High flow nasal cannula oxygen therapy versus non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease with acute-moderate hypercapnic respiratory failure: a randomized controlled non-inferiority trial.

BACKGROUND: Although cumulative studies have demonstrated a beneficial effect of high-flow nasal cannula oxygen (HFNC) in acute hypercapnic respiratory failure, randomized trials to compare HFNC with non-invasive ventilation (NIV) as initial treatment in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients with acute-moderate hypercapnic respiratory failure are limited. The aim of this randomized, open label, non-inferiority trial was to compare treatment failure rates between HFNC and NIV in such patients. METHODS: Patients diagnosed with AECOPD with a baseline arterial blood gas pH between 7.25 and 7.35 and PaCO2 ≥ 50 mmHg admitted to two intensive care units (ICUs) at a large tertiary academic teaching hospital between March 2018 and December 2022 were randomly assigned to HFNC or NIV. The primary endpoint was the rate of treatment failure, defined as endotracheal intubation or a switch to the other study treatment modality. Secondary endpoints were rates of intubation or treatment change, blood gas values, vital signs at one, 12, and 48 h, 28-day mortality, as well as ICU and hospital lengths of stay. RESULTS: 225 total patients (113 in the HFNC group and 112 in the NIV group) were included in the intention-to-treat analysis. The failure rate of the HFNC group was 25.7%, while the NIV group was 14.3%. The failure rate risk difference between the two groups was 11.38% (95% CI 0.25-21.20, P = 0.033), which was higher than the non-inferiority cut-off of 9%. In the per-protocol analysis, treatment failure occurred in 28 of 110 patients (25.5%) in the HFNC group and 15 of 109 patients (13.8%) in the NIV group (risk difference, 11.69%; 95% CI 0.48-22.60). The intubation rate in the HFNC group was higher than in the NIV group (14.2% vs 5.4%, P = 0.026). The treatment switch rate, ICU and hospital length of stay or 28-day mortality in the HFNC group were not statistically different from the NIV group (all P > 0.05). CONCLUSION: HFNC was not shown to be non-inferior to NIV and resulted in a higher incidence of treatment failure than NIV when used as the initial respiratory support for AECOPD patients with acute-moderate hypercapnic respiratory failure. TRIAL REGISTRATION: chictr.org (ChiCTR1800014553). Registered 21 January 2018, http://www.chictr.org.cn.

Copper-catalyzed asymmetric 1,2-arylboration of enamines: access to chiral borate-containing 3,3'-disubstituted isoindolinones.

An enantioselective copper-catalyzed 1,2-arylboration reaction of enamines has been developed by employing (R)-xyl-BINAP as a chiral ligand. A number of chiral borate-containing 3,3'-disubstituted isoindolinones were obtained in moderate to good yields and good to excellent enantioselectivities from the reactions of N-(o-iodobenzoyl)enamines and bis(pinacolato)diboron (B2pin2) under mild reaction conditions. Synthetic transformations of the products were conducted to demonstrate the practicality of this reaction.

Ponatinib vs Imatinib in Frontline Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.

Importance: In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I. Objective: To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL. Design, Setting, and Participants: Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022. Intervention: Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease-(MRD) negative complete remission. Main Outcomes and Measures: The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase-quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival. Results: Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%). Conclusions and Relevance: Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib. Trial Registration: ClinicalTrials.gov Identifier: NCT03589326.

Adjusting for subsequent therapies in the TOURMALINE-MM1 study shows clinically meaningful improvement in overall survival with addition of ixazomib to lenalidomide and dexamethasone.

