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Contains fulltext : 172407.pdf (Publisher’s version ) (Closed access) IMPORTANCE: Digital ulcers in patients with systemic sclerosis are associated with pain and poor quality of life. Endothelin-1 promotes vasculopathy in systemic sclerosis after macitentan, an endothelin-1 blocker. OBJECTIVE: To evaluate the efficacy of macitentan in reducing the number of new digital ulcers in patients with systemic sclerosis. DESIGN, SETTING, AND PARTICIPANTS: Two international, randomized, double-blind, placebo-controlled trials (DUAL-1, DUAL-2) were conducted between January 2012 and February 2014. Participants were patients with systemic sclerosis and active digital ulcers at baseline. Target enrollment for each study was 285 patients. INTERVENTIONS: Patients were randomized (1:1:1) to receive oral doses of 3 mg of macitentan, 10 mg of macitentan, or placebo once daily and stratified according to number of digital ulcers at baseline (3). MAIN OUTCOMES AND MEASURES: The primary outcome for each trial was the cumulative number of new digital ulcers from baseline to week 16. Treatment effect was expressed as the ratio between treatment groups. RESULTS: In DUAL-1, among 289 randomized patients (mean age 51.2 years; 85.8% women), 226 completed the study. The adjusted mean number of new digital ulcers per patient over 16 weeks was 0.94 in the 3-mg macitentan group (n = 95) and 1.08 in the 10-mg macitentan group (n = 97) compared with 0.85 in the placebo group (n = 97) (absolute difference, 0.09 [95% CI, -0.37 to 0.54] for 3 mg of macitentan vs placebo and 0.23 [-0.27 to 0.72] for 10 mg of macitentan vs placebo). Among 265 patients randomized in DUAL-2 (mean age 49.6 years; 81.9% women), 216 completed the study. In DUAL-2, the adjusted mean number of new digital ulcers was 1.44 in the 3-mg macitentan group (n = 88) and 1.46 in the 10-mg macitentan group (n = 88) compared with 1.21 in the placebo group (n = 89) (absolute difference, 0.23 [95% CI, -0.35 to 0.82] for 3 mg of macitentan vs placebo and 0.25 [95% CI, -0.34 to 0.84] for 10 mg of macitentan vs placebo). Adverse events more frequently associated with macitentan than with placebo were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis. CONCLUSIONS AND RELEVANCE: Among patients with systemic sclerosis and active ischemic digital ulcers, treatment with macitentan did not reduce new digital ulcers over 16 weeks. These results do not support the use of macitentan for the treatment of digital ulcers in this patient population. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT01474109, NCT01474122.

Objective. The main objective was to determine the 2-year clinical benefit and safety of etanercept (ETN) in children with the juvenile idiopathic arthritis (JIA) categories of extended oligoarthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). Methods. CLIPPER was a 96-week, phase IIIb, open-label, multicenter study. Patients with eoJIA, ERA, or PsA received ETN 0.8 mg/kg once weekly (50 mg max) for up to 96 weeks. The proportions of patients reaching the JIA American College of Rheumatology (ACR) 30/50/70/90/100 and inactive disease responses at Week 96 were calculated. Adverse events (AE) were collected throughout the study (intention-to-treat sample). Results. There were 127 patients (eoJIA n = 60, ERA n = 38, PsA n = 29) who received >= 1 dose of ETN. The mean disease duration was 31.6 (eoJIA), 23.0 (ERA), and 21.8 (PsA) months. At Week 96, JIA ACR 30/50/70/90/100/inactive disease responses (95% CI) were achieved by 84.3% (76.7, 90.1), 83.5% (75.8, 89.5), 78.7% (70.6, 85.5), 55.1% (46.0, 63.9), 45.7% (36.8, 54.7), and 27.6% (20.0, 36.2) of patients, respectively. The most common AE (no. events, events per 100 patient-yrs) overall were headache (23, 10.7), pyrexia (12, 5.6), and diarrhea (10, 4.6). The most common infections were upper respiratory tract infection (83, 38.6), pharyngitis (50, 23.2), gastroenteritis (22, 10.2), bronchitis (19, 8.8), and rhinitis (17, 7.9). No cases of malignancy, active tuberculosis, demyelinating disorders, or death were reported. Conclusion. Over 96 weeks of therapy, ETN demonstrated sustained efficacy at treating the clinical symptoms of all 3 JIA categories, with no major safety issues.

