Research priorities for the management of major trauma: an international priority setting partnership with the James Lind Alliance.

OBJECTIVE: The objective of this study is to determine research priorities for the management of major trauma, representing the shared priorities of patients, their families, carers and healthcare professionals. DESIGN/SETTING: An international research priority-setting partnership. PARTICIPANTS: People who have experienced major trauma, their carers and relatives, and healthcare professionals involved in treating patients after major trauma. The scope included chest, abdominal and pelvic injuries as well as major bleeding, multiple injuries and those that threaten life or limb. METHODS: A multiphase priority-setting exercise was conducted in partnership with the James Lind Alliance over 24 months (November 2021-October 2023). An international survey asked respondents to submit their research uncertainties which were then combined into several indicative questions. The existing evidence was searched to ensure that the questions had not already been sufficiently answered. A second international survey asked respondents to prioritise the research questions. A final shortlist of 19 questions was taken to a stakeholder workshop, where consensus was reached on the top 10 priorities. RESULTS: A total of 1572 uncertainties, submitted by 417 respondents (including 132 patients and carers), were received during the initial survey. These were refined into 53 unique indicative questions, of which all 53 were judged to be true uncertainties after reviewing the existing evidence. 373 people (including 115 patients and carers) responded to the interim prioritisation survey and 19 questions were taken to a final consensus workshop between patients, carers and healthcare professionals. At the final workshop, a consensus was reached for the ranking of the top 10 questions. CONCLUSIONS: The top 10 research priorities for major trauma include patient-centred questions regarding pain relief and prehospital management, multidisciplinary working, novel technologies, rehabilitation and holistic support. These shared priorities will now be used to guide funders and teams wishing to research major trauma around the globe.

Multicentre pilot randomised control trial of a self-directed exergaming intervention for poststroke upper limb rehabilitation: research protocol.

INTRODUCTION: Technology-facilitated, self-directed upper limb (UL) rehabilitation, as an adjunct to conventional care, could enhance poststroke UL recovery compared with conventional care alone, without imposing additional resource burden. The proposed pilot randomised controlled trial (RCT) aims to assess whether stroke survivors will engage in self-directed UL training, explore factors associated with intervention adherence and evaluate the study design for an RCT testing the efficacy of a self-directed exer-gaming intervention for UL recovery after stroke. METHODS AND ANALYSIS: This is a multicentre, internal pilot RCT; parallel design, with nested qualitative methods. The sample will consist of stroke survivors with UL paresis, presenting within the previous 30 days. Participants randomised to the intervention group will be trained to use an exergaming device and will be supported to adopt this as part of their self-directed rehabilitation (ie, without formal support/supervision) for a 3-month period. The primary outcome will be the Fugl Meyer Upper Extremity Assessment (FM-UE) at 6 months poststroke. Secondary outcomes are the Action Research Arm Test (ARAT), the Barthel Index and the Modified Rankin Scale. Assessment time points will be prior to randomisation (0-1 month poststroke), 3 months and 6 months poststroke. A power calculation to inform sample size required for a definitive RCT will be conducted using FM-UE data from the sample across 0-6 months time points. Semistructured qualitative interviews will examine factors associated with intervention adoption. Reflexive thematic analysis will be used to code qualitative interview data and generate key themes associated with intervention adoption. ETHICS AND DISSEMINATION: The study protocol (V.1.9) was granted ethical approval by the Health Research Authority, Health and Care Research Wales, and the London- Harrow Research Ethics Committee (ref. 21/LO/0054) on 19 May 2021. Trial results will be submitted for publication in peer-reviewed journals, presented at national and international stroke meetings and conferences and disseminated among stakeholder communities. TRIAL REGISTRATION NUMBER: NCT04475692.

Improving personalised care, through the development of a service evaluation tool to assess, understand and monitor delivery.

