Use of Most Bothersome Symptom as a Coprimary Endpoint in Migraine Clinical Trials: A Post-Hoc Analysis of the Pivotal ZOTRIP Randomized, Controlled Trial.

ObjectiveTo better understand the utility of using pain freedom and most bothersome headache-associated symptom (MBS) freedom as co-primary endpoints in clinical trials of acute migraine interventions.BackgroundAdhesive dermally applied microarray (ADAM) is an investigational system for intracutaneous drug administration. The recently completed pivotal Phase 2b/3 study (ZOTRIP), evaluating ADAM zolmitriptan for the treatment of acute moderate to severe migraine, was one of the first large studies to incorporate MBS freedom and pain freedom as co-primary endpoints per recently issued guidance by the US Food and Drug Administration. In this trial, the proportion of patients treated with ADAM zolmitriptan 3.8 mg, who were pain-free and MBS-free at 2 hours post-dose, was significantly higher than for placebo.MethodsWe undertook a post-hoc analysis of data from the ZOTRIP trial to examine how the outcomes from this trial compare to what might have been achieved using the conventional co-primary endpoints of pain relief, nausea, photophobia, and phonophobia.ResultsOf the 159 patients treated with ADAM zolmitriptan 3.8 mg or placebo, prospectively designated MBS were photophobia (n = 79), phonophobia (n = 43), and nausea (n = 37). Two-hour pain free rates in those with photophobia as the MBS were 36% for ADAM zolmitriptan 3.8 mg and 14% for placebo (P = .02). Corresponding rates for those with phonophobia as the MBS were 14% and 41% (P = .05). For those whose MBS was nausea, corresponding values were 56% and 16%, respectively (P = .01). Two-hour freedom from the MBS for active drug vs placebo were 67% vs 35% (P < .01) for photophobia, 55% vs 43% (P = .45) for phonophobia, and 89% vs 58% for nausea (P = .04). MBS freedom but not pain freedom was achieved in 28%. Only 1 patient (1%) achieved pain freedom, but not MBS freedom. The proportion with both pain and MBS freedom was highest (56%) among those whose MBS was nausea.ConclusionIn this study, the use of MBS was feasible and seemed to compare favorably to the previously required 4 co-primary endpoints

Point-light biological motion perception activates human premotor cortex

Motion cues can be surprisingly powerful in defining objects and events. Specifically, a handful of point-lights attached to the joints of a human actor will evoke a vivid percept of action when the body is in motion. The perception of point-light biological motion activates posterior cortical areas of the brain. On the other hand, observation of others' actions is known to also evoke activity in motor and premotor areas in frontal cortex. In the present study, we investigated whether point-light biological motion animations would lead to activity in frontal cortex as well. We performed a human functional magnetic resonance imaging study on a high-field-strength magnet and used a number of methods to increase signal, as well as cortical surface-based analysis methods. Areas that responded selectively to point-light biological motion were found in lateral and inferior temporal cortex and in inferior frontal cortex. The robust responses we observed in frontal areas indicate that these stimuli can also recruit action observation networks, although they are very simplified and characterize actions by motion cues alone. The finding that even point-light animations evoke activity in frontal regions suggests that the motor system of the observer may be recruited to "fill in" these simplified displays

The Effect of Variability on the Estimation of Quasar Black Hole Masses

We investigate the time-dependent variations of ultraviolet (UV) black hole mass estimates of quasars in the Sloan Digital Sky Survey (SDSS). From SDSS spectra of 615 high-redshift (1.69 < z < 4.75) quasars with spectra from two epochs, we estimate black hole masses, using a single-epoch technique which employs an additional, automated night-sky-line removal, and relies on UV continuum luminosity and CIV (1549A) emission line dispersion. Mass estimates show variations between epochs at about the 30% level for the sample as a whole. We determine that, for our full sample, measurement error in the line dispersion likely plays a larger role than the inherent variability, in terms of contributing to variations in mass estimates between epochs. However, we use the variations in quasars with r-band spectral signal-to-noise ratio greater than 15 to estimate that the contribution to these variations from inherent variability is roughly 20%. We conclude that these differences in black hole mass estimates between epochs indicate variability is not a large contributer to the current factor of two scatter between mass estimates derived from low- and high-ionization emission lines.Comment: 76 pages, 15 figures, 2 (long) tables; Accepted for publication in ApJ (November 10, 2007

