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Better understanding of breathlessness perception addresses an unmet clinical need for more effective treatments for intractable dyspnoea, a prevalent symptom of multiple medical conditions. The insular-cortex is predominantly activated in brain-imaging studies of dyspnoea, but its precise role remains unclear. We measured experimentally-induced hypercapnic air-hunger in three insular-glioma patients before and after surgical resection. Tests involved one-minute increments in inspired CO 2 , raising end-tidal P CO 2 to 7.5 mmHg above baseline (38.5 ± 5.7 mmHg), whilst ventilation was constrained (10.7 ± 2.3 L/min). Patients rated air-hunger on a visual analogue scale (VAS). Patients had lower stimulus-response (2.8 ± 2 vs. 11 ± 4 %VAS/mmHg; p  = 0.004), but similar threshold (40.5 ± 3.9 vs. 43.2 ± 5.1 mmHg), compared to healthy individuals. Volunteered comments implicated diminished affective valence. After surgical resection; sensitivity increased in one patient, decreased in another, and other was unable to tolerate the ventilatory limit before any increase in inspired CO 2 .We suggest that functional insular-cortex is essential to register breathlessness unpleasantness and could be targeted with neuromodulation in chronically-breathless patients. Neurological patients with insula involvement should be monitored for blunted breathlessness to inform clinical management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Chapman, Farrell, Plaha, Green and Moosavi.)

Background: Current guidelines strongly recommend the use of validated classifications to support optical diagnosis of lesions with advanced endoscopic imaging in the lower gastrointestinal tract. However, the optimal strategy in inflammatory bowel disease (IBD) is still a matter of debate., Objectives: To analyze the accuracy of endoscopic classifications or single predictors for in vivo lesion characterization during endoscopic surveillance of IBD with advanced endoscopic imaging., Design: Systematic review., Data Sources and Methods: Medline and PubMed were used to extract all studies which focused on lesion characterization of neoplastic and non-neoplastic lesions in IBD. The diagnostic accuracy of endoscopic classifications and single endoscopic predictors for lesion characterization were analyzed according to type of patients, lesions, and technology used. When available, the rates of true and false positives or negatives for neoplasia were pooled and the sensitivity (SE), specificity (SP), positive predictive value, and negative predictive value (NPV) were calculated., Results: We included 35 studies (2789 patients; 5925 lesions - 1149 neoplastic). Advanced endoscopic imaging included dye-based chromoendoscopy, virtual chromoendoscopy (VCE), magnification and high-definition endoscopy, confocal laser endomicroscopy (CLE), endocytoscopy, and autofluorescence imaging. The Kudo classification of pit patterns was most frequently used, with pooled SE 83%, SP 83%, and NPV 95%. The endoscopic criteria with the highest accuracy, with minimum SE ⩾ 90%, SP ⩾ 80%, and NPV ⩾ 90% were: the Kudo-IBD classification used with VCE (Fuji Intelligent Color Enhancement and i-SCAN); combined irregular surface and vascular patterns used with narrow band imaging; the Mainz classification used with CLE. Multiple clinical and technical factors were found to influence the accuracy of optical diagnosis in IBD., Conclusion: No single endoscopic factor has yet shown sufficient accuracy for lesion characterization in IBD surveillance. Conventional classifications developed in the non-IBD setting have lower accuracy in IBD. The use of new classifications adapted for IBD (Kudo-IBD), and new technologies based on in vivo microscopic analysis show promise., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Competing Interests: Competing interests: None declared.

Background: Using two large datasets from Dorset, we previously reported an internally validated multivariable risk model for predicting the risk of GI malignancy in IDA-the IDIOM score. The aim of this retrospective observational study was to validate the IDIOM model using two independent external datasets., Methods: The external validation datasets were collected, in a secondary care setting, by different investigators from cohorts in Oxford and Sheffield derived under different circumstances, comprising 1117 and 474 patients with confirmed IDA respectively. The data were anonymised prior to analysis. The predictive performance of the original model was evaluated by estimating measures of calibration, discrimination and clinical utility using the validation datasets., Results: The discrimination of the original model using the external validation data was 70% (95% CI 65, 75) for the Oxford dataset and 70% (95% CI 61, 79) for the Sheffield dataset. The analysis of mean, weak, flexible and across the risk groups' calibration showed no tendency for under or over-estimated risks in the combined validation data. Decision curve analysis demonstrated the clinical value of the IDIOM model with a net benefit that is higher than 'investigate all' and 'investigate no-one' strategies up to a threshold of 18% in the combined validation data, using a risk cut-off of around 1.2% to categorise patients into the very low risk group showed that none of the patients stratified in this risk group proved to have GI cancer on investigation in the validation datasets., Conclusion: This external validation exercise has shown promising results for the IDIOM model in predicting the risk of underlying GI malignancy in independent IDA datasets collected in different clinical settings., (© 2021. The Author(s).)

