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**Abstract:**



AMA Research Challenge 2023

VEGF, Neuregulin, and Postoperative Vasoplegia Following Cardiopulmonary Bypass Surgery

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Background
Lung cancer is the leading cause of cancer deaths worldwide. The increasing use of minimally invasive surgical approaches has expanded the scope of treatment options for patients with lung cancer. However, these operations are not risk-free as there have been several reported cases of intraoperative catastrophes, with major hemorrhage from the pulmonary artery being the most common. The objective of this study was to develop a computer vision-based approach to reliably identify the pulmonary artery during robotic right lower lobectomies. 

Methods
Twelve patients with biopsy-proven Stage I non-small-cell lung cancer of the right lower lobe underwent robotic lobectomy with mediastinal lymph node dissection. Complete videos of each operation were obtained, and video fragments of the pulmonary artery were identified by two board-certified thoracic surgeons. Annotation masks of the pulmonary artery were then created using Computer Vision Annotation Tool, an open-source web-based annotation tool. The labeled data was next used to train a state-of-the-art instance segmentation algorithm called Mask Regional-Convolutional Neural Network (Mask R-CNN) using an 80:20 random sample split from ten cases for training and validation, respectively. Two cases were utilized for generalization testing. Three custom performance metrics commonly utilized in deep learning-based instance segmentation were used to evaluate our approach: Intersection over Union (IoU), Average Precision at IoU threshold of 50% (AP50) and at 75% (AP75). 

Results
Annotation masks of the pulmonary artery were created in 4,139 images across twelve cases of robotic right lower lobectomy. 2,893 and 684 annotated images across ten (83.3%) cases were used for training and validation, respectively; and 261 and 301 annotated images from two (16.7%) cases were used for generalization testing. A mean IoU of 87.7% was achieved in the validation dataset. The AP50 attained by our model was 96.7% and AP75 was 82.3%. In generalizability testing, when the model was tested on data never exposed to it, it was able to partially generalize with a mean IoU of 86.0%. 

Conclusion
Our study shows that our Mask R-CNN model was able to identify surgical anatomy during robotic lobectomy with high accuracy in the validation dataset. While still at an early stage, more variable labeled data and collaborative efforts are needed to improve the generalizability of our model. We envision such a computer vision system to be valuable in early surgeon training and incorporate future real-time augmentation of video feedback to improve outcomes.






Using Artificial Intelligence for Automatic Detection of the Pulmonary Artery During Robotic Right Lower Lobectomies

Background: Endoscopy is commonly used to diagnose upper gastrointestinal (GI) system disorders. However, excess mucus can significantly impair visualization, and reducing mucus intra-procedurally can increase procedure time. Several studies have evaluated the efficacy of pre-medication with mucolytic agents prior to gastroscopy to improve the diagnostic yield of endoscopy and reduce procedural time. Here, we systematically review recent evidence assessing the efficacy of mucolytic agents, including N-acetyl cysteine (NAC), in improving visibility in upper GI endoscopy.
Methods: Studies were identified by interrogating the PubMed database using the search terms "endoscopy" and "N-acetyl cysteine" for the period of 2016-2023. Only randomized control trials were included in the search. Records written in languages other than English were excluded. Ten (10) records matching these criteria were retrieved. Title and abstract screening resulted in five (5) records, which were subsequently extracted.
Results: The studies were conducted in the United Kingdom, Chile, Portugal, Thailand, and the Czech Republic. Four (4) studies consisted of randomized, double-blinded, placebo-controlled trials, while the remaining study was a randomized, non-blinded controlled trial. Four (4) of the studies showed that pre-administration of NAC (600 mg) plus simethicone (100 mg) significantly improved the visibility of the upper GI tract (esophagus, stomach, and duodenum) when compared to placebo control. The only study that failed to show an improvement in visibility scores was attributed to sub-threshold doses of NAC (400 mg) and simethicone (20 mg). Although none of the studies included an arm consisting of NAC alone, one study comparing simethicone +/- NAC showed superior visibility when NAC was administered at a high dose (1000 mg), while another study comparing simethicone +/- NAC failed to show improvement when NAC was administered at a moderate dose (600 mg). Lastly, one study found that the procedure time and volume of mucosal cleansing solution required were significantly reduced when NAC and simethicone were administered together.


