The Impact of Gastroesophageal Reflux Disease and Proton Pump Inhibitor Use on the Risk of Repeat Catheter Ablation for Atrial Fibrillation.

INTRODUCTION: Gastroesophageal reflux disease (GERD) has been associated with increased incidence/recurrence of atrial fibrillation (AF). However, the impact of GERD and proton pump inhibitor (PPI) therapy on outcomes of AF catheter ablation remains unclear. We aimed to assess the association between the presence of GERD and risk of repeat AF ablation, stratified by PPI therapy. METHODS: A retrospective cohort study was conducted on patients with paroxysmal/persistent AF undergoing initial ablation in January 2011-September 2015. GERD was defined by endoscopic findings, objective reflux testing, or clinical symptoms. The association between GERD/PPI use and time to repeat ablation was evaluated by time-to-event analysis with censoring at the last clinic follow-up within 1 year. RESULTS: Three hundred eighty-one subjects were included. Patients with GERD (n = 80) had a higher 1-year repeat ablation rate compared with those with no GERD (25% vs 11.3%, P = 0.0034). Stratifying by PPI use, patients with untreated GERD (37.5%) more likely needed repeat ablation compared with reflux-free (11.3%, P = 0.0003) and treated GERD (16.7%, P = 0.035) subjects. On multivariable Cox regression analyses, GERD was an independent risk factor of repeat ablation (hazard ratio [HR] 3.30, confidence interval [CI] 1.79-6.08, P = 0.0001). Specifically, untreated GERD was associated with earlier repeat ablation compared with no GERD (HR 4.02, CI 1.62-12.05, P = 0.0013). However, no significant difference in repeat ablation risk was noted between reflux-free and PPI-treated GERD groups. DISCUSSION: GERD was an independent predictor for risk of repeat AF ablation within 1 year, even after controlling for major cardiovascular comorbidities and confounders. PPI therapy modulated this risk, as repeat ablation-free survival for PPI-treated GERD was noninferior to reflux-free patients.

Concurrent abnormal non-acid reflux is associated with additional chronic rejection risk in lung transplant patients with increased acid exposure.

Acid reflux has been associated with allograft injury and rejection in lung transplant patients; however, the pathogenic role of non-acid reflux remains debated. We aimed to evaluate the impact of concurrent abnormal non-acid reflux with acid reflux on chronic rejection in lung transplant patients with acid reflux. This was a retrospective cohort study of lung transplant recipients who underwent pre-transplant combined impedance-pH study off acid suppression. Only subjects with acid exposure >4% were included. Non-acid reflux (pH > 4) episodes >27 was considered abnormal per prior normative studies. Chronic rejection was defined as chronic lung allograft dysfunction (CLAD) per International Society for Heart and Lung Transplantation criteria. Time-to-event analyses were performed using Cox proportional hazards and Kaplan-Maier methods, with censoring at death, anti-reflux surgery, or last follow-up. In total, 68 subjects (28 abnormal/40 normal non-acid reflux) met inclusion criteria for the study. Baseline demographic/clinical characteristics were similar between groups. Among this cohort of patients with increased acid exposure, subjects with concurrent abnormal non-acid reflux had significantly higher risk of CLAD than those without on Kaplan-Meier analysis (log-ranked P = 0.0269). On Cox multivariable regression analysis controlling for body mass index, age at transplantation, and proton pump inhibitor use, concurrent abnormal non-acid reflux remained independently predictive of increased CLAD risk (hazard ratio 2.31, confidence interval: 1.03-5.19, P = 0.04). Presence of concurrent abnormal non-acid reflux in lung transplant subjects with increased acid exposure is associated with additional risk of chronic rejection. Non-acid reflux may also contribute to pathogenicity in lung allograft injury/rejection, supporting a potential role for impedance-based testing in this population.

Allergic phenotype identified on allergen testing is associated with proton pump inhibitor nonresponse in eosinophilic esophagitis.

