Mechanical ventilation for the treatment of severe excessive dynamic airway collapse

[Excerpt] We read with interest the case report by Ismael et al1 describing a patient with Sjo¨gren’s syndrome and cystic lung disease who could not be weaned from a ventilator due to severe central excessive dynamic airway collapse (EDAC) of the lower part of the trachea and proximal bronchi. EDAC corresponds to the expiratory bulging of the tracheobronchial wall without known airway structural abnormalities, leading to a decrease of at least 50% in internal diameter.2 It is a rare and underdiagnosed entity, commonly confused with other respiratory diseases such as asthma and COPD. Although noninvasive procedures such as cervicothoracic computed tomography scan on inspiration and expiration may suggest the disorder, the accepted standard method for diagnosis is bronchoscopy.3-7 (...).(undefined

Desempenho termo-energético de edifícios residenciais em clima temperado

This study sought to link architectural and thermal aspects of buildings to contribute to the design practice by providing an information set related to issues of comfort and energy consumption, obtained through a methodological process involving an experimental component (involving summer and winter monitoring in residential buildings in Lisbon where over 60% of the main façade is glazed) and a numerical component (thermal simulations with the use of the EnergyPlus dynamic program, with modeling and calibration of representative geometric models of frequent typologies). This, therefore, allowed the observation of different parameters, enabling the establishment of performance comparisons between a broad spectrum of solutions (Matrix of current solutions) under a typical Mediterranean climate like that of the city of Lisbon. Thus, this study presents a set of results that demonstrates the potential for designing and constructing buildings with different (in particular large) areas of glazing in temperate climates.O presente estudo procura interligar aspectos da Arquitetura e da Térmica dos Edifícios visando contribuir para a prática de projeto disponibilizando um conjunto de informações relacionadas com as questões de conforto e consumo de energia, obtidas a partir de um processo metodológico fundamentado numa componente experimental (medições in loco de Verão e Inverno, sobretudo em unidades de edifícios residenciais em Lisboa com áreas de envidraçados superiores a 60% da fachada principal) e numa componente numérica (simulações térmicas recorrendo ao programa dinâmico EnergyPlus, num processo que envolveu modelação e calibração de modelos geométricos representativos de tipologias frequentes); o que permitiu a observação de diferentes parâmetros com possibilidade de comparar o desempenho entre um espectro alargado de soluções correntes (Matriz de soluções) sob um clima tipicamente mediterrâneo como o da cidade de Lisboa. Desta forma, sendo assim apresentado um conjunto de resultados que comprovam a possibilidade de se projetar e construir edifícios residenciais com diferentes áreas de envidraçados, principalmente com grandes proporções, em Clima Temperado.Este estudio trata de vincular los aspectos de la Arquitectura y la Térmica de los edificios para contribuir a la práctica de diseño que proporcionan un conjunto de información relacionada a las cuestiones de comodidad y el consumo de energía.  Obtenido en un proceso metodológico basado en un componente experimental (realización de monitoreo de verano e invierno en edificios residenciales en Lisboa con superficie acristalada superior al 60% de la fachada principal) y un componente numérico (simulaciones térmicas que utilizan el programa dinámico EnergyPlus en un proceso que involucró la modelación y calibración de modelos geométricos representativos de tipologías frecuentes). Esto permitió la observación de diferentes parámetros con la posibilidad de comparar el rendimiento en un amplio espectro de soluciones actuales (soluciones Matriz) bajo un clima típicamente mediterráneo, como el de la ciudad de Lisboa. De esta manera, se presenta un conjunto de resultados que demuestran la capacidad de diseñar y construir edificios de viviendas con diferentes áreas de vidrio, especialmente de grandes proporciones, en Clima Templado

Comprehensive assessment of environmental fungus-reactive T cells response in hypersensitivity pneumonitis patients

Hypersensitivity pneumonitis (HP) is an interstitial lung disease that results in parenchymal and small airways inflammation and culminates in breathlessness, negatively impacting patient’s quality of life and survival. HP is initiated by an exaggerated immune response triggered by the inhalation of a variety of environmental antigens. The identification of the triggering antigen is a cornerstone of the diagnostic algorithm, and importantly, exposure avoidance ameliorates the clinical outcomes. However, the inciting antigen is not identified in a large proportion of patients. A difficult to identify, but common inciting antigen, is exposure to household fungi.info:eu-repo/semantics/publishedVersio

