RBD-specific polyclonal F(ab´)2 fragments of equine antibodies in patients with moderate to severe COVID-19 disease: A randomized, multicenter, double-blind, placebo-controlled, adaptive phase 2/3 clinical trial

Background: passive immunotherapy is a therapeutic alternative for patients with COVID-19. Equine polyclonal antibodies (EpAbs) could represent a source of scalable neutralizing antibodies against SARS-CoV-2. Methods: we conducted a double-blind, randomized, placebo-controlled trial to assess efficacy and safety of EpAbs (INM005) in hospitalized adult patients with moderate and severe COVID-19 pneumonia in 19 hospitals of Argentina. Primary endpoint was improvement in at least two categories in WHO ordinal clinical scale at day 28 or hospital discharge (ClinicalTrials.gov number NCT04494984). Findings: between August 1st and October 26th, 2020, a total of 245 patients were enrolled. Enrolled patients were assigned to receive two blinded doses of INM005 (n = 118) or placebo (n = 123). Median age was 54 years old, 65 1% were male and 61% had moderate disease at baseline. Median time from symptoms onset to study treatment was 6 days (interquartile range 5 to 8). No statistically significant difference was noted between study groups on primary endpoint (risk difference [95% IC]: 5 28% [-3 95; 14 50]; p = 0 15). Rate of improvement in at least two categories was statistically significantly higher for INM005 at days 14 and 21 of follow-up. Time to improvement in two ordinal categories or hospital discharge was 14 2 (§ 0 7) days in the INM005 group and 16 3 (§ 0 7) days in the placebo group, hazard ratio 1 31 (95% CI 1 0 to 1 74). Subgroup analyses showed a beneficial effect of INM005 over severe patients and in those with negative baseline antibodies. Overall mortality was 6 9% the INM005 group and 11 4% in the placebo group (risk difference [95% IC]: 0 57 [0 24 to 1 37]). Adverse events of special interest were mild or moderate; no anaphylaxis was reported. Interpretation: Albeit not having reached the primary endpoint, we found clinical improvement of hospitalized patients with SARS-CoV-2 pneumonia, particularly those with severe disease.Fil: Lopardo, Gustavo. Municipalidad de Vicente Lopez (buenos Aires). Hospital Municipal Doctor Bernardo Houssay.; ArgentinaFil: Belloso, Waldo H.. Hospital Italiano; ArgentinaFil: Nannini, Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Colonna, Mariana. Inmunova; ArgentinaFil: Sanguineti, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Inmunova; ArgentinaFil: Zylberman, Vanesa. Inmunova; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Muñoz, Luciana. Inmunova; ArgentinaFil: Dobarro, Martín. Sanatorio Sagrado Corazón; ArgentinaFil: Lebersztein, Gabriel. Sanatorio Sagrado Corazón; ArgentinaFil: Farina, Javier. Gobierno de la Provincia de Buenos Aires. Hospital de Alta Complejidad Cuenca Alta Doctor Nestor Carlos Kirchner.; ArgentinaFil: Vidiella, Gabriela. Sanatorio Agote. Dr. Luis Agote; ArgentinaFil: Bertetti, Anselmo. Sanatorio Guemes Sociedad Anonima.; ArgentinaFil: Crudo, Favio. Universidad Nacional de San Antonio de Areco; ArgentinaFil: Alzogaray, Maria Fernanda. Instituto Medico Platense.; ArgentinaFil: Barcelona, Laura. Municipalidad de Vicente Lopez (buenos Aires). Hospital Municipal Doctor Bernardo Houssay.; ArgentinaFil: Teijeiro, Ricardo. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Doctor Ignacio Pirovano; ArgentinaFil: Lambert, Sandra. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; ArgentinaFil: Scublinsky, Darío. Clinica Zabala.; ArgentinaFil: Iacono, Marisa. Provincia del Neuquen. Hospital Provincial Neuquen "dr. E. Castro Rendon"; ArgentinaFil: Stanek, Vanina. Hospital Italiano; ArgentinaFil: Solari, Rubén. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Cruz, Pablo. No especifíca;Fil: Casas, Marcelo Martín. Clinica Adventista Belgrano; ArgentinaFil: Abusamra, Lorena. Hospital Municipal Dr. Diego Thompson; ArgentinaFil: Luciardi, Héctor Lucas. Provincia de Tucuman. Ministerio de Salud. Sistema Provincial de Salud. Hosp. Centro de Salud "zenon Santillan"; ArgentinaFil: Cremona, Alberto. Hospital Italiano de La Plata; ArgentinaFil: Caruso, Diego. Hospital Español; ArgentinaFil: de Miguel, Bernardo. No especifíca;Fil: Perez Lloret, Santiago. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires"; Argentina. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Millán, Susana. No especifíca;Fil: Kilstein, Yael. No especifíca;Fil: Pereiro, Ana. Fundación Mundo Sano; ArgentinaFil: Sued, Omar. Fundación Huésped; ArgentinaFil: Cahn, Pedro. Fundación Huésped; ArgentinaFil: Spatz, Linus. Inmunova; ArgentinaFil: Goldbaum, Fernando Alberto. Inmunova; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad Nacional de San Martin. Centro de Rediseño E Ingenieria de Proteinas.; Argentin

