Mixed Representations of Sound and Action in the Auditory Midbrain.

Linking sensory input and its consequences is a fundamental brain operation. During behavior, the neural activity of neocortical and limbic systems often reflects dynamic combinations of sensory and task-dependent variables, and these "mixed representations" are suggested to be important for perception, learning, and plasticity. However, the extent to which such integrative computations might occur outside of the forebrain is less clear. Here, we conduct cellular-resolution two-photon Ca2+ imaging in the superficial "shell" layers of the inferior colliculus (IC), as head-fixed mice of either sex perform a reward-based psychometric auditory task. We find that the activity of individual shell IC neurons jointly reflects auditory cues, mice's actions, and behavioral trial outcomes, such that trajectories of neural population activity diverge depending on mice's behavioral choice. Consequently, simple classifier models trained on shell IC neuron activity can predict trial-by-trial outcomes, even when training data are restricted to neural activity occurring prior to mice's instrumental actions. Thus, in behaving mice, auditory midbrain neurons transmit a population code that reflects a joint representation of sound, actions, and task-dependent variables.

Auditory Corticofugal Neurons Transmit Auditory and Non-auditory Information During Behavior.

Layer 5 pyramidal neurons of sensory cortices project "corticofugal" axons to myriad sub-cortical targets, thereby broadcasting high-level signals important for perception and learning. Recent studies suggest dendritic Ca2+ spikes as key biophysical mechanisms supporting corticofugal neuron function: these long-lasting events drive burst firing, thereby initiating uniquely powerful signals to modulate sub-cortical representations and trigger learning-related plasticity. However, the behavioral relevance of corticofugal dendritic spikes is poorly understood. We shed light on this issue using 2-photon Ca2+ imaging of auditory corticofugal dendrites as mice of either sex engage in a GO/NO-GO sound-discrimination task. Unexpectedly, only a minority of dendritic spikes were triggered by behaviorally relevant sounds under our conditions. Task related dendritic activity instead mostly followed sound cue termination and co-occurred with mice's instrumental licking during the answer period of behavioral trials, irrespective of reward consumption. Temporally selective, optogenetic silencing of corticofugal neurons during the trial answer period impaired auditory discrimination learning. Thus, auditory corticofugal systems' contribution to learning and plasticity may be partially nonsensory in nature.

Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments.

Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.

Effect of Brain-Gut Behavioral Treatments on Abdominal Pain in Irritable Bowel Syndrome: Systematic Review and Network Meta-Analysis.

BACKGROUND & AIMS: Some brain-gut behavioral treatments (BGBTs) are beneficial for global symptoms in irritable bowel syndrome (IBS). United States management guidelines suggest their use in patients with persistent abdominal pain, but their specific effect on this symptom has not been assessed systematically. METHODS: We searched the literature through December 16, 2023, for randomized controlled trials (RCTs) assessing efficacy of BGBTs for adults with IBS, compared with each other or a control intervention. Trials provided an assessment of abdominal pain resolution or improvement at treatment completion. We extracted data as intention-to-treat analyses, assuming dropouts to be treatment failures and reporting pooled relative risks (RRs) of abdominal pain not improving with 95% confidence intervals (CIs), ranking therapies according to the P score. RESULTS: We identified 42 eligible randomized controlled trials comprising 5220 participants. After treatment completion, the BGBTs with the largest numbers of trials and patients recruited demonstrating efficacy for abdominal pain, specifically, included self-guided/minimal contact cognitive behavioral therapy (CBT) (RR, 0.71; 95% CI, 0.54-0.95; P score, 0.58), face-to-face multicomponent behavioral therapy (RR, 0.72; 95% CI, 0.54-0.97; P score, 0.56), and face-to-face gut-directed hypnotherapy (RR, 0.77; 95% CI, 0.61-0.96; P score, 0.49). Among trials recruiting only patients with refractory global IBS symptoms, group CBT was more efficacious than routine care for abdominal pain, but no other significant differences were detected. No trials were low risk of bias across all domains, and there was evidence of funnel plot asymmetry. CONCLUSIONS: Several BGBTs, including self-guided/minimal contact CBT, face-to-face multicomponent behavioral therapy, and face-to-face gut-directed hypnotherapy may be efficacious for abdominal pain in IBS, although none was superior to another.

