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On-orbit servicing and active debris removal missions will rely on the use of unmanned satellite equipped with a manipulator. Capture of the target object will be the most challenging phase of these missions. During the capture manoeuvre, the manipulator must avoid collisions with elements of the target object (e.g., solar panels). The dynamic equations of the satellite-manipulator system must be used during the trajectory planning because the motion of the manipulator influences the position and orientation of the satellite. In this paper, we propose application of the bidirectional rapidly exploring random trees (BiRRT) algorithm for planning a collision-free trajectory of a manipulator mounted on a free-floating satellite. A new approach based on pseudo-velocities method (PVM) is used for construction of nodes of the trajectory tree. Initial nodes of the second tree are selected from the set of potential final configurations of the system. The proposed method is validated in numerical simulations performed for a planar case (3-DoF manipulator). The obtained results are compared with the results obtained with two other trajectory planning methods based on the RRT algorithm. It is shown that in a simple test scenario, the proposed BiRRT PVM algorithm results in a lower manipulator tip position error. In a more difficult test scenario, only the proposed method was able to find a solution. Practical applicability of the BiRRT PVM method is demonstrated in experiments performed on a planar air-bearing microgravity simulator where the trajectory is realised by a manipulator mounted on a mock-up of the free-floating servicing satellite.

Objective To assess the association of genetic polymorphisms of signal transducer and activator of transcription (STAT) 4 with thrombotic manifestations in patients with autoimmune diseases, including antiphospholipid syndrome (APS).Methods A group of 395 adult, non-related patients (331 women and 64 men) with autoimmune diseases and 150 healthy control subjects were genotyped for 4 STAT4 single-nucleotide polymorphisms (SNPs): rs7574865, rs10181656, rs7582694 and rs11684030. The risk alleles associations with antiphospholipid antibodies (APLA) and the occurrence of thrombotic events were then analysed in the group of patients.Results Among 395 patients almost half were diagnosed with APS: 97 with primary (PAPS) and 83 with secondary (SAPS). Differences in frequencies of the risk alleles for the following 3 SNPs: G/C rs7582694, rs10181656 C/G, and rs7574865 G/T were stronger associated with APS than with systemic lupus erythematosus or other autoimmune diseases. All 3 SNPs were associated with prothrombotic, triple positive APLA profile: OR = 1.68 (1.04 to 2.70, 95% CI), p = 0.032; OR = 1.61 (1.1 to 2.59, 95% CI), p = 0.048; and OR = 1.61 (1.0 to 2.59, 95% CI), p = 0.048; respectively. The association of the 2 STAT4 risk alleles, i.e., SNP rs7582694 (C) and rs10181656 (G) was stronger for venous thromboembolism: OR = 1.6 (1.1 to 2.5, 95% CI), p = 0.03 and OR = 1.5 (1.1 to 2.5, 95% CI), p = 0.02; respectively.Conclusions SNPs in the STAT4 gene, i.e., rs7582694(C), rs1018165(G), and rs7574865(T) are associated with venous thromboembolic events in autoimmune disease patients, therefore they might identify subjects at risk of venous thromboembolism.

OBJECTIVES: The study aimed to characterise the Polish population of (ANCA)-associated vasculitides (AAV) with respiratory involvement (RI), in comparison to the subgroup without lung manifestations and the other cohorts. METHODS: Retrospective analysis of the Polish population of AAV with RI was conducted, based on data from the POLVAS registry. Standard descriptive statistics, χ2 test, and Mann-Whitney U test were used to perform comparisons. RESULTS: Among 461 cases qualified to this study, there were 316 cases with RI (68.5%), 206 with granulomatosis with polyangiitis (GPA) (65.2%), 80 with eosinophilic granulomatosis with polyangiitis (EGPA) (25.3%) and 30 with microscopic polyangiitis (MPA) (9.5%). Proportion of RI in GPA, MPA, and EGPA accounted for 67.8%; 40.0%; 97.6%, respectively. The number of relapses was higher in the RI group (median 1.0 vs. 0.0; p=0.01). In the subgroup of combined GPA and MPA with RI, the trends toward higher proportion of deaths (11.7% vs. 5.7%; p=0.07), relapses requiring hospitalisation (52.2% vs. 42.4%, p=0.07) and relapses requiring admission to the intensive care unit (5.6% vs. 1.4%, p=0.09) were observed, median maximal concentration of CRP was higher (46 vs. 25 mg/l; p=0.01) and more aggressive treatment was administered. CONCLUSIONS: Prevalence of RI in the Polish population of AAV is similar to the values reported in the literature, however, the proportion observed in GPA is closer to those presented in Asian than Western European cohorts. RI seems to be associated with a more severe course of disease and its presence prompts more aggressive treatment.

