Metformin is a metabolic modulator and radiosensitiser in rectal cancer.

Resistance to neoadjuvant chemoradiation therapy, is a major challenge in the management of rectal cancer. Increasing evidence supports a role for altered energy metabolism in the resistance of tumours to anti-cancer therapy, suggesting that targeting tumour metabolism may have potential as a novel therapeutic strategy to boost treatment response. In this study, the impact of metformin on the radiosensitivity of colorectal cancer cells, and the potential mechanisms of action of metformin-mediated radiosensitisation were investigated. Metformin treatment was demonstrated to significantly radiosensitise both radiosensitive and radioresistant colorectal cancer cells in vitro. Transcriptomic and functional analysis demonstrated metformin-mediated alterations to energy metabolism, mitochondrial function, cell cycle distribution and progression, cell death and antioxidant levels in colorectal cancer cells. Using ex vivo models, metformin treatment significantly inhibited oxidative phosphorylation and glycolysis in treatment naïve rectal cancer biopsies, without affecting the real-time metabolic profile of non-cancer rectal tissue. Importantly, metformin treatment differentially altered the protein secretome of rectal cancer tissue when compared to non-cancer rectal tissue. Together these data highlight the potential utility of metformin as an anti-metabolic radiosensitiser in rectal cancer.

Conversation Analysis Based Simulation (CABS): A method for improving communication skills training for healthcare practitioners.

BACKGROUND: Actors portraying simulated patients are widely used in communication skills training in healthcare, but debates persist over the authenticity of these interactions. However, healthcare professionals value simulation-based training because of the opportunity to think and react in real time, which alternatives cannot provide. OBJECTIVE: To describe a method for the use of simulation which maximises authenticity by grounding training in real, observed, patterns of patient communication. DESIGN: Naturally occurring care interactions were video recorded and analysed using conversation analysis (CA) to identify communication patterns. We focused on sites of recurring interactional trouble as areas for training, and identified more and less effective ways of dealing with these. We used the CA findings to train actors portraying simulated patients, based on the observed interactional patterns. SETTINGS AND PARTICIPANTS: Patients living with dementia and healthcare practitioners (HCPs) on two acute healthcare of the elderly wards in the English East Midlands. OUTCOME MEASURES: One month later HCPs reported using the skills learned in clinical practice. Masked-ratings of before and after simulated patient encounters confirmed these self-reports in relation to one key area of training. RESULTS: The Conversation Analysis Based Simulation (CABS) method used in this setting showed positive results across a range of quantitative and qualitative outcome measures. What is significant for the transferability of the method is that qualitative feedback from trainees highlighted the ability of the method to not only illuminate their existing effective practices, but to understand why these were effective and be able to articulate them to others. DISCUSSION/CONCLUSION: While the CABS method was piloted in the dementia care setting described here, it has potential applicability across healthcare settings where simulated consultations are used in communication skills training. Grounding simulated interaction in the observed communication patterns of real patients is an important means of maximising authenticity. PATIENT AND PUBLIC CONTRIBUTION: The VideOing to Improve dementia Communication Education (VOICE) intervention which piloted the CABS method was developed by a multidisciplinary team, including three carers of people with dementia. People living with dementia were involved in the rating of the before and after video simulation assessments.

The facilitators and barriers to improving functional activity and wellbeing in people with dementia: a qualitative study from the process evaluation of Promoting Activity, Independence and Stability in Early Dementia (PrAISED).

