34587 Efficacy of ruxolitinib cream for the treatment of atopic dermatitis by anatomic region: Pooled analysis from two randomized phase 3 studies

Atopic dermatitis (AD) is a highly pruritic inflammatory skin disease. Two phase 3 studies (TRuE-AD1/TRuE-AD2) enrolled patients aged ≥12 years with AD for ≥2 years, an Investigator’s Global Assessment (IGA) score of 2/3, and 3%–20% affected body surface area. Patients (total N = 1249; median age, 32 years) were randomized (2:2:1) to twice-daily 0.75% ruxolitinib (Janus kinase [JAK] 1/JAK2 inhibitor) cream, 1.5% ruxolitinib cream, or vehicle cream for 8 weeks of double-blind treatment, and thereafter continued in a long-term, 44-week period of the studies. In this pooled analysis, mean percentage change from baseline in Eczema Area and Severity Index (EASI) anatomic region subscores is reported up to Week 8 (n = 1208). For the head and neck region, patients applying 0.75%/1.5% ruxolitinib cream (vs vehicle) achieved mean improvements of 59.3%/55.8% (vs 13.4%), 70.4%/71.3% (vs 22.4%), and 70.0%/78.7% (vs 45.0%) at Weeks 2, 4, and 8, respectively (all P \u3c.0001). Results were similar for the upper limbs region (48.5%/54.7% [vs 13.3%], 66.6%/70.3% [vs 25.0%], and 73.5%/74.9% [vs 35.1%] all P \u3c.0001). For the trunk region, patients achieved mean improvements of 49.8%/60.0% (vs 12.1%), 67.3%/73.8% (vs 15.0%), and 72.7%/81.0% (vs 15.6%) at Weeks 2, 4, and 8, respectively (all P \u3c.0001). Similar results were observed for the lower limbs region (46.0%/48.2% [vs 16.3%], 65.9%/66.2% [vs 13.9%], and 76.3%/74.9% [vs 39.8%]; all P \u3c.0001). Ruxolitinib cream was well tolerated, with an adverse event profile similar to vehicle. In summary, ruxolitinib cream demonstrated significant improvements vs vehicle in patients with AD across anatomic regions as early as Week 2

Use of an alternative method to evaluate erythema severity in a clinical trial: difference in vehicle response with evaluation of baseline and postdose photographs for effect of oxymetazoline cream 1·0% for persistent erythema of rosacea in a phase IV study.

BackgroundOnce-daily topical oxymetazoline cream 1·0% significantly reduced persistent facial erythema of rosacea in trials requiring live, static patient assessments.ObjectivesTo evaluate critically the methodology of clinical trials that require live, static patient assessments by determining whether assessment of erythema is different when reference to the baseline photograph is allowed.MethodsIn two identically designed, randomized, phase III trials, adults with persistent facial erythema of rosacea applied oxymetazoline or vehicle once daily. This phase IV study evaluated standardized digital facial photographs from the phase III trials to record ≥ 1-grade Clinician Erythema Assessment (CEA) improvement at 1, 3, 6, 9 and 12 h postdose.ResultsAmong 835 patients (oxymetazoline n = 415, vehicle n = 420), significantly greater proportions of patients treated with oxymetazoline vs. vehicle achieved ≥ 1-grade CEA improvement. For the comparison between phase IV study results and the original phase III analysis, when reference to baseline photographs was allowed while evaluating post-treatment photographs, the results for oxymetazoline were similar to results of the phase III trials (up to 85.7%), but a significantly lower proportion of vehicle recipients achieved ≥ 1-grade CEA improvement (up to 29.7% [phase 4] vs. 52.3% [phase 3]; P<0.001). In the phase IV study, up to 80·2% of patients treated with oxymetazoline achieved at least moderate erythema improvement vs. up to 22·9% of patients treated with vehicle. The association between patients' satisfaction with facial skin redness and percentage of erythema improvement was statistically significant.ConclusionsAssessment of study photographs, with comparison to baseline, confirmed significant erythema reduction with oxymetazoline on the first day of application. Compared with the phase III trial results, significantly fewer vehicle recipients attained ≥ 1-grade CEA improvement, suggesting a mitigated vehicle effect. This methodology may improve the accuracy of clinical trials evaluating erythema severity

