RCAAP Repository

O cancro do pâncreas é das malignidades mais agressivas e mortais. Esta doença raramente é diagnosticada num estadio em que a resseção cirúrgica é viável. A maioria dos doentes, a quando do diagnóstico, encontram-se num estadio avançado onde as opções terapêuticas são limitadas. Para além disso, as características peculiares do microambiente tumoral do cancro do pâncreas, com um estroma fibrótico extremamente denso, compromete a distribuição eficaz dos fármacos anticancerígenos. A quimioterapia sistémica é a única opção terapêutica para doentes com cancro do pâncreas avançado – FOLFIRINOX ou gemcitabina+nab-paclitaxel. No entanto, ainda não existe na clínica marcadores eficazes com valor preditivo que permitem identificar qual a melhor terapêutica para cada doente. Consequentemente, os doentes são submetidos a múltiplas rondas de tratamento e toxicidades desnecessárias, até encontrar a terapia que seja mais eficaz. A imunoterapia também tem sido explorada como terapia complementar para o tratamento do cancro do pâncreas, incluindo inibidores de checkpoint imunológicos. Contudo, o microambiente tumoral rico em fibroblastos e células imunes com atividade imunossupressora, constitui um obstáculo significativo. Além disso, muitos dos doentes não são elegíveis para este tipo de terapia e portanto estratégias mais personalizadas estão a ser a investigadas em ensaios clínicos. Desta forma, um teste capaz de prever as respostas de cada doente antes do tratamento, seria de grande valor para o tratamento personalizado do cancro do pâncreas. O principal objetivo deste projeto de investigação foi testar as principais opções terapêuticas para o cancro do pâncreas em estadio avançado - FOLFIRINOX e gemcitabina+nab-paclitaxel - utilizando o modelo xenógrafo de peixe-zebra. Com este objetivo, xénografos de peixe-zebra foram gerados utilizando linhas celulares humanas de cancro do pâncreas (Panc-1 e MIA PaCa-2), e várias características tumorais foram analisadas por microscopia confocal, incluindo dinâmica tumoral – proliferação e morte celular – e composição do microambiente tumoral. Os efeitos citotóxicos do nivolumab em monoterapia e em combinação com gemcitabina+nabpaclitaxel (ensaio clínico a decorrer) também foram avaliados. Os resultados demonstraram que as linhas celulares de cancro do pâncreas apresentam diferentes capacidades de implantação no modelo de xénografos de peixe-zebra. Relativamente às terapias anticancerígenas, os nossos resultados demonstraram que os xénografos de peixe-zebra são capazes de revelar respostas tumorais ao FOLFIRINOX e gemcitabina+nab-paclitaxel, incluindo comprometimento da proliferação celular e indução da apoptose. Neste projeto, testámos também a imunoterapia com o anticorpo anti-PD-1- nivolumab. Surpreendentemente os xénografos de peixe-zebra submetidos ao nivolumab em monoterapia e em combinação com gemcitabina+nab-paclitaxel também revelaram sensibilidade celular, com indução significativa da apoptose e redução do tamanho tumoral. De seguida, decidimos caracterizar o microambiente tumoral em particular o infiltrado de neutrófilos e macrófagos. Aos 4 dias pós-injeção, a percentagem de neutrófilos aumentou em relação ao primeiro dia, e os macrófagos do tipo M2 (atividade pró-tumoral) passaram a dominar o microambiente tumoral. Para estudar o papel destes infiltrados na tumorigénese, gerámos xenógrafos em mutantes hipomórficos. A redução de neutrófilos, levou a um aumento do tamanho tumoral, enquanto que a redução de macrófagos, levou a um efeito contrário – diminuição do tamanho tumoral. Estes dados sugerem que os neutrófilos e macrófagos têm um papel antagónico, os neutrófilos com um papel anti-tumoral e os macrófagos pró-tumoral. Sumariamente, os nossos resultados realçam a viabilidade de usar xénografos de peixe-zebra como um modelo in vivo para o screening de respostas tumorais às opções terapêuticas do cancro do pâncreas, e para o estudo da complexidade do microambiente tumoral.

