A randomised trial of anti-GM-CSF otilimab in severe COVID-19 pneumonia (OSCAR).

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19. METHODS: In this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18-79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28. RESULTS: In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI -0.8-11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2-33.1%, p=0.009) was observed in the predefined 70-79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI -9.3-11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19. CONCLUSIONS: There was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile.

Optical pulling and pushing forces via Bloch surface waves.

For flexible tailoring of optical forces, as well as for extraordinary optomechanical effects, additional degrees of freedom should be introduced into a system. Here, we demonstrate that photonic crystals are a versatile platform for optical manipulation due to both Bloch surface waves (BSWs) and the complex character of the reflection coefficient paving a way for controlled optomechanical interactions. We demonstrate enhanced pulling and pushing transversal optical forces acting on a single dipolar bead above a one-dimensional photonic crystal due to directional excitation of BSWs. Our results demonstrate angle- or wavelength-assisted switching between BSW-induced optical pulling and pushing forces. Easy to fabricate for any desired spectral range, photonic crystals are shown to be prospective for precise optical sorting of nanoparticles, which are difficult to sort with conventional optomechanical methods. Our approach opens opportunities for novel, to the best of our knowledge, optical manipulation schemes and platforms, and enhanced light-matter interaction in optical trapping setups.

Phase 3 trial of coronavir (favipiravir) in patients with mild to moderate COVID-19.

Favipiravir has demonstrated efficacy against the SARS-CoV-2 virus in several preliminary studies. This study aimed to evaluate the efficacy and safety of favipiravir for treatment of mild to moderate COVID-19 in outpatients and hospitalized patients. We conducted an open-label, randomized, active-controlled trial of a generic form of favipiravir in patients with COVID-19 confirmed by PCR-test. Eligible patients (18-60 years) after stratification were randomly assigned (in a 2:1 ratio) to receive either favipiravir (1800 mg BID on day 1, followed by 800 mg BID for up to 9 days), or standard of care (SOC) treatment (umifenovir + intranasal interferon alpha-2b, or hydroxychloroquine) for up to 10 days. The co-primary outcomes were the time to clinical improvement and the time to viral clearance. Among 190 patients assessed for eligibility 168 were randomized to favipiravir (n=112) or to SOC (n=56) group. The median time to clinical improvement was 6.0 days (IQR 4.0; 9.3) in the favipiravir group and 10.0 (IQR 5.0; 21.0) days in the SOC group; the median difference was 4 days (HR 1.63; 95% CI 1.14-2.34; P=0.007). The statistically significant difference in the median time to viral clearance was observed only for hospitalized patients: 3.0 (IQR 3.0; 3.0) days in the favipiravir group vs. 5.0 (IQR 4.5; 5.5) days in the SOC group (HR 2.11; 95% CI 1.04-4.31; P=0.038). The rate of viral elimination on Day 5 in the favipiravir group was significantly higher than in SOC group: 81.2% vs. 67.9% (RR 1.22; 05% CI 1.00-1.48; P=0.022). The rate of clinical improvement on Day 7 in the favipiravir group was 1.5-fold higher than in SOC group: 52.7% vs. 35.8% (RR 1.50; 95% CI 1.02-2.22; P=0.020). Favipiravir was well-tolerated and the most common adverse reactions were asymptomatic hyperuricemia, transient elevation of ALT & AST, and mild gastrointestinal disorders. Favipiravir was superior to the SOC in shortening the time to clinical improvement in patients with mild to moderate COVID-19.

Management of Cough in Patients with Chronic Obstructive Pulmonary Disease: Results of the Multicenter Randomized Placebo-Controlled Clinical Trial.

