Impact of Lung Function on Asthma Exacerbation Rates in Children Treated with Dupilumab: The VOYAGE Study.

Background: Severe, uncontrolled asthma and asthma exacerbations in children are associated with abnormal lung function and airway development, and increased risk of chronic obstructive lung disease in adulthood. The rationale for this post hoc analysis was to explore the relationship between changes in asthma exacerbation rates and lung function in children treated with dupilumab. Methods: This post hoc analysis included children aged 6 to 11 years with uncontrolled, moderate-to-severe type 2 asthma (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide ≥20 ppb) who received dupilumab or placebo in the phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959). Endpoints were the proportion of patients achieving clinically meaningful improvements (≥5% or ≥10%) in pre-bronchodilator percent-predicted forced expiratory volume in 1 second (ppFEV1) by Week 12, annualized severe asthma exacerbation rates from Week 12-52, and mean change from baseline in ppFEV1 to Week 12. Results: At Week 12 of VOYAGE, 141/236 (60%) of children treated with dupilumab and 57/114 (50%) of children receiving placebo showed improvements of ≥5% in ppFEV1; 106/236 (45%) children receiving dupilumab and 36/114 (32%) receiving placebo achieved improvements in ppFEV1 ≥10%. During the Week 12-52 treatment period, dupilumab vs placebo significantly reduced severe exacerbation rates in all subgroups by 52-60% (all P<0.05). Dupilumab treatment resulted in rapid and sustained improvements in ppFEV1 (Week 12 least squares mean difference [95% CI] vs placebo: 3.54 [0.30, 6.78] percentage points; P=0.03) in children who achieved improvements of ≥5%. Conclusion: Dupilumab vs placebo significantly improved pre-bronchodilator ppFEV1, with a higher proportion of patients achieving a clinically meaningful response at Week 12. Dupilumab also significantly reduced severe exacerbation rates, independent of pre-bronchodilator ppFEV1 response at Week 12. Trial Registration: NCT02948959.

Long-term efficacy of dupilumab in severe asthma by baseline oral corticosteroid dose.

Background: Dupilumab has been shown to improve clinical outcomes long term while reducing oral corticosteroid (OCS) dose in patients with severe OCS-dependent asthma. This post hoc analysis assesses the impact of OCS dose at baseline (≤10 or >10 mg·day-1) on long-term outcomes of dupilumab treatment. Methods: Annualised severe asthma exacerbation rates, forced expiratory volume in 1 s (FEV1), measures of asthma control and quality of life, and OCS dose were evaluated in patients from the phase 3 VENTURE trial with severe OCS-dependent asthma, further categorised by OCS dose ≤10 or >10 mg·day-1 at parent study baseline (PSBL), who enrolled in TRAVERSE. Results: Dupilumab reduced the annualised exacerbation rate in VENTURE, and it remained low throughout TRAVERSE (0.202-0.265 (OCS ≤10 mg·day-1 at PSBL) and 0.221-0.366 (OCS >10 mg·day-1 at PSBL)). Improvements in pre-bronchodilator FEV1, asthma control and quality of life observed in VENTURE dupilumab patients were sustained throughout TRAVERSE. Patients on placebo during VENTURE showed rapid improvements in FEV1 upon initiating dupilumab in TRAVERSE, which were sustained to the end of TRAVERSE. Reductions in OCS dose observed in VENTURE were maintained throughout TRAVERSE, with more than two-thirds of patients achieving reductions in OCS doses to ≤5 mg·day-1 by TRAVERSE week 48. Conclusions: Improvements in clinical outcomes and reductions in OCS dose with dupilumab observed in VENTURE were maintained throughout TRAVERSE, regardless of baseline disease severity. Patients who switched from placebo in VENTURE to dupilumab in TRAVERSE had improved clinical outcomes and reductions in OCS dose comparable to those given dupilumab in VENTURE.

Dupilumab pharmacokinetics and effect on type 2 biomarkers in children with moderate-to-severe asthma.