BACKGROUND AND AIM: Food/environmental allergens have been associated with eosinophilic esophagitis (EoE); however, the correlation between allergy profiles and disease responsiveness to proton pump inhibitor (PPI) therapy remains unclear. We aimed to assess the association between food/environmental allergies identified on allergen testing and histologic response to PPI in patients with treatment-naive EoE. METHODS: Adults with newly diagnosed EoE who underwent formal testing for food/environmental allergies at a tertiary center were included. All patients underwent twice-daily PPI for 8 weeks with subsequent repeat endoscopy and biopsy to assess histologic response. Patients with <15 eosinophils/hpf on post-PPI mucosal biopsies were classified as responders (PPI-r-EoE), while those with ≥15 eosinophils/hpf were nonresponders (PPI-nr-EoE). RESULTS: Sixty-one patients met inclusion criteria (21 PPI-r-EoE vs 40 PPI-nr-EoE). Demographic, clinical, and endoscopic finding variables were similar between groups. Positive food allergen test was more prevalent among PPI-nr-EoE patients (82.5% vs 42.9%, P = 0.003). On multivariable analysis, positive food allergen testing remained an independent predictor for PPI nonresponse (aOR 0.15, CI: 0.04-0.58, P = 0.0006). Positive environmental allergen testing was highly prevalent, with no significant differences between groups (77.5% vs 95.2%, P = 0.14). However, higher number of positive environmental allergens (23.3% [≥5 allergens] vs 73.3% [<5 allergens], P = 0.003) and specific aeroallergens correlated with PPI-nr-EoE. CONCLUSION: Positive food allergy testing and increased environmental allergens predicted lower likelihood of histologic response to PPI in EoE. Our findings support an allergic phenotype of EoE that may less likely respond to PPI therapy. Formal allergen testing may play a role in therapy selection and tailored management in EoE.

Obesity Is Associated with Altered Rectal Sensitivity in Chronic Constipation.

BACKGROUND: Defecation dysfunction may contribute to chronic constipation (CC), but the impact of obesity on anorectal physiology in CC remains unclear. We aimed to evaluate the relationship between obesity and anorectal function on physiologic testing in patients presenting with CC. METHODS: This was a retrospective cohort study of consecutive adults who underwent high resolution anorectal manometry (HRAM) at a tertiary center for CC. Patient demographics, clinical history, surgical/obstetric history, medications, and HRAM results were reviewed. Patients were classified into obese (BMI > 30 kg/m2) vs non-obese (BMI < 30 kg/m2) groups at the time of HRAM. Fisher-exact/student t-test for univariate analyses and general linear regression for multivariable analysis were performed. RESULTS: 383 adults (mean 50.3 years; 85.8% female) with CC were included. On HRAM, patients with obesity had lower anal sphincter resting tone (37.3 vs 48.5 mmHg, p = 0.005) and maximum squeeze pressure (104.8 mmHg vs 120.0 mmHg, p = 0.043). No significant differences in dyssynergia (61% vs 53%, p = 0.294) and failed balloon expulsion (18% vs 25%, p = 0.381) were found between obese and non-obese groups. On balloon distention testing, the maximum tolerated (163.5 vs 147.6 mL, p = 0.042) and urge sensation (113.9 vs 103.7 mL, p = 0.048) volumes were significantly increased among patients with obesity. After adjusting for potential confounders, obesity remained independently associated with increased maximum tolerated volume (ß-coefficient 13.7, p = 0.049). CONCLUSION: Obesity was independently associated with altered rectal sensitivity among patients with CC. Altered rectal sensation may play an important role in CC among patients with obesity. Anorectal physiology testing should be considered to understand the pathophysiology and guide management.

Use of a Novel Artificial Intelligence System Leads to the Detection of Significantly Higher Number of Adenomas During Screening and Surveillance Colonoscopy: Results From a Large, Prospective, US Multicenter, Randomized Clinical Trial.

INTRODUCTION: Adenoma per colonoscopy (APC) has recently been proposed as a quality measure for colonoscopy. We evaluated the impact of a novel artificial intelligence (AI) system, compared with standard high-definition colonoscopy, for APC measurement. METHODS: This was a US-based, multicenter, prospective randomized trial examining a novel AI detection system (EW10-EC02) that enables a real-time colorectal polyp detection enabled with the colonoscope (CAD-EYE). Eligible average-risk subjects (45 years or older) undergoing screening or surveillance colonoscopy were randomized to undergo either CAD-EYE-assisted colonoscopy (CAC) or conventional colonoscopy (CC). Modified intention-to-treat analysis was performed for all patients who completed colonoscopy with the primary outcome of APC. Secondary outcomes included positive predictive value (total number of adenomas divided by total polyps removed) and adenoma detection rate. RESULTS: In modified intention-to-treat analysis, of 1,031 subjects (age: 59.1 ± 9.8 years; 49.9% male), 510 underwent CAC vs 523 underwent CC with no significant differences in age, gender, ethnicity, or colonoscopy indication between the 2 groups. CAC led to a significantly higher APC compared with CC: 0.99 ± 1.6 vs 0.85 ± 1.5, P = 0.02, incidence rate ratio 1.17 (1.03-1.33, P = 0.02) with no significant difference in the withdrawal time: 11.28 ± 4.59 minutes vs 10.8 ± 4.81 minutes; P = 0.11 between the 2 groups. Difference in positive predictive value of a polyp being an adenoma among CAC and CC was less than 10% threshold established: 48.6% vs 54%, 95% CI -9.56% to -1.48%. There were no significant differences in adenoma detection rate (46.9% vs 42.8%), advanced adenoma (6.5% vs 6.3%), sessile serrated lesion detection rate (12.9% vs 10.1%), and polyp detection rate (63.9% vs 59.3%) between the 2 groups. There was a higher polyp per colonoscopy with CAC compared with CC: 1.68 ± 2.1 vs 1.33 ± 1.8 (incidence rate ratio 1.27; 1.15-1.4; P < 0.01). DISCUSSION: Use of a novel AI detection system showed to a significantly higher number of adenomas per colonoscopy compared with conventional high-definition colonoscopy without any increase in colonoscopy withdrawal time, thus supporting the use of AI-assisted colonoscopy to improve colonoscopy quality ( ClinicalTrials.gov NCT04979962).

