The treatment of achalasia patients with esophageal varices: an international study.

Background: Treatment options for achalasia include endoscopic and surgical techniques that carry the risk of esophageal bleeding and perforation. The rare coexistence of esophageal varices has only been anecdotally described and treatment is presumed to carry additional risk. Methods: Experience from physicians/surgeons treating this rare combination of disorders was sought through the International Manometry Working Group. Results: Fourteen patients with achalasia and varices from seven international centers were collected (mean age 61 ± 9 years). Five patients were treated with botulinum toxin injections (BTI), four had dilation, three received peroral endoscopic myotomy (POEM), one had POEM then dilation, and one patient underwent BTI followed by Heller's myotomy. Variceal eradication preceded achalasia treatment in three patients. All patients experienced a significant symptomatic improvement (median Eckardt score 7 vs 1; p < 0.0001) at 6 months follow-up, with treatment outcomes resembling those of 20 non-cirrhotic achalasia patients who underwent similar therapy. No patients had recorded complications of bleeding or perforation. Conclusion: This study shows an excellent short-term symptomatic response in patients with esophageal achalasia and varices and demonstrates that the therapeutic outcomes and complications, other than transient encephalopathy in both patients who had a portosystemic shunt, did not differ to disease-matched patients without varices.

The 2018 ISDE achalasia guidelines.

Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body. As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition. New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia. With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL). The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK. A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI). Only statements with an approval rate >80% were accepted in the guidelines. Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines. These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease.

Evaluation of outcome after cardiomyotomy for achalasia using the Chicago classification.

BACKGROUND: Achalasia can be subdivided into manometric subtypes according to the Chicago classification. These subtypes are proposed to predict outcome after treatment. This hypothesis was tested using a database of patients who underwent laparoscopic Heller's cardiomyotomy with anterior fundoplication. METHODS: All patients who underwent Heller's cardiomyotomy for achalasia between June 1993 and March 2015 were identified from an institutional database. Manometry tracings were retrieved and re-reported according the Chicago classification. Outcome was assessed by a postal questionnaire, and designated a success if the modified Eckardt score was 3 or less, and the patient had not undergone subsequent surgery or pneumatic dilatation. Difference in outcome after cardiomyotomy was analysed with a mixed-effects logistic regression model. RESULTS: Sixty, 111 and 24 patients had type I, II and II achalasia respectively. Patients with type III achalasia were more likely to be older than those with type I or II (mean age 63 versus 50 and 49 years respectively; P = 0·001). Some 176 of 195 patients returned questionnaires after surgery. Type III achalasia was less likely to have a successful outcome than type II (odds ratio (OR) 0·38, 95 per cent c.i. 0·15 to 0·94; P = 0·035). There was no significant difference in outcome between types I and II achalasia (II versus I: OR 0·87, 0·47 to 1·60; P 0·663). The success rate at 3-year follow-up was 69 per cent (22 of 32) for type I, 66 per cent (33 of 50) for type II and 31 per cent (4 of 13) for type III. CONCLUSION: Type III achalasia is a predictor of poor outcome after cardiomyotomy. There was no difference in outcome between types I and II achalasia.

Intra-bolus pressure and esophagogastric gradient, assessed with high-resolution manometry, are associated with acid exposure and proximal migration of refluxate.

