Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease

The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD

Quantized spin wave modes in magnetic tunnel junction nanopillars

We present an experimental and theoretical study of the magnetic field dependence of the mode frequency of thermally excited spin waves in rectangular shaped nanopillars of lateral sizes 60x100, 75x150, and 105x190 nm2, patterned from MgO-based magnetic tunnel junctions. The spin wave frequencies were measured using spectrally resolved electrical noise measurements. In all spectra, several independent quantized spin wave modes have been observed and could be identified as eigenexcitations of the free layer and of the synthetic antiferromagnet of the junction. Using a theoretical approach based on the diagonalization of the dynamical matrix of a system of three coupled, spatially confined magnetic layers, we have modeled the spectra for the smallest pillar and have extracted its material parameters. The magnetization and exchange stiffness constant of the CoFeB free layer are thereby found to be substantially reduced compared to the corresponding thin film values. Moreover, we could infer that the pinning of the magnetization at the lateral boundaries must be weak. Finally, the interlayer dipolar coupling between the free layer and the synthetic antiferromagnet causes mode anticrossings with gap openings up to 2 GHz. At low fields and in the larger pillars, there is clear evidence for strong non-uniformities of the layer magnetizations. In particular, at zero field the lowest mode is not the fundamental mode, but a mode most likely localized near the layer edges.Comment: 16 pages, 4 figures, (re)submitted to PR

Molecular detection of avian gyrovirus type 2 (AGV2) in specific pathogen free (SPF) chickens housed on commercial broiler litter.

Projeto/Plano de Ação: 02.11.01.012

Nonrelativistic Chern-Simons Vortices on the Torus

A classification of all periodic self-dual static vortex solutions of the Jackiw-Pi model is given. Physically acceptable solutions of the Liouville equation are related to a class of functions which we term Omega-quasi-elliptic. This class includes, in particular, the elliptic functions and also contains a function previously investigated by Olesen. Some examples of solutions are studied numerically and we point out a peculiar phenomenon of lost vortex charge in the limit where the period lengths tend to infinity, that is, in the planar limit.Comment: 25 pages, 2+3 figures; improved exposition, corrected typos, added one referenc

Electrically controlled long-distance spin transport through an antiferromagnetic insulator

Spintronics uses spins, the intrinsic angular momentum of electrons, as an alternative for the electron charge. Its long-term goal is in the development of beyond-Moore low dissipation technology devices. Recent progress demonstrated the long-distance transport of spin signals across ferromagnetic insulators. Antiferromagnetically ordered materials are however the most common class of magnetic materials with several crucial advantages over ferromagnetic systems. In contrast to the latter, antiferromagnets exhibit no net magnetic moment, which renders them stable and impervious to external fields. In addition, they can be operated at THz frequencies. While fundamentally their properties bode well for spin transport, previous indirect observations indicate that spin transmission through antiferromagnets is limited to short distances of a few nanometers. Here we demonstrate the long-distance, over tens of micrometers, propagation of spin currents through hematite (\alpha-Fe2O3), the most common antiferromagnetic iron oxide, exploiting the spin Hall effect for spin injection. We control the spin current flow by the interfacial spin-bias and by tuning the antiferromagnetic resonance frequency with an external magnetic field. This simple antiferromagnetic insulator is shown to convey spin information parallel to the compensated moment (N\'eel order) over distances exceeding tens of micrometers. This newly-discovered mechanism transports spin as efficiently as the net magnetic moments in the best-suited complex ferromagnets. Our results pave the way to ultra-fast, low-power antiferromagnet-insulator-based spin-logic devices that operate at room temperature and in the absence of magnetic fields

Functional connectivity of the Precuneus reflects effectiveness of visual restitution training in chronic hemianopia

Contains fulltext : 222045.pdf (publisher's version ) (Open Access

Monitoring response to anti-angiogenic mTOR inhibitor therapy in vivo using 111In-bevacizumab

