United States

Background:
Adverse Childhood Experiences (ACEs) are stressful events in early life (neglect, parental substance abuse, household mental illness, etc.) that are associated with an increased lifetime risk for chronic diseases, including cardiovascular disease (CVD). It is estimated that 64% of US adults have at least one ACE and 17% have four or more ACEs. Endothelial dysfunction is a key early marker of cardiovascular disease and may provide insight into subclinical vascular changes. This study aimed to investigate whether exposure to ACE’s is associated with impaired endothelial function in young, apparently healthy adults.
Methods:
Twenty-nine young adults (ages 18–29), apparently healthy, were stratified into high (&gt;4 ACEs; n=14) and low (≤4 ACEs; n=15) ACE exposure based on the self-reported standardized ACE questionnaire. Endothelial function was assessed using brachial artery flow-mediated dilation (FMD), a validated, noninvasive ultrasound technique that measures vascular response at rest, occlusion, and post-occlusion. Additional physiological measures were collected, including body mass index (BMI), systolic and diastolic blood pressure, heart rate, C-reactive protein (CRP), and hemoglobin A1c (HbA1c). Group comparisons were performed using independent t-tests, with p &lt; 0.05 considered statistically significant.
Results:
Participants who reported a high number of ACEs presented with significantly lower FMD compared to those who experienced lower numbers of ACEs (&gt; 4 ACEs: 6.7 ± 4.0% vs. ≤4 ACEs: 10.6 ± 5.0 %; p = 0.041), indicating reduced endothelial function. When normalized to shear rate, FMD remained significantly lower in the high ACE group (&gt; 4 ACEs: 0.2 ± 0.1 vs. ≤4 ACEs: 0.4 ± 0.3; p = 0.030). Baseline artery diameter (p = 0.242), peak diameter (p = 0.503), and diameter during occlusion (p = 0.277) were similar between the groups. Additionally, no significant differences were observed in physiological parameters (BMI, SBP, DBP, HR, CRP, and HbA1c).
Conclusion:
These results demonstrate that young, apparently healthy adults with a history of increased childhood adversity exhibit reduced endothelial function, an early marker of CVD development and increased CVD risk. Estimates, based on previous literature, show that a 3.9% reduction in the FMD test as observed in the high ACE group may correspond to an estimated 34% increased future CVD risk. These findings support existing literature suggesting that adversity early in life may serve as a subclinical indicator of increased risk of premature CVD potentially identifying vulnerability before traditional clinical markers emerge.

AMA Research Challenge 2025 

Endothelial Health After Adversity: How Childhood Adversity May Increase Cardiovascular Risk

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AMA Research Challenge 2024 

Join the AMA Research Challenge poster symposium and semifinals to explore top research posters and score posters in the semifinals (an AMA member exclusive opportunity).

