Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3)

OBJECTIVE: To evaluate apremilast treatment in patients with active psoriatic arthritis, including current skin involvement, despite prior therapy with conventional disease-modifying antirheumatic drugs and/or biologic agents. METHODS: Patients (N=505) were randomised (1:1:1) to placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily. Rescue therapy with apremilast was designated at week 16 for placebo patients not achieving 20% improvement in swollen and tender joint counts. At week 24, the remaining placebo patients were then randomised to apremilast 20 mg twice daily or 30 mg twice daily. The efficacy and safety of apremilast were assessed over 52 weeks. RESULTS: At week 16, significantly more patients receiving apremilast 20 mg twice daily (28%) and 30 mg twice daily (41%) achieved 20% improvement in American College of Rheumatology response criteria versus placebo (18%; p=0.0295 and p \u3c 0.0001, respectively), and mean decrease in the Health Assessment Questionnaire-Disability Index score was significantly greater with apremilast 30 mg twice daily (-0.20) versus placebo (-0.07; p=0.0073). In patients with baseline psoriasis body surface area involvement \u3e /=3%, significantly more apremilast 30 mg twice daily patients achieved 50% reduction from baseline Psoriasis Area and Severity Index score (41%) versus placebo (24%; p=0.0098) at week 16. At week 52, observed improvements in these measures demonstrated sustained response with continued apremilast treatment. Most adverse events were mild to moderate in severity; the most common were diarrhoea, nausea, headache and upper respiratory tract infection. CONCLUSIONS: Apremilast demonstrated clinically meaningful improvements in psoriatic arthritis and psoriasis at week 16; sustained improvements were seen with continued treatment through 52 weeks. Apremilast was generally well tolerated and demonstrated an acceptable safety profile. TRIAL REGISTRATION NUMBER: NCT01212770

Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1)

BackgroundApremilast works intracellularly to regulate inflammatory mediators.ObjectiveESTEEM 1 evaluated efficacy/safety of apremilast at 30 mg twice a day for moderate to severe plaque psoriasis.MethodsThis phase III, multicenter, double-blind, placebo-controlled study randomized adults (2:1) to apremilast or placebo. At week 16, the placebo group switched to apremilast through week 32, followed by a randomized treatment withdrawal phase to week 52. Binary end points were analyzed using χ2 test; continuous end points used analysis of covariance.ResultsIn all, 844 patients were randomized (n = 282, placebo; n = 562, apremilast). At week 16, significantly more patients taking apremilast achieved 75% or greater reduction from baseline Psoriasis Area and Severity Index score (PASI-75) (33.1%) versus placebo (5.3%, P < .0001; primary end point). Most (61.0%) patients rerandomized to apremilast at week 32 achieved PASI-75 at week 52 versus 11.7% rerandomized to placebo. Of patients rerandomized to apremilast at week 32, mean percentage change from baseline PASI score was −88% to −81% (weeks 32-52). During the placebo-controlled period, 55.7% and 69.3% of patients randomized to placebo and apremilast, respectively, had 1 or more adverse events. Most adverse events were mild/moderate in severity. No new significant adverse events emerged with continued apremilast exposure versus the placebo-controlled period.LimitationsData were limited to 52 weeks and may not generalize to nonplaque psoriasis.ConclusionsApremilast was effective in moderate to severe plaque psoriasis

Challenges of Early Years leadership preparation: a comparison between early and experienced Early Years practitioners in England

Leadership has been under-researched in the Early Years (EY) sector of primary schools in England, especially in leading change for professional development. The aim of this paper is to theorise what the leadership culture for EY practitioners looks like, and how Initial Teacher Training providers and schools are preparing practitioners for leadership. Using case studies of EY practitioners in different stages of their career in primary schools, we offer an insight into their preparedness for leadership in EY, the implication being that leadership training requires an understanding and embedding of the EY culture and context. Interviews with both sample groups allowed for deeper insight into the lived world. Interviews were also conducted with the head teachers to gain an overview of the leadership preparation they provided. The main findings suggest that newer EY practitioners are better prepared for leadership from their university training in comparison to more experienced EY practitioners

Bright polar mesospheric clouds formed by main engine exhaust from the space shuttle's final launch

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94747/1/jgrd18009.pd

Comparison of observed and general circulation model derived continental subsurface heat flux in the Northern Hemisphere

Heat fluxes in the continental subsurface were estimated from general circulation model (GCM) simulations of the climate of the last millennium and compared to those obtained from subsurface geothermal data. Since GCMs have bottom boundary conditions (BBCs) that are less than 10 m deep and thus may be thermodynamically restricted in the continental subsurface, we used an idealized land surface model (LSM) with a very deep BBC to estimate the potential for realistic subsurface heat storage in the absence of bottom boundary constraints. Results indicate that there is good agreement between observed fluxes and GCM simulated fluxes for the 1780-1980 period when the GCM simulated temperatures are coupled to the LSM with deep BBC. These results emphasize the importance of placing a deep BBC in GCM soil components for the proper simulation of the overall continental heat budget. In addition, the agreement between the LSM surface fluxes and the borehole temperature reconstructed fluxes lends additional support to the overall quality of the GCM (ECHO-G) paleoclimatic simulations