Assessment of Pharmaceutical Equivalence: Difference Test or Equivalence Test?

Pharmaceutical equivalence is an important step towards the confirmation of similarity and Interchangeability among pharmaceutical products, particularly regarding those that win not be tested for bioequivalence. The aim of this paper is to compare traditional difference testing to two one-side equivalence tests in the assessment of pharmaceutical equivalence, by means of equivalence studies between similar, generic and reference products of acyclovir cream, atropine sulfate injection, meropenem for injection, and metronidazole injection. All tests were performed in accordance with the Brazilian Pharmacopeia or the United States Pharmacopeia. All four possible combinations of results arise in these comparisons of difference testing and equivalence testing. Most of the former did not show significant difference, whereas the latter presented similarity. We concluded that equivalence testing is more appropriate than difference testing, what can make it a useful tool to assess pharmaceutical equivalence in products that will not be tested for bioequivalence.

Thermo and mechanical cycling and veneering method do not influence Y-TZP core/veneer interface bond strength

Objectives: The purpose of this study was to evaluate the influence of thermal and mechanical cycling and veneering technique on the shear bond strength of Y-TZP (yttrium oxide partially stabilized tetragonal zirconia polycrystal) core–veneer interfaces. Materials and methods: Cylindrical Y-TZP specimens were veneered either by layering (n = 20) or by pressing technique (n = 20). A metal ceramic group (CoCr) was used as control (n = 20). Ten specimens for each group were thermal and mechanical cycled and then all samples were subjected to shear bond strength in a universal testing machine with a 0.5 mm/min crosshead speed. Mean shear bond strength (MPa) was analysed with a 2-way analysis of variance and Tukey’s test ( p < 0.05). Failure mode was determined using stereomicroscopy and scanning electron microscopy (SEM). Results: Thermal and mechanical cycling had no influence on the shear bond strength for all groups. The CoCr group presented the highest bond strength value ( p < 0.05) (34.72 7.05 MPa). There was no significant difference between Y-TZP veneered by layering (22.46 2.08 MPa) or pressing (23.58 2.1 MPa) technique. Failure modes were predominantly adhesive for CoCr group, and cohesive within veneer for Y-TZP groups. Conclusions: Thermal and mechanical cycling, as well as the veneering technique does not affect Y-TZP core–veneer bond strength. Clinical significance: Different methods of veneering Y-TZP restorations would not influence the clinical performance of the core/veneer interfaces.

Evaluation of inductively coupled plasma mass spectrometry for determining Ca, Cu, Fe, Mg, Mn, Se and Zn in bovine semen samples using a simple sample dilution method

A simple and fast method for the determination of Ca, Cu, Fe, Mg, Mn, Se and Zn in bovine semen by quadrupole inductively coupled plasma spectrometry (q-ICP-MS) is described. Prior to analysis, samples (200 µL) were diluted 1:50 in a solution containing 0.01% v/v Triton® X-100 and 0.5% v/v nitric acid and directly analyzed by ICP-MS. The limits of detection of the method are 0.3, 0.03, 0.2, 0.04, 0.04, 0.03 and 0.03 µg L-1 for 44Ca, 63Cu, 57Fe, 24Mg, 64Zn, 82Se and 55Mn, respectively. For purposes of comparison and method validation, four ordinary bovine semen samples were directly analyzed by ICP-MS and by flame atomic absorption spectrometry (FAAS) or graphite furnace atomic absorption spectrometry (GF AAS), with no statistical difference between the techniques at the 95% level when applying the t-test. Then, the proposed method was applied in the determinations of Ca, Cu, Fe, Mg, Mn, Se and Zn in collected samples of bovine semen from different breeds, which are used in reproduction programs and artificial insemination.

