Addressing Inequities in SARS-CoV-2 Vaccine Uptake: The Boston Medical Center Health System Experience.

Academic medical centers could play an important role in increasing access to and uptake of SARS-CoV-2 vaccines, especially in Black and Latino communities that have been disproportionately affected by the pandemic. This article describes the vaccination program developed by the Boston Medical Center (BMC) health system (New England's largest safety-net health system), its affiliated community health centers (CHCs), and community partners. The program was based on a conceptual framework for community interventions and aimed to increase equitable access to vaccination in the hardest-hit communities through community-based sites in churches and community centers, mobile vaccination events, and vaccination on the BMC campus.

Obstacles to Variational Quantum Optimization from Symmetry Protection.

The quantum approximate optimization algorithm (QAOA) employs variational states generated by a parameterized quantum circuit to maximize the expected value of a Hamiltonian encoding a classical cost function. Whether or not the QAOA can outperform classical algorithms in some tasks is an actively debated question. Our work exposes fundamental limitations of the QAOA resulting from the symmetry and the locality of variational states.

Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer.

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest.

Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors.

SHP2 is a nonreceptor protein tyrosine phosphatase within the mitogen-activated protein kinase (MAPK) pathway controlling cell growth, differentiation, and oncogenic transformation. SHP2 also participates in the programed cell death pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of SHP2 has been widely investigated, including in our previous reports describing SHP099 (2), which binds to a tunnel-like allosteric binding site.

6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors.

Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator because of its role in the programmed cell death PD-L1/PD-1 pathway. In the preceding manuscript, we described the optimization of a fused, bicyclic screening hit for potency, selectivity, and physicochemical properties in order to further expand the chemical diversity of allosteric SHP2 inhibitors. In this manuscript, we describe the further expansion of our approach, morphing the fused, bicyclic system into a novel monocyclic pyrimidinone scaffold through our understanding of SAR and use of structure-based design.

Dual Allosteric Inhibition of SHP2 Phosphatase.

SHP2 is a cytoplasmic protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell proliferation, differentiation, and survival. Recently, we reported an allosteric mechanism of inhibition that stabilizes the auto-inhibited conformation of SHP2. SHP099 (1) was identified and characterized as a moderately potent, orally bioavailable, allosteric small molecule inhibitor, which binds to a tunnel-like pocket formed by the confluence of three domains of SHP2.

FDA's pediatric device consortia: national program fosters pediatric medical device development.

Objectives: This article reports on the progress made in addressing pediatric medical device needs through the establishment of the Pediatric Device Consortia Grant Program. Pediatric practitioners should be aware of both the imperative for well-studied devices for children and the existence of recently created resources to help foster the development of such products.

Methods: This article discusses some of the challenges associated with pediatric device development and describes the implementation of section 305 of the Pediatric Medical Device Safety and Improvement Act of 2007.