were considered impaired CAR in accordance with prior studies. Placental pathologic diagnoses were made using Amsterdam guidelines. We used a student's t-test to determine differences between mean time spent with impaired CAR in HLHS neonates with normal versus abnormal placentas. In subgroup analyses, we compared those with normal placentas to neonates with vascular malperfusion lesions of the placenta. 

Results: In our cohort of 26 neonates with HLHS, we analyzed an average of 86 hours of continuous monitoring (range 18-153). There was a total of 18 (69%) patients with evidence of placental pathology and 8 (31%) with normal placentas. COx showed a wide range in time spent with impaired CAR between subjects (range 0-35%, Fig 1). Mean time spent with impaired CAR in those with normal placentas was significantly less than those with placental histopathology (3.0 ± 1.8% vs. 8.4 ± 9.0%; p=0.02, Fig 2). In exploratory subgroup analyses, those with vascular malperfusion lesions of the placenta had similar time spent with impaired CAR (8.8 ± 6.5%; n=5) to those with normal placentas (p=0.12). 

Conclusion: In neonates with severe forms of CHD such as HLHS, placental histopathologies may increase the risk of brain injury through disrupted development of CAR.

Placental Effects on Early Postnatal Cerebral Autoregulation in Neonates with Hypoplastic Left Heart Syndrome

Background
Transfusion during cardiac surgery is independently associated with adverse outcomes, yet no tool currently provides a validated estimate of transfusion-free aortic repair. We developed and validated a point-based clinical tool to predict the likelihood of bloodless proximal thoracic aortic aneurysm (TAA) repair and support personalized surgical planning.

Methods
We retrospectively analyzed 1,074 patients who underwent open proximal TAA repair between 2012 and 2023 at a single academic center. Bloodless operation was defined as complete avoidance of allogeneic blood products throughout hospitalization. Predictive factors were identified via multivariable logistic regression with internal cross-validation. For risk score model development, the sample was randomly divided into 4/5 training and 1/5 validation cohorts. Model performance was assessed using area under the curve (AUC), Brier score, and F-score. A point system was derived from model coefficients. Observed and predicted probabilities in the validation cohort were compared to assess accuracy.

Results
Of 1,074 patients, 668 (62.2%) received transfusion, while 406 (37.8%) achieved bloodless repair. Eight independent predictors of bloodless surgery (p<0.05) were incorporated into the scoring system: body surface area (BSA) (OR=2.429), hypertension (OR=0.679), reoperation (OR=0.526), heart failure (OR=0.617), preoperative hemoglobin (OR=1.134), extent of repair (OR=0.729), concomitant procedure (OR=0.404), and hypothermic temperature (OR=1.095). The model demonstrated strong discrimination (AUC = 0.761), calibration (Brier = 0.192), and positive predictive value (F-score = 0.758). In the point system, BSA > 1.9 m² and hemoglobin > 13.1 g/dL (8 points each) conferred the greatest positive influence, while extensive repair involving both proximal and distal extension (-8 points) conferred the greatest negative influence. Possible point totals range from -34 to 16, while observed totals in our validation cohort range from -34 to 13. The point system accurately stratified patients into three probability tiers for bloodless repair, with strong alignment between predicted and observed rates; the “unlikely” group was the most congruent.

Conclusion
This is the first validated, clinically applicable scoring tool to predict bloodless proximal TAA repair. It offers a novel, actionable framework for risk stratification in patients where transfusion avoidance is paramount, such as Jehovah’s Witnesses or those at high risk for transfusion-related complications, and may support surgical decision-making, resource allocation, and patient counseling in cardiac surgery.


Predicting Bloodless Aortic Aneurysm Repair: A Validated Scoring Tool


Background 
Coronary artery calcification, particularly in the form of calcified nodules (CN), presents a significant challenge in percutaneous coronary intervention (PCI), especially in patients with end-stage renal disease (ESRD) and acute coronary syndromes. We report a case of a 67-year-old woman with ESRD on hemodialysis, prior right coronary artery stent, and hypertension who presented with acute dyspnea and mild chest discomfort. She was hypoxic, requiring BiPAP support. Laboratory tests revealed a BNP of 1736.9 pg/mL and troponin of 580 ng/L. Chest X-ray showed pulmonary edema, and ECG demonstrated nonspecific ST changes. Initial management included IV heparin and urgent hemodialysis.

