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2-year follow-up data from our randomised controlled trial showed that peroral endoscopic myotomy is associated with a significantly higher efficacy than pneumatic dilation as initial treatment of therapy-naive patients with achalasia. Here we report therapeutic success rates in patients treated with peroral endoscopic myotomy compared with pneumatic dilation at the 5-year follow-up.We did a multicentre, randomised controlled trial in six hospitals in the Netherlands, Germany, Italy, Hong Kong, and the USA. Adults aged 18-80 years with newly diagnosed symptomatic achalasia (based on an Eckardt score3) were eligible for inclusion. Patients were randomly assigned (1:1) to peroral endoscopic myotomy or pneumatic dilation using web-based randomisation with a random block size of 8 and stratification according to site. Randomisation concealment for treatment type was double blind until official study enrolment. Treatment was unmasked because of the different technical approach of each procedure. Patients in the pneumatic dilation group were dilated with a single series of 30-35 mm balloons. The need for subsequent dilations in the pneumatic dilation group, and the need for dilation after initial treatment in the peroral endoscopic myotomy group, was considered treatment failure. The primary outcome was therapeutic success (Eckardt score ≤3 in the absence of severe treatment-related complications and no need for retreatment). Analysis of the primary outcome was by modified intention to treat, including all patients randomly assigned to a group, excluding those patients who did not receive treatment or were lost to follow-up. Safety was assessed in all included patients. This study is registered at the Dutch Trial Registry, NTR3593, and is completed.Between Sept 21, 2012, and July 20, 2015, 182 patients were assessed for eligibility, 133 of whom were included in the study and randomly assigned to peroral endoscopic myotomy (n=67) or pneumatic dilation (n=66). 5-year follow-up data were available for 62 patients in the peroral endoscopic myotomy group and 63 patients in the pneumatic dilation group. 50 (81%) patients in the peroral endoscopic myotomy group had treatment success at 5 years, compared with 25 (40%) in the pneumatic dilation group, an adjusted absolute difference of 41% (95% CI 25-57; p0·0001). Reasons for failure were no initial effect of treatment (one patient in the peroral endoscopic myotomy group vs 12 patients in the pneumatic dilation group) and recurrent symptoms causing treatment failure (11 patients in the peroral endoscopic myotomy group [seven patients between 2 and 5 years] vs 25 patients in the pneumatic dilation group [nine patients between 2 and 5 years]); one patient in the pneumatic dilation group had treatment failure due to an adverse event. Proton-pump inhibitor use (mostly daily) was significantly higher after peroral endoscopic myotomy than after pneumatic dilation among patients still in clinical remission (23 [46%] of 50 patients vs three [13%] of 24 patients; p=0·008). 5-year follow-up endoscopy of patients still in clinical remission showed reflux oesophagitis in 14 (33%) of 42 patients in the peroral endoscopic myotomy group (12 [29%] grade A or B, two [5%] grade C or D) and two (13%) of 16 patients in the pneumatic dilation group (two [13%] grade A or B, none grade C or D; p=0·19). No intervention-related serious adverse events occurred between 2 and 5 years after treatment. The following non-intervention-related serious adverse events occurred between 2 and 5 years: a stroke (one [2%]) in the peroral endoscopic myotomy group; and death due to a melanoma (one [2%]) and dementia (one [2%]) in the pneumatic dilation group.Based on this study, peroral endoscopic myotomy should be proposed as an initial treatment option for patients with achalasia. Although our study has shown that peroral endoscopic myotomy has greater long-term efficacy with a low risk of major treatment-related complications, this should not lead to abandonment of pneumatic dilation from clinical practice. Ideally, all treatment options should be discussed with treatment-naive patients with achalasia and a shared decision should be made.Fonds NutsOhra and European Society of Gastrointestinal Endoscopy.