BACKGROUND: The PRomoting Activity, Independence and Stability in Early Dementia (PrAISED) study delivered an exercise and functional activity programme to participants living with dementia. A Randomised Controlled Trial showed no measurable benefits in activities of daily living, physical activity or quality of life. OBJECTIVE: To explore participants' responses to PrAISED and explain why an intervention that might be expected to have produced measurable health gains did not do so. METHODS: A process evaluation using qualitative methods, comprising interviews and researcher notes. SETTING: Data were collected in participants' homes or remotely by telephone or videoconferencing. SAMPLE: A total of 88 interviews were conducted with 44 participants living with dementia (n = 32 intervention group; n = 12 control group) and 39 caregivers. A total of 69 interviews were conducted with 26 therapists. RESULTS: Participants valued the intervention as proactively addressing health issues that were of concern to them, and as a source of social contact, interaction, information and advice. Facilitators to achieving positive outcomes included perceiving progress towards desired goals, positive expectations, therapists' skills and rapport with participants, and caregiver support. Barriers included: cognitive impairment, which prevented independent engagement and carry-over between sessions; chronic physical health problems and intercurrent acute illness and injury; 'tapering' (progressively infrequent supervision intended to help develop habits and independent activity); and the COVID-19 pandemic. CONCLUSIONS: Self-directed interventions may not be appropriate in the context of dementia, even in the mild stages of the condition. Dementia-specific factors affected outcomes including caregiver support, rapport with therapists, availability of supervision, motivational factors and the limitations of remote delivery. The effects of cognitive impairment, multimorbidity and frailty overwhelmed any positive impact of the intervention. Maintenance of functional ability is valued, but in the face of inevitable progression of disease, other less tangible outcomes become important, challenging how we frame 'health gain' and trial outcomes.

Promoting Activity, Independence, and Stability in Early Dementia and mild cognitive impairment (PrAISED): randomised controlled trial.

OBJECTIVE: To determine the effectiveness of an exercise and functional activity therapy intervention in adults with early dementia or mild cognitive impairment compared with usual care. DESIGN: Randomised controlled trial. SETTING: Participants' homes and communities at five sites in the United Kingdom. PARTICIPANTS: 365 adults with early dementia or mild cognitive impairment who were living at home, and family members or carers. INTERVENTION: The intervention, Promoting activity, Independence, and Stability in Early Dementia and mild cognitive impairment (PrAISED), was a specially designed, dementia specific, rehabilitation programme focusing on strength, balance, physical activity, and performance of activities of daily living, which was tailored and progressive and addressed risk and the psychological needs of people with dementia. Up to 50 therapy sessions were provided over 12 months. The control group received usual care plus a falls risk assessment. Procedures were adapted during the covid-19 pandemic. MAIN OUTCOME MEASURES: The primary outcome was score on the carer (informant) reported disability assessment for dementia scale 12 months after randomisation. Secondary outcomes were self-reported activities of daily living, physical activity, quality of life, balance, functional mobility, fear of falling, frailty, cognition, mood, carer strain, service use at 12 months, and falls between months 4 and 15. RESULTS: 365 patient participants were randomised, 183 to intervention and 182 to control. The median age of participants was 80 years (range 65-95), median Montreal cognitive assessment score was 20 out of 30 (range 13-26), and 58% (n=210) were men. Intervention participants received a median of 31 therapy sessions (interquartile range 22-40) and reported completing a mean 121 minutes of PrAISED exercise each week. Primary outcome data were available for 149 intervention and 141 control participants. Scores on the disability assessment for dementia scale did not differ between groups: adjusted mean difference -1.3, 95% confidence interval -5.2 to 2.6; Cohen's d effect size -0.06, 95% confidence interval -0.26 to 0.15; P=0.51). Upper 95% confidence intervals excluded small to moderate effects on any of the range of outcome measures. Between months 4 and 15 the intervention group experienced 79 falls and the control group 200 falls (adjusted incidence rate ratio 0.78, 95% confidence interval 0.5 to 1.3; P=0.3). CONCLUSION: The intensive PrAISED programme of exercise and functional activity training did not improve activities of daily living, physical activity, or quality of life; reduce falls; or improve any other secondary health status outcomes, despite good uptake. Future research should consider alternative approaches to maintaining ability and wellbeing in people with dementia. TRIAL REGISTRATION: ISRCTN Registry ISRCTN15320670.

Filial Cannibalism Leads to Chronic Nest Failure of Eastern Hellbender Salamanders (Cryptobranchus alleganiensis).

