Embedding real-time in stochastic process algebras

We present a stochastic process algebra including immediate actions, deadlock and termination, and explicit stochastic delays, in the setting of weak choice between immediate actions and passage of time. The operational semantics is a spent time semantics, avoiding explicit clocks. We discuss the embedding of weak-choice real-time process theories and analyze the behavior of parallel composition in the weak choice framework

Effect of secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2-year results from the randomised phase III MEASURE 1 study.

OBJECTIVE: To evaluate the effect of secukinumab, an interleukin-17A inhibitor, on clinical signs and symptoms and radiographic changes through 2 years in patients with ankylosing spondylitis (AS). METHODS: In the phase III MEASURE 1 study, patients were randomised to receive intravenous secukinumab 10 mg/kg (at baseline, week 2 and week 4) followed by subcutaneous secukinumab 150 mg (intravenous 150 mg; n=125) or 75 mg (intravenous 75 mg; n=124) every four weeks, or matched placebo (n=122). Placebo-treated patients were re-randomised to subcutaneous secukinumab 150 or 75 mg from week 16. Clinical efficacy assessments included Assessment of SpondyloArthritis international Society 20 (ASAS20) response rates through week 104. Radiographic changes at week 104 were assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). RESULTS: 97 (77.6%) and 103 (83.1%) patients in the intravenous 150 mg and intravenous 75 mg groups, respectively, completed week 104. In the full analysis set (intent-to-treat), ASAS20 response rates at week 104 were 73.7% and 68.0% in the intravenous 150 mg and intravenous 75 mg groups, respectively. Among patients with evaluable X-rays who were originally randomised to secukinumab (n=168), mean change in mSASSS from baseline to week 104 was 0.30±2.53. Serious adverse events were reported in 12.2% and 13.4% of patients in the 150 mg and 75 mg groups, respectively. CONCLUSIONS: Secukinumab improved AS signs and symptoms through 2 years of therapy, with no unexpected safety findings. Data from this study suggest a low mean progression of spinal radiographic changes, which will need to be confirmed in longer-term controlled studies. TRIAL REGISTRATION NUMBER: NCT01358175

Seabed geomorphology: a two-part classification system

The BGS has developed a two- part classification system (‘Morphology’ and ‘Geomorphology’) to facilitate work on a new ‘S eabed Geomorphology’ mapping initia tive, and this classification system is the focus of this report. As stated in the Foreword, the rationale and the basic framework of the classification system were conceived and es tablished within BGS, but recent collaboration within the MAREANO -Norway, INFOMAR -Ireland, and MAREMAP -UK (MIM) partnership has led to significant improvement of the classifi cation system, and this report. To further support this effort, existing BGS GIS tools (SIGMA) ha ve been adapted to apply this two-part classification system for more efficient geom orphological mapping in the marine environment. This report: provides a brief background on seabed mapping and characterisation, as well as how this science has been addressed historically within BGS; describes the current motiva tion to conduct seabed geom orphological mapping, and the requirement for a new set of t ools to facilitate this work; describes the logical framework that underpins the classification system; outlines the attributes of the classification system, how it can be applied, and discusses the advantages and limitations of the approach. It is anticipated that through testing and usage, the classification syst em will be revised and improved over time, with updated versions released through MIM partnershi p. It is also planned that a further ‘user guide’ report will be produced for the classifi cation system and the GIS tools, including thematic details (e.g. background information on ‘coastal’ or ‘glacial’ features) and a feature glossary

Low serum albumin and the acute phase response predict low serum selenium in HIV-1 infected women

BACKGROUND: Low serum selenium has been associated with lower CD4 counts and greater mortality among HIV-1-seropositive individuals, but most studies have not controlled for serum albumin and the presence of an acute phase response. METHODS: A cross-sectional study was conducted to evaluate relationships between serum selenium concentrations and CD4 count, plasma viral load, serum albumin, and acute phase response markers among 400 HIV-1-seropositive women. RESULTS: In univariate analyses, lower CD4 count, higher plasma viral load, lower albumin, and the presence of an acute phase response were each significantly associated with lower serum selenium concentrations. In multivariate analyses including all four of these covariates, only albumin remained significantly associated with serum selenium. For each 0.1 g/dl increase in serum albumin, serum selenium increased by 0.8 μg/l (p < 0.001). Women with an acute phase response also had lower serum selenium (by 5.6 μg/l, p = 0.06). CONCLUSION: Serum selenium was independently associated with serum albumin, but not with CD4 count or plasma viral load, in HIV-1-seropositive women. Our findings suggest that associations between lower serum selenium, lower CD4 count, and higher plasma viral load may be related to the frequent occurrence of low serum albumin and the acute phase response among individuals with more advanced HIV-1 infection

Dual neutralisation of interleukin-17A and interleukin-17F with bimekizumab in patients with active ankylosing spondylitis: results from a 48-week phase IIb, randomised, double-blind, placebo-controlled, dose-ranging study

