Search

Purpose-The purpose of this paper is to report upon the design, implementation and findings of a research study investigating the perceptions of electronic library resources within the UK further education sector. While such resources are widely available to the sector, very little qualitative investigation has been done as to its impact upon teaching and learning and how it is viewed by those who have access to it.Design/methodology/approach-The research uses a case study in which staff and students at three separate further education colleges are encouraged to explore and share their experiences of using electronic library resources. This is achieved through structured interviews with teaching staff and focused student discussion groups. Extensive reference to relevant literature is also employed as a method.Findings-The findings of the research are entirely qualitative, and are reported through a sequence of annotated quotations, which reveal personal experiences and perceptions of using electronic library resources and the influence and impact they have had on teaching and learning activity.Research limitations/implications-The findings are limited to one case study, using three different colleges in the Merseyside area of the UK.Originality/value-The qualitative data provided through the research provides insight into electronic resource use within a cross section of the further education sector. It is therefore of use to those studying the impact of electronic resources, particularly within the further education sector. The research provides evidence which can be used to inform future e-resources policy. The findings can also be used to shape e-resources guidelines for practitioners in the further education sector. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Elderly patients who suffer trauma have a higher mortality and use disproportionately more trauma resources than younger patients. To compare these 2 groups and determine the outcomes and characteristics of elderly patients, we reviewed patients in these 2 groups admitted and treated in our tertiary care provincial trauma centre. METHODS: From the provincial trauma registry we selected a cohort of 40 geriatric patients (group 1) (> or = 65 yr of age) with an ISS of 16 or more who were admitted to and spent time in our trauma service for more than 48 hours and compared them with a similar randomly selected cohort of 44 patients (group 2) aged 20-30 years. Family physicians were contacted for follow-up of these patients 2 years after discharge. We considered length of hospital stay, complications, disposition of the patients and use of consultation services. RESULTS: Patients in group 1 had a mean age of 72.1 years (range from 65-98 yr) and a mean ISS of 27.3 (range from 17-50). Patients in group 2 had a mean age of 26.3 years (range from 22-29 yr) and a mean ISS of 26.3 (range from 17-54). Hospital stay was significantly longer in the group 1: 34.5 days (95% confidence interval [CI]: 24-44 d) versus 21.6 days (95% CI: 15-28 d). More elderly patients experienced complications (35 v. 13, p < 0.001) and required medical consultations (35 v. 26, p < 0.001). In-hospital death rates were 8% (3 of 40) and 4% (2 of 44) respectively (p = 0.3). Fewer geriatric patients could be discharged home (35% [14 of 40] v. 27% [22 of 44], p = 0.056) or to rehabilitation facilities (28% [11 of 40] v. 34% [15 of 44], p = 0.3). Five geriatric patients were discharged to nursing homes (p = 0.007). Of the geriatric patients discharged to rehabilitation facilities or home, 75% were independent 2 years after discharge. CONCLUSIONS: Aggressive care for geriatric trauma patients is warranted, and resources should be directed toward rehabilitation. Based on our findings, we expect that creating a directed care pathway for these patients, targetting complications and earlier discharge, will further improve their outcomes. [ABSTRACT FROM AUTHOR]