Systematically implementing personalised care has far reaching benefits to individuals, communities and health and social care systems. If done well, personalised care can result in better health outcomes and experiences, more efficient use of health services and reduced health inequalities. Despite these known benefits, implementation of personalised care has been slow. Evaluation is an important step towards achieving the ambition of universally delivered personalised care. There are currently few comprehensive assessments or tools that are designed to understand the implementation of personalised care at a service or system level, or the cultural, practical and behavioural factors influencing this. The aim of this paper is to describe the development and testing of a system-wide evaluation tool. The tool offers a process through which healthcare systems can better understand the current delivery of personalised care and the factors influencing this. With a focus on implementation, the development of the tool was informed by the Consolidated Framework for Implementation Research, and its content is structured using behaviour change theory (COM-B Theory of Behaviour Change Model). The tool consists of four mirrored surveys, which were developed using an iterative exploratory design. This included a series of testing cycles, in which its structure and content were continually refined. To date, it has been used by 24 clinical services, involving 397 service users, 313 front-line practitioners, 73 service managers and 40 commissioners. These services have used the evaluation process to initiate quality improvement, targeted at one of the more aspects of personalised care. The use of the COM-B model increases the likelihood of those improvements being sustained, through identification of the core factors that enable or limit personalised care behaviours among healthcare staff. We have shown this process to be applicable in a wide range of settings, thus it potentially has broad applicability as a tool for cultural change and quality improvement. The next stage of this work will focus on implementation and evaluation, to fully understand if and how the tool can be used to drive improvements in personalised care delivery.

Understanding implementation of a complex intervention in a stroke rehabilitation research trial: A qualitative evaluation using Normalisation Process Theory.

BACKGROUND: The Implicit Learning in Stroke study was a pilot cluster randomised controlled trial, investigating the use of different motor learning strategies in acute stroke rehabilitation. Participating Stroke Units (n = 8) were from the South East/West regions of the UK, with the experimental intervention (implicit learning) being delivered by clinical teams. It required therapists to change how they gave instructions and feedback to patients during rehabilitation. This paper reports the processes underpinning implementation of the implicit learning intervention. The evaluation aimed to i) understand how therapists made sense of, engaged with and interpreted the effects of the intervention; ii) compare this to the experience reported by patients; iii) extrapolate learning of broader relevance to the design and conduct of research involving complex interventions in stroke rehabilitation. METHODS: Qualitative evaluation, with data collected through focus groups with clinical staff (n = 20) and semi structured interviews with people with stroke (n = 19). Mixed inductive and theory driven analysis, underpinned by Normalisation Process Theory. RESULTS: How therapists made sense of and experienced the intervention impacted how it was implemented. The intervention was delivered by individual therapists, and was influenced by their individual values, beliefs and concerns. However, how teams worked together to build a shared (team) understanding, also played a key role. Teams with a more "flexible" interpretation, reported the view that the intervention could have benefits in a wide range of scenarios. Those with a more fixed, "rule based" interpretation, found it harder to implement, and perceived the benefits to be more limited. Therapists' concerns that the intervention may impair therapeutic relationships and patient learning were not reflected in how patients experienced it. CONCLUSIONS: Changing practice, whether in a research study or in the "real world", is complex. Understanding the process of implementation is crucial to effective research delivery. Implementation frameworks facilitate understanding, and subsequently the systematic and iterative development of strategies for this to be addressed. How teams (rather than individuals) work together is central to how complex interventions are understood and implemented. It is possible that new complex interventions work best in contexts where there are 'flexible' cultures. Researchers should consider, and potentially measure this, before they can effectively implement and evaluate an intervention. TRIAL REGISTRATION: Clinical Trials - NCT03792126.

Examining Usability, Acceptability, and Adoption of a Self-Directed, Technology-Based Intervention for Upper Limb Rehabilitation After Stroke: Cohort Study.

