Multi-Scored Sleep Databases: How to Exploit the Multiple-Labels in Automated Sleep Scoring.

STUDY OBJECTIVES Inter-scorer variability in scoring polysomnograms is a well-known problem. Most of the existing automated sleep scoring systems are trained using labels annotated by a single scorer, whose subjective evaluation is transferred to the model. When annotations from two or more scorers are available, the scoring models are usually trained on the scorer consensus. The averaged scorer's subjectivity is transferred into the model, losing information about the internal variability among different scorers. In this study, we aim to insert the multiple-knowledge of the different physicians into the training procedure. The goal is to optimize a model training, exploiting the full information that can be extracted from the consensus of a group of scorers. METHODS We train two lightweight deep learning based models on three different multi-scored databases. We exploit the label smoothing technique together with a soft-consensus (LSSC) distribution to insert the multiple-knowledge in the training procedure of the model. We introduce the averaged cosine similarity metric (ACS) to quantify the similarity between the hypnodensity-graph generated by the models with-LSSC and the hypnodensity-graph generated by the scorer consensus. RESULTS The performance of the models improves on all the databases when we train the models with our LSSC. We found an increase in ACS (up to 6.4%) between the hypnodensity-graph generated by the models trained with-LSSC and the hypnodensity-graph generated by the consensus. CONCLUSION Our approach definitely enables a model to better adapt to the consensus of the group of scorers. Future work will focus on further investigations on different scoring architectures and hopefully large-scale-heterogeneous multi-scored datasets

Randomized Trial of Osilodrostat for the Treatment of Cushing Disease

Context : Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal. Objective : We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11βhydroxylase inhibitor, compared with placebo in patients with Cushing disease. Methods : LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC≤ULN at week 12. The key secondary endpoint was the proportion achieving mUFC≤ULN at week 36 (after 24 weeks' open-label osilodrostat). Results : Seventy-three patients (median age, 39 years [range, 19-67]; mean/median mUFC, 3.1×ULN/2.5×ULN) received randomized treatment with osilodrostat (n=48) or placebo (n=25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC≤ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P<0.0001). Response was maintained at week 36, when 81% (95% CI 69.9, 89.1) of all patients achieved mUFC≤ULN. The most common adverse events during the placebo-controlled period (osilodrostat vs placebo) were decreased appetite (37.5% vs 16.0%), arthralgia (35.4% vs 8.0%), and nausea (31.3% vs 12.0%). Conclusion : Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable

Randomized trial of osilodrostat for the treatment of cushing disease

CONTEXT: Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal. OBJECTIVE: We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11βhydroxylase inhibitor, compared with placebo in patients with Cushing disease. METHODS: LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion ≥ 1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC ≤ ULN at week 12. The key secondary endpoint was the proportion achieving mUFC ≤ ULN at week 36 (after 24 weeks’ open-label osilodrostat). RESULTS: Seventy-three patients (median age, 39 years [range, 19-67]; mean/median mUFC, 3.1 × ULN/2.5 × ULN) received randomized treatment with osilodrostat (n = 48) or placebo (n = 25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC ≤ ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P < 0.0001). Response was maintained at week 36, when 81% (95% CI 69.9, 89.1) of all patients achieved mUFC ≤ ULN. The most common adverse events during the placebo-controlled period (osilodrostat vs placebo) were decreased appetite (37.5% vs 16.0%), arthralgia (35.4% vs 8.0%), and nausea (31.3% vs 12.0%). CONCLUSION: Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable