United States

Background: Iron is often accumulated in liver during pathologic conditions such as cirrhosis and cancer. Elevated expression of glucose transporter GLUT3 is associated with reduced overall survival in patients with hepatocellular carcinoma. However, it is not known if iron can regulate GLUT3 expression and contribute to tumor proliferation. In the present study, we found that iron increases the GLUT3 expression in liver and treatment with iron chelators reversed the iron mediated upregulation of Glut3 expression. 

Methods: Human liver cell line, HepG2 was treated with Ferric ammonic citrate (FAC) to simulate iron overload in vitro. We treated C57BL/6J mice with 2% carbonyl high iron diet (HID) or iron dextran intraperitoneal injection once a week for 6 weeks (1 g/kg body wt) to induce systemic iron overload. Previous research from our lab has shown that fenofibrate, a PPAR-𝛼 agonist, acts as an iron chelator. So, we used fenofibrate or deferiprone as iron chelators to decrease intracellular iron levels. To quantify GLUT3 mRNA and protein levels, we used GLUT3 specific primers for RT-PCR, and GLUT3 antibody for immunostaining. Data was analyzed for statistical significance using the student’s t test. 

Results: We found that treatment of liver cell line, HepG2 with FAC resulted in a ~1.5-2-fold increase in GLUT3 mRNA expression. HID fed mice as well as iron dextran injected mice showed a ~3-5-fold increase in GLUT3 mRNA expression in the liver. The treatment of iron chelators deferiprone or fenofibrate along with iron reversed the GLUT3 upregulation. This demonstrated that increase in intracellular iron levels upregulate hepatocyte GLUT3 mRNA expression. We found a similar correlation between iron and GLUT3 protein levels, as immunostaining confirmed that GLUT3 protein levels were upregulated during iron overload, and fenofibrate treatment along with iron normalized the GLUT3 protein levels both in vitro and in vivo.

Conclusion: The present study confirms that hepatocyte iron accumulation leads to an increase in GLUT3 mRNA and protein expression. Future studies are aimed at determining how iron regulates the GLUT3 expression in liver, and to check if iron mediated GLUT3 upregulation contributes to the hyperproliferation of tumor cells. In addition, the therapeutic utility of fenofibrate in regulating the GLUT3 expression and cellular proliferation during tumor progression will be assessed.

AMA Research Challenge 2023

Iron overload upregulates glucose transporter GLUT3 expression in mouse liver

poster

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Background: Good health in childhood is consistently associated with good health in adulthood; less is known about the mechanisms that account for this relationship. Good adult health, such as lower chronic disease burden, has been linked to a higher sense of purpose in life. Childhood health has not yet been associated with adult purpose in life, but the related literature on adverse childhood experiences indicates that greater adversity is associated with both lower purpose and worse health in adulthood. The purpose of the present study is to examine purpose in life as a mediator between subjective childhood health and adult chronic disease burden.

Methods: In this secondary data analysis, we examined the relationship between childhood health, adult health, and purpose in life using data from the Health and Retirement study. Specifically, we ran multiple regression analyses to test all components of our research question: the association between childhood health and purpose in life, purpose in life and adult health, and childhood health and adult health with and without accounting for purpose in life.

Results: Adjusting for sociodemographic and health-related covariates, better childhood health was associated with higher purpose in life and lower adult chronic disease burden. The association between better subjective childhood health and lower adult chronic disease burden was mediated, in part, by adult purpose in life.

Conclusion: These results indicate that purpose in life is a partial mediator between subjective childhood health and adult chronic disease burden. Though the literature on the relationship between biological mechanisms and adult health is extensive, the current study indicates that these mechanisms do not account for all predictors of health in adulthood. Through the present study, we have found that psychological factors, such as purpose in life, also serve as predictors of adult health.