Background: The American Foregut Society (AFS) is dedicated to advancing patient care and digestive health within the realm of foregut disease. One of the most common and debilitating esophageal conditions is gastroesophageal reflux disease (GERD). The Hill grade is an endoscopic classification of the esophagogastric junction (EGJ) based on the appearance of the gastroesophageal flap valve from a retroflexed view of the hiatus. This endoscopic classification provides insight into the anatomic disruption of the EGJ which has been shown to correlate with GERD. However, clinical utilization of this classification by endoscopists has been limited due to the perceived relevance and subjectivity of the classification. With the advent of endoscopic treatment options for GERD, there is renewed enthusiasm to develop a grading system of the EGJ that can objectively define anatomical impairment and reduce interobserver grading variability. Methods: The AFS convened a 13-member working group tasked with reviewing the Hill grade classification and formulating a proposal for its revision utilizing a modified Delphi method. This white paper summarizes the output from this working group. Results: The working group concluded that all components of the antireflux barrier—the lower esophageal sphincter and its sling fibers, the crural diaphragm, and the gastroesophageal flap valve—contribute to EGJ integrity. Using defined objective parameters of extent of hiatal axial herniation and crural disruption and presence or absence of a flap valve, the new AFS classification stratifies EGJ integrity from normal (grade 1) to increasing degrees of EGJ disruption (grade 2-4) beginning with loss of the flap valve and progressing to increasing degrees of crural disruption and hiatus hernia. This AFS classification also stipulates appropriate endoscopic methodology to utilize in making the assessment and provides a basic nomenclature for communication among endoscopists. Conclusions: The AFS endoscopic classification of the EGJ expands on the Hill classification by including assessment of axial hiatal hernia length (L), hiatal aperture diameter (D), and presence or absence of the flap valve (F) making it more comprehensive - LDF components. Future directions include validation studies correlating the ability of the AFS classification in predicting the presence and severity of GERD.

Esophagogastric junction (EGJ) outflow obstruction (EGJOO) per Chicago Classification v4.0 (CCv4.0) represents a high-resolution manometry (HRM) diagnosis with uncertain clinical significance. This study aimed to evaluate functional lumen imaging probe (FLIP) panometry among patients with EGJOO on HRM/CCv4.0 to assess clinical/manometric associations and treatment outcomes.An observational cohort study was performed on patients who completed FLIP during endoscopy and had an HRM/CCv4.0 diagnosis of EGJOO, i.e., HRM-EGJOO (inconclusive). Abnormal FLIP panometry motility classifications were applied to identify FLIP-confirmed conclusive EGJOO. Rapid drink challenge on HRM and timed barium esophagram were also assessed. Clinical management plan was determined by treating physicians and assessed through chart review. Clinical outcome was defined using the Eckardt score (ES) during follow-up evaluation: ES3 was considered a good outcome.Of 139 adult patients with manometric EGJOO (inconclusive per CCv4.0), a treatment outcome ES was obtained in 55 after achalasia-type treatment (i.e., pneumatic dilation, peroral endoscopic myotomy, laparoscopic Heller myotomy, or botulinum toxin injection) and 36 patients after other nonachalasia-type treatment. Among patients with conclusive EGJOO by HRM-FLIP complementary impression, 77% (33/43) had a good outcome after achalasia-type treatment, whereas 0% (0/12) of patients had a good outcome after nonachalasia-type treatment. Of patients with normal EGJ opening on FLIP, one-third of patients treated with achalasia-type treatment had a good outcome, while 9 of the 10 treated conservatively had a good outcome.FLIP panometry provides a useful complement to clarify the clinical significance of an HRM/CCv4.0 EGJOO diagnosis and help direct management decisions.

Eosinophilic esophagitis (EoE) is an esophageal immune-mediated disease characterized by eosinophilic inflammation and epithelial remodeling, including basal cell hyperplasia (BCH) and loss of differentiation. Although BCH correlates with disease severity and with persistent symptoms in patients in histological remission, the molecular processes driving BCH remain poorly defined. Here, we demonstrate that despite the presence of BCH in all EoE patients examined, no increase in basal cell proportion was observed by scRNA-seq. Instead, EoE patients exhibited a reduced pool ofKRT15+ COL17A1+quiescent cells, a modest increase inKI67+dividing epibasal cells, a substantial increase inKRT13+ IVL+suprabasal cells, and a loss of differentiated identity in superficial cells. Suprabasal and superficial cell populations demonstrated increased quiescent cell identity scoring in EoE with the enrichment of signaling pathways regulating pluripotency of stem cells. However, this was not paired with increased proliferation. Enrichment and trajectory analyses identified SOX2 and KLF5 as potential drivers of the increased quiescent identity and epithelial remodeling observed in EoE. Notably, these findings were not observed in GERD. Thus, our study demonstrates that BCH in EoE results from an expansion of non-proliferative cells that retain stem-like transcriptional programs while remaining committed to early differentiation.

