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

Investigation of T cell populations in coeliac disease and intestinal transplantation using functional, transcriptomic, and T cell receptor repertoire analysis approaches

Coeliac disease (CD) is caused by an adaptive immune response to gluten, however the gluten- specific CD4+ T cell response is insufficient to cause tissue damage in isolation. CD8+ intra-epithelial T cells (IELs) mediate epithelial cell damage in CD, which is thought to occur in a TCR-independent manner, while the role of γδ IELs, which are increased in CD, remains enigmatic. I sought to investigate CD8+ and γδ T cell populations in CD. After optimisation of intestinal tissue dissociation, TCR repertoire sequencing (TCRseq) and single- cell RNA sequencing (scRNAseq) (Chapter 3), I examined intestinal CD8+ and γδ T cells in CD using flow cytometry, bulk and single-cell RNAseq, and TCRseq (Chapter 4). I confirmed previously reported changes in γδ TCR repertoires in CD, and identified perturbations in the CD8+ TCR repertoire, including enrichment of TRBV28-expressing clonotypes in CD. Bulk and scRNAseq approaches identified an activated, cytotoxic, highly regulated, tissue-resident population of CD8+ T cells associated with CD, which were associated with these TRBV28 clonotypes, consistent with a TCR-driven CD8+ T cell process involved in CD pathogenesis. This work on CD led further research in two directions, examining the wider landscape of human γδ T cells and their relationships to other innate-like T cells, and exploring CD8+ T cell heterogeneity in tissue resident populations in the human gut. First, I examined transcriptional, phenotypic, and functional heterogeneity in human γδ T cells (Chapter 5). scRNAseq and flow cytometry of circulating γδ T cells revealed a Vδ2+ γδ T cell effector spectrum, from an innate-like, cytokine-responsive CD26bright population to a highly cytotoxic GPR56+ population. CD26bright Vδ2+ T cells were highly similar to MAIT cells, in transcriptional profile, phenotype, and function, in particular in their IFNγ- and IL-26-dominated response to cytokine stimulation. In addition, unexpected heterogeneity within naive non-Vδ2 T cell populations was identified, including a SOX4+ subset that expressed the gut-homing chemokine receptor CCR9. Second, I used intestinal transplantation as a model to study tissue resident memory (TRM) CD8+ T cells in the small intestine (Chapter 6). scRNAseq identified two transcriptionally distinct subsets of bona fide CD8+ TRM cells in the human gut, differing in their expression of cytotoxic molecules, chemokine receptors, and integrins. Further flow cytometry and functional assays demonstrated that these populations differed in phenotype and function. In sum, I have explored CD8+ and γδ T cell biology in coeliac disease, health, and intestinal transplantation. The work raises questions about the nature of classification systems of cell types in immunology, and the shared and distinct features of unconventional and innate-like T cells.</p

Randomized controlled trial of plain English and visual abstracts for disseminating surgical research via social media

Background: Patients are increasingly taking an active role in the design and delivery of surgical research. Public communication of results should also be encouraged, but this is often limited to non‐expert commentary. This study assessed the role of plain English abstracts disseminated via social media in engaging patients and clinicians in the communication of surgical research. Methods: A three‐arm randomized controlled trial with crossover of two intervention arms was performed. Manuscripts accepted for publication in BJS were allocated to one of three arms and disseminated via Twitter: plain English abstracts, visual abstracts and standard tweets. The primary outcome was online engagement (a composite of tweets, replies and likes) by members of the public within 14 days. The secondary outcome was online engagement by healthcare professionals. Results: Forty‐one manuscripts were randomized to plain English abstracts (14), visual abstracts (14) and standard tweets (13). The number of public engagements was low, with a mean of 1·8 (range 0–8), 2·5 (0–11), and 1·2 (0–4) for plain English abstracts, visual abstracts and standard tweets respectively. The mean number of engagements by healthcare professionals was 29·4 (6–66), 45·3 (6–161) and 28·8 (10–52) respectively. Overall, visual abstracts attracted a significantly greater number of engagements than plain English ones (P < 0·001). Conclusion: Online, public engagement with surgical research was low. Overall engagement (predominantly from healthcare professionals) was enhanced by the use of visual abstracts

‘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

Human intestinal tissue-resident memory T cells comprise transcriptionally and functionally distinct subsets

Tissue-resident memory T (T_RM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However, transcriptional heterogeneity of human intestinal T_RM cells remains undefined. Here, we investigate transcriptional and functional heterogeneity of human T_RM cells through study of donor-derived T_RM cells from intestinal transplant recipients. Single-cell transcriptional profiling identifies two transcriptional states of CD8+ T_RM cells, delineated by ITGAE and ITGB2 expression. We define a transcriptional signature discriminating these populations, including differential expression of cytotoxicity- and residency-associated genes. Flow cytometry of recipient-derived cells infiltrating the graft, and lymphocytes from healthy gut, confirm these CD8+ T_RM phenotypes. CD8+ CD69+CD103+ T_RM cells produce interleukin-2 (IL-2) and demonstrate greater polyfunctional cytokine production, whereas β2-integrin+CD69+CD103− T_RM cells have higher granzyme expression. Analysis of intestinal CD4+ T cells identifies several parallels, including a β2-integrin+ population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal CD4+ and CD8+ T_RM cells

Adenovirus vectors activate Vδ2+ γδT cells in a type I interferon-, TNF-, and IL-18-dependent manner

Vδ2+ γδT cells are unconventional T cells that can be activated by cytokines without TCR signaling. Adenovirus vaccine vectors activated Vδ2+ γδT cells in an interleukin 18-, TNF-, and type I interferon-dependent manner. This stimulatory capacity was associated with adenovirus vectors of non-species C origin, including the ChAdOx1 vaccine platform