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Abstract The function of many bacterial processes depends on the formation of functional membrane microdomains (FMMs), which resemble the lipid rafts of eukaryotic cells. However, the mechanism and the biological function of these membrane microdomains remain unclear. Here, we show that FMMs in the pathogen methicillin-resistant Staphylococcus aureus (MRSA) are dedicated to confining and stabilizing proteins unfolded due to cellular stress. The FMM scaffold protein flotillin forms a clamp-shaped oligomer that holds unfolded proteins, stabilizing them and favoring their correct folding. This process does not impose a direct energy cost on the cell and is crucial to survival of ATP-depleted bacteria, and thus to pathogenesis. Consequently, FMM disassembling causes the accumulation of unfolded proteins, which compromise MRSA viability during infection and cause penicillin re-sensitization due to PBP2a unfolding. Thus, our results indicate that FMMs mediate ATP-independent stabilization of unfolded proteins, which is essential for bacterial viability during infection.

Despite the high efficiency of current SARS-CoV-2 mRNA vaccines in reducing COVID-19 morbidity and mortality, waning immunity and the emergence of resistant variants underscore the need for novel vaccination strategies. This study explores a heterologous mRNA/Modified Vaccinia virus Ankara (MVA) prime/boost regimen employing a trimeric form of the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein compared to a homologous MVA/MVA regimen. In C57BL/6 mice, the RBD was delivered during priming via an mRNA vector encapsulated in nanoemulsions (NE) or lipid nanoparticles (LNP), followed by a booster with a replication-deficient MVA-based recombinant virus (MVA-RBD). This heterologous mRNA/MVA regimen elicited strong anti-RBD binding and neutralizing antibodies (BAbs and NAbs) against both the ancestral SARS-CoV-2 strain and different variants of concern (VoCs). Additionally, this protocol induced robust and polyfunctional RBD-specific CD4 and CD8 T cell responses, particularly in animals primed with mLNP-RBD. In K18-hACE2 transgenic mice, the LNP-RBD/MVA combination provided complete protection from morbidity and mortality following a live SARS-CoV-2 challenge compared with the partial protection observed with mNE-RBD/MVA or MVA/MVA regimens. Although the mNE-RBD/MVA regimen only protects half of the animals, it was able to induce antibodies with Fc-mediated effector functions besides NAbs. Moreover, viral replication and viral load in the respiratory tract were markedly reduced and decreased pro-inflammatory cytokine levels were observed. These results support the efficacy of heterologous mRNA/MVA vaccine combinations over homologous MVA/MVA regimen, using alternative nanocarriers that circumvent intellectual property restrictions of current mRNA vaccine formulations.

Introduction: Cerebral venous thrombosis (CVT) is an uncommon cause of stroke that mainly affects young adults. Early, accurate diagnosis can reduce the rate and severity of complications. Objective: The aim of this study was to analyse the clinical characteristics, management, and treatment of CVT in different centres in Spain. Methods: We conducted a multicentre, retrospective, descriptive study of patients hospitalised due to CVT between 2008 and 2017 at 10 Spanish centres. Results: We included 256 patients, with a mean age (SD) of 49.8 (18.7) years; 51% of patients were women. The most frequent symptoms were headache (73%), focal deficits (50%), epileptic seizures (33%), and encephalopathy (21%). The most frequent localisations were the superior sagittal sinus (12.5%), the transverse sinus (10.9%), and 2 or more sinuses or veins (66.4%). Thrombophilia was the most frequent known aetiology (24%), and was most commonly associated with the prothrombin G20210A mutation (19%). Forty-six percent of patients were treated with antithrombotics for 3 to 6 months, 21% for one year, and 22.6% required indefinite anticoagulation. Endovascular therapy was performed in 5% of cases, and 33% required neurosurgery. Regarding outcomes, 75% of patients were independent at 3 months (modified Rankin Scale [mRS] score ≤ 2), with papilloedema (P = .03), focal deficits (P = .001), and encephalopathy (P 3). The in-hospital mortality rate was 4.3%, with a 3-month mortality rate of 6.3%. Conclusion: The diverse risk factors and variable presentation of CVT represent a challenge in the diagnosis and treatment of this condition. To improve prognosis and reduce mortality, it is essential to establish management protocols for this entity. Resumen: Introducción: La trombosis venosa cerebral (TVC) es una causa poco común de ictus que afecta principalmente a adultos jóvenes. Un diagnóstico precoz y preciso puede reducir la tasa y gravedad de las complicaciones. Objetivo: Analizar las características clínicas, manejo y tratamiento de la TVC en diferentes centros de nuestro país. Métodos: Estudio descriptivo retrospectivo multicéntrico de pacientes hospitalizados por TVC entre 2008 y 2017 en 10 centros sanitarios en nuestro país. Resultados: Se incluyeron 256 pacientes, edad media 49,8 ± 18,7 años y el 51% fueron mujeres. Los síntomas más frecuentes fueron: cefalea (73%), déficits focales (50%), crisis epilépticas (33%) y encefalopatía (21%). Las localizaciones más frecuentes fueron: seno longitudinal superior (12,5%), transverso (10,9%) y afectación de dos o más senos o venas (66,4%). La etiología conocida más frecuente fue la trombofilia (24%), siendo la mutación de la protrombina G20210A la más común (19%). El 46% fue tratado con antitrombóticos durante 3-6 meses, el 21% durante 1 año y un 22,6% de los pacientes requirieron anticoagulación indefinida. En un 5% de los sujetos fue preciso terapia endovascular y un 33% requirió neurocirugía. En relación al pronóstico, el 75% fueron independientes a los 3 meses con una puntuación en la escala de Rankin modificada (mRS) ≤ 2 y la presencia de papiledema (p = 0,03), déficit focal (p = 0,001) y encefalopatía (p 3). La tasa de mortalidad intrahospitalaria fue del 4,3% y el 6,3% de los pacientes fallecieron a los 3 meses. Conclusión: La diversidad de factores de riesgo y la presentación variable suponen un desafío en el diagnóstico y tratamiento de la TVC. Para mejorar el pronóstico y reducir la mortalidad es fundamental la instauración de protocolos en el manejo de esta patología.