Postprandial symptoms in disorders of gut-brain interaction and their potential as a treatment target.

Postprandial, or meal-related, symptoms, such as abdominal pain, early satiation, fullness or bloating, are often reported by patients with disorders of gut-brain interaction, including functional dyspepsia (FD) or irritable bowel syndrome (IBS). We propose that postprandial symptoms arise via a distinct pathophysiological process. A physiological or psychological insult, for example, acute enteric infection, leads to loss of tolerance to a previously tolerated oral food antigen. This enables interaction of both the microbiota and the food antigen itself with the immune system, causing a localised immunological response, with activation of eosinophils and mast cells, and release of inflammatory mediators, including histamine and cytokines. These have more widespread systemic effects, including triggering nociceptive nerves and altering mood. Dietary interventions, including a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols, elimination of potential food antigens or gluten, IgG food sensitivity diets or salicylate restriction may benefit some patients with IBS or FD. This could be because the restriction of these foods or dietary components modulates this pathophysiological process. Similarly, drugs including proton pump inhibitors, histamine-receptor antagonists, mast cell stabilisers or even tricyclic or tetracyclic antidepressants, which have anti-histaminergic actions, all of which are potential treatments for FD and IBS, act on one or more of these mechanisms. It seems unlikely that food antigens driving intestinal immune activation are the entire explanation for postprandial symptoms in FD and IBS. In others, fermentation of intestinal carbohydrates, with gas release altering reflex responses, adverse reactions to food chemicals, central mechanisms or nocebo effects may dominate. However, if the concept that postprandial symptoms arise from food antigens driving an immune response in the gastrointestinal tract in a subset of patients is correct, it is paradigm-shifting, because if the choice of treatment were based on one or more of these therapeutic targets, patient outcomes may be improved.

Prevalence of irritable bowel syndrome and functional dyspepsia after acute gastroenteritis: systematic review and meta-analysis.

OBJECTIVE: Disorders of gut-brain interaction may arise after acute gastroenteritis. Data on the influence of pathogen type on the risk of postinfection IBS (PI-IBS), as on postinfection functional dyspepsia (PI-FD), are limited. We conducted a systematic review and meta-analysis to determine prevalence of PI-IBS or PI-FD after acute gastroenteritis. DESIGN: We included observational studies recruiting ≥50 adults and reporting prevalence of IBS or FD after acute gastroenteritis with ≥3-month follow-up. A random effects model was used to estimate prevalence and ORs with 95% CIs. RESULTS: In total, 47 studies (28 170 subjects) were eligible. Overall prevalence of PI-IBS and PI-FD were 14.5% and 12.7%, respectively. IBS persisted in 39.8% of subjects in the long-term (>5 years follow-up) after diagnosis. Individuals experiencing acute gastroenteritis had a significantly higher odds of IBS (OR 4.3) and FD (OR 3.0) than non-exposed controls. PI-IBS was most associated with parasites (prevalence 30.1%), but in only two studies, followed by bacteria (18.3%) and viruses (10.7%). In available studies, Campylobacter was associated with the highest PI-IBS prevalence (20.7%) whereas Proteobacteria and SARS-CoV-2 yielded the highest odds for PI-IBS (both OR 5.4). Prevalence of PI-FD was 10.0% for SARS-CoV-2 and 13.6% for bacteria (Enterobacteriaceae 19.4%). CONCLUSION: In a large systematic review and meta-analysis, 14.5% of individuals experiencing acute gastroenteritis developed PI-IBS and 12.7% PI-FD, with greater than fourfold increased odds for IBS and threefold for FD. Proinflammatory microbes, including Proteobacteria and subcategories, and SARS-CoV-2, may be associated with the development of PI-IBS and PI-FD.

Recurrent Circuits Amplify Corticofugal Signals and Drive Feedforward Inhibition in the Inferior Colliculus.