BACKGROUND: Upper limb (UL) recovery after stroke is strongly dependent upon rehabilitation dose. Rehabilitation technologies present pragmatic solutions to dose enhancement, complementing therapeutic activity within conventional rehabilitation, connecting clinicians with patients remotely, and empowering patients to drive their own recovery. To date, rehabilitation technologies have been poorly adopted. Understanding the barriers to adoption may shape strategies to enhance technology use and therefore increase rehabilitation dose, thus optimizing recovery potential. OBJECTIVE: We examined the usability, acceptability, and adoption of a self-directed, exercise-gaming technology within a heterogeneous stroke survivor cohort and investigated how stroke survivor characteristics, technology usability, and attitudes toward technology influenced adoption. METHODS: A feasibility study of a novel exercise-gaming technology for self-directed UL rehabilitation in early subacute stroke survivors (N=30) was conducted in an inpatient, acute hospital setting. Demographic and clinical characteristics were recorded; participants' performance in using the system (usability) was assessed using a 4-point performance rating scale (adapted from the Barthel index), and adherence with the system was electronically logged throughout the trial. The technology acceptance model was used to formulate a survey examining the acceptability of the system. Spearman rank correlations were used to examine associations between participant characteristics, user performance (usability), end-point technology acceptance, and intervention adherence (adoption). RESULTS: The technology was usable for 87% (n=26) of participants, and the overall technology acceptance rating was 68% (95% CI 56%-79%). Participants trained with the device for a median of 26 (IQR 16-31) minutes daily over an enrollment period of 8 (IQR 5-14) days. Technology adoption positively correlated with user performance (usability) (ρ=0.55; 95% CI 0.23-0.75; P=.007) and acceptability as well as domains of perceived usefulness (ρ=0.42; 95% CI 0.09-0.68; P=.03) and perceived ease of use (ρ=0.46; 95% CI 0.10-0.74; P=.02). Technology acceptance decreased with increased global stroke severity (ρ=-0.56; 95% CI -0.79 to -0.22; P=.007). CONCLUSIONS: This technology was usable and acceptable for the majority of the cohort, who achieved an intervention dose with technology-facilitated, self-directed UL training that exceeded conventional care norms. Technology usability and acceptability were determinants of adoption and appear to be mediated by stroke severity. The results demonstrate the importance of selecting technologies for stroke survivors on the basis of individual needs and abilities, as well as optimizing the accessibility of technologies for the target user group. Facilitating changes in stroke survivors' beliefs and attitudes toward rehabilitation technologies may enhance adoption. Further work is needed to understand how technology can be optimized to benefit those with more severe stroke.

Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones.

B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the inhibition of BCL6. We sought to improve the cellular potency and in vivo exposure of the non-degrading isomer, CCT373567, of our recently published degrader, CCT373566. The major limitation of our inhibitors was their high topological polar surface areas (TPSA), leading to increased efflux ratios. Reducing the molecular weight allowed us to remove polarity and decrease TPSA without considerably reducing solubility. Careful optimization of these properties, as guided by pharmacokinetic studies, led to the discovery of CCT374705, a potent inhibitor of BCL6 with a good in vivo profile. Modest in vivo efficacy was achieved in a lymphoma xenograft mouse model after oral dosing.

The Posttaumatic Adjustment Scale (PAS) is an effective measure in predicting psychological distress in patients following major trauma.

