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Background: Obesity is strongly associated with prevalence of obstructive sleep apnea (OSA), and weight loss has been shown to reduce disease severity. Objective: To investigate whether liraglutide 3.0 mg reduces OSA severity compared with placebo using the primary end point of change in apnea–hypopnea index (AHI) after 32 weeks. Liraglutide’s weight loss efficacy was also examined. Subjects/Methods: In this randomized, double-blind trial, non-diabetic participants with obesity who had moderate (AHI 15–29.9 events h −1 ) or severe (AHI ⩾30 events h −1 ) OSA and were unwilling/unable to use continuous positive airway pressure therapy were randomized for 32 weeks to liraglutide 3.0 mg ( n =180) or placebo ( n =179), both as adjunct to diet (500 kcal day −1 deficit) and exercise. Baseline characteristics were similar between groups (mean age 48.5 years, males 71.9%, AHI 49.2 events h −1 , severe OSA 67.1%, body weight 117.6 kg, body mass index 39.1 kg m −2 , prediabetes 63.2%, HbA 1c 5.7%). Results: After 32 weeks, the mean reduction in AHI was greater with liraglutide than with placebo (−12.2 vs −6.1 events h −1 , estimated treatment difference: −6.1 events h −1 (95% confidence interval (CI), −11.0 to −1.2), P =0.0150). Liraglutide produced greater mean percentage weight loss compared with placebo (−5.7% vs −1.6%, estimated treatment difference: −4.2% (95% CI, −5.2 to −3.1%), P <0.0001). A statistically significant association between the degree of weight loss and improvement in OSA end points ( P <0.01, all) was demonstrated post hoc . Greater reductions in glycated hemoglobin (HbA 1c ) and systolic blood pressure (SBP) were seen with liraglutide versus placebo (both P <0.001). The safety profile of liraglutide 3.0 mg was similar to that seen with doses ⩽1.8 mg. Conclusions: As an adjunct to diet and exercise, liraglutide 3.0 mg was generally well tolerated and produced significantly greater reductions than placebo in AHI, body weight, SBP and HbA 1c in participants with obesity and moderate/severe OSA. The results confirm that weight loss improves OSA-related parameters.

Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides. We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate. Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients. In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.).

An emerging long obstacle placed in a boundary layer developing under a free surface generates a complex horseshoe vortex (HSV) system, which is composed of a set of vortices exhibiting a rich variety of dynamics. The present experimental study examines such flow structure and characterizes precisely, using particle image velocimetry (PIV) measurements, the evolution of the HSV geometrical and dynamical properties over a wide range of dimensionless parameters (Reynolds number $Re_{h}\\in [750,8300]$ , boundary layer development ratio $h/\\unicode[STIX]{x1D6FF}\\in [1.25,4.25]$ and obstacle aspect ratio $W/h\\in [0.67,2.33]$ ). The dynamical study of the HSV is based on the categorization of the motions of HSV vortices that result in an enhanced specific bi-dimensional typology, separating a coherent (due to vortex–vortex interactions) and an irregular evolution (due to the appearance of small-scale instabilities). This precise categorization is made possible thanks to the use of vortex tracking methods applied to PIV measurements; a semi-empirical model for the motion of the HSV vortices is then proposed to highlight some important mechanisms of the HSV dynamics, such as (i) the influence of the surrounding vortices on vortex motion and (ii) the presence of a phase shift between the motion of all vortices. Finally, the study of the HSV’s geometrical properties (vortex position and characteristic lengths and frequencies) evolution with the flow parameters shows that strong dependencies exist between the streamwise extension of the HSV and the obstacle width, and between the HSV vortex number and its elongation. Comparison of these data with prior studies for immersed obstacles reveals that emerging obstacles lead to greater adverse pressure gradients and down-flows in front of the obstacle. This implies a precocious separation of the boundary layer, leading to a larger HSV streamwise extension, and a lower vertical extension of the HSV, leading to smaller HSV vortices.