Background: Activin receptor-like kinase 1 (ALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasia, a devastating disorder that leads to arteriovenous malformations. Here, we show that ALK1 controls endothelial cell polarization against the direction of blood flow and flow-induced endothelial migration from veins through capillaries into arterioles. Methods: Using Cre lines that recombine in different subsets of arterial, capillary-venous, or endothelial tip cells, we show that capillary-venous Alk1 deletion was sufficient to induce arteriovenous malformation formation in the postnatal retina. Results: ALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flow in vivo and in vitro. Mechanistically, ALK1-deficient cells exhibited increased integrin signaling interaction with vascular endothelial growth factor receptor 2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacologic inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations in Alk1-deficient mice. Conclusions: Our study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of arteriovenous malformation formation in hereditary hemorrhagic telangiectasia disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia.

HER2 is a prognostic and predictive biomarker in breast cancer, normally assessed in tumour biopsy and used to guide treatment choices. Circulating tumour cells (CTCs) escape the primary tumour and enter the bloodstream, exhibiting great metastatic potential and representing a real-time snapshot of the tumour burden. Liquid biopsy offers the unique opportunity for low invasive sampling in cancer patients and holds the potential to provide valuable information for the clinical management of cancer patients. This study assesses the performance of the RUBYchip™, a microfluidic system for CTC capture based on cell size and deformability, and compares it with the only FDA-approved technology for CTC enumeration, CellSearch®. After optimising device performance, 30 whole blood samples from metastatic breast cancer patients were processed with both technologies. The expression of HER2 was assessed in isolated CTCs and compared to tissue biopsy. Results show that the RUBYchipTM was able to isolate CTCs with higher efficiency than CellSearch®, up to 10 times more, averaging all samples. An accurate evaluation of different CTC subpopulations, including HER2+ CTCs, was provided. Liquid biopsy through the use of the RUBYchipTM in the clinic can overcome the limitations of histological testing and evaluate HER2 status in patients in real-time, helping to tailor treatment during disease evolution.

Heart failure (HF) is a major health problem with a significant impact on morbidity, mortality, quality of life and healthcare costs. Despite the positive impact of disease-modifying therapies developed over the last four decades, HF mortality and hospitalization remain high. We aim at reviewing the evidence supporting the use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, as a novel strategy for HF with reduced ejection fraction (HFrEF) treatment. The consistent observation of a reduction in HF hospitalizations in type-2 diabetes cardiovascular safety trials EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 and VERTIS raised the hypothesis that SGLT-2 inhibitors could have an impact in HF treatment. This hypothesis was first confirmed in 2019 with the DAPA-HF publication showing that dapagliflozin on top of optimized HFrEF therapy, reduced HF-hospitalizations and cardiovascular mortality. This was reinforced by the EMPEROR-Reduced publication in 2020 showing that empagliflozin on top of optimized HFrEF therapy, reduced HF-hospitalizations. Both studies established SGLT-2 inhibitors as a fourth pillar of HFrEF prognosis-modifying therapy, in addition to the gold standard triple neurohormonal modulation/blockade.

A temática da qualidade de vida no trabalho e a satisfação profissional tem assumido um papel cada vez mais relevante no mundo das organizações e na psicologia dos recursos humanos. A presente investigação tem como objectivo central comparar a qualidade de vida no trabalho e a satisfação profissional entre teletrabalhadores e trabalhadores tradicionais, que são profissionais da tecnologia da informação. Para avaliar a qualidade de vida no trabalho foi aplicado o instrumento designado de Inventário sobre a Qualidade de Vida no Trabalho (Rafael & Lima, 2007a, 2008a) e indicadores de Satisfação Profissional. A amostra é constituída por 51 profissionais empregados, teletrabalhadores e trabalhadores tradicionais. Os resultados obtidos revelam que os teletrabalhadores apresentam um nível mais elevado de QVT em geral, comparativamente com os trabalhadores tradicionais. Da mesma maneira, verifica-se que existem níveis de SP mais elevados nos teletrabalhadores por comparação aos trabalhadores tradicionais.