BACKGROUND & AIMS: This study aimed to assess the accuracy of functional luminal imaging probe (FLIP) Panometry to detect esophagogastric junction (EGJ) obstruction assigned by high-resolution manometry (HRM) and the Chicago Classification version 4.0 (CCv4.0). METHODS: 687 adult patients that completed FLIP and HRM for primary esophageal motility evaluation and 35 asymptomatic volunteers (“controls”) were included. EGJ opening was evaluated with 16-cm FLIP during sedated endoscopy via EGJ-distensibility index (DI) and maximum EGJ diameter. HRM was classified according to CCv4.0 and focused on studies with a conclusive disorder of EGJ outflow (i.e. achalasia subtypes I, II, or III; or EGJ outflow obstruction with abnormal timed barium esophagram) or normal EGJ outflow. RESULTS: All 35 controls had EGJ-DI >3.0mm(2)/mmHg and maximum EGJ diameter >16mm. Per HRM and CCv4.0, 245 patients had a conclusive disorder of EGJ outflow and 314 patients had normal EGJ outflow. Among the 241 patients with reduced EGJ opening (REO: EGJ-DI

BACKGROUND & AIMS: Functional luminal imaging probe (FLIP) Panometry can evaluate esophageal motility in response to sustained esophageal distension at the time of sedated endoscopy. This study aimed to describe a classification of esophageal motility using FLIP Panometry and evaluate it against high-resolution manometry (HRM) and Chicago Classification v4.0 (CCv4.0). METHODS: 539 adult patients that completed FLIP and HRM with a conclusive CCv4.0 diagnosis were included in the primary analysis. 35 asymptomatic volunteers (“controls”) and 148 patients with an inconclusive CCv4.0 diagnosis or systemic sclerosis were also described. Esophagogastric junction (EGJ) opening and the contractile response to distension (i.e. secondary peristalsis) were evaluated with 16-cm FLIP performed during sedated endoscopy and analyzed using a customize software program. HRM was classified according to CCv4.0. RESULTS: In the primary analysis, 156 patients (29%) had normal motility on FLIP Panometry, defined by normal EGJ opening (NEO) and a normal or borderline contractile response; 95% of these patients had normal motility or ineffective esophageal motility on HRM. 202 patients (37%) had obstruction with weak contractile response, defined as reduced EGJ opening and absent contractile response or impaired/disordered contractile response, on FLIP Panometry; 92% of these patients had a disorder of EGJ outflow per CCv4.0. CONCLUSIONS: Classifying esophageal motility in response to sustained distension with FLIP Panometry parallels the swallow-associated motility evaluation provided with HRM and CCv4.0. Thus, FLIP Panometry provides a well-tolerated method that can complement, or in some cases be an alternative to HRM, for evaluating esophageal motility disorders.

Background: Cough characteristics vary between patients, and this can impact clinical diagnosis and care. The purpose of part two of this state-of-the-art review is to update the American College of Chest Physicians (CHEST) 2006 guideline on global physiology and pathophysiology of cough. Study Design and Methods: A review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 using prespecified search terms. Results: We describe the demographics of typical patients with cough in the clinical setting, including how cough characteristics change across age. We summarize the effect of common clinical conditions impacting cough mechanics and the physical properties of mucus on airway clearance. Interpretation: This is the second of a two-part update to the 2006 CHEST cough guideline; it complements part one on basic phenomenology of cough by providing an extended clinical picture of cough along with the factors that alter cough mechanics and efficiency in patients. A greater understanding of the physiology and pathophysiology of cough will improve clinical management.

