Índice de masa corporal y eficacia y seguridad del ticagrelor frente al prasugrel en pacientes con síndrome coronario agudo / Body mass index and efficacy and safety of ticagrelor versus prasugrel in patients with acute coronary syndromes

Introducción y objetivos Siguen sin estudio la eficacia y la seguridad del ticagrelor frente al prasugrel en pacientes con síndrome coronario agudo (SCA) según el índice de masa corporal (IMC). Se evaluaron la eficacia y la seguridad del ticagrelor frente a prasugrel en pacientes con SCA según el IMC. Métodos Se agrupó a los pacientes (n=3.987) en 3 categorías: con peso normal (IMC <25; n=1.084), sobrepeso (IMC ≥ 25 <30; n=1.890) y obesidad (IMC ≥ 30; n=1.013). El objetivo primario de eficacia fue la incidencia de muerte por cualquier causa, infarto de miocardio o accidente cerebrovascular a 1 año. El objetivo secundario de seguridad fue la incidencia de hemorragias de tipo 3-5 de la Bleeding Academic Research Consortium a 1 año. Resultados El objetivo primario se produjo en 63 pacientes asignados a ticagrelor y 39 asignados a prasugrel en el grupo de peso normal (el 11,7 frente al 7,5%; HR=1,62; IC95%, 1,09-2,42; p=0,018), 78 pacientes asignados a ticagrelor y 58 asignados a prasugrel en el grupo de sobrepeso (el 8,3 frente al 6,2%; HR=1,36; IC95%, 0,97-1,91; p=0,076) y 43 pacientes asignados a ticagrelor y 37 asignados a prasugrel en el grupo de obesidad (el 8,6 frente al 7,3%; HR=1,18; IC95%, 0,76-1,84; p=0,451). La incidencia de eventos hemorrágicos a 1 año en los pacientes con peso normal (el 6,5 frente al 6,6%; p=0,990), sobrepeso (el 5,6 frente al 5,0%; p=0,566) u obesidad (el 4,4 frente al 2,8%; p=0,219) no difirió entre el ticagrelor y el prasugrel. No hubo una interacción significativa entre el brazo de tratamiento y el IMC en relación con el objetivo primario (pinteracción=0,578) o el secundario (pinteracción=0,596). Conclusiones En pacientes con SCA, el IMC no influyó significativamente en el efecto del tratamiento con ticagrelor en términos de eficacia o seguridad frente al prasugrel (AU)

Introduction and objectives The efficacy and safety of ticagrelor vs prasugrel in patients with acute coronary syndromes (ACS) according to body mass index (BMI) remain unstudied. We assessed the efficacy and safety of ticagrelor vs prasugrel in patients with ACS according to BMI. Methods Patients (n=3987) were grouped into 3 categories: normal weight (BMI <25kg/m2; n=1084), overweight (BMI ≥ 25 to <30kg/m2; n=1890), and obesity (BMI ≥ 30kg/m2; n=1013). The primary efficacy endpoint was the 1 year incidence of all-cause death, myocardial infarction, or stroke. The secondary safety endpoint was the 1 year incidence of Bleeding Academic Research Consortium type 3 to 5 bleeding. Results The primary endpoint occurred in 63 patients assigned to ticagrelor and 39 patients assigned to prasugrel in the normal weight group (11.7% vs 7.5%; HR, 1.62; 95%CI, 1.09-2.42; P=.018), 78 patients assigned to ticagrelor and 58 patients assigned to prasugrel in the overweight group (8.3% vs 6.2%; HR, 1.36; 95%CI, 0.97-1.91; P=.076), and 43 patients assigned to ticagrelor and 37 patients assigned to prasugrel in the obesity group (8.6% vs 7.3%; HR, 1.18; 95%CI, 0.76-1.84; P=.451). The 1-year incidence of bleeding events did not differ between ticagrelor and prasugrel in patients with normal weight (6.5% vs 6.6%; P=.990), overweight (5.6% vs 5.0%; P=.566) or obesity (4.4% vs 2.8%; P=.219). There was no significant treatment arm-by-BMI interaction regarding the primary endpoint (Pint=.578) or secondary endpoint (Pint=.596). Conclusions In patients with ACS, BMI did not significantly impact the treatment effect of ticagrelor vs prasugrel in terms of efficacy or safety (AU)

Quantitative anatomy of the round window and cochlear aqueduct in guinea pigs.

In order to analyze the entry of solutes through the round window membrane, a quantitative description of round window anatomy in relationship to scala tympani is required. High-resolution magnetic resonance microscopy was used to visualize the fluid spaces and tissues of the inner ear in three dimensions in isolated, fixed specimens from guinea pigs. Each specimen was represented as consecutive serial slices, with a voxel size of approximately 25 microm(3). The round window membrane, and its relationship to the terminal portion of scala tympani in the basal turn, was quantified in six specimens. In each image slice, the round window membrane and scala tympani were identified and segmented. The total surface area of the round window membrane averaged 1.18 mm(2) (S.D. 0.08, n=6). The length and variation of cross-sectional area as a function of distance for the cochlear aqueduct was determined in five specimens. The cochlear aqueduct was shown to enter scala tympani at the medial limit of the round window membrane, which corresponded to a distance of approximately 1 mm from the end of the scala when measured along its mid-point. These data are of value in simulating drug and other solute movements in the cochlear fluids and have been incorporated into a public-domain simulation program available at http://oto.wustl.edu/cochlea/.