BACKGROUND: Diagnosis of antiphospholipid syndrome (APS) requires persistent presence of lupus anticoagulant (LAC), anticardiolipin (aCL) IgG/IgM, or anti-β2 glycoprotein I (aβ2GPI) IgG/IgM antibodies. Other antiphospholipid antibodies (aPL) such as antiphosphatidylserine/prothrombin antibodies (aPS/PT) are promising in assessment of thrombotic APS (TAPS).AIM: To evaluate the added value of aPS/PT IgG and IgM in TAPS.MATERIAL AND METHODS: aPS/PT IgG/IgM, aCL IgG/IgM, aβ2GPI IgG/IgM, and LAC were determined in 757 patients (TAPS and controls). aPS/PT cut-off values were calculated, aPS/PT titers and positivity were compared between TAPS and controls, type of thrombosis, and antibody profiles. Likelihood ratios (LR), odds ratios (OR) and aPL-score were determined.RESULTS: aPS/PT IgG and IgM were associated with TAPS and triple positivity. In-house calculated cut-offs were higher for IgM (43 units), compared to manufacturer's cut-off (30 units). Thresholds of 90 (IgG)/200 (IgM) units were determined as high-titer cut-off. Higher aPS/PT titers were observed in triple positive patients and showed higher LR and OR for TAPS. aPS/PT was independently associated with TAPS when adjusted for aCL/aβ2GPI, but not when adjusted for LAC. In isolated LAC positive patients, aPS/PT was positive in 27.1% TAPS patients and in 77.3% patients with autoimmune disease. Diagnostic value of aPL-score did not differ with and without including aPS/PT.CONCLUSION: aPS/PT positivity, especially with high antibody titer, is associated with TAPS diagnosis. Analysis on top of current laboratory criteria is not essential in TAPS diagnosis, but aPS/PT could be useful in patients with thrombosis and a double positive aPL profile (aCL+/aβ2GPI+).

Background: Although estimates of suboptimal adherence to oral corticosteroids in asthma range from 30% to 50%, no ideal method for measurement exists; the impact of poor adherence in severe asthma is likely to be particularly high. Research Questions: What is the prevalence of suboptimal adherence detected by self-reporting and direct measures? Is suboptimal adherence associated with disease activity? Study Design and Methods: Data were included from individuals with severe asthma taking part in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) study and prescribed daily oral corticosteroids. Participants completed the Medication Adherence Report Scale, a five-item questionnaire used to grade adherence on a scale from 1 to 5, and provided a urine sample for analysis of prednisolone and metabolites by liquid chromatography-mass spectrometry. Results: Data from 166 participants were included in this study: mean (SD) age, 54.2 (± 11.9) years; FEV 1, 65.1% (± 20.5%) predicted; female, 58%; 37% completing the Medication Adherence Report Scale reported suboptimal adherence; and 43% with urinary corticosteroid data did not have detectable prednisolone or metabolites in their urine. Good adherence by both methods was detected in 49 of the 142 (35%) of participants in whom both methods were performed; adherence detection did not match between methods in 53%. Self-reported high adherers had better asthma control and quality of life, whereas directly measured high adherers had lower blood eosinophil levels. Interpretation: Low adherence is a common problem in severe asthma, whether measured directly or self-reported. We report poor agreement between the two methods, suggesting some disassociation between self-assessment of medication adherence and regular oral corticosteroid use, which suggests that each approach may provide complementary information in clinical practice.

Airway inflammation in asthma is accompanied by reconstruction of the bronchial wall extracellular matrix that most likely occurs with a contribution of matrix metalloproteinases (MMPs). Recently we have reported that omalizumab may decrease reticular basement membrane (RBM) thickness together with fibronectin deposits in asthmatic airways, although mechanisms involved are unknown.In the present study, we have investigated the impact of omalizumab on MMPs concentrations in bronchoalveolar lavage fluid (BAL) of asthmatic subjects in relation to airway remodeling changes in histology.The study group consisted of 13 severe allergic asthmatics treated with omalizumab for at least 12 months. In each subject, clinical and laboratory parameters, bronchoscopy with BAL, and endobronchial biopsy were evaluated before and after the biologic therapy. RBM thickness, fibronectin, and collagen deposits in bronchial mucosa specimens were analyzed in histology. The investigations also included BAL cytology and BAL concentrations of MMP-2, -3, and -9.Omalizumab was related to a decrease in all measured MMPs in BAL (Our data suggest that omalizumab therapy is associated with decreased BAL MMPs concentration in the subgroup of asthma patients. The decline was linked with a reduction in the RBM thickness what might play a beneficial role in airway remodeling.

In this document, the Group for Haemostasis of the Polish Society of Haematology and Transfusion Medicine presents the guidelines for the use of emicizumab. Emicizumab (Hemlibra®, F. Hoffmann — La Roche, Basel, Switzerland) has been licensed for use in the European Union in 2018. In Poland, this medicinal product has been available for patients with congenital hemophilia A and inhibitors against factor VIII since March 2020. This paper is a supplement to the 2017 guidelines for management of patients with haemophilia A and B and inhibitors against factor VIII or IX.

