Summary
Background
Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis.
Objectives
To determine the 16‐week efficacy and safety of two oral tofacitinib doses vs. placebo in ...patients with moderate‐to‐severe chronic plaque psoriasis.
Methods
Patients in two similarly designed phase III studies (OPT Pivotal 1, NCT01276639, n = 901; OPT Pivotal 2, NCT01309737, n = 960) were initially randomized 2 : 2 : 1 to tofacitinib 10 or 5 mg or placebo, twice daily. Coprimary efficacy end points (week 16) included the proportion of patients achieving Physician's Global Assessment (PGA) of ‘clear’ or ‘almost clear’ (PGA response) and the proportion achieving ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75).
Results
Across OPT Pivotal 1 and OPT Pivotal 2, 745 patients received tofacitinib 5 mg, 741 received tofacitinib 10 mg and 373 received placebo. At week 16, a greater proportion of patients achieved PGA responses with tofacitinib 5 and 10 mg twice daily vs. placebo (OPT Pivotal 1, 41·9% and 59·2% vs. 9·0%; OPT Pivotal 2, 46·0% and 59·1% vs. 10·9%; all P < 0·001). Higher PASI 75 rates were observed with tofacitinib vs. placebo (OPT Pivotal 1, 39·9%, 59·2% and 6·2%, respectively, for tofacitinib 5 and 10 mg twice daily and placebo; OPT Pivotal 2, 46·0%, 59·6% and 11·4%; all P < 0·001 vs. placebo). Adverse event (AE) rates appeared generally similar across groups; rates of serious AEs, infections, malignancies and discontinuations due to AEs were low. Twelve patients reported herpes zoster across the tofacitinib treatment groups in both studies vs. none in the respective placebo groups. The most common AE across groups was nasopharyngitis.
Conclusions
Oral tofacitinib demonstrated significant efficacy vs. placebo during the initial 16 weeks of treatment in patients with moderate‐to‐severe psoriasis. Safety findings were consistent with prior studies.
What's already known about this topic?
The management of moderate‐to‐severe chronic plaque psoriasis has benefited from the introduction of biological therapies, but unmet needs still remain.
Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis.
A phase IIb study demonstrated that oral tofacitinib is efficacious and well tolerated in the treatment of patients with plaque psoriasis over a 12‐week period.
What does this study add?
These phase III studies demonstrated that oral tofacitinib 5 and 10 mg twice daily is efficacious and well tolerated in the treatment of plaque psoriasis in a large, global patient population over a 16‐week period.
These studies provide support for tofacitinib as an innovative oral systemic option for the treatment of patients with psoriasis in the future.
This is the first book to combine classical vehicle dynamics with electronic control. The equation-based presentation of the theory behind vehicle dynamics enables readers to develop a thorough ...understanding of the key attribute to both a vehicle's driveability and its active safety. Supported by MATLAB tools, the key areas that affect vehicle dynamics are explored including tire mechanics, the steering system, vehicle roll, traction and braking, 4WS and vehicle dynamics, vehicle dynamics by vehicle and human control, and controllabiliy. As a professional reference volume, this book is an essential addition to the resources available to anyone working in vehicle design and development. Written by a leading authority in the field (who himself has considerable practical experience), the book has a unique blend of theory and practice that will be of immense value in this applications based field.