Resumen: Introducción: La trombosis venosa cerebral (TVC) es una causa poco común de ictus que afecta principalmente a adultos jóvenes. Un diagnóstico precoz y preciso puede reducir la tasa y gravedad de las complicaciones. Objetivo: Analizar las características clínicas, manejo y tratamiento de la TVC en diferentes centros de nuestro país. Métodos: Estudio descriptivo retrospectivo multicéntrico de pacientes hospitalizados por TVC entre 2008 y 2017 en 11 centros sanitarios en nuestro país. Resultados: Se incluyeron 256 pacientes, edad media 49,8 ± 18,7 años y el 51% fueron mujeres. Los síntomas más frecuentes fueron: cefalea (73%), déficits focales (50%), crisis epilépticas (33%) y encefalopatía (21%). Las localizaciones más frecuentes fueron: seno longitudinal superior (12,5%), transverso (10,9%) y afectación de dos o más senos o venas (66,4%). La etiología conocida más frecuente fue la trombofilia (24%), siendo la mutación de la protrombina G20210A la más común (19%). El 46% fue tratado con antitrombóticos durante 3-6 meses, el 21% durante un año y un 22,6% de los pacientes requirieron anticoagulación indefinida. En un 5% de los sujetos fue preciso terapia endovascular y un 33% requirió neurocirugía. En relación al pronóstico, el 75% fueron independientes a los 3 meses con una puntuación en la escala de Rankin modificada (mRS) ≤ 2 y la presencia de papiledema (p = 0,03), déficit focal (p = 0,001) y encefalopatía (p 3). La tasa de mortalidad intrahospitalaria fue del 4,3% y el 6,3% de los pacientes fallecieron a los 3 meses. Conclusión: La diversidad de factores de riesgo y la presentación variable suponen un desafío en el diagnóstico y tratamiento de la TVC. Para mejorar el pronóstico y reducir la mortalidad es fundamental la instauración de protocolos en el manejo de esta patología. Abstract: Introduction: Cerebral venous thrombosis (CVT) is an uncommon cause of stroke that mainly affects young adults. Early, accurate diagnosis can reduce the rate and severity of complications. Objective: The aim of this study was to analyse the clinical characteristics, management, and treatment of CVT in different centres in Spain. Methods: We conducted a multicentre, retrospective, descriptive study of patients hospitalised due to CVT between 2008 and 2017 at 11 Spanish centres. Results: We included 256 patients, with a mean age (SD) of 49.8 (18.7) years; 51% of patients were women. The most frequent symptoms were headache (73%), focal deficits (50%), epileptic seizures (33%), and encephalopathy (21%). The most frequent localisations were the superior sagittal sinus (12.5%), the transverse sinus (10.9%), and 2 or more sinuses or veins (66.4%). Thrombophilia was the most frequent known aetiology (24%), and was most commonly associated with the prothrombin G20210A mutation (19%). Forty-six percent of patients were treated with antithrombotics for 3-6 months, 21% for one year, and 22.6% required indefinite anticoagulation. Endovascular therapy was performed in 5% of cases, and 33% required neurosurgery. Regarding outcomes, 75% of patients were independent at 3 months (modified Rankin Scale [mRS] score ≤ 2), with papilloedema (P = .03), focal deficits (P = .001), and encephalopathy (P 3). The in-hospital mortality rate was 4.3%, with a 3-month mortality rate of 6.3%. Conclusion: The diverse risk factors and variable presentation of CVT represent a challenge in the diagnosis and treatment of this condition. To improve prognosis and reduce mortality, it is essential to establish management protocols for this entity.