Introduction Patients with systemic sclerosis experience endothelial dysfunction and damage even in the absence of clinical manifestations. Aim To evaluate various methods for assessing the endothelial function for their applicability to clinical practice. Material and methods Forty-two patients (7 men and 35 women) with systemic sclerosis and 36 controls (11 men and 25 women) matched for age, sex, body mass index, smoking habit, and comorbidities were enrolled in the study. We assessed each participant for typical risk factors for cardiovascular diseases and measured serum levels of vascular cell adhesion molecule-1 (VCAM-1) and thrombomodulin together with flow-mediated dilatation (FMD) of the brachial artery and intima-media thickness (IMT) of the common carotid artery using ultrasonography. Results Patients with systemic sclerosis did not differ from controls in serum levels of VCAM-1 and thrombomodulin, however, the statistical analysis with adjustment for potential confounders revealed increased levels of thrombomodulin in the patients (p = 0.03). They also had a 45% lower relative increase of FMD (FMD%), and 13% higher IMT (p < 0.01, both, also after adjustment for potential confounders). In a simple regression model, lower FMD% was determined by age (β = –0.57, 95% confidence interval (CI): –0.72 to –0.43) and C-reactive protein levels (β = –0.38, 95% CI: –0.55 to –0.22). Thicker IMT was related to age (β = 0.64, 95% CI: 0.52–0.67), glomerular filtration rate (β = –0.34, 95% CI: –0.5 to –0.18), and blood thrombomodulin levels (β = 0.45, 95% CI: 0.13–0.76). Conclusions Patients with systemic sclerosis present with endothelial dysfunction which may be detected using ultrasonographic methods. The exact mechanism of observed abnormalities is unknown, but it is possibly related to the chronic inflammation and ischemia-reperfusion injury.

Inherited thrombocytopenias (IT) comprise a highly heterogeneous group of rare haemostatic disorders which vary in terms of degree of thrombocytopenia, platelet size, pattern of inheritance and clinical course. Due to difficult diagnosis and frequently mild clinical phenotype these disorders are often underdiagnosed. The purpose of this review is to provide clinical and laboratory characteristics of the most important types of IT. The currently available therapeutic options for these conditions are also recapitulated and discussed.

Background Anticardiolipin (aCL) and anti-β2 glycoprotein I (aβ2GPI) immunoglobulin A (IgA) antiphospholipid antibodies (aPL) have shown to associate with thrombosis and pregnancy morbidity. However, inclusion of IgA aPL in the classification criteria of the antiphospholipid syndrome (APS) has been debated. We investigated the value of aCL and aβ2GPI IgA aPL in the detection of thrombosis and pregnancy morbidity in addition to the current aPL panel for APS. Methods We included 1,068 patients from eight European medical centers: 259 thrombotic APS patients, 122 obstetric APS patients, 204 non-APS thrombosis patients, 33 non-APS obstetric patients, 60 APS patients with unspecified clinical manifestations, 196 patients with autoimmune diseases, and 194 controls. aCL and aβ2GPI IgG/M/A were detected with four commercial assays and lupus anticoagulant was determined by the local center. Results Positivity for IgA aPL was found in 17 to 26% of the patients with clinical manifestations of APS and in 6 to 13% of the control population. Both aCL and aβ2GPI IgA were significantly associated with thrombosis and pregnancy morbidity. Isolated IgA positivity was rare in patients with clinical manifestations of APS (0.3–5%) and not associated with thrombosis and/or pregnancy morbidity. Addition of IgA to the current criterion panel did not increase odds ratios for thrombosis nor pregnancy morbidity. Conclusion aCL and aβ2GPI IgA are associated with clinical manifestations of APS. However, isolated IgA positivity was rare and not associated with thrombosis or pregnancy morbidity. These data do not support testing for aCL and aβ2GPI IgA subsequent to conventional aPL assays in identifying patients with thrombosis or pregnancy morbidity.