275 Effects of ruxolitinib cream on sleep and quality of life over 52 weeks in black patients with atopic dermatitis

Atopic dermatitis (AD) is an inflammatory skin disease with phenotypic differences across race and can affect sleep and quality of life (QoL). In 2 phase 3 studies of identical design (TRuE-AD1/TRuE-AD2), patients (pts; ≥12 y with AD for ≥2 y; Investigator’s Global Assessment score 2/3; 3%–20% affected body surface area) were randomized (2:2:1) to twice-daily 0.75% or 1.5% ruxolitinib (RUX; Janus kinase [JAK]1/JAK2 inhibitor) cream or vehicle for 8 wk (continuous treatment), followed by a long-term safety period (LTS; as-needed treatment) up to Wk 52. Pts randomized to RUX cream remained on their regimen during the LTS; pts on vehicle were rerandomized to either RUX cream strength. For Black pts who were initially randomized to the 0.75% RUX cream/1.5% RUX cream/vehicle to 0.75% RUX cream/vehicle to 1.5% RUX cream groups and continued in the LTS (n=91/97/25/22), sleep-related impairment and sleep disturbance scores per Patient-Reported Outcomes Measurement Information System at baseline (BL) were 16.3/16.4/15.0/17.5 and 18.9/19.7/17.9/19.8, respectively. Scores had decreased (less impairment) at LTS start in the RUX cream groups (Wk 8; 14.2/14.7/16.1/15.5 and 16.7/17.5/19.0/19.4) and were below BL at Wk 52 in all groups (14.3/14.8/13.9/14.4 and 18.0/18.0/17.4/16.3). Dermatology Life Quality Index (DLQI) scores were decreased at Wk 8 (mean change from BL, −7.4/−6.6/−3.8/−4.8); decreased scores were maintained to Wk 52 (−7.1/−6.5/−5.6/−8.8). Results were similar for children’s DLQI (Wk 8, −4.0/−6.9/−4.0/−3.0 [n=12/9/1/3]; Wk 52, −5.6/−11.6/−12.0/−7.3 [n=9/7/1/4]). In summary, sleep and QoL improved with RUX cream; improvements were maintained for 44 wk with as-needed use in Black pts

287 Effects of ruxolitinib cream on pruritus in black patients with atopic dermatitis

Atopic dermatitis (AD) is an inflammatory skin disease that has phenotypic differences across race and can be more severe in Black patients. In two phase 3 identical design studies (TRuE-AD1/TRuE-AD2), patients (≥12 years old with AD for ≥2 years, Investigator’s Global Assessment [IGA] score 2/3, 3%–20% affected body surface area) were randomized (2:2:1) to twice-daily 0.75% or 1.5% ruxolitinib (Janus kinase [JAK]1/JAK 2 inhibitor) cream or vehicle for 8 weeks. Here we describe the effect of ruxolitinib cream on itch in Black patients using pooled data from the 2 studies (n=292). Mean itch numerical rating scale (NRS) score at baseline was 5.3/5.4 for ruxolitinib cream (0.75%/1.5%) and 5.7 for vehicle. Reductions in mean itch NRS score with ruxolitinib cream (0.75%/1.5%) were evident within approximately 12 hours of first application (–0.6/–0.7 vs −0.2 for vehicle), with statistically significant reductions by Day 4 vs vehicle (–1.4/–1.6 vs –0.6; both P\u3c0.05). For those with baseline itch NRS ≥4 (n=187; 64.0%), more patients achieved ≥4-point itch NRS improvement vs vehicle by Day 2 (6.1%/16.4% vs 0%); this increased to 15.9%/26.6% vs 3.0% on Day 7 and 30.1%/43.2% vs 17.5% at Week 8 (P=0.212/P=0.009). More patients applying 0.75%/1.5% ruxolitinib cream vs vehicle reported no days of itch per question 1 of the Patient-Oriented Eczema Measure (POEM) at Week 2 (19.0%/19.4% vs 5.3%); this increased at Week 8 (34.0%/30.8% vs 12.2%). In summary, ruxolitinib cream monotherapy over 8 weeks was associated with rapid and considerable itch relief in Black patients with AD

Bimekizumab infection rates in patients with moderate to severe plaque psoriasis: Analysis of pooled data from 2 years of treatment in phase 3 and 3b clinical trials