Background: Crohn's disease (CD) is a major form of inflammatory bowel disease (IBD) which has relapsing and remitting symptoms. Better ways to detect and monitor active disease are required for early diagnosis and optimal outcomes. We assessed fecal myeloperoxidase (fMPO), a neutrophil-derived enzyme that produces hypochlorous acid, as a marker of disease activity in children with CD., Methods: This observational study assessed myeloperoxidase (MPO) levels in fecal samples from children aged <17 years with CD (51 with active or 42 inactive disease) measured by enzyme-linked immunosorbent assay (ELISA) and compared to controls (35 healthy siblings and 15 unrelated well children). Results were correlated with fecal calprotectin, serum C-reactive protein, urinary glutathione sulfonamide (a biomarker of hypochlorous acid), and disease activity scores. Differences between groups were assessed by analysis of variance. Receiver-operating-characteristic curves were used to assess how biomarkers predicted disease and disease activity., Results: Fecal myeloperoxidase activity and fMPO protein correlated with fecal calprotectin (r = 0.78, P < .0001, and r = 0.81, P < .0001, respectively). Fecal myeloperoxidase activity and protein levels were significantly higher (P ≤ .0001) in individuals with active disease compared to healthy sibling controls, unrelated well children, and those with inactive disease. A 9.7 µg/g fMPO protein cutoff distinguished inactive from active disease (sensitivity = 75%, specificity = 76%). Urinary GSA was elevated in children with active disease (P < .0001) and correlated with fMPO protein (r = 0.43, P = .0002) in a subset of 72 children with IBD and controls., Conclusions: Fecal myeloperoxidase may be superior to fCal at reflecting disease severity in children with CD and produces the damaging oxidant hypochlorous acid during active inflammation., (© 2024 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background: Over the past decade, cancer immunotherapies have revolutionized the treatment of melanoma; however, responses vary across patient populations. Recently, baseline tumor size has been identified as an independent prognostic factor for overall survival in patients with melanoma receiving immune checkpoint inhibitors. MG1 is a novel oncolytic agent with broad tumor tropism that has recently entered early-phase clinical trials. The aim of this study was to characterize T-cell responses in human and mouse melanoma models following MG1 treatment and to establish if features of the tumor immune microenvironment (TIME) at two distinct tumor burdens would impact the efficacy of oncolytic virotherapy., Methods: Human three-dimensional in vitro priming assays were performed to measure antitumor and antiviral T-cell responses following MG1 infection. T-cell receptor (TCR) sequencing, T2 killing assay, and peptide recall assays were used to assess the evolution of the TCR repertoire, and measure specific T-cell responses, respectively. In vivo, subcutaneous 4434 melanomas were characterized using RNA sequencing, immunohistochemistry, and flow cytometry. The effectiveness of intratumoral MG1 was assessed in advancing 4434 tumors and the generation of antitumor and antiviral T cells measured by splenocyte recall assays. Finally, combination MG1 and programmed cell death protein-1 antibody (αPD-1) therapy was investigated in advanced 4434 tumors., Results: MG1 effectively supported priming of functional cytotoxic T cells (CTLs) against tumor-associated antigens as well as virus-derived peptides, as assessed using peptide recall and T2 killing assays, respectively. TCR sequencing revealed that MG1-primed CTL comprised larger clusters of similar CDR3 amino acid sequences compared with controls. In vivo testing of MG1 demonstrated that MG1 monotherapy was highly effective at treating early disease, resulting in 90% cures; however, the efficacy of MG1 reduced as the disease burden (local tumor size) increased, and the addition of αPD-1 was required to overcome resistance in more advanced disease. Differential gene expression profiles revealed that increased tumor burden was associated with an immunologically colder TIME. Furthermore, analysis of TCR signaling in advancing tumors demonstrated a different dynamic of TCR engagement compared with smaller tumors, in particular a shift in antigen recognition by CD4+ cells, from conventional to regulatory subsets., Conclusion: Addition of αPD-1 to MG1 is required to overcome viral therapy resistance in immunologically 'colder' more advanced melanoma, highlighting the importance of tumor burden to different types of immunotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Orthopedic surgical patients who use nicotine are at a high risk for postoperative complications including infection, respiratory failure, cardiac arrest, and death. Periprosthetic joint infections may result from nicotine-induced immunosuppression and microvascular changes, increasing perioperative morbidity and mortality. These complications result in higher health care costs, increased length of stay, and loss of reimbursement due to readmissions. Four weeks of nicotine cessation prior to arthroplasty decreases these risks; however, perioperative teams may lack reliable nicotine screening and cessation education methods. This project identified inconsistencies in nicotine screening and cessation counseling in the preoperative setting, which contributed to surgery cancellations among patients who required to demonstrate nicotine cessation preoperatively. Standardization of preoperative nicotine screening and patient cessation education resources can improve the identification of orthopedic patients who use nicotine and provide concrete, proven methods of achieving nicotine cessation prior to elective primary arthroplasty. Investment from perioperative staff is essential to ensure success., Competing Interests: All authors declare that they have no conflicts of interest., (Copyright © 2024 by National Association of Orthopaedic Nurses.)

Aims: To explore how psychological well-being is maintained by healthcare professionals (HCPs) employed in a cancer setting during the COVID-19 pandemic., Design: A qualitative design using diaries and interviews to collect data was used to gain insights into how HCPs managed their well-being during the pandemic., Methods: Interpretative Phenomenological Analysis (IPA) was used to analyse diaries and interviews completed by 66 HCPs during the second pandemic lockdown period (December 2020-April 2021). A total of 102 HCPs were recruited, drawn from five groups: nursing staff, radiographers, medical staff, allied health professionals (AHPs) (non-radiographers) and support staff., Results: The majority of participants adjusted to the challenges of the pandemic using positive coping strategies, although difficult days required the mobilization of additional resources. Emotion management was regulated through peer relationships, professional roles and the workplace, sustained through communities of practice involving knowledge exchange, shared goals and social interactions. Maintaining high-quality patient care was a source of job satisfaction, providing a route through which positive emotions could be channelled; however, it was juxtaposed with threats to well-being from busy workloads and variable organizational responsiveness. Work routines provided a platform for well-being, underpinned by the sharing of problems and solutions within peer networks., Conclusion: This study has highlighted the dynamic nature of well-being amongst HCPs during the pandemic. Well-being interventions should build on the preferred coping strategies of HCPs, focusing on the way individuals coalesce in groups to learn from and support one another., Impact: HCPs may experience different psychological responses when exposed to a pandemic situation. This study identifies the strategies used by HCPs to maintain positive psychological well-being within professional roles, whilst adjusting to emerging well-being threats. Key components of HCP's well-being are addressed, which are relevant to clinical practice and the broader healthcare workforce., Patient or Public Contribution: Research team members included public representatives who contributed to the development, methods, data collection and analysis of the study. They supported the development of the Research Assistant by providing mock interview skills training., (© 2023 John Wiley & Sons Ltd.)