This article aims at predicting the oscillation frequency of open-channel lateral cavities, which are common sheltered zones of riverine environments, and have important ecological impact. Using a theoretical analysis based on an existing model for acoustic cavities and a free-surface lateral cavity experiment, we show that the vortex shedding in the mixing layer between the cavity and the open channel is always constrained by gravity waves even for low Froude numbers ($F<0.6$). This expands previous results from the literature showing the impact of gravity waves on the vortex shedding frequency for high Froude number ($F>0.6$). Measurements of the free-surface oscillation and transverse velocity oscillation frequencies reveal a unique frequency along the mixing layer, equal to the free-surface oscillation frequency anywhere in the cavity. Hence, it is shown that the vortex shedding frequency in an open-channel lateral cavity always equals a match between a natural frequency of the cavity and a solution of the feedback model developed herein for low to moderate Froude numbers.

Due to an increasing demand for environmentally sustainable products, miscanthus and maize stover represent interesting lignocellulosic resources for conversion into biofuels and biomaterials. The overall purpose was to compare miscanthus and maize regarding cell-wall composition and stem anatomy for conversion into bioethanol and polymer composites using partial least squares regressions. For each of the two crops, six contrasted genotypes were cultivated in complete block design, and harvested. Internodes below the main cob for maize, and on the first aboveground internode for miscanthus, were analyzed for biochemistry and anatomy. Their digestibility was predicted using crop-specific near infrared calibrations, and the mechanical properties were evaluated in stem-based composites. On average, the internode cross-section of miscanthus anatomy was characterized by a thick rind (26.2%) and few but dense pith-bundles (3.5 nb/mm2), while cell-wall constituted 95.2% of the dry matter with high lignin (243.2 mg/g) and cellulose concentrations (439.7 mg/g). Maize internode-anatomy showed large cross-sections (397.5 mm2), pith with the presence of numerous bundles and non-lignified-pith fractions (22.3% of the section). Its cell-wall biochemistry displayed high concentrations of hemicelluloses, galactose, arabinose, xylose, and ferulic acid. Cell-wall, lignin, and cellulose concentrations were positively correlated with rind-fraction and pith-bundle-density, which explained strong mechanical properties as shown in miscanthus. Hemicelluloses, galactose, arabinose, and ferulic acid concentrations were positively correlated with pith fraction and stem cross-section, revealing high digestibility as shown in maize. This underlines interesting traits for further comparative genetic studies, as maize represents a good model for digestibility and miscanthus for composites.

Open-channel junctions are common occurrences in sewer networks and flow rate measurement often occurs near these singularities. Local flow structures are 3D, impact on the representativeness of the local flow measurements and thus lead to deviations in the flow rate estimation. The present study aims (i) to measure and simulate the flow pattern in a junction flow, (ii) to analyse the impact of the junction on the velocity distribution according to the distance from the junction and thus (iii) to evaluate the typical error derived from the computation of the flow rate close to the junction.

The sustainable development of miscanthus as a bioenergy feedstock requires optimizing its fertilizer inputs and, therefore, determining its nitrogen (N) requirements. The ‘critical nitrogen dilution curve’ is a powerful tool to characterize such N requirements; it relates the N concentration ([N]) in aboveground organs to their biomass, defining two domains depending on whether the N factor limits biomass growth or not. We aimed to develop such a tool in miscanthus. Using a rhizome N depletion strategy with green cutting pre-treatment over several years before the start of the experiment, we grew, in 2014, two cultivated species, Miscanthus × giganteus ( M × g ) and Miscanthus sinensis ( Msin ), at four fertilizer levels (0, 80, 160 and 240 kg N ha −1 ). We found a strong nitrogen fertilization effect. The shoot [N] decreased as the aboveground biomass increased in both species and in all of the treatments. [N] was strongly correlated with leaf/stem biomass ratio. The N treatments enabled the identification of the observed critical points, i.e. points with the maximum biomass ( W ) and the lowest [N], on each measurement date. These points could be fitted to the following critical dilution curve that was common between M × g and Msin : N concentration ( Nc ) (critical [N], g N kg −1 ) = 27.0  W −0.48 when W  > 1 t ha −1 and Nc  = 27.0 when W  ≤ 1. This curve was validated by literature data, separated into N-limited or not-limited conditions. The similarity of the curves between the two species was due to compensation between leaf/stem biomass ratio and [N] in the stems. This curve is helpful to diagnose the crop N status and define the optimal fertilizer requirements of miscanthus crops.

