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The incidence of esophageal adenocarcinoma (EAC) has surged by 600% in recent decades, with a dismal 5-year survival rate of just 15%. Barrett's esophagus (BE), affecting about 2% of the population, raises the risk of EAC by 40-fold. Despite this, the transcriptomic changes during the BE to EAC progression remain unclear. Our study addresses this gap through comprehensive transcriptomic profiling to identify key mRNA signatures and genomic alterations, such as gene fusions. We performed RNA-sequencing on BE and EAC tissues from 8 individuals, followed by differential gene expression, pathway and network analysis, and gene fusion prediction. We identified mRNA changes during the BE-to-EAC transition and validated our results with single-cell RNA-seq datasets. We observed upregulation of keratin family members in EAC and confirmed increased levels of keratin 14 (KRT14) using immunofluorescence. More differentiated BE marker genes are downregulated during progression to EAC, suggesting undifferentiated BE subpopulations contribute to EAC. We also identified several gene fusions absent in paired BE and normal esophagus but present in EAC. Our findings are critical for the BE-to-EAC transition and have the potential to promote early diagnosis, prevention, and improved treatment strategies for EAC.
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BACKGROUND AND AIM: Post-reflux swallow-induced peristaltic wave (PSPW) index and mean nocturnal baseline impedance (MNBI) have been shown to influence proton pump inhibitor (PPI) response in GERD patients. However, currently, little data concerning these variables in patients with reflux hypersensitivity (RH) are available. In this study, we aimed to evaluate, in RH patients, the prevalence of PPI responders and nonresponders and investigate the predictive value of impedance-pH variables, including PSPW and MNBI, on responses to PPI. METHODS: A total of 108 RH patients who met ROME IV criteria were prospectively recruited from June 2018 to December 2022. The prevalence of PPI responders/nonresponders was calculated, and impedance-pH variables were compared between the response and nonresponse groups. Multiple logistic regression was used to investigate predictors for PPI response. RESULTS: Among 108 patients with RH, 60 patients (55.56%) were the PPI responders, and 48 (44.44%) were the nonresponders. Compared with the nonresponders, the PPI responders had a lower PSPW index (47.05 ± 4.43 vs 51.33 ± 3.50, P = 0.004) and a decreased value of MNBI (1866.68 ± 390.62 vs 2181.14 ± 338.42, P = 0.017). Multivariate logistic regression revealed that only the pathologic PSPW index (OR: 2.064) and MNBI (OR: 1.800) significantly influenced PPI response. CONCLUSIONS: Nearly half of RH patients were PPI nonresponders. Impedance-pH monitoring was more valuable than pH-only monitoring in associating PPI response to reflux in RH patients owing to the appraisal of the PSPW index and MNBI.
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BACKGROUND: Particulate matter exposure (PM) is a cause of aerodigestive disease globally. The destruction of the World Trade Center (WTC) exposed first responders and inhabitants of New York City to WTC-PM and caused obstructive airways disease (OAD), gastroesophageal reflux disease (GERD) and Barrett's Esophagus (BE). GERD not only diminishes health-related quality of life but also gives rise to complications that extend beyond the scope of BE. GERD can incite or exacerbate allergies, sinusitis, bronchitis, and asthma. Disease features of the aerodigestive axis can overlap, often necessitating more invasive diagnostic testing and treatment modalities. This presents a need to develop novel non-invasive biomarkers of GERD, BE, airway hyperreactivity (AHR), treatment efficacy, and severity of symptoms. METHODS: Our observational case-cohort study will leverage the longitudinally phenotyped Fire Department of New York (FDNY)-WTC exposed cohort to identify Biomarkers of Airway Disease, Barrett's and Underdiagnosed Reflux Noninvasively (BAD-BURN). Our study population consists of n = 4,192 individuals from which we have randomly selected a sub-cohort control group (n = 837). We will then recruit subgroups of i. AHR only ii. GERD only iii. BE iv. GERD/BE and AHR overlap or v. No GERD or AHR, from the sub-cohort control group. We will then phenotype and examine non-invasive biomarkers of these subgroups to identify under-diagnosis and/or treatment efficacy. The findings may further contribute to the development of future biologically plausible therapies, ultimately enhance patient care and quality of life. DISCUSSION: Although many studies have suggested interdependence between airway and digestive diseases, the causative factors and specific mechanisms remain unclear. The detection of the disease is further complicated by the invasiveness of conventional GERD diagnosis procedures and the limited availability of disease-specific biomarkers. The management of reflux is important, as it directly increases risk of cancer and negatively impacts quality of life. Therefore, it is vital to develop novel noninvasive disease markers that can effectively phenotype, facilitate early diagnosis of premalignant disease and identify potential therapeutic targets to improve patient care. TRIAL REGISTRATION: Name of Primary Registry: "Biomarkers of Airway Disease, Barrett's and Underdiagnosed Reflux Noninvasively (BADBURN)". Trial Identifying Number: NCT05216133 . Date of Registration: January 31, 2022.
