A dual role for the N-terminal domain of the IL-3 receptor in cell signalling

The interleukin-3 (IL-3) receptor is a cell-surface heterodimer that links the haemopoietic, vascular and immune systems and is overexpressed in acute and chronic myeloid leukaemia progenitor cells. It belongs to the type I cytokine receptor family in which the α-subunits consist of two fibronectin III-like domains that bind cytokine, and a third, evolutionarily unrelated and topologically conserved, N-terminal domain (NTD) with unknown function. Here we show by crystallography that, while the NTD of IL3Rα is highly mobile in the presence of IL-3, it becomes surprisingly rigid in the presence of IL-3 K116W. Mutagenesis, biochemical and functional studies show that the NTD of IL3Rα regulates IL-3 binding and signalling and reveal an unexpected role in preventing spontaneous receptor dimerisation. Our work identifies a dual role for the NTD in this cytokine receptor family, protecting against inappropriate signalling and dynamically regulating cytokine receptor binding and function.Sophie E. Broughton, Timothy R. Hercus, Tracy L. Nero, Winnie L. Kan ... Timothy P. Hughes, Angel F. Lopez ... et al

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Prevalence of dilated mid-ascending aorta in individuals 15 years and older: In search of optimal diagnostic criteria and their effect on the burden of disease

Background:Controversy regarding the definition of the upper limit of normal (ULN) for dilated mid-ascending aorta (mAA) stems from variation in criteria, based on several small-sized studies with small datasets of normal subjects (DONS). The present study was carried out to demonstrate this variation in the prevalence of mAA dilation and to identify the optimal definition by creating the largest DONS. Methods:Echocardiographic studies of patients ≥ 15 years of age performed at a large tertiary care center over 4 years ( n = 49,330) were retrospectively evaluated. The leading-edge-to-leading-edge technique was used to measure the mAA in diastole. The largest-to-date DONS ( n = 2334) was created, including those who were normal on medical record review, did not have any of the 28 causes of dilated aorta, and had normal echocardiograms. Because age had the strongest correlation with mAA (multivariate adjusted R2 = 0.26), as compared with sex, height, and weight, we created a new ULN based on the DONS with narrow age stratification (10-year intervals). Results:The prevalence of dilated mAA varied between 17% and 23% when absolute criteria were used with sex stratification, and it varied between 6% and 11% when relative criteria (relative to age, body surface area, and sex) were used. Based on new criteria from the DONS, it was 7.6%, with a ULN of 3.07-3.64 cm in women and 3.3-3.91 cm in men. Conclusions:These data demonstrate the undesirable variation in the prevalence of dilated mAA based on prior criteria and propose a new ULN for dilated mAA

Refining the upper limit of normal for the ascending aorta: In search of optimal criteria -- a large database study of normal individuals

Objectives: The cutoff for dilated mid-ascending aorta (mAA) is controversial and has several definitions. The present study was carried out to determine the prevalence of mAA dilation based on published definitions and to identify the optimal cutoff. Methods: Echocardiographic studies of patients \u3e15 years of age performed at a large tertiary care center over 4 years, n = 49,330, were retrospectively evaluated. Leading-edge-to-leading-edge technique was used to measure the mAA in diastole. Several cutoff criteria were included. In addition, we defined normals in our database as those who, after 28 causes of dilated aorta were excluded, were normal both clinically and echocardiographically (n = 2334). Results: The mean age was 64.2 ± 17.1 years, and 31.5% were men. The prevalence of dilated mAA based on absolute criteria with sex stratification varied between 17% and 23% and based on relative criteria (to age, body surface area, and sex) varied between 6% and 11%. It further decreased to 7.6% on the addition of narrow age stratification (10 year intervals) performed on normals in our database. The multivariate adjusted R2 (for variation in mAA diameter) was 0.25 for age, decreasing to 0.12 for weight and 0.07 for sex and height. Conclusions: The lowest prevalence of 7.6% probably represents the optimal cutoff for dilated mAA because it includes age, which explains most of the variation in mAA, in narrow (10 year) intervals only performed in our normals, which represents the largest sample size to date