Clinical grade ACE2 as a universal agent to block SARS-CoV-2 variants

The recent emergence of multiple SARS-CoV-2 variants has caused considerable concern due to both reduced vaccine efficacy and escape from neutralizing antibody therapeutics. It is, therefore, paramount to develop therapeutic strategies that inhibit all known and future SARS-CoV-2 variants. Here, we report that all SARS-CoV-2 variants analyzed, including variants of concern (VOC) Alpha, Beta, Gamma, Delta, and Omicron, exhibit enhanced binding affinity to clinical grade and phase 2 tested recombinant human soluble ACE2 (APN01). Importantly, soluble ACE2 neutralized infection of VeroE6 cells and human lung epithelial cells by all current VOC strains with markedly enhanced potency when compared to reference SARS-CoV-2 isolates. Effective inhibition of infections with SARS-CoV-2 variants was validated and confirmed in two independent laboratories. These data show that SARS-CoV-2 variants that have emerged around the world, including current VOC and several variants of interest, can be inhibited by soluble ACE2, providing proof of principle of a pan-SARS-CoV-2 therapeutic

Rheumatoid arthritis - treatment: 180. Utility of Body Weight Classified Low-Dose Leflunomide in Japanese Rheumatoid Arthritis

Background: In Japan, more than 20 rheumatoid arthritis (RA) patients died of interstitial pneumonia (IP) caused by leflunomide (LEF) were reported, but many of them were considered as the victims of opportunistic infection currently. In this paper, efficacy and safety of low-dose LEF classified by body weight (BW) were studied. Methods: Fifty-nine RA patients were started to administrate LEF from July 2007 to July 2009. Among them, 25 patients were excluded because of the combination with tacrolimus, and medication modification within 3 months before LEF. Remaining 34 RA patients administered 20 to 50 mg/week of LEF were followed up for 1 year and enrolled in this study. Dose of LEF was classified by BW (50 mg/week for over 50 kg, 40 mg/week for 40 to 50 kg and 20 to 30 mg/week for under 40 kg). The average age and RA duration of enrolled patients were 55.5 years old and 10.2 years. Prednisolone (PSL), methotrexate (MTX) and etanercept were used in 23, 28 and 2 patients, respectively. In case of insufficient response or adverse effect, dosage change or discontinuance of LEF were considered. Failure was defined as dosages up of PSL and MTX, or dosages down or discontinuance of LEF. Last observation carried forward method was used for the evaluation of failed patients at 1 year. Results: At 1 year after LEF start, good/ moderate/ no response assessed by the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score, including a 28-joint count (DAS28)-C reactive protein (CRP) were showed in 14/ 10/ 10 patients, respectively. The dosage changes of LEF at 1 year were dosage up: 10, same dosage: 5, dosage down: 8 and discontinuance: 11 patients. The survival rate of patients in this study was 23.5% (24 patients failed) but actual LEF continuous rate was 67.6% (11 patients discontinued) at 1 year. The major reason of failure was liver dysfunction, and pneumocystis pneumonia was occurred in 1 patient resulted in full recovery. One patient died of sepsis caused by decubitus ulcer infection. DAS28-CRP score was decreased from 3.9 to 2.7 significantly. Although CRP was decreased from 1.50 to 0.93 mg/dl, it wasn't significant. Matrix metalloproteinase (MMP)-3 was decreased from 220.0 to 174.2 ng/ml significantly. Glutamate pyruvate transaminase (GPT) was increased from 19 to 35 U/l and number of leukocyte was decreased from 7832 to 6271 significantly. DAS28-CRP, CRP, and MMP-3 were improved significantly with MTX, although they weren't without MTX. Increase of GPT and leukopenia were seen significantly with MTX, although they weren't without MTX. Conclusions: It was reported that the risks of IP caused by LEF in Japanese RA patients were past IP history, loading dose administration and low BW. Addition of low-dose LEF is a potent safe alternative for the patients showing unsatisfactory response to current medicines, but need to pay attention for liver function and infection caused by leukopenia, especially with MTX. Disclosure statement: The authors have declared no conflicts of interes

Oral abstracts 3: RA Treatment and outcomesO13. Validation of jadas in all subtypes of juvenile idiopathic arthritis in a clinical setting

