Background Temporal artery biopsy (TAB) is considered the gold standard for diagnosing Giant Cell Arteritis (GCA). The aim of this study was to compare the functional utility of the 2016 revised ACR (rACR) criteria against the original ACR criteria with a view to avoiding TABs in select groups. We also aimed to investigate the temporal relationship of positive biopsies. Methods A retrospective study was conducted of patients undergoing TAB from August 2014 to August 2016, at a DGH. Data collected included patient demographics, history, biochemistry, time to TAB from commencement of steroids and histology. The ACR and the rACR scores and the relative TAB results were analysed using ROC to determine statistical measures of performance. Different score thresholds were applied to propose a clinical tool to be used as an adjunct in the management of suspected GCA. Results and Discussion Forty two TABs were performed during this period of which 10 were males and 32 females. ROC analysis showed significant relationships between both ACR and rACR to TAB result. The AUC for rACR was 0.880 (p < 0.001) and for ACR was 0.737 (p = 0.023). The median time to TAB from referral was 10 days (IQR 6–13). The diagnostic yield was highest within 8 days (41%) of all positive biopsies. Conclusion This study demonstrates the potential value of the rACR criteria and a simple clinical tool is proposed to stratify relevant patients with a view to avoiding unnecessary TAB. Prolonged wait between referral to TAB is also likely to reduce its validity. Highlights

Evidence before this study: Acute appendicitis is the most common general surgical emergency in children. Its diagnosis remains challenging and children presenting with acute right iliac fossa (RIF) pain may be admitted for clinical observation or undergo normal appendicectomy (removal of a histologically normal appendix). A search for external validation studies of risk prediction models for acute appendicitis in children was performed on MEDLINE and Web of Science on 12 January 2017 using the search terms ["appendicitis" OR "appendectomy" OR "appendicectomy"] AND ["score" OR "model" OR "nomogram" OR "scoring"]. Studies validating prediction models aimed at differentiating acute appendicitis from all other causes of RIF pain were included. No date restrictions were applied. Validation studies were most commonly performed for the Alvarado, Appendicitis Inflammatory Response Score (AIRS), and Paediatric Appendicitis Score (PAS) models. Most validation studies were based on retrospective, single centre, or small cohorts, and findings regarding model performance were inconsistent. There was no high quality evidence to guide selection of the optimum model and threshold cutoff for identification of low-risk children in the UK and Ireland. Added value of this study: Most children admitted to hospital with RIF pain do not undergo surgery. When children do undergo appendicectomy, removal of a normal appendix (normal appendicectomy) is common, occurring in around 1 in 6 children. The Shera score is able to identify a large low-risk group of children who present with acute RIF pain but do not have acute appendicitis (specificity 44%). This low-risk group has an overall 1 in 30 risk of acute appendicitis and a 1 in 270 risk of perforated appendicitis. The Shera score is unable to achieve a sufficiently high positive predictive value to select a high-risk group who should proceed directly to surgery. Current diagnostic performance of ultrasound is also too poor to select children for surgery. Implications of all the available evidence: Routine pre-operative risk scoring could inform shared decision making by doctors, children, and parents by supporting safe selection of lowrisk patients for ambulatory management, reducing unnecessary admissions and normal appendicectomy. Hospitals should ensure seven-day-a-week availability of ultrasound for medium and high-risk patients. Ultrasound should be performed by operators trained to assess for acute appendicitis in children. For children in whom diagnostic uncertainty remains following ultrasound, magnetic resonance imaging (MRI) or low-dose computed tomography (CT) are second-line investigations.

Aims/hypothesis Podocyte loss or injury is one of the earliest features observed in the pathogenesis of diabetic kidney disease (DKD), which is the leading cause of end-stage renal failure worldwide. Dysfunction in the IGF axis, including in IGF binding proteins (IGFBPs), is associated with DKD, particularly in the early stages of disease progression. The aim of this study was to investigate the potential roles of IGFBPs in the development of type 2 DKD, focusing on podocytes. Methods IGFBP expression was analysed in the Pima DKD cohort, alongside data from the Nephroseq database, and in ex vivo human glomeruli. Conditionally immortalised human podocytes and glomerular endothelial cells were studied in vitro, where IGFBP-1 expression was analysed using quantitative PCR and ELISAs. Cell responses to IGFBPs were investigated using migration, cell survival and adhesion assays; electrical cell-substrate impedance sensing; western blotting; and high-content automated imaging. Results Data from the Pima DKD cohort and from the Nephroseq database demonstrated a significant reduction in glomerular IGFBP-1 in the early stages of human type 2 DKD. In the glomerulus, IGFBP-1 was predominantly expressed in podocytes and controlled by phosphoinositide 3-kinase (PI3K)–forkhead box O1 (FoxO1) activity. In vitro, IGFBP-1 signalled to podocytes via β1-integrins, resulting in increased phosphorylation of focal-adhesion kinase (FAK), increasing podocyte motility, adhesion, electrical resistance across the adhesive cell layer and cell viability. Conclusions/interpretation This work identifies a novel role for IGFBP-1 in the regulation of podocyte function and that the glomerular expression of IGFBP-1 is reduced in the early stages of type 2 DKD, via reduced FoxO1 activity. Thus, we hypothesise that strategies to maintain glomerular IGFBP-1 levels may be beneficial in maintaining podocyte function early in DKD. Graphical abstract

De-identified individual participant data will be available including data dictionaries. Specifically, a case may be submitted for provision of individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices). Study documentation including the study protocol and statistical analysis plan may also be requested. Data will be available following publication ending 5 years after this date as per data handling measures specified in the study protocol. Access will be granted to requestors submitting a methodologically sound proposal to the corresponding author CO

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