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To date, head-to-head trials comparing the efficacy and safety of biological disease-modifying antirheumatic drugs within the same class, including TNF inhibitors, in patients with active rheumatoid arthritis despite methotrexate therapy are lacking. We aimed to compare the efficacy and safety of two different TNF inhibitors and to assess the efficacy and safety of switching to the other TNF inhibitor without a washout period after insufficient primary response to the first TNF inhibitor at week 12. In this 104-week, randomised, single-blind (double-blind until week 12 and investigator blind thereafter), parallel-group, head-to-head superiority study (EXXELERATE), eligible patients from 151 centres worldwide were aged 18 years or older with a diagnosis of rheumatoid arthritis at screening, as defined by the 2010 ACR/EULAR criteria, and had prognostic factors for severe disease progression, including a positive rheumatoid factor, or anti-cyclic citrullinated peptide antibody result, or both. Participants were randomly assigned (1:1) via an interactive voice and web response system with no stratification to receive certolizumab pegol plus methotrexate or adalimumab plus methotrexate. All study staff were kept masked throughout the study and participants were masked until week 12. At week 12, patients were classified as responders (by either achieving low disease activity [LDA] according to Disease Activity Score 28-erythrocyte sedimentation rate [DAS28-ESR] ≤3·2 or DAS28-ESR reduction ≥1·2 from baseline) or as non-responders. Non-responders to the first TNF inhibitor to which they were randomised were switched to the other TNF inhibitor with no washout period. Primary endpoints were the percentage of patients achieving a 20% improvement according to the American College of Rheumatology criteria (ACR20) at week 12 and LDA at week 104 (week 12 non-responders were considered LDA non-responders). This study is registered with ClinicalTrials.gov, number NCT01500278. Between Dec 14, 2011, and Nov 11, 2013, 1488 patients were screened of whom 915 were randomly assigned; 457 to certolizumab pegol plus methotrexate and 458 to adalimumab plus methotrexate. No statistically significant difference was observed in ACR20 response at week 12 (314 [69%] of 454 patients and 324 [71%] of 454 patients; odds ratio [OR] 0·90 [95% CI 0·67–1·20]; p=0·467) or DAS28-ESR LDA at week 104 (161 [35%] of 454 patients and 152 [33%] of 454 patients; OR 1·09 [0·82–1·45]; p=0·532) between certolizumab pegol plus methotrexate and adalimumab plus methotrexate, respectively. At week 12, 65 non-responders to certolizumab pegol were switched to adalimumab and 57 non-responders to adalimumab were switched to certolizumab pegol; 33 (58%) of 57 patients switching to certolizumab pegol and 40 (62%) of 65 patients switching to adalimumab responded 12 weeks later by achieving LDA or a DAS28-ESR reduction 1·2 or greater. 389 [75%] of 516 patients who received certolizumab pegol plus methotrexate and 386 [74%] of 523 patients who received adalimumab plus methotrexate reported treatment-emergent adverse events. Three deaths (1%) occurred in each group. No serious infection events were reported in the 70-day period after treatment switch. These results show that certolizumab pegol plus methotrexate is not superior to adalimumab plus methotrexate. The data also show the clinical benefit and safety of switching to a second TNF inhibitor without a washout period after primary failure to a first TNF inhibitor. UCB Pharma.

Background: The efficacy and safety of bimekizumab (BKZ), an inhibitor of interleukin (IL)-17F in addition to IL-17A, has been established in axial spondyloarthritis (axSpA). Early assessment of new bone formation is possible using 18F-fluoride positron emission tomography-computerised tomography (PET-CT) imaging to quantitatively monitor osteoblastic activity. Objectives: This exploratory study, initiated before phase IIb/III studies, assessed the efficacy and safety of BKZ in patients with radiographic (r-)axSpA and its effect on new bone formation. Design: Patients were randomised 2:1 to BKZ 160 mg every 2 weeks (Q2W; Weeks 0–10) then 320 mg Q4W (Weeks 12–44), or the reference drug: certolizumab pegol (CZP) 400 mg Q2W (Weeks 0–4), then 200 mg Q2W (Weeks 6–10), 400 mg Q4W (Weeks 12–44). Methods: Primary (Axial Spondyloarthritis Disease Activity Score (ASDAS) change from baseline (CfB)) and secondary endpoints (ASDAS-ID, ASDAS-MI) were assessed at Week 12. PET-positive axSpA lesion counts and osteoblastic activity quantification (mean SUVauc) were performed at baseline and Weeks 12 and 48 in the sacroiliac joints and spine (PET-CT substudy; not powered to evaluate differences). Results: In total, 76 patients were randomised; 26/76 entered the PET-CT substudy. At Week 12, the mean ASDAS CfB with BKZ was −2.1 (CZP: −1.8); ASDAS-ID and ASDAS-MI were achieved by 23.9% (11/46) (CZP: 20.8% (5/24)) and 60.9% (28/46) (CZP: 45.8% (11/24)) patients. Across treatments, clinical efficacy was maintained or increased further at Week 48. In the PET-CT substudy, the total number of PET-positive axSpA lesions and mean SUVauc were substantially reduced from baseline at Week 12 with BKZ and CZP, with reductions maintained or further reduced at Week 48. Treatments were well tolerated with no new safety signals. Conclusion: Dual inhibition of IL-17A and IL-17F with BKZ resulted in improved clinical outcomes and reduced osteoblastic activity in patients with r-axSpA, suggesting the potential of BKZ to reduce disease activity and new bone formation within 12 weeks of treatment. CZP findings were consistent with previous data. No new safety signals were identified. Trial registration: ClinicalTrials.gov, NCT03215277 (https://clinicaltrials.gov/study/NCT03215277).

