Diapedesis-Induced Integrin Signaling via LFA-1 Facilitates Tissue Immunity by Inducing Intrinsic Complement C3 Expression in Immune Cells.

Intrinsic complement C3 activity is integral to human T helper type 1 (Th1) and cytotoxic T cell responses. Increased or decreased intracellular C3 results in autoimmunity and infections, respectively. The mechanisms regulating intracellular C3 expression remain undefined. We identified complement, including C3, as among the most significantly enriched biological pathway in tissue-occupying cells. We generated C3-reporter mice and confirmed that C3 expression was a defining feature of tissue-immune cells, including T cells and monocytes, occurred during transendothelial diapedesis, and depended on integrin lymphocyte-function-associated antigen 1 (LFA-1) signals. Immune cells from patients with leukocyte adhesion deficiency type 1 (LAD-1) had reduced C3 transcripts and diminished effector activities, which could be rescued proportionally by intracellular C3 provision. Conversely, increased C3 expression by T cells from arthritis patients correlated with disease severity. Our study defines integrins as key controllers of intracellular complement, demonstrates that perturbations in the LFA-1-C3-axis contribute to primary immunodeficiency, and identifies intracellular C3 as biomarker of severity in autoimmunity.

Regulatory B cells: origin, phenotype, and function.

Regulatory B (Breg) cells are immunosuppressive cells that support immunological tolerance. Through the production of interleukin-10 (IL-10), IL-35, and transforming growth factor ß (TGF-ß), Breg cells suppress immunopathology by prohibiting the expansion of pathogenic T cells and other pro-inflammatory lymphocytes. Recent work has shown that different inflammatory environments induce distinct Breg cell populations. Although these findings highlight the relevance of inflammatory signals in the differentiation of Breg cells, they also raise other questions about Breg cell biology and phenotype. For example, what are the functional properties and phenotype of Breg cells? Can a Breg cell arise at every stage in B cell development? Is inflammation the primary requisite for Breg cell differentiation? Here, we use these questions to discuss the advances in understanding Breg cell biology, with a particular emphasis on their ontogeny; we propose that multiple Breg cell subsets can be induced in response to inflammation at different stages in development.

Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis.

OBJECTIVES: To define the host mechanisms contributing to the pathological interferon (IFN) type 1 signature in Juvenile dermatomyositis (JDM). METHODS: RNA-sequencing was performed on CD4+, CD8+, CD14+ and CD19+ cells sorted from pretreatment and on-treatment JDM (pretreatment n=10, on-treatment n=11) and age/sex-matched child healthy-control (CHC n=4) peripheral blood mononuclear cell (PBMC). Mitochondrial morphology and superoxide were assessed by fluorescence microscopy, cellular metabolism by 13C glucose uptake assays, and oxidised mitochondrial DNA (oxmtDNA) content by dot-blot. Healthy-control PBMC and JDM pretreatment PBMC were cultured with IFN-α, oxmtDNA, cGAS-inhibitor, TLR-9 antagonist and/or n-acetyl cysteine (NAC). IFN-stimulated gene (ISGs) expression was measured by qPCR. Total numbers of patient and controls for functional experiments, JDM n=82, total CHC n=35. RESULTS: Dysregulated mitochondrial-associated gene expression correlated with increased ISG expression in JDM CD14+ monocytes. Altered mitochondrial-associated gene expression was paralleled by altered mitochondrial biology, including 'megamitochondria', cellular metabolism and a decrease in gene expression of superoxide dismutase (SOD)1. This was associated with enhanced production of oxidised mitochondrial (oxmt)DNA. OxmtDNA induced ISG expression in healthy PBMC, which was blocked by targeting oxidative stress and intracellular nucleic acid sensing pathways. Complementary experiments showed that, under in vitro experimental conditions, targeting these pathways via the antioxidant drug NAC, TLR9 antagonist and to a lesser extent cGAS-inhibitor, suppressed ISG expression in pretreatment JDM PBMC. CONCLUSIONS: These results describe a novel pathway where altered mitochondrial biology in JDM CD14+ monocytes lead to oxmtDNA production and stimulates ISG expression. Targeting this pathway has therapeutical potential in JDM and other IFN type 1-driven autoimmune diseases.

The Global Leadership Mentoring Community: An evaluation of its impact on nursing leadership.