TOURMALINE-MM1, the only blinded randomized study in patients with relapsed and/or refractory multiple myeloma (RRMM; ≥1 prior therapy) in the last 10 years, investigated ixazomib + lenalidomide + dexamethasone (IRd) versus lenalidomide + dexamethasone (Rd). Final overall survival (OS) data were based on a median follow-up of 85 months. In RRMM trials where patients have had 1-3 relapses after initial treatment, a high proportion receive subsequent therapy. Application of salvage therapies in blinded trials and newer modes of therapy can increasingly complicate the interpretation of OS. This analysis explores the impact of subsequent therapies on OS outcomes in TOURMALINE-MM1. The inverse probability of censoring weights (IPCW) method, marginal structural model (MSM), and rank-preserving structural failure time model (RPSFTM) were utilized to adjust for confounding on OS, introduced by subsequent therapies. Analyses were conducted for the intent-totreat (ITT) population and ≥2 prior lines subgroup. Unadjusted hazard ratio (HR) for IRd versus Rd was 0.94 (95% confidence interval [CI]: 0.78-1.13) in the ITT population. After adjusting for the impact of subsequent therapies by the RPSFTM method, estimated HR for IRd versus Rd in the ITT population was 0.89 (95% CI: 0.74-1.07). Adjusting with IPCW and MSM methods also showed an improvement in HR, favoring IRd. IRd may be particularly beneficial in patients with ≥2 prior lines of therapy (IPCW and MSM HR=0.52, 95% CI: 0.30-0.88; RPSFTM HR=0.68, 95% CI: 0.51-0.91). These analyses highlight the growing challenge of demonstrating OS benefit in MM patients and the importance of assessing confounding introduced by subsequent therapies when interpreting OS.

A WOx/MoOx hybrid oxide based SERS FET and investigation on its tunable SERS performance.

Active control of the surface-enhanced Raman scattering (SERS) enhancement shows great potential for realizing smart detection of different molecules. However, conventional methods usually involve time-consuming structural design or a sophisticated fabrication process. Herein, we reported an electrically tunable field effect transistor (FET) comprising a WOx/MoOx hybrid as the SERS active layer. In the experiment, WOx/MoOx hybrids were first prepared by mixing different molar ratios of WOx and MoOx oxides. Then, R6G molecules were used as Raman reporters, showing that the intensity of the SERS signal observed on the most optimal hybrids (molar ratio = 1 : 3) could be increased by two times as high as that observed on a single WOx or MoOx based substrate, which was ascribed to enhanced charge transfer efficiency by the constructed nano-heterojunction between the WOx and MoOx oxides. Thereafter, a back-gate FET was fabricated on a SiO2/Si substrate, and the most optimal WOx/MoOx hybrid was deposited as the gate channel and the SERS active layer. After that, a series of gate biases (from -15 V to 15 V) were implemented to actively tune the SERS performance of the FET. It is evident that the SERS EF can be further tuned from 2.39 × 107 (-15 V) to 6.55 × 107 (+10 V), which is ∼7.4/4.1 times higher than that observed on the pure WOx device (8.81 × 106) or pure MoOx (1.61 × 107) device, respectively. Finally, the mechanism behind the electrical tuning strategy was investigated. It is revealed that a positive voltage would bend the conduction band down, which increased the electron density near the Fermi level. Consequently, it triggered the resonance charge transfer and significantly improved the SERS performance. In contrast, a negative gate voltage attracted the holes to the Fermi level, which deferred the charge transfer process, and caused the reduction of the SERS enhancement.

Nonlinear photonic crystals for completely independent asymmetric holographic imaging.

Nonlinear photonic crystals (NPCs) are microstructures characterized by a spatially modulated second-order nonlinear coefficient that have been extensively used for the generation and beam-shaping of coherent light at new frequencies. NPCs for asymmetric optical transmission have a significant impact on novel and multifunction photonic devices. However, nonreciprocal NPCs capable of completely independent asymmetric holographic imaging for the opposite propagation directions have not been reported. Here, we propose a holographic combiner for a different independent image generation at the second-harmonic (SH) wavelength when illuminated from opposite sides of NPCs. The design of the holographic combiner is based on a 3D nonlinear detour phase holography and an orbital angular momentum (OAM) multiplexing nonlinear holography. This work achieves completely independent asymmetric holographic imaging at the SH frequency by using NPCs, which may have potential applications in classical and quantum optical devices.

Experimental study on alkali reduction of film-coated porous ecological concrete by microbial calcium carbonate precipitation technology.

