Quantitative multi-modality imaging analysis of a fully bioresorbable stent: a head-to-head comparison between QCA, IVUS and OCT

The bioresorbable vascular stent (BVS) is totally translucent and radiolucent, leading to challenges when using conventional invasive imaging modalities. Agreement between quantitative coronary angiography (QCA), intravascular ultrasound (IVUS) and optical coherence tomography (OCT) in the BVS is unknown. Forty five patients enrolled in the ABSORB cohort B1 study underwent coronary angiography, IVUS and OCT immediately post BVS implantation, and at 6 months. OCT estimated stent length accurately compared to nominal length (95% CI of the difference: −0.19; 0.37 and −0.15; 0.47 mm2 for baseline and 6 months, respectively), whereas QCA incurred consistent underestimation of the same magnitude at both time points (Pearson correlation = 0.806). IVUS yielded low accuracy (95% CI of the difference: 0.77; 3.74 and −1.15; 3.27 mm2 for baseline and 6 months, respectively), with several outliers and random variability test–retest. Minimal lumen area (MLA) decreased substantially between baseline and 6 months on QCA and OCT and only minimally on IVUS (95% CI: 0.11; 0.42). Agreement between the different imaging modalities is poor: worst agreement Videodensitometry-IVUS post-implantation (ICCa 0.289); best agreement IVUS-OCT at baseline (ICCa 0.767). All pairs deviated significantly from linearity (P < 0.01). Passing-Bablok non-parametric orthogonal regression showed constant and proportional bias between IVUS and OCT. OCT is the most accurate technique for measuring stent length, whilst QCA incurs systematic underestimation (foreshortening) and solid state IVUS incurs random error. Volumetric calculations using solid state IVUS are therefore not reliable. There is poor agreement for MLA estimation between all the imaging modalities studied, including IVUS-OCT, hence their values are not interchangeable

The role of particle engineering in relation to formulation and de-agglomeration principle in the development of a dry powder formulation for inhalation of cetrorelix

We formulated cetrorelix acetate, as an adhesive mixture for use in dry powder inhalation. To achieve the highest possible deposition efficiency we investigated both the influence of different micronization techniques and different inhalers. The Novolizer with an air classifier as the powder de-agglomeration principle and the ISF inhaler were used for in vitro deposition experiments (cascade impaction). Micronization by milling as the classical approach and micronization by spray drying and spray freeze drying as advanced particle engineering techniques were investigated to determine whether advanced techniques are necessary to obtain high fine particle fractions (FPF) for this specific drug. It was found that the effects obtained with a certain micronization technique depended on the complex interaction of the physical characteristics of the drug substance with the type of formulation chosen, as well as with the de-agglomeration principle used. The combination of particle engineering by spray drying and the use of the air classifier technology resulted in a fine particle fraction of 66%, while spray freeze drying yielded extremely fragile particles resulting in a FPF of only 25%. The behaviour of the milled material showed similar trends as the spray dried material but FPF values were lower. It was concluded that when a drug is to be formulated as a powder for inhalation with high fine particle fractions, it is profitable to use advanced particle engineering techniques, however the applied technique should be tuned with the characteristics of the formulation type and process as well as with device development. (C) 2004 Elsevier B.V. All rights reserved

Pulse Densitometer Indocyanine Green Dilution Curves: A Simple Applicable and Accurate Method for Determination of Cardiac Shunts

Objective. Adequate hemodynamic evaluation is crucial in the management of patients with congenital heart disease. Although non-invasive diagnostic tools have reduced the need for invasive procedures, cardiac catheterization is still mandatory for absolute quantification of pressures, flows and vascular resistances in selected patients. We therefore investigated the feasibility of a new technique, non-invasive pulse densitometry (PD) in patients with intracardiac shunts and compared its results with the established standards: cuvette densitometry (CD) and oximetry (OX). Design. Measurement method comparison study. Outcome measure. In 12 patients with intracardiac shunt, dye dilution curves, using both pulse and cuvette densitometry, were recorded and oximetry was performed. Left-to-right shunt expressed as percentage of pulmonary blood flow Qp, was calculated from dye dilution and oximetry. In 4 patients with atrial septal defect, dye dilution curves were also recorded after closure of the defect with a device. Results. The mean difference +/- SD between the shunt derived from PD and CD was 2.8 +/- 10.0% of Qp, 95% confidence interval -2.5 to 8.2. (Shunt-PD vs. Shunt-CD was 32.3 +/- 23.9% vs. 29.5 +/- 23.9% of Qp resp., n = 16). The mean difference +/- SD between the shunt derived from PD and OX was 0.8 +/- 9.8% of Qp, 95% confidence interval -5.4 to 7.0 (Shunt-PD vs. Shunt-OX was 41.5 +/- 20.3% vs. 40.7 +/- 19.7% of Qp resp., n = 12). Conclusion. Transcutaneous recording of dye dilution curves with a pulse dye densitometer allows easy and accurate quantification of intracardiac left-to-right shunt flows over a wide range in both children and adults with congenital heart diseases

