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

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Opioids are widely used in the treatment of severe pain. The clinical use of the opioids is limited by serious side effects such as respiratory depression, constipation, development of tolerance, and physical dependence and addiction liabilities. Most of the currently available opioid analgesics exert their analgesic and adverse effects primarily through the opioid μ receptors. A large number of biochemical and pharmacological studies and studies using genetically modified animals have provided convincing evidence regarding the existence of modulatory interactions between opioid μ and δ receptors. Several studies indicate that δ receptor agonists as well as δ receptor antagonists can provide beneficial modulation to the pharmacological effects of μ agonists. For example, δ agonists can enhance the analgesic potency and efficacy of μ agonists, and δ antagonists can prevent or diminish the development of tolerance and physical dependence by μ agonists. On the basis of these observations, the development of new opioid ligands possessing mixed μ agonist/δ agonist profile and mixed μ agonist/δ antagonist profile has emerged as a promising new approach to analgesic drug development. A brief overview of μ-δ interactions and recent developments in identification of ligands possessing mixed μ agonist/δ agonist and μ agonist/δ antagonist activities is provided in this report

Early parental deprivation in the marmoset monkey produces long-term changes in hippocampal expression of genes involved in synaptic plasticity and implicated in mood disorder.

In mood disorder, early stressors including parental separation are vulnerability factors, and hippocampal involvement is prominent. In common marmoset monkeys, daily parental deprivation during infancy produces a prodepressive state of increased basal activity and reactivity in stress systems and mild anhedonia that persists at least to adolescence. Here we examined the expression of eight genes, each implicated in neural plasticity and in the pathophysiology of mood disorder, in the hippocampus of these same adolescent marmosets, relative to their normally reared sibling controls. We also measured hippocampal volume. Early deprivation led to decreases in hippocampal growth-associated protein-43 (GAP-43) mRNA, serotonin 1A receptor (5-HT(1A)R) mRNA and binding ([3H]WAY100635), and to increased vesicular GABA transporter mRNA. Brain-derived neurotrophic factor (BDNF), synaptophysin, vesicular glutamate transporter 1 (VGluT1), microtubule-associated protein-2, and spinophilin transcripts were unchanged. There were some correlations with in vivo biochemical and behavioral indices, including VGluT1 mRNA with reward-seeking behavior, and serotonin 1A receptor mRNA with CSF cortisol. Early deprivation did not affect hippocampal volume. We conclude that early deprivation in a nonhuman primate, in the absence of subsequent stressors, has a long-term effect on the hippocampal expression of genes implicated in synaptic function and plasticity. The reductions in GAP-43 and serotonin 1A receptor expressions are comparable with findings in mood disorder, supporting the possibility that the latter reflect an early developmental contribution to disease vulnerability. Equally, the negative results suggest that other features of mood disorder, such as decreased hippocampal volume and BDNF expression, are related to different aspects of the pathophysiological process