AIMS: To determine whether a psychological screening tool - the Posttraumatic Adjustment Scale (PAS), predicts later psychological distress for admissions to a Major Trauma Centre (MTC) and to identify whether there was an unmet need in relation to the psychological support offered. METHODS: Patient demographics and details of their injuries were retrieved from the Trauma Audit & Research Network (TARN) database. All patients admitted to Leeds General Infirmary MTC were approached for inclusion in the study over a three-month period. The PAS was administered to all participants at baseline. Following discharge, patients were sent two validated psychological measures via post, the Impact of Events Scale - Revised (IES-R) and the Clinical Outcomes in Routine Evaluation System (CORE-10). Relationships between continuous variables were examined using a Spearman's rank test (SR). The diagnostic accuracy of the different psychological screening systems was examined and compared using Receiver Operator Characteristic (ROC) analysis. RESULTS: Eighty-two patients completed the PAS, 26 of whom had been referred to clinical psychology and 56 who were not. Fifty-seven of these patients (70%) returned follow-up IES-R and CORE-10 data, 20 who had been referred to psychology and 37 who had not. The PAS-P score recorded shortly after admission correlated strongly with the CORE-10 (SR rs 0.54, p<0.0001) and IES-R (SR rs 0.63, p<0.0001) scores recorded at early follow up. A PAS-P of more than 10 predicted the development of PTSD symptoms (IES-R 33 or more) or moderate global psychological distress (CORE-10 15 or more) with 72% sensitivity and 71% specificity. To identify patients who went on to develop psychological symptoms according to either measure (IES-R 33 or more or CORE-10 15 or more), the PAS-P was more sensitive than clinician referral (71% vs 52%, p<0.05) with similar specificity (72% vs 75%, p=0.78). CONCLUSIONS: In an unselected group of trauma inpatients treated in a MTC, the PAS is an effective means of identifying those who are likely to go on to suffer PTSD symptoms or psychological distress. It may useful to use the PAS as a measure to formalise psychology referrals.

Principles into Practice: An Observational Study of Physiotherapists use of Motor Learning Principles in Stroke Rehabilitation.

OBJECTIVE(S): To describe a) how motor learning principles are applied during post stroke physiotherapy, with a focus on lower limb rehabilitation; and b) the context in which these principles are used, in relation to patient and/or task characteristics. DESIGN: Direct non-participation observation of routine physiotherapy sessions, with data collected via video recording. A structured analysis matrix and pre-agreed definitions were used to identify, count and record: type of activity; repetitions; instructional and feedback statements (frequency and type); strategies such as observational learning and augmented feedback. Data was visualised using scatter plots, and analysed descriptively. SETTING: 6 UK Stroke Units PARTICIPANTS: 89 therapy sessions were observed, involving 55 clinicians and 57 patients. RESULTS: Proportion of time spent active within each session ranged from 26% to 98% (mean 85, SD 19). The frequency of task repetition varied widely, with a median of 3.7 repetitions per minute (IQR 2.1-8.6). Coaching statements were common (mean 6.46 per minute), with 52% categorised as instructions, 14% as feedback, and 34% as verbal cues/motivational statements. 13% of instructions and 6% of feedback statements were externally focussed. Examining the use of different coaching behaviours in relation to patient characteristics found no associations. Overall, practice varied widely across the dataset. CONCLUSIONS: To optimise the potential for motor skill learning, therapists must manipulate features of their coaching language (what they say, how much and when) and practice design (type, number, difficulty and variability of task). There is an opportunity to implement motor learning principles more consistently, to benefit motor skill recovery following stroke. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (NCT03792126). CONTRIBUTION OF THE PAPER.

Positive postpartum well-being: What works for women.

BACKGROUND: Women's experiences of pregnancy, birth and motherhood extend beyond healthcare provision and the immediate postpartum. Women's social, cultural and political environments shape the positive or negative effects of their experiences through this transition. However, there is limited research concerning the factors that women identify as being protective or promotive of maternal well-being in the perinatal period and motherhood transition. OBJECTIVE: To explore women's views on the factors within healthcare, social, cultural, organizational, environmental and political domains that do or can work well in creating positive perinatal experiences. DESIGN, SETTING AND PARTICIPANTS: A qualitative descriptive study with embedded public and participant involvement (PPI). Participants were 24 women who were maternity care service users giving birth in Ireland. RESULTS: Three themes were developed. The first theme, 'tone of care', related to women's interactions with and attitudes of healthcare professionals in setting the tone for the care they experienced. The second theme, 'postpartum presence and support', concerned the professional postpartum supports and services that women found beneficial in the motherhood transition. The final theme, 'flexibility for new families' addresses social and organizational issues around parents returning to paid employment. DISCUSSION AND CONCLUSION: Women suggested multiple avenues for promoting positive perinatal experiences for women giving birth in Ireland, which may be implemented at healthcare and policy levels. Women identified that maternal health education focuses on supporting informed decision-making processes as a positive and worry-alleviating resource. Additionally, women valued being met by healthcare professionals who regard women as the decision makers in their care experience. Exchanges in which healthcare professionals validate and encourage women in their mothering role and actively involve their partners as caregivers left lasting positive impressions. Extended and professional postpartum support was a common issue, and phone lines or drop-in clinics were suggested as invaluable and affirming assets where women could access personalized support with healthcare professionals who had the knowledge and skills to genuinely approach women's concerns. Social and organizational considerations involved supporting parents to balance their responsibilities as new or growing families in the return to work. PUBLIC OR PATIENT CONTRIBUTION: Maternity care service users were involved in the interviews and manuscript preparation.

Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo.

The transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader CCT369260 to CCT373566, a highly potent probe suitable for sustained depletion of BCL6 in vivo. We observed a sharp degradation SAR, where subtle structural changes conveyed the ability to induce degradation of BCL6. CCT373566 showed modest in vivo efficacy in a lymphoma xenograft mouse model following oral dosing.

Fully automated platelet differential interference contrast image analysis via deep learning.

Platelets mediate arterial thrombosis, a leading cause of myocardial infarction and stroke. During injury, platelets adhere and spread over exposed subendothelial matrix substrates of the damaged blood vessel wall. The mechanisms which govern platelet activation and their interaction with a range of substrates are therefore regularly investigated using platelet spreading assays. These assays often use differential interference contrast (DIC) microscopy to assess platelet morphology and analysis performed using manual annotation. Here, a convolutional neural network (CNN) allowed fully automated analysis of platelet spreading assays captured by DIC microscopy. The CNN was trained using 120 generalised training images. Increasing the number of training images increases the mean average precision of the CNN. The CNN performance was compared to six manual annotators. Significant variation was observed between annotators, highlighting bias when manual analysis is performed. The CNN effectively analysed platelet morphology when platelets spread over a range of substrates (CRP-XL, vWF and fibrinogen), in the presence and absence of inhibitors (dasatinib, ibrutinib and PRT-060318) and agonist (thrombin), with results consistent in quantifying spread platelet area which is comparable to published literature. The application of a CNN enables, for the first time, automated analysis of platelet spreading assays captured by DIC microscopy.

Analyzing Lymphatic Vessel Patterning in Adult Tissue.

Whole-mount immunostaining allows intact tissue to be surveyed in three dimensions, avoiding the more restricted fields of view provided by visualizing thin sections. This technique is particularly useful for imaging lymphatic and blood networks by high-resolution confocal microscopy, revealing how such vessels are spatially positioned, the subcellular arrangements of individual antigens, and interactions with individual cells within the interstitium or vessel lumen. The purpose of this chapter is to provide a practical guide for obtaining images of lymphatic vessels following immunofluorescence staining, primarily in mouse skin.

Cumulative live birth rates among gestational surrogates in altruistic surrogacy arrangements.

Understanding the likelihood of a live birth is important for fertility treatment planning, particularly when one cycle fails and further treatment may be contemplated. This study aims to estimate the chance of live birth among gestational surrogates undergoing altruistic surrogacy arrangements between 2009 and 2016 in Victoria, Australia. A total of 81 gestational surrogates with 170 embryo transfer cycles were included. Of the 170 embryo transfer cycles, the majority were single embryo transfers (SETs; 97.1%), using frozen/thawed embryos (97.6%) which had been fertilized by intracytoplasmic sperm injection (77.6%). The cumulative live birth rate was 23.5% (95% CI, 15.6-33.8%) after the first cycle and increased to 50.6% (95% CI, 40.0-61.2%) after the sixth cycle. Of the 41 deliveries, 40 were singletons and one was a twin delivery. Two of the 42 deliveries were preterm, two were low birthweight and one was small for gestational age. The findings imply that surrogacy treatment can be offered up to six consecutive embryo transfer cycles to gestational surrogates. SET is encouraged in surrogacy practice to improve perinatal outcomes. These estimates can be used in counselling and decision-making for intended parents and gestational surrogates to continue a surrogacy treatment and informing public policy on assisted reproductive technology treatment.