Influence of Goertler vortices spanwise wavelength on heat transfer rates

The boundary layer over concave surfaces can be unstable due to centrifugal forces, giving rise to Goertler vortices. These vortices create two regions in the spanwise direction—the upwash and downwash regions. The downwash region is responsible for compressing the boundary layer toward the wall, increasing the heat transfer rate. The upwash region does the opposite. In the nonlinear development of the Goertler vortices, it can be observed that the upwash region becomes narrow and the spanwise–average heat transfer rate is higher than that for a Blasius boundary layer. This paper analyzes the influence of the spanwise wavelength of the Goertler the heat transfer. The equation is written in vorticity-velocity formulation. The time integration is done via a classical fourth-order Runge-Kutta method. The spatial derivatives are calculated using high-order compact finite difference and spectral methods. Three different wavelengths are analyzed. The results show that steady Goertler flow can increase the heat transfer rates to values close to the values of turbulence, without the existence of a secondary instability. The geometry (and computation domain) are presented

New Improved Version of J 1 ...J 4 Interferometry Method and its Application to Nanometric Vibration Measurements

Piezoelectric ceramics, such as PZT, can generate subnanometric displacements, bu t in order to generate multi- micrometric displacements, they should be either driven by high electric voltages (hundreds of volts ), or operate at a mechanical resonant frequency (in narrow band), or have large dimensions (tens of centimeters). A piezoelectric flextensional actuator (PFA) is a device with small dimensions that can be driven by reduced voltages and can operate in the nano- and micro scales. Interferometric techniques are very adequate for the characterization of these devices, because there is no mechanical contact in the measurement process, and it has high sensitivity, bandwidth and dynamic range. A low cost open-loop homodyne Michelson interferometer is utilized in this work to experimentally detect the nanovi brations of PFAs, based on the spectral analysis of the interfero metric signal. By employing the well known J 1 ...J 4 phase demodulation method, a new and improved version is proposed, which presents the following characteristics: is direct, self-consistent, is immune to fading, and does not present phase ambiguity problems. The proposed method has resolution that is similar to the modified J 1 ...J 4 method (0.18 rad); however, differently from the former, its dynamic range is 20% larger, does not demand Bessel functions algebraic sign correction algorithms and there are no singularities when the static phase shift between the interferometer arms is equal to an integer multiple of  /2 rad. Electronic noise and random phase drifts due to ambient perturbations are taken into account in the analysis of the method. The PFA nanopositioner characterization was based on the analysis of linearity betw een the applied voltage and the resulting displacement, on the displacement frequency response and determination of main resonance frequencies.

Size-selective investigations of spectral and emission properties of small particles and nanotubes

