Structural and dynamical equilibrium properties of hard board-like particles in parallel confinement.

We performed Monte Carlo and dynamic Monte Carlo simulations to model the diffusion of monodispersed suspensions composed of impenetrable cuboidal particles, specifically hard board-like particles (HBPs), in the presence of parallel hard walls. The impact of the walls was investigated by adjusting the size of the simulation box while maintaining constant packing fractions, fixed at η = 0.150, for systems consisting of HBPs with prolate, dual-shaped, and oblate geometries. We observed that increasing the distance between the walls led to the recovery of an isotropic bulk phase, while local particle organization near the walls remained stable. Due to their shape, oblate HBPs exhibit more efficient anchoring at wall surfaces compared to prolate shapes. The formation of nematic-like particle assemblies near the walls, confirmed by theoretical calculations based on density functional theory, significantly influenced local particle dynamics. This effect was particularly pronounced to the extent that a modest portion of cuboids near the walls tended to diffuse exclusively in planes parallel to the confinement, even more efficiently than observed in the bulk regions.

Dentin remineralization using a stimuli-responsive engineered small molecule GSK3 antagonists-functionalized adhesive.

OBJECTIVES: Tideglusib has shown great performance in terms of dentin regenerative properties. This study aims to evaluate bonding ability, of demineralized dentin infiltrated with polymeric nanoparticles (NPs) doped with tideglusib (TG) (TG-NPs). METHODS: Dentin conditioned surfaces were infiltrated with NPs and TG-NPs. Bonded interfaces were created and stored for 24 h and then submitted to mechanical, chemical and thermal challenging. The resin-dentin interface was evaluated through a doubled dye fluorescent technique and a calcium chelator fluorophore under a confocal laser scanning microscopy, and by field emission scanning electron microscopy. RESULTS: Dentin surfaces treated with TG-NPs and load cycled produced higher bond strength than the rest of the groups. Immersion of dentin specimens treated with undoped-NPs in collagenase solution attained the lowest microtensile bond strength (MTBS) values. Both porosity and nanoleakage decreased when dentin was infiltrated with TG-NPs, that revealed strong signals of xylenol orange stain at both hybrid layer and dentinal tubules. The presence of NPs, in general, inducted the presence of mineralized interfaces after mechanical loading and thermocycling. CONCLUSIONS: Nanoparticles doped with tideglusib promoted the highest dentin bonding efficacy among groups, as they facilitated the maximum bond strength values with creation of mineral deposits at the hybrid layer and dentinal walls. Tideglusib enabled scarce porosity, nanoleakage and advanced sealing among dentin groups. SIGNIFICANCE: Doping hydrophilic polymeric NPs with tideglusib, infiltrated in etched dentin represents a reproducible technique to create reparative dentin at the resin-dentin interface, by inducing therapeutic bioactivity.

Experiencias de docentes y estudiantes en la educación remota de emergencia: oportunidades para mejorar la educación del pregrado en medicina / Faculty and student experience during remote emergency education: opportunities for improving undergraduate medical education

Introducción: Los ciclos clínicos de pregrado representan los escenarios principales en los que los estudiantes de medicina consolidan los conocimientos. Sin embargo, a principios de 2020, la mayoría de los estudiantes fue confinada en sus domicilios debido a la pandemia por el SARS-CoV-2. Los procesos formativos continuaron desde los hogares por medio de la educación remota de emergencia, una modalidad de enseñanza basada en el uso intensivo de la tecnología que, a pesar de hacerse de manera improvisada, respondió a la situación educativa de urgencia. El propósito de este estudio fue indagar la experiencia educativa de estudiantes y docentes que se encontraban en los años clínicos de pregrado de la carrera de medicina con el fin de identificar las oportunidades de mejora en la enseñanza a partir de la crisis sanitaria vivida. Sujetos y métodos: Se realizó un estudio cualitativo de carácter descriptivo con la técnica de grupos focales. El análisis se basó en la reducción de datos, en la triangulación entre estamentos y en la bibliografía del tema. Resultados: Se realizaron 16 grupos focales con un total de 148 participantes. Se identificaron cuatro categorías generales: a) enseñanza y aprendizaje; b) evaluación de la práctica clínica; c) identidad profesional, y d) sugerencias en busca de mejoras en la formación de los médicos Conclusiones: Las reflexiones reconocen la necesidad de incorporar las tecnologías digitales de una manera planeada y diseñada en conjunto por expertos y docentes para adaptarlas a las necesidades de los contextos educativos, y continuar con modelos híbridos o combinados para mejorar la educación médica.(AU)

Introduction: During medical education, undergraduate clinical cycles represent the main scenarios where students consolidate knowledge. However, in the early 2020s, most students were confined to their homes due to the SARS-Cov-2 pandemic. In this situation, the digital network allowed the educational processes to continue from their homes through remote emergency education (REE), a teaching modality based on the intensive use of technology that, despite having been improvised, responded to the emergency educational situation. Therefore, this study aimed to investigate the educational experience of students and teachers in the undergraduate clinical years of the medical degree in order to identify opportunities for improvement in teaching after the health crisis. Subjects and methods: A descriptive qualitative study was carried out with a phenomenological approach through the focus group technique. The qualitative analysis was based on data reduction and triangulation between strata and subject literature. Results: Sixteen focus groups were integrated with a total of 148 participants. Four categories were identified: a) teaching and learning; b) evaluation of clinical practice; c) professional identity, and d) suggestions for improvement in the training of physicians. Conclusions: The reflections lead to recognizing the need to incorporate digital technology designed by experts and teachers to adapt them to the real needs of the educational contexts and to continue with a hybrid or combined model that supports the improvement of medical education.(AU)

Dexamethasone-doped nanoparticles improve mineralization, crystallinity and collagen structure of human dentin.

