Search

Objective Cryopyrin-associated periodic syndromes ( CAPS) result from gain-of-function mutations in the NLRP3 gene, which causes excessive release of interleukin-1β ( IL-1β) and systemic inflammation. While pathogenetic NLRP3 variant phenotypes are well-characterized, low-penetrance NLRP3 variants represent a significant clinical challenge. The aims of this study were to determine the clinical phenotype, the in vitro biologic phenotype, and the effect of anti- IL-1 treatment in patients with low-penetrance NLRP3 variants. Methods A multicenter study of consecutive symptomatic patients with low-penetrance NLRP3 variants recruited from 7 centers between May 2012 and May 2013 was performed. The observed findings were transferred into a study database, from which they were extracted for analysis. Controls were patients with a known pathogenetic NLRP3 variant. Clinical presentation and CAPS markers of inflammation were captured. Functional assays of inflammasome activation, including caspase 1 activity, NF-κB release, cell death, and IL-1β release, were performed. Treatment effects of IL-1 were determined. Comparisons between low-penetrance and pathogenetic NLRP3 variants were performed. Results The study included 45 patients, 21 of which were female (47%); 26 of the patients (58%) were children. NLRP3 low-penetrance variants identified in the patients were Q703K (n = 19), R488K (n = 6), and V198M (n = 20). In the controls, 28 had pathogenetic NLRP3 variants. Patients with low-penetrance NLRP3 variants had significantly more fever (76%) and gastrointestinal symptoms (73%); eye disease, hearing loss, and renal involvement were less common. Functional inflammasome testing identified an intermediate phenotype in low-penetrance NLRP3 variants as compared to wild-type and pathogenetic NLRP3 variants. All treated patients responded to IL-1 inhibition, with complete response documented in 50% of patients. Conclusion Patients with low-penetrance NLRP3 variants display a distinct clinical phenotype and an intermediate biologic phenotype, including IL-1β and non- IL-1β-mediated inflammatory pathway activation. [ABSTRACT FROM AUTHOR]

Background & Aims: Cognitive load theory assumes that the higher the learner's prior knowledge (i.e., the more expert the learner), the lower the intrinsic cognitive load (complexity) experienced for a given problem. While this is the case in many scenarios, there can be cases in which the converse is also true, resulting in more expert learners reporting higher intrinsic cognitive load than novices for the same problem. This can occur in relation to problems involving complex systems (e.g., ecological systems), for which novices' problem representations may underestimate problem complexity and therefore report lower intrinsic load than experts. This finding is borne out in the current paper., Samples, Methods & Results: In Study 1 with 118 participants from the Black Forest area in Germany, participants with higher levels of forestry and ecological expertise evaluated a problem relating to the restructuring of the Black Forest to adapt to climate change as more complex than did novices. In Study 2 (within-subjects design, n = 66 primary-school students), we conceptually replicated this finding in a domain more typical of cognitive load theory studies, mathematics. We found that higher prior knowledge also reduced the underestimation of the complexity of 'tricky', but frequently used, mathematics word problems., Conclusion: Our findings suggest that cognitive load theory's assumptions about intrinsic load and prior knowledge should be refined, as there seems to exist a sub-set of problem-solving tasks for which the traditional relationship between prior knowledge and reported ICL is reversed., (© 2022 The Authors. British Journal of Educational Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)