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Objectives: It is thought that esophageal hypersensitivity in combination with an impaired mucosal barrier function contributes to PPI-resistant reflux symptoms. Ziverel, a bioadhesive agent that coats the esophageal wall, was shown to have a positive effect on reflux symptoms. However, the mechanisms of action are unclear. We aimed to assess the effect of Ziverel on esophageal sensitivity to acid and mucosal barrier function., Methods: We performed a double-blind randomized placebo-controlled crossover trial in PPI-refractory patients with reflux symptoms. Patients were assigned (1:1) to 14 days of Ziverel followed by 14 days of placebo or opposite treatment order. The effect was evaluated using acid perfusion tests, an upper endoscopy with electrical tissue impedance spectroscopy (ETIS) and esophageal biopsies. The primary outcome was the esophageal sensitivity based on perfusion sensitivity score. Secondary outcomes included mucosal barrier function and reflux symptoms and correlations between the different outcomes., Results: Perfusion sensitivity score was not significantly different during treatment with Ziverel (106 (73-115)) and placebo (102 (67-110)) ( p  = 0.508) along with total RDQ score (2.6 (1.9-3.3) vs 2.8 (1.6-3.5) p  = 0.456). ETIS showed comparable values during treatment with Ziverel (13514 (8846-19734)Ω·m) and placebo (13217 (9127-24942)Ω·m ( p  = 0.650)). Comparing Ziverel and placebo no difference was seen in transepithelial electrical resistance (TEER) 203 (163-267) Ω.cm 2 vs 205 (176-240) Ω.cm 2 ( p  = 0.445) and fluorescein flux 775 (17-6964) nmol/cm 2 /h vs 187 (4-12209) nmol/cm 2 /h ( p  = 0.638)., Conclusion: Ziverel did not show a benefit on acid sensitivity, reflux symptoms or esophageal mucosal integrity compared to placebo in PPI-refractory patients with reflux symptoms. Trial registration : Netherlands Trial Register number: NL7670.

Objective: As achalasia is a chronic disorder, long-term follow-up data comparing different treatments are essential to select optimal clinical management. Here, we report on the 10-year follow-up of the European Achalasia Trial comparing endoscopic pneumodilation (PD) with laparoscopic Heller myotomy (LHM)., Design: A total of 201 newly diagnosed patients with achalasia were randomised to either a series of PDs (n=96) or LHM (n=105). Patients completed symptom (Eckardt score) and quality-of-life questionnaires, underwent functional tests and upper endoscopy. Primary outcome was therapeutic success defined as Eckardt score < 3 at yearly follow-up. Secondary outcomes were the need for retreatment, lower oesophageal sphincter pressure, oesophageal emptying, gastro-oesophageal reflux and the rate of complications., Results: After 10 years of follow-up, LHM (n=40) and PD (n=36) were equally effective in both the full analysis set (74% vs 74%, p=0.84) and the per protocol set (74% vs 86%, respectively, p=0.07). Subgroup analysis revealed that PD was superior to LHM for type 2 achalasia (p=0.03) while there was a trend, although not significant (p=0.05), that LHM performed better for type 3 achalasia. Barium column height after 5 min at timed barium oesophagram was significantly higher for patients treated with PD compared with LHM, while other parameters, including gastro-oesophageal reflux, were not different., Conclusions: PD and LHM are equally effective even after 10 years of follow-up with limited risk to develop gastro-oesophageal reflux. Based on these data, we conclude that PD and LHM can both be proposed as initial treatment of achalasia., Competing Interests: Competing interests: GEB is Associate Editor of this journal., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aims: It has been suggested that STW5 (Iberogast) reduces heartburn symptoms in patients with functional dyspepsia, but underlying mechanisms of action are unclear. The aim of this study is to investigate whether STW5 affects esophageal sensitivity or esophageal motility, thereby reducing occurrence and perception of reflux events., Methods: We performed a double-blind, randomized, placebo-controlled, crossover trial in patients with functional dyspepsia (Rome IV) and reflux symptoms. After 4 weeks of treatment with either placebo or STW5, patients were studied with an esophageal acid perfusion test and ambulatory 24-hour pH-impedance monitoring., Results: A total of 18 patients (7 men, median age 54, range [19-76]), were included in the study. Although we found no statistical difference in our primary outcome the total Reflux Disease Questionnaire score 2.33 (0.25-4.33) vs 2.67 (1.17-4.00), P = 0.347, "gastroesophageal reflux disease" and "regurgitation" subscale scores were lower after STW5 treatment compared to placebo ( P = 0.049 and P = 0.007). There was no statistical difference in number of reflux events, acid exposure time and acid sensitivity scores between STW5 and placebo. In a subgroup analysis of patients with pH-metry confirmed gastroesophageal reflux disease, treatment with STW5 significantly reduced the total number of acidic reflux events ( P = 0.028). Moreover, in patients with reflux esophagitis, the median lag time to acid perception increased after STW5 treatment ( P = 0.042)., Conclusions: We found some indications pointing towards a beneficial effect of STW5 on reflux symptoms in dyspeptic patients, with reduction of esophageal hypersensitivity as a potential underlying mechanism. Our findings will have to be confirmed in larger studies.

