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© Europa Digital & Publishing 2023. All rights reserved, Significant coronary artery disease (CAD) is a frequent finding in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI), and the management of these two conditions becomes of particular importance with the extension of the procedure to younger and lower-risk patients. Yet, the preprocedural diagnostic evaluation and the indications for treatment of significant CAD in TAVI candidates remain a matter of debate. In this clinical consensus statement, a group of experts from the European Association of Percutaneous Cardiovascular Interventions (EAPCI) in collaboration with the European Society of Cardiology (ESC) Working Group on Cardiovascular Surgery aims to review the available evidence on the topic and proposes a rationale for the diagnostic evaluation and indications for percutaneous revascularisation of CAD in patients with severe aortic stenosis undergoing transcatheter treatment. Moreover, it also focuses on commissural alignment of transcatheter heart valves and coronary re-access after TAVI and redo-TAVI.

Introduction: Frailty is a multidimensional syndrome characterized by the loss of functional reserve, associated with higher mortality and less functional survival in cardiac surgery patients. The Edmonton Frail Scale (EFS) is a comprehensive tool devised for brief frailty detection. To the best of our knowledge, there are no culturally adapted and validated frailty screening tools that enable the identification of vulnerability domains suited for use in the preoperative setting in Portugal. This was the motivation for this study. Objectives: To assess the validity and reproducibility of the Portuguese version of the EFS. Methods: Prospective observational study, in a sample of elective cardiac surgery patients. The Edmonton Frail Scale (EFS) translation and backtranslation were performed. Demographic and clinical data were collected, and the translated EFS translated, Geriatric Depression Scale, and Mini Mental State Examination Portuguese versions, Katz and Clinical Frailty Scales were administered. To assess validity Mann-Whitney test, Spearman's correlation coefficient, marginal homogeneity test and Kappa coefficient were employed. Reproducibility was assessed estimating kappa coefficient for the frailty diagnosis and the 11 EFS items. Intra-class correlation coefficients and the corresponding 95% confidence interval were estimated using linear mixed effects model. Results: The EFS Portuguese version revealed construct validity for frailty identification, as well as criterion validity for cognition and mood domains. Reproducibility was demonstrated, with k=0.62 (95% confidence interval (CI) 0.42-0.82) and intraclass correlation (ICC)=0.94 (95% CI 0.89-0.97) in inter-observer test and k=0.48 (95% CI 0.26-0.70) and ICC=0.85 (95% CI 0.72-0.92) in intra-observer test. Conclusions: The EFS Portuguese version is valid and reproducible for use, suiting pre-operative frailty screening in a cardiac surgery setting. Introdução: A fragilidade é uma síndrome multidimensional caracterizada pela perda de reserva funcional, associada a maior mortalidade e menor sobrevivência funcional após cirurgia cardíaca. A Escala de Fragilidade de Edmonton (EFS) é uma ferramenta abrangente de deteção de fragilidade. Não existe ainda em Portugal uma ferramenta de rastreio culturalmente adaptada e validada que permita a identificação de domínios específicos de vulnerabilidade para utilização no pré-operatório. Objetivos: Avaliar a validade e reprodutibilidade da versão portuguesa da EFS. Métodos: Estudo prospetivo observacional, realizado numa amostra de doentes propostos para cirurgia cardíaca. A EFS foi traduzida e retrotraduzida. Colheram-se dados demográficos e clínicos, aplicaram-se as versões traduzidas da EFS, Escala de Depressão Geriátrica e MMSE, as escalas de Katz e Clinical Frailty Scale. Validade avaliada utilizando o teste de Mann-Whitney, o coeficiente de correlação de Spearman, o teste de homogeneidade marginal e o coeficiente Kappa. Reprodutibilidade avaliada pelo cálculo do coeficiente kappa para o diagnóstico de fragilidade e para os 11 itens da escala. Coeficientes de correlação intraclasse e correspondentes intervalos de confiança a 95% estimados usando um modelo linear de efeitos mistos. Resultados: A versão portuguesa da EFS demonstrou validade de constructo, assim como validade de critério nos domínios de cognição e humor. É reprodutível, com k=0,62 (95% IC 0,42-0,82) e CCI=0,94 (95% IC 0,89-0,97) no teste interobservador e k=0,48 (95% IC 0,26-0,70) e CCI=0,85 (95% IC 0,72-0,92) no teste intraobservador. Conclusões: A versão portuguesa da EFS é adequada para rastreio pré-operatório de fragilidade em cirurgia cardíaca. info:eu-repo/semantics/publishedVersion

PMID: 26270678 PMCID:4598775 The carbohydrate antigens Tn and sialyl-Tn (STn) are expressed in most carcinomas and usually absent in healthy tissues. These antigens have been correlated with cancer progression and poor prognosis, and associated with immunosuppressive microenvironment. Presently they are used in clinical trials as therapeutic vaccination, but with limited success due to their low immunogenicity. Alternatively, anti-Tn and/or STn antibodies may be used to harness the immune system against tumor cells. Whilst the development of antibodies against these antigens had a boost two decades ago for diagnostic use, so far no such antibody entered into clinical trials. Possible limitations are the low specificity and efficiency of existing antibodies and that novel antibodies are still necessary. The vast array of methodologies available today will allow rapid antibody development and novel formats. Following the advent of hybridoma technology, the immortalization of human B cells became a methodology to obtain human monoclonal antibodies with better specificity. Advances in molecular biology including phage display technology for high throughput screening, transgenic mice and more recently molecularly engineered antibodies enhanced the field of antibody production. The development of novel antibodies against Tn and STn taking advantage of innovative technologies and engineering techniques may result in innovative therapeutic antibodies for cancer treatment. publishersversion published

Copyright © Ordem dos Médicos 2022, Introduction: Assessment of SARS-CoV-2 seroprevalence may detect the real spread of the virus because antibody data can provide a long-lasting measure of infection. Existing serological studies in Portugal have tested new serology methods, albeit with small sample sizes and a lack the focus on geographical regions with a high rate of infection cases. The aim of this study was to estimate the serological prevalence of SARS-CoV-2 in Vila Nova de Gaia, the most populous municipality in the north of Portugal and one of those most affected during the first pandemic wave. Material and Methods: A cross-sectional observational study was conducted between June 23rd and July 17th, 2020. Included in the cohort were 18- to 74-year-old men and women living in the municipality of Vila Nova de Gaia, who were sampled through a nonprobabilistic quota-based approach. Cases with a previous RT-PCR diagnosis of COVID-19 were excluded. Sociodemographic and clinical information was collected using a self-administered, written questionnaire. Blood samples were collected for serological laboratory analysis to detect and quantify SARS-CoV-2 anti-IgG antibodies. Results: We tested 2754 participants. Our results show a SARS-CoV-2 seroprevalence of 3.03% (95% confidence interval: 2.37% – 3.87%). Being a smoker (odds ratio: 0.382, 95% confidence interval: 0.147 – 0.99) and having symptoms of COVID-19 (odds ratio: 2.480, 95% confidence interval: 1.360 – 4.522) were consistently associated with lower and higher odds of SARS-CoV-2 antibody presence, respectively, regardless of the analytic design. Moreover, without adjusting for any variables, having had contact with an infected person within the household was associated with increased odds of a positive test (odds ratio: 9.684, 95% confidence interval: 4.06 – 23.101); after adjusting, having self-reported chronic diseases (odds ratio: 0.448, 95% confidence interval: 0.213 – 0.941) was associated with decreased odds. Conclusion: This was the first study to estimate the serological prevalence of SARS-CoV-2 in one of the most populous municipalities in Portugal, representing the first step in the development of an epidemiological surveillance system in Portugal, which can help to improve the diagnosis of COVID-19., Introdução: A estimativa da seroprevalência de SARS-CoV-2 pode detetar a real disseminação do vírus uma vez que os dados sobre anticorpos podem permitir determinar a evolução da infeção ao longo do tempo. Em Portugal, os estudos serológicos existentes têm sido utilizados sobretudo para testar novos métodos, sendo, no entanto, realizados com amostras de pequena dimensão. Além disso, estes estudos não se têm focado nas regiões geográficas com o maior número de casos de infeção. Este estudo teve como principal objetivo estimar a prevalência serológica de SARS-CoV-2 em Vila Nova de Gaia, Portugal, o município mais populoso do norte do país e um dos mais afetados pela primeira onda da pandemia. Material e Métodos: Estudo observacional transversal conduzido entre 23 de junho e 17 de julho de 2020. Foram incluídos adultos, com idades compreendidas entre os 18 e os 74 anos, de ambos os sexos, residentes numa das 15 freguesias do município de Vila Nova de Gaia. Foi seguida uma amostragem com recurso a uma abordagem não probabilística por quotas. Casos de indivíduos com um diagnóstico prévio de COVID-19 com teste RT-PCR foram excluídos. Os dados sociodemográficos e clínicos foram recolhidos através de questionário autopreenchido, em papel. Foram ainda recolhidas amostras de sangue para análise laboratorial serológica para deteção e quantificação de anticorpos anti-IgG contra SARS-CoV-2. Resultados: Foram testados 2754 participantes. Os nossos resultados mostram uma seroprevalência de SARS-CoV-2 de 3,03% (intervalo de confiança 95%: 2,37 – 3,87%). Ser fumador (OR: 0,382, intervalo de confiança 95%: 0,147 – 0,99) e apresentar sintomas de COVID-19 (OR: 2,480, intervalo de confiança 95%: 1,36 – 4,522) foram observados como estando associados a menor e maior probabilidade de presença de anticorpos SARS-CoV-2, independentemente do desenho analítico. Sem ajustamento para qualquer variável, o contacto com uma pessoa infetada dentro do domicílio (OR: 9,684, intervalo de confiança 95%: 4,06 - 23,101) esteve associado com aumento da chance de ter um teste positivo. Após ajustamento, ter doenças crónicas autorreportadas (OR: 0,448, intervalo de confiança 95%: 0,213 - 0,941) esteve associada à diminuição da chance de ter um teste COVID-19 positivo. Conclusão: Este foi o primeiro estudo a estimar a prevalência serológica do SARS-CoV-2 num dos municípios mais populosos de Portugal, constituindo o primeiro passo para o desenvolvimento de um sistema de vigilância epidemiológica em Portugal, que pode ajudar a melhorar o diagnóstico da COVID-19., This research was funded by Fundação Álvaro Carvalho (funding manager), Fundação Vox Populi, Fundação Manuel Viegas Guerreiro, and the Claude and Sofia Marion Foundation. The writing of the paper was also funded by the Fundação para a Ciência e a Tecnologia under the grants UIDB/04295/2020, UIDP/04295/2020, UIDB/04293/2020, and UIDP/04923/2020.

