Review article: A practical approach to persistent gastrointestinal symptoms in inflammatory bowel disease in remission.

BACKGROUND: Persistent gastrointestinal symptoms are prevalent in adult patients with inflammatory bowel disease (IBD), even when endoscopic remission is reached. These symptoms can have profound negative effects on the quality of life of affected patients and can be difficult to treat. They may be caused by IBD-related complications or comorbid disorders, but they can also be explained by irritable bowel syndrome (IBS)-like symptoms. AIMS: To provide a practical step-by-step guide to diagnose and treat persistent gastrointestinal symptoms in patients with IBD in remission via a personalised approach. METHODS: We scrutinised relevant literature on causes, diagnostics and treatment of persistent gastrointestinal symptoms (abdominal pain or discomfort, bloating, abdominal distension, diarrhoea, constipation and faecal incontinence) in patients with IBD in remission. RESULTS: A graphical practical guide for several steps in diagnosing, identifying potential triggers and adequate treatment of persistent gastrointestinal symptoms in IBD in remission is provided based on supporting literature. The first part of this review focuses on the diagnostic and treatment approaches for potential IBD-related complications and comorbidities. The second part describes the approach to IBS-like symptoms in IBD in remission. CONCLUSIONS: Persistent gastrointestinal symptoms in IBD in remission can be traced back to potential pathophysiological mechanisms in individual patients and can be treated adequately. For both IBD-related complications and comorbidities and IBS-like symptoms in IBD in remission, pharmacological, dietary, lifestyle or psychological treatments can be effective. A systematic and personalised approach is required to reduce the burden for patients, healthcare systems, and society.

Two randomized crossover multicenter studies investigating gastrointestinal symptoms after bread consumption in individuals with noncoeliac wheat sensitivity: do wheat species and fermentation type matter?

BACKGROUND: Many individuals reduce their bread intake because they believe wheat causes their gastrointestinal (GI) symptoms. Different wheat species and processing methods may affect these responses. OBJECTIVES: We investigated the effects of 6 different bread types (prepared from 3 wheat species and 2 fermentation conditions) on GI symptoms in individuals with self-reported noncoeliac wheat sensitivity (NCWS). METHODS: Two parallel, randomized, double-blind, crossover, multicenter studies were conducted. NCWS individuals, in whom coeliac disease and wheat allergy were ruled out, received 5 slices of yeast fermented (YF) (study A, n = 20) or sourdough fermented (SF) (study B, n = 20) bread made of bread wheat, spelt, or emmer in a randomized order on 3 separate test days. Each test day was preceded by a run-in period of 3 d of a symptom-free diet and separated by a wash-out period of ≥7 d. GI symptoms were evaluated by change in symptom score (test day minus average of the 3-d run-in period) on a 0-100 mm visual analogue scale (ΔVAS), comparing medians using the Friedman test. Responders were defined as an increase in ΔVAS of ≥15 mm for overall GI symptoms, abdominal discomfort, abdominal pain, bloating, and/or flatulence. RESULTS: GI symptoms did not differ significantly between breads of different grains [YF bread wheat median ΔVAS 10.4 mm (IQR 0.0-17.8 mm), spelt 4.9 mm (-7.6 to 9.4 mm), emmer 11.0 mm (0.0-21.3 mm), P = 0.267; SF bread wheat 10.5 mm (-3.1 to 31.5 mm), spelt 11.3 mm (0.0-15.3 mm), emmer 4.0 mm (-2.9 to 9.3 mm), P = 0.144]. The number of responders was also comparable for both YF (6 to wheat, 5 to spelt, and 7 to emmer, P = 0.761) and SF breads (9 to wheat, 7 to spelt, and 8 to emmer, P = 0.761). CONCLUSIONS: The majority of NCWS individuals experienced some GI symptoms for ≥1 of the breads, but on a group level, no differences were found between different grains for either YF or SF breads. CLINICAL TRIAL REGISTRY: clinicaltrials.gov, NCT04084470 (https://classic. CLINICALTRIALS: gov/ct2/show/NCT04084470).

