Impact of prior lenalidomide or proteasome inhibitor exposure on the effectiveness of ixazomib-lenalidomide-dexamethasone for relapsed/refractory multiple myeloma: A pooled analysis from the INSURE study.

OBJECTIVES: To characterize the impact of prior exposure and refractoriness to lenalidomide or proteasome inhibitors (PIs) on the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma (RRMM). METHODS: INSURE is a pooled analysis of adult RRMM patients who had received IRd in ≥2 line of therapy from three studies: INSIGHT MM, UVEA-IXA, and REMIX. RESULTS: Overall, 391/100/68 were lenalidomide-naïve/-exposed/-refractory and 37/411/110 were PI-naïve/-exposed/-refractory. Median duration of therapy (DOT) was 15.3/15.6/4.7 months and median progression-free survival (PFS) was 21.6/25.8/5.6 months in lenalidomide-naïve/exposed/refractory patients. Median DOT and PFS in PI-naïve/exposed/refractory patients were 20.4/15.2/6.9 months and not reached/19.8/11.4 months, respectively. The proportion of lenalidomide-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to adverse events (AEs) was ixazomib, 31.6/28.2/28.0% and 18.6/6.7/10.5%; lenalidomide, 21.9/28.2/16.0% and 16.1/6.7/10.5%; dexamethasone, 18.4/20.5/16.0% and 10.6/0/10.5%, respectively. The proportion of PI-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to AEs was: ixazomib, 44.4/28.8/27.8% and 22.2/16.7/15.7%; lenalidomide, 33.3/22.0/19.4% and 16.7/15.9/11.8%; dexamethasone, 33.3/17.4/16.7% and 16.7/9.5/7.8%, respectively. REMIX AE discontinuation rates were unavailable. CONCLUSION: IRd appeared to be effective in RRMM patients in routine clinical practice regardless of prior lenalidomide or PI exposure, with better outcomes seen in lenalidomide- and/or PI-nonrefractory versus refractory patients.

In-class transition from bortezomib-based therapy to IRd is an effective approach in newly diagnosed multiple myeloma.

Aim: To compare the effectiveness of in-class transition to all-oral ixazomib-lenalidomide-dexamethasone (IRd) following parenteral bortezomib (V)-based induction versus continued V-based therapy in US oncology clinics. Patients & methods: Non-transplant eligible patients with newly diagnosed multiple myeloma (MM) receiving in-class transition to IRd (N = 100; US MM-6), or V-based therapy (N = 111; INSIGHT MM). Results: Following inverse probability of treatment weighting, overall response rate was 73.2% with IRd versus 57.5% with V-based therapy (p < 0.0001). Median duration of treatment was 10.8 versus 5.3 months (p < 0.0001). Overall, 18/24% of patients discontinued IRd/V-based therapy due to adverse events. Conclusion: IRd after V-based induction was associated with significantly improved overall response rate and duration of treatment than continued V-based combination therapy. Clinical Trial Registration: US MM-6: NCT03173092; INSIGHT MM: NCT02761187 (ClinicalTrials.gov).

INSURE: a pooled analysis of ixazomib-lenalidomide-dexamethasone for relapsed/refractory myeloma in routine practice.

Aim: We pooled data from three observational studies (INSIGHT MM, UVEA-IXA and REMIX) to investigate the real-world effectiveness of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory myeloma. Materials & methods: INSIGHT MM was a prospective study conducted in countries across Europe, Asia and North/Latin America while UVEA-IXA and REMIX were multicenter, retrospective/prospective studies conducted in Europe. Patients who had received IRd as ≥2nd line of therapy were analyzed. Primary outcomes were time-to-next treatment (TTNT) and progression-free survival (PFS). Results: Overall, 564 patients were included (median follow-up: 18.5 months). Median TTNT and PFS were 18.4 and 19.9 months; both outcomes were numerically longer for earlier versus later lines. Median treatment duration was 14.0 months. Overall response rate was 64.6%. No new safety concerns were noted. Conclusion: The effectiveness of IRd in routine practice appears similar to the efficacy observed in TOURMALINE-MM1. IRd benefit in earlier versus later lines was consistent with previous reports.

Economic burden in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), with or without brain metastases, receiving first-line ALK inhibitors.

