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Victoria Federico Paly,1 Laura Amanda Vallejo-Aparicio,2 Alan Martin,3 José Luis Izquierdo,4 Juan Antonio Riesco,5 Juan José Soler-Cataluña,6 Catarina Abreu,7 Chandroday Biswas,8 Afisi S Ismaila9,10 1ICON plc, Philadelphia, PA, USA; 2GSK, Madrid, Spain; 3GSK, Brentford, UK; 4Hospital Universitario de Guadalajara, Guadalajara, Spain; 5Hospital San Pedro de Alcántara, Cáceres, Spain; 6Hospital Arnau de Vilanova, Valencia, Spain; 7ICON Plc, New York, NY, USA; 8ICON Plc, Bengaluru, Karnataka, India; 9Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 10Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, CanadaCorrespondence: Afisi S Ismaila, Value Evidence and Outcomes, GSK, 1250 South Collegeville Road, Collegeville, PA, 19426-0989, USA, Tel +1 919 315 8229, Email afisi.s.ismaila@gsk.comPurpose: Given between-country differences in healthcare systems, treatment costs, and disease management guidelines, country-specific cost-effectiveness analyses are important. This study evaluated the cost-effectiveness of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI and UMEC/VI among patients with symptomatic chronic obstructive pulmonary disease (COPD) at risk of exacerbations from a Spanish healthcare system perspective.Patients and Methods: Baseline data and treatment effects from the IMPACT trial were populated into the validated GALAXY COPD progression model. Utilities were estimated using Spanish observational data. Direct healthcare costs (2019 €) were informed by Spanish public sources. A 3% discount rate for costs and benefits was applied. The time horizon and treatment duration were 3 years (base case). One-way sensitivity, scenario, and probabilistic sensitivity analyses were performed.Results: FF/UMEC/VI treatment resulted in fewer exacerbations over 3 years (4.130 vs 3.648) versus FF/VI, with a mean (95% confidence interval [CI]) incremental cost of € 444 (€ 149, € 713) per patient and benefit of 0.064 (0.053, 0.076) quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio (ICER) of € 6887 per QALY gained. FF/UMEC/VI was a dominant treatment strategy versus UMEC/VI, resulting in fewer exacerbations (4.130 vs 3.360), with a mean (95% CI) incremental cost of –€ 450 (–€ 844, –€ 149) and benefit of 0.054 (0.043, 0.064) QALYs. FF/UMEC/VI was cost-effective versus FF/VI and UMEC/VI across all analyses.Conclusion: FF/UMEC/VI was predicted to be a cost-effective treatment option versus FF/VI or UMEC/VI in symptomatic COPD patients at risk of exacerbations in Spain, across all scenarios and sensitivity analyses.Keywords: chronic obstructive pulmonary disease, cost-effectiveness, single-inhaler triple therapy, Spain, triple inhaled therapy