Some plants do not grow due to the high pH levels of ecological concrete pore solutions. In this paper, we design and build an integrated device featuring a combined microbial film and a transverse/U-shaped grouting film. We have applied to the China Intellectual Property Office for an invention patent on this device. The device overcomes the blockage of the grouting port caused by microbial and vertical grouting. The vertical grouting tube leaves holes inside a specimen, reducing the compressive strength, while the integrated device optimizes and decreases variation in the recycling of microbial bacteria. The reduction in the pore alkalinity of porous ecological concrete resulting from the microbial grouting film of this device is larger than that resulting from a microbial sprayed film. The pH values of porous ecological concrete with microbial grouting films and microbial sprayed films are obtained by the pure slurry soaking method and solid-liquid extraction method, respectively. The pH value is lower for the film obtained by the pure slurry soaking method than for that obtained by the solid-liquid extraction method. Conversely, the pH value of porous ecological concrete with a microbial grouting film is reduced to approximately 8 at an age of 56 days. The compressive strengths of the porous ecological concrete specimens with the two films are almost the same. The results of this study provide the necessary theoretical basis for developing alkali reduction technology for porous ecological concrete with environmental and economic benefits.

Asymmetric wavefront shaping with nonreciprocal 3D nonlinear detour phase hologram.

Asymmetric control of light with nonlinear material is of great significance in the design of novel micro-photonic components, such as asymmetric imaging devices and nonreciprocal directional optical filters. However, the use of nonlinear photonic crystals for asymmetric optical transmission, to the best of our knowledge, is still an untouched area of research. Herein we propose the 3D nonlinear detour phase holography for realizing asymmetric SH wavefront shaping by taking advantage of the dependence of the SH phase on the propagation direction of the excitation beam. With the proposed method, the designed nonreciprocal 3D nonlinear detour phase hologram yields SH phases with opposite signs for the forward and backward transmission situations. Moreover, the quasi-phase-matching scheme and orbital angular momentum conservation in the asymmetric SH wavefront shaping process are also discussed. This study conceptually extends the 2D nonlinear detour phase holography into 3D space to build the nonreciprocal 3D nonlinear detour phase hologram for achieving SH twin-image elimination and asymmetric SH wavefront shaping, offering new possibilities for the design of nonreciprocal optical devices.

Ixazomib Versus Placebo as Postinduction Maintenance Therapy in Newly Diagnosed Multiple Myeloma Patients: An Analysis by Age and Frailty Status of the TOURMALINE-MM4 Study.

BACKGROUND: The TOURMALINE-MM4 trial demonstrated a significant and clinically meaningful progression-free survival (PFS) benefit with ixazomib versus placebo as postinduction maintenance in nontransplant, newly-diagnosed multiple myeloma patients, with a manageable and well-tolerated toxicity profile. MATERIALS AND METHODS: In this subgroup analysis, efficacy and safety were assessed by age (< 65, 65-74, and ≥ 75 years) and frailty status (fit, intermediate-fit, and frail). RESULTS: In this analysis, PFS benefit with ixazomib versus placebo was seen across age subgroups, including patients aged < 65 years (hazard ratio [HR], 0.576; 95% confidence interval [CI], 0.299-1.108; P = .095), 65-74 years (HR, 0.615; 95% CI, 0.467-0.810; P < .001), and ≥ 75 years (HR, 0.740; 95% CI, 0.537-1.019; P = .064). PFS benefit was also seen across frailty subgroups, including fit (HR, 0.530; 95% CI, 0.387-0.727; P < .001), intermediate-fit (HR, 0.746; 95% CI, 0.526-1.058; P = .098), and frail (HR, 0.733; 95% CI, 0.481-1.117; P = .147) patients. With ixazomib versus placebo, rates of grade ≥ 3 treatment-emergent adverse events (TEAEs; 28-44% vs. 10-36%), serious TEAEs (15-29% vs. 3-29%), and discontinuation due to TEAEs (7-19% vs. 5-11%) were higher or similar across age and frailty subgroups, and generally somewhat higher in older age groups and intermediate-fit/frail patients in both arms. Treatment with ixazomib versus placebo did not adversely affect patient-reported quality-of-life scores across age and frailty status subgroups. CONCLUSION: Ixazomib is a feasible and effective maintenance option for prolonging PFS across this heterogeneous patient population.

Moderate white light exposure enhanced spatial memory retrieval by activating a central amygdala-involved circuit in mice.