INTRODUCTION: This observational study describes the real-world economic burden in patients with anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) receiving a first-line ALK inhibitor, and the economic impact of brain metastases (BM). METHODS: Administrative claims data (Truven Health MarketScan® Commercial Claims and Encounters database and Medicare Supplemental and Coordination of Benefits database; January 1, 2015-March 31, 2020) for adult patients with ALK+ NSCLC who received a first-line ALK inhibitor were retrospectively reviewed. Healthcare costs and resource utilization were calculated on a per-patient-per-month (PPPM) basis and stratified by the presence or absence of BM prior to first-line ALK inhibitor. Factors associated with costs were identified. RESULTS: A total of 496 patients were eligible for analysis. Mean PPPM total healthcare costs were $21,961 for all patients receiving up to 1 year of a first-line ALK inhibitor. Patients were significantly more likely to have higher mean PPPM total costs if they had BM prior to first-line ALK inhibitor (vs. no BM; odds ratio: 1.11; 95% confidence interval: 1.02, 1.21; p = 0.013). Mean PPPM days of hospital stay (p = 0.0056), and inpatient hospital visits (p = 0.0030) were significantly higher for patients with BM compared to no BM. The main cost drivers for non-inpatient procedures for all patients were medications, radiation therapy, and other diagnostic procedures. CONCLUSIONS: The economic burden in patients with ALK+ NSCLC receiving a first-line ALK inhibitor was high. Patients with ALK+ NSCLC and BM had higher healthcare costs and resource utilization than patients without BM.

Flexible wavelength-, pulse-controlled mode-locked all-fiber laser based on a fiber Lyot filter.

In this paper, we report a flexible wavelength-, pulse-controlled mode-locked all-fiber laser based on a novel fiber optic Lyot filter. The wavelength, pulse duration and spectral bandwidth of passive mode-locked lasers can be tuned by controlling the polarization controller. The proposed Lyot filter was constructed by a single-mode fiber insertion between two polarization-maintaining fibers. The filter bandwidth and laser output tunability were based on the birefringence characteristics of the polarization-maintaining fibers. This all-fiber laser is simple and stable and can be used for various applications where width-tunable or wavelength-tunable pulses are necessary.

Ultra-broadband flat-top circular polarizer based on chiral fiber gratings near the dispersion turning point.

Based on the dual-resonance principle around the dispersion turning point, a scheme of chiral long-period fiber gratings (CLPGs) formed by twisting a high-birefringence (Hi-Bi) fiber is herein proposed to realise ultra-broadband flat-top circular polarizers. The coupling bandwidth is approximately seven times larger than that of traditional CLPGs. In addition, by introducing chirp characteristics in these CLPGs, an ultra-broadband flat-top circular polarizer with ∼200 nm@3 dB was conveniently achieved. Subsequently, by optimising the chirped CLPGs, a circular polarizer with a bandwidth extinction ratio of approximately 30 dB and a high level of ∼100 nm at 1 dB was realised. It was shown that the mode-controlling performances of the CLPGs can be remarkably improved, which has significant applications in light-field regulation. Finally, for the first time, it was proved that the CLPG cannot generate a vortex beam.

Excitation of high-quality orbital angular momentum vortex beams in an adiabatically helical-twisted single-mode fiber.

A novel method to control the parameters of a chiral fiber grating structure is proposed. Mode couplings are controlled in real time during the twisting fabrication process. This chiral grating structure can satisfy the phase-matching condition for generating high-quality orbital angular momentum (OAM) beams, with an order mode of conversion efficiency over 99.9%. Both theoretical analysis and experimental results of this OAM mode conversion have been investigated, with good agreement. The results demonstrate a dual-OAM beam converter with a charge of ±1 for the right- and left-handed CLPGs, respectively. The high-quality OAM beam generated in this twisted single-mode fiber process may find excellent applications in optical communications.

Ixazomib-lenalidomide-dexamethasone in routine clinical practice: effectiveness in relapsed/refractory multiple myeloma.

Aim: To evaluate the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma in routine clinical practice. Patients & methods: Patient-level data from the global, observational INSIGHT MM and the Czech Registry of Monoclonal Gammopathies were integrated and analyzed. Results: At data cut-off, 263 patients from 13 countries were included. Median time from diagnosis to start of IRd was 35.8 months; median duration of follow-up was 14.8 months. Overall response rate was 73%, median progression-free survival, 21.2 months and time-to-next therapy, 33.0 months. Ixazomib/lenalidomide dose reductions were required in 17%/36% of patients; 32%/30% of patients discontinued ixazomib/lenalidomide due to adverse events. Conclusion: The effectiveness and safety of IRd in routine clinical practice are comparable to those reported in TOURMALINE-MM1. Clinical trial registration: NCT02761187 (ClinicalTrials.gov).

