United States

Background
The CDC reports that the prevalence of obesity in US adults has risen to nearly 42%. The underlying mechanisms of obesity, insulin resistance, and the metabolic syndrome are not well characterized. This study aims to identify how adipose cellular senescence affects metabolic outcomes in the context of obesity and aging. 
Senescent cells have a proclivity to aggregate in adipose and act on neighboring tissues through the release of markers dictated by their senescence-associated secretory phenotypes. It is theorized that inflammatory cytokines may contribute to the pathogenesis of cardiometabolic disease. Furthermore, a high volume of adipocytes may be associated with increased immune cells and fat oxidation, contributing to the development of insulin resistance.
Methods
The ongoing clinical trial in the Musi lab will enroll 160 subjects to account for a dropout rate of approximately 25%. 120 subjects will complete the study. Based on their baseline characteristics they will be divided in the following groups:

Younger Lean (n=24) Group, age 18-30 years, BMI 18.5-24.9 kg/m²
Older Lean (n=24) Group, age ≥ 65 years, BMI 18.5-24.9 kg/m²
Older Obese (n=72) Group, age ≥ 65 years, BMI 30-39.9 kg/m²

Subjects will be enrolled and studied at Cedars Sinai Medical Center in Los Angeles, California (n=120 completers). We will recruit patients of any sex, race, and ethnic background. All subjects will be nondiabetic (fasting plasma glucose &lt; 126 mg/dl, 2-h glucose during oral glucose tolerance test &lt;200 mg/dl, and A1c &lt;6.5%), community-dwelling, and sedentary (≤1.5 h of exercise per week).

Exclusion criteria include history of diabetes, participation in structured exercise &gt;1.5h per week, chronic inflammatory / neurologic / autoimmune / pulmonary disorders, GI or heart disease, use of anti-arrhythmic or weight altering medications, smoking/alcohol use, previous bariatric surgery, and use of/allergy to senolytic agents.

All subjects will undergo initial screening, OGTT analysis, DXA/cardiopulmonary testing, insulin clamp and adipose/skin biopsy (which will be used for sn RNA-seq analyses of senescence). The older obese cohort will be further randomized into three arms: lifestyle intervention (n=24), senolytics (n=24), or placebo (n=24). They will undergo repeat adipose biopsies, snRNA-seq, and metabolic/physiologic assessment after respective 10-week interventions

Conclusion
Characterizing the relationship between adipose senescence and metabolic outcomes will provide greater insight into the underlying mechanism of insulin resistance. While preliminary murine data are promising, assessing these hypotheses in human subjects will reveal the degree to which senolytic agents can improve metabolic function. Furthermore, this study study may help us gain better understanding of the aging process and identify potential molecular targets for prevention of metabolic disease.

AMA Research Challenge 2024 

Effect of Adipose Senescent Cell Burden on Metabolic Outcomes in Older Obese Subjects

Background
The CDC reports that the prevalence of obesity in US adults has risen to nearly 42%. The underlying mechanisms of obesity, insulin resistance, and the metabolic syndrome are not well characterized. This study aims to identify how adipose cellular senescence affects metabolic outcomes in the context of obesity and aging. 
Senescent cells have a proclivity to aggregate in adipose and act on neighboring tissues through the release of markers dictated by their senescence-associated secretory phenotypes. It is theorized that inflammatory cytokines may contribute to the pathogenesis of cardiometabolic disease. Furthermore, a high volume of adipocytes may be associated with increased immune cells and fat oxidation, contributing to the development of insulin resistance.
Methods
The ongoing clinical trial in the Musi lab will enroll 160 subjects to account for a dropout rate of approximately 25%. 120 subjects will complete the study. Based on their baseline characteristics they will be divided in the following groups:

Younger Lean (n=24) Group, age 18-30 years, BMI 18.5-24.9 kg/m²
Older Lean (n=24) Group, age ≥ 65 years, BMI 18.5-24.9 kg/m²
Older Obese (n=72) Group, age ≥ 65 years, BMI 30-39.9 kg/m²

Subjects will be enrolled and studied at Cedars Sinai Medical Center in Los Angeles, California (n=120 completers). We will recruit patients of any sex, race, and ethnic background. All subjects will be nondiabetic (fasting plasma glucose < 126 mg/dl, 2-h glucose during oral glucose tolerance test <200 mg/dl, and A1c <6.5%), community-dwelling, and sedentary (≤1.5 h of exercise per week).