Objetivo: A obesidade representa um importante problema de saúde, afetando mais de 800 milhões de adultos mundialmente. É um dos maiores fatores de risco para desenvolver síndrome metabólica, um conjunto de condições que afeta cerca de 25% da população mundial. A cirurgia bariátrica, além de resultar na perda significativa de peso, é comprovadamente responsável pela remissão de doenças relacionadas com a obesidade, como a síndrome metabólica. O nosso objetivo, neste estudo, é avaliar a qualidade de vida pós-operatória e sua associação com a síndrome metabólica. Métodos: Numa unidade especializada em cirurgia bariátrica, 454 pacientes foram recrutados durante as consultas de acompanhamento pós-operatório entre Agosto e Novembro de 2022 e responderam ao questionário "Moorehead-Ardelt II" para avaliação da qualidade de vida (QoL). Os dados dos pacientes foram obtidos através de registos eletrónicos. A presença de síndrome metabólica foi definida de acordo com os critérios modificados da International Diabetes Federation. Resultados: A qualidade de vida pós-operatória foi significativamente melhor nos pacientes metabolicamente saudáveis no momento da avaliação (p=0,016). Em pacientes metabolicamente doentes no pré-operatório, QoL é melhor no subgrupo que sofreu melhoria do seu estado metabólico e com ≥3 anos de seguimento (p=0,029). O subgrupo de acompanhamento a longo prazo (≥3 anos) apresenta consistentemente melhores resultados de QoL em todos os fatores avaliados. Conclusão: A presença de síndrome metabólica após a cirurgia metabólica parece estar relacionada com pior qualidade de vida. A alteração do estado metabólico tem um efeito tardio na qualidade de vida, com o aparecimento de benefícios após 3 anos de acompanhamento. A síndrome metabólica é o principal determinante da qualidade de vida, principalmente quando analisados tempos de seguimento mais longos. Purpose: Obesity is a major health problem, affecting over 800 million adults worldwide. It is a major risk factor for developing metabolic syndrome, a cluster of conditions that affect about 25% of the world population. Bariatric surgery, besides significant weight loss, has provenly been responsible for the remission of obesity-related diseases, such as metabolic syndrome. Our aim is to evaluate postoperative quality of life and its association with metabolic syndrome. Methods: In a specialized bariatric unit, 454 patients were recruited during postoperative follow-up appointments between August and November of 2022 and answered the "Moorehead-Ardelt II questionnaire" for evaluation of quality of life (QoL). Patient's data were retrieved retrospectively, using patient's electronic records. The presence of metabolic syndrome was defined according to the International Diabetes Federation modified criteria. Results: Postoperative QoL was significantly better in the metabolically healthy patients at the time the assessment occurred (p=0,016). Within pre-operative metabolically unhealthy patients, QoL is better in the subgroup that suffered changes in their metabolic status and has ≥3 years of follow-up (p=0,029). The long-term follow-up subgroup (≥3 years) has consistently better results in the QoL score in every factor evaluated. Conclusion: Having metabolic syndrome after undergoing metabolic surgery appears to be related to worse quality of life. Change in metabolic status has a delayed effect on quality of life, with benefits appearing after 3 years of follow-up. Metabolic syndrome is a main determinant of quality of life, especially when analyzing longer follow-up times.

© 2022 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND), Purpose: Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance. Experimental design: We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab. Results: In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab. Conclusions: Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC., M. Martins' research was supported by Liga Portuguesa Contra o Cancro (LPCC): Terry Fox Fundation; Investigador FCT- Fundação para a Ciência e Technologia (IF/00409/2014) and IMM Bridge grant; RC-D research was supported by Fundação para a Ciência e Technologia (SFRH/BD/139138/2018). A. Fernandes was supported by LPCC-IMM BIOBANK; R. Fior was supported by Champalimaud Foundation and L. Costa was supported by Merck Serono.

Purpose:Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance.Experimental Design:We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab.Results:In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab.Conclusions:Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC.

Supplementary Figure from Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer

Supplementary Data from Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer

BackgroundCyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have changed the paradigm of Estrogen-receptor positive (ER+) / human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC) treatment and represent a new standard of care in metastatic setting. Neutropenia is a well-established adverse event associated with CDK4/6i treatment, but the impact of these agents in BC patients’ immune profile is unknown. This study aimed to characterize changes in host circulating immune cell subsets in BC patients undergoing CDK4/6i therapy and investigate how these changes associate with clinical benefit, by assessing progression-free survival (PFS). MethodsA prospective cohort of metastatic ER+/HER2- BC patients treated with CDK4/6i (palbociclib or ribociclib) was included. Baseline and every 12−14-week peripheral blood samples were collected and objective tumor status evaluated by RECIST criteria at the same time points. Cohort was categorized in CDK4/6i therapy non-responders (CDK4/6i NResp, progression < 6.0 months) and responders (CDK4/6i Resp, PFS ≥6.0 months) using primary resistance to endocrine therapy definition of metastatic BC. A total of 66 different immune populations were assessed by flow cytometry, mainly: B cells, natural killer T (NKT), natural killer (NK), effector (Eff; CD4+, CD8+ and γδ T), effector memory (EM; CD4+, CD8+ and γδ T), central memory (CM; CD4+, CD8+ and γδ T) and naive (CD4+, CD8+ and γδ T), and regulatory T (Treg subtypes I, II and III) cells. Statistical analysis of longitudinal data was performed using Linear Mixed Effects models (LME) and Generalized estimation equations models (GEE) in R (version 3.6.1) and RStudio (version 1.2.5019). Models allowed to estimate and compare variation rates of each cell population in time. ResultsA total of 26 patients were included, with a median age of 58 years (min-max, 27−79). All patients received letrozole or fulvestrant, together with LHRH agonist if premenopausal. Fifteen patients received palbociclib and 11 ribociclib, with 17 (65.4%) and 9 (34.6%) patients treated in 1st and 2nd line, respectively.With a median follow-up of 17.18 months (CI 95% 12.84 - 21.52), 6 (23.1%) patients were CDK4/6i NResp, with a median PFS (mPFS) of 3.61 months (IQR 2.28 - 4.42); only two patients in 1st line setting had PFS Citation Format: Soraia Lobo-Martins, Patrícia Corredeira, Patrícia Borges Alves, Marília Antunes, Ângela Rodrigues, António Quintela, André Mansinho, Pedro Filipe, Leonor Ribeiro, Rita Teixeira de Sousa, Conceição Pinto, Catarina Abreu, Gisela Gordino, Julie Ribot, Karine Serre, Marta Martins, Ana Cavaco, Sandra Casimiro, Bruno Silva-Santos, Luís Costa. Immune cell populations in peripheral blood of metastatic breast cancer patients under CDK4/6 inhibitors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-37.