BACKGROUND: Type 2 inflammation is common in children with asthma. Dupilumab, a human antibody, blocks the signaling of interleukin -4 and -13, key and central drivers of type 2 inflammation. In the LIBERTY ASTHMA VOYAGE (NCT02948959) study, dupilumab reduced severe asthma exacerbations and improved lung function in children aged 6 to 11 years with uncontrolled, moderate-to-severe asthma. OBJECTIVE: To assess the pharmacokinetics of dupilumab and type 2 biomarker changes in children with type 2 asthma in VOYAGE. METHODS: Patients were randomized to dupilumab 100 mg (≤30 kg) or 200 mg (>30 kg) or placebo every 2 weeks for 52 weeks. Dupilumab concentrations and changes in type 2 biomarkers were assessed at each visit. RESULTS: Dupilumab concentrations in serum reached a steady state by week 12, with mean concentrations of 51.2 mg/L and 79.4 mg/L in children receiving dupilumab 100 mg every 2 weeks and 200 mg every 2 weeks, respectively (therapeutic range in adults and adolescents: 29-80 mg/L). Reductions in type 2 biomarkers were comparable between regimens, and greater in patients treated with dupilumab vs placebo. In children treated with dupilumab 100 mg and 200 mg every 2 weeks, the median percent changes (Q1-Q3) from baseline at week 52 were, respectively, -78.6% (-86.3 to -69.80) and -78.6% (-84.9 to -70.1) for serum total immunoglobulin E, -53.6% (-66.4 to -34.6) and -43.7% (-58.6 to -28.5) for thymus and activation-regulated chemokine; -25.7% (-60.0 to 27.6) and -33.3% (-60.6 to 16.6) for blood eosinophils, and -47.7% (-73.8 to 18.9) and -55.6% (-73.6 to -20.0) for fractional exhaled nitric oxide. CONCLUSION: Weight-tiered dose regimens achieved mean concentrations within the dupilumab therapeutic range. The median decreases in type 2 biomarker levels were similar between dose regimens. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02948959.

Dupilumab-Treated Patients with Asthma in the Real World: The RAPID Global Registry.

BACKGROUND: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation. In clinical studies, dupilumab reduced the risk of severe asthma exacerbations, and improved forced expiratory volume in 1 s and quality of life in patients with uncontrolled moderate-to-severe asthma. OBJECTIVES: The objectives of RAPID (NCT04287621) are to characterize patients with asthma initiating dupilumab in routine clinical practice and to collect information on long-term effectiveness and safety in these patients. METHODS: RAPID is a global, prospective, observational registry that will enroll approximately 1000 patients (aged ≥ 12 years) with asthma from 150 sites globally. Dupilumab treatment will be initiated in routine clinical practice according to country-specific prescribing information, per physician discretion as part of routine care. Patients will be followed prospectively for up to 3 years, with postbaseline assessments at months 1 and 3, and every 3 months thereafter. PLANNED OUTCOMES: Baseline data collected will include patient demographics, disease characteristics, and medication history. Patient adherence and persistence will be recorded alongside health-care resource utilization, and effectiveness of dupilumab will be assessed (clinician assessment) as per standard of care. Quality of life, asthma control, type 2 inflammatory comorbidities, work productivity, and physical activity limitation will be assessed. Incidence and severity of adverse events will be recorded. CONCLUSION: RAPID is the first global registry to characterize patients beginning dupilumab treatment for asthma in clinical practice and will expand on prior clinical studies by providing real-world data. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04287621.

Divalent Yb-Doped Silica Glass and Fiber with High Quantum Efficiency for White Light Source.

The 4f135d-4f14 energy transition of Yb2+ ions can cover the whole white light wavelength, Yb2+-doped materials have thus been a hot research field. In order to obtain a white light source, many kinds of Yb2+-doped materials have been prepared. In this study, divalent Yb2+-doped silica fiber was fabricated using rod-in-tube technology. The fiber core of Yb2+-doped silica glass was prepared with high-temperature melting technology under vacuum conditions. The spectroscopic properties of the Yb2+-doped glass and fiber were studied. The experiments indicate that divalent Yb2+-doped glass has a high quantum efficiency and super-broadband fluorescence in the visible region with an excitation wavelength of 405 nm. In addition, the results suggest that Yb2+-doped fiber has a potential for application in visible fiber lasers and fiber amplification.

High-order orbital angular momentum generation in a helically twisted pig-nose-shaped core microstructured optical fibers.

We propose a helically twisted pig-nose-shaped core microstructured optical fiber (HPC-MOF) for orbital angular momentum (OAM) mode generation. It comprises seven air-hole rings hexagonally arranged with two air holes and one air-hole ring replaced, forming two cores in a line 3 µm from the fiber center and one ring-shaped core. The fiber is helically twisted along the rotation axis. In this fiber, supermodes in inner dual-core can be coupled to high-order modes in outer ring-core, yielding OAM ring-shaped modes at different certain wavelengths, and various OAM modes at different twist rates were investigated in this paper. We demonstrate the distinct coupling differences of symmetric and antisymmetric supermodes in inner dual-core when the supermode coupled to ring-core mode. A modal matching rule is presented to characterize the coupling differences, which is suitable for describing supermode coupling characteristics in HPC-MOFs. Compared to conventional methods, these properties indicate that the fiber can generate higher-order OAM modes and more easily integrate into all-fiber optical communication systems, with potential in OAM generators, light-controlling devices, and integrated optics applications.

Orbital-angular-momentum-amplifying helical vector modes in Yb3+-doped three-core twisted microstructure fiber.