Exclusion criteria include history of diabetes, participation in structured exercise >1.5h per week, chronic inflammatory / neurologic / autoimmune / pulmonary disorders, GI or heart disease, use of anti-arrhythmic or weight altering medications, smoking/alcohol use, previous bariatric surgery, and use of/allergy to senolytic agents.

All subjects will undergo initial screening, OGTT analysis, DXA/cardiopulmonary testing, insulin clamp and adipose/skin biopsy (which will be used for sn RNA-seq analyses of senescence). The older obese cohort will be further randomized into three arms: lifestyle intervention (n=24), senolytics (n=24), or placebo (n=24). They will undergo repeat adipose biopsies, snRNA-seq, and metabolic/physiologic assessment after respective 10-week interventions

Conclusion
Characterizing the relationship between adipose senescence and metabolic outcomes will provide greater insight into the underlying mechanism of insulin resistance. While preliminary murine data are promising, assessing these hypotheses in human subjects will reveal the degree to which senolytic agents can improve metabolic function. Furthermore, this study study may help us gain better understanding of the aging process and identify potential molecular targets for prevention of metabolic disease.

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Title 

Impact of Continuous Glucose Monitors on Non-Insulin-Dependent Type 2 Diabetes Mellitus in an Alaska Native and American Indian Population

Background

Diabetes Mellitus Type 2 (T2DM) is a chronic condition affecting millions worldwide, leading to significant morbidity and mortality. Effective blood glucose management is critical in reducing complications, particularly microvascular events. Traditional blood glucose monitoring via single point-of-care finger sticks poses compliance challenges for patients. Continuous Glucose Monitors (CGMs) offer a less invasive and more effective alternative, enhancing glycemic control and improving quality of life. However, research has predominantly focused on insulin-dependent patients, leaving a knowledge gap regarding the benefits for non-insulin-dependent T2DM patients, especially among Alaskan Natives and American Indians (AN/AI). This study aims to evaluate the impact of CGM use on disease burden in non-insulin-dependent T2DM patients within an AN/AI population.

Aim

To evaluate the impact of CGM use on disease burden in non-insulin-dependent T2DM patients within an AN/AI population. Identify areas for further research regarding CGM use in T2DM patients


Methods

This retrospective study utilized deidentified data from the Electronic Health Record at an outpatient Indian Health Service clinic located in the Northwest United States. The study included patients diagnosed with non-insulin-dependent T2DM who used CGMs between 2019 and 2023. Health metrics analyzed included vitals, A1C levels, glucose readings, cholesterol levels, and liver and kidney function. Data were collected over a period of CGM use, and initial and follow-up measurements were compared to assess the impact on disease management. Statistical analyses, including paired t-tests, were conducted to evaluate trends and significant changes in health outcomes.

Results

The study included 93 patients (37 males, 55 females) with a mean age of 55 years (range 29-83 years). Results of the paired t-test indicated a significant difference between baseline A1C levels (9.5  2.4, MeanSD) and A1C levels one-year post-CGM use (7.6  2.2), t(92) = 7.5, p < .001. These findings suggest that CGM use significantly reduces A1C levels in non-insulin-dependent T2DM patients. Further analysis of T2DM disease burden is ongoing to investigate these findings and explore additional health metrics.

Conclusion

The use of CGMs in non-insulin-dependent T2DM patients within an AN/AI population significantly improves glycemic control, as evidenced by the substantial reduction in A1C levels over one year. These preliminary findings indicate that CGMs could play a pivotal role in managing T2DM beyond insulin-dependent populations, potentially leading to improved health outcomes and quality of life. Further research is warranted to support broader CGM use among non-insulin-dependent diabetes patients. This study underscores the importance of expanding CGM accessibility to enhance diabetes management comprehensively.

