Effects of Codeine on Esophageal Peristalsis in Patients With Ineffective Esophageal Motility:Studies Using High-resolution Manometry

Background/Aims@#This study aims to evaluate the effects of acute codeine administration on primary and secondary esophageal peristalsis in patients with ineffective esophageal motility (IEM). @*Methods@#Eighteen IEM patients (8 women; mean age 37.8 years, range 23-64 years) were enrolled in the study. The patients underwent highresolution manometry exams, consisting of 10 single wet swallows, multiple rapid swallows, and ten 20 mL rapid air injections to trigger secondary peristalsis. All participants completed 2 separate sessions, including acute administration of codeine (60 mg) and placebo, in a randomized order. @*Results@#Codeine significantly increased the distal contractile integral (566 ± 81 mmHg · s · cm vs 247 ± 36 mmHg · s · cm, P = 0.001) andshortened distal latency (5.7 ± 0.2 seconds vs 6.5 ± 0.1 seconds, P < 0.001) for primary peristalsis compared with these parameters after placebo treatment. The mean total break length decreased significantly after codeine treatment compared with the length after placebo (P= 0.003). Codeine significantly increased esophagogastric junction-contractile integral (P= 0.028) but did not change the 4-second integrated relaxation pressure (P= 0.794). Codeine significantly decreased the frequency of weak (P= 0.039) and failed contractions (P= 0.009), resulting in increased frequency of normal primary peristalsis (P < 0.136). No significant differences in the ratio of impaired multiple rapid swallows inhibition and parameters of secondary peristalsis were detected. @*Conclusions@#In IEM patients, acute administration of codeine increases contraction vigor and reduces distal latency of primary esophageal peristalsis, but has no effect on secondary peristalsis. Future studies are required to further elucidate clinical relevance of these findings, especially in the setting of gastroesophageal reflux disease with IEM.

Impact of Esophageal Motility on Microbiome Alterations in Symptomatic Gastroesophageal Reflux Disease Patients With Negative Endoscopy: Exploring the Role of Ineffective Esophageal Motility and Contraction Reserve

Background/Aims@#Ineffective esophageal motility (IEM) is common in patients with gastroesophageal reflux disease (GERD) and can be associated with poor esophageal contraction reserve on multiple rapid swallows. Alterations in the esophageal microbiome have been reported in GERD, but the relationship to presence or absence of contraction reserve in IEM patients has not been evaluated. We aim to investigate whether contraction reserve influences esophageal microbiome alterations in patients with GERD and IEM. @*Methods@#We prospectively enrolled GERD patients with normal endoscopy and evaluated esophageal motility and contraction reserve with multiple rapid swallows during high-resolution manometry. The esophageal mucosa was biopsied for DNA extraction and 16S ribosomal RNA gene V3-V4 (Illumina)/full-length (Pacbio) amplicon sequencing analysis. @*Results@#Among the 56 recruited patients, 20 had normal motility (NM), 19 had IEM with contraction reserve (IEM-R), and 17 had IEM without contraction reserve (IEM-NR). Esophageal microbiome analysis showed a significant decrease in microbial richness in patients with IEM-NR when compared to NM. The beta diversity revealed different microbiome profiles between patients with NM or IEM-R and IEM-NR (P = 0.037). Several esophageal bacterial taxa were characteristic in patients with IEM-NR, including reduced Prevotella spp.and Veillonella dispar, and enriched Fusobacterium nucleatum. In a microbiome-based random forest model for predicting IEM-NR, an area under the receiver operating characteristic curve of 0.81 was yielded. @*Conclusions@#In symptomatic GERD patients with normal endoscopic findings, the esophageal microbiome differs based on contraction reserve among IEM. Absent contraction reserve appears to alter the physiology and microbiota of the esophagus.

Artificial intelligence predicts direct-acting antivirals failure among hepatitis C virus patients: A nationwide hepatitis C virus registry program

Background/Aims@#Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1–3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. @*Methods@#We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. @*Results@#The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. @*Conclusions@#Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

Esophageal Bolus Domain Pressure and Peristalsis Associated With Experimental Induction of Esophagogastric Junction Outflow Obstruction