In dieser Arbeit wurde die Elektronenemission von Nanopartikeln auf Oberflächen mittels spektroskopischen Photoelektronenmikroskopie untersucht. Speziell wurden metallische Nanocluster untersucht, als selbstorganisierte Ensembles auf Silizium oder Glassubstraten, sowie ferner ein Metall-Chalcogenid (MoS2) Nanoröhren-Prototyp auf Silizium. Der Hauptteil der Untersuchungen war auf die Wechselwirkung von fs-Laserstrahlung mit den Nanopartikeln konzentriert. Die Energie der Lichtquanten war kleiner als die Austrittsarbeit der untersuchten Proben, so dass Ein-Photonen-Photoemission ausgeschlossen werden konnte. Unsere Untersuchungen zeigten, dass ausgehend von einem kontinuierlichen Metallfilm bis hin zu Clusterfilmen ein anderer Emissionsmechanismus konkurrierend zur Multiphotonen-Photoemission auftritt und für kleine Cluster zu dominieren beginnt. Die Natur dieses neuen Mechanismus` wurde durch verschiedenartige Experimente untersucht. Der Übergang von einem kontinuierlichen zu einem Nanopartikelfilm ist begleitet von einer Zunahme des Emissionsstroms von mehr als eine Größenordnung. Die Photoemissions-Intensität wächst mit abnehmender zeitlicher Breite des Laserpulses, aber diese Abhängigkeit wird weniger steil mit sinkender Partikelgröße. Die experimentellen Resultate wurden durch verschiedene Elektronenemissions-Mechanismen erklärt, z.B. Multiphotonen-Photoemission (nPPE), thermionische Emission und thermisch unterstützte nPPE sowie optische Feldemission. Der erste Mechanismus überwiegt für kontinuierliche Filme und Partikel mit Größen oberhalb von mehreren zehn Nanometern, der zweite und dritte für Filme von Nanopartikeln von einer Größe von wenigen Nanometern. Die mikrospektroskopischen Messungen bestätigten den 2PPE-Emissionsmechanismus von dünnen Silberfilmen bei „blauer“ Laseranregung (hν=375-425nm). Das Einsetzen des Ferminiveaus ist relativ scharf und verschiebt sich um 2hν, wenn die Quantenenergie erhöht wird, wogegen es bei „roter“ Laseranregung (hν=750-850nm) deutlich verbreitert ist. Es zeigte sich, dass mit zunehmender Laserleistung die Ausbeute von niederenergetischen Elektronen schwächer zunimmt als die Ausbeute von höherenergetischen Elektronen nahe der Fermikante in einem Spektrum. Das ist ein klarer Hinweis auf eine Koexistenz verschiedener Emissionsmechanismen in einem Spektrum. Um die Größenabhängigkeit des Emissionsverhaltens theoretisch zu verstehen, wurde ein statistischer Zugang zur Lichtabsorption kleiner Metallpartikel abgeleitet und diskutiert. Die Elektronenemissionseigenschaften bei Laseranregung wurden in zusätzlichen Untersuchungen mit einer anderen Anregungsart verglichen, der Passage eines Tunnelstroms durch einen Metall-Clusterfilm nahe der Perkolationsschwelle. Die elektrischen und Emissionseigenschaften von stromtragenden Silberclusterfilmen, welche in einer schmalen Lücke (5-25 µm Breite) zwischen Silberkontakten auf einem Isolator hergestellt wurden, wurden zum ersten Mal mit einem Emissions-Elektronenmikroskop (EEM) untersucht. Die Elektronenemission beginnt im nicht-Ohmschen Bereich der Leitungsstrom-Spannungskurve des Clusterfilms. Wir untersuchten das Verhalten eines einzigen Emissionszentrums im EEM. Es zeigte sich, dass die Emissionszentren in einem stromleitenden Silberclusterfilm Punktquellen für Elektronen sind, welche hohe Emissions-Stromdichten (mehr als 100 A/cm2) tragen können. Die Breite der Energieverteilung der Elektronen von einem einzelnen Emissionszentrum wurde auf etwa 0.5-0.6 eV abgeschätzt. Als Emissionsmechanismus wird die thermionische Emission von dem „steady-state“ heißen Elektronengas in stromdurchflossenen metallischen Partikeln vorgeschlagen. Größenselektierte, einzelne auf Si-Substraten deponierte MoS2-Nanoröhren wurden mit einer Flugzeit-basierten Zweiphotonen-Photoemissions-Spektromikroskopie untersucht. Die Nanoröhren-Spektren wiesen bei fs-Laser Anregung eine erstaunlich hohe Emissionsintensität auf, deutlich höher als die SiOx Substratoberfläche. Dagegen waren die Röhren unsichtbar bei VUV-Anregung bei hν=21.2 eV. Eine ab-initio-Rechnung für einen MoS2-Slab erklärt die hohe Intensität durch eine hohe Dichte freier intermediärer Zustände beim Zweiphotonen-Übergang bei hν=3.1 eV.

A Phase Space Box-counting based Method for Arrhythmia Prediction from Electrocardiogram Time Series

