Berotralstat (BCX7353) is a recently approved, oral, once-daily kallikrein inhibitor for hereditary angioedema (HAE) prophylaxis. In the APeX-2 trial, berotralstat reduced HAE attack rates over 24 ...weeks, with a favorable safety and tolerability profile.
Evaluate berotralstat safety, tolerability, and effectiveness over 48 weeks.
APeX-2 is a phase 3, parallel-group, multicenter trial (NCT03485911) in patients with HAE due to C1 esterase inhibitor deficiency. Part 1 was double-blind and placebo-controlled, with patients randomized to 24 weeks of berotralstat 150 mg, 110 mg, or placebo. In part 2, patients continued berotralstat the same dose or, if initially randomized to placebo, were rerandomized to berotralstat 150 mg or 110 mg through weeks 24 to 48. The primary end point was safety and tolerability.
One hundred eight patients received 1 or more doses of berotralstat in part 2. Treatment-emergent adverse events (TEAEs) occurred in 30 of 39 patients (77%) in the placebo group during part 1, and 25 of 34 patients (74%) re-randomized from placebo to berotralstat 110 mg or 150 mg in part 2, with drug-related TEAEs in 13 of 39 (33%), and 11 of 34 (32%) in the same groups. Most TEAEs were mild or moderate, with no serious drug-related TEAEs. The most common TEAEs were upper respiratory tract infections, abdominal pain, diarrhea, and vomiting. Mean (±standard error of the mean) monthly attack rates at baseline and week 48 were 3.06 (±0.25) and 1.06 (±0.25) in the berotralstat 150mg 48-week group and 2.97 (±0.21) and 1.35 (±0.33) in the berotralstat 110mg 48-week group.
The safety, tolerability, and effectiveness of berotralstat were maintained over 48 weeks of treatment.
High altitude mountaintop observatories provide the opportunity to study aerosol properties in the free troposphere without the added expense and difficulty of making airborne measurements. ...Climatologies for free tropospheric aerosol radiative properties in cloud-free air, including light scattering, light absorption, light extinction, single scattering albedo, Ångström exponent, hemispheric backscatter fraction and radiative forcing efficiency, from twelve high altitude (2.2–5.1
km) measurement platforms are presented at low relative humidity and at standard temperature and pressure. These climatologies utilize data from ten mountaintop observatories in the 20–50ºN latitude band: Mauna Loa, USA; Lulin Mountain, Taiwan; Nepal Climate Observatory — Pyramid; Izaña, Spain; Mount Waliguan, China; Beo Moussala, Bulgaria; Mount Bachelor, USA; Monte Cimone, Italy; Jungfraujoch, Switzerland; Whistler Mountain, Canada. Results are also included from two multi-year, in-situ aerosol vertical profiling programs: Southern Great Plains, USA and Bondville, USA. The amount of light absorption and scattering observed at these high altitude sites either peaks in the spring or it has a broad spring to summer enhancement. The seasonal variation of the aerosol single scattering albedo, backscatter fraction and Ångström exponent changes from site to site but the timing can be related to aerosol sources and transport processes known to impact the individual sites. The seasonal variation of in-situ aerosol light extinction from these high altitude measurements is in excellent agreement with extinction values derived from CALIPSO lidar measurements. Analysis of the systematic variability among in-situ aerosol properties shows that these relationships can be used to infer aerosol types. In particular, the relationship between single scattering albedo and Ångström exponent can indicate the presence of dust aerosol. Radiative forcing efficiency (RFE
=
aerosol forcing/aerosol optical depth) is used to assess the importance of single scattering albedo and backscatter fraction on aerosol forcing by eliminating aerosol amount (i.e., aerosol optical depth) from the calculation. Variability in monthly cycles of RFE corresponds with changes in single scattering albedo and hemispheric backscatter fraction. Utilizing site-specific, climatological values of single scattering albedo and backscatter fraction to calculate RFE results in departures from the monthly median values of RFE typically in the range 10–30%. The greatest discrepancy occurs for months with low aerosol loading where the observed variability of single scattering albedo and backscatter fraction is the greatest. At most sites the radiative forcing efficiency at low aerosol loading (light scattering
<
10
Mm
−1) is slightly less negative (more warming) than at higher aerosol loading.