* Get a thorough understand of why vehicles respond they way they do with a complete treatment of vehicle dynamics from theory to application* Full of case studies and worked examples using MATLAB/Simulink * Covers all variables of vehicle dynamics including tire and vehicle motion, control aspects, human control and external disturbances
With the continuous advancements in microelectromechanical systems (MEMS) fabrication technology, inertial sensors like accelerometers and gyroscopes can be designed and manufactured with smaller ...footprint and lower power consumption. In the literature, there are several reported accelerometer designs based on MEMS technology and utilizing various transductions like capacitive, piezoelectric, optical, thermal, among several others. In particular, capacitive accelerometers are the most popular and highly researched due to several advantages like high sensitivity, low noise, low temperature sensitivity, linearity, and small footprint. Accelerometers can be designed to sense acceleration in all the three directions (X, Y, and Z-axis). Single-axis accelerometers are the most common and are often integrated orthogonally and combined as multiple-degree-of-freedom (MDoF) packages for sensing acceleration in the three directions. This type of MDoF increases the overall device footprint and cost. It also causes calibration errors and may require expensive compensations. Another type of MDoF accelerometers is based on monolithic integration and is proving to be effective in solving the footprint and calibration problems. There are mainly two classes of such monolithic MDoF accelerometers, depending on the number of proof masses used. The first class uses multiple proof masses with the main advantage being zero calibration issues. The second class uses a single proof mass, which results in compact device with a reduced noise floor. The latter class, however, suffers from high cross-axis sensitivity. It also requires very innovative layout designs, owing to the complicated mechanical structures and electrical contact placement. The performance complications due to nonlinearity, post fabrication process, and readout electronics affects both classes of accelerometers. In order to effectively compare them, we have used metrics such as sensitivity per unit area and noise-area product. This paper is devoted to an in-depth review of monolithic multi-axis capacitive MEMS accelerometers, including a detailed analysis of recent advancements aimed at solving their problems such as size, noise floor, cross-axis sensitivity, and process aware modeling.
Summary
Kawasaki disease (KD) vasculitis is an acute febrile illness of childhood characterized by systemic vasculitis of unknown origin, and is the most common cause of acquired heart disease among ...children in the United States. While histological evidence of myocarditis can be found in all patients with acute KD, only a minority of patients are clinically symptomatic and a subset demonstrate echocardiographic evidence of impaired myocardial function, as well as increased left ventricular mass, presumed to be due to myocardial edema and inflammation. Up to a third of KD patients fail to respond to first‐line therapy with intravenous immunoglobulin (IVIG), and the use of interleukin (IL)‐1 receptor antagonist (IL‐1Ra, anakinra) is currently being investigated as an alternative therapeutic approach to treat IVIG‐resistant patients. In this study, we sought to investigate the effect of IL‐1Ra on myocardial dysfunction and its relation to myocarditis development during KD vasculitis. We used the Lactobacillus casei cell‐wall extract (LCWE)‐induced murine model of KD vasculitis and investigated the effect of IL‐1Ra pretreatment on myocardial dysfunction during KD vasculitis by performing histological, magnetic resonance imaging (MRI) and echocardiographic evaluations. IL‐1Ra pretreatment significantly reduced KD‐induced myocardial inflammation and N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) release. Both MRI and echocardiographic studies on LCWE‐injected KD mice demonstrated that IL‐1Ra pretreatment results in an improved ejection fraction and a normalized left ventricular function. These findings further support the potential beneficial effects of IL‐1Ra therapy in preventing the cardiovascular complications in acute KD patients, including the myocarditis and myocardial dysfunction associated with acute KD.
Here we show that similar to what is observed in children with Kawasaki Disease (KD), LCWE‐induced KD vasculitis in mice is also associated with myocarditis and myocardial dysfunction with ventricular enlargement. We found that treatment with the IL‐1R antagonist (Anakinra) improved myocardial function, ejection fraction and left ventricular function in this experimental mouse model of KD vasculitis. These findings further support the potential beneficial effects of IL‐1Ra therapy in preventing the cardiovascular complications in acute KD patients, including the myocarditis and myocardial dysfunction associated with acute KD.