For decades the rationale for treatment of gastro-oesophageal reflux disease (GORD) with acid suppressors, such as proton pump inhibitors (PPIs), was that symptoms were attributable to reflux of acidic stomach contents into the oesophagus. However, recent advances in the understanding of how brain–gut interactions can modulate the perception of visceral stimuli have complicated the concept of GORD.1 It is increasingly evident that altered perception of reflux is an important underlying cause of symptoms.2 A number of syndromes related to visceral hypersensitivity and central nervous system dysregulation are now recognised as ‘functional’ gastrointestinal (GI) disorders, potentially localised to the oesophagus,3 bowel, stomach, duodenum, anorectum, gallbladder, or multiple GI sites in the same patient. These functional syndromes are common; an internet-based health survey of almost 6000 adults in the US, Canada, and the UK found that 35% had symptoms compatible with some functional GI disorder and 7% met diagnostic criteria for a functional oesophageal disorder.4 This could potentially account for a large fraction of the adults with weekly reflux symptoms in population-based assessments (global prevalence ∼13%).5 However, it being impractical to investigate all of these patients, the recognition of altered perception as a major determinant of reflux symptoms has had little impact on management in general practice. To provide guidance for the management of uninvestigated reflux symptoms in primary care, a series of sponsored (Reckitt Benckiser Healthcare Ltd, UK) workshops were held among gastroenterologists, GI surgeons, and GPs. The objective was to translate recent research findings into clinical practice strategies. Epidemiological data suggest that the prevalence of GORD has increased considerably since the mid-1990s. However, wider public awareness of the link between reflux symptoms and oesophageal cancer6 has likely contributed to the increased presentation of symptomatic patients in primary care. Additionally, the more we understand the …

La Clasificación de Chicago v4.0 (CCv4.0) es el esquema actualizado para clasificar las alteraciones de la motilidad esofágica utilizando la métrica de la manometría de alta resolución (HRM). Para desarrollar la CCv4.0, 52 expertos internacionales diversos separados en siete subgrupos de trabajo utilizaron una metodología formalmente validada, en un periodo de dos años. Las actualizaciones claves de la CCv4.0 consisten en un protocolo de HRM más riguroso y expansivo que incorpora las posiciones en decúbito supino y sedestación, así como pruebas provocadoras; una definición refinada de la obstrucción del flujo de salida de la unión esofagogástrica (EGJOO), criterios diagnósticos más estrictos para la motilidad esofágica inefectiva, y descripción de la métrica basal de la EGJ. Adicionalmente, la CCv4.0 se propuso definir el diagnóstico de alteración de la motilidad como conclusivo o no conclusivo con base en los síntomas asociados, los hallazgos en las pruebas provocadoras, y los resultados de los exámenes de apoyo como el esofagograma con tableta de bario y/o la prueba con sonda para imagen endoluminal funcional. Estos cambios buscan minimizar la ambigüedad presente en iteraciones previas de la Clasificación de Chicago; además proveen criterios más estandarizados y rigurosos para los patrones de alteración de la peristalsis y obstrucción de la EGJ.

Introduction High-resolution manometry (HRM) is generally considered the primary method to evaluate esophageal motility; functional luminal imaging probe (FLIP) panometry represents a novel method to do so and is completed during sedated endoscopy. This study aimed to compare HRM and FLIP panometry in predicting esophageal retention on timed barium esophagram (TBE). Methods A total of 329 adult patients who completed FLIP, HRM, and TBE for primary esophageal motility evaluation were included. An abnormal TBE was defined by a 1-minute column height >5 cm or impaction of a 12.5-mm barium tablet. The integrated relaxation pressure (IRP) on HRM was assessed in the supine and upright patient positions. Esophagogastric junction (EGJ) opening was evaluated with 16-cm FLIP performed during sedated endoscopy through EGJ-distensibility index and maximum EGJ diameter. Results Receiver operating characteristic curves to identify an abnormal TBE demonstrated AUC (95% confidence interval) of 0.79 (0.75-0.84) for supine IRP, 0.79 (0.76-0.86) for upright IRP, 0.84 (0.79-0.88) for EGJ-distensibility index, and 0.88 (0.85-0.92) for maximum EGJ diameter. Logistic regression to predict abnormal TBE showed odds ratios (95% confidence interval) of 1.8 (0.84-3.7) for consistent IRP elevation and 39.7 (16.4-96.2) for reduced EGJ opening on FLIP panometry. Of 40 patients with HRM-FLIP panometry discordance, HRM-IRP was consistent with TBE in 23% while FLIP panometry was consistent with TBE in 78%. Discussion FLIP panometry provided superior detection of esophageal retention over IRP on HRM. However, application of a complementary evaluation involving FLIP panometry, HRM, and TBE may be necessary to accurately diagnose esophageal motility disorders.