OBJECTIVES: Bioactive materials have been used for functionalization of adhesives to promote dentin remineralization. This study aims to evaluate bonding ability and both mechanical and chemical behavior of demineralized dentin infiltrated with polymeric nanoparticles doped with dexamethasone (Dex-NPs). METHODS: Dentin conditioned surfaces were infiltrated with NPs, Dex-NPs or Dex-Zn-NPs. Bonded interfaces were also created and stored for 24 h or 21d, and then submitted to microtensile bond strength testing. Dentin remineralization was analyzed by Nanohardness, Young's modulus and Raman analysis. RESULTS: At 21d of storage, dentin treated with undoped-NPs attained the lowest nanohardness and Young's modulus. Dex-NPs and Zn-Dex-NPs increased dentin nanohardness and Young's modulus after 21d Raman analysis showed high remineralization, crystallinity, crosslinking and better structure of collagen when functionalized Dex-NPs were present at the dentin interface. CONCLUSIONS: Infiltration of dentin with Dex-NPs promoted functional remineralization as proved by nanomechanical and morpho-chemical evaluation tests. Dexamethasone in dentin facilitated crystallographic maturity, crystallinity and improved maturity and secondary structure of dentin collagen. CLINICAL SIGNIFICANCE: Using dexamethasone-functionalized NPs before resin infiltration is a clear option to obtain dentin remineralization, as these NPs produce the reinforcement of the dentin structure, which will lead to the improvement of the longevity of resin restorations.

Evidence of SARS-CoV-2 infection in postmortem lung, kidney, and liver samples, revealing cellular targets involved in COVID-19 pathogenesis.

There is an urgent need to understand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-host interactions involved in virus spread and pathogenesis, which might contribute to the identification of new therapeutic targets. In this study, we investigated the presence of SARS-CoV-2 in postmortem lung, kidney, and liver samples of patients who died with coronavirus disease (COVID-19) and its relationship with host factors involved in virus spread and pathogenesis, using microscopy-based methods. The cases analyzed showed advanced stages of diffuse acute alveolar damage and fibrosis. We identified the SARS-CoV-2 nucleocapsid (NC) in a variety of cells, colocalizing with mitochondrial proteins, lipid droplets (LDs), and key host proteins that have been implicated in inflammation, tissue repair, and the SARS-CoV-2 life cycle (vimentin, NLRP3, fibronectin, LC3B, DDX3X, and PPARγ), pointing to vimentin and LDs as platforms involved not only in the viral life cycle but also in inflammation and pathogenesis. SARS-CoV-2 isolated from a patient´s nasal swab was grown in cell culture and used to infect hamsters. Target cells identified in human tissue samples included lung epithelial and endothelial cells; lipogenic fibroblast-like cells (FLCs) showing features of lipofibroblasts such as activated PPARγ signaling and LDs; lung FLCs expressing fibronectin and vimentin and macrophages, both with evidence of NLRP3- and IL1ß-induced responses; regulatory cells expressing immune-checkpoint proteins involved in lung repair responses and contributing to inflammatory responses in the lung; CD34+ liver endothelial cells and hepatocytes expressing vimentin; renal interstitial cells; and the juxtaglomerular apparatus. This suggests that SARS-CoV-2 may directly interfere with critical lung, renal, and liver functions involved in COVID-19-pathogenesis.

Radiomics-Based Assessment of OCT Angiography Images for Diabetic Retinopathy Diagnosis.