© The Author(s) 2021. 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/., Colorectal cancer (CRC) is one of the most lethal malignancies. The extreme heterogeneity in survival rate is driving the need for new prognostic biomarkers. Human endogenous retroviruses (hERVs) have been suggested to influence tumor progression, oncogenesis and elicit an immune response. We examined multiple next-generation sequencing (NGS)-derived biomarkers in 114 CRC patients with paired whole-exome and whole-transcriptome sequencing (WES and WTS, respectively). First, we demonstrate that the median expression of hERVs can serve as a potential biomarker for prognosis, relapse, and resistance to chemotherapy in stage II and III CRC. We show that hERV expression and CD8+ tumor-infiltrating T-lymphocytes (TILs) synergistically stratify overall and relapse-free survival (OS and RFS): the median OS of the CD8-/hERV+ subgroup was 29.8 months compared with 37.5 months for other subgroups (HR = 4.4, log-rank P < 0.001). Combing NGS-based biomarkers (hERV/CD8 status) with clinicopathological factors provided a better prediction of patient survival compared to clinicopathological factors alone. Moreover, we explored the association between genomic and transcriptomic features of tumors with high hERV expression and establish this subtype as distinct from previously described consensus molecular subtypes of CRC. Overall, our results underscore a previously unknown role for hERVs in leading to a more aggressive subtype of CRC., The biobanking of CRC from Hospital Santa Maria, Lisbon, Portugal, was supported by a grant from the Official Portuguese Funding Agency for Science and Technology (FCT: PIC/IC/82821/2007).

This article reviews the epidemiology and treatment of bone metastases. Also, it revisits the mechanism of action, indications, benefits, and complications of antiresorptive agents; discusses the adverse event profile of these agents; and addresses the prevention and management of these side effects.For this review, peer-reviewed articles, research publications, and relevant clinical guidelines identified from PubMed were used.Bone metastases are common in advanced cancer and much more frequently than in primary bone cancer, especially in adults. Bisphosphonates and Denosumab are potent antiresorptives and significantly reduce the risk of skeletal-related events. These complications are related to poor quality of life, bone pain, functional disability, and decreased survival. Prolonged therapy with these antiresorptive agents in patients with advanced malignancy is generally well tolerated, but some side effects are potentially serious and require periodic monitoring. Furthermore, some of them can be avoided.The role of health care providers and specially nurses on identifying patients at risk of complications from these antiresorptive agents, and providing information on how to prevent them, is essential for health and quality of life maintenance in these patients.

This report aims to give a buy recommendation for Harley Davidson, Inc, one of world ́s largest motorcycle manufacturers in the world. This company has been experiencing a setback in the last years, mainly regarding its sales, which suffered the biggest drop in 2020 due to Covid- 19. Currently, Harley is still recovering from the negative period. In the future, we believe the company will improve its situation, not only based on the positive growth rate, but also based on the return we consider it will give to its shareholders. The company faces an intense competitive environment, which forces it to pursue different strategies in order to reach unexploited demographic markets and geographic expansion.