Background: Anti-tumour necrosis factor (anti-TNF) therapy increases the risk of tuberculosis (TB). Given limitations of screening techniques, it remains uncertain if patients receiving anti-TNF in TB endemic regions should be screened for latent infection with chemoprophylaxis restricted to those with proven infection, or if all patients should receive chemoprophylaxis., Aims: To compare the incidence of active TB with infliximab (IFX) following targeted and universal TB chemoprophylaxis, and to determine the rates of adverse events (AE) related to TB chemoprophylaxis METHODS: A multi-centre retrospective cohort study was performed at 18 hospitals in China of 1968 adult patients with IBD receiving IFX from 2009 to 2017. TB screening prior to IFX was performed with chest X-ray and/or computed tomography [CT] and immune reactivity testing (interferon-γ release assay and/or tuberculin skin test). Patients were followed-up for a minimum of 3 months after IFX discontinuation, or until last hospital visit if IFX therapy was ongoing. Targeted strategy was defined as TB chemoprophylaxis only for patients with a positive latent TB screen, with universal strategy defined as TB chemoprophylaxis for all patients., Results: Mean follow-up was 1.07 ± 0.87 years with a total follow-up of 2102 patient-years. There were 1433 patients in the targeted and 483 patients in the universal TB chemoprophylaxis groups, with no significant difference in the incidence rates of active TB between groups (673.3 per 100 000 population per year vs 891.5 per 100 000 population per year, P = 0.60). In the targeted group, 55/1433 patients received TB chemoprophylaxis compared with 483/483 in the universal group, with significantly fewer AEs related to TB chemoprophylaxis in the targeted compared to the universal group (0.35% (5/1433) vs 6.8% (33/483), P < 0.05)., Conclusions: In this study of patients receiving IFX in a TB endemic area, universal chemoprophylaxis was not associated with a reduced risk of active TB when compared to a targeted chemoprophylaxis strategy, and AEs were more common. This supports the use of targeted TB chemoprophylaxis when anti-TNF therapy is initiated in TB endemic regions., (© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: 5-aminosalicylates (5-ASA) are widely used in inflammatory bowel disease (IBD), but emerging evidence suggests that they may be safely withdrawn in significant subsets of patients. This is important to address: 5-ASA therapy accounts for up to 25% of total healthcare costs in ulcerative colitis (UC), while almost a third of patients with Crohn's disease (CD) receive long-term 5-ASA despite no clear evidence of benefit. Further, rationalising medication burden may improve overall adherence and outcome., Aims: To summarise the rationale for 5-ASA withdrawal, review the current evidence in both UC and CD and consider the data surrounding colorectal cancer (CRC) prevention, guiding an evidence-based withdrawal strategy., Methods: PubMed was searched to identify relevant studies. Only papers published in English were reviewed, with priority given to randomised clinical trials and meta-analyses., Results: For patients with UC, consideration of 5-ASA withdrawal should be made on a case-by-case basis, but it appears safest for those in deep remission without any of the following risk factors: younger age (<40 years), remission for less than 2 years, a history of multiple flares, extensive disease. 5-ASA withdrawal should also be considered in patients with UC escalated to biologic therapy who have achieved remission and in all patients with CD. Although 5-ASA therapy may have chemopreventive benefits for CRC, the cost-benefit ratio appears significant, and this indication is not justified by evidence in those who have achieved remission and are continuing therapy with other agents, or in those in sustained remission without a history of extensive disease., Conclusions: Although the majority of patients with IBD receive 5-ASA during their disease course, safe withdrawal appears possible in many, with important implications for both health economics and patient experience. A number of unanswered questions, however, remain., (© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

The interplay between NOD2 and TLR2 following recognition of components of the bacterial cell wall peptidoglycan is well-established, however their role in redirecting metabolic pathways in myeloid cells to degrade pathogens and mount antigen presentation remains unclear. We show NOD2 and TLR2 mediate phosphorylation of the deubiquitinase ataxin-3 via RIPK2 and TBK1. In myeloid cells ataxin-3 associates with the mitochondrial cristae protein MIC60, and is required for oxidative phosphorylation. Depletion of ataxin-3 leads to impaired induction of mitochondrial reactive oxygen species (mROS) and defective bacterial killing. A mass spectrometry analysis of NOD2/TLR2 triggered ataxin-3 deubiquitination targets revealed immunometabolic regulators, including HIF-1α and LAMTOR1 that may contribute to these effects. Thus, we define how ataxin-3 plays an essential role in NOD2 and TLR2 sensing and effector functions in myeloid cells.