Funding The study received support from the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR). OBJECTIVES: To investigate factors associated with severe COVID-19 in people with psoriasis (PsO), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: Demographic data, clinical characteristics and COVID-19 outcome severity of adults with PsO, PsA and axSpA were obtained from two international physician-reported registries. A three-point ordinal COVID-19 severity scale was defined: no hospitalisation, hospitalisation (and no death) and death. ORs were estimated using multivariable ordinal logistic regression. RESULTS: Of 5045 cases, 18.3% had PsO, 45.5% PsA and 36.3% axSpA. Most (83.6%) were not hospitalised, 14.6% were hospitalised and 1.8% died. Older age was non-linearly associated with COVID-19 severity. Male sex (OR 1.54, 95% CI 1.30 to 1.83), cardiovascular, respiratory, renal, metabolic and cancer comorbidities (ORs 1.25-2.89), moderate/high disease activity and/or glucocorticoid use (ORs 1.39-2.23, vs remission/low disease activity and no glucocorticoids) were associated with increased odds of severe COVID-19. Later pandemic time periods (ORs 0.42-0.52, vs until 15 June 2020), PsO (OR 0.49, 95% CI 0.37 to 0.65, vs PsA) and baseline exposure to TNFi, IL17i and IL-23i/IL-12+23i (OR 0.57, 95% CI 0.44 to 0.73; OR 0.62, 95% CI 0.45 to 0.87; OR 0.67, 95% CI 0.45 to 0.98; respectively; vs no disease-modifying antirheumatic drug) were associated with reduced odds of severe COVID-19. CONCLUSION: Older age, male sex, comorbidity burden, higher disease activity and glucocorticoid intake were associated with more severe COVID-19. Later pandemic time periods, PsO and exposure to TNFi, IL17i and IL-23i/IL-12+23i were associated with less severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with PsO, PsA and axSpA during COVID-19 waves or similar future respiratory pandemics. publishersversion published

Funding: The authors would like to thank the scientific and technical assistance from the CEDOC Cell Culture, Flow Cytometry and Microscopy facilities. We also thank the Electron Microscopy Facility of Instituto Gulbenkian de Ciência for technical assistance. The authors also thank Dorothy Bennett and Elena Sviderskaya (St. George's University of London, UK), Susana Lopes (CEDOC, NOVA Medical School) and Paulo Matos (National Health Institute Doutor Ricardo Jorge, Portugal) for the kind gift of reagents and Paulo Matos also for expert advice. This article was supported by the LYSOCIL project. This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 811087. This article was also supported by Fundaçao para a Ciência e a Tecnologia ˜ (FCT), Portugal through grant PTDC/BIA-CEL/29765/2017, PhD fellowships to HM, MVN, LBL and LCC (PD/BD/114118/2015, PD/BD/137442/2018, SFRH/BD/131938/2017 and 2020.8812.BD, respectively), the FCT Investigator Program to DCB (IF/00501/2014/ CP1252/CT0001), and FCT Unit iNOVA4Health – UIDB/04462/2020 and UIDP/04462/2020, a programme financially supported by FCT / Ministério da Ciência, Tecnologia e Ensino Superior, through national funds. In the skin epidermis, melanin is produced and stored within melanosomes in melanocytes, and then transferred to keratinocytes. Different models have been proposed to explain the melanin transfer mechanism, which differ essentially in how melanin is transferred - either in a membrane-bound melanosome or as a melanosome core, i.e., melanocore. Here, we investigated the endocytic route followed by melanocores and melanosomes during internalization by keratinocytes, by comparing the uptake of melanocores isolated from the supernatant of melanocyte cultures, with melanosomes isolated from melanocytes. We show that inhibition of actin dynamics impairs the uptake of both melanocores and melanosomes. Moreover, depletion of critical proteins involved in actin-dependent uptake mechanisms, namely Rac1, CtBP1/BARS, Cdc42 or RhoA, together with inhibition of Rac1-dependent signaling pathways or macropinocytosis suggest that melanocores are internalized by phagocytosis, whereas melanosomes are internalized by macropinocytosis. Interestingly, we found that Rac1, Cdc42 and RhoA are differently activated by melanocore or melanosome stimulation, supporting the existence of two distinct internalization routes of melanin internalization. Furthermore, we show that melanocore uptake induces Protease-activated receptor-2 (PAR-2) internalization by keratinocytes to a higher extent than melanosomes. Since skin pigmentation was shown to be regulated by PAR-2 activation, our results further support the melanocore-based mechanism of melanin transfer and further refine this model, which can now be described as coupled melanocore exo/phagocytosis. publishersversion published

Publisher Copyright: © 2023 by the authors. Background. Several reports have demonstrated the impact of the COVID-19 pandemic on the management and outcome of patients with ST-segment elevation myocardial infarction (STEMI). The aim of the current analysis is to investigate the potential gender difference in the effects of the COVID-19 pandemic on mechanical reperfusion and 30-day mortality for STEMI patients within the ISACS-STEMI COVID-19 Registry. Methods. This retrospective multicenter registry was performed in high-volume primary percutaneous coronary intervention (PPCI) centers on four continents and included STEMI patients undergoing PPCIs in March–June 2019 and 2020. Patients were divided according to gender. The main outcomes were the incidence and timing of the PPCI, (ischemia time ≥ 12 h and door-to-balloon ≥ 30 min) and in-hospital or 30-day mortality. Results. We included 16683 STEMI patients undergoing PPCIs in 109 centers. In 2020 during the pandemic, there was a significant reduction in PPCIs compared to 2019 (IRR 0.843 (95% CI: 0.825–0.861, p < 0.0001). We did not find a significant gender difference in the effects of the COVID-19 pandemic on the numbers of STEMI patients, which were similarly reduced from 2019 to 2020 in both groups, or in the mortality rates. Compared to prepandemia, 30-day mortality was significantly higher during the pandemic period among female (12.1% vs. 8.7%; adjusted HR [95% CI] = 1.66 [1.31–2.11], p < 0.001) but not male patients (5.8% vs. 6.7%; adjusted HR [95% CI] = 1.14 [0.96–1.34], p = 0.12). Conclusions. The COVID-19 pandemic had a significant impact on the treatment of patients with STEMI, with a 16% reduction in PPCI procedures similarly observed in both genders. Furthermore, we observed significantly increased in-hospital and 30-day mortality rates during the pandemic only among females. Trial registration number: NCT 04412655. publishersversion published

Publisher Copyright: © 2022 The Authors. International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd. We report a rare case of long-standing Hailey-Hailey disease in a Caucasian Portuguese 69-year-old woman, recently diagnosed with rheumatoid arthritis. The patient's skin lesions remained active and exudative despite topical and oral treatments with corticosteroids, tetracyclines, antifungals, and oral treatment with azathioprine. After introduction of methotrexate for rheumatoid arthritis treatment, the skin lesions regressed, with significant impact on the patient's quality of life. This case report supports the clinical evidence of methotrexate's potential role in Hailey-Hailey disease treatment. publishersversion published

Macroautophagy/autophagy is a self-degradative process necessary for cells to maintain their energy balance during development and in response to nutrient deprivation. Autophagic processes are tightly regulated and have been found to be dysfunctional in several pathologies. Increasing experimental evidence points to the existence of an interplay between autophagy and cilia. Cilia are microtubule-based organelles protruding from the cell surface of mammalian cells that perform a variety of motile and sensory functions and, when dysfunctional, result in disorders known as ciliopathies. Indeed, selective autophagic degradation of ciliary proteins has been shown to control ciliogenesis and, conversely, cilia have been reported to control autophagy. Moreover, a growing number of players such as lysosomal and mitochondrial proteins are emerging as actors of the cilia-autophagy interplay. However, some of the published data on the cilia-autophagy axis are contradictory and indicate that we are just starting to understand the underlying molecular mechanisms. In this review, the current knowledge about this axis and challenges are discussed, as well as the implication for ciliopathies and autophagy-associated disorders. publishersversion published

Introduction: adolescence is a critical stage of rapid biological, emotional and social change and development. Adolescents and young adults (AYA) with asthma and allergies need to develop the knowledge and skills to self-manage their health independently. Healthcare professionals (HCP), parents and their wider network play an essential role in supporting AYA in this process. Previous work showed significant limitations in transition care across Europe. In 2020, the first evidence-based guideline on effective transition for AYA with asthma and allergies was published by EAACI.Aim: we herein summarize practical resources to support this guideline's implementation in clinical practice.Methods: for this purpose, multi-stakeholder Task Force members searched for resources in peer review journals and grey literature. These resources were included if relevant and of good quality and were pragmatically rated for their evidence-basis and user friendliness.Results: resources identified covered a range of topics and targeted healthcare professionals, AYA, parents/carers, schools, workplace and wider community. Most resources were in English, web-based and had limited evidence-basis.Conclusions: this position paper provides a valuable selection of practical resources for all stakeholders to support effective transitional care for AYA with asthma and allergies. Future research should focus on developing validated, patient-centred tools to further assist evidence-based transition care.

Background Transcatheter aortic valve implantation (TAVI) has rapidly evolved and changed the field of structural cardiovascular intervention. Its advances lead to a marked reduction in the risk of complications and improved outcomes. However, TAVI is still associated with potential serious complications. Case summary A 73-year-old man with severe aortic stenosis underwent TAVI using a 34-mm self-expanding aortic bioprosthesis. After valve deployment, the patient rapidly progressed to cardiac arrest. Acute left main occlusion, due to high valve implantation, was promptly recognized and advanced life support immediately initiated. Concomitantly, the valve was successfully retrieved toward the ascending aorta using the snare technique, resulting in immediate restoration of flow and successful cardiopulmonary resuscitation. Subsequently, a 29-mm balloon-expandable aortic bioprosthesis was uneventfully implanted. After TAVI, the patient had a remarkable clinical evolution and was discharged home at hospitalization day five without relevant electrocardiographic nor echocardiographic disturbances. At six-month follow-up, the patient remains asymptomatic and transthoracic echocardiography revealed a normofunctional aortic bioprosthesis with preserved left ventricular ejection fraction. Discussion Acute coronary occlusion is a rare and life-threating complication of TAVI that may be prevented with accurate procedure planning. Pre-procedural computed tomography angiography is essential for a comprehensive patient evaluation, allowing appropriate valve selection, a key factor for successful management. Self-expandable valve retrieval with snare technique can be an appropriate strategy for the management of this complication. This case highlights the importance of performing these procedures in highly experienced centres and with fully equipped catheterization laboratories to allow timely interventions when facing unexpected events.