Although chitinase-3-like-1 (CHI3L1), predominately produced by epithelial cells and macrophages, is relevant to pulmonary disease in cystic fibrosis (CF), fecal levels have not yet been assessed in children with CF. Fecal CHI3L1 was measured with a commercial immunoassay using fecal samples provided by children with CF and healthy control (HC) children. Higher median (interquartile range) fecal CHI3L1 levels were seen in the 52 children with CF than in the 35 controls: 15.97 (3.34-50.53) ng/g versus 2.93 (2.13-9.27) ng/g ( P = 0.001). Fecal CHI3LI did not differ according to sex. In the children with CF, fecal CHI3L1 levels did not correlate with growth parameters nor were the levels affected by pancreatic insufficiency. Children with CF had higher fecal CHI3L1 levels, suggesting underlying gut inflammation. Further work is required to confirm the current findings and to ascertain the longer-term significance of elevated CHI3L1., Competing Interests: C.Y.O. has consulted and served on advisory boards for Vertex Pharmaceuticals (unrelated to this manuscript). A.S.D. has served on advisory boards for Janssen, Abbvie, and Nestle (all unrelated to this manuscript). The remaining authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Combination herpes simplex virus (HSV) oncolytic virotherapy and BRAF inhibitors (BRAFi) represent promising immunogenic treatments for BRAF mutant melanoma, but an improved understanding of the immunobiology of combinations is needed to improve on the benefit of immune checkpoint inhibitors (ICI)., Methods: Using a BRAF V600E -driven murine melanoma model, we tested the immunogenicity of HSV/BRAFi in immunocompetent C57BL mice. In addition to standard FACS analysis, we used the 'Timer of Cell Kinetics and Activity' system, which can analyze the temporal dynamics of different T cell subsets. This immune data was used to inform the selection of ICI for triple combination therapy, the effects of which were then further characterized using transcriptomics., Results: Adding BRAFi treatment to HSV improved anti-tumor effects in vivo but not in vitro. Immune characterization showed HSV or dual therapy led to fewer intratumoral Treg, although with a more activated phenotype, together with more effector CD8 +T cells. Tocky analysis further showed that HSV/BRAFi dual treatment reduced the Tocky signal (reflecting engagement with cognate antigen), in both Treg and conventional subsets of CD4+, but not in CD8 +cells. However, a higher percentage of Treg than of conventional CD4 +maintained frequent engagement with antigens on treatment, reflecting a predominance of suppressive over effector function within the CD4 +compartment. The only T cell subset which correlated with a reduction in tumor growth was within Tocky signal positive conventional CD4+, supporting their therapeutic role. Targeting CD25 high, antigen-engaged Treg with a depleting anti-CD25 ICI, achieved complete cures in 100% of mice with triple therapy. Transcriptomic analysis confirmed reduction in Foxp3 on addition of anti-CD25 to HSV/BRAFi, as well as increases in expression of genes reflecting interferon signaling and cytotoxic activity., Conclusions: Combination HSV/BRAFi is an immunogenic therapy for BRAF mutant melanoma, but cannot fully control tumors. Dual therapy results in changes in T cell dynamics within tumors, with relatively maintained antigen signaling in Treg compared with conv CD4+. Antigen-engaged CD4 +effectors correlate with tumor growth control, and depletion of Treg by addition of an anti-CD25 ICI, releasing suppression of conventional CD4 +effectors by Treg, enhances survival and activates immune signaling within tumors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Microscopic ulceration is an independent predictor of melanoma death. Here, we used systems biology to query the role of host and tumour-specific processes in defining the phenotype. Albumin level as a measure of systemic inflammation was predictive of fewer tumour-infiltrating lymphocytes and poorer survival in the Leeds Melanoma Cohort. Ulcerated melanomas were thicker and more mitotically active (with corresponding transcriptomic upregulated cell cycle pathways). Sequencing identified tumoural p53 and APC mutations, and TUBB2B amplification as associated with the phenotype. Ulcerated tumours had perturbed expression of cytokine genes, consistent with protumourigenic inflammation and histological and transcriptomic evidence for reduced adaptive immune cell infiltration. Pathway/network analysis of multiomic data using neural networks highlighted a role for the β-catenin pathway in the ulceration, linking genomic changes in the tumour to immunosuppression and cell proliferation. In summary, the data suggest that ulceration is in part associated with genomic changes but that host factors also predict melanoma death with evidence of reduced immune responses to the tumour., (© 2021 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

Peer mentors may offer distinctive forms of support to people with advanced cancer. Whilst peer mentor programmes are known, little is understood about recruiting and training peer mentors to support those with advanced cancer. The purpose of this study is to determine the feasibility of recruiting and training peer mentors for a novel peer mentor intervention to promote well-being in people with advanced cancer. Feasibility study testing proactive introduction to a trained peer mentor for 12 weeks in the context of a randomized controlled two-arm trial and nested qualitative process evaluation was used. Peer mentors have/had cancer, recruited via an open call. Two-day training included a new bespoke module on coping with cancer. Descriptive recruitment and training data were captured, supplemented by qualitative interviews, analysed thematically. Forty-eight people expressed interest, mostly female (69%), with breast cancer (32%), and recruited via social media (49%). Twelve people completed training, with attrition often due to availability or mentors' own health; many had advanced cancer themselves. They wanted to 'give something back', but also formed supportive bonds with fellow mentors. It is feasible to recruit and train people with lived experience of cancer to be peer mentors, but those with particular characteristics may predominate. Broad social media based recruitment may have merit in widening the pool of potential peer mentors., (© 2020. The Author(s).)

