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BackgroundDupilumab (monoclonal antibody inhibiting IL-4/IL-13 signalling) is approved for use in adolescents aged ≥ 12 years with inadequately controlled moderate-to-severe atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16-week, randomised, placebo-controlled phase III trial in adolescents (NCT03054428).ObjectivesTo characterize the pharmacokinetics of dupilumab, and long-term safety and efficacy in adolescents.MethodsThis was a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study with a phase III open-label extension (OLE) in adolescents with moderate-to-severe AD. In the phase IIa study, patients received one dupilumab dose (2 mg kg-1 or 4 mg kg-1 ) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8-week safety follow-up. Patients then enrolled in the OLE, continuing 2 mg kg-1 or 4 mg kg-1 dupilumab weekly. Primary end points were dupilumab concentration-time profile and incidence of treatment-emergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI).ResultsForty adolescents received dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, target-mediated pharmacokinetics. Mean ± SD trough dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg L-1 and 161 ± 60 mg L-1 for 2 mg kg-1 and 4 mg kg-1 , respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kg-1 ], 47% [4 mg kg-1 ]) and AD exacerbation (29%, 42%). After one dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean ± SD reduction -34% ± 20% (2 mg kg-1 ) and -51% ± 29% (4 mg kg-1 )]. With continuing treatment, EASI scores improved further [week 52: -85% ± 12% (2 mg kg-1 ) and -84% ± 20% (4 mg kg-1 )].ConclusionsIn adolescents with moderate-to-severe AD, dupilumab's pharmacokinetic profile was similar to that in a

Background: Dupilumab (DPL), a fully human monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13, key drivers of type 2 inflammation. In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), add-on DPL 200 or 300 mg every 2 weeks (q2w) vs matched placebo (PBO) reduced severe asthma exacerbations and improved pre-bronchodilator (BD) FEV1 in patients (pts) with uncontrolled, moderate-to-severe asthma. Treatment effects were greater with elevated levels of type 2 biomarkers at baseline (BL). Aim(s): To assess DPL efficacy in pts with moderate asthma defined as asthma pts with BL pre-BD FEV 60-80% predicted (60-90% in adolescents), on medium-dose ICS and >=1 controller, without a minimum requirement for BL blood eosinophil count or FeNO. Method(s): Negative binomial models were used to analyze annualized severe asthma exacerbation rates during the 52-week treatment period and mixed-effects models with repeated measures were used to analyze change from BL in pre-BD FEV1 at Week 12. Result(s): 517/1,902 pts (27%) had pre-BD FEV 60-80% predicted and were on medium-dose ICS at BL. In these pts, DPL 200/300mg q2w reduced annualized severe exacerbation rates by 44%/51% respectively vs PBO (P=0.06/P=0.01). DPL 200/300mg q2w vs PBO also improved FEV at Week 12 with a LS mean difference of 0.11L/0.09L, respectively (P=0.01/P=0.05). Overall, the most frequent adverse event in DPL 200/300mg vs PBO groups was injection-site reaction (15%/18% vs 5%/10%). Conclusion(s): Dupilumab meaningfully reduced severe exacerbations and improved FEV1 in moderate asthma pts with pre-BD FEV 60-80% predicted and on medium-dose ICS, and was generally well tolerated.

Background: Dupilumab (DPL), a fully human monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13, key drivers of type 2 inflammation. In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), add-on DPL 200 or 300 mg every 2 weeks (q2w) vs matched placebo (PBO) reduced severe asthma exacerbations and improved pre-bronchodilator (BD) FEV1 in patients (pts) with uncontrolled, moderate-to-severe asthma. Treatment effects were greater with elevated levels of type 2 biomarkers at baseline (BL). Aim(s): To assess DPL efficacy in pts with moderate asthma defined as asthma pts with BL pre-BD FEV 60-80% predicted (60-90% in adolescents), on medium-dose ICS and >=1 controller, without a minimum requirement for BL blood eosinophil count or FeNO. Method(s): Negative binomial models were used to analyze annualized severe asthma exacerbation rates during the 52-week treatment period and mixed-effects models with repeated measures were used to analyze change from BL in pre-BD FEV1 at Week 12. Result(s): 517/1,902 pts (27%) had pre-BD FEV 60-80% predicted and were on medium-dose ICS at BL. In these pts, DPL 200/300mg q2w reduced annualized severe exacerbation rates by 44%/51% respectively vs PBO (P=0.06/P=0.01). DPL 200/300mg q2w vs PBO also improved FEV at Week 12 with a LS mean difference of 0.11L/0.09L, respectively (P=0.01/P=0.05). Overall, the most frequent adverse event in DPL 200/300mg vs PBO groups was injection-site reaction (15%/18% vs 5%/10%). Conclusion(s): Dupilumab meaningfully reduced severe exacerbations and improved FEV1 in moderate asthma pts with pre-BD FEV 60-80% predicted and on medium-dose ICS, and was generally well tolerated.