Achalasia is a debilitating major motor disorder of the oesophagus. Hypervigilance and symptom-specific anxiety substantially impact dysphagia symptom reporting, and quality of life is a critical patient outcome. Earlier achalasia symptom scales did not consider these constructs in their psychometric development.To develop a new symptom measure, the Achalasia Patient-Reported Outcomes (APRO) Questionnaire METHODS: Four gastroenterologists with achalasia expertise generated preliminary items. Patients reviewed items via cognitive interviews. Patients undergoing high-resolution manometry completed the APRO with Oesophageal Hypervigilance and Anxiety Scale, Northwestern Oesophageal Quality of Life Scale, and three measures of reflux and dysphagia. Full APRO psychometric assessment (reliability, validity, factor structure) was done. Cluster analysis evaluated APRO + symptom-anxiety/hypervigilance patient phenotypes.We included 961 patients with normal motility and 296 with achalasia. The APRO yielded three subscales: dysphagia, reflux, chest pain with two items for weight change and diet modifications. Reliability and validity were excellent. Twenty-five percent of achalasia patients may have high levels of anxiety/hypervigilance despite low symptoms, while 8% may report severe symptoms with low anxiety/hypervigilance. The APRO significantly predicted quality of life, but less cognitive-affective processes.The APRO is a reliable and valid measure of achalasia symptoms that addresses the limitations of existing questionnaires. Symptom anxiety and hypervigilance moderate the relationship between APRO and quality of life; 33% of patients with achalasia exhibit concerning patterns in symptom severity, anxiety and hypervigilance that may contribute to poorer outcomes.

The esophagogastric junction (EGJ) is located at the distal end of the esophagus and acts as a valve allowing swallowed food to enter the stomach and preventing acid reflux. Irregular weakening or stiffening of the EGJ muscles results in changes to its opening and closing patterns which can progress into esophageal disorders. Therefore, understanding the physics of the opening and closing cycle of the EGJ can provide mechanistic insights into its function and can help identify the underlying conditions that cause its dysfunction. Using clinical functional lumen imaging probe (FLIP) data, we plotted the pressure-cross-sectional area loops at the EGJ location and distinguished two major loop types – a pressure dominant loop (PDL) and a tone dominant loop (TDL). In this study, we aimed to identify the key characteristics that define each loop type and determine what causes the inversion from one loop to another. To do so, the clinical observations are reproduced using 1D simulations of flow inside a FLIP device located in the esophagus, and the work done by the EGJ wall over time is calculated. This work is decomposed into active and passive components, which reveal the competing mechanisms that dictate the loop type. These mechanisms are esophagus stiffness, fluid viscosity, and the EGJ relaxation pattern.

Background Proton pump inhibitors (PPIs) are widely used to treat and prevent acid-related disorders. Despite high efficacy, PPI safety has been increasingly scrutinised. However, no comprehensive review summarising investigations of various adverse events is available. Aims To perform an umbrella review to comprehensively assess associations between adverse events and PPI use. Methods In accordance with PRISMA, an umbrella review of systematic reviews with meta-analyses was conducted. PubMed and EMBASE were searched from 2015 to July 2019. AMSTAR 2 and GRADE were used to assess quality and certainty of evidence. Author-reported quality assessments were also reviewed. Results Forty-two systematic reviews with meta-analyses, supported predominantly by observational evidence, were included. The most comprehensive studies reported statistically significant associations with PPI use for several outcomes, including: fractures (eg, hip; RR = 1.20; 95% CI = 1.14-1.28; n = 2 103 800), kidney disease (eg, acute kidney injury; RR = 1.61; 95% CI = 1.16-2.22; n = 2 396 640), infections (eg, Clostridioides difficile; OR = 1.99; 95% CI = 1.73-2.30; n = 356 683), gastric cancer (OR = 2.50; 95% CI = 1.74-3.85; n = 943 070) and gastrointestinal events (eg, fundic gland polyps; OR = 2.46; 95% CI = 1.42-4.27; n = 40 218). No associations with non-gastric cancers, or neurological disease were concluded, with conflicting evidence for cardiovascular outcomes. Certainty based on GRADE was very low for most outcomes. Conclusions This review identified several published associations between PPIs and adverse outcomes, however, further investigation is needed to understand their clinical significance and the likelihood of causal relationship. If higher quality evidence is generated substantiating the potential risks, it may be necessary for clinicians to consider alternative treatment strategies, especially when PPI efficacy is suboptimal.