Conclusion: Our survey of recent randomized control trials supports that pre-medication with NAC (600-1000 mg) and simethicone (100 mg) significantly improves the visibility of the upper GI mucosal surfaces during upper endoscopic procedures and, therefore, may improve diagnostic yield in settings where visibility is impaired. This approach may be particularly useful in lower-resource settings where less sophisticated endoscopic tools are utilized.

Efficacy of N-Acetyl Cysteine in the Prevention of Post-Operative Atrial Fibrillation and Acute Kidney Injury Post-Cardiac Surgery: A Systematic Review

Background: Estimated Glomerular Filtration Rate (eGFR) is the standard method for determining kidney function and chronic kidney disease (CKD) stage classification. In the Spina Bifida (SB) population, eGFR estimates from a creatinine-based equation may not accurately represent kidney function due to the lower muscle mass in this population. We hypothesized that estimating equations utilizing Cystatin-C (CysC) would yield different CKD classifications than Creatinine (Cr) – based equations for the adult SB population. 

Methods: We conducted a retrospective chart review of all patients seen in an adult urology clinic with a diagnosis of spina bifida from 2004-2021 that were managed in our urology clinic with creatinine and cystatin C values available. All patients were > 18 years old. A cross-sectional study of patients with a CysC and concurrent Cr measurement was performed; the most recent lab values were utilized if multiple existed. Three adult eGFR equations were utilized. Patients were staged based on CKD classification (GFR > 90, GFR 60-90, GFR <60). A Chi-square test was conducted to determine the difference in CKD classification based on each equation.

Results: A total of 105 SB patients (63% female) were included in cross-sectional analysis. The mean age was 33 ± 6.5 years. Medical comorbidities including diabetes (12.4%), hypertension (28.6%), obesity (34.2%) were noted. Table 1 shows the difference in eGFR and CKD classifications between equations. On Chi-square analysis, CKD classifications were significantly different by the type of equation used (p = 0.007). Pair-wise comparison showed that significance was driven by the difference between cystatin C and creatinine equations (p = 0.002) and the cystatin C and combined equations (p = 0.05). 

Conclusion: In an adult SB population, CysC-based equations result in lower eGFRs and different CKD classifications. Determining an appropriate eGFR measurement is essential to assessing and managing renal function in these medically complex patients.

Variability in Cystatin C and Creatinine-Based equations for Chronic Kidney Disease Staging in Adult Spina Bifida Patients

Background:
Financial difficulties have been associated with cancer patients delaying or deferring necessary care, resulting in later presentation with more advanced disease and worse clinical outcomes. Various sociodemographic factors have been linked to financial toxicity endured by cancer patients and negative clinical outcomes, including race, baseline financial status, region of residence, and insurance status. The association between specific financial factors and various clinical outcomes in particular forms of cancer requires further investigation.

Methods:
A cross-sectional study was conducted assessing 488,853 prostate cancer patients from the Surveillance, Epidemiology, and End Results (SEER) Program between the years of 2010 and 2018. The association between annual household income (HHI) and outcomes of prostate cancer were examined using ANOVA and Chi-square analyses comparing clinical measures based on categorical HHI groupings.

Results:
The average age across all HHI classifications was 66.63 years. Analysis demonstrated that a significantly higher percentage of African American patients fell within the <=35k and 35-55k income categories compared to other races (p<0.001). Patients with a lower HHI had higher PSA levels (12.10 vs. 10.90, 10.61, and 10.37 for <=35k, 35-55k, 55-75k, and >=75k, respectively, p<0.001) and the highest rate of disease metastasis to bone (6.3%, 5.6%, 5.7%, and 5.8% for <=35k, 35-55k, 55-75k, and > 75k, respectively, p<0.001) upon diagnosis. Patients in lower income brackets also demonstrated lower rates of undergoing surgical treatment (31.9%,
36.9%, 37.6%, and 35.1% for <=35K, 35-55k, 55-75k, and > 75k, respectively, p<0.001). Lastly, patients with lower HHI demonstrated progressively higher rates of cancer-specific-mortality (8.4%, 6.8%, 6.5% and 5.1% for <=35k, 35-55k, 55-75k, and >75k, respectively, p<0.001), as well as higher overall mortality (21.2%, 18.0%, 15.0%, and 11.9% for <=35k, 35-55k, 55-75k, and >75k, respectively, p<0.001).