Purpose: To evaluate the diagnostic accuracy of machine learning (ML) techniques applied to radiomic features extracted from OCT and OCT angiography (OCTA) images for diabetes mellitus (DM), diabetic retinopathy (DR), and referable DR (R-DR) diagnosis. Design: Cross-sectional analysis of a retinal image dataset from a previous prospective OCTA study (ClinicalTrials.govNCT03422965). Participants: Patients with type 1 DM and controls included in the progenitor study. Methods: Radiomic features were extracted from fundus retinographies, OCT, and OCTA images in each study eye. Logistic regression, linear discriminant analysis, support vector classifier (SVC)-linear, SVC-radial basis function, and random forest models were created to evaluate their diagnostic accuracy for DM, DR, and R-DR diagnosis in all image types. Main Outcome Measures: Area under the receiver operating characteristic curve (AUC) mean and standard deviation for each ML model and each individual and combined image types. Results: A dataset of 726 eyes (439 individuals) were included. For DM diagnosis, the greatest AUC was observed for OCT (0.82, 0.03). For DR detection, the greatest AUC was observed for OCTA (0.77, 0.03), especially in the 3 × 3 mm superficial capillary plexus OCTA scan (0.76, 0.04). For R-DR diagnosis, the greatest AUC was observed for OCTA (0.87, 0.12) and the deep capillary plexus OCTA scan (0.86, 0.08). The addition of clinical variables (age, sex, etc.) improved most models AUC for DM, DR and R-DR diagnosis. The performance of the models was similar in unilateral and bilateral eyes image datasets. Conclusions: Radiomics extracted from OCT and OCTA images allow identification of patients with DM, DR, and R-DR using standard ML classifiers. OCT was the best test for DM diagnosis, OCTA for DR and R-DR diagnosis and the addition of clinical variables improved most models. This pioneer study demonstrates that radiomics-based ML techniques applied to OCT and OCTA images may be an option for DR screening in patients with type 1 DM. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Consenso MAPA (Male Aesthetic Patient Approach) de belleza masculina. Consenso español sobre el manejo del paciente estético masculino / MAPA (Male Aesthetic Patient Approach) consensus of male beauty. Spanish consensus on the male aesthetic patient approach

Introducción y objetivo: La demanda masculina de tratamiento estético es cada vez más relevante. Sin embargo, todavía son pocas las evidencias sobre Medicina Estética en el hombre y aunque algunos estudios incluyen recomendaciones sobre las pautas de tratamiento con toxina y con rellenos para el varón, no todas son válidas en nuestro entorno mediterráneo. Por ello se ha elaborado el consenso MAPA (Male Aesthetic Patient Approach) a modo de guía de orientación práctica para ayudar al médico estético que se inicia en el tratamiento del paciente masculino. Material y Método: Un panel de 9 expertos en Medicina Estética de diferentes zonas de España con amplia experiencia en el uso de la toxina Abobotulinum y rellenos de ácido hialurónico se reunieron para poner en común sus conocimientos y prácticas clínicas habituales y desarrollar recomendaciones fundamentales en el campo de la Medicina Estética masculina. Resultados: Los temas discutidos incluyeron cuestiones relativas a la práctica clínica, perfil de pacientes tratados, planificación del tratamiento en función del objetivo deseado y principales técnicas de Medicina Estética recomendadas para los hombres. Finalmente, también se debatieron recomendaciones sobre los tratamientos a aplicar en cada área de tratamiento facial. Conclusiones: Este consenso recoge las opiniones, consejos y experiencia de médicos estéticos españoles con amplia experiencia en el uso de la toxina Abobotulinum y rellenos de ácido hialurónico para ayudar a los profesionales a conseguir los mejores resultados posibles en términos de eficacia y satisfacción del paciente masculino. (AU)

Background and objective: The male demand for aesthetic treatment is increasingly relevant. However, there is still little evidence on Aesthetic Medicine in men and although some studies include recommendations on treatment guidelines with toxins and fillers for male patients, not all are valid in our Mediterranean setting. For this reason, the MAPA (Male Aesthetic Patient Approach) consensus has been drawn up, a practical orientation guide to help the aesthetic doctor who is beginning to treat male patients. Methods: A panel of 9 experts in Aesthetic Medicine from different areas of Spain with extensive experience in the use of Abobotulinum toxin and hyaluronic acid fillers met to share their knowledge and usual clinical practices, and develop a series of fundamental recommendations in the field of male Aesthetic Medicine. Results: The topics discussed included questions related to clinical practice, profile of patients treated, treatment planning based on the desired end goal, and main Aesthetic Medicine techniques recommended for men. Finally, a series of recommendations on treatments to be applied in each area of facial treatment were also discussed. Conclusions: This consensus has collected the opinions, advice and experience of aesthetic doctors with extensive experience in the use of Abobotulinum toxin and hyaluronic acid fillers to help professionals achieve the best possible results in terms of efficacy and satisfaction in male patients. (AU)

Short versus standard implants at sinus augmented sites: a systematic review and meta-analysis.

