JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis

Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules associated with one of the major pathways through which many cytokines exert and integrate their function, and as such they are increasingly recognized as playing critical role in the pathogenesis subserving various immune-mediated diseases, including RA, PsA, SpAs, IBD, skin disorders (e.g. alopecia areata, atopic dermatitis), single-gene disorders like interferonopathies, and others. JAKs are the key initiating players of the JAK/STAT pathway. Upon binding of their respective effector molecules (cytokines, IFNs, growth factors and others) to type I and type II receptors, JAKs are activated, and through phosphorylation of themselves and of other molecules (including STATs), they mediate signal transduction to the nucleus. A class of drugs—called JAK inhibitors or JAKinibs—that block one or more JAKs has been developed in the last decade, and now numbers >20 members. Although, so far, JAK inhibitors have been marketed only for RA and PsA, these drugs have been tested in phase 2 and phase 3 clinical trials for other inflammatory conditions and beyond. In this review, we summarize the clinical data, including efficacy and safety, available for JAK inhibitors used in some immune-mediated conditions other than RA

The role of IL-23 and the use IL-23 inhibitors in psoriatic arthritis

Background: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis characterised by musculoskeletal and extra-articular manifestations, most notably psoriasis. While the underlying pathogenetic mechanisms are not yet fully understood, a central role has been identified for the IL-23/IL-17 pathway. Objectives: We aimed to briefly describe the role of IL-23 in the pathogenesis of PsA and to describe the available anti-IL-23 agents and their place in the management of PsA. Methods: This is a narrative review of the current literature, focussing on the results of the phase 3 studies in PsA for the IL-23 p40 inhibitor ustekinumab and the more recent IL-23 p19 inhibitors guselkumab, risankizumab and tildrakizumab. Results: IL-23 triggers expression of IL-17 and other effector cytokines in a variety of cells, leading to tissue inflammation and injury. Targeting IL-23, particularly with p19 inhibitors, appears to be an effective and safe strategy for multiple clinical domains in PsA, most notably the skin, with some differences in efficacy emerging between these agents. Conclusion: The development of IL-23 inhibitors represents a significant advance in the management of psoriatic disease. In the absence of head-to-head studies, future data emerging from real-world experiences of individual IL-23 p19 inhibitors will help inform the use of these agents in relation to other biologics in PsA

Maternal and Newborn Health Implementation Research: Programme Outcomes, Pathways of Change and Partnerships for Equitable Health Systems in Uganda

Editorial special issue: MANIFEST - maternal and neonatal implementation for equitable systems study.DFI

Nanoscale local modification of PMMA refractive index by tip-enhanced femtosecond pulsed laser irradiation

Investigation techniques based on tip-enhanced optical effects, capable to yield spatial resolutions down to nanometers level, have enabled a wide palette of important discoveries over the past twenty years. Recently, their underlying optical setups are beginning to emerge as useful tools to modify and manipulate matter with nanoscale spatial resolution. We try to contribute to these efforts by reporting a method that we found viable to modify the surface refractive index of polymethyl methacrylate (PMMA), an acrylic polymer material. The changes in the refractive index are accomplished by focusing a femtosecond pulsed near-infrared laser beam on the apex of a metalized nano-sized tip, traditionally used in scanning probe microscopy (SPM) applications. The adopted illumination strategy yields circular-shaped modifications of the refractive index occurring at the surface of the PMMA sample, exhibiting a lateral size <200 nm, under 790 nm illumination, representing a four-fold increase in precision compared to the current state-of-the-art. The light intensity enhancement effects taking place at the tip apex makes possible achieving refractive index changes at low laser pulse energies (<0.5 nJ), which represents two orders of magnitude advantage over the current state-of-the art. The presented nanoimprinting method is very flexible, as it can be used with different power levels and can potentially be operated with other materials. Besides enabling modifications of the refractive index with high lateral resolution, this method can pave the way towards other important applications such the fabrication of photonic crystal lattices or surface waveguides