Lay abstract Proteasome inhibitors are drugs used in multiple myeloma (MM), a blood cancer that develops from cells in the bone marrow. Ixazomib is the first oral proteasome inhibitor to be approved for use in MM, when given in combination with two other oral drugs, lenalidomide and dexamethasone, to adult patients who have received one prior therapy. Our study, which was conducted in routine clinical practice, found that the effectiveness and safety of ixazomib + lenalidomide + dexamethasone in previously treated MM patients were similar to those seen in the Phase III clinical trial on which approval was based. These findings are important because they suggest that MM patients in everyday practice can achieve the same benefits from this treatment as patients in clinical trials, despite often being in poorer health.

Strong circular dichroism enhancement by plasmonic coupling between graphene and h-shaped chiral nanostructure.

Circular dichroism (CD) is useful in polarization conversion, negative refraction chemical analysis, and bio-sensing. To achieve strong CD signals, researchers constantly break the symmetry of nanostructures. However, how to further enhance the CD based on a new mechanism has become a new challenge in this field. In this work, a hybrid plasmonic chiral system composed of an array of graphene ribbons (GRs) over h-shaped sliver chiral nanostructures (HSCNs) is theoretically investigated. Results demonstrate that the plasmonic coupling between HSCNs and GRs results in different enhanced absorptions for different circularly polarized lights. The absorbance of right circularly polarized light is enhanced to perfect absorption; the absorption of left circularly polarized light is enhanced weakly. It leads to the CD effect of HSCNs@GRs approaching 88%. The loss distributions of HSCNs and HSCNs@GRs reveal that the absorption is enhanced and transferred from HSCNs to GRs. Moreover, the current distributions of HSCNs@GRs are simplified to equivalent LC resonant circuits, which can qualitatively explain the change of CD signals by tuning geometrical parameters of HSCNs@GRs. The findings of this work provide a new method of enhancing chirality and benefit the design of graphene-based chiral optoelectronic devices.

Tunable broadband circular polarizer based on ultrahigh-order surface plasmonic resonance.

Circular polarizers have potential applications in optical communication and liquid crystal display. In this paper, a multilayer twisted nanoring-rod nanostructure is designed. The finite element method is used to explore the surface plasmon of the structure under the excitation of left-handed circularly polarized light and right-handed circularly polarized light. The results show that the structure can be used as a polarizer in the tunable operating bandwidth of 400-1290 nm, and tunability is achieved by changing the filling medium near the structure instead of the geometric parameters of the nanostructures. We qualitatively reveal the physical mechanism of this phenomenon from the perspective of plasmon resonance coupling by plotting the charge distribution at several specific wavelengths.

Chiral long-period gratings: fabrication, highly sensitive torsion sensing, and tunable single-band filtering.

A promising technology for fabricating chiral long-period gratings (CLPGs) is demonstrated using a commercial fusion splicer. The key aspect of this technology is the incorporation of a fully automatic program we designed for the fusion splicer. High-quality CLPGs are successfully fabricated from single-mode fibers, which have very flat surfaces and low insertion loss. We also investigate the tuning characteristics of the transmission spectrum with the mechanical twist rate in CLPGs for torsion sensing application. The torsion sensitivity is improved and the shift in resonance wavelength versus the mechanical twist rate shows an almost perfect linear relationship. In addition, by choosing appropriate fabrication parameters, the fabricated CLPGs can be used as tunable single-band-rejection filters in a broad wavelength range.

An alternative empirical likelihood method in missing response problems and causal inference.

Missing responses are common problems in medical, social, and economic studies. When responses are missing at random, a complete case data analysis may result in biases. A popular debias method is inverse probability weighting proposed by Horvitz and Thompson. To improve efficiency, Robins et al. proposed an augmented inverse probability weighting method. The augmented inverse probability weighting estimator has a double-robustness property and achieves the semiparametric efficiency lower bound when the regression model and propensity score model are both correctly specified. In this paper, we introduce an empirical likelihood-based estimator as an alternative to Qin and Zhang (2007). Our proposed estimator is also doubly robust and locally efficient. Simulation results show that the proposed estimator has better performance when the propensity score is correctly modeled. Moreover, the proposed method can be applied in the estimation of average treatment effect in observational causal inferences. Finally, we apply our method to an observational study of smoking, using data from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions clinical trial. Copyright © 2016 John Wiley & Sons, Ltd.

Slow light and fast light in microfiber double-knot resonator with a parallel structure.