The reflectance spectra of the most abundant meteorites, ordinary chondrites, are different from those of the abundant S-type (mnemonic for siliceous) asteroids. This discrepancy has been thought to ...be due to space weathering, which is an alteration of the surfaces of airless bodies exposed to the space environment. Here we report evidence of space weathering on particles returned from the S-type asteroid 25143 Itokawa by the Hayabusa spacecraft. Surface modification was found in 5 out of 10 particles, which varies depending on mineral species. Sulfur-bearing Fe-rich nanoparticles exist in a thin (5 to 15 nanometers) surface layer on olivine, low-Ca pyroxene, and plagioclase, which is suggestive of vapor deposition. Sulfur-free Fe-rich nanoparticles exist deeper inside (<60 nanometers) ferromagnesian silicates. Their texture suggests formation by metamictization and in situ reduction of Fe2+.
Context.
The Hayabusa2 spacecraft launched by Japan Aerospace Exploration Agency has been conducting observations of the asteroid (162173) Ryugu since June 2018. The Telescopic Optical Navigation ...Camera (ONC-T) onboard Hayabusa2 has obtained thousands of images under a variety of illumination and viewing conditions.
Aims.
Our objective is to examine and validate the camera calibration, derive a photometric correction for creating global albedo maps, and to interpret the photometric modeling results to characterize the surface of Ryugu.
Methods.
We observed (162173) Ryugu with the Gemini-South telescope, and combined these measurements with other published ground-based observations of the asteroid. The ground-based observations were compared with the data obtained by ONC-T in order to validate the radiometric calibration mutually. We used a combination of the Hapke disk-integrated and disk-resolved model equations to simultaneously analyze the combined ground- and spacecraft-based data.
Results.
The average spectrum of Ryugu was classified as Cb-type following the SMASSII taxonomy and C/F-type following the Tholen taxonomy based on spacecraft observations. We derived Hapke model parameters for all seven color filters, which allowed us to photometrically correct images to within an error of <10% for ~80% of the image pixels used in the modeling effort. Using this model, we derived a geometric albedo of 4.0 ± 0.5% (
v
band) for Ryugu. The average reflectance factor at the standard illumination condition was 1.87 ± 0.14% in the
v
band. Moreover we measured a phase reddening of (2.0 ± 0.7) × 10
−3
μ
m
−1
deg
−1
for Ryugu, similar to that observed for the asteroid (101955) Bennu.
Conclusions.
The global color map showed that the general trend was for darker regions to also be redder regions, however there were some distinct exceptions to this trend. For example, Otohime Saxum was bright and red while Kibidango crater was dark and blue. The darkness and flatness of Ryugu’s reflectance might be caused by a high abundance of organic materials.
Summary
Background Conventional systemic therapies for plaque psoriasis have not fully met the needs of patients, and although current biologic treatments are generally well tolerated, concerns ...exist with respect to long‐term safety. Interleukin (IL)‐17A is believed to be an important effector cytokine in the pathogenesis of psoriasis and is produced by Th17 cells, a class of helper T cells that act outside the established Th1/Th2 paradigm for regulation of innate and adaptive immunity.
Objectives To assess the efficacy and safety of different doses of secukinumab, a fully human anti‐IL‐17A IgG1κ monoclonal antibody, in patients with moderate‐to‐severe plaque psoriasis.
Methods Patients (n = 125) were randomized 1 : 1 : 1 : 1 : 1 to receive subcutaneous doses of placebo (n = 22) or secukinumab 1 × 25 mg (n = 29), 3 × 25 mg (n = 26), 3 × 75 mg (n = 21) or 3 × 150 mg (n = 27) at weeks 0, 4 and 8. After the 12‐week treatment period, patients entered a follow‐up period of 24 weeks. The primary efficacy outcome was at least 75% improvement from baseline in the Psoriasis Area and Severity Index score (PASI 75); secondary outcomes included the Investigator’s Global Assessment (IGA) and PASI 90 and 50 response rates.
