Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial.

BACKGROUND: Additional safe and efficacious vaccines are needed to control the COVID-19 pandemic. We aimed to analyse the efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate. METHODS: HERALD is a randomised, observer-blinded, placebo-controlled, phase 2b/3 clinical trial conducted in 47 centres in ten countries in Europe and Latin America. By use of an interactive web response system and stratification by country and age group (18-60 years and ≥61 years), adults with no history of virologically confirmed COVID-19 were randomly assigned (1:1) to receive intramuscularly either two 0·6 mL doses of CVnCoV containing 12 µg of mRNA or two 0·6 mL doses of 0·9% NaCl (placebo) on days 1 and 29. The primary efficacy endpoint was the occurrence of a first episode of virologically confirmed symptomatic COVID-19 of any severity and caused by any strain from 15 days after the second dose. For the primary endpoint, the trial was considered successful if the lower limit of the CI was greater than 30%. Key secondary endpoints were the occurrence of a first episode of virologically confirmed moderate-to-severe COVID-19, severe COVID-19, and COVID-19 of any severity by age group. Primary safety outcomes were solicited local and systemic adverse events within 7 days after each dose and unsolicited adverse events within 28 days after each dose in phase 2b participants, and serious adverse events and adverse events of special interest up to 1 year after the second dose in phase 2b and phase 3 participants. Here, we report data up to June 18, 2021. The study is registered at ClinicalTrials.gov, NCT04652102, and EudraCT, 2020-003998-22, and is ongoing. FINDINGS: Between Dec 11, 2020, and April 12, 2021, 39 680 participants were enrolled and randomly assigned to receive either CVnCoV (n=19 846) or placebo (n=19 834), of whom 19 783 received at least one dose of CVnCoV and 19 746 received at least one dose of placebo. After a mean observation period of 48·2 days (SE 0·2), 83 cases of COVID-19 occurred in the CVnCoV group (n=12 851) in 1735·29 person-years and 145 cases occurred in the placebo group (n=12 211) in 1569·87 person-years, resulting in an overall vaccine efficacy against symptomatic COVID-19 of 48·2% (95·826% CI 31·0-61·4; p=0·016). Vaccine efficacy against moderate-to-severe COVID-19 was 70·7% (95% CI 42·5-86·1; CVnCoV 12 cases in 1735·29 person-years, placebo 37 cases in 1569·87 person-years). In participants aged 18-60 years, vaccine efficacy against symptomatic disease was 52·5% (95% CI 36·2-64·8; CVnCoV 71 cases in 1591·47 person-years, placebo, 136 cases in 1449·23 person-years). Too few cases occurred in participants aged 61 years or older (CVnCoV 12, placebo nine) to allow meaningful assessment of vaccine efficacy. Solicited adverse events, which were mostly systemic, were more common in CVnCoV recipients (1933 [96·5%] of 2003) than in placebo recipients (1344 [67·9%] of 1978), with 542 (27·1%) CVnCoV recipients and 61 (3·1%) placebo recipients reporting grade 3 solicited adverse events. The most frequently reported local reaction after any dose in the CVnCoV group was injection-site pain (1678 [83·6%] of 2007), with 22 grade 3 reactions, and the most frequently reported systematic reactions were fatigue (1603 [80·0%] of 2003) and headache (1541 [76·9%] of 2003). 82 (0·4%) of 19 783 CVnCoV recipients reported 100 serious adverse events and 66 (0·3%) of 19 746 placebo recipients reported 76 serious adverse events. Eight serious adverse events in five CVnCoV recipients and two serious adverse events in two placebo recipients were considered vaccination-related. None of the fatal serious adverse events reported (eight in the CVnCoV group and six in the placebo group) were considered to be related to study vaccination. Adverse events of special interest were reported for 38 (0·2%) participants in the CVnCoV group and 31 (0·2%) participants in the placebo group. These events were considered to be related to the trial vaccine for 14 (<0·1%) participants in the CVnCoV group and for five (<0·1%) participants in the placebo group. INTERPRETATION: CVnCoV was efficacious in the prevention of COVID-19 of any severity and had an acceptable safety profile. Taking into account the changing environment, including the emergence of SARS-CoV-2 variants, and timelines for further development, the decision has been made to cease activities on the CVnCoV candidate and to focus efforts on the development of next-generation vaccine candidates. FUNDING: German Federal Ministry of Education and Research and CureVac.

Human Microcirculation-on-Chip Models in Cancer Research: Key Integration of Lymphatic and Blood Vasculatures.

Cancer metastasis is a highly complex and multistep process, which is initiated by the invasion of tumor cells into the microcirculation system. A diverse variety of organ-on-chip models are described investigating this critical event. However, most of these models solely integrate the blood vasculature and overlook the fundamental role of the lymphatic system despite the solid evidence showing that cancer cells mainly use this vascular network to initiate metastasis. Herein, the latest advances in the field of organ-on-chip models of the human microcirculation system in cancer research are reviewed. The reported models are employed to investigate the mechanistic determinants of tumor physiopathology and for the screening of new anticancer drugs under the scope of the microcirculation bed. Overall, the development of complete microcirculation-on-chip models integrating the blood and lymphatic vasculatures is expected to provide key insights into the drug delivery process, the screening of novel therapeutic compounds, or the mechanism of tumor invasion and metastasis, among others.