The pulp and paper industry, a major global sector, supports economies and jobs while contributing to various products. While providing valuable products, and despite Best Available Techniques (BAT) being used, managing wastewater effectively remains a key area for developing technologies and alternatives for environmental protection. Activated sludge (AS) systems are commonly used for effluent treatment, where microorganisms composition influences reactor efficiency. Current monitoring strategies show limited correlation with chemical parameters. Metabarcoding, a DNA sequencing approach, offers a promising alternative to profile microbial communities comprehensively. Utilizing MinION and Illumina sequencing, this study reveals the prokaryotic and eukaryotic microbial communities in AS from an extended aeration-activated sludge reactor from a pulp mill for the first time. Eukaryotic composition evaluated by 18S amplicon sequencing revealed Protists as the dominant group, followed by Animalia and Fungi. Within these groups, the most abundant phyla detected were Ciliophora (75 % on average), Rotifera (90 % on average), and Cryptomycota (60 % on average), respectively. Genera like Prorodon and Limnias stand out due to their high relative abundance within the Protist and Animalia group, respectively. A comparative analysis with routine microorganism composition assessment by microscopy revealed consistent taxonomic trends, affirming the feasibility of amplicon sequencing for routine microbial community surveillance. Furthermore, the incorporation of metabarcoding enhanced the depth of results. Prokaryotic composition analyzed by 16S amplicon sequencing revealed microorganisms previously described as relevant to the wastewater treatment process but highlighted dominant specific groups even when compared to other pulp facilities. Genera like Terrimonas, Defluviicoccus, and Methylocaldum appear as the most abundant among the identified genera. For proper reactor operation, microorganisms must aggregate around organic matter in flocs, which reflect reactor health and are composed of 5 % eukaryotes and 95 % prokaryotes. Hence, the characterization of both groups of microorganisms is crucial. Differences in communities between the wastewater treatment plant's aeration zones emphasize the importance of comprehensive community characterization. The study underscores metabarcoding's potential as a monitoring tool, for future linking of microbial communities with process patterns for improved environmental management in the pulp and paper industry and emphasizes the importance of establishing unique baselines for microbial communities in activated sludge systems.

This research work arises from the need to design specific techniques for the characterisation of cultural sites. Assuming the increasing complexity of the protection typologies, the expansion of working scales gives thanks to technology and the pursuit of social sustainability objectives. Thus, its main objective is to search for innovative tools that other disciplines can contribute to the work of architects specialising in heritage studies. To this end, the research explores the main methodologies, maps, guides, and registers of landscape and historic landscape characterisation developed in Europe, particularly in Spain, over the last 40 years. Considering this intense and profound evolution of landscape analysis, useful strategies for the assessment of cultural sites from their conception in the 21st century arise. Nevertheless, landscape characterisation methods have been mainly developed and applied by geographers and are absent in many urban and territorial heritage studies. In response, this article proposes a new methodological approach focusing on contextual values to be used in the assessment of architectural heritage at the territorial scale.

Background: The COVID-19 pandemic, caused by SARS-CoV-2, has highlighted the need for vaccines targeting both neutralizing antibodies (NAbs) and long-lasting cross-reactive T cells covering multiple viral proteins to provide broad and durable protection against emerging variants. Methods: To address this, here we developed two vaccine candidates, namely (i) DNA-CoV2-TMEP, expressing the multiepitopic CoV2-TMEP protein containing immunodominant and conserved T cell regions from SARS-CoV-2 structural proteins, and (ii) MVA-CoV2-B2AT, encoding a bi-cistronic multiepitopic construct that combines conserved B and T cell overlapping regions from SARS-CoV-2 structural proteins. Results: Both candidates were assessed in vitro and in vivo demonstrating their ability to induce robust immune responses. In C57BL/6 mice, DNA-CoV2-TMEP enhanced the recruitment of innate immune cells and stimulated SARS-CoV-2-specific polyfunctional T cells targeting multiple viral proteins. MVA-CoV2-B2AT elicited NAbs against various SARS-CoV-2 variants of concern (VoCs) and reduced viral replication and viral yields against the Beta variant in susceptible K18-hACE2 mice. The combination of MVA-CoV2-B2AT with a mutated ISG15 form as an adjuvant further increased the magnitude, breadth and polyfunctional profile of the response. Conclusion: These findings underscore the potential of these multiepitopic proteins when expressed from DNA or MVA vectors to provide protection against SARS-CoV-2 and its variants, supporting their further development as next-generation COVID-19 vaccines.

Abstract Background Galcanezumab has shown efficacy and effectiveness in the treatment of episodic and chronic migraine (CM), however, the population represented in randomized clinical trials (RCTs) differs from the population observed in real-world setting. To describe the long-term effectiveness and tolerability of galcanezumab in clinical practice in patients excluded from RCTs. Methods Multicenter prospective cohort study of consecutive patients with chronic and high-frequency episodic migraine (HFEM) with prior failure to three or more migraine preventive drugs, treated with galcanezumab and followed up for 12 months. Results We enrolled 1055 patients, aged 50 (IQR: 42–58), 82.9% female, 76.4% chronic migraine, 69% with at least one exclusion criteria for RCTs, including age > 65 (n = 121), concomitant use of onabotulinumtoxinA (n = 185), daily headache at baseline (n = 347), chronic painful syndromes (n = 206), fibromyalgia (n = 101) or treatment resistance (n = 957). The median number of prior preventive treatments was 4 (IQR: 3–5). The retention rate was 90.8%, 76.8% and 71.4% at 3, 6 and 12 months. The main reasons for treatment discontinuation were lack of effectiveness (21.1%) and inadequate tolerability (6.6%). The 30%, 50% and 75% responder rates were 62.6%, 49.8% and 24.2% between weeks 8–12; 60.9%, 48.8% and 24.6% between weeks 20–24; and 59.7%, 48.3% and 24.6% between weeks 44–48. Daily headache at baseline (OR: 0.619; 95%CI: 0.469–0.817) and patient’s age (OR: 1.016; 95%CI: 1.005–1.026) were associated with 50% response at weeks 20–24. The variables that were associated with a higher reduction of headache days between weeks 20–24 were patient’s age (0.068; 95% CI: 0.018–0.119) and headache days per month at baseline (0.451; 95% CI: 0.319–0.583), while psychiatric comorbidity (-1.587; 95% CI: -2.626—0.538) and daily headache at baseline (-2.718; 95% CI: -4.58—0.869) were associated with fewer reduction in the number of headache days between weeks 20–24. Conclusion This study provides class III evidence of effectiveness and tolerability of galcanezumab in patients with HFEM and CM with comorbidities that would result in exclusion of the pivotal RCTs. Nonetheless, the clinical results over a 12-month period were similar to the efficacy observed in randomized controlled trials. Few patients discontinued the drug due to inadequate tolerability.

