REPLACE trial

Adverse reactions at therapeutic doses are usually minimal and transient. With long-term use, initial side effects usually disappear. The following reactions were reported in 2 heart valve replacement trials comparing dipyridamole and warfarin therapy to either warfarin alone or warfarin and placebo dizziness, abdominal distress, headache, and rash. 

Nimodipine has been routinely used to reduce cerebral vasospasm in patients with subarachnoid hemorrhage. A randomized, double-blind, placebo-controlled trial was stopped early because of excess mortality (8/75 versus 1/74 deaths with nimodipine and placebo respectively), which was attributed to an increased incidence of surgical bleeding (4). In addition, its use for cerebral protection in a cardiac valve replacement trial involving cardiopulmonary bypass was also terminated prematurely because of increased cerebrovascular complications and excessive blood loss in a small subgroup of patients (5). In traumatic subarachnoid hemorrhage, a... 

Direct methods replaced trial and error and other methods of deducing model structures in the middle of the 20th century. In these techniques, statistical relationships between the amplitudes and phases of the strong reflections were established, and the mathematical methodology between these quantities was worked out, particularly by Hauptmann and Karle, in the 1940 s and 1950 s. (The Nobel Prize was awarded to these scientists in 1985 for these studies.) A number of algorithms, which exploited the growing power of electronic computers, used this mathematical framework to derive structures directly from the experimental data set of position, intensity and hkl index. The use of these programs allows the structures of molecular compounds with up to 100 or so atoms to be... 

A mammalian system has been used to determine the fate in vivo of bovine jS-D-glucuronidase administered intravenously to mice that are deficient in the enzyme sensitive and reliable discrimination between bovine-liver and residual, murine-tissue jS-D-glucuronidase activities was achieved by inactivation of the former with heat. The bovine activity was cleared rapidly from circulation following injection, and was recovered almost exclusively in the liver, where 72% is localized in the lysosomes. The mammalian system provides an in vivo model that enables the protection and delivery of an exogenous enzyme to be evaluated prior to replacement trials in patients with inherited diseases caused by an enzyme deficiency. 

As pointed out in Chap. 5, replacing simple columns by complex columns tends to reduce the vapor (and heat) load but requires more of the heat to be added or removed at extreme levels. This means that the introduction of complex columns in the design might prejudice heat integration opportunities. Thus the introduction of complex distillation arrangements needs to be considered simultaneously with the heat integration. This can be carried out manually with some trial and error or using an automated procedure such as that of Kakhu and Flower. ... 

A fermented-egg product (EEP), patented as an attractive bait for synanthropic flies, has been shown to be attractive to coyotes and repeUent to deer (79). Its components are variable, with relative concentrations of 77% fatty acids, 13% bases, and 10% (primarily) neutrals composed of at least 54 volatiles such as ethyl esters, dimethyl disulfide, and 2-mercaptoethanol. Synthetic formulations have been evaluated to find a replacement for a patented fermented-egg protein product that attracts coyotes and repels deer. Ten aUphatic acids (C-2 to C-8), four amines (pentyl, hexyl, heptyl, and trimethyl), dimethyl disulfide, 2-mercaptoethanol, and 54 more volatiles (C-1 to C-5 esters of C-1 to C-8 acids) have been tested as synthetic fermented egg (SEE) (80) in approximately the same proportions that are present in EEP. Weathering was a problem that caused decreased efficacy, which suggests trials of controUed-release formulations. Eourteen repeUents have been examined against white-taU deer in Peimsylvania in choice tests when treated onto sheUed com (81). 

Several of the products discussed herein are under intense development. One product, based on recombinant hemoglobin, is in early human trials as of this writing. Other hemoglobin-based solutions are also under review at the EDA. Replacement of red blood cells using massive amounts of protein, free in solution, is an unprecedented therapeutic adventure. 

At the in vivo assay level, the classic ip-ip (iateraperitoneal) in vivo model has been replaced as a selection criteria for advancement of new dmg candidates to clinical trial. More stringent alternative models iaclude subcutaneous or subrenal capsule implantation of tumor followed by iatravenous dmg dosiag (7) and the human tumor xenograft models ia aude mice (8). 

Nature In an experiment in which one samples from a relatively small group of items, each of which is classified in one of two categories, A or B, the hypergeometric distribution can be defined. One example is the probabihty of drawing two red and two black cards from a deck of cards. The hypergeometric distribution is the analog of the binomial distribution when successive trials are not independent, i.e., when the total group of items is not infinite. This happens when the drawn items are not replaced. 