Abstract Background The ability to image vascular endothelial growth factor (VEGF) could enable prospective, non-invasive monitoring of patients receiving anti-angiogenic therapy. This study investigates the specificity and pharmacokinetics of 111In-bevacizumab binding to VEGF and its use for assessing response to anti-angiogenic therapy with rapamycin. Specificity of 111In-bevacizumab binding to VEGF was tested in vitro with unmodified radiolabelled bevacizumab in competitive inhibition assays. Uptake of 111In-bevacizumab in BALB/c nude mice bearing tumours with different amounts of VEGF expression was compared to that of isotype-matched control antibody (111In-IgG1κ) with an excess of unlabelled bevacizumab. Intratumoural VEGF was evaluated using ELISA and Western blot analysis. The effect of anti-angiogenesis therapy was tested by measuring tumour uptake of 111In-bevacizumab in comparison to 111In-IgG1κ following administration of rapamycin to mice bearing FaDu xenografts. Uptake was measured using gamma counting of ex vivo tumours and effect on vasculature by using anti-CD31 microscopy. Results Specific uptake of 111In-bevacizumab in VEGF-expressing tumours was observed. Rapamycin led to tumour growth delay associated with increased relative vessel size (8.5 to 10.3, P = 0.045) and decreased mean relative vessel density (0.27 to 0.22, P = 0.0015). Rapamycin treatment increased tumour uptake of 111In-bevacizumab (68%) but not 111In-IgGκ and corresponded with increased intratumoural VEGF165. Conclusions 111In-bevacizumab accumulates specifically in VEGF-expressing tumours, and changes after rapamycin therapy reflect changes in VEGF expression. Antagonism of mTOR may increase VEGF in vivo, and this new finding provides the basis to consider combination studies blocking both pathways and a way to monitor effects

Machine learning based natural language processing of radiology reports in orthopaedic trauma

OBJECTIVES: To compare different Machine Learning (ML) Natural Language Processing (NLP) methods to classify radiology reports in orthopaedic trauma for the presence of injuries. Assessing NLP performance is a prerequisite for downstream tasks and therefore of importance from a clinical perspective (avoiding missed injuries, quality check, insight in diagnostic yield) as well as from a research perspective (identification of patient cohorts, annotation of radiographs). METHODS: Datasets of Dutch radiology reports of injured extremities (n = 2469, 33% fractures) and chest radiographs (n = 799, 20% pneumothorax) were collected in two different hospitals and labeled by radiologists and trauma surgeons for the presence or absence of injuries. NLP classification was applied and optimized by testing different preprocessing steps and different classifiers (Rule-based, ML, and Bidirectional Encoder Representations from Transformers (BERT)). Performance was assessed by F1-score, AUC, sensitivity, specificity and accuracy. RESULTS: The deep learning based BERT model outperforms all other classification methods which were assessed. The model achieved an F1-score of (95 ± 2)% and accuracy of (96 ± 1)% on a dataset of simple reports (n= 2469), and an F1 of (83 ± 7)% with accuracy (93 ± 2)% on a dataset of complex reports (n= 799). CONCLUSION: BERT NLP outperforms traditional ML and rule-base classifiers when applied to Dutch radiology reports in orthopaedic trauma

The Ricci flow on noncommutative two-tori

In this paper we construct a version of Ricci flow for noncommutative 2-tori, based on a spectral formulation in terms of the eigenvalues and eigenfunction of the Laplacian and recent results on the Gauss-Bonnet theorem for noncommutative tori.Comment: 18 pages, LaTe

High-dose posaconazole for azole-resistant aspergillosis and other difficult-to-treat mould infections

Background: Oral follow-up therapy is problematic in moulds with reduced azole-susceptibility, such as azole-resistant Aspergillus fumigatus infection. Currently, only intravenous liposomal amphotericin B (L-AmB) is advocated by guidelines for the treatment of azole-resistant aspergillosis infections. Preclinical research indicates that high-dose posaconazole (HD-POS) might be a feasible option provided that high drug exposure (ie POS serum through levels >3 mg/L) can be achieved and is safe. Objectives: To describe our experience with the use of oral HD-POS as treatment strategies for patients infected with pathogens with a POS MIC close to the clinical breakpoint. Patients/Methods: We review evidence supporting the use of HD-POS and describe our experience on safety and efficacy in 16 patients. In addition, we describe the adverse events (AE) observed in 25 patients with POS concentrations at the higher end of the population distribution during treatment with the licensed dose. Results: Sixteen patients were treated intentionally with HD-POS for voriconazoleresistant invasive aspergillosis (7/16), mucormycosis (4/16), salvage therapy for IA (4/16) and IA at a sanctuary site (spondylodiscitis) in 1. Grade 3- 4 AEs were observed in 6, and all of them were considered at least possibly related. Grade 3- 4 AEs were observed in 5 of the 25 patients with spontaneous high POS serum through levels considered at least possibly related using Naranjo scale. Conclusions: High-dose posaconazole is a treatment option if strict monitoring for both exposure and for AE is possible