The effect of expectancy versus actual gluten intake on gastrointestinal and extra-intestinal symptoms in non-coeliac gluten sensitivity: a randomised, double-blind, placebo-controlled, international, multicentre study.

BACKGROUND: Many individuals without coeliac disease or wheat allergy reduce their gluten intake because they believe that gluten causes their gastrointestinal symptoms. Symptoms could be affected by negative expectancy. Therefore, we aimed to investigate the effects of expectancy versus actual gluten intake on symptoms in people with non-coeliac gluten sensitivity (NCGS). METHODS: This randomised, double-blind, placebo-controlled, international, multicentre study was done at the University of Leeds (Leeds, UK), Maastricht University (Maastricht, the Netherlands), and Wageningen University and Research (Wageningen, the Netherlands). People aged 18-70 years with self-reported NCGS (ie, gastrointestinal symptoms within 8 h of gluten consumption) without coeliac disease and wheat allergy were recruited. Participants had to follow a gluten-free or gluten-restricted diet for at least 1 week before (and throughout) study participation and had to be asymptomatic or mildly symptomatic (overall gastrointestinal symptom score ≤30 mm on the Visual Analogue Scale [VAS]) while on the diet. Participants were randomly assigned (1:1:1:1; blocks of eight; stratified by site and gender) to one of four groups based on the expectation to consume gluten-containing (E+) or gluten-free (E-) oat bread for breakfast and lunch (two slices each) and actual intake of gluten-containing (G+) or gluten-free (G-) oat bread. Participants, investigators, and those assessing outcomes were masked to the actual gluten assignment, and participants were also masked to the expectancy part of the study. The primary outcome was overall gastrointestinal symptom score on the VAS, which was measured at and corrected for baseline (before breakfast) and hourly for 8 h, with lunch served after 4 h, and analysed per-protocol. Safety analysis included all participants incorporated in the per-protocol analysis. The study is registered at ClinicalTrials.gov, NCT05779358, and has ended. FINDINGS: Between Oct 19, 2018, and Feb 14, 2022, 165 people were screened and 84 were randomly assigned to E+G+ (n=21), E+G- (n=21), E-G+ (n=20), or E-G- (n=22). One person in the E+G+ group was excluded due to not following test day instructions, leaving 83 participants in the per-protocol analysis. Median age was 27·0 years (IQR 21·0-45·0), 71 (86%) of 83 people were women, and 12 (14%) were men. Mean overall gastrointestinal symptom score was significantly higher for E+G+ (16·6 mm [95% CI 13·1 to 20·0]) than for E-G+ (6·9 mm [3·5 to 10·4]; difference 9·6 mm [95% CI 3·0 to 16·2], p=0·0010) and E-G- (7·4 mm [4·2 to 10·7]; difference 9·1 mm [2·7 to 15·6], p=0·0016), but not for E+G- (11·7 mm [8·3 to 15·1]; difference 4·9 mm [-1·7 to 11·5], p=0·28). There was no difference between E+G- and E-G+ (difference 4·7 mm [-1·8 to 11·3], p=0·33), E+G- and E-G- (difference 4·2 mm [-2·2 to 10·7], p=0·47), and E-G+ and E-G- (difference -0·5 mm [-7·0 to 5·9], p=1·0). Adverse events were reported by two participants in the E+G- group (itching jaw [n=1]; feeling lightheaded and stomach rumbling [n=1]) and one participant in the E-G+ group (vomiting). INTERPRETATION: The combination of expectancy and actual gluten intake had the largest effect on gastrointestinal symptoms, reflecting a nocebo effect, although an additional effect of gluten cannot be ruled out. Our results necessitate further research into the possible involvement of the gut-brain interaction in NCGS. FUNDING: Government of the Netherlands Topsector Agri & Food Top Consortium for Knowledge and Innovation, AB Mauri Global Bakery Ingredients, Baking Industry Research Trust, Borgesius-Albert Heijn, CSM Innovation Centre, the International Maize and Wheat Improvement Center (CIMMYT), DSM Food Specialties, Fazer, Healthgrain Forum, the International Association for Cereal Science and Technology, the International Wheat Gluten Association, Lantmännen, Mondelez International, Nederlands Bakkerij Centrum, Nutrition & Santé, Puratos, Rademaker, Sonneveld Group, and Zeelandia HJ Doeleman.