Background Classification of the antiphospholipid syndrome (APS) relies predominantly on detecting antiphospholipid antibodies (aPLs). Antibodies against a domain I (DI) epitope of anti-beta 2glycoprotein I (beta 2GPI) proved to be pathogenic, but are not included in the current classification criteria. Objectives Investigate the clinical value of detecting anti-DI IgG in APS. Patients/Methods From eight European centers 1005 patients were enrolled. Anti-cardiolipin (CL) and anti-beta 2GPI were detected by four commercially available solid phase assays; anti-DI IgG by the QUANTA Flash (R) beta 2GPI domain I assay. Results Odds ratios (ORs) of anti-DI IgG for thrombosis and pregnancy morbidity proved to be higher than those of the conventional assays. Upon restriction to patients positive for anti-beta 2GPI IgG, anti-DI IgG positivity still resulted in significant ORs. When anti-DI IgG was added to the criteria aPLs or used as a substitute for anti-beta 2GPI IgG/anti-CL IgG, ORs for clinical symptoms hardly improved. Upon removing anti-DI positive patients, lupus anticoagulant remained significantly correlated with clinical complications. Anti-DI IgG are mainly present in high-risk triple positive patients, showing higher levels. Combined anti-DI and triple positivity confers a higher risk for clinical symptoms compared to only triple positivity. Conclusions Detection of anti-DI IgG resulted in higher ORs for clinical manifestations than the current APS classification criteria. Regardless of the platform used to detect anti-beta 2GPI/anti-CL, addition of anti-DI IgG measured by QUANTA Flash (R) did not improve the clinical associations, possibly due to reduced exposure of the pathogenic epitope of DI. Our results demonstrate that anti-DI IgG potentially helps in identifying high-risk patients.

Background The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with the persistent presence of lupus anticoagulant (LAC), anti-cardiolipin (aCL) and/or anti-beta 2glycoprotein I (a beta 2GPI) antibodies of the immunoglobulin G/immunoglobulin M (IgG/IgM) isotype. However, the role of aCL and a beta 2GPI IgM as a serologic marker in APS is debated. Objectives We aimed to assess the diagnostic and clinical value of IgM antiphospholipid antibodies (aPL) in APS within the classification criteria. Patients/Methods Our multicenter study comprised 1008 patients, including APS patients and controls. Anti-CL and a beta 2GPI IgG and IgM antibodies were detected with four commercially available solid phase assays. Results Positivity for aCL and/or a beta 2GPI antibodies was significantly correlated with thrombosis and pregnancy morbidity, independent of the isotype and solid phase assay. Higher odds ratios were obtained for IgG compared to IgM positivity. Isolated IgM was rare in thrombotic APS, but more frequent in obstetric APS, ranging from 3.5% to 5.4% and 5.7% to 12.3%, respectively, dependent on the solid phase assay. In a multivariate logistic regression analysis of aPL, IgM positivity was found to be associated with pregnancy morbidity. However, detection of IgM was not independently associated with thrombosis. Combined positivity for LAC, IgG, and IgM was highly associated with thrombosis and pregnancy morbidity. Conclusions Our data support testing for aCL and a beta 2GPI IgM in women suspected of obstetric APS. However, no added value was found for testing IgM in patients suspected of thrombotic APS. Still, IgM aPL might be useful as a second-line test to improve thrombotic risk stratification.

Introduction Mixed connective tissue disease (MCTD) is a chronic immune-mediated disorder defined by the combined presence of serum anti-RNP antibodies and distinct clinical features including progressive lung fibrosis. The aim of this study was to evaluate potential associations between lung fibrosis in MCTD and specific clinical and laboratory findings including results of nailfold capillaroscopy (NFC) examination. Material and methods Patients with MCTD who were admitted to the Departments of Allergy and Immunology or Dermatology at the University Hospital of Krakow (Poland) in 2015–2018 were identified based on comprehensive individual record review. Diagnosis of MCTD required fulfilment of at least one of the four widely accepted sets of diagnostic criteria. Clinical and laboratory data were collected, and statistical analysis was performed to identify potential predictors of interstitial lung disease (ILD). Results Thirty patients (90% females) aged 22–81 years met the study inclusion criteria. The mean duration of symptoms associated with MCTD was 7.3 months. Photosensitivity and Raynaud’s phenomenon were the most common clinical manifestations (90% and 70%, respectively). Hand oedema, sclerodactyly and the presence of giant capillaries in NFC correlated significantly with the risk of lung involvement. In multivariate analysis, the presence of enlarged loops in NFC (giant capillaries) was identified as an independent factor for ILD (R 2 = 0.82, p < 0.0000001). Conclusions The NFC examination should be considered in all patients with a diagnosis of MCTD. The presence of giant capillaries may be a promising marker for interstitial lung disease in these patients, especially among those with a short duration of disease (i.e. < 1 year).

IntroductionAsthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication.MethodsBaseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort; 12–18-month longitudinal samples were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods.ResultsA total of 90 metabolites were identified, with 40 significantly altered (p−20), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10−4), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings.ConclusionsThis is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.

Asthma is a heterogeneous disease with multiple clinical presentations (phenotypes). Neutrophilic asthma is characterised by increased sputum neutrophils and generally has a poor response to corticosteroids and limited other therapeutic options. Neutrophilia originates from different factors, including the defective resolution of inflammation or bacterial infections. An association between airway bacterial imbalance (disturbance) and the neutrophilic phenotype has been reported, suggesting that airway microbiota composition is involved in neutrophilic asthma. Rather than being a separate entity, neutrophilic asthma may be in part, an alliance between innate immunity and microbiota composition that prompts protective mechanisms against invading pathogens.

