Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations.

Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether and biaryl as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CL compounds while maintaining a WT selectivity margin.

Income inequality and the erosion of democracy in the twenty-first century.

Among the most pressing problems societies face today are economic inequality and the erosion of democratic norms and institutions. In fact the two problems-inequality and democratic erosion-are linked. In a large cross-national statistical study of risk factors for democratic erosion, we establish that economic inequality is one of the strongest predictors of where and when democracy erodes.

Patient- and Family-Centered Outcomes After Intensive Care Unit Admission.

Background: Family satisfaction with intensive care is a measure of patient experience and patient-centered care. Among the factors that might influence family satisfaction are the timing of patient admittance to the intensive care unit (ICU), the ICU environment, and individual health care providers.

Objective: To evaluate family satisfaction with the ICU and to explore associations between satisfaction and specific characteristics of the ICU stay.