Circulating Neutrophil Extracellular Trap (NET)-forming neutrophils in rheumatoid arthritis exacerbation are majority dual endothelin-1/signal peptide receptor (DEspR)+ subtype.

Neutrophil extracellular traps (NETs) are associated with rheumatoid arthritis pathogenesis and severity. Since homeostatic NET-forming neutrophils [NET+Ns] have beneficial roles in defense against pathogens, their distinction from pro-injury [NET+N] subtypes is important, especially if they are to be therapeutically-targeted. Having identified circulating, pro-injury DEspR+CD11b+ [NET+Ns] in patients with neutrophilic secondary tissue injury, we determined whether DEspR+ [NET+Ns] are present in RA-flares. Whole blood samples of patients with RA-flares on maintenance therapy (n=6), were analyzed by flow cytometry (FCM) and immunofluorescence cytology followed by semi-automated quantitative confocal microscopy (qIFC). We assessed clinical parameters, levels of neutrophils and [NET+Ns], and plasma S100A8/A9. qIFC detected circulating DEspR+CD11b+ neutrophils and [NET+Ns] in RA-flare patients but not healthy controls. DEspR+ [NET+Ns] were positive for citrullinated histone H3 (citH3+), extruded DNA, decondensed but recognizable polymorphic nuclei, and [NET+N] doublet-interactions in mostly non-ruptured NET-forming neutrophils. Circulating DNA+/DEspR+/CD11b+/citH3+ microvesicles (netMVs) were observed. FCM detected increased %DEspR+CD11b+ neutrophils and DEspR+ cell-cell doublets whose levels trended with DAS28 scores, as did plasma S100A8/A9 levels. This study identifies circulating DEspR+/CD11b+ neutrophils and [NET+Ns] in RA-flare patients on maintenance therapy. Detection of circulating DEspR+citH3+ [NET+Ns] and netMVs indicate a systemic neutrophilic source of citH3-antigen concordant with multi-joint RA pathogenesis. Increased S100A8/A9 alarmin levels are associated with cell injury and released upon NET-formation. As a ligand for TLR4, S100A8/A9 forms a positive feedback loop for TLR4-induced DEspR+ neutrophils. These data identify DEspR+ neutrophils and [NET+Ns] in RA pathogenesis as a potential biomarker and/or therapeutic target.

Developing a rural paediatrician workforce: Using social network analysis to examine influence on reasons to go rural.

AIM: This pilot study examines how rural and remote junior doctors' career decisions are influenced by collegial relationships within the discipline of general paediatrics. METHODS: Social network analysis (SNA) was undertaken by structured interviews with 10 paediatricians working in regional towns in Western Australia. UNICET software was used to determine the interactions between individual networks to look for overlap and common influencers. RESULTS: Ten rural paediatricians were interviewed. An individual was found to have key measures of centrality at the core of the entire social network of rural general paediatricians. This included a high degree of 'betweenness' (connections within social networks), and a high broker index (connections between separate areas of a network or between networks) demonstrated by that person combining three disconnected networks into a single coherent network. This central individual was a recently appointed consultant with links to senior paediatricians, peers and junior trainees, and may be instrumental in recruitment and retention in the rural paediatric workforce. CONCLUSION: Improving understanding of the impact of social networks, and decision-making processes that influence rural career choices, can inform innovative solutions to develop sustainable strategies for recruiting and retaining the rural paediatric workforce. Applying this model on a larger scale may provide more data to support evidence-based programmes that enable this within the Australian context.

Scholarly literature on nurses and pharmacogenomics: A scoping review.

BACKGROUND: Pharmacogenomics is the bioscience investigating how genes affect medication responses. Nurses are instrumental in medication safety. Pharmacogenomics is slowly being integrated into healthcare, and knowledge and understanding of it is now pertinent to nursing practice. PURPOSE: This paper aims to map the scholarly literature on pharmacogenomics in relation to nurses. METHODS: A scoping review was conducted in four databases: CINAHL, Embase (Ovid), ProQuest Health and Medicine and PubMed using the search terms pharmacogenomic*, pharmacogenetic*, PGx*, and nurs*, resulting in 263 articles of which 77 articles met the inclusion criteria. FINDINGS: Most articles (85 %, n = 65) were non-empirical and 12 presented empirical data (15 %, n = 12). The articles were USA-centric (81 %, n = 62) and represented a broad range of nursing specialties. CONCLUSION: The majority of scholarly literature on nurses and pharmacogenomics is narrative reviews. Further empirical research is warranted to investigate nurses' current knowledge levels and potential involvement with pharmacogenomics in clinical practice.

New insights into healthy ageing, inflammageing and frailty using metabolomics.

