It has been two decades since screening new molecules and potential clinical drug candidates against the hERG potassium channel became a routine part of safety pharmacology. The earliest heuristic ...for what was an adequate safety margin to separate molecules with a potential liability to cause the arrhythmia torsade de pointes (TdP) from those with no such liability emerged in 2002 and was determined to be a hERG IC50 value 30-fold above the therapeutic free plasma concentration (Webster, Leishman, & Walker, 2002). In the intervening years nonclinical and clinical ICH guidance has been introduced and intense scrutiny has been applied to the QT interval of the electrocardiogram in animals and man. Has the 30-fold heuristic stood the test of time?
The hERG margins between the IC50 value and the therapeutic unbound plasma concentrations were examined for 367 compounds. These margins were compared against the categories used by www.CredibleMeds.com to classify a drug's TdP risk. A subset of 336 of these drugs were compared against their US product labels with respect to black box warnings on QTc prolongation or TdP, warnings and precautions on QTc or TdP, and QTc language in the clinical pharmacology section.
Against the CredibleMeds classification the means of the margins for Known, Conditional, or Possible Risk of TdP, and Not Listed (presumably no TdP liability) were 4.8, 28, 71 and 339, respectively. Against the US label language the means of margins for black boxes and warnings were 3.1 and 26, respectively. The average margins associated with, positive QTc outcome, negative QTc outcome and no QTc language were 16, 479 and 204, respectively. Based on ROC curves the optimal hERG margin thresholds to separate “Known risk of TdP” from “Not Listed” and, QTc prolongation positive from QTc negative were 37- and 50-fold, respectively.
The observed optimal margin of 50-fold in the current study is not appreciably different from a previously reported 45-fold optimal margin (Gintant, 2011). The margin falls between the margins for negative (QTc outcome or no QTc language) and positive (positive QTc outcome, warnings or black boxes) compounds. The observed optimal margin of 37-fold in the current study is not appreciably different from the commonly used 30-fold optimal margin (Webster et al., 2002). This margin falls between those for drugs with a known or conditional TdP risk and those where it is at best a possible risk, and from the 240 drugs not listed on www.CredibleMeds.com. It is expected that there would be a small numerical difference (e.g. 37 vs. 50, or as previously published 30 vs. 45) between optimal cut-offs for the TdP liability and QTc prolongation predictions since some QTc positive drugs are described on CredibleMeds.com as having only a “Possible Risk of TdP” as they are not associated with TdP when used as directed.
The fact that the margins in each category form distributions is also expected given biologic variability. However, we argue that a more consistent manner of assessing hERG potency and evaluating relevant exposures would be likely to reduce the spread in these distributions and make margins even more useful as a decision-making data point.
The sensitivity of gravitational-wave detectors is limited by the mechanical loss associated with the amorphous coatings of the detectors' mirrors. Amorphous silicon has higher refraction index and ...lower mechanical loss than current high-index coatings, but its optical absorption at the wavelength used for the detectors is at present large. The addition of hydrogen to the amorphous silicon network reduces both optical absorption and mechanical loss for films prepared under a range of conditions at all measured wavelengths and temperatures, with a particularly large effect on films grown at room temperature. The uptake of hydrogen is greatest in the films grown at room temperature, but still below 1.5 at.% H, which show an ultralow optical absorption (below 10 ppm) measured at 2000 nm for 500-nm-thick films. These results show that hydrogenation is a promising strategy to reduce both optical absorption and mechanical loss in amorphous silicon, and may enable fabrication of mirror coatings for gravitational-wave detectors with improved sensitivity.
I have long maintained that equipoise between empathy and the rational, decisive nature of obstetric care is central to good doctoring. I had exacting standards for how to communicate facts with ...feeling while shielding my own. Then, after experiencing my own obstetric emergency and preterm birth, this changed. In this reflection, I explore how recognizing the intersections between facts and feelings has made me a better physician.
We recently reported that bone marrow-derived dendritic cells (DC) from aged miced are less effective than their young counterparts in inducing the regression of B16-ovalbumin (OVA) melanomas. To ...examine the underlying mechanisms, we investigated the effect of aging on DC tumor antigen presentation and migration. Although aging does not affect the ability of DCs to present OVA peptide((257-264)), DCs from aged mice are less efficient than those from young mice in stimulating OVA-specific T cells in vitro. Phenotypic analysis revealed a selective decrease in DC-specific/intracellular adhesion molecule type-3-grabbing nonintegrin (DC-SIGN) level in aged DCs. Adoptive transfer experiments showed defective in vivo DC trafficking in aging. This correlates with impaired in vitro migration and defective CCR7 signaling in response to CCL21 in aged DCs. Interestingly, vaccination of young mice using old OVA peptide((257-264))-pulsed DCs (OVA PP-DC) resulted in impaired activation of OVA-specific CD8(+) T cells in vivo. Effector functions of these T cells, as determined by IFN-gamma production and cytotoxic activity, were similar to those obtained from mice vaccinated with young OVA PP-DCs. A decreased influx of intratumor CD8(+) T cells was also observed. Importantly, although defective in vivo migration could be restored by increasing the number of old DCs injected, the aging defect in DC tumor surveillance and OVA-specific CD8(+) T-cell induction remained. Taken together, our findings suggest that defective T-cell stimulation contributes to the observed impaired DC tumor immunotherapeutic response in aging.
