Tofacitinib versus methotrexate in rheumatoid arthritis

Background : Methotrexate is the most frequently used first-line antirheumatic drug. We report the findings of a phase 3 study of monotherapy with tofacitinib, an oral Janus kinase inhibitor, as compared with methotrexate monotherapy in patients with rheumatoid arthritis who had not previously received methotrexate or therapeutic doses of methotrexate. Methods : We randomly assigned 958 patients to receive 5 mg or 10 mg of tofacitinib twice daily or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks; 956 patients received a study drug. The coprimary end points at month 6 were the mean change from baseline in the van der Heijde modified total Sharp score (which ranges from 0 to 448, with higher scores indicating greater structural joint damage) and the proportion of patients with an American College of Rheumatology (ACR) 70 response (>= 70% reduction in the number of both tender and swollen joints and >= 70% improvement in three of five other criteria: the patient's assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician). Results : Mean changes in the modified total Sharp score from baseline to month 6 were significantly smaller in the tofacitinib groups than in the methotrexate group, but changes were modest in all three groups (0.2 points in the 5-mg tofacitinib group and <0.1 point in the 10-mg tofacitinib group, as compared with 0.8 points in the methotrexate group [ P<0.001 for both comparisons]). Among the patients receiving tofacitinib, 25.5% in the 5-mg group and 37.7% in the 10-mg group had an ACR 70 response at month 6, as compared with 12.0% of patients in the methotrexate group (P<0.001 for both comparisons). Herpes zoster developed in 31 of 770 patients who received tofacitinib (4.0%) and in 2 of 186 patients who received methotrexate (1.1%). Confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels. Conclusions : In patients who had not previously received methotrexate or therapeutic doses of methotrexate, tofacitinib monotherapy was superior to methotrexate in reducing signs and symptoms of rheumatoid arthritis and inhibiting the progression of structural joint damage. The benefits of tofacitinib need to be considered in the context of the risks of adverse events

The Athena x-ray optics development and accommodation

The Athena mission, under study and preparation by ESA as its second Large-class science mission, requires the largest X-ray optics ever flown, building on a novel optics technology based on mono crystalline silicon. Referred to as Silicon Pore Optics technology (SPO), the optics is highly modular and benefits from technology spin-in from the semiconductor industry. The telescope aperture of about 2.5 meters is populated by around 700 mirror modules, accurately co-aligned to produce a common focus. The development of the SPO technology is a joint effort by European industrial and research entities, working together to address the challenges to demonstrate the imaging performance, robustness and efficient series production of the Athena optics. A technology development plan was established and is being regularly updated to reflect the latest developments, and is fully funded by the ESA technology development programmes. An industrial consortium was formed to ensure coherence of the individual technology development activities. The SPO technology uses precision machined mirror plates produced using the latest generation top quality 12 inch silicon wafers, which are assembled into rugged stacks. The surfaces of the mirror plates and the integral support structure is such, that no glue is required to join the individual mirror plates. Once accurately aligned with respect to each other, the surfaces of the mirror plates merge in a physical bonding process. The resultant SPO mirror modules are therefore very accurate and stable and can sustain the harsh conditions encountered during launch and are able to tolerate the space environment expected during operations. The accommodation of the Athena telescope is also innovative, relying on a hexapod mechanism to align the optics to the selected detector instruments located in the focal plane. System studies are complemented by dedicated technology development activities to demonstrate the capabilities before the adoption of the Athena mission

CD4-independent infection of human peripheral blood dendritic cells with isolates of human immunodeficiency virus type 1