References 

1. Lin R, Brown F, James S, Jones J, Ekinci E. Continuous glucose monitoring: A review of the evidence in type 1 and 2 diabetes mellitus. Diabetes Med. 2021;38(5):e14528. doi:10.1111/dme.14528 
2. Ang, E., Lee, Z. X., Moore, S., & Nana, M. (2020). Flash glucose monitoring (FGM): A clinical review on glycemic outcomes and impact on quality of life. Journal of Diabetes and Its Complications, 34(6), 107559. 
3. Tanaka, N., Yabe, D., Murotani, K., Ueno, S., Kuwata, H., Hamamoto, Y., Kurose, T., Takahashi, N., Akashi, T., Matsuoka, T., Osonoi, T., Minami, M., Shimono, D., Seino, Y., & Positive SMBG Study Group Investigators (2018). Mental distress and health-related quality of life among type 1 and type 2 diabetes patients using self-monitoring of blood glucose: A cross-sectional questionnaire study in Japan. Journal of diabetes investigation, 9(5), 1203–1211. https://doi.org/10.1111/jdi.12827
4. Farhan, H. A., Bukhari, K., Grewal, N., Devarasetty, S., & Munir, K. (2022). Use of continuous glucose monitor as a motivational device for lifestyle modifications to improve glycemic control in patients with type 2 diabetes treated with non-insulin therapies. BMJ Case Reports, 15(6). https://doi.org/10.1136/bcr-2021-248579 
5. Bilous, R. W., Donnelly, R., & Idris, I. (2021). Handbook of diabetes (5th ed.). Wiley Blackwell.
6. Park J, Kim G, Kim BS, et al. Insulin Fact Sheet in Type 1 and 2 Diabetes Mellitus and Trends of Antidiabetic Medication Use in Insulin Users with Type 2 Diabetes Mellitus: 2002 to 2019. Diabetes Metab J. 2023;47(2):211-219. doi:10.4093/dmj.2022.0346

Impact of Continuous Glucose Monitors on Non-Insulin-Dependent Type 2 Diabetes Mellitus in an Alaska Native and American Indian Population

Introduction
The prevalence of diabetes has increased drastically over the last couple of decades. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) stimulate glucose-dependent insulin release and inhibit glucagon secretion from pancreatic islet cells, and have a recognized side effect of substantial weight loss. Weight loss has been associated with improved metabolic control and a reduction in comorbidities such as cardiovascular disease and the remission of type 2 diabetes. Therefore, pharmacological methodologies may become an attractive alternative to invasive surgical procedures. This systematic review analyzed semaglutide against alternative GLP-1 RAs in facilitating weight loss and evaluated their associated adverse effects (AEs) in diabetic patients.

Methods
A systematic search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was performed in PubMed, Embase, and Cochrane Library for studies comparing semaglutide against other GLP-1 RAs on weight loss. A narrative synthesis and meta-analysis using SPSS program version 29 were performed to analyze the differences in weight loss between cohorts.

Results
Nine studies with 5,445 patients whose mean age was 60.01 years (range: 55.50-70.00) and mean follow-up of 32.5 weeks (4.0-58.7) were included. Three studies compared semaglutide against liraglutide, four studies compared semaglutide against dulaglutide, two studies compared semaglutide against tirzepatide, and one study compared semaglutide against exenatide. Meta-analysis showed that semaglutide (5.14% [range: 4.95-5.80%]) had a significantly greater mean weight loss compared to liraglutide (2.89% [2.00-3.35%]), and dulaglutide (4.71% [2.07-6.81%]). Tirzepatide (10.33% [range: 8.22-11.90%]) had a significantly greater mean weight loss compared to semaglutide (5.48% [4.88-6.08%]). Common AEs included minor and moderate gastrointestinal (GI) events. 

Conclusions
Semaglutide demonstrated increased weight loss compared to dulaglutide, liraglutide, and exenatide. However, newer dual agonists such as tirzepatide produced a greater weight loss compared to semaglutide, which may be attributed to its ability to act as a dual agonist of GLP-1 and gastric inhibitory polypeptide receptors. An important consideration is the high rate of AEs. GI AEs are the most commonly experienced AEs with semaglutide intervention, most specifically nausea and vomiting, with higher rates observed in patients with lower BMI. Additionally, there have been recently developed GLP-1 RAs acting on multiple receptors which may provide even greater weight loss and clinical outcomes for diabetic patients. Future studies should compare specific GLP-1 RAs to better outline the most efficacious and safe formulation of GLP-1 RAs for weight loss.