The inferior colliculus (IC) is a midbrain hub critical for perceiving complex sounds, such as speech. In addition to processing ascending inputs from most auditory brainstem nuclei, the IC receives descending inputs from auditory cortex that control IC neuron feature selectivity, plasticity, and certain forms of perceptual learning. Although corticofugal synapses primarily release the excitatory transmitter glutamate, many physiology studies show that auditory cortical activity has a net inhibitory effect on IC neuron spiking. Perplexingly, anatomy studies imply that corticofugal axons primarily target glutamatergic IC neurons while only sparsely innervating IC GABA neurons. Corticofugal inhibition of the IC may thus occur largely independently of feedforward activation of local GABA neurons. We shed light on this paradox using in vitro electrophysiology in acute IC slices from fluorescent reporter mice of either sex. Using optogenetic stimulation of corticofugal axons, we find that excitation evoked with single light flashes is indeed stronger in presumptive glutamatergic neurons compared with GABAergic neurons. However, many IC GABA neurons fire tonically at rest, such that sparse and weak excitation suffices to significantly increase their spike rates. Furthermore, a subset of glutamatergic IC neurons fire spikes during repetitive corticofugal activity, leading to polysynaptic excitation in IC GABA neurons owing to a dense intracollicular connectivity. Consequently, recurrent excitation amplifies corticofugal activity, drives spikes in IC GABA neurons, and generates substantial local inhibition in the IC. Thus, descending signals engage intracollicular inhibitory circuits despite apparent constraints of monosynaptic connectivity between auditory cortex and IC GABA neurons.SIGNIFICANCE STATEMENT Descending "corticofugal" projections are ubiquitous across mammalian sensory systems, and enable the neocortex to control subcortical activity in a predictive or feedback manner. Although corticofugal neurons are glutamatergic, neocortical activity often inhibits subcortical neuron spiking. How does an excitatory pathway generate inhibition? Here we study the corticofugal pathway from auditory cortex to inferior colliculus (IC), a midbrain hub important for complex sound perception. Surprisingly, cortico-collicular transmission was stronger onto IC glutamatergic compared with GABAergic neurons. However, corticofugal activity triggered spikes in IC glutamate neurons with local axons, thereby generating strong polysynaptic excitation and feedforward spiking of GABAergic neurons. Our results thus reveal a novel mechanism that recruits local inhibition despite limited monosynaptic convergence onto inhibitory networks.

Population coding of time-varying sounds in the nonlemniscal inferior colliculus.

The inferior colliculus (IC) of the midbrain is important for complex sound processing, such as discriminating conspecific vocalizations and human speech. The IC's nonlemniscal, dorsal "shell" region is likely important for this process, as neurons in these layers project to higher-order thalamic nuclei that subsequently funnel acoustic signals to the amygdala and nonprimary auditory cortices, forebrain circuits important for vocalization coding in a variety of mammals, including humans. However, the extent to which shell IC neurons transmit acoustic features necessary to discern vocalizations is less clear, owing to the technical difficulty of recording from neurons in the IC's superficial layers via traditional approaches. Here, we use two-photon Ca2+ imaging in mice of either sex to test how shell IC neuron populations encode the rate and depth of amplitude modulation, important sound cues for speech perception. Most shell IC neurons were broadly tuned, with a low neurometric discrimination of amplitude modulation rate; only a subset was highly selective to specific modulation rates. Nevertheless, neural network classifier trained on fluorescence data from shell IC neuron populations accurately classified amplitude modulation rate, and decoding accuracy was only marginally reduced when highly tuned neurons were omitted from training data. Rather, classifier accuracy increased monotonically with the modulation depth of the training data, such that classifiers trained on full-depth modulated sounds had median decoding errors of ∼0.2 octaves. Thus, shell IC neurons may transmit time-varying signals via a population code, with perhaps limited reliance on the discriminative capacity of any individual neuron.NEW & NOTEWORTHY The IC's shell layers originate a "nonlemniscal" pathway important for perceiving vocalization sounds. However, prior studies suggest that individual shell IC neurons are broadly tuned and have high response thresholds, implying a limited reliability of efferent signals. Using Ca2+ imaging, we show that amplitude modulation is accurately represented in the population activity of shell IC neurons. Thus, downstream targets can read out sounds' temporal envelopes from distributed rate codes transmitted by populations of broadly tuned neurons.

Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Most patients with irritable bowel syndrome (IBS) are managed in primary care. When first-line therapies for IBS are ineffective, the UK National Institute for Health and Care Excellence guideline suggests considering low- dose tricyclic antidepressants as second-line treatment, but their effectiveness in primary care is unknown, and they are infrequently prescribed in this setting. METHODS: This randomised, double-blind, placebo-controlled trial (Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment [ATLANTIS]) was conducted at 55 general practices in England. Eligible participants were aged 18 years or older, with Rome IV IBS of any subtype, and ongoing symptoms (IBS Severity Scoring System [IBS-SSS] score ≥75 points) despite dietary changes and first-line therapies, a normal full blood count and C-reactive protein, negative coeliac serology, and no evidence of suicidal ideation. Participants were randomly assigned (1:1) to low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months, with dose titration over 3 weeks (up to 30 mg once daily), according to symptoms and tolerability. Participants, their general practitioners, investigators, and the analysis team were all masked to allocation throughout the trial. The primary outcome was the IBS-SSS score at 6 months. Effectiveness analyses were according to intention-to-treat; safety analyses were on all participants who took at least one dose of the trial medication. This trial is registered with the ISRCTN Registry (ISRCTN48075063) and is closed to new participants. FINDINGS: Between Oct 18, 2019, and April 11, 2022, 463 participants (mean age 48·5 years [SD 16·1], 315 [68%] female to 148 [32%] male) were randomly allocated to receive low-dose amitriptyline (232) or placebo (231). Intention-to-treat analysis of the primary outcome showed a significant difference in favour of low-dose amitriptyline in IBS-SSS score between groups at 6 months (-27·0, 95% CI -46·9 to -7·10; p=0·0079). 46 (20%) participants discontinued low-dose amitriptyline (30 [13%] due to adverse events), and 59 (26%) discontinued placebo (20 [9%] due to adverse events) before 6 months. There were five serious adverse reactions (two in the amitriptyline group and three in the placebo group), and five serious adverse events unrelated to trial medication. INTERPRETATION: To our knowledge, this is the largest trial of a tricyclic antidepressant in IBS ever conducted. Titrated low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care across multiple outcomes, and was safe and well tolerated. General practitioners should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, with appropriate support to guide patient-led dose titration, such as the self-titration document developed for this trial. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme (grant reference 16/162/01).

Novel Symptom Subgroups in Individuals With Irritable Bowel Syndrome Predict Disease Impact and Burden.

BACKGROUND & AIMS: Current classification systems based on bowel habit fail to capture the multidimensional nature of irritable bowel syndrome (IBS). We previously derived and validated a classification system, using latent class analysis, incorporating factors beyond bowel habit. We applied this in another cohort of people with IBS to assess its ability to capture the impact of IBS on the individual, the health care system, and society. METHODS: We collected demographic, symptom, and psychological health data from adults in the community self-identifying as having IBS, and meeting Rome IV criteria. We applied our latent class analysis model to identify the 7 subgroups (clusters) described previously, based on overall gastrointestinal symptom severity and psychological burden. We assessed quality of life, health care costs (£1 = $1.20), employment status, annual income, work productivity, and ability to perform work duties in each cluster. RESULTS: Of 1278 responders, 752 (58.8%) met Rome IV criteria. The 7-cluster model fit the data well. The patients in the 4 clusters with the highest psychological burden, and particularly those in cluster 6 with high overall gastrointestinal symptom severity and high psychological burden, showed lower educational levels, higher gastrointestinal symptom-specific anxiety, were more likely to have consulted a gastroenterologist, and used more drugs for IBS. IBS-related and generic quality of life were impaired significantly in these 4 clusters and significantly fewer individuals reported earning ≥£30,000 per year. Productivity and the ability to work, manage at home, engage in social and private leisure activities, and maintain close relationships all were impacted significantly, and IBS-related health care costs over the previous 12 months were highest in these 4 clusters. In those in cluster 6, costs were more than £1000 per person per year. CONCLUSIONS: Our clusters identify groups of individuals with significant impairments in quality of life, earning potential, and ability to work and function socially, who are high utilizers of health care.

Systematic Review and Meta-analysis: Efficacy of Mesalamine in Irritable Bowel Syndrome.

