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The most important goal of therapy in psoriatic arthritis (PsA) is to reach the remission state of disease. Nowadays, data on molecular players of clinical remission and effective disease inactivation are scarce: gene expression analysis could highlight markers characteristic of PsA remission state. Our aim was to analyze the gene expression profile of patients with clinically inactive (drug-induced remission) PsA versus healthy controls and PsA active state. From a cohort of 300 patients affected by PsA according to CASPAR criteria, we selected 40 patients (peripheral arthritis subset) with >1-year remission by TNFα antagonism assessed by DAPSA ≤ 4 (R) and 40 PsA with active disease state by DAPSA > 14 score (no bDMARDs ongoing) (A), and 40 healthy controls (HC) matching for mean age and gender ratio. Both PsA groups were not on corticosteroid treatment. Each condition has been profiled first using pooled RNAs from peripheral blood (biological duplicates) by Affymetrix Human GeneChip HTA 2.0. To identify a transcript as differentially expressed in both duplicates, a fold change (FC) 1.5 and p-value 0.05 has been set. Then, from the comparative list of differential expressed genes (DEGs) in R vs HC state, coding mRNAs were selected and interactions analyzed by STRING software, biological functions and annotations by Gene Onthology (GO). From these analysis, 12 genes were validated in the whole PsA cohort (R+A) and HCs, by quantitative real-time PCR (RT-qPCR) in triplicate (TaqMan chemistry, GAPDH housekeeping, 2–ΔΔCt for relative quantification, FC cutoff ±1.5 for differential analysis). The transcriptomic analysis generated 3 comparative lists of mRNAs (R vs HC= 125; R vs A= 1184; A vs HC= 378 transcripts). Then, we focused on remission state analyzing the mRNAs list R vs HC. Filtering data for coding DEGs, was made a list of 24 genes further analyzed for functions and interactions: STRING analysis created one interactions network and GO highlighted in which biological processes these DEGs are involved (Fig panels 1A, 1B). Validation analysis by rt-qPCR in the PsA cohort (R+A) and HCs confirmed the downregulation of c-FOS and the upregulation of CCDC50 (alias YMER) genes in the R vs HC conditions (pvalue= 0.004). The dysregulation of further genes in other comparisons was measured, as shown in Tab and Fig panel 1C. Observing the amount of DEGs, is evident that the drug-induced remission state is more similar to healthy condition, however this trend of “similarity” does not mean “identical”. The bioinformatic analysis showed that DEGs in the R vs HC conditions are primarily involved in biological processes related to immune system as well as correlates in an interactions network. Our molecular characterization of clinical remission revealed that effective disease inactivation appears to be molecularly-driven by two key genes, c-FOS and CCD50 (YMER), both involved in the NF-κB signalling pathway modulation. [Display omitted] Coding DEGs mis-regulated in the remission state. Differentially expressed genes (DEGs) in the Remission (R) state vs Healthy Controls (HC) analyzed for multiple-proteins interaction by STRING software V10.5 (panel A) and biological functions by Gene Set Enrichment Analysis (panel B). DEGs validations by RT-qPCR, confirmed the CCD50 and c-FOS dysregulation in the R state (panel C, RQ= Relative Quantification, t test RvsHC pvalue=0,004). DEGs by RT-qPCR. Validated differentially expressed genes (DEGs) in the remission (R) state vs healthy controls (HC) selected from the microarray analysis comparative list (FC cutoff ±1.5). Differential analysis (40 R vs 40 HC vs 40 Active) was made by FoldChange (FC) cutoff ±1.5 (overexpressed ≥ 1.5; - 1.5 ≥ downregulated). None declared GENE SYMBOLGene chip Array R vs HCRemission vs HCActive vs HCRemission vs ActiveALPL-1.7-1.11.3-1.25ANPEP-1.681.01.1-1.1BPI-1.57-1.11.27-1.5CCDC501.51.5-1.251.8CEACAM8-2.3-1.21.2-1.5CHI3L1-1.59-1.1-1.0-1.0DEFA1B-2.3-1.41.9-2.7FCAR-1.56-1.11.1-1.3FOS-1.51-2.0-1.5-1.4KLRB11.52-1-1.61.6PADI2-1.54-1.11.0-1.1TNFSF14-1.511.11.2-1.1