Background: Minimising placebo response is essential for drug development., Aim: To conduct a meta-analysis to determine placebo response and remission rates in trials and identify the factors affecting these rates., Methods: MEDLINE, EMBASE and CENTRAL were searched from inception to April 2014 for placebo-controlled trials of pharmacological interventions for Crohn's disease. Placebo response and remission rates for induction and maintenance trials were pooled by random-effects and mixed-effects meta-regression models to evaluate effects of study-level characteristics on these rates., Results: In 100 studies containing 67 induction and 40 maintenance phases and 7638 participants, pooled placebo remission and response rates for induction trials were 18% [95% confidence interval (CI) 16-21%] and 28% (95% CI 24-32%), respectively. Corresponding values for maintenance trials were 32% (95% CI 25-39%) and 26% (95% CI 19-35%), respectively. For remission, trials enrolling patients with more severe disease activity, longer disease duration and more study centres were associated with lower placebo rates, whereas more study visits and longer study duration was associated with higher placebo rates. For response, findings were opposite such that trials enrolling patients with less severe disease activity and longer study duration were associated with lower placebo rates. Placebo rates varied by drug class and route of administration, with the highest placebo response rates observed for biologics., Conclusions: Placebo rates vary according to whether trials are designed for induction or maintenance and the factors influencing them differ for the endpoints of remission and response. These findings have important implications for clinical trial design in Crohn's disease., (© 2017 John Wiley & Sons Ltd.)

Pyogenic liver abscess has a variable clinical presentation. Its management requires input from several disciplines and is often coordinated by a gastroenterologist. This review examines demographics, clinical presentation, aetiology, diagnosis and prognosis; a suggested management approach, including antibiotic selection, radiological intervention and indications for surgery, is offered from a physician's perspective.

In the UK contemporary estimates of dietary Fe intakes rely upon food Fe content data from the 1980s or before. Moreover, there has been speculation that the natural Fe content of foods has fallen over time, predominantly due to changes in agricultural practices. Therefore, we re-analysed common plant-based foods of the UK diet for their Fe content (the '2000s analyses') and compared the values with the most recent published values (the '1980s analyses') and the much older published values (the '1930s analyses'), the latter two being from different editions of the McCance and Widdowson food tables. Overall, there was remarkable consistency between analytical data for foods spanning the 70 years. There was a marginal, but significant, apparent decrease in natural food Fe content from the 1930s to 1980s/2000s. Whether this represents a true difference or is analytical error between the eras is unclear and how it could translate into differences in intake requires clarification. However, fortificant Fe levels (and fortificant Fe intake based upon linked national data) did appear to have increased between the 1980s and 2000s, and deserve further attention in light of recent potential concerns over the long-term safety and effectiveness of fortificant Fe. In conclusion, the overall Fe content of plant-based foods is largely consistent between the 1930s and 2000s, with a fall in natural dietary Fe content negated or even surpassed by a rise in fortificant Fe but for which the long-term effects are uncertain.

Aortic stiffness and chronic kidney disease are closely linked by shared risk factors and associated increased cardiovascular mortality. At lower levels of renal function, aortic stiffness is independently associated with glomerular filtration rate. However, the longitudinal impact of aortic stiffness on renal function has not been reported previously. A cohort of 133 patients with chronic kidney disease stages 3 and 4 (estimated glomerular filtration rate: 15 to 59 mL/min per 1.73 m(2)) underwent prospective measurement of arterial stiffness parameters and monitoring of renal function. Aortic pulse wave velocity measurement was performed in 120 patients. The mean age was 69+/-12 years (mean+/-SD; 103 men, 30 women, and 23.3% diabetic). Mean systolic blood pressure was 155+/-21 mm Hg, and mean diastolic blood pressure was 83+/-11 mm Hg. The mean Modification of Diet in Renal Disease estimated glomerular filtration rate was 32+/-11 mL/min per 1.73 m(2). Change in renal function was measured using reciprocal creatinine plots and the dichotomous combined end point of > or = 25% decline in renal function or start of renal replacement therapy. After stepwise multivariate analysis, aortic pulse wave velocity was independently associated with gradient of reciprocal creatinine plot (r=0.46; P=0.014). In multivariate analysis of the end point of > or = 25% decline in renal function or start of renal replacement therapy, independent predictors were aortic pulse wave velocity (r=0.48; P=0.002), systolic blood pressure (r=0.17; P=0.039), and urine protein:creatinine ratio (r=0.20; P=0.021). We, therefore, conclude that aortic stiffening is independently associated with rate of change in renal function in patients with chronic kidney disease stages 3 and 4.