AbstractIn species that provide parental care, parents will sometimes cannibalize their own young (i.e., filial cannibalism). Here, we quantified the frequency of whole-clutch filial cannibalism in a species of giant salamander (eastern hellbender; Cryptobranchus alleganiensis) that has experienced precipitous population declines with unknown causes. We used underwater artificial nesting shelters deployed across a gradient of upstream forest cover to assess the fates of 182 nests at 10 sites over 8 years. We found strong evidence that nest failure rates increased at sites with low riparian forest cover in the upstream catchment. At several sites, reproductive failure was 100%, mainly due to cannibalism by the caring male. The high incidence of filial cannibalism at degraded sites was not explained by evolutionary hypotheses for filial cannibalism based on poor adult body condition or low reproductive value of small clutches. Instead, larger clutches at degraded sites were most vulnerable to cannibalism. We hypothesize that high frequencies of filial cannibalism of large clutches in areas with low forest cover could be related to changes in water chemistry or siltation that influence parental physiology or that reduce the viability of eggs. Importantly, our results identify chronic nest failure as a possible mechanism contributing to population declines and observed geriatric age structure in this imperiled species.

Thinking inside the box: intracellular roles for complement system proteins come into focus.

Over the last decade, perspectives on the complement system in the context of cancer have shifted, with complement proteins now implicated in many of the hallmarks of cancer. Systemically, the generation of complement anaphylatoxin C5a, the most potent inflammatory mediator of the cascade, occurs following convertase-mediated cleavage of complement component C5. In a recent manuscript, Ding et al., propose that in colorectal cancer cells, C5 cleavage can occur intracellularly and in a convertase-independent manner, identifying cathepsin D as an enzyme capable of cleaving C5 into C5a [1]. Intracellular C5a is functional and promotes ß-catenin stabilisation via the assembly of a KCTD5/cullin3/Roc-1 complex. Importantly, the blockade of C5aR1 prevents tumorigenesis. This study adds to a growing body of evidence indicating that complement proteins, previously thought to primarily have extracellular or membrane-bound functions, also have important intracellular roles.

Chronic pain in people living with dementia: challenges to recognising and managing pain, and personalising intervention by phenotype.

Pain is common in people with dementia, and pain can exacerbate the behavioural and psychological symptoms of dementia. Effective pain management is challenging, not least in people with dementia. Impairments of cognition, communication and abstract thought can make communicating pain unreliable or impossible. It is unclear which biopsychosocial interventions for pain management are effective in people with dementia, and which interventions for behavioural and psychological symptoms of dementia are effective in people with pain. The result is that drugs, physical therapies and psychological therapies might be either underused or overused. People with dementia and pain could be helped by assessment processes that characterise an individual's pain experience and dementia behaviours in a mechanistic manner, phenotyping. Chronic pain management has moved from a 'one size fits all' approach, towards personalised medicine, where interventions recommended for an individual depend upon the key mechanisms underlying their pain, and the relative values they place on benefits and adverse effects. Mechanistic phenotyping through careful personalised evaluation would define the mechanisms driving pain and dementia behaviours in an individual, enabling the formulation of a personalised intervention strategy. Central pain processing mechanisms are particularly likely to be important in people with pain and dementia, and interventions to accommodate and address these may be particularly helpful, not only to relieve pain but also the symptoms of dementia.

A Distinctive γδ T Cell Repertoire in NOD Mice Weakens Immune Regulation and Favors Diabetic Disease.

Previous studies in mice and humans suggesting that γδ T cells play a role in the development of type 1 diabetes have been inconsistent and contradictory. We attempted to resolve this for the type 1 diabetes-prone NOD mice by characterizing their γδ T cell populations, and by investigating the functional contributions of particular γδ T cells subsets, using Vγ-gene targeted NOD mice. We found evidence that NOD Vγ4+ γδ T cells inhibit the development of diabetes, and that the process by which they do so involves IL-17 production and/or promotion of regulatory CD4+ αß T cells (Tregs) in the pancreatic lymph nodes. In contrast, the NOD Vγ1+ cells promote diabetes development. Enhanced Vγ1+ cell numbers in NOD mice, in particular those biased to produce IFNγ, appear to favor diabetic disease. Within NOD mice deficient in particular γδ T cell subsets, we noted that changes in the abundance of non-targeted T cell types also occurred, which varied depending upon the γδ T cells that were missing. Our results indicate that while certain γδ T cell subsets inhibit the development of spontaneous type 1 diabetes, others exacerbate it, and they may do so via mechanisms that include altering the levels of other T cells.

Impact of COVID-19 lockdown on physical exercise among participants receiving the Promoting Activity, Independence and Stability in Early Dementia (PrAISED) intervention: a repeated measure study.