Background:
Adverse Childhood Experiences (ACEs) are stressful events in early life (neglect, parental substance abuse, household mental illness, etc.) that are associated with an increased lifetime risk for chronic diseases, including cardiovascular disease (CVD). It is estimated that 64% of US adults have at least one ACE and 17% have four or more ACEs. Endothelial dysfunction is a key early marker of cardiovascular disease and may provide insight into subclinical vascular changes. This study aimed to investigate whether exposure to ACE’s is associated with impaired endothelial function in young, apparently healthy adults.
Methods:
Twenty-nine young adults (ages 18–29), apparently healthy, were stratified into high (>4 ACEs; n=14) and low (≤4 ACEs; n=15) ACE exposure based on the self-reported standardized ACE questionnaire. Endothelial function was assessed using brachial artery flow-mediated dilation (FMD), a validated, noninvasive ultrasound technique that measures vascular response at rest, occlusion, and post-occlusion. Additional physiological measures were collected, including body mass index (BMI), systolic and diastolic blood pressure, heart rate, C-reactive protein (CRP), and hemoglobin A1c (HbA1c). Group comparisons were performed using independent t-tests, with p < 0.05 considered statistically significant.
Results:
Participants who reported a high number of ACEs presented with significantly lower FMD compared to those who experienced lower numbers of ACEs (> 4 ACEs: 6.7 ± 4.0% vs. ≤4 ACEs: 10.6 ± 5.0 %; p = 0.041), indicating reduced endothelial function. When normalized to shear rate, FMD remained significantly lower in the high ACE group (> 4 ACEs: 0.2 ± 0.1 vs. ≤4 ACEs: 0.4 ± 0.3; p = 0.030). Baseline artery diameter (p = 0.242), peak diameter (p = 0.503), and diameter during occlusion (p = 0.277) were similar between the groups. Additionally, no significant differences were observed in physiological parameters (BMI, SBP, DBP, HR, CRP, and HbA1c).
Conclusion:
These results demonstrate that young, apparently healthy adults with a history of increased childhood adversity exhibit reduced endothelial function, an early marker of CVD development and increased CVD risk. Estimates, based on previous literature, show that a 3.9% reduction in the FMD test as observed in the high ACE group may correspond to an estimated 34% increased future CVD risk. These findings support existing literature suggesting that adversity early in life may serve as a subclinical indicator of increased risk of premature CVD potentially identifying vulnerability before traditional clinical markers emerge.

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Background
Unrecognized myocardial infarction (UMI) is associated with higher mortality compared with no myocardial infarction (MI) in both asymptomatic individuals and symptomatic patients suspected
of having coronary artery disease (CAD) undergoing cardiac testing. We aimed to understand the mechanisms underlying the higher mortality associated with UMI.

Methods
We conducted a retrospective cohort study of consecutive patients with obstructive CAD who underwent clinical cardiovascular magnetic resonance imaging (CMR). Patients were classified into 4 groups based on their history of MI (HxMI) and the presence of MI on CMR (CMRMI): +CAD,-HxMI,+CMRMI; +CAD,+HxMI,+CMRMI; +CAD,+HxMI,-CMRMI; and +CAD,-HxMI,-CMRMI. Outcomes included all-cause death, non-fatal MI or death due to MI, heart failure (HF) hospitalization or death due to HF, and sudden cardiac death (SCD). Statistical analyses included Kaplan-Meier survival analysis, Cox proportional hazards regression, and Fine-Gray competing risks modeling.

Results
Among 2,511 +CAD patients, 933 (37%) had -HxMI. Of these, 59% had +CMRMI. Over a median follow-up of 6.4 years, +CAD,-HxMI,+CMRMI patients had higher mortality compared with +CAD,-HxMI,-CMRMI patients (hazard ratio 1.62; 95% confidence interval 1.26-2.09; p<0.001). Furthermore, +CAD,-HxMI,+CMRMI patients experienced more HF events than +CAD,-HxMI,-CMRMI patients. However, there were no significant differences in MI events or SCD. Among +CAD,+HxMI patients, 14% had -CMRMI, and their mortality was not different from that of +CAD,-HxMI,-CMRMI patients.

Conclusion
+CAD,-HxMI,+CMRMI patients had higher mortality than +CAD,-HxMI,-CMRMI patients, primarily due to greater HF events. While both CAD-related and myocardial disease related outcomes contribute to the higher mortality associated with UMI, the primary mechanism is HF outcomes.

Long-term Outcomes of Unrecognized Myocardial Infarction in Patients With Coronary Artery Disease

