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In the case of valbenazine, which was recently approved for tardive dyskinesia, a small company pursued thoughtful, efficient trial design and an unusual application of remote assessment in clinical trials, and the FDA took an engaged and flexible approach to review. A well-executed development program that addresses both regulatory and clinical requirements is critical for making novel therapeutics available as quickly as possible to patients with unmet medical needs. In the case of valbenazine, which was recently approved by the U.S. Food and Drug Administration (FDA) for tardive dyskinesia — a debilitating, iatrogenic movement disorder that primarily affects patients with psychiatric illnesses — a small company pursued thoughtful, efficient trial design and an unusual application of remote assessment in clinical trials. The FDA took an engaged and flexible approach to review, which led to its first approval of a drug for . . .

The aim of the study was to evaluate the exposure–response (E–R) relationships of blood pressure (BP) and heart rate (HR) changes in healthy adults taking methylphenidate (MPH). Intensive time profiles of BP and HR from healthy adults in placebo and MPH treatment arms of seven clinical trials from the FDA internal database were utilized for this analysis. The analysis model contains a circadian component for placebo effect and an E–R component to describe drug effect. Internal validation was performed using goodness-of-fit plots and visual predictive check. A meta-database based on a systemic literature search was constructed and used for external validation of the developed models. We found that circadian models could quantify the time profiles of BP/HR in placebo arms. Linear models could describe the correlations between MPH concentrations, and BP/HR changes. The BP and HR changes were highly dependent on the shapes of MPH pharmacokinetic (PK) profiles without an apparent time delay. MPH has the greatest effect on HR, followed by systolic BP, and diastolic BP. Internal validation revealed that the developed models could adequately describe the circadian rhythms of HR and BP in placebo arms and the E–R relationships of MPH. External validation showed the models had good predictive capability of the literature data. In conclusion, the developed models adequately characterized the circadian rhythm and the MPH induced effects on BP and HR. The changes in BP and HR were highly correlated with MPH blood levels with no apparent delay. The time courses of BP and HR are similar to the MPH PK profiles. As a result, the immediate-release formulation may yield larger maximum BP and HR effect than the extended-release formulation under similar dose.

To better define the control of immune system regulation, we generated an atlas of microRNA (miRNA) expression from 63 mouse immune cell populations and connected these signatures with assay for transposase-accessible chromatin using sequencing (ATAC–seq), chromatin immunoprecipitation followed by sequencing (ChIP–seq) and nascent RNA profiles to establish a map of miRNA promoter and enhancer usage in immune cells. miRNA complexity was relatively low, with >90% of the miRNA compartment of each population comprising <75 miRNAs; however, each cell type had a unique miRNA signature. Integration of miRNA expression with chromatin accessibility revealed putative regulatory elements for differentially expressed miRNAs, including miR-21a, miR-146a and miR-223. The integrated maps suggest that many miRNAs utilize multiple promoters to reach high abundance and identified dominant and divergent miRNA regulatory elements between lineages and during development that may be used by clustered miRNAs, such as miR-99a/let-7c/miR-125b, to achieve distinct expression. These studies, with web-accessible data, help delineate the cis -regulatory elements controlling miRNA signatures of the immune system. Brown and colleagues generated an atlas of miRNA expression profiles from primary mouse immune cell populations and connected these signatures with ATAC–seq, ChIP–seq and nascent RNA profiles to establish a map of miRNA promoter and enhancer usage in immune cells.

A 10 channel transmitter and receiver DWDM photonic integrated circuit pair is demonstrated, that is capable of transmitting and receiving data at 40 Gbit/s per channel for an aggregate data communication rate of 400 Gbit/s.