Granulocyte colony-stimulating factor (G-CSF) is increasingly being used to prevent febrile neutropenia associated with chemotherapy. Large-vessel vasculitis (LVV) has been recognized as a rare side effect of G-CSF treatment. We report a case of G-CSF associated LVV in a patient with breast cancer. While clear pathogenic mechanisms remain unknown, G-CSF may cause vasculitis due to inflammatory cytokines production. This adverse reaction should be recognized in patients with suggestive symptoms following the administration of pegfilgrastim. A 56-year-old woman with luminal B breast cancer who had undergone surgery and adjuvant chemotherapy, initially with paclitaxel, was started on a doxorubicin plus cyclophosphamide protocol, followed by supportive use of long-acting G-CSF pegfilgrastim. Following the administration of pegfilgrastim, the patient developed intermittent fever and was given empiric antibiotics in the outpatient setting with no improvement. There were no signs of cancer progression, and the contrast-enhanced CT scan highlighted wall thickening of the aortic arch and the proximal segment of the subclavian artery, which was not present in previous imaging studies. The patient was diagnosed with LVV, and a differential diagnosis was performed to rule out paraneoplastic setting, immune-mediated diseases, infection or other drug-induced vasculitis. Treatment with steroids was initiated and tapered with significant improvement and resolution of the radiological signs of aortitis.

Colorectal cancer (CRC) is one of the most frequent and lethal cancer types worldwide. While surgery with chemotherapy and radiotherapy remains the only curative approach for localized CRC, for metastatic disease the therapeutic landscape has significantly evolved over the last years. Development and approval of novel targeted therapies, such as monoclonal antibodies against EGFR and VEGF, have significantly increased the median survival of patients with metastatic disease, with some trials reporting a benefit over 40 months. Increasing accessibility of high throughput sequencing has unraveled several new therapeutic targets. Actionable alterations, such as HER2 overexpression, BRAF mutations, and NTRK fusions, are currently available in metastatic disease, providing significant therapeutic opportunities for these patients, while new emerging agents, as immune checkpoint inhibitors, promise better treatment options in the near future. In this chapter, an overview of established and future CRC targeted therapies in the clinical setting is provided, as well as their mechanism of action, limitations, and future applicability.

Phyllodes tumor is a rare fibroepithelial tumor of the breast that account for less than 1% of all breast neoplasms [1]. Clinically, it is typically a large, smooth and fast-growing mass that forms from the periductal stroma of the breast [2]. Phyllodes tumor can be considered benign, borderline, or malignant and the percentage of malignant tumors ranges from 23 to 50%. This classification depends on histologic features, as the degree of stromal cellularity and atypia, mitotic count and stromal overgrowth [2]. In this review, we aim to characterize the main clinical and radiological findings of the phyllodes tumors, as well as the anatomopathological findings. We report a case of a huge malignant phyllodes tumor in a 62-year old woman who presented with a large breast mass with 10-month disease evolution time. The patient underwent total mastectomy and the pathology analysis revealed a malignant tumor.

Lemierre Syndrome is a severe complication of an otorhinolaryngologic infection, resulting in septic thrombophlebitis, bacteriemia and septic emboli, most often in young and previously healthy patients. We present a case of a 24-year-old female patient, that develops an episode of syncope and multiorganic dysfunction, two days after the diagnosis of acute tonsillopharyngitis treated with intramuscular penicillin and anti-inflammatory drugs. Due to worsening of the clinical status, a computed tomography was performed and radiological findings were in keeping with Lemierre Syndrome. The continuous worsening of respiratory and cardiovascular dysfunction led to intensive care unit admission where the patient was submitted to extra-corporeal membrane oxygenation support. Despite being a rare entity, Lemierre Syndrome is potentially life-threatening, therefore it should be recognized as soon as possible. Given its unspecific clinical presentation, a high index of suspicion and radiological evaluation with computed tomography are needed to establish the diagnosis.