Objectives Bimekizumab selectively neutralises both interleukin (IL)-17A and IL-17F. We report efficacy and safety in a phase IIb dose-ranging study in patients with active ankylosing spondylitis (AS).Methods Adults with AS (fulfilling modified New York criteria) were randomised 1:1:1:1:1 to bimekizumab 16 mg, 64 mg, 160 mg, 320 mg or placebo every 4 weeks for 12 weeks (double-blind period). At week 12, patients receiving bimekizumab 16 mg, 64 mg or placebo were re-randomised 1:1 to bimekizumab 160 mg or 320 mg every 4 weeks to week 48; other patients continued on their initial dose (dose-blind period). The primary end point was Assessment of SpondyloArthritis international Society (ASAS) 40 response at week 12 (non-responder imputation (NRI) for missing data).Results 303 patients were randomised: bimekizumab 16 mg (n=61), 64 mg (n=61), 160 mg (n=60), 320 mg (n=61) or placebo (n=60). At week 12, significantly more bimekizumab-treated patients achieved ASAS40 vs placebo (NRI: 29.5%-46.7% vs 13.3%; p<0.05 all comparisons; OR vs placebo 2.6-5.5 (95% CI 1.0 to 12.9)). A significant dose-response was observed (p<0.001). The primary end point was supported by all secondary efficacy outcomes. At week 48, 58.6% and 62.3% of patients receiving bimekizumab 160 and 320 mg throughout the study achieved ASAS40, respectively (NRI); similar ASAS40 response rates were observed in re-randomised patients. During the double-blind period, treatment-emergent adverse events occurred in 26/60 (43.3%) patients receiving placebo and 92/243 (37.9%) receiving bimekizumab.Conclusions Bimekizumab provided rapid and sustained improvements in key outcome measures in patients with active AS, with no unexpected safety findings versus previous studies.Pathophysiology and treatment of rheumatic disease

Interleukin-17A Is Produced by CD4+ but Not CD8+ T Cells in Synovial Fluid Following T Cell Receptor Activation and Regulates Different Inflammatory Mediators Compared to Tumor Necrosis Factor in a Model of Psoriatic Arthritis Synovitis

Objective: Interleukin-17A (IL-17A) and tumor necrosis factor (TNF) contribute to the pathogenesis of psoriatic arthritis (PsA). However, their functional relationship in PsA synovitis has not been fully elucidated. Additionally, although CD8+ T cells in PsA have been recognized via flow cytometry as a source of IL-17A production, it is not clear whether CD8+ T cells secrete IL-17A under more physiologically relevant conditions in the context from PsA synovitis. This study was undertaken to clarify the roles of IL-17A and TNF in the synovial fluid (SF) from patients with PsA and investigate the impact of CD8+ T cells on IL-17A production. Methods: IL-17A+ T cells were identified by flow cytometry in SF samples from 20 patients with active PsA, blood samples from 22 treatment-naive patients with PsA, and blood samples from 22 healthy donors. IL-17A+ T cells were sorted from 12 PsA SF samples and stimulated using anti-CD3/anti-CD28 or phorbol myristate acetate (PMA) and ionomycin ex vivo, alone (n = 3) or together with autologous monocytes (n = 3) or PsA fibroblast-like synoviocytes (FLS) (n = 5–6). To evaluate the differential allogeneic effects of neutralizing IL-17A and TNF, SF CD4+ T cells and PsA FLS cocultures were also used (n = 5–6). Results: Flow cytometry analyses of SF samples from patients with PsA showed IL-17A positivity for CD4+ and CD8+ T cells (IL-17A, median 0.71% [interquartile range 0.35–1.50%] in CD4+ cells; median 0.44% [interquartile range 0.17–1.86%] in CD8+ T cells). However, only CD4+ T cells secreted IL-17A after ant

Increased expression of carbonic anhydrase I in the synovium of patients with ankylosing spondylitis

<p>Abstract</p> <p>Background</p> <p>One of the most distinctive features of ankylosing spondylitis (AS) is new bone formation and bone resorption at sites of chronic inflammation. Previous studies have indicated that the hyperplasia and inflammation of synovial tissues are significantly related to the pathogenic process of AS. The present study used a proteomic approach to identify novel AS-specific proteins by simultaneously comparing the expression profiles of synovial membranes from patients with AS, rheumatoid arthritis (RA) and osteoarthritis (OA).</p> <p>Methods</p> <p>Synovial tissues were collected from the hip joints of patients with AS and knee joints of patients with RA or OA (n = 10 for each disease) during joint replacement surgery. Proteins extracted from the synovial tissues were separated by 2-D electrophoresis (2-DE), and the proteins with significantly increased expression in the AS samples were subjected to MALDI-TOF/TOF-MS analysis. The results were verified using western blotting and immunohistochemistry. Levels of the candidate proteins in synovial fluids from knee joints (n = 40 for each disease) were measured using ELISA.</p> <p>Results</p> <p>The proteomic approach revealed significantly increased expression of carbonic anhydrase I (CA1) in the synovial membrane of patients with AS as compared with the RA and OA tissue samples. Immunohistochemistry and western blotting analysis confirmed the findings described above. The ELISA detected a higher level of CA1 in synovial fluids from patients with AS than those with OA. The mean value of the CA1 level was also higher in AS patients as compared with RA patients. This study also detected increased expression of alpha-1-antitrypsin in the synovial tissues from AS patients, which is in agreement with other reports.</p> <p>Conclusion</p> <p><it>In vitro </it>experiments by other groups indicated that CA1 catalyzes the generation of HCO₃^-through the hydration of CO₂, which then combines with Ca²⁺to form a CaCO3 precipitate. Calcification is an essential step of bone formation. Substantial evidence indicates that carbonic anhydrase also stimulates bone resorption. Hence, overexpression of CA1 in the synovial tissues of AS patients may promote improper calcification and bone resorption in AS.</p