Background:
Lipid profiles (LP) are commonly used to assess cardiovascular disease (CVD) risk, yet they do not differentiate between LDL subtypes. Lipoprotein(a) [Lp(a)] is a highly atherogenic LDL variant with pro-inflammatory and pro-thrombotic properties that significantly contribute to atherosclerosis and vascular inflammation. Despite its clinical relevance, Lp(a) is frequently overlooked, and its elevated levels—present in 20–30% of the population—pose an independent risk for CVD, even when LDL-C is within normal ranges. The underutilization of Lp(a) testing may contribute to missed opportunities for early risk stratification. This study examines the utility of integrating Lp(a) testing into routine cardiovascular risk assessments, particularly for certain at-risk populations. It evaluates the frequency of physician-ordered Lp(a) testing, the prevalence of elevated Lp(a) levels, and its implications for otherwise healthy individuals.
Methods:
A systematic literature review of various study types was conducted to assess research on Lp(a) testing patterns, prevalence, and its association with CVD risk. PubMed, Google Scholar, and OpenEvidence were utilized. Keywords used in the search included “Lipoprotein(a),” “cardiovascular risk,” “CVD biomarkers,” and “ordering pattern.” Studies not focused primarily on Lp(a) were excluded.
Results:
One study found that only 1% of patients in a large northern California health system underwent Lp(a) testing between 2010 and 2021, while another reported that just 31% of physicians routinely assessed Lp(a) levels. Elevated Lp(a) was observed in 20–30% of individuals, and even among those with LDL-C <100 mg/dL, Lp(a) levels >50 mg/dL were associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. A key limitation of this study is the lack of consideration for the cost of Lp(a) testing, which may impact physician ordering patterns and accessibility for patients.
Conclusion:
Standard LDL-C evaluation alone may be insufficient for comprehensive CVD risk assessment. Given the strong association between elevated Lp(a) and CVD, routine testing in at-risk populations is warranted to improve early detection and intervention strategies. 


Lipoprotein (a) as a key biomarker for a comprehensive cardiovascular risk assessment

Background:
Mycosis fungoides (MF) is the most common variant of cutaneous T-cell lymphoma, a heterogeneous group of non-Hodgkin lymphomas that primarily affect the skin. Narrowband UVB (NB-UVB) phototherapy is a first-line treatment for early-stage MF across Fitzpatrick skin types (FSTs). However, existing NB-UVB guidelines are largely derived from studies with limited skin type diversity. In a 2023 pilot study, our group demonstrated that MF patients with higher FSTs experience slower improvement on NB-UVB. Here, we validate and expand these findings using a multicenter cohort.

Methods:
We conducted a retrospective chart review of MF patients at Columbia, Johns Hopkins, and Emory Universities who underwent NB-UVB monotherapy between January 2010 and June 2025. Patients were included if they had demonstrable disease within 90 days of NB-UVB initiation and at least two documented disease severity assessments (measured as % total body surface area [TBSA] involved). Patients receiving concurrent systemic therapy and radiation were excluded. Patients were stratified by FST (I-III vs IV-VI).

Timepoints were categorized as baseline, mid-year, year-end, and end of follow-up. The primary outcome was the change in TBSA involvement at each timepoint. Statistical analyses included Chi-square and Fisher’s exact tests for categorical variables, and Wilcoxon rank-sum and Welch t tests for continuous variables; α = 0.05.

Results:
A total of 114 patients (63 FST I-III, 51 FST IV-VI) met inclusion criteria. Baseline demographic and disease characteristics differed between groups: patients with FST IV-VI were younger (mean age 49 vs 60 years, p < 0.001) and more likely to present with hypopigmented MF (43% vs 4.8%, p < 0.001). Patients with FST I-III experienced significantly greater percent reductions in TBSA than those with FST IV-VI, with reductions of 73% versus 35% at mid-year (p = 0.009), 78% versus 26% at year-end (p = 0.009), and 78% versus 47% at end of follow-up (p = 0.006). Absolute TBSA reductions mirrored these trends, with greater improvement observed in FST I-III at year-end (−14 vs −10, p = 0.037).

Conclusion:
Across three academic centers, patients with FST I-III demonstrated significantly greater clinical improvement on NB-UVB than patients with FST IV-VI at mid-year, year-end, and end of follow-up. Potential contributors include disease presentation differences, variability in dosing regimens, and post-inflammatory hyperpigmentation mimicking persistent disease in patients with skin of color, leading to perception of lesser improvement. Larger retrospective and prospective studies are needed to elucidate these disparities and inform treatment strategies to promote equitable outcomes.