We review Pólya vector fields associated to holomorphic functions as an important pedagogical tool for making the complex integral understandable to the students, briefly mentioning its use in other dimensions. Techniques of differential geometry are then used to refine the study of holomorphic functions from a metric (Riemannian), affine differential or differential viewpoint. We prove that the only nontrivial holomorphic functions, whose Pólya vector field is torse-forming in the cannonical geometry of the plane, are the special Möbius transformations of the form f(z)=b(z+d)−1. We define and characterize several types of affine connections, related to the parallelism of Pólya vector fields. We suggest a program for the classification of holomorphic functions, via these connections, based on the various indices of nullity of their curvature and torsion tensor fields.

Regardless of the precision or complexity of the reliability analysis method used, the quantitative assessment of the reliability of a system requires knowledge of the values of the reliability indicators of the component elements. Obtaining realistic results for the reliability of the system is conditioned by the credibility of the values of the reliability indicators of the elements. Information on the reliability of the elements is useful both for beneficiaries (for the purpose of optimizing maintenance) and for manufacturers (for the purpose of applying corrections in design and manufacturing).

This paper outlines for construction specialists the concept of \"passive house\", presenting the actual status of research and breakthroughs within this field within the country and abroad but also the directives of the European Council and European Parliament regarding this concept. Last, but certainly not least, it showcases some of the flaws of the , because it fails to bring forth viable solutions for a number of dire issues.

ObjectiveInterleukin (IL)-17A has emerged as pivotal in driving tissue pathology in immune-mediated inflammatory diseases. The role of IL-17F, sharing 50% sequence homology and overlapping biological function, remains less clear. We hypothesised that IL-17F, together with IL-17A, contributes to chronic tissue inflammation, and that dual neutralisation may lead to more profound suppression of inflammation than inhibition of IL-17A alone.MethodsPreclinical experiments assessed the role of IL-17A and IL-17F in tissue inflammation using disease-relevant human cells. A placebo-controlled proof-of-concept (PoC) clinical trial randomised patients with psoriatic arthritis (PsA) to bimekizumab (n=39) or placebo (n=14). Safety, pharmacokinetics and clinical efficacy of multiple doses (weeks 0, 3, 6 (240 mg/160 mg/160 mg; 80 mg/40 mg/40 mg; 160 mg/80 mg/80 mg and 560 mg/320 mg/320 mg)) of bimekizumab, a humanised monoclonal IgG1 antibody neutralising both IL-17A and IL-17F, were investigated.ResultsIL-17F induced qualitatively similar inflammatory responses to IL-17A in skin and joint cells. Neutralisation of IL-17A and IL-17F with bimekizumab more effectively suppressed in vitro cytokine responses and neutrophil chemotaxis than inhibition of IL-17A or IL-17F alone. The PoC trial met both prespecified efficacy success criteria and showed rapid, profound responses in both joint and skin (pooled top three doses vs placebo at week 8: American College of Rheumatology 20% response criteria 80.0% vs 16.7% (posterior probability >99%); Psoriasis Area and Severity Index 100% response criteria 86.7% vs 0%), sustained to week 20, without unexpected safety signals.ConclusionsThese data support IL-17F as a key driver of human chronic tissue inflammation and the rationale for dual neutralisation of IL-17A and IL-17F in PsA and related conditions.Trial registration numberNCT02141763; Results.