N/

A four-helix bundle stores copper for methane oxidation

Methane-oxidising bacteria (methanotrophs) require large quantities of copper for the membrane-bound (particulate) methane monooxygenase (pMMO). Certain methanotrophs are also able to switch to using the iron-containing soluble MMO (sMMO) to catalyse methane oxidation, with this switchover regulated by copper. MMOs are Nature’s primary biological mechanism for suppressing atmospheric levels of methane, a potent greenhouse gas. Furthermore, methanotrophs and MMOs have enormous potential in bioremediation and for biotransformations producing bulk and fine chemicals, and in bioenergy, particularly considering increased methane availability from renewable sources and hydraulic fracturing of shale rock. We have discovered and characterised a novel copper storage protein (Csp1) from the methanotroph Methylosinus trichosporium OB3b that is exported from the cytosol, and stores copper for pMMO. Csp1 is a tetramer of 4-helix bundles with each monomer binding up to 13 Cu(I) ions in a previously unseen manner via mainly Cys residues that point into the core of the bundle. Csp1 is the first example of a protein that stores a metal within an established protein-folding motif. This work provides a detailed insight into how methanotrophs accumulate copper for the oxidation of methane. Understanding this process is essential if the wide-ranging biotechnological applications of methanotrophs are to be realised. Cytosolic homologues of Csp1 are present in diverse bacteria thus challenging the dogma that such organisms do not use copper in this location

Classifying and scoring of molecules with the NGN: new datasets, significance tests, and generalization

<p>Abstract</p> <p/> <p>This paper demonstrates how a Neural Grammar Network learns to classify and score molecules for a variety of tasks in chemistry and toxicology. In addition to a more detailed analysis on datasets previously studied, we introduce three new datasets (BBB, FXa, and toxicology) to show the generality of the approach. A new experimental methodology is developed and applied to both the new datasets as well as previously studied datasets. This methodology is rigorous and statistically grounded, and ultimately culminates in a Wilcoxon significance test that proves the effectiveness of the system. We further include a complete generalization of the specific technique to arbitrary grammars and datasets using a mathematical abstraction that allows researchers in different domains to apply the method to their own work.</p> <p>Background</p> <p>Our work can be viewed as an alternative to existing methods to solve the quantitative structure-activity relationship (QSAR) problem. To this end, we review a number approaches both from a methodological and also a performance perspective. In addition to these approaches, we also examined a number of chemical properties that can be used by generic classifier systems, such as feed-forward artificial neural networks. In studying these approaches, we identified a set of interesting benchmark problem sets to which many of the above approaches had been applied. These included: ACE, AChE, AR, BBB, BZR, Cox2, DHFR, ER, FXa, GPB, Therm, and Thr. Finally, we developed our own benchmark set by collecting data on toxicology.</p> <p>Results</p> <p>Our results show that our system performs better than, or comparatively to, the existing methods over a broad range of problem types. Our method does not require the expert knowledge that is necessary to apply the other methods to novel problems.</p> <p>Conclusions</p> <p>We conclude that our success is due to the ability of our system to: 1) encode molecules losslessly before presentation to the learning system, and 2) leverage the design of molecular description languages to facilitate the identification of relevant structural attributes of the molecules over different problem domains.</p

Measurements of branching fraction ratios and CP-asymmetries in suppressed B^- -> D(-> K^+ pi^-)K^- and B^- -> D(-> K^+ pi^-)pi^- decays

We report the first reconstruction in hadron collisions of the suppressed decays B^- -> D(-> K^+ pi^-)K^- and B^- -> D(-> K^+ pi^-)pi^-, sensitive to the CKM phase gamma, using data from 7 fb^-1 of integrated luminosity collected by the CDF II detector at the Tevatron collider. We reconstruct a signal for the B^- -> D(-> K^+ pi^-)K^- suppressed mode with a significance of 3.2 standard deviations, and measure the ratios of the suppressed to favored branching fractions R(K) = [22.0 \pm 8.6(stat)\pm 2.6(syst)]\times 10^-3, R^+(K) = [42.6\pm 13.7(stat)\pm 2.8(syst)]\times 10^-3, R^-(K)= [3.8\pm 10.3(stat)\pm 2.7(syst]\times 10^-3, as well as the direct CP-violating asymmetry A(K) = -0.82\pm 0.44(stat)\pm 0.09(syst) of this mode. Corresponding quantities for B^- -> D(-> K^+ pi^-)pi^- decay are also reported.Comment: 8 pages, 1 figure, accepted by Phys.Rev.D Rapid Communications for Publicatio

A survey of psychosocial adaptation in long-term survivors of pediatric liver transplants

We assessed 41 children and adolescents who had received liver transplants at least 4 years ago, for social, behavioral, and emotional adaptation; physical function; and family stress. We compared their level of adaptive functioning to published data from chronically ill and medically well children. On many measures, transplant recipients had equivalent levels of function to the comparison groups. However, 6- to 11-year-old patients showed mild social and scholastic deficits. Patients' parents report less negative impact of the illness on the family than do parents of other chronically ill children. A listing of medication side effects and the degree to which they are problematic was obtained.published_or_final_versio