A Multicenter Retrospective Study of Narrowband UVB Response Across Skin Types in Mycosis Fungoides

Background
Cutaneous T-cell Lymphoma (CTCL) is notorious for its ability to mimic benign dermatologic conditions. Thus, CTCL often has a delayed biopsy and diagnosis until months or even years down the line. This can increase baseline disease burden and worsen clinical outcomes. Previous studies have shown ranges of diagnostic delay from about two to six years for various types of CTCL, yet close to none explicitly stratify and analyze delay by Fitzpatrick skin types and subsequently explore possible disparities.
Methods
A single academic center CTCL database with a total of 266 patients with various types and stages of CTCL from 2004-2023 was retrospectively analyzed. Patients were excluded if pertinent study data was missing. Delay in diagnosis was calculated as months from patient-reported symptom onset to biopsy-proven diagnosis. Prolonged delay was pre-specified as greater than or equal to 2 years based on previous literature. Fitzpatrick skin type was dichotomized into types I-II and III-VI. Demographic, Mann-Whitney U (months delay vs Fitzpatrick binary), and χ2 analyses (prolonged delay vs advanced CTCL stage and prolonged delay vs systemic treatment) were performed on de-identified data using R Statistical Software (v4.5.1) via standard code, dplyr, and ggplot2 packages.
Results
Median diagnostic delay was 36 months (IQR 12-84) for 193 patients, and 61% experienced a diagnostic delay greater than 24 months. There was no statistically significant difference in diagnostic delay based on Fitzpatrick skin type (W=3193, p=0.79). About 19% were at least stage IIB, however, there was no association between prolonged delay and advanced stage at diagnosis (χ2=0.51, p=0.47). Additionally, there was no association between prolonged delay and receipt of systemic treatment (χ2=6.06, p=0.054).
Conclusion
CTCL maintained a median three-year diagnostic delay and no statistical shift in this delay across two sets of Fitzpatrick skin types. This reinforces CTCL’s clinical complexity, and underscores the need for larger, multi-center cohort studies that can verify if there is an association between diagnostic delay and higher Fitzpatrick skin type. In turn, this will help inform concrete early biopsy protocols to advance quality of care and health outcomes across Fitzpatrick skin types.

Multiyear Diagnostic Delay in Cutaneous T-cell Lymphoma: 2004-2023 U.S. Cohort Based on Fitzpatrick Skin Type

ABSTRACT:
INTRODUCTION
The increasing prevalence of metabolic diseases, such as non-alcoholic fatty liver disease
(NAFLD) and morbid obesity, has led to extensive research into the role of gut microbiota
and dietary factors in their development. This systematic review aims to synthesize current
evidence on how gut microbiome dysbiosis, and dietary patterns influence these conditions
and to evaluate potential therapeutic strategies. The gut microbiota, a diverse community of
microorganisms, plays a crucial role in regulating host metabolism and immune responses.
Disruptions in microbiota composition, referred to as dysbiosis, have been linked to the
development and progression of various metabolic disorders. This review examines the
intricate relationships between gut microbiota, metabolic health, and dietary influences to
identify potential intervention strategies.
METHODOLOGY
A comprehensive search was conducted across multiple databases to identify studies
investigating the impact of gut microbiota and diet on metabolic diseases. The review
includes longitudinal cohort studies, meta-analyses, and mechanistic research. Studies were
selected based on their focus on gut microbiota composition, dietary effects, and microbial
therapies in relation to NAFLD and obesity.
RESULTS AND DISCUSSION
Dysbiosis and impaired gut barrier function are closely associated with the progression of
metabolic-associated liver diseases and obesity. Microbial metabolites, such as short-chain
fatty acids (SCFAs), play significant roles in modulating liver metabolism and systemic
inflammation. Changes in gut microbiota composition over time correlate with variations in
metabolic parameters. Probiotic and prebiotic interventions demonstrate potential in
improving lipid profiles and insulin resistance.
CONCLUSION
Dietary interventions, probiotics, prebiotics, and emerging microbiota-targeted therapies have
shown promise in restoring gut microbiota balance and improving metabolic health.
However, the path forward requires addressing significant research gaps. These include the
need for large-scale, longitudinal studies to establish causal relationships between dietary-
induced microbiota changes and metabolic diseases, as well as exploring the roles of non-
bacterial components of the microbiota, such as fungi, viruses, and archaea.
Furthermore, personalized nutrition strategies that account for individual variability in
genetics, baseline microbiota composition, and lifestyle factors hold the potential to
revolutionize the prevention and treatment of metabolic diseases.

