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Key summary points Aim To seek information on delirium assessment processes and pathways in non-intensive clinical care settings in the United Kingdom (UK), and to assess usage of specific delirium assessment tools: the 4 'A's Test (4AT), Confusion Assessment Method and Single Question to identify Delirium (SQiD). Findings In total, 95% of National Health Service (NHS) units (hospitals, trusts and health boards) reported use of formal delirium assessment processes and 85% of units had guidelines or pathways in place. The 4AT was the most widely used tool, with 80% of units reporting use; the Confusion Assessment Method was reportedly used in 45% of units and the SQiD in 36% of units. Message This study shows real-world, large-scale uptake of delirium detection methods and delirium guidelines in UK hospitals, which contributes to ongoing efforts to improve delirium care. Supplementary Information The online version contains supplementary material available at 10.1007/s41999-021-00507-2., Purpose Our aim was to collect information on delirium assessment processes and pathways in non-intensive care settings in the United Kingdom (UK). Methods We sent a Freedom of Information request to 169 UK National Health Service (NHS) hospitals, trusts and health boards (units) in July 2020 to obtain data on usage of delirium assessment tools in clinical practice and delirium pathways or guidelines. Results We received responses from 154/169 units (91% response rate). Of these, 146/154 (95%) units reported use of formal delirium assessment processes and 131/154 (85%) units had guidelines or pathways in place. The 4’A’s Test (4AT) was the most widely used tool, with 117/146 (80%) units reporting use. The Confusion Assessment Method was used in 65/146 (45%) units, and the Single Question to identify Delirium (SQiD) in 52/146 (36%) units. Conclusions Our findings show that the 4AT is the most commonly used tool in the UK, with 80% of units reporting use. This study adds to our knowledge of real-world uptake of delirium detection methods at scale. Future studies should evaluate real-world implementation of delirium assessment tools further via (1) tool completion rates and (2) rates of positive scores against the expected of prevalence delirium in the clinical population concerned. Supplementary Information The online version contains supplementary material available at 10.1007/s41999-021-00507-2.

There is an increasing body of knowledge demonstrating that genes involved in cell fate decisions during development also play a role in the continuous cell fate decisions made by the mature immune system in response to foreign antigen. This review concentrates on the role of the Notch and Sonic hedgehog (Shh) signalling pathways in the development and function of CD4+ T lymphocytes.

Context: The endometrium is a multicellular, steroid-responsive tissue that undergoes dynamic remodeling every menstrual cycle in preparation for implantation and, in absence of pregnancy, menstruation. Androgen receptors are present in the endometrium. Objective: The objective of the study was to investigate the impact of androgens on human endometrial stromal cells (hESC). Design: Bioinformatics was used to identify an androgen-regulated gene set and processes associated with their function. Regulation of target genes and impact of androgens on cell function were validated using primary hESC. Setting: The study was conducted at the University Research Institute. Patients: Endometrium was collected from women with regular menses; tissues were used for recovery of cells, total mRNA, or protein and for immunohistochemistry. Results: A new endometrial androgen target gene set (n = 15) was identified. Bioinformatics revealed 12 of these genes interacted in one pathway and identified an association with control of cell survival. Dynamic androgen-dependent changes in expression of the gene set were detected in hESC with nine significantly down-regulated at 2 and/or 8 h. Treatment of hESC with dihydrotestosterone reduced staurosporine-induced apoptosis and cell migration/proliferation. Conclusions: Rigorous in silico analysis resulted in identification of a group of androgen-regulated genes expressed in human endometrium. Pathway analysis and functional assays suggest androgen-dependent changes in gene expression may have a significant impact on stromal cell proliferation, migration, and survival. These data provide the platform for further studies on the role of circulatory or local androgens in the regulation of endometrial function and identify androgens as candidates in the pathogenesis of common endometrial disorders including polycystic ovarian syndrome, cancer, and endometriosis.

The Hedgehog signalling pathway is crucial for normal vertebrate growth and development. Recent studies would suggest that signalling capability is retained in the post-embryonic organism. Shh signalling has been identified in the adult immune system, participating in CD4+ T lymphocyte activation. Studies on fibrotic pulmonary disorders have demonstrated Shh in both human and mouse lung restricted to areas of active disease. Acute lung injury has also shown upregulated expression and together this data is highly suggestive for a functional role for Shh signalling in adult lung injury and disease. We propose that hedgehog signalling may contribute to epithelial injury and repair and act as an intermediary in cross-talk between damaged epithelium and the immune/inflammatory system.