BackgroundDupilumab (monoclonal antibody inhibiting IL-4/IL-13 signalling) is approved for use in adolescents aged ≥ 12 years with inadequately controlled moderate-to-severe atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16-week, randomised, placebo-controlled phase III trial in adolescents (NCT03054428).ObjectivesTo characterize the pharmacokinetics of dupilumab, and long-term safety and efficacy in adolescents.MethodsThis was a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study with a phase III open-label extension (OLE) in adolescents with moderate-to-severe AD. In the phase IIa study, patients received one dupilumab dose (2 mg kg-1 or 4 mg kg-1 ) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8-week safety follow-up. Patients then enrolled in the OLE, continuing 2 mg kg-1 or 4 mg kg-1 dupilumab weekly. Primary end points were dupilumab concentration-time profile and incidence of treatment-emergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI).ResultsForty adolescents received dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, target-mediated pharmacokinetics. Mean ± SD trough dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg L-1 and 161 ± 60 mg L-1 for 2 mg kg-1 and 4 mg kg-1 , respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kg-1 ], 47% [4 mg kg-1 ]) and AD exacerbation (29%, 42%). After one dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean ± SD reduction -34% ± 20% (2 mg kg-1 ) and -51% ± 29% (4 mg kg-1 )]. With continuing treatment, EASI scores improved further [week 52: -85% ± 12% (2 mg kg-1 ) and -84% ± 20% (4 mg kg-1 )].ConclusionsIn adolescents with moderate-to-severe AD, dupilumab's pharmacokinetic profile was similar to that in a

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This paper presents the results of the computational-fluid-dynamics code XFlow for the test case proposed in the 2nd High-Lift Prediction Workshop. The target of this international workshop is to assess the accuracy of numerical predictions provided by a wide selection of computational-fluid-dynamics codes and applied to the aeronautical industry. It deals with a full aircraft in high-lift configuration with unstowed flap and slat, including slat tracks, flap track fairings, and slat pressure tube bundles. XFlow is a particle-based kinetic solver, based on the lattice Boltzmann method. It is well suited for such low-speed flows because the standard lattice Boltzmann method is limited to low Mach number. It employs large-eddy simulation turbulence modeling with the wall-adapting local eddy model, coupled with a generalized law of the wall to model the boundary-layer prediction. Traditional computational-fluid-dynamics software requires a time-consuming meshing process that is prone to errors, which significantly affects the mesh quality and thus the outcome of a simulation. Furthermore, the complex geometries such as elements in small gaps add an extra complication to generate the mesh. In contrast, the method employed by XFlow avoids the traditional meshing process using an octree structure, with spatial refinement related by a factor of 2 based on the input geometry. The discretization stage is strongly accelerated, thus reducing engineering costs and complex geometry computations are affordable in a straightforward way. The research presented in this paper starts with a grid validation study (case 1) with the DLR F11 geometry in configuration 2. Because the lattice Boltzmann method approach used by XFlow simplifies the integration of geometrical details, the full polar characteristic is directly investigated with configuration 5 (case 3) that includes the actual model configuration on the aerodynamic performances. The configuration 5 geometry includes slat tracks

The terminal Pleistocene and Early Holocene, a period from 15 000 to 18 000 Before Present (BP), was critical in establishing the current Holarctic fauna, with temperate-climate species largely replacing cold-adapted ones at mid-latitudes. However, the timing and nature of this process remain unclear for many taxa, a point that impacts on current and future management strategies. Here, we use an ancient DNA dataset to test more directly postglacial histories of the water vole (Arvicola amphibius, formerly A terrestris), a species that is both a conservation priority and a pest in different parts of its range. We specifically examine colonization of Britain, where a complex genetic structure can be observed today. Although we focus on population history at the limits of the species' range, the inclusion of additional European samples allows insights into European postglacial colonization events and provides a molecular perspective on water vole taxonomy.