United States

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 We postulate that this is in part due to limited or outdated research on the prevalences and clinical manifestations of MnDs.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. 
  



AMA Research Challenge 2024 

Informing Clinical Insights: A Retrospective Analysis to Describe Micronutrient Deficiencies

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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.

PEG10, a potential target biomarker in hepatocellular carcinoma

Since the beginning of the COVID-19 pandemic, there have been over 775 million reported cases worldwide. A significant proportion of these patients suffer from long-COVID, experiencing symptoms such as severe fatigue, myalgias, and gastrointestinal (GI) dysfunction. Both chronic post-infectious disorders and GI conditions are linked to persistent sympathetic nervous system activation (PSA), however the specific interactions between long-COVID and GI disorders requires additional investigation. We hypothesized that individuals with pre-existing GI disorders would have higher rates of long-COVID. We also postulated that long-COVID increases the risk for GI disorder diagnosis.

We utilized de-identified electronic health record data from TriNetX, a global health research network with over 124 million patients. We constructed queries to identify subjects with upper functional (UF), lower functional (LF), upper structural (US), or lower structural (LS) GI disorder diagnoses. Afterwards, we analyzed the prevalence of long-COVID (defined as new malaise and fatigue symptoms lasting ≥1 month post-infection and not present in the previous 4 years) in patients with and without GI conditions. Additionally, we compared the rates of GI symptom development in patients with and without long-COVID diagnosis. Changes in GI disorder incidence in the 4 years before and after the pandemic onset (January 1, 2020) were also examined. Data were evaluated with chi-squared analysis.

Subjects with long-COVID had higher pre-COVID GI disorder prevalence compared to subjects without long-COVID [UF (1.12%), LF (2.33%), US (13.13%), and LS (0.80%)] (p<0.001). There was also a 0.65%, 0.83%, 4.93% increase in UF, LF, and LS post-COVID diagnoses prevalence, respectively, and a 5.77% decrease in US diagnoses (p<0.001) between patients with long-COVID and without long-COVID. In the general population, post-pandemic, the prevalence of LF and US diagnoses increased by 0.14% and 0.38% (p<0.001), while UF and LS diagnoses decreased by 0.015% and 0.17% (p<0.001). 

These results suggest that GI disorders, especially upper structural and functional GI disorders, pose a higher risk for long-COVID symptoms. However, the nuanced prevalences of GI conditions following long-COVID reflect a need for further research on the long-term impacts and mechanisms of PSA-mediated GI tract dysfunction following SARS-CoV-2 infection.

The Impact of Gastrointestinal Conditions on Long-COVID: Insights from a Global Health Network

Background: Colorectal Cancer (CRC) is the third most common and deadly cancer in the United States (U.S.). Widespread adoption and utilization of screening programs and patient education have likely contributed to the decline in CRC incidence, but morbidity and mortality still remain high. Racial disparities at every step in the cancer care continuum have been well-reported among large U.S. cohort studies, with Black patients experiencing worse outcomes. Care access, screening enrollment, and timely receipt of cancer treatment are known contributing factors. Our project’s aim was to investigate if racial disparities in CRC care exist in the more-equal access health care system of the national Veterans Affairs (VA) system.

Methods: In this retrospective cohort study, patient data was collected from the VA Central Cancer Registry. All veterans with incidental or first-time diagnosis of CRC from January 2017 to December 2021 were included and categorized as Non-Hispanic White (White) or Non-Hispanic Black (Black) race. Patients of other races were excluded given limited sample size.

Variables of interest included: sociodemographic factors (age, sex, VA priority group, rural vs. urban); BMI; tobacco and alcohol use; diabetes mellitus; and Deyo-Charlson comorbidity score. Study outcomes included stage at diagnosis (American Joint Committee on Cancer staging system), receipt of cancer treatment, and survival. Treatment included surgical resection, chemotherapy, or radiation therapy in any or no combination.

Results: A total of 8,021 patients with CRC (76.3% White, 23.7% Black) were identified, with a median age of 71 (IQR 66-76). Black patients were more likely to be younger at time of cancer diagnosis (median 68 years) compared to White patients (median 71 years; p-value<0.05). On multivariable analysis, after adjusting for the above listed variables of interest, there were no statistically significant differences in the following outcomes by race: stage at diagnosis (odds ratio (OR) 0.98; 95% confidence interval (CI) 0.87-1.11); receipt of any cancer treatment (additionally adjusted for stage: OR 0.86; 95% CI 0.74-1.00); or overall survival (additionally adjusted for stage and treatment: OR 0.97; 95% CI 0.87-1.08).