Background: Tendons heal by fibrotic repair, increasing the likelihood of reinjury. Animal tendon injury and overuse models have identified transforming growth factor beta (TGF-β) and bone morphogenetic proteins (BMPs) as growth factors actively involved in the development of fibrosis, by mediating extracellular matrix synthesis and cell differentiation., Purpose: To understand how TGF-β and BMPs contribute to fibrotic processes using tendon-derived cells isolated from healthy and diseased human tendons., Study Design: Controlled laboratory study., Methods: Tendon-derived cells were isolated from patients with a chronic rotator cuff tendon tear (large to massive, diseased) and healthy hamstring tendons of patients undergoing anterior cruciate ligament repair. Isolated cells were incubated with TGF-β1 (10 ng/mL) or BMP-2 (100 ng/mL) for 3 days. Gene expression was measured by real-time quantitative polymerase chain reaction. Cell signaling pathway activation was determined by Western blotting., Results: TGF-β1 treatment induced ACAN mRNA expression in both cell types but less in the diseased compared with healthy cells ( P < .05). BMP-2 treatment induced BGN mRNA expression in healthy but not diseased cells ( P < .01). In the diseased cells, TGF-β1 treatment induced increased ACTA2 mRNA expression ( P < .01) and increased small mothers against decapentaplegic (SMAD) signaling ( P < .05) compared with those of healthy cells. Moreover, BMP-2 treatment induced ACTA2 mRNA expression in the diseased cells only ( P < .05)., Conclusion: Diseased tendon-derived cells show reduced expression of the proteoglycans aggrecan and biglycan in response to TGF-β1 and BMP-2 treatments. These same treatments induced enhanced fibrotic differentiation and canonical SMAD cell signaling in diseased compared with healthy cells., Clinical Relevance: Findings from this study suggest that diseased tendon-derived cells respond differently than healthy cells in the presence of TGF-β1 and BMP-2. The altered responses of diseased cells may influence fibrotic repair processes during tendon healing.

Tendinopathy accounts for over 30% of primary care consultations and represents a growing healthcare challenge in an active and increasingly ageing population. Recognising critical cells involved in tendinopathy is essential in developing therapeutics to meet this challenge. Tendon cells are heterogenous and sparsely distributed in a dense collagen matrix; limiting previous methods to investigate cell characteristics ex vivo. We applied next generation CITE-sequencing; combining surface proteomics with in-depth, unbiased gene expression analysis of > 6400 single cells ex vivo from 11 chronically tendinopathic and 8 healthy human tendons. Immunohistochemistry validated the single cell findings. For the first time we show that human tendon harbours at least five distinct COL1A1/2 expressing tenocyte populations in addition to endothelial cells, T-cells, and monocytes. These consist of KRT7/SCX+ cells expressing microfibril associated genes, PTX3+ cells co-expressing high levels of pro-inflammatory markers, APOD+ fibro-adipogenic progenitors, TPPP3/PRG4+ chondrogenic cells, and ITGA7+ smooth muscle-mesenchymal cells. Surface proteomic analysis identified markers by which these sub-classes could be isolated and targeted in future. Chronic tendinopathy was associated with increased expression of pro-inflammatory markers PTX3, CXCL1, CXCL6, CXCL8, and PDPN by microfibril associated tenocytes. Diseased endothelium had increased expression of chemokine and alarmin genes including IL33.

Background: Advanced cancer affects people's lives, often causing stress, anxiety and depression. Peer mentor interventions are used to address psychosocial concerns, but their outcomes and effect are not known. Our objective was to determine the feasibility of delivering and investigating a novel peer mentor intervention to promote and maintain psychological wellbeing in people with advanced cancer., Methods: A mixed methods design incorporating a two-armed controlled trial (random allocation ratio 1:1) of a proactive peer mentor intervention plus usual care, vs. usual care alone, and a qualitative process evaluation. Peer mentors were recruited, trained, and matched with people with advanced cancer. Quantitative data assessed quality of life, coping styles, depression, social support and use of healthcare and other supports. Qualitative interviews probed experiences of the study and intervention., Results: Peer mentor training and numbers (n = 12) met feasibility targets. Patient participants (n = 12, from 181 eligible who received an information pack) were not recruited to feasibility targets. Those who entered the study demonstrated that intervention delivery and data collection were feasible. Outcome data must be treated with extreme caution due to small numbers, but indicate that the intervention may have a positive effect on quality of life., Conclusions: Peer mentor interventions are worthy of further study and researchers can learn from these feasibility data in planning participant recruitment and data collection strategies. Pragmatic trials, where the effectiveness of an intervention is tested in real-world routine practice, may be most appropriate. Peer mentor interventions may have merit in enabling survivors with advanced cancer cope with their disease., Trial Registration: The trial was prospectively registered 13.6.2016: ISRCTN10276684 .