Purpose in Life as a Mediator Between Childhood Health and Adult Chronic Disease Burden

Background: Cognitive impairment encompasses a broad range of degenerative conditions that affect an individual's memory, attention, language, perception, and problem-solving skills. While significant strides have been made in the assessment of cognitive impairment once it has already overtly manifested, researchers are becoming more interested in identifying subclinical signs of impairment using the Dual Task Paradigm. Dual tasking most often involves the performance of a motor and cognitive task simultaneously; poor dual task performance has been widely associated with cognitive impairment. The development of novel technologies offers the ability to assess dual task performance in increasingly precise ways. 
This systematic literature review is the first to comprehensively investigate how studies so far have used novel technologies to assess dual task performance as a function of cognitive impairment. With no effective cure, and mild cognitive impairment having a high conversion rate to dementia, this field holds significant potential for enabling tailored interventions, monitoring and preventing disease progression, and better overall care.

Methods: 1775 papers from 4 databases were found between January 2010-July 2023 using targeted key-word search. Following title, abstract, and full-paper screening, 142 studies were included in this review. Studies were stratified based on their objectives, type of DT (motor-cognitive, motor-motor, etc.), technology, what technologies measured as a marker of DT performance/CI, and how effective they were in fulfilling their objectives. 

Results: Counting backwards was the most widely used cognitive task (52%) as they increase cognitive load, thereby enhancing DT impairments to a greater degree. Since 2010, sensors have been the only technology used every year (2010-2023). By 2022, sensors were used in over twice as many studies as any other technology, due to their innumerable uses and ability to measure fine motor discrepancies at high precision. A future area of study gaining traction is the use of multiple technologies simultaneously for a more robust assessment of DT performance. Additionally, researchers have successfully applied AI/machine learning to DT performance metrics to predict the presence and degree of CI in patients (some with over 90% accuracy rate!). 

Conclusion: This comprehensive review has identified several study designs and technologies that offer the possibility of diagnosing subclinical cognitive impairment earlier and more precisely. These methods can be easily and cost-effectively incorporated into clinical practice.

The Use of Novel Technologies in Assessing Dual Task Performance as a Function of Cognitive Impairment: A Systematic Literature Review

Background: Frailty is a multifaceted phenomenon describing overall physical decline and is associated with increased patient mortality and increased healthcare utilization. Previous studies have associated clinical measures of frailty (e.g., Liver Frailty Index™) with post-liver transplant morbidity and mortality. It is imperative to establish an objective biomarker of frailty in liver transplant patients. The purpose of this prospective study is to determine if a previously established age-associated peripheral biomarker of biological age and cellular senescence, p16INK4a expression in CD3+ T cells, with liver transplant recipient outcomes. 

Methods: Patients undergoing liver transplantation at a single center were consented and enrolled pre-transplant between 09/2022-4/22/23. Clinical frailty assessments were performed in accordance with the previously established Liver Frailty Index™. CD3+ cells were isolated from blood samples taken at the time of enrollment, pre-transplant, as well as 14-, 30-, and 90-days post-transplant. RT-qPCR was utilized to quantify p16INK4a expression. Briefly, total RNA was isolated and p16INK4a expression was quantified using TaqMan™ qRT-PCR. 18s rRNA was used as a housekeeping control and statistical analysis was performed in GraphPad Prism v9.4.1.

Results: Ten patients undergoing liver transplant were enrolled. Seven patients (70%) presented with alcoholic steatohepatitis as an indication for liver transplant and three (30%) presented with primary biliary cholangitis. The median length of stay was 12 days (IQR 6-34). Pearson correlation analysis of baseline frailty score and baseline p16INK4a expression demonstrates a statistically significant direct relationship (r = 0.7356, p-value = 0.0153). Furthermore, baseline p16INK4a expression and patient length of stay demonstrate a statistically significant direct relationship (r = 0.7036, p-value = 0.0232). Interestingly, baseline p16INK4a expression did not correlate well with Sodium Model for End-Stage Liver Disease (NaMELD) or patient age (r = 0.2960, p-value = 0.4063; r = 0.0591, p-value = 0.8713). Normalized p16INK4a expression at 30-day post-transplant to baseline expression revealed variability. 

Conclusion: Recipient frailty negatively impacts liver transplant outcomes. We discovered that peripheral CD3+ T-cell p16INK4a expression is highly correlated with baseline clinical frailty and length of hospital stay in liver recipients. In contrast, age and NaMELD did not correlate with p16INK4a expression. Furthermore, p16INK4a expression changed multiple fold during the perioperative period. Our data indicate that p16INK4a is strongly associated with clinical frailty, independent of age, and malleable. Notably, therapeutics to selectively remove p16INK4a-expressing cells are currently being tested clinically. 