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Mestrado em Gestão e Estratégia Industrial Com a tecnologia a introduzir-se no dia-a-dia de qualquer empresa e de qualquer consumidor, é imperativo que o mundo digital veio para permanecer. Para acompanhar a presença e o crescimento contínuo da tecnologia, as empresas precisam de se adaptar, os consumidores necessitam de aprender e enquanto hábitos antigos se perdem, novas formas de viver vão surgindo. A presente dissertação foca-se no estudo da utilização de aplicativos bancários (mobile banking apps) por parte dos consumidores em geral. O modelo conceptual proposto para este propósito estuda a influencia de determinadas variáveis no risco percebido do consumidor ao utilizar esta tecnologia, bem como na intenção de continuidade de utilização da mesma. Para a estimação do modelo foram utilizadas 112 respostas válidas obtidas através de um inquérito online. Os resultados obtidos mostram que apenas a satisfação do consumidor apresenta uma influência positiva e significativa na intenção de continuidade de utilização de apps bancárias. O estudo mostrou ainda que variáveis como a utilidade percebida, a confiança e a qualidade apresentam um impacto positivo significativo na satisfação do consumidor. Foi possível verificar ainda que a qualidade percebida por parte do consumidor apresenta uma influência negativa no risco percebido. Ou seja, quanto maior for a qualidade percebida da App menor será a perceção de risco acerca da mesma. Por sua vez, o risco percebido mostrou ter um efeito negativo e significativo na confiança. Por fim, a perceção da facilidade de utilização de uma app bancária impacta positivamente e significativamente a utilidade percebida por parte do consumidor final. With technology being introduced into the daily lives of any company and any consumer, it is imperative that the digital world has arrived to stay. To keep up with the presence and continuous growth of technology, companies need to adapt, consumers need to learn and while old habits are lost, new ways of living are emerging. This dissertation focuses on the study of the use of mobile banking apps by consumers in general. The conceptual model proposed for this purpose studies the influence of certain variables on the perception of perceived risk when using this technology, as well as the continuance intention of using it. To estimate the model, 112 valid responses obtained through an online survey were used. The results obtained show that only user satisfaction has a positive and significant influence on the continuance intention of using mobile banking apps. The study also showed that variables such as the perceived usefulness, trust and perceived quality have a significant positive impact on user satisfaction. It was also possible to verify that the perceived quality of the consumer has a negative influence on the perceived risk. In other words, the higher the perceived quality of the App, the lower the is perceived risk about it. In turn, the perceived risk was shown to have a negative and significant effect on trust. Finally, the perceived ease of use of a mobile banking app positively and significantly impacts the perceived usefulness. info:eu-repo/semantics/publishedVersion

Introduction: The IMPACT study (NTC02164513) showed the clinical benefit of single-inhaler triple therapy (fluticasone furoate [FF]/umeclidinium [UMEC]/vilanterol [VI]) vs dual therapy with FF/VI and UMEC/VI in symptomatic COPD patients at risk of exacerbations. This was also demonstrated in subgroups with either ≥2 moderate or ≥1 severe exacerbation in the prior year (SG1), or Objective: Assess the cost-effectiveness of FF/UMEC/VI vs FF/VI and UMEC/VI by exacerbation history from a Spanish national healthcare system perspective. Methods: A published model of linked risk equations to predict disease progression, costs, and health outcomes was populated with baseline characteristics and treatment efficacy for SG1 and SG2 from the IMPACT study. Direct costs (€2019) and utilities were based on Spanish public sources and literature. A 3% discount rate for costs and treatment effects was used. Outputs included costs, quality-adjusted life years (QALYs) and incremental cost effectiveness ratios (ICER) over 3 years. Results: In SG1, patients receiving FF/UMEC/VI were predicted to gain 0.059 QALYs with an incremental cost of €414 vs FF/VI (ICER=€7,017/QALY) and 0.059 QALYs gain with cost savings of €675 vs UMEC/VI (ICER=Dominant). In SG2, FF/UMEC/VI had a 0.059 QALY gain an incremental cost of €308 vs FF/VI (ICER=€5,259/QALY) and 0.032 QALYs and €252 vs UMEC/VI (ICER=€7,817/QALY). Conclusions: FF/UMEC/VI is a cost-effective treatment option vs. dual therapies for symptomatic COPD at risk of exacerbations in Spain, irrespective of exacerbation history. Funding: GSK HO-17-17596

Hypotonia is a nonspecific sign with many possible underlying aetiologies. The clinical history and neurological examination are vital, providing clues to a methodical and systematic investigation. It is essential to accomplish an early etiological diagnosis to implement adequate therapy (when available), establish prognosis and offer genetic counselling. The authors present two clinical cases that reflect the diagnostic challenge in evaluating a newborn or infant with hypotonia., Portuguese Journal of Pediatrics, Vol. 51 No. 3 (2020)