Influenza viruses are major human pathogens, responsible for respiratory diseases affecting millions of people worldwide, with high morbidity and significant mortality. Infections by influenza can be controlled by vaccines and antiviral drugs. However, this virus is constantly under mutations, limiting the effectiveness of these clinical antiviral strategies. It is therefore urgent to develop new ones. Influenza hemagglutinin (HA) is involved in receptor binding and promotes the pH-dependent fusion of viral and cell endocytic membranes. HA-targeted peptides may emerge as a novel antiviral option to block this viral entry step. In this study, we evaluated three HA-derived (lipo)peptides using fluorescence spectroscopy. Peptide membrane interaction assays were performed at neutral and acidic pH to better resemble the natural conditions in which influenza fusion occurs. We found that peptide affinity towards membranes decreases upon the acidification of the environment. Therefore, the released peptides would be able to bind their complementary domain and interfere with the six-helix bundle formation necessary for viral fusion, and thus for the infection of the target cell. Our results provide new insight into molecular interactions between HA-derived peptides and cell membranes, which may contribute to the development of new influenza virus inhibitors.

Introduction/aims: Fasciculations can be symptomatic, yet not progress to amyotrophic lateral sclerosis (ALS), a condition categorized as benign fasciculation syndrome (BFS). We aimed to assess electrodiagnostic changes and clinical course over time in patients with BFS. Methods: This was a retrospective review of medical records of patients who were referred because of a suspicion of ALS or who had directly asked for a consultation because of a personal concern regarding ALS. All clinical and electromyography (EMG) investigations were performed by the same neurologist, following an established protocol. In addition, laboratory testing and imaging studies were performed as determined to be clinically necessary. Results: We included 37 subjects (mean age 46 ± 14.7 y, 29 male, 7 healthcare professionals). Most patients had experienced fasciculations in both upper and lower limb muscles (62.2%); the remaining patients had fasciculations only in their lower limbs. EMG in seven subjects showed chronic neurogenic potentials in addition to fasciculation potentials; all of these were older men. Follow-up data were available in 24 patients (median 4.7 y), 21 with repeat EMGs, including all those with neurogenic EMG changes at baseline (median 6.5 y). Two-thirds of patients reported symptomatic improvement: 57.1% of those with abnormal EMG and 61.1% with normal EMG. The EMG changes were stable. Discussion: Prognosis of BFS is favorable, regardless of minor EMG abnormalities. The latter do not necessarily imply progression to ALS.

Transcripts containing premature termination codons (PTCs) can be subject to nonsense-associated alternative splicing (NAS). Two models have been evoked to explain this, scanning and splice motif disruption. The latter postulates that exonic cis motifs, such as exonic splice enhancers (ESEs), are disrupted by nonsense mutations. We employ genome-wide transcriptomic and k-mer enrichment methods to scrutinize this model. First, we show that ESEs are prone to disruptive nonsense mutations owing to their purine richness and paucity of TGA, TAA and TAG. The motif model correctly predicts that NAS rates should be low (we estimate 5-30%) and approximately in line with estimates for the rate at which random point mutations disrupt splicing (8-20%). Further, we find that, as expected, NAS-associated PTCs are predictable from nucleotide-based machine learning approaches to predict splice disruption and, at least for pathogenic variants, are enriched in ESEs. Finally, we find that both in and out of frame mutations to TAA, TGA or TAG are associated with exon skipping. While a higher relative frequency of such skip-inducing mutations in-frame than out of frame lends some credence to the scanning model, these results reinforce the importance of considering splice motif modulation to understand the etiology of PTC-associated disease.

Cardiovascular disease (CVD) remains the world’s number one cause of death, either in developed or in developing countries. Therefore, cardiovascular health should concern every living person in the world. From hereditary conditions to lifestyle habits (such as smoking, eating habits, exercise, and others) and societal and environmental contexts (such as air pollution), our hearts are faced with numerous threats. The World Heart Federation (WHF), which I have the privilege to lead for the next two years, is at the helm of the effort to achieve our high-level ambition of cardiovascular health for everyone by leading and inspiring the cardiovascular community. This gives WHF an obligation and an opportunity to shape the future of cardiovascular health, to lead and anticipate the changes we wish for our patients, the professionals, and the global community. We do that by influencing policies, sharing knowledge, and inspiring action.

Introduction: Chronic pain (CP) negatively impacts the lives of almost 2 billion people worldwide, including approximately 37% of adults in Portugal. As most of these patients are followed by a general practitioner, identifying the prevalence and characterizing the pain of patients who visit primary care units will provide valuable insights into the CP landscape in Portugal. Methods: To achieve this goal, an observational, cross-sectional study was conducted in 58 primary care units of mainland Portugal between June 2017 and March 2018. Interviews were conducted with 8445 patients, and 578 CP patients were characterized. Results: We observed that one third of patients suffered from CP, and of these, approximately one third felt that their pain management was insufficient. Most of the population was 55 years old or older, retired, and had more than three comorbidities. However, age and the number and type of comorbidities were not predictors of pain intensity. Additionally, most of the population had pain or discomfort that hindered their mobility and the performance of their everyday activities. This decrease in the quality of life led to feelings of anxiety and depression, which were associated with pain intensity. Conclusion: Given the high prevalence of CP, strategies to improve the quality of life of these patients and decrease the negative impacts, as well as awareness campaigns to increase the populations' knowledge of this condition, are essential for the suitable and timely treatment of CP.

This work aims to analyse the mediator-event structure and its influence over an artistic intervention through the project intervention model with the population. First, the concept is presented through its theoretical and practical aspects, while identifying and reflecting around national Portuguese and foreign instances of mediator-events. It is intended to understand if the artistic and educational interventions through the project model can benefit a mediator-event program adapted for the co-participation between worlds, studied in the current Portuguese panorama. It is studied how this structure can evolve and contribute to the development of a radical pedagogy through the lenses and ingredients of Maria Acaso (2007) and if it might exist a pedagogical dynamic within a horizontal program within the mediator-event. To this end, the work reflects upon the contributions and limits of the mediator-event and its intervention is analysed, through a qualitative data analysis. A scheme of a mediator-event structure is elaborated, compatible with the development of horizontal programs, associated with arts education in connection to radical pedagogies. In a second phase, the feasibility of radical pedagogy is studie and discussed within the scope of the horizontal program Viagem Sentimental with the Portuguese choreographer Francisco Camacho, a program integrated within the mediator event Festival Todos 18’. This study uses several interviews collected from artists, programmers and participants from Festival Todos 18’ and 19’, as well as notes from a field paper diary, collected over several weeks between June and September 2018, along the programs Viagem Sentimental rehearsals with Francisco Camacho, Conversa com Crianças with Rita Pedro, Vala Comum with Andresa Soares, Bruno Humberto e João Ferro Martins, as well as the sewing workshops organized with Vera Alvelos at Festival Todos 18’ e 19’ in São Vicente, Lisbon. Finally, three ingredients are identified to contribute to an update on the intervention with communities in the area of contemporary cultural production.

The fundamental idea of this theoretical/practical thesis is the invention, and subsequent development, of paper, both as a support and, later, as raw material in art. Paper has been, for centuries, one of the most important acquisitions of humanity. Paper has been, is and will be, both in daily life and in the aesthetic development, at the origin of future countless activities, particularly those of artistic nature. From the Renaissance on, paper has fostered the democratization of art and culture. It has been the vehicle for several paradigmatic changes over time. The scope of the present work is the transition from the Classical Art stage of Paper used as a support, to the Modern Art stage, when it became a medium per se. It is the transition from a contemplative art to a tactile, spatial art interacting with the viewer. This was only made possible due to the physical/chemical properties of paper. The importance of paper as vehicle and as material for painting and sculpture opened up possibilities for new aesthetics and forms of expression in the development of Modern Art. In spite of the technological progress of the Digital Era, there is always a document in paper support to physically register artistic works, which makes us understand the perennial nature of paper in plastic arts. The present thesis is, albeit its historical nature, essentially of scientific nature, about paper as raw material and the plastic and expressive potentialities of its perennial nature. The scope of the practical part of the present research work is the art of Installation and the potential of papermaking technique in plastic arts.

(1) Background: the Miombo woodlands comprise the most important vegetation from southern Africa and are dominated by tree legumes with an ecology highly driven by fires. Here, we report on the characterization of bacterial communities from the rhizosphere of Brachystegia boehmii in different soil types from areas subjected to different regimes. (2) Methods: bacterial communities were identified through Illumina MiSeq sequencing (16S rRNA). Vigna unguiculata was used as a trap to capture nitrogen-fixing bacteria and culture-dependent methods in selective media were used to isolate plant growth promoting bacteria (PGPB). PGP traits were analysed and molecular taxonomy of the purified isolates was performed. (3) Results: Bacterial communities in the Miombo rhizosphere are highly diverse and driven by soil type and fire regime. Independent of the soil or fire regime, the functional diversity was high, and the different consortia maintained the general functions. A diverse pool of diazotrophs was isolated, and included symbiotic (e.g., Mesorhizobium sp., Neorhizobium galegae, Rhizobium sp., and Ensifer adhaerens), and non-symbiotic (e.g., Agrobacterium sp., Burkholderia sp., Cohnella sp., Microvirga sp., Pseudomonas sp., and Stenotrophomonas sp.) bacteria. Several isolates presented cumulative PGP traits. (4) Conclusions: Although the dynamics of bacterial communities from the Miombo rhizosphere is driven by fire, the maintenance of high levels of diversity and functions remain unchanged, constituting a source of promising bacteria in terms of plant-beneficial activities such as mobilization and acquisition of nutrients, mitigation of abiotic stress, and modulation of plant hormone levels.