The Importance of p16INK4a: A Biomarker of Frailty in Liver Transplant Recipients

Genital dermatoses can severely affect patients’ quality of life, including their sexual life. We sought to examine the impact of genital psoriasis among psoriatic patients, their response to treatments, and how often genital psoriasis is evaluated by dermatologists. A cross-sectional qualitative study was completed. Patients 18 years or older seen for psoriasis by one of the attending dermatologists or those receiving phototherapy from the Massachusetts General Hospital Outpatient Dermatologic Clinic were recruited. Fifty-five subjects were enrolled in the study and completed a 23-item questionnaire. Only 23.6% of participants had ever been asked if they had a genital rash by a dermatologist. 60% of participants indicated a dermatologist had never examined the genital area. 43.6% of participants indicated they had had at some point some form of itching, burning, pain, or involvement in the genital areas. Of these, 45.8% indicated that their dermatologist did not ask/diagnose the genital rash. These patients ranked genital itching 4.61/10, pain 4.09/10, and stinging/burning 3.86/10. 80% of participants indicated that they were self-conscious or experienced some form of embarrassment because of their skin psoriasis. 29.1% of participants described that their overall psoriasis has caused some form of sexual difficulty for them. 50% of participants with involvement in their genital area indicated experiencing some form of sexual difficulty. When looking at the gender breakdown of sexual difficulty, 62.5% of female patients indicated significant sexual difficulty compared to just 25% of male patients. This qualitative study of patients with psoriasis adds to the growing body of knowledge regarding genital psoriasis. It shows that even though almost half of the patients enrolled in the study had a rash or some form of symptoms in their genital regions, a majority of patients had never had their genital area examined by a dermatologist for psoriasis nor had they ever been asked if they had a genital rash. For those patients with symptoms in the genital areas, there was mild to moderate discomfort experienced by patients in regards to pain, stinging, and itching in the genital regions. A majority of these patients, specifically female patients, experienced significant sexual difficulty due to their genital psoriasis. In the future, providers should regularly examine and ask patients with psoriasis about potential genital involvement. Given the significant sexual difficulty and embarrassment patients felt from their skin psoriasis, providers should also ask about the psycho-social burden patients may experience from their psoriasis. 


Provider evaluation and patient experience among patients with genital psoriasis

Background
The aging population in the United States is increasing with a concurrent increase in the prevalence of cognitive impairment. Modifiable and non-modifiable risk factors play a role in the pathogenesis of cognitive impairment, including obesity. The association between obesity and cognitive function in older adults is not well characterized. This study aims to examine the longitudinal effect of obesity defined by both Body Mass Index (BMI) and waist circumference (WC) on cognitive function in older adults.
Methods
This study utilized 10 years of data from the National Health and Aging Trends Survey (NHATS), a nationally representative survey of US adults aged ≥ 65. Participants with missing anthropometric data or a diagnosis of dementia at baseline were excluded. Cognitive function was assessed using standardized tests in the cognitive subdomains of memory, orientation, and executive function, as well as an overall cognitive domain. Obesity and overweight were defined as a BMI ≥ 30 and ≥ 25 respectively. High WC was defined as ≥ 88 cm in women or ≥ 102 cm in men. Proportional hazards modeling was used to assess the relationship between obesity and incident cognitive impairment with adjustment for demographic characteristics and comorbidities.
Results
The study included a total of 10,735 participants in the BMI cohort and 10,023 participants in the WC cohort after exclusion criteria were applied. The incidence rate of overall cognitive impairment increased over 10 years of study data in both BMI and WC cohorts from 19.1 to 25.6 and 18.5 to 25.1 per hundred person-years respectively. Higher BMI was associated with a decreased risk of cognitive impairment - participants with obesity-range BMI had an adjusted HR of 0.8 (0.73-0.88), participants with overweight-range BMI had adjusted HR of 0.9 (0.83-0.97), and participants with high WC had adjusted HR of 0.96 (0.89-1.03) for overall cognitive impairment. These associations were consistent across all cognitive subdomains.
Conclusion
This study provides evidence of a protective effect of higher BMI on the development of cognitive impairment in older adults in a dose-dependent fashion. Higher WC did not demonstrate a significant protective cognitive effect. The relationships demonstrated in this study suggest a complex interplay between body composition and neurological decline in this population. Further study is needed into the mechanisms underpinning these findings. These findings have implications for weight management guidelines and interventions in the geriatric population.


