Classification of intestinal T-cell receptor repertoires using machine learning methods can identify patients with coeliac disease regardless of dietary gluten status.

In coeliac disease (CeD), immune-mediated small intestinal damage is precipitated by gluten, leading to variable symptoms and complications, occasionally including aggressive T-cell lymphoma. Diagnosis, based primarily on histopathological examination of duodenal biopsies, is confounded by poor concordance between pathologists and minimal histological abnormality if insufficient gluten is consumed. CeD pathogenesis involves both CD4+ T-cell-mediated gluten recognition and CD8+ and γδ T-cell-mediated inflammation, with a previous study demonstrating a permanent change in γδ T-cell populations in CeD. We leveraged this understanding and explored the diagnostic utility of bulk T-cell receptor (TCR) sequencing in assessing duodenal biopsies in CeD. Genomic DNA extracted from duodenal biopsies underwent sequencing for TCR-δ (TRD) (CeD, n = 11; non-CeD, n = 11) and TCR-γ (TRG) (CeD, n = 33; non-CeD, n = 21). We developed a novel machine learning-based analysis of the TCR repertoire, clustering samples by diagnosis. Leave-one-out cross-validation (LOOCV) was performed to validate the classification algorithm. Using TRD repertoire, 100% (22/22) of duodenal biopsies were correctly classified, with a LOOCV accuracy of 91%. Using TCR-γ (TRG) repertoire, 94.4% (51/54) of duodenal biopsies were correctly classified, with LOOCV of 87%. Duodenal biopsy TRG repertoire analysis permitted accurate classification of biopsies from patients with CeD following a strict gluten-free diet for at least 6 months, who would be misclassified by current tests. This result reflects permanent changes to the duodenal γδ TCR repertoire in CeD, even in the absence of gluten consumption. Our method could complement or replace histopathological diagnosis in CeD and might have particular clinical utility in the diagnostic testing of patients unable to tolerate dietary gluten, and for assessing duodenal biopsies with equivocal features. This approach is generalisable to any TCR/BCR locus and any sequencing platform, with potential to predict diagnosis or prognosis in conditions mediated or modulated by the adaptive immune response. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

'Attorneys of the poor': Training physicians to tackle health inequalities.

The stellar gains in life expectancy and health over the past century have been accompanied by an increase in societal and health inequalities. This health gap between the most and least fortunate in our society is widening, driven by complex social determinants of health, as well as healthcare systems themselves. Physicians are not just well-qualified and well-placed to act as advocates for change, but have a moral duty to do so: to stand by silently is to be complicit. Following a workshop on health inequalities and medical training at the Royal College of Physicians Trainees Committee, we sought to examine how health inequalities could be addressed through changes to the medical education system. We discuss the arguments for reform in recruitment to medicine, and changes to undergraduate, postgraduate and continuing medical education in order to equip the profession to deliver meaningful improvements in health inequalities. We propose a population health credential as a mechanism by which specialists can gain additional skills to take on leadership roles addressing health inequalities, allowing them to support colleagues in public health and bring in specialty-specific knowledge and experience.

The role of the future physician: building on shifting sands.

The role of the future physician in the NHS is of interest to current doctors, patients, policymakers and the wider public. Amid the COVID-19 pandemic, it has never been more clear that the healthcare needs of the population, and the technical and scientific advances with which to solve them, are rapidly evolving and the medical workforce must adapt to these changes to deliver personalised healthcare. This article considers the current challenges that need to be addressed to deliver a future physician-led healthcare service that works for its patients. Key themes are expanded upon, including the changing healthcare workforce, digital and technological innovation, service delivery, complex conditions and changing patient demographics. The impact and challenges of the ongoing COVID-19 pandemic on these factors are highlighted. Avenues for development are suggested, both in postgraduate medical training and the health service as a whole. These changes will be required to deliver the physicians of the future, imbued with the skills and attributes they will need to provide a high standard of care in the mid-21st century.