A low respiratory arousal threshold (ArTH) has been linked to reduced continuous positive airway pressure (CPAP) adherence in obstructive sleep apnea (OSA) via a multi-trait model developed in the RIC Show more
A low respiratory arousal threshold (ArTH) has been linked to reduced continuous positive airway pressure (CPAP) adherence in obstructive sleep apnea (OSA) via a multi-trait model developed in the RICCADSA trial. Our objective was to validate the prior model in a large, real-world cohort and explore alternative linear and non-linear approaches for predicting CPAP adherence. Does a previously derived multi-trait model linking low ArTH to poor CPAP adherence remain valid in a diverse real-world population and do alternative linear or non-linear approaches offer improved predictive performance? Adults with OSA from the SNOOzzzE-cohort who initiated CPAP within 1 year of in-lab polysomnography (2017-2019) were included. Pathophysiological traits (Vpassive, Vactive, loop gain, ArTH, ventilatory response to arousal) were estimated from polysomnography. Poor (vs good) adherence was defined as ≤2.48h/night at month 1 (1 Among 744 participants (45% women, 47% non-White), median CPAP adherence was 4.8 h/night at 1 month. The prior model's AUC was 0.51 (95%-CI 0.46-0.55), with no usage differences between predicted poor vs good adherers. A new linear model overfit in training (AUC=0.85) but failed in testing (AUC=0.55). LPA identified a "Low ArTH Driven" cluster with persistently lower adherence at months 2-3 (P<.05) and a "Low ArTH & High loop gain" cluster whose usage stabilized after month 1. The prior model did not generalize to this diverse clinical cohort. LPA identified a "Low ArTH Driven" endotype with persistently low CPAP adherence, suggesting potential for targeted interventions pending external validation. Show less
Alzheimer's disease is characterized, in part, by the accumulation of β-amyloid (Aβ) in the brain. Aβ is produced via the proteolysis of APP by BACE1 and γ-secretase. Since BACE1 is the rate-limiting Show more
Alzheimer's disease is characterized, in part, by the accumulation of β-amyloid (Aβ) in the brain. Aβ is produced via the proteolysis of APP by BACE1 and γ-secretase. Since BACE1 is the rate-limiting enzyme in the production of Aβ, and a target for therapeutics, it is of interest to know when its proteolytic function evolved and for what purpose. Here, we take a functional evolutionary approach to show that BACE1 likely evolved from a gene duplication event near the base of the animal clade and that BACE1 APP/Aβ proteolytic function evolved during early animal diversification, hundreds of millions of years before the evolution of the APP/Aβ substrate. Our examination of BACE1 APP/Aβ proteolytic function includes cnidarians, ctenophores, and choanoflagellates. The most basal BACE1 ortholog is found in cnidarians, while ctenophores, placozoa, and choanoflagellates have genes equally orthologous to BACE1 and BACE2. BACE1 from a cnidarian ( Show less