Reversal of PAP Failure With the REPAP Protocol.

BACKGROUND: Re-titrations, an atypical approach to reverse PAP failure, was investigated retrospectively. METHODS: Application of our re-titration of PAP (REPAP) protocol in subjects with previous PAP failure assessed original technology (masks, modes, and pressures) in 273 subjects, of which 70% reported co-occurring psychiatric conditions. The REPAP protocol emphasized changes in pressure modes and settings to address expiratory pressure intolerance and residual breathing events; mask changes were facilitated. Objective sleep and breathing metrics and subjective post-titration ratings were analyzed in subsequent PAP users and non-users. RESULTS: Following REPAP protocol (average follow-up = 2 y), 196 of 273 subjects with previous PAP failure were PAP users, and 77 were non-users. Previous PAP failure was attributed to technology factors, including pressure intolerance, mask discomfort, adaptation difficulties, and no benefits. At second opinion re-titration, mask changes resolved discomfort, mouth breathing, or leak (91.2% of sample); pressure mode changes resolved expiratory pressure intolerance (83.5%); and pressure setting changes decreased residual breathing events and improved air flow (96.7%), all of which were associated with renewed PAP use. PAP users showed objective sleep improvements on re-titrations and reported better sleep quality than non-users. Multiple logistic regressions showed 2 subjective, re-initiation predictors: (1) post-re-titration ratings of better sleep quality and (2) less anticipated difficulty in using PAP after initial or multiple re-titrations. User rates were significantly higher for subjects completing multiple (n = 158) versus one (n = 115) re-titration (80% vs 61%, P = .001). In multiple re-titration subjects, PAP users showed significance or a trend for lower apnea-hypopnea index (P = .02, g = 0.48) and respiratory disturbance index (P = .07, g = 0.36) compared with non-users. Available user downloads averaged >5 h/night. CONCLUSIONS: Technology-related problems due to mask discomfort/leak, pressure intolerance, and residual breathing events were associated with PAP failure in subjects seeking second opinions. Technological solutions (changes in masks, modes, and pressures) were addressed during REPAP protocol, after which 72% of subjects re-initiated PAP use. These technological interventions were associated with improved objective and subjective sleep variables and reversal of PAP failure.

Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins.

Residence within a customized vacuole is a highly successful strategy used by diverse intracellular microorganisms. The parasitophorous vacuole membrane (PVM) is the critical interface between Plasmodium parasites and their possibly hostile, yet ultimately sustaining, host cell environment. We show that torins, developed as ATP-competitive mammalian target of rapamycin (mTOR) kinase inhibitors, are fast-acting antiplasmodial compounds that unexpectedly target the parasite directly, blocking the dynamic trafficking of the Plasmodium proteins exported protein 1 (EXP1) and upregulated in sporozoites 4 (UIS4) to the liver stage PVM and leading to efficient parasite elimination by the hepatocyte. Torin2 has single-digit, or lower, nanomolar potency in both liver and blood stages of infection in vitro and is likewise effective against both stages in vivo, with a single oral dose sufficient to clear liver stage infection. Parasite elimination and perturbed trafficking of liver stage PVM-resident proteins are both specific aspects of torin-mediated Plasmodium liver stage inhibition, indicating that torins have a distinct mode of action compared with currently used antimalarials.