AIM: To evaluate a year-long mentorship program, pairing nurses from different regions across the world to support their global leadership capability, and identifying additional consequences of their participation. BACKGROUND: Investment in developing nurse leaders continues as a strategic global imperative. Building on the first cohort's recommendations, this second program illustrates continued progress. PROGRAM EVALUATION: Using the logic model of program evaluation, this non-empirical paper uses data collected from anonymized questionnaires and participants' stories to help improve the program, illustrating innovative practices to develop the confidence and competence of emerging and established nurse leaders globally. DISCUSSION: The value of mentorship was recognized, and there were gains for both mentors and mentees in the development of leadership confidence and competence. Through engagement and collaboration with the whole community, participants were encouraged to understand their own and others' cultures avoiding assumptions and stereotypes. CONCLUSION: This evaluation illustrates that in addition to helping improve future programs, mentorship has enabled the growth of individuals' skill sets and the confidence to reach out to peers across the world to understand the meaning of global health and to make a meaningful contribution to the challenges they face. IMPLICATIONS FOR NURSING PRACTICE: Nurse managers should be encouraged to develop and formalize a mentoring culture to benefit the leadership competence and well-being of their workforce. IMPLICATIONS FOR NURSING POLICY: Every nurse has a responsibility to invest in nursing leadership for themselves and others. Mentorship can assist nurse leaders to build workforce capability to lead and contribute to the policy agenda locally, nationally, and internationally. Starting early and at the individual level, global mentorship programs can develop leadership expertise to help nurses find their voice and strengthen their confidence and competence to lead and therefore build the strategic leaders of the future.

Case study: the development of specialist nurse roles in Malta.

Specialist nurses play a significant role in healthcare. This study investigated and evaluated the primary and extended roles and the development of specialist nurses in Malta. METHODS: A qualitative case study design and purposive sampling techniques were used to gain a deep understanding of the complex issues surrounding specialist nurses from multiple data sets. A survey of the total specialist nurse population in 2013 (n=27), in-depth interviews with a group of specialist nurses (n=9) and four focus groups with key professionals and policy stakeholders (total n=28) were carried out. Data were collected between 2013 and 2015 and analysed using thematic analysis. FINDINGS: Three themes emerged: the roles and attributes of specialist nurses in Malta; the development of specialist nurses; and the influences on the advancement of specialist nursing practice in Malta. Although these data are nearly a decade old, no further research has been carried out. CONCLUSIONS: A legally accepted set of definitions as well as preparation and evaluation of the specialist nurse role from a national policy perspective is needed. Attitudes and systems that limit specialist nurses need to be challenged.

B cell contribution to immunometabolic dysfunction and impaired immune responses in obesity.

Obesity increases the risk of type 2 diabetes mellitus, cardiovascular disease, fatty liver disease, and cancer. It is also linked with more severe complications from infections, including COVID-19, and poor vaccine responses. Chronic, low-grade inflammation and associated immune perturbations play an important role in determining morbidity in people living with obesity. The contribution of B cells to immune dysregulation and meta-inflammation associated with obesity has been documented by studies over the past decade. With a focus on human studies, here we consolidate the observations demonstrating that there is altered B cell subset composition, differentiation, and function both systemically and in the adipose tissue of individuals living with obesity. Finally, we discuss the potential factors that drive B cell dysfunction in obesity and propose a model by which altered B cell subset composition in obesity underlies dysfunctional B cell responses to novel pathogens.

Cytokine production by human B cells: role in health and autoimmune disease.

B cells are classically considered solely as antibody-producing cells driving humoral immune responses to foreign antigens in infections and vaccinations as well as self-antigens in pathological settings such as autoimmunity. However, it has now become clear that B cells can also secrete a vast array of cytokines, which influence both pro- and anti-inflammatory immune responses. Indeed, similarly to T cells, there is significant heterogeneity in cytokine-driven responses by B cells, ranging from the production of pro-inflammatory effector cytokines such as IL-6, through to the release of immunosuppressive cytokines such as IL-10. In this review, focusing on human B cells, we summarize the key findings that have revealed that cytokine-producing B cell subsets have critical functions in healthy immune responses and contribute to the pathophysiology of autoimmune diseases.

Investing in nursing and its leadership to secure global health: Are we making progress?

Investing in nursing and its leadership has been a key global priority in achieving world health. This paper aims to explore what it means to invest in nursing and its leadership and whether we are progressing in its endeavour. Consideration is given to whose responsibility it is to invest, the importance of education to support strategic nurse leaders and enable them to have a voice to lead as well as create a culture in which their staff wish to stay. Further, the paper explores the importance of each country accepting responsibility for developing and funding its strategic workforce plan and paying nurse professionals fairly and taking steps to reduce workforce shortages. Finally, the paper examines the progress the United Kingdom is making and concludes that investment in nursing is everyone's business, the government, healthcare organisations, society and above all nurses themselves. Collectively, we must step up to influence change and have nursing voices heard.

Biomarkers Associated with Organ-Specific Involvement in Juvenile Systemic Lupus Erythematosus.

Juvenile systemic lupus erythematosus (JSLE) is characterised by onset before 18 years of age and more severe disease phenotype, increased morbidity and mortality compared to adult-onset SLE. Management strategies in JSLE rely heavily on evidence derived from adult-onset SLE studies; therefore, identifying biomarkers associated with the disease pathogenesis and reflecting particularities of JSLE clinical phenotype holds promise for better patient management and improved outcomes. This narrative review summarises the evidence related to various traditional and novel biomarkers that have shown a promising role in identifying and predicting specific organ involvement in JSLE and appraises the evidence regarding their clinical utility, focusing in particular on renal biomarkers, while also emphasising the research into cardiovascular, haematological, neurological, skin and joint disease-related JSLE biomarkers, as well as genetic biomarkers with potential clinical applications.