Light exposure can profoundly affect neurological functions and behaviors. Here, we show that short-term exposure to moderate (400 lux) white light during Y-maze test promoted spatial memory retrieval and induced only mild anxiety in mice. This beneficial effect involves the activation of a circuit including neurons in the central amygdala (CeA), locus coeruleus (LC), and dentate gyrus (DG). Specifically, moderate light activated corticotropin-releasing hormone (CRH) positive (+) CeA neurons and induced the release of corticotropin-releasing factor (CRF) from their axon terminals ending in the LC. CRF then activated tyrosine hydroxylase-expressing LC neurons, which send projections to DG and release norepinephrine (NE). NE activated ß-adrenergic receptors on CaMKIIα-expressing DG neurons, ultimately promoting spatial memory retrieval. Our study thus demonstrated a specific light scheme that can promote spatial memory without excessive stress, and unraveled the underlying CeA-LC-DG circuit and associated neurochemical mechanisms.

Single cell molecular alterations reveal target cells and pathways of conditioned fear memory.

OBJECTIVES: Recent evidence indicates that hippocampus is important for conditioned fear memory (CFM). Though few studies consider the roles of various cell types' contribution to such a process, as well as the accompanying transcriptome changes during this process. The purpose of this study was to explore the transcriptional regulatory genes and the targeted cells that are altered by CFM reconsolidation. METHODS: A fear conditioning experiment was established on adult male C57 mice, after day 3 tone-cued CFM reconsolidation test, hippocampus cells were dissociated. Using single cell RNA sequencing (scRNA-seq) technique, alterations of transcriptional genes expression were detected and cell cluster analysis were performed and compared with those in sham group. RESULTS: Seven non-neuronal and eight neuronal cell clusters (including four known neurons and four newly identified neuronal subtypes) has been explored. Among them, CA subtype 1 has characteristic gene markers of Ttr and Ptgds, which is speculated to be the outcome of acute stress and promotes the production of CFM. The results of KEGG pathway enrichment indicate the differences in the expression of certain molecular protein functional subunits in long-term potentiation (LTP) pathway between two types of neurons (DG and CA1) and astrocytes, thus providing a new transcriptional perspective for the role of hippocampus in the CFM reconsolidation. More importantly, the correlation between the reconsolidation of CFM and neurodegenerative diseases-linked genes is substantiated by the results from cell-cell interactions and KEGG pathway enrichment. Further analysis shows that the reconsolidation of CFM inhibits the risk-factor genes App and ApoE in Alzheimer's Disease (AD) and activates the protective gene Lrp1. CONCLUSIONS: This study reports the transcriptional genes expression changes of hippocampal cells driven by CFM, which confirm the involvement of LTP pathway and suggest the possibility of CFM-like behavior in preventing AD. However, the current research is limited to normal C57 mice, and further studies on AD model mice are needed to prove this preliminary conclusion.

MRD dynamics during maintenance for improved prognostication of 1280 patients with myeloma in the TOURMALINE-MM3 and -MM4 trials.

Measurable residual disease (MRD) evaluation may help to guide treatment duration in multiple myeloma (MM). Paradoxically, limited longitudinal data exist on MRD during maintenance. We investigated the prognostic value of MRD dynamics in 1280 transplant-eligible and -ineligible patients from the TOURMALINE-MM3 and -MM4 randomized placebo-controlled phase 3 studies of 2-year ixazomib maintenance. MRD status at randomization showed independent prognostic value (median progression-free survival [PFS], 38.6 vs 15.6 months in MRD- vs MRD+ patients; HR, 0.47). However, MRD dynamics during maintenance provided more detailed risk stratification. A 14-month landmark analysis showed prolonged PFS in patients converting from MRD+ to MRD- status vs those with persistent MRD+ status (76.8% vs 27.6% 2-year PFS rates). Prolonged PFS was observed in patients with sustained MRD- status vs those converting from MRD- to MRD+ status (75.0% vs 34.2% 2-year PFS rates). Similar results were observed at a 28-month landmark analysis. Ixazomib maintenance vs placebo improved PFS in patients who were MRD+ at randomization (median, 18.8 vs 11.6 months; HR, 0.65) or at the 14-month landmark (median, 16.8 vs 10.6 months; HR, 0.65); no difference was observed in patients who were MRD-. This is the largest MM population undergoing yearly MRD evaluation during maintenance reported to date. We demonstrate the limited prognostic value of a single-time point MRD evaluation, because MRD dynamics over time substantially impact PFS risk. These findings support MRD- status as a relevant end point during maintenance and confirm the increased progression risk in patients converting to MRD+ from MRD- status. These trials were registered at www.clinicaltrials.gov as #NCT02181413 and #NCT02312258.