Based on the theoretical model of a microfiber double-knot resonator with a parallel structure, numerical simulations on the transmission spectrum, the phase, and the group time delay of the resonator as a function of wavelengths are given. We find that with this kind of resonator both slow light and fast light can be obtained at different resonant wavelengths. Experimentally, such a kind of microfiber resonator was fabricated successfully. The transmission spectrum of the fabricated resonator is well consistent with the theoretical simulation. A slow-light delay of about 38 ps and a fast-light advance of about 40 ps are demonstrated at different wavelengths, which might benefit the resonator to the applications in data delay lines, optical buffers, and optical memories.

Online fabrication scheme of helical long-period fiber grating for liquid-level sensing.

We present a novel online fabrication scheme of helical long-period fiber gratings (H-LPFGs) by directly twisting a standard single-mode fiber (SMF) in a microheater. This is done by taking advantage of the inherent core-cladding eccentricity in SMF. We adopt a fiber optic rotary joint to eliminate the accompanying twisting spiral for real-time spectral monitoring and a stepping mechanical system to accurately control the twisting length in fabrication. As a consequence, low-cost and high-quality H-LPFGs can be readily fabricated. Meanwhile, by using this kind of H-LPFG, we design a simple and low-cost wavelength-interrogated liquid-level sensor with a high sensitivity of 0.1 nm/mm.

Improved multiple-wavelength Brillouin-Raman fiber laser assisted by four-wave mixing with a micro-air cavity.

In this paper, a multiple-wavelength Brillouin-Raman fiber laser (MBRFL) with enhanced performance is presented. This is attributed to the improved Fresnel reflection, thus strengthening four-wave mixing in the fiber laser cavity due to the insertion of a micro-air cavity. As a result, compared with the conventional MBRFL without a micro-air cavity, the thresholds of Brillouin Stokes (BS) lines are observed to be reduced, and more BS lines can be generated. In the experiment, a MBRFL having 40 BS lines is achieved with good stability on laser wavelengths and output power. In view of the fact that more BS lines can be established with a simple scheme and low pump power, our MBRFL promises to be employed as a multiwavelength source for optical communication.

Suppression of seizures based on the multi-coupled neural mass model.

Epilepsy is one of the most common serious neurological disorders, which affects approximately 1% of population in the world. In order to effectively control the seizures, we propose a novel control methodology, which combines the feedback linearization control (FLC) with the underlying mechanism of epilepsy, to achieve the suppression of seizures. The three coupled neural mass model is constructed to study the property of the electroencephalographs (EEGs). Meanwhile, with the model we research on the propagation of epileptiform waves and the synchronization of populations, which are taken as the foundation of our control method. Results show that the proposed approach not only yields excellent performances in clamping the pathological spiking patterns to the reference signals derived under the normal state but also achieves the normalization of the pathological parameter, where the parameters are estimated from EEGs with Unscented Kalman Filter. The specific contribution of this paper is to treat the epilepsy from its pathogenesis with the FLC, which provides critical theoretical basis for the clinical treatment of neurological disorders.

Healthcare resource utilization and costs among patients with alpha-1 antitrypsin deficiency with liver and/or lung disease: a longitudinal retrospective study in the USA.

Aim: To evaluate all-cause and liver-associated healthcare resource utilization (HCRU) and costs among patients with alpha-1 antitrypsin deficiency (AATD) with liver disease (LD) and/or lung disease (LgD). Materials & methods: This was a retrospective analysis of linked administrative claims data from the IQVIA PharMetrics® Plus and the IQVIA Ambulatory Electronic Medical Records (AEMR) databases from 1 July 2021 to 31 January 2022. Patients with AATD in the IQVIA PharMetrics Plus database were included with ≥1 inpatient or ≥2 outpatient medical claims ≥90 days apart with a diagnosis of AATD, or with records indicating a protease inhibitor (Pi)*ZZ/Pi*MZ genotype in the IQVIA AEMR database with linkage to IQVIA PharMetrics Plus. For a patient's identified continuous enrollment period, patient time was assigned to health states based on the initial encounter with an LD/LgD diagnosis. A unique index date was defined for each health state, and HCRU and costs were calculated per person-year (PPY). Results: Overall, 5136 adult and pediatric patients from the IQVIA PharMetrics Plus and IQVIA AEMR databases were analyzed. All-cause and liver-associated HCRU and costs were substantially higher following onset of LD/LgD. All-cause cost PPY ranged from US $11,877 in the absence of either LD/LgD to US $74,015 in the presence of both LD and LgD. Among liver transplant recipients in the AATD with LD health state, liver-associated total costs PPY were US $87,329 1-year pre-transplantation and US $461,752 1-year post-transplantation. In the AATD with LgD and AATD with LD and LgD health states, patients who received augmentation therapy were associated with higher all-cause total costs PPY and lower liver-associated total costs PPY than their counterparts who did not receive augmentation therapy. Conclusion: Patients with AATD had increased HCRU and healthcare costs in the presence of LD and/or LgD. HCRU and healthcare costs were highest in the AATD with LD and LgD health state.