Poor Subjective Sleep Quality Predicts Symptoms in Irritable Bowel Syndrome Using the Experience Sampling Method.

INTRODUCTION: Sleep quality may affect symptom experience in irritable bowel syndrome (IBS). Our aim was to investigate the relationship between sleep quality and gastrointestinal (GI) symptoms using actigraphy and the experience sampling method. METHODS: Patients with IBS were recruited from a tertiary Neurogastroenterology clinic and the community. GI symptoms and mood were recorded on a smartphone application, 10 times per day, over 7 consecutive days. Subjective sleep quality was recorded every morning to reflect the night before. Objective measures of sleep quality were estimated from wrist-worn actigraphy. Cross-lagged structural equation models were built to assess the directionality of sleep-symptom relationships over time. RESULTS: Eighty patients with IBS completed the study (mean age: 37 years [range 20-68], 89% female, 78% community). Approximately 66% had a Pittsburgh Sleep Quality Index score ≥ 8, indicating a clinically significant sleep disturbance. Approximately 82% (95% CI: 72-90) screened positive for a sleep disorder, most commonly insomnia. In cross-lagged analysis, poor subjective sleep quality predicted next-day abdominal pain (0.036 < P < 0.040) and lower GI symptoms (0.030 < P < 0.032), but not vice versa. No significant relationship with GI symptoms was found for any objective sleep measure using actigraphy. DISCUSSION: Poor subjective sleep quality was associated with higher next-day lower GI symptom levels, but not vice versa. Objective sleep measures did not predict next-day abdominal symptoms, potentially supporting the conclusion that it is the perception of sleep quality that is most influential. This study may be used to guide future research into the effect of sleep interventions on GI symptoms.

Patient Information Summarization in Clinical Settings: Scoping Review.

BACKGROUND: Information overflow, a common problem in the present clinical environment, can be mitigated by summarizing clinical data. Although there are several solutions for clinical summarization, there is a lack of a complete overview of the research relevant to this field. OBJECTIVE: This study aims to identify state-of-the-art solutions for clinical summarization, to analyze their capabilities, and to identify their properties. METHODS: A scoping review of articles published between 2005 and 2022 was conducted. With a clinical focus, PubMed and Web of Science were queried to find an initial set of reports, later extended by articles found through a chain of citations. The included reports were analyzed to answer the questions of where, what, and how medical information is summarized; whether summarization conserves temporality, uncertainty, and medical pertinence; and how the propositions are evaluated and deployed. To answer how information is summarized, methods were compared through a new framework "collect-synthesize-communicate" referring to information gathering from data, its synthesis, and communication to the end user. RESULTS: Overall, 128 articles were included, representing various medical fields. Exclusively structured data were used as input in 46.1% (59/128) of papers, text in 41.4% (53/128) of articles, and both in 10.2% (13/128) of papers. Using the proposed framework, 42.2% (54/128) of the records contributed to information collection, 27.3% (35/128) contributed to information synthesis, and 46.1% (59/128) presented solutions for summary communication. Numerous summarization approaches have been presented, including extractive (n=13) and abstractive summarization (n=19); topic modeling (n=5); summary specification (n=11); concept and relation extraction (n=30); visual design considerations (n=59); and complete pipelines (n=7) using information extraction, synthesis, and communication. Graphical displays (n=53), short texts (n=41), static reports (n=7), and problem-oriented views (n=7) were the most common types in terms of summary communication. Although temporality and uncertainty information were usually not conserved in most studies (74/128, 57.8% and 113/128, 88.3%, respectively), some studies presented solutions to treat this information. Overall, 115 (89.8%) articles showed results of an evaluation, and methods included evaluations with human participants (median 15, IQR 24 participants): measurements in experiments with human participants (n=31), real situations (n=8), and usability studies (n=28). Methods without human involvement included intrinsic evaluation (n=24), performance on a proxy (n=10), or domain-specific tasks (n=11). Overall, 11 (8.6%) reports described a system deployed in clinical settings. CONCLUSIONS: The scientific literature contains many propositions for summarizing patient information but reports very few comparisons of these proposals. This work proposes to compare these algorithms through how they conserve essential aspects of clinical information and through the "collect-synthesize-communicate" framework. We found that current propositions usually address these 3 steps only partially. Moreover, they conserve and use temporality, uncertainty, and pertinent medical aspects to varying extents, and solutions are often preliminary.