Introduction: The COVID-19 pandemic has caused an unexpected boost to telemedicine. We analyse the impact of the pandemic on telemedicine applied in Spanish headache consultations, review the literature, and issue recommendations for the implementation of telemedicine in consultations. Method: The study comprised 3 phases: 1) review of the MEDLINE database since 1958 (first reported experience with telemedicine); 2) Google Forms survey sent to all members of the Spanish Society of Neurology’s Headache Study Group (GECSEN); and 3) online consensus of GECSEN experts to issue recommendations for the implementation of telemedicine in Spain. Results: COVID-19 has increased waiting times for face-to-face consultations, increasing the use of all telemedicine modalities: landline telephone (from 75% before April 2020 to 97% after), mobile telephone (from 9% to 27%), e-mail (from 30% to 36%), and video consultation (from 3% to 21%). Neurologists are aware of the need to expand the availability of video consultations, which are clearly growing, and other e-health and m-health tools. Conclusions: The GECSEN recommends and encourages all neurologists who assist patients with headaches to implement telemedicine resources, with the optimal objective of offering video consultation to patients under 60-65 years of age and telephone calls to older patients, although each case must be considered on an individual basis. Prior approval and advice must be sought from legal and IT services and the centre’s management. Most patients with stable headache and/or neuralgia are eligible for telemedicine follow-up, after a first consultation that must always be held in person. Resumen: Introducción: La pandemia COVID-19 ha provocado un inusitado impulso a la Telemedicina (TM). Analizamos el impacto de la pandemia en la TM aplicada en las consultas de cefaleas españolas, revisamos la literatura y lanzamos unas recomendaciones para implantar la TM en las consultas. Método: Tres fases: 1) Revisión de la base Medline desde el año 1958 (primera experienciade TM); 2) Formulario Google Forms enviado a todos los neurólogos del Grupo de Estudio de Cefaleas de la Sociedad Espa˜nola de Neurología (GECSEN), y 3) Consenso on-line de expertos GECSEN para emitir recomendaciones para implantar la TM en. España. Resultados: La pandemia por COVID-19 ha empeorado los tiempos de espera presenciales, incrementando el uso de todas las modalidades de TM antes y después de abril de 2020: teléfono fijo (del 75% al 97%), teléfono móvil (del 9% al 27%), correo electrónico (del 30% al 36%), y videoconsulta (del 3% al 21%). Los neurólogos son conscientes de la necesidad de ampliar la oferta con videoconsultas, claramente in crescendo, y otras herramientas de e-health y m-health. Conclusiones: Desde el GECSEN recomendamos y animamos a todos los neurólogos que asisten a pacientes con cefaleas a implantar recursos de TM, teniendo como objetivo óptimo la videoconsulta en menores de 60-65 años y la llamada telefónica en mayores, si bien cada caso debe individualizarse. Se deberá contar previamente con la aprobación y asesoramiento de los servicios jurídicos e informáticos y de la dirección del centro. La mayoría de los pacientes con cefalea y/o neuralgia estable son candidatos a seguimiento mediante TM, tras una primera visita que tiene que ser siempre presencial.

