Baricitinib therapy response in rheumatoid arthritis patients associates to STAT1 phosphorylation in monocytes

Baricitinib is a Janus kinase (JAK) 1 and 2 inhibitor approved for treating rheumatoid arthritis (RA). The JAK/STAT system is essential in the intracellular signaling of different cytokines and in the activation process of the monocyte lineage. This study verifies the effects of baricitinib on STAT phosphorylation in monocytes of RA patients and evaluates the correlation between STAT phosphorylation and response to therapy. We evaluated the disease activity of patients (DAS28CRP) at baseline (T0) and after 4 and 12 weeks (T1-T3) of treatment with baricitinib, dividing them into responders (n = 7) and non-responders (n = 7) based on the reduction of DAS28CRP between T0 and T1 of at least 1.2 points. Through flow cytometry, STAT1 phosphorylation was analyzed at T0/T1/T3 in monocytes, at basal conditions and after IL2, IFN alpha, and IL6 stimulation. We showed that monocyte frequency decreased from T0 to T1 only in responders. Regarding the phosphorylation of STAT1, we observed a tendency for higher basal pSTAT1 in monocytes of non-responder patients and, after 4 weeks, a significant reduction of cytokine-induced pSTAT1 in monocytes of responders compared with non-responders. The single IFN alpha stimulation only partially recapitulated the differences in STAT1 phosphorylation between the two patient subgroups. Finally, responders showed an increased IFN signature at baseline compared with non-responders. These results may suggest that monocyte frequency and STAT1 phosphorylation in circulating monocytes could represent early markers of response to baricitinib therapy

ps1 15 expression of adhesion molecules cd44v3 and cd44v6 on t cells in sle patients correlation with clinical phenotype and disease activity

Background Adhesion molecule CD44 enables T lymphocytes' adhesion to endothelium and during inflammation contributes to T cell migration into target organs. CD44 isoforms seem to be involved in the infiltration of peripheral tissues in SLE. A higher expression of CD44v3 and v6 has been observed on T cells from SLE patients compared to healthy subjects (HS) and the expression levels seem to correlate with disease activity. The aim of this study was to investigate the expression of the CD44v3/v6 isoforms on T cells of SLE patients to evaluate their correlation with disease activity and disease phenotypes. Patients and methods 33 female patients (mean age ±SD 45.7±12.3 years, mean disease duration ±SD 14±7.8 years) affected by SLE according to the 1997 ACR criteria, were enrolled. Disease activity was evaluated by SLEDAI-2K. 15 patients were in remission (SLEDAI-2k=0), and 18 patients had an active disease (SLEDAI-2K=4 or higher). 16 HS (mean age ±SD 33.3±12.0 years) were also recruited. Expression of CD44v3/v6 was determined by flow cytometry analysis. Results Expression of CD44v3 on CD4 +T cells and on CD8 +T cells was higher in active patients compared to HS (p=0.0097 and p=0.0096). CD44v3 on CD8 +T cells was also higher in active patients compared to patients in remission (p=0.038). CD44v6 was higher on CD4 +and CD8+T cells from active patients compared to HS (p=0.003 and p=0.0036) and compared to patients in remission (p=0.01 and p=0.02) Fig.1. In active patients the ratio CD44v3/v6 was unbalanced towards isoform v6 on both T cell populations. When using a ROC curve analysis, comparing HS and SLE patients, CD44v6 on CD4 +T cells was the most sensible and specific one (specificity of 81.8%, sensitivity of 75%). Expression of CD44v6 on CD4 +and CD8+T cells correlated with the SLEDAI-2k (p=0.03, r=0.38 and p=0.02, r=0.39). The expression of CD44v6 and of CD44v3 on CD8 +T cells is associated with renal involvement and arthritis respectively (p Conclusions CD44v3 and v6 expression is significantly associated with different degree of disease activity and with different disease manifestations. Isoform v6 on CD4 +T cells could be useful as a disease biomarker

Sensory theories of developmental dyslexia: three challenges for research.

Recent years have seen the publication of a range of new theories suggesting that the basis of dyslexia might be sensory dysfunction. In this Opinion article, the evidence for and against several prominent sensory theories of dyslexia is closely scrutinized. Contrary to the causal claims being made, my analysis suggests that many proposed sensory deficits might result from the effects of reduced reading experience on the dyslexic brain. I therefore suggest that longitudinal studies of sensory processing, beginning in infancy, are required to successfully identify the neural basis of developmental dyslexia. Such studies could have a powerful impact on remediation.This is the accepted manuscript. The final version is available from NPG at http://www.nature.com/nrn/journal/v16/n1/abs/nrn3836.html

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Planck 2015 results I. Overview of products and scientific results

The European Space Agency's Planck satellite, which is dedicated to studying the early Universe and its subsequent evolution, was launched on 14 May 2009. It scanned the microwave and submillimetre sky continuously between 12 August 2009 and 23 October 2013. In February 2015, ESA and the Planck Collaboration released the second set of cosmology products based on data from the entire Planck mission, including both temperature and polarization, along with a set of scientific and technical papers and a web-based explanatory supplement. This paper gives an overview of the main characteristics of the data and the data products in the release, as well as the associated cosmological and astrophysical science results and papers. The data products include maps of the cosmic microwave background (CMB), the thermal Sunyaev-Zeldovich effect, diffuse foregrounds in temperature and polarization, catalogues of compact Galactic and extragalactic sources (including separate catalogues of Sunyaev-Zeldovich clusters and Galactic cold clumps), and extensive simulations of signals and noise used in assessing uncertainties and the performance of the analysis methods. The likelihood code used to assess cosmological models against the Planck data is described, along with a CMB lensing likelihood. Scientific results include cosmological parameters derived from CMB power spectra, gravitational lensing, and cluster counts, as well as constraints on inflation, non-Gaussianity, primordial magnetic fields, dark energy, and modified gravity, and new results on low-frequency Galactic foregrounds

Immunogenicity of anti-tumour necrosis factor drugs in rheumatic diseases.

Despite the significant advantages in clinical practice associated with TNFinhibitors, a loss of response over time is sometimes observed, in some cases possibly due to immunogenicity, i.e. the development of antibodies direct against the drug. This review evaluates the immunogenicity of different antiTNF agents, and discusses its effects on efficacy and safety. Available evidence indicates that all anti-TNF drugs may induce an immune response. However, the variation in the occurrence of antidrug antibodies, as well as the variation in the impact of antibodies on the efficacy and safety, can be explained by drug conformation itself, use of concomitant immunosuppressants and differences in dosing regimen and route of administration. The association between the development of anti-drug antibodies and low drug serum concentrations is clinically relevant since it is likely related to low response. Strict monitoring of neutralising antibodies might be useful for tailoring therapeutic strategy. There is no evidence of cross-reactivity among different drugs: immunogenicity (the development of specific anti-drug antibodies to one TNF inhibitor) does not seem to affect the effectiveness of another anti-TNF agents; therefore, switching to another drug of the same class might be effective in patients who have developed anti-drug antibodies to a TNF inhibitor