► We present annual and monthly climatologies of aerosol optical properties at 12 high altitude sites. ► There is an west to east increase in amount of aerosol across northern hemisphere. ► Seasonal values of extinction are consistent with CALIPSO extinction measurements. ► Systematic relationships among aerosol optical properties are related to sources and processing. ► For clean conditions the aerosol particles are darker and smaller and hence, less cooling.
In QSAR, a statistical model is generated from a training set of molecules (represented by chemical descriptors) and their biological activities (an “activity model”). The aim of the field of domain ...applicability (DA) is to estimate the uncertainty of prediction of a specific molecule on a specific activity model. A number of DA metrics have been proposed in the literature for this purpose. A quantitative model of the prediction uncertainty (an “error model”) can be built using one or more of these metrics. A previous publication from our laboratory ( Sheridan R. P. J. Chem. Inf. Model. 2013, 53, 2837−2850 ) suggested that QSAR methods such as random forest could be used to build error models by fitting unsigned prediction errors against DA metrics. The QSAR paradigm contains two useful techniques: descriptor importance can determine which DA metrics are most useful, and cross-validation can be used to tell which subset of DA metrics is sufficient to estimate the unsigned errors. Previously we studied 10 large, diverse data sets and seven DA metrics. For those data sets for which it is possible to build a significant error model from those seven metrics, only two metrics were sufficient to account for almost all of the information in the error model. These were TREE_SD (the variation of prediction among random forest trees) and PREDICTED (the predicted activity itself). In this paper we show that when data sets are less diverse, as for example in QSAR models of molecules in a single chemical series, these two DA metrics become less important in explaining prediction error, and the DA metric SIMILARITYNEAREST1 (the similarity of the molecule being predicted to the closest training set compound) becomes more important. Our recommendation is that when the mean pairwise similarity (measured with the Carhart AP descriptor and the Dice similarity index) within a QSAR training set is less than 0.5, one can use only TREE_SD, PREDICTED to form the error model, but otherwise one should use TREE_SD, PREDICTED, SIMILARITYNEAREST1.
Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by recurrent episodes of swelling of the skin, larynx, gastrointestinal tract, genitals, and extremities that can be ...disruptive to patient quality of life. Dysregulation of plasma kallikrein activity leads to increased production and accumulation of bradykinin in HAE and causes attacks of angioedema. Plasma kallikrein is a serine protease essential for the formation of bradykinin. Berotralstat is a potent, highly selective, orally bioavailable small‐molecule plasma kallikrein inhibitor that has been approved to prevent attacks of HAE in adults and children 12 years of age and older. Population pharmacokinetic (PK) analyses were conducted to describe the PK of berotralstat (BCX7353; Orladeyo™) and to evaluate the covariates that may explain variability in PK. The PK of berotralstat were characterized by population PK modeling of data from 13 clinical studies and a total of 771 healthy subjects and patients with HAE. The PK profile was well described by a three‐compartment model with first‐order absorption including an absorption lag time and linear elimination. Among the covariates tested, the effects of bilirubin and food were found not to be clinically significant and were removed from the model. Covariate analysis indicated significant effects of dose on bioavailability and weight on berotralstat clearance and volume. Despite the covariate effect of weight, simulations in adolescents and adults who were underweight, low weight, and overweight demonstrated similar predicted exposures to those observed at therapeutic doses in a clinical trial. Therefore, no dose adjustment is required in these HAE patient subpopulations.
Cold‐pool formation in a narrow valley Vosper, S. B.; Hughes, J. K.; Lock, A. P. ...
Quarterly journal of the Royal Meteorological Society,
January 2014 Part B, 2014, 2014-01-00, 20140101, Volume:
140, Issue:
679
Journal Article
Peer reviewed
Open access
A numerical model simulation of the formation of a cold pool within a narrow valley during a clear calm night is presented. The results are compared with measurements made during the COLd air Pooling ...EXperiment (COLPEX). It is demonstrated that the model provides a realistic simulation of the observed cold pool. The cold pool begins to form approximately 1.5 hours before sunset, when the near‐surface air within the valley starts to cool more rapidly than the air on the surrounding hills. The model potential temperature budget is used to determine which physical processes are most important for the evolution of the cold pool. The results show that sheltering provided by the valley causes a turbulent heat flux divergence over the lowest 5 m above the valley floor, which is large compared with the other terms in the budget. This causes relatively rapid cooling of the air adjacent to the ground. On the surrounding hills the turbulent heat flux divergence is larger than in the valley, but the enhanced cooling this provides is approximately balanced by an almost equally large warming tendency from advection. The net effect of these two terms is small compared with that in the valley and therefore the cooling rate is smaller. Above 5 m, the cooling in the valley is dominated by local transport of cold air away from the surface into the interior valley atmosphere.