The motivation for writing this book stems from our engagement with three undeniable trends in the twenty-frst century: a geographical trend of escalating urbanisation in a world shaken by multiple interdependent crises, a political trend of recognising the challenges following from this and placing them centrally into global plans for sustainable development, and thirdly, a trend in science policy of proclaiming the importance of interdisciplinary and transdisciplinary (ITD) research, not least to inform policymaking. While torn between challenges and opportunities, one aspect that seems to unite all urban sustainability agendas is an appeal for transformative change and for knowledge that can make it happen. Our collaborative book, Enabling the City, occupies this inconvenient, uncomfortable, inarticulate space – but a space almost universally acclaimed as necessary to solve the difcult processes and urban challenges of today. This book focuses on how inter- and transdisciplinary processes of knowledge production may contribute to transformation at a local level, inescapably infuenced by global trends.

Osteoarthritis (OA) is the most common form of arthritis affecting more than 500 million people globally. It accounts for more pain and functional disability than any other musculoskeletal disease and is an important source of high societal and economic costs. Although the pathophysiology of OA is poorly understood, the risk factors associated with disease development are well-established. They include age, obesity, sex, previous incidence of joint injuries, meniscal damage, joint instability, malalignment, genetics, bone shape (including anatomical deformities), muscle weakness and sarcopenia, and metabolic disease. Although OA can affect any synovial joint, including joints in the hand, according to studies on the global burden of disease in 2010 and 2017, knee OA represents the greatest societal burden.

O presente estudo teve como objectivo geral conhecer as representações que os alunos do 3º ciclo têm sobre a violência escolar. Mais especificamente, foram consideradas as seguintes questões de estudo: Como se distribuem os alunos pela vitimização na escola? Como se distribuem os alunos pela disrupção escolar? Que relação existe entre as dimensões da vitimização e da disrupção escolar? Que relação existe entre as dimensões da vitimização e o desempenho escolar? Que relação existe entre as dimensões da vitimização e a escolaridade desejada? Como se diferenciam os alunos na vitimização em função da autoridade parental? A amostra incluiu 328 alunos, do distrito de Setúbal, do 3º Ciclo. Como instrumentos de avaliação, foram utilizados três questionários: o PVS, “Peer Victimization Scale”, de Mynard e Joseph (2000), a EDEP, uma “Escala de Disrupção Escolar Professada pelos Alunos”, de Veiga (1996) e um conjunto de perguntas gerais sobre o aluno e seus contextos. A análise dos resultados permitiu responder às questões de estudo, destacando-se, aqui, um grupo de alunos que referem ser vítimas de bullying na escola, especificamente, 21,4% afirmam ser vítimas de agressão verbal, 11,1% agressão social, 7,5% agressão física e 7,1% agressão relativa à propriedade. Observou-se, também, que 19% dos alunos referem ter comportamentos disruptivos dentro da sala de aula, falando sem autorização e estando distraídos. Como esperado, foram encontradas relações significativas entre a vitimização e a disrupção escolar; a vitimização não apareceu significativamente correlacionada com o rendimento escolar nem com a escolaridade desejada. Verificou-se, ainda, que os alunos que são vítimas percepcionam o pai como tendo um tipo de autoridade indiferente. Os resultados aproximam-se de estudos revistos, à luz dos quais foram discutidos. O estudo apresenta, no final, sugestões para novas investigações.

Today’s processes of urbanisation and the significant projected growth and shift of dynamic urbanisation to the South and East all imply complex challenges related to urban development. As a result of the global significance of urban trends, the sustainable development agenda is also changing to reflect this priority – through goal-driven changes. Inter-and transdisciplinary approaches are an expression of depth and degrees of collaboration and diversity, and debates around their need are premised on fundamental questions about the nature and legitimacy of knowledge: what it is, who holds it and who is entitled to contribute to its production. The experience and knowledge within the urban realm could be better integrated into the more recent discussion on transdisciplinarity and transformative science for a more sustainable future. The chapter also presents an overview of the key concepts discussed in this book.