The sustainable development of miscanthus as a bioenergy feedstock requires optimizing its fertilizer inputs and, therefore, determining its nitrogen (N) requirements. The 'critical nitrogen dilution curve' is a powerful tool to characterize such N requirements; it relates the N concentration ([N]) in aboveground organs to their biomass, defining two domains depending on whether the N factor limits biomass growth or not. We aimed to develop such a tool in miscanthus. Using a rhizome N depletion strategy with green cutting pre-treatment over several years before the start of the experiment, we grew, in 2014, two cultivated species, Miscanthus x giganteus (Mxg) and Miscanthus sinensis (Msin), at four fertilizer levels (0, 80, 160 and 240 kg N ha.sup.-1). We found a strong nitrogen fertilization effect. The shoot [N] decreased as the aboveground biomass increased in both species and in all of the treatments. [N] was strongly correlated with leaf/stem biomass ratio. The N treatments enabled the identification of the observed critical points, i.e. points with the maximum biomass (W) and the lowest [N], on each measurement date. These points could be fitted to the following critical dilution curve that was common between Mxg and Msin: N concentration (Nc) (critical [N], g N kg.sup.-1) = 27.0 W.sup.-0.48 when W > 1 t ha.sup.-1 and Nc = 27.0 when W [less than or equal to] 1. This curve was validated by literature data, separated into N-limited or not-limited conditions. The similarity of the curves between the two species was due to compensation between leaf/stem biomass ratio and [N] in the stems. This curve is helpful to diagnose the crop N status and define the optimal fertilizer requirements of miscanthus crops.

The recirculations are essential in river engineering because they form silting zones and favour the development of specific fauna and flora. This paper deals with the behaviour of the recirculation zones occurring downstream the sudden expansion of an open channel. An Acoustic Doppler Velocimeter is used to measure the flow details. The mean flow property such as the length of the recirculation, the average velocity field and velocity gradient are obtained. Then the self-similarity of the velocity profile is retrieved . The numerical simulation for the similar conditions are preformed with the CFD software STAR CCM+. When compared with the experiments, the two approaches correspond well in terms of length of recirculation zone and also regarding details such as the velocity gradient profiles. Finally, the eddy viscosity concept is tested and the turbulent viscosity coefficient are obtained along the streamwise axis for all flows.