Conclusions:
These data suggest that prostate cancer patients with lower household income are diagnosed with more aggressive disease, tend to undergo surgery at lower rates, develop more advanced disease, and endure worse clinical outcomes than those in higher income brackets. African Americans appear to be disproportionately affected compared to other races. Healthcare providers should be made aware of the clear associations between lower income and more aggressive disease at diagnosis, lower rates of surgical treatment, and worse cancer-specific and overall mortality so that adequate support may be provided regardless of financial difficulties.

The impact of household income on prostate cancer diagnosis, treatment, and outcomes

Background
Kidney stones are a common urological affliction in North America, affecting approximately 7 to 13% of the population. Abdominal pain is a frequent symptom, often prompting patients to present to the emergency department, where a CT scan confirms the diagnosis. A significant number of these patients undergo urological management in the form of temporary ureteral stent placement in the acute setting. The American Urological Association has guidelines which offer a framework for appropriate therapeutic interventions for renal colic, ranging from pain management and trial of medical expulsive therapy to surgery. This analysis seeks to evaluate the application of these guidelines at a tertiary medical center in patients who present with abdominal pain and are diagnosed with nephrolithiasis.
Methods
Chart review was conducted for patients who underwent ureteral stent placement for nephrolithiasis from January 1st to December 31st, 2022 at the University of Cincinnati Medical Center in Cincinnati, OH. Stones were classified based on size: less than 5 millimeters, between 5 and 10 millimeters and more than 10 millimeters. We assessed for infection, defined as more than 10,000 WBC/L or evidence of leukocyte esterase or nitrates on urinalysis, elevated creatinine, intractable pain, and presence of hydronephrosis on the affected side.
Results
Of the 174 patients who received stent placement in 2022 for a diagnosis of nephrolithiasis, 103 underwent the procedure emergently at the time of initial presentation. 94/103 (91.2%) had stones < 10 mm and 1 of these 94 (1.1%) received a stent in the absence of severe pain, infection, or elevated creatinine. 19/94 (20.2%) received stenting due to pain alone, and 75/94 (79.8%) had multiple indications (per AUA guidelines) for the procedure. 59 patients with a stone size < 10 mm underwent stenting after discharge and failure of medical therapy; 53 (89.8%) of these patients had at least one possible indication for stenting at the time of initial presentation.
Conclusion
Peer-reviewed guidelines offer a valuable framework to improve patient care by correlating therapy with appropriate indications. The AUA’s 2016 guidelines for surgical stone management encourage a trial of medical therapy for stones < 10 mm if not accompanied by infection or renal failure. Our findings suggest that these guidelines are effectively preventing unnecessary surgical intervention, as evidenced by the low rate of stenting without appropriate indications (1.1%), but may be driving overly conservative decision making, as a significant number of patients were discharged with medical therapy who may have benefited from emergent stenting.

A Retrospective Review of Emergent Ureteral Stenting for Renal Colic Attributable to Nephrolithiasis in the Emergency Department


