Lifestyle Medicine for the Prevention and Treatment of Pancreatitis and Pancreatic Cancer.

The incidence of pancreatitis and pancreatic cancer is on the upswing in the USA. These conditions often lead to higher healthcare costs due to the complex nature of diagnosis and the need for specialized medical interventions, surgical procedures, and prolonged medical management. The economic ramification encompasses direct healthcare expenses and indirect costs related to productivity losses, disability, and potential long-term care requirements. Increasing evidence underscores the importance of a healthy lifestyle in preventing and managing these conditions. Lifestyle medicine employs evidence-based interventions to promote health through six key pillars: embracing a whole-food, plant-predominant dietary pattern; regular physical activity; ensuring restorative sleep; managing stress effectively; removing harmful substances; and fostering positive social connections. This review provides a comprehensive overview of lifestyle interventions for managing and preventing the development of pancreatitis and pancreatic cancer.

Factors That Influence the Speed and Completion of Double Balloon Enteroscopy in Patients with Arteriovenous Malformations.

BACKGROUND: Double balloon enteroscopy remains a resource and time-intensive procedure that is not available in many endoscopy units. AIMS: We aimed to identify variables impacting the speed and completion of double balloon enteroscopy. METHODS: We retrospectively reviewed 550 patients. Using a mean time and distance for both the antegrade and retrograde approach, we determined the procedure speed and assessed factors that influenced it. In addition, we assessed the factors that contributed to a complete double balloon enteroscopy. RESULTS: A total of 386 antegrade and 164 retrograde double balloon enteroscopies were performed. Greater than 10 AVMs requiring treatment was a negative predictor (AOR 0.25, CI 0.11-0.51, p < 0.001), whereas age greater than 60 years (AOR 2.66, CI 1.18-6.65, p = 0.025) was a positive predictor of a fast antegrade enteroscopy. For retrograde, prior abdominal surgery was the only factor that trended to significance (AOR 0.38, CI 0.14-0.99, p = 0.052). A total of 120 combined procedures were performed. Female gender (AOR 2.62, CI 1.16-6.24, p = 0.02), history of prior abdominal surgery (AOR 0.31, CI 0.13-0.70, p = 0.006) and Boston bowel pre-preparation score of greater than 6 (AOR 4.50, CI 1.59-14.30, p = 0.006) were the only significant predictors of a complete procedure. CONCLUSION: By applying double balloon enteroscopy speed, a novel method of measuring procedure efficiency, we were able to more reliably identify the factors that will negatively impact the speed and success of the procedure.

Prospective, Multi-Institutional, Real-Time Next-Generation Sequencing of Pancreatic Cyst Fluid Reveals Diverse Genomic Alterations That Improve the Clinical Management of Pancreatic Cysts.

BACKGROUND & AIMS: Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time. METHODS: The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound-guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens. RESULTS: Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations. CONCLUSIONS: PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.

Post-EMR for colorectal polyps, thermal ablation of defects reduces adenoma recurrence: A meta-analysis.

Background and study aims Adenoma recurrence is one of the key limitations of endoscopic mucosal resection (EMR), which occurs in 15 % to 30 % of cases during first surveillance colonoscopy. The main hypothesis behind adenoma recurrence is leftover micro-adenomas at the margins of post-EMR defects. In this systematic review and meta-analysis, we evaluated the efficacy of snare tip soft coagulation (STSC) at the margins of mucosal defects to reduce adenoma recurrence and bleeding complications. Methods Electronic databases such as PubMed and the Cochrane library were used for systematic literature search. Studies with polyps only resected by piecemeal EMR and active treatment: with STSC, comparator: non-STSC were included. A random effects model was used to calculate the summary of risk ratio and 95 % confidence intervals. The main outcome of the study was to compare the effect of STSC versus non-STSC with respect to adenoma recurrence at first surveillance colonoscopy after thermal ablation of post-EMR defects. Results Five studies were included in the systematic review and meta-analysis. The total number patients who completed first surveillance colonoscopy (SC1) in the STSC group was 534 and in the non-STSC group was 514. The pooled adenoma recurrence rate was 6 % (37 of 534 cases) in the STSC arm and 22 % (115 of 514 cases) in the non-STSC arm, (odds ratio [OR] 0.26, 95 % confidence interval [CI], 0.16-0.41, P  = 0.001). The pooled delayed post-EMR bleeding rate 19 % (67 of 343) in the STSC arm and 22 % (78 of 341) in the non-STSC arm (OR 0.82, 95 %CI, 0.57-1.18). Conclusions Thermal ablation of post-EMR defects significantly reduces adenoma recurrence at first surveillance colonoscopy.