Psoriatic Arthritis (PsA) is a multifactorial disease, where the relative burden of genetic, epigenetic and environmental factors in clinical course and damage accrual is not yet definitively clarified. In clinical practice, there is a real need for useful candidate biomarkers in PsA diagnosis and disease progression, by exploring its underlying transcriptomic and epigenomic mechanisms. This work aims to profile the transcriptome in monozygotic (MZ) twins with psoriatic arthritis (PsA) highly concordant for clinical presentation, but discordant for the radiographic outcomes' severity. We describe i) the clinical case of two MZ twins; ii) their comparative gene expression profiling (HTA 2.0 Affymetrix) and iii) signal pathways and pathophysiological processes in which differentially expressed genes are involved (in silico analysis by the IPA software, QIAGEN). One hundred sixty-three transcripts and 36 coding genes (28 up and 8 down) were differentially expressed between twins, and in the brother with the most erosive form, the transcriptomic profiling highlights the overexpression of genes known to be involved in immunomodulatory processes and on a broad spectrum of PsA manifestations. Twins' clinical cases are still a gold mine in medical research: twin brothers are ideal experimental models in estimating the relative importance of genetic versus nongenetic components as determinants of complex phenotypes, non-Mendelian and multifactorial diseases as PsA.

To explore the potential role of circulating endothelial cells (CECs) and their progenitors (EPCs) as biomarkers of disease activity and damage accrual in patients with Behçet's syndrome (BS), by using a standardised and reliable flow cytometry protocol. CECs and EPCs were assessed in 32 BS patients and 11 gender/age/smoking habits matched healthy controls (HC). They were identified by flow cytometry as alive/nucleated/CD45-negative/CD34-bright/CD146-positive and alive/nucleated/CD45-negative/CD34-bright/CD309-positive events, respectively. In BS patients, demographic and clinical features, including disease activity (assessed by Behçet's disease current disease activity form, BDCAF) and irreversible damage accrual (by the vasculitis damage index, VDI) were recorded. Uni- and multivariate analysis were performed to compare the CECs and EPCs concentrations in BS vs HC and to identify potential associations with demographic or clinical features. The CECs concentration was significantly higher in the BS patients than HCs [median (IQR) 15.0 (7.5-23.0) vs 6.0 (2.0-13.0) CECs/mL, p=0.024]. In BS patients, no significant associations were found between CECs and demographic features, present and past clinical manifestations, BDCAF score and ongoing treatment. A significant association was observed between CECs and organ damage, as assessed by the VDI (rho 0.356, p=0.045). Higher levels of CECs were especially associated with vascular damage [median (IQR) 23.0 (14.0-47.0) vs 13.0 (6.0-19.0) CECs/mL, p=0.011], including arterial aneurysm and stenosis, complicated venous thrombosis, cerebrovascular accident. The concentration of EPCs did not significantly differ between the BS and HC [median 26.5 (13.0-46.0) vs 19.0 (4.0-42.0) EPCs/mL, p=0.316] and no significant associations were observed between their levels and any clinical characteristic. Our study suggests that the CECs concentration is significantly higher in BS than healthy subjects, and it mainly correlates with vascular damage. A longitudinal extension of the present study on a wider cohort would be useful to validate the potential role of CECs as a marker or, hopefully, predictor of vascular damage in BS.

The authors developed an agent-based model in which household agents can choose between two behavioral strategies that offer different levels of protection against environmentally mediated disease transmission. One behavioral strategy is initially set as more protective, leading households to adopt it widely, but its efficacy is sensitive to variable weather conditions and stressors such as floods or droughts that modify the disease transmission system. The efficacy of the second strategy is initially moderate relative to the first and is insensitive to environmental changes. The authors examined how social cohesion (defined as the average number of household social network connections) influences health outcomes when households attempt to identify an optimal strategy by copying the behaviors of socially connected neighbours who seem to have adapted successfully in the past. In the face of uncertainty in predicting future environmental stressors due to climate change, strategies to improve effective adaptation to optimal disease prevention strategies should balance between intervention efforts that promote protective behaviours based on current scientific understanding and the need to guard against the crystallization of inflexible norms. Developing generalizable models allows us to integrate a wide range of theories and multiple datasets pertaining to the relationship between social mechanisms and adaptation, which can provide further understanding of future climate change impacts. Models such as the one the authors present can generate hypotheses about the mechanisms that underlie the dynamics of adaptation events and suggest specific points of measurement to assess the impact of these mechanisms. They can be incorporated as modules within predictive simulations for specific socio-ecological contexts. (6 Figures, 48 References)