In-situ EBSD observations of moving austenite-ferrite interfaces during intercritical annealing

Novel Aerospace Materials(OLD) MSE-

Formulation and process development of (recombinant human) deoxyribonuclease I as a powder for inhalation

A formulation and process development study was performed to formulate recombinant human deoxyribonuclease I as a powder for inhalation. First, excipient compatibility (with bovine DNase as a model substance) was examined with a stability study at stressed conditions (60 and 85 degrees C) while monitoring for occurrence of the Maillard reaction. Next, powders for inhalation were prepared by spray drying and spray freeze drying. We found that spray drying with inulin as stabilizer resulted in the best powder for inhalation. Finally, an ex-vivo test with the spray dried rhDNase I/inulin powder significantly decreased elastic and viscous moduli of sputum from five cystic fibrosis patients

In situ high-temperature EBSD and 3D phase field studies of the austenite-ferrite transformation in a medium Mn steel

In this research, in situ high-temperature electron backscattered diffraction (EBSD) mapping is applied to record and analyze the migration of the α/3 interfaces during cyclic austenite-ferrite phase transformations in a medium manganese steel. The experimental study is supplemented with related 3D phase field (PF) simulations to better understand the 2D EBSD observations in the context of the 3D transformation events taking place below the surface. The in situ EBSD observations and PF simulations show an overall transformation behavior qualitatively similar to that measured in dilatometry. The behavior and kinetics of individual austenite-ferrite interfaces during the transformation is found to have a wide scatter around the average interface behavior deduced on the basis of the dilatometric measurements. The trajectories of selected characteristic interfaces are analyzed in detail and yield insight into the effect of local conditions in the vicinity of interfaces on their motion, as well as the misguiding effects of 2D observations of processes taking place in 3D.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.(OLD) MSE-3Novel Aerospace Material

Spray freeze drying to produce a stable Delta(9)-tetrahydrocannabinol containing inulin-based solid dispersion powder suitable for inhalation

The purpose of this study is to investigate whether spray freeze drying produces an inhalable solid dispersion powder in which Delta(9)-tetrahydrocannabinol (THC) is stabilised. Solutions of THC and inulin in a mixture of tertiary butanol (TBA) and water were spray freeze dried. Drug loads varied from 4 to 30 wt.%. Various powder characteristics of the materials were determined. Stability of THC was determined and compared with freeze dried material. The powders, dispersed with an inhaler based on air classifier technology, were subjected to laser diffraction analysis and cascade impactor analysis. Highly porous particles having large specific surface areas (about go m(2)/g) were produced. At high drug loads, THC was more effectively stabilised by spray freeze drying than by freeze drying. Higher cooling rates during spray freeze drying result in improved incorporation. Fine particle fractions of up to 50% were generated indicating suitability for inhalation. It was concluded that spray freeze drying from a water-TBA mixture is a suitable process to include lipophilic drugs (THC) in inulin glass matrices. High cooling rates during the freezing process result in effective stabilisation of THC. The powders can be dispersed into aerosols with a particle size appropriate for inhalation. (c) 2005 Elsevier B.V. All rights reserved

Efficacy of a new pulmonary cyclosporine a powder formulation for prevention of transplant rejection in rats