Baseline Peripheral Eosinophil Count Independently Predicts Proton Pump Inhibitor Response in Eosinophilic Esophagitis.

GOALS: To assess the predictive value of baseline peripheral absolute eosinophil counts (AECs) for proton pump inhibitor (PPI) response in eosinophilic esophagitis (EoE). BACKGROUND: PPI leads to histologic remission in ~50% of EoE patients, although there are few distinguishing clinical features between PPI-responsive (PPI-r-EoE) and nonresponsive (PPI-nr-EoE) diseases. Peripheral eosinophilia is present in ~50% of EoE cases and is associated with eosinophil density on esophageal biopsy and worse clinical outcomes. The association between peripheral eosinophilia and PPI-responsiveness in EoE remains unclear. STUDY: This is a retrospective cohort study of adult EoE patients at a tertiary center between 2012 and 2016. All patients underwent twice daily PPI trials for ≥8 weeks followed by repeat esophageal biopsies and were classified as PPI-r-EoE or PPI-nr-EoE based on histologic response (<15 eosinophils/high power field). Baseline peripheral AEC was obtained within 1 month before index endoscopy. Analyses were performed using Fisher exact/Student t test (univariate) and logistic regression (multivariable). RESULTS: One hundred eighty-three patients (91 PPI-nr-EoE and 92 PPI-r-EoE) were included. Mean peripheral AEC was higher among PPI-nr-EoE patients (0.41 vs 0.24 K/µL, P = 0.013). Baseline peripheral eosinophilia (>0.5 K/µL) was more prevalent among patients with PPI-nr-EoE (70.4% vs 45.5%, P = 0.023) and a history of food impaction (51.9% vs 23.7%, P = 0.0082). On multivariable analyses, peripheral eosinophilia remained an independent predictor for PPI response (adjacent odds ratio = 2.86, CI: 1.07-7.62, P = 0.036) and food impaction (adjacent odds ratio = 2.80, CI: 1.07-7.35, P = 0.037). CONCLUSIONS: Baseline peripheral eosinophilia independently predicts PPI nonresponse and food impaction in EoE patients. Peripheral AEC may help therapy selection in EoE and prevent delays in achieving histologic remission.

Optimizing the Management Algorithm for Esophageal Dysphagia After Index Endoscopy: Cost-Effectiveness and Cost-Minimization Analysis.

INTRODUCTION: Guidelines advise esophageal motility testing for dysphagia when structural disorders are ruled out, but cost concerns impede adoption. We evaluated cost-effective positioning of esophageal motility testing in the algorithm to evaluate esophageal dysphagia. METHODS: We developed a decision analytic model comparing 3 strategies: (i) esophageal manometry, (ii) screening impedance planimetry followed by esophageal manometry if needed, or (iii) nonalgorithmic usual care. Diagnostic test accuracy was adapted to expected rates of esophageal motility disorders in general gastroenterology populations. We modeled routine testing for all patients with nonstructural/mechanical dysphagia compared with selective testing with strong suspicion for achalasia. Cost outcomes were defined on national commercial and Medicare datasets stratified on age and sex. Health outcomes were modeled on populations with achalasia. The time horizon was 1 year. RESULTS: Motility testing was preferred over nonalgorithmic usual care due to cost savings rather than health gains. To commercial insurers, routine esophageal manometry for nonstructural/mechanical dysphagia would be cost-saving below a reimbursed cost of $2,415. Screening impedance planimetry would be cost saving below a reimbursed cost of $1,130. The limit for reimbursed costs would be lower for patients older than 65 years to achieve cost savings mainly due to insurance. Sex did not significantly influence cost-effectiveness. Patients and insurers preferred routine screening impedance planimetry before manometry when the index of suspicion for achalasia was below 6%. DISCUSSION: Aligning with practice guidelines, routine esophageal motility testing seems cost saving to patients and insurers compared with nonalgorithmic usual care to evaluate nonstructural/mechanical dysphagia. Choice of testing should be guided by index of suspicion.