Role of gut microbes in non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus

Background: Nutcracker Syndrome is a rare anatomic reduction of the aorto-mesenteric angle (<22°) and distance (<8mm), causing flow congestion and significant pain. It is more commonly symptomatic in 20-40-year-old females, concerning for obstetric consequences due to prolonged pelvic congestion syndrome, anemia, and chronic pain. 
Methods: This single-center retrospective cohort study included 73 female patients who underwent surgical repair for NCS between 2019 and 2025. Statistical comparisons were made using chi-squared and t-tests (significance threshold p < 0.05). Binomial and multivariate logistic regression were performed using Jamovi version 2.6.26 to calculate odds ratios (OR). 
Results: Non-parous patients more often had gastroparesis (p=0.003), POTS (p=0.00004), EDS (p=0.003), mast cell activation syndrome (p=0.0009), and abdominal pain (p=0.005). Parous women more commonly experienced pelvic congestion and heaviness (p=0.003, 0.0007), leg swelling (p=0.005), and varicose veins (p=0.020). Parous patients used more opioids pre-operatively (33.3% vs 13.5%, p=0.031) and no difference was seen post-operatively (50.0% vs 48.6%). Pelvic congestion syndrome prior to surgery predicts symptom resolution (p=0.019, OR=3.9). History of childbirth (OR=4.7) and concurrent antidepressant use (OR=8.4) were independently associated with pre-operative opioid use. 
Conclusions: Parous and non-parous women with NCS present with distinct pain profiles, likely influenced by lasting hemodynamic changes of pregnancy and differences in comorbid conditions. Increased use of opioids by parous patients pre-operatively could be contributed to higher rates of pelvic congestion syndrome and misattributed pain blamed on postpartum and gynecologic causes, portending a longer time to diagnosis. Understanding differences in presentation and likelihood of opioid use is critical, as NCS is rare and prompt recognition is imperative to addressing chronic pain to improve quality of life.


Pain and Parity in Nutcracker Syndrome: A Comparative Surgical Cohort Study 

Background
Surgical site infections (SSIs) are one of the most frequent and costly postoperative complications, specifically in open abdominal procedures. Even transient hyperglycemia following surgery, commonly caused by the body's stress response, can compromise immune function and impair wound healing. While the association between diabetes and SSIs is established, the impact of postoperative hyperglycemia, particularly in non-diabetic patients, remains less clearly defined. This study evaluates whether postoperative hyperglycemia increases the risk of SSIs after open abdominal surgery.
Methods
A retrospective cohort analysis was conducted utilizing the TriNetX research platform, which compiles de-identified electronic health records from more than 180 healthcare organizations. Adult patients (≥18 years) who underwent open abdominal surgeries such as exploratory laparotomy, appendectomy, and colectomy were identified. Patients were categorized into two cohorts based on serum glucose levels measured within seven days postoperatively. The two groups were hyperglycemia (glucose ≥180 mg/dL) and normoglycemia (glucose <180 mg/dL). Propensity score matching balanced the cohorts on key demographics (age, sex, race, ethnicity), comorbidities including diabetes mellitus (ICD-10: E08–E13), hypertension (ICD-10: I10–I1A), ischemic heart disease (ICD-10: I20–I25), chronic kidney disease (ICD-10: N18), heart failure (ICD-10: I50), chronic obstructive pulmonary disease (ICD-10: J44), cerebrovascular disease (ICD-10: I60–I69), and baseline laboratory values (BMI, hemoglobin, creatinine, prothrombin time, albumin). The outcome was the incidence of SSIs within 30 days of surgery, identified using ICD-10 code T81.4.
Results
After matching, 78,147 patients were included in each cohort. The average age was 59 years, and the prevalence of diabetes (41.3%) and hypertension (59.8%) was similar. SSIs occurred in 6.0% of patients with postoperative hyperglycemia compared to 5.3% of those with normoglycemia, yielding a risk difference of 0.7% (95% CI: 0.5–1.0%, p < 0.001). Postoperative hyperglycemia was associated with a 13.7% increased risk of SSIs (risk ratio 1.137, 95% CI: 1.092, 1.184, p < 0.001). Additionally, the odds ratio for developing SSIs in the hyperglycemia group was 1.146 (95% CI: 1.098, 1.196, p < 0.001).