BACKGROUND & AIMS: Some patients with irritable bowel syndrome (IBS) demonstrate low-grade inflammation in the intestine. Mesalamine, which has anti-inflammatory effects, may be an efficacious treatment for IBS, but studies are conflicting. We conducted a systematic review and meta-analysis to assess efficacy and safety of mesalamine in IBS. METHODS: We searched the medical literature up to September 14, 2022, to identify randomized controlled trials (RCTs) of mesalamine in IBS. We judged efficacy and safety using dichotomous assessments of effect on global IBS symptoms, abdominal pain, bowel habit or stool frequency, and occurrence of any adverse event. We pooled data using a random effects model, with efficacy and safety reported as pooled relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: We identified 8 eligible RCTs (820 patients). Mesalamine was more efficacious than placebo for global IBS symptoms (RR of global symptoms not improving, 0.86; 95% CI, 0.79-0.95; number needed to treat = 10; 95% CI, 6-27), but not for abdominal pain or bowel habit or stool frequency. Subgroup analyses demonstrated efficacy of mesalamine in IBS with diarrhea for global IBS symptoms (RR, 0.88; 95% CI, 0.79-0.99), but not patients with other predominant bowel habits or those with post-infection IBS. Adverse event rates were no higher with mesalamine (RR, 1.20; 95% CI, 0.89-1.63) but were reported in only 5 trials. CONCLUSIONS: Mesalamine may be modestly efficacious for global symptoms in IBS, particularly IBS with diarrhea, but quality of evidence was low. Adequately powered high quality RCTs of mesalamine in IBS are needed.

Assessing Diagnostic Performance of Modifications to the Rome IV Criteria for Irritable Bowel Syndrome.

The gold standard symptom-based criteria for diagnosis of irritable bowel syndrome (IBS) are the Rome IV criteria.1 These are more restrictive than their predecessor, Rome III, because the cardinal feature required to meet criteria for IBS was changed to presence of abdominal pain alone, rather than abdominal pain or discomfort.2 This change was made because discomfort was believed to be an ambiguous term, with no equivalent in some languages. In addition, symptom frequency required for the presence of abdominal pain was increased to 1 day per week from 2 to 3 days per month. This has led to reduced sensitivity for detecting IBS and a 50% decrease in the prevalence of the disorder in the community.3,4 In a cross-sectional survey applying both Rome IV and III criteria to people living with IBS, 89% of those with Rome III-defined IBS not meeting Rome IV criteria did not meet Rome IV criteria because of this change in pain frequency.5 Previous iterations of the Rome criteria have performed only modestly in predicting a diagnosis of IBS.6-8 However, in a validation study, the Rome IV criteria outperformed Rome III,9 largely because their more restrictive nature made them more specific than Rome III. We assessed whether modifications to the Rome IV criteria led to a better trade-off between sensitivity and specificity.

Efficacy and Safety of Drugs for Gastroparesis: Systematic Review and Network Meta-analysis.

BACKGROUND & AIMS: Although there have been multiple drugs tested in gastroparesis, their relative efficacy and safety are unknown. We evaluated this in a network meta-analysis of randomized controlled trials (RCTs). METHODS: We searched the literature to September 7, 2022. We judged the efficacy of drugs based on global symptoms of gastroparesis; individual symptoms, including nausea, vomiting, abdominal pain, bloating, or fullness; and safety according to total adverse events and adverse events leading to withdrawal. We extracted data as intention-to-treat analyses, assuming dropouts to be treatment failures and reporting pooled relative risks (RRs) of not improving with 95% confidence intervals (CIs), ranking drugs according to P-score. RESULTS: We identified 29 RCTs (3772 patients). Based on global symptoms, clebopride ranked first for efficacy (RR, 0.30; 95% CI, 0.16-0.57; P-score = .99) followed by domperidone (RR, 0.68; 95% CI, 0.48-0.98; P-score = .76). No other drug was superior to placebo. Only 2 drug classes were efficacious: in rank order, oral dopamine antagonists (RR, 0.58; 95% CI, 0.44-0.77; P-score = .96) and tachykinin-1 antagonists (RR, 0.69; 95% CI, 0.52-0.93; P-score = .83). For individual symptoms, oral metoclopramide ranked first for nausea (RR 0.46; 95% CI, 0.21-1.00; P-score = .95), fullness (RR 0.67; 95% CI, 0.35-1.28; P-score = .86), and bloating (RR 0.53; 95% CI, 0.30-0.93; P-score = .97), based on only 1 small trial. Only prucalopride was more likely to be associated with adverse events than placebo. CONCLUSIONS: In a network meta-analysis, oral dopamine antagonists and tachykinin-1 antagonists were more efficacious than placebo for gastroparesis, but confidence in the evidence was low to moderate for most comparisons. There is an unmet need for efficacious therapies for gastroparesis.