Abnormal bolus reflux on impedance-pH testing independently predicts 3-year pulmonary outcome and mortality in pulmonary fibrosis.

BACKGROUND AND AIM: Gastroesophageal reflux has been associated with idiopathic pulmonary fibrosis (IPF), although the directionality of the relationship has been debated. Data on the value of objective reflux measures in predicting IPF disease progression and mortality remain limited. We aimed to evaluate the association between multichannel intraluminal impedance and pH testing (MII-pH) and 3-year pulmonary outcomes in IPF patients. METHODS: This was a retrospective cohort study of adults with IPF who underwent pre-lung transplant MII-pH off acid suppression at a tertiary center. Patients were followed for 3 years after MII-pH for poor pulmonary outcomes (hospitalization for respiratory exacerbation or death). A secondary analysis was performed using mortality as outcome of interest. Time-to-event analyses using Kaplan-Meier and Cox regression were performed to evaluate associations between MII-pH and poor outcomes. RESULTS: One hundred twenty-four subjects (mean age = 61.7 ± 8 years, 62% male) were included. Increased bolus exposure time (BET) on MII-pH was associated with decreased time to poor pulmonary outcomes and death (log-ranked P-value = 0.017 and 0.031, respectively). On multivariable Cox regression analyses controlling for potential confounders including age, sex, smoking history, body mass index, proton pump inhibitor use, baseline pulmonary function, and anti-fibrotic therapy, increased BET was an independent predictor for poor pulmonary outcomes [hazard ratio 3.18 (95% confidence interval: 1.25-8.09), P = 0.015] and mortality [hazard ratio 11.3 (95% confidence interval: 1.37-63.9), P = 0.025] over 3 years. CONCLUSIONS: Increased BET on MII-pH is an independent predictor of poor pulmonary outcomes and mortality over 3 years in IPF patients. These findings also support a role for gastroesophageal reflux in IPF disease progression and the potential impact of routine reflux testing and treatment.

Pre-Lung transplant reflux testing demonstrates high prevalence of gastroesophageal reflux in cystic fibrosis and reduces chronic rejection risk.

BACKGROUND: Gastroesophageal reflux (GER) has been associated with poor outcomes after lung transplantation for chronic lung disease, including increased risk of chronic rejection. GER is common in cystic fibrosis (CF), but factors influencing the likelihood of pre-transplant pH testing, and the impact of testing on clinical management and transplant outcomes in patients with CF are unknown. AIM: To evaluate the role of pre-transplant reflux testing in the evaluation of lung transplant candidates with CF. METHODS: This was a retrospective study from 2007-2019 at a tertiary medical center that included all patients with CF undergoing lung transplant. Patients with pre-transplant anti-reflux surgery were excluded. Baseline characteristics (age at transplantation, gender, race, body mass index), self-reported GER symptoms prior to transplantation, and pre-transplant cardiopulmonary testing results, were recorded. Reflux testing consisted of either 24-h pH- or combined multichannel intraluminal impedance and pH monitoring. Post-transplant care included a standard immunosuppressive regimen, and regular surveillance bronchoscopy and pulmonary spirometry in accordance with institutional practice as well as in symptomatic patients. The primary outcome of chronic lung allograft dysfunction (CLAD) was defined clinically and histologically per International Society of Heart and Lung Transplantation criteria. Statistical analysis was performed with Fisher's exact test to assess differences between cohorts, and time-to-event Cox proportional hazards modeling. RESULTS: After applying inclusion and exclusion criteria, a total of 60 patients were included in the study. Among all CF patients, 41 (68.3%) completed reflux monitoring as part of pre-lung transplant evaluation. Objective evidence of pathologic reflux, defined as acid exposure time > 4%, was found in 24 subjects, representing 58% of the tested group. CF patients with pre-transplant reflux testing were older (35.8 vs 30.1 years, P = 0.01) and more commonly reported typical esophageal reflux symptoms (53.7% vs 26.3%, P = 0.06) compared to those without reflux testing. Other patient demographics and baseline cardiopulmonary function did not significantly differ between CF subjects with and without pre-transplant reflux testing. Patients with CF were less likely to undergo pre-transplant reflux testing compared to other pulmonary diagnoses (68% vs 85%, P = 0.003). There was a decreased risk of CLAD in patients with CF who underwent reflux testing compared to those who did not, after controlling for confounders (Cox Hazard Ratio 0.26; 95%CI: 0.08-0.92). CONCLUSION: Pre-transplant reflux testing revealed high prevalence of pathologic reflux in CF patients and was associated with decreased risk of CLAD. Systematic reflux testing may enhance outcomes in this patient population.