Conclusion
Postoperative hyperglycemia significantly increases the risk of surgical site infections following open abdominal surgery. These findings suggest that postoperative glucose monitoring and glycemic management may reduce infection risk and improve surgical outcomes. Further prospective studies are needed to determine optimal glucose thresholds and intervention approaches that minimize complications without introducing additional risks.


Postoperative Hyperglycemia and the Risk of Surgical Site Infections in Open Abdominal Surgery

Background 
As the aging population increases in the United States, social isolation and loneliness have become increasingly prevalent among older adults, contributing to increased risks of cardiovascular disease, cognitive decline, and mortality (Courtin & Knapp, 2015). National estimates indicate that 29% of adults aged 50 to 80 report social isolation, while 33% report feelings of loneliness (Malani et al., 2025). Although technology-based interventions show promise in promoting social connectedness (Sen & Prybutok, 2021), few studies provide detailed frameworks for designing intergenerational phone-based programs connecting older adults with younger adults (Noble et al., 2022; Office et al., 2020). 

This study aims to describe the design, recruitment process, and feasibility of an intergenerational phone-based intervention (Phone Pals) to reduce self-identified loneliness and social isolation among older adults, and to create a replicable model for use in other medical schools and institutions. 

Methods 
Older adults are recruited through surveys distributed across Presbyterian Villages of Michigan senior living communities. Inclusion criteria includes self-identification of loneliness or social isolation. Undergraduate and medical student volunteers are recruited via email outreach to campus honors programs and student organizations. Older adults and students are randomly matched to promote transparency and reproducibility. Each pair engages in weekly 30-minute phone conversations over a 12-week period. As an orientation, older adults receive an overview of the program and guidelines on expectations, while student volunteers complete training that includes readings on geriatric issues and discussion guides covering social support, daily activities, and health maintenance. Primary outcomes include loneliness (UCLA Loneliness Scale) and perceptions of younger generations (Allophilia Scale). Semi-structured interviews will be conducted pre- and post-intervention to evaluate participant experiences and assess program satisfaction. 

Results 
Currently, 13 older adults and 12 student volunteers have enrolled. All training materials and implementation protocols have been finalized, with program initiation scheduled in the coming weeks. This initial stage demonstrates that recruiting participants, organizing logistics, and building enthusiasm among older adults and student volunteers can be effectively achieved. 

Conclusions 
Preliminary findings indicate that developing an intergenerational phone-based intervention is both feasible and adaptable. The Phone Pals program offers a detailed, scalable design that institutions can use to address social isolation among older adults. By combining accessible training materials and consistent telephone engagement, this approach can strengthen social connectedness and improve intergenerational attitudes. This study addresses a pressing public health challenge and provides a replicable strategy relevant to health systems. By documenting the design process, Phone Pals lays a foundation for other institutions to implement similar programs and contribute to empowering older adults.

Phone Pals: Development and Implementation of an Intergenerational Phone-Based Program to Address Social Isolation and Loneliness in Older Adults

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. 


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

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.

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