IntroductionExcessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA) can impair vigilance/attention. Solriamfetol, a dopamine/norepinephrine reuptake inhibitor... Show moreIntroductionExcessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA) can impair vigilance/attention. Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved to treat EDS associated with narcolepsy (75-150 mg/day) or OSA (37.5-150 mg/day). The analysis reported here explored the use of the Sleep, Activity, Fatigue, and Task Effectiveness (SAFTE) model (used in transport industries to model performance based on accumulated sleep and circadian variability) as a substitute for healthy controls using psychomotor vigilance task (PVT) data collected during clinical studies. MethodsData were analyzed from two phase 2 studies of solriamfetol in adults with OSA (NCT02806895, EudraCT 2015-003930-28) or narcolepsy (NCT02806908, EudraCT 2015-003931-36). Participants were randomly assigned 1:1 to solriamfetol 150 mg/day (3 days) followed by 300 mg/day (4 days), or placebo (7 days), then crossed over to the other treatment. Actual task effectiveness scores were calculated from average PVT inverse reaction time (pre-dose; 2 h post-dose; 6 h post-dose). Actigraphy-derived sleep intervals were used in SAFTE to determine modeled healthy control task effectiveness scores. ResultsIn participants with OSA (N = 31) on placebo or solriamfetol, actual and modeled healthy control task effectiveness did not differ at any time point. In participants with narcolepsy (N = 20) on placebo, actual task effectiveness at 2 h post-dose was lower than modeled healthy control task effectiveness (nominal P = 0.03), a difference not present with solriamfetol. There was no main effect of solriamfetol on actual or modeled healthy control task effectiveness across time points. ConclusionThis study represents a novel application of the SAFTE biomathematical model to approximate healthy controls in sleep disorder research and provides valuable lessons that may optimize future research. Future studies should perform a priori power analyses for model-tested outcomes and use sleep measures that capture sleep fragmentation characteristic of sleep disorders for sleep input (e.g., total sleep time rather than time in bed). Show less
Human induced pluripotent stem cell (hiPSC)-derived hair-bearing skin organoids offer exciting new possibilities for modeling diseases like epidermolysis bullosa (EB). These inherited diseases... Show moreHuman induced pluripotent stem cell (hiPSC)-derived hair-bearing skin organoids offer exciting new possibilities for modeling diseases like epidermolysis bullosa (EB). These inherited diseases affect 1 in 30,000 people worldwide and result from perturbed expression and/or structure of components of the epidermal-dermal junction (EDJ). To establish whether hiPSC-derived skin organoids might be able to capture salient features of EB, it is thus important to characterize their EDJ. Here, we report successful generation of hair-bearing skin organoids from two hiPSC lines that exhibited fully stratified interfollicular epidermis. Using immunofluorescence and electron microscopy, we showed that basal keratinocytes in organoids adhere to laminin-332 and type IV collagen-rich basement membrane via type I hemidesmosomes and integrin 81-based adhesion complexes. Importantly, we demonstrated that EDJs in organoids are almost devoid of type VII collagen, a fibril that mediates anchorage of the epidermis to dermis. This should be considered when using skin organoids for EB modeling. Show less
Objective: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving in participants with excessive daytime sleepiness (EDS) associated with... Show moreObjective: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving in participants with excessive daytime sleepiness (EDS) associated with obstructive sleep apnoea (OSA). Methods: Eligible participants were aged 21-75 years with OSA and EDS (Maintenance of Wakefulness Test mean sleep latency <30 minutes and Epworth Sleepiness Scale score >= 10). Participants were randomised 1:1 to solriamfetol (150 mg/day [3 days], then 300 mg/day [4 days]) or placebo for 7 days, before crossover to the other treatment paradigm. On Day 7 of each period, standardised on-road driving tests occurred (2 and 6 hours postdose). Standard deviation of lateral position (SDLP) was the primary endpoint. Results: Solriamfetol significantly reduced SDLP at 2 (n = 34; least squares mean difference, -1.1 cm; 95% CI, -1.85, -0.32; p = 0.006) and 6 hours postdose (n = 32; least squares mean difference, -0.8 cm; 95% CI, -1.58, -0.03; p = 0.043). Two hours postdose, 4 placebo-treated and 1 solriamfetol-treated participants had incomplete driving tests; 6 hours postdose, 7 and 3 participants, respectively, had incomplete tests. Common treatment-emergent adverse events included headache, nausea, and insomnia. Conclusions: Solriamfetol 300 mg/day significantly improved on-the-road driving performance in participants with EDS associated with OSA. Show less
Perrin, P.; Janssen, L.; Janssen, H.; Broek, B. van den; Voortman, L.M.; Elsland, D. van; ... ; Neefjes, J. 2021
The endosomal system constitutes a highly dynamic vesicle network used to relay materials and signals between the cell and its environment. (1)Once internalized, endosomes gradually mature into... Show moreThe endosomal system constitutes a highly dynamic vesicle network used to relay materials and signals between the cell and its environment. (1)Once internalized, endosomes gradually mature into late acidic compartments and acquire a multivesicular body (MVB) organization through invagination of the limiting membrane (LM) to form intraluminal vesicles (ILVs). (2)Cargoes sequestered into ILVs can either be delivered to lysosomes for degradation or secreted following fusion of the MVB with the plasma membrane. (3)It has been speculated that commitment to ILVs is not a terminal event, and that a return pathway exists, allowing "back-fusion" or "retrofusion" of intraluminal membranes to the LM.(4) The existence of retrofusion as a way to support membrane equilibrium within the MVB has been widely speculated in various cell biological contexts, including exosome uptake(5) and major histocompatibility complex class II (MHC class II) antigen presentation. (6-9) Given the small physical scale, retrofusion of ILVs cannot be measured with conventional techniques. To circumvent this, we designed a chemically tunable cell-based system to monitor retrofusion in real time. Using this system, we demonstrate that retrofusion occurs as part of the natural MVB lifestyle, with attributes parallel to those of viral infection. Furthermore, we find that retrofusion and exocytosis coexist in an equilibrium, implying that ILVs inert to retrofusion comprise a significant fraction of exosomes destined for secretion. MVBs thus contain three types of ILVs: those committed to lysosomal degradation, those retrofusing ILVs, and those subject to secretion in the form of exosomes. Show less