Funding Information: This research was funded by the International Atomic Energy Agency under Research Contract No. 18202 (CRP F23030). Authors acknowledge FCT—Fundação para a Ciência e a Tecnologia I.P. for the national funds in the scope of the project UIDB/04349/2020+UIDP/04349/2020, UIDB/00100/2020 and UIDB/00329/2020. Publisher Copyright: © 2022 by the authors. Frequently, deep partial and full-thickness skin wounds do not spontaneously regenerate. To restore the normal function of skin, epidermal and dermal components have to be supplied to the wound bed by grafting various substrates. Available options are limited and frequently costly. Herein, authors present a possible approach using 3D skin scaffolds capable of mimicking structure and biological functions of the extracellular matrix, providing, in parallel, a good environment for cell attachment, proliferation and differentiation. Low-molecular weight chitosan-based membranes were prepared by freeze-drying and ionizing radiation techniques to be used as skin scaffolds. Poly (vinyl alcohol), PVA, vinyl pyrrolidone, VP, and gelatin from cold water fish were incorporated. Information regarding membranes’ physical-chemical properties from SEM analysis, swelling and weight loss, together with biological response through in vitro assays (using Human Caucasian Fetal Foreskin Fibroblast) allowed the selection of an optimized batch of membranes that was used as skin scaffold in a dorsal rat model wound. The in vivo implantation assays (in Wistar rats) resulted in very promising results: (i) healing process faster than control; (ii) good vascularization; (iii) viable new tissues morphologically functional. publishersversion published

We evaluated the relevance of plasma homocysteine (HC) and the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) in sickle cell disease (SCD) and associated vaso-occlusive crisis (VOC) and ischemic stroke (IS). We identified in Embase and Medline 22 studies on plasma HC and 22 on MTHFR genotypes. Due to age-related HC differences, adult and paediatric SCD were separated: 879 adult SCD and 834 controls (CTR) yielded a neutral effect size; 427 paediatric SCD and 625 CTR favoured SCD (p = 0.001) with wide heterogeneity (I2 = 95.5%) and were sub-grouped by country: six studies (Dutch Antilles n = 1, USA n = 5) yielded a neutral effect size, four (India n = 1, Arab countries n = 3) favoured SCD (p < 0.0001). Moreover, 249 SCD in VOC and 419 out of VOC yielded a neutral effect size. The pooled prevalence of the MTHFR TT genotype in 267 SCD equalled that of 1199 CTR (4.26% vs. 2.86%, p = 0.45), and in 84 SCD with IS equalled that of 86 without IS (5.9% vs. 3.7%, p = 0.47); removal of one paediatric study yielded a significant effect size (p = 0.006). Plasma HC in paediatric SCD from Middle East and India was higher, possibly due to vitamin deficiencies. Despite its low prevalence in SCD, the MTHFR TT genotype relates to adult IS. publishersversion published

Neutrophils are prominent immune components of solid tumors, which can protect against the onset of cancer (N1) or have pro-tumor activity (N2). Circulating neutrophils, divided into high density neutrophils (HDN) and low density neutrophils (LDN), functionally mirror those N1 and N2 cells, respectively. LDN, a rare subset in non-pathological conditions, have been extensively studied in cancer, due to their frequency in this disease and their pro-tumor phenotype. However, this has been mainly demonstrated in animal models and proper validation in humans is an urgent need. Here, we further enlighten the clinical impact of LDN in a cohort of breast cancer (BC) patients. We observed that LDN were practically absent in healthy donors’ blood, while were significantly increased in the blood of BC patients, particularly with metastatic disease. Relevant for a clinical translation, within the population of non-metastatic patients, LDN were more prevalent in patients with poor response to neoadjuvant chemotherapy than in responders. The association of a higher incidence of circulating LDN and the worse prognosis of BC patients could be explained by the pro-tumor/immunosuppressive characteristics exhibited by these cells. Namely, there are more LDN expressing the immunosuppressive marker PD-L1, than HDN. Additionally, LDN also showed increased expression of activation markers; a robust formation of neutrophil extracellular traps; an augmented phagocytic activity; and a higher capacity to release reactive oxygen species, which may contribute for tumor development and metastization. Moreover, the percentage of LDN in BC patients’ blood was negatively correlated with activated cytotoxic T lymphocytes and positively correlated with the immunosuppressive CCR4+ regulatory T cells, corroborating their impairment on the anti-tumor immune responses, which was further demonstrated ex vivo. Hence, this study reveals the potential of LDN as a clinical meaningful biomarker of BC response to treatment and opens new avenues for developing targeted immunotherapies.

Patients with inflammatory rheumatic and musculoskeletal diseases (iRMDs) are often treated with immunomodulatory or immunosuppressive medications; consequently, they have been excluded alongside other immunocompromised patients from late stages of SARS-CoV-2 vaccine trials. SARS-CoV-2 vaccine efficacy in this population is unclear, though initial data are reassuring overall. However, a slightly lower SARS-CoV-2 immunogenicity of vaccines has been documented in some patients with iRMD.1 2 Some common rheumatic and musculoskeletal disease (RMD) medications have been highlighted as possible influential factors on immunogenicity, particularly rituximab (RTX), mycophenolate mofetil (MMF), methotrexate (MTX), abatacept and glucocorticoids.3–7 The European Alliance of Associations for Rheumatology (EULAR) launched a COVID-19 registry in March 2020, capturing COVID-19 outcomes in the European RMD population. Questions on reinfection and vaccination were added in January 2021. A further EULAR registry (COVAX) was launched in February 2021 to collect data on COVID-19 vaccination and related adverse events among patients with RMD. Here we describe a series of patients who contracted SARS-CoV-2 infection after COVID-19 vaccination between 19 January 2021 and 27 July 2021. The series consists of 38 adults with iRMDs, 8 from the COVID-19 registry (

Funding Information: This work was supported by AbbVie and by iNOVA4Health – UIDB/04462/2020, a program financially supported by Fundação para a Ciência e Tecnologia (FCT) / Ministério da Educação e Ciência, through national funds. RM and TFM were recipients of PhD fellowships funded by FCT (SFRH/BD/132163/2017 and PD/BD/128377/2017, respectively) and CB was funded by “The Discoveries Centre for Regenerative and Precision Medicine” (European Commission Horizon 2020 Research and Innovation programme, under the Grant Agreement 739572). Publisher Copyright: © 2021, The Author(s). The current standard preclinical oncology models are not able to fully recapitulate therapeutic targets and clinically relevant disease biology, evidenced by the 90% attrition rate of new therapies in clinical trials. Three-dimensional (3D) culture systems have the potential to enhance the relevance of preclinical models. However, the limitations of currently available cellular assays to accurately evaluate therapeutic efficacy in these models are hindering their widespread adoption. We assessed the compatibility of the lactate dehydrogenase (LDH) assay in 3D spheroid cultures against other commercially available readout methods. We developed a standardized protocol to apply the LDH assay to ex vivo cultures, considering the impact of culture growth dynamics. We show that accounting for growth rates and background release levels of LDH are sufficient to make the LDH assay a suitable methodology for longitudinal monitoring and endpoint assessment of therapeutic efficacy in both cell line-derived xenografts (xenospheres) and patient-derived explant cultures. This method has the added value of being non-destructive and not dependent on reagent penetration or manipulation of the parent material. The establishment of reliable readout methods for complex 3D culture systems will further the utility of these tumor models in preclinical and co-clinical drug development studies. publishersversion published

Funding: This research is being carried out under the Active and Assisted Living Programme under project number AAL-2019-6-168-CP, with funding by the European Union and the national funding agencies from the Netherlands, Portugal, and Switzerland: The Netherlands Organisation for Health Research and Development, Fundação para a Ciência e Tecnologia, and Innosuisse—Swiss Innovation Agency. BACKGROUND: The death of a partner is a critical life event in later life, which requires grief work as well as the development of a new perspective for the future. Cognitive behavioral web-based self-help interventions for coping with prolonged grief have established their efficacy in decreasing symptoms of grief, depression, and loneliness. However, no study has tested the efficacy for reducing grief after losses occurring less than 6 months ago and the role of self-tailoring of the content. OBJECTIVE: This study aims to evaluate the clinical efficacy and acceptance of a web-based self-help intervention to support the grief process of older adults who have lost their partner. It will compare the outcomes, adherence, and working alliance in a standardized format with those in a self-tailored delivery format and investigate the effects of age, time since loss, and severity of grief at baseline as predictors. Focus groups to understand user experience and a cost-effectiveness analysis will complement the study. METHODS: The study includes 3 different randomized control trials. The trial in Switzerland comprises a waitlist control group and 2 active arms consisting of 2 delivery formats, standardized and self-tailored. In the Netherlands and in Portugal, the trials follow a 2-arm design that will be, respectively, complemented with focus groups on technology acceptance and cost-effectiveness analysis. The main target group will consist of adults aged >60 years from the general population in Switzerland (n≥85), the Netherlands (n≥40), and Portugal (n≥80) who lost their partner and seek help for coping with grief symptoms, psychological distress, and adaptation problems in daily life. The trials will test the intervention's clinical efficacy for reducing grief (primary outcome) and depression symptoms and loneliness (secondary outcomes) after the intervention. Measurements will take place at baseline (week 0), after the intervention (week 10), and at follow-up (week 20). RESULTS: The trials started in March 2022 and are expected to end in December 2022 or when the needed sample size is achieved. The first results are expected by January 2023. CONCLUSIONS: The trials will provide insights into the efficacy and acceptance of a web-based self-help intervention among older adults who have recently lost a partner. Results will extend the knowledge on the role of self-tailoring, working alliance, and satisfaction in the effects of the intervention. Finally, the study will suggest adaptations to improve the acceptance of web-based self-help interventions for older mourners and explore the cost-effectiveness of this intervention. Limitations include a self-selective sample and the lack of cross-cultural comparisons. TRIAL REGISTRATION: Switzerland: ClinicalTrials.gov NCT05280041; https://clinicaltrials.gov/ct2/show/NCT05280041; Portugal: ClinicalTrials.gov NCT05156346; https://clinicaltrials.gov/ct2/show/NCT05156346. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/37827. publishersversion published

Funding: This study was partially funded by National Funds through FCT – Fundac¸ão para a Ciência e a Tecnologia, I.P. (under the project UIDB/04279/2020, granted to RC and MA) and by the Israel Science Foundation (ISF, Grant Number 1437/18, granted to RT). While factors contributing to between-subjects differences in pain have been studied extensively, factors contributing to the within-subjects variability of pain reports are yet unexplored. The aim of this investigation was to assess possible associations between short-term memory and the within-subjects variability of pain reports in healthy and chronic pain patients. Healthy participants were recruited at the University of Haifa, Israel, and Fibromyalgia patients were recruited at a rheumatology department in a central hospital in Lisbon, Portugal. Following consent, both cohorts underwent the same procedures, including the digit-span test, assessing short-term memory, and the FAST procedure, assessing within-subject variability of pain intensity reports in response to experimental pain. One-hundred twenty-one healthy volunteers and 29 Fibromyalgia patients completed the study. While a significant correlation was found between the within-subjects variability and the total score of the short-term memory task (Spearman’s r = 0.394, P = 0.046) in the Fibromyalgia group, a marginal correlation emerged in the healthy cohort (r = 0.174, P = 0.056). A possible interpretation of these results is that in the patients’ group, at least some of the within-subjects variability of pain intensity reports might be due to error measurement derived by poorer short-term memory, rather than true fluctuations in perception. publishersversion published

Funding Information: The ESCEO Working Group was funded by the ESCEO. The ESCEO receives unrestricted educational grants to support its educational and scientific activities from non-governmental organizations, not-for-profit organizations, non-commercial or corporate partners. Publisher Copyright: © 2022, The Author(s). Oral bisphosphonates are a key intervention in the treatment of osteoporosis and in reducing the risk of fragility fractures. Their use is supported by over 3 decades of evidence; however, patient adherence to oral bisphosphonates remains poor in part due to complex dosing instructions and adverse events, including upper gastrointestinal symptoms. This problem has led to the development of novel oral bisphosphonate formulations. Buffered, effervescent alendronate is dissolved in water and so seeks to reduce upper gastro-intestinal adverse events, and gastro-resistant risedronate aims to reduce the complexity of dosing procedure (e.g. fasting prior to consumption) whilst still maintaining the efficacy of fracture risk reduction. Clinical trials and real-world data have been employed to demonstrate some benefits in terms of reduced upper gastro-intestinal adverse events, adherence, persistence and health economic outcomes. This report describes the result of an ESCEO (European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis) expert working group, which explores where oral bisphosphonates sit in current clinical practice guidelines, review their risk–benefit profile and the consequences of poor adherence before exploring novel oral bisphosphonate formulations and their potential clinical and health economic impact. Further research is required but there are signs that these novel, oral bisphosphonate formulations may lead to improved tolerance of oral bisphosphonates and thus, improved adherence and fracture outcomes. publishersversion published