Ineffective esophageal motility is associated with acute rejection after lung transplantation independent of gastroesophageal reflux.

BACKGROUND: Gastroesophageal reflux is associated with poorer outcomes after lung transplant, likely through recurrent aspiration and allograft injury. Although prior studies have demonstrated a relationship between impedance-pH results and transplant outcomes, the role of esophageal manometry in the assessment of lung transplant patients remains debated, and the impact of esophageal dysmotility on transplant outcomes is unclear. Of particular interest is ineffective esophageal motility (IEM) and its associated impact on esophageal clearance. AIM: To assess the relationship between pre-transplant IEM diagnosis and acute rejection after lung transplantation. METHODS: This was a retrospective cohort study of lung transplant recipients at a tertiary care center between 2007 and 2018. Patients with pre-transplant anti-reflux surgery were excluded. Manometric and reflux diagnoses were recorded from pre-transplant esophageal function testing. Time-to-event analysis using Cox proportional hazards model was applied to evaluate outcome of first episode of acute cellular rejection, defined histologically per International Society of Heart and Lung Transplantation guidelines. Subjects not meeting this endpoint were censored at time of post-transplant anti-reflux surgery, last clinic visit, or death. Fisher's exact test for binary variables and student's t-test for continuous variables were performed to assess for differences between groups. RESULTS: Of 184 subjects (54% men, mean age: 58, follow-up: 443 person-years) met criteria for inclusion. Interstitial pulmonary fibrosis represented the predominant pulmonary diagnosis (41%). During the follow-up period, 60 subjects (33.5%) developed acute rejection. The all-cause mortality was 16.3%. Time-to-event univariate analyses demonstrated significant association between IEM and acute rejection [hazard ratio (HR): 1.984, 95%CI: 1.03-3.30, P = 0.04], confirmed on Kaplan-Meier curve. On multivariable analysis, IEM remained independently associated with acute rejection, even after controlling for potential confounders such as the presence of acid and nonacid reflux (HR: 2.20, 95%CI: 1.18-4.11, P = 0.01). Nonacid reflux was also independently associated with acute rejection on both univariate (HR: 2.16, 95%CI: 1.26-3.72, P = 0.005) and multivariable analyses (HR: 2.10, 95%CI: 1.21-3.64, P = 0.009), adjusting for the presence of IEM. CONCLUSION: Pre-transplant IEM was associated with acute rejection after transplantation, even after controlling for acid and nonacid reflux. Esophageal motility testing may be considered in lung transplant to predict outcomes.

Relationship Between Esophageal Disease and Pulmonary Fibrosis.

Esophageal disorders are prevalent among patients with chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). Gastroesophageal reflux disease (GERD) has been associated with IPF prevalence, severity, and respiratory decline. The pathophysiologic relationship between GERD and IPF is likely bidirectional, with aspiration of refluxate leading to lung inflammation and fibrosis, while the restrictive pulmonary physiology may contribute to altered transdiaphragmatic pressure gradient and increased reflux. Esophageal symptoms are frequently absent and do not predict esophageal dysfunction or pathologic reflux in patients with IPF, and objective diagnostic tools including upper endoscopy, ambulatory reflux monitoring, and high-resolution manometry are often needed. Impedance-based testing that identifies both weakly/non-acidic and acid reflux may provide important additional diagnostic value beyond pH-based acid testing alone. Novel metrics and maneuvers, including advanced impedance measures on impedance-pH study and provocative testing on HRM, may hold promise to future diagnostic advancements. The main treatment options include medical therapy with acid suppressants and anti-reflux surgery, although their potential benefits in pulmonary outcomes of IPF require further validations. Future directions of research include identifying phenotypes of IPF patients who may benefit from esophageal testing and treatment, determining the optimal testing strategy and protocol, and prospectively assessing the value of different esophageal therapies to improve outcomes while minimizing risks. This review will discuss the pathophysiology, evaluation, and management of esophageal diseases, particularly GERD, in patients with IPF, as informed by the most recent publications in the field, in hopes of identifying targets for future study and research.

Up-Front Endoscopy Maximizes Cost-Effectiveness and Cost-Satisfaction in Uninvestigated Dyspepsia.