Semaglutide versus other GLP-1 Agonists on Weight Loss in Type 2 Diabetes Patients

Background
Hypertension is a major global health concern. While education level has been associated with hypertension diagnosis, the relationship is complex and potentially influenced by factors such as family income and health insurance coverage. This study aimed to explore these associations using nationally representative data.
Methods
We conducted a cross-sectional analysis using data from the 2017-March 2020 NHANES survey, focusing on US adults aged >35 years. Education level was self-reported in 5 categories, and hypertension status was based on previous diagnoses. Statistical analysis was performed using Stata Software version 18, employing chi-square tests with a significance level of 0.05.
Results
Among participants with hypertension (46.96%), only 20.93% had a college degree or higher. Of those with health insurance (87.28%), 26.96% had a college degree or higher. In the subset with family income-to-poverty ratio >1 (82.52%), 46.30% reported hypertension. These findings suggest a complex interplay between education, hypertension, and socioeconomic factors.
Conclusion
This study revealed significant associations between education level, hypertension diagnosis, and socioeconomic factors. The findings highlight the potential roles of income and health insurance as confounders or effect modifiers in this relationship. Further research is needed to elucidate these complex interactions and inform targeted public health interventions.

Education Level and Hypertension Among US Adults: NHANES Analysis

Title: Informing Clinical Insights: A Retrospective Analysis to Describe Micronutrient Deficiencies 
  
Purpose/Background:  
Medical students learn that micronutrients (vitamins and minerals) play a crucial role in most metabolic and physiological processes. However, many micronutrient deficiencies (MnDs) are not routinely tested for. We postulate that this is in part due to limited or outdated research on the prevalences and clinical manifestations of MnDs. This descriptive retrospective cohort study examines MnD prevalence of an ‘at risk’ patient population, with future studies aiming to correlate MnDs with a defined set of clinical presentations. We show that MnDs are more prevalent than current literature suggests and could potentially be the missing diagnostic link when treating disease states. These findings highlight a call to action for further research and updated medical education. 
  
Methods:  
Data from EHR analysis included 583 patients who presented to Grace Health, a FQHC hospital in Battle Creek, Michigan between August 2019 - June 2023. Inclusion criteria consisted of all patients ages 18 to 99 who were identified as being at risk due to evidence of systemic dysfunction and a history of insufficient nutritional intake as defined by the “Healthy Eating Index” and the “National Health and Nutritional Exam Survey.” Automated chart reviews and data retrieval was performed. Associations of MnDs with multiple variables, such as various patient presentations and symptoms, housing status, education level, BMI, activity level, tobacco use, drug use, and other clinical markers were detected. 

Results:   
432 out of the 583 patients (74%) who met the inclusion criteria and had labs drawn were shown to have one or more MnD. 36.8% of these patients had a vitamin C deficiency, 29% had a vitamin B6 deficiency, 12.1% had a vitamin A deficiency, and 11.3% had a zinc deficiency, with the remainder composing vitamin B1, B3, B5, B9, and B12 deficiencies. 
  
Conclusions:  
This descriptive study highlights the significant prevalence of MnDs in an average community, suggesting the prognostic importance of nutritional status nationwide. These results demonstrate that MnDs are only detected if health care providers suspect and test for them. Therefore, this study serves as a platform underpinning the importance of further studies comparing outcomes and prevalence with varied control groups, and on the development and efficacy of routinely used standardized nutritional status indexes, screening tools, and risk stratification scores. At a foundational level, these results emphasize a need for enhancing medical school curriculum to include disease states caused by MnDs and the nutritional education that supports comprehensive patient care. 
  



Informing Clinical Insights: A Retrospective Analysis to Describe Micronutrient Deficiencies

Background
Colorectal cancer is the second leading cause of cancer-related death in the United States and it is expected to cause over 50,000 deaths in the US in 2024. Numerous studies have demonstrated increased survival in distal colon cancer compared to in the proximal side. We assessed the survivorship of colon cancer based on subsite over a 46-year period to determine if a more precise location differs in survivorship compared to what is already known.

Methods
This is a retrospective, cohort study using the Surveillance, Epidemiology, and End Results (SEER) database using SEER*Stat (9.0.30.0). All complete records with colon cancer were extracted from the period 1975-2020. Demographic information was tabulated and compared between groups using a chi square or t-test for counts and means respectively. Our primary outcome was disease-specific survival time for the first 10-years after diagnosis. Records were censored for death not attributable to colon cancer, loss to followup, or survival at 10 years after diagnosis or at the end of the study period. Disease-specific Kaplan-Meir curves were calculated for patients with cancer in each location. Ten-year disease specific survival rates were further investigated by multivariate cox regression to adjust for patient race, age at diagnosis, and marital status. Adjusted hazard ratios were calculated and compared for patients with tumors in each location. 