This paper reports measurements of atmospheric neutrino and antineutrino interactions in the MINOS Far Detector, based on 2553 live-days (37.9 kton-years) of data. A total of 2072 candidate events are observed. These are separated into 905 contained-vertex muons and 466 neutrino-induced rock-muons, both produced by charged-current \\(\\nu_{\\mu}\\) and \\(\\bar{\\nu}_{\\mu}\\) interactions, and 701 contained-vertex showers, composed mainly of charged-current \\(\\nu_{e}\\) and \\(\\bar{\\nu}_{e}\\) interactions and neutral-current interactions. The curvature of muon tracks in the magnetic field of the MINOS Far Detector is used to select separate samples of \\(\\nu_{\\mu}\\) and \\(\\bar{\\nu}_{\\mu}\\) events. The observed ratio of \\(\\bar{\\nu}_{\\mu}\\) to \\(\\nu_{\\mu}\\) events is compared with the Monte Carlo simulation, giving a double ratio of \\(R^{data}_{\\bar{\\nu}/\\nu}/R^{MC}_{\\bar{\\nu}/\\nu} = 1.03 \\pm 0.08 (stat.) \\pm 0.08 (syst.)\\). The \\(\\nu_{\\mu}\\) and \\(\\bar{\\nu}_{\\mu}\\) data are separated into bins of \\(L/E\\) resolution, based on the reconstructed energy and direction of each event, and a maximum likelihood fit to the observed \\(L/E\\) distributions is used to determine the atmospheric neutrino oscillation parameters. This fit returns 90% confidence limits of \\(|\\Delta m^{2}| = (1.9 \\pm 0.4) \\times 10^{-3} eV^{2}\\) and \\(sin^{2} 2\\theta > 0.86\\). The fit is extended to incorporate separate \\(\\nu_{\\mu}\\) and \\(\\bar{\\nu}_{\\mu}\\) oscillation parameters, returning 90% confidence limits of \\(|\\Delta m^{2}|-|\\Delta \\bar{m}^{2}| = 0.6^{+2.4}_{-0.8} \\times 10^{-3} eV^{2}\\) on the difference between the squared-mass splittings for neutrinos and antineutrinos.

We report an improved measurement of muon anti-neutrino disappearance over a distance of 735km using the MINOS detectors and the Fermilab Main Injector neutrino beam in a muon anti-neutrino enhanced configuration. From a total exposure of 2.95e20 protons on target, of which 42% have not been previously analyzed, we make the most precise measurement of the anti-neutrino \"atmospheric\" delta-m squared = 2.62 +0.31/-0.28 (stat.) +/- 0.09 (syst.) and constrain the anti-neutrino atmospheric mixing angle >0.75 (90%CL). These values are in agreement with those measured for muon neutrinos, removing the tension reported previously.

We have searched for sidereal variations in the rate of antineutrino interactions in the MINOS Near Detector. Using antineutrinos produced by the NuMI beam, we find no statistically significant sidereal modulation in the rate. When this result is placed in the context of the Standard Model Extension theory we are able to place upper limits on the coefficients defining the theory. These limits are used in combination with the results from an earlier analysis of MINOS neutrino data to further constrain the coefficients.

We report constraints on antineutrino oscillation parameters that were obtained by using the two MINOS detectors to measure the 7% muon antineutrino component of the NuMI neutrino beam. In the Far Detector, we select 130 events in the charged-current muon antineutrino sample, compared to a prediction of 136.4 +/- 11.7(stat) ^{+10.2}_{-8.9}(syst) events under the assumption |dm2bar|=2.32x10^-3 eV^2, snthetabar=1.0. Assuming no oscillations occur at the Near Detector baseline, a fit to the two-flavor oscillation approximation constrains |dm2bar|<3.37x10^-3 eV^2 at the 90% confidence level with snthetabar=1.0.

We report the results of a search for \\(\\nu_{e}\\) appearance in a \\(\\nu_{\\mu}\\) beam in the MINOS long-baseline neutrino experiment. With an improved analysis and an increased exposure of \\(8.2\\times10^{20}\\) protons on the NuMI target at Fermilab, we find that \\(2\\sin^2(\\theta_{23})\\sin^2(2\\theta_{13})<0.12\\ (0.20)\\) at 90% confidence level for \\(\\delta\\mathord{=}0\\) and the normal (inverted) neutrino mass hierarchy, with a best fit of \\(2\\sin^2(\\theta_{23})\\sin^2(2\\theta_{13})\\,\\mathord{=}\\,0.041^{+0.047}_{-0.031}\\ (0.079^{+0.071}_{-0.053})\\). The \\(\\theta_{13}\\mathord{=}0\\) hypothesis is disfavored by the MINOS data at the 89% confidence level.