BACKGROUND: Chronic cough declines quality of life and increases risk of complications in patients with chronic obstructive pulmonary disease (COPD). Reducing cough severity and associated negative effects is important therapeutic goal in COPD. Rengalin with anti- and protussive activity is based on technologically processed antibodies to bradykinin, histamine and morphine. AIM: To evaluate efficacy and safety of Rengalin in treatment of cough in patients with COPD. METHODS: Patients (n=238, mean age 64.3±8.2 years) with stable COPD and persistent cough despite maintenance therapy (anticholinergics, beta-2-adrenergic agonists, inhaled corticosteroids) were included and randomized in the study. The severity of cough assessment (according to the "Cough Severity Score"), COPD impact on patient's life (COPD Assessment Test, CAT), and spirometry were performed at screening. Patients took Rengalin or Placebo 2 tablets 2 times daily for 4 weeks. The endpoints were proportion of patients who responded to treatment, dynamics of cough severity, and severity of COPD symptoms. Intention-to-treat (per protocol) analysis was performed. RESULTS: Positive response to Rengalin was recorded in 83.6 [85.7]% (vs 72.6 [72.7]% in Placebo group, p=0.0422 [p=0.0163]). Double decrease of cough severity was reported in 42.2 [43.8]% in Rengalin group (versus 32.7 [32.7]% in Placebo; p=0.1373 [p=0.0907]). The total CAT score decreased by 3.3±4.2 [3.6±3.9] points (versus 2.5±4.1 [2.5±4.2] in Placebo group); the difference between groups was 0.79±4.16 [1.04±4.02] points (p=0.0870 [p=0.0416]). The number of patients with adverse events (AEs) in Rengalin (n=13) and Placebo (n=12) groups did not have significant differences (p=1.00). No AEs with certain relationship with study drug were registered. CONCLUSION: Rengalin is an effective and safe drug in patients with stable COPD and persistent cough, despite stable doses of maintenance therapy according to the GOLD guidelines. Four-week therapy decreases severity of cough by two times in more than 40% of patients. TRIAL REGISTRATION: ClinicalTrials.gov (id: NCT03159091).

Forest fire induces short-term shifts in soil food webs with consequences for carbon cycling.

We tested for fire-induced (5-6 years post-fire) changes in the structure and functioning of the soil food web along a 3000-km north-south transect across European Russia, spanning all major forest types in the northern hemisphere outside the tropics. The total biomass of the detrital food web, including microbes and invertebrates, was not affected by fire. However, fire reduced the biomass of microfauna and mites, but had no impact on mesofauna or macrofauna. Fire also reduced rates of carbon (C) mobilisation by soil biota. Our results demonstrate that fire-induced shifts in soil food webs have significant short-term effects on forest soil C cycling, but that these effects vary across forest types and geographic locations.

Ecotoxicological effects of traffic-related pollutants in roadside soils of Moscow.

The objective of this research is to find correlations between traffic-related contaminants in the roadside soils and their ecotoxicity. The study was conducted in Moscow in the vicinity of a highway of 125 000 vehicles per day. The topsoils (0-3 cm depth) were sampled perpendicular to the road at 1-, 6-, 10-, 18- and 50-m distances from the roadbed. Total petroleum hydrocarbons (TPH), polycyclic aromatic hydrocarbons (PAH), heavy metals (HM) in total and phyto-available forms, and deicing salts (DS) were determined. A battery of soil-contacting organisms was tested: phytotoxicity of rye (H. vulgare L.) and garden cress (L. sativum L.); E. foetida earthworm growth rate and mortality; basal and substrate-induced respiration activity, nitrogen fixation and the denitrification activity of the soil microbial complex. To determine the possible risk to aquatic ecosystems, the algal toxicity test (S. quadricauda) was provided. Correlations between "chemical" data and intensity of "biological" effects were analyzed. Concentrations of most contaminants declined to the background values with distance from the road increase. However, the toxicity of roadside soils was obtained for all examined organisms within the whole 50 m zone. Live organisms exhibited different sensitivities to roadside soils pollution. The intensity of inhibition effects decreased in order: higher plants > earthworms and microorganisms > algae. The risk for aquatic ecosystems was assessed as low. Higher plants toxicity correlated with TPH, PAH, some HM, and DS; earthworm toxicity correlated with TPH, some PAH, HM, and DS; microorganism toxicity correlated with TPH and DS; algae had no observed correlations with contaminants. TPH and DS were general ecotoxicants affecting all organisms. Higher plants may be considered the PAH indicators and earthworms as HM indicators. A set of higher plants and earthworms may be recommended as the reduced test-battery of relevant organisms for cost-effective assessment of the toxicity of roadside soils.

The Cyanotoxin BMAA Induces Heterocyst Specific Gene Expression in Anabaena sp. PCC 7120 under Repressive Conditions.

