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Combination of waning immunity and lower effectiveness against new SARS-CoV-2 variants of approved COVID-19 vaccines necessitates new vaccines. We evaluated two doses, 28 days apart, of ARCT-154, a self-amplifying mRNA COVID-19 vaccine, compared with saline placebo in an integrated phase 1/2/3a/3b controlled, observer-blind trial in Vietnamese adults (ClinicalTrial.gov identifier: NCT05012943). Primary safety and reactogenicity outcomes were unsolicited adverse events (AE) 28 days after each dose, solicited local and systemic AE 7 days after each dose, and serious AEs throughout the study. Primary immunogenicity outcome was the immune response as neutralizing antibodies 28 days after the second dose. Efficacy against COVID-19 was assessed as primary and secondary outcomes in phase 3b. ARCT-154 was well tolerated with generally mild–moderate transient AEs. Four weeks after the second dose 94.1% (95% CI: 92.1–95.8) of vaccinees seroconverted for neutralizing antibodies, with a geometric mean-fold rise from baseline of 14.5 (95% CI: 13.6–15.5). Of 640 cases of confirmed COVID-19 eligible for efficacy analysis most were due to the Delta (B.1.617.2) variant. Efficacy of ARCT-154 was 56.6% (95% CI: 48.7– 63.3) against any COVID-19, and 95.3% (80.5–98.9) against severe COVID-19. ARCT-154 vaccination is well tolerated, immunogenic and efficacious, particularly against severe COVID-19 disease. In this randomized, controlled integrated phase 1/2/3a/3b clinical trial, the authors show that the self-amplifying mRNA COVID-19 vaccine ARCT-154 shows good immunogenicity and is safe and efficient against COVID-19 (57% against any COVID-19, and 95% against severe COVID-19).

Ornithine transcarbamylase (OTC) catalyses the reaction from ornithine to citrulline in the urea cycle. Ornithine transcarbamylase deficiency (OTCD) results in episodes of hyperammonemia. Arcturus Therapeutics developed a lipid nanoparticle (LNP)‐encapsulated OTC‐mRNA (LUNAR‐OTC) that results in a replacement enzyme and is currently undergoing clinical trials. In this study, the efficacy of LUNAR OTC‐mRNA drug in the spfash mouse model was examined by measuring the OTC enzyme activity and protein expression in the liver and plasma of OTC‐mRNA‐treated mice. Using purified citrulline‐D4 as the substrate improved the sensitivity of the OTC activity assay and allowed us to quantify the ornithine‐D4 product from the mouse plasma samples. OTC activity in the liver showed a clear dose response: The lowest dose, 0.3 mg/kg, resulted in higher activity than that of the untreated group, and the highest dose, 3 mg/kg, resulted in completely restored OTC activity in the liver. OTC activity in plasma was also dose‐dependent. A clear positive correlation between the OTC activity in the liver and that in the plasma suggests that the plasma OTC activity assay may serve as a surrogate for measuring OTC activity in liver biopsy samples. In addition, the OTC protein expression levels correlated well with the OTC activity in liver samples, but there was no quantifiable OTC protein in the plasma samples. This finding suggests that the sensitivity of the OTC activity assay is superior to that of the protein expression assay. Overall, the results of this study suggest that the OTC activity assay described here can be used as a clinical pharmacodynamic endpoint to measure the effectiveness of OTCD treatment. Patients of ornithine transcarbamylase (OTC) deficiency lack the OTC activity in the liver. Using an OTC deficiency mouse model, we demonstrated that LUNAR‐OTC, an OTC mRNA medicine, enables full restoration of OTC activity in mouse liver. Moreover, the OTC activity in the plasma is a surrogate assay for OTC activity in the liver, which can serve as a pharmacodymaic endpoint without the necessity of liver biopsies.

ABSTRACT A self-transcribing and replicating RNA (STARR™) based vaccine (LUNAR®-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 full length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolong SARS-CoV-2 spike glycoprotein expression. A single prime vaccination in mice led to robust antibody responses, with neutralizing antibody titers increasing up to day 60. Activation of cell mediated immunity produced a strong viral antigen specific CD8+ T lymphocyte response. Assaying for intracellular cytokine staining for IFN-γ and IL-4 positive CD4+ T helper lymphocytes as well as anti-spike glycoprotein IgG2a/IgG1 ratios supported a strong Th1 dominant immune response. Finally, single LUNAR-COV19 vaccination at both 2 μg and 10 μg doses completely protected human ACE2 transgenic mice from both mortality and even measurable infection following wild-type SARS-CoV-2 challenge. Our findings collectively suggest the potential of Lunar-COV19 as a single dose vaccine. Competing Interest Statement Daiki Matsuda, Elizabeth Allen, Paula Hartma3, Jenny Park, Maher Alayyoubi, Hari Bhaskaran, Adrian Dukanovic, Belle Bao, Brenda Clemente, Jerel Vega, Scott Roberts, Jose A. Gonzalez, Marciano Sablad, Rodrigo Yelin, Wendy Taylor, Kiyoshi Tachikawa, Suezanne Parker, Priya Karmali, Jared Davis, Sean M. Sullivan, Steve G. Hughes, Pad Chivukula are salaried employees of Arcturus Therapeutics, Inc. San Diego CA

Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity. As phase 1 of the Earth Microbiome Project, analysis of 16S ribosomal RNA sequences from more than 27,000 environmental samples delivers a global picture of the basic structure and drivers of microbial distribution. Earth's microbial diversity In this meta-analysis of studies from the Earth Microbiome Project, Luke Thompson et al . have developed a standardized collection, curation and analysis pipeline to examine 16S ribosomal RNA (rRNA) tag sequences of more than 27,000 samples (representing soil, water, animal-associated and plant-associated habitats), providing global context for the basic structure and drivers of bacterial and archaeal distribution. The work not only provides an important reference database and framework for future studies in microbial ecology, but also reveals patterns in community composition as well as the global distribution of particular organisms. These findings provide a deeper understanding of dispersal and niche colonization.

ObjectiveOccupational exposure to pesticides is a known risk for disrupting cellular immune response in flower workers due to their use of multiple chemical products, poor work conditions, and inadequate protection. Recently, the analysis of pesticide use patterns has emerged as an alternative to studying exposure to mixtures of these products. This study aimed to evaluate the association between exposure to different patterns of pesticide use and the cytokine profile of flower workers in the State of Mexico and Morelos, Mexico.MethodsA cross-sectional study was carried out on a population of 108 flower workers. Serum levels of IL-4, IL-5, IL-6, IL-8, IL-10 cytokines were analyzed by means of multiplex analysis, and TNF-α and IFN-γ using an ELISA test. Pesticide use patterns were generated by principal components analysis.ResultsThe analysis revealed that certain patterns of pesticide use, combining insecticides and fungicides, were associated with higher levels of pro-inflammatory cytokines, particularly IL-6 and IFN-γ.ConclusionThese findings indicate that pesticides may possess immunotoxic properties, contributing to increased inflammatory response. However, further comprehensive epidemiological studies are needed to establish a causal relationship.

Basilar artery occlusion (BAO) may be clinically occult due to variable and non-specific symptomatology. We evaluated the qualitative and quantitative determination of a hyperdense basilar artery (HDBA) on non-contrast computed tomography (NCCT) brain for the diagnosis of BAO. We conducted a case control study of patients with confirmed acute BAO vs a control group of suspected acute stroke patients without BAO. Two EM attending physicians, one third-year EM resident, and one medical student performed qualitative and quantitative assessments for the presence of a HDBA on axial NCCT images. Our primary outcome measures were sensitivity and specificity for BAO. Our secondary outcomes were inter-rater and intra-rater reliability of the qualitative and quantitative assessments. We included 60 BAO and 65 control patients in our analysis. Qualitative assessment of the hyperdense basilar artery sign was poorly sensitive (54%-72%) and specific (55%-89%). Quantitative measurement improved the specificity of hyperdense basilar artery assessment for diagnosing BAO, with a threshold of 61.0-63.8 Hounsfield units demonstrating relatively high specificity of 85%-94%. There was moderate inter-rater agreement for the qualitative assessment of HDBA (Fleiss' kappa statistic 0.508, 95% confidence interval: 0.435-0.581). Agreement improved for quantitative assessments, but still fell in the moderate range (Shrout-Fleiss intraclass correlation coefficient: 0.635). Intra-rater reliability for the quantitative assessments of the two attending physician reviewers demonstrated substantial consistency. Our results highlight the importance of carefully examining basilar artery density when interpreting the NCCT of patients with altered consciousness or other signs and symptoms concerning for an acute basilar artery occlusion. If the Hounsfield unit density of the basilar artery exceeds 61 Hounsfield units, BAO should be highly suspected.

• Premise of the study: Phenotypic acclimation of individual plants and genetic differentiation by natural selection within invasive populations are two potential mechanisms that may confer fitness advantages and allow plants to cope with environmental variation. The invasion of Spartina densiflora across a wide latitudinal gradient from California (USA) to British Columbia (Canada) provides a natural model system to study the potential mechanisms underlying the response of invasive populations to substantial variation in climate and other environmental variables. • Methods: We examined morphological and physiological leaf traits of Spartina densiflora plants in populations from invaded estuarine sites across broad latitudinal and climate gradients along the Pacific west coast of North America and in favorable conditions in a common garden experiment. • Key results: Our results show that key foliar traits varied widely among populations. Most foliar traits measured in the field were lower than would be expected under ideal growing conditions. Photosynthetic pigment concentrations at higher latitudes were lower than those observed at lower latitudes. Greater leaf rolling, reduced leaf lengths, and lower chlorophyll and higher carbon concentrations were observed with anoxic sediments. Lower chlorophyll to carotenoids ratios and reduced nitrogen concentrations were correlated with sediment salinity. Our results suggest that the variations of foliar traits recorded in the field are a plastic phenotypic response that was not sustained under common garden conditions. • Conclusions: Spartina densiflora shows wide differences in its foliar traits in response to environmental heterogeneity in salt marshes, which appears to be the result of phenotypic plasticity rather than genetic differentiation.