Case Presentation 
Cardiac catheterization revealed a chronic total occlusion of the proximal left circumflex artery with a prominent, heavily calcified nodule, along with a patent RCA stent. Elevated pulmonary capillary wedge pressure (28 mmHg, V wave 36 mmHg) and TEE confirmed secondary mitral regurgitation. Due to the presence of a calcified nodule—a known cause of stent underexpansion and poor outcomes—PCI was planned using advanced calcium modification strategies. Intravascular ultrasound (IVUS) was used to assess lesion morphology. Rotational atherectomy with a 1.5 mm burr debulked the lesion, followed by intravascular lithotripsy (IVL) using a 4 × 12 mm balloon (100 pulses) to fracture residual calcium. A 4 × 28 mm Megatron drug-eluting stent was deployed with optimal expansion. The patient was successfully weaned off BiPAP after dialysis and discharged on optimized heart failure therapy.

Discussion 
This case underscores the complexity of managing CNs in ESRD patients with NSTEMI and pulmonary edema. CNs are particularly resistant to conventional balloon angioplasty. A combination of IVUS-guided assessment, rotational atherectomy, and IVL enabled effective modification of both superficial and deep calcium, achieving optimal stent expansion. The strategy aligns with findings from the Disrupt CAD III trial, which demonstrated >92% success rates with IVL in severely calcified lesions. Such techniques are particularly valuable in ESRD, where vascular calcification is often severe and multifocal.


IVUS-Guided PCI Using Rotational Atherectomy and Lithotripsy for a Calcified Coronary Nodule in ESRD Presenting with NSTEMI and Pulmonary Edema

Background 
Percutaneous endoscopic gastrostomy (PEG) is frequently utilized to provide long-term enteral nutrition for patients with impaired swallowing ability. Most PEG-related complications are considered minor, such as peristomal wound infections, tube dislodgement, and leakage. Entero-colo-cutaneous fistulas are rare (0.5%-3%) but represent serious complications following PEG tube placement, particularly in patients with altered gastrointestinal anatomy. Here, we present the case of a 51-year-old female with the formation of an entero-colo-cutaneous fistula after PEG tube insertion post Roux-en-Y procedure. 

Case Presentation 
A 51-year-old woman with a medical history significant for resected anaplastic oligodendroglioma diagnosed approximately 12 years prior, refractory epilepsy, and tracheostomy dependence, previously underwent Roux-en-Y gastric bypass surgery for morbid obesity. Postoperatively, she developed chronic dysphagia, necessitating placement of a percutaneous endoscopic gastrostomy (PEG) tube for long-term enteral nutrition. Five months following PEG placement, the patient exhibited intolerance to enteral feeding. Abdominal computed tomography (CT) revealed malposition of the PEG tube, which had traversed the colon, leading to the development of an entero-colo-cutaneous fistula. The PEG was subsequently removed, and enteral nutrition was continued via a Dobhoff tube. Given her surgically altered anatomy and poor candidacy for re-intervention, PEG replacement was deferred. Although the cutaneous fistula opening closed externally, serial imaging demonstrated a persistent and progressively enlarging fistulous tract between the small intestine and colon. Medical management included acid suppression therapy to reduce gastric secretions and calorically restricted tube feeds to manage obesity-related comorbidities. 

Discussion 
Entero-colo-cutaneous fistulas are rare following PEG tube placement but are more frequently observed in patients with prior Roux-en-Y gastric bypass, primarily due to intra-abdominal adhesions that increase colonic fixation and the risk of inadvertent colonic injury during tube insertion. Additionally, gradual internal migration of the PEG tube’s internal bumper toward the jejunal limb may contribute to the development and persistence of the fistulous tract over time. Diagnosis of such fistulas can be particularly challenging as many patients remain asymptomatic for an extended period, with symptoms typically emerging only after tube dislodgement or attempted replacement. In the present case, the patient exhibited intolerance to enteral feeds five months post-PEG placement, without classic signs such as feculent vomiting or diarrhea, underscoring the variability in clinical presentation. This case emphasizes the need for heightened clinical suspicion in patients with prior gastric surgery, especially Roux-en-Y gastric bypass. Conservative management, consisting of PEG tube removal and initiation of alternative enteral nutrition, is considered for clinically stable patients. However, surgical intervention is required in cases complicated by sepsis, peritonitis, or a high-output fistula.