Caspofungin, an echinocandin antifungal agent, is active against invasive Aspergillus and Candida infections. In a phase I study in healthy volunteers, mild transient increases in serum aminotransferases were observed with the concomitant administration of caspofungin and cyclosporin A (CsA). As a result, it is recommended that the concomitant use of the two drugs be limited to those settings with appropriate risk-benefit balance. We retrospectively assessed safety data in 14 patients with refractory invasive mycoses who were treated concomitantly with CsA and caspofungin before the drug was licensed in Spain. In all, 13 patients were adults (median age, 31.5 years; range, 14-67 years). The average duration of concomitant therapy was 15 days (range, 2-43 days). No clinically significant elevations of serum aminotransferases were observed, and no patient had concomitant therapy discontinued or interrupted due to a drug-related adverse event. In this study of a limited number of patients, the coadministration of caspofungin and CsA was generally well tolerated.

Batching jobs in a manufacturing system is a very common policy in most industries. Main reasons for batching are avoidance of set ups and/or facilitation of material handling. Examples of batch-wise production systems are ovens found in aircraft industry and in semiconductor manufacturing. Starting from the early nineties much research efforts have been put in constructing strategies for the dynamic control of these systems in order to reduce cycle times. Typically, these so-called "look-ahead strategies" base their scheduling decision on the information on a few near future product arrivals. In this paper we give a literature overview of the developed strategies, consider basic insights in their construction and highlight issues for further research.

The choroid, a vascular meshwork between the retina and sclera, plays a major role in providing oxygen and nutrition to the outer layers of the retina.1 In recent years, increased awareness of its role in ocular development and its known association with many diseases of the posterior pole have stimulated a renewed focus on understanding choroidal anatomy and physiology.2 A number of methods, including histology3 and ultrasonography,4 have previously been used to quantify choroidal thickness (CT); however, the overall precision of these approaches is still lacking. Fortunately, the recent introduction of spectral domain optical coherence tomography (SD-OCT) and the description of “enhanced depth imaging” scanning protocols have afforded a new opportunity to improve the accuracy of quantitative choroidal assessment. As a result, changes in CT have now been studied using different OCT technologies over a wide range of ocular pathologies (e.g., glaucoma,5 inherited retinal diseases,6 high myopia,7 central serous chorioretinopathy,8 polypoidal choroidal vasculopathy,9 neovascular age-related macular degeneration [AMD],9 and Vogt Koyanagi Harada disease10). Although the use of OCT has provided many new insights into choroidal morphology, to date there exists a notable disparity between the CT measurements obtained in different studies. For example, several studies on the cross-sectional variation of CT measurements in “normal” subjects have shown CT to be greatest at the fovea, with decreasing thickness more nasally than temporally.9,11,12 Other results suggest that the foveal CT is thinner than the choroid superior to the fovea.13 These discrepancies may arise due to the use of different image acquisition methodologies, a generally limited field of view for scanning, and inconsistencies in choosing the exact locations for repeated CT measurement. Regardless, the exact spatial distribution of CT changes in the macular region of human eyes remains unclear. In addition, most OCT-derived studies have focused on assessment of CT in the macular region alone, examining the correlation between macular CT changes and disease expression. However, unlike the neurosensory retina, a complex and highly organized neural structure with the fovea as its unmistaken center, the choroid is a vascular layer with a potentially very different topography. Determination of choroidal spatial distribution may thus be difficult, and potentially inaccurate, in the context of macular scanning alone. In this report, we aim to address these issues by obtaining larger, two-dimensional (2D) maps of the spatial distribution of the choroid in the posterior pole and identifying its specific patterns in healthy volunteers using SD-OCT.