BACKGROUND: Short implants are proposed as a less invasive alternative with fewer complications than standard implants in combination with sinus lift. The aim of this systematic review and meta-analysis was to state the efficacy of placing short implants (≤ 6 mm) compared to standard-length implants (≥ 8 mm) performing sinus lift techniques in patients with edentulous posterior atrophic jaws. Efficacy will be evaluated through analyzing implant survival (IS) and maintenance of peri-implant bone (MBL). METHODS: Screening process was done using the National Library of Medicine (MEDLINE by PubMed), EMBASE, the Cochrane Oral Health, and Web of Science (WOS). The articles included were randomized controlled trials. Risk of bias was evaluated according to The Cochrane Collaboration's tool. Weighted means were calculated. Heterogeneity was determined using Higgins (I2). A random-effects model was applied. Secondary outcomes such as surgical time, patient satisfaction, mucositis and peri-implantitis, pain, and swelling were analyzed. RESULTS: Fourteen studies (597 patients and 901 implants) were evaluated. IS was 1.02 risk ratio, ranging from 1.00 to 1.05 (CI 95%) (p = 0.09), suggesting that IS was similar when both techniques were used. MBL was higher in patients with standard-length implants plus sinus lift elevation (p = 0.03). MBL was 0.11 (0.01-0.20) mm (p = 0.03) and 0.23 (0.07-0.39) mm (p = 0.005) before and after 1 year of follow-up, respectively, indicating that the marginal bone loss is greater for standard-length implants. DISCUSSION: Within the limitations of the present study, as relatively small sample size, short dental implants can be used as an alternative to standard-length implants plus sinus elevation in cases of atrophic posterior maxilla. Higher MBL was observed in the groups where standard-length implants were used, but implant survival was similar in both groups. Moreover, with short implants, it was observed a reduced postoperative discomfort, minimal invasiveness, shorter treatment time, and reduced costs. CLINICAL CLINICAL RELEVANCE: The low MBL promoted by short implants does contribute to a paradigm shift from sinus grafting with long implants to short implants. Further high-quality long-term studies are required to confirm these findings.

Safety and immunogenicity of anti-SARS-CoV-2 heterologous scheme with SOBERANA 02 and SOBERANA Plus vaccines: Phase IIb clinical trial in adults.

BACKGROUND: SOBERANA 02 has been evaluated in phase I and IIa studies comparing homologous versus heterologous schedule (this one, including SOBERANA Plus). Here, we report results of immunogenicity, safety, and reactogenicity of SOBERANA 02 in a two- or three-dose heterologous scheme in adults. METHOD: Phase IIb was a parallel, multicenter, adaptive, double-blind, randomized, and placebo-controlled trial. Subjects (n = 810) aged 19-80 years were randomized to receive two doses of SARS-CoV-2 RBD conjugated to tetanus toxoid (SOBERANA 02) and a third dose of dimeric RBD (SOBERANA Plus) 28 days apart; two production batches of active ingredients of SOBERANA 02 were evaluated. Primary outcome was the percentage of seroconverted subjects with ≥4-fold the anti-RBD immunoglobulin G (IgG) concentration. Secondary outcomes were safety, reactogenicity, and neutralizing antibodies. FINDINGS: Seroconversion rate in vaccinees was 76.3% after two doses and 96.8% after the third dose of SOBERANA Plus (7.3% in the placebo group). Neutralizing IgG antibodies were detected against D614G and variants of concern (VOCs) Alpha, Beta, Delta, and Omicron. Specific, functional antibodies were detected 7-8 months after the third dose. The frequency of serious adverse events (AEs) associated with vaccination was very low (0.1%). Local pain was the most frequent AE. CONCLUSIONS: Two doses of SOBERANA 02 were safe and immunogenic in adults. The heterologous combination with SOBERANA Plus increased neutralizing antibodies, detectable 7-8 months after the third dose. TRIAL REGISTRY: https://rpcec.sld.cu/trials/RPCEC00000347 FUNDING: This work was supported by Finlay Vaccine Institute, BioCubaFarma, and the Fondo Nacional de Ciencia y Técnica (FONCI-CITMA-Cuba, contract 2020-20).

Safety and immunogenicity of the FINLAY-FR-1A vaccine in COVID-19 convalescent participants: an open-label phase 2a and double-blind, randomised, placebo-controlled, phase 2b, seamless, clinical trial.

BACKGROUND: A phase 1, clinical trial to evaluate FINLAY-FR-1A vaccine in COVID-19 convalescent individuals was completed. Here, we report results of the phase 2, clinical trial. METHODS: We studied 450 convalescent participants with a history of asymptomatic, mild, or moderate COVID-19 at the National Institute of Hematology and Immunology and the National Centre for Sexual Education in Havana, Cuba. The study included adults aged 19-78 years who had recovered from COVID-19 and had had a negative PCR test at least 2 months before the initiation of the study. Phase 2 was done sequentially in two stages. The first stage to assess safety comprised an open, non-controlled phase 2a study in participants aged 60-78 years who received a single dose of the FINLAY-FR-1A vaccine (50 µg of recombinant dimeric receptor binding domain [RBD]). The second stage comprised the placebo-controlled, double-blind, phase 2b trial in participants aged 19-78 years, where participants were randomly assigned (4:1) into two groups: an experimental group vaccinated with a single dose of the FINLAY-FR-1A vaccine, and a control (placebo) group injected with vaccine excipient. The primary outcomes were safety, evaluated 28 days after vaccination by the occurrence of serious adverse events in all participants, and successful immune response, assessed by neutralising antibody ELISA, and defined as half-maximal surrogate virus neutralisation titres of 250 or more. Secondary endpoints included vaccine immunogenicity assessed by ELISA anti-RBD and live-virus neutralisation test. All randomly assigned participants were included in the safety analysis (safety population), and immunogenicity was evaluated in participants without study interruptions (per-protocol population). The trial is registered with the Cuban Public Registry of Clinical Trials, RPCEC00000366-En and WHO-ICTRP and is complete. FINDINGS: From April 9, 2021, to April 17, 2021, 663 COVID-19 convalescent participants were enrolled in the study; 213 participants did not meet the selection criteria and 450 volunteers were recruited. 20 participants aged 60-78 years were included in the open, single-group, phase 2a study and 430 participants were randomly assigned to the experimental (n=344) or control groups (n=86) in the phase 2b study of participants aged 19-78 years. 19 (95%) of 20 phase 2a volunteers achieved a successful immune response after vaccination. No vaccine-associated serious adverse events were reported in the whole study population. Minor adverse events were found, the most common being pain at the injection site (105 [29%] of 364 in the intervention group; 13 [15%] of 86 in the placebo group). A successful immune response was found in 289 (81%) of 358 participants 28 days after vaccination. The vaccine elicited a greater than 31-times increase in anti-RBD-IgG antibodies compared with prevaccination rates, and the seroconversion rate was 302 (84%) of 358 on day 28 after vaccination; the geometric mean titres of live-virus neutralisation test increased from 15·4 (95% CI 10·3-23·2) to 400·3 (272·4-588·1) and high response was found against alpha, beta, and delta variants of concern. INTERPRETATION: A single dose of the FINLAY-FR-1A vaccine against SARS-CoV-2 strengthened the pre-existing natural immunity, with excellent safety profile. FUNDING: Cuba's Ministry of Science, Technology, and Environment.