Probing the Complex and Variable X-ray Absorption of Markarian 6 with XMM-Newton

We report on an X-ray observation of the Seyfert 1.5 galaxy Mrk 6 obtained with the EPIC instruments onboard XMM-Newton. Archival BeppoSAX PDS data from 18-120 keV were also used to constrain the underlying hard power-law continuum. The results from our spectral analyses generally favor a double partial-covering model, although other spectral models such as absorption by a mixture of partially ionized and neutral gas cannot be firmly ruled out. Our best-fitting model consists of a power law with a photon index of 1.81+/-0.20 and partial covering with large column densities up to 10^{23} cm**-2. We also detect a narrow emission line consistent with Fe Kalpha fluorescence at 6.45+/-0.04 keV with an equivalent width of ~93+/-25 eV. Joint analyses of XMM-Newton, ASCA, and BeppoSAX data further provide evidence for both spectral variability (a factor of ~2 change in absorbing column) and absorption-corrected flux variations (by ~60%) during the ~4 year period probed by the observations.Comment: 7 pages, 2 figures. accepted for publication in the Astronomical Journa

Neutropaenia in early rheumatoid arthritis: frequency, predicting factors, natural history and outcome

Objectives To determine the frequency, severity and natural history of neutropaenia in early rheumatoid arthritis (RA), explore its associations with clinical features and assess its impact on clinical management. Methods: The Scottish Early Rheumatoid Arthritis inception cohort prospectively recruited patients with newly diagnosed RA and followed them up every 6 months. Patients with RA who developed at least one episode of neutropaenia (grade 1: &lt;2.0×10^9/L; grade 2: &lt;1.5×10^9/L; grade 3: &lt;1.0×10^9/L; grade 4: &lt;0.5×10^9/L) were compared with those who did not. Comparisons were also made between patients who experienced one or more episodes of neutropaenia and between patients with different neutropaenia grades. Results: 77 neutropaenia episodes were recorded in 58 of 771 (7.5%) patients with RA, who were followed up for a median (range) of 18 (6–48) months. Neutropaenia occurred at a median (range) of 12 (0–120) months after RA diagnosis. The majority had mild neutropaenia (grade 1: n=42; grade 2: n=14; grade 3: n=1; grade 4: n=1). Neutropaenia was transient (single episode) in the majority (44; 75.8%) of cases but led to treatment discontinuation in 14 (24.1%) patients. Patients who developed neutropaenia were more likely to be female (p=0.01) and non-smokers (p=0.007) and had lower baseline neutrophil levels (p&lt;0.0001). Binomial regression analysis confirmed the latter (p&lt;0.0001, B: −0.491) as neutropaenia predictor. The rate of infections did not differ between patients who developed neutropaenia and those who did not (p=0.878). Conclusion: Neutropaenia was a common finding in this cohort. It was usually mild, transient and not associated with increased infection rates. Neutropaenia occurrence was associated with non-smoking, female gender and lower baseline neutrophil levels

Bringing Agriculture into the GATT: Negotiating a Framework for Action

International Relations/Trade,

Depression and anxiety in an Early Rheumatoid Arthritis inception cohort. Associations with demographic, socioeconomic and disease features

Objective: Depression and anxiety are not uncommon in Rheumatoid arthritis (RA). It is increasingly recognised that they are associated with high disease activity and worse disease outcomes. We aimed to examine the frequency of depression and anxiety in an early RA inception cohort and to explore associations with disease-related measures. Methods: The Scottish Early Rheumatoid Arthritis inception cohort recruited newly diagnosed RA patients followed-up 6-monthly. Anxiety and depression were assessed using the hospital anxiety and depression scale. Associations with demographic characteristics and disease-related measures were examined at baseline, 6 months and 12 months. Results: 848 RA patients were included. The prevalence of anxiety and depression at baseline was 19.0% and 12.2%, respectively. Depression and anxiety scores correlated with DAS28 at all time-points (all p&lt;0.0001). In multivariable linear regression, anxiety score at baseline was associated with younger age and Health Assessment Questionnaire (HAQ) score. Anxiety scores at 6 months and 12 months were associated with low body mass index (BMI), baseline anxiety score and current patient global score and HAQ. Depression score at baseline was associated with younger age, being single and HAQ, while depression scores at 6 months and 12 months were associated with male gender (only at 6 months), baseline anxiety and depression scores and current patient global score, HAQ and C-reactive protein (CRP) levels. Conclusion: Depression and anxiety are associated with disease activity, worse functional status and other variables in early RA. There is a close relationship between CRP and depression but not anxiety