Subject(s)
Barrett Esophagus , Biomarkers , Firefighters , Gastroesophageal Reflux , September 11 Terrorist Attacks , Humans , Barrett Esophagus/diagnosis , Barrett Esophagus/etiology , Gastroesophageal Reflux/diagnosis , Biomarkers/blood , Case-Control Studies , Firefighters/statistics & numerical data , New York City , Occupational Exposure/adverse effects , Particulate Matter/adverse effects , Particulate Matter/analysis , Observational Studies as Topic , MaleABSTRACT
Background: Cholelithiasis or cholecystectomy may contribute to the development of gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC) through bile reflux; however, current observational studies yield inconsistent findings. We utilized a novel approach combining meta-analysis and Mendelian randomization (MR) analysis, to assess the association between them. Methods: The literature search was done using PubMed, Web of Science, and Embase databases, up to 3 November 2023. A meta-analysis of observational studies assessing the correlations between cholelithiasis or cholecystectomy, and the risk factors for GERD, BE, and EACwas conducted. In addition, the MR analysis was employed to assess the causative impact of genetic pre-disposition for cholelithiasis or cholecystectomy on these esophageal diseases. Results: The results of the meta-analysis indicated that cholelithiasis was significantly linked to an elevated risk in the incidence of BE (RR, 1.77; 95% CI, 1.37-2.29; p < 0.001) and cholecystectomy was a risk factor for GERD (RR, 1.37; 95%CI, 1.09-1.72; p = 0.008). We observed significant genetic associations between cholelithiasis and both GERD (OR, 1.06; 95% CI, 1.02-1.10; p < 0.001) and BE (OR, 1.21; 95% CI, 1.11-1.32; p < 0.001), and a correlation between cholecystectomy and both GERD (OR, 1.04; 95% CI, 1.02-1.06; p < 0.001) and BE (OR, 1.13; 95% CI, 1.06-1.19; p < 0.001). After adjusting for common risk factors, such as smoking, alcohol consumption, and BMI in multivariate analysis, the risk of GERD and BE still persisted. Conclusion: Our study revealed that both cholelithiasis and cholecystectomy elevate the risk of GERD and BE. However, there is no observed increase in the risk of EAC, despite GERD and BE being the primary pathophysiological pathways leading to EAC. Therefore, patients with cholelithiasis and cholecystectomy should be vigilant regarding esophageal symptoms; however, invasive EAC cytology may not be necessary.
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A hiatal hernia occurs when the contents of the abdominal cavity, most often the stomach, protrude into the chest cavity through the esophageal hiatus. The hiatus is an elliptical-shaped outlet, typically formed by parts of the right diaphragmatic crus surrounding the distal esophagus. This ailment can transpire due to either the broadening of the specific diaphragmatic opening or a shortening in the overall length of the esophagus, leading to herniation of the stomach into the thoracic region. Raised pressure in the abdominal region may also be one of the culprits. Patients with a hiatal hernia usually remain asymptomatic, but patients might have difficulty swallowing both liquids and solids in the advanced stages of the disease. The disease is rarely accompanied by reflux of gastric acid into the esophagus due to decreased activity of the lower esophageal sphincter, leading to increased complaints of epigastric pain and ulceration near the gastroesophageal junction. Long-standing cases can increase the risk of developing Barrett's esophagus with dysplasia, which may advance to esophageal carcinoma in later stages. Advanced age and obesity are significant risk factors for hiatal hernia. Obese individuals, in particular, experience higher intra-abdominal pressure, which significantly raises the likelihood of developing a hiatal hernia. The hernia may be diagnosed through an upper gastrointestinal endoscopy or radiologically through a chest X-ray in the posterior-anterior view, defining the border of the esophagus. Hence, this facilitates a more seamless and precise diagnosis. Surgical fundoplication treatment improves the patient's condition better than solitary medical management. Overall, addressing the condition surgically often yields more favorable outcomes and enhances the patient's quality of life. Hiatal hernia usually presents with no or minimal clinical manifestations. Thus, this case report highlights the importance of comprehensive clinical management of such cases.