International audience; The antiphospholipid syndrome (APS) is diagnosed by the presence of lupus anticoagulant and/or antibodies against cardiolipin or β2-glycoprotein-1 and the occurrence of thrombosis or pregnancy morbidity. The assessment of overall coagulation is known to differ in APS patients compared to normal subjects. The accelerated production of key factor thrombin causes a prothrombotic state in APS patients, and the reduced efficacy of the activated protein C pathway promotes this effect. Even though significant differences exist in the coagulation profile between normal controls and APS patients, it is not possible to rely on a single test result to diagnose APS. A neural network is a computing system inspired by the human brain that can be trained to distinguish between healthy subjects and patients based on subject specific data. In a first cohort of patients, we developed a neural networking that diagnoses APS. We clinically validated this neural network in a separate cohort consisting of APS patients, normal controls, controls visiting the hospital for other indications and two diseased control groups (thrombosis patients and auto-immune disease patients). The positive predictive value ranged from 62% in the hospital controls to 91% in normal controls and the negative predictive value of the neural network ranged from 86% in the thrombosis control group to 95% in the hospital controls. The sensitivity of the neural network was higher than 90% in all control groups. In conclusion, we developed a neural network that accurately diagnoses APS in the validation cohort. After further clinical validation in newly diagnosed patients, this neural network could possibly be clinically implemented to diagnose APS based on thrombin generation data.

Background: Anticardiolipin (aCL) and anti-β2 glycoprotein I (aβ2GPI) immunoglobulin (Ig) G/IgM antibodies are 2 of the 3 laboratory criteria for classification of antiphospholipid syndrome (APS). The threshold for clinically relevant levels of antiphospholipid antibodies (aPL) for the diagnosis of APS remains a matter of debate. The aim of this study was to evaluate the variation in cutoffs as determined in different clinical laboratories based on the results of a questionnaire as well as to determine the optimal method for cutoff establishment based on a clinical approach.Methods: The study included samples from 114 patients with thrombotic APS, 138 patients with non-APS thrombosis, 138 patients with autoimmune disease, and 183 healthy controls. aCL and aβ2GPI IgG/IgM antibodies were measured at 1 laboratory using 4 commercial assays. Assay-specific cutoff values for aPL were obtained by determining 95th and 99th percentiles of 120 compared to 200 normal controls by different statistical methods.Results: Normal reference value data showed a nonparametric distribution. Higher cutoff values were found when calculated as 99th rather than 95th percentiles. These values also showed a stronger association with thrombosis. The use of 99th percentile cutoffs reduced the chance of false positivity but at the same time reduced sensitivity. The decrease in sensitivity was higher than the gain in specificity when 99th percentiles were calculated by methods wherein no outliers were eliminated.Conclusions: We present cutoff values for aPL determined by different statistical methods. The 99th percentile cutoff value seemed more specific. However, our findings indicate the need for standardized statistical criteria to calculate 99th percentile cutoff reference values.

Background The anti-phospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with persistent presence of anti-phospholipid antibodies (aPL). Laboratory criteria include aPL detection by coagulation tests for lupus anticoagulant (LAC) or solid phase assays measuring anti-β2 glycoprotein I (aβ2GPI) or anti-cardiolipin (aCL) immunoglobulin (Ig) G/IgM antibodies. External quality control programs illustrate that commercially available aPL assays produce variable results. Objective We aimed to investigate the agreement and diagnostic accuracy of solid phase assays. Materials and Methods In this multi-centre study, 1,168 patient samples were tested on one site for aCL and aβ2GPI IgG/IgM antibodies by four solid phase test systems. Samples included APS patients, controls and monoclonal antibodies (MoAB) against different epitopes of β2GPI. LAC was determined by the local centre. Results aCL IgM assays resulted in the most discrepancies (60%), while aCL IgG and aβ2GPI IgM assays resulted in lower discrepancies (36%), suggesting better agreement. Discrepant samples displayed lower median aPL titers. Dependent on the solid phase test system, odds ratios (ORs) for thrombosis and pregnancy morbidity ranged from 1.98 to 2.56 and 3.42 to 4.78, respectively. Three platforms showed lower sensitivity for MoAB directed against the glycine (Gly) 40-arginine (Arg) 43 epitope of domain I of β2GPI. Conclusion Poor agreement was observed between different commercially available aCL and aβ2GPI IgG/IgM assays, hampering uniformity in the identification of aPL-positive patients. Clinical association was globally concordant between solid phase test systems considering results of the four aPL together. An assay sensitive in detecting the MoAB against Gly40-Arg43 of domain I of β2GPI reached the highest OR for thrombosis.