Daytime functioning is impaired in people with insomnia disorder. Currently available dual orexin receptor antagonists have shown efficacy in insomnia disorder, but do not address all aspects of this disease. We aimed to assess safety and efficacy of daridorexant, a novel orexin receptor antagonist, on night-time and daytime symptoms of insomnia. We did two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials at 156 sites in 18 countries. Adults (aged ≥18 years) with insomnia disorder were randomly assigned using interactive response technology (1:1:1) to receive daridorexant 50 mg, 25 mg, or placebo (study 1) or daridorexant 25 mg, 10 mg, or placebo (study 2) every evening for 3 months. Participants, investigators, and site personnel were masked to treatment allocation. The primary endpoints were change from baseline in wake time after sleep onset (WASO) and latency to persistent sleep (LPS), measured by polysomnography, at months 1 and 3. The secondary endpoints were change from baseline in self-reported total sleep time and the sleepiness domain score of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) at months 1 and 3. Study-wise type I error rate (5%) was controlled for all pairwise comparisons. Efficacy was analysed in all randomly assigned participants, and safety in all participants who received at least one dose of treatment. The studies are registered at ClinicalTrials.gov, NCT03545191 (study 1) and NCT03575104 (study 2). Between June 4, 2018 and Feb 25, 2020, 930 participants were randomly assigned to receive daridorexant 50 mg (n=310), daridorexant 25 mg (n=310), or placebo (n=310) in study 1. Between May 29, 2018, and May 14, 2020, 924 participants were randomly assigned to receive daridorexant 25 mg (n=309), daridorexant 10 mg (n=307), or placebo (n=308) in study 2. In study 1, WASO and LPS were significantly reduced among participants in the daridorexant 50 mg group compared with participants in the placebo group at month 1 (least squares mean [LSM] difference −22·8 min [95% CI −28·0 to −17·6], p<0·0001 for WASO; –11·4 min [−16·0 to −6·7], p<0·0001 for LPS) and month 3 (−18·3 min [−23·9 to −12·7], p<0·0001 for WASO; −11·7 min [−16·3 to −7·0], p<0·0001 for LPS). WASO and LPS were significantly reduced among participants in the daridorexant 25 mg group compared with the placebo group at month 1 (LSM difference −12·2 min [−17·4 to −7·0], p<0·0001 for WASO; –8·3 min [−13·0 to −3·6], p=0·0005 for LPS) and month 3 (−11·9 min [−17·5 to −6·2], p<0·0001 for WASO; −7·6 min [−12·3 to −2·9], p=0·0015 for LPS). Compared with placebo, participants in the daridorexant 50 mg group had significantly improved self-reported total sleep time at month 1 (LSM difference 22·1 min [14·4 to 29·7], p<0·0001) and month 3 (19·8 min [10·6 to 28·9], p<0·0001), and IDSIQ sleepiness domain scores at month 1 (–1·8 [–2·5 to –1·0], p<0·0001) and month 3 (–1·9 [–2·9 to –0·9], p=0·0002). Compared with the placebo group, participants in the daridorexant 25 mg group had significantly improved self-reported total sleep time at month 1 (LSM difference 12·6 min [5·0 to 20·3], p=0·0013) and month 3 (9·9 min [0·8 to 19·1], p=0·033), but not IDSIQ sleepiness domain scores (–0·8 [–1·5 to 0·01], p=0·055 at month 1; –1·0 [–2·0 to 0·01], p=0·053 at month 3). In study 2, WASO was significantly reduced among participants in the daridorexant 25 mg group compared with participants in the placebo group at month 1 (LSM difference −11·6 min [−17·6 to −5·6], p=0·0001) and month 3 (−10·3 min [−17·0 to −3·5], p=0·0028), whereas no significant differences in LPS were observed at month 1 (–6·5 min [–12·3 to –0·6], p=0·030) or month 3 (–9·0 [–15·3 to –2·7], p=0·0053). Compared with the placebo group, participants in the daridorexant 25 mg group had significant improvement in self-reported total sleep time at month 1 (LSM difference 16·1 min [8·2 to 24·0], p<0·0001) and month 3 (19·1 [10·1 to 28·0], p<0·0001), but not in IDSIQ sleepiness domain scores (–0·8 [–1·6 to 0·1], p=0·073 at month 1; –1·3 [–2·2 to –0·3], p=0·012 at month 3). Compared with the placebo group, no significant differences were observed among participants in the daridorexant 10 mg group for WASO (LSM difference –2·7 min [–8·7 to 3·2], p=0·37 at month 1; –2·0 [–8·7 to 4·8], p=0·57 at month 3), LPS (–2·6 min [–8·4 to 3·2], p=0·38 at month 1; –3·2 min [–9·5 to 3·1], p=0·32 at month 3), self-reported total sleep time (13·4 min [5·5 to 21·2], p=0·0009 at month 1; 13·6 min [4·7 to 22·5], p=0·0028 at month 3), nor IDSIQ sleepiness domain scores (–0·4 [–1·3 to 0·4], p=0·30 at month 1; –0·7 [–1·7 to 0·2], p=0·14 at month 3). Overall incidence of adverse events was comparable between treatment groups (116 [38%] of 308 participants in the daridorexant 50 mg group, 117 [38%] of 310 in the daridorexant 25 mg group, and 105 [34%] of 309 in the placebo group in study 1; 121 [39%] of 308 participants in the daridorexant 25 mg group, 117 [38%] of 306 in the daridorexant 10 mg group, and 100 [33%] of 306 in the placebo group). Nasopharyngitis and headache were the most common adverse events in all groups. One death (cardiac arrest) occurred in the daridorexant 25 mg group in study 1, which was not deemed to be treatment-related. Daridorexant 25 mg and 50 mg improved sleep outcomes, and daridorexant 50 mg also improved daytime functioning, in people with insomnia disorder, with a favourable safety profile. Idorsia Pharmaceuticals.