Resumen: Introducción: La pandemia COVID-19 ha provocado un inusitado impulso a la telemedicina (TM). Analizamos el impacto de la pandemia en la TM aplicada en las consultas de cefaleas españolas, revisamos la literatura y lanzamos unas recomendaciones para implantar la TM en las consultas. Método: Tres fases: 1) Revisión de la base Medline desde el año 1958 (primera experiencia de TM); 2) Formulario Google Forms enviado a todos los neurólogos del Grupo de Estudio de Cefaleas de la Sociedad Española de Neurología (GECSEN), y 3) Consenso on-line de expertos GECSEN para emitir recomendaciones para implantar la TM en España. Resultados: La pandemia por COVID-19 ha empeorado los tiempos de espera presenciales, incrementando el uso de todas las modalidades de TM antes y después de abril de 2020: teléfono fijo (del 75% al 97%), teléfono móvil (del 9% al 27%), correo electrónico (del 30% al 36%) y videoconsulta (del 3% al 21%). Los neurólogos son conscientes de la necesidad de ampliar la oferta con videoconsultas, claramente in crescendo, y otras herramientas de e-health y m-health. Conclusiones: Desde el GECSEN recomendamos y animamos a todos los neurólogos que asisten a pacientes con cefaleas a implantar recursos de TM, teniendo como objetivo óptimo la videoconsulta en menores de 60-65 años y la llamada telefónica en mayores, si bien cada caso debe individualizarse. Se deberá contar previamente con la aprobación y asesoramiento de los servicios jurídicos e informáticos y de la dirección del centro. La mayoría de los pacientes con cefalea y/o neuralgia estable son candidatos a seguimiento mediante TM, tras una primera visita que tiene que ser siempre presencial. Abstract: Introduction: The COVID-19 pandemic has caused an unexpected boost to telemedicine. We analyse the impact of the pandemic on telemedicine applied in Spanish headache consultations, review the literature, and issue recommendations for the implementation of telemedicine in consultations. Method: The study comprised 3 phases: 1) review of the MEDLINE database since 1958 (first reported experience with telemedicine); 2) Google Forms survey sent to all members of the Spanish Society of Neurology's Headache Study Group (GECSEN); and 3) online consensus of GECSEN experts to issue recommendations for the implementation of telemedicine in Spain. Results: COVID-19 has increased waiting times for face-to-face consultations, increasing the use of all telemedicine modalities: landline telephone (from 75% before April 2020 to 97% after), mobile telephone (from 9% to 27%), e-mail (from 30% to 36%), and video consultation (from 3% to 21%). Neurologists are aware of the need to expand the availability of video consultations, which are clearly growing, and other e-health and m-health tools. Conclusions: The GECSEN recommends and encourages all neurologists who assist patients with headaches to implement telemedicine resources, with the optimal objective of offering video consultation to patients under 60-65 years of age and telephone calls to older patients, although each case must be considered on an individual basis. Prior approval and advice must be sought from legal and IT services and the centre's management. Most patients with stable headache and/or neuralgia are eligible for telemedicine follow-up, after a first consultation that must always be held in person.

Abstract Background Anti-CGRP monoclonal antibodies have shown notable effectiveness and tolerability in migraine patients; however, data on their use in elderly patients is still lacking, as clinical trials have implicit age restrictions and real-world evidence is scarce. In this study, we aimed to describe the safety and effectiveness of erenumab, galcanezumab and fremanezumab in migraine patients over 65 years old in real-life. Methods In this observational real-life study, a retrospective analysis of prospectively collected data from 18 different headache units in Spain was performed. Migraine patients who started treatment with any anti-CGRP monoclonal antibody after the age of 65 years were included. Primary endpoints were reduction in monthly migraine days after 6 months of treatment and the presence of adverse effects. Secondary endpoints were reductions in headache and medication intake frequencies by months 3 and 6, response rates, changes in patient-reported outcomes and reasons for discontinuation. As a subanalysis, reduction in monthly migraine days and proportion of adverse effects were also compared among the three monoclonal antibodies. Results A total of 162 patients were included, median age 68 years (range 65–87), 74.1% women. 42% had dyslipidaemia, 40.3% hypertension, 8% diabetes, and 6.2% previous cardiovascular ischaemic disease. The reduction in monthly migraine days at month 6 was 10.1 ± 7.3 days. A total of 25.3% of patients presented adverse effects, all of them mild, with only two cases of blood pressure increase. Headache and medication intake frequencies were significantly reduced, and patient-reported outcomes were improved. The proportions of responders were 68%, 57%, 33% and 9% for reductions in monthly migraine days ≥ 30%, ≥ 50%, ≥ 75% and 100%, respectively. A total of 72.8% of patients continued with the treatment after 6 months. The reduction in migraine days was similar for the different anti-CGRP treatments, but fewer adverse effects were detected with fremanezumab (7.7%). Conclusions Anti-CGRP mAbs are safe and effective treatments in migraine patients over 65 years old in real-life clinical practice. Graphical Abstract

Augmentative and Alternative Communication (aac) strategies ease communication tasks for people who require accessible solutions. These strategies are usually addressed by technological solutions such as mobile applications. This research seeks clues on the development of such applications by analyzing user interactions with Android application PictoDroid Lite, an aac communicator. This study considered a data set containing more than 85,000 interactions of users from more than 50 countries. The goal was to identify the primary needs reflected in the users’ behavior and how these applications handle them, providing other researchers and developers with relevant information about how users interact with these applications. We detected areas of improvement regarding the adaptation to users’ needs in terms of profiling, smart suggestions, and time habits.