Relatório de estágio de mestrado em Educação (área de especialização em Mediação Educacional), O presente trabalho insere-se na última etapa do 2º ano do Mestrado em Educação, área de especialização Mediação Educacional da Universidade do Minho. O projeto baseia-se numa investigação-ação e está alicerçado numa diversidade de instrumentos e técnicas de investigação qualitativa a partir de uma análise de necessidades. O presente projeto intitula-se como “Os desafios da mediação numa escola onde reinam as emoções” e tem como a finalidade contribuir para a construção de uma cultura de convivência pacífica dentro e fora do contexto escolar. Com base na análise do disgnóstico de necessidades concebeu-se um plano de ação fracionado em três ações, nomeadamente a criação de um gabinete de mediação, a implementação de programa Ser + e a conceção de uma oficina de alunos mediadores escolares. O objetivo principal do gabinete de mediação foi gerenciar e resolver os conflitos que surgem em um contexto escolar, envolvendo qualquer ator educativo - alunos, professores, assistentes operacionais e pais. No que diz respeito ao programa SER +, destinou-se a três grupos do 2º ciclo, mais precisamente no 6º ano, e visou desenvolver competências socioemocionais fundamentais no bom relacionamento interpessoal. Em relação à Oficina dos Mediadores, pretendeu capacitar os alunos participantes, através de uma formação, de gestão e resolução de conflitos entre pares. Em suma, e realizando uma apreciação final, o seguinte projeto alcançou resultados muito positivos: desenvolvemos e treinamos competências socioemocionais com 64 alunos do 6º ano, capacitamos 15 alunos com ferramentas e técnicas de resolução de conflitos para intervirem no contexto escolar e ajudamos a resolver 11 casos de conflitos escolares. Dos resultados emergem implicações para a mediação educacional em contexto escolar que discutiremos no final deste relatório., The present work is part of the last stage of the 2nd year of the Master's degree in Education, area of specialization in Educational Mediation at the University of Minho. The project is based on action research and on a diversity of qualitative research methods and techniques from a needs’ analysis. This, the present project is titled "The Challenges of mediation in a school where emotions reign" and has as its purpose to contribute to the construction of a culture of peaceful coexistence within and outside the school context. Based on the analysis of the needs, a three-action action plan was conceived, namely the creation of a mediation office, the implementation of a program called "Ser+" and the design of a workshop/club of student mediators School. The main objective of the mediation office was to manage and resolve conflicts that arise in a school context, involving any educational actor - students, teachers, operational assistants and parents. With regard to the SER + program, it was aimed at three groups of the 2nd cycle, more precisely in the 6th year, and aimed to develop fundamental socio-emotional skills in good interpersonal relationships. Regarding the Mediators' Workshop, it intended to train the participating students, through training, management and resolution of conflicts amongst peers. In short, and performing a final appreciation, the following project achieved very positive results: we developed and trained socio-emotional skills with 64 6th graders, we trained 15 students with conflict resolution tools and techniques to intervene in the school context and help to solve 11 cases of school conflicts. From the results implications emerged for educational mediation in the school context that we will discuss at the end of this report.

Phyllodes tumor is a rare fibroepithelial tumor of the breast that account for less than 1% of all breast neoplasms [1]. Clinically, it is typically a large, smooth and fast-growing mass that forms from the periductal stroma of the breast [2]. Phyllodes tumor can be considered benign, borderline, or malignant and the percentage of malignant tumors ranges from 23 to 50%. This classification depends on histologic features, as the degree of stromal cellularity and atypia, mitotic count and stromal overgrowth [3]. We report a case of a huge malignant phyllodes tumor in a 62-year old woman who presented with a large breast mass with 10-month disease evolution time. The patient underwent total mastectomy and the pathology analysis revealed a malignant tumor.

Dissertação de Mestrado em Psicologia Clínica

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)., The fibroblast growth factor (FGF) signaling pathway plays a key role in tumorigenesis and is recognized as a potential therapeutic target. In this study, the authors aimed to assess the impact of serum FGF23 levels in the prognosis of patients with cancer and bone metastases from solid tumors. A cohort of 112 patients with cancer and metastatic bone disease were treated with bone-targeted agents (BTA). Serum baseline FGF23 was quantified by ELISA and dichotomized in FGF23high and FGF23low groups. Additionally, the association between FGF23 and overall survival (OS) and time to skeletal-related events (TTSRE) was investigated. Baseline characteristics were balanced between groups, except for the median urinary N-terminal telopeptide (uNTX) level. After a median follow-up of 26.0 months, a median OS of 34.4 and 12.2 months was found in the FGF23low and FGF23high groups, respectively (multivariate HR 0.18, 95% CI 0.07⁻0.44, p = 0.001; univariate HR 0.27, p = 0.001). Additionally, TTSRE was significantly longer for patients with FGF23low (13.0 vs 2.0 months, p = 0.04). Overall, this study found that patients with FGF23low at baseline had longer OS and TTSRE. Further studies are warranted to define its role as a prognostic biomarker and in the use of drugs targeting the FGF axis., This research received funding from an anonymous non-pharma related individual in the form of donation. This study was supported by project UID/BIM/50005/2019 of Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through State Budget funding.

