Extra-Articular Symptoms in Constellation with Selected Serum Cytokines and Disease Activity in Spondyloarthritis

Objectives. In this study, we assessed the extra-articular symptoms in constellation with selected serum cytokines and disease activity in spondyloarthritis (SpA). Patients and Methods. We studied 287 SpA patients: 131 had AS, 110 had PsA, and 46 had SAPHO. We assessed extra-articular symptoms in all cases. In 191 SpA patients, we measured serum interleukin-6 (IL-6), interleukin-18 (IL-18), interleukin-23 (IL-23), endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). Results. Patients with acute anterior uveitis (AAU) had higher VAS (P=0.0008), BADSDAI (P=0.0001), ASDAS-ESR (P=0.04), CRP (P=0.006), IL-6 (P=0.02), and IL-18 (P=0.03) levels. Patients with inflammatory bowel disease (IBD) had higher VAS (P=0.03), CRP (P=0.0009), and IL-6 (P=0.0003) levels. Patients with skin psoriasis had lower VAS (P=0.001) and BASDAI (P=0.00007) levels. Patients with psoriatic onycholysis had lower VAS (P=0.006), BASDAI (P=0.00001), and CRP (P=0.02) and higher IL-23 (P=0.04) levels. Patients with PPP had lower BASDAI (P=0.04) and higher ET-1 (P=0.001) levels. Conclusions. SpA patients with increased serum IL-18 and decreased serum ET-1 had an increased risk of extra-articular symptoms. In SpA patients, increased disease activity was associated with an increased risk of AAU and IBD and a decreased risk of skin psoriasis, psoriatic onycholysis, and PPP

Evaluation of Xa inhibitors as potential inhibitors of the SARS-CoV-2 Mpro protease

Based on previous large-scale in silico screening several factor Xa inhibitors were proposed to potentially inhibit SARS-CoV-2 $M^{pro}$. In addition to their known anticoagulants activity this potential inhibition could have an additional therapeutic effect on patients with COVID-19 disease. In this study we examined the binding of the Apixaban, Betrixaban and Rivaroxaban to the SARS-CoV-2 $M^{pro}$ with the use of the MicroScale Thermophoresis technique. Our results indicate that the experimentally measured binding affinity is weak and the therapeutic effect due to the SARS-CoV-2 $M^{pro}$ inhibition is rather negligible

Long-term amorphous drug stability predictions using easily calculated, predicted, and measured parameters

The purpose of this study was to develop a predictive model of the amorphous stability of drugs with particular relevance for poorly water-soluble compounds. Twenty-five representative neutral poorly soluble compounds with a diverse range of physicochemical properties and chemical structures were systematically selected from an extensive library of marketed drug products. The physical stability of the amorphous form, measured over a 6 month period by the onset of crystallization of amorphous films prepared by melting and quench-cooling, was assessed using polarized light microscopy. The data were used as a response variable in a statistical model with calculated/predicted or measured molecular, thermodynamic, and kinetic parameters as explanatory variables. Several multiple linear regression models were derived, with varying balance between calculated/predicted and measured parameters. It was shown that inclusion of measured parameters significantly improves the predictive ability of the model. The best model demonstrated a prediction accuracy of 82% and included the following as parameters: melting and glass transition temperatures, enthalpy of fusion, configurational free energy, relaxation time, number of hydrogen bond donors, lipophilicity, and the ratio of carbon to heteroatoms. Good predictions were also obtained with a simpler model, which was comprised of easily acquired quantities: molecular weight and enthalpy of fusion. Statistical models are proposed to predict long-term amorphous drug stability. The models include readily accessible parameters, which are potentially the key factors influencing amorphous stability. The derived models can support faster decision making in drug formulation development

Association of distinct fine specificities of anti-citrullinated peptide antibodies with elevated immune responses to Prevotella intermedia in a subgroup of patients with rheumatoid arthritis and periodontitis

