A Quality Improvement Initiative to Improve Health Care Transition Planning at Adolescent Well Visits.

OBJECTIVE: Health care transition (HCT) planning supports adolescents as they move from pediatric to adult health care and is recommended for all youth. HCT planning uptake remains low, with little known about HCT in the adolescent well child check (WCC) setting. We sought to increase rates of HCT planning at WCCs by adapting best practices for HCT from specialty and chronic care. METHODS: This quality improvement initiative at 12 to 17-year-old WCCs at four Internal Medicine-Pediatrics primary care clinics, was based on the first three of the "Six Core Elements" of HCT framework and integrated into the electronic health record. Two uptake measures were assessed via chart review after three plan-do-study-act (PDSA) cycles, with two provider surveys and an implementation science analysis further informing interpretation. RESULTS: By the final PDSA cycle, the percentage of 14 to 17-year-old WCCs at which HCT planning was discussed and a screening tool completed increased from 5% to 31%, and the percentage of 12 to 13-year-old WCCs at which the HCT policy was discussed increased from 6% to 47%. Provider survey results revealed endorsement of HCT goals, but time and technological barriers, which were further elucidated in the implementation science analysis. CONCLUSIONS: This quality improvement initiative increased rates of HCT planning during adolescent WCCs. While limited to three Core Elements and Internal Medicine-Pediatrics clinics, strengths include measures capturing all WCCs, contextualized by provider surveys and an implementation science framework. Lessons from this effort can inform future tailored HCT initiatives at adolescent WCCs.

Out-of-Season Influenza during a COVID-19 Void in the State of Rio de Janeiro, Brazil: Temperature Matters.

An out-of-season H3N2 type A influenza epidemic occurred in the State of Rio de Janeiro, Brazil during October-November 2021, in between the Delta and Omicron SARS-CoV-2 surges, which occurred in July-October 2021 and January-April 2022, respectively. We assessed the contribution of climate change and influenza immunization coverage in this unique, little publicized phenomenon. State weather patterns during the influenza epidemic were significantly different from the five preceding years, matching typical winter temperatures, associated with the out-of-season influenza. We also found a mismatch between influenza vaccine strains used in the winter of 2021 (trivalent vaccine with two type A strains (Victoria/2570/2019 H1N1, Hong Kong/2671/2019 H3N2) and one type B strain (Washington/02/2019, wild type) and the circulating influenza strain responsible for the epidemic (H3N2 Darwin type A influenza strain). In addition, in 2021, there was poor influenza vaccine coverage with only 56% of the population over 6 months old immunized. Amid the COVID-19 pandemic, we should be prepared for out-of-season outbreaks of other respiratory viruses in periods of COVID-19 remission, which underscore novel disease dynamics in the pandemic era. The availability of year-round influenza vaccines could help avoid unnecessary morbidity and mortality given that antibodies rapidly wane. Moreover, this would enable unimmunized individuals to have additional opportunities to vaccinate during out-of-season outbreaks.

Computational-based discovery of FAK FERM domain chemical probes that inhibit HER2-FAK cancer signaling.

The N-terminal FERM domain of focal adhesion kinase (FAK) contributes to FAK scaffolding and interacts with HER2, an oncogene and receptor tyrosine kinase. The interaction between HER2 and FAK drives resistance to FAK-kinase domain inhibitors through FAK Y397 transphosphorylation and FAK re-activation upon inhibition. As such, FAK FERM remains an attractive drug discovery target. In this report, we detail an alternative approach to targeting FAK through virtual screening-based discovery of chemical probes that target FAK FERM. We validated the binding interface between HER2 and FAK using site-directed mutagenesis and GST pull-down experiments. We assessed the ligandability of key-binding residues of HER2 and FAK utilizing computational tools. We developed a virtual screening method to screen ~200,000 compounds against the FAK FERM domain, identifying 20 virtual chemical probes. We performed GST pull-down screening on these compounds, discovering two hits, VS4 and VS14, with nanomolar IC50 s in disrupting HER2-FAK. We performed further testing, including molecular docking, immunofluorescence, phosphorylation, and cellular invasion assays to evaluate the compounds' biological effects. One probe, VS14, was identified with the ability to block both auto- and transphosphorylation of Y397. In all, these studies identify two new probes that target FAK FERM, enabling future investigation of this domain.

Development of a High-Throughput Fluorescence Polarization Assay to Detect Inhibitors of the FAK-Paxillin Interaction.

Focal adhesion kinase (FAK) is a promising cancer drug target due to its massive overexpression in multiple solid tumors and its critical role in the integration of signals that control proliferation, invasion, apoptosis, and metastasis. Previous FAK drug discovery and high-throughput screening have exclusively focused on the identification of inhibitors that target the kinase domain of FAK. Because FAK is both a kinase and scaffolding protein, the development of novel screening assays that detect inhibitors of FAK protein-protein interactions remains a critical need. In this report, we describe the development of a high-throughput fluorescence polarization (FP) screening assay that measures the interactions between FAK and paxillin, a focal adhesion-associated protein. We designed a tetramethylrhodamine (TAMRA)-tagged paxillin peptide based on the paxillin LD2 motif that binds to the focal adhesion targeting (FAT) domain with significant dynamic range, specificity, variability, stability, and a Z'-factor suitable for high-throughput screening. In addition, we performed a pilot screen of 1593 compounds using this FP assay, showing its feasibility for high-throughput drug screening. Finally, we identified three compounds that show dose-dependent competition of FAT-paxillin binding. This assay represents the first described high-throughput screening assay for FAK scaffold inhibitors and can accelerate drug discovery efforts for this promising drug target.