BACKGROUND & AIMS: Practice guidelines promote a routine noninvasive, non-endoscopic initial approach to investigating dyspepsia without alarm features in young patients, yet many patients undergo prompt upper endoscopy. We aimed to assess tradeoffs among costs, patient satisfaction, and clinical outcomes to inform discrepancy between guidelines and practice. METHODS: We constructed a decision-analytic model and performed cost-effectiveness/cost-satisfaction analysis over a 1-year time horizon on patients with uninvestigated dyspepsia without alarm features referred to gastroenterology. A RAND/UCLA expert panel informed model design. Four competing diagnostic/management strategies were evaluated: prompt endoscopy, testing for Helicobacter pylori and eradicating if present (test-and-treat), testing for H pylori and performing endoscopy if present (test-and-scope), and empiric acid suppression. Outcomes were derived from systematic reviews of clinical trials. Costs were informed by prospective observational cohort studies and national commercial/federal cost databases. Health gains were represented using quality-adjusted life years. RESULTS: From the patient perspective, costs and outcomes were similar for all strategies (maximum out-of-pocket difference of $30 and <0.01 quality-adjusted life years gained/year regardless of strategy). Prompt endoscopy maximized cost-satisfaction and health system reimbursement. Test-and-scope maximized cost-effectiveness from insurer and patient perspectives. Results remained robust on multiple one-way sensitivity analyses on model inputs and across most willingness-to-pay thresholds. CONCLUSIONS: Noninvasive management strategies appear to result in inferior cost-effectiveness and patient satisfaction outcomes compared with strategies promoting up-front endoscopy. Therefore, additional studies are needed to evaluate the drivers of patient satisfaction to facilitate inclusion in value-based healthcare transformation efforts.

Routine Reflux Testing Guides Timely Antireflux Treatment to Reduce Acute and Chronic Rejection After Lung Transplantation.

INTRODUCTION: Gastroesophageal reflux has been associated with poorer lung transplantation outcomes, although no standard approach to evaluation/management has been adopted. We aimed to evaluate the effect of timely antireflux treatment as guided by routine reflux testing on postlung transplant rejection outcomes. METHODS: This was a retrospective cohort study of lung transplant recipients at a tertiary center. All patients underwent pretransplant ambulatory pH monitoring. Timely antireflux treatment was defined as proton pump inhibitor initiation or antireflux surgery within 6 months of transplantation. Patients were separated into 3 groups: normal pH monitoring (-pH), increased reflux (+pH) with timely treatment, and +pH with delayed treatment. Rejection outcomes included acute rejection, bronchiolitis obliterans syndrome, and chronic lung allograft dysfunction per International Society for Heart and Lung Transplantation criteria. Time-to-event analyses using Cox proportional hazard models were applied. Patients not meeting outcomes were censored at death or last clinic visit. RESULTS: One hundred seventy-five patients (59% men/mean 56.3 yr/follow-up: 496 person-years) were included. On multivariable analyses, +pH/delayed treatment patients had higher risks of acute rejection (adjust hazard ratio [aHR]:3.81 [95% confidence interval [CI]: 1.90-7.64], P = 0.0002), bronchiolitis obliterans syndrome (aHR: 2.22 [95% CI: 1.07-4.58], P = 0.03), and chronic lung allograft dysfunction (aHR: 2.97 [95% CI: 1.40-6.32], P = 0.005) than +pH/timely treatment patients. Similarly, rejection risks were increased among +pH/delayed treatment patients vs -pH patients (all P < 0.05). No significant differences in rejection risks were noted between +pH/timely treatment patients and -pH patients. Failure/complications of antireflux treatment were rare and similar among groups. DISCUSSION: Timely antireflux treatment, as directed by pretransplant reflux testing, was associated with reduced allograft rejection risks and demonstrated noninferiority to patients without reflux. A standardized peri-transplant test-and-treat algorithm may guide timely reflux management to improve lung transplant outcomes.

Overlapping Transcriptional Profile in Proton Pump Inhibitor Responsive and Nonresponsive Eosinophilic Esophagitis.

INTRODUCTION: We compared esophageal mucosal gene transcript expression in proton pump inhibitor (PPI) responsive (PPI-R) eosinophilic esophagitis (EoE), PPI nonresponsive (PPI-NR) EoE, and healthy controls. METHODS: Transcript expression in midesophagus biopsies was determined using NanoString and a custom panel of EoE-specific genes. The top upregulated and downregulated genes with ≥2-fold difference in expression and statistically significant ( P < 0.05) were identified. RESULTS: Nearly all the top upregulated (17 of 20) and downregulated (5 of 5) genes in EoE, compared with healthy controls, were shared between the PPI-R and PPI-NR groups. DISCUSSION: Esophageal mucosal transcript expressions are remarkably similar in PPI-R EoE and PPI-NR EoE compared with healthy controls.