Corrigendum: Diet associations in endometriosis: a critical narrative assessment with special reference to gluten.

[This corrects the article DOI: 10.3389/fnut.2023.1166929.].

Satisfaction With Life in IBS Is Associated With Psychological Burden Rather than Gastrointestinal Symptom Severity.

INTRODUCTION: Irritable bowel syndrome (IBS) has a major impact on emotional, social, and professional life. This study aimed to evaluate general life satisfaction, a subjective measure of well-being, in IBS patients, and to determine which factors are associated with higher life satisfaction. METHODS: IBS patients (n = 195, mean age 51.4 ± 16.5 years, 73.8% female) recruited from primary and secondary/tertiary care completed questionnaires regarding gastrointestinal symptoms, quality of life, psychological factors, and life satisfaction (Satisfaction With Life Scale, 5 items, range 5-35). A finite mixture model analysis was performed to identify latent classes. Multivariable linear regression was used to identify variables associated with life satisfaction. RESULTS: Overall, 71.3% of the patients were satisfied about their life (Satisfaction With Life Scale-score ≥21). Three latent subgroups could be identified with significantly higher life satisfaction in the subgroup with higher mental quality of life, fewer anxiety and depressive symptoms, lower gastrointestinal specific anxiety, and lower gastrointestinal symptom severity, compared with the other 2 groups. Multivariable linear regression showed that higher physical quality of life (B0.168, P < 0.001) and higher mental quality of life (B0.199, P < 0.001) were associated with higher life satisfaction. Using multivariable regression, no significant association was found between gastrointestinal symptom severity and life satisfaction. DISCUSSION: Higher physical and mental quality of life, but not gastrointestinal symptom severity, were independently associated with higher general life satisfaction in IBS. These findings reinforce the clinical need in IBS treatment to focus on the full extent of the disorder and not merely on gastrointestinal symptom improvement. ClinicalTrials.gov Identifier: NCT00775060.

Comparing the efficacy of data-driven denoising methods for a multi-echo fMRI acquisition at 7T.

In functional magnetic resonance imaging (fMRI) of the brain the measured signal is corrupted by several (e.g. physiological, motion, and thermal) noise sources and depends on the image acquisition. Imaging at ultrahigh field strength is becoming increasingly popular as it offers increased spatial accuracy. The latter is of particular benefit in brainstem neuroimaging given the small cross-sectional area of most nuclei. However, physiological noise scales with field strength in fMRI acquisitions. Although this problem is in part solved by decreasing voxel size, it is clear that adequate physiological denoising is of utmost importance in brainstem-focused fMRI experiments. Multi-echo sequences have been reported to facilitate highly effective denoising through TE-dependence of Blood Oxygen Level Dependent (BOLD) signals, in a denoising method referred to as multi-echo independent component analysis (ME-ICA). It has not been explored previously how ME-ICA compares to other data-driven denoising approaches at ultrahigh field strength. In the current study, we compared the efficacy of several denoising methods, including anatomical component based correction (aCompCor), Automatic Removal of Motion Artifacts (ICA-AROMA) aggressive and non-aggressive options, ME-ICA, and a combination of ME-ICA and aCompCor. We assessed several data quality metrics, including temporal signal-to-noise ratio (tSNR), delta variation signal (DVARS), spectral density of the global signal, functional connectivity and Shannon spectral entropy. Moreover, we looked at the ability of each method to uncouple the global signal and respiration. In line with previous reports at lower field strengths, we demonstrate that after applying ME-ICA, the data is best post-processed in order to remove spatially diffuse noise with a method such as aCompCor. Our findings indicate that ME-ICA combined with aCompCor and the aggressive option of ICA-AROMA are highly effective denoising approaches for multi-echo data acquired at 7T. ME-ICA combined with aCompCor potentially preserves more signal-of-interest as compared to the aggressive option of ICA-AROMA.