Efficacy of Probiotics in Irritable Bowel Syndrome: Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Some probiotics may be beneficial in irritable bowel syndrome (IBS), but differences in species and strains used, as well as endpoints reported, have hampered attempts to make specific recommendations as to which should be preferred. We updated our previous meta-analysis examining this issue. METHODS: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to March 2023). Randomized controlled trials (RCTs) recruiting adults with IBS, comparing probiotics with placebo were eligible. Dichotomous symptom data were pooled to obtain a relative risk of global symptoms, abdominal pain, or abdominal bloating or distension persisting after therapy, with a 95% confidence interval (CI). Continuous data were pooled using a standardized mean difference with a 95% CI. Adverse events data were also pooled. RESULTS: We identified 82 eligible trials, containing 10,332 patients. Only 24 RCTs were at low risk of bias across all domains. For global symptoms, there was moderate certainty in the evidence for a benefit of Escherichia strains, low certainty for Lactobacillus strains and Lactobacillus plantarum 299V, and very low certainty for combination probiotics, LacClean Gold S, Duolac 7s, and Bacillus strains. For abdominal pain, there was low certainty in the evidence for a benefit of Saccharomyces cerevisae I-3856 and Bifidobacterium strains, and very low certainty for combination probiotics, Lactobacillus, Saccharomyces, and Bacillus strains. For abdominal bloating or distension there was very low certainty in the evidence for a benefit of combination probiotics and Bacillus strains. The relative risk of experiencing any adverse event, in 55 trials, including more than 7000 patients, was not significantly higher with probiotics. CONCLUSIONS: Some combinations of probiotics or strains may be beneficial in IBS. However, certainty in the evidence for efficacy by GRADE criteria was low to very low across almost all of our analyses.

Negative Impact of Disorders of Gut-Brain Interaction on Health-Related Quality of Life: Results From the Rome Foundation Global Epidemiology Survey.

BACKGROUND & AIMS: This study used the database from the Rome Foundation Global Epidemiology Survey to assess the differences in quality of life overall, and by age and sex, across individual disorders of gut-brain interaction (DGBI), gastrointestinal anatomical region(s), and number of overlapping DGBI. METHODS: Data were collected via the Internet in 26 countries, using the Rome IV diagnostic questionnaire and a supplemental questionnaire including the Patient-Reported Outcomes Measurement Information Systems Global-10 quality of life measure. Factorial analyses of variance were used to explore physical and mental quality of life, adjusting for multiple comparisons. RESULTS: Among the 54,127 respondents, quality of life deteriorated significantly with increasing number of overlapping DGBI, with respondents reporting ≥2 DGBI having significantly poorer quality of life than those with only 1 DGBI or those without any DGBI. Men with DGBI reported better quality of life than women, and those aged ≥65 years reported better quality of life than those <65 years. Age, sex, number of overlapping DGBI, somatization, anxiety, depression, and functional experiences (concern, embarrassment, or stress associated with bowel functioning) relating to DGBI, were significant predictors of poorer physical and mental quality of life. CONCLUSIONS: This study is the most comprehensive assessment of quality of life to date in adults living with a DGBI. It provides a representative picture of DGBI impact on adults in the global adult population and highlights the significant detrimental impact of living with a DGBI on quality of life.

Novel Irritable Bowel Syndrome Subgroups are Reproducible in the Global Adult Population.

BACKGROUND & AIMS: Current classification systems for irritable bowel syndrome (IBS) based on bowel habit do not consider psychological impact. We validated a classification model in a UK population with confirmed IBS, using latent class analysis, incorporating psychological factors. We applied this model in the Rome Foundation Global Epidemiological Survey (RFGES), assessing impact of IBS on the individual and the health care system, and examining reproducibility. METHODS: We applied our model to 2195 individuals in the RFGES with Rome IV-defined IBS. As described previously, we identified 7 clusters, based on gastrointestinal symptom severity and psychological burden. We assessed demographics, health care-seeking, symptom severity, and quality of life in each. We also used the RFGES to derive a new model, examining whether the broader concepts of our original model were replicated, in terms of breakdown and characteristics of identified clusters. RESULTS: All 7 clusters were identified. Those in clusters with highest psychological burden, and particularly cluster 6 with high overall gastrointestinal symptom severity, were more often female, exhibited higher levels of health care-seeking, were more likely to have undergone previous abdominal surgeries, and had higher symptom severity and lower quality of life (P < .001 for trend for all). When deriving a new model, the best solution consisted of 10 clusters, although at least 2 seemed to be duplicates, and almost all mapped on to the previous clusters. CONCLUSIONS: Even in the community, our original clusters derived from patients with physician-confirmed IBS identified groups of individuals with significantly higher rates of health care-seeking and abdominal surgery, more severe symptoms, and impairments in quality of life.