Dendritic cells (DC) are members of a distinct family of bone marrow-derived leukocytes. DC are potent accessory cells for a number of T cell-mediated immune responses, including autologous and allogeneic mixed leukocyte reactions, and mitogen- and antigenstimulated lymphocyte proliferation. In the present study, DC purified from human peripheral blood were inoculated with various strains (IIIB, SF2, WMJ1, SF162, 89.6 and clone HXB2) of human immunodeficiency virus type 1 (HIV-1) displaying different patterns of cellular tropism. Viral replication was demonstrated by detection of p24 antigen (Ag) intracellularly and in culture supernatants, and by Southern and Northern blot analyses for the presence of HIV DNA and RNA, respectively, within infected cells. Cellfree and cell-associated p24 Ag levels rose substantially when DC were inoculated with strains SF162, 89.6 and clone HXB2. In contrast, p24 Ag levels rose only marginally after inoculation of DC with strains IIIB, SF2 and WMJ1. Purified DC did not express detectable membrane CD4, although CD4 mRNA was detected by reverse transcriptase PCR. The presence of anti-CD4 monoclonal antibodies failed to block infection of DC by any of the HIV strains tested, suggesting the existence of a CD4-independent alternative pathway of viral entry. The possibility that DC serve as a reservoir for HIV-1 must be considered

Development and manufacturing of SPO X-ray mirrors

The Silicon Pore Optics (SPO) technology has been established as a new type of X-ray optics enabling future X-ray observatories such as ATHENA. SPO is being developed at cosine together with the European Space Agency (ESA) and academic as well as industrial partners. The SPO modules are lightweight, yet stiff, high-resolution X-ray optics, allowing missions to reach a large effective area of several square meters. These properties of the optics are mainly linked to the mirror plates consisting of mono-crystalline silicon. Silicon is rigid, has a relatively low density, a very good thermal conductivity and excellent surface finish, both in terms of figure and surface roughness. For Athena, a large number of mirror plates is required, around 100,000 for the nominal configuration. With the technology spin-in from the semiconductor industry, mass production processes can be employed to manufacture rectangular shapes SPO mirror plates in high quality, large quantity and at low cost. Within the last years, several aspects of the SPO mirror plate have been reviewed and undergone further developments in terms of effective area, intrinsic behavior of the mirror plates and mass production capability. In view of flight model production, a second source of mirror plates has been added in addition to the first plate supplier. The paper will provide an overview of most recent plate design, metrology and production developments

Status of the demonstration of the critical technologies of the ATHENA telescope

The ATHENA (Advanced Telescope for High ENergy Astrophysics) mission is the current 2nd 'Large' mission (L2) in the ESA Cosmic Vision programme currently. It is currently at Phase B1 but the mission concept will now enter a reformulation phase that will follow a design-to-cost approach. This paper describes the main technologies behind its reference X-ray telescope based on the modular Silicon Pore Optics (SPO) technology. The large X-ray mirror is the mission enabler being specifically developed for ATHENA, in a joint effort by industry, research institutions and ESA. All aspects of the optics are being addressed, from the mirror plates and their coatings to the mirror modules and their assembly into the ATHENA telescope, as well as the facilities required to build and test the flight optics, demonstrating performance, robustness, and programmatic compliance. An overview of the status of the design and demonstration of the telescope is given. The risks that have successfully been mitigated are made explicit and the remaining risks are identified.</p

NewATHENA optics technology

The re-formulation phase of the next generation x-ray observatory ATHENA (Advanced Telescope for High ENergy Astrophysics) – now NewATHENA - is being utilized for further improvements of the optics technology. The Silicon Pore Optics (SPO) remains the technology of choice, since it uniquely combines a low mass, large effective area, and good angular resolution, addressing the challenge of the NewATHENA X-ray optics. The performance and preparation for the cost-effective implementation of the flight optics is being further evolved in a joint effort by industry, research institutions and ESA. The SPO technology greatly benefits from investments in the semiconductor industry and maximizes technology spin-in. Dedicated facilities have been and are being created to produce the required mirror plates, assemble them into stacks and mirror modules, integrate them into the complete telescope and measure the performance and compatibility with the NewATHENA technical and programmatic requirements. An overview of the activities preparing the implementation of the NewATHENA optics is provided