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No study has unequivocally proven that chemotherapy prolongs overall survival (OS) in advanced esophageal cancer. We conducted a Phase III randomized study in first-line advanced unresectable/metastatic esophageal/GEJ cancer. Patients aged 18-70 years, with performance status 0-2, were randomized to best supportive care (BSC) alone, or BSC with weekly paclitaxel 80 mg/m2. BSC comprised, as indicated, education, counselling, radiation, stenting, feeding tube placement, nutritional supplementation, medications like analgesics, and referral to a support group and palliative care. The primary endpoint was OS; secondary endpoints included progression free survival (PFS), response, toxicity, and QoL. Between May 2016-December 2020, we recruited 281 patients: 143 to chemotherapy and 138 to BSC. Histopathology was squamous in 269 (95.7%) patients. Median number of paclitaxel doses was 12 (IQR, 7-23). Median OS was 4.2 months (95% CI, 3.42-5.32) in BSC, and 9.2 months (95% CI, 8.02-10.48) in chemotherapy; HR, 0.49 (95% CI, 0.39-0.64); p < .001. As compared to BSC, chemotherapy increased response (2.9% to 39%), median PFS (2.1 to 4.2 months), 1-year OS (11% to 32%), 2-year OS (0 to 9%), median dysphagia-free survival (2.9 to 14.8 months), and global and esophagus-specific QoL, without significantly increasing all-grade or grade ≥3 toxicities. Using ESMO clinical benefit scale and ASCO Value Framework, palliative chemotherapy scored as having "substantial value." Our study provides the first level 1 evidence that chemotherapy prolongs survival in advanced esophageal/GEJ carcinoma. BSC alone is no longer appropriate. Weekly paclitaxel is an attractive option, especially in LMICs with limited access to immunotherapy.
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The z-line refers to the squamocolumnar junction which marks the transition between the normal stratified squamous epithelium of the distal esophagus and the columnar epithelium of the gastric cardia. An "irregular" z-line refers to an irregular appearing squamocolumnar junction characterized by the presence of columnar mucosa less than 1 cm in length that extends above the gastroesophageal junction. In contrast, Barrett's esophagus is diagnosed when columnar mucosa of at least 1 cm is seen in the distal esophagus extending above the gastroesophageal junction with biopsies demonstrating specialized intestinal metaplasia. Current guidelines recommend against taking routine biopsies from a normal or irregular z-line in the absence of visible abnormalities and advise against endoscopic surveillance in this patient population, in large part due to multiple studies demonstrating lack of progression to advanced neoplasia such as high-grade dysplasia or esophageal adenocarcinoma in patients with an irregular z-line. Despite these recommendations, a sizable number of patients without Barrett's esophagus undergo biopsies from the z-line and are subsequently recommended to have surveillance endoscopies. Furthermore, patients with an irregular z-line are often mislabelled as Barrett's esophagus resulting in significant downstream consequences including higher healthcare costs and reduced health-related quality of life. In this review, we highlight the importance of landmark identification of the distal esophagus and gastroesophageal junction at the time of endoscopy, share recommendations from current guidelines related to the z-line, examine rates of neoplastic progression in those with an irregular z-line, discuss consequences of routinely biopsying an irregular z-line, and highlight strategies on how to approach an irregular z-line if seen on endoscopy. A careful, high-quality endoscopic examination can help to identify visible abnormalities at the z-line, which, if present, should be targeted for biopsies to rule out dysplasia and neoplasia.