Objective In addition to the long-established link with smoking, periodontitis (PD) is also a risk factor for rheumatoid arthritis (RA). To elucidate the mechanism by which PD could induce antibodies to citrullinated peptides (ACPA), we examine the antibody response to a novel citrullinated peptide from cytokeratin type I 13 identified in gingival crevicular fluid (GCF), and compare the response to 4 other citrullinated peptides in patients with RA, well-characterized for PD and smoking. Methods The citrullinomes of GCF and periodontal tissue from people with PD were mapped by mass spectrometry. Antibodies to citrullinated peptides from cytokeratin type I 13 (cCK13), tenascin-C (cTNC5), vimentin (cVIM), enolase (CEP-1) and fibrinogen β (cFIBβ) were examined by ELISA in patients with RA (n=287) and osteoarthritis (OA) (n=330), and cross-reactivity assessed by inhibition assays. Results A novel citrullinated peptide cCK13-1 (444TSNASGR-cit-TSDV-cit-RP458) identified in GCF, exhibited elevated antibody responses in RA patients (24%). Anti-cCK13-1 antibodies correlated with anti-cTNC5 antibodies, and absorption experiments confirmed this was not due to cross-reactivity. Only anti-cCK13-1 and anti-cTNC5 were associated with antibodies to the periodontal pathogen Prevotella intermedia (p=0.05 and p =0.001 respectively), but not with antibodies to Porphyromonas gingivalis arginine gingipains. Antibodies to CEP-1, cFIBβ and cVIM correlated with each other, and with smoking and shared epitope risk factors in RA. Conclusion This study identifies two groups of ACPA fine specificities associated with different RA risk factors; one predominantly linked to smoking and shared epitope, the other linking anti- cTNC5 and cCK13-1 to infection with the periodontal pathogen P. intermedia

First, do no harm - Missing data treatment to support lake ecological condition assessment

Indicators of ecological condition status of water bodies associated with field measurements are often subject to data gaps. This obstacle can often lead to abandonment of assessment. Furthermore, it can lead to the use of methods, based merely on their availability. In response to these challenges, a systematic approach for expert-analyst interaction for missing data treatment is proposed. A combination of algorithms with hierarchical clustering of results is used. A particular emphasis is put on the preparation and interpretation of input data and the role of an expert in the workflow. The proposed approach enhances the decision-making process by improving communication and transparency throughout interactions between experts, analysts and decision makers. Future research should focus on assessing the scale of the ecological data drift phenomenon, which, based on the observed climate change, anthropological pressure and biodiversity loss, may impact the broad concept of indicator construction for lake water ecological assessmen

Nivolumab for relapsed/refractory classical Hodgkin lymphoma after brentuximab vedotin failure – Polish Lymphoma Research Group real-life experience

AimPolish centers analyzed retrospectively the real-life experience with nivolumab in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) patients, after brentuximab vedotin (BV ) failure. BackgroundDespite the effective frontline treatment, for cHL patients relapsing after autologous stem cell transplantation, the only effective strategy remains the novel agents. Nivolumab, a checkpoint inhibitor, demonstrates the clinical benefit with an acceptable safety profile. Materials and methodsRetrospective analysis included 16 adult patients with R/R cHL after BV failure. All patients received single-agent nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. ResultsAfter six cycles of nivolumab the overall response rate was 81% (complete remission rate of 56%, partial remission rate of 25%). The median PFS was not reached after a median follow-up of 19 months. Adverse events (AEs) of any grade occurred in 12 patients (75%), including grade 3 AEs observed in 5 patients (31%). There were no AEs of grade 4 or 5. After a median of 25 nivolumab doses, 62% of responding patients proceeded to allogeneic stem cell transplantation. ConclusionNivolumab monotherapy demonstrated a high efficacy and safety in R/R cHL patients after BV failure. More patients and longer follow-up may further establish the potential benefit