Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine.

INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.

The utility of a symptom model to predict the risk of oesophageal cancer.

OBJECTIVE: To assess whether extra-oesophageal symptoms are predictive of oesophageal malignancy. METHODS: A prospective, single-centre cross-sectional questionnaire study at a tertiary referral unit for oesophageal cancer using the Comprehensive Reflux Symptoms Scale (CReSS) questionnaire tool. Respondents with oesophageal malignancy were compared with historical cohorts undergoing airway examination or upper gastrointestinal endoscopy and found to have benign diagnoses. We developed a model for predicting oesophageal cancer using linear discriminant analysis and logistic regression, assessed by Monte Carlo cross validation. RESULTS: Respondents with oesophageal malignancy (n = 146; mean age 70.5; male: female, 71:29) were compared with those undergoing airway examination (n = 177) and upper gastrointestinal endoscopy (n = 351), found to have benign diagnoses. No single questionnaire item, or group of co-varying items (factors), reliably discriminated oesophageal cancer from other diagnoses. Individual items which suggested higher risk of oesophageal malignancy included dysphagia (area under the curve (AUC) 0.68), low appetite (AUC 0.66), and early satiety (AUC 0.58). Conversely, throat pain (AUC 0.38), bloating (AUC 0.38) and heartburn (AUC 0.37) were inversely related to cancer risk. A forward stepwise regression analysis including a subset of 12 CReSS questionnaire items together with age and sex derived a model predictive of oesophageal malignancy in this cohort (AUC 0.89). CONCLUSION: We demonstrate a model comprised of 12 questionnaire items and 2 demographic parameters as a potential predictive tool for oesophageal malignancy diagnosis in this study population. Translating this model for predicting oesophageal malignancy in the general population is a valuable topic for future research.

Prominent members of the human gut microbiota express endo-acting O-glycanases to initiate mucin breakdown.

The thick mucus layer of the gut provides a barrier to infiltration of the underlying epithelia by both the normal microbiota and enteric pathogens. Some members of the microbiota utilise mucin glycoproteins as a nutrient source, but a detailed understanding of the mechanisms used to breakdown these complex macromolecules is lacking. Here we describe the discovery and characterisation of endo-acting enzymes from prominent mucin-degrading bacteria that target the polyLacNAc structures within oligosaccharide side chains of both animal and human mucins. These O-glycanases are part of the large and diverse glycoside hydrolase 16 (GH16) family and are often lipoproteins, indicating that they are surface located and thus likely involved in the initial step in mucin breakdown. These data provide a significant advance in our knowledge of the mechanism of mucin breakdown by the normal microbiota. Furthermore, we also demonstrate the potential use of these enzymes as tools to explore changes in O-glycan structure in a number of intestinal disease states.

Challenging Unjust Authority and Creating a Profession.

The emergence of the trained nurse as a new profession for women coincided with the transformation of hospitals from refuges for the sick and poor into treatment facilities. The hospital was an apt setting for learning nursing's fundamentals, but the domestic demands of the setting soon took precedence over nursing education. Nursing superintendents struggled to honor the right of pupil nurses to an education over the might of the hospital's demands. The 20th anniversary of the Trained Nurse Movement in 1893 proved the decisive moment when nursing superintendents created professional associations and gathered the nursing diaspora into a coherent force. Recourse to the law followed with nurses seeking legal validation of their authority over nursing education. Now, as then, a nurse's authority is a right that has to be protected when the might of individuals and institutions, both subtle and blatant, interferes with nurses caring for the well-being of society.