Non-responsive coeliac disease : a comprehensive review from the NHS England national centre for refractory coeliac disease

Coeliac disease is a common small intestinal enteropathy which manifests following ingestion of gluten in genetically susceptible individuals. Since gluten was identified as the driving factor in coeliac disease, the gluten-free diet (GFD) has remained the mainstay of treatment. While most individuals will display improvement in symptoms and signs of coeliac disease following institution of the GFD, up to 30% will continue to experience symptoms and/or have persisting intestinal inflammation. These individuals can be classified as having non-responsive coeliac disease (NRCD), which may be associated with dietary indiscretion, slow healing, refractory coeliac disease, and/or an alternative condition. The purpose of this review is to provide an overview of the causes of NRCD in adults, highlight a systematic approach to investigate these patients, and appraise the latest management aspects of this subset of coeliac disease

Cost-benefits and environmental impact of the no-biopsy approach for the diagnosis of coeliac disease in adults

Objective: Recent evidence suggests that adult patients with IgA tissue transglutaminase levels of ≥10× the upper limit of normal could be accurately diagnosed with coeliac disease without undergoing endoscopy and biopsy. We aimed to evaluate the cost-benefits and the environmental impact of implementing the no-biopsy approach for diagnosing coeliac disease in clinical practice. Design: We calculated the overall direct and indirect costs of the conventional serology-biopsy approach and the no-biopsy approach for the diagnosis of coeliac disease based on the national average unit costs and the Office of National Statistics data. We further estimated the environmental impact of avoiding endoscopy based on the estimated greenhouse gas emissions from endoscopy. Results: Approximately 3000 endoscopies for suspected coeliac disease could be avoided each year in the UK. Implementing the no-biopsy approach for the diagnosis of coeliac disease in adults could save the National Health Service over £2.5 million in direct and indirect costs per annum and reduce endoscopy carbon footprint by 87 tonnes of CO2 per year, equivalent to greenhouse gas emissions from driving 222 875 miles, carbon emissions from charging over 10 million smartphones and the carbon sequestrated by 1438 trees grown for 10 years. Conclusion: The implementation of this non-invasive green approach could be an essential first step in the ‘Reduce’ strategy advocated by the British Society of Gastroenterology and other international endoscopy societies for sustainable endoscopy practice

Accuracy of the no-biopsy approach for the diagnosis of coeliac disease in adults: a systematic review and meta-analysis

BACKGROUND & AIMS: Current international guidelines recommend duodenal biopsies to confirm the diagnosis of coeliac disease in adult patients. However, growing evidence suggests that IgA anti-tissue transglutaminase (tTg) antibody levels ≥10 times the upper limit of normal (ULN) can accurately predict coeliac disease, eliminating the need for biopsy. We performed a systematic review and meta-analysis to evaluate the accuracy of the no-biopsy approach to confirm the diagnosis of coeliac disease in adults. METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library and Web of Science from January 1998 to October 2023 for studies reporting the sensitivity and specificity of IgA-tTG ≥10×ULN against duodenal biopsies (Marsh grade ≥2) in adults with suspected coeliac disease. We used a bivariate random-effects model to calculate the summary estimates of sensitivity, specificity, positive and negative likelihood ratios. The positive and negative likelihood ratios were used to calculate the positive predictive value (PPV) of the no-biopsy approach across different pre-test probabilities of coeliac disease. The methodological quality of the included studies was evaluated using the QUADAS-2 tool. This study was registered with PROSPERO, number CRD42023398812. RESULTS: A total of 18 studies comprising 12,103 participants from 15 countries were included. The pooled prevalence of biopsy-proven coeliac disease in the included studies was 62% (95% CI, 40% - 83%). The proportion of patients with IgA-tTG ≥10×ULN was 32% (95% CI, 24% - 40%). The summary sensitivity of IgA-tTG ≥10×ULN was 51% (95% CI, 42% - 60%), and the summary specificity was 100% (95% CI, 98% - 100%). The area under the summary receiver operating characteristic curve was 0.83 (95% CI, 0.77 - 0.89). The PPV of the no-biopsy approach to identify patients with coeliac disease was 65%, 88%, 95%, and 99% if coeliac disease prevalence was 1%, 4%, 10% and 40%, respectively. Between-study heterogeneity was moderate (I2 =30.3%), and additional sensitivity analyses did not significantly alter our findings. Only one study had a low risk of bias across all domains. CONCLUSION: The results of this meta-analysis suggest that selected adult patients with IgA-tTG ≥10×ULN and a moderate to high pre-test probability of coeliac disease could be diagnosed without undergoing invasive endoscopy and duodenal biopsy

Measurement of the B0-anti-B0-Oscillation Frequency with Inclusive Dilepton Events