Conclusion: The well-described racial disparities in timing of cancer diagnosis, receipt of care, and survival seen in patients with CRC throughout the U.S. are not observed in the more equitable VA health care system. These findings highlight that equal access to care, including screening and surveillance programs, largely eliminates racial disparities in CRC outcomes. Adoption of similar systematic efforts in health care systems outside of the VA could lead to reduction in cancer care disparities.

The Impact of Race on Colorectal Cancer Outcomes in the Nationwide Veterans Affairs Health Care System


Background: The COVID-19 pandemic led to a decrease in colorectal cancer (CRC) screening. Preceding the pandemic, CRC screening rates had shown an increase across all racial groups. However, post- pandemic, there has been a decline in screening rates among AA, which will exacerbate existing disparities. 

Objective: This study aims to analyze CRC screening data collected before and after the COVID-19 pandemic to understand the distribution of pandemic- associated screening decreases on CRC disparities in the AA population. 

Methods: A systematic literature search through PubMed, Embase, and Google Scholar was done using keywords “Colorectal cancer screening”, “Covid 19”, “Colorectal Cancer”, “Colonoscopy”, and “African Americans”. The initial search resulted in 367 articles, of which nine studies in the USA (Ohio, Missouri, NYC, California) met the inclusion criteria (adults, 18+, English). We assessed patient colonoscopy records and reviewed the literature to correlate the influence of factors such as reallocation of health resources, financial burdens, decreased advocacy, and psychosocial factors on CRC screening. 

Results: African Americans had a 47% decrease (from 50,129 to 26,713) in CRC screening colonoscopy from 2019 to 2020, whereas Whites had a 39% decrease (from 403,596 to 244,414). Spanish patients had a 31% decrease (from 19,842 to 13,615). Quartile 1 HHI had a 36% decrease (from 455 to 290). Quartile 4 HHI had a 33% decrease (from 166 to 111). Quartile 1 education had a 18% decrease (from 1,905 to 1,557). Quartile 4 education had a 14% decrease (from 2,237 to 1,935). Patients from low SVI had a 20% decrease (from 23,136 to 18,402). High SVI patients had a 22% decrease (from 25,859 to 20,064). 

Conclusion: The pandemic led to an overall decrease in colonoscopies that was significantly more pronounced among AA, especially those from low socioeconomic backgrounds. To address this, enhanced screening programs are essential to mitigate the impact of pandemic-related delays or cancellations on screenings. These efforts are crucial to counteracting the exacerbation of existing disparities tied to socioeconomic status and healthcare access. 


Understanding and Addressing Pre- and Post- COVID-19 Disparities in CRC Screening and Outcomes among African Americans

Background
Protocolizing pain management perioperatively can reduce opioid exposure in children. Our group designed a multi-modal, opioid free pain management protocol with intent to decrease opioids in children undergoing hernia repair. The purpose of this study is to evaluate protocol usage and outcomes after implementation.
Methods
The protocol utilizes non-opioid analgesics, nerve blocks, and child life perioperatively. Patient characteristics, pre plus intra-operative (PIO) and post-operative (PO) opioid use, and protocol adherence were compared pre- and post-implementation. Adherence was stratified by level of opioid use - high (no PIO or PO use), medium (no PIO but + PO use), and low (+PIO, +PO use).
Results
After seven months, 175 cases were analyzed with 103 pre- and 72 post-implementation. There were no significant differences in demographics or hernia type. The median age and weight were 4.00 years (IQR 1.60, 6.00) and 17.60 kg (IQR 11.97, 24.90). Post-implementation, there was a significant increase in nerve blocks (37 (51.4%) vs. 6 (5.8%), p<.0001) and PIO non-opioid analgesics (64 (88.9%) vs. 24 (23.3%), p<.0001). We also saw a significant decrease in PIO opioids (8 (11.1%) vs. 89 (86.4%), p<.0001). Additionally, we noted a significant increase in PO non-opioid pain medications (38 (52.8%) vs. 34 (33%), p=.012). And again, there was a significant decrease in PO opioid usage in the post-implementation group (22 (30.6%) vs. 77 (74.8%), p <.0001). Pain scores where not significantly affected. No significant differences were found in PO complications, including nausea, vomiting or respiratory events. 89% of cases had either high or medium protocol adherence.
Conclusion
Our protocol decreased the use of opioids in pediatric patients undergoing hernia repair. Adherence to the protocol was good and resulted in increased use of non-opioid analgesics for pain.

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