Efficacy of biological therapies and small molecules in induction and maintenance of remission in luminal Crohn's disease: systematic review and network meta-analysis.

OBJECTIVE: There are numerous biological therapies and small molecules licensed for luminal Crohn's disease (CD), but these are often studied in placebo-controlled trials, meaning relative efficacy is uncertain. We examined this in a network meta-analysis. DESIGN: We searched the literature to 1 July 2022, judging efficacy according to induction of clinical remission, clinical response and maintenance of clinical remission, and according to previous exposure or non-exposure to biologics. We used a random effects model and reported data as pooled relative risks (RRs) with 95% CIs, ranking drugs according to p-score. RESULTS: We identified 25 induction of remission trials (8720 patients). Based on failure to achieve clinical remission, infliximab 5 mg/kg ranked first versus placebo (RR=0.67, 95% CI 0.56 to 0.79, p-score 0.95), with risankizumab 600 mg second and upadacitinib 45 mg once daily third. However, risankizumab 600 mg ranked first for clinical remission in biologic-naïve (RR=0.66, 95% CI 0.52 to 0.85, p-score 0.78) and in biologic-exposed patients (RR=0.74, 95% CI 0.67 to 0.82, p-score 0.92). In 15 maintenance of remission trials (4016 patients), based on relapse of disease activity, upadacitinib 30 mg once daily ranked first (RR=0.61, 95% CI 0.52 to 0.72, p-score 0.93) with adalimumab 40 mg weekly second, and infliximab 10 mg/kg 8-weekly third. Adalimumab 40 mg weekly ranked first in biologic-naïve patients (RR=0.59, 95% CI 0.48 to 0.73, p-score 0.86), and vedolizumab 108 mg 2-weekly first in biologic-exposed (RR=0.70, 95% CI 0.57 to 0.86, p-score 0.82). CONCLUSION: In a network meta-analysis, infliximab 5 mg/kg ranked first for induction of clinical remission in all patients with luminal CD, but risankizumab 600 mg was first in biologic-naïve and biologic-exposed patients. Upadacitinib 30 mg once daily ranked first for maintenance of remission.

Comparison of drugs for active eosinophilic oesophagitis: systematic review and network meta-analysis.

BACKGROUND: There is currently no recommendation regarding preferred drugs for active eosinophilic oesophagitis (EoE) because their relative efficacy is unclear. We conducted an up-to-date network meta-analysis to compare proton pump inhibitors, off-label and EoE-specific topical steroids, and biologics in EoE. METHODS: We searched MEDLINE, Embase, Embase Classic and the Cochrane Central Register of Controlled Trials from inception to June 2023. We included randomised controlled trials (RCTs) comparing efficacy of all drugs versus each other, or placebo, in adults and adolescents with active EoE. Results were reported as pooled relative risks with 95% CIs to summarise effect of each comparison tested, with drugs ranked according to P score RESULTS: Seventeen RCTs were eligible for systematic review. Of these, 15 studies containing 1813 subjects with EoE reported extractable data for the network meta-analysis. For histological remission defined as ≤6 eosinophils/high-power field (HPF), lirentelimab 1 mg/kg monthly ranked first. For histological remission defined as ≤15 eosinophils/HPF, budesonide orally disintegrating tablet (BOT) 1 mg two times per day ranked first. For failure to achieve symptom improvement, BOT 1 mg two times per day and budesonide oral suspension (BOS) 2 mg two times per day were significantly more efficacious than placebo. For failure to achieve endoscopic improvement based on the EoE Endoscopic Reference Score, BOT 1 mg two times per day and BOS 1 mg two times per day or 2 mg two times per day were significantly more efficacious than placebo. CONCLUSIONS: Although this network meta-analysis supports the efficacy of most available drugs over placebo for EoE treatment, significant heterogeneity in eligibility criteria and outcome measures among available trials hampers the establishment of a solid therapeutic hierarchy.