Cochlear fluid space dimensions for six species derived from reconstructions of three-dimensional magnetic resonance images.

OBJECTIVES: To establish the dimensions and volumes of the cochlear fluid spaces. STUDY DESIGN: Fluid space volumes, lengths, and cross-sectional areas were derived for the cochleas from six species: human, guinea pig, bat, rat, mouse, and gerbil. METHODS: Three-dimensional reconstructions of the fluid spaces were made from magnetic resonance microscopy (MRM) images. Consecutive serial slices composed of isotropic voxels (25 microm3) representing the entire volume of fixed, isolated cochleas were obtained. The boundaries delineating the fluid spaces, including Reissner's membrane, were resolved for all specimens, except for the human, in which Reissner's membrane was not consistently resolved. Three-dimensional reconstructions of the endolymphatic and perilymphatic fluid spaces were generated. Fluid space length and variation of cross-sectional area with distance were derived by an algorithm that followed the midpoint of the space along the length of the spiral. The total volume of each fluid space was derived from a voxel count for each specimen. RESULTS: Length, volume, and cross-sectional areas are provided for six species. In all cases, the length of the endolymphatic fluid space was consistently longer than that of either perilymphatic scala, primarily as a result of a greater radius of curvature. For guinea pig specimens, the measured volumes of the fluid spaces were considerably lower than those suggested by previous reports based on histological data. CONCLUSIONS: The quantification of cochlear fluid spaces provided by this study will enable the more accurate calculation of drug and other solute movements in fluids of the inner ear during experimental or clinical manipulations.

A fast spin echo technique with circular sampling.

This paper presents a fast spin echo (FSE) imaging method that employs circular sampling of k-space. The technique has been implemented on a 2 Tesla imaging system and validated on both phantoms and living animals. Experimental studies have shown that circular sampling can produce artifact-free FSE images without the need of phase correction. Although not fully explored, preliminary results also show that circular sampling may have advantages over the conventional rectilinear FSE in signal-to-noise ratio and imaging efficiency. A major disadvantage is the increased sensitivity to off-resonance effects. The authors expect that the FSE technique with circular sampling will find its applications in magnetic resonance microscopy, neuro-functional imaging, and real-time dynamic studies.

MR microimaging of the lung using volume projection encoding.

Radial acquisition (RA) techniques have been extended to produce isotropic, three-dimensional images of lung in live laboratory animals at spatial resolution down to 0.013 mm3 with a signal-to-noise ratio of 30:1. The pulse sequence and reconstruction algorithm have been adapted to allow acquisition of image matrices of up to 256(3) in less than 15 min. Scan-synchronous ventilation has been incorporated to limit breathing motion artifacts. The imaging sequence permits randomizing and/or discarding selected views to minimize the consequences of breathing motion. The signal in lung parenchyma was measured as a function of flip angle (alpha) for different repetition times and found to follow the predictions for which there is an optimum excitation (Ernst) angle. A single T1 relaxation value of 780 +/- 54 ms fits all data from six guinea pigs at 2.0 T. This T1 value parameterizes the signal and allows for a priori optimization, such as calculation of the Ernst angle appropriate for lung imaging.

Progression of a focal ischemic lesion in rat brain during treatment with a novel glycine/NMDA antagonist: an in vivo three-dimensional diffusion-weighted MR microscopy study.

Stroke was induced in two groups of anesthetized rats by occlusion of the middle cerebral artery (MCA) and ipsilateral common carotid artery. Group 1 (control) received vehicle and group 2 received the glycine N-methyl-D-aspartate (NMDA) antagonist ZD9379. Stroke volume was assessed by three-dimensional diffusion-weighted MR microscopy at 2.5 and 6 hours of MCA occlusion. At 2.5 hours, stroke volumes were identical in the two groups. At 6 hours, stroke volumes had increased by 15% in the control group; in contrast, the treated group showed a 40% reduced stroke volume. Conclusions from this in vivo study were as follows: (a) our technique allows more efficient and accurate measurement of stroke volume with an improvement in resolution over a previous method; (b) the ability to measure stroke volume at multiple time points shows volume change and assessment of time dependency of drug treatment; (c) at 6 hours, the glycine antagonist ZD9379 reduced stroke volume by 40%.

Reconstructions and cross-sectional area measurements from magnetic resonance microscopic images of the cochlea.