Human ageing is a normal process and does not necessarily result in the development of frailty. A mix of genetic, environmental, dietary, and lifestyle factors can have an impact on ageing, and whether an individual develops frailty. Frailty is defined as the loss of physiological reserve both at the physical and cellular levels, where systemic processes such as oxidative stress and inflammation contribute to physical decline. The newest "omics" technology and systems biology discipline, metabolomics, enables thorough characterisation of small-molecule metabolites in biological systems at a particular time and condition. In a biological system, metabolites-cellular intermediate products of metabolic reactions-reflect the system's final response to genomic, transcriptomic, proteomic, epigenetic, or environmental alterations. As a relatively newer technique to characterise metabolites and biomarkers in ageing and illness, metabolomics has gained popularity and has a wide range of applications. We will give a comprehensive summary of what is currently known about metabolomics in studies of ageing, with a focus on biomarkers for frailty. Metabolites related to amino acids, lipids, carbohydrates, and redox metabolism may function as biomarkers of ageing and/or frailty development, based on data obtained from human studies. However, there is a complexity that underpins biological ageing, due to both genetic and environmental factors that play a role in orchestrating the ageing process. Therefore, there is a critical need to identify pathways that contribute to functional decline in people with frailty.

Nursing students' experience of bullying and/or harassment during clinical placement.

PROBLEM OR BACKGROUND: Bullying is a recognised problem in nursing. Nursing students are particularly vulnerable. Bullying and harassment of nursing students can be detrimental to both students and recipients of care. AIM: This study aims to identify the incidence and nature of bullying and/or harassment experienced by nursing students in Sri Lanka. METHODS: A cross-sectional survey consisting of eight demographic questions and 15 items specific to the experience of bullying and harassment was administered to nursing students online. FINDINGS: A total of 656 students from 26 nursing education institutions in Sri Lanka participated. The majority were female with a mean age of 24.4 years. More than a quarter of respondents reported that they had experienced bullying and/or harassment while on clinical placement, with a further 16.7 % being unsure. Most bullying or harassment (55 %) occurred in hospitals with 29 % experienced in community settings. Registered nurses, including nurse managers and clinical facilitators were the most common perpetrators. Verbal abuse was the most frequent type of behaviour reported. DISCUSSION: These findings support existing literature that indicates that bullying of nursing students is an international phenomenon. The context of this study provides clues as to how culture may influence the problem. There is a need to better understand bullying and harassment in the environments in which it occurs, in order to identify strategies that can bridge cultures and settings. CONCLUSION: The incidence of bullying and harassment of nursing students in Sri Lanka is concerning. Further research is needed to identify and evaluate targeted strategies to help prevent negative outcomes in all nursing contexts.

A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.

Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 - have been identified in humans with congenital malformations defined as congenital NAD deficiency disorder (CNDD). Here, we identified 13 further individuals with biallelic NADSYN1 variants predicted to be damaging, and phenotypes ranging from multiple severe malformations to the complete absence of malformation. Enzymatic assessment of variant deleteriousness in vitro revealed protein domain-specific perturbation, complemented by protein structure modeling in silico. We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes. While for Nadsyn1+/- mothers, any B3 vitamer was suitable to raise NAD, preventing embryo loss and malformation, Nadsyn1-/- mothers required supplementation with amidated NAD precursors (nicotinamide or nicotinamide mononucleotide) bypassing their metabolic block. The circulatory NAD metabolome in mice and humans before and after NAD precursor supplementation revealed a consistent metabolic signature with utility for patient identification. Our data collectively improve clinical diagnostics of NADSYN1-dependent CNDD, provide guidance for the therapeutic prevention of CNDD, and suggest an ongoing need to maintain NAD levels via amidated NAD precursor supplementation after birth.

miRNA-132-5p mediates a negative feedback regulation of IL-8 secretion through S100A8/A9 downregulation in neutrophil-like HL-60 cells.

Background: Neutrophils are an important source of pro-inflammatory and immunomodulatory cytokines. This makes neutrophils efficient drivers of interactions with immune and non-immune cells to maintain homeostasis and modulate the inflammatory process by notably regulating the release of cytokines. Ca2+-dependent regulatory mechanism encompassing cytokine secretion by neutrophils are not still identified. In this context, we propose to define new insights on the role of Ca2+-binding proteins S100A8/A9 and on the regulatory role of miRNA-132-5p, which was identified as a regulator of S100A8/A9 expression, on IL-8 secretion. Methods: Differentiated HL-60 cells, a human promyelocytic leukemia cell line that can be induced to differentiate into neutrophil-like cells, were used as a model of human neutrophils and treated with N- formyl-methionyl-leucyl-phenylalanine (fMLF), a bacterial peptide that activates neutrophils. shRNA knockdown was used to define the role of selected targets (S100A8/A9 and miRNA-132-5p) on IL-8 secretion. Results and discussion: Different types of cytokines engage different signaling pathways in the secretion process. IL-8 release is tightly regulated by Ca2+ binding proteins S100A8/A9. miRNA-132-5p is up-regulated over time upon fMLF stimulation and decreases S100A8/A9 expression and IL-8 secretion. Conclusion: These findings reveal a novel regulatory loop involving S100A8/A9 and miRNA-132-5p that modulates IL-8 secretion by neutrophils in inflammatory conditions. This loop could be a potential target for therapeutic intervention in inflammatory diseases.