IntroductionWhile there has been considerable progress in the development of vaccines against SARS-CoV-2, largely based on the S (spike) protein of the virus, less progress has been made with vaccines delivering different viral antigens with cross-reactive potential.MethodsIn an effort to develop an immunogen with the capacity to induce broad antigen presentation, we have designed a multi-patch synthetic candidate containing dominant and persistent B cell epitopes from conserved regions of SARS-CoV-2 structural proteins associated with long-term immunity, termed CoV2-BMEP. Here we describe the characterization, immunogenicity and efficacy of CoV2-BMEP using two delivery platforms: nucleic acid DNA and attenuated modified vaccinia virus Ankara (MVA).ResultsIn cultured cells, both vectors produced a main protein of about 37 kDa as well as heterogeneous proteins with size ranging between 25-37 kDa. In C57BL/6 mice, both homologous and heterologous prime/boost combination of vectors induced the activation of SARS-CoV-2-specific CD4 and CD8 T cell responses, with a more balanced CD8+ T cell response detected in lungs. The homologous MVA/MVA immunization regimen elicited the highest specific CD8+ T cell responses in spleen and detectable binding antibodies (bAbs) to S and N antigens of SARS-CoV-2. In SARS-CoV-2 susceptible k18-hACE2 Tg mice, two doses of MVA-CoV2-BMEP elicited S- and N-specific bAbs as well as cross-neutralizing antibodies against different variants of concern (VoC). After SARS-CoV-2 challenge, all animals in the control unvaccinated group succumbed to the infection while vaccinated animals with high titers of neutralizing antibodies were fully protected against mortality, correlating with a reduction of virus infection in the lungs and inhibition of the cytokine storm.DiscussionThese findings revealed a novel immunogen with the capacity to control SARS-CoV-2 infection, using a broader antigen presentation mechanism than the approved vaccines based solely on the S antigen.

Respiratory disorders caused by allergy have been associated to bronchiolar inflammation leading to life-threatening airway narrowing. However, whether airway allergy causes alveolar dysfunction contributing to the pathology of allergic asthma remains unaddressed. To explore whether airway allergy causes alveolar dysfunction that might contribute to the pathology of allergic asthma, alveolar structural and functional alterations were analyzed during house dust mite (HDM)-induced airway allergy in mice, by flow cytometry, light and electron microscopy, monocyte transfer experiments, assessment of intra-alveolarly-located cells, analysis of alveolar macrophage regeneration in Cx3cr1cre:R26-yfp chimeras, analysis of surfactant-associated proteins, and study of lung surfactant biophysical properties by captive bubble surfactometry. Our results demonstrate that HDM-induced airway allergic reactions caused severe alveolar dysfunction, leading to alveolar macrophage death, pneumocyte hypertrophy and surfactant dysfunction. SP-B/C proteins were reduced in allergic lung surfactant, that displayed a reduced efficiency to form surface-active films, increasing the risk of atelectasis. Original alveolar macrophages were replaced by monocyte-derived alveolar macrophages, that persisted at least two months after the resolution of allergy. Monocyte to alveolar macrophage transition occurred through an intermediate stage of pre-alveolar macrophage and was paralleled with translocation into the alveolar space, Siglec-F upregulation, and downregulation of CX3CR1. These data support that the severe respiratory disorders caused by asthmatic reactions not only result from bronchiolar inflammation, but additionally from alveolar dysfunction compromising an efficient gas exchange.

El riesgo es definido como el producto de la casualidad y la vulnerabilidad. Se relaciona con la probabilidad de un evento negativo, tal como la sequía y las consecuencias previsibles de la ocurrencia del evento. Desde la óptica de la agricultura, la amenaza climática más común es la sequía que; vista a escala global, tiene repercusiones mayores parecidas a los ciclones, inundaciones y tormentas. El objetivo de la presente investigación, es generar una estrategia innovadora para la mitigación del riesgo de la sequía, con utilización de la tecnología lluvia sólida y la sostenibilidad del sector agropecuario en la zona sierra del cantón Guaranda. La metodología del estudio es la acción participativa, por medio de la creación de grupos focales liderados por los agricultores de la provincia de Guaranda. La investigación es de tipo descriptiva y de campo, en concordancia con la observación directa. Los resultados indican que, los cultivos de maíz (Zea mays) y papa (Solanum tuberosum) tuvieron un comportamiento y homogeneidad superior al momento de absorber el agua almacenada en el polímero denominado lluvia sólida, en el cultivo de Solanum tuberosum el campo de lluvia solida se obtuvo un peso de tubérculos de 0.95Kg y en campo testigo fue de 0.92%, la Zea mays la cosecha fue de 175 DDS en campo lluvia sólida y 196 DDS en campo testigo. El tamaño, grosor y peso que presentaron los cultivos; demuestran lo efectivo y estable de esta tecnología sobre en las diferentes etapas fenológicas del cultivo. Las conclusiones denotan que la tecnología lluvia sólida representa una alternativa novedosa para los agricultores, sobre todo en sectores donde se hace presente la sequía como factor perturbador en el proceso de cultivos. Es importante destacar, los estudios previos que deben realizarse, para lograr el máximo beneficio del polímero.

Background: The COVID-19 pandemic, caused by SARS-CoV-2, has highlighted the need for vaccines targeting both neutralizing antibodies (NAbs) and long-lasting cross-reactive T cells covering multiple viral proteins to provide broad and durable protection against emerging variants. Methods: To address this, here we developed two vaccine candidates, namely (i) DNA-CoV2-TMEP, expressing the multiepitopic CoV2-TMEP protein containing immunodominant and conserved T cell regions from SARS-CoV-2 structural proteins, and (ii) MVA-CoV2-B2AT, encoding a bi-cistronic multiepitopic construct that combines conserved B and T cell overlapping regions from SARS-CoV-2 structural proteins. Results: Both candidates were assessed in vitro and in vivo demonstrating their ability to induce robust immune responses. In C57BL/6 mice, DNA-CoV2-TMEP enhanced the recruitment of innate immune cells and stimulated SARS-CoV-2-specific polyfunctional T cells targeting multiple viral proteins. MVA-CoV2-B2AT elicited NAbs against various SARS-CoV-2 variants of concern (VoCs) and reduced viral replication and viral yields against the Beta variant in susceptible K18-hACE2 mice. The combination of MVA-CoV2-B2AT with a mutated ISG15 form as an adjuvant further increased the magnitude, breadth and polyfunctional profile of the response. Conclusion: These findings underscore the potential of these multiepitopic proteins when expressed from DNA or MVA vectors to provide protection against SARS-CoV-2 and its variants, supporting their further development as next-generation COVID-19 vaccines. [ABSTRACT FROM AUTHOR]