Diet and carcinogenesis of gastric cancer.

PURPOSE OF REVIEW: Several recent studies have corroborated a strong association between diet and gastric cancer risk; investigators have also identified dietary factors that protect against gastric cancer. This review summarizes the literature on this topic and guides future research directions. RECENT FINDINGS: High-salt intake disrupts the gastric mucosal defense barrier, promoting Helicobacter pylori colonization and penetration of other carcinogenic compounds. Processed foods, processed meats, red meat, alcohol, foods with high dietary fat, and dietary cholesterol increase the risk of gastric carcinogenesis. On the other hand, increased consumption of fruits, vegetables, whole grains, nuts, and a low-salt diet may offer a protective effect. SUMMARY: Despite decreases in gastric cancer incidence because of increased identification and treatment of H. pylori , gastric cancer remains one of the most common cancers worldwide with a high mortality rate. This disturbing statistic highlights the importance of reducing and eliminating other risk factors for gastric cancer. There is a strong body of evidence that alcohol, processed foods, high salt intake, high fat intake, and foods with animal products (meats, eggs, and dairy) increase the risk of gastric cancer. A diet that is high in whole grains, fruits, vegetables, nuts and is low in salt may reduce the risk of gastric cancer.

Splenic injury is an under-recognized adverse event of in-patient colonoscopy: a nationwide analysis.

Background and study aims Splenic injury (SI) during colonoscopy is an underappreciated adverse event. Our aim was to examine the occurrence and outcomes of patients who developed SI after inpatient colonoscopy using a nationwide dataset. Patients and methods Retrospective, observational study using the National Inpatient Sample (NIS) between 2012 and 2018. All patients with ICD9/10CM procedural codes for colonoscopy with or without SI were included. The primary outcome was the association between SI and inpatient colonoscopy. Secondary outcomes were inpatient morbidity, mortality, resource utilization, splenectomy rates, hospital length of stay and total hospital costs and charges. Comparative analyses were performed between patients with and without SI. Multivariate regression analyses were utilized. Results A total of 2,258,040 of inpatient colonoscopies were included. Of these, 240 had associated SI and 25 patients required splenectomy (10.4 %). The incidence of colonoscopy-associated SI remained relatively stable between 2012 and 2018 (0.033 % versus 0.020 %, respectively). The mean age of patients with and without SI was 63.7 and 64.1 years, respectively. The occurrence of SI was calculated as 10.63 cases per 100,000 inpatient colonoscopies. Patients who had associated SI displayed significantly higher odds of inpatient mortality (aOR: 14.45) and ICU stay (aOR: 10.11) compared to those without SI. Conclusions Splenic injury confers significantly higher odds of inpatient mortality, and resource utilization. The incidence of SI related to colonoscopy remained stable during the study period. Although uncommon, SI should be considered when encountering patients with abdominal pain after colonoscopy.

Evaluation of a U.S. National Cohort to Determine Utilization in Colectomy Rates for Ulcerative Colitis Among Ethnicities.

BACKGROUND: Colectomy is the curative management for ulcerative colitis (UC). Multiple studies have reported racial disparities for colectomy before the advent of anti-TNF alpha agents. The aim of this study was to describe racial and geographic differences in colectomy rates among hospitalized patients with UC after anti-TNF therapy was introduced. METHODS: We examined all patients discharged from the hospital between 2010 and 2014 with a primary diagnosis of UC or of complications of UC. The data were evaluated for race and colectomy rates among the hospitalized patients with UC. RESULTS: The unadjusted national colectomy rate among hospitalized patients with UC between 2010 and 2014 was 3.90 per 1000 hospitalization days (95% confidence interval, 3.72-4.08). The undajusted colectomy rates in African American (2.33 vs 4.35; P < 0.001) and Hispanic patients (3.99 vs 4.35; P ≤ 0.009) were considerably lower than those for White patients. After adjustment for confounders, the incidence rate ratio for African American as compared to White patients was 0.43 (95% confidence interval, 0.32-0.58; P < 0.001). Geographic region of the United States also showed significant variation in colectomy rates, with western regions having the highest rate (4.76 vs 3.20; P < 0.001). CONCLUSIONS: Racial and geographical disparities persist for the rate of colectomy among hospitalized patients with UC. The national database analysis reveals that colectomy rates for hospitalized African American and Hispanic patients were lower than those for White patients. Further studies are important to determine the social and biologic foundations of these disparities.

Colchicine as an Alternative First-Line Treatment of Sclerosing Mesenteritis: A Retrospective Study.