Arrhythmia is one kind of cardiovascular diseases that give rise to the number of deaths and potentially yields immedicable danger. Arrhythmia is a life threatening condition originating from disorganized propagation of electrical signals in heart resulting in desynchronization among different chambers of the heart. Fundamentally, the synchronization process means that the phase relationship of electrical activities between the chambers remains coherent, maintaining a constant phase difference over time. If desynchronization occurs due to arrhythmia, the coherent phase relationship breaks down resulting in chaotic rhythm affecting the regular pumping mechanism of heart. This phenomenon was explored by using the phase space reconstruction technique which is a standard analysis technique of time series data generated from nonlinear dynamical system. In this project a novel index is presented for predicting the onset of ventricular arrhythmias. Analysis of continuously captured long-term ECG data recordings was conducted up to the onset of arrhythmia by the phase space reconstruction method, obtaining 2-dimensional images, analysed by the box counting method. The method was tested using the ECG data set of three different kinds including normal (NR), Ventricular Tachycardia (VT), Ventricular Fibrillation (VF), extracted from the Physionet ECG database. Statistical measures like mean (μ), standard deviation (σ) and coefficient of variation (σ/μ) for the box-counting in phase space diagrams are derived for a sliding window of 10 beats of ECG signal. From the results of these statistical analyses, a threshold was derived as an upper bound of Coefficient of Variation (CV) for box-counting of ECG phase portraits which is capable of reliably predicting the impeding arrhythmia long before its actual occurrence. As future work of research, it was planned to validate this prediction tool over a wider population of patients affected by different kind of arrhythmia, like atrial fibrillation, bundle and brunch block, and set different thresholds for them, in order to confirm its clinical applicability.

The factorization method for real elliptic problems

The Factorization Method localizes inclusions inside a body from measurements on its surface. Without a priori knowing the physical parameters inside the inclusions, the points belonging to them can be characterized using the range of an auxiliary operator. The method relies on a range characterization that relates the range of the auxiliary operator to the measurements and is only known for very particular applications. In this work we develop a general framework for the method by considering symmetric and coercive operators between abstract Hilbert spaces. We show that the important range characterization holds if the difference between the inclusions and the background medium satisfies a coerciveness condition which can immediately be translated into a condition on the coefficients of a given real elliptic problem. We demonstrate how several known applications of the Factorization Method are covered by our general results and deduce the range characterization for a new example in linear elasticity.

Generating vegetation-spectra as a basis for global monitoring of annual vegetation cycles using DOAS satellite observations

Vegetation-cycles are of general interest for many applications. Be it for harvest-predictions, global monitoring of climate-change or as input to atmospheric models.rnrnCommon Vegetation Indices use the fact that for vegetation the difference between Red and Near Infrared reflection is higher than in any other material on Earth’s surface. This gives a very high degree of confidence for vegetation-detection.rnrnThe spectrally resolving data from the GOME and SCIAMACHY satellite-instrumentsrnprovide the chance to analyse finer spectral features throughout the Red and Near Infrared spectrum using Differential Optical Absorption Spectroscopy (DOAS). Although originally developed to retrieve information on atmospheric trace gases, we use it to gain information on vegetation. Another advantage is that this method automatically corrects for changes in the atmosphere. This renders the vegetation-information easily comparable over long time-spans.rnThe first results using previously available reference spectra were encouraging, but also indicated substantial limitations of the available reflectance spectra of vegetation. This was the motivation to create new and more suitable vegetation reference spectra within this thesis.rnThe set of reference spectra obtained is unique in its extent and also with respect to its spectral resolution and the quality of the spectral calibration. For the first time, this allowed a comprehensive investigation of the high-frequency spectral structures of vegetation reflectance and of their dependence on the viewing geometry.rnrnThe results indicate that high-frequency reflectance from vegetation is very complex and highly variable. While this is an interesting finding in itself, it also complicates the application of the obtained reference spectra to the spectral analysis of satellite observations.rnrnThe new set of vegetation reference spectra created in this thesis opens new perspectives for research. Besides refined satellite analyses, these spectra might also be used for applications on other platforms such as aircraft. First promising studies have been presented in this thesis, but the full potential for the remote sensing of vegetation from satellite (or aircraft) could bernfurther exploited in future studies.