Given the cultural and environmental potential presented by historical water infrastructures in urban contexts, this article states the evidence of a not much documented urban phenomenon in Portugal, the refurbishment of water heritage protected areas motivated by European-based regeneration projects. By employing a case-study design, four good practices -placed in Évora, Lisbon, Braga and Guimarães-are chosen to enlighten this growing and aware trend. The assets located there -the Água de Prata Aqueduct, the Águas Livres Aqueduct, the Sete Fontes water-supply system and the Zona de Couros industrial area, respectively-are geographical, historical and culturally characterised, while the projects that concern them are documented by visiting the areas and analysing the available sources. Then, open-data platforms and heritage protection decrees are processed to graphically code the topography, hydrology, urban land use, infrastructures, landmarks and protected areas, employing QGIS free software for Geographic Information Systems. As a result, the four practices are documented, discussed and compared. A table assesses and summarises their pre-existing and currently added values and a series of diagrams illustrates the landscape changes generated. These graphics validate the practices and update the status of the assets, enhancing the rediscovery of the existing landscapes and showing the main challenges and future opportunities faced by these areas.

Resumen: Introducción: La cefalea es un motivo de consulta frecuente en atención primaria (AP), sin embargo, se trata de una patología infradiagnosticada e infratratada. Uno de los posibles factores es la falta de formación de los profesionales de AP en cefaleas. Métodos: Estudio descriptivo transversal mediante encuesta autoadministrada a los médicos de AP de nuestro sector sanitario. Se recogieron variables sociodemográficas, variables relacionadas con la formación previa en neurología y cefaleas y variables en relación con sus necesidades formativas. Resultados: Completaron la encuesta 104 médicos de AP, de los cuales el 53% fueron mujeres y la edad media fue 49 años. La mayoría de los encuestados trabajan en un centro de salud urbano (42,3%) y se han formado vía MIR (77,9%). El 65,4% dedica más tiempo a una consulta de cefaleas que a otras consultas y solo un 32,7% utiliza la Clasificación Internacional de Cefaleas. El 68,3% declara tener un interés alto o muy alto en cefaleas y al 75,9% le gustaría mejorar su formación, eligiendo cursos teórico-prácticos y ponencias de actualización como la herramienta más útil. Un 90% utiliza triptanes en su práctica clínica diaria y el 78% emplea tratamientos preventivos. El fármaco más utilizado es amitriptilina y solo un 22,1% elige topiramato. Conclusiones: Los profesionales de AP están en contacto constante con pacientes con cefaleas y muestran interés en la formación en esta patología, lo que podría ayudarnos a diseñar programas docentes dirigidos a mejorar la calidad asistencial en este ámbito. Abstract: Introduction: Headache is a frequent reason for consultation with primary care (PC) physicians. However, the condition is underdiagnosed and undertreated. One reason for this may be the lack of specific training on headache in PC. Methods: We conducted a descriptive cross-sectional study of data gathered with a self-administered survey that was completed by PC physicians from our health district. We collected sociodemographic data and information on previous training in neurology and headache, and training needs. Results: The survey was completed by 104 PC physicians, 53% of whom were women; mean age was 49 years. Most respondents worked in urban settings (42.3%) and had been trained via residency (77.9%). Although 65.4% spent more time with patients with headache than with other patients, only 32.7% used the International Classification of Headache Disorders. In our sample, 68.3% of respondents reported a high or very high interest in headache, and 75.9% wished to receive further training on the condition; theoretical and practical courses and update lectures were regarded as the most useful tools. In clinical practice, 90% used triptans and 78% used preventive treatments. The most frequently used drug was amitriptyline; only 22.1% choose topiramate. Conclusions: PC physicians are in frequent contact with patients with headache and show interest in receiving training on this condition. This could be helpful in designing training programmes aimed at improving quality of care in this area.