Funding Information: The World Health Organization World Mental Health (WMH) Survey Initiative is supported by the United States National Institute of Mental Health (NIMH; R01 MH070884), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, the United States Public Health Service (R13-MH066849, R01-MH069864, and R01 DA016558), the Fogarty International Center (FIRCA R03-TW006481), the Pan American Health Organization, Eli Lilly and Company, Ortho-McNeil Pharmaceutical Inc., GlaxoSmithKline, and Bristol-Myers Squibb. We thank the staff of the WMH Data Collection and Data Analysis Coordination Centres for assistance with instrumentation, fieldwork, and consultation on data analysis. None of the funders had any role in the design, analysis, interpretation of results, or preparation of this paper. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of the World Health Organization, other sponsoring organizations, agencies, or governments. The Argentina survey—Estudio Argentino de Epidemiología en Salud Mental (EASM)—was supported by a grant from the Argentinian Ministry of Health (Ministerio de Salud de la Nación)—(Grant Number 2002-17270/13-5). The 2007 Australian National Survey of Mental Health and Wellbeing is funded by the Australian Government Department of Health and Ageing. The Colombian National Study of Mental Health (NSMH) is supported by the Ministry of Social Protection. The Mental Health Study Medellín—Colombia was carried out and supported jointly by the Center for Excellence on Research in Mental Health (CES University) and the Secretary of Health of Medellín. The World Mental Health Japan (WMHJ) Survey is supported by the Grant for Research on Psychiatric and Neurological Diseases and Mental Health (H13-SHOGAI-023, H14-TOKUBETSU-026, H16-KOKORO-013, H25-SEISHIN-IPPAN-006) from the Japan Ministry of Health, Labour and Welfare. The Mexican National Comorbidity Survey (MNCS) is supported by The National Institute of Psychiatry Ramon de la Fuente (INPRFMDIES 4280) and by the National Council on Science and Technology (CONACyT-G30544- H), with supplemental support from the PanAmerican Health Organization (PAHO). Te Rau Hinengaro: The New Zealand Mental Health Survey (NZMHS) is supported by the New Zealand Ministry of Health, Alcohol Advisory Council, and the Health Research Council. The Northern Ireland Study of Mental Health was funded by the Health & Social Care Research & Development Division of the Public Health Agency. The Peruvian World Mental Health Study was funded by the National Institute of Health of the Ministry of Health of Peru. The Portuguese Mental Health Study was carried out by the Department of Mental Health, Faculty of Medical Sciences, NOVA University of Lisbon, with collaboration of the Portuguese Catholic University, and was funded by Champalimaud Foundation, Gulbenkian Foundation, Foundation for Science and Technology (FCT) and Ministry of Health. The Romania WMH study projects "Policies in Mental Health Area" and "National Study regarding Mental Health and Services Use" were carried out by National School of Public Health & Health Services Management (former National Institute for Research & Development in Health), with technical support of Metro Media Transilvania, the National Institute of Statistics-National Centre for Training in Statistics, SC, Cheyenne Services SRL, Statistics Netherlands and were funded by Ministry of Public Health (former Ministry of Health) with supplemental support of Eli Lilly Romania SRL. The Psychiatric Enquiry to General Population in Southeast Spain—Murcia (PEGASUS-Murcia) Project has been financed by the Regional Health Authorities of Murcia (Servicio Murciano de Salud and Consejería de Sanidad y Política Social) and Fundación para la Formación e Investigación Sanitarias (FFIS) of Murcia. The US National Comorbidity Survey Replication (NCS-R) is supported by the National Institute of Mental Health (NIMH; U01-MH60220) with supplemental support from the National Institute of Drug Abuse (NIDA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (RWJF; Grant 044708), and the John W. Alden Trust. A complete list of all within-country and cross-national WMH publications can be found at http://www.hcp.med.harvard.edu/wmh . Publisher Copyright: © 2022, The Author(s). Purpose: Lesbian,gay, and bisexual (LGB) individuals, and LB women specifically, have anincreased risk for psychiatric morbidity, theorized to result from stigma-baseddiscrimination. To date, no study has investigated the mental healthdisparities between LGB and heterosexual AQ1individuals in a largecross-national population-based comparison. The current study addresses thisgap by examining differences between LGB and heterosexual participants in 13cross-national surveys, and by exploring whether these disparities wereassociated with country-level LGBT acceptance. Since lower social support hasbeen suggested as a mediator of sexual orientation-based differences inpsychiatric morbidity, our secondary aim was to examine whether mental healthdisparities were partially explained by general social support from family andfriends. Methods: Twelve-monthprevalence of DSM-IV anxiety, mood, eating, disruptive behavior, and substancedisorders was assessed with the WHO Composite International DiagnosticInterview in a general population sample across 13 countries as part of theWorld Mental Health Surveys. Participants were 46,889 adults (19,887 males; 807LGB-identified). Results: Maleand female LGB participants were more likely to report any 12-month disorder (OR2.2, p < 0.001 and OR 2.7, p < 0.001, respectively) and most individualdisorders than heterosexual participants. We found no evidence for anassociation between country-level LGBT acceptance and rates of psychiatricmorbidity between LGB and heterosexualAQ2 participants. However, among LBwomen, the increased risk for mental disorders was partially explained by lowergeneral openness with family, although most of the increased risk remainedunexplained. Conclusion: These results provide cross-national evidence for an association between sexual minority status and psychiatric morbidity, and highlight that for women, but not men, this association was partially mediated by perceived openness with family. Future research into individual-level and cross-national sexual minority stressors is needed. publishersversion published

Copyright © 2022 International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. All rights reserved. OBJECTIVES: Few countries integrate patient-reported outcome measures (PROMs) in routine performance assessment and those that do focus on elective surgery. This study addresses the challenges of using PROMs to evaluate care in chronic conditions. We set out a modeling strategy to assess the extent to which changes over time in self-reported health status by patients with inflammatory chronic rheumatic disease are related to their biological drug therapy and rheumatology center primarily responsible for their care. METHODS: Using data from the Portuguese Register of Rheumatic Diseases, we assess health status using the Health Assessment Questionnaire-Disability Index for rheumatic patients receiving biological drugs between 2000 and 2017. We specify a fixed-effects model using the least squares dummy variables estimator. RESULTS: Patients receiving infliximab or rituximab report lower health status than those on etanercept (the most common therapy) and patients in 4 of the 26 rheumatology centers report higher health status than those at other centers. CONCLUSIONS: PROMs can be used for those with chronic conditions to provide the patient's perspective about the impact on their health status of the choice of drug therapy and care provider. Care for chronic patients might be improved if healthcare organizations monitor PROMs and engage in performance assessment initiatives on a routine basis. publishersversion published

Publisher Copyright: © 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background: Non-REM sleep symptoms remain poorly understood in alpha-synucleinopathies. Aims: The aims of the study were to compare sleep stability and transitions, arousals, and sleep cycle structure between isolated rapid eye movement (REM) sleep behavior disorder (iRBD), Parkinson’s disease (PD), and dementia with Lewy Bodies (DLB). Materials and Methods: Sleep transition and stability measures were assessed in one-night video-polysomnography records. Transition measures were the number of shifts between Wake and REM, Wake and NREM, and REM and NREM. Stability measures were the number of passages within the same sleep stage. We assessed arousals, the number/duration of sleep cycles (defined as a sequence of any NREM stage to REM), and the duration of N3 and REM sleep in each cycle. These variables were compared between two sets of groups (PD vs. DLB vs. iRBD and RDB+ vs. RBD−). Results: We assessed 54 PD, 24 DLB, and 21 iRBD patients (54 RBD+, 22 RBD−). There were no significant differences regarding sleep stability measures. Arousal indices in N1 and N2 stages were significantly higher in PD compared with iRBD. 24% of the sample did not have any sleep cycle. PD had significantly fewer cycles than iRBD. Differences became non-significant when adjusting for medication. There was no effect of group or time of night in REM or N3 duration. There were no significant differences between RBD+ and RBD−. Discussion: There were no significant differences in stability/transition measures. Arousals and disturbance in sleep cycling were higher in PD, but the difference was no longer significant after adjusting for medication. Conclusion: Different alpha-synucleinopathies have a similar degree of non-REM sleep instability, but medication could worsen symptoms in PD. publishersversion published

Funding This work was supported by ERDF through the operation POCI-01−0145-ERDF-007746 funded by the Programa Operacional Competitividade e Internacionalização − COMPETE2020 and by FCT - Fundação para a Ciência e a Tecnologia, IP national support through CINTESIS, R&D Unit (UIDB/4255/2020), CHRC (UIDP/04923/2020 and UIDB/04923/2020) and through the project reference PTDC/BAA-AGR/7419/2020. Gut microbiota modulation might constitute a mechanism mediating the effects of beer on health. In this randomized, double-blinded, two-arm parallel trial, 22 healthy men were recruited to drink 330 mL of nonalcoholic beer (0.0% v/v) or alcoholic beer (5.2% v/v) daily during a 4-week follow-up period. Blood and faecal samples were collected before and after the intervention period. Gut microbiota was analyzed by 16S rRNA gene sequencing. Drinking nonalcoholic or alcoholic beer daily for 4 weeks did not increase body weight and body fat mass and did not changed significantly serum cardiometabolic biomarkers. Nonalcoholic and alcoholic beer increased gut microbiota diversity which has been associated with positive health outcomes and tended to increase faecal alkaline phosphatase activity, a marker of intestinal barrier function. These results suggest the effects of beer on gut microbiota modulation are independent of alcohol and may be mediated by beer polyphenols. publishersversion published

Parkinson's disease is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra with no effective cure available. MicroRNA-124 has been regarded as a promising therapeutic entity for Parkinson's disease due to its pro-neurogenic and neuroprotective roles. However, its efficient delivery to the brain remains challenging. Here, we used umbilical cord blood mononuclear cell-derived extracellular vesicles as a biological vehicle to deliver microRNA (miR)-124-3p and evaluate its therapeutic effects in a mouse model of Parkinson's disease. In vitro, miR-124-3p-loaded small extracellular vesicles induced neuronal differentiation in subventricular zone neural stem cell cultures and protected N27 dopaminergic cells against 6-hydroxydopamine-induced toxicity. In vivo, intracerebroventricularly administered small extracellular vesicles were detected in the subventricular zone lining the lateral ventricles and in the striatum and substantia nigra, the brain regions most affected by the disease. Most importantly, although miR-124-3p-loaded small extracellular vesicles did not increase the number of new neurons in the 6-hydroxydopamine-lesioned striatum, the formulation protected dopaminergic neurons in the substantia nigra and striatal fibers, which fully counteracted motor behavior symptoms. Our findings reveal a novel promising therapeutic application of small extracellular vesicles as delivery agents for miR-124-3p in the context of Parkinson's disease.