Long-term results of robotic-assisted nasopharyngectomy for recurrent nasopharyngeal carcinoma.

BACKGROUND: We have previously reported our early experience in robotic-assisted nasopharyngectomy. The current case series is a report of our experience in 33 robotic-assisted nasopharyngectomy. METHODS: Prospective series of patients who underwent robotic-assisted nasopharyngectomy for local recurrent nasopharyngeal carcinoma from January 2010 to March 2019. RESULTS: Thirty-one patients underwent robotic-assisted nasopharyngectomy with two additional second procedure for positive margin. Median age is 55 years (29-85). Twenty-five patients had rT1 disease and six patients had tumor invaded sphenoid floor (rT3). Median operative time was 227 min and median blood loss was 200 ml. The median follow-up period for all patients were 38 months. Four patients had local recurrence. Five-year local control rate, overall survival, and disease-free survival are 85.1%, 55.7%, and 69.1%, respectively. CONCLUSION: Robotic-assisted nasopharyngectomy for recurrent nasopharyngectomy was showed to have a high local control rate. The operating time was comparable to open surgery.

Failed Swallows on High-Resolution Manometry Independently Correlates With Severity of LPR Symptoms.

BACKGROUND: Abnormal esophageal motility is prevalent in gastroesophageal reflux disease patients; however, its relationship with laryngopharyngeal reflux (LPR) symptom severity remains unclear. Altered esophageal transit may contribute to LPR symptoms. We aimed to examine the relationship between reflux symptom index (RSI), a validated questionnaire for LPR symptoms, and abnormal esophageal motility on high-resolution manometry (HRM). METHODS: A total of 133 consecutive patients (55.9 ± 14.6 years, 69.9% female) with suspected LPR referred for HRM and multichannel intraluminal impedance-pH study (MII-pH) at a tertiary center from March 2015 to October 2017 were included. RSI questionnaire was prospectively collected prior to motility testing. Authors analyzing HRM and MII-pH were blinded to RSI findings. Statistical analyses were performed using Student's t test or Pearson's correlation (univariate) and general linear regression (multivariable). RESULTS: Mean RSI was higher among patients with ineffective esophageal motility than those with normal motility (23.7 vs 18.6, P = 0.01). Significant positive correlation was found between RSI and percent failed swallows (R2 = 0.21, P = 0.03), but not percent weak swallows. On multivariable analysis, percent ineffective (failed or weak) swallows was significantly associated with RSI (ß-coefficient: 0.072, P = 0.05) after controlling for age, gender, BMI, smoking, prior PPI use, and reflux on MII-pH. When analyzed separately, percent failed swallows (ß-coefficient: 0.095, P= 0.02), but not percent weak swallows, independently predicted higher RSI. CONCLUSIONS: Ineffective swallows, particularly failed swallows, are independently associated with higher RSI in patients with suspected LPR, even after controlling for reflux on MII-pH. Esophageal dysmotility may play a role in suspected LPR symptoms independent of reflux. HRM should be routinely considered in evaluating these patients.

Opioid-Associated Anorectal Dysfunction in Chronic Constipation.

INTRODUCTION: The role of anorectal and defecatory dysfunction in opioid-related constipation is unclear. We aimed to evaluate the relationship between opioid use and rectal sensation, defecatory function, and balloon expulsion on anorectal physiology testing. METHODS: This was a retrospective cohort study of consecutive adults undergoing high-resolution anorectal manometry (HRAM) at a tertiary center for constipation. Clinical characteristics, medication use, and HRAM findings were obtained. Statistical analyses were performed using Fisher-exact/student t-test for univariate analyses and logistic/general linear regression for multivariable analyses to compare patients with no opioid use, recent (< 3 months) use, and distant (> 3 months) use. RESULTS: 424 patients (49.8 ± 17.2 years; 85.6% female) were included. Compared to those without opioid history, patients with recent use had increased volumes for first rectal sensation (70.4 mL vs 59.4, p = 0.043), urge (120.5 mL vs 101.5, p = 0.017), and maximal tolerance (170.2 mL vs 147.2, p = 0.0018), but not patients with distant use. Recent opioid use was associated with increased risk of dyssynergic defecation (DD) (61.8% vs 46.4%, p = 0.035), but not failed balloon expulsion. On multivariable models controlling for potential confounders, recent opioid use, but not distant use, remained independently correlated with increased volumes for first rectal sensation (ß-coefficient 9.78, p = 0.019), urge (ß-coefficient 16.7, p = 0.0060), and maximal tolerance (ß-coefficient 22.9, p = 0.0032), and higher risk for DD (aOR = 2.18, p = 0.026). CONCLUSION: Recent opioid use was an independent risk factor for rectal hyposensitivity and DD on HRAM in patients with constipation, but that effect may decrease with discontinuation of use. Anorectal physiology testing should be considered in patients with opioid-associated constipation.