Background & Aims: The aim of the study was to evaluate the effect of an electronic positional therapy wearable device on nocturnal gastroesophageal reflux measured by pH-impedance reflux monitoring., Methods: We performed a single-center, prospective, interventional study in 30 patients with nocturnal reflux symptoms and a nocturnal esophageal acid exposure time (AET) ≥1.5% measured off acid-suppressive medication by ambulatory pH-impedance reflux monitoring. Patients were treated with an electronic positional therapy wearable device for 2 weeks. The device vibrates in the right lateral decubitus position so it conditions patients to avoid that sleep position. After 2 weeks treatment, the pH-impedance study was repeated. Primary outcome was the change in nocturnal AET. Secondary outcomes include change in number of reflux episodes and reflux symptoms., Results: Complete data were available for 27 patients (13 females, mean age 49.8 years). The median nocturnal AET decreased from 6.0% (IQR, 2.3-15.3) to 3.1% (0.1-10.8) after 2 weeks of treatment (p = 0.079). The number of reflux episodes was significantly reduced after 2 weeks of treatment (baseline: 8.0 (3.0-12.3) vs. end: 3.0 (1.0-8.0); p = 0.041). Treatment led to a statistically significant decrease in time spent in right lateral decubitus position (baseline: mean 36.9% ± 15.2% vs. end: 2.7% ± 8.2%; p = <0.001) and an increase in the left lateral decubitus position (baseline 29.2% ± 14.8% vs. end: 63.3% ± 21.9%; p = <0.001). Symptom improvement was reported by 70.4% of the patients., Conclusions: Sleep positional therapy using an electronic wearable device promotes sleeping in the left lateral decubitus position and improves reflux parameters measured by pH-impedance reflux monitoring., (© 2023 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background & Aims: Experimental studies have suggested that sleep position plays a role in the occurrence of nocturnal gastroesophageal reflux and the left lateral decubitus position is most favorable. The aim of this study was to evaluate the effect of a novel electronic sleep positional therapy wearable device on sleep position and nocturnal reflux symptoms., Methods: We performed a double-blind, randomized, sham-controlled trial in patients with nocturnal symptoms of gastroesophageal reflux. Patients were advised to sleep in the left lateral decubitus position and were assigned randomly (1:1) to an electronic sleep positional therapy wearable device, programmed to either produce a vibration when in the right lateral position (intervention) or only during the first 20 minutes (sham). The primary outcome was treatment success, defined as a 50% or more reduction in the nocturnal reflux score. Secondary outcomes included change in sleep position and reflux symptoms., Results: One hundred patients were randomized. In the intention-to-treat analysis, the rate of treatment success was 44% in the intervention group (22 of 50) vs 24% in the sham group (12 of 50) (risk difference, 20%; 95% CI, 1.8%-38.2%; P = .03). Treatment led to a significant avoidance of sleeping in the right lateral decubitus position (intervention 2.2% vs sham 23.5%; P = .000) and increased time sleeping in the left lateral decubitus position (intervention 60.9% vs sham 38.5%; P = .000). More reflux-free nights were observed in the intervention group (intervention 9 nights [interquartile range, 6-11 nights] vs sham 6 nights [interquartile range, 3-9 nights]; P = .01)., Conclusions: Sleep positional therapy using an electronic wearable device promotes sleeping in the left lateral decubitus position and effectively alleviates nocturnal reflux symptoms compared with sham treatment (https://www.trialregister.nl, NL8655)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: 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., Methods: 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 score >3) 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., Findings: 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; p<0·0001). 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., Interpretation: 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., Funding: Fonds NutsOhra and European Society of Gastrointestinal Endoscopy., Competing Interests: Declaration of interests PFo received consultancy fees from Olympus and Cook Endoscopy. HN declares the following financial relationships with a commercial interest: consulting for Boston Scientific, Olympus, Medtronic, Cook, and Microtech; and grant or research support from Pentax and Erbe. TB declares the following financial relationships with a commercial interest: consulting for Olympus and Erbe. TF received speaker or consulting fees from Dr Wilmar Schwab, Sanofi-Aventis Deutschland, Takeda Pharma Vertriebs, Falk Foundation, Medizinisches Forum, Forum Medizinische Fortbildung, Promedia Medizintechnik A Ahnfeldt, MEDICE Arzneimittel Pütter, ABOCA Group, Reckitt Benckiser Deutschland, Bayer Vital. PWYC declares the following financial relationships with a commercial interest: board membership for Cornerstone Robotics; advisory committees or review panels for EndoVision and EndoMaster; and consulting for Boston Scientific. GC reported the following financial relationships with a commercial interest: advisory committees or review panels for Olympus and Cook Endoscopy; and grant or research support from Boston Scientific. JEP received research funding from National Institutes of Health National Institute of Diabetes and Digestive and Kidney Disease, and declares the following financial relationships with a commercial interest: consulting for Medtronic, ethicon, diversatek, Ironwood, Phathom, and Neurogastrx; patent held or filed (FLIP-AI) for Medtronic; and speaking and teaching for Medtronic and ethicon. AJB received research funding from Nutricia, Dr Falk Pharma, Thelial, Side Sleep Technologies and Bayer and received speaker or consulting fees from Laborie, Medtronic, Dr Falk Pharma, Alimentiv, Sanofi/Regeneron, and AstraZeneca. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Nocturnal gastroesophageal reflux symptoms have a major impact on sleep quality and are associated with complicated gastroesophageal reflux disease (GERD). We performed a systematic review to assess the data on the effectiveness of the currently available interventions for the treatment of nocturnal reflux symptoms., Methods: We searched PubMed, EMBASE, and the Cochrane Library. All prospective, controlled, and uncontrolled clinical trials in adult patients describing interventions (lifestyle modifications, surgical and pharmacological) for nocturnal gastroesophageal reflux symptoms were assessed for eligibility. A narrative descriptive summary of findings is presented together with summary tables for study characteristics and quality assessment., Key Results: The initial reference search yielded 3067 citations; 66 citations were screened in full text, of which 31 articles were included. Studies on lifestyle modifications include head of bed elevation (n = 5), prolonging dinner-to-bed time (n = 2), and promoting left lateral decubitus position (n = 2). Placebo-controlled clinical trials investigating proton pump inhibitors (PPIs) (n = 11) show success rates ranging from 34.4% to 80.8% in the PPI group versus 10.4%-51.7% in the placebo group. Laparoscopic fundoplication is reserved for severe disease only. There is insufficient evidence for a recommendation on the use of nasal continuous positive airway pressure (nCPAP), hypnotics, baclofen and adding bedtime H2 receptor antagonists for reducing nocturnal reflux. CONCLUSION INFERENCES: A sequential treatment strategy, including head of bed elevation, prolonging dinner-to-bed time, promoting left lateral decubitus position and treatment with acid-suppressive medication is recommended for nocturnal gastroesophageal reflux symptoms. Currently, there is insufficient evidence for the use of nCPAP, hypnotics, baclofen and adding bedtime H2 receptor antagonists., (© 2022 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Introduction: Although inability to belch has previously been linked to dysfunction of the upper esophageal sphincter (UES), its underlying pathogenesis remains unclear. Our aim was to study mechanisms underlying inability to belch and the effect of UES botulinum toxin (botox) injections in these patients., Methods: We prospectively enrolled consecutive patients with symptoms of inability to belch. Patients underwent stationary high-resolution impedance manometry (HRIM) with belch provocation and ambulatory 24-h pH-impedance monitoring before and 3 months after UES botox injection., Results: Eight patients (four males, age 18-37 years) were included. Complete and normal UES relaxation occurred in response to deglutition in all patients. A median number of 33(15-64) gastroesophageal gas reflux episodes were observed. Despite the subsequent increase in esophageal pressure (from -4.0 [-7.7-4.2] to 8 [3.3-16.1] mmHg; p < 0.012), none of the gastroesophageal gas reflux events resulted in UES relaxation. Periods of continuous high impedance levels, indicating air entrapment (median air presence time 10.5% [0-43]), were observed during 24-h impedance monitoring. UES botox reduced UES basal pressure (from 95.7[41.2-154.0] to 29.2 [16.7-45.6] mmHg; p < 0.02) and restored belching capacity in all patients. As a result, esophageal air presence time decreased from 10.5% (0-43.4) to 0.7% (0.1-18.6; p < 0.02) and esophageal symptoms improved in all patients (VAS 6.0 [1.0-7.9] to 1.0 [0.0-2.5]; p < 0.012)., Conclusion: The results of this study underpin the existence of a syndrome characterized by an inability to belch and support the hypothesis that ineffective UES relaxation, with subsequent esophageal air entrapment, may lead to esophageal symptoms., (© 2021 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Introduction: The aim of this study was to investigate the effect of spontaneous sleep positions on the occurrence of nocturnal gastroesophageal reflux., Methods: In patients referred for ambulatory pH-impedance reflux monitoring, the concurrent sleep position was measured using a sleep position measurement device (measuring left, right, supine, and prone positions)., Results: Fifty-seven patients were included. We observed a significantly shorter acid exposure time in the left (median 0.0%, P25-P75, 0.0%-3.0%), compared with the right lateral position (median 1.2%, 0.0%-7.5%, P = 0.022) and the supine position (median 0.6%, 0.00%-8.3%, P = 0.022). The esophageal acid clearance time was significantly shorter in the left lateral decubitus position (median 35 seconds, 16-115 seconds), compared with the supine (median 76 seconds, 22-257 seconds, P = 0.030) and right lateral positions (median 90 seconds, 26-250 seconds, P = 0.002)., Discussion: The left lateral decubitus position is associated with significantly shorter nocturnal esophageal acid exposure time and faster esophageal acid clearance compared with the supine and right lateral decubitus positions (see visual abstract)., (Copyright © 2021 by The American College of Gastroenterology.)

Objective: There is no evidence-based treatment for persistent dysphagia after laparoscopic fundoplication. The aim of this study was to evaluate the effect of pneumatic dilation on persistent dysphagia after laparoscopic fundoplication., Design: We performed a multicentre, single-blind, randomised sham-controlled trial of patients with persistent dysphagia (>3 months) after laparoscopic fundoplication. Patients with an Eckardt symptom score ≥4 were randomly assigned to pneumatic dilation (PD) using a 35 mm balloon or sham dilation. Primary outcome was treatment success, defined as an Eckardt score <4 and a minimal reduction of 2 points in the Eckardt score after 30 days. Secondary outcomes included change in stasis on timed barium oesophagogram, change in high-resolution manometry parameters and questionnaires on quality of life, reflux and dysphagia symptoms., Results: Forty-two patients were randomised. In the intention-to-treat analysis, the success rates of PD (7/21 patients (33%)) and sham dilation (8/21 patients (38%)) were similar after 30 days (risk difference -4.7% (95% CI (-33.7% to 24.2%) p=0.747). There was no significant difference in change of stasis on the timed barium oesophagogram after 2 min (PD vs sham: median 0.0 cm, p25-p75 range 0.0-4.3 cm vs median 0.0 cm, p25-p75 range 0.0-0.0; p=0.122) or change in lower oesophageal sphincter relaxation pressure (PD vs sham: 10.54±6.25 vs 14.60±6.17 mm Hg; p=0.052). Quality of life, reflux and dysphagia symptoms were not significantly different between the two groups., Conclusion: Pneumatic dilation with a 35 mm balloon is not superior to sham dilation for the treatment of persistent dysphagia after fundoplication., Competing Interests: Competing interests: JT received grant