Fabrication of complexed nanostructure using AAO template for ultrasensitive SERS detection.

In the study of surface-enhanced Raman scattering (SERS) processes, a simple and fast approach is needed to ensure the large-scale preparation of SERS substrates. This article uses anodic aluminum oxide (AAO) as a template to assemble gold nanoparticles (Au NPs) into an ordered array. By changing the pore size of AAO and silanizing the pores, the number and density of Au NPs entering the pores through liquid-liquid two-phase self-assembly (LLSA) can be effectively regulated. Using Rh6G (Rhodamine 6G) and CV (Crystal Violet) molecules as probe molecules, substrate sensitivity was evaluated with an enhancement factor of up to 6.34 × 107. In addition, the uniformity of the substrate is good, with a relative standard deviation (RSD) of 9.94%, and the logarithmic concentration and the Raman signal presented significant linear correlations R2 was 0.997 and 0.985, respectively. The detection limit of the substrate for APM (aspartame) as a solvent is as low as 0.0078 g/L. Finally, the substrate was subjected to high sensitivity testing on two types of beverages containing APM sold, proving the practicality of the substrate. It is expected to achieve simple and rapid detection in food additive trace detection in the future.

Burden of Infection in Patients With and Without Secondary Immunodeficiency Disease Following Diagnosis of a Mature B Cell Malignancy.

BACKGROUND: This retrospective cohort study compared patient characteristics and burden of infection in patients with mature B cell malignancies with and without secondary immunodeficiency disease (SID). PATIENTS AND METHODS: Data were extracted from the Humedica database (H-DB) and Guardian Research Network (GRN) database from October 1, 2015 to March 10, 2020, including a 6-month pre-index period (PIP) and 12-month follow-up. Patients aged ≥18 years diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma, multiple myeloma, or non-Hodgkin's lymphoma in the PIP were stratified into 2 cohorts: SID (hypogammaglobulinemia [using ICD-10-CM codes] or serum IgG levels <5.0 g/L, both with signs and symptoms of SID or at least 1 infection) and no-SID. Patients with SID or primary immunodeficiency diseases in the PIP were excluded. RESULTS: Overall, 2221 patients with SID (H-DB/GRN: n = 1959/262), and 19,141 patients without SID (n = 17,598/1543) were included. Baseline characteristics were similar across cohorts. At 12-month follow-up, significantly more patients with SID had experienced ≥1 infection and ≥1 severe bacterial infection than those without SID (both P < .001). H-DB/GRN mean (standard deviation) number of severe bacterial infections was 7.6 (9.9)/2.9 (2.7) for the SID cohort versus 5.2 (6.8)/2.4 (2.2) for the no-SID cohort. CONCLUSION: This study confirms that patients with mature B cell malignancies and SID face a significantly higher burden of infections than those without SID.

Identification of CmACL genes in melon and analysis of their potential functions in fruit sugar and acid accumulation.

Citric acid is the most important organic acid in melon and has a great influence on fruit flavor quality. ATP-citrate (pro-S) lyase (ACL) is a key regulator in the acetyl-CoA pathway and plays an important role in citric acid metabolism. In this study we analyzed the structure and phylogenetics of CmACL genes and their functions in sugar and acid accumulation in melon. A total of four CmACL genes were identified in the melon genome, and phylogenetic analysis assigned these genes into the α subfamily (CmACLα1 and CmACLα2) and the ß subfamily (CmACLß1 and CmACLß2). Conserved motif and gene structure analyses showed that members of the same subfamily shared identical conserved motifs and gene structures, and probably have similar biological functions. Analysis of cis-acting elements revealed that CmACL promoter sequences contained regulatory elements related to light, stress, phytohormones, and growth and development, indicating that CmACL genes may be involved in melon growth and stress responses. The prediction of protein interaction network showed that CmACL proteins were closely related to the proteins belonging to tricarboxylic acid cycle, glyoxylic acid cycle and glycolytic pathway, suggesting that CmACL proteins may play an important role in sugar and acid metabolism. The expression of CmACLß1 was significantly and positively correlated with sucrose content, and CmACLß2 expression was significantly positively correlated with citric acid content, suggesting that CmACLß1 and CmACLß2 have important roles in sugar and acid accumulation in melon. Our results offer novel insights and avenues for the regulation of sugar and acid levels in melon and provide a theoretical foundation for breeding high-quality melon cultivars.