[Reaction: see text] Addition of lithium bis(trimethylsilyl)amide to perfluorinated ketones 1a-j affords (E)-N-TMS-ketimines 2a-j that are reduced in situ to afford racemic perfluoromethylated amine hydrochloride salts 3a-j in 54-97% yields. Solvolysis of the N-Si bond in MeOH leads to formation of bench-stable, isolable N-H imine Z/E isomer mixtures along with a methanol adduct. Enantioselective reduction of these three-component mixtures provides the first catalytic asymmetric synthesis of trifluoromethylated amines in 72-95% yields and 75-98% ee.

PurposeThis study aims to quantify the magnitude of missed dispensings in commercial claims databases.MethodsA retrospective cohort study has been used linking PharMetrics, a commercial claims database, to a prescription database (LRx) that captures pharmacy dispensings independently of payment method, including cash transactions. We included adults with dispensings for opioids, diuretics, antiplatelet medications, or anticoagulants. To determine the degree of capture of dispensings, we calculated the number of subjects with the following: (1) same number of dispensings in both databases; (2) at least one dispensing, but not all dispensings, missed in PharMetrics; and (3) all dispensings missing in PharMetrics. Similar analyses were conducted using dispensings as the unit of analysis. To assess whether a dispensing in LRx was in PharMetrics, the dispensing in PharMetrics had to be for the same medication class and within ±7 days in LRx.ResultsA total of 1 426 498 subjects were included. Overall, 68% of subjects had the same number of dispensings in both databases. In 13% of subjects, PharMetrics identified ≥1 dispensing but also missed ≥1 dispensing. In 19% of the subjects, PharMetrics missed all the dispensings. Taking dispensings as the unit of analysis, 25% of the dispensings present in LRx were not captured in PharMetrics. These patterns were similar across all four classes of medications. Of the dispensings missing in PharMetrics, 48% involved a subject who had >1 health insurance plan.ConclusionsCommercial claims databases provide an incomplete picture of all prescriptions dispensed to patients. The lack of capture goes beyond cash transactions and potentially introduces substantial misclassification bias. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

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CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 ( Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.

Remote monitoring of crew, spacecraft, and environmental health has always been an integral part of the National Aeronautics and Space Administration's (NASA's) operations. Crew safety and mission success face a number of challenges in outerspace, including physiological adaptations to microgravity, radiation exposure, extreme temperatures and vacuum, and psychosocial reactions to space flight. The NASA effort to monitor and maintain crew health, system performance, and environmental integrity in space flight is a sophisticated and coordinated program of telemedicine combining cutting-edge engineering with medical expertise. As missions have increased in complexity, NASA telemedicine capabilities have grown apace, underlying its role in the field. At the same time, the terrestrial validation of telemedicine technologies to bring healthcare to remote locations provides feedback, improvement, and enhancement of the space program. As NASA progresses in its space exploration program, astronauts will join missions lasting months, even years, that take them millions of miles from home. These long-duration missions necessitate further technological breakthroughs in tele-operations and autonomous technology. Earth-based monitoring will no longer be real-time, requiring telemedicine capabilities to advance with future explorers as they travel deeper into space. The International Space Station will serve as a testbed for the telemedicine technologies to enable future missions as well as improve the quality of healthcare delivery on Earth.