support from Sofar, received consulting fees from Ironwood and received speaker fees from Truvion. AJB received grant support from Bayer, Norgine, Nutricia, SST, and received speaker and/or consulting fees from Reckitt Benckiser, Laborie, Medtronic, Regeneron, Celgene, Arena, Esocap, Calypso, AstraZeneca and DrFalk., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although nighttime reflux symptoms are common, the presence of nocturnal reflux is seldom confirmed with a standard 24 hours pH study., Aim: To study patients with supine nighttime reflux symptoms using prolonged wireless pH monitoring., Methods: In this retrospective study, patients with typical acid reflux symptoms were studied using 96-h pH monitoring. Patients with nighttime reflux symptoms were compared to those without. Night-to-night variability and diagnostic accuracy of 24-, 48- and 72-hours pH studies compared to the 96-hours "gold standard" were evaluated., Results: Of the 105 included patients (61.9% females; mean age 46.8 ± 14.4 years), 86 (81.9%) reported nighttime reflux symptoms, of which 67.4% had pathological supine nocturnal acid exposure in at least one night. There was high variance in night-to-night acid exposure (94% [IQR0-144]), which was larger than the variance in upright acid exposure (58% [IQR32-88]; P < 0.001). When analysing the first 24 hours of the pH study, 32% of patients were diagnosed with pathological supine nighttime acid exposure versus 51% of patients based upon the 96-hours pH-test. The diagnostic accuracy and yield improved with study duration (P < 0.001). Reflux episodes with a lower nadir pH or longer acid clearance time were more prone to provoke nightly symptoms., Conclusions: The majority of patients with nocturnal reflux symptoms had pathological acid exposure in at least one night of the prolonged pH recording. A high night-to-night variability in acid exposure reduces the clinical value and diagnostic yield of pH monitoring limited to 24 hours. Prolonged testing is a more appropriate diagnostic tool for patients with nocturnal reflux symptoms., (© 2021 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Chronic intestinal pseudo-obstruction (CIPO) is a severe intestinal motility disorder of which the pathophysiology is largely unknown. This study aimed at gaining insight in fasted and fed small bowel motility in CIPO patients using cine-MRI with caloric stimulation., Methods: Eight adult patients with manometrically confirmed CIPO were prospectively included. Patients underwent a cine-MRI protocol after an overnight fast, comprising fasting-state scans and scans after ingestion of a meal (Nutridrink, 300 kcal). Small bowel motility was quantified resulting in a motility score in arbitrary units (AU) and visually assessed by three radiologists. Findings were compared with those in 16 healthy volunteers., Key Results: Motility scores (median, IQR) in CIPO patients were 0.21 (0.15-0.30) in the fasting state and 0.23 (0.15-0.27) directly postprandially. In healthy volunteers, corresponding motility scores were 0.15 (0.13-0.18) and 0.22 (0.19-0.25), respectively. The postprandial change in motility score was +1% (-19 to +21%) in CIPO and +39% (+23 to +50%) in healthy volunteers (p = 0.001*). Visual analysis revealed increased small bowel contractility in four, normal in two, and decreased in two CIPO patients., Conclusions & Inferences: Surprisingly, we found hyperactive small bowel motility in half of the CIPO patients, suggestive of uncoordinated motility. A wide variation in motility patterns was observed, both higher, lower, and comparable contractility compared with healthy subjects. No clear postprandial activation was seen in patients. Cine-MRI helps to gain insight in this complex disease and can potentially impact treatment decisions in the future., (© The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Introduction: This study aimed to assess the diagnostic yield of routine esophageal biopsies in patients with refractory reflux symptoms., Methods: We prospectively enrolled consecutive patients referred for upper endoscopy and collected histological, clinical, and endoscopic data., Results: Of the 301 included patients, 14 (4.7%) patients met the clinicopathological diagnostic definition of eosinophilic esophagitis. Presence of dysphagia, food bolus impaction, atopic background, and typical endoscopic features were the factors with the strongest association and diagnostic accuracy for eosinophilic esophagitis. The diagnostic yield in patients lacking symptoms of dysphagia or endoscopic features was negligible (0% and 1.9%, respectively)., Discussion: Routine esophageal biopsy sampling in patients with refractory reflux symptoms has a low diagnostic yield. Esophageal biopsies should only be obtained in patients with refractory reflux symptoms who also present with dysphagia (see Visual abstract, Supplementary Digital Content 2, http://links.lww.com/AJG/B792).

Background and Purpose: Establishing normative values of high-resolution esophageal manometry is necessary for accurate interpretation and comparison of measurements. In this systematic review, we aimed to summarize normal values for different esophageal high-resolution manometry systems. Moreover, we assessed the effect of body position, bolus consistency, and provocative maneuvers on these normative thresholds. We searched Medline, Embase, and the Cochrane Library from January 1st, 2006, to January 20th, 2020, for studies that reported normative data of high-resolution manometry in healthy volunteers. We assessed methodological quality of the included studies and planned a descriptive analysis. We analyzed data from 54 articles describing normative thresholds in high-resolution manometry using solid-state or water-perfused systems. Forty-six studies performed the manometry study in the supine position with liquid swallows, whereas sixteen studies described normative values in the upright position. Twelve studies assessed normative values for different bolus consistencies, and nine studies evaluated different provocative maneuvers. There is a considerable variety of normative values for esophageal high-resolution manometry depending on the equipment used and the protocols performed to obtain measurements. This should be taken into account when evaluating measurements in clinical practice and when comparing results of published research studies., (© 2020 John Wiley & Sons Ltd.)