Background: Juvenile Arthritis Disease Activity Score (JADAS) is a 4 variable composite disease activity (DA) score for JIA (including active 10, 27 or 71 joint count (AJC), physician global (PGA), parent/child global (PGE) and ESR). The validity of JADAS for all ILAR subtypes in the routine clinical setting is unknown. We investigated the construct validity of JADAS in the clinical setting in all subtypes of JIA through application to a prospective inception cohort of UK children presenting with new onset inflammatory arthritis. Methods: JADAS 10, 27 and 71 were determined for all children in the Childhood Arthritis Prospective Study (CAPS) with complete data available at baseline. Correlation of JADAS 10, 27 and 71 with single DA markers was determined for all subtypes. All correlations were calculated using Spearman's rank statistic. Results: 262/1238 visits had sufficient data for calculation of JADAS (1028 (83%) AJC, 744 (60%) PGA, 843 (68%) PGE and 459 (37%) ESR). Median age at disease onset was 6.0 years (IQR 2.6-10.4) and 64% were female. Correlation between JADAS 10, 27 and 71 approached 1 for all subtypes. Median JADAS 71 was 5.3 (IQR 2.2-10.1) with a significant difference between median JADAS scores between subtypes (p < 0.01). Correlation of JADAS 71 with each single marker of DA was moderate to high in the total cohort (see Table 1). Overall, correlation with AJC, PGA and PGE was moderate to high and correlation with ESR, limited JC, parental pain and CHAQ was low to moderate in the individual subtypes. Correlation coefficients in the extended oligoarticular, rheumatoid factor negative and enthesitis related subtypes were interpreted with caution in view of low numbers. Conclusions: This study adds to the body of evidence supporting the construct validity of JADAS. JADAS correlates with other measures of DA in all ILAR subtypes in the routine clinical setting. Given the high frequency of missing ESR data, it would be useful to assess the validity of JADAS without inclusion of the ESR. Disclosure statement: All authors have declared no conflicts of interest. Table 1Spearman's correlation between JADAS 71 and single markers DA by ILAR subtype ILAR Subtype Systemic onset JIA Persistent oligo JIA Extended oligo JIA Rheumatoid factor neg JIA Rheumatoid factor pos JIA Enthesitis related JIA Psoriatic JIA Undifferentiated JIA Unknown subtype Total cohort Number of children 23 111 12 57 7 9 19 7 17 262 AJC 0.54 0.67 0.53 0.75 0.53 0.34 0.59 0.81 0.37 0.59 PGA 0.63 0.69 0.25 0.73 0.14 0.05 0.50 0.83 0.56 0.64 PGE 0.51 0.68 0.83 0.61 0.41 0.69 0.71 0.9 0.48 0.61 ESR 0.28 0.31 0.35 0.4 0.6 0.85 0.43 0.7 0.5 0.53 Limited 71 JC 0.29 0.51 0.23 0.37 0.14 -0.12 0.4 0.81 0.45 0.41 Parental pain 0.23 0.62 0.03 0.57 0.41 0.69 0.7 0.79 0.42 0.53 Childhood health assessment questionnaire 0.25 0.57 -0.07 0.36 -0.47 0.84 0.37 0.8 0.66 0.4

Modelling of the bladed disk vibration with damping elements in blade shroud

The requirement for wide operation range of steam turbine can cause, that the blades work close to resonant frequency. For decreasing of blade’s vibration there are placed damping elements in the blade shroud. These elements are calculated for dissipation of the vibration energy. The analytical method of blade and bladed disk modal analysis is introduced. The method enables to include blades both with and without damping elements in shroud. The mathematical model of the bladed disk is prepared for including damping effects in contact planes

Blade dynamic stress analysis of rotating bladed disks

The paper deals with mathematical modelling of steady forced bladed disk vibrations and with dynamic stress calculation of the blades. The blades are considered as 1D kontinuum elastic coupled with three-dimensional elastic disk centrally clamped into rotor rotating with constant angular speed. The steady forced vibrations are generated by the aerodynamic forces acting along the blade length. By using modal synthesis method the mathematical model of the rotating bladed disk is condensed to calculate steady vibrations. Dynamic stress analysis of the blades is based on calculation of the time dependent reduced stress in blade cross-sections by using Hubert-Misses-Hencky stress hypothesis. The presented method is applied to real turbomachinery rotor with blades connected on the top with shroud

Monitorowanie ultradrobnych cząstek w pomieszczeniach na terenach czeskich sił zbrojnych

Ultrafine particles and nanoparticles in the air are evaluated as a risk factor for the development of respiratory and other health symptoms due to their inhalation from the ambient air. The Czech Army professionals are expected to have frequent presence in a polluted environment and regular exposure to air with increased concentration of airborne pollutants. The report evaluates the presence of ultra-fine particles (in the range of about 7.6–299.6 nm) in rooms often used by soldiers during their working hours when they are not deployed. The purpose is to assess whether the presence of troops in these workplaces is safe and does not pose a risk of adverse health effects in itself. Testing took place in three military rooms (classroom 1, classroom 2 and exercise flight simulator room). Seven samples of air were analysed in time by the scanning mobility particle sizer in succession. Mean particle concentrations were found at 1.79×104, 7.53×103 and 8.39×103 N·cm-3 for the classroom 1, classroom 2 and exercise flight simulator room. Conclusions of the research have shown that particle concentrations in the places of the Czech Army can reach values that border the immission limits stated by the World Health Organisation.Najdrobniejsze cząstki i nanocząsteczki w powietrzu są oceniane jako czynnik ryzyka dla dróg oddechowych i innych objawów zdrowotnych spowodowanych ich wdychaniem z otaczającego powietrza. Oczekuje się, że specjaliści z czeskiej armii będą często obecni w zanieczyszczonym środowisku i będą regularnie narażeni na kontakt z powietrzem o zwiększonej koncentracji zanieczyszczeń. Raport ocenia obecność ultradrobnych cząstek (w zakresie około 7,6–299,6 nm) w pomieszczeniach często używanych przez żołnierzy w godzinach pracy. Celem jest ocena, czy obecność wojsk w tych miejscach pracy jest bezpieczna i sama w sobie nie stwarza ryzyka negatywnych skutków zdrowotnych. Testowanie odbyło się w trzech pomieszczeniach wojskowych (sala 1, sala 2 i sala do ćwiczeń). Siedem próbek powietrza analizowano w czasie przez separator cząstek. Stwierdzone średnie stężenia cząstek 1,79 × 104, 7,53 × 103 i 8,39 × 103 [N · cm-3] w sali lekcyjnej 1, klasie 2 i sali do ćwiczeń. Wnioski z badań wykazały, że stężenia cząstek w wybranych pomieszczeniach czeskiej armii mogą osiągnąć wartości graniczące z limitami imisji podanymi przez Światową Organizację Zdrowia