BACKGROUND: The potential decrease in daily physical activity associated with the COVID-19 pandemic lockdowns may have a negative impact on people living with dementia. Given the limited literature around the effects of home confinement in people living with dementia, this study investigated changes in physical exercise levels of participants in the intervention arm of the Promoting Activity, Independence and Stability in Early Dementia (PrAISED) Randomised Controlled Trial during the first COVID-19 national lockdown. It hypothesised that participants would maintain physical exercise levels. METHODS: A repeated measure (three time points) study involving 30 participants (mean age = 78.0 years, 15 male and 15 female, 22 (73.0%) living with their primary caregiver), from four regions in England receiving the PrAISED intervention. PrAISED is an individually tailored intervention of physical exercises and functional activities. Trained therapists deliver therapy sessions over a period of 52 weeks. Study participants received therapy sessions via phone or video calling during the COVID-19 lockdown. This study investigated self-reported minutes of physical exercise recorded on study calendars for the months of February (i.e., baseline - pre-lockdown), May (i.e., T1 - during lockdown), and August (i.e., T2-post-lockdown) 2020. RESULTS: Participants reported a statistically significant increase in activity levels between February and May (Wilcoxon Z = -2.013, p = 0.044) and a statistically significant decrease between May and August (Wilcoxon Z = -2.726, p = 0.004). No significant difference was found in the physical activity levels from pre- to post-lockdown (Wilcoxon Z = 0.485, p = 0.620). CONCLUSION: Despite concerns that the restrictions associated with the COVID-19 pandemic might lead to reductions in physical exercise, participants in receipt of the PrAISED intervention increased their amount of physical exercise during lockdown. Our findings support the potential of remote support for people living with dementia to help them maintain physical exercise levels in circumstances where face-to-face service provision is not possible. TRIAL REGISTRATION: The PrAISED trial and process evaluation have received ethical approval number 18/YH/0059 from the Bradford/Leeds Ethics Committee. The Clinical Trial Identifier for PrAISED is: ISRCTN15320670 ( https://doi.org/10.1186/ISRCTN15320670 ). Registration was made on 04/09/2018.

Becoming aware of γδ T cells.

The discovery that B cells and αß T cells exist was predictable: These cells gave themselves away through their products and biological effects. In contrast, there was no reason to anticipate the existence of γδ T cells. Even the accidental discovery of a novel TCR-like gene (later named γ) that did not encode TCR α or ß proteins did not immediately change this. TCR-like γ had no obvious function, and its early expression in the thymus encouraged speculation about a possible role in αß T cell development. However, the identification of human PBL-derived cell-lines which expressed CD3 in complex with the TCR-like γ protein, but not the αß TCR, first indicated that a second T cell-type might exist, and the TCR-like γ chain was observed to co-precipitate with another protein. Amid speculation about a possible second TCR, this potential dimeric partner was named δ. To determine if the δ protein was indeed TCR-like, we undertook to sequence it. Meanwhile, a fourth TCR-like gene was discovered and provisionally named x. TCR-like x had revealed itself through genomic rearrangements early in T cell development, and was an attractive candidate for the gene encoding δ. The observation that δ protein sequences matched the predicted amino acid sequences encoded by the x gene, as well as serological cross-reactivity, confirmed that the TCR-like x gene indeed encoded the δ protein. Thus, the γδ heterodimer was established as a second TCR, and the cells that express it (the γδ T cells) consequently represented a third lymphocyte-population with the potential of recognizing diverse antigens. Soon, it became clear that γδ T cells are widely distributed and conserved among the vertebrate species, implying biological importance. Consistently, early functional studies revealed their roles in host resistance to pathogens, tissue repair, immune regulation, metabolism, organ physiology and more. Albeit discovered late, γδ T cells have repeatedly proven to play a distinct and often critical immunological role, and now generate much interest.

PD-1 blockade enhances chemotherapy toxicity in oesophageal adenocarcinoma.