BACKGROUND: Sclerosing mesenteritis is a rare condition characterized by chronic inflammation and fibrotic changes of the mesentery. AIMS: To determine the long-term management and outcomes of patients with sclerosing mesenteritis. METHODS: Patients with biopsy-proven sclerosing mesenteritis at the Mayo Clinic between January 2006 and December 2016 were identified. Clinical data were collected retrospectively. RESULTS: One hundred and three patients were identified, median age 68.0 years (range 35.0-85.3). Most patients were symptomatic (87.4%) at presentation. Patients received no treatment (52.4%), medical therapy (42.7%) or surgery (4.9%) on initial diagnosis. The most common initial regimens were prednisone plus tamoxifen (41.9%), prednisone alone (23.3%), and prednisone plus colchicine (11.6%) with 55.6%, 57.2%, and 60% of patients improving, respectively, p = 0.85 for a difference in response rates. At least half of the patients responded to prednisone plus tamoxifen, prednisone plus colchicine, or prednisone alone at 6.0, 7.2, and 8.4 months, respectively. At a median follow-up of 45.6 months (95% CI 24.1-69.7), 65.4% of patients were receiving medical therapy. Of those receiving tamoxifen-based, steroid-based, or steroid-sparing regimens, 100%, 87.5%, and 77.8% had improved by their last follow-up appointment respectively, p = 0.15. CONCLUSION: Prednisone plus colchicine has a similar efficacy to prednisone plus tamoxifen for the initial and long-term treatment of sclerosing mesenteritis. The majority of patients were initiated on medical therapy over the long term with most reporting symptomatic improvement within a year. Death from SM was rare.

Umbralisib-Induced Immune-Mediated Colitis: A Concerning Adverse Effect of the Novel PI3Kδ/CK1ε Inhibitor.

Novel chemotherapeutic agents are developed to treat recurrent/relapsed lymphoid malignancies. Umbralisib, a novel phosphatidylinositol 3-kinase inhibitor with a selective isoform binding, has shown an improved efficacy and safety profile in clinical trials. Immune-mediated colitis, a frequently observed dose-limiting adverse event of phosphatidylinositol 3-kinase inhibitors, has been mostly observed at supratherapeutic doses in the trials, with grade 1 or 2 diarrhea being the most common adverse event at the therapeutic dose (800 mg PO QD). We present a grade-3 colitis that can be attributed to umbralisib-mediated immune toxicity in a patient with chronic lymphocytic leukemia at the therapeutic dose.

A multicenter, prospective, inpatient feasibility study to evaluate the use of an intra-colonoscopy cleansing device to optimize colon preparation in hospitalized patients: the REDUCE study.

BACKGROUND: High quality bowel preparation prior to colonoscopy can be difficult to achieve in the inpatient setting. Hospitalized patients are at risk for extended hospital stays and low diagnostic yield due to inadequate bowel preparation. The Pure-Vu System is a novel device intended to fit over existing colonoscopes to improve intra-colonoscopy bowel preparation. The objective of the REDUCE study was to conduct the first inpatient study to evaluate optimization of bowel preparation quality following overnight preparation when using the Pure-Vu System during colonoscopy. METHODS: This multicenter, prospective feasibility study enrolled hospitalized subjects undergoing colonoscopy. Subjects recorded the clarity of their last bowel movement using a 5-point scale prior to colonoscopy. After one night of preparation, all enrolled subjects underwent colonoscopy utilizing the Pure-Vu System. The primary endpoint was improvement of colon cleanliness from baseline to post-cleansing with the Pure-Vu System as assessed by the improvement in Boston Bowel Preparation Scale (BBPS). An exploratory analysis was conducted to assess whether the clarity of the last bowel movement could predict inadequate bowel preparation. RESULTS: Ninety-four subjects were included. BBPS analyses showed significant improvements in bowel preparation quality across all evaluable colon segments after cleansing with Pure-Vu, including left colon (1.74 vs 2.89; p < 0.0001), transverse colon (1.74 vs 2.91; p < 0.0001), and the right colon (1.41 vs 2.88; p < 0.0001). Prior to Pure-Vu, adequate cleansing (BBPS scores of ≥ 2) were reported in 60%, 62%, and 47% for the left colon, transverse colon, and right colon segments, respectively. After intra-colonoscopy cleansing with the Pure-Vu System, adequate colon preparation was reported in 100%, 99%, and 97% of the left colon, transverse colon, and right colon segments, respectively. Subjects with lower bowel movement clarity scores were more likely to have inadequate bowel preparation prior to cleansing with Pure-Vu. CONCLUSIONS: In this feasibility study, the Pure-Vu System appears to be effective in significantly improving bowel preparation quality in hospitalized subjects undergoing colonoscopy. Clarity of last bowel movement may be useful indicator in predicting poor bowel preparation. Larger studies powered to evaluate clinical outcomes, hospital costs, and blinded BBPS assessments are required to evaluate the significance of these findings. Trial registration Evaluation of the Bowel Cleansing in Hospitalized Patients Using Pure-Vu System (NCT03503162).

