Impaired natural killer cell phenotype and function in idiopathic and heritable pulmonary arterial hypertension

BACKGROUND: Beyond their role as innate immune effectors, natural killer (NK) cells are emerging as important regulators of angiogenesis and vascular remodeling. Pulmonary arterial hypertension (PAH) is characterized by severe pulmonary vascular remodeling and has long been associated with immune dysfunction. Despite this association, a role for NK cells in disease pathology has not yet been described. METHODS AND RESULTS: Analysis of whole blood lymphocytes and isolated NK cells from PAH patients revealed an expansion of the functionally defective CD56(-)/CD16(+) NK subset that was not observed in patients with chronic thromboembolic pulmonary hypertension. NK cells from PAH patients also displayed decreased levels of the activating receptor NKp46 and the killer immunoglobulin-like receptors 2DL1/S1 and 3DL1, reduced secretion of the cytokine macrophage inflammatory protein-1β, and a significant impairment in cytolytic function associated with decreased killer immunoglobulin-like receptor 3DL1 expression. Genotyping patients (n=222) and controls (n=191) for killer immunoglobulin-like receptor gene polymorphisms did not explain these observations. Rather, we show that NK cells from PAH patients exhibit increased responsiveness to transforming growth factor-β, which specifically downregulates disease-associated killer immunoglobulin-like receptors. NK cell number and cytotoxicity were similarly decreased in the monocrotaline rat and chronic hypoxia mouse models of PAH, accompanied by reduced production of interferon-γ in NK cells from hypoxic mice. NK cells from PAH patients also produced elevated quantities of matrix metalloproteinase 9, consistent with a capacity to influence vascular remodeling. CONCLUSIONS: Our work is the first to identify an impairment of NK cells in PAH and suggests a novel and substantive role for innate immunity in the pathobiology of this disease

Stillbirth and loss: family practices and display

This paper explores how parents respond to their memories of their stillborn child over the years following their loss. When people die after living for several years or more, their family and friends have the residual traces of a life lived as a basis for an identity that may be remembered over a sustained period of time. For the parent of a stillborn child there is no such basis and the claim for a continuing social identity for their son or daughter is precarious. Drawing on interviews with the parents of 22 stillborn children, this paper explores the identity work performed by parents concerned to create a lasting and meaningful identity for their child and to include him or her in their families after death. The paper draws on Finch's (2007) concept of family display and Walter's (1999) thesis that links continue to exist between the living and the dead over a continued period. The paper argues that evidence from the experience of stillbirth suggests that there is scope for development for both theoretical frameworks

Professional perspectives on facilitators and barriers for high quality provision of health, education and social care services to disabled children in England during the COVID-19 pandemic: a qualitative study

This is the final version. Available on open access from BMJ Publishing Group via the DOI in this recordData availability statement: Data are available upon reasonable request.Objectives To understand how health, education and social care services for disabled children changed during the COVID-19 pandemic, what did or did not work well and what the impacts of service changes were on both professionals and families.Design Qualitative study using semistructured interviews.Setting Telephone and video call interviews and focus groups with professionals working in one of five local authority areas in England.Participants 78 health, education and social care professionals working with children in one of five local authority areas in England.Results There was a significant disruption to services and reduced contact with families during the early stages of the pandemic; nevertheless, professionals were able to reflect on innovative ways they interacted with and sought to support and maintain health, education and social care provision to disabled children and their families. As waitlists have substantially increased, this and the longevity of the pandemic were perceived to have had negative consequences for staff health and well-being, the health and psychosocial outcomes of children and young people, and their parent carers.Conclusions Key learning from this study for service recovery and planning for future emergencies is the need to be able to identify disabled children, classify their level of need and risk, assess the impact of loss of services and maintain clear communication across services to meet the needs of disabled children. Finally, services need to work collaboratively with families to develop child-centred care to strengthen resilience during service disruption.Data are available upon reasonable request.National Institute for Health and Care Research (NIHR

Longitudinal Peer Network Data in Higher Education

This chapter employs a longitudinal social network approach to research small group teaching in higher education. Longitudinal social network analyses can provide in-depth understanding of the social dynamics in small groups. Specifically, it is possible to investigate and disentangle the processes by which students make or break social connections with peers and are influenced by them, as well as how those processes relate to group compositions and personal attributes, such as achievement level. With advanced methods for modelling longitudinal social networks, researchers can identify social processes affecting small group teaching and learning

A reassuring presence: An evaluation of Bradford District Hospice at Home service

Within the United Kingdom, a developing role for primary care services in cancer and palliative care has resulted in an increase in palliative home care teams. The provision of professional care in the home setting seeks to provide necessary services and enhanced choice for patients whose preference is to die at home. A mismatch between patient preference for home death and the actual number of people who died at home was identified within Bradford, the locality of this study. In response to this mismatch, and reflecting the policy environment of wishing to enhance community service provision, the four Primary Care Trusts (PCTs) in the city sought to offer support to patients who wished to remain in their own homes through the final stages of a terminal illness. To offer this support they set up a dedicated hospice at home team. This would provide services and support for patients in achieving a dignified, symptom free and peaceful death, allowing families to maximise time spent together. The aim of the study was to evaluate the Bradford hospice at home service from the perspective of carers, nurses and General Practitioners. Postal questionnaires were sent to carers (n = 289), district nurses (n = 508) and GP's (n = 444) using Bradford's hospice at home service. Resulting quantitative data was analysed using the Statical Package for Social Sciences (SPSS) and qualitative data was analysed using grounded theory techniques. The data from carers, district nurses and GPs provide general support for the Bradford hospice at home service. Carers valued highly the opportunity to 'fulfil a promise' to the individual who wished to be cared for at home. District nurses and GPs cited the positive impact of access to specialist expertise. This was a 'reassuring presence' for primary healthcare teams and offered 'relief of carer anxiety' by providing prompt, accessible and sensitive care. Carers and health professionals welcomed the increased possibility of patients being cared for at home. The study identified the need to focus on improving skill levels of staff and on ensuring continuity of care

Granulomas Following Subcutaneous Injection With Aluminum Adjuvant-Containing Products in Sheep

The use of vaccines including aluminum (Al)–based adjuvants is widespread among small ruminants and other animals. They are associated with the appearance of transient injection site nodules corresponding to granulomas. This study aims to characterize the morphology of these granulomas, to understand the role of the Al adjuvant in their genesis, and to establish the presence of the metal in regional lymph nodes. A total of 84 male neutered lambs were selected and divided into 3 treatment groups of 28 animals each: (1) vaccine (containing Al-based adjuvant), (2) adjuvant-only, and (3) control. A total of 19 subcutaneous injections were performed in a time frame of 15 months. Granulomas and regional lymph nodes were evaluated by clinicopathological means. All of the vaccine and 92.3% of the adjuvant-only lambs presented injection-site granulomas; the granulomas were more numerous in the group administered the vaccine. Bacterial culture in granulomas was always negative. Histologically, granulomas in the vaccine group presented a higher degree of severity. Al was specifically identified by lumogallion staining in granulomas and lymph nodes. Al median content was significantly higher (P <.001) in the lymph nodes of the vaccine group (82.65 µg/g) compared with both adjuvant-only (2.53 µg/g) and control groups (0.96 µg/g). Scanning transmission electron microscopy demonstrated aggregates of Al within macrophages in vaccine and adjuvant-only groups. In these two groups, Al-based adjuvants induce persistent, sterile, subcutaneous granulomas with macrophage-driven translocation of Al to regional lymph nodes. Local translocation of Al may induce further accumulation in distant tissues and be related to the appearance of systemic signs