Diet associations in endometriosis: a critical narrative assessment with special reference to gluten.

Endometriosis is characterized by the presence of endometrium-like tissue outside the uterus. The etiology remains largely unknown. Despite adequate treatment, patients can still experience symptoms or side effects resulting in therapy incompliance and in self-management strategies such as dietary measures is increasing. A gluten free diet is thought to be contributory in reducing endometriosis-related pain, thereby optimizing quality of life. However, data is conflicting and currently provides no evidence for causality. This narrative review aims to put the effect of dietary self-management strategies on endometriosis in a balanced perspective, especially the effect of gluten and a gluten free diet. Several studies have found a strong overlap in symptoms, metabolic and immune responses associated with endometriosis and those associated with celiac disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome and non-celiac wheat sensitivity. However, it remains unclear whether these diseases and/or disorders are causal to an increased risk of endometriosis. Some studies have found a positive effect on the risk of endometriosis, endometriosis-related symptoms and quality of life (QoL) when women either avoided certain nutrients or foods, or applied a specific nutrient supplementation. This includes the avoidance of red meat, an increasing intake of foods rich in anti-oxidants, omega-3, micronutrients and dietary fibers (e.g., fruit, vegetables) and the appliance of a gluten free diet. However, data from the available studies were generally graded of low quality and it was noted that placebo and/or nocebo effects influenced the reported positive effects. In addition, such effects were no longer seen when adjusting for confounders such as overweight, when a translation was made from in vitro to in vivo, or when the nutrients were not supplemented as isolated sources but as part of a mixed daily diet. Finally, some studies showed that long-term adherence to a gluten free diet is often associated with an impaired diet quality and nutrient intake, leading to negative health outcomes and reduced QoL. Concluding, scientific evidence on the efficacy of dietary interventions on well-defined clinical endpoints of endometriosis is lacking and recommending a gluten free diet to women solely diagnosed with endometriosis should therefore not be advised.

Predictive Genetic Biomarkers for the Development of Peritoneal Metastases in Colorectal Cancer.

Metastatic colorectal cancer (CRC) is a common cause of cancer-related mortality, of which peritoneal metastases (PMs) have the worse outcome. Metastasis-specific markers may help predict the spread of tumor cells and select patients for preventive strategies. This exploratory pilot study aimed to gain more insight into genetic alterations in primary CRC tumors, which might be a predictive factor for the development of PM. Forty patients with T3 stage CRC were retrospectively divided in three groups: without metachronous metastases during 5-year follow-up (M0, n = 20), with metachronous liver metastases (LM, n = 10) and with metachronous PM (PM, n = 10). Patients with synchronous metastases were excluded. Primary formalin-fixed paraffin-embedded tumor samples were analyzed via comprehensive genome sequencing (TSO500 analysis) to identify DNA alterations and RNA fusion transcripts in 523 genes and 55 genes, respectively. Thirty-eight samples were included for final analysis. Four M0 tumors and one PM tumor were microsatellite instable. BRAF mutations were uniquely identified in three microsatellite-stable (MSS) PM tumors (37.5%, p = 0.010). RNA analysis showed an additional FAM198A-RAF1 fusion in one PM sample. BRAF p.V600E mutations were only present in PM patients with MSS tumors. Greater attention should be paid to BRAF-mutated tumors in relation to the development of metachronous PM.