BackgroundRA patients suffer of a life expectancy significantly reduced with respect to the general population mainly due to cardiovascular (CV) disease. Endothelial dysfunction (ED), the early step in atherosclerotic process, is more evident in RA than in the general population. Peripheral arterial tonometry (PAT), a simple, rapid, and objective tool for evaluation of ED, measures small digital artery reactive hyperaemia after an ischemic stimulus in forearm. PAT shows high grade of correlation with coronary ED and predicts future CV events in the general population.ObjectivesTo define prevalence and determinants of peripheral ED in RA.MethodsData from 633 RA patients free of previous CV events prospectivelly enrolled in the EDRA study* (ClinicalTrials.gov: NCT02341066) were analysed. Reactive hyperemia index (LnRHI) was evaluated by PAT using the EndoPAT2000 device: ED was defined by LnRHI <0.51. Linear and logistic regression analysis were performed to define independent predictors of ED in RA patients. A p-value <0.05 was considered statistically significant.ResultsPeripheral ED was documented in 212 out of 633 RA patients (33.3%). A linear regression for multiple variables (stepwise method) performed including into the models variables showing significant association with LnRHI at the univariate regression analysis (systolic blood pressure, HDL cholesterol levels, triglycerides levels, smoking habit and ACPA positivity; Age and gender were forced) showed that only higher levels of triglycerides [B coefficient (95%IC) = -0,001 (-0,001–0,00); p<0.05] negativity for ACPA [B coefficient (95%IC) = -0,070 (-0,135–0,005); p<0.05] and smoking habit [B coefficient (95%IC) =0,01 (0,043–0,156); p<0.05] were independently related to lower values of LnRHI. No significant correlation between peripheral ED and RA activity (DAS-28, CDAI, SDAI, HAQ), burden of systemic inflammation (CRP, ESR) and type of immunosuppressive treatment (steroids, NSAIDs, DMARDs and bDMARDs) was found. At logistic regression analysis ACPA negativity [OR ((95%IC) = 1.57 (1.04–2.21); p<0.05] and smoking habit [OR ((95%IC) = 1.64 (1.06–2.53); p<0.05] indipendently conferred a major risk of peripheral ED.ConclusionsThis study demonstrates for the first time a very high prevalence of peripheral ED in patient with RA free of previous CV events. Triglycerides levels and smoking habit, among traditional cardiovascular risk factor, showed a significant correlation with lower peripheral ED. Surprisingly ACPA negativity confers an increased risk for ED in RA population. Moreover, other than expected, systemic inflammation does not appear to influence peripheral ED in RA population. In conclusion our data further support the notion that atherogenesis in RA is only partially driven by traditional CV factors. The negative association between ACPA and ED warrants further investigation.Acknowledgements*The EDRA study is a project funded by Italian Ministry of Health and by Regione Sardegna (RAS) (GR-2011–02352816; Ricerca Finalizzata 2011).Disclosure of InterestNone declared

A bstract It has been shown that a special set of three-point amplitudes between two massive spinning states and a graviton reproduces the linearised stress-energy tensor for a Kerr black hole in the classical limit. In this work we revisit this result and compare it to the analysis of the amplitudes describing the interaction of leading Regge states of the open and closed superstring. We find an all-spin result for the classical limit of two massive spinning states interacting with a photon or graviton. This result differs from Kerr and instead matches the current four-vector and the stress-energy tensor generated by a classical string coupled to electromagnetism and gravity respectively. For the superstring amplitudes, contrary to the black-hole case, we find that the spin to infinity limit is necessary to reproduce the classical spin multipoles.

A bstract Quantum higher-spin theory applied to Compton amplitudes has proven to be surprisingly useful for elucidating Kerr black hole dynamics. Here we apply the framework to compute scattering amplitudes and observables for a binary system of two rotating black holes, at second post-Minkowskian order, and to all orders in the spin-multipole expansion for certain quantities. Starting from the established three-point and conjectured Compton quantum amplitudes, the infinite-spin limit gives classical amplitudes that serve as building blocks that we feed into the unitarity method to construct the 2-to-2 one-loop amplitude. We give scalar box, vector box, and scalar triangle coefficients to all orders in spin, where the latter are expressed in terms of Bessel-like functions. Using the Kosower-Maybee-O’Connell formalism, the classical 2PM impulse is computed, and in parallel we work out the scattering angle and eikonal phase. We give novel all-order-in-spin formulae for certain contributions, and the remaining ones are given up to O S 11 . Since Kerr 2PM dynamics beyond O S ≥ 5 is as of yet not completely settled, this work serves as a useful reference for future studies.