Safety and immunogenicity of anti-SARS CoV-2 vaccine SOBERANA 02 in homologous or heterologous scheme: Open label phase I and phase IIa clinical trials.

BACKGROUND: SOBERANA 02 is a COVID-19 vaccine based on SARS-CoV-2 recombinant RBD conjugated to tetanus toxoid (TT). SOBERANA Plus antigen is dimeric-RBD. Here we report safety and immunogenicity from phase I and IIa clinical trials using two-doses of SOBERANA 02 and three-doses (homologous) or heterologous (with SOBERANA Plus) protocols. METHOD: We performed an open-label, sequential and adaptive phase I to evaluate safety and explore the immunogenicity of SOBERANA 02 in two formulations (15 or 25 µg RBD-conjugated to 20 µg of TT) in 40 subjects, 19-59-years-old. Phase IIa was open-label including 100 volunteers 19-80-years, receiving two doses of SOBERANA 02-25 µg. In both trials, half of volunteers were selected to receive a third dose of the corresponding SOBERANA 02 and half received a heterologous dose of SOBERANA Plus. Primary outcome was safety. The secondary outcome was immunogenicity evaluated by anti-RBD IgG ELISA, molecular neutralization of RBD:hACE2 interaction, live-virus-neutralization and specific T-cells response. RESULTS: The most frequent adverse event (AE) was local pain, other AEs had frequencies ≤ 5%. No serious related-AEs were reported. Phase IIa confirmed the safety in 60 to 80-years-old subjects. In phase-I SOBERANA 02-25 µg elicited higher immune response than SOBERANA 02-15 µg and progressed to phase IIa. Phase IIa results confirmed the immunogenicity of SOBERANA 02-25 µg even in 60-80-years. Two doses of SOBERANA02-25 µg elicited an immune response similar to that of the Cuban Convalescent Serum Panel and it was higher after the homologous and heterologous third doses. The heterologous scheme showed a higher immunological response. Anti-RBD IgG neutralized the delta variant in molecular assay, with a 2.5-fold reduction compared to D614G neutralization. CONCLUSIONS: SOBERANA 02 was safe and immunogenic in persons aged 19-80 years, eliciting neutralizing antibodies and specific T-cell response. Highest immune responses were obtained in the heterologous three doses protocol. TRIAL REGISTRY: https://rpcec.sld.cu/trials/RPCEC00000340, https://rpcec.sld.cu/trials/RPCEC00000347.

Casimir Contribution to the Interfacial Hamiltonian for 3D Wetting.

Previous treatments of three-dimensional (3D) short-ranged wetting transitions have missed an entropic or low-temperature Casimir contribution to the binding potential describing the interaction between the unbinding interface and wall. This we determine by exactly deriving the interfacial model for 3D wetting from a more microscopic Landau-Ginzburg-Wilson Hamiltonian. The Casimir term changes the interpretation of fluctuation effects occurring at wetting transitions so that, for example, mean-field predictions are no longer obtained when interfacial fluctuations are ignored. While the Casimir contribution does not alter the surface phase diagram, it significantly increases the adsorption near a first-order wetting transition and changes completely the predicted critical singularities of tricritical wetting, including the nonuniversality occurring in 3D arising from interfacial fluctuations. Using the numerical renormalization group, we show that, for critical wetting, the asymptotic regime is extremely narrow with the growth of the parallel correlation length characterized by an effective exponent in quantitative agreement with Ising model simulations, resolving a long-standing controversy.

Safety, tolerability, and immunogenicity of a SARS-CoV-2 recombinant spike RBD protein vaccine: A randomised, double-blind, placebo-controlled, phase 1-2 clinical trial (ABDALA Study).