Objective: After treatment, achalasia patients often develop reflux symptoms. Aim of this case-control study was to investigate mechanisms underlying reflux symptoms in treated achalasia patients by analysing oesophageal function, acidification patterns and symptom perception., Design: Forty treated achalasia patients (mean age 52.9 years; 27 (68%) men) were included, 20 patients with reflux symptoms (RS+; Gastro-Oesophageal Reflux Disease Questionnaire (GORDQ) ≥8) and 20 without reflux symptoms (RS-: GORDQ <8). Patients underwent measurements of oesophagogastric junction distensibility, high-resolution manometry, timed barium oesophagogram, 24 hours pH-impedance monitoring off acid-suppression and oesophageal perception for acid perfusion and distension. Presence of oesophagitis was assessed endoscopically., Results: Total acid exposure time during 24 hours pH-impedance was not significantly different between patients with (RS+) and without (RS-) reflux symptoms. In RS+ patients, acid fermentation was higher than in RS- patients (RS+: mean 6.6% (95% CI 2.96% to 10.2%) vs RS-: 1.8% (95% CI -0.45% to 4.1%, p=0.03) as well as acid reflux with delayed clearance (RS+: 6% (95% CI 0.94% to 11%) vs RS-: 3.4% (95% CI -0.34% to 7.18%), p=0.051). Reflux symptoms were not related to acid in both groups, reflected by a low Symptom Index. RS+ patients were highly hypersensitive to acid, with a much shorter time to heartburn perception (RS+: 4 (2-6) vs RS-:30 (14-30) min, p<0.001) and a much higher symptom intensity (RS+: 7 (4.8-9) vs RS-: 0.5 (0-4.5) Visual Analogue Scale, p<0.001) during acid perfusion. They also had a lower threshold for mechanical stimulation., Conclusion: Reflux symptoms in treated achalasia are rarely caused by gastro-oesophageal reflux and most instances of oesophageal acidification are not reflux related. Instead, achalasia patients with post-treatment reflux symptoms demonstrate oesophageal hypersensitivity to chemical and mechanical stimuli, which may determine symptom generation., Competing Interests: Competing interests: FAP: None. JMO: Received speaker and/or consulting fees from Laborie. AJS: None. AJB: Received research funding from Nutricia, Norgine and Bayer and received speaker and/or consulting fees from Laborie, EsoCap, Diversatek, Medtronic, Falk Pharma, Calypso Biotech, Thelial, Robarts, Reckett Benkiser, Regeneron, Celgene, Bayer, Norgine, AstraZeneca, Almirall, Arena and Allergan., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Accurate information on the natural course of giant paraesophageal hernia is scarce, challenging therapeutic decisions whether or not to operate., Objective: We aimed to investigate the long-term outcomes, including hernia-related deaths and complications (e.g. volvulus, gastrointestinal bleeding, strangulation) of patients with giant paraesophageal hernia that were conservatively managed, and to determine factors associated with clinical outcome., Methods: We retrospectively analysed charts of patients diagnosed with giant paraesophageal hernia between January 1990 and August 2019, collected from a university hospital in The Netherlands. Included patients were subdivided into three groups based on primary therapeutic decision at diagnosis. Radiological, clinical and surgical characteristics, along with long-term outcomes at most recent follow-up, were collected., Results: We included 293 patients (91 men, mean age 70.3 ± 12.4 years) with a mean duration of follow-up of 64.0 ± 58.8 months. Of the 186 patients that were conservatively treated, a total hernia-related mortality of 1.6% was observed. Hernia-related complications, varying from uncomplicated volvulus to strangulation, occurred in 8.1% of patients. Only 1.1% of patients included in this study required emergency surgery. Logistic regression analysis revealed the presence of symptoms (odds ratio (OR) 4.4, 95% confidence interval (CI) 1.8-20.6), in particular obstructive symptoms (vomiting, OR 15.7, 95% CI 4.6-53.6; epigastric pain, OR 4.4, 95% CI 1.2-15.8 and chest pain, OR 6.1, 95% CI 1.8-20.6) to be associated with the occurrence of hernia-related complications., Conclusions: Hernia-related death and morbidity is low in conservatively managed patients. The presence of obstructive symptoms was found to be associated with the occurrence of complications during follow-up. Conservative therapy is an appropriate therapeutic strategy for asymptomatic patients.

Hypercontractile esophagus (HE), also known as jackhammer esophagus, is an esophageal motility disorder. Nowadays, high-resolution manometry (HRM) is used to diagnose the disorder. According to the latest iteration of the Chicago classification, HE is present when at least 2 out 10 liquid swallow-induced peristaltic waves have an abnormally high Distal Contractile Integral. In the era of conventional manometry, a similar condition, referred to as nutcracker esophagus, was diagnosed when the peristaltic contractions had an abnormally high mean amplitude. Although the HRM diagnosis of HE is relatively straight-forward, effective management of the disorder is challenging as the correlation with symptoms is variable and treatment effects are dubious. In this mini-review, we discuss the most troublesome uncertainties that still surround HE, in the light of new data on etiology and epidemiology published in this issue of Neurogastroenterology and Motility., (© 2020 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background & Aims: Identification of factors associated with achalasia treatment outcome might help physicians select therapies based on patient characteristics. We performed a systematic review and meta-analysis to identify factors associated with treatment response., Methods: We searched MEDLINE, EMBASE, and the Cochrane Library through February 21, 2019, for randomized controlled trials and cohort, case-control, and cross-sectional studies that reported patient-specific outcomes of treatment (botulinum toxin injection, pneumatic dilation, peroral endoscopic myotomy, or