Results After 12 weeks of treatment, secukinumab 3 × 150 mg and 3 × 75 mg resulted in significantly higher PASI 75 response rates vs. placebo (82% and 57% vs. 9%; P < 0·001 and P = 0·002, respectively). Higher PASI 75 response rates compared with placebo were maintained throughout the follow‐up period with these dosages week 36, 26% (n = 7) and 19% (n = 4) vs. 4% (n = 1), respectively, with a gradual decline of PASI 75 response over time after the dosing period. IGA response rates were significantly higher in the 3 × 150 mg group vs. placebo at week 12 (48% vs. 9%; P = 0·005) and were consistently higher for the 3 × 150 mg and 3 × 75 mg groups vs. placebo at all time points from week 4 onward. The PASI 90 response rate was significantly higher in the 3 × 150 mg group vs. placebo (52% vs. 5%) at week 12 and remained higher during the follow‐up period. Secukinumab was well tolerated. Two cases of neutropenia (≤ grade 2) were reported in the 3 × 150 mg cohort.
Conclusions Treatment with subcutaneous secukinumab 3 × 75 mg and 3 × 150 mg met the primary outcome of PASI 75 response achievement after 12 weeks, demonstrating efficacy in moderate‐to‐severe psoriasis.
What’s already known about this topic?
•
Conventional systemic therapies for plaque psoriasis have not fully met patient needs; biologics, although effective and generally well tolerated, have a still‐developing long‐term safety profile.
•
Monoclonal antibodies against interleukin (IL)‐17A have shown early promise.
What does this study add?
•
In this study, the investigational anti‐IL‐17 monoclonal secukinumab (3 × 150 mg, 3 × 75 mg subcutaneously) produced significantly higher rates of 75% improvement from baseline in Psoriasis Area and Severity Index score vs. placebo, and was well tolerated in moderate‐to‐severe plaque psoriasis.
•
Secukinumab may offer new therapeutic options in plaque psoriasis.
The Hayabusa2 spacecraft investigated the small asteroid Ryugu, which has a rubble-pile structure. We describe an impact experiment on Ryugu using Hayabusa2's Small Carry-on Impactor. The impact ...produced an artificial crater with a diameter >10 meters, which has a semicircular shape, an elevated rim, and a central pit. Images of the impact and resulting ejecta were recorded by the Deployable CAMera 3 for >8 minutes, showing the growth of an ejecta curtain (the outer edge of the ejecta) and deposition of ejecta onto the surface. The ejecta curtain was asymmetric and heterogeneous and it never fully detached from the surface. The crater formed in the gravity-dominated regime; in other words, crater growth was limited by gravity not surface strength. We discuss implications for Ryugu's surface age.
Cloud service providers have been shifting their workloads to microservices to take advantage of their modularity, flexibility, agility, and scalability. However, numerous obstacles remain to ...achieving the most out of microservice deployments, especially in terms of a Quality of Service (QoS). One possible approach to overcoming these obstacles is to perform autoscaling, which is the ability of cloud infrastructure and services to scale themselves up or down by changing their resource pool. There are two major categories of autoscaling: reactive and proactive. In reactive autoscaling, a feedback loop based on current workload resource usage is implemented to guide resource scaling. One disadvantage of reactive autoscaling is that it may result in inconsistencies between workload demand and resource allocation. In proactive autoscaling, a prediction model is used to guide the future allocation of resources according to current workload metrics. In this paper, a novel proactive autoscaling method is introduced where a two-state, machine-learning Random Forest (RF) model is designed to forecast the future CPU and memory utilization values required by the microservice workload. These predicted values are then used to adjust the resource pool both vertically (hardware resources) and horizontally (microservice replicas). The RF proactive autoscaler has been implemented on a home-grown, open-source microservice prototyping platform and verified using real-world workloads. The experiments show that the RF proactive autoscaler outperforms state-of-the-art ones in terms of allocated resources and latency. The increase in the utilization of allocated resources can reach 90% and the improvement in end-to-end latency, measured by the <inline-formula> <tex-math notation="LaTeX">95^{th} </tex-math></inline-formula> percentile, can reach 95%.
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