Background: Receptor activator of NF-kB (RANK) pathway regulates bone remodeling and is involved in breast cancer (BC) progression. RANK over-expression in primary BC associates with poor prognosis and metastasis development. In patients with BC, RANK and RANK-ligand (RANKL) single nucleotide polymorphisms (SNPs) have also been associated with BC risk and bone metastasis (BM)-free survival , respectively. Here we analyze the association of five RANK missense SNPs with prognosis of patients with BM from BC. Methods: Missense RANK SNPs (rs34945627, rs12721431, rs35184120, rs35993683, rs61751992) were genotyped in germline DNA from a retrospective cohort of 76 patients with BM from BC, under bisphosphonates; and a cohort of 80 healthy volunteers (samples from Biobanco-IMM, Lisbon, Portugal). Genotypic allelic frequencies were assessed using TaqMan assays (Applied Biosystems). SNP rs34945627 was analyzed with regard to clinicopathological characteristics, skeletal-related events (SRE), bone progression-free interval (BPFi), and overall survival (OS). Univariate association with clinicopathological characteristics was performed using Fisher's exact test and Wilcoxon rank-sum test; univariate differences between survival rates were tested for significance using the log-rank test, while multivariate analysis for survival was tested using Cox proportional hazards models. Results: SNP rs34945627 had a minor allele frequency of 11.84% (n=9) in BC patients versus 1.25% (n=1) in healthy individuals, whereas the remaining SNPs had a minor allele frequency of 2.60% (n=2) in BC patients. Therefore, for inferential analysis only SNP rs34945627 was considered. No differences between alleles were observed regarding clinicopathological characteristics, including treatment. Homozygous patients (CC) had increased OS when compared to heterozygous patients (CT) controlling for age at diagnosis, visceral involvement, radiographic pattern of BM and baseline urine NTX (adjusted HR 5.76, 95% CI 2.10-15.81; p Conclusions: RANK SNP rs34945627 seems to be a marker of poor prognosis in patients with BC and BM. Further studies are required to characterize the biological and clinical significance of this finding. Citation Format: Casimiro S, Ferreira A, Alho I, Melo M, Brás R, Costa AL, Sousa AR, Mansinho A, Abreu C, Pulido C, Macedo D, Pacheco TR, Costa L. The prognostic role of RANK single nucleotide polymorphisms in breast cancer patients with bone metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-06.

BACKGROUND:Changes in health care delivery create opportunities to improve systems to better meet the needs of low-income families while achieving quality benchmarks.METHODS:Families of healthy newborns receiving primary care at a single large urban safety-net hospital participated. Intervention families were randomly assigned a family specialist who provided support until the 6-month routine health care visit. The Developmental Understanding and Legal Collaboration for Everyone (DULCE) intervention is based on the Strengthening Families approach and incorporated components of the Healthy Steps and Medical-Legal Partnership models. Medical record reviews determined use of preventive and emergency care. Surveys conducted at baseline, postintervention (6 months), and follow-up (12 months) were used to determine hardship and attainment of concrete supports.RESULTS:Three hundred thirty families participated in the study. At baseline, 73% of families reported economic hardships. Intervention parents had an average of 14 contacts with the family specialist, and 5 hours of total contact time. Intervention infants were more likely to have completed their 6-month immunization schedule by age 7 months (77% vs 63%, P < .005) and by 8 months (88% vs 77%, P < .01). Intervention infants were more likely to have 5 or more routine preventive care visits by age 1 year (78% vs 67%, P < .01) and were less likely to have visited the emergency department by age 6 months (37% vs 49.7%, P < .03). The DULCE intervention accelerated access to concrete resources (P = .029).CONCLUSIONS:Assignment to the Project DULCE intervention led to improvements in preventive health care delivery and utilization and accelerated access to concrete supports among low-income families.