Background: The aim of this pilot study was to determine the pharmacokinetics of cyclosporine A powder for inhalation (iCsA) and its rejection prevention efficacy in an experimental lung transplantation model in rats. Methods: Single-dose pharmacokinetics (10 mg/kg) of pulmonary and orally administered cyclosporine A was determined in whole blood and in lung and kidney tissue. The efficacy of iCsA (2.5 and 5 mg/kg) in inhibiting rejection was determined in an orthotopic left-lung transplantation rat model and compared with orally administered CsA (5 and 10 mg/kg). The ventilation score of lung allografts was assessed with roentgenograms. At Day 10 post-operatively, the rats were terminated and lungs were prepared for histologic analysis. Results: In the pharmacokinetics study, AUC(0-48) values in blood for iCsA and oral CsA were similar (47,790 +/- 1,739 and 46,987 +/- 2,439 ng h ml(-1), respectively). In contrast, iCsA levels in lung tissue were much higher than oral CsA levels (AUC: 9,152,977 +/- 698,920 vs 84,149 +/- 8,134 ng h g(-1), respectively), showing the effectiveness of the pulmonary administration. In the rejection study, non-treated animals showed complete rejection after 8 days according to roentgenography. Treatment with 5 mg/kg iCsA reduced rejection on Day 10, whereas the 2.5-mg/kg dose did not inhibit rejection. Oral CsA at 10 mg/kg reduced rejection, whereas the 5-mg/kg dose showed hardly any effect on rejection. Conclusions: We found that iCsA is an effective immunosuppressive formulation, and may become a valuable asset for clinical use in combination with systemic immunosuppression. J Heart Lung Transplant 2009;28:486-92. Copyright (C) 2009 by the International Society for Heart and Lung Transplantation

Mature Enzymatic Collagen Cross-Links, Hydroxylysylpyridinoline and Lysylpyridinoline, in the Aging Human Vitreous

PURPOSE. The vitreous body of the human eye undergoes progressive morphologic changes with aging. Since the enzymatic collagen cross-links hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) are known to be important for the integrity of the collagen matrix, the presence in the vitreous on aging was studied. METHODS. Vitreous bodies (VBs; n = 143) from 119 donors (age 4-80 years; mean +/- SD, 54.3 +/- 17.0 years) were carefully dissected. After weighing and freeze-drying, all samples were analyzed by high performance liquid chromatography. Left and right eyes of 24 donors were compared and, for age-related phenomena, 119 single eyes were used. RESULTS. Within one donor, no significant differences were found between left and right eyes. On aging, VB wet weight (4.42 +/- 0.84 g) accumulates until 35 years and decreases thereafter. Collagen content (0.30 +/- 0.14 mg), HP per triple helix (TH; 0.55 +/- 0.18), and (HP plus LP)/TH (0.61 +/- 0.19) increase until 50 years followed by a decrease, whereas LP/TH (0.057 +/- 0.018) accumulates until 50 years and remains constant thereafter. The ratio between HP and LP (range, 0.42 - 31.0; median, 10.0) is constant over time. CONCLUSIONS. The accumulation of enzymatic collagen cross-links until 50 years is consistent with collagen maturation and possible collagen synthesis in the human vitreous body. The decline of collagen cross-links after 50 years is consistent with collagen breakdown. (Invest Ophthalmol Vis Sci. 2009; 50: 1041-1046) DOI: 10.1167/iovs.08-171

18FDG positron emission tomography versus 67Ga scintigraphy as prognostic test during chemotherapy for non-Hodgkin's lymphoma

A prospective study was performed, comparing gallium scintigraphy ( 67Ga) and positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (18FDG), to monitor the response of aggressive non-Hodgkin's lymphoma during treatment. 67Ga and 18FDG scans were performed in 26 patients after two cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) therapy. The scans were reviewed independently by four experienced nuclear physicians, who were blinded for the alternative scan technique and follow-up. Eleven out of 26 patients remained free from progression with a mean follow up of 25 ± 5 months, whereas 14 patients relapsed, and one died of lung cancer. Interobserver variation was significantly greater for 67Ga than for 18FDG PET. Some 64% of patients who had a negative early restaging 18FDG PET remained free from progression versus 50% of patients with negative 67Ga scans. Only 25% of patients with a positive PET remained disease free versus 42% of 67Ga-positive patients. Time to progression was associated with 18FDG PET results, but not with those by 67Ga. 18FDG PET had better test characteristics than 67Ga for the evaluation of early response in aggressive non-Hodgkin's lymphoma patients