Development of lower limb training interventions that promote an external focus of attention in people with stroke: a modified Delphi survey.

OBJECTIVE: To produce guidance and validated examples of tasks that promote an external focus of attention, for use in lower limb rehabilitation in an inpatient stroke care setting. DESIGN: Electronic survey, using e-Delphi methodology. PARTICIPANTS: A multi-professional expert panel of 14 clinicians and researchers, with expertise in stroke rehabilitation and/or motor learning. METHOD: Each survey round consisted of two parts: 1) classification of specific exercise examples, shown using video and 2) the categorization of specific tratement adjuncts. The panel was asked to comment on: likely focus of attention of the performer; instructions that would promote an external focus of attention; and how the task set-up could be modified to promote an external focus of attention. Rounds 2 and 3 included a summary of results from the previous round, and revised/new examples. The panel were also asked to state their level of agreement with a series of statements that arose from the free text. Three rounds of survey were completed and the a priori threshold for agreement was set at 80%. RESULTS: Eighteen iterations of exercises were presented, and 12 were accepted as promoting an external focus of attention. In addition, six additional statements were generated based on open responses, leading to further specific guidance on facilitating an external focus of attention in clinical practice. CONCLUSIONS: Commonly used rehabilitation exercises can be adapted to promote an external focus of attention, by altering the therapist's use of instructions and/or altering the task set up. Treatment principles and examples of tasks that promote an external focus have been produced.

Research priorities for the management of complex fractures: a UK priority setting partnership with the James Lind Alliance.

OBJECTIVE: To determine research priorities for the management of complex fractures, which represent the shared priorities of patients, their families, carers and healthcare professionals. DESIGN/SETTING: A national (UK) research priority setting partnership. PARTICIPANTS: People who have experienced a complex fracture, their carers and relatives, and relevant healthcare professionals and clinical academics involved in treating patients with complex fractures. The scope includes open fractures, fractures to joints broken into multiple pieces, multiple concomitant fractures and fractures involving the pelvis and acetabulum. METHODS: A multiphase priority setting exercise was conducted in partnership with the James Lind Alliance over 21 months (October 2019 to June 2021). A national survey asked respondents to submit their research uncertainties which were then combined into several indicative questions. The existing evidence was searched to ensure that the questions had not already been sufficiently answered. A second national survey asked respondents to prioritise the research questions. A final shortlist of 18 questions was taken to a stakeholder workshop, where a consensus was reached on the top 10 priorities. RESULTS: A total of 532 uncertainties, submitted by 158 respondents (including 33 patients/carers) were received during the initial survey. These were refined into 58 unique indicative questions, of which all 58 were judged to be true uncertainties after review of the existing evidence. 136 people (including 56 patients/carers) responded to the interim prioritisation survey and 18 questions were taken to a final consensus workshop between patients, carers and healthcare professionals. At the final workshop, a consensus was reached for the ranking of the top 10 questions. CONCLUSIONS: The top 10 research priorities for complex fracture include questions regarding rehabilitation, complications, psychological support and return to life-roles. These shared priorities will now be used to guide funders and teams wishing to research complex fractures over the coming decade.

Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket.

We describe the optimization of modestly active starting points to potent inhibitors of BCL6 by growing into a subpocket, which was occupied by a network of five stably bound water molecules. Identifying potent inhibitors required not only forming new interactions in the subpocket but also perturbing the water network in a productive, potency-increasing fashion while controlling the physicochemical properties. We achieved this goal in a sequential manner by systematically probing the pocket and the water network, ultimately achieving a 100-fold improvement of activity. The most potent compounds displaced three of the five initial water molecules and formed hydrogen bonds with the remaining two. Compound 25 showed a promising profile for a lead compound with submicromolar inhibition of BCL6 in cells and satisfactory pharmacokinetic (PK) properties. Our work highlights the importance of finding productive ways to perturb existing water networks when growing into solvent-filled protein pockets.