Unveiling common molecular pathways linked to ILDs with progressive fibrosing phenotype: the role of MUC5B

Progressive fibrosing ILDs (PF-ILDs) comprise a heterogeneous group of lung disorders associated with high morbidity and mortality, that exhibit a continuous worsening phenotype despite standard treatment. Among PF-ILDs are pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (HP), involving complex interactions between host genetics and different environmental triggers, shaping the immune milieu that ultimately drives the fibrotic cascade in a susceptible patient. The MUC5B promoter variant rs35705950 is the common genetic variant associated with the greatest risk of developing IPF. As IPF and fibrotic HP present phenotypic resemblances, we aim to analyze the role of rs35705950 MUC5B single nucleotide polymorphism (SNP) in common molecular pathways linked to PF-ILDs. Herein, taking advantage of our extensive ILD patients’ cohort, we found that MUC5B rs35705950 GT and TT genotypes frequency was dramatically increased in IPF and fibrotic HP compared to healthy controls.info:eu-repo/semantics/publishedVersio

Resistance profile of osimertinib in pre-treated patients with EGFR T790M-mutated non-small cell lung cancer

Background: Osimertinib efficacy in pre-treated patients with epidermal growth factor receptor (EGFR) T790M-mutated non-small cell lung cancer (NSCLC) has been demonstrated in clinical trials, but real-world data, particularly regarding resistance profile, remains limited. This study aims to analyze the resistance mechanisms acquired after treatment with Osimertinib. Methods: Clinical outcomes and molecular results from re-biopsies at the time of osimertinib progression of EGFR T790M-mutated NSCLC patient were analyzed. Results: Twenty-one patients with stage IV adenocarcinoma were included [median 69 years; 57.1% female; 85.7% never-smokers; 23.8% ECOG performance status (PS) >= 2]. Median PFS and OS were 13.4 (95% CI: 8.0-18.9) and 26.4 (95% IC: 8.9-43.8) months, respectively. At the time of analysis, 10 patients had tumor progression (47.6%). T790M loss occurred in 50%, being associated with earlier progression (median PFS 8.1 vs. 21.4 months, p = 0.011). Diverse molecular alterations were identified, including C797S mutation (n = 1), PIK3CA mutation (n = 2), MET amplification (n = 1), CTNNB1 mutation (n = 1), and DCTN1-ALK fusion (n = 1). Histological transformation into small cell carcinoma occurred in one patient. Conclusions: This real-world life study highlights the relevance of re-biopsy at the time of disease progression, contributing to understand resistance mechanisms and to guide treatment strategies

Identificação de variantes moleculares do humano e patogénio associados à heterogeneidade da tuberculose