Trans-sphincteric pressure gradient (TSPG) seems to play a relevant role in eliciting refluxes during transient lower esophageal sphincter relaxations (TLESRs). Intra-bolus pressure (IBP) is considered to be correlated to esophageal wall tone. We aimed to evaluate the relationship between IBP, TSPG during TLESRs and the dynamic properties of refluxate in gastroesophageal reflux disease. Sixteen non-erosive reflux disease (NERD), 10 erosive disease (ERD) patients and 12 healthy volunteers (HVs), underwent 24-hour impedance-pH monitoring and combined high-resolution manometry-impedance before and 60 minutes. After a meal, ERD patients presented a significantly lower mean IBP (4.7 ± 1.6 mmHg) respect to NERD patients (8.9 ± 2.8 mmHg) and HVs (9.2 ± 3.2 mmHg). NERD patients with physiological abnormal acid exposure time showed a mean IBP (10.4 ± 3.1 mmHg) significantly higher than that in NERD with pathological abnormal acid exposure time (5.1 ± 1.5 mmHg). The TSPG value was significantly higher during TLESRs accompanied by reflux than during TLESRs not associated with reflux, both in patients and in HVs. A significant direct correlation was found between IBP, TSPG and proximal spread of refluxes in patients and in HVs. Gastroesophageal reflux disease patients display different degrees of esophageal distension. An increased compliance of the distal esophagus may accommodate larger volumes of refluxate and likely facilitates the injuries development. Higher TSPG values appear to facilitate the occurrence of refluxes during TLESRs. In patients with NERD, higher TSPG and IBP values favor proximal spread of refluxate and hence may play a relevant role in symptom generation.

Systematic review: relationships between sleep and gastro-oesophageal reflux.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) adversely impacts on sleep, but the mechanism remains unclear. AIM: To review the literature concerning gastro-oesophageal reflux during the sleep period, with particular reference to the sleep/awake state at reflux onset. METHODS: Studies identified by systematic literature searches were assessed. RESULTS: Overall patterns of reflux during the sleep period show consistently that oesophageal acid clearance is slower, and reflux frequency and oesophageal acid exposure are higher in patients with GERD than in healthy individuals. Of the 17 mechanistic studies identified by the searches, 15 reported that a minority of reflux episodes occurred during stable sleep, but the prevailing sleep state at the onset of reflux in these studies remains unclear owing to insufficient temporal resolution of recording or analysis methods. Two studies, in healthy individuals and patients with GERD, analysed sleep and pH with adequate resolution for temporal alignment of sleep state and the onset of reflux: all 232 sleep period reflux episodes evaluated occurred during arousals from sleep lasting less than 15 s or during longer duration awakenings. Six mechanistic studies found that transient lower oesophageal sphincter relaxations were the most common mechanism of sleep period reflux. CONCLUSIONS: Contrary to the prevailing view, subjective impairment of sleep in GERD is unlikely to be due to the occurrence of reflux during stable sleep, but could result from slow clearance of acid reflux that occurs during arousals or awakenings from sleep. Definitive studies are needed on the sleep/awake state at reflux onset across the full GERD spectrum.

Automated impedance-manometry analysis detects esophageal motor dysfunction in patients who have non-obstructive dysphagia with normal manometry.

BACKGROUND: Automated integrated analysis of impedance and pressure signals has been reported to identify patients at risk of developing dysphagia post fundoplication. This study aimed to investigate this analysis in the evaluation of patients with non-obstructive dysphagia (NOD) and normal manometry (NOD/NM). METHODS: Combined impedance-manometry was performed in 42 patients (27F : 15M; 56.2 ± 5.1 years) and compared with that of 24 healthy subjects (8F : 16M; 48.2 ± 2.9 years). Both liquid and viscous boluses were tested. MATLAB-based algorithms defined the median intrabolus pressure (IBP), IBP slope, peak pressure (PP), and timing of bolus flow relative to peak pressure (TNadImp-PP). An index of pressure and flow (PFI) in the distal esophagus was derived from these variables. KEY RESULTS: Diagnoses based on conventional manometric assessment: diffuse spasm (n = 5), non-specific motor disorders (n = 19), and normal (n = 11). Patients with achalasia (n = 7) were excluded from automated impedance-manometry (AIM) analysis. Only 2/11 (18%) patients with NOD/NM had evidence of flow abnormality on conventional impedance analysis. Several variables derived by integrated impedance-pressure analysis were significantly different in patients as compared with healthy: higher PNadImp (P < 0.01), IBP (P < 0.01) and IBP slope (P < 0.05), and shorter TNadImp_PP (P = 0.01). The PFI of NOD/NM patients was significantly higher than that in healthy (liquid: 6.7 vs 1.2, P = 0.02; viscous: 27.1 vs 5.7, P < 0.001) and 9/11 NOD/NM patients had abnormal PFI. Overall, the addition of AIM analysis provided diagnoses and/or a plausible explanation in 95% (40/42) of patients who presented with NOD. CONCLUSIONS & INFERENCES: Compared with conventional pressure-impedance assessment, integrated analysis is more sensitive in detecting subtle abnormalities in esophageal function in patients with NOD and normal manometry.