laparoscopic Heller myotomy). We assessed the methodologic quality of the included studies using the quality in prognosis studies tool. We planned qualitative and quantitative analyses., Results: We analyzed data from 75 studies (8 randomized controlled trials, 27 prospective cohort studies, and 40 retrospective studies) on a total of 34 different factors associated with outcomes (3 demographic, 17 clinical, and 14 diagnostic factors). Qualitative assessment showed age, manometric subtype, and presence of a sigmoid-shaped esophagus as factors associated with outcomes of treatment for achalasia with a strong level of evidence. The cumulative evidence for the association with chest pain, symptom severity, and lower esophageal sphincter pressure was inconclusive. A meta-analysis confirmed that older age (mean difference, 7.9 y; 95% CI, 1.5-14.3 y) and manometric subtype 3 (odds ratio, 7.1; 95% CI, 4.1-12.4) were associated with clinical response., Conclusions: In a systematic review and meta-analysis, we found age and manometric subtype to be associated with outcomes of treatment for achalasia. This information should be used to guide treatment decisions., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Importance: Case series suggest favorable results of peroral endoscopic myotomy (POEM) for treatment of patients with achalasia. Data comparing POEM with pneumatic dilation, the standard treatment for patients with achalasia, are lacking., Objective: To compare the effects of POEM vs pneumatic dilation as initial treatment of treatment-naive patients with achalasia., Design, Setting, and Participants: This randomized multicenter clinical trial was conducted at 6 hospitals in the Netherlands, Germany, Italy, Hong Kong, and the United States. Adult patients with newly diagnosed achalasia and an Eckardt score greater than 3 who had not undergone previous treatment were included. The study was conducted between September 2012 and July 2015, the duration of follow-up was 2 years after the initial treatment, and the final date of follow-up was November 22, 2017., Interventions: Randomization to receive POEM (n = 67) or pneumatic dilation with a 30-mm and a 35-mm balloon (n = 66), with stratification according to hospital., Main Outcomes and Measures: The primary outcome was treatment success (defined as an Eckardt score ≤3 and the absence of severe complications or re-treatment) at the 2-year follow-up. A total of 14 secondary end points were examined among patients without treatment failure, including integrated relaxation pressure of the lower esophageal sphincter via high-resolution manometry, barium column height on timed barium esophagogram, and presence of reflux esophagitis., Results: Of the 133 randomized patients, 130 (mean age, 48.6 years; 73 [56%] men) underwent treatment (64 in the POEM group and 66 in the pneumatic dilation group) and 126 (95%) completed the study. The primary outcome of treatment success occurred in 58 of 63 patients (92%) in the POEM group vs 34 of 63 (54%) in the pneumatic dilation group, a difference of 38% ([95% CI, 22%-52%]; P < .001). Of the 14 prespecified secondary end points, no significant difference between groups was demonstrated in 10 end points. There was no significant between-group difference in median integrated relaxation pressure (9.9 mm Hg in the POEM group vs 12.6 mm Hg in the pneumatic dilation group; difference, 2.7 mm Hg [95% CI, -2.1 to 7.5]; P = .07) or median barium column height (2.3 cm in the POEM group vs 0 cm in the pneumatic dilation group; difference, 2.3 cm [95% CI, 1.0-3.6]; P = .05). Reflux esophagitis occurred more often in the POEM group than in the pneumatic dilation group (22 of 54 [41%] vs 2 of 29 [7%]; difference, 34% [95% CI, 12%-49%]; P = .002). Two serious adverse events, including 1 perforation, occurred after pneumatic dilation, while no serious adverse events occurred after POEM., Conclusions and Relevance: Among treatment-naive patients with achalasia, treatment with POEM compared with pneumatic dilation resulted in a significantly higher treatment success rate at 2 years. These findings support consideration of POEM as an initial treatment option for patients with achalasia., Trial Registration: Netherlands Trial Register number: NTR3593.

Background and Aims: One of the most used treatments for achalasia is pneumatic dilation of the lower esophageal sphincter to improve esophageal emptying. Multiple treatment protocols have been described with a varying balloon size, number of dilations, inflation pressure, and duration. We aimed to identify the most efficient and safe treatment protocol., Methods: We performed a systematic review and meta-analysis of studies on pneumatic dilation in patients with primary achalasia. Clinical remission was defined as an Eckardt score ≤3 or adequate symptom reduction measured with a similar validated questionnaire. We compared the clinical remission rates and occurrence of complications between different treatment protocols., Results: We included 10 studies with 643 patients. After 6 months, dilation with a 30-mm or 35-mm balloon gave comparable mean success rates (81% and 79%, respectively), whereas a series of dilations up to 40 mm had a higher success rate of 90%. Elective additional dilation in patients with insufficient symptom resolution was somewhat more effective than performing a predefined series of dilations: 86% versus 75% after 12 months. Perforations occurred most often during initial dilations, and significantly more often using a 35-mm balloon than a 30-mm balloon (3.2 vs 1.0%); P = 0.027. A subsequent 35-mm dilation was safer than an initial dilation with 35 mm (0.97% vs 9.3% perforations), P = 0.0017., Conclusions: The most efficient and safe method of dilating achalasia patients is a graded approach starting with a 30-mm dilation, followed by an elective 35-mm dilation and 40 mm when there is insufficient symptom relief., (© 2019 The Authors. Neurogastroenterology & Motility Published by John Wiley & Sons Ltd.)