BACKGROUND: This study aimed to quantify normative values of phase-specific intrabolus pressure (IBP) and esophageal distensibility using 4D analysis of high-resolution-impedance-manometry (HRIM). METHODS: HRIM studies of supine swallows from 34 normal controls were analyzed with respect to the four phases of bolus transit: 1) accommodation, 2) compartmentalization, 3) peristalsis/esophageal emptying, and 4) ampullary emptying. Phase-specific IBP, bolus volume, and distensibility index (DI) in the esophageal body and esophagogastric junction (EGJ) during phases 1–3 were extracted. RESULTS: The median (5–95(th)/IQR) IBP values were: phase 1: 4.0 (−2.0–10.4/1.9–5.8) mmHg, phase 2: 5.7 (0.2–14.1/3.6–8.9) mmHg, and phase 3: 11.2 (2.9–19.4/7.7–15.1) mmHg. The median bolus volume calculated by integrating impedance planimetry cross-sectional areas was 4.1 ml during the compartmentalization phase. The EGJ-DI at max EGJ diameter during phase 2 and 3 was 2.8 (1.1–9.5/1.8–3.7) mm(2)/mmHg and 6.0 (3.2–20.3/5.1–7.8) mm(2)/mmHg, respectively. The phase 3 EGJ-DI values (6.0 (3.2–20.3/5.1–7.8) mm(2)/mmHg) were similar to those calculated using functional lumen imaging probe (FLIP) at the 60-ml volume on the same subjects (5.8 (3.5–7.2/5.0–6.4) mm(2)/mmHg). CONCLUSIONS & INFERENCES: 4D-HRIM provides a standardized methodology to track the nadir impedance and provide measurements of IBP during maximal distention across phases 1–3 of bolus transit. Median IBP and delta IBP were different across the phases, supporting the need to define IBP by phase. Additionally, the EGJ-DI calculated during phase 3 was similar to the 60-ml EGJ-DI from FLIP in the same subjects suggesting that 4D-HRIM can quantify EGJ opening during primary peristalsis.

Refractory reflux-like symptoms have a substantial impact on patients and healthcare providers. The aim of the survey was to qualitatively assess the needs and attitudes of practicing clinicians around the management of refractory reflux symptoms and refractory gastroesophageal reflux disease (rGERD).An International Working Group for the Classification of Oesophagitis (IWGCO) steering committee invited clinicians to complete an online survey including 17 questions.Of the 113 clinicians who completed the survey, 70% were GIs, 20% were primary care physicians, and 10% were other specialties. Functional heartburn was considered the most common reason for an incomplete response to proton pump inhibitor (PPI) therapy (82%), followed by stress/anxiety (69%). More GIs identified esophageal hypersensitivity as a cause, while more non-GIs identified esophageal dysmotility and non-reflux-related esophageal conditions. As the first step, most clinicians would order investigations (70-88%). Overall, 72% would add supplemental therapy for patients with partial response, but only 58% for those with non-response. Antacid/alginate was the most common choice overall, while non-GIs were more likely to add a prokinetic than were GIs (47.8 vs. 24.1%). Approximately 40% of clinicians would switch PPIs in patients with partial response, but only 29% would do so in non-responders. Preferences for long-term therapy were highly variable. The most common initial investigation was upper endoscopy. Choice of esophageal manometry and pH monitoring was more variable, with no clear preference for whether pH monitoring should be conducted on, or off, PPI therapy.The survey identified a number of challenges for clinicians, especially non-GI physicians, treating patients with refractory reflux-like symptoms or rGERD on a daily basis.

The purpose of this state-of-the-art review is to update the American College of Chest Physicians 2006 guideline on global physiology and pathophysiology of cough. A review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 and using prespecified search terms. We describe the basic phenomenology of cough patterns, behaviors, and morphological features. We update the understanding of mechanical and physiological characteristics of cough, adding a contemporary view of the types of cough and their associated behaviors and sensations. New information about acoustic characteristics is presented, and recent insights into cough triggers and the patient cough hypersensitivity phenotype are explored. Lastly, because the clinical assessment of patients largely focuses on the duration rather than morphological features of cough, we review the morphological features of cough that can be measured in the clinic. This is the first of a two-part update to the American College of Chest Physicians 2006 cough guideline; it provides a more global consideration of cough phenomenology, beyond simply the mechanical aspects of a cough. A greater understanding of the typical features of cough, and their variations, may allow a more informed interpretation of cough measurements and the clinical relevance for patients.