Funding Information: We acknowledge financial support from the ACR and EULAR. The ACR and EULAR were not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Publisher Copyright: © 2022 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. Objective: Some patients with rheumatic diseases might be at higher risk for coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS). We aimed to develop a prediction model for COVID-19 ARDS in this population and to create a simple risk score calculator for use in clinical settings. Methods: Data were derived from the COVID-19 Global Rheumatology Alliance Registry from March 24, 2020, to May 12, 2021. Seven machine learning classifiers were trained on ARDS outcomes using 83 variables obtained at COVID-19 diagnosis. Predictive performance was assessed in a US test set and was validated in patients from four countries with independent registries using area under the curve (AUC), accuracy, sensitivity, and specificity. A simple risk score calculator was developed using a regression model incorporating the most influential predictors from the best performing classifier. Results: The study included 8633 patients from 74 countries, of whom 523 (6%) had ARDS. Gradient boosting had the highest mean AUC (0.78; 95% confidence interval [CI]: 0.67-0.88) and was considered the top performing classifier. Ten predictors were identified as key risk factors and were included in a regression model. The regression model that predicted ARDS with 71% (95% CI: 61%-83%) sensitivity in the test set, and with sensitivities ranging from 61% to 80% in countries with independent registries, was used to develop the risk score calculator. Conclusion: We were able to predict ARDS with good sensitivity using information readily available at COVID-19 diagnosis. The proposed risk score calculator has the potential to guide risk stratification for treatments, such as monoclonal antibodies, that have potential to reduce COVID-19 disease progression. publishersversion published

Allergy and respiratory disorders are common in young athletic individuals. In the context of elite sport, it is essential to secure an accurate diagnosis in order to optimise health and performance. It is also important, however, to consider the potential impact or consequences of these disorders, in recreationally active individuals engaging in structured exercise and/or physical activity to maintain health and well-being across the lifespan. This EAACI Task Force was therefore established, to develop an up-to-date, research-informed position paper, detailing the optimal approach to the diagnosis and management of common exercise-related allergic and respiratory conditions. The recommendations are informed by a multidisciplinary panel of experts including allergists, pulmonologists, physiologists, and sports physicians. The report is structured as a concise, practically focussed document, incorporating diagnostic and treatment algorithms, to provide a source of reference to aid clinical decision making. Throughout, we signpost relevant learning resources to consolidate knowledge and understanding and conclude by highlighting future research priorities and unmet needs. publishersversion published

Funding Information: The Republic of Turkey Ministry of National Education for the PhD studentship. Publisher Copyright: © 2022 The Author(s) Objectives: To develop evidence-based expert recommendations for non-pharmacological treatments for pain, fatigue, sleep problems, and depression in fibromyalgia. Methods: An international, multidisciplinary Delphi exercise was conducted. Authors of EULAR and the Canadian Fibromyalgia Guidelines Group, members of the American Pain Society and clinicians with expertise in fibromyalgia were invited. Participants were asked to select non-pharmacological interventions that could be offered for specific fibromyalgia symptoms and to classify them as either core or adjunctive treatments. An evidence summary was provided to aid the decision making. Items receiving >70% votes were accepted, those receiving

Funding Information: The present publication was funded by Fundação Ciência e Tecnologia, IP national support through CHRC (UIDP/04923/2020). The same institution supported the first author (LAG) under an individual PhD grant (SFRH/BD/145636/2019). EpiReumaPt was supported by unrestricted grants from Direção-Geral da Saúde, Fundação Calouste Gulbenkian, Fundação Champalimaud, Fundação AstraZeneca, Abbvie, Merck, Sharp & Dohme, Pfizer, Roche, Servier, Bial, D3A Medical Systems, Happybrands, Center de Medicina Laboratorial, Germano de Sousa, Clínica Médica da Praia da Vitória, CAL-Clínica, Galp Energia, Açoreana Seguros, and individual rheumatologists. Data were provided by the EpiDoC Unit - CEDOC with permission. Publisher Copyright: © Objectives To estimate the prevalence of medical care-seeking among adults with low back pain (LBP) and to characterise and compare use of diagnostic procedures and medical management between primary and secondary care. Design Cross-sectional study. Setting Data from the EpiReumaPt, a nationwide population-based study conducted in Portugal including a representative sample of non-institutionalised adults (n=10 661) stratified by administrative territorial units was analysed. Participants Individuals who self-reported history of LBP within the previous 12 months (n=6434) and sought medical care for this problem in the same period (n=2618). Outcome measures Patients' self-reported diagnostic workup and management procedures performed by medical care for LBP collected through a structured questionnaire. Medical care procedures were stratified by level of care. Results The prevalence of medical care-seeking for LBP was 38.0% (95% CI 35.9% to 40.1%). Primary care in isolation (45.3%) was the most sought level of care. Emergency departments (25.9%) and orthopaedics (19.4%) were the most sought secondary medical specialties. Several pathoanatomical diagnoses were used, supported by laboratory or imaging tests (91.1%). Disc herniation (20.4%) and osteoarthritis (19.7%) were the most frequent diagnoses, and X-ray (63.7%) was the most frequent diagnostic procedure self-reported by individuals. Most (75.1%) reported being treated for LBP: 80.4% with oral medication and 49.9% with injectables. The mean duration of pharmacological treatment was 104.24 (SD, 266.80) days. The use of pathoanatomical diagnoses, laboratory or imaging tests, and pharmacological treatments were generally more frequent for secondary care (p

Funding: This study was funded by ARIA. MASK-air® has been supported by EU grants (EU Structural and Development grant, POLLAR: EIT Health and Structural and Development Funds) and educational grants from Mylan-Viatris, ALK, GSK, Novartis and Uriach. Open Access funding enabled and organized by Projekt DEAL. BACKGROUND: Co-medication is common among patients with allergic rhinitis (AR), but its dimension and patterns are unknown. This is particularly relevant since AR is understood differently across European countries, as reflected by rhinitis-related search patterns in Google Trends. This study aims to assess AR co-medication and its regional patterns in Europe, using real-world data. METHODS: We analysed 2015-2020 MASK-air® European data. We compared days under no medication, monotherapy, and co-medication using the visual analogue scale (VAS) levels for overall allergic symptoms ("VAS Global Symptoms") and impact of AR on work. We assessed the monthly use of different medication schemes, performing separate analyses by region (defined geographically or by Google Trends patterns). We estimated the average number of different drugs reported per patient within one year. RESULTS: We analysed 222,024 days (13,122 users), including 63,887 days (28.8%) under monotherapy, and 38,315 (17.3%) under co-medication. The median "VAS Global Symptoms" was 7 for no medication days, 14 for monotherapy and 21 for co-medication (p

© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/)., Chronic adolescent cannabinoid receptor agonist exposure has been shown to lead to persistent increases in depressive-like behaviors. This has been a key obstacle to the development of cannabinoid-based therapeutics. However, most of the published work has been performed with only three compounds, namely Δ9-tetrahydrocannabinol, CP55,940 and WIN55,212-2. Hypothesizing that different compounds may lead to distinct outcomes, we herein used the highly potent CB1R/CB2R full agonist HU-210, and first aimed at replicating cannabinoid-induced long-lasting effects, by exposing adolescent female Sprague-Dawley rats to increasing doses of HU-210, for 11 days and testing them at adulthood, after a 30-day drug washout. Surprisingly, HU-210 did not significantly impact adult anxious- or depressive-like behaviors. We then tested whether chronic adolescent HU-210 treatment resulted in short-term (24h) alterations in depressive-like behavior. Remarkably, HU-210 treatment simultaneously induced marked antidepressant- and prodepressant-like responses, in the modified forced swim (mFST) and sucrose preference tests (SPT), respectively. Hypothesizing that mFST results were a misleading artifact of HU-210-induced behavioral hyperreactivity to stress, we assessed plasmatic noradrenaline and corticosterone levels, under basal conditions and following an acute swim-stress episode. Notably, we found that while HU-210 did not alter basal noradrenaline or corticosterone levels, it greatly augmented the stress-induced increase in both. Our results show that, contrary to previously studied cannabinoid receptor agonists, HU-210 does not induce persisting depressive-like alterations, despite inducing marked short-term increases in stress-induced reactivity. By showing that not all cannabinoid receptor agonists may induce long-term negative effects, these results hold significant relevance for the development of cannabinoid-based therapeutics., Work was supported by project funding from Fundação para a Ciência e para a Tecnologia (FCT) (PTDC/MED-FAR/30933/2017 and PTDC/MED-FAR/4834/2021) and by H2020-WIDESPREAD-05-2017-Twinning (EpiEpinet) under grant agreement No. 952455. MF-F (SFRH/BD/147505/2019), NR (PD/BD/113463/2015), JF-G (PD/BD/114441/2016) and CM-L (SFRH/BD/118238/2016) are supported by PhD fellowships from FCT. The funding sources had no involvement in study design, preparation of the manuscript, or decision regarding its submission.

Funding: The Portuguese Mental Health Study was carried out by the Department of Mental Health, Faculty of Medical Sciences, NOVA University of Lisbon, with collaboration of the Portuguese Catholic University, and was funded by Champalimaud Foundation, Gulbenkian Foundation, Foundation for Science and Technology (FCT) and Ministry of Health Background Depressive and anxiety disorders are highly comorbid, which has been theorized to be due to an underlying internalizing vulnerability. We aimed to identify groups of participants with differing vulnerabilities by examining the course of internalizing psychopathology up to age 45. Methods We used data from 24158 participants (aged 45+) in 23 population-based cross-sectional World Mental Health Surveys. Internalizing disorders were assessed with the Composite International Diagnostic Interview (CIDI). We applied latent class growth analysis (LCGA) and investigated the characteristics of identified classes using logistic or linear regression. Results The best-fitting LCGA solution identified eight classes: A healthy class (81.9%), three childhood-onset classes with mild (3.7%), moderate (2.0%), or severe (1.1%) internalizing comorbidity, two puberty-onset classes with mild (4.0%) or moderate (1.4%) comorbidity, and two adult-onset classes with mild comorbidity (2.7% and 3.2%). The childhood-onset severe class had particularly unfavorable sociodemographic outcomes compared to the healthy class, with increased risks of being never or previously married (OR = 2.2 and 2.0, p < 0.001), not being employed (OR = 3.5, p < 0.001), and having a low/low-Average income (OR = 2.2, p < 0.001). Moderate or severe (v. mild) comorbidity was associated with 12-month internalizing disorders (OR = 1.9 and 4.8, p < 0.001), disability (B = 1.1-2.3, p < 0.001), and suicidal ideation (OR = 4.2, p < 0.001 for severe comorbidity only). Adult (v. childhood) onset was associated with lower rates of 12-month internalizing disorders (OR = 0.2, p < 0.001). Conclusions We identified eight transdiagnostic trajectories of internalizing psychopathology. Unfavorable outcomes were concentrated in the 1% of participants with childhood onset and severe comorbidity. Early identification of this group may offer opportunities for preventive interventions. publishersversion published