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BACKGROUND: The traction-induced esophageal growth (Foker) process for the treatment of long gap esophageal atresia (LGEA) relies on applying progressive tension to the esophagus to induce growth. Due to its anti-fibrotic and muscle-relaxing properties, we hypothesize that Botulinum Toxin A (BTX) can enhance traction-induced esophageal growth. METHODS: A retrospective two-center cohort study was conducted on children who underwent a BTX-enhanced Foker process for LGEA repair from 2021 to 2023. BTX (10 units/ml, 2 units/kg, per esophageal pouch) was applied at the time of traction initiation. Time on traction, complications, and anastomotic outcomes were compared against historical controls (Foker process without BTX) from 2014 to 2021. RESULTS: Twenty infants (LGEA type A:12, B:4, C:4; 35% reoperative; median [IQR] age 3 [2-5] months), underwent BTX-enhanced Foker process (thoracotomy with external traction: 9; minimally invasive [MIS] multi-staged internal traction: 11). Mean gap lengths were similar between BTX-enhanced external and external traction control patients (mean [SD], 50.6 mm [12.6] vs. 44.5 mm [11.9], p = 0.21). When compared to controls, the BTX-enhanced external traction process was significantly faster (mean [SD], 12.1 [1.6] days vs. 16.6 [13.2] without BTX, p = 0.04) despite similar preoperative gap lengths. There was no difference in time on traction for those undergoing a minimally invasive process. There were no significant differences in complications or anastomotic outcomes in either cohort. CONCLUSION: Botulinum toxin may play a role in accelerating the traction-induced esophageal growth process for LGEA repair. Minimizing time on traction can decrease sedation and paralysis burden while on external traction. Further studies are needed to elucidate the effects of BTX on the esophagus. LEVEL OF EVIDENCE: Level III. TYPE OF STUDY: Retrospective, Two-center, Cohort study.
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Esophageal and gastroesophageal junction (GEJ) malignancies are aggressive, and survival is poor once metastasis occurs. The most common sites of metastatic involvement include the liver, lymph nodes, lung, peritoneum, adrenal glands, bone, and brain, while skeletal muscle (SM) involvement is rare. We report a case of a 68-year-old female who presented with intractable emesis for one month and was found to have a primary GEJ adenocarcinoma measuring up to 6.7 cm. Endoscopic biopsy revealed poorly differentiated GEJ adenocarcinoma with positive AE1/AE3 immunostains. Positron emission tomography/computed tomography and magnetic resonance imaging revealed metastases to the omentum and left lower extremity SMs, including the proximal adductor longus, adductor magnus, and gluteus minimus. This study reviews the literature on SM metastasis in esophageal and GEJ cancer, GEJ cancer classification, incidence, treatment, and prognosis.
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Acute esophageal necrosis (AEN), also known as Gurvits syndrome, is a rare and potentially life-threatening condition characterized by necrosis of the esophageal mucosa. Acute esophageal necrosis is often associated with critical conditions, such as myocardial infarction, diabetic ketoacidosis (DKA), coronavirus disease 2019 (COVID-19) infection, or post-surgical complications. Patients typically present with nausea, hematemesis, acute dysphagia, and melena. Given its high mortality rate, prompt detection with upper endoscopy and early initiation of treatment are crucial. Most cases of Gurvits syndrome are managed conservatively using intravenous fluids, proton pump inhibitors, and antibiotics. Herein, we present a case series of AEN in the setting of DKA. Both patients received supportive care and were discharged in a stable condition.
Subject(s)
Diabetic Ketoacidosis , Necrosis , Humans , Diabetic Ketoacidosis/complications , Male , Middle Aged , Female , Esophagus/pathology , Esophageal Diseases/pathology , COVID-19/complications , Adult , Acute DiseaseABSTRACT
Foreign bodies such as bone with a sharp end can penetrate the esophageal wall and lie extramurally. When a foreign body is not found on rigid oesophagoscopy, reassessing with imaging is important. The transcervical approach is a better alternative for such patients to remove the foreign bodies.