Chemotherapy upregulates immune checkpoint (IC) expression on the surface of tumour cells and IC-intrinsic signalling confers a survival advantage against chemotherapy in several cancer-types including oesophageal adenocarcinoma (OAC). However, the signalling pathways mediating chemotherapy-induced IC upregulation and the mechanisms employed by ICs to protect OAC cells against chemotherapy remain unknown. Longitudinal profiling revealed that FLOT-induced IC upregulation on OE33 OAC cells was sustained for up to 3 weeks post-treatment, returning to baseline upon complete tumour cell recovery. Pro-survival MEK signalling mediated FLOT-induced upregulation of PD-L1, TIM-3, LAG-3 and A2aR on OAC cells promoting a more immune-resistant phenotype. Single agent PD-1, PD-L1 and A2aR blockade decreased OAC cell viability, proliferation and mediated apoptosis. Mechanistic insights demonstrated that blockade of the PD-1 axis decreased stem-like marker ALDH and expression of DNA repair genes. Importantly, combining single agent PD-1, PD-L1 and A2aR blockade with FLOT enhanced cytotoxicity in OAC cells. These findings reveal novel mechanistic insights into the immune-independent functions of IC-intrinsic signalling in OAC cells with important clinical implications for boosting the efficacy of the first-line FLOT chemotherapy regimen in OAC in combination with ICB, to not only boost anti-tumour immunity but also to suppress IC-mediated promotion of key hallmarks of cancer that drive tumour progression.

Diagnostic Accuracy of Blood-based Biomarkers for Pancreatic Cancer: A Systematic Review and Meta-analysis.

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate below 5%. Carbohydrate antigen 19-9 (CA19-9) is the most commonly used blood-based biomarker for PDAC in current clinical practice, despite having been shown repeatedly to be inaccurate and have poor diagnostic performance. This review aims to assess the reported diagnostic accuracy of all blood-based biomarkers investigated to date in PDAC, by directly comparing individual biomarkers and multi-biomarker panels, both containing CA19-9 and not (novel). A systematic review was conducted in accordance with PRISMA standards in July 2020. Individualized search strategies for three academic databases identified 5,885 studies between the years 1973 and 2020. After two rounds of screening, 250 studies were included. Data were extracted and assessed for bias. A multivariate three-level meta-analysis with subgroup moderators was run in R using AUC values as effect size. On the basis of this model, the pooled AUC value for all multi-biomarker panels (AUC = 0.898; 95% confidence interval (CI): 0.88-0.91) was significantly higher than all single biomarkers (AUC = 0.803; 95% CI: 0.78-0.83; P < 0.0001). The pooled AUC value for CA19-9 alone was significantly lower compared with the multi-biomarker panels containing CA19-9 (P < 0.0001). For the novel biomarkers, the pooled AUC for single biomarkers was also significantly lower compared with multi-biomarker panels (P < 0.0001). Novel biomarkers that have been repeatedly examined across the literature, such as TIMP-1, CEA, and CA125, are highlighted as promising. These results suggest that CA19-9 may be best used as an addition to a panel of biomarkers rather than alone, and that multi-biomarker panels generate the most robust results in blood-based PDAC diagnosis. Significance: In a systematic review and three-level multivariate meta-analysis, it is shown for the first time that blood-based multi-biomarker panels for the diagnosis of PDAC exhibit superior performance in comparison with single biomarkers. CA19-9 is demonstrated to have limited utility alone, and to perform poorly in patient control cohorts of both healthy and benign individuals. Multi-biomarker panels containing CA19-9 produce the best diagnostic performance overall.

Avoiding repair, maintaining face: Responding to hard-to-interpret talk from people living with dementia in the acute hospital.

People living with dementia (PLWD) are almost always admitted to the acute hospital for reasons unrelated to their dementia, finding themselves in the unfamiliar environment of a Health Care of Older Persons acute ward. The effect of this environment creates a challenge not just for a PLWD themselves, but also for the staff who care for them. Concerns have been raised by both policy makers and staff about the quality of communication between hospital staff and PLWD. Using conversation analysis, we examined 41 video recordings of healthcare professional (HCP)/PLWD interactions collected across three acute inpatient wards in a large teaching hospital in the UK. In this paper, we focus our analysis on hard-to-interpret talk (talk where there are problems in hearing, speaking and/or understanding), and the ways in which healthcare professionals respond to this. Repair of hard- to- interpret talk is common in ordinary interaction, but we find that HCPs in this setting use a range of approaches to avoid direct repair. These approaches are: the use of non-committal responses and continuers such as 'yeah' or nods; the use of repetitions or partial repetitions; responding to the emotional tone displayed in the PLWD's utterance; closing the current topic and shifting to the next; and treating the PLWD's talk as related to the task at hand. We suggest that the use of these approaches may be one way in which HCPs manage respecting the personhood of the PLWD, by preserving face and enabling a continuation of an interaction in which the PLWD can take an active part. Our paper provides an empirical demonstration of the high level of interactional skill involved in dementia care work. It also illustrates how these skills can be described and specified, and hence incorporated into the recommendations and tips that are produced for communication with PLWD.