Background/Aims@#Intrabolus pressures are important for esophageal bolus transport and may detect obstructed bolus flow. This study measured the effect esophageal outflow obstruction experimentally induce by a leg-lift protocol. @*Methods@#Twenty-five gastroesophageal reflux disease patients referred for esophageal manometry and a normal motility diagnosis were included. Supine liquid swallows were tested. Leg-lift protocol generated esophageal outflow obstruction by increasing abdominal pressure. Esophageal pressure topography and intrabolus pressure metrics were calculated. These included, (1) mid-domain bolus distension pressure during esophageal emptying (DPE, mmHg) and (2) ramp pressure (mmHg/sec), generated by compression of the bolus between the peristaltic contraction and esophagogastric junction (EGJ). @*Results@#EGJ relaxation pressure was increased by leg-lift from 13 (11-17) to 19 (14-30) mmHg (P< 0.005) and distal contractile integral also increased from 1077 (883-1349) to 1620 (1268-2072) mmHg · cm · sec (P < 0.001) as a physiological response to obstruction. All bolus pressures were increased by leg lift; DPE increased from 17 (15-20) to 27 (19-32) mmHg (P< 0.001), and ramp pressure increased from 3 (1-4) to 5 (2-9) mmHg/sec (P < 0.05). @*Conclusion@#Measuring pressures within the intrabolus domain can quantify changes related to obstruction to outflow and may serve as adjunct measures for confirming a diagnosis EGJ outflow obstruction.

The lesson of supplementary treatment with Chinese medicine on severe laboratory-confirmed SARS patients.

Chinese medicine (CM) has been used to control infectious diseases for thousands of years. In 2003 outbreaks of severe acute respiratory syndrome (SARS) occurred in China, Hong Kong and Taiwan. In view of the possible beneficial effect of CM on SARS, we conducted this study to examine whether CM is of any benefit as a supplementary treatment of SARS. Four severe laboratory-confirmed SARS patients received routine western-medicine treatment plus different supplementary treatment: CM A, CM B and CM C (placebo control). We reported the course of the cases in terms of changes in chest radiographic scores. Case 1 treated as a placebo control passed away on the 9th day after onset of disease. The other three cases treated with CM A or CM B survived. The initial findings seemed to indicate a favorable effect of CM on management of SARS. The findings need to be verified with a larger sample. Using CM as a supplementary treatment of severe SARS seems to indicate that natural herbal medicine can be used against avian influenza. Hence, such related experience or clinical trials should be taken into consideration when facing the possible outbreak of avian influenza in the future.

Knowledge, Attitude, and Practice Survey of Gastroparesis in Asia by Asian Neurogastroenterology and Motility Association

Background/Aims@#Gastroparesis is identified as a subject that is understudied in Asia. The scientific committee of the Asian Neurogastroenterology and Motility Association performed a Knowledge, Attitude, and Practices survey on gastroparesis among doctors in Asia. @*Methods@#The questionnaire was created and developed through a literature review of current gastroparesis works of literature by the scientific committee of Asian Neurogastroenterology and Motility Association. @*Results@#A total of 490 doctors from across Asia (including Bangladesh, China, Hong Kong, Indonesia, Japan, Malaysia, Myanmar, the Philippines, Singapore, South Korea, Taiwan, Thailand, and Vietnam) participated in the survey. Gastroparesis is a significant gastrointestinal condition. However, a substantial proportion of respondents was unable to give the correct definition and accurate diagnostic test. The main reason for lack of interest in diagnosing gastroparesis was “the lack of reliable diagnostic tests” (46.8%) or “a lack of effective treatment” (41.5%). Only 41.7% of respondents had access to gastric emptying scintigraphy. Most doctors had never diagnosed gastroparesis at all (25.2%) or diagnosed fewer than 5 patients a year (52.1%). @*Conclusions@#Gastroparesis can be challenging to diagnose due to the lack of instrument, standardized method, and paucity of research data on normative value, risk factors, and treatment studies in Asian patients. Future strategies should concentrate on how to disseminate the latest knowledge of gastroparesis in Asia. In particular, there is an urgent need to estimate the magnitude of the problems in high risk and idiopathic patients as well as a standardized diagnostic procedure in Asia.

2020 Seoul Consensus on the Diagnosis and Management of Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) is a condition in which gastric contents regurgitate into the esophagus or beyond, resulting in either troublesome symptoms or complications. GERD is heterogeneous in terms of varied manifestations, test findings, and treatment responsiveness. GERD diagnosis can be established with symptomatology, pathology, or physiology. Recently the Lyon consensus defined the “proven GERD” with concrete evidence for reflux, including advanced grade erosive esophagitis (Los Angeles classification grades C and or D esophagitis), long-segment Barrett’s mucosa or peptic strictures on endoscopy or distal esophageal acid exposure time > 6% on 24-hour ambulatory pH-impedance monitoring. However, some Asian researchers have different opinions on whether the same standards should be applied to the Asian population. The prevalence of GERD is increasing in Asia. The present evidence-based guidelines were developed using a systematic review and meta-analysis approach. In GERD with typical symptoms, a proton pump inhibitor test can be recommended as a sensitive, cost-effective, and practical test for GERD diagnosis.Based on a meta-analysis of 19 estimated acid-exposure time values in Asians, the reference range upper limit for esophageal acid exposure time was 3.2% (95% confidence interval, 2.7-3.9%) in the Asian countries. Esophageal manometry and novel impedance measurements, including mucosal impedance and a post-reflux swallow-induced peristaltic wave, are promising in discrimination of GERD among different reflux phenotypes, thus increasing its diagnostic yield. We also propose a long-term strategy of evidence-based GERD treatment with proton pump inhibitors and other drugs.