[A plea for the reduction in upper gastrointestinal endoscopy: upper gastrointestinal endoscopy is not the solution for dyspepsia]. / Pleidooi voor minder gastroscopieën.

Upper gastrointestinal (GI) endoscopies are often performed in patients with dyspepsia. The diagnostic yield, however, is known to be limited, in particular in patients below 60 years without alarm symptoms. Furthermore, there are limits to the endoscopy capacity. In the Netherlands, an upper GI endoscopy may be requested by the general practitioner (also known as open access endoscopy) or medical specialists. Approximately 40% of the open access upper GI endoscopies is not indicated according to the Dutch guidelines, resulting in substantial costs weighed against limited diagnostic yield. In this article we outline several potential solutions to reduce the number of unnecessary upper GI endoscopies. These include providing patients with digital education, consulting a gastroenterologist, educating health care professionals on the diagnostic yield and reduction of the financial compensation through health insurance policy.

Comorbidities, biomarkers and cause specific mortality in patients with irritable bowel syndrome: A phenome-wide association study.

BACKGROUND: Irritable bowel syndrome (IBS) is one of the most common functional digestive disorders. Our understanding about its comorbidities, biomarkers, or long-term risks is still incomplete. OBJECTIVE: To characterize comorbidities and biomarkers for IBS and establish the effect of IBS on overall- and cause specific mortality. METHODS: We analyzed data from the population-based cohort of the UK Biobank (UKB) with 493,974 participants, including self-reported physician-diagnosed (n = 20,603) and ICD-10 diagnosed (n = 7656) IBS patients, with a mean follow-up of 11 years. We performed a phenome-wide association study (PheWAS) and competing risk analysis to characterize common clinical features in IBS patients. RESULTS: In PheWAS analyses, 260 PheCodes were significantly overrepresented in self-reported physician-diagnosed IBS patients, 633 in patients with ICD-10 diagnosed IBS (ICD-10-IBS), with 221 (40%) overlapping. In addition to gastrointestinal diseases, psychiatric, musculoskeletal, and endocrine/metabolic disorders represented the most strongly associated PheCodes in IBS patients. Self-reported physician-diagnosed IBS was not associated with increased overall mortality and the risk of death from cancer was decreased (hazard ratio [HR] = 0.78 [95% CI = 0.7-0.9]). Lastly, we evaluated changes in serum metabolites in IBS patients and identified glycoprotein acetyls (GlycA) as a potential biomarker in IBS. One standard deviation increase in GlycA raised the risk of self-reported IBS/ICD-10 coded by 9%-20% (odds ratio [OR] = 1.09 [95% CI = 1.1-1.1]/OR = 1.20 [95% CI = 1.1-1.3]) and the risk of overall mortality in ICD-10-IBS patients by 28% (HR = 1.28 [95% CI = 1.1-1.5]). CONCLUSION: Our large-scale association study determined IBS patients having an increased risk of several different comorbidities and that GlycA was increased in IBS patients.

[Dietary interventions in irritable bowel syndrome: 10 tips]. / Voedingsinterventies voor het prikkelbaredarmsyndroom.

Diet plays an important role in the development of abdominal symptoms in Irritable Bowel Syndrome (IBS). Most patients indicate that their symptoms are triggered or modulated by specific food. Both, patients and treating physicians, often prefer dietary interventions as a treatment for IBS, when compared to pharmacological or psychotherapy. Selecting the most effective dietary intervention for an individual patient is a challenge. It is crucial to identify patient specific food related triggers and to evaluate the patients' treatment expectations prior to start of the intervention. In this article we will discuss the approaches that may lead to the most successful dietary intervention for IBS, via 10 tips for the daily practice.