Ingestible sensors are potentially a powerful tool for monitoring human health. Sensors have been developed that can, for example, provide pH and pressure readings or monitor medication, but capsules that can provide key information about the chemical composition of the gut are still not available. Here we report a human pilot trial of an ingestible electronic capsule that can sense oxygen, hydrogen, and carbon dioxide. The capsule uses a combination of thermal conductivity and semiconducting sensors, and their selectivity and sensitivity to different gases is controlled by adjusting the heating elements of the sensors. Gas profiles of the subjects were obtained while modulating gut microbial fermentative activities by altering their intake of dietary fibre. Ultrasound imaging confirmed that the oxygen-equivalent concentration profile could be used as an accurate marker for the location of the capsule. In a crossover study, variations of fibre intake were found to be associated with differing small intestinal and colonic transit times, and gut fermentation. Regional fermentation patterns could be defined via hydrogen gas profiles. Our gas capsule offers an accurate and safe tool for monitoring the effects of diet of individuals, and has the potential to be used as a diagnostic tool for the gut. NATuRE ELECTRONiCS
Evolution of treatment targets in IBD has increased the need for objective monitoring of disease activity to guide therapeutic strategy. Although mucosal healing is the current target of therapy in IBD, endoscopy is invasive, expensive and unappealing to patients. GI ultrasound (GIUS) represents a non-invasive modality to assess disease activity in IBD. It is accurate, cost-effective and reproducible. GIUS can be performed at the point of care without specific patient preparation so as to facilitate clinical decision-making. As compared with ileocolonoscopy and other imaging modalities (CT and MRI), GIUS is accurate in diagnosing IBD, detecting complications of disease including fistulae, strictures and abscesses, monitoring disease activity and detecting postoperative disease recurrence. International groups increasingly recognise GIUS as a valuable tool with paradigm-changing application in the management of IBD; however, uptake outside parts of continental Europe has been slow and GIUS is underused in many countries. The aim of this review is to present a pragmatic guide to the positioning of GIUS in IBD clinical practice, providing evidence for use, algorithms for integration into practice, training pathways and a strategic implementation framework.
Healthy siblings of patients with CD manifest immune and microbiological abnormalities associated with CD distinct from their genotype-related risk and provide an excellent model in which to investigate early CD pathogenesis.
Transitional 2 B cells home to gut-associated lymphoid tissue and present an activated phenotype in healthy subjects, but gut immune compartments are depleted in SLE.
Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
Background and Aims Gastrointestinal ultrasound is useful in the assessment of patients with Crohn’s disease, but its application in ulcerative colitis [UC] is less well established. Here we systematically review the role of gastrointestinal ultrasound in patients with UC. Methods Searches of the PUBMED and EMBASE databases were performed with the following search strategy: [ultrasound OR sonography] AND [intestinal OR bowel] AND [ulcerative colitis OR inflammatory bowel disease]. The final search was performed in August 2019. Results Of 6769 studies identified in the search with a further two studies found from other sources, 50 studies met the inclusion criteria. Increased bowel wall thickness and detection of increased blood flow by colour Doppler were the most often applied criteria for defining disease activity and distribution. When compared with other reference investigations, gastrointestinal ultrasound accurately determined disease extent, severity and response to medical therapy. While further information can be obtained from haemodynamic measurements of the abdominal vessels and contrast-enhanced ultrasound, their clinical value was uncertain. Likewise, hydrocolonic sonography has few advantages over standard gastrointestinal ultrasound examination. Of several scoring systems proposed, there is disparity between the measures and a general lack of validation. There has been limited application of gastrointestinal ultrasound in acute severe ulcerative colitis with toxic megacolon, and, while performing well in children, normal limits differ from those in adults. Conclusion Current evidence indicates that gastrointestinal ultrasound has utility in the non-invasive assessment of patients with UC. Continued advances in technology with better image resolution, validation of scoring systems and application at the point of care by gastroenterologists are likely to contribute to increased use of gastrointestinal ultrasound in routine clinical practice.
Background Clinical application of therapeutic drug monitoring (TDM) to optimise anti‐TNF therapies in patients with IBD depends upon target ranges. Aims To review methodology used to determine therapeutic ranges and critically compare and contrast its application to infliximab and adalimumab. Methods A systematic review was performed, and relevant literature was summarised and critically examined. Results Upper limits of the therapeutic range are determined by toxicity, a plateau response and cost. Lower limits are determined by optimal concentration on the target of action in vitro and/or in vivo, or by correlation of drug levels with clinical efficacy using area‐under‐receiver‐operator‐curve (AUROC) analysis. In 43 studies, there were huge variations in time at which infliximab and adalimumab levels were measured, the end‐points used (clinical remission to mucosal healing), the clinical setting (active disease vs maintenance phase) and the reason for TDM (proactive vs reactive). In the maintenance phase for infliximab, lower trough limits 2.8‐5.7 µg/mL are reported depending upon end‐points used, with consistent AUROC 0.68‐0.77. Adalimumab TDM targets are even less consistent with a lower limit 5.9‐11.8 µg/mL (AUROC 0.66‐0.83) in some studies, but no cut‐off can be identified that is significantly associated with outcome in others, related to inherent pharmacokinetic and pharmacodynamic differences, and heterogeneity of study design. Conclusions Evidence for exposure‐response relationship is stronger for infliximab than adalimumab. Due to heterogeneity in settings for drug level measurements, therapeutic ranges vary. These factors need to be taken into account when interpreting the evidence and extending this to therapeutic strategies for IBD patients.
The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn’s disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10−10, OR = 2.3[95% CI = 1.75–3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1–5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.
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