The increasing number of human biomonitoring (HBM) studies undertaken in recent decades has brought to light the need to harmonise procedures along all phases of the study, including sampling, data collection and analytical methods to allow data comparability. The first steps towards harmonisation are the identification and collation of HBM methodological information of existing studies and data gaps. Systematic literature reviews and meta-analyses have been traditionally put at the top of the hierarchy of evidence, being increasingly applied to map available evidence on health risks linked to exposure to chemicals. However, these methods mainly capture peer-reviewed articles, failing to comprehensively identify other important, unpublished sources of information that are pivotal to gather a complete map of the produced evidence in the area of HBM. Within the framework of the European Human Biomonitoring Initiative (HBM4EU) initiative-a project that joins 30 countries, 29 from Europe plus Israel, the European Environment Agency and the European Commission-a comprehensive work of data triangulation has been made to identify existing HBM studies and data gaps across countries within the consortium. The use of documentary analysis together with an up-to-date platform to fulfil this need and its implications for research and practice are discussed.

Background: Previous systematic reviews have not shown clear benefit of glucocorticoids for acute viral bronchiolitis, but their use remains considerable. Recent large trials add substantially to current evidence and suggest novel glucocorticoid-including treatment approaches. Objectives: To review the efficacy and safety of systemic and inhaled glucocorticoids in children with acute viral bronchiolitis. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2012, Issue 12), MEDLINE (1950 to January week 2, 2013), EMBASE (1980 to January 2013), LILACS (1982 to January 2013), Scopus® (1823 to January 2013) and IRAN MedEx (1998 to November 2009). Selection criteria: Randomised controlled trials (RCTs) comparing short-term systemic or inhaled glucocorticoids versus placebo or another intervention in children under 24 months with acute bronchiolitis (first episode with wheezing). Our primary outcomes were: admissions by days 1 and 7 for outpatient studies; and length of stay (LOS) for inpatient studies. Secondary outcomes included clinical severity parameters, healthcare use, pulmonary function, symptoms, quality of life and harms. Data collection and analysis: Two authors independently extracted data on study and participant characteristics, interventions and outcomes. We assessed risk of bias and graded strength of evidence. We meta-analysed inpatient and outpatient results separately using random-effects models. We pre-specified subgroup analyses, including the combined use of bronchodilators used in a protocol. Main results: We included 17 trials (2596 participants); three had low overall risk of bias. Baseline severity, glucocorticoid schemes, comparators and outcomes were heterogeneous. Glucocorticoids did not significantly reduce outpatient admissions by days 1 and 7 when compared to placebo (pooled risk ratios (RRs) 0.92; 95% confidence interval (CI) 0.78 to 1.08 and 0.86; 95% CI 0.7 to 1.06, respectively). There was no benefit in LOS for inpatients (mean difference -0.18 days; 95% CI -0.39 to 0.04). Unadjusted results from a large factorial low risk of bias RCT found combined high-dose systemic dexamethasone and inhaled epinephrine reduced admissions by day 7 (baseline risk of admission 26%; RR 0.65; 95% CI 0.44 to 0.95; number needed to treat 11; 95% CI 7 to 76), with no differences in short-term adverse effects. No other comparisons showed relevant differences in primary outcomes. Authors' conclusions: Current evidence does not support a clinically relevant effect of systemic or inhaled glucocorticoids on admissions or length of hospitalisation. Combined dexamethasone and epinephrine may reduce outpatient admissions, but results are exploratory and safety data limited. Future research should further assess the efficacy, harms and applicability of combined therapy.

Mitochondria are crucial to support synaptic activity, particularly through ATP production and Ca2+ homeostasis. This implies that mitochondria need to be well distributed throughout the different neuronal sub-compartments. To achieve this, a tight and precise regulation of several neuronal cytoskeleton players is necessary to transport and dock mitochondria. As post-mitotic cells, neurons are highly dependent on mitochondrial quality control mechanisms and several cytoskeleton proteins have been implicated in mitophagy. Therefore, all of these processes are orchestrated by the crosstalk between mitochondria and the neuronal cytoskeleton to form a coordinated and tuned symphony.