Fast and accurate numerical solutions in some problems of particle and radiation transport: synthetic acceleration for the method of short characteristics, Doppler-broadened scattering kernel, remote sensing of the cryosphere

The aim of this work is to present various aspects of numerical simulation of particle and radiation transport for industrial and environmental protection applications, to enable the analysis of complex physical processes in a fast, reliable, and efficient way. In the first part we deal with speed-up of numerical simulation of neutron transport for nuclear reactor core analysis. The convergence properties of the source iteration scheme of the Method of Characteristics applied to be heterogeneous structured geometries has been enhanced by means of Boundary Projection Acceleration, enabling the study of 2D and 3D geometries with transport theory without spatial homogenization. The computational performances have been verified with the C5G7 2D and 3D benchmarks, showing a sensible reduction of iterations and CPU time. The second part is devoted to the study of temperature-dependent elastic scattering of neutrons for heavy isotopes near to the thermal zone. A numerical computation of the Doppler convolution of the elastic scattering kernel based on the gas model is presented, for a general energy dependent cross section and scattering law in the center of mass system. The range of integration has been optimized employing a numerical cutoff, allowing a faster numerical evaluation of the convolution integral. Legendre moments of the transfer kernel are subsequently obtained by direct quadrature and a numerical analysis of the convergence is presented. In the third part we focus our attention to remote sensing applications of radiative transfer employed to investigate the Earth's cryosphere. The photon transport equation is applied to simulate reflectivity of glaciers varying the age of the layer of snow or ice, its thickness, the presence or not other underlying layers, the degree of dust included in the snow, creating a framework able to decipher spectral signals collected by orbiting detectors.

Extracting evolutionary information from the spectral decomposition of early-type galaxies.

Holding the major share of stellar mass in galaxies and being also old and passively evolving, early-type galaxies (ETGs) are the primary probes in investigating these various evolution scenarios, as well as being useful means to provide insights on cosmological parameters. In this thesis work I focused specifically on ETGs and on their capability in constraining galaxy formation and evolution; in particular, the principal aims were to derive some of the ETGs evolutionary parameters, such as age, metallicity and star formation history (SFH) and to study their age-redshift and mass-age relations. In order to infer galaxy physical parameters, I used the public code STARLIGHT: this program provides a best fit to the observed spectrum from a combination of many theoretical models defined in user-made libraries. the comparison between the output and input light-weighted ages shows a good agreement starting from SNRs of ∼ 10, with a bias of ∼ 2.2% and a dispersion 3%. Furthermore, also metallicities and SFHs are well reproduced. In the second part of the thesis I performed an analysis on real data, starting from Sloan Digital Sky Survey (SDSS) spectra. I found that galaxies get older with cosmic time and with increasing mass (for a fixed redshift bin); absolute light-weighted ages, instead, result independent from the fitting parameters or the synthetic models used. Metallicities, instead, are very similar from each other and clearly consistent with the ones derived from the Lick indices. The predicted SFH indicates the presence of a double burst of star formation. Velocity dispersions and extinctiona are also well constrained, following the expected behaviours. As a further step, I also fitted single SDSS spectra (with SNR∼ 20), to verify that stacked spectra gave the same results without introducing any bias: this is an important check, if one wants to apply the method at higher z, where stacked spectra are necessary to increase the SNR. Our upcoming aim is to adopt this approach also on galaxy spectra obtained from higher redshift Surveys, such as BOSS (z ∼ 0.5), zCOSMOS (z 1), K20 (z ∼ 1), GMASS (z ∼ 1.5) and, eventually, Euclid (z 2). Indeed, I am currently carrying on a preliminary study to estabilish the applicability of the method to lower resolution, as well as higher redshift (z 2) spectra, just like the Euclid ones.

Perturbation theory for spectral subspaces

In der vorliegenden Arbeit wird die Variation abgeschlossener Unterräume eines Hilbertraumes untersucht, die mit isolierten Komponenten der Spektren von selbstadjungierten Operatoren unter beschränkten additiven Störungen assoziiert sind. Von besonderem Interesse ist hierbei die am wenigsten restriktive Bedingung an die Norm der Störung, die sicherstellt, dass die Differenz der zugehörigen orthogonalen Projektionen eine strikte Normkontraktion darstellt. Es wird ein Überblick über die bisher erzielten Resultate gegeben. Basierend auf einem Iterationsansatz wird eine allgemeine Schranke an die Variation der Unterräume für Störungen erzielt, die glatt von einem reellen Parameter abhängen. Durch Einführung eines Kopplungsparameters wird das Ergebnis auf den Fall additiver Störungen angewendet. Auf diese Weise werden zuvor bekannte Ergebnisse verbessert. Im Falle von additiven Störungen werden die Schranken an die Variation der Unterräume durch ein Optimierungsverfahren für die Stützstellen im Iterationsansatz weiter verschärft. Die zugehörigen Ergebnisse sind die besten, die bis zum jetzigen Zeitpunkt erzielt wurden.