The term nursery implies a special place for juvenile nekton (fishes and decapod crustaceans) where density, survival, and growth of juveniles and movement to adult habitat are enhanced over those in ...adjoining juvenile habitat types. We reviewed recent literature concerning these four topics and conducted meta-analyses for density and survival data. Most studies of mangroves as nurseries have addressed only occurrence or density of fishes or decapods, have not used quantitative sampling methods, and have not compared alternate habitats. Comparison of nekton densities among alternate habitats suggests that, at times, lower densities may be typical of mangroves when compared to seagrass, coral reef, marsh, and non-vegetated habitats. There is little direct consumption of mangrove detritus by nekton. C, N, and S isotope studies reveal little retention of mangrove production by higher consumers. Densities of prey for transient fishes and decapods may be greater within mangroves than elsewhere, but there has been no verification that food availability affects growth or survival. Experimental evidence indicates that mangrove roots and debris provide refuge for small nekton from predators, thus enhancing overall survival. There is no evidence that more individuals move to adult habitats from mangroves than from alternate inshore habitats. There is an obvious need to devise appropriate experiments to test the nursery functions of mangroves. Such data may then be one more reason to add support for mangrove conservation and preservation.
A new classification and regression tool, Random Forest, is introduced and investigated for predicting a compound's quantitative or categorical biological activity based on a quantitative description ...of the compound's molecular structure. Random Forest is an ensemble of unpruned classification or regression trees created by using bootstrap samples of the training data and random feature selection in tree induction. Prediction is made by aggregating (majority vote or averaging) the predictions of the ensemble. We built predictive models for six cheminformatics data sets. Our analysis demonstrates that Random Forest is a powerful tool capable of delivering performance that is among the most accurate methods to date. We also present three additional features of Random Forest: built-in performance assessment, a measure of relative importance of descriptors, and a measure of compound similarity that is weighted by the relative importance of descriptors. It is the combination of relatively high prediction accuracy and its collection of desired features that makes Random Forest uniquely suited for modeling in cheminformatics.
Continuous measurements of the optical and microphysical properties of aerosol particles have been made at the Department of Energy's Atmospheric Radiation Measurement Program Southern Great Plains ...Cloud and Radiation Testbed (CART) site covering the 4‐year period from July 1996 through June 2000. Hourly, daily, and monthly statistics have been calculated that illustrate aerosol variability over a range of timescales. A pronounced peak in total particle number, centered on the midafternoon hours (local time), is evident in the hourly statistics. A broad early morning peak in the concentration of particles >0.1‐μm aerodynamic diameter corresponds with a similar peak in aerosol light‐scattering coefficient, σsp. No strong cycles were observed in the daily statistics, suggesting that day of the week has only a minor influence on the observed aerosol variability. The σsp at a wavelength of 550 nm for the 4‐year period showed a median value of 33 Mm−1 and was highest in February and August. The median fraction of aerosol light scattering at 550 nm due to particles <1‐μm aerodynamic diameter was 0.85 over the entire record. The median aerosol light absorption coefficient, σap, for the 4‐year period was ∼1.5 Mm−1 and was observed to be highest in late summer and autumn. The σap showed an increasing trend of nearly 0.5 Mm−1 yr, possibly due to increased agricultural field burning in the area. The occurrence of an autumn decrease in single‐scattering albedo, ω0, was observed and may be caused by regional‐scale agricultural or transportation activities or seasonal changes in atmospheric flow patterns. The median value for ω0 over the 4‐year period was 0.95, but this value has decreased ∼1–2% yr−1 presumably due to increased agricultural burning. Numerous field fires during the second half of 1999 influenced the surface aerosol at the CART site causing substantial variability of aerosol optical properties. The aerosol hygroscopic growth factor (f(RH)), corresponding to a relative humidity increase of 40–85%, showed a median value of 1.83 for 1999, although much lower values were observed during periods that were probably influenced by locally generated smoke and dust aerosols (median f(RH) = 1.55 and 1.59, respectively).
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