Purpose: In the UK, there are over 40,000 childhood cancer survivors (CCS); this figure grows approximately 1300 annually. Two-thirds are at risk of developing serious disabling or life-threatening conditions due to adverse late effects of the cancer or treatment received in childhood. Life-long, follow-up care for the surveillance and management of late effects is recommended. This study explored CCS' views and experiences of long-term follow-up (LTFU) care within a cancer centre., Methods: Paper questionnaires (n = 113) and qualitative interviews (n = 13)., Results: The majority (n = 83, 80%) of CCS reported being satisfied with their LTFU care and felt that it was important to attend long-term survivorship follow-up (n = 97, 86%). However, some were not well informed about their cancer treatment history, purpose for attending the clinic or the potential for late effects. Barriers associated with LTFU included; provision of information, lack of interpersonal relationships, practical and logistic challenges., Conclusions: Barriers identified can be addressed through strategies including provision of verbal and written information and care plans to increase CCS' knowledge of their cancer history, risk of late effects and the purpose of LTFU care, both at transition and throughout their survivorship journey; patient-centred services that enhance patient choice and flexibility of access to multiple specialities; and use of risk stratified pathways to encourage supported self-management based on cancer type, co-morbidity, and level of professional involvement required. Improving regular provision of information at critical time-points, and exploring a flexible, patient-centred delivery of LFTU care based on risk, could increase attendance and self-management in CCS., Competing Interests: Declaration of competing interest The authors declare there are no conflicts of interest for this study., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Diseased and injured tendons develop fibrosis, driven by factors including TGF-β, BMPs and CTGF. IL-1β and its signal transducer Erk1/2 are known to regulate TGF-β expression in animal tendons. We utilised tissues and cells isolated from patients with shoulder tendon tears and tendons of healthy volunteers to advance understanding of how inflammation induces fibrosis in diseased human tendons. ERK1/2 expression was reduced in torn (diseased) compared to healthy patient tendon tissues. We next investigated the fibrotic responses of tendon-derived cells isolated from healthy and diseased human tendon tissues in an inflammatory milieu. IL-1β treatment induced profound ERK1/2 signalling, TGFB1 and BMP2 mRNA expression in diseased compared to healthy tendon-derived cells. In the diseased cells, the ERK1/2 inhibitor (PD98059) completely blocked the IL-1β-induced TGFB1 and partially reduced BMP2 mRNA expression. Conversely, the same treatment of healthy cells did not modulate IL-1β-induced TGFB1 or BMP2 mRNA expression. ERK1/2 inhibition did not attenuate IL-1β-induced CTGF mRNA expression in healthy or diseased tendon cells. These findings highlight differences between ERK1/2 signalling pathway activation and expression of TGF-β1 and BMP-2 between healthy and diseased tendon tissues and cells, advancing understanding of inflammation induced fibrosis during the development of human tendon disease and subsequent repair.

Tendon stromal cells isolated from patients with chronic shoulder rotator cuff tendon tears have dysregulated resolution responses. Current therapies do not address the biological processes concerned with persistent tendon inflammation; therefore, new therapeutic approaches that target tendon stromal cells are required. We examined whether two specialized proresolving mediators (SPMs), lipoxin B4 (LXB4) and resolvin E1 (RvE1), modulate the bioactive lipid mediator profiles of IL-1β-stimulated tendon cells derived from patients with shoulder tendon tears and healthy volunteers. We also examined whether LXB4 or RvE1 treatments moderated the proinflammatory phenotype of tendon tear stromal cells. Incubation of IL-1β-treated patient-derived tendon cells in LXB4 or RvE1 up-regulated concentrations of SPMs. RvE1 treatment of diseased tendon stromal cells increased 15-epi-LXB4 and regulated postaglandin F2α. LXB4 or RvE1 also induced expression of the SPM biosynthetic enzymes 12-lipoxygenase and 15-lipoxygenase. RvE1 treatment up-regulated the proresolving receptor human resolvin E1 compared with vehicle-treated cells. Incubation in LXB4 or RvE1 moderated the proinflammatory phenotype of patient-derived tendon tear cells, regulating markers of tendon inflammation, including podoplanin, CD90, phosphorylated signal transducer and activator of transcription 1, and IL-6. LXB4 and RvE1 counterregulate inflammatory processes in tendon stromal cells, supporting the role of these molecules as potential therapeutics to resolve tendon inflammation., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Resolution of inflammation is poorly understood in Achilles tendon disorders. Herein, we investigated the bioactive lipid mediator profiles of tendon-derived stromal cells isolated from patients with Achilles tendinopathy (AT) or Achilles rupture (AR) under baseline and IL-1β-stimulated conditions. We also determined whether incubating these cells with 2 of the mediators produced by tendon-derived stromal cells, 15-epi-Lipoxin A 4 (15-epi-LXA 4 ) or maresin (MaR)-1, moderated their proinflammatory phenotype. Under baseline conditions, AT cells showed concurrent increased levels of proinflammatory eicosanoids and proresolving mediators compared with AR cells. IL-1β treatment induced profound prostaglandin E 2 release in AR compared with AT cells. Incubation of IL-1β treated AT and AR tendon-derived stromal cells in 15-epi-LXA 4 or MaR1 reduced proinflammatory eicosanoids and potentiated the release of proresolving mediators. These mediators also induced specialized proresolving mediator (SPM) biosynthetic enzymes arachidonate lipoxygenase (ALOX) 12 and ALOX15 and up-regulated the proresolving receptor ALX compared with vehicle-treated cells. Incubation in 15-epi-LXA 4 or MaR1 also moderated the proinflammatory phenotype of AT and AR cells, regulating podoplanin, CD90, signal transducer and activator of transcription (STAT)-1, IL-6, IFN regulatory factor (IRF) 5, and TLR4 and suppressed c-Jun N-terminal kinase 1/2/3, Lyn, STAT-3, and STAT-6 phosphokinase signaling. In summary, we identify proresolving mediators that are active in AT and AR and propose SPMs, including 15-epi-LXA 4 or MaR1, as a potential strategy to counterregulate inflammatory processes in these cells.-Dakin, S. G., Colas, R. A., Newton, J., Gwilym, S., Jones, N., Reid, H. A. B., Wood, S., Appleton, L., Wheway, K., Watkins, B., Dalli, J., Carr, A. J. 15-Epi-LXA 4 and MaR1 counter inflammation in stromal cells from patients with Achilles tendinopathy and rupture.