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OBJECTIVE: To describe the circumflex left aortic arch as a new form of canine congenital vascular ring anomaly leading to esophageal constriction. ANIMALS: 3 large-breed dogs of variable age: a 9-month-old entire male German Shepherd Dog-Rottweiler cross, a 17-week-old entire male German Shepherd Dog, and a 9-year-old neutered female Labrador Retriever, seen between April 2022 and May 2023. CLINICAL PRESENTATION: Dogs presented for chronic postprandial regurgitation and poor growth. One dog presented for a hard mass on the caudal mandibular region. RESULTS: Computed tomography revealed a normal leftward-oriented cranial half and an abnormal caudal half of the aortic arch crossing toward the right dorsal hemithorax leading to esophageal constriction in all dogs. In addition, 1 dog presented with a right patent ductus arteriosus and 1 with an aberrant right subclavian artery. CLINICAL RELEVANCE: Circumflex left aortic arch is a newly discovered rare type of congenital vascular ring anomaly in dogs, which presents a similar anatomical derangement to the human form. Clinical signs include postprandial regurgitation and poor growth. Circumflex left aortic arch vascular anomaly cannot be surgically corrected via the left thoracotomy that is commonly used for the more common vascular ring anomalies in dogs. Computed tomography is a useful diagnostic modality for the diagnosis of this condition, detection of concomitant congenital vascular malformations, evaluation of associated pathologies, and surgical planning.
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Benign and malignant diseases of the upper gastrointestinal tract show gender-specific differences. The frequent gastroesophageal reflux disease is a prime example: men have an erosive reflux disease more often than women and are also younger at the time of onset. The rate of progression to a metaplastic Barrett's esophagus is also higher in men. In the case of achalasia, there are indications that surgical treatment by laparoscopic Heller's myotomy and semifundoplication 180° according to Dor leads to a markedly better improvement in the symptoms in women compared to men, although they showed a more pronounced dilation of the tubular esophagus. The female hormone status influences the localization and histopathology of adenocarcinoma of the esophagogastric junction and gastric carcinoma. Premenopausal and postmenopausal carcinomas differ significantly in women. In addition, high microsatellite instability (MSI high) is more frequent in women and is associated with a generally significantly better prognosis. The MSI high gastric carcinomas of women show better survival than MSI high carcinomas of men. The future inclusion of gender-specific aspects in studies of the upper gastrointestinal tract is desirable in order to generate adequate data and to enable differentiated treatment stratification in the future.
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BACKGROUND: Identifying children needing endoscopic evaluation for suspected eosinophilic esophagitis (EoE) is crucial for prompt diagnosis and management. AIMS: We aimed to develop a clinical prediction tool to distinguish children with EoE from children without the disease before endoscopy. METHODS: We conducted a retrospective case-control study of children undergoing upper endoscopy at a tertiary care center. Clinical characteristics before endoscopy were extracted from 380 EoE cases and 380 controls without EoE. We built a predictive model for case-control status and performed age-stratified analyses. RESULTS: After multivariable analysis, history of adaptive eating behaviors, food allergy, food impaction, male sex, and regurgitation were independently associated with EoE, and abdominal pain and failure to thrive with control status (AUC 0.81). Food allergy and male sex were predictors of EoE across all ages. Regurgitation and adaptive eating behaviors were specific to EoE in early (0-5 years) (AUC 0.74) and middle childhood (6-11 years) (AUC 0.82), while dysphagia and food impaction were specific to EoE in the adolescence (12-17 years) (AUC 0.87). CONCLUSION: We determined age-specific clinical features that predict EoE with good discrimination in a pediatric population before endoscopy. Validation of this model in an independent population can confirm the utility of this tool.
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Small cell carcinoma of the esophagus (SCCE) is a rare and highly malignant type of esophageal cancer with no standard treatment, facing challenges of resistance to conventional therapies. This study presents the cases of one extensive-stage and two limited-stage SCCE patients treated with chemoimmunotherapy. The two limited-stage patients underwent surgery post-treatment and experienced notable and enduring positive responses. This represents the first documented application of neoadjuvant chemoimmunotherapy in limited-stage SCCE patients. Additionally, comprehensive immunohistochemical analysis and whole exome sequencing were performed on the case patients. The findings revealed that infiltration of CD8+ T cells and PD-L1 expression in the SCCE tumor were key factors for favorable responses in SCCE patients receiving chemoimmunotherapy.