Background: Hypnotherapy for irritable bowel syndrome (IBS) has been used primarily in patients with refractory symptoms in specialised departments and delivered on an individual basis. We aimed to test the hypothesis that hypnotherapy would be more effective than educational supportive therapy, and that group hypnotherapy would be non-inferior to individual hypnotherapy for patients with IBS referred from primary and secondary care., Methods: We did a multicentre randomised controlled trial (IMAGINE) in 11 hospitals in the Netherlands. Patients with IBS, aged 18-65 years, who were referred from primary or secondary care were randomly allocated (3:3:1) in blocks of six using a computer-based random number table procedure by staff not involved in the treatment to receive six sessions of individual or group hypnotherapy or group educational supportive therapy (control group). The primary outcome was adequate relief of IBS symptoms, with responders defined as patients who reported adequate relief when asked once weekly on three or four occasions in 4 consecutive weeks. We compared hypnotherapy (both groups) with control in the intention-to-treat population (excluding individuals subsequently found to be ineligible for enrolment), and assessed non-inferiority of group hypnotherapy versus individual hypnotherapy in the per-protocol population (with a non-inferiority margin of 15%) at 3 months and 12 months. This trial is registered with ISRCTN, number ISRCTN22888906, and is completed., Findings: Between May 31, 2011, and April 6, 2016, 494 patients referred for psychological treatment for IBS were assessed for eligibility, of whom 354 were randomly allocated to the three groups: 150 to individual hypnotherapy, 150 to group hypnotherapy, and 54 to educational supportive therapy. After exclusion of individuals subsequently found to be ineligible for enrolment, 142 patients in the individual hypnotherapy group, 146 in the group hypnotherapy group, and 54 in the control group were included in the intention-to-treat population. Of these, 22 (15%) patients in the individual hypnotherapy group, 22 (15%) in the group hypnotherapy group, and 11 (20%) in the control group dropped out before or during therapy. In the intention-to-treat analysis, the adequate response rate was 40·8% (95% CI 31·7-50·5) in the individual hypnotherapy group, 33·2% (24·3-43·5) in the group hypnotherapy group, and 16·7% (7·6-32·6) in the control group at 3 months. At 12 months, 40·8% (31·3-51·1) of patients in the individual hypnotherapy group, 49·5% (38·8-60·0) of patients in the group hypnotherapy group, and 22.6% (11·5-39·5) of patients in the control group reported adequate relief. Hypnotherapy was more effective than control at 3 months (odds ratio 2·9, 95% CI 1·2-7·4, p=0·0240) and 12 months (2·8, 1·2-6·7, p=0·0185). In the per-protocol analysis, 49·9% (39·2-60·6) in the individual hypnotherapy group and 42·7% (32·3-53·8) in the group hypnotherapy group had adequate relief at 3 months, and 55·5% (43·4-67·1) of individual and 51·7% (40·2-63·0) of group hypnotherapy patients reported adequate relief at 12 months. Group hypnotherapy was therefore non-inferior to individual hypnotherapy. Eight unexpected serious adverse reactions (six in the individual hypnotherapy group and two in the group hypnotherapy group) were reported, most of which were cancer or inflammatory bowel disease, and were judged by the medical ethics committee as not being related to the therapy., Interpretation: Hypnotherapy should be considered as a possible treatment for patients with IBS in primary and secondary care. Furthermore, group therapy could allow many more patients to be treated for the same cost., Funding: None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Esophageal stasis is a hallmark of achalasia. Timed barium esophagogram (TBE) is used to measure stasis but exposes patients to ionizing radiation. It is suggested that esophageal stasis can be objectified on high-resolution manometry (HRM) as well using a rapid drinking challenge test (RDC). We aimed to assess esophageal stasis in achalasia by a RDC during HRM and compare this to TBE., Methods: Thirty healthy subjects (15 male, age 40 [IQR 34-49]) and 90 achalasia patients (53 male, age 47 [36-59], 30 untreated/30 treated symptomatic/30 treated asymptomatic) were prospectively included to undergo HRM with RDC and TBE. RDC was performed by drinking 200 mL of water. Response to RDC was measured by basal and relaxation pressure in the esophagogastric junction (EGJ) and esophageal pressurization during the last 5 seconds., Key Results: EGJ basal and relaxation pressure during RDC were higher in achalasia compared to healthy subjects (overall P < .01). Esophageal body pressurization was significantly higher in untreated (43 [33-35 mm Hg]) and symptomatic treated patients (25 [16-32] mm Hg) compared to healthy subjects (6 [3-7] mm Hg) and asymptomatic treated patients (11 [8-15] mm Hg, overall P < .01). A strong correlation was observed between esophageal pressurization during RDC and barium column height at 5 minutes on TBE (r = .75, P < .01), comparable to the standard predictor of esophageal stasis, IRP (r = .66, P < .01)., Conclusions & Inferences: The RDC can reliably predict esophageal stasis in achalasia and adequately measure treatment response to a degree comparable to TBE. We propose to add this simple test to each HRM study in achalasia patients., (© 2018 The Authors. Neurogastroenterology & Motility Published by John Wiley & Sons Ltd.)

The purpose of this study was to describe a newly developed speech therapy program as an innovating therapeutic approach and to assess the results of this intervention in patients with supragastric belching. This is a retrospective analysis of prospectively gathered data from 73 patients with supragastric belching who were treated with speech therapy between 2007 and 2017. Of these, 48 were included for evaluation of therapy. Thirty patients had supragastric belching proven by 24-h impedance measurements. Eighteen patients were diagnosed by an experienced speech language pathologist as having supragastric belching according to precise criteria. Speech therapy consists of explanation, creating awareness of esophageal air influx and exercises to discontinue the supragastric belching mechanism. Therapy effect was measured by comparing visual analogue scale (VAS) scores on belching and related symptoms. The median symptom duration at the start of therapy was 2 years. Supragastric belching symptoms decreased significantly with a total median VAS score of 406 (291-463) prior to treatment and a median VAS score of 125 (17-197) following treatment. Forty patients (83%) had a sufficient to major result with a median therapy duration of 3 months and ten sessions. Speech therapy was an effective treatment in the majority of patients with supragastric belching.