Genetic polymorphism (rs1800693) of TNFRSF1A (type 1 tumour necrosis factor receptor) encodes a potentially anti-inflammatory soluble truncated form of the p55 receptor, which is associated with predisposition to multiple sclerosis but protection against ankylosing spondylitis (AS). We analysed 2917 UK Caucasian cases by linear and logistic regression for associations of rs1800693 with disease severity assessed by the Bath Ankylosing Spondylitis measures of disease activity and function (BASDAI, BAS-G and BASFI) and/or responses to anti-TNF therapy. In contrast to predictions, rs1800693 GG homozygotes actually had significantly worse BASDAI (mean 4.2, 95% CI: 4-4.5) than AA homozygotes (mean 3.8, 95% CI: 3.7-4) in both the unadjusted (difference = 0.4, p = 0.006) and adjusted analyses (difference = 0.2-0.5, p = 0.002-0.04 depending on the adjustment model). We found no evidence that rs1900693 predicted functional status (BASFI) or global disease scores (BAS-G), and it exerted no influence on either the intention to treat with or efficacy of anti-TNF treatment.

Background: Vitamin D deficiency is highly prevalent in children with inflammatory bowel disease (IBD). This may contribute to an increased risk of poor bone health and may also influence the course of disease. An optimal treatment strategy of vitamin D therapy in children with IBD has not yet been established., Aim: To analyse the published intervention studies of vitamin D therapy in children with IBD., Methods: A systematic review was conducted of clinical studies involving children with IBD (including Crohn disease or ulcerative colitis) who had received vitamin D therapy. Studies up to March 31 st 2018 were identified through MEDLINE, PubMed, EMBASE and the Cochrane Library. Search terms included synonyms of the following terms: vitamin D, paediatric, supplementation, IBD. References of included articles based on abstract were searched for other relevant articles. All relevant articles were accessed and reviewed in full text. Studies fitting the set criteria were included and the remainder were excluded., Results: Two hundred and seventy-seven discrete articles were identified. Following assessment of these articles included in the initial search and application of inclusion and exclusion criteria, ten published studies were included in this review. The included studies showed a heterogeneity in study design, inclusion and exclusion criteria, baseline demographics and treatment strategies. Treatment regimens differed in length, supplemented form of vitamin D and factors based upon which dosage was adjusted. Each of the reports included in this review concluded their vitamin D regimens to be safe and well-tolerated. Few of the included studies reported secondary outcomes on the efficacy of vitamin D treatment upon the clinical course of disease or markers of inflammation. The majority of included trials were not sufficient in raising serum vitamin D levels to an adequate level (30 ng/mL) in children with IBD with vitamin D deficiency., Conclusion: The included trials featured diverse treatment regimens that were predominantly insufficient in correcting vitamin D deficiency or maintaining adequate levels in children with IBD. Better treatment regimens are required for the management of vitamin D deficiency in children with IBD., Competing Interests: Conflict-of-interest statement: All authors have no conflicts of interest to report.

Aims: To explore how cancer services may positively promote and support patients' well-being throughout treatment. Specifically to identify components of care that are important to patients and meet their needs., Background: Patients commonly experience stress and uncertainty during their cancer journey which can have a negative impact on their psychological health and quality of life. Comparatively, little is known about how patients may experience positive well-being during their treatment experience., Design: Qualitative study using semi-structured interviews., Methods: Interviews were conducted between 2014 - 2015 with a purposive sample of 30 individuals who were at the beginning, middle or end of treatment for lung, colorectal and head and neck cancer. The majority were outpatients and receiving radiotherapy, chemotherapy or a combination of these. The recordings were analysed using thematic analysis., Results: Patients may obtain a range of positive health benefits derived from contact with staff, patients and public. Positive emotional gains were based on "being in safe hands" and part of the collective effort to eradicate cancer. This appeared to assist patients achieve favourable treatment responses, however, a range of factors encouraged and hindered them to express concerns., Conclusion: Interactions with staff, patients and the hospital environment supported well-being in those receiving cancer treatment. Findings demonstrate additional areas for research including the development of interventions to facilitate peer support and the implementation of communication strategies that promote well-being., (© 2018 John Wiley & Sons Ltd.)