Background and objective: CGRP, a neuropeptide involved in migraine pathophysiology, is also known to play a role in the respiratory system and in immunological conditions such as sepsis. We analyzed the impact of the use of CGRP antagonists in patients with migraine during the COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus. Methods: This is a multicentre cross-sectional study. From May to November 2020, through a national survey distributed by the Spanish Society of Neurology, we collected data about the presence of COVID-19 symptoms including headache and their characteristics and severity in patients with migraine treated with anti-CGRP monoclonal antibodies (mAb), and compared them with patients with migraine not receiving this treatment. We also conducted a subanalysis of patients with COVID-19 symptoms. Results: We recruited 300 patients with migraine: 51.7% (155/300) were taking anti-CGRP mAbs; 87.3% were women (262/300). Mean age (standard deviation) was 47.1 years (11.6). Forty-one patients (13.7%) met diagnostic criteria for COVID-19, with no statistically significant difference between patients with and without anti-CGRP mAb treatment (16.1% vs 11.0%, respectively; P = .320). Of the patients with COVID-19, 48.8% (20/41) visited the emergency department and 12.2% (5/41) were hospitalised. Likewise, no clinical differences were found between the groups of patients with and without anti-CGRP mAb treatment. Conclusion: Anti-CGRP mAbs may be safe in clinical practice, presenting no association with increased risk of COVID-19. Resumen: Antecedentes y objetivo: El péptido relacionado con el gen de la calcitonina (CGRP, por sus siglas en inglés), es un neuropéptido involucrado en la fisiopatología de la migraña, que también es conocido por participar en la regulación del sistema respiratorio y en algunas enfermedades inmunológicas como la sepsis. Hemos analizado el impacto del uso de los antagonistas de CGRP en pacientes con migraña durante la pandemia de COVID-19, causada por el coronavirus SARS-CoV-2. Métodos: Estudio transversal multicéntrico desarrollado entre mayo y noviembre de 2020, en el que la Sociedad Española de Neurología distribuyó a nivel nacional una encuesta de la que recogimos datos sobre la presencia, las características y la gravedad de síntomas de COVID-19, entre los que se encontraba la cefalea, en pacientes con migraña tratados con anticuerpos monoclonales (AcM) anti-CGRP, y los comparamos con los de pacientes con migraña que no recibían dicho tratamiento. También realizamos un subanálisis de los pacientes con síntomas de COVID-19. Resultados: Identificamos 300 pacientes con migraña: 51,7% (155/300) recibían AcM anti-CGRP; el 87,3% eran mujeres (262/300) y la edad media (desviación estándar) de la muestra fue de 47,1 (11,6) años. Un total de 41 pacientes (13,7%) cumplían los criterios diagnósticos de COVID-19, sin diferencias estadísticamente significativas entre los pacientes que recibían tratamiento con AcM anti-CGRP y los que no (16,1% y 11,0%, respectivamente; p = 0,320). De los pacientes con COVID-19, el 48,8% (20/41) acudieron a urgencias y el 12,2% (5/41) fueron hospitalizados. Igualmente, no se detectaron diferencias clínicas entre los pacientes que recibían dicho tratamiento y los que no. Conclusión: El tratamiento con AcM anti-CGRP parece un recurso seguro en la práctica clínica, y no se asocia a un mayor riesgo de COVID-19.

Introduction: Headache is a frequent reason for consultation with primary care (PC) physicians. However, the condition is underdiagnosed and undertreated. One reason for this may be the lack of specific training on headache in PC. Methods: We conducted a descriptive cross-sectional study of data gathered with a self-administered survey that was completed by PC physicians from our health district. We collected sociodemographic data and information on previous training in neurology and headache, and training needs. Results: The survey was completed by 104 PC physicians, 53% of whom were women; mean age was 49 years. Most respondents worked in urban settings (42.3%) and had been trained via residency (77.9%). Although 65.4% spent more time with patients with headache than with other patients, only 32.7% used the International Classification of Headache Disorders. In our sample, 68.3% of respondents reported a high or very high interest in headache, and 75.9% wished to receive further training on the condition; theoretical and practical courses and update lectures were regarded as the most useful tools. In clinical practice, 90% used triptans and 78% used preventive treatments. The most frequently used drug was amitriptyline; only 22.1% choose topiramate. Conclusions: PC physicians are in frequent contact with patients with headache and show interest in receiving training on this condition. This could be helpful in designing training programmes aimed at improving quality of care in this area. Resumen: Introducción: La cefalea es un motivo de consulta frecuente en atención primaria (AP), sin embargo, se trata de una patología infradiagnosticada e infratratada. Uno de los posibles factores es la falta de formación de los profesionales de AP en cefaleas. Métodos: Estudio descriptivo transversal mediante encuesta auto-administrada a los médicos de AP de nuestro sector sanitario. Se recogieron variables sociodemográficas, variables relacionadas con la formación previa en neurología y cefaleas y variables en relación con sus necesidades formativas. Resultados: Completaron la encuesta 104 médicos de atención primaria, de los cuales el 53% fueron mujeres y la edad media fue 49 años. La mayoría de los encuestados trabajan en un centro de salud urbano (42,3%) y se han formado vía MIR (77,9%). El 65,4% dedican más tiempo a una consulta de cefaleas que a otras consultas y sólo un 32,7% utilizan la Clasificación Internacional de Cefaleas. El 68,3% declaran tener un interés alto o muy alto en cefaleas y al 75,9% les gustaría mejorar su formación, eligiendo cursos teórico-prácticos y ponencias de actualización como la herramienta más útil. Un 90% utiliza triptanes en su práctica clínica diaria y el 78% emplea tratamientos preventivos. El fármaco más utilizado es amitriptilina y sólo un 22,1% elige topiramato. Conclusiones: Los profesionales de AP están en contacto constante con pacientes con cefaleas y muestran interés en la formación en esta patología, lo que podría ayudarnos a diseñar programas docentes dirigidos a mejorar la calidad asistencial en este ámbito.