Cyanobacteria synthesize neurotoxic ß-N-methylamino-l-alanine (BMAA). The roles of this non-protein amino acid in cyanobacterial cells are insufficiently studied. During diazotrophic growth, filamentous cyanobacteria form single differentiated cells, called heterocysts, which are separated by approximately 12⁻15 vegetative cells. When combined nitrogen is available, heterocyst formation is blocked and cyanobacterial filaments contain only vegetative cells. In the present study, we discovered that exogenous BMAA induces the process of heterocyst formation in filamentous cyanobacteria under nitrogen-replete conditions that normally repress cell differentiation. BMAA treated cyanobacteria form heterocyst-like dark non-fluorescent non-functional cells. It was found that glutamate eliminates the BMAA mediated derepression. Quantitative polymerase chain reaction (qPCR) permitted to detect the BMAA impact on the transcriptional activity of several genes that are implicated in nitrogen assimilation and heterocyst formation in Anabaena sp. PCC 7120. We demonstrated that the expression of several essential genes increases in the BMAA presence under repressive conditions.

Synthesis and antimicrobial activity of novel structural hybrids of benzofuroxan and benzothiazole derivatives.

New compounds containing both benzofuroxan and benzothiazole scaffolds were synthesized through electrophile/nucleophile combination of nitrobenzofuroxan derivatives and 2-mercapto- or 2-aminobenzothiazole derivatives and their biological effect on the natural strain Vibrio genus and different bacterial lux-biosensors was studied. Among all the compounds synthesized, that obtained from 2-mercaptobenzothiazole and 7-chloro-4,6-dinitrobenzofuroxan was toxic for bacterial cells, and also able to activated the 1st type Quorum Sensing system. The reaction between 7-chloro-4,6-dinitrobenzofuroxan and 2-aminobenzothiazole derivatives gave two products, one bearing the benzofuroxan moiety linked to the exocyclic amino nitrogen, and the second derived from the attack of two molecules of electrophile to both the nitrogen atoms of the benzothiazole reagent. Their relative ratio is modifiable by tuning the reagents ratio and the reaction time.

Poultry-beneficial solid-state Bacillus amyloliquefaciens B-1895 fermented soybean formulation.

Birds were given a new formulation of the Bacillus amyloliquefaciens B-1895 solid-state fermented soybean that retained the spores of the aforementioned organism. Mass dynamics, feed flow rate and broiler performance were observed to evaluate the efficacy of the formulation. At each time point, the live mass was greater than that of the control group, reaching a difference of 7-8% by day 28. A difference of 5.3-8.8% was observed in feed conversion per kilogram live mass (1.97 kg in the controls as compared with 1.81-1.87 kg in experimental groups). This indicates a positive effect of the B. amyloliquefaciens B-1895 formulation on the live mass of broilers as well as on feed consumption.

Desert gerbils affect bacterial composition of soil.

Rodents affect soil microbial communities by burrow architecture, diet composition, and foraging behavior. We examined the effect of desert rodents on nitrogen-fixing bacteria (NFB) communities by identifying bacteria colony-forming units (CFU) and measuring nitrogen fixation rates (ARA), denitrification (DA), and CO2 emission in soil from burrows of three gerbil species differing in diets. Psammomys obesus is folivorous, Meriones crassus is omnivorous, consuming green vegetation and seeds, and Dipodillus dasyurus is predominantly granivorous. We also identified NFB in the digestive tract of each rodent species and in Atriplex halimus and Anabasis articulata, dominant plants at the study site. ARA rates of soil from burrows of the rodent species were similar, and substantially lower than control soil, but rates of DA and CO2 emission differed significantly among burrows. Highest rates of DA and CO2 emission were measured in D. dasyurus burrows and lowest in P. obesus. CFU differed among bacteria isolates, which reflected dietary selection. Strains of cellulolytic representatives of the family Myxococcaceae and the genus Cytophaga dominated burrows of P. obesus, while enteric Bacteroides dominated burrows of D. dasyurus. Burrows of M. crassus contained both cellulolytic and enteric bacteria. Using discriminant function analysis, differences were revealed among burrow soils of all rodent species and control soil, and the two axes accounted for 91 % of the variance in bacterial occurrences. Differences in digestive tract bacterial occurrences were found among these rodent species. Bacterial colonies in P. obesus and M. crassus burrows were related to bacteria of A. articulata, the main plant consumed by both species. In contrast, bacteria colonies in the burrow soil of D. dasyurus were related to bacteria in its digestive tract. We concluded that gerbils play an important role as ecosystem engineers within their burrow environment and affect the microbial complex of the nitrogen-fixing organisms in soils.