High-flow nasal cannula oxygen therapy versus noninvasive ventilation for patients with blunt chest trauma: protocol for a randomized controlled trial.

BACKGROUND: High-flow nasal cannula oxygen therapy (HFNC) is recommended by some scholars as an optimized respiratory support method for blunt chest trauma (BCT) patients. The basis of this recommendation is limited, however, and the efficacy of HFNC or noninvasive ventilation (NIV) in BCT patients has not yet been rigorously explored. This study aims to determine if HFNC is non-inferior to NIV in reducing treatment failure in moderate to severe BCT patients with acute respiratory failure. METHODS: This will be a prospective, open-label, multicenter, non-inferiority, randomized controlled trial. Moderate to severe BCT patients with acute respiratory failure (100mmHg < PaO2/FiO2 ≦ 200mmHg) who do not need immediate intubation will be randomized to HFNC or NIV within 48 h after trauma. The primary outcome is treatment failure, defined as invasive ventilation or a switch in respiratory support modality (from HFNC to NIV or vice-versa). Secondary outcomes include arterial blood gas analysis and vital signs at 2 and 12 h after initiating HFNC or NIV treatment, as well as patients' comfort scores, dyspnea scores, daily number of nursing airway care interventions, incidence of pneumonia or pneumothorax, facial skin breakdown, duration of NIV or HFNC, 28-day mortality, and total ICU and hospital lengths of stay. Based on an α error of 5% and a ß error of 80%, with a non-inferiority limit of 9%, a sample size of 562 will be required to accomplish the trial goal, considering potential patient dropouts and nonparametric analysis. DISCUSSION: We hypothesize that HFNC will be non-inferior to NIV in reducing treatment failure in moderate to severe BCT with acute respiratory failure. The results should be useful for judging whether HFNC could be an effective alternative to NIV to treat moderate to severe BCT patients, especially for those who do not tolerate or have contraindications for NIV. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1800017313 . Registered on July 24, 2018.

Bias and Type I error Control in Correcting Treatment Effect for Treatment Switching Using Marginal Structural Models in Phase III Oncology Trials.

This research focuses on the bias and type I error control issues when the marginal structural models (MSMs) are applied to evaluate the causal survival benefits of active intervention versus control in randomized clinical trials (RCTs) with treatment switching after disease progression. When MSMs are applied in the RCT setting, the question of interest, model specifications, strategies for type I error control, bias reduction, etc. differ somewhat from those for observational studies. This manuscript discusses the approaches used to accommodate these differences. Through Monte Carlo simulations and a case study, our research demonstrates that, with sufficient attention paid to issues applicable to RCTs in particular, MSMs may perform better than the inverse probability of censoring weighting (IPCW) method in analyzing the survival endpoint in RCTs with treatment switching because more information is used by the MSM.

Mid-infrared biomimetic moth-eye-shaped polarization-maintaining and angle-insensitive metalens.

Metalenses can potentially reduce the size and complexity of existing cameras, displays, and other optical devices, owing to their capability of flexible manipulation of the polarization, amplitude, and phase of light. However, metalenses capable of maintaining polarization and broadband wavefront shaping under arbitrarily polarized excitation have not been studied. In this study, we present the first demonstration of a biomimetic moth-eye-shaped metalens for polarization-maintaining, broadband and angle-insensitive focusing under an arbitrarily polarized excitation in the mid-infrared waveband (3.1-8.0 µm). Modulation and focusing efficiencies of 92% and 90%, respectively, were achieved. Moreover, a bifocal moth-eye-shaped metalens operating at normal and oblique incidences was realized. Compared to previously reported metalenses, the one proposed in this study exhibited a better focusing under oblique incidence, ensuring light transmission as effectively as a traditional lens. This study paves the way for the development of polarization-maintaining, broadband, and angle-insensitive microscale optical devices and imaging systems.