Results
We identified 300,661 patients with colon cancer from 1975-2020. The median age was 69.1 years, 49.1% were male, and 83.9% were white. Tumors in the distal colon (HR 0.95, 95% CI 0.934-0.956, p<0.0002) had a better 10-year survival versus tumors in the proximal colon (HR 1.06, 95% CI 1.046-1.071, p<0.0001). Tumors in the ascending colon had the highest 10-survival rate (HR 0.894, 95% CI 0.879-0.908, p<0.0001) and tumors in the splenic flexure had the lowest 10-year survival rate (HR 1.183, 95% CI 1.15-1.217, p<0.0001).

Conclusion
We have shown that despite the overall survival being higher in the distal colon compared to the proximal colon, variations exist within these locations. Tumors located in the splenic flexure had the highest 10-year risk of death and tumors in the ascending colon had the lowest 10-year risk of death amongst the subsites, despite the overall rates within their respective areas in the colon showing the opposite outcomes. Further studies are needed to determine if any differences exist within these subsites to cause these findings and if patients may benefit from subsite specific treatments and screening.

Colon Cancer Survival Based on Anatomic Subsite: A National 
Survival Analysis From 1975 to 2020

Abstract Title
Double Trouble in the Gut: Unraveling the Tangled Tale of Eosinophilic Esophagitis and 
Inflammatory Bowel Disease
Background
Eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) are both immunologically 
mediated gastrointestinal disorders. While previous studies have suggested a possible association 
between these conditions, results have been inconsistent.
Methods
We conducted a retrospective cohort study using the TriNetX database, examining IBD patients
from 2013 to 2022. We stratified the data by type of IBD, age, sex, and race to assess the incidence 
and risk factors of EoE in patients with IBD. Additionally, we evaluated the 5-year clinical 
outcomes of patients with concurrent EoE and IBD compared to those with either condition alone.
Propensity score matching was performed for age, sex, race, BMI, smoking, PSC, steroid use, 
other autoimmune diseases, IBD medications, and surgery history. Risk was quantified using 
adjusted odds ratios (aOR) with 95% confidence intervals (CI).
Results
Among 234,582 patients with IBD (mean age 45.4, female sex 52.5%, White race 74.8%, CD 
52.8%), the risk of EoE was higher in the IBD cohort (aOR: 2.88, CI: 2.59-3.19) compared to the 
non-IBD cohort. Following subgroup analysis in the UC cohort, younger age (<40) and male sex 
were associated with a higher risk of EoE, while in the CD cohort, younger age, male sex, obesity, 
and history of CD-related surgery were significant risk factors. For the clinical outcomes study, 
853 patients with UC and EoE and 1,162 with CD and EoE were matched with control cohorts. 
The UC-EoE cohort showed an increased risk of IV steroid use (aOR: 1.46, CI: 1.19-1.79) but no 
difference in oral steroid use, advanced therapy initiation, or colectomy. The CD-EoE cohort 
demonstrated higher risks of IV steroid use, advanced therapy use, and PSC, with no significant 
difference in colectomy rates. In another analysis of 887 patients with EoE and IBD, the EoE-IBD 
cohort exhibited a lower risk of a composite outcome of esophageal dilation and/or Dupilumab use 
(aOR: 0.39, CI: 0.29-0.52), with no difference in esophageal dilations alone or food impactions.
Conclusion
Our study reveals a roughly threefold increased risk of EoE in patients with IBD. Additionally, 
patients with coexisting EoE and IBD experience worse clinical outcomes, particularly those with 
CD, highlighting the need for close outpatient monitoring and follow-up. Interestingly, patients 
with EoE and IBD may benefit from immune-modifying therapies used for IBD, resulting in more 
favorable outcomes compared to those with EoE alone.

Double Trouble in the Gut: Unraveling the Tangled Tale of Eosinophilic 
Esophagitis and Inflammatory Bowel Disease

Background
Colorectal cancer is one of the leading causes of cancer in the United States and there are estimated to be over 150,000 new cases in 2024. Although the rate of new cases of colorectal cancer has decreased over the past few decades, some populations are experiencing increased incidence rates. Native American and Alaskan Native (NA/AN) populations are known to have higher rates of colorectal cancer when compared to whites. In this study we examined the regional and gender related rates in recent new cases of colorectal cancer.