After nearly 3 decades of regulatory activity concerning new drugs' potential for delayed cardiac repolarization an integrated risk assessment paradigm for small molecule drugs has been established. ...Regulatory guidance also suggests that for large, targeted proteins and monoclonal antibodies no quantitative clinical QTc assessment is necessary. The expansion of new drug modalities prompts the question: “Should these new modalities be treated like small molecule drugs or like monoclonal antibodies?”
Little research exists about embedded remediation (ER) in college journalism and mass communication (JMC) programs. ER could support students who are underprepared for college-level writing. Because ...ER would affect faculty’s professional practice, this study explored its feasibility by investigating JMC faculty perceptions of ER and its feasibility. Qualitative inquiry via focus groups with a purposeful sample (n = 17) was used to explore perceptions and barriers to implementation and a conceptual framework including Experiential Learning Theory and the Teaching-for-Learning model was used in analysis. Four themes were identified: (a) growing concerns, (b) externalizing remediation, (c) institutional challenges, and (d) taking action.
ABSTRACT
We present spectra of Eris from the MMT 6.5 m Telescope and Red Channel Spectrograph (5700–9800 Å, 5 Å pixel
−1
) on Mt. Hopkins, AZ, and of Pluto from the Steward Observatory 2.3 m ...Telescope and Boller and Chivens Spectrograph (7100–9400 Å, 2 Å pixel
−1
) on Kitt Peak, AZ. In addition, we present laboratory transmission spectra of methane–nitrogen and methane–argon ice mixtures. By anchoring our analysis in methane and nitrogen solubilities in one another as expressed in the phase diagram of Prokhvatilov & Yantsevich, and comparing methane bands in our Eris and Pluto spectra and methane bands in our laboratory spectra of methane and nitrogen ice mixtures, we find Eris' bulk methane and nitrogen abundances are ∼10% and ∼90% and Pluto's bulk methane and nitrogen abundances are ∼3% and ∼97%. Such abundances for Pluto are consistent with values reported in the literature. It appears that the bulk volatile composition of Eris is similar to the bulk volatile composition of Pluto. Both objects appear to be dominated by nitrogen ice. Our analysis also suggests, unlike previous work reported in the literature, that the methane and nitrogen stoichiometry is constant with depth into the surface of Eris. Finally, we point out that our Eris spectrum is also consistent with a laboratory ice mixture consisting of 40% methane and 60% argon. Although we cannot rule out an argon-rich surface, it seems more likely that nitrogen is the dominant species on Eris because the nitrogen ice 2.15 μm band is seen in spectra of Pluto and Triton.
Abstract
We present an overview and first results from a
M
-band spectroscopic survey of planet-forming disks performed with iSHELL on the Infrared Telescope Facility, using two slits that provide ...resolving power
R
≈ 60,000–92,000 (5–3.3 km s
−1
). iSHELL provides a nearly complete coverage at 4.52–5.24
μ
m in one shot, covering >50 lines from the R and P branches of
12
CO and
13
CO for each of multiple vibrational levels, and providing unprecedented information on the excitation of multiple emission and absorption components. Some of the most notable new findings of this survey are: (1) the detection of two CO Keplerian rings at <2 au (in HD 259431), (2) the detection of H
2
O rovibrational lines at 5
μ
m (in AS 205 N), and (3) the common kinematic variability of CO lines over timescales of 1–14 yr. By homogeneously analyzing this survey together with a previous survey of cooler stars, we discuss a unified view of CO spectra where emission and absorption components scan the disk surface across radii from a dust-free region within dust sublimation out to ≈10 au. We classify two fundamental types of CO line shapes interpreted as emission from Keplerian rings (double-peak lines) and a disk surface plus a low-velocity part of a wind (triangular lines), where CO excitation reflects different emitting regions (and their gas-to-dust ratio) rather than just the irradiation spectrum. A disk+wind interpretation for the triangular lines naturally explains several properties observed in CO spectra, including the line blueshifts, line shapes that turn into narrow absorption at high inclinations, and the frequency of disk winds as a function of the stellar type.
PDF