A unique motor response to sustained esophageal distension, repetitive antegrade contractions (RACs), is observed using functional luminal imaging probe (FLIP) panometry. However, physiologic mechanisms related to this response are unexplored. This study aimed to evaluate the impact of cholinergic inhibition with atropine on the esophageal contractile response to sustained distention, including RACs, among healthy volunteers.8 asymptomatic volunteers (ages 22-45) were evaluated in a crossover study design with 16-cm FLIP positioned across the esophagogastric junction and distal esophagus during sedated upper endoscopy. The FLIP study involving stepwise volumetric distension was performed twice in each subject, at baseline and again after atropine (15 mcg/kg) was administered intravenously. FLIP panometry was analyzed to assess the contractile response to distension.Antegrade contractions, lumen-occluding contractions, and a RAC pattern were observed in 8/8, 8/8, and 7/8(88%) subjects, respectively, at baseline and in 5/8 (63%), 2/8 (25%) and 2/8 (25%) subjects after atropine. The rate of contractions in the RAC pattern was similar (6-7 contractions per minute) before and after atropine. Compared with the baseline study, distension-induced contractility was triggered at higher fill volumes after atropine. FLIP pressures were lower in response to volumetric filling after atropine than at baseline.The vigor and triggering of the esophageal contractile response to distension is reduced by cholinergic inhibition in asymptomatic controls. The observation that the rate of contractions did not change when patients developed repetitive contractile responses suggests that this rate is not modified by cholinergic inhibition once contractility is triggered.

Background This is an update of the section on complications that are associated with coughing in the 2006 CHEST cough guidelines that addresses two aims: (1) to systematically identify and thematically categorize the diverse complications of cough by providing a guide for future studies and (2) to identify gaps in the literature for future research. Research Question What are the potential complications that are associated with the act of coughing that have been reported in infants, children, adolescents, and adults? Study Design and Methods A scoping review was performed with the use of PubMed and SCOPUS databases that were searched from their beginning until September 6, 2019. Results Two hundred forty-seven publications met our inclusion criteria. To these, we added 38 articles from the 2006 complications paper that were not identified in the literature search plus the paper itself for a final total of 286 publications that formed the basis of this review. Since 2006, three new categories of complications have been reported: ear, nose and throat; disease transmission; and laboratory testing. Multiple additional complications that fall outside of these three categories have also been identified and included in the following categories: cardiovascular, constitutional symptoms, dermatologic, GI, genitourinary, musculoskeletal, neurologic, ophthalmologic, psychosocial/quality of life, and respiratory. Not previously highlighted is that some of the complications led to serious morbidity that included death, especially in patients with comorbid conditions, and potentially resulted in harm to others when cough resulted in a motor vehicle accident. Interpretation Our work identified a large number of cough complications that we thematically categorized primarily by organ system so that future studies of each system or each complication can be conducted. The gap in the literature that future studies should address is to identify the frequency of the complications and the strength of their association with cough. Only then will one be able to describe the findings in a manner that allows specific recommendations for avoiding these complications. In the meantime, patients with cough should be evaluated and treated according to evidence-based guidelines to mitigate or prevent the myriad of potential complications that are associated with coughing.

Endoscopic eradication therapy (EET) is an effective treatment for Barrett’s esophagus (BE); however, disease recurrence remains problematic requiring surveillance post-treatment. While data regarding predictors of recurrence are limited, uncontrolled reflux may play a significant role. Our aim was to develop a scoring system based on histopathologic reflux in surveillance biopsies following EET to identify patients at high risk for recurrence of BE. Patients were identified from two centers in the treatment with resection and endoscopic ablation techniques for BE consortium. Hematoxylin and eosin-stained slides of surveillance biopsies post-EET were assessed for histologic changes associated with reflux from a cohort of patients who also underwent pH-metry (derivation cohort). We developed a novel scoring system (Recurrent Epithelial Changes from Uncontrolled Reflux [RECUR]) composed of dilated intercellular spaces, epithelial ballooning, basal cell hyperplasia, and parakeratosis, to identify patients with abnormal esophageal acid exposure. This scoring system was then used to grade surveillance biopsies from patients with or without recurrence of BE following EET (validation cohort). Of 41 patients in the derivation cohort, 19.5% had abnormal acid exposure times (AET) while on proton pump inhibitor therapy. The mean (SD) RECUR score for patients with AET