Background: Multiple vaccine candidates against COVID-19 are currently being evaluated. We evaluate the safety and immunogenicity protein of a novel SARS-CoV-2 virus receptor-binding domain (RBD) vaccine. Methods: A phase 1-2, randomised, double-blind, placebo-controlled trial was carried out in "Saturnino Lora" Hospital, Santiago de Cuba, Cuba. Subjects (healthy or those with controlled chronic diseases) aged between 19 and 80 years, who gave written informed consent were eligible. Subjects were randomly assigned (1:1:1, in blocks) to three groups: placebo, 25 µg and 50 µg RBD vaccine (Abdala). The product was administered intramuscularly, 0·5 mL in the deltoid region. During the first phase, two immunization schedules were studied: 0-14-28 days (short) and 0-28-56 days (long). In phase 2, only the short schedule was evaluated. The organoleptic characteristics and presentations of vaccine and placebo were identical. All participants (subjects, clinical researchers, statisticians, laboratory technicians, and monitors) remained masked during the study period. The main endpoints were safety and the proportion of subjects with seroconversion of anti-RBD IgG antibodies, analysed by intention to treat and per protocol, respectively. The trial is registered with the Cuban Public Registry of Clinical Trials, RPCEC00000346. Findings: Between Dec 7, 2020, and Feb 9, 2021, 792 subjects were included; 132 (66 in each vaccination schedule, divided into 22 for each group) in phase 1, and 660 (220 in each group plus 66 from the short scheme of phase 1) in phase 2. The product was well tolerated. No severe adverse events were reported. During phase 1, the incidence of adverse events in the 25 µg, 50 µg, and placebo arms for the short schedule were 6/22 (27·3%), 6/22 (27·3%), 3/22 (13·6%), respectively, and for the long schedule were 8/22 (36·4%), 9/22 (40·9%), 4/22 (18·2%), respectively. In phase 2, adverse reactions were reported by 53/242 (21·9%), 75/242 (31·0%) and 41/242 (16·9%) participants in the 25 µg, 50 µg, and placebo group, respectively. Adverse reactions were minimal, mostly mild, and from the injection site, which resolved in the first 24-48 hours. In phase 1, seroconversion at day 56 was seen in 95·2% of the participants (20/21) in the 50 µg group, 81% (17/21) in the 25 µg group, and none in the placebo group (0/22). For the long schedule, seroconversion at day 70 was seen in 100% of the participants (21/21) in the 50 µg group, 94·7% (18/19) in the 25 µg group, and none in the placebo group (0/22). In phase 2, seroconversion of anti-RBD IgG antibodies at day 56 was seen in 89·2% of the participants in the 50 µg group (214/240; 95% CI 84·5-92·82), 77·7% in the 25 µg group (185/238; 72·0-82·9) and 4·6% in the placebo group (11/239; 2·3-8·1). Compared with the placebo arm, the differences in the proportion of participants with seroconversion were 73·1% (95% CI 66·8-79·5) and 84·6% (79·4-89·7) in the 25 µg and 50 µg groups, respectively. The seroconversion rate in the 50 µg group was significantly higher than in the 25 µg group (p=0·0012). Interpretation: The Abdala vaccine was safe, well tolerated, and induced humoral immune responses against SARS-CoV-2. These results, in the context of the emergency COVID-19 pandemic, support the 50 µg dose, applied in a 0-14-28 days schedule, for further clinical trials to confirm vaccine efficacy. Funding: Centre for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba.

Consenso ibérico de buenas prácticas clínicas en tratamientos estéticos con toxina botulínica tipo A / Iberian consensus of good clinical practices in aesthetic treatments with Abobotulinum toxin A

Introducción y objetivo: Con la evolución de la experiencia en el uso de la toxina botulínica tipo A para tratamientos estéticos se necesitan guías actualizadas de buenas prácticas clínicas. El objetivo de este trabajo fue desarrollar recomendaciones actualizadas para buenas prácticas en el uso clínico diario, con el fin de optimizar el manejo del paciente estético y los resultados obtenidos con la toxina botulínica tipo A. Material y método: Un panel de 44 participantes con amplia experiencia en el uso de la toxina Abobotulinum se reunió para revisar y discutir la evidencia disponible y la práctica clínica en la aplicación estética de la toxina Abobotulinum A. Resultados: Los temas discutidos para la creación de este consenso incluyeron cuestiones directamente relacionadas con el uso y las propiedades de la toxina botulínica tipo A (Azzalure®) y temas generales relativos a la práctica clínica: precisión y campo de efecto de la toxina botulínica tipo A, duración del efecto, rapidez en el inicio de acción, protocolos de tratamiento, tratamientos combinados de toxina botulínica tipo A y ácido hialurónico para mayor satisfacción del paciente y armonía facial, recomendaciones post-tratamiento, diagnóstico y valoración previa del paciente para un efecto óptimo, edad en la que los pacientes comienzan a ser tratados con la toxina y su recomendación como tratamiento preventivo según las escalas de envejecimiento Glogau I o II, manejo de las expectativas del paciente y valoración de la satisfacción del mismo. Conclusiones: Este consenso ha recogido las opiniones, consejos y experiencia de médicos estéticos con amplia experiencia en el uso de la toxina botulínica tipo A para ayudar a los profesionales a conseguir los mejores resultados posibles en términos de eficacia y satisfacción del paciente. (AU)