Relevance of the Diversity among Members of the Trypanosoma Cruzi Trans-Sialidase Family Analyzed with Camelids Single-Domain Antibodies

The sialic acid present in the protective surface mucin coat of Trypanosoma cruzi is added by a membrane anchored trans-sialidase (TcTS), a modified sialidase that is expressed from a large gene family. In this work, we analyzed single domain camelid antibodies produced against trans-sialidase. Llamas were immunized with a recombinant trans-sialidase and inhibitory single-domain antibody fragments were obtained by phage display selection, taking advantage of a screening strategy using an inhibition test instead of the classic binding assay. Four single domain antibodies displaying strong trans-sialidase inhibition activity against the recombinant enzyme were identified. They share the same complementarity-determining region 3 length (17 residues) and have very similar sequences. This result indicates that they likely derived from a unique clone. Probably there is only one structural solution for tight binding inhibitory antibodies against the TcTS used for immunization. To our surprise, this single domain antibody that inhibits the recombinant TcTS, failed to inhibit the enzymatic activity present in parasite extracts. Analysis of individual recombinant trans-sialidases showed that enzymes expressed from different genes were inhibited to different extents (from 8 to 98%) by the llama antibodies. Amino acid changes at key positions are likely to be responsible for the differences in inhibition found among the recombinant enzymes. These results suggest that the presence of a large and diverse trans-sialidase family might be required to prevent the inhibitory response against this essential enzyme and might thus constitute a novel strategy of T. cruzi to evade the host immune system

Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

The Crystal Structure and Mode of Action of Trans-Sialidase, a Key Enzyme in Trypanosoma Cruzi Pathogenesis

International audienceTrans-sialidases (TS) are GPI-anchored surface enzymes expressed in specific developmental stages of trypanosome parasites like Trypanosoma cruzi, the etiologic agent of Chagas disease, and T. brucei, the causative agent of sleeping sickness. TS catalyzes the transfer of sialic acid residues from host to parasite glycoconjugates through a transglycosidase reaction that appears to be critical for T. cruzi survival and cell invasion capability. We report here the structure of the T. cruzi trans-sialidase, alone and in complex with sugar ligands. Sialic acid binding is shown to trigger a conformational switch that modulates the affinity for the acceptor substrate and concomitantly creates the conditions for efficient transglycosylation. The structure provides a framework for the structure-based design of novel inhibitors with potential therapeutic applications

Improved assessment methods for static and fatigue resistance of old metal railway bridges

This paper presents the recommendations and advices proposed for the assessment of old riveted structures within the set of guidelines developed in the Sustainable Bridges Integrated Project. The proposed assessment methods focuses on fatigue and ultimate load limit states. Three main topics are developed. For the first one, emphasis is given to the analysis of material properties in connection with fatigue of riveted structure. The second topic is associated with the development of new assessment methods for load capacity of riveted structures. This concerns the study of plastic capacity of cross sections formed by riveted slender plates. The third item is then related to the assessment of fatigue life of riveted and welded bridges. Several advices are also given concerning assessment improvement based on new data information

Improved assessment methods for static and fatigue resistance of old metal railway bridges

This paper presents the recommendations and advices proposed for the assessment of old riveted structures within the set of guidelines developed in the Sustainable Bridges Integrated Project. The proposed assessment methods focuses on fatigue and ultimate load limit states. Three main topics are developed. For the first one, emphasis is given to the analysis of material properties in connection with fatigue of riveted structure. The second topic is associated with the development of new assessment methods for load capacity of riveted structures. This concerns the study of plastic capacity of cross sections formed by riveted slender plates. The third item is then related to the assessment of fatigue life of riveted and welded bridges. Several advices are also given concerning assessment improvement based on new data information