Methods
A retrospective cohort study was performed on 28,609 patients from 2016 to 2020 using the CDC and NCI 2022 submission data from years 1999-2020. Analysis of NA/AN patients was restricted to areas where healthcare services were provided by the Indian Health Service (IHS). Analysis of white patients was restricted to those who lived in IHS Purchased/Referred Care Delivery Areas, which consisted of counties containing NA/AN reservations. Rates were age-adjusted to the US standard population in 2000.

Results
The overall rate of colorectal cancer in the United States was 35.1 per 100,000 in whites and 50.1 per 100,000 in NA/AN, a 1.42 times higher rate in NA/AN. The rate in white males was 39.8 per 100,000 and 57.3 per 100,000 in NA/AN males, a 1.44 times higher rate in NA/AN males. The rate in white females was 31.1 per 100,000 and 44.3 per 100,000 in NA/AN females, a 1.42 times higher rate in NA/AN females. The highest regional rate difference in NA/AN versus whites was in the Alaska region, where NA/ANs had a 2.58 times higher rate of colorectal cancer compared to whites (90.3 vs 35.0 per 100,000). The highest gender-related rate difference was seen in the Alaska region, where NA/AN females had a 2.77 times higher rate of colorectal cancer compared to white females (87.2 vs 31.5 per 100,000).

Conclusion
Our study has demonstrated that Native American and Alaskan Natives have much higher rates of colorectal cancer compared to whites. This rate is even higher in certain regions, particularly the Alaska region. This finding suggests that much more research needs to be done about these regional differences, particularly in Alaska, to determine if any genetic factors or access to care issues exist in these areas. Physicians in these higher risk areas must be aware of these findings and ensure that their patients get colorectal cancer screening appropriately.

Elevated Rate of Colorectal Cancer in the Native Populations in 
Alaska Compared to in Other Regions

Introduction 
Non-alcoholic fatty liver disease (NAFLD) can involve advanced fibrosis and has implications with cardiovascular and liver disease related mortality. The definitive diagnosis of NAFLD and non-alcoholic steatohepatitis (NASH) is liver biopsy. We aim to evaluate and compare the accuracy of the fibrosis-4 (Fib-4) index in predicting hepatic fibrosis among young and adult age groups with biopsy proven NAFLD or NASH. 

Methods 
We conducted a retrospective chart review to identify patients who were 18 years of age and over who underwent a liver biopsy between 2020 and 2023. Data was collected on patient demographics, comorbidities, and liver biopsy findings. Stage of fibrosis was determined using the Metavir Scoring System (F0-F4). Exclusion criteria for the study focused on identification of other causes of acute or chronic liver disease. Patients were split into two age groups: young (18-44 years) and older (45 years or more). All statistical analyses were conducted using Stata V.18 to compute means and frequencies of patient data to determine accuracy of Fib-4 index. 

Results 
A total of 254 patients were included with a mean age of 53.1 years, 62.2% females, and 80.3% Caucasians. The majority of patients had metabolic syndrome (50.8%), obesity (75.2%), hypertension (62.6%), and dyslipidemia (64.9%). Fib-4 index was interpretable in 171 out of 254 patients, out of which 28.7% were predicted to have advanced fibrosis. Fib-4 index was indeterminate in the remaining 83 patients out of whom 6% had advanced fibrosis on liver biopsy. Overall, Fib-4 index had low sensitivity (10%) and higher specificity (65.7%) in predicting advanced fibrosis with the best outcomes seen in the young age group (Table 1). Area under the receiver operating characteristic (AUROC) curve analysis showed unsatisfactory accuracy of Fib-4 index in the overall sample and older age group with AUROC of 52.6% and 40.9%, respectively. There was good accuracy for the young age group with AUROC of 81.6%. Overall, the Fib-4 index had a better negative predictive value, indicating better accuracy with predicting non-advanced fibrosis cases. 

Conclusion
Our study suggests that there is utility of interpretable Fib-4 index scores in increasing the pre-test probability of non-advanced fibrosis (F0-F2) in both the young and older age groups. Liver biopsy may be needed to exclude advanced fibrosis. Those with indeterminate Fib-4 index scores will benefit from further investigation to determine the degree of liver fibrosis. 







Evaluation of Accuracy of Fibrosis-4 (Fib-4) Index in Various Age Groups with Biopsy-Proven NAFLD or NASH: A Tertiary Health Care Network Retrospective Study

Background: Lactulose is an osmotic laxative used to treat hepatic encephalopathy (HE) in patients with cirrhosis. Here, we examined lactulose-induced hypernatremia (HN) in patients with cirrhosis being treated for HE.