Normative Ambulatory Reflux Monitoring Metrics for Laryngopharyngeal Reflux: A Systematic Review of 720 Healthy Individuals.

OBJECTIVES: To review the normative data for acid, weakly acid, and nonacid proximal esophageal (PRE) and hypopharyngeal reflux (HRE) events in diagnosing laryngopharyngeal reflux (LPR) using ambulatory reflux monitoring. DATA SOURCES: PubMed, Cochrane Library, and Scopus. REVIEW METHODS: A literature search was conducted about the normative data for PRE and HRE on multichannel intraluminal impedance-pH monitoring (MII-pH), hypopharyngeal-esophageal MII-pH (HEMII-pH), or oropharyngeal pH monitoring using PICOTS (population, intervention, comparison, outcome, timing, and setting) and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statements. Outcomes reviewed included device characteristics, impedance/pH sensor placements, study duration, number/average and percentiles of PRE or HRE occurrence, and the event characteristics (pH, composition, and position). RESULTS: Of 154 identified studies, 18 met criteria for analysis, including 720 healthy individuals. HEMII-pH, MII-pH, and oropharyngeal pH monitoring were used in 7, 6, and 5 studies, respectively. The definition and inclusion/exclusion criteria of healthy individuals varied substantially across studies, with 6 studies considering only digestive symptoms to exclude potential LPR patients. Substantial heterogeneity across studies was noted, including impedance/pH sensor placements/configurations and definitions of composition (liquid, gas, mixed) and type (acid, weakly acid, nonacid) of PRE/HRE. The 95th percentile thresholds were 10 to 73 events for PRE, 0 to 10 events for HRE on HEMII-pH, and 40 to 128 for events with pH <6.0 on oropharyngeal pH monitoring. Most HREs were nonacid and occurred upright. The mean HRE among healthy individuals was 1. CONCLUSION: The low number of studies and the heterogeneity in inclusion criteria, definitions, and characterization of PRE and HRE limit the establishment of consensual normative criteria for LPR on ambulatory reflux monitoring. Future large multicenter studies are needed.

Novel Advanced Impedance Metrics on Impedance-pH Testing Predict Lung Function Decline in Idiopathic Pulmonary Fibrosis.

INTRODUCTION: Gastroesophageal reflux has been associated with idiopathic pulmonary fibrosis (IPF). Mean nocturnal baseline impedance (MNBI) is a marker of esophageal mucosal integrity, whereas postreflux swallow-induced peristaltic wave (PSPW) index reflects esophageal chemical clearance. Both metrics offer novel ways to assess reflux burden on multichannel intraluminal impedance-pH testing (MII-pH), but their role in extraesophageal reflux remains unclear. We aimed to evaluate the relationship between these novel metrics and lung function decline in patients with IPF. METHODS: Adults with IPF undergoing prelung transplant MII-pH were enrolled. All patients completed pulmonary function testing (PFT) at the time of MII-pH and at the 1-year follow-up. MNBI was calculated by averaging baseline impedance at three 10-minute intervals (1 AM/2 AM/3 AM). PSPW index was the proportion of all reflux episodes, followed by a peristaltic swallow within 30 seconds. Univariate (Student t-test/Pearson correlation) and multivariable (general linear regression) analyses were performed. RESULTS: One hundred twenty-five subjects (mean age = 61.7 years, 62% men) were included. Forced expiratory volume in one second and forced vital capacity declined more significantly over 12 months in subjects with lower distal MNBI, proximal MNBI, and PSPW index (all P < 0.05). On multivariable analyses adjusting for age, sex, proton pump inhibitor use, and baseline lung function, distal MNBI (ß = -10.86, P = 0.024; ß = -8.03, P = 0.045), proximal MNBI (ß = -13.5, P = 0.0068; ß = -9.80, P = 0.025), and PSPW index (ß = -18.1, P = 0.010; ß = -12.55, P = 0.050) remained predictive of greater forced expiratory volume in one second and forced vital capacity decline. DISCUSSION: Low distal MNBI, proximal MNBI, and PSPW index independently predicted more severe lung function decline over 1 year in patients with IPF. These impedance metrics may have prognostic value and support a role for reflux in IPF pathogenesis.