Recent advances in oncology have improved the treatment outcomes and life expectancy of cancer patients; therefore, late effects of oncological treatment are of high clinical importance. Recent studies have shown that cardiovascular events are among the leading causes of premature morbidity in cancer survivors. Cardiotoxicity of some chemotherapeutic agents have been already confirmed; however, this issue seems to be more complex. Endothelium dysfunction is one of the first recognisable signs of atherosclerosis, which occurs long before the development of overt cardiovascular disease. Thus, it could be considered as an initial step, leading to increased risk of cardiovascular events. This process is not easy to recognise; however, there are some laboratory tests and imagining techniques that provide an insight into the progression of endothelial dysfunction. In this review we discuss the influence of oncological treatment on endothelium, according to the hypothesis that it increases cardiovascular morbidity and mortality in cancer survivors. Additionally, we present diagnostic and therapeutic measures that could reduce cardiovascular risk in cancer patients.

Background Anti beta 2glycoprotein I (a beta 2GPI) and anticardiolipin (aCL) IgG/IgM show differences in positive/negative agreement and titers between solid phase platforms. Method-specific semiquantitative categorization of titers could improve and harmonize the interpretation across platforms. Aim To evaluate the traditional 40/80-unit thresholds used for aCL and a beta 2GPI for categorization into moderate/high positivity with different analytical systems, and to compare with alternative thresholds. Material and methods aCL and a beta 2GPI thresholds were calculated for two automated systems (chemiluminescent immunoassay [CLIA] and multiplex flow immunoassay [MFI]) by receiver operating characteristic curve analysis on 1108 patient samples, including patients with and without antiphospholipid syndrome (APS), and confirmed on a second population (n = 279). Alternatively, regression analysis on diluted standard material was applied to identify thresholds. Thresholds were compared to 40/80 threshold measured by an enzyme-linked immunosorbent assay (ELISA). Additionally, likelihood ratios (LR) were calculated. Results Threshold levels of 40/80 units show poor agreement between ELISA and automated platforms for classification into low/moderate/high positivity, especially for aCL/a beta 2GPI IgG. Agreement for semiquantitative interpretation of antiphospholipid antibodies (aPL) IgG between ELISA and CLIA/MFI improves with alternative thresholds. LR for aPL IgG increase for thrombotic and obstetric APS based on 40/80 thresholds for ELISA and adapted thresholds for the other systems, but not for IgM. Conclusion Use of 40/80 units as medium/high thresholds is acceptable for aCL/a beta 2GPI IgG ELISA, but not for CLIA and MFI. Alternative semiquantitative thresholds for non-ELISA platforms can be determined by a clinical approach or by using monoclonal antibodies. Semiquantitative reporting of aPL IgM has less impact on increasing probability for APS.

INTRODUCTION Patients with granulomatosis with polyangiitis (GPA) show increased tendency toward thromboembolic phenomena in exacerbation of their disease. OBJECTIVES The aim of the study was to evaluate thrombin generation potential and fibrinolytic plasma activity in patients with GPA, both in exacerbation and in remission. PATIENTS AND METHODS We included 38 patients with GPA: 18 with exacerbated GPA and 20 in remission. The control group included 39 healthy participants matched for age and sex. Plasma thrombogenic potential was assessed using calibrated automated thrombography. Plasma fibrinolytic potential was assessed using clot lysis time (CLT). We also measured levels of inflammatory markers, thrombomodulin, and fibrinolysis proteins in all participants. RESULTS In the whole group of patients with GPA, endogenous thrombin potential was higher by about 25% (P

INTRODUCTION ANCA-associated vasculitides (AAV) is a group of rare disorders where inflammation and damage of the small blood vessels lead to dysfunction of the supplied organs. In severe flares of the disease patients may require intensive care unit (ICU) admission and treatment. The study aims to characterize Polish patients with AAV who were admitted to the ICU and compare them to the others. MATERIAL AND METHODS An observational, retrospective study based on the POLVAS - registry of Polish adult patients with AAV was carried out. Patients admitted to the ICU (ICU group) were identified and compared with the patients who did not require ICU admission (non-ICU group). Characteristics and comparison between groups were made using standard statistic descriptive methods. RESULTS 30 patients admitted to the ICU were identified among 573 cases included in the registry. All patients in the ICU group with available data were ANCA positive. The clinical manifestations related to the ICU admission were respiratory, renal and central nervous system involvement. The treatment regimen for remission induction was similar in both groups. Almost half of the patients in the ICU-group (48.3%) required dialysis, whereas in the non-ICU group it was 21.8% (P = 0.01). Infections were also more frequent in the ICU group (72.4% vs. 36.9% P < 0.001). The mortality rate among patients who needed ICU treatment was significantly higher when compared to the rest of the patients (53.6% vs. 7.8%; P < 0.001). CONCLUSIONS In the Polish AAV cohort one in twenty patients required ICU admission. This group was characterized by multiple organ involvement and high mortality.