Background. Previous reports suggest that community-acquired pneumonia (CAP) is associated with an enhanced risk of cardiovascular complications. However, a contemporary and comprehensive characterization of this association is lacking. Methods. In this multicenter study, 1182 patients hospitalized for CAP were prospectively followed for up to 30 days after their hospitalization for this infection. Study endpoints included myocardial infarction, new or worsening heart failure, atrial fibrillation, stroke, deep venous thrombosis, cardiovascular death, and total mortality. Results. Three hundred eighty (32.2%) patients experienced intrahospital cardiovascular events (CVEs) including 281 (23.8%) with heart failure, 109 (9.2%) with atrial fibrillation, 89 (8%) with myocardial infarction, 11 (0.9%) with ischemic stroke, and 1 (0.1%) with deep venous thrombosis; 28 patients (2.4%) died for cardiovascular causes. Multivariable Cox regression analysis showed that intrahospital Pneumonia Severity Index (PSI) class (hazard ratio [HR], 2.45, P = .027; HR, 4.23, P < .001; HR, 5.96, P < .001, for classes III, IV, and V vs II, respectively), age (HR, 1.02, P = .001), and preexisting heart failure (HR, 1.85, P < .001) independently predicted CVEs. One hundred three (8.7%) patients died by day 30 postadmission. Thirty-day mortality was significantly higher in patients who developed CVEs compared with those who did not (17.6% vs 4.5%, P < .001). Multivariable Cox regression analysis showed that intrahospital CVEs (HR, 5.49, P < .001) independently predicted 30-day mortality (after adjustment for age, PSI score, and preexisting comorbid conditions). Conclusions. CVEs, mainly those confined to the heart, complicate the course of almost one-third of patients hospitalized for CAP. More importantly, the occurrence of CVEs is associated with a 5-fold increase in CAP-associated 30-day mortality.

Opioid receptors are found throughout the gastrointestinal tract, including the large intestine. Many patients treated with opioids experience opioid-induced constipation (OIC). Laxatives are not effective in most patients, and in those who do initially respond, the efficacy of laxatives generally diminishes over time. In addition, OIC does not spontaneously resolve for most patients. However, complications of opioids extend far beyond simply slowing gastrointestinal transit. Opioid use can affect intestinal permeability through a variety of mechanisms. Toll-like receptors are a crucial component of innate immunity and are tightly regulated within the gut epithelium. Pathologic µ-opioid receptor (MOR) and toll-like receptor signaling, resulting from chronic opioid exposure, disrupts intestinal permeability leading to potentially harmful bacterial translocation, elevated levels of bacterial toxins, immune activation, and increased cytokine production. Peripherally active MOR antagonists, including methylnaltrexone, are effective at treating OIC. Benefits extend beyond simply blocking the MOR; these agents also act to ameliorate opioid-induced disrupted intestinal permeability. In this review, we briefly describe the physiology of the gastrointestinal epithelial border and discuss the impact of opioids on gastrointestinal function. Finally, we consider the use of peripherally active MOR antagonists to treat disrupted intestinal permeability resulting from opioid use and discuss the potential for improved morbidity and mortality in patients treated with methylnaltrexone for opioid-induced bowel disorders.

A bstract We develop massive higher-spin theory as a framework for describing dynamics of rotating compact objects, such as Kerr black holes. In this paper, we explore gauge interactions up to quartic order and corresponding Compton amplitudes of higher-spin massive objects coupled to electromagnetism and Yang-Mills theory. Their classical counterparts are known as root-Kerr gauge-theory solutions, whose amplitudes are closely related to those of Kerr black holes. We use three distinct approaches: (i) massive higher-spin gauge symmetry to introduce cubic interactions for all spins and the quartic interactions up to spin 3, which is implemented both off shell and via Ward identities; (ii) a chiral higher-spin approach to construct quartic Lagrangians with correct degrees of freedom to all spins; (iii) on-shell functional patterns before and after taking the classical limit to constrain the Compton amplitudes. As final results, we arrive at simple local formulae for the candidate root-Kerr Compton amplitudes both in the quantum regime and classical limit, to all orders in spin. This is a precursor to the gravitational Kerr case, which is presented in a follow-up paper.