A colorimetric strategy based on dynamic chemistry for direct detection of Trypanosomatid species.

Leishmaniasis and Chagas disease are endemic in many countries, and re-emerging in the developed countries. A rapid and accurate diagnosis is important for early treatment for reducing the duration of infection as well as for preventing further potential health complications. In this work, we have developed a novel colorimetric molecular assay that integrates nucleic acid analysis by dynamic chemistry (ChemNAT) with reverse dot-blot hybridization in an array format for a rapid and easy discrimination of Leishmania major and Trypanosoma cruzi. The assay consists of a singleplex PCR step that amplifies a highly homologous DNA sequence which encodes for the RNA component of the large ribosome subunit. The amplicons of the two different parasites differ between them by single nucleotide variations, known as "Single Nucleotide Fingerprint" (SNF) markers. The SNF markers can be easily identified by naked eye using a novel micro Spin-Tube device "Spin-Tube", as each of them creates a specific spot pattern. Moreover, the direct use of ribosomal RNA without requiring the PCR pre-amplification step is also feasible, further increasing the simplicity of the assay. The molecular assay delivers sensitivity capable of identifying up to 8.7 copies per µL with single mismatch specificity. The Spin-Tube thus represents an innovative solution providing benefits in terms of time, cost, and simplicity, all of which are crucial for the diagnosis of infectious disease in developing countries.

High plasma adenosine levels in overweight/obese pregnant women.

We aim to investigate whether overweight/obese pregnant women have elevated plasma levels of adenosine associated with increased consumption of high-calorie food. Sixty women were included. They were divided into lean (n = 23 and n = 12) or overweight/obese (n = 7 and n = 18) non-pregnant and pregnant women, respectively. Clinical records and maternal blood samples were collected after informed consent. A self-reported dietary questionnaire was also completed. Plasma adenosine levels were determined with high-performance liquid chromatography. Biochemical parameters, including glucose, total protein, and lipid profile, were determined using standard colorimetric assays. Adenosine levels were higher in pregnant women than in non-pregnant women (18.7 ± 1.6 vs 10.8 ± 1.3 nM/µg protein, respectively, p < 0.0001). Overweight/obese pregnant women (21.9 ± 2.5 nM/µg protein) exhibited higher adenosine levels than lean pregnant (14.5 ± 1.0 nM/µg protein, p = 0.04) or non-pregnant women (11.7 ± 1.5 nM/µg protein, p = 0.0005). Also, pregnant women with elevated weight gain exhibited higher (26.2 ± 3.7 nM/µg protein) adenosine levels than those with adequate weight gain (14.9 ± 1.4 nM/µg protein, p = 0.03). These differences were not statistically significant compared with those of pregnant women with reduced weight gain (17.4 ± 2.1 nM/µg protein, p = 0.053). Body mass index and adenosine only in pregnant women were positively correlated (r = 0.39, p = 0.02). While, polyunsaturated fatty acid (PUFA) consumption was negatively correlated with plasma adenosine levels only in non-pregnant women (r = -0.33, p = 0.03). Pregnancy is associated with high plasma adenosine levels, which are further elevated in pregnant women who are overweight/obese. High PUFA intake might reduce plasma adenosine levels in non-pregnant women.

Novel bead-based platform for direct detection of unlabelled nucleic acids through Single Nucleobase Labelling.

Over the last decade, circulating microRNAs have received attention as diagnostic and prognostic biomarkers. In particular, microRNA122 has been demonstrated to be an early and more sensitive indicator of drug-induced liver injury than the widely used biomarkers such as alanine aminotransferase and aspartate aminotransferase. Recently, microRNA122 has been used in vitro to assess the cellular toxicity of new drugs and as a biomarker for the development of a rapid test for drug overdose/liver damage. In this proof-of-concept study, we report a PCR-free and label-free detection method that has a limit of detection (3 standard deviations) of 15 fmoles of microRNA122, by integrating a dynamic chemical approach for "Single Nucleobase Labelling" with a bead-based platform (Luminex®) thereby, in principle, demonstrating the exciting prospect of rapid and accurate profiling of any microRNAs related to diseases and toxicology.

Synthesis of 6,8,9 poly-substituted purine analogue libraries as pro-apoptotic inducers of human leukemic lymphocytes and DAPK-1 inhibitors.