Nursing Now: nurses at the heart of the challenge to improve global health.

Elizabeth Rosser, Acting Executive Dean, Bournemouth University, discusses two initiatives to promote nursing around the world and make improvements in global health.

The importance of relationships in international collaborations.

Elizabeth Rosser, Acting Executive Dean, Bournemouth University, considers the human aspects of global partnerships and the sense of belonging that comes with actively engaging with others in the profession.

International Nurses Day: cause for celebration.

Elizabeth Rosser, Acting Executive Dean, Bournemouth University, reflects on a symbolic moment in the nursing year and the progress made by nurses.

Why education matters: reflections on the last 50 years.

Elizabeth Rosser, Professor of Nursing and acting Executive Dean of Faculty, Bournemouth University, reflects on her own nursing journey and the importance of nurse education.

Responsibility, research and reasoning: nursing through 70 years of the NHS.

B Gail Thomas, Emeritus Professor, and Elizabeth Rosser, Professor and Acting Executive Dean, of Bournemouth University, chart the evolution of nurses into modern autonomous professionals. erosser@bournemouth.ac.uk.

Strong leadership: the case for global connections.

AIMS AND OBJECTIVES: To identify how nurse leaders view and experience the opportunities offered by one of the largest global nursing organisations Sigma Theta Tau International. BACKGROUND: Worldwide, nursing leadership is challenged with addressing the complex issues impacting on care delivery. International nursing organisations are a means to bring together individuals to promote leadership and scholarship for nursing practice to promote patient safety and quality care. The newly established all-England chapter of Sigma Theta Tau International is a recent addition to the society in terms of nurse leadership in Europe, as such faces challenges as it establishes its identity and seeks to interpret the organisational vision: to advance world health through nursing leadership and scholarship. Moving forward, members views were sought on the goals of the chapter and how they may be enacted. DESIGN: In July 2013, all chapter members at that time had been nominated on the basis of achievement in nurse leadership; all were invited to participate in an online survey. The online questionnaire contained a series of closed and open questions. RESULTS: Most respondents joined because they believed in the vision and networking opportunities Sigma Theta Tau International provides. Three themes were extracted from the data: the value of networking and communication, leadership and the development of culturally sensitive organisations and the need for shared scholarship for nursing practice. CONCLUSION: Findings indicate the growth of effective leadership at all levels of nursing could be harnessed through successful collaboration and keen support for robust connections between practice and education to promote quality care. RELEVANCE TO CLINICAL PRACTICE: Whilst challenging, globalisation presents an opportunity for a nursing society such as Sigma Theta Tau International to work collaboratively to address healthcare issues. A nursing society that explores and resolves its own complex issues by actively promoting leadership and collaborative scholarship reveals a potential to empower the profession to share our collective solutions towards enhancing clinical practice.

Supporting clinical leadership through action: The nurse consultant role.

AIMS AND OBJECTIVES: To evaluate the effectiveness of an action learning set to enhance clinical leadership and extend their scope and confidence more strategically. BACKGROUND: As the most senior clinical role in most healthcare systems, the consultant nurse role is a solitary one. They are required to develop personal resilience, commitment and a belief in their ability to lead, with new consultants needing a strong support network to succeed. DESIGN: Following a 2-year action learning set, four nurse consultants, one therapy consultant, and a university educationalist engaged in a cooperative inquiry approach using four cycles of discussion, reflection, analysis and action over an 18-month period from March 2015-July 2016, to learn how to change and enhance their working practices. Data were analysed thematically. RESULTS: Four themes emerged where the action learning set (i) offered structure and support, (ii) enabled a wider influence and (iii) empowered them to lead. The cooperative inquiry helped them realise how much they had gained from their collective learning and they felt empowered to lead. CONCLUSION: Their motivation to "make a difference" remains palpable. The outcomes of the cooperative inquiry included an enhanced understanding of the importance of openness and trust and a willingness to share and learn from each other in a respectful and confidential environment with a receptiveness to change. Self-leadership has clearly been accepted and embraced, and their collaboration has improved communication across the organisation, enhanced their strategic leadership capability and given confidence to disseminate externally. RELEVANCE TO CLINICAL PRACTICE: The action learning set offered structure to support these clinical leaders to keep them focused across the breadth of their role. Additionally, peer review with external facilitation has enabled these clinical leaders to gain a wider influence and empowered them to lead.

Consultation on the new roles of supervisor and assessor.

Elizabeth Rosser, Deputy Dean (Education and Professional Practice) and Professor of Nursing at Bournemouth University, outlines three new practice and education roles proposed by the Nursing and Midwifery Council.

Proposed changes to nurse education: get ready to have your say.

Elizabeth Rosser, Deputy Dean (Education and Professional Practice) and Professor of Nursing at Bournemouth University, examines the radical changes to undergraduate nurse education currently proposed.