"FREED instils a bit of hope in the eating disorder community that things can change.": an investigation of clinician views on implementation facilitators and challenges from the rapid scaling of the First Episode Rapid Early Intervention for Eating Disorders programme.

Introduction: First Episode Rapid Early Intervention for Eating Disorders (FREED) is the leading eating disorder (ED) early intervention model for young people. Research has shown that it reduces the duration of untreated illness, improves clinical outcomes, and has cost savings. However, less is known about the experience of implementing FREED. This study aimed to investigate the views and experiences of adopting, implementing, and sustaining FREED from the perspective of clinical staff. Methods: Seven focus groups were conducted involving 26 clinicians. Thematic analysis was used, with the Non-Adoption, Abandonment and Challenges to Scale-up, Spread and Sustainability (The NASSS framework) framework being applied to organise subthemes and determine facilitators and barriers. The NASSS framework was also used to rate the complexity of themes as either simple (straightforward, predictable, few components), complicated (multiple interrelating components), or complex (dynamic, unpredictable, not easily divisible into constituent components). Results: There were 16 subthemes identified under seven broader themes representing each domain of the NASSS framework. Key barriers and areas of complexity included factors related to EDs as an illness (e.g., high acuity and prevalence), and organisational complexity (e.g., staffing shortages, lack of managerial/team support). Key facilitators included positive clinician/adopter attitudes, a supportive national network, and the ability for FREED to be flexible/adaptable over time. Conclusion: The FREED model appears to be desirable to clinical staff. Wider team and managerial support was perceived to be particularly important to its successful implementation, as were the national network and supervision. Key areas of complexity include staffing issues and high ED acuity/prevalence. These barriers to implementation need to be managed and investment continued to expand and improve early intervention for EDs further.

Activation of automethylated PRC2 by dimerization on chromatin.

Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator that trimethylates lysine 27 of histone 3 (H3K27me3) and is essential for embryonic development and cellular differentiation. H3K27me3 is associated with transcriptionally repressed chromatin and is established when PRC2 is allosterically activated upon methyl-lysine binding by the regulatory subunit EED. Automethylation of the catalytic subunit EZH2 stimulates its activity by an unknown mechanism. Here, we show that PRC2 forms a dimer on chromatin in which an inactive, automethylated PRC2 protomer is the allosteric activator of a second PRC2 that is poised to methylate H3 of a substrate nucleosome. Functional assays support our model of allosteric trans-autoactivation via EED, suggesting a novel mechanism mediating context-dependent activation of PRC2. Our work showcases the molecular mechanism of auto-modification coupled dimerization in the regulation of chromatin modifying complexes.

Guidelines for screening and managing hypertension in children.

ABSTRACT: Pediatric hypertension has risen to an overall prevalence of 16.3%. If left untreated, hypertension in children and adolescents can have significant implications for cardiovascular and renal health into adulthood, including stroke, coronary artery disease, kidney disease, and heart failure. In 2017, the American Academy of Pediatrics (AAP) released updated guidelines for the screening, evaluation, and management of pediatric hypertension. This article reviews the definition of pediatric hypertension, describes why the guidelines were updated, and defines treatment protocol. By familiarizing themselves with and applying these guidelines, clinicians will be able to appropriately screen and manage hypertension in children to prevent morbidity into adulthood.

NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain.

NLRP3 is a cytosolic pattern recognition receptor that senses microbes and endogenous danger signals. Upon activation, NLRP3 forms an inflammasome with the adapter ASC, resulting in caspase-1 activation, release of proinflammatory cytokines and cell death. How NLRP3 activation is regulated by transcriptional and posttranslational mechanisms to prevent aberrant activation remains incompletely understood. Here, we identify three conserved phosphorylation sites in NLRP3 and demonstrate that NLRP3 activation is controlled by phosphorylation of its pyrin domain (PYD). Phosphomimetic residues in NLRP3 PYD abrogate inflammasome activation and structural modeling indicates that phosphorylation of the PYD regulates charge-charge interaction between two PYDs that are essential for NLRP3 activation. Phosphatase 2A (PP2A) inhibition or knock-down drastically reduces NLRP3 activation, showing that PP2A can license inflammasome assembly via dephosphorylating NLRP3 PYD. These results propose that the balance between kinases and phosphatases acting on the NLRP3 PYD is critical for NLRP3 activation.