Tese de Doutoramento em MedicinaTuberculosis (TB) imposes high human and economic tolls. One of the most striking features of TB is the variability of infection outcomes, which has been classically attributed to environmental and host determinants. More recently, studies uncovering Mycobacterium tuberculosis complex (MTBC) genomic diversity have shown the potential importance of pathogen-related factors to the disease pathogenesis. We approached this question from different angles, by combining the study of the pathogen properties, the host immune response and the clinical features of TB, within a cohort of 681 culture-confirmed pulmonary TB (PTB) cases diagnosed at the Hospital de São João, a major healthcare center in Porto, Portugal, between 2007 and 2013. We started by developing a severity assessment tool for stratifying mortality risk in PTB patients. Five risk features were selected for the prediction model: hypoxemic respiratory failure (OR 4.7, 95% CI 2.8-7.9), age ≥50 years (OR 2.9, 95% CI 1.7-4.8), bilateral lung involvement (OR 2.5, 95% CI 1.4-4.4), ≥1 significant comorbidity – HIV infection, diabetes mellitus, liver failure or cirrhosis, congestive heart failure and chronic respiratory disease – (OR 2.3, 95% CI 1.3- 3.8), and hemoglobin <12 g/dL (OR 1.8, 95% CI 1.1-3.1). A TB risk assessment tool (TReAT) was developed, stratifying patients with low (score ≤2), moderate (score 3-5) and high (score ≥6) mortality risk. The mortality associated with each group was 2.9%, 22.9% and 53.9%, respectively. The model performed equally well in the validation cohort. After focusing on the host clinical prognostic predictors, in the second part of the project we assessed the impact of M. tuberculosis diversity on the disease clinical severity. We started by developing a clinical decision tree to classify the severity of the disease and by applying it to a selected group of 133 individuals that in our cohort did not present known predictor or precipitator TB factors. We found that, for this group of patients, no association existed between the severity of disease and the phylogeny of the infecting bacteria. We also found that M. tuberculosis isolates from patients with mild disease grew significantly slower, while strains associated to moderate outcome had a longer lag phase and reached the highest plateau, after a steep exponential phase. To gain in-depth knowledge of the genetic basis for differential mycobacterial growth, we performed whole genome sequencing analysis. We detected several single nucleotide polymorphisms (SNPs) in genes that were previously associated with growth suppression and identified novel gene candidates involved in membrane transport and biosynthetic pathways. Finally, in the third part of this work, we studied the architecture of the immune response triggered by the different isolates of M. tuberculosis. Sixteen clinical isolates associated with different clinical severity of TB were selected and used to infect peripheral blood mononuclear cells (PBMCs) from nontreated/ non-recent latent TB infected (LTBI) donors or past/cured TB patients. Independently of the host genetics, we identified two distinct groups of M. tuberculosis isolates: high versus low inflammatory triggers. Furthermore, we report that PBMCs from past TB patients produced less IL-1β than those from LTBI participants in response to a variety of isolates, whereas the opposite was observed for IL-1RA. LTBI subjects elicited responses with significantly higher IL- 1β/IL-1RA ratios than those from TB patients, thus suggesting this ratio as a discriminator of risk for latent to active TB progression. Overall, we provide a new clinical prediction rule for the risk of death in TB patients and propose a new classification tree for TB severity. On the pathogen side, we unveiled the differential growth of clinical isolates associated with moderate outcomes of TB as a distinctive feature. On the host side, we suggest the ratio IL-1β/IL-1RA as a possible biomarker of disease resistance versus susceptibility to TB. Our findings present new platforms for active and latent TB management and open new avenues for basic research, to unveil host and pathogen determinants of TB outcomes.A tuberculose (TB) continua a impor elevados custos económicos e humanos. Uma das características mais notáveis da TB é a variabilidade de resultados da infeção, que tem sido classicamente atribuída a determinantes ambientais e do hospedeiro. Trabalhos mais recentes estudaram a diversidade genómica do Mycobacterium tuberculosis complex (MTBC) e revelaram o potencial impacto dos fatores da bactéria na patogénese da TB. Esta questão foi abordada por diferentes ângulos, combinando o estudo das propriedades do patogénio, a resposta imune do hospedeiro e as características clínicas de TB, a partir de uma coorte de 681 casos de TB pulmonar confirmados por cultura, diagnosticados no Hospital de São João, um centro clínico de excelência do Porto, Portugal, entre 2007 e 2013. Começámos por desenvolver uma ferramenta de avaliação de gravidade clínica para estratificar o risco de mortalidade de doentes com TB pulmonar. Cinco fatores de risco foram selecionados para o modelo de predição: insuficiência respiratória hipoxémica (OR 4.7, 95% CI 2.8-7.9), idade ≥50 anos (OR 2.9, 95% CI 1.7-4.8), envolvimento pulmonar