The discovery of novel and potent indazole NLRP3 inhibitors enabled by DNA-encoded library screening.

NLRP3 is an intracellular sensor protein that detects a broad range of danger signals and environmental insults. Its activation results in a protective pro-inflammatory response designed to impair pathogens and repair tissue damage via the formation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent secretory release of the pro-inflammatory cytokines IL-1ß and IL-18 as well as to gasdermin d-mediated pyroptotic cell death. Herein, we describe the discovery of a novel indazole series of high affinity, reversible inhibitors of NLRP3 activation through screening of DNA-encoded libraries and the potent lead compound 3 (BAL-0028, IC50 = 25 nM) that was identified directly from the screen. SPR studies showed that compound 3 binds tightly (KD range 104-123 nM) to the NACHT domain of NLRP3. A CADD analysis of the interaction of compound 3 with the NLRP3 NACHT domain proposes a binding site that is distinct from those of ADP and MCC950 and includes specific site interactions. We anticipate that compound 3 (BAL-0028) and other members of this novel indazole class of neutral inhibitors will demonstrate significantly different physical, biochemical, and biological properties compared to NLRP3 inhibitors previously identified.

Whole-body MRI in children: state of the art.

Whole-body magnetic resonance imaging (WBMRI) is an increasingly popular technique in paediatric imaging. It provides high-resolution anatomical information, with the potential for further exciting developments in acquisition of functional data with advanced MR sequences and hybrid imaging with radionuclide tracers. WBMRI demonstrates the extent of disease in a range of multisystem conditions and, in some cases, disease burden prior to the onset of clinical features. The current applications of WBMRI in children are hereby reviewed, along with suggested anatomical stations and sequence protocols for acquisition.

A novel resident-as-teacher curriculum: the role of experiential learning and coaching.

This article was migrated. The article was marked as recommended. Background: Canadian family medicine residency programs have the challenge of training in a wide breadth of topics and competencies within a two-year program, including training residents to be effective teachers. There has been a gap in knowledge with regards to the most effective method to train residents to teach. We developed, implemented, and evaluated a novel multi-level resident-as-teacher (RAT) coaching curriculum to provide training and authentic experiences for family medicine residents in teaching medical students. Methods: A curriculum centred around multi-level coaching was designed where family medicine faculty members directly observed and provided feedback to family medicine residents teaching small group clinical skills to first and second year medical students. Family medicine residents received didactic training on how to provide effective feedback to students and manage small group dynamics, after reviewing the learning objectives that students were to achieve. This was followed by the authentic small group teaching experiences. A survey was sent out by email to all residents and faculty members who had participated in the RAT curriculum at the end of the 2013-2014 and 2014-2015 academic years. Quantitative survey data were analyzed using descriptive statistics (frequencies, percentages, correlation coefficients (Spearman's rho)). Qualitative analysis was completed through thematic analysis of respondents' written comments to open-ended survey questions. Results: 80% of 127 residents strongly agreed (26%) or agreed (54%) that the RAT program effectively developed their teaching skills. 57% either strongly agreed (17%) or agreed (40%) that the direct observation and feedback from faculty coaches helped to improve their teaching skills. There was a significant positive correlation between residents' perceptions of the usefulness of the feedback from faculty coaches and residents' perceptions of the overall RAT program's effectiveness in developing their teaching skills (r=0.42; p=0.001). Qualitative analysis revealed that residents perceived the RAT program to have solidified their own knowledge base for the content covered in the sessions. Residents also perceived a benefit of near-peer teaching for the medical students and an elevated family physicians' profile as teachers. They found the active learning experience increased their self-awareness of their teaching skills. Time away from clinical rotations and preparation time were derived as a potential drawback of the program. All faculty coaches agreed or strongly agreed that the RAT curriculum improved the teaching skills of family medicine residents. Thematic analysis of the faculty coaches' comments revealed that participating as coaches allowed for their own professional development in that their feedback and coaching skills improved. Conclusions: Our experiences and program evaluation of a novel multi-level resident-as-teacher coaching curriculum show that direct observation with feedback of authentic teaching activities is highly valued, and appears to be effective in developing resident teaching skills while fostering interest in future teaching.