A 3-Decade Analysis of Pancreatic Adenocarcinoma After Solid Organ Transplant.

OBJECTIVE: Solid organ transplant (SOT) recipients have moderately increased risk of pancreatic adenocarcinoma (PAC). We evaluated the incidence and survival of PAC in 2 cohorts and aimed to identify potential risk factors. METHODS: This study performed a retrospective cohort analysis. Cohort A was extracted from the United Network of Organ Sharing data set and cohort B from SOT recipients evaluated at 3 Mayo Clinic transplant centers. The primary outcome was age-adjusted annual incidence of PAC. Descriptive statistics, hazard ratios, and survival rates were compared. RESULTS: Cohort A and cohort B included 617,042 and 29,472 SOT recipients, respectively. In cohort A, the annual incidence rate was 12.78 per 100,000 in kidney-pancreas, 13.34 in liver, and 21.87 in heart-lung transplant recipients. Receiving heart-lung transplant, 50 years or older, and history of cancer (in either recipient or donor) were independent factors associated with PAC. Fifty-two patients developed PAC in cohort B. Despite earlier diagnosis (21.15% with stage I-II), survival rates were similar to those reported for sporadic (non-SOT) patients. CONCLUSIONS: We report demographic and clinical risk factors for PAC after SOT, many of which were present before transplant and are common to sporadic pancreatic cancer. Despite the diagnosis at earlier stages, PAC in SOT portends a very poor survival.

P032 Clinical Usefulness of Double Balloon Enteroscopy in Patients With Established or Suspected Small Bowel Crohn's Disease.

BACKGROUND: The diagnosis of isolated small bowel Crohn's disease (CD) can be challenging. Symptoms are non-specific and both imaging and capsule endoscopy (CE) may be misleading as several diseases may mimic CD. Double balloon enteroscopy (DBE) allows a more extensive endoscopic and histologic evaluation of the small bowel. Our aim was to describe the diagnostic utility and impact of DBE on management of patients with known CD and in patients with suspected/rule-out CD. METHODS: Retrospective review of our institution's DBE database from February 2009 to May 2013. Adult patients referred for DBE for further evaluation of known or suspected CD (due to symptoms, abnormal imaging and/or CE) were included. Patient demographics, clinical characteristics, imaging and CE results, prior DBE, indication for DBE, DBE findings, DBE adverse events, pathology findings, final diagnosis, treatment prior and post DBE and follow-up DBE were abstracted from the electronic medical record. RESULTS: A total of 108 patients were included, 61 (56%) females, mean age 52 years (range 20-83). Indications for DBE included: disease activity assessment/therapeutic in 10 patients with established diagnosis of CD and for diagnostic purposes in 98 patients with suspected CD (31 patients due to abnormal imaging, 29 due to abnormal CE and 26 due to both abnormal imaging and CE). Upper, lower, bidirectional upper and lower, and stomal DBE were performed in 21, 24, 62 and 1 patients, respectively. DBE revealed active disease in 8/10 patients with known CD with one patient undergoing dilation of a stricture. Changes in management were recommended for all patients with active disease - start thiopurine (2), optimize thiopurine dose (1), start biologics (3) change biologics (1), systemic steroids (1) and budesonide (1). The patient who underwent stricture dilation ultimately required surgery. A definitive diagnosis of CD (both endoscopic and histologic) was reached in only 39/98 (40%) patients who were referred for suspected CD. Changes in management were recommended in 32/39 (82%) patients. Interestingly, 24/98 patients had been diagnosed with CD at outside institutions and were recommended to initiate therapy for CD. Of these, CD was confirmed in only 15/24 (63%) patients. Adverse events included perforation in 1 patient (1%) who required surgical management and mouth swelling/abrasion in 3 patients (3%). Follow-up DBE to re-assess disease activity was performed in 10/49 (20%) patients with definitive diagnosis of CD, average time between procedures 4.5 years (range 0.7-11.6). One patient with CD was diagnosed with lymphoma 2.4 years after initial DBE. Changes in management were recommended in 6 patients: de-escalation of therapy (3, two underwent surgery), start thiopurine and/or biologic (2) and switch biologics (1). No complications were seen at follow-up DBE. CONCLUSION: DBE is a useful technique to confirm a diagnosis in patients who have suspected CD and can help establish a diagnosis of several diseases that may mimic CD on CT scan or CE. Additionally, DBE in patients with established diagnosis of small bowel CD is an effective tool to assess disease activity and guide therapy. Serious complications are infrequent.