Background Asthma prevalence is 339 million globally. ‘Severe asthma’ (SA) comprises subjects with uncontrolled asthma despite proper management. Objectives To compare asthma from diverse ethnicities and environments. Methods A cross-sectional analysis of two adult cohorts, a Brazilian (ProAR) and a European (U-BIOPRED). U-BIOPRED comprised of 311 non-smoking with Severe Asthma (SAn), 110 smokers or ex-smokers with SA (SAs) and 88 mild to moderate asthmatics (MMA) while ProAR included 544 SA and 452 MMA. Although these projects were independent, there were similarities in objectives and methodology, with ProAR adopting operating procedures of U-BIOPRED. Results Among SA subjects, age, weight, proportion of former smokers and FEV1 pre-bronchodilator were similar. The proportion of SA with a positive skin prick tests (SPT) to aeroallergens, the scores of sino-nasal symptoms and quality of life were comparable. In addition, blood eosinophil counts (EOS) and the % of subjects with EOS > 300 cells/μl were not different. The Europeans with SA however, were more severe with a greater proportion of continuous oral corticosteroids (OCS), worse symptoms and more frequent exacerbations. FEV1/FVC pre- and post-bronchodilator were lower among the Europeans. The MMA cohorts were less comparable in control and treatment, but similar in the proportion of allergic rhinitis, gastroesophageal reflux disease and EOS >3%. Conclusions ProAR and U-BIOPRED cohorts, with varying severity, ethnicity and environment have similarities, which provide the basis for global external validation of asthma phenotypes. This should stimulate collaboration between asthma consortia with the aim of understanding SA, which will lead to better management.

Background Granulomatosis with polyangiitis (GPA) is a rare granulomatous vasculitis affecting small- and medium-sized blood vessels. In optimally treated patients with long-standing disease, the common cause of death is atherosclerosis even in the absence of typical risk factors. Objective To evaluate endothelial dysfunction in GPA patients. Methods 44 patients (21 men and 23 women) diagnosed with GPA and 53 controls matched for age, sex, BMI and typical risk factors for cardiovascular diseases (22 men and 31 women) were enrolled in the study. We measured each participant’s serum levels of vascular cell adhesion molecule-1 (VCAM-1), interleukin 6 (IL-6), and thrombomodulin. We also studied flow-mediated dilatation (FMD) of the brachial artery, intima-media thickness (IMT) of the common carotid artery and aortic stiffness using echocardiography. Results Patients with GPA showed a 15.9% increase in serum levels of VCAM-1 (p = 0.01), 66% of IL-6 (p

The vibro-acoustic environment generated during a rocket launch induces dynamic loads which may damage critical components of spacecraft and scientific instruments. The research is focused on the vibro-acoustic response of the Wide Field Imager (WFI) instrument subjected to an intense diffuse sound field. Noise-induced structural vibrations in low- to mid-frequency can be computed by means of coupled FEM-BEM numerical models. Nevertheless, this approach is unsuited to calculations of cavity-structure interactions of light-weight and thin structures. In this paper the application and assessment of the elasto-acoustic FEM-FEM coupling approach for the cavity - optical blocking thin foil filter interactions is investigated. The diffuse sound field excitation is reconstructed by matching values of the sound pressure level to these obtained from experimental measurements. The viscosity effects on the wave propagation in thin layers are included by using the visco-thermal fluid model. The accuracy and efficiency of this approach are investigated and results obtained are compared to measured data from a reverberant test chamber. The results show that a very good agreement is obtained in terms of the acoustic pressure in the vicinity of the optical blocking filter. The behaviour of mechanical vibrations is correctly reproduced, although some considerable discrepancies in the levels of the vibrations are observed. The case of strong coupling between the cavity acoustic field and the filter membrane is finally discussed.