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. OBJECTIVE: To propose a new decision algorithm combining biomarkers measured in a tumor biopsy with clinical variables, to predict recurrence after liver transplantation (LT). SUMMARY BACKGROUND DATA: Liver cancer is one of the most frequent causes of cancer-related mortality. LT is the best treatment for hepatocellular carcinoma (HCC) patients but the scarcity of organs makes patient selection a critical step. Additionally, clinical criteria widely applied in patient eligibility decisions miss potentially curable patients while selecting patients that relapse after transplantation. METHODS: A literature systematic review singled out candidate biomarkers whose RNA levels were assessed by quantitative PCR in tumor tissue from 138 HCC patients submitted to LT (>5 y follow up, 32% beyond Milan criteria). The resulting four gene signature was combined with clinical variables to develop a decision algorithm using machine learning approaches. The method was named HepatoPredict. RESULTS: HepatoPredict identifies 99% disease-free patients (>5 y) from a retrospective cohort, including many outside clinical criteria (16%-24%), thus reducing the false negative rate. This increased sensitivity is accompanied by an increased positive predictive value (88,5%-94,4%) without any loss of long-term overall survival or recurrence rates for patients deemed eligible by HepatoPredict; those deemed ineligible display marked reduction of survival and increased recurrence in the short and long term. CONCLUSIONS: HepatoPredict outperforms conventional clinical-pathologic selection criteria, (Milan, UCSF) providing superior prognostic information. Accurately identifying which patients most likely benefit from LT enables an objective stratification of waiting lists and information-based allocation of optimal versus suboptimal organs. publishersversion published

Angiogenesis is a complex process encompassing endothelial cell proliferation, migration, and tube formation. While numerous studies describe that curcumin exerts antitumor properties (e.g., targeting angiogenesis), information regarding other dietary curcuminoids such as demethoxycurcumin (DMC) and bisdemethoxycurcumin (BisDMC) is scant. In this study, we evaluated the antiangiogenic activities of these three curcuminoids at physiological concentrations (0.1¿5 ¿M) on endothelial cell migration and tubulogenesis and the underlying associated mechanisms on human aortic endothelial cells (HAECs). Results showed that the individual compounds and a representative mixture inhibited the tubulogenic and migration capacity of endothelial cells dose-dependently, while sparing cell viability. Notably, DMC and BisDMC at 0.1 and 1 ¿M showed higher capacity than curcumin inhibiting tubulogenesis. These compounds also reduced phosphorylation of the VEGFR2 and the downstream ERK and Akt pathways in VEGF165-stimulated cells. In silico analysis showed that curcuminoids could bind the VEGFR2 antagonizing the VEGF-mediated angiogenesis. These findings suggest that physiologically concentrations of curcuminoids might counteract pro-angiogenic stimuli relevant to tumorigenic processes., J.A.G.-B. was supported by Standard European Marie Curie Individual Fellowship from the European Commission. This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Grant Agreement No 838991, and by the project PID2019-103914RB-I00 from the Ministry of Science and Innovation (MICINN, Spain)

Funding Information: The work was performed under the JRC Exploratory Research project CIAO—Modelling COVID-19 pathogenesis using the Adverse Outcome Pathway (AOP). Julija Filipovska for her careful reading and valuable inputs. Funding: This research was funded by the Academy of Finland (grand number 322761) for D.G., G.d.G. and L.A.S. and by Fundação para a Ciência e Tecnologia through CEECIND/01049/2020 for H.S. For the other authors, this research received no external funding. Addressing factors modulating COVID-19 is crucial since abundant clinical evidence shows that outcomes are markedly heterogeneous between patients. This requires identifying the factors and understanding how they mechanistically influence COVID-19. Here, we describe how eleven selected factors (age, sex, genetic factors, lipid disorders, heart failure, gut dysbiosis, diet, vitamin D deficiency, air pollution and exposure to chemicals) influence COVID-19 by applying the Adverse Outcome Pathway (AOP), which is well-established in regulatory toxicology. This framework aims to model the sequence of events leading to an adverse health outcome. Several linear AOPs depicting pathways from the binding of the virus to ACE2 up to clinical outcomes observed in COVID-19 have been developed and integrated into a network offering a unique overview of the mechanisms underlying the disease. As SARS-CoV-2 infectibility and ACE2 activity are the major starting points and inflammatory response is central in the development of COVID-19, we evaluated how those eleven intrinsic and extrinsic factors modulate those processes impacting clinical outcomes. Applying this AOP-aligned approach enables the identification of current knowledge gaps orientating for further research and allows to propose biomarkers to identify of high-risk patients. This approach also facilitates expertise synergy from different disciplines to address public health issues. publishersversion published

Copyright © 2022 Ribeiro, Simões, Rocha, Vala, Pinto, Ministro, Poli, Diegues, Pina, Benadjaoud, Flamant, Tamarat, Osório, Pais, Casal, Pinto, Matthiesen, Fiuza and Constantino Rosa Santos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms., The contribution of radiotherapy, per se, to late cardiotoxicity remains controversial. To clarify its impact on the development of early cardiac dysfunction, we developed an experimental model in which the hearts of rats were exposed, in a fractionated plan, to clinically relevant doses of ionizing radiation for oncological patients that undergo thoracic radiotherapy. Rat hearts were exposed to daily doses of 0.04, 0.3, and 1.2 Gy for 23 days, achieving cumulative doses of 0.92, 6.9, and 27.6 Gy, respectively. We demonstrate that myocardial deformation, assessed by global longitudinal strain, was impaired (a relative percentage reduction of >15% from baseline) in a dose-dependent manner at 18 months. Moreover, by scanning electron microscopy, the microvascular density in the cardiac apex was significantly decreased exclusively at 27.6 Gy dosage. Before GLS impairment detection, several tools (qRT-PCR, mass spectrometry, and western blot) were used to assess molecular changes in the cardiac tissue. The number/expression of several genes, proteins, and KEGG pathways, related to inflammation, fibrosis, and cardiac muscle contraction, were differently expressed in the cardiac tissue according to the cumulative dose. Subclinical cardiac dysfunction occurs in a dose-dependent manner as detected by molecular changes in cardiac tissue, a predictor of the severity of global longitudinal strain impairment. Moreover, there was no dose threshold below which no myocardial deformation impairment was detected. Our findings i) contribute to developing new markers and exploring non-invasive magnetic resonance imaging to assess cardiac tissue changes as an early predictor of cardiac dysfunction; ii) should raise red flags, since there is no dose threshold below which no myocardial deformation impairment was detected and should be considered in radiation-based imaging and -guided therapeutic cardiac procedures; and iii) highlights the need for personalized clinical approaches., This work was supported by the European Community’s Horizon 2020 Program supported the MEDIRAD—Implications of Medical Low Dose Radiation Exposure granted by the Euratom Research and Training Program 2014-2014 under agreement No. 755523. The MS work was financed by the Portuguese Mass Spectrometry Network, integrated in the National Roadmap of Research Infrastructures of Strategic Relevance (ROTEIRO/0028/2013; LISBOA-01-0145-FEDER-022125). ARP and ATP were supported by a fellowship (SFRH/BD/121684/2016 and SFRH/BPD/123181/2016, respectively) and IV received a fellowship for Programmatic Funding (UIDP/00306/2020), all from Fundação para a Ciência e Tecnologia.

Funding Information: The study had no funding. Reuma.pt is a database that has diverse funding entities, mentioned in the online site. Disclosure statement: The authors have declared no conflicts of interest Publisher Copyright: © 2022. Acta Reumatologica Portuguesa.All Rights Reserved. Introduction: Hand osteoarthritis (HOA) is a prevalent rheumatic disease that may cause significant disability. The Functional index for HOA (FIHOA) is a validated questionnaire to evaluate loss of function in patients with HOA. Objective: To undertake a cross-cultural adaptation and validation of FIHOA into Portuguese. Patients and methods: First, the original French version of FIHOA had been forward-backward translated into Portuguese, according to the guidelines for cross-cultural adaptation. Secondly, patients with primary HOA were consecutively recruited in three Portuguese rheumatology outpatient clinics between May 2016 and April 2018. The final consensual Portuguese version of FIHOA was administered to 52 patients. A numerical rating scale (NRS – 0 to 100mm) for hand pain and for perceived hand dysfunction was also registered. Ten randomly selected patients were re-administered the same tools 5 to 15 days later. Internal consistency, test-retest reliability, internal construct validity and external validity related to dysfunction NRS were evaluated. Results: Fifty-two patients were evaluated: all right-handed, 96% women, mean age of 63 (10) years and 8 (6) years of disease duration. Mean (SD) pain and dysfunction were 47 (25) and 46 (25), respectively, with 68% patients being symptomatic. Mean (SD) FIHOA was 7 (5). Cronbach’s alpha for internal consistency was high and adequate (0.87) and corrected item-total correlation revealed adequate performance. For reliability, Spearman’s rho coefficient was 0.88 and total intraclass correlation coefficient (ICC) between test and retest was 0.87, showing good reliability. Factor analysis revealed three factors accounting for 71% of the variance of the score, with the first one (including questions 1, 2, 3 and 10) being responsible for 47% of the variance. Spearman’s rho between FIHOA and dysfunction NRS was 0.5, showing a moderate but significant correlation and moderate external validity. Conclusion: The Portuguese version of FIHOA is a consistent, reliable, and valid instrument to measure loss of function in HOA Portuguese patients publishersversion published

BackgroundObesity leads to poor health outcomes and may adversely affect work productivity. This study, aimed to investigate the obesity- attributable costs of absenteeism among working adults in Portugal.MethodsThe study population included individuals actively working at baseline from the Epidemiology of Chronic Diseases Cohort (EpiDoC), a large Portuguese population-based prospective study. Body mass index was measured at baseline and in two follow-up interviews. Absenteeism in each wave of the EpiDoC was assessed by the question “Did you have a sick leave in the previous 12 months? yes/no”, followed by “How many days did you miss work due to sickness in the previous twelve months?”. Body mass index (BMI) was classified into underweight, normal weight, overweight, and obese, based on the standard World Health Organization definition.Association between obesity and absenteeism was estimated with the negative binomial regression model adjusted for BMI, chronic diseases, and lifestyle. Obesity- attributable costs were calculated using lost gross income during the time absent from work, through the human-capital approach.ResultsThe EpiDoC included 4338 working adults at baseline. Of these, 15.2% were obese at the beginning of the study and 22.7% of the population had been absent from work in the last 12 months. Participants with obesity missed 66% more days at work (IRR: 1.66; CI 95%:1.13–2.44; (p = 0.009.) than those with normal weight. The odds of having been absent from work were 1.4 times higher in obese compared to non-obese individuals (CI 95%: 1.18–1.67;p ConclusionObesity imposes a financial burden due to absenteeism in Portugal. Employers and national health regulators should seek effective ways to reduce these costs.