Entero-Colo-Cutaneous Fistula Following PEG Placement in a Post-Gastric Bypass Patient: A Rare and Challenging Complication

Background: DiGeorge Syndrome is a relatively common genetic disorder, the cardinal features of which are often remembered by the acronym, ‘CATCH-22.’ While this acronym helps highlight the medical morbidities and genetic bases of the syndrome, it tends to ignore its profound psychiatric burden. The current literature posits that approximately 70% of affected individuals have a lifetime prevalence of at least one psychiatric condition, with over one-third developing psychosis by early adulthood, making DiGeorge Syndrome the most significant risk factor for developing schizophrenia, second only to having a monozygotic twin or both parents diagnosed with schizophrenia. 

Case Presentation: We present the case of a 21-year-old female with a known diagnosis of DiGeorge Syndrome who presented with marked conceptual disorganization, delusions of reference and grandeur, pronounced grandiosity, and auditory hallucinations. The patient appeared disheveled, with an inappropriate affect, significant distractibility, and agitation, which complicated the clinical assessment. She reported her mood to be 'very bad' and endorsed ongoing suicidal ideation with intent. The patient had a complex psychiatric history with multiple psychiatric hospitalizations dating back to early adolescence, frequently complicated by medication non-adherence. The most recent hospitalization occurred one month prior, following a psychotic episode with imminent concerns for suicidal and homicidal ideation. Following a thorough psychiatric evaluation and collateral information, a diagnosis of Schizoaffective Disorder, current episode Bipolar, was established. Due to the complex presentation, the patient was started on a regimen of Olanzapine/samidorphan 200 mg and Quetiapine 300 mg. Despite this aggressive pharmacologic approach, there was limited improvement after two weeks. Therefore, given the urgency, Paliperidone Palmitate 1.5 ml was added as an augmentation agent. Additionally, her Olanzapine/samidorphan dose was increased to twice daily, and her nighttime Quetiapine dose was doubled to address the imminent risk to herself and others. Clozapine was considered unsuitable due to concerns about medication adherence and current medical morbidities. 

Discussion: DiGeorge Syndrome is the most significant molecular risk factor for schizophrenia-spectrum disorders, believed to be linked to COMT gene mutations. Psychosis in DiGeorge tends to appear early, be complex, and resistant to treatment. Its comorbidities, like hypocalcemia, disabilities, and metabolic disturbances, 
complicate care. Research shows psychosis often develops gradually, with 20-60% showing sub-threshold symptoms, allowing early intervention. With this case report, the authors aim to highlight the complex psychiatric challenges of DiGeorge and recommend comprehensive screening for early sub-threshold symptoms to enable timely intervention.

More Than CATCH-22: Probing the Profound Psychiatric Burden of DiGeorge Syndrome

Abstract Title
What defines a ‘goals of care’ conversation for surgeons? 

Background
In the age of increased patient autonomy, “shared-decision making” and patient-focused approaches to treatment plans, there is increasing interest in how goals are discussed in clinical practice. Many studies analyze how physicians approach end-of-life and informed consent conversations with their patients. However, little is known about what constitutes a ‘goals of care’ (GOC) conversation for surgeons and their attitudes around these conversations. We aimed to evaluate attending surgeon attitudes, definitions, practices, and beliefs regarding ‘goals of care’ conversations. 

Methods
A 20-30 question Qualtrics survey was distributed by email to attending surgeons from the departments of surgery including general surgery, cardiothoracic, colorectal, minimally invasive, oncology, transplant, pediatric, plastic and reconstructive, and urology at Washington University in St. Louis School of Medicine (WUSM) with a combination of Likert-type, multiple choice, and free-text questions about GOC. Fifty-two surgeons completed the survey. All responses were anonymous and securely stored on the WUSM Box platform. Analysis was done using IBM SBSS software. To expand upon our qualitative data, seven survey participants were interviewed. Interviews were conducted over Zoom by the same interviewer. Interviews were transcribed and analyzed using NVivo. 