2020 Seoul Consensus on the Diagnosis and Management of Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) is a condition in which gastric contents regurgitate into the esophagus or beyond, resulting in either troublesome symptoms or complications. GERD is heterogeneous in terms of varied manifestations, test findings, and treatment responsiveness. GERD diagnosis can be established with symptomatology, pathology, or physiology. Recently the Lyon consensus defined the “proven GERD” with concrete evidence for reflux, including advanced grade erosive esophagitis (Los Angeles classification grades C and or D esophagitis), long-segment Barrett’s mucosa or peptic strictures on endoscopy or distal esophageal acid exposure time > 6% on 24-hour ambulatory pH-impedance monitoring. However, some Asian researchers have different opinions on whether the same standards should be applied to the Asian population. The prevalence of GERD is increasing in Asia. The present evidence-based guidelines were developed using a systematic review and meta-analysis approach. In GERD with typical symptoms, a proton pump inhibitor test can be recommended as a sensitive, cost-effective, and practical test for GERD diagnosis.Based on a meta-analysis of 19 estimated acid-exposure time values in Asians, the reference range upper limit for esophageal acid exposure time was 3.2% (95% confidence interval, 2.7-3.9%) in the Asian countries. Esophageal manometry and novel impedance measurements, including mucosal impedance and a post-reflux swallow-induced peristaltic wave, are promising in discrimination of GERD among different reflux phenotypes, thus increasing its diagnostic yield. We also propose a long-term strategy of evidence-based GERD treatment with proton pump inhibitors and other drugs.

Clinicopathology of severe acute respiratory syndrome: an autopsy case report.

In mid-April 2003, a major outbreak of severe acute respiratory syndrome (SARS) developed in Taiwan. During the outbreak, SARS-associated coronavirus (SARS-CoV) was documented in 346 patients and 73 of them died. Autopsy was performed in 9 of the suspected SARS patients who died during the outbreak, but SARS was the cause of death in only 1 of these patients. Here we report the histological features of this patient and their clinicopathological correlations. The patient, a 36-year-old Indonesian woman, was a caretaker working for a Taiwanese family. She stayed in Taipei Jen-Chi Hospital from April 10 to April 19 to take care of her elderly employer. She developed fever on April 21 and respiratory distress on April 25, and received ribavirin, intravenous immunoglobulin, and steroid. The respiratory distress persisted and worsened, and intubation was performed on April 27. The respiratory condition improved initially after mechanical ventilation, but subcutaneous emphysema and pneumomediastinum developed on May 1. Her condition deteriorated rapidly and she died on May 2, 11 days after the onset of fever. Autopsy was performed on the same day. Histologically, the lungs showed severe diffuse alveolar damage and bronchopneumonia, but no viral inclusion. The spleen and lymph nodes revealed lymphoid depletion and the liver showed microvesicular steatosis. No specific pathological change was seen in the gastrointestinal tract and kidneys. SARS-CoV genome was detected in the nasopharyngeal aspirate and the autopsy lung specimen.

Relevance of Ultrastructural Alterations of Intercellular Junction Morphology in Inflamed Human Esophagus

BACKGROUND/AIMS: Detailed characterization of the ultrastructural morphology of intercellular space in gastroesophageal reflux disease has not been fully studied. We aimed to investigate whether subtle alteration in intercellular space structure and tight junction proteins might differ among patients with gastroesophageal reflux disease. METHODS: Esophageal biopsies at 5 cm above the gastroesophageal junction were obtained from 6 asymptomatic controls, 10 patients with reflux symptoms but without erosions, and 18 patients with erosions. The biopsies were morphologically evaluated by transmission electron microscopy, and by using immunohistochemistry for tight junction proteins (claudin-1 and claudin-2 proteins). RESULTS: The expressions of tight junction proteins did not differ between asymptomatic controls and gastroesophageal reflux disease patients. In patients with gastroesophageal reflux disease, altered desmosomal junction morphology was only found in upper stratified squamous epithelium. Dilated intercellular space occurred only in upper stratified squamous epithelium and in patients with erosive esophagitis. CONCLUSIONS: This study suggests that dilated intercellular space may not be uniformly present inside the esophageal mucosa and predominantly it is located in upper squamous epithelium. Presence of desmosomal junction alterations is associated with increased severity of gastroesophageal reflux disease. Besides dilated intercellular space, subtle changes in ultrastructural morphology of intercellular space allow better identification of inflamed esophageal mucosa relevant to acid reflux.