Optimal Chiller and Thermal Energy Storage Design for Building HVAC Systems

In the context of indoor building temperature regulation, a controller calculates the inputs for the HVAC system that result in appropriate thermal comfort conditions. Additionally, if electricity prices are time dependent, these control actions will also impact economic expenditures. To improve economic performance, Thermal Energy Storage (TES) is typically used in conjunction with HVAC to time-shift chiller cooling loads to times of low energy price. The method of Economic Model Predictive Control (EMPC) has been demonstrated to effectively reduce expenditures. Since TES and chiller sizes have a direct impact on achievable operational savings, an economic analysis considering the investment costs associated with these equipments is necessary. This work presents a novel algorithm intended to optimally select equipment sizes based on Net Present Value analysis and utilizing the recently developed methods of Economic Linear Optimal Control (ELOC) and constrained ELOC. Implementation of the numeric optimization is illustrated with a case study

Federating distributed clinical data for the prediction of adverse hypotensive events

The ability to predict adverse hypotensive events, where a patient's arterial blood pressure drops to abnormally low (and dangerous) levels, would be of major benefit to the fields of primary and secondary health care, and especially to the traumatic brain injury domain. A wealth of data exist in health care systems providing information on the major health indicators of patients in hospitals (blood pressure, temperature, heart rate, etc.). It is believed that if enough of these data could be drawn together and analysed in a systematic way, then a system could be built that will trigger an alarm predicting the onset of a hypotensive event over a useful time scale, e.g. half an hour in advance. In such circumstances, avoidance measures can be taken to prevent such events arising. This is the basis for the Avert-IT project (http://www.avert-it.org), a collaborative EU-funded project involving the construction of a hypotension alarm system exploiting Bayesian neural networks using techniques of data federation to bring together the relevant information for study and system development

Investigation of an Underslung Normal-wedge Inlet at Free-stream Mach Numbers from 1.50 to 1.99

Two normal -wedge-inlet configurations (straight and sweptback splitter plates) were investigated in the Lewis 8- by 6-foot supersonic wind tunnel at Mach numbers of 1.50 to 1.99. Negligible differences occurred in the performances of the two normal-wedge inlets. In comparison with a previously tested scoop inlet, the normal-wedge configuration showed superior thrust-minus-drag characteristics at Mach 1.99. However the scoop inlet was better at Mach numbers of 1.80 and 1.50

CELLULAR EVENTS IN THE IMMUNE RESPONSE : ANALYSIS AND IN VITRO RESPONSE OF MOUSE SPLEEN CELL POPULATIONS SEPARATED BY DIFFERENTIAL FLOTATION IN ALBUMIN GRADIENTS

Cell suspensions from the spleens of normal mice or mice injected with sheep erythrocytes were separated on a discontinous bovine serum albumin density gradient. Four bands or subpopulations were obtained and were assayed for antibody-forming cells, and for antigen-sensitive precursor cells. The antibody-forming cells were assayed by the hemolytic plaque assay and the antigen-sensitive precursors were assayed by the number of plaque-forming cells which developed after 3 or 5 day's culture with antigen. It was found that both antibody-forming cells and their precursors were present in the denser region of the gradient when spleen cell suspensions were taken from unimmunized mice. In contrast, both antibody-forming cells and precursors floated to the top in cell suspensions from mice sacrificed 1, 2, or 3 days after antigen injection. The change in density was detectable as early as 12 hr and was complete by 18 hr. The cell which changed in density was specific for the antigen that brought about that change. The significance of these findings is discussed