The $B^0$-$\bar B^0$ oscillation frequency has been measured with a sample of 23 million \B\bar B pairs collected with the BABAR detector at the PEP-II asymmetric B Factory at SLAC. In this sample, we select events in which both B mesons decay semileptonically and use the charge of the leptons to identify the flavor of each B meson. A simultaneous fit to the decay time difference distributions for opposite- and same-sign dilepton events gives $\Delta m_d = 0.493 \pm 0.012{(stat)}\pm 0.009{(syst)}$ ps$^{-1}$.Comment: 7 pages, 1 figure, submitted to Physical Review Letter

High-throughput automated scoring of Ki67 in breast cancer tissue microarrays from the Breast Cancer Association Consortium (BCAC)

Automated methods are needed to facilitate high-throughput and reproducible scoring of Ki67 and other markers in breast cancer tissue microarrays (TMAs) in large-scale studies. To address this need, we developed an automated protocol for Ki67 scoring and evaluated its performanc

Accuracy of a no-biopsy approach for the diagnosis of coeliac disease across different adult cohorts

Objective We aimed to determine the predictive capacity and diagnostic yield of a 10-fold increase in serum IgA antitissue transglutaminase (tTG) antibody levels for detecting small intestinal injury diagnostic of coeliac disease (CD) in adult patients. Design The study comprised three adult cohorts. Cohort 1: 740 patients assessed in the specialist CD clinic at a UK centre; cohort 2: 532 patients with low suspicion for CD referred for upper GI endoscopy at a UK centre; cohort 3: 145 patients with raised tTG titres from multiple international sites. Marsh 3 histology was used as a reference standard against which we determined the performance characteristics of an IgA tTG titre of ≥10×ULN for a diagnosis of CD. Results Cohort 1: the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 54.0%, 90.0%, 98.7% and 12.5%, respectively. Cohort 2: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 50.0%, 100.0%, 100.0% and 98.3%, respectively. Cohort 3: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 30.0%, 83.0%, 95.2% and 9.5%, respectively. Conclusion Our results show that IgA tTG titres of ≥10×ULN have a strong predictive value at identifying adults with intestinal changes diagnostic of CD. This study supports the use of a no-biopsy approach for the diagnosis of adult CD

New entity of adult ultra-short coeliac disease: the first international cohort and case–control study

Background: Ultra-short coeliac disease (USCD) is defined as villous atrophy only present in the duodenal bulb (D1) with concurrent positive coeliac serology. We present the first, multicentre, international study of patients with USCD. Methods: Patients with USCD were identified from 10 tertiary hospitals (6 from Europe, 2 from Asia, 1 from North America and 1 from Australasia) and compared with age-matched and sex-matched patients with conventional coeliac disease. Findings: Patients with USCD (n=137, median age 27 years, IQR 21–43 years; 73% female) were younger than those with conventional coeliac disease (27 vs 38 years, respectively, p<0.001). Immunoglobulin A-tissue transglutaminase (IgA-tTG) titres at index gastroscopy were lower in patients with USCD versus conventional coeliac disease (1.8×upper limit of normal (ULN) (IQR 1.1–5.9) vs 12.6×ULN (IQR 3.3–18.3), p<0.001). Patients: with USCD had the same number of symptoms overall (median 3 (IQR 2–4) vs 3 (IQR 1–4), p=0.875). Patients with USCD experienced less iron deficiency (41.8% vs 22.4%, p=0.006). Both USCD and conventional coeliac disease had the same intraepithelial lymphocytes immunophenotype staining pattern; positive for CD3 and CD8, but not CD4. At follow-up having commenced a gluten-free diet (GFD) (median of 1181 days IQR: 440–2160 days) both USCD and the age-matched and sex-matched controls experienced a similar reduction in IgA-tTG titres (0.5 ULN (IQR 0.2–1.4) vs 0.7 ULN (IQR 0.2–2.6), p=0.312). 95.7% of patients with USCD reported a clinical improvement in their symptoms. Interpretation: Patients with USCD are younger, have a similar symptomatic burden and benefit from a GFD. This study endorses the recommendation of D1 sampling as part of the endoscopic coeliac disease diagnostic workup

Measurement of the CP-Violating Asymmetry Amplitude sin2β\beta

We present results on time-dependent CP-violating asymmetries in neutral B decays to several CP eigenstates. The measurements use a data sample of about 88 million Y(4S) --> B Bbar decays collected between 1999 and 2002 with the BABAR detector at the PEP-II asymmetric-energy B Factory at SLAC. We study events in which one neutral B meson is fully reconstructed in a final state containing a charmonium meson and the other B meson is determined to be either a B0 or B0bar from its decay products. The amplitude of the CP-violating asymmetry, which in the Standard Model is proportional to sin2beta, is derived from the decay-time distributions in such events. We measure sin2beta = 0.741 +/- 0.067 (stat) +/- 0.033 (syst) and |lambda| = 0.948 +/- 0.051 (stat) +/- 0.017 (syst). The magnitude of lambda is consistent with unity, in agreement with the Standard Model expectation of no direct CP violation in these modes