Oxyberberine Prevented Lipopolysaccharide-Induced Acute Lung Injury through Inhibition of Mitophagy.

Acute lung injury (ALI) is a serious respiratory syndrome characterized with uncontrolled inflammatory response. Oxyberberine has strong potential for clinical usage since it showed strong anti-inflammatory, antifungal, and antiarrhythmic effects in various diseases. In the present study, we evaluated whether oxyberberine can inhibit lipopolysaccharide- (LPS-) induced ALI in vivo and further evaluated the possible involvement of mitophagy in vitro by using A549 cells, a human lung epithelial cell line. Our in vivo study shows that oxyberberine significantly inhibited LPS-induced lung pathological injury and lung edema, as indicated by the changes in lung wet/dry ratio and total protein levels in the BALF in mice. Moreover, oxyberberine inhibited inflammation, as indicated by the changes of neutrophil accumulation and production of proinflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and IL-6 in both the lung and bronchoalveolar lavage fluid (BALF) in ALI mice. Our in vitro study shows that LPS significantly decreased the protein level of mitochondrial proteins, including cytochrome c oxidase subunit IV (COX IV), p62, and mitofusin-2 (Mfn2) in A549 cells. In addition, LPS induced significant Parkin1 translocation from cytoplasm to mitochondria. These changes were significantly inhibited by oxyberberine. Notably, the inhibitory effect of oxyberberine was almost totally lost in the presence of lysosome fusion inhibitor bafilomycin A1 (Baf), a mitophagy inhibitor. In conclusion, the present study demonstrated that oxyberberine alleviated LPS-induced inflammation in ALI via inhibition of Parkin-mediated mitophagy.

Nonlinear detour phase holography.

Nonlinear photonic crystals are capable of highly efficient nonlinear wavefront manipulation, providing a promising platform for compact and large-scale integrated nonlinear devices. However, the current nonlinear encoding methods for nonlinear photonic crystals inherently require a number of disordered and complex microstructures, which are quite challenging in a real fabrication process. Herein we propose and experimentally demonstrate a nonlinear detour phase method for nonlinear wavefront manipulation in nonlinear photonic crystals. With the proposed method, the designed nonlinear detour phase hologram only requires a set of basic building blocks with simple shapes, which are easy to fabricate by using the femtosecond laser writing technique. The second-harmonic hologram is demonstrated by designing the nonlinear detour phase patterns, and the quasi-phase-matching scheme in the second-harmonic holographic imaging process is also discussed. This study conceptually extends the conventional detour phase method into the nonlinear regime, offering new possibilities for compact nonlinear micro-devices with multi-functions.

Large second-harmonic vortex beam generation with quasi-nonlinear spin-orbit interaction.

A harmonic vortex beam is a typical vector beam with a helical wavefront at harmonic frequencies (e.g., second and third harmonics). It provides an additional degree of freedom beyond spin- and orbital-angular momentum, which may greatly increase the capacity for communicating and encoding information. However, conventional harmonic vortex beam generators suffer from complex designs and a low nonlinear conversion efficiency. Here, we propose and experimentally demonstrate the generation of a large second-harmonic (SH) vortex beam with quasi-nonlinear spin-orbit interaction (SOI). High-quality SH vortex beams with large topological charges up to 28 are realized experimentally. This indicated that the quasi-angular-momentum of a plasmonic spiral phase plate at the excitation wavelength (topological charge, q) could be imprinted on the harmonic signals from the attached WS2 monolayer. The generated harmonic vortex beam has a topological charge of ln=2nq (n is the harmonic order). The results may open new avenues for generating harmonic optical vortices for optical communications and enables novel multi-functional hybrid metasurface devices to manipulate harmonic beams.

Ixazomib as Postinduction Maintenance for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial.