Background and objective: With the evolution of the experience in the use of botulinum toxin type A for aesthetic treatments, updated guidelines of good clinical practices are needed. The objective of this work was to develop updated recommendations for good practices in daily clinical use, in order to optimize the mana- gement of the aesthetic patient and the results obtained with botulinum toxin type A. Methods: A panel of 44 participants with extensive experience in the use of Abobotulinum toxin met to review and discuss the available evidence and clinical practice in the aesthetic application of Abobotulinum toxin A. Results: The topics discussed for the creation of this consensus included questions directly related to the use and properties of botulinum toxin type A (Azzalure®) and general topics related to clinical practice: precision and field of effect of botulinum toxin type A, duration of effect, speed of onset of action, treatment protocols, combined treatments of botulinum toxin type A and hyaluronic acid for greater patient satisfaction and facial harmony, post-treatment recommendations, diagnosis and prior assessment of the patient for optimal effect, age at which patients begin to be treated with the toxin and its recommendation as a preventive treatment according to the Glogau I or II aging scales, management of patient expectations and assessment of patient satisfaction. Conclusions: This consensus has collected the opinions, advice and experience of aesthetic doctors with extensive experience in the use of botulinum toxin type A to help professionals achieve the best possible results in terms of efficacy and patient satisfaction. (AU)

A single dose of SARS-CoV-2 FINLAY-FR-1A vaccine enhances neutralization response in COVID-19 convalescents, with a very good safety profile: An open-label phase 1 clinical trial.

BACKGROUND: As a first step towards a vaccine protecting COVID-19 convalescents from reinfection, we evaluated FINLAY-FR-1A vaccine in a clinical trial. METHODS: Thirty COVID-19 convalescents aged 22-57 years were studied: convalescents of mild COVID-19, asymptomatic convalescents, both with PCR-positive at the moment of diagnosis; and individuals with subclinical infection detected by viral-specific IgG. They received a single intramuscular injection of the FINLAY-FR-1A vaccine (50 µg of the recombinant dimeric receptor binding domain). The primary outcomes were safety and reactogenicity, assessed over 28 days after vaccination. The secondary outcome was vaccine immunogenicity. Humoral response at baseline and following vaccination was evaluated by ELISA and live-virus neutralization test. The effector T cellular response was also assessed. Cuban Public Registry of Clinical Trials, WHO-ICTRP: https://rpcec.sld.cu/en/trials/RPCEC00000349-En. FINDINGS: No serious adverse events were reported. Minor adverse events were found, the most common, local pain: 3 (10%) and redness: 2 (6·7%). The vaccine elicited a >21 fold increase in IgG anti-RBD antibodies 28 days after vaccination. The median of inhibitory antibody titres (94·0%) was three times greater than that of the COVID-19 convalescent panel. Virus neutralization titres higher than 1:160 were found in 24 (80%) participants. There was also an increase in RBD-specific T cells producing IFN-γ and TNF-α. INTERPRETATION: A single dose of the FINLAY-FR-1A vaccine against SARS-CoV-2 was an efficient booster of pre-existing natural immunity, with excellent safety profile. FUNDING: Partial funding for this study was received from the Project-2020-20, Fondo de Ciencia e Innovación (FONCI), Ministry of Science, Technology and the Environment, Cuba.   RESUMEN. ANTECEDENTES: Como un primer paso hacia una vacuna que proteja a los convalecientes de COVID-19 de la reinfección, evaluamos la vacuna FINLAY-FR-1A en un ensayo clínico. MÉTODOS: Se estudiaron treinta convalecientes de COVID-19 de 22 a 57 años: convalecientes de COVID-19 leve y convalecientes asintomáticos, ambos con prueba PCR positiva al momento del diagnóstico; e individuos con infección subclínica detectada por IgG específica viral. Los participantes recibieron una dosis única por vía intramuscular de la vacuna FINLAY-FR-1A (50 µg del dominio de unión al receptor recombinante dimérico del SARS CoV-2). Las variables de medida primarias fueron la seguridad y la reactogenicidad, evaluadas durante 28 días después de la vacunación. La variable secundaria, la inmunogenicidad. La respuesta humoral, al inicio del estudio y después de la vacunación, se evaluó por ELISA y mediante la prueba de neutralización del virus vivo. También se evaluó la respuesta de células T efectoras. Registro Público Cubano de Ensayos Clínicos, WHO-ICTRP: https://rpcec.sld.cu/en/trials/RPCEC00000349-En. RESULTADOS: No se reportaron eventos adversos graves. Se encontraron eventos adversos leves, los más comunes, dolor local: 3 (10%) y enrojecimiento: 2 (6·7%). La vacuna estimuló un incremento >21 veces de los anticuerpos IgG anti-RBD 28 días después de la vacunación. La mediana de los títulos de anticuerpos inhibidores (94·0%) fue aproximadamente tres veces mayor que la del panel de convalecientes de COVID-19. Se encontraron títulos de neutralización viral superiores a 1:160 en 24 (80%) de los participantes. También hubo un aumento en las células T específicas de RBD que producen IFN-γ y TNF-α. INTERPRETACIÓN: Una sola dosis de la vacuna FINLAY-FR-1A contra el SARS-CoV-2 reforzó eficazmente la inmunidad natural preexistente, con un excelente perfil de seguridad. FINANCIAMIENTO: Se recibió un financiamiento parcial del Proyecto-2020-20, Fondo de Ciencia e Innovación (FONCI), Ministerio de Ciencia, Tecnología y Medio Ambiente, Cuba.