We used in silico models to investigate the impact of the dimensions of myotomy, contraction pattern, the tone of the esophagogastric junction (EGJ), and musculature at the myotomy site on esophageal wall stresses potentially leading to the formation of a blown-out myotomy (BOM). We performed three sets of simulations with an in silico esophagus model, wherein the myotomy-influenced region was modeled as an elliptical section devoid of muscle fibers. These sets investigated the effects of the dimensions of myotomy, differing esophageal contraction types, and differing esophagogastric junction (EGJ) tone and wall stiffness at the myotomy affected region on esophageal wall stresses potentially leading to BOM. Longer myotomy was found to be accompanied by a higher bolus volume accumulated at the myotomy site. With respect to esophageal contractions, deformation at the myotomy site was greatest with propagated peristalsis, followed by combined peristalsis and spasm, and pan-esophageal pressurization. Stronger EGJ tone with respect to the wall stiffness at the myotomy site was found to aid in increasing deformation at the myotomy site. In addition, we found that an esophagus with a shorter myotomy performed better at emptying the bolus than that with a longer myotomy. Shorter myotomies decrease the chance of BOM formation. Propagated peristalsis with EGJ outflow obstruction has the highest chance of BOM formation. We also found that abnormal residual EGJ tone may be a co-factor in the development of BOM, whereas remnant muscle fibers at myotomy site reduce the risk of BOM formation. NEW & NOTEWORTHY Blown-out myotomy (BOM) is a complication observed after myotomy, which is performed to treat achalasia. In silico simulations were performed to identify the factors leading to BOM formation. We found that a short myotomy that is not transmural and has some structural architecture intact reduces the risk of BOM formation. In addition, we found that high esophagogastric junction tone due to fundoplication is found to increase the risk of BOM formation.

Ambulatory reflux monitoring performed off proton pump inhibitor (PPI) is the gold standard diagnostic test for nonerosive gastroesophageal reflux disease (GERD). However, the diagnostic metrics and optimal duration of monitoring are not well defined. This study evaluated the performance of multiple metrics across distinct durations of wireless reflux monitoring off PPI against the ability to discontinue PPI therapy in patients with suboptimal PPI response.This single-arm clinical trial performed over 4 years at 2 centers enrolled adults with troublesome GERD symptoms and inadequate response to8 weeks of PPI. Participants underwent 96-hour wireless pH monitoring off PPI. Primary outcome was whether the subject successfully discontinued PPI or resumed PPI within 3 weeks.Of 132 participants, 30% discontinued PPI. Among multiple metrics assessed, total acid exposure time (AET) of 4.0% performed best in predicting PPI discontinuation (odds ratio 2.9 [95% confidence interval 1.4, 6.4]; P = 0.006), with other thresholds of AET and DeMeester score performing comparably. AET was significantly higher on day 1 of monitoring compared with other days, and prognostic performance significantly declined when only assessing the first 48 hours of monitoring (area under the curve for 96 hours 0.63 vs area under the curve for 48 hours 0.57; P = 0.01).This clinical trial highlights the AET threshold of 4.0% as a high-performing prognostic marker of PPI discontinuation. 96 hours of monitoring performed better than 48 hours, in predicting ability to discontinue PPI. These data can inform current diagnostic approaches for patients with GERD symptoms who are unresponsive to PPI therapy.

A FLIP device gives cross-sectional area along the length of the esophagus and one pressure measurement, both as a function of time. Deducing mechanical properties of the esophagus including wall material properties, contraction strength, and wall relaxation from these data are a challenging inverse problem. Knowing mechanical properties can change how clinical decisions are made because of its potential for in-vivo mechanistic insights. To obtain such information, we conducted a parametric study to identify peristaltic regimes by using a 1D model of peristaltic flow through an elastic tube closed on both ends and also applied it to interpret clinical data. The results gave insightful information about the effect of tube stiffness, fluid/bolus density and contraction strength on the resulting esophagus shape through quantitive representations of the peristaltic regimes. Our analysis also revealed the mechanics of the opening of the contraction area as a function of bolus flow resistance. Lastly, we concluded that peristaltic driven flow displays three modes of peristaltic geometries, but all physiologically relevant flows fall into two peristaltic regimes characterized by a tight contraction.