A helical Yb3+-doped three-core microstructure fiber (YTMF) amplifier is proposed in this paper, so as to solve the problem of generation and transmission of the orbital angular momentum (OAM) beams. The fiber is composed of three Yb3+-doped cores with a regular triangle shape and a longitudinal helical structure. The experimental results show that the 1064nm laser can be amplified due to the fluorescence amplification characteristics of the doped material Yb3+. Furthermore, theoretical analysis indicates the modes in YTMF at 1064nm, which is located in the amplified wavelength, can support nine modes carrying OAM. Therefore, the related experiments were performed and verified that the transmission modes can respectively carry 1, 2, and 3-order OAM at 1064nm in different coupling cases. These excellent properties indicate that the combination of doped materials and helical fiber provide favorable conditions for the generation and amplification of OAM, which provides a basis for the further development of OAM beams in the field of quantum communication and dense space division multiplexing.

Multi-functional double rare-earth-doped ball sensor based on a hollow-core microstructure fiber.

In this Letter, we demonstrated an ∞-type multi-functional sensor through splicing double rare-earth-doped balls (REDBs) with a hollow-core microstructure fiber. Utilizing the different thermal expansion and thermo-optic coefficients of silica and rare earth, the interference of REDBs will be more sensitive to temperature. On both ends of the dual-ball, we spliced the anti-resonance fiber (ARF) to satisfy the broad waveband transmission. In addition, the special anti-resonance loss peak of the ARF can make the amplitude change of the signal more obvious. The experiments prove that a multi-functional sensor is capable of detecting versatile parameters, such as the illumination response, liquid concentration, and ambient temperature. In addition, the temperature sensitivity can reach 1 nm/°C, and the illumination response is obvious. We also analyze the concentration of P-Methylthiophenol, a substance harmful to human beings in the environment. Its resolution can reach 3.125E-5 mol/L. These results indicate that the sensor can be used in underground mine detection, environmental monitoring, and so on.

Sensitive real-time monitoring of refractive indices and components using a microstructure optical fiber microfluidic sensor.

Based on the surface plasmon resonance of metal and anti-resonant principles of hole-core microstructure optical fiber (MSF), in this Letter, we demonstrate a MSF microfluidic sensor that combines silver film and hole-core MSF to achieve the sensitive real-time monitoring of refractive indices and components. The large hole core is a common channel for guiding light and flowing measured liquid. Because of the interaction between light and continuous flow measured liquid, the component and refractive indices can be simultaneously monitored by the characteristic absorption wavelength and the surface plasmon resonant peak position, respectively. These results indicate that the MSF microfluidic sensor is an ideal multi-parameter measurement optical sensor.

[Research on spectral characteristics of Yb3+ doped double-cladding large-mode-area micro-structured optical fiber].

Yb3+ doped double-cladding large-mode-area micro-structured optical fibers (Micro-structured fibers, MSF) are the ideal medium for the super high-power optical fiber laser applications. In the present paper, the authors fabricated the Yb3+ doped silica-based glass using the method of non-chemical vapor deposition, and fabricated the Yb3+ doped double-cladding large-mode-area MSF by stack-drawing method using this glass as the core of MSF, according to the design requirements. Fluorescence spectrum of the MSF was obtained using Ti: sapphire femtosecond laser with the wavelength of 975 nm and LD laser with the wavelength of 980 nm as pumping source. The experimental results show that the optical fiber has strong fluorescence at the wavelength of 1 050 nm, and it can inhibit generation of cooperative luminescence effectively.

[Investigation on the fabrication and spectrum properties of Yb3+ -doped silicate laser glasses].

Two kinds of Yb3+ doped silicate laser glass with little difference were produced by high temperature of melting process. The absorption and emission spectra of the two glass samples were tested by the correlative spectrographs; the integral absorption cross section, stimulated emission cross section, fluorescence line-width, fluorescence lifetime, least particle count, saturation pump intensity and least pump intensity of the Yb3+ -doped laser glasses were calculated respectively, and by comparison it was found that the chart of the absorption cross section is similar to the stimulated emission cross section calculated by the reciprocity method, and is very different from the stimulated emission cross section calculated by the Fuchbauer-Ladenburger method. This result is precisely in line with the theoretical analysis. The line-types of the absorption spectra of the two glass samples are almost the same, and the first peak value of absorption is located at 975 nm while the second peak value is at 908 nm. As the two components of the samples are not very different, the accord of the line-types of the absorption spectra indicates that the makeup of the glass material is the primary factor influencing the line-type of the absorption spectra. The fluorescence spectra of the two glass samples are very different, and the first fluorescence peak value of sample one is located at 993 nm with the second peak value at 1029 nm, while the first fluorescence peak value of sample two is located at 1 035 nm with the second peak value at 994 nm. The cause of the major difference in the fluorescence spectra of two samples lies in the different doping density of Yb3+. By comparison we found that the laser performance of sample two is better than that of sample one. The test shows that both samples are suitable for drawing fiber.