Trajectories of Cognitive Decline by Obesity Status in Older Adults

Background
Schistosomiasis, also known as Bilharzia, is a disease caused by schistosomes, a type of trematode or fluke parasite. Transmission occurs through contact with parasite-infested water. There are three major schistosome species that cause severe infection in humans, each with a preference for a specific organ system. The disease is predominantly found in rural areas with inadequate sanitation of freshwater sources and is endemic in Africa, Asia, and South America. Infected individuals excrete schistosome eggs, which hatch and infect freshwater snails, serving as intermediate hosts. The cercariae that develop within the snails can penetrate human skin and enter the bloodstream. Adult schistosomes migrate to various organ systems via the venous system, most commonly affecting the gastrointestinal and genitourinary tracts. Clinical manifestations and chronic inflammation are associated with the presence of schistosome eggs. Schistosomiasis can involve multiple organ systems, with symptoms varying depending on the affected system. Genitourinary schistosomiasis can lead to hematuria, dysuria, and pelvic pain. Diagnosis involves antigen detection, imaging, and tissue sampling. Chronic infection can result in bladder fibrosis and calcification, as well as an increased risk of bladder cancer, particularly squamous cell carcinoma. Early detection and treatment with Praziquantel are crucial in reducing the risk of cancer development.

Case Presentation
A 26-year-old man with a history of intermittent gross hematuria presented to his primary care physician. Previous evaluation at a local hospital revealed a possible clot or mass in the bladder, but further investigation was not pursued. The recent presentation showed gross hematuria with small clots, and urinalysis confirmed the presence of red blood cells. Urine culture, cytology, and STI panel were negative. CT Urogram with contrast revealed plaque-like and nodular wall thickening of the bladder. Cystoscopy showed diffuse white-yellow deposits, and pathology confirmed the diagnosis of schistosomiasis. CT of the abdomen and pelvis was valuable in assessing the extent of involvement. The patient was referred to infectious disease for treatment.

Discussion
As global travel increases, physicians are more likely to encounter uncommon conditions such as schistosomiasis, which may not be endemic to their population or location. Awareness, early detection, and immediate treatment are crucial to prevent long-term complications and improve patient outcomes. This case emphasizes the importance of staying informed about rare conditions and utilizing imaging techniques to provide timely and appropriate care to patients.

A Case Report on Chronic Schistosomiasis

Introduction 
Accurate diagnosis and interpretation of signs and symptoms are crucial for effective patient management. However, there are instances when medical findings can be deceiving, indicating a particular condition or outcome when the situation is more complex or unexpected. 

This distinctive case illustrates such an example of a deceptive, almost benign finding which led to a more portentous diagnosis. Such instances remind us of the ever-evolving nature of medicine and the importance of maintaining a critical mindset when interpreting clinical data. 

Case Presentation 
A 31-year-old, apparently healthy male visited his doctor with concerns about a seemingly innocent rash on his shoulder that had been present for a year. What started as a small, 1x2 cm rash had recently become an elevated 5x7 cm rash and had also started appearing in multiple other parts of his body, like his groin, back, postauricular, scalp, and axillary regions. 

Due to the lesion's persistence, a biopsy was conducted revealing Kaposi Sarcoma (KS). Further evaluation led to the diagnosis of full-blown HIV AIDs with a CD4 count of 12. After ruling out opportunistic infections, he was started on Highly Active Antiretroviral Therapy (HAART) and chemoprophylaxis for Mycobacterium Avium Complex and Toxoplasmosis. 

However, the patient developed odynophagia, oral thrush, cough, and shortness of breath despite being on prophylaxis and was therefore admitted with esophageal candidiasis and Pneumocystis carinii pneumonia, for which he underwent a prolonged course of therapy. 