OpenAI’s ChatGPT (Generative Pre-trained Transformer), one of the world’s first widely used Large Language Models (LLM), uses billions of parameters to generate user-informed text. In the healthcare sector, this chatbot encompasses a range of medical knowledge that can be tailored to the user’s needs, from assisting medical students with United States Medical Licensing Exam (USMLE) questions to proposing treatment options for oncologists. Upon its release, professionals began assessing the value of ChatGPT by pushing its limits within medical knowledge; however, it is imperative to explore ChatGPT’s role in patient care to best demonstrate and provide direction for how health professionals will work with AI as technology develops. To truly assess the potential of AI and LLMs in complex medical reasoning, we tested the ability of ChatGPT-3.5 to provide differentials on case records of the Massachusetts General Hospital published in the New England Journal of Medicine (NEJM). 40 case records from the Massachusetts General Hospital published in the NEJM in 2022 were presented to ChatGPT-3.5. From these prompts, we recorded whether the final diagnosis, as referenced in the NEJM, was included in the complete differential diagnosis list and whether ChatGPT’s ”most likely diagnosis” aligned with the final diagnosis noted in NEJM. In 17/40 cases (42.5%), ChatGPT did include the final diagnosis in its’ original differential list. After narrowing down its’ differential list, ChatGPT correctly determined the final diagnosis in 11 cases (27.5%) and eliminated the correct diagnosis in 6 cases (15%). ChatGPT-3.5 has a knowledge cutoff date of September 2021; therefore, we were able to examine ChatGPT’s ability to use clinical reasoning to diagnose rather than use its search functions to locate published articles. As future Chatbot functions will likely be linked to the internet for up-to-date functioning, we uniquely demonstrate ChatGPT’s baseline ability to assess complex clinical case presentations and diagnose alongside some of the world’s top physicians. ChatGPT’s ability to produce a differential list nearly instantaneously presents a first-of-its-kind opportunity to assist in brainstorming differentials, provide teaching moments for students, and as a general “consult” for physicians that may not have access to collaborate with every specialty. These findings suggest that while artificial intelligence, such as ChatGPT, has the potential to augment clinical decision-making, careful consideration of its limitations and ongoing research are crucial to ensure its reliable and effective use in clinical practice. We propose future clinical problem-solving cases to consider utilizing AI as an augmented clinical opinion.

ChatGPT: An Augmented Clinical Opinion

Capillary malformations, commonly known as port-wine stains, are vascular anomalies that typically present at birth as a pink or purple patch of skin. Pulsed dye laser (PDL) is the current mainstay in treatment, however, limitations of PDL include the requirement of multiple treatments and that complete, lasting blanching is rarely achieved with monotherapy. There is recent research on the addition of pharmacologic agents, including sirolimus as an adjunct to PDL treatment.
Sirolimus is known to have anti-angiogenic effects, which may impact revascularization after PDL treatment. Recent studies report improvement in color and texture of port-wine stain using dual therapy as compared to PDL monotherapy. Dual therapy has also been shown to exhibit greater improvement and maintenance of results with fewer PDL treatments.
The goal of this paper is to determine if there is a significant difference in port-wine stain clinical outcomes for PDL and adjunctive sirolimus, and discuss its implications for the treatment of port-wine stains in the future.

A systematic literature review using PubMed, Cochrane, and Embase was used to assess the role that sirolimus therapy can have on PDL treatment outcomes for port-wine stain. Key search terms included “port wine stain PDL sirolimus”, “port wine stain PDL”, and “port wine stain PDL and topical treatment”.

Prominent findings report that the inclusion of topical sirolimus 0.2% as adjunct therapy to PDL led to significant improvement in both patient and investigator assessments of colorimetry, measured every 2 months for an 8 month study duration (p-value=0.041 and 0.039, respectively). PDL monotherapy was found to also provide significant improvement in colorimetry 12.33 ± 3.46 vs. 8.53 ± 3.81, at baseline and at month 8, respectively (p-value = 0.002). Range was between 0-15, with higher values correlating with darker shades. 

These findings indicate that dual therapy with sirolimus and PDL may improve clinical outcomes. However, certain features including age, location of port-wine stain, and sirolimus concentration may influence these and should guide clinician recommendations. Sirolimus usage should be determined by accounting for its adverse effects (itching, dryness, contact dermatitis) and considering the high cost of compounding the formula with a higher dosage to sustain efficacy.

Sirolimus may have a positive impact on PDL treatment outcomes in patients suffering from port-wine stains, but certain considerations need to be accounted for in order to assess whether dual therapy is recommended. These findings indicate notable implications for the future of port-wine stain treatment, in which positive clinical outcomes can be achieved more easily and comfortably.

Adjunctive Sirolimus with Pulsed Dye Laser for Treatment of Capillary Malformations

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.

Iron overload upregulates glucose transporter GLUT3 expression in mouse liver

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.

Next from AMA Research Challenge 2023

Using Artificial Intelligence for Automatic Detection of the Pulmonary Artery During Robotic Right Lower Lobectomies