A 18-member library of 6,8,9-poly-substituted purines was prepared from pyrimidines, primary alcohols, and N,N-dimethylamides under basic conditions via a novel one-pot synthetic pathway controlled by amide sizes and the novel analogues were tested against two leukemia cell lines: Jurkat (acute T cell leukemia) and K562 (chronic erythroleukemia) cells. Compounds having a benzoxy group at C6 position of the aromatic ring exhibited antiproliferative activity in Jurkat cells whereas all compounds induced a lower effect on K562 cells. Analysis of cell cycle, Annexin-V staining, and cleavage of initiator caspases assays showed that the active purine analogues induce cell death by apoptosis. Based on these results, a new purine derivative was synthesized, 6-benzyloxy-9-tert-butyl-8-phenyl-9H-purine (6d), which displayed the highest activity of the series against Jurkat cell lines. Finally, (33)P-radiolabeled kinase assays using 96 recombinant human kinases known to be involved in apoptotic events were performed. Just one of the kinases tested, DAPK-1, was inhibited 50% or more by the phenotypic hits at 10 µM, suggesting that the inhibition of this target could be responsible for the induction of cell death by apoptosis. In agreement with the phenotypic results, the most active antiproliferative agent, 6d, displayed also the lowest IC50 value against recombinant DAPK1 (2.5 µM), further supporting the potential role of this protein on the observed functional response. DAPK-1 inhibition led by 6d together with its pro-apoptotic properties against the Jurkat line makes it an interesting candidate to further investigate the role of DAPK1 kinase in triggering apoptosis in cancer cells, a role which is attracting recent interest.

La explotación sexual comercial infantil: una ganancia subjetiva / A exploração sexual comercial infantil: um ganho subjetivo / Child sexual commercial exploitation: a subjective gain

La explotación sexual comercial infantil (Esci) es un problema que crece día a día en nuestro país, y afecta considerablemente el desarrollo físico y psicológico de los menores y las menores de edad involucrados en estas prácticas. El estudio realizado por el grupo de investigación Crecer del programa de psicología de la Universidad Surcolombiana de Neiva, sintetizado en este artículo, abordó esta problemática en los municipios de Neiva, Campoalegre y Pitalito, del departamento del Huila, a través de un enfoque metodológico cualitativo. El estudio permitió encontrar que para los niños, niñas y adolescentes participantes en esta investigación, la explotación sexual comercial infantil representa una ganancia subjetiva, ante una historia de carencias económicas y afectivas.

A exploração sexual comercial infantil (ESCI) é um problema que cresce dia a dia em nosso pais e afeta atenciosamente o desenvolvimento físico e psicológico dos menores e das menores envolvidas nestas práticas. O estudo realizado pelo grupo de pesquisa Crecer do programa de Psicologia da Universidade Surcolombiana de Neiva e sintetizado neste artigo abordou esta problemática nas municipalidades de Neiva, Campoalegre e Pitalito, no estado do Huila, através duma abordagem metodológica qualitativa. O estudo permitiu descobrir que para os meninos, as meninas e adolescentes participantes nesta pesquisa, a exploração sexual comercial infantil representa um ganho subjetivo com relação a uma história de carências econômicas e afetivas.

Child Sexual Commercial Exploitation (CSCE) is an ever growing issue in our country which affects considerably the physical and psychological development of minors involved in this practice. This study developed by CRECER research group belonging to the Psychology Program at Universidad Surcolombiana in Neiva, Colombia, summarized in this article, approached this problem in the municipalities of Neiva, Campoalegre and Pitalito, in the Province of Huila, through a qualitative methodological approach. A finding from this study is that for the girls, boys and adolescents participating in it, child sexual commercial exploitation represents a subjective gain before a story of economic and affective lacks.

Talla materna y crecimiento del lactante nacido pretérmino / Maternal height and growth of Chilean premature infants

El objetivo fue estudiar la asociación entre la talla materna y el crecimiento post natal de los hijos nacidos pretérmino adecuados para la edad gestacional (AEG) en el Hospital Herminda Martín de Chillán, durante sus primeros 4 meses de vida y analizar los factores de riesgo que influyen en ese crecimiento. Se estudiaron 80 niños nacidos entre enero y septiembre de 1995, con peso de nacimiento menor a 2500 gramos y edad gestacional mayor igual 36 semanas. Se les aplicó encuesta socioeconómica a la madre, registrándose el crecimiento en el consultorio de atención primaria donde eran controlados. La talla materna se categorizó, de cuerdo a la media ñ 1 desviación estándar (154,7 ñ 7.1cm), en tres grupos 52 se catalogaron como madres de talla media (entre 147,58 y 161,79 cm), 14 como madres de talla baja (entre 161.8cm y 175cm). Los hijos de madres de talla alta tienden acrecer mejor que los de talla baja en los primeros 4 meses de vida, estando más afectada la talla/edad (15,3 versus 13,6 cm). La escolaridad de la madre influye sobre el crecimiento y estado nutricional del niño donde las madres de talla alta con más de 8 años de estudio sus hijos al cuarto mes de vida presenta un mejor estado nutricional por puntaje z T/E que los de madres de talla baja. Concluimos que los lactantes prematuros nacidos en el Hospital Herminda Martín de Chillán (Chile) hijos de madres de talla baja tienen un menor crecimiento que los hijos de madres de talla alta en los primeros 4 meses de vida