Divergent effects of exendin-4 and interleukin-6 on rat colonic secretory and contractile activity are associated with changes in regional vagal afferent signaling.

BACKGROUND: The pro-inflammatory cytokine, interleukin (IL)-6 is elevated in individuals with the functional bowel disorder, irritable bowel syndrome (IBS). IL-6 can independently modify intestinal secreto-motor function, thereby contributing to IBS pathophysiology. Additionally, hormonal changes may underlie symptom flares. Post-prandial exacerbation of IBS symptoms has been linked to secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1), which can also influence colonic secreto-motor activity. This study aimed to ascertain if the effects of GLP-1 on colonic secretory and contractile activity was impacted by elevated IL-6 levels and if sensory signals regarding such changes were reflected in altered vagal afferent activity. METHODS: Colonic secretory currents and circular muscle contractile activity was investigated in Sprague Dawley rats using Ussing chamber and organ bath electrophysiology. Regional afferent signaling was assessed using extracellular electrophysiological recordings from colonic vagal afferents. KEY RESULTS: Application of the GLP-1 receptor agonist, exendin-4 (Ex-4) in the presence of IL-6 potentiated colonic secretory currents and transepithelial resistance. Vagal afferent fibers originating in the submucosal layer exhibited larger responses to Ex-4 when IL-6 was also present. In contrast, co-application of Ex-4 and IL-6 to gut-bath chambers suppressed circular muscle contractile activity. The activity in extrinsic afferents originating in the colonic myenteric layer was similarly suppressed. CONCLUSIONS & INFERENCES: Application of Ex-4 in the presence of IL-6 had divergent modulatory effects on colonic secretion and contractile activity. Similar patterns were observed in vagal afferent signaling originating in the submucosal and myenteric neuronal layers, indicating regional afferent activity reflected immune- and endocrine-mediated changes in colonic function.

Complement in Tumourigenesis and the Response to Cancer Therapy.

In recent years, our knowledge of the complement system beyond innate immunity has progressed significantly. A modern understanding is that the complement system has a multifaceted role in malignancy, impacting carcinogenesis, the acquisition of a metastatic phenotype and response to therapies. The ability of local immune cells to produce and respond to complement components has provided valuable insights into their regulation, and the subsequent remodeling of the tumour microenvironment. These novel discoveries have advanced our understanding of the immunosuppressive mechanisms supporting tumour growth and uncovered potential therapeutic targets. This review discusses the current understanding of complement in cancer, outlining both direct and immune cell-mediated roles. The role of complement in response to therapies such as chemotherapy, radiation and immunotherapy is also presented. While complement activities are largely context and cancer type-dependent, it is evident that promising therapeutic avenues have been identified, in particular in combination therapies.

Tele-Rehabilitation for People with Dementia during the COVID-19 Pandemic: A Case-Study from England.

Introduction: The Promoting Activity, Independence and Stability in Early Dementia (PrAISED) is delivering an exercise programme for people with dementia. The Lincolnshire partnership National Health Service (NHS) foundation Trust successfully delivered PrAISED through a video-calling platform during the Coronavirus Disease 2019 (COVID-19) pandemic. METHODS: This qualitative case-study aimed to identify participants that video delivery worked for, to highlight its benefits and its challenges. Interviews were conducted between May and August 2020 with five participants with dementia and their caregivers (n = 10), as well as five therapists from the Lincolnshire partnership NHS foundation Trust. The interviews were analysed through thematic analysis. RESULTS: Video delivery worked best when participants had a supporting caregiver and when therapists showed enthusiasm and had an established rapport with the client. Benefits included time efficiency of sessions, enhancing participants' motivation, caregivers' dementia awareness, and therapists' creativity. Limitations included users' poor IT skills and resources. DISCUSSION: The COVID-19 pandemic required innovative ways of delivering rehabilitation. This study supports that people with dementia can use tele-rehabilitation, but success is reliant on having a caregiver and an enthusiastic and known therapist.