Susceptibility to dysphagia after fundoplication revealed by novel automated impedance manometry analysis.

BACKGROUND: Conventional measures of esophageal pressures or bolus transport fail to identify patients at risk of dysphagia after laparoscopic fundoplication. METHODS: Liquid and viscous swallows were evaluated with impedance/manometry in 19 patients with reflux disease before and after surgery. A new method of automated impedance manometry (AIM) analysis correlated esophageal pressure with impedance data and automatically calculated a range of pressure and bolus movement variables. An iterative analysis determined whether any variables were altered in relation to dysphagia. Standard measures of esophago-gastric junction pressure, bolus presence time, and total bolus transit time were also evaluated. KEY RESULTS: At 5 months postop, 15 patients reported some dysphagia, including 7 with new-onset dysphagia. For viscous boluses, three AIM-derived pressure-flow variables recorded preoperatively varied significantly in relation to postoperative dysphagia. These were: time from nadir esophageal impedance to peak esophageal pressure (TNadImp-PeakP), median intra-bolus pressure (IBP, mmHg), and the rate of bolus pressure rise (IBP slope, mmHgs(-1) ). These variables were combined to form a dysphagia risk index (DRI=IBP×IBP_slope/TNadImp-PeakP). DRI values derived from preoperative measurements were significantly elevated in those with postoperative dysphagia (DRI=58, IQR=21-408 vs no dysphagia DRI=9, IQR=2-19, P<0.02). A DRI >14 was optimally predictive of dysphagia (sensitivity 75% and specificity 93%). CONCLUSIONS & INFERENCES: Before surgery, a greater and faster compression of a swallowed viscous bolus with less bolus flow time relates to postoperative dysphagia. Thus, susceptibility to postfundoplication dysphagia is related to a pre-existing sub-clinical variation of esophageal function.

General practitioners' knowledge of and attitudes to inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic disease requiring long-term management. General practitioners (GPs) are often the first point of contact for initial symptoms and flares. Thus we assessed GPs' attitudes to and knowledge of IBD. METHODS: A state-wide postal survey of GPs was performed collecting demographic details, practice and attitudes in IBD-specific management and knowledge. RESULTS: Of 1800 GPs surveyed in South Australia, 409 responded; 58% were male, 80% Australian trained and 73% practised in metropolitan areas. Most GPs (92%) reported seeing zero to five IBD patients per month. Overall, 37% of the GPs reported being generally 'uncomfortable' with IBD management. Specifically, they were only somewhat comfortable in providing/using maintenance therapy, steroid therapy or unspecified therapy for an acute flare. They were uncomfortable with the use of immunomodulators and biologicals (71 and 91% respectively). No GP reported never referring, referring sometimes (12%), often (34%) or always (55%). Most (87%) GPs rated their communication with private specialists positively; while only 32% were satisfied with support from public hospitals. Of concern, most (70%) monitored patients on immunosuppression on a case-by-case basis rather than by protocol. In multivariable analyses, GPs' IBD-specific knowledge did not influence comfort with overall management, nor did knowledge influence GP comfort with any particular therapy. CONCLUSION: Individual GPs care for few IBD patients and have variable attitudes in their practice. Whether improvement can realistically be achieved given individual GP's paucity of patients is questionable. These data support the provision of better support and specific action plans for IBD patients.

Objective definition and detection of transient lower esophageal sphincter relaxation revisited: is there room for improvement?