Sonic hedgehog (Shh) is important in the growth and differentiation of a variety of cell types, including the development of T cells in the thymus. This prompted us to investigate whether Shh signaling is a functional component of the physiological response of human mature CD4+ T cells following Ag recognition. In this study, we demonstrate that Shh and its receptor Patched (Ptc) are expressed on resting and activated human peripheral CD4+ T cells. In approximately one-half of the randomly selected, anonymous blood donors tested, exposure of anti-CD3/28 Ab-activated CD4+ T cells to the biologically active N-terminal Shh peptide increased the transcription of ptc, thereby demonstrating that Shh signaling had occurred. Furthermore, the addition of exogenous Shh amplified the production of IL-2, IFN-γ, and IL-10 by activated CD4+ T cells. The synthesis of IL-2 and IFN-γ, but not IL-10, by CD4+ T cells was down-regulated by the addition of neutralizing anti-Shh Ab. Cell surface expression of CD25 and CD69 on activated T cells was up-regulated by exogenous Shh, whereas in the presence of the neutralizing anti-Shh Ab expression it was reduced. Collectively, our findings demonstrate that Shh-mediated signaling is a physiological component of T cell responses, which acts to modulate CD4+ T cell effector function.

Sonic hedgehog (Shh) signaling is important in the growth and differentiation of many cell types and recently has been reported to play a role in T cell development in the thymus. This prompted us to investigate whether or not Shh contributes to the clonal expansion of peripheral CD4+ T cells. In this study, we demonstrate that Shh and other components of the signaling pathway patched, smoothened, and Gli1 (glioma-associated oncogene) are expressed in peripheral CD4+ T cells. The addition of the biologically active amino-terminal Shh peptide had no effect on resting CD4+ T cells, but significantly enhanced proliferation of anti-CD3/28 Ab-activated CD4+ T cells. This was not due to antiapoptotic effects, but by promoting entry of T cells into the S-G2 proliferative phase of the cell cycle. Neutralizing anti-Shh Ab reduced T cell proliferation by inhibiting cell transition into the S-G2 phase, suggesting that endogenously produced Shh plays a physiological role in the clonal expansion of T cells. Furthermore, we have observed a significant up-regulation of Shh and Gli1 (glioma-associated oncogene) mRNA in activated CD4+ T cells with or without addition of exogenous Shh, which corresponds with maximal CD4+ T cell proliferation, whereas bcl-2 was only up-regulated in activated cells in the presence of Shh. Our findings suggest that endogenously produced Shh may play a role in sustaining normal CD4+ T cell proliferation and exogenously added Shh enhances this response.

Immunological tolerance is defined as a state of specific non-responsiveness to a particular antigen induced by previous exposure to that same antigen. The mucosal surfaces comprise the upper and lower respiratory tracts, the gastrointestinal tract and the urogenitary tract, and are a major site of antigenic challenge. The immune system associated with the mucosa has the extraordinary potential to discriminate between antigens that are harmless (e.g. inhaled and dietary antigens) and those that are associated with pathogens. Normally soluble proteins delivered through the mucosal surfaces do not elicit a strong systemic immune response but instead induce a transient local immune response that is replaced by long-term peripheral unresponsiveness – this is termed mucosal tolerance. The phenomenon of oral tolerance is well established and considerable attention has focussed on defining the underlying mechanisms. However, only comparatively recently was the induction of tolerance via the respiratory mucosa described, and it is this form of mucosal tolerance which forms the basis of this review.

Severe combined immunodeficient (SCID) mice were transplanted with biopsy material from 18 cases of Hodgkin’s disease (HD) and 23 biopsies from non-Hodgkin’s lymphoma. Five of the HD (3 lymphocyte predominant, 1 nodular sclerosing and 1 mixed cellularity) and 7 of the non-Hodgkin’s lymphomas (3 centroblastic, 1 immunoblastic, 1 follicular lymphoma and 2 biopsies from a case of large cell anaplastic lymphoma) produced tumours in mice. All the SCID HD-derived tumours had a B-cell phenotype and expressed the Epstein-Barr virus (EBV) gene products, EBER RNA, EBNA-2 and LMP-1. Morphologically these tumours resembled polymorphous immunoblastic lymphomas. The EBV-positive tumours all expressed CD23 and CD43. All HD-derived SCID tumours showed clonal immunoglobulin heavy chain rearrangements. One tumour derived from a follicular lymphoma showed similar morphology and phenotype and an identical pattern of EBV gene expression to the HD-derived tumours. Three centroblastic and one immunoblastic lymphoma derived tumours were EBV-negative. These showed a near identical B-cell phenotype to original biopsies and showed identical immunoglobulin gene rearrangements to the original tumours. Tumours derived from the large cell anaplastic lymphoma showed two types of lymphoproliferation in SCID mice; first immunoblastic tumours expressing EBER RNA, EBNA-2 and LMP-1, with immunoglobulin gene rearrangements differing from those of the original tumour; secondly large cell anaplastic tumours showing EBER RNA with little or no LMP-1 or EBNA-2 expression, and immunoglobulin gene rearrangements identical to those of the original tumour.