Relative Contribution of Disease Activity and Psychological Health to Prognosis of Inflammatory Bowel Disease During 6.5 Years of Longitudinal Follow-Up.

BACKGROUND & AIMS: Symptoms of common mental disorders, such as anxiety or depression, are common in inflammatory bowel disease (IBD) and may affect prognosis. However, unlike clinical or biochemical markers of disease activity, psychological health is not a recommended therapeutic target. We assessed relative contribution of poor psychological health and clinical or biochemical activity to prognosis. METHODS: Demographic features, IBD subtype, treatments, and anxiety and depression scores were recorded at baseline for 760 adults, with clinical activity determined using validated scoring systems. Fecal calprotectin was analyzed in 379 (49.9%) patients (≥250 µg/g used to define biochemical activity). Glucocorticosteroid prescription or flare, escalation, hospitalization, intestinal resection, or death were assessed during 6.5 years of follow-up. Occurrence was compared using multivariate Cox regression across 4 patient groups according to presence of disease remission or activity, with or without symptoms of a common mental disorder, at baseline. RESULTS: In total, 718 (94.5%) participants provided data. Compared with clinical remission without symptoms of a common mental disorder at baseline, need for glucocorticosteroid prescription or flare (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.58-3.54), escalation (HR, 1.65; 95% CI, 1.14--2.40), and death (HR, 4.99; 95% CI, 1.80-13.88) were significantly higher in those with clinical activity and symptoms of a common mental disorder. Rates in those with clinical remission and symptoms of a common mental disorder at baseline or those with clinical activity without symptoms of a common mental disorder were not significantly higher. Similarly, with biochemical activity and symptoms of a common mental disorder, rates of glucocorticosteroid prescription or flare (HR, 2.48; 95% CI, 1.38-4.46), escalation (HR, 2.97; 95% CI, 1.74-5.06), hospitalization (HR, 3.10; 95% CI, 1.43-6.68), and death (HR, 6.26; 95% CI, 2.23-17.56) were significantly higher. CONCLUSIONS: Psychological factors are important determinants of poor prognostic outcomes in IBD and should be considered as a therapeutic target.

What is the Prevalence of Clinically Significant Endoscopic Findings in Subjects With Dyspepsia? Updated Systematic Review and Meta-analysis.

BACKGROUND & AIMS: The prevalence of clinically significant endoscopic findings in people with dyspepsia and understanding how symptoms can predict endoscopic pathology can help inform dyspepsia guidelines. We evaluated this in an updated systematic review and meta-analysis. METHODS: We searched MEDLINE, EMBASE, Cochrane CENTRAL, and the Cochrane Database of Systematic Reviews from 2010 through to January 2022 to identify relevant articles. Eligible studies enrolled adults from the community, workplace, blood donation or screening clinics, family physician offices, or internal medicine clinics. Studies were required to report prevalence of dyspepsia and perform esophagogastroduodenoscopy (EGD). Prevalence of clinically significant endoscopic findings in subjects with and without dyspepsia was pooled for all studies and compared using odds ratios and 95% confidence intervals (CIs). The data were pooled with those of the 9 studies included in the prior review. RESULTS: Of 511 papers evaluated, 184 reported prevalence of dyspepsia. Fifteen reported prevalence of endoscopic findings among 41,763 participants (40.4% with dyspepsia). Erosive esophagitis was the most common abnormality (pooled prevalence, 11.0%; 95% CI, 8.9%-13.2%) followed by peptic ulcer (pooled prevalence, 4.4%; 95% CI, 2.5%-6.7%). The only finding encountered more frequently in individuals with dyspepsia, compared with those without, was peptic ulcer (odds ratio, 1.61; 95% CI, 1.08-2.39). More than 85% of EGDs were completely normal. Gastroesophageal cancer was rare (<0.4%) and equally prevalent among those with and without dyspepsia. CONCLUSIONS: Erosive esophagitis was the most common clinically significant finding at EGD, whereas gastroesophageal cancers were rare. Most pathology, including esophagitis and cancer, were found in similar proportions in both groups. These findings support noninvasive approaches to managing dyspepsia in the community, with EGD reserved for those at high risk of malignancy.