BACKGROUND: The advent of drugs that inhibit transient lower esophageal sphincter relaxation (TLESR) necessitates accurate identification and scoring. We assessed the intra- and inter-assessor variability of the existing objective criteria for TLESR, improving them where necessary. METHODS: Two 3-h postprandial esophageal manometric and pH recordings were performed in 20 healthy volunteers. Each recording was duplicated. The recordings were analyzed by five experienced observers for TLESRs based on their expert opinion. TLESRs were also analyzed for the presence of the original four criteria as well as inhibition of the crural diaphragm (ID), a prominent after-contraction (AC), acid reflux and an esophageal common cavity. KEY RESULTS: The overall inter- and intra-observer agreements for TLESRs scored, according to observer's expert opinion, were 59% (range 56-67%) and 74% (60-89%), respectively. When TLESRs were restricted to those fulfilling the original criteria, these agreements fell to 46% (40-53%) and 60% (44-67%), respectively. Cleaning the recordings by removal of technically flawed sections improved agreements by 5%. Inclusion of additional criteria (ID and AC) resulted in inter- and intra-observer agreements of 62% (52-70%) and 69% (53-79%), respectively. A consensus analysis performed collectively by three observers and based on the new criteria (original ± ID and AC) resulted in 84% agreement between the paired recordings. CONCLUSIONS & INFERENCES: The original criteria for the definition of TLESRs allows for substantial inter- and intra-observer variability, which can be reduced by incorporation of additional objective criteria. However, the highest level of intra-observer agreement can be achieved by consensus analysis.

The effects of high-dose esomeprazole on gastric and oesophageal acid exposure and molecular markers in Barrett's oesophagus.

BACKGROUND: Acid reflux is often difficult to control medically. AIM: To assess the effect of 40 mg twice daily esomeprazole (high-dose) on gastric and oesophageal pH and symptoms, and biomarkers relevant to adenocarcinoma, in patients with Barrett's oesophagus (BO). METHODS: Eighteen patients, treated with proton pump inhibitors as prescribed by their treating doctor, had their therapy increased to high-dose esomeprazole for 6 months. RESULTS: At entry into the study, 9/18 patients had excessive 24-h oesophageal acid exposure, and gastric pH remained <4 for >16 h in 8/18. With high-dose esomeprazole, excessive acid exposure occurred in 2/18 patients, and gastric pH <4 was decreased from 38% of overall recording time and 53% of the nocturnal period to 15% and 17%, respectively (P < 0.001). There was a reduction in self-assessed symptoms of heartburn (P = 0.0005) and regurgitation (P < 0.0001), and inflammation and proliferation in the Barrett's mucosa. There was no significant change in p53, MGMT or COX-2 expression, or in aberrant DNA methylation. CONCLUSIONS: High-dose esomeprazole achieved higher levels of gastric acid suppression and control of oesophageal acid reflux and symptoms, with significant decreases in inflammation and epithelial proliferation. There was no reversal of aberrant DNA methylation.

The ageing gut: diminished symptom response to a standardized nutrient stimulus.

BACKGROUND The prevalence of dyspepsia and the severity of reflux symptoms decreases with advancing age. We postulate that advancing age influences sensory function and this will be associated with a diminished symptom response to a standardized meal stimulus.Our aim was to assess the influence of age on visceral sensory function. METHODS Baseline gastrointestinal symptoms and anxiety and depression were assessed in 53 healthy volunteers using validated questionnaires. After an 8-h fast, subjects received 200 mL of a standardized enteral feeding solution every 5 min up to a cumulative volume of 800 mL. After each 200 mL drink, five key symptoms were assessed (fullness, abdominal pain, retrosternal/abdominal burning, nausea and regurgitation) using a standardized instrument on visual analogue scales (0-100). The cumulative symptom score across all symptoms was calculated. KEY RESULTS Fullness was the most prominent symptom reported (79.8 +/- 9.5) followed by nausea (14.9 +/- 4.9) and pain (9.8 +/- 4.5); these three items accounted for more than 90% of the overall symptom load. The cumulative pain and nausea scores during a standardized nutrient challenge were significantly and inversely correlated with age (r = -0.43, P = 0.002 and r = -0.28, P = 0.045). Subjects >60 years of age reported significantly lower pain and nausea scores (0.9 +/- 0.9, 4.5 +/- 3.9) than did subjects <40 years (22 +/- 11.9, P = 0.002; 29.3 +/- 12, P = 0.043). CONCLUSIONS & INFERENCES Symptom responses to a standardized nutrient challenge, in particular pain and nausea, are inversely correlated with age.