Funding: This work was supported by the European Brain Council (EBC). This work is also supported by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. Background: Despite well-established guidelines for managing major depressive disorder (MDD), its extensive disability burden persists. This Value of Treatment mission from the European Brain Council aimed to elucidate the nature and extent of 'gaps' between best-practice and current32 practice care, specifically to: 1. Identify current treatment gaps along the care pathway and determine the extent of these gaps in comparison with the stepped-care model. 2. Recommend policies intending to better meet patient needs (i.e., minimise treatment gaps). Methods: After agreement upon a set of relevant treatment gaps, data pertaining to each gap were gathered and synthesised from several sources across six European countries. Subsequently a modified-Delphi approach was undertaken to attain consensus amongst an expert panel on proposed recommendations for minimising treatment gaps. Results: 4 recommendations were made to increase the depression diagnosis 40 rate (from ~50% episodes), aiming to both increase the number of patients seeking help, and the likelihood of a practitioner to correctly detect depression. These should reduce time to treatment (from ~1-8 years after illness onset) and increase rates of treatment; 9 further recommendations aimed to increase rates of treatment (from ~25-50% of patients currently treated), mainly focused on targeting the best treatment to each patient. To improve follow-up after treatment initiation (from ~30-65% followed up within 3 months), 7 recommendations focused on increasing continuity of care. For those not responding, 10 recommendations focused on ensuring access to more specialist care (currently at rates of ~5-25% of patients). Conclusions: The treatment gaps in depression care are substantial and concerning, from the proportion of people not entering care pathways to those stagnating in primary care with impairing and persistent illness. A wide range of recommendations can be made to enhance care throughout the pathway. publishersversion epub_ahead_of_print

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/., Background: Rheumatic diseases are associated with an increase in overall risks of tuberculosis (TB). The aim of this study was to evaluate the frequency of TB and the frequency of latent TB infection (LTBI), in clinical practice, for juvenile idiopathic arthritis (JIA) patients from high and low risk of TB incidence endemic countries. Methods: This is an international, multicenter, cross-sectional, observational study of data collection from Brazil and Registry of Portugal at REUMA.PT. The inclusion criteria were patients with Juvenile Idiopathic Arthritis (JIA) with age ≤ 18 years who underwent screening for Mycobacterium tuberculosis infection [tuberculin skin test (TST) and/or interferon gamma release assay (IGRA)]. Chest X-rays and history of exposure to TB were also assessed. Results: 292 JIA patients were included; mean age 14.3 years, mean disease duration 7.5 years, 194 patients (66.4%) performed only TST, 14 (4.8%) only IGRA and 84 (28.8%) both. The frequency of LTBI (10.6%) and TB was similar between the two countries. The reasons for TB screening were different; in Brazil it was performed more often at JIA onset while in Portugal it was performed when starting Disease Modified Anti-Rheumatic Drugs (DMARD) treatment (p < 0.001). Isoniazid therapy was prescribed in 40 (13.7%) patients (31 with LTBI and 9 with epidemiologic risks and/or due to contact with sick people). Only three patients (1%) developed active TB. Conclusion: We found nearly 10% of patients with LTBI, a small percentage of patients with treatment due to epidemiologic risks and only 1% with active TB. Distinct reasons and screening methods for LTBI were observed between the two countries.

Funding Information: AE, FD, GDP, LG, VG, AJ, JK, AL, JM, SNM, MO, MP, MC declare no conflicts of interest. MG reports speaking fees from Baxter and Philips. TDC is supported by Research Foundation Flanders (Grant nr G085920N). MA reports Research Grant from GE, Honoraria from Fisher and Paykel, Pfizer, Orion and Gilead. GC reports grants, personal fees as Speakers’ Bureau Member and Advisory Board Member from Integra and Neuroptics, all outside the submitted work. ACM is supported by a Clinician Scientist Fellowship from the Medical Research Council (MR/V006118/1). SE declares no financial COIs and the following non-financial disclosures: Cochrane editor, American Society of Anesthesiologist data review board member. LF reports research funding from NIHR, Baxter, Ortho-Clinical Diagnostics, Exthera Medical and lecture fees from Baxter, Fresenius, Paion, all outside the submitted work. GG received payment for lectures from Getinge, Draeger Medical, Fisher&Paykel, Biotest, MSD, Gilead and unrestricted research grants from Fisher&Paykel and MSD (all unrelated to the present work). MCMD declares potential conflict of interest with BD. PP declares potential conflicts of interest with Pfizer, MSD and Gilead. SJS reports personal fees from Springer-Verlag, GmbH (Vienna, Austria) for educational commitments grants and non-financial support from ESICM (Bruxelles, Belgium), Fresenius (Germany), Liberate Medical LLC (Crestwood, USA), STIMIT AG (Nidau, Switzerland) Reactive Robotics GmbH (Munich, Germany) as well as from Technical University of Munich, Germany, from national (e.g. DGAI) and international (e.g. ESICM) medical societies (or their congress organizers) in the field of anesthesiology and intensive care, all outside the submitted work; SJS holds stocks in small amounts from Alphabeth Inc., Bayer AG, Rhön-Klinikum AG, and Siemens AG. These did not have any influence on this study. AW reports Honorarium for delivery of educational material for Vygon, GE. JLT declares potential conflict of interest with Getinge. JDW has consulted for Pfizer, MSD (honoraria paid to institution), and is a senior clinical investigator funded by the Research Foundation Flanders (FWO, Ref. 1881020N). Purpose: To accommodate the unprecedented number of critically ill patients with pneumonia caused by coronavirus disease 2019 (COVID-19) expansion of the capacity of intensive care unit (ICU) to clinical areas not previously used for critical care was necessary. We describe the global burden of COVID-19 admissions and the clinical and organizational characteristics associated with outcomes in critically ill COVID-19 patients. Methods: Multicenter, international, point prevalence study, including adult patients with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and a diagnosis of COVID-19 admitted to ICU between February 15th and May 15th, 2020. Results: 4994 patients from 280 ICUs in 46 countries were included. Included ICUs increased their total capacity from 4931 to 7630 beds, deploying personnel from other areas. Overall, 1986 (39.8%) patients were admitted to surge capacity beds. Invasive ventilation at admission was present in 2325 (46.5%) patients and was required during ICU stay in 85.8% of patients. 60-day mortality was 33.9% (IQR across units: 20%–50%) and ICU mortality 32.7%. Older age, invasive mechanical ventilation, and acute kidney injury (AKI) were associated with increased mortality. These associations were also confirmed specifically in mechanically ventilated patients. Admission to surge capacity beds was not associated with mortality, even after controlling for other factors. Conclusions: ICUs responded to the increase in COVID-19 patients by increasing bed availability and staff, admitting up to 40% of patients in surge capacity beds. Although mortality in this population was high, admission to a surge capacity bed was not associated with increased mortality. Older age, invasive mechanical ventilation, and AKI were identified as the strongest predictors of mortality. publishersversion published

Funding Information: This work was funded by the Fundação para a Ciência and Tecnologia (FCT, Portugal) under RESEARCH4COVID 19 call with reference 283_596885654 and co-funded by ANI under INOV4COVID (Funding to V.M.B.). M.J.A. is funded by the FCT (CEECIND/02373/2020). M.A. is funded by a Junior Researcher working contract from FCT and Instituto Gulbenkian de Ciência (IGC, Portugal). This work benefited from COVID19 emergency funds 2020 from Calouste Gulbenkian Foundation and from Oeiras city council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank the technical support of IGC’s Advanced Imaging Facility (AIF-UIC). Background Adults are being vaccinated against SARS-CoV-2 worldwide, but the longitudinal protection of these vaccines is uncertain, given the ongoing appearance of SARS-CoV-2 variants. Children remain largely unvaccinated and are susceptible to infection, with studies reporting that they actively transmit the virus even when asymptomatic, thus affecting the community. Methods We investigated if saliva is an effective sample for detecting SARS-CoV-2 RNA and antibodies in children, and associated viral RNA levels to infectivity. For that, we used a saliva-based SARS-CoV-2 RT-qPCR test, preceded or not by RNA extraction, in 85 children aged 10 years and under, admitted to the hospital regardless of COVID-19 symptomatology. Amongst these, 29 (63.0%) presented at least one COVID-19 symptom, 46 (54.1%) were positive for SARS-CoV-2 infection, 28 (32.9%) were under the age of 1, and the mean (SD) age was 3.8 (3.4) years. Saliva samples were collected up to 48 h after a nasopharyngeal swab-RT-qPCR test. Results In children aged 10 years and under, the sensitivity, specificity, and accuracy of saliva-RT-qPCR tests compared to NP swab-RT-qPCR were, respectively, 84.8% (71.8%–92.4%), 100% (91.0%–100%), and 91.8% (84.0%–96.6%) with RNA extraction, and 81.8% (68.0%–90.5%), 100% (91.0%–100%), and 90.4% (82.1%–95.0%) without RNA extraction. Rescue of infectious particles from saliva was limited to CT values below 26. In addition, we found significant IgM positive responses to SARS-CoV-2 in children positive for SARS-CoV-2 by NP swab and negative by saliva compared to other groups, indicating late infection onset (>7–10 days). Conclusions Saliva is a suitable sample type for diagnosing children aged 10 years and under, including infants aged

Funding: Supported by the Macula Foundation, Inc. (New York, NY, USA) and by Fundação para a Ciência e Tecnologia (FCT)–Portugal, cofunded by FEDER under the PT2020 Partnership Agreement (to MCS, including project PTDC/MED-PAT/30385/2017, iNOVA4Health-UIDB/04462/2020). ACF was funded by a FCT PhD studentship (PD/BD/135503/2018). DC was supported in part by a studentship from Fundação Luso-Americana para o Desenvolvimento (FLAD, USA R&D@PhD–Proj 2020/0140). Purpose: To characterize macular blood flow connectivity in vivo using high-resolution optical coherence tomography (HighRes OCT). Methods: Cross-sectional, observational study. Dense (6-µm interscan distance) perifoveal HighRes OCT raster scans were performed on healthy participants. To mitigate the limitations of projection-resolved OCT-angiography, flow and structural data were used to observe the vascular structures of the superficial vascular complex (SVC) and the deep vascular complex. Vascular segmentation and rendering were performed using Imaris 9.5 software. Inflow and outflow patterns were classified according to vascular diameter and branching order from superficial arteries and veins, respectively. Results: Eight eyes from eight participants were included in this analysis, from which 422 inflow and 459 outflow connections were characterized. Arteries had direct arteriolar connections to the SVC (78%) and to the intermediate capillary plexus (ICP, 22%). Deep capillary plexus (DCP) inflow derived from small-diameter vessels succeeding ICP arterioles. The most prevalent outflow pathways coursed through superficial draining venules (74%). DCP draining venules ordinarily merged with ICP draining venules and drained independently of superficial venules in 21% of cases. The morphology of DCP draining venules in structural HighRes OCT is distinct from other vessels crossing the inner nuclear layer and can be used to identify superficial veins. Conclusions: Vascular connectivity analysis supports a hybrid circuitry of blood flow within the human parafoveal macula. Translational Relevance: Characterization of parafoveal macular blood flow connectivity in vivo using a precise segmentation of HighRes OCT is consistent with ground-truth microscopy studies and shows a hybrid circuitry. publishersversion published