Results
Of the 39 surgeons that responded to the question of whether it is important to ask a patient about their goals, all 39 responded that it was important, with 25 (64.1%) responding it is “extremely important.” Yet, 11 of 39 respondents (28.2%) reported not asking patients about their goals before obtaining surgical consent with 30% of these respondents reporting the reason as “irrelevant to treatment.” The most common factors considered when having a GOC conversation were prognosis, diagnosis, and what the available treatments for the patient were. Only 12 of 38 surgeons (31.6%) considered their own comfort with the operative options when conducting a GOC conversation. When asked to define goals of care in their own words, many responded that it signifies discussing what a patient’s desired outcome is. In addition, despite 100% of respondents viewing GOC conversations as important, 22 of 39 respondents (56.4%) had not received any formal education on how to conduct GOC conversations. 

Conclusion
Despite surgeons acknowledging the importance of GOC conversations, many do not ask patients about goals consistently. Further, GOC conversations appear to be context dependent. Finally, many do not receive formal education regarding GOC and conducting GOC conversations. 


Goals of Care Discussions in Surgery: Defining them, conducting them, and learning from them

Background 
Ultrasound education is essential in medical training, but students often struggle to mentally convert 2D images into 3D structures. To address this, we developed a 3D-printed model with defined geometric features, encapsulated it in ballistic gel to simulate soft tissue, and provided it alongside an unencapsulated version for tactile reference. 

Methods 
First-year medical students were divided into experimental and control groups over eight academic blocks. Experimental groups had access to the models, while controls used traditional resources. Test scores assessing 3D spatial understanding were collected before, during, and after their ultrasound curriculum. Model use was voluntary, and engagement was not tracked. 

Results 
Test score analysis showed no significant difference between groups. We hypothesize that low model usage contributed to these results. 

Conclusion 
3D-printed models may enhance ultrasound education but likely require structured integration and mandatory use to demonstrate measurable benefits. Future studies should incorporate usage tracking and curriculum-based implementation. 


Evaluating 3D-Printed Models for Enhancing Spatial Visualization in Ultrasound Imaging

Background
The San Antonio Refugee Health Clinic provides free care to over 1,300 refugees annually. From January to April 2024, 25 patients presented with diabetes-related issues; 40% had HbA1c levels above 7% (uncontrolled diabetes), 30% above 6.5% (diabetes), and 30% above 5.8% (prediabetes). Diabetes progression carries severe risks, including cardiovascular disease, myonecrosis, and liver disease. Refugees often face barriers such as lack of insurance, language difficulties, and limited transportation, complicating chronic disease management. Given the high diabetes prevalence and limited literature on refugee health, this project assessed diabetes knowledge and self-management confidence.

Methods
Starting in October 2024, patients with diabetes completed a survey while waiting to see their provider. The survey assessed diabetes knowledge and self-management confidence using targeted questions and a 5-point Likert scale. Patients then received instruction and a glucometer for at-home blood sugar monitoring.

Results
By December 2024, eight Pashto-speaking patients from Afghanistan completed the initial survey. The average knowledge score was 68.75% (SD = 16.54), with a median of 75% and a range of 50%. The most challenging topics were understanding lifestyle changes versus medication, with 50% answering incorrectly, and diabetes pathophysiology, with 37.5% answering incorrectly. Self-management confidence was high, averaging 4.1/5 (SD = 1.05) with a median of 4.5/5.

Conclusion
Although refugee patients reported high confidence in managing diabetes, they demonstrated limited knowledge of key concepts such as diabetes pathophysiology and the importance of lifestyle changes. This underscores the need for culturally and linguistically tailored educational interventions to improve diabetes outcomes. We will monitor our intervention’s long-term impact through a follow-up knowledge assessment and HbA1c tracking.


Enhancing Diabetes Care and Self-Management in Refugee Patients: A Quality Improvement Initiative

Background
Hereditary Hemochromatosis (HH), particularly due to HFE C282Y homozygosity, leads to progressive iron overload due to increased intestinal absorption. In individuals assigned female at birth, cyclic menstrual blood loss after onset of menses may delay the clinical manifestation of hereditary hemochromatosis. In cisgender males, however, this manifests earlier and more severely due to the absence of any mechanisms of blood loss. 