Impact of nadir lower oesophageal sphincter pressure on bolus clearance assessed by combined manometry and multi-channel intra-luminal impedance measurement.

This study aimed to assess the relationship between nadir lower oesophageal sphincter pressure (LOSP) and wave amplitude (WA) in oesophageal bolus clearance. Concurrent oesophageal manometry and impedance were performed in 146 subjects [41 healthy, 24 non-obstructive dysphagia (NOD) and 81 gastro-oesophageal reflux (GOR)]. Patients with achalasia and diffuse oesophageal spasm were excluded. Swallow responses were categorized by nadir LOSP. For each category of nadir LOSP, WA at the distal 2 recording sites were grouped into bins of 10 mmHg and the proportion of waves in each bin associated with a normal bolus presence time (BPT) was determined. Nadir LOSP, distal BPT, total bolus transit time and the proportion of impaired oesophageal clearance in patients with NOD were greater than those of healthy subjects and patients with GOR. Overall, responses with impaired oesophageal clearance had significantly lower WA (54 +/- 1 vs 81 +/- 1 mmHg; P < 0.0001) and higher nadir LOSP (2.7 +/- 0.4 vs 1.0 +/- 0.1 mmHg, P < 0.001). For each level of nadir LOSP, there was a direct relationship between distal WA and successful bolus clearance of both liquid and viscous boluses from the distal oesophagus. As nadir LOSP increased, the relationship between WA and bolus clearance shifted to the right and higher amplitudes were required to achieve the same effectiveness of clearance. Hypotensive responses with nadir LOSP > or = 3 mmHg were less likely to clear than those with nadir LOSP < 3 mmHg, for both liquid (7/29 vs 162/276; P < 0.001) or viscous boluses (11/46 vs 176/279; P < 0.0001). Nadir LOSP is an important determinant of bolus clearance from the distal oesophagus, particularly in patients with NOD.

Functional association between proximal and distal gastric motility during fasting and duodenal nutrient stimulation in humans.

A functional integration exists between proximal and distal gastric motor activity in dogs but has not been demonstrated in humans. To determine the relationship between proximal and distal gastric motor activity in humans. Concurrent proximal (barostat) and distal (antro-pyloro-duodenal (APD) manometry) gastric motility were recorded in 10 healthy volunteers (28 +/- 3 years) during (i) fasting and (ii) two 60-min duodenal infusions of Ensure((R)) (1 and 2 kcal min(-1)) in random order. Proximal and APD motor activity and the association between fundic and propagated antral waves (PAWs) were determined. During fasting, 32% of fundic waves (FWs) were followed by a PAW. In a dose-dependent fashion, duodenal nutrients (i) increased proximal gastric volume, (ii) reduced fundic and antral wave (total and propagated) activity, and (iii) increased pyloric contractions. The proportion of FWs followed by a distal PAW was similar between both infusions and did not differ from fasting. During nutrient infusion, nearly all PAWs were antegrade, propagated over a shorter distance and less likely to traverse the pylorus, compared with fasting. In humans, a functional association exists between proximal and distal gastric motility during fasting and duodenal nutrient stimulation. This may have a role in optimizing intra-gastric meal distribution.

Gastric feed intolerance is not increased in critically ill patients with type II diabetes mellitus.