ObjectiveEvaluate the efficacy and safety of dual neutralisation of interleukin (IL)-17A and IL-17F with bimekizumab, a monoclonal IgG1 antibody, in addition to certolizumab pegol (CZP) in patients with rheumatoid arthritis (RA) and inadequate response (IR) to certolizumab pegol.MethodsDuring this phase 2a, double-blind, proof-of-concept (PoC) study (NCT02430909), patients with moderate-to-severe RA received open-label CZP 400 mg at Weeks 0, 2 and 4, and 200 mg at Week 6. Patients with IR at Week 8 (Disease Activity Score 28-joint count C-reactive protein (DAS28(CRP))>3.2) were randomised 2:1 to CZP (200 mg every 2 weeks (Q2W)) plus bimekizumab (240 mg loading dose then 120 mg Q2W) or CZP plus placebo. The primary efficacy and safety variables were change in DAS28(CRP) between Weeks 8 and 20 and incidence of treatment-emergent adverse events (TEAEs).ResultsOf 159 patients enrolled, 79 had IR at Week 8 and were randomised to CZP plus bimekizumab (n=52) or CZP plus placebo (n=27). At Week 20, there was a greater reduction in DAS28(CRP) in the CZP-IR plus bimekizumab group compared with the CZP-IR plus placebo group (99.4% posterior probability). The most frequent TEAEs were infections and infestations (CZP plus bimekizumab, 50.0% (26/52); CZP plus placebo, 22.2% (6/27)).ConclusionsPoC was confirmed based on the rapid decrease in disease activity achieved with 12 weeks of CZP plus bimekizumab. No unexpected or new safety signals were identified when neutralising IL-17A and IL-17F in patients with RA concomitantly treated with CZP, but the rate of TEAEs was higher with dual inhibition.

Cost-optimized airline resource schedules often imply a lack of delay tolerance in case of unforeseen disruptions, e.g. late check-ins, technical defects or airport and airspace congestion. Therefore, the consideration of timeliness and robustness has become an important topic in robust resource scheduling and a wide range of sophisticated scheduling approaches has been developed in recent years. However, these approaches depend on assumptions made concerning delay occurrences. A better understanding of delay mechanisms may lead to a better trade-off between cost-efficiency and robustness and is therefore the purpose of this paper. We provide a data-driven detection of decision rules for daytime delay trends, depending on spatio-temporal attributes. The focus is on interpretable rules whose prediction accuracy is compared to random forests as a non-parametric, automated modeling approach. The obtained results give an insight into both the nature of primary delay occurrence and the methodical potential of delay prediction in the context of robust resource scheduling.

The Ditrău Alkaline Massif (DAM) is an igneous massif in the Eastern Carpathian Mountains of Romania. Numerous geochronological and geochemical studies have proposed a long formation history (ca. 70 m.y.) of the DAM from Middle Triassic to Cretaceous times, which is hardly reconcilable with geochemical evolutionary models and the geotectonic environment during the Mesozoic in this part of the Eastern Carpathian Mountains. In order to put tighter age constraints on the igneous processes forming the DAM, two nepheline syenites from the so-called Ghiduţ and Lăzarea suites were investigated. Based on field and geochemical evidence, the two rock suites represent the younger part of the DAM intrusives. Detailed zircon characterization, in situ zircon SIMS U-Pb dating, and geochemical modelling were used to establish the timing of zircon crystallization and thus to set time constraints on the igneous formation of these parts of the DAM. The intrusion of the dated Ghiduţ suite sample took place at 232 ± 1 Ma in the Karnium, whereas the Lăzarea suite nepheline syenite sample was intruded at 225 ± 1 Ma in the Norium. Together with published geochemical and geochronological data, three different magmatic events can thus be identified: Ghiduţ suite at 231.1 ± 0.8 Ma, Ditrău suite at 230.7 ± 0.2 Ma, and Lăzarea suite at 224.9 ± 1.1 Ma. Although the ages of the events 1 and 2 are statistically indistinguishable, the combination of geochemical and petrochronological data certainly favor independent intrusion events. Thus, the igneous events forming the younger parts of the DAM encompassed a time span of ca. 13 m.y. Additionally, each igneous event can tentatively be divided in an older syenitic stage and a younger nepheline syenitic one, each with an age difference of some 100,000 years. No indication of any post 215 Ma igneous or hydrothermal activity was found. The new data and interpretation significantly improve our understanding of the temporal and geochemical evolution of the DAM and of alkaline complexes as such, demonstrating that the underlying igneous processes (melt generation, assimilation, fractionation, and the duration of plumbing systems) work on the same time scale for both sorts of magmatic rock suites.

Diatoms are one of the most common types of phytoplankton, found seldom in soil but in high amounts in both salty waters and fresh waters, generating almost 20% of the oxygen that the planet produces every year. Diatoms are used in the monitorization of the environment’s conditions and also in observations regarding the quality of soil and water, and also in soil microorganisms traceability. The samples have been collected from both soil and Gheorgheni Lake every month during a year at the same date. There is a lack of diatoms in winter (December, January) and reappearing in smaller numbers in February. March is the most prolific month regarding the identified number of species. October is the most abundant month regarding the diatoms per analyzed sample. In November, the number of diatoms is pretty high, but comparing to October, the numbers are lowering. This variation from month to month is mostly due to the water temperature that keeps on changing. If we were to compare November 2017 to November 2018, we can notice a significant rise of diatoms and also a rise in species identified per sample from one year to another. The trophic characterization of aquatic ecosystems based on the phytoplankton indicates a high value of primary production (Polytrophic) in the Gheorgheni Lake. We can observe the seasonal variation of diatom species due to temperature variation specific to each season. The most abundant species identified during the monitoring is Synedra acus, having a larger spectrum of temperature in which it grows and it is one of the most resistant when it comes to anthropic pollution.