Clinical history, questionnaire data and response to antisecretory therapy are insufficient to make a conclusive diagnosis of GERD in isolation, but are of value in determining need for further investigation. Conclusive evidence for reflux on oesophageal testing include advanced grade erosive oesophagitis (LA grades C and D), long-segment Barrett's mucosa or peptic strictures on endoscopy or distal oesophageal acid exposure time (AET) >6% on ambulatory pH or pH-impedance monitoring. A normal endoscopy does not exclude GERD, but provides supportive evidence refuting GERD in conjunction with distal AET <4% and <40 reflux episodes on pH-impedance monitoring off proton pump inhibitors. Reflux-symptom association on ambulatory reflux monitoring provides supportive evidence for reflux triggered symptoms, and may predict a better treatment outcome when present. When endoscopy and pH or pH-impedance monitoring are inconclusive, adjunctive evidence from biopsy findings (histopathology scores, dilated intercellular spaces), motor evaluation (hypotensive lower oesophageal sphincter, hiatus hernia and oesophageal body hypomotility on high-resolution manometry) and novel impedance metrics (baseline impedance, postreflux swallow-induced peristaltic wave index) can add confidence for a GERD diagnosis; however, diagnosis cannot be based on these findings alone. An assessment of anatomy, motor function, reflux burden and symptomatic phenotype will therefore help direct management. Future GERD management strategies should focus on defining individual patient phenotypes based on the level of refluxate exposure, mechanism of reflux, efficacy of clearance, underlying anatomy of the oesophagogastric junction and psychometrics defining symptomatic presentations., Competing Interests: Competing interests: CPG: consulting: Ironwood, Torax, Quintiles; teaching and speaking: Medtronic, Diversatek, Reckitt-Benckiser. ES: consulting: AbbVie, Allergan, MSD, Takeda, Sofar, Janssen; teaching and speaking: Medtronic, Reckitt-Benckiser, Malesci, Zambon. FZ: research support: Medtronic, Sandhill Scientific; consulting: Allergan, Reckitt-Benckiser; speaking and teaching: Ipsen Pharma, Biocodex, Coloplast, Takeda, Vifor Pharma, Mayoly Spindler. PJK: consulting: Ironwood. FM: teaching and speaking: Laborie, Medtronic; consulting: Allergan, Endostim. AJPMS: none. MV: Vanderbilt University and Diversatek co-own patent on mucosal impedance technology. DS: research support: Diversatek, Reckitt-Benckiser; OMOM, Jinshan Science & Technology (Group) Co. Ltd., Chongqing, China. MRF: research support: Given Imaging/Covidien, Reckitt Benckiser, Mui Scientific. Educational events: Given Imaging/Covidien, MMS, Sandhill Scientific Instruments. Speaking and teaching: Given Imaging/Covidien, Reckitt Benckiser, Shire, Almirall. MV: consulting: Torax. RT: teaching: Laborie. JT: consulting: Ironwood. AJB: research support: Danone, Bayer; speaking and/or consulting: MMS, Astellas, AstraZeneca, Bayer, Almirall and Allergan. JP: research support: Impleo; speaking and/or consulting: Medtronic, Diversatek, Torax, Ironwood, Takeda, AstraZeneca; stock options: Crospon. SR: research support: Sandhill Scientific, Crospon; teaching: Medtronic; speaker: Mayoly Spindler., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Achalasia patients with longstanding disease are considered to be at risk for developing esophageal cancer. Endoscopic screening is not standardized and detection of dysplastic lesions is difficult, for which Lugol chromoendoscopy could be helpful. Aim was to evaluate the efficacy of screening for esophageal dysplasia and carcinoma in patients with longstanding achalasia using Lugol chromoendoscopy., Methods: In this cohort study achalasia patients underwent three-annual screening by Lugol chromoendoscopy between January 2000 and March 2016. Patients with low-grade dysplasia (LGD) underwent yearly screening, patients with high-grade dysplasia (HGD) or carcinoma were treated., Results: In total, 230 achalasia patients (144 male, median age 52 years (IQR 43-63) at first endoscopy) were included. Three patients (1.3%, 2 male, age 68 years (range 50-87)) developed esophageal squamous cell carcinoma (ESCC), without LGD at the preceding screening. Incidence rate for ESCC was 63 (95% CI 13-183) per 100 000 persons-years. LGD was observed in 4 patients (1.7%, 2 male, age 64 years (range 57-73)), without progression to HGD/ESCC during a follow-up of 9 (IQR 7-14) years. ESCC/LGD was diagnosed 30 (IQR 14-36) years after onset of symptoms and 22 (IQR 4-13) years after diagnosis. Lugol chromoendoscopy tripled the detection rate of suspected lesions (111 lesions white light versus 329 lesions Lugol), but only 8% was histopathological confirmed ESCC or LGD., Conclusion: Achalasia patients with longstanding disease (>20 years) have an increased risk to develop esophageal dysplasia and carcinoma. Endoscopic screening using white light and Lugol chromoendoscopy does not accurately identify precursor lesions for ESCC and therefore cannot be systematically recommended.

Background: Eosinophilic esophagitis (EoE) is a chronic esophageal inflammation that may lead to stricture formation. This narrowing can cause major complications including food impactions. Despite increasing interest in EoE accurate data on its natural course is scarce. Therefore, we aimed to investigate the natural course of EoE and to evaluate the association between undiagnosed disease and the occurrence of complications over two decades in a large cohort., Methods: We retrospectively analyzed charts of patients diagnosed with EoE between 1996 and 2015, collected from 15 hospitals throughout the Netherlands. Histologic, clinical, and endoscopic characteristics were identified and stratified by age and diagnostic delay., Results: We included 721 patients (524 males, 117 children (≤18 years)). Dysphagia and food impactions were more common in adults whereas children more often presented with vomiting and abdominal pain (all p < 0.001). The prevalence of fibrotic endoscopic features was higher in adults (76%) than in children (39%) (p < 0.001). As time with undiagnosed disease progressed the percentage of patients with strictures and food impactions increased from 19% and 24% (diagnostic delay ≤ 2 years) to 52% and 57% (diagnostic delay ≥ 21 years) (p < 0.001), respectively. In a multivariate logistic regression model, diagnostic delay (odds ratio (OR) = 1.09; 95% confidence interval (CI) = 1.05-1.13) and male gender (OR = 2.69, 95% CI = 1.61-4.50) were the major risk factors for stricture presence., Conclusion: During the natural course of EoE, progression from an inflammatory to a fibrostenotic phenotype occurs. With each additional year of undiagnosed EoE the risk of stricture presence increases with 9%.