bilateral (OR 2.5, 95% CI 1.4-4.4), ≥1 comorbilidade significativa – infeção HIV, diabetes mellitus, insuficiência hepática ou cirrose, insuficiência cardíaca congestiva e doença respiratória crónica – (OR 2.3, 95% CI 1.3-3.8), e hemoglobina <12 g/dL (OR 1.8, 95% CI 1.1-3.1). Desenvolveu-se a tuberculosis risk assessment tool (TReAT), estratificando doentes com baixo (pontuação ≤2), moderado (pontuação 3-5) e alto (pontuação ≥6) risco de mortalidade. A mortalidade em cada grupo foi de 2.9%, 22.9% e 53.9%, respetivamente. O modelo manteve um bom desempenho na coorte de validação. Após nos termos focado nos preditores clínicos de prognóstico do hospedeiro, na segunda parte do projeto quisemos analisar o impacto da diversidade de M. tuberculosis na gravidade da doença. Desenvolvemos uma árvore de decisão clínica para classificar a gravidade da doença e aplicámo-la a um grupo selecionado de 133 doentes que na nossa coorte não apresentavam fatores preditores ou precipitantes conhecidos de TB. Neste grupo não se verificou uma associação entre a gravidade clínica e a filogenia da bactéria infetante. Porém, mostrámos que os isolados de M. tuberculosis de indivíduos com doença ligeira crescem de forma significativamente mais lenta, enquanto que as estirpes associadas com TB moderada apresentam uma fase lag mais longa e atingem um patamar mais elevado, após uma fase uma íngreme fase exponencial. Para conhecer em detalhe as bases genéticas do crescimento micobacteriano, realizámos uma análise de sequenciação genómica. Detetaram-se diversos single nucleotide polymorphisms (SNPs) em genes que previamente tinham sido associados com a supressão de crescimento e identificámos novos genes candidatos envolvidos no transporte de membrana e em vias biossintéticas. Finalmente, na terceira parte do trabalho, estudámos a arquitetura da resposta imune desencadeada por diferentes estirpes de M. tuberculosis. Dezasseis isolados clínicos associados a diferentes gravidades clínicas de TB foram selecionados e usados para infetar células mononucleares do sangue periférico (PBMCs) de dadores com infeção latente não recente e não tratada ou de doentes com TB passada/curada. Independentemente da genética do hospedeiro, identificámos dois grupos distintos de isolados de M. tuberculosis muito e pouco inflamatórias. Além disso, mostrámos que PBMCs de doentes com TB passada produzem menos IL-1β em resposta a uma variedade de isolados, enquanto o oposto se verificou para IL-1RA. Dadores com infeção latente apresentaram respostas com razão IL-1β/IL-1RA significativamente mais elevada. Em suma, propomos uma nova regra de predição clínica para o risco de mortalidade por TB e uma nova árvore de classificação de gravidade da doença. Na vertente do patogénio, desvendámos um perfil de crescimento distinto dos isolados clínicos associados com TB moderada. Na vertente do hospedeiro, os nossos resultados sugerem que a razão IL-1β/IL-1RA poderá ser um biomarcador de resistência versus suscetibilidade para TB. Estes dados fornecem novas plataformas para a investigação básica dos determinantes do hospedeiro e patogénio na heterogeneidade da TB.The work presented in this dissertation was performed in the Microbiology and Infection Research Domain of the Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal (ICVS/3B’s – PT Government Associate Laboratory, Braga/Guimarães, Portugal); in Centro Hospitalar São João, Porto, Portugal; and at the Institute for Molecular and Cell Biology (IBMC), University of Porto, Portugal. The financial support was provided by Fundação Amélia de Mello/José de Mello Saúde, Sociedade Portuguesa de Pneumologia (SPP) and by a Research Grant from the European Society for Clinical and Infectious Diseases (ESCMID). The study was cofunded by Programa Operacional Regional do Norte (ON.2 – O Novo Norte), Quadro de Referência Estratégico Nacional (QREN), through the Fundo Europeu de Desenvolvimento Regional (FEDER)

Desempenho termo-energético de edifícios residenciais em clima temperado

Este estudio trata de vincular los aspectos de la Arquitectura y la Térmica de los edificios para contribuir a la práctica de diseño que proporcionan un conjunto de información relacionada a las cuestiones de comodidad y el consumo de energía.  Obtenido en un proceso metodológico basado en un componente experimental (realización de monitoreo de verano e invierno en edificios residenciales en Lisboa con superficie acristalada superior al 60% de la fachada principal) y un componente numérico (simulaciones térmicas que utilizan el programa dinámico EnergyPlus en un proceso que involucró la modelación y calibración de modelos geométricos representativos de tipologías frecuentes). Esto permitió la observación de diferentes parámetros con la posibilidad de comparar el rendimiento en un amplio espectro de soluciones actuales (soluciones Matriz) bajo un clima típicamente mediterráneo, como el de la ciudad de Lisboa. De esta manera, se presenta un conjunto de resultados que demuestran la capacidad de diseñar y construir edificios de viviendas con diferentes áreas de vidrio, especialmente de grandes proporciones, en Clima Templado

Pneumonia intersticial descamativa em doente com conectividade indiferenciada

Descamative interstitial Pneumonia in a patient with undifferentiated connective tissue diseaseHomem caucasiