Randomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia ...(CLL) have been lacking.
In a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have
aberrations to receive six cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity, <10
i.e., <1 CLL cell in 10,000 leukocytes) as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival.
A total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%; 97.5% confidence interval CI, 80.6 to 91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; P<0.001 for both comparisons), but it was not significantly higher in the venetoclax-rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P = 0.32). Three-year progression-free survival was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P<0.001). Progression-free survival at 3 years was also higher with venetoclax-obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to 0.68; P<0.001), but not with venetoclax-rituximab (80.8%; hazard ratio, 0.79; 97.5% CI, 0.53 to 1.18; P = 0.18). Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%).
Venetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. (Funded by AbbVie and others; GAIA-CLL13 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.).
Bacteria and viruses are equally associated with the risk of acute episodes of asthma-like symptoms in young children, suggesting antibiotics as a potential treatment for such episodes. We aimed to ...assess the effect of azithromycin on the duration of respiratory episodes in young children with recurrent asthma-like symptoms, hypothesising that it reduces the duration of the symptomatic period.
In this randomised, double-blind, placebo-controlled trial, we recruited children aged 1-3 years, who were diagnosed with recurrent asthma-like symptoms from the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort; a birth cohort consisting of the general Danish population of Zealand, including Copenhagen. Exclusion criteria were macrolide allergy, heart, liver, neurological, and kidney disease, and, before each treatment, one or more clinical signs of pneumonia (respiratory frequency of ≥50 breaths per min; fever of ≥39°C; C-reactive protein concentration of ≥476·20 nmol/L ≥50 mg/L). Each episode of asthma-like symptoms lasting at least 3 days was randomly allocated to a 3-day course of azithromycin oral solution of 10 mg/kg per day or placebo after thorough examination by a study physician at the Copenhagen Prospective Studies on Asthma research unit. Each episode was randomly allocated independently of previous treatment from a computer-generated list of random numbers in blocks of ten (generated at the Pharmacy of Glostrup). Investigators and children were masked until the youngest child turned 3 years of age and throughout the data validation and analysis phases. The primary outcome was duration of the respiratory episode after treatment, verified by prospective daily diaries and analysed with Poisson regression. Analyses were per protocol (excluding those without a primary outcome measure or who did not receive treatment). This trial is registered with ClinicalTrials.gov, number NCT01233297.
Between Nov 17, 2010, and Jan 28, 2014, we randomly allocated 158 asthma-like episodes in 72 children (79 50% to azithromycin and 79 50% to placebo). The mean duration of the episode after treatment was 3·4 days for children receiving azithromycin compared with 7·7 days for children receiving placebo. Azithromycin caused a significant shortening of the episode of 63·3% (95% CI 56·0-69·3; p<0·0001). The effect size increased with early initiation of treatment, showing a reduction in episode duration of 83% if treatment was initiated before day 6 of the episode compared with 36% if initiated on or after day 6 (p<0·0001). We noted no differences in clinical adverse events between the azithromycin (18 23% of 78 episodes included in final analysis) and placebo (24 30% of 79) groups (p=0·30), but we did not investigate bacterial resistance patterns after treatment.
Azithromycin reduced the duration of episodes of asthma-like symptoms in young children, suggesting that this drug could have a role in acute management of exacerbations. Further research is needed to disentangle the inflammatory versus antimicrobial aspects of this relation.
Lundbeck Foundation, Danish Ministry of Health, Danish Council for Strategic Research, Capital Region Research Foundation.
•Two different a-C:H coatings in various thicknesses on Si (100) have been studied.•For both types no significant difference in surface morphology is detectable.•The grain number with respect to ...their height appears randomly distributed.•In average no grain higher than 14nm and larger than 0.05μm2 was observed.•A height to area correlation confines all detected grains to a limited region.
Silicon (100) has been gradually covered by amorphous hydrogenated carbon (a-C:H) films via an industrial process. Two types of these diamond-like carbon (DLC) coatings, one more flexible (f-DLC) and one more robust (r-DLC), have been investigated. Both types have been grown by a radio frequency plasma-enhanced chemical vapor deposition (RF-PECVD) technique with acetylene plasma. Surface morphologies have been studied in detail by atomic force microscopy (AFM) and Raman spectroscopy has been used to investigate the DLC structure. Both types appeared to have very similar morphology and sp2 carbon arrangement. The average height and area for single grains have been analyzed for all depositions. A random distribution of grain heights was found for both types. The individual grain structures between the f- and r-type revealed differences: the shape for the f-DLC grains is steeper than for the r-DLC grains. By correlating the average grain heights to the average grain areas for all depositions a limited region is identified, suggesting a certain regularity during the DLC deposition mechanisms that confines both values. A growth of the sp2 carbon entities for high r-DLC depositions is revealed and connected to a structural rearrangement of carbon atom hybridizations and hydrogen content in the DLC structure.
Pure polyvinyl alcohol (PVA) and PVA reinforced with cellulose microfibers (PVA/CMF) composite films were coated with amorphous carbon layers (a-C:H, 50 and 100 nm thick) using radio frequency plasma ...enhanced chemical vapour deposition (RF-PECVD). The effects of cellulose microfibers on the polymer coatability were investigated. The reinforcement of PVA with CMF fibres leads only to a small variation for the resulting coatings. The measurements for the 50 nm samples differ chemically due to the different interlayer phase through the different base materials. Increasing of the layer thickness leads to an equalization of the layer for both materials. Deposited carbon layers were characterized surface morphologically by ex-situ atomic force microscopy (AFM), surface wettability by contact angle (CA) measurements. The chemical composition was analysed by surface sensitive synchrotron X-ray based techniques (near edge X-ray absorption fine structure (NEXAFS) and X-ray photoelectron spectroscopy (XPS)) and diffuse reflectance infrared Fourier transform spectroscopy (DRIFT).
Amorphous carbon layers (a-C:H) were successfully deposited on polyvinyl alcohol (PVA) and cellulose microfiber (CMF) reinforced PVA. Differences in the chemical composition of deposited carbon layers (sp2/sp3) were detected with synchrotron based techniques in combination with changes in their morphology and wettability showing clear substrate effects when used with microfiber reinforcement.
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•Effective coating of PVA and PVA/CMF with stable a-C:H films.•Topmost chemical composition of sp3/sp2 changes with thickness and basic material.•Effects of cellulose microfibers (CMF) on the resulting surface characteristics are investigated.•Substrate effects detectable due to used CMF fillers.
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► Interaction of plasma generated carbon with polyethylene material is examined. ► A model for the coating of soft plastic material with hard DLC is presented. ► Interlayer formation ...between these unequal materials is proven. ► The formation mechanism and thickness depend on the DLC type. ► The interlayer develops during the coating process.
The coating of materials with diamond-like carbon (DLC) is a very common way to change and improve their basic characteristics. Although DLC is used on several substrates, the chemical and physical properties throughout the coating process on plastics are yet sparsely investigated. Two types of protective coatings one sp3-enriched (robust, r-type) and one with more sp2-centers (flexible, f-type) have been realized on polyethylene by PECVD deposition. SEM and AFM analysis of coated samples of DLC types revealed diverse surface topographies on different scales and images appeared even differently smoothed by the carbonaceous deposits. Grains of both DLC types are platelet-shaped and nearly double in size for the robust type indicating fundamental differences in the epitaxial DLC growth. NEXAFS spectroscopy showed significant details of carbon centers in chemically different neighborhood displaying a characteristic fingerprint behavior. Comparison of deposition models revealed a mechanism of interlayer formation which is discussed in detail. Interlayer formation is clearly the appropriate explanation of the process for the current carbon deposition between these two unequal materials. An improved understanding of hard DLC and soft polyethylene assembly is given in the presented work.
Polyhydroxybutyrate (PHB) is a bio-based, biodegradable and commercially used polymer, which in its native form is unfortunately not generally applicable. A widely used technique to adapt polymers to ...a wider range of applications is the surface modification with amorphous hydrogenated carbon (a-C:H) layers, realized by plasma-enhanced chemical vapor deposition (PE-CVD). However, this process creates intrinsic stress in the layer-polymer system which can even lead to full layer failure. The aim of this study was to investigate how the carbon layer is affected when the basic polymer film to be coated can follow the stress and bend (single side attachment) and when it cannot do so because it is firmly clamped (full attachment). For both attachment methods, the a-C:H layers were simultaneously deposited on PHB samples. Ex-situ characterization was performed using a scanning electron microscope (SEM) for surface morphology and contact angle (CA) measurements for wettability. In addition, the stress prevailing in the layer was calculated using the Stoney equation. Diffuse reflectance infrared Fourier transform spectroscopy (DRIFT) measurements were used to investigate the chemical composition of the coating surface.
The increasing use of polymers is related to a growing disposal problem. Switching to biodegradable polymers such as polybutylene adipate terephthalate (PBAT) is a feasible possibility, but after ...industrial production of commercially available material PBAT is not suitable for every application. Therefore, surface refinements with amorphous hydrogenated carbon films (a-C:H) produced by plasma-assisted chemical vapor deposition (PE-CVD) changing the top layer characteristics are used. Here, 50 µm-thick PBAT films are coated with a-C:H layers up to 500 nm in 50 nm steps. The top surface sp2/sp3 bonding ratios are analyzed by X-ray photoelectron spectroscopy (XPS) and near-edge X-ray absorption fine structure (NEXAFS) both synchrotron-based. In addition, measurements using diffuse reflectance infrared Fourier transform spectroscopy (DRIFT) were performed for detailed chemical composition. Surface topography was analyzed by scanning electron microscopy (SEM) and the surface wettability by contact angle measurements. With increasing a-C:H layer thickness not only does the topography change but also the sp2 to sp3 ratio, which in combination indicates internal stress-induced phenomena. The results obtained provide a more detailed understanding of the mostly inorganic a-C:H coatings on the biodegradable organic polymer PBAT via in situ growth and stepwise height-dependent analysis.
Diamond-like carbon (DLC) films on polyethylene terephthalate (PET) are nowadays intensively studied composites due to their excellent gas barrier properties and biocompatibility. Despite their ...applicative features being highly explored, the interface properties and structural film evolution of DLC coatings on PET during deposition processes are still sparsely investigated. In this study two different types of DLC films were gradually deposited on PET by radio frequency plasma-enhanced chemical vapor deposition (RF-PECVD) using acetylene plasma. The surface morphology of the deposited samples has been analyzed by atomic force microscopy (AFM). Their chemical composition was investigated by diffusive reflectance infrared Fourier transform (DRIFT) and Raman spectroscopy analysis and the surface wettability by contact angle measurements. Subplantation processes and interface effects are revealed through the morphological and chemical analysis of both types. During plasma deposition processes the increasing carbon load causes the rise of intrinsic film stress. It is proven that stress release phenomena cause the transition between polymer-like to a more cross-linked DLC network by folding dehydrogenated chains into closed 6-fold rings. These findings significantly lead to an enhanced understanding in DLC film growth mechanism by RF-PECVD processes.
To investigate the corrosion protection behavior of naturally derived cocoyl sarcosine in combination with N-b-hydroxyethyl oleyl imidazole for steel CR4 in 0.1 M NaCl, different evaluation systems ...(weight loss, electrochemical measurements, and spray corrosion tests) were used. Both compounds were tested in different concentrations (25–100 mmol/L) and with variable dip coating times (1–30 min), first individually and then in combination, to check any synergistic effects for surface protection. Both showed only an insignificant corrosion inhibiting effect with less than 50% efficiency at all concentrations and dip coating times if used alone. In contrast, compound combinations revealed an improved corrosion inhibition correlated with higher concentrations. Across all methods, the compound combination concentration of 100 mmol/L resulted in improved efficiency of up to 83% for gravimetric tests, up to 84% for the impedance measure and more than 91% for potentiodynamic polarization. Dip coating variations proved 10 min to be the best option for all compounds with a maximum efficiency of up to 86% for the compound combination.
The production of isolated metallic nanoparticles with multifunctionalized properties, such as size and shape, is crucial for biomedical, photocatalytic, and energy storage or remediation ...applications. This study investigates the initial particle formations of gold nanoparticles (AuNPs) bioproduced in the cyanobacteria
sp. using high-resolution transmission electron microscopy images for digital image analysis. The developed method enabled the discovery of cerium nanoparticles (CeNPs), which were biosynthesized in the cyanobacteria
. The particle size distributions for AuNPs and CeNPs were analyzed. After 10 h, the average equivalent circular diameter for AuNPs was 4.8 nm, while for CeNPs, it was approximately 5.2 nm after 25 h. The initial shape of AuNPs was sub-round to round, while the shape of CeNPs was more roundish due to their amorphous structure and formation restricted to heterocysts. The local PSDs indicate that the maturation of AuNPs begins in the middle of vegetative cells and near the cell membrane, compared to the other regions of the cell.
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