Discussion 
KS, a multicentric angioproliferative neoplasm, with its distinctive skin lesion gained public attention as an AIDS defining malignancy. Although common during the height of the AIDS epidemic, with the advent of effective HAART therapy, KS has become an uncommon differential. 

A metanalysis of studies between 1967 to 2013 revealed that KS was highest in people affected by HIV (481.54 per 100 000 person-years). 

Studies also report an annual decrease of 3.6% in KS incidence after the introduction of HAART world-wide. 

At the time of presentation, our patient had extensive diffuse KS which served as the tip of the iceberg, which led to his diagnosis and prompt initiation of HAART. 

In conclusion, the significance of possessing a broad clinical knowledge base and exercising the highest level of suspicion cannot be overstated. By embracing a comprehensive approach to patient care and maintaining a healthy skepticism towards clinical presentations, practitioners can enhance diagnostic accuracy, optimize treatment outcomes, and ultimately improve patient safety and well-being. As we navigate the challenges of modern medicine, fostering a culture of continuous learning, critical thinking, and unwavering suspicion will undoubtedly contribute to the advancement of healthcare and the provision of exemplary patient care.

From Innocence to Diagnosis - The Hidden Impact of a Disregarded Rash​

This case report presents a thirty-nine-year-old cisgender MSM patient who has multiple serological confirmations of HIV-1 RNA viral load for more than 12 years. Despite the absence of antiretroviral therapy (ART), this patient has consistently displayed a lack of clinical disease progression and has maintained a relatively low viral load. If not for their viremic controller status, this patient would have likely developed AIDS per the natural history of HIV infection. Over the course of three-months post-intervention, our observation revealed that initiating ART in this HIV-1 positive viremic controller yielded notable increases in CD4 and absolute neutrophil cell counts, accompanied by a reduction in viral load copies to undetectable levels. These findings suggest a substantial decrease in the patient's likelihood of developing comorbidities. Here we analyze the changes in HIV reservoirs before and after the implementation of ART into the treatment plan. Similar cases such as this have been reported, but the literature has yet to gather a sufficient volume to properly inform physicians and scientists on proper management of EC. Disseminating a case of this nature within the medical community holds significant relevance for enhancing our understanding and management of HIV-1 disease progression, improving the quality of life particularly among controllers. Furthermore, future studies investigating the cellular and molecular mechanisms underlying this demonstration of innate immunity hold significant importance in the broader quest for discovering a cure HIV-1.

Male HIV-1 Viremic Controller: Case Report

Emphysematous gastritis is a rare infection caused by gas-forming organisms infiltrating stomach mucosa. Early diagnosis is critical for successful medical treatment and avoidance of associated high morbidity and mortality. Management can be further complicated by potential contribution of fungal infections, particularly in immunosuppressed patients. This case reviews the inpatient conservative management of emphysematous gastritis in an immunosuppressed patient with known Candida esophagitis.

Medical management of emphysematous gastritis precipitated by an azole-resistant Candida infection

A broad differential exists for infectious esophagitis including fungal, viral, and bacterial pathogens. Although often seen in immunocompromised patients, certain risk factors should prompt consideration of unusual etiologies in immunocompetent hosts. This case explores a 24-year-old female with known eosinophilic esophagitis (EoE), initially presenting with odynophagia and globus sensation, found to have HSV esophagitis. It is known that HSV esophagitis predominantly occurs in hosts with impaired immunity resulting from chemotherapy, transplantation, or HIV infection: all risk factors that this patient did not have. This poster presentation explores the pathophysiological relationship between EoE and HSV esophagitis in an otherwise immunocompetent host as well as the role of occupational exposures as risk for primary HSV infection. Our goal is that this case 1) prompts physicians to consider uncommon etiologies for presumed infectious esophagitis to expedite treatment and clinical improvement, and 2) inspires further research into the relationship between EoE and HSV esophagitis as well as the preferred treatment regimen.

Next from AMA Research Challenge 2023

Purpose in Life as a Mediator Between Childhood Health and Adult Chronic Disease Burden