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

Functional neurological disorder: new subtypes and shared mechanisms.

Functional neurological disorder is common in neurological practice. A new approach to the positive diagnosis of this disorder focuses on recognisable patterns of genuinely experienced symptoms and signs that show variability within the same task and between different tasks over time. Psychological stressors are common risk factors for functional neurological disorder, but are often absent. Four entities-functional seizures, functional movement disorders, persistent perceptual postural dizziness, and functional cognitive disorder-show similarities in aetiology and pathophysiology and are variants of a disorder at the interface between neurology and psychiatry. All four entities have distinctive features and can be diagnosed with the support of clinical neurophysiological studies and other biomarkers. The pathophysiology of functional neurological disorder includes overactivity of the limbic system, the development of an internal symptom model as part of a predictive coding framework, and dysfunction of brain networks that gives movement the sense of voluntariness. Evidence supports tailored multidisciplinary treatment that can involve physical and psychological therapy approaches

Ancient Origin of cGAS-STING Reveals Mechanism of Universal 2′,3′ cGAMP Signaling

In humans, the cGAS-STING immunity pathway signals in response to cytosolic DNA via 2′,3′ cGAMP, a cyclic dinucleotide (CDN) second messenger containing mixed 2′–5′ and 3′–5′ phosphodiester bonds. Prokaryotes also produce CDNs, but these are exclusively 3′ linked, and thus the evolutionary origins of human 2′,3′ cGAMP signaling are unknown. Here we illuminate the ancient origins human cGAMP signaling by discovery of a functional cGAS-STING pathway in Nematostella vectensis, an anemone species >500 million years diverged from humans. Anemone cGAS appears to produce a 3′,3′ CDN that anemone STING recognizes through nucleobase-specific contacts not observed in human STING. Nevertheless, anemone STING binds mixed-linkage 2′,3′ cGAMP indistinguishably from human STING, trapping a unique structural conformation not induced by 3′,3′ CDNs. These results reveal that human mixed-linkage cGAMP achieves universal signaling by exploiting a deeply conserved STING conformational intermediate, providing critical insight for therapeutic targeting of the STING pathway