Primary Care Management of Chronic Constipation in Asia: The ANMA Chronic Constipation Tool

Chronic constipation (CC) may impact on quality of life. There is substantial patient dissatisfaction; possible reasons are failure to recognize underlying constipation, inappropriate dietary advice and inadequate treatment. The aim of these practical guidelines intended for primary care physicians, and which are based on Asian perspectives, is to provide an approach to CC that is relevant to the existing health-care infrastructure. Physicians should not rely on infrequent bowel movements to diagnose CC as many patients have one or more bowel movement a day. More commonly, patients present with hard stool, straining, incomplete feeling, bloating and other dyspeptic symptoms. Physicians should consider CC in these situations and when patients are found to use laxative containing supplements. In the absence of alarm features physicians may start with a 2-4 week therapeutic trial of available pharmacological agents including osmotic, stimulant and enterokinetic agents. Where safe to do so, physicians should consider regular (as opposed to on demand dosing), combination treatment and continuous treatment for at least 4 weeks. If patients do not achieve satisfactory response, they should be referred to tertiary centers for physiological evaluation of colonic transit and pelvic floor function. Surgical referral is a last resort, which should be considered only after a thorough physiological and psychological evaluation.

Atypical Symptoms in Patients With Gastroesophageal Reflux Disease

BACKGROUND/AIMS: Atypical symptoms are common in gastroesophageal reflux disease (GERD). Patients with non-erosive reflux disease (NERD) and erosive reflux disease (ERD) exhibit different clinical characteristics and responses to acid suppression treatment. We aimed to compare atypical characteristics in patients with NERD and ERD. We also investigated the presence of histological esophagitis in patients with NERD and ERD. METHODS: Eligible patients completed a questionnaire regarding reflux symptoms and concomitant atypical symptoms. Endoscopic biopsies with histological examination were performed. RESULTS: Of the 210 patients with GERD, 90 patients with ERD and 120 patients with NERD were studied. ERD patients were characterized by higher prevalence of hiatal hernia (P = 0.001) and smoking (P = 0.047). The prevalence of GERD was greater in the age group between 41 and 60 years regardless of endoscopic finding. There was no difference in the prevalence of atypical symptoms or histological esophagitis between NERD and ERD. In all subjects, heartburn was associated with dysphagia (r = 0.16, P = 0.01), dyspepsia (r = 0.22, P = 0.008) and hiccup (r = 0.19, P = 0.003), whereas acid regurgitation was associated with dyspepsia (r = 0.21, P = 0.014), belching (r = 0.15, P = 0.018) and hiccup (r = 0.19, P = 0.002). CONCLUSIONS: Atypical symptoms did not correlate with the presence of histological esophagitis. Atypical symptoms were equally prevalent in patients with NERD and ERD. The existence of atypical symptoms appears to be associated with the presence of typical reflux symptoms irrespective of endoscopic and histological reflux esophagitis.

Impact of Sleep Dysfunction on Anorectal Motility in Healthy Humans

BACKGROUND/AIMS: Sleep dysfunction is associated with altered gastrointestinal function and subsequently exacerbations of gastrointestinal problems. We aimed to investigate whether sleep dysfunction would influence anorectal motility as determined by anorectal manometry. The effect of anxiety on anorectal motility was also determined. METHODS: A total of 24 healthy volunteers underwent anorectal manometry. The anorectal parameters included resting and squeeze sphincter pressure, sensory thresholds in response to balloon distension, sphincter length, rectal compliance, and rectoanal inhibitory reflex. Sleep dysfunction was subjectively assessed by using Pittsburgh Sleep Quality Index (PSQI). Anxiety was assessed by the application of the State-Trait Anxiety Inventory questionnaire. RESULTS: There were sixteen subjects without sleep dysfunction (7 women; mean age, 22 years) and eight subjects with sleep dysfunction (2 women; mean age, 22 years). There was no group difference in the volume threshold for rectoanal inhibitory reflux, rectal compliance or sphincter length (P = NS). Anal sphincter pressure did not differ between the groups (P = NS). The rectal sensitivity for different levels of stimulation did not differ between the groups (P = NS). Sleep quality as determined by PSQI correlated with rectal compliance (r = 0.66, P = 0.007). Although there was no differences in any manometric parameters between subjects with and without anxiety, the anxiety score correlated with rectal compliance (r = 0.57, P = 0.003). CONCLUSIONS: Despite a positive association between rectal compliance and the level of subjective sleep or anxiety, sleep dysfunction did not apparently affect most of anorectal function in healthy subjects, nor did anxiety.