In this study, magnetic resonance (MR) microscopy was used to obtain serial sections through the cochleae of mustached bats. As previously reported, 25 microns isotropic voxels can be obtained. Specific areas in each slice were segmented and then three-dimensional (3-D) reconstructions of the perilymphatic and endolymphatic spaces and spiral ligament were obtained. Quantitative measurements of the cross-sectional areas were made with customized macros written for the public-domain software, NIH Image. Results of this study revealed enlargements of the scalae and spiral ligament in areas known to be involved with processing of the animal's biosonar and fine-frequency analysis.

Detection and quantification of endolymphatic hydrops in the guinea pig cochlea by magnetic resonance microscopy.

Three-dimensional magnetic resonance microscopy (MRM) was used to study normal and hydropic cochleae of the guinea pig. With this technique consecutive serial slices representing the entire volume of isolated, fixed cochleae were obtained. The voxels (volume elements) making up the contiguous slices were isotropic (25 microns 3) and in each slice the boundaries of scala media, including the position of Reissner's membrane, were clearly delineated. Three-dimensional reconstructions of the endolymphatic and perilymphatic scale were generated. Custom software was developed to quantify cross-sectional area (CSA) of all scalae. In the normal cochlea all 3 scalae, including scala media, showed a gradual decrease in CSA from base to apex. Marked differences existed between our findings and previously reported cochlear dimensions, especially for the perilymphatic scalae in the basal turn. In hydropic cochleae the scala media was enlarged to a varying extent in different turns and marked changes in the degree of distension of Reissner's membrane occurred along the cochlea. MRM and subsequent computer analysis of the isotropic data provide excellent methods for imaging and quantifying the fluid spaces of normal and hydropic cochleae.

Imaging the cochlea by magnetic resonance microscopy.

The isolated, fixed cochlea of the mustached bat was studied with three dimensional magnetic resonance (MR) microscopy. The cochlea of this animal is about 4 mm in diameter and its entire volume was imaged. With the field of view and matrix size used, the volume elements (voxels) making up the volume data set were isotropic 25 x 25 x 25 micron cubes. Three dimensional (3D) MR microscopy based on isotropic voxels has many advantages over commonly used light microscopy: 1) it is non destructive; 2) it is much less time consuming; 3) no dehydration is required and shrinkage is minimized; 4) the data set can be used to create sections in any desired plane; 5) the proper alignment of sections is inherent in the 3D acquisition so that no reference points are required; 6) the entire data set can be viewed from any point of view in a volume rendered image; 7) the data is digital and features can be enhanced by computer image processing; and 8) the isotropic dimensions of the voxels make the data well-suited for structural reconstructions and measurements. Good images of the osseous spiral lamina, spiral ligament, scala tympani, scala vestibuli, and nerve bundles were obtained. The vestibular (Reissner's) membrane was easily identified in the mustached bat and it appears to bulge into the scala vestibuli. The visibility of this structure suggests that MR microscopy would be well-suited for studies of endolymphatic hydrops.

MR microscopy of the rat lung using projection reconstruction.

Projection reconstruction has been implemented with self-refocused selection pulses on a small bore, 2.0 T MR microscope, to allow imaging of lung parenchyma. Scan synchronous ventilation and cardiac gating have been integrated with the sequence to minimize motion artifacts. A systematic survey of the pulse sequence parameters has been undertaken in conjunction with the biological gating parameters to optimize resolution and signal-to-noise (SNR). The resulting projection images with effective echo time of < 300 microseconds allow definition of lung parenchyma with an SNR improvement of approximately 15 x over a more conventional 2DFT short echo gradient sequence.

Simulation testing of mechanisms for inducing the formation of the contractile ring in cytokinesis.

There is persuasive evidence that the role of the mitotic apparatus (MA) in cytokinesis is to control the location of the cleavage furrow. The geometric aspects of this interaction between the MA and the cortex are complex and, thus, computer simulation can be a useful means for testing hypotheses about the induction process. White and Borisy (1983. J. Theor. Biol. 101:289-316) used computer simulations to show that long-range signals from the asters, varying inversely as various powers of distance, produce summed effects that are minima at the equator of spherical cells. Their results have seemed to support the "polar relaxation" class of hypotheses, in which the effect of the asters is to weaken cortical contractility so that contraction becomes maximized at the equator because it is least inhibited there. However, the experimental studies of Rappaport and Rappaport (1988. J. Exp. Zool. 247:92-98) indicate that the asters actually strengthen cortical contractility. In this paper, we use computer simulation to determine how signals from the MA will need to vary in effect as functions of distance to cause cortical contractility to become maximized where the furrows are to be induced. Although we confirm that inverse power inhibitory signals could induce equatorial furrows in spherical cells, we also find that this ability is destroyed by flattening, constricting, or distorting cells into cylinders, geometries for which Rappaport's experiments show furrows form (1986. Int. Rev. Cytol. 105:245-281). We then show that stimulatory signals of the right kind would induce furrows at the locations observed, in spherical cells as well as cells distorted by experimental manipulation. These signals must be constant out to a threshold distance but decrease abruptly beyond that distance. We also show that this ability depends on having the "drop-off" threshold occur at just the right distance relative to the dimensions of the cell and separation of the asters.