The Impact of Peer Support on Patient Outcomes in Adults With Physical Health Conditions: A Scoping Review.

Little is known about the impact of peer support programmes on physical health populations or on the methods used to evaluate such programmes. The present study undertakes a scoping review of research related to peer support programmes or interventions in physical health populations, guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR). The search was carried out across the Medline, PsycINFO, and Cochrane databases and focused on papers that evaluated peer support intervention(s) in adults with physical health conditions. The search identified an initial 7,903 records, which were narrowed down to 21 records that met the inclusion criteria; their findings were narratively synthesized. The scoping review found considerable heterogeneity among eligible records in terms of their study design, outcome measurements and findings reported. Qualitative methods of evaluation generated more consistent findings compared to objective outcome measures and suggested that peer support was beneficial for patients' health and wellbeing by reducing feelings of isolation and creating a sense of community as well as providing an opportunity for information consolidation. The scoping review highlights the inconsistencies in methods used to evaluate peer support interventions and programmes in healthcare settings among different physical health populations. It also draws attention to the lack of peer support research in particular areas, including in acute physical health populations such as in major trauma. The scoping review emphasizes the need for future studies to address this gap in peer support research.

Hyaluronan and Its Receptors: Key Mediators of Immune Cell Entry and Trafficking in the Lymphatic System.

Entry to the afferent lymphatics marks the first committed step for immune cell migration from tissues to draining lymph nodes both for the generation of immune responses and for timely resolution of tissue inflammation. This critical process occurs primarily at specialised discontinuous junctions in initial lymphatic capillaries, directed by chemokines released from lymphatic endothelium and orchestrated by adhesion between lymphatic receptors and their immune cell ligands. Prominent amongst the latter is the large glycosaminoglycan hyaluronan (HA) that can form a bulky glycocalyx on the surface of certain tissue-migrating leucocytes and whose engagement with its key lymphatic receptor LYVE-1 mediates docking and entry of dendritic cells to afferent lymphatics. Here we outline the latest insights into the molecular mechanisms by which the HA glycocalyx together with LYVE-1 and the related leucocyte receptor CD44 co-operate in immune cell entry, and how the process is facilitated by the unusual character of LYVE-1 • HA-binding interactions. In addition, we describe how pro-inflammatory breakdown products of HA may also contribute to lymphatic entry by transducing signals through LYVE-1 for lymphangiogenesis and increased junctional permeability. Lastly, we outline some future perspectives and highlight the LYVE-1 • HA axis as a potential target for immunotherapy.

In Sickness and in Health: The Immunological Roles of the Lymphatic System.

The lymphatic system plays crucial roles in immunity far beyond those of simply providing conduits for leukocytes and antigens in lymph fluid. Endothelial cells within this vasculature are distinct and highly specialized to perform roles based upon their location. Afferent lymphatic capillaries have unique intercellular junctions for efficient uptake of fluid and macromolecules, while expressing chemotactic and adhesion molecules that permit selective trafficking of specific immune cell subsets. Moreover, in response to events within peripheral tissue such as inflammation or infection, soluble factors from lymphatic endothelial cells exert "remote control" to modulate leukocyte migration across high endothelial venules from the blood to lymph nodes draining the tissue. These immune hubs are highly organized and perfectly arrayed to survey antigens from peripheral tissue while optimizing encounters between antigen-presenting cells and cognate lymphocytes. Furthermore, subsets of lymphatic endothelial cells exhibit differences in gene expression relating to specific functions and locality within the lymph node, facilitating both innate and acquired immune responses through antigen presentation, lymph node remodeling and regulation of leukocyte entry and exit. This review details the immune cell subsets in afferent and efferent lymph, and explores the mechanisms by which endothelial cells of the lymphatic system regulate such trafficking, for immune surveillance and tolerance during steady-state conditions, and in response to infection, acute and chronic inflammation, and subsequent resolution.