Methods: We identified all patients admitted with cirrhosis and HE at our institution from 1/1/18 to 12/31/23. Treatment details and complete clinical data were abstracted. Matching, followed by propensity score calculation, was used to control for the severity of underlying liver disease using a case control study design (HN patients were matched to patients with HE, but without HN). The primary endpoint was hospital mortality, and secondary endpoints included total and rectal lactulose dose (g), time to mental status resolution, and hospital length of stay (LOS). 

Results: Among 6,742 patients admitted with cirrhosis, 1,809 (27%) were admitted with HE as the primary diagnosis. Of these, 158 patients with liver transplantation were excluded. Of the remaining 1,651 patients, 347 patients (21%) had a sodium level > 145 mEq/L, and 106 patients (6%) had a sodium ≥ 150 mEq/L (hypernatremia (HN) group). Cirrhosis was most commonly caused by alcohol or MASH; the median MELD was 24. In HN patients, the median admission sodium was 137 and the peak was 152; all patients received lactulose. The median average daily lactulose dose to peak sodium was higher in the HN group than in controls (85 vs. 38 g, p<0.001). 67 (63%) patients in the HN group received rectal lactulose and had a median sodium level of 154 mEq/L. Rectal lactulose was the strongest independent predictor of hypernatremia (OR = 4.469, p<0.001). The time to mental status resolution and LOS were 2.4 and 2.4 times longer, respectively, in the HN than in the control group (both p<0.001). Overall, 64 patients (60%) in the HN group died compared to 37 (35%) in the group without HN (p<0.001). Hypernatremia was an independent predictor of mortality (OR = 3.596, 95% CI 1.712 – 7.552, p <0.05).

Conclusion: Lactulose-induced HN is associated with poor outcomes, and patients receiving rectal or high dose lactulose had a remarkably high mortality rate. The data lead us to urge careful monitoring of sodium levels in patients with HE who are treated with lactulose.

Lactulose-induced hypernatremia in cirrhotic patients with hepatic encephalopathy

Background
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide, largely due to late diagnosis, high rates of tumor recurrence, and resistance to conventional chemotherapy. Despite advancements in surgical techniques and chemotherapeutic regimens, the prognosis for HCC patients remains poor. Consequently, there is an urgent need for novel therapeutic strategies. The identification of molecular targets has revolutionized treatment in various malignancies, such as lung cancer, highlighting the necessity for similar approaches in HCC. Paternally expressed gene 10 (PEG10), an imprinted gene located on chromosome 7, has been found to be overexpressed in a variety of human cancers, particularly those affecting the gastrointestinal tract. This study aims to investigate the expression of PEG10 in HCC and evaluate its potential as a prognostic biomarker.
Methods
To assess the expression levels of PEG10, mRNA was quantified in human normal liver cell lines and HCC cell lines using quantitative reverse transcription polymerase chain reaction (qRT-PCR). A recombinant plasmid containing PEG10 was utilized in a tumorigenicity assay in a nude mice model to evaluate the in vivo tumor-promoting effects of PEG10. Furthermore, PEG10 mRNA levels were analyzed in a human HCC cDNA array, which included samples from patients with various stages of HCC, inflammatory liver diseases/ non-tumor tissues.
Results
Our findings indicate that PEG10 expression is weak in normal liver cells but significantly elevated in HCC cell lines. In vivo experiments demonstrated that PEG10 enhances tumorigenicity compared to control groups, suggesting its role in promoting tumor growth. Additionally, analysis of the human HCC cDNA array revealed significant differences in PEG10 mRNA levels between early-stage and late-stage HCC, inflammatory liver disease and HCC, and non-tumor and tumor tissues.
Conclusion
PEG10 plays a critical role in the pathogenesis of hepatocellular carcinoma, with augmented expression specifically in HCC and not in benign liver conditions. This differential expression suggests that PEG10 may serve as a valuable diagnostic marker, particularly for well-differentiated HCC. Furthermore, the tumorigenic properties of PEG10 highlight its potential as a molecular target for future therapeutic interventions in HCC. Continued research into the mechanisms regulating PEG10 expression and function could pave the way for novel, targeted treatment strategies, ultimately improving outcomes for patients with HCC.

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