Protocol for the process evaluation of the Promoting Activity, Independence and Stability in Early Dementia (PrAISED), following changes required by the COVID-19 pandemic.

INTRODUCTION: The Promoting Activity, Independence and Stability in Early Dementia (PrAISED) randomised controlled trial (RCT) is evaluating a home-based, face-to-face, individually tailored, activity and exercise programme for people living with dementia. Social distancing requirements following the COVID-19 pandemic necessitated rapid changes to intervention delivery. METHODS AND ANALYSIS: A mixed-methods process evaluation will investigate how the changes were implemented and the impact that these have on participants' experience. An implementation study will investigate how the intervention was delivered during the pandemic. A study on the mechanisms of impact and context will investigate how these changes were experienced by the PrAISED participants, their carers and the therapists delivering the intervention. The study will commence in May 2020. ETHICS AND DISSEMINATION: The PrAISED RCT and process evaluation have received ethical approval number 18/YH/0059. The PrAISED process evaluation will enable us to understand how distancing and isolation affected participants, their activity and exercise routines and whether the therapy programme could be continued with remote support. This will be valuable both in explaining trial results and also contribute to understanding and designing new ways of delivering home-based services and rehabilitation interventions for people with dementia and their carers. TRIAL REGISTRATION NUMBER: ISRCTN15320670; Pre-results.

When people living with dementia say 'no': Negotiating refusal in the acute hospital setting.

A quarter of UK acute hospital beds are occupied by people living with dementia (PLWD). Concerns have been raised by both policy makers and carers about the quality of communication between hospital staff and PLWD. PLWD may experience communication impairments such as word finding difficulties, limited ability to construct coherent narratives and difficulties understanding others. Since much healthcare delivery occurs through talk, healthcare professionals (HCPs) and PLWD are likely to experience increased communication barriers. Consistent with this, HCPs report stress and reduced job satisfaction associated with difficulty communicating with PLWD. HCPs face these challenges whilst striving to deliver person-centred care, respecting the autonomy and wishes of the patient before them. However, best practice recommendations in the field tend not to be based on actual interactional evidence. This paper investigates recurring interactional difficulties around HCP requests to carry out health and social care tasks and subsequent reluctance or refusal on the part of PLWD. Using conversation analysis, we examined 41 video recordings of HCP/PLWD interactions collected across three acute inpatient wards. We identify both the nature of the refusals, and any mitigation offered, and explore the requests preceding them in terms of entitlement and contingency. We also explore the nature of HCP requests which precede PLWD agreement with a course of action. We conclude that several features of requests can be seen to precede acceptance, principally the use of higher entitlement requests, and the lowering of contingencies. Our findings underline the importance of examining the contextual interactional detail involved in the negotiation of healthcare, which here leads to an understanding of how design of HCP requests can impact on an important healthcare activity being carried out. They also emphasise the power of conversation analytic methods to identify areas of frequent interactional trouble in dementia care which have not previously been articulated.

Two functionally distinct subsets of IL-17 producing γδ T cells.

The γδ T cells play an important role in both mice and humans as a source of the cytokine IL-17, which is key for immune resistance to certain pathogens. In mice, most of these IL-17 producers, termed γδT-17 cells, actually comprise two distinct types: those expressing an invariant Vγ6Vδ1+ TCR and those expressing a Vγ4+ TCR. Murine γδT-17 cells acquire an inherent bias to produce IL-17 and other "type 17" cytokines during thymic development. The similarities and differences between the two mouse γδT-17 types are reviewed here, and the potential implications of their differences are discussed. There is some evidence that two distinct TCR-defined IL-17-producing γδ T cell subsets also exist in humans, but unlike the mouse γδT-17 cells, these cells are probably not imprinted with an IL-17 bias during thymic development, but rather acquire an IL-17 bias in the periphery.