Background: The global incidence of paediatric inflammatory bowel disease (IBD) is increasing. Much of the evidence attesting to this has arisen from North America and Europe. There is a relative paucity of information on the epidemiology of paediatric IBD in the Southern Hemisphere. The present study aimed to document the prospectively collected incidence of paediatric IBD in New Zealand in 2015., Methods: All patients younger than 16 years of age and diagnosed with IBD in New Zealand between 1 January 2015 and 31 December 2015 were identified. Demographic and disease phenotypic details were collected and entered into a secure database. Age-specific population data for New Zealand were obtained and national incidence rates for IBD and its subtypes were calculated., Results: The prospectively calculated incidence of paediatric IBD, Crohn disease, ulcerative colitis (UC), and IBD unclassified in New Zealand in 2015 were 5.2 (95% confidence interval 3.9-6.8), 3.5 (2.4-4.8), 1.0 (0.5-1.8), and 0.7 (0.3-1.4) per 100,000 children, respectively., Conclusions: Incidence rates of paediatric IBD in New Zealand are comparable to the highest rates published in the literature from Western Europe and North America. Ongoing prospective ascertainment of the incidence of paediatric IBD is required to better understand the environmental factors, which are accounting for this increase in disease burden.

Background: Recent investigation of human tissue and cells from positional tendons such as the rotator cuff has clarified the importance of inflammation in the development and progression of tendon disease. These mechanisms remain poorly understood in disease of energy-storing tendons such as the Achilles. Using tissue biopsies from patients, we investigated if inflammation is a feature of Achilles tendinopathy and rupture., Methods: We studied Achilles tendon biopsies from symptomatic patients with either mid-portion tendinopathy or rupture for evidence of abnormal inflammatory signatures. Tendon-derived stromal cells from healthy hamstring and diseased Achilles were cultured to determine the effects of cytokine treatment on expression of inflammatory markers., Results: Tendinopathic and ruptured Achilles highly expressed CD14+ and CD68+ cells and showed a complex inflammation signature, involving NF-κB, interferon and STAT-6 activation pathways. Interferon markers IRF1 and IRF5 were highly expressed in tendinopathic samples. Achilles ruptures showed increased PTGS2 and interleukin-8 expression. Tendinopathic and ruptured Achilles tissues expressed stromal fibroblast activation markers podoplanin and CD106. Tendon cells isolated from diseased Achilles showed increased expression of pro-inflammatory and stromal fibroblast activation markers after cytokine stimulation compared with healthy hamstring tendon cells., Conclusions: Tissue and cells derived from tendinopathic and ruptured Achilles tendons show evidence of chronic (non-resolving) inflammation. The energy-storing Achilles shares common cellular and molecular inflammatory mechanisms with functionally distinct rotator cuff positional tendons. Differences seen in the profile of ruptured Achilles are likely to be attributable to a superimposed phase of acute inflammation and neo-vascularisation. Strategies that target chronic inflammation are of potential therapeutic benefit for patients with Achilles tendon disease., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: The incidence of paediatric inflammatory bowel disease (IBD) around the world is increasing. Canterbury, New Zealand, has one of the highest Crohn disease (CD) incidence rates published. The present study aimed to document the incidence of paediatric IBD in Canterbury between 1996 and 2015., Methods: All patients diagnosed with IBD in Canterbury, while younger than 16 years, between January 1, 1996 and December 31, 2015 were identified. Demographic and disease phenotypic details were collected and entered into a secure database. Age-specific population data for Canterbury were obtained and annual incidence rates were then calculated., Results: The mean annual incidence rate over the 20-year period was 7.18/100,000 (95% confidence interval 5.55-8.81) children. There was a 4-fold increase in the incidence of paediatric IBD in Canterbury between 1996 and 2015. The ratio of CD to ulcerative colitis (UC) diagnosed was 8.4:1. Disease phenotype of CD and UC, based on the Paris classification, were comparable with other studies., Conclusions: The incidence of paediatric IBD in Canterbury has increased dramatically during the last 2 decades. Some of the observed incidence rates are among the highest documented anywhere in the world. The preponderance of CD over UC in the present study is the highest published.

Objective: To explore whether the Folkman and Greer theoretical model of appraisal and coping reflects the processes used by people living with advanced cancer., Methods: Interview data from a longitudinal qualitative study with people with advanced (stage 3 or 4) cancer (n = 26) were mapped onto the concepts of the Folkman and Greer theoretical model. Qualitative interviews conducted in home settings, 4-12 weeks apart (n = 45) examined coping strategies, why people thought they were effective, and in what circumstances. Interviews were coded and analysed using techniques of constant comparison., Results: Mapping coping strategies clearly onto the problem- or emotion-focused elements of the model proved problematic. Fluctuating symptoms, deterioration over time, and uncertain timescales in advanced cancer produce multiple events simultaneously or in quick succession. This demands not only coping with a single event but also frequent repositioning, often to an earlier point in the coping process. In addition, there is substantial ongoing potential for some degree of distress rather than purely "positive emotion" as the final stage in the process is death with several points of permanent loss of capability in the interim., Conclusions: The Folkman and Greer theoretical model is helpful in deconstructing the discrete "problem-focused" or "emotion-focused" coping mechanisms participants describe, but its formulation as a linear process with a single, positive, outcome is insufficiently flexible to capture the evolution of coping for people with advanced cancer., (Copyright © 2017 John Wiley & Sons, Ltd.)