OBJECTIVE: To examine the occurrence of feed intolerance in critically ill patients with previously diagnosed type II diabetes mellitus (DM) who received prolonged gastric feeding. DESIGN AND SETTING: Retrospective study in a level 3 mixed ICU. PATIENTS: All mechanically ventilated, enterally fed patients (n = 649), with (n = 118) and without type II DM (n = 531) admitted between January 2003 and July 2005. INTERVENTIONS: Patients with at least 72 h of gastric feeding were identified by review of case notes and ICU charts. The proportion that developed feed intolerance was determined. All patient received insulin therapy. RESULTS: The proportion of patients requiring gastric feeding for at least 72 h was similar between patients with and without DM (42%, 50/118, vs. 42%, 222/531). Data from patients with DM were also compared with a group of 50 patients matched for age, sex and APACHE II score, selected from the total non-diabetic group. The occurrence of feed intolerance (DM 52% vs. matched non-DM 50% vs. unselected non-diabetic 58%) and the time taken to develop feed intolerance (DM 62.6 +/- 43.8 h vs. matched non-DM 45.3 +/- 54.6 vs. unselected non-diabetic 50.6 +/- 59.5) were similar amongst the three groups. Feed intolerance was associated with a greater use of morphine/midazolam and vasopressor support, a lower feeding rate and a longer ICU length of stay. CONCLUSIONS: In critically ill patients who require prolonged enteral nutrition, a prior history of DM type II does not appear to be a further risk factor for feed intolerance.

Relationship between the mechanism of gastro-oesophageal reflux and oesophageal acid exposure in patients with reflux disease.

This study investigated the relationship between the oesophageal acid exposure time and the underlying manometric motor events in patients with gastro-oesophageal reflux disease (GORD). In 31 patients, 3-hour oesophageal motility and pH were measured after a test meal. Ten patients underwent 24-hour ambulatory manometry and pH recording. In the 3-hour postprandial study, of 367 reflux episodes 79% was associated with a transient lower oesophageal sphincter relaxation (TLOSR), 14% with absent basal lower oesophageal sphincter (LOS) pressure and the remaining 7% with other mechanisms, representing 62, 28 and 10% of the acid exposure time, respectively. Acid reflux duration per motor mechanism was longer for absent basal LOS pressure than for TLOSR (189 +/- 23 s and 41 +/- 5 s, respectively, P < 0.001). In the 24-hour ambulatory study, the contribution of TLOSRs to reflux frequency vs acid exposure time were 65 vs 54% interprandially and 74 vs 53% after the meal. During the night, absence of basal LOS pressure accounted for 36% of reflux events representing 71% of acid exposure time. In conclusion, the duration of oesophageal acid exposure following a TLOSR is shorter than reflux during absent basal LOS pressure. TLOSRs are, the major contributor to oesophageal acid exposure during the day. At night, however, reflux during absent basal LOS pressure is the major contributor to acid exposure.

Assessment of oesophageal motor function using combined perfusion manometry and multi-channel intra-luminal impedance measurement in normal subjects.

Multichannel intraluminal impedance (MII) is being used increasingly to assess oesophageal bolus clearance. However, there is no good standardization of the impedance parameters that define 'effective bolus clearance'. The aim of this study was to define these important impedance parameters and to determine their normal values. Concurrent perfusion manometry and MII were performed in 42 healthy volunteers. Ten, 5-mL liquid (saline) boluses and then, 10x5-mL low impedance viscous boluses were tested in each subject in the right-lateral position. Normal values for bolus presence time (BPT) at each site and total bolus transit time (TBTT) were determined from either 'normal' peristaltic responses (amplitude>or=30 mmHg in distal oesophagus) or 'super-normal' peristaltic responses (amplitudes>or=50 mmHg at all sites). The relationship between BPT and TBTT within a response and per-individual performance was determined. A total of 840 swallows of liquids and viscous responses were analysed. BPT and TBTT of viscous swallows were longer than those for liquids. Non-peristaltic responses were significantly more likely not to clear a viscous than a liquid bolus. Within a response, the number of sites with prolonged BPT strongly predicted the incidence of prolonged TBTT. Using impedance criteria, normal oesophageal bolus clearance is defined when an individual completely clears at least 70% of liquid responses and at least 60% of viscous responses. This study provides normal values for impedance measurement of bolus clearance when combined with perfusion manometry. These values will allow standardization of impedance application in oesophageal function testing, in both research and clinical setting.