Subject(s)
Carcinoma, Small Cell , Esophageal Neoplasms , Immunotherapy , Neoadjuvant Therapy , Humans , Esophageal Neoplasms/therapy , Esophageal Neoplasms/drug therapy , Neoadjuvant Therapy/methods , Carcinoma, Small Cell/therapy , Carcinoma, Small Cell/drug therapy , Male , Immunotherapy/methods , Middle Aged , B7-H1 Antigen/metabolism , Treatment Outcome , Aged , Biomarkers, Tumor , CD8-Positive T-Lymphocytes/immunology , Female , Exome SequencingABSTRACT
Fish bone foreign bodies (FFBs) are relatively common but can present diagnostic challenges. Herein, we report a case of a 43-year-old female who initially presented to the Emergency Department with fever and throat discomfort after a choking incident, which led to a misdiagnosis of a viral infection after negative chest X-ray findings. Persistent symptoms, including new-onset vocal cord paralysis, prompted further investigation and an otolaryngology - head and neck surgery referral one month later. During the otolaryngology visit eight months after the initial incident, laryngoscopy revealed left true vocal cord paralysis and a subsequent CT scan revealed a 2.3 cm fishbone in the esophagus. Surgical removal involved flexible esophagoscopy and open neck exploration with careful dissection to avoid vascular injury. This case highlights the limitations of initial diagnostic methods, such as X-rays, and the necessity for heightened clinical vigilance and advanced imaging modalities like CT scans for persistent or evolving symptoms, particularly vocal cord paralysis. This case also supports multidisciplinary surgical management in cases of suspected esophageal FFBs involving the internal jugular vein and common carotid artery to prevent serious complications. Laryngoscope, 2024.
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BACKGROUND: Previous observational studies have shown that the prevalence of gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE) is associated with socioeconomic status. However, due to the methodological limitations of traditional observational studies, it is challenging to definitively establish causality. AIM: To explore the causal relationship between the prevalence of these conditions and socioeconomic status using Mendelian randomization (MR). METHODS: We initially screened single nucleotide polymorphisms (SNPs) to serve as proxies for eight socioeconomic status phenotypes for univariate MR analysis. The inverse variance weighted (IVW) method was used as the primary analytical method to estimate the causal relationship between the eight socioeconomic status phenotypes and the risk of GERD and BE. We then collected combinations of SNPs as composite proxies for the eight socioeconomic phenotypes to perform multivariate MR (MVMR) analyses based on the IVW MVMR model. Furthermore, a two-step MR mediation analysis was used to examine the potential mediation of the associations by body mass index, major depressive disorder (MDD), smoking, alcohol consumption, and sleep duration. RESULTS: The study identified three socioeconomic statuses that had a significant impact on GERD. These included household income [odds ratio (OR): 0.46; 95% confidence interval (95%CI): 0.31-0.70], education attainment (OR: 0.23; 95%CI: 0.18-0.29), and the Townsend Deprivation Index at recruitment (OR: 1.57; 95%CI: 1.04-2.37). These factors were found to independently and predominantly influence the genetic causal effect of GERD. Furthermore, the mediating effect of educational attainment on GERD was found to be mediated by MDD (proportion mediated: 10.83%). Similarly, the effect of educational attainment on BE was mediated by MDD (proportion mediated: 10.58%) and the number of cigarettes smoked per day (proportion mediated: 3.50%). Additionally, the mediating effect of household income on GERD was observed to be mediated by sleep duration (proportion mediated: 9.75%). CONCLUSION: This MR study shed light on the link between socioeconomic status and GERD or BE, providing insights for the prevention of esophageal cancer and precancerous lesions.
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AXIOS stents create an anastomotic connection between 2 lumens, facilitating bypass of blockages and strictures as well as drainage of large fluid collections. Historically, AXIOS stents have primarily been used for draining pancreatic fluid collections, with no documented cases of their use within the esophagus until now. In this article, we present a case of a 65-year-old man with cirrhosis admitted for dysphagia. On evaluation, he was diagnosed with type 1 achalasia and concurrent esophageal varices. A novel approach was used, utilizing an AXIOS stent, to provide both symptomatic relief and targeted treatment for his varices.