YB-1 (Y-box binding protein 1) is a multifunctional cold-shock protein that has been implicated in all hallmarks of cancer. Elevated YB-1 protein level was associated with poor prognosis in several types of cancers, including breast cancer (BC), where it is a marker of decreased overall survival (OS) and distant metastasis-free survival across all subtypes. YB-1 is also secreted by different cell types and may act as an extracellular mitogen; however the pathological implications of the secreted form of YB-1 (sYB-1) are unknown. Our purpose was to retrospectively evaluate the association between YB-1 measured by ELISA in serum and disease characteristics and outcomes in patients with BC and bone metastases (BM). In our cohort, sYB-1 was detected in the serum of 22 (50%) patients, and was associated with the presence of extra-bone metastases (p=0.044). Positive sYB-1 was also associated with faster bone disease progression (HR 3.1, 95% CI 1.09-8.95, P=0.033), but no significant differences were observed concerning OS, and time to development of skeletal-related events. Moreover, patients with positive sYB-1 also had higher levels of IL-6, a known osteoclastogenic inducer. Therefore, detection of sYB-1 in patients with BC and BM may indicate a higher tumor burden, in bone and extra-bone locations, and is a biomarker of faster bone disease progression.

Dissertação de Mestrado em Ensino do 1º e 2º Ciclos do Ensino Básico O presente Relatório de Estágio, imprescindível para a obtenção do grau de Mestre em Ensino do 1º e 2º Ciclos do Ensino Básico, teve por base o estágio pedagógico realizado na Escola Básica dos 2º e 3º ciclos, Diogo Cão, em Vila Real. Este retrata a prática letiva realizada no ensino das Ciências da Natureza numa turma de 6º ano de escolaridade. A turma em que se baseia este estudo é constituída por 19 alunos com idades compreendidas entre os 10 e 12 anos de idade. É uma turma com capacidades cognitivas e ritmos de aprendizagem lentos. Pretende-se com este trabalho refletir sobre a importância do ensino das ciências para o desenvolvimento pessoal, social e profissional dos alunos. Uma vez, que temos de adquirir a capacidade de entender a ciência e de desenvolver formas de pensar que nos permitam adaptar à contínua evolução do mundo, atuando de forma autónoma e crítica. É a ciência que nos permite adquirir os conhecimentos que nos ajudarão a resolver os problemas da nossa sociedade. Neste estudo irão ser defendidas propostas metodológicas epistemologicamente fundamentadas em quadros construtivistas como alternativas válidas a práticas de ensino das ciências. Apresentamos os vários métodos, estratégias e recursos de ensino-aprendizagem aplicados, tendo sempre em conta o modelo aceite para o ensino das ciências, que se enquadra numa perspetiva construtivista de ensino-aprendizagem, fundamentando teoricamente as opções didáticas adotadas. Incluímos também todas as planificações sobre os temas lecionados, cuja elaboração resulta dos pressupostos teóricos do construtivismo e tendo sempre em conta os benefícios dos métodos, estratégias e recursos descritos. This dissertation, compulsory to obtain the Master’s Degree in Elementary Teaching, is based on the teacher training held at the elementary school Diogo Cão, in Vila Real. It deals with the teaching Sciences practice to a sixth grade class. This class was formed by 19 students ranging from 10 to 12 years old. They presented low cognitive skills and a slow learning pace. It intends to reflect on the importance of teaching Sciences in students’ personal, social and professional development, since we all should acquire the ability to grasp science and to develop ways of thinking which allow us to adapt to the ongoing world evolution, and also to act autonomously and critically on it. Science provides us with the knowledge to solve society problems. This paper will defend method proposals epistemologically sustained in constructivist teaching frames as valid alternatives to teaching Sciences techniques. The various teaching methods, strategies and resources used are always laid on the widely accepted model of teaching Sciences, which is framed by the teaching and learning constructivist perspective. All the taught content planning is also included. This planning was done having the theoretical constructive presuppositions in mind, as well as the method benefits, and the described strategies and resources.

Copyright © 2015 Ana Lúcia Costa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Chemotherapy-induced nausea and vomiting (CINV) is still a common and debilitating side effect despite recent advances in its prevention and treatment. The intrinsic emetogenicity of chemotherapy agents allowed grouping into four risk groups (high, moderate, low, and minimal risk of emetogenicity). The prevention of acute and delayed CINV for intravenous agents and one day regimens is well studied, although, there are few data about management of CINV induced by oral cytotoxic agents and targeted therapies, usually administered in extended regimens of daily oral use. Until now treatment of nausea and vomiting caused by oral antineoplastic agents remains largely empirical. The level of evidence of prophylactic antiemetics recommended for these agents is low. There are differences in the classification of emetogenic potential of oral antineoplastic agents between the international guidelines and different recommendations for prophylactic antiemetic regimens. Herein we review the evidence for antiemetic regimens for the most used oral antineoplastic agents for solid tumors and propose antiemetic regimens for high to moderate risk and low to minimal risk of emetogenicity.

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