Environmental Factors and Hyperacute Stroke Care Activity During the COVID-19 Pandemic: An Interrupted Time-Series Analysis.

BACKGROUND AND AIMS: Concerns have arisen regarding patient access and delivery of acute stroke care during the COVID-19 pandemic. We investigated key population level events on activity of the three hyperacute stroke units (HASUs) within Greater Manchester and East Cheshire (GM & EC), whilst adjusting for environmental factors. METHODS: Weekly stroke admission & discharge counts in the three HASUs were collected locally from Emergency Department (ED) data and Sentinel Stroke National Audit Programme core dataset prior to, and during the emergence of the COVID-19 pandemic (Jan 2020 to May 2020). Whilst adjusting for local traffic-related air pollution and ambient measurement, an interrupted time-series analysis using a segmented generalised linear model investigated key population level events on the rate of stroke team ED assessments, admissions for stroke, referrals for transient ischaemic attack (TIA), and stroke discharges. RESULTS: The median total number of ED stroke assessments, admissions, TIA referrals, and discharges across the three HASU sites prior to the first UK COVID-19 death were 150, 114, 69, and 76 per week. The stable weekly trend in ED assessments and stroke admissions decreased by approximately 16% (and 21% for TIAs) between first UK hospital COVID-19 death (5th March) and the implementation of the Act-FAST campaign (6th April) where a modest 4% and 5% increase per week was observed. TIA referrals increased post Government intervention (23rd March), without fully returning to the numbers observed in January and February. Trends in discharges from stroke units appeared unaffected within the study period reported here. CONCLUSION: Despite adjustment for environmental factors stroke activity was temporarily modified by the COVID-19 pandemic. Underlying motivations within the population are still not clear. This raises concerns that patients may have avoided urgent health care risking poorer short and long-term health outcomes.

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-γ Inhibitors.

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally.

Design and Synthesis of Soluble and Cell-Permeable PI3Kδ Inhibitors for Long-Acting Inhaled Administration.

PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesized to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work, we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimization for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation. Addition of basic substituents to a region of the molecule pointing to solvent was tolerated (enzyme inhibition pIC50 > 9), and by careful manipulation of the pKa and lipophilicity, we were able to discover compounds (20b, 20f) with good lung retention and cell potency that could be taken forward to in vivo studies where significant target engagement could be demonstrated.