A Mechanistic Model and Therapeutic Interventions for COVID-19 Involving a RAS-Mediated Bradykinin Storm

Neither the disease mechanism nor treatments for COVID-19 are currently known. Here, we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin1-9 produced by ACE2. Here, we perform a new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) from COVID-19 patients that were used to sequence the virus. Comparison with BALF from controls identifies a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes explain many of the symptoms being observed in COVID-19

A flexible framework for planning and evaluating early-stage health interventions: FRAME-IT

Health interventions exhibit three stages of maturity: early-, mid-, and late-stages. Early-stage interventions have innovative content necessitating evaluation; however existing evaluation frameworks omit constructs and guidelines relevant to this evaluation. Early-stage interventions require planning and evaluation that supports creating, testing, and exploring content to establish general feasibility and enable refinement for further testing, prior to randomised controlled trialling and wider dissemination. Feasibility, Reach-out, Acceptability, Maintenance, Efficacy, Implementation, Tailorability (FRAME-IT) was developed for a mixed methods feasibility study of a novel well-being intervention. FRAME-IT was conceived as a complementary framework to Reach, Efficacy, Adoption, Implementation, Maintenance (RE-AIM; Glasgow et al., 1999) which is better suited for mid- and late- stage interventions. FRAME-IT is proposed to support: (1) early-stage intervention planning and design, by guiding research focus and data sourcing strategy with relevant constructs; (2) comprehensive evaluation, by including constructs appropriate for early-stage interventions, i.e. feasibility, acceptability, and tailorability; (3) future intervention scalability, by including and adapting some of RE-AIM’s constructs to encourage a smoother translation of research into practice as interventions are scaled-up.N/

REDCap (“Research Electronic Data Capture” for clinical research) Software Partner.

REDCap is a secure web application for building and managing online surveys and databases. While REDCap can be used to collect virtually any type of data in any environment (including compliance with 21 CFR Part 11, FISMA, HIPAA, and GDPR), it is specifically geared to support online and offline data capture for research studies and operations. The REDCap Consortium, a vast support network of collaborators, is composed of thousands of active institutional partners in over one hundred countries who utilize and support their own individual REDCap systems