© 2022 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L.U. INTRODUCTION: During the Covid-19 pandemic there has been a general belief that hospital admissions for non-infectious causes, especially cardiovascular disease, have fallen. OBJECTIVES: To assess the impact of the pandemic on admissions for ST-elevation myocardial infarction (STEMI) during the first pandemic wave. METHODS: We performed a multicenter retrospective analysis of consecutive patients presenting with STEMI in two Portuguese hospital centers in two sequential periods - P1 (March 1 to April 30) and P2 (May 1 to June 30). Patients' clinical data and hospital outcomes were compared between the two periods for the years 2017 to 2019 and for 2020. RESULTS: During P1 in 2020, a reduction in the number of STEMI patients was observed in comparison with previous years (26.0±4.2 vs. 16.5±4.9 cases per month; p=0.033), as well as an increase in the number of mechanical complications (0.0% vs. 3.0%; p=0.029). Percutaneous coronary interventions in the setting of failed thrombolysis were more frequent (1.9% vs. 9.1%; p=0.033). An overall trend for longer delays in key timings of STEMI care bundles was noted. Mortality was higher during P1 compared to previous years (1.9% vs. 12.1%; p=0.005). CONCLUSIONS: During the first Covid-19 wave fewer patients presented with STEMI at the catheterization laboratory for percutaneous coronary intervention. These patients presented more mechanical complications and higher mortality. publishersversion published

BACKGROUND: Health literacy is considered a determinant of self-management behaviors and health outcomes among people with diabetes. The assessment of health literacy is central to understanding the health needs of a population. This study aimed to adapt the Health Literacy Questionnaire (HLQ) to the Portuguese context and to examine the psychometric properties of a population of people with diabetes. METHODS: Data were collected using a self-administrated questionnaire from 453 people with diabetes in a specialized diabetes care unit. Analysis included item difficulty level, composite scale reliability, and confirmatory factor analysis (CFA). RESULTS: The HLQ showed that the items were easily understood by participants. Composite reliability ranged from 0.74 to 0.83. A nine-factor CFA model was fitted to the 44 items. Given the very restricted model, the fit was quite satisfactory [χ2wlsmv = 2147.3 (df = 866), p = 0.001; CFI = 0.931, TLI = 0.925, RMSEA = 0.057 (90% C.I. 0.054-0.060), and WRMR = 1.528]. CONCLUSION: The Portuguese version of the HLQ has shown satisfactory psychometric properties across its nine separate scales in people with diabetes. Given the strong observed properties of the HLQ across cultures, languages, and diseases, the HLQ is likely to be a useful tool in a range of Portuguese settings. publishersversion published

Funding Information: LC is funded by an FCT PhD fellowship (2020.08812.BD). AT is funded by an FCT PhD fellowship (2021.06204.BD). MP is funded by Liga Portuguesa Contra o Cancro – Núcleo Regional do Sul (LPCC-NRS). DB lab is supported by Fundação para a Ciência e a Tecnologia (FCT) through grant PTDC/BIA-CEL/29765/2017. This publication was funded by the iNOVA4Health - UIDB/04462/2020 and UIDP/04462/2020, a program financially supported by FCT/Ministério da Educação e Ciência through national funds and co-funded by FEDER under the PT2020 Partnership Agreement. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. Publisher Copyright: Copyright © 2022 Cabaço, Tomás, Pojo and Barral. Skin cancers are among the most common cancers worldwide and are increasingly prevalent. Cutaneous melanoma (CM) is characterized by the malignant transformation of melanocytes in the epidermis. Although CM shows lower incidence than other skin cancers, it is the most aggressive and responsible for the vast majority of skin cancer-related deaths. Indeed, 75% of patients present with invasive or metastatic tumors, even after surgical excision. In CM, the photoprotective pigment melanin, which is produced by melanocytes, plays a central role in the pathology of the disease. Melanin absorbs ultraviolet radiation and scavenges reactive oxygen/nitrogen species (ROS/RNS) resulting from the radiation exposure. However, the scavenged ROS/RNS modify melanin and lead to the induction of signature DNA damage in CM cells, namely cyclobutane pyrimidine dimers, which are known to promote CM immortalization and carcinogenesis. Despite triggering the malignant transformation of melanocytes and promoting initial tumor growth, the presence of melanin inside CM cells is described to negatively regulate their invasiveness by increasing cell stiffness and reducing elasticity. Emerging evidence also indicates that melanin secreted from CM cells is required for the immunomodulation of tumor microenvironment. Indeed, melanin transforms dermal fibroblasts in cancer-associated fibroblasts, suppresses the immune system and promotes tumor angiogenesis, thus sustaining CM progression and metastasis. Here, we review the current knowledge on the role of melanin secretion in CM aggressiveness and the molecular machinery involved, as well as the impact in tumor microenvironment and immune responses. A better understanding of this role and the molecular players involved could enable the modulation of melanin secretion to become a therapeutic strategy to impair CM invasion and metastasis and, hence, reduce the burden of CM-associated deaths. publishersversion published

Funding Information: The present publication was funded by Fundação Ciência e Tecnologia, IP national support through CHRC (UIDP/04923/2020). Funding Information: We thank our colleagues at “Centro de Genética Preditiva e Preventiva, Instituto de Biologia Molecular e Celular, Instituto de Investigacão e Inovacaão em Saúde, Porto” and Laboratory of Immunology, NOVA Medical School, Lisboa. The present publication was funded by Fundação Ciência e Tecnologia, IP national support through CHRC (UIDP/04923/2020). Publisher Copyright: Copyright © 2022 Castro, Maia, Batalha, Freixo, Martins, Neves, Cordeiro and Neves. DNA ligase IV deficiency is a rare autosomal recessive disorder associated with impaired DNA repair mechanisms. Most patients with DNA repair defects present with neurologic deficits, combined immunodeficiency, bone marrow failure, and/or hematologic neoplasia. We present 3 unrelated cases of ligase IV deficiency with different clinical presentations. Patient 1 presented at the age of 5 with bone marrow failure, dysmorphic features, and T and B lymphopenia. A compound heterozygous variant L19W/K635fs in the LIG4 gene was identified. Patient 2 presented at the age of 16 with recurrent infections. He had agammaglobulinemia and absent B cells. A homozygous R278H in the LIG4 gene was identified. Patient 3 was referred for vitiligo and B-cell lymphopenia (low class-switched B cells) and hypogammaglobulinemia. Homozygous R278H in LIG4 was also identified. In the last few years, the spectrum of clinical manifestations caused by ligase IV deficiency has widened, making it very difficult to establish an accurate clinical diagnosis. The use of NGS allows a proper diagnosis and provides a better prognosis and adequate family counseling. publishersversion published

Funding: We thank Liliana Bento for valuable assistance in formatting the manuscript. This article was supported by the LYSOCIL project. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 811087. CGA has funding from Maratona da Saúde 2016 and Fundaçao para a Ciência e a Tecnologia ˜ , I.P. (CEECIND/00410/2017). FMP is a Wellcome Investigator in Science and a Royal Society Wilson merit award holder. Since the discovery of lysosomes more than 70 years ago, much has been learned about the functions of these organelles. Lysosomes were regarded as exclusively degradative organelles, but more recent research has revealed that they play essential roles in several other cellular functions, such as nutrient sensing, intracellular signalling, and metabolism. Methodological advances played a key part in generating our current knowledge about the biology of this multifaceted organelle. In this review, we cover current methods used to analyse lysosome morphology, positioning, motility, and function. We highlight the principles behind these methods, the methodological strategies, and their advantages and limitations. To extract accurate information and avoid misinterpretations, we discuss the best strategies to identify lysosomes and assess their characteristics and functions. With this review, we aim to stimulate an increase in the quantity and quality of research on lysosomes and further ground-breaking discoveries on an organelle that continues to surprise and excite cell biologists. publishersversion published

Funding: This research was funded by Fundação para a Ciência e Tecnologia (FCT) through the projects iNOVA4Health, Translational Medicine program—UIDB/Multi/04462/2020; UIDB/50008/2020 and PTDC/CTM-REF/2679/2020. Graphene is the material elected to study molecules and monolayers at the molecular scale due to its chemical stability and electrical properties. The invention of scanning tunneling microscopy has deepened our knowledge on molecular systems through imaging at an atomic resolution, and new possibilities have been investigated at this scale. Interest on studies on biomolecules has been demonstrated due to the possibility of mimicking biological systems, providing several applications in nanomedicine: drug delivery systems, biosensors, nanostructured scaffolds, and biodevices. A breakthrough came with the synthesis of molecular systems by stepwise methods with control at the atomic/molecular level. This article presents a review on self-assembled monolayers of biomolecules on top of graphite with applications in biodevices. Special attention is given to porphyrin systems adsorbed on top of graphite that are able to anchor other biomolecules. publishersversion published

Os agentes anestésicos representam uma causa importante de anafilaxia a fármacos, sendo os relaxantes neuromusculares (RNM) dos principais responsáveis pelos casos de anafilaxia perioperatória. O cisatracúrio é o RNM mais recente, sendo um estereoisómero do atracúrio que se acreditava não ter potencial de libertação de histamina e, consequentemente, causar menos reações alérgicas do que os outros RNM. No entanto, têm sido relatados vários casos de reação anafilática grave após administração de cisatracúrio, não existindo, do nosso conhecimento, registo na literatura de nenhum em Portugal. As autoras apresentam dois casos de anafilaxia perioperatória grave (grau 4 na escala de Ring & Messmer) com paragem cardiorrespiratória. Na investigação alergológica foram realizados testes cutâneos, cujos intradérmicos se revelaram positivos para o cisatracúrio (1:100) em ambos os doentes. É importante alertar que este RNM não será tão desprovido de potencial alergénico como previamente pensado e esse facto deve ser considerado na investigação de uma reação alérgica que ocorra durante a indução anestésica.

Aims/hypothesis Imbalances in glucose metabolism are hallmarks of clinically silent prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) representing dysmetabolism trajectories leading to type 2 diabetes. CD26/dipeptidyl peptidase 4 (DPP4) is a clinically proven molecular target of diabetes-controlling drugs but the DPP4 gene control of dysglycaemia is not proven. Methods We dissected the genetic control of post-OGTT and insulin release responses by the DPP4 gene in a Portuguese population-based cohort of mainly European ancestry that comprised individuals with normoglycaemia and prediabetes, and in mouse experimental models of Dpp4 deficiency and hyperenergetic diet. Results In individuals with normoglycaemia, DPP4 single-nucleotide variants governed glycaemic excursions (rs4664446, p=1.63x10−7) and C-peptide release responses (rs2300757, p=6.86x10−5) upon OGTT. Association with blood glucose levels was stronger at 30 min OGTT, but a higher association with the genetic control of insulin secretion was detected in later phases of the post-OGTT response, suggesting that the DPP4 gene directly senses glucose challenges. Accordingly, in mice fed a normal chow diet but not a high-fat diet, we found that, under OGTT, expression of Dpp4 is strongly downregulated at 30 min in the mouse liver. Strikingly, no genetic association was found in prediabetic individuals, indicating that post-OGTT control by DPP4 is abrogated in prediabetes. Furthermore, Dpp4 KO mice provided concordant evidence that Dpp4 modulates post-OGTT C-peptide release in normoglycaemic but not dysmetabolic states. Conclusions/interpretation These results showed the DPP4 gene as a strong determinant of post-OGTT levels via glucose-sensing mechanisms that are abrogated in prediabetes. We propose that impairments in DPP4 control of post-OGTT insulin responses are part of molecular mechanisms underlying early metabolic disturbances associated with type 2 diabetes. Graphical abstract