Background:ANCA associated vasculitides (AAV) are a heterogeneous group of rare diseases with unknown etiology and the broad clinical spectrum ranging from life-threatening systemic disease, through single organ involvement to minor isolated skin changes. Unfortunately the clinical classification, ANCA specificity or genetic characteristics alone is not able to categorize AAV patients in a satisfactory manner. As a consequence advanced statistical techniques were used to identify and stratify AAV subphenotypes [1, 2]. Here we have analyzed influence of the ANCA type on clinical manifestations and demographic characteristics in various types of AAV, based on data from the POLVAS registryObjectives:We decided to retrospectively analyze a large cohort of Polish AAV patients deriving from several referral centers – members of the Scientific Consortium of the Polish Vasculitis Registry (POLVAS) – and concentrate on demographic and clinical characteristics of anti-PR3 and anti-MPO positive patients regardless of their clinical diagnosis.Methods:We conducted a systematic multicenter retrospective study of adult patients diagnosed with AAV between Jan 1990 and Dec 2016. Patients were enrolled by 9 referral centers. We analyzed dichotomous variables: gender; ANCA status – anti-PR3+ or anti-MPO+, ANCA negative; organ involvement - skin, eye, ENT, respiratory, heart, GI, renal, urinary, CNS, peripheral nerves and polytomous variable (number of relapses), supported by quantitative covariates (e.g., age at diagnosis, CRP at diagnosis, maximal serum creatinine concentration ever)[3].Results:MPO-positive patients (both GPA and EGPA phenotype) were older at the time of diagnosis with a substantial percentage diagnosed > 65 years of age, and with high rate of renal involvement. Interestingly, while in the whole group of patients diagnosed with EGPA male to female ratio was 1:2, the MPO+ EGPA patients showed M:F ratio of 1:1.The analysis of ANCA negative AAV reveled significant differences in GPA, ANCA negative group is characterized with significantly lower frequency of renal involvement compared to rest GPA (11,5% vs 63,7%) pConclusion:ANCA specificity is indispensable as a separate variable in any clinically relevant analysis of AAV subcategories. MPO+ group is characterized by older age at time of diagnosis, male to female ration 1:1, kidney involvement, and shows more homogenous clinical phenotype than PR3+ AAV patients. In our group ANCA negative AAV never lead to ESRD (end stage renal disease) or even transient dialysis.References:[1]Mahr A, Specks U, Jayne D. Subclassifying ANCA-associated vasculitis: a unifying view of disease spectrum. Rheumatol Oxf Engl 2019;58:1707–9. https://doi.org/10.1093/rheumatology/kez148.[2]Wójcik K, Biedroń G, Wawrzycka-Adamczyk K, Bazan-Socha S, Ćmiel A, Zdrojewski Z et al. Subphenotypes of ANCA-associated vasculitis identified by latent class analysis. Clin Exp Rheumatol. 2020 Sep 1. Epub PMID: 32896241.[3]Wójcik K, Wawrzycka-Adamczyk K, Włudarczyk A, Sznajd J, Zdrojewski Z, Masiak A, et al. Clinical characteristics of Polish patients with ANCA-associated vasculitides—retrospective analysis of POLVAS registry. Clinical Rheumatology. 1 wrzesień 2019;38(9):2553–63.Disclosure of Interests:None declared

Asthma therapy with monoclonal antibodies is a promising and effective approach for those with a severe and refractory type of disease. Although such a targeted therapy is considered to be safe, unusual complications may occur. We present a case of a 45 year-old female patient with severe allergic asthma and chronic spontaneous urticaria, who developed autoimmune polyendocrine syndrome type 2 (APS-2) after 26 months of omalizumab administration. The patient was diagnosed with primary adrenal insufficiency (Addison's disease) and Hashimoto's thyroiditis accompanied by autoimmune atrophic gastritis. According to our knowledge this is the first description of APS-2 that developed in conjunction with omalizumab treatment, although we have no evidence that the observed phenomenon indicated a cause-effect relationship to omalizumab.

Objectives: Neutrophil apoptosis is mandatory for resolving inflammation and is regulated by expression of pro- and anti-apoptotic genes. We studied neutrophils isolated from patients with granulomatosis with polyangiitis (GPA) to investigate apoptosis alterations and to identify transcriptional and circulating factors affecting this process. Method: We enrolled 36 patients (18 in active stage, 18 in remission) and 18 healthy controls. Circulating levels of tumour necrosis factor-α (TNF-α), granulocyte–macrophage colony-stimulating factor (GM-CSF), macrophage migration inhibitory factor, plasminogen activator inhibitor-1, interferon-γ, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, platelet endothelial cell adhesion molecule-1, soluble Fas (sFas), sFas ligand, survivin, and pentraxin-3 (PTX3) were evaluated by enzyme-linked immunosorbent assay/Luminex; circulating apoptotic neutrophils by flow cytometry; and apoptosis-related gene transcripts by real-time polymerase chain reaction. Results: Patients had decreased fractions of circulating apoptotic neutrophils and delayed neutrophil apoptosis was present in vitro. Circulating levels of TNF-α, GM-CSF, sFas, and PTX3 were higher in GPA. Delayed neutrophil apoptosis was accompanied by decreased mRNA of pro-apoptotic genes and transcription factors (DIABLO, PMAIP1, BAX, CASP3, CASP7, RUNX3, E2F1, TP53) and increased anti-apoptotic CFLAR and BCL2A1 mRNA. TNF-α and sFas levels correlated with circulating apoptotic neutrophils and expression of apoptosis genes. Stimulation with TNF-α of neutrophils from controls significantly down-regulated E2F1 and CASP3 expression. Conclusions: Circulating neutrophils in GPA have anti-apoptotic phenotype involving both intrinsic and extrinsic pathways of apoptosis. This is accompanied by increased levels of circulating pro-survival factors (GM-CSF, TNF-α, sFas), independent of disease activity. Anti-apoptotic phenotype of neutrophils in GPA is reproduced by exposure to low concentrations of TNF-α.