Impact of topical budesonide on prevention of esophageal stricture after mucosal resection.

BACKGROUND AND AIMS: EMR and endoscopic submucosal dissection (ESD) are treatment modalities for Barrett's esophagus involving high-grade dysplasia or early cancer. Injectional corticosteroid therapy decreases the risk of procedure-related esophageal stricture (ES) formation. Our aim was to assess the efficacy of topical budesonide on the rate of ES formation after EMR or ESD. METHODS: Patients included prospectively from 3 tertiary endoscopy centers received 3 mg budesonide orally twice a day for 8 weeks after esophageal EMR or ESD of 50% or more of the esophageal circumference between January 1, 2014 and June 30, 2018. These patients were matched (1:3 ratio) retrospectively with a consecutive patient cohort who underwent EMR or ESD of 50% or more of the esophageal circumference without concomitant corticosteroid therapy. The primary endpoint was the presence of ES at the 12-week follow-up. RESULTS: Twenty-five patients (budesonide) were matched with 75 patients (no budesonide). Most underwent EMR for Barrett's esophagus with biopsy-proven high-grade dysplasia or suspected T1a cancer. Although most baseline characteristics did not differ significantly, patients in the budesonide cohort tended to have a higher proportion of circumferential EMR. The proportion of patients with ES was not significantly lower in the budesonide cohort (16% vs 28%). On logistic regression analysis, budesonide remained associated with a lower incidence of ES (P = .023); however, when controlling for baseline characteristics with a propensity score weighted logistic regression model, there was no significant effect on ES formation (P = .176). CONCLUSIONS: Topical budesonide might be associated with a reduction of ES after EMR or ESD; however, further studies are needed to verify our results.

Lymphocytic Esophagitis: Assessing Risk Factors and Clinical Outcomes.

BACKGROUND: Lymphocytic esophagitis is a rare esophageal condition. Our knowledge of potential risk factors and treatment outcomes of lymphocytic esophagitis is limited. AIM: To investigate potential risk factors associated with the development of lymphocytic esophagitis and compare clinical characteristics and treatment outcomes of patients diagnosed with lymphocytic esophagitis to patients diagnosed with eosinophilic esophagitis. METHODS: This is a multicenter retrospective study. Lymphocytic esophagitis patients were identified based on pathology results between 1997 and 2019. Control groups consisted of patients with normal esophageal biopsies and patients diagnosed with eosinophilic esophagitis. Thirteen potential risk factors for lymphocytic esophagitis were analyzed using univariate and multivariate models including IBD, achalasia, hyperlipidemia, hypothyroidism, celiac sprue, CVID, H. pylori, thymoma, aspirin, opioids, ACE-I, metformin, and statin use. Comparative statistics were performed. RESULTS: Ninety-four adult patients with lymphocytic esophagitis, 344 with eosinophilic esophagitis, and 5202 control patients with normal esophageal biopsies were analyzed. Age older than 60 [adjusted odd ratio (AOR) 1.03, 95% CI 1.02-1.05, p = 0.001], aspirin use (2.7, 95% CI 1.4-4.9, p = 0.001), statin use (2.2, 95% CI 1.2-4.2, p = 0.01), or a diagnosis of achalasia (2.4, 95% 1.08-5.67, p = 0.03) were associated with lymphocytic esophagitis. Compared to eosinophilic esophagitis, lymphocytic esophagitis patients were more likely to respond to medical treatment (95% CI 2.54-12.8, p = 0.0001). CONCLUSIONS: Our data suggests that lymphocytic esophagitis is more likely to be found in older female patients and is significantly associated with achalasia, statin, and aspirin use. Compared to eosinophilic esophagitis, lymphocytic esophagitis is more likely to respond to treatment with medical therapy.

Energy Drinks: A Reversible Risk Factor for Atrophic Gastritis and Gastric Intestinal Metaplasia.

Energy drinks (ED) are becoming increasingly popular, but little has been reported about their stomach effects. To our knowledge, there is no literature suggesting an association with the development of atrophic gastritis (AG) or gastric intestinal metaplasia (GIM). AG and GIM have been associated with an increased risk of gastric cancer. Reversal of these lesions has shown to reduce the incidence of gastric cancer but has only been studied to eradicate Helicobacter pylori. This case describes a female who consumed high amounts of ED and was subsequently diagnosed with AG and GIM. Interestingly, the pathologies resolved upon cessation of ED.