On-The-Fly Syntheziser Programming with Fuzzy Rule Learning.

This manuscript explores fuzzy rule learning for sound synthesizer programming within the performative practice known as live coding. In this practice, sound synthesis algorithms are programmed in real time by means of source code. To facilitate this, one possibility is to automatically create variations out of a few synthesizer presets. However, the need for real-time feedback makes existent synthesizer programmers unfeasible to use. In addition, sometimes presets are created mid-performance and as such no benchmarks exist. Inductive rule learning has shown to be effective for creating real-time variations in such a scenario. However, logical IF-THEN rules do not cover the whole feature space. Here, we present an algorithm that extends IF-THEN rules to hyperrectangles, which are used as the cores of membership functions to create a map of the input space. To generalize the rules, the contradictions are solved by a maximum volume heuristics. The user controls the novelty-consistency balance with respect to the input data using the algorithm parameters. The algorithm was evaluated in live performances and by cross-validation using extrinsic-benchmarks and a dataset collected during user tests. The model's accuracy achieves state-of-the-art results. This, together with the positive criticism received from live coders that tested our methodology, suggests that this is a promising approach.

Unraveling response to temozolomide in preclinical GL261 glioblastoma with MRI/MRSI using radiomics and signal source extraction.

Glioblastoma is the most frequent aggressive primary brain tumor amongst human adults. Its standard treatment involves chemotherapy, for which the drug temozolomide is a common choice. These are heterogeneous and variable tumors which might benefit from personalized, data-based therapy strategies, and for which there is room for improvement in therapy response follow-up, investigated with preclinical models. This study addresses a preclinical question that involves distinguishing between treated and control (untreated) mice bearing glioblastoma, using machine learning techniques, from magnetic resonance-based data in two modalities: MRI and MRSI. It aims to go beyond the comparison of methods for such discrimination to provide an analytical pipeline that could be used in subsequent human studies. This analytical pipeline is meant to be a usable and interpretable tool for the radiology expert in the hope that such interpretation helps revealing new insights about the problem itself. For that, we propose coupling source extraction-based and radiomics-based data transformations with feature selection. Special attention is paid to the generation of radiologist-friendly visual nosological representations of the analyzed tumors.

On the use of pairwise distance learning for brain signal classification with limited observations.

The increasing access to brain signal data using electroencephalography creates new opportunities to study electrophysiological brain activity and perform ambulatory diagnoses of neurological disorders. This work proposes a pairwise distance learning approach for schizophrenia classification relying on the spectral properties of the signal. To be able to handle clinical trials with a limited number of observations (i.e. case and/or control individuals), we propose a Siamese neural network architecture to learn a discriminative feature space from pairwise combinations of observations per channel. In this way, the multivariate order of the signal is used as a form of data augmentation, further supporting the network generalization ability. Convolutional layers with parameters learned under a cosine contrastive loss are proposed to adequately explore spectral images derived from the brain signal. The proposed approach for schizophrenia diagnostic was tested on reference clinical trial data under resting-state protocol, achieving 0.95 ±â€¯0.05 accuracy, 0.98 ±â€¯0.02 sensitivity and 0.92 ±â€¯0.07 specificity. Results show that the features extracted using the proposed neural network are remarkably superior than baselines to diagnose schizophrenia (+20pp in accuracy and sensitivity), suggesting the existence of non-trivial electrophysiological brain patterns able to capture discriminative neuroplasticity profiles among individuals. The code is available on Github: https://github.com/DCalhas/siamese_schizophrenia_eeg.

Weighted contrastive divergence.

Learning algorithms for energy based Boltzmann architectures that rely on gradient descent are in general computationally prohibitive, typically due to the exponential number of terms involved in computing the partition function. In this way one has to resort to approximation schemes for the evaluation of the gradient. This is the case of Restricted Boltzmann Machines (RBM) and its learning algorithm Contrastive Divergence (CD). It is well-known that CD has a number of shortcomings, and its approximation to the gradient has several drawbacks. Overcoming these defects has been the basis of much research and new algorithms have been devised, such as persistent CD. In this manuscript we propose a new algorithm that we call Weighted CD (WCD), built from small modifications of the negative phase in standard CD. However small these modifications may be, experimental work reported in this paper suggests that WCD provides a significant improvement over standard CD and persistent CD at a small additional computational cost.