This case review presents the hypothetical case of Finley, a 30-year-old transmasculine patient with a history of heavy menstrual bleeding and iron supplementation, who rapidly develops clinical iron overload after initiating testosterone therapy. The case examines how the interaction between testosterone, erythropoietin, and iron metabolism can unmask a latent genetic condition. Additionally, it highlights the need for proper history taking before the initiation of gender-affirming hormone therapy, proactive iron monitoring and supplementation reassessment during gender-affirming care, especially in patients with known or potential genetic risk.

Methods
Finley is homozygous for the HFE C282Y mutation but does not have a diagnosis of hemochromatosis due to lack of clinical presentation. His ongoing heavy menstrual blood loss has functioned as a natural compensatory mechanism, keeping serum iron and ferritin levels low despite his genetic predisposition to iron overload. 

Finley visits an endocrinologist to initiate gender affirming care and begin testosterone therapy in his transition to a transgender man. Upon standard medical history taking, his endocrinologist inquires about any prescription medications to which Finley denies. Finley does not disclose his use of over-the-counter iron supplements as he does not perceive this information to be clinically significant. 

Finley initiates medical transition through testosterone therapy of 100 mg IM administered once a week. Follow-ups are scheduled with his endocrinologist for 3, 6 and 10 months. 

Results
Finley’s blood panels at his 10-month follow-up visit show ferritin, TSAT, hematocrit, ALT and AST values elevated well above the reference ranges. The hepatic ultrasound early signs of hepatic steatosis. DNA analysis of the HFE gene showed HFE C282Y homozygosity, consistent with a diagnosis of HH. 

Conclusion
This scenario emphasizes the critical need for comprehensive pre-treatment evaluation in transgender patients initiating hormonal therapy, including detailed menstrual, supplementation, and family histories. Standard history-taking procedures may fail to elicit pertinent information, such as long-term iron supplementation, emphasizing the need for specific and directed questioning. Routine monitoring of iron indices and liver function should be considered, particularly in patients with known risk factors or suggestive clinical histories.

Testosterone Therapy in a Transgender Man with C282Y Hemochromatosis, Heavy Menses, and Prior Iron Supplementation: A Hypothetical Case Study

Pre-eclampsia affects 2–8% of pregnancies globally and remains a major contributor to maternal morbidity and mortality, particularly in low- and middle-income countries where healthcare access and resources are limited. The condition is characterized by defective extravillous trophoblast invasion into the maternal spiral arteries, leading to impaired placental perfusion and systemic endothelial dysfunction. Established risk factors include nulliparity, chronic hypertension, extremes of maternal age, obesity, and low socioeconomic status. Exposure to high-altitude has also been proposed as a potential risk factor, though findings across regions have been inconsistent and underexplored in population-level studies. This study aimed to evaluate the association between altitude—treated as a continuous variable—and the risk of pre-eclampsia in Ecuador, while accounting for sociodemographic and healthcare-related factors.

We conducted a nationwide epidemiological study using publicly available maternal health records from Ecuador’s National Institute of Statistics and Census (INEC) from 2021 to 2023. Altitudes were geospatially mapped to maternal residential addresses and verified against national elevation data. Generalized additive models (GAMs) with cubic splines were used to assess potential non-linear associations between altitude and pre-eclampsia risk. Models were fitted using Restricted Maximum Likelihood (REML) and adjusted for key confounders including maternal age, ethnicity, funding model, type of care, and residential setting.

In adjusted models, altitude was not significantly associated with an increased risk of pre-eclampsia. However, pre-eclampsia risk was significantly elevated among women at the extremes of maternal age (p<0.001) and among those receiving publicly funded care (p<0.001), underscoring the influence of socioeconomic disparities. Ethnicity also emerged as a significant determinant of pre-eclampsia risk, though no interaction effect was observed between ethnicity and altitude.

These findings suggest that in Ecuador, altitude alone may not be an independent driver of pre-eclampsia risk. The absence of a measurable altitude effect may reflect unique demographic, genetic, and environmental characteristics specific to the region. Given the persistent burden of pre-eclampsia and its ties to social determinants of health, further multi-regional studies incorporating both environmental and socioeconomic factors are needed to clarify contextual risk drivers. Such evidence can inform targeted screening strategies and guide more equitable allocation of maternal health resources, especially in geographically and economically diverse settings.



Next from 2025 AMA Research Challenge – Member Premier Access

Placental Effects on Early Postnatal Cerebral Autoregulation in Neonates with Hypoplastic Left Heart Syndrome