A new information fusion method for land-use classification using high resolution satellite imagery

Satellite image classification involves designing and developing efficient image classifiers. With satellite image data and image analysis methods multiplying rapidly, selecting the right mix of data sources and data analysis approaches has become critical to the generation of quality land-use maps. In this study, a new postprocessing information fusion algorithm for the extraction and representation of land-use information based on high-resolution satellite imagery is presented. This approach can produce land-use maps with sharp interregional boundaries and homogeneous regions. The proposed approach is conducted in five steps. First, a GIS layer - ATKIS data - was used to generate two coarse homogeneous regions, i.e. urban and rural areas. Second, a thematic (class) map was generated by use of a hybrid spectral classifier combining Gaussian Maximum Likelihood algorithm (GML) and ISODATA classifier. Third, a probabilistic relaxation algorithm was performed on the thematic map, resulting in a smoothed thematic map. Fourth, edge detection and edge thinning techniques were used to generate a contour map with pixel-width interclass boundaries. Fifth, the contour map was superimposed on the thematic map by use of a region-growing algorithm with the contour map and the smoothed thematic map as two constraints. For the operation of the proposed method, a software package is developed using programming language C. This software package comprises the GML algorithm, a probabilistic relaxation algorithm, TBL edge detector, an edge thresholding algorithm, a fast parallel thinning algorithm, and a region-growing information fusion algorithm. The county of Landau of the State Rheinland-Pfalz, Germany was selected as a test site. The high-resolution IRS-1C imagery was used as the principal input data.

Evaluation and quantification of spectral information in tissue by confocal microscopy

A confocal imaging and image processing scheme is introduced to visualize and evaluate the spatial distribution of spectral information in tissue. The image data are recorded using a confocal laser-scanning microscope equipped with a detection unit that provides high spectral resolution. The processing scheme is based on spectral data, is less error-prone than intensity-based visualization and evaluation methods, and provides quantitative information on the composition of the sample. The method is tested and validated in the context of the development of dermal drug delivery systems, introducing a quantitative uptake indicator to compare the performances of different delivery systems is introduced. A drug penetration study was performed in vitro. The results show that the method is able to detect, visualize and measure spectral information in tissue. In the penetration study, uptake efficiencies of different experiment setups could be discriminated and quantitatively described. The developed uptake indicator is a step towards a quantitative assessment and, in a more general view apart from pharmaceutical research, provides valuable information on tissue composition. It can potentially be used for clinical in vitro and in vivo applications.

Application of Discrete Fourier Inter-Coefficient Difference for Assessing Genetic Sequence Similarity

Digital signal processing (DSP) techniques for biological sequence analysis continue to grow in popularity due to the inherent digital nature of these sequences. DSP methods have demonstrated early success for detection of coding regions in a gene. Recently, these methods are being used to establish DNA gene similarity. We present the inter-coefficient difference (ICD) transformation, a novel extension of the discrete Fourier transformation, which can be applied to any DNA sequence. The ICD method is a mathematical, alignment-free DNA comparison method that generates a genetic signature for any DNA sequence that is used to generate relative measures of similarity among DNA sequences. We demonstrate our method on a set of insulin genes obtained from an evolutionarily wide range of species, and on a set of avian influenza viral sequences, which represents a set of highly similar sequences. We compare phylogenetic trees generated using our technique against trees generated using traditional alignment techniques for similarity and demonstrate that the ICD method produces a highly accurate tree without requiring an alignment prior to establishing sequence similarity.