PURPOSE: Maintenance therapy prolongs progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing autologous stem cell transplantation (ASCT) but has generally been limited to immunomodulatory agents. Other options that complement the induction regimen with favorable toxicity are needed. PATIENTS AND METHODS: The phase III, double-blind, placebo-controlled TOURMALINE-MM4 study randomly assigned (3:2) patients with NDMM not undergoing ASCT who achieved better than or equal to partial response after 6-12 months of standard induction therapy to receive the oral proteasome inhibitor (PI) ixazomib or placebo on days 1, 8, and 15 of 28-day cycles as maintenance for 24 months. The primary endpoint was PFS since time of randomization. RESULTS: Patients were randomly assigned to receive ixazomib (n = 425) or placebo (n = 281). TOURMALINE-MM4 met its primary endpoint with a 34.1% reduction in risk of progression or death with ixazomib versus placebo (median PFS since randomization, 17.4 v 9.4 months; hazard ratio [HR], 0.659; 95% CI, 0.542 to 0.801; P < .001; median follow-up, 21.1 months). Ixazomib significantly benefitted patients who achieved complete or very good partial response postinduction (median PFS, 25.6 v 12.9 months; HR, 0.586; P < .001). With ixazomib versus placebo, 36.6% versus 23.2% of patients had grade ≥ 3 treatment-emergent adverse events (TEAEs); 12.9% versus 8.0% discontinued treatment because of TEAEs. Common any-grade TEAEs included nausea (26.8% v 8.0%), vomiting (24.2% v 4.3%), and diarrhea (23.2% v 12.3%). There was no increase in new primary malignancies (5.2% v 6.2%); rates of on-study deaths were 2.6% versus 2.2%. CONCLUSION: Ixazomib maintenance prolongs PFS with no unexpected toxicity in patients with NDMM not undergoing ASCT. To our knowledge, this is the first PI demonstrated in a randomized clinical trial to have single-agent efficacy for maintenance and is the first oral PI option in this patient population.

High-flow nasal cannula oxygen therapy versus non-invasive ventilation for chronic obstructive pulmonary disease patients after extubation: a multicenter, randomized controlled trial.

BACKGROUND: High-flow nasal cannula (HFNC) oxygen therapy is being increasingly used to prevent post-extubation hypoxemic respiratory failure and reintubation. However, evidence to support the use of HFNC in chronic obstructive pulmonary disease (COPD) patients with hypercapnic respiratory failure after extubation is limited. This study was conducted to test if HFNC is non-inferior to non-invasive ventilation (NIV) in preventing post-extubation treatment failure in COPD patients previously intubated for hypercapnic respiratory failure. METHODS: COPD patients with hypercapnic respiratory failure who were already receiving invasive ventilation were randomized to HFNC or NIV at extubation at two large tertiary academic teaching hospitals. The primary endpoint was treatment failure, defined as either resumption of invasive ventilation or switching to the other study treatment modality (NIV for patients in the NFNC group or vice versa). RESULTS: Ninety-six patients were randomly assigned to the HFNC group or NIV group. After secondary exclusion, 44 patients in the HFNC group and 42 patients in the NIV group were included in the analysis. The treatment failure rate in the HFNC group was 22.7% and 28.6% in the NIV group-risk difference of - 5.8% (95% CI, - 23.8-12.4%, p = 0.535), which was significantly lower than the non-inferior margin of 9%. Analysis of the causes of treatment failure showed that treatment intolerance in the HFNC group was significantly lower than that in the NIV group, with a risk difference of - 50.0% (95% CI, - 74.6 to - 12.9%, p = 0.015). One hour after extubation, the mean respiratory rates of both groups were faster than their baseline levels before extubation (p < 0.050). Twenty-four hours after extubation, the respiratory rate of the HFNC group had returned to baseline, but the NIV group was still higher than the baseline. Forty-eight hours after extubation, the respiratory rates of both groups were not significantly different from the baseline. The average number of daily airway care interventions in the NIV group was 7 (5-9.3), which was significantly higher than 6 (4-7) times in the HFNC group (p = 0.006). The comfort score and incidence of nasal and facial skin breakdown of the HFNC group was also significantly better than that of the NIV group [7 (6-8) vs 5 (4-7), P < 0.001] and [0 vs 9.6%, p = 0.027], respectively. CONCLUSION: Among COPD patients with severe hypercapnic respiratory failure who received invasive ventilation, the use of HFNC after extubation did not result in increased rates of treatment failure compared with NIV. HFNC also had better tolerance and comfort than NIV. TRIAL REGISTRATION: chictr.org ( ChiCTR1800018530 ). Registered on 22 September 2018, http://www.chictr.org.cn/usercenter.aspx.