The definitions are here given under the assumption that the wave function XP is either antisymmetric or symmetric for a trial function without symmetry property, one has to replace the binomial factor NCV before the integrand by a factor l/p and sum over the N(N—l). . . (N—p+l) possible integrals which are obtained by placing the fixed coordinates x, x 2,. . ., x P in various ways in the N places of the first factor W and the fixed coordinates xv x2,. . xv similarly in the second factor W. By using Eq. II.8 we then obtain... 

From the point of view of principles, it is interesting to note that the method based on the generalized form of Eq. III. 129 seems to be very closely connected both with Wigner s classical theory described in Section III.B and with Bohm and Pines plasma model (Krisement 1957). Following Krisement, we will replace the various trial functions flt /2,. . ., fn in Eq. III.9 by a single average function /, and Wigner s basic wave function (Eq. II1.7) takes then the simple form... 

X-Ray diffraction from single crystals is the most direct and powerful experimental tool available to determine molecular structures and intermolecular interactions at atomic resolution. Monochromatic CuKa radiation of wavelength (X) 1.5418 A is commonly used to collect the X-ray intensities diffracted by the electrons in the crystal. The structure amplitudes, whose squares are the intensities of the reflections, coupled with their appropriate phases, are the basic ingredients to locate atomic positions. Because phases cannot be experimentally recorded, the phase problem has to be resolved by one of the well-known techniques the heavy-atom method, the direct method, anomalous dispersion, and isomorphous replacement.1 Once approximate phases of some strong reflections are obtained, the electron-density maps computed by Fourier summation, which requires both amplitudes and phases, lead to a partial solution of the crystal structure. Phases based on this initial structure can be used to include previously omitted reflections so that in a couple of trials, the entire structure is traced at a high resolution. Difference Fourier maps at this stage are helpful to locate ions and solvent molecules. Subsequent refinement of the crystal structure by well-known least-squares methods ensures reliable atomic coordinates and thermal parameters. 

The effects that changes in vegetation have on soil carbon pools and nutrient availability are also difficult to evaluate. However, several models have been successful in predicting vegetation-soil nutrient relationships because they assume that such changes occur as a result of different rates of decomposition and nutrient release from leaf litter of different taxa 50, 60), Such predictions could be tested and the models refined or parameterized for new taxa by measuring soil nutrient availability and respiration in stands of different species on the same soil type. For example, fifty years ago the U.S. Civilian Conservation Corps (CCC) established such stands as species trial plots measurements in some indicate large differences in soil nutrient availability (48), Further measurements in these stands would now occur at the same time-scale at which we expect the feedback between species replacement and soil processes to occur. 

This procedure would generate the density amplitudes for each n, and the density operator would follow as a sum over all the states initially populated. This does not however assure that the terms in the density operator will be orthonormal, which can complicate the calculation of expectation values. Orthonormality can be imposed during calculations by working with a basis set of N states collected in the Nxl row matrix (f) which includes states evolved from the initially populated states and other states chosen to describe the amplitudes over time, all forming an orthonormal set. Then in a matrix notation, (f) = (f)T (t), where the coefficients T form IxN column matrices, with ones or zeros as their elements at the initial time. They are chosen so that the square NxN matrix T(f) = [T (f)] is unitary, to satisfy orthonormality over time. Replacing the trial functions in the TDVP one obtains coupled differential equations in time for the coefficient matrices. 

Consequently, S-1360, a triazole analogue of DKA, was the first integrase strand transfer inhibitor (INSTI) to enter clinical trials, but the development was stopped during phase Eli (Billich 2003). Subsequently, a novel series of potent INSTIs, which replaced the 1,3-diketo acid moiety by an isosteric 8-hydroxy-1,6-naphthyridine core, showed improved metabohc stabihty (Zhuang et al. 2003). The compound L-870,810 moved into clinical trials, where it provided proof of concept in antiretroviral therapy-experienced and antiretroviral therapy-naive... 

Speas C, Rushing S, Backfield M. Web based data entry in a hormone replacement therapy clinical trial for a data coordinating center. Controlled Clin Trials 2000 20 2S-91S. 

Finite-element techniques can cope with large, highly non-linear deformations, making it possible to model soft tissues such as skin. When relatively large areas of skin are replaced during plastic surgery, there is a problem that excessive distortion of the apphed skin will prevent adequate adhesion. Finite-element models can be used to determine, either by rapid trial-and-error modelhng or by mathematical optimisation, the best way of... 

KOMULAINEN M, KROGER H, TUPPURAINEN M T, HEIKKINEN A M, ALHAVA E, HONKANEN R, lURVELIN I and SAARiKOSKi s (1999) Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D3 in early postmenopausal women a population-based 5-year randomized trial. J Clin Endocrinol Metab 84, 546-52. 

As a normalized trial function 0 for the determination of the ground-state energy by the variation method, we select the unperturbed eigenfunction r2) of the perturbation treatment, except that we replace the atomic number Zby a parameter Z ... 

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