Objectives: This study will explore how help is constructed during and following radiotherapy for patients with cancer., Methods: Grounded theory methods were used in the study to explore the way in which family members and friends constructed a role for themselves in relation to patients receiving radiotherapy. A total of 22 helpers were interviewed. Patients were being treated for a range of cancers including breast, prostate, colorectal, and head and neck., Results: Respondents in this study consistently defined themselves as "helpers" rather than "carers." While radiotherapy as a treatment modality was mostly seen as noninvasive, the cancer diagnosis cast a long shadow over the lives of helpers and patients creating a separation in longstanding relationships. Helpers experienced this separation as "otherness." Help became an important vehicle for bridging this separation. Individuals developed different ways of knowing about the patient as the basis for providing help. Two different types of help were identified in this study: the behind the scenes, largely invisible work that helpers undertook to help the patient without their knowledge and the explicit visible help that was much more commonly negotiated and discussed between helpers and patients., Conclusions: The study provides the basis for a greater understanding on the part of professionals into the impact of diagnosis and radiotherapy treatment on family and friends. In doing so, the study identifies opportunities for the experience of helpers to be recognised and supported by professionals., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Fecal calprotectin may be used as a non-invasive method to assess the effect of novel therapies on the gut in cystic fibrosis (CF)., Method: Stools from CF patients and healthy controls (HC) (0-10years old) were prospectively collected for evaluation of temporal trends., Results: 130 CF samples (64 subjects) and 114 HC samples (101 subjects) were collected. Overall, fecal calprotectin levels were different in CF patients and HC from 0 to 10years (P=0.0002). Fecal calprotectin in CF was significantly lower than HC from 0 to 1years (P=0.03) and demonstrated an upward trajectory until 4years. From >4 to 10years calprotectin was consistently higher in CF patients compared with HC (P=0.007)., Conclusions: Fecal calprotectin levels in children with CF and HC were age-dependent and had distinct trajectories. Careful interpretation of calprotectin is required if used in drug trials for CF, particularly in children less than 4years old., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: The incidence of pediatric inflammatory bowel disease (IBD) around the world is increasing. However, there is a scarcity of data on the epidemiology of pediatric IBD in the Southern Hemisphere. This study aimed to document the point prevalence of pediatric IBD in New Zealand on June 30, 2015., Methods: All patients in New Zealand, under 16 years of age, with a diagnosis of IBD on June 30, 2015 were identified. Demographic and disease phenotypic details were collected and entered into a secure database. Age-specific population data for New Zealand were obtained and national and regional prevalence rates were calculated., Results: The point prevalence of pediatric IBD, Crohn's disease, ulcerative colitis, and inflammatory bowel disease unclassified in New Zealand on June 30, 2015 was (95% confidence intervals) 21.7 (18.9-24.8), 16.5 (14.0-19.2), 3.3 (2.2-4.6), and 1.9 (1.2-3.0) per 100,000 children, respectively. There was a striking disparity between the prevalence rates in the North and South Islands., Conclusions: The point prevalence of pediatric IBD in New Zealand represents the first-ever national, population-based prevalence rates of pediatric IBD published. Results from the Paediatric IBD in New Zealand (PINZ) study are also the first to show markedly higher prevalence rates of IBD in the southern part of a country compared with its northern counterpart. Ongoing prospective ascertainment of the incidence of pediatric IBD is required.

Objectives: To understand successful strategies used by people to cope well when living with advanced cancer; to explore how professionals can support effective coping strategies; to understand how to support development of effective coping strategies for patients and family carers., Design: Qualitative serial (4-12 week intervals) interview study with people with advanced cancer and their informal carers followed by focus groups. The iterative design had a novel focus on positive coping strategies. Interview analysis focused on patients and carers as individuals and pairs, exploring multiple dimensions of their coping experiences. Focus group analysis explored strategies for intervention development., Participants: 26 people with advanced (stage 3-4) breast, prostate, lung or colorectal cancer, or in receipt of palliative care, and 24 paired nominated informal/family carers., Setting: Participants recruited through outpatient clinics at two tertiary cancer centres in Merseyside and Manchester, UK, between June 2012 and July 2013., Results: 45 patient and 41 carer interviews were conducted plus 4 focus groups (16 participants). People with advanced cancer and their informal/family carers develop coping strategies which enable effective management of psychological wellbeing. People draw from pre-diagnosis coping strategies, but these develop through responding to the experience of living with advanced cancer. Strategies include being realistic, indulgence, support, and learning from others, which enabled participants to regain a sense of wellbeing after emotional challenge. Learning from peers emerged as particularly important in promoting psychological wellbeing through the development of effective 'everyday', non-clinical coping strategies., Conclusions: Our findings challenge current models of providing psychological support for those with advanced cancer which focus on professional intervention. It is important to recognise, enable and support peoples' own resources and coping strategies. Peer support may have potential, and could be a patient-centred, cost effective way of managing the needs of a growing population of those living with advanced cancer., Competing Interests: The authors have declared that no competing interests exist.

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.