Protocol for a Formative Study to Develop a Self-rehabilitation Intervention for Functional Mobility Among Community- Dwelling Stroke Survivors in Lmics (preprint)

Background Stroke is a significant source of acquired adult neurological disability. The increased burden of stroke in Low and Lower-middle Income Countries is currently approaching epidemic level. The consequences of stroke have long-standing effects and require long-term management of the resultant limitations. However, lack of resources, inadequate number of professionals, poor awareness, and lack of technical capacity have made the accessibility and availability of stroke rehabilitation services difficult in Low and Lower-middle Income Countries. Moreover, the effect of the COVID 19 pandemic has worsened the already existing challenges faced by stroke rehabilitation in these regions. The development of specific and appropriate stroke rehabilitation approaches that can be self-administered, targeting community-dwelling stroke survivors in Low and Lower-middle Income Countries settings, is highly important. Methods A formative research design is proposed to support the development of a culturally-adaptable Task-Specific Training programme to be delivered through tele-rehabilitation that can be self-administered by community-dwelling stroke survivors. Focus group discussions with community-dwelling stroke survivors will be conducted to gather information regarding challenges they faced in carrying out daily activities. The gathered information will be used to inform the development of a Task-specific self-rehabilitation Training model. A Delphi technique will be employed to refine the items in the initial model and come up with a Task-specific, self-rehabilitation programme target at improving functional ability among community-dwelling stroke survivors. Discussion Stroke rehabilitation services are grossly inadequate in countries categorized as Low and Lower-middle Income, particularly for community-dwelling stroke survivors in sub-Saharan Africa. This paper presents the methods for the development of a culturally-suitable intervention model for improving functional mobility among community-dwelling stroke survivors in Low and Lower-middle Income Countries.

Strategies to target SARS-CoV-2 entry and infection using dual mechanisms of inhibition by acidification inhibitors.

Many viruses utilize the host endo-lysosomal network for infection. Tracing the endocytic itinerary of SARS-CoV-2 can provide insights into viral trafficking and aid in designing new therapeutic strategies. Here, we demonstrate that the receptor binding domain (RBD) of SARS-CoV-2 spike protein is internalized via the pH-dependent CLIC/GEEC (CG) endocytic pathway in human gastric-adenocarcinoma (AGS) cells expressing undetectable levels of ACE2. Ectopic expression of ACE2 (AGS-ACE2) results in RBD traffic via both CG and clathrin-mediated endocytosis. Endosomal acidification inhibitors like BafilomycinA1 and NH4Cl, which inhibit the CG pathway, reduce the uptake of RBD and impede Spike-pseudoviral infection in both AGS and AGS-ACE2 cells. The inhibition by BafilomycinA1 was found to be distinct from Chloroquine which neither affects RBD uptake nor alters endosomal pH, yet attenuates Spike-pseudovirus entry. By screening a subset of FDA-approved inhibitors for functionality similar to BafilomycinA1, we identified Niclosamide as a SARS-CoV-2 entry inhibitor. Further validation using a clinical isolate of SARS-CoV-2 in AGS-ACE2 and Vero cells confirmed its antiviral effect. We propose that Niclosamide, and other drugs which neutralize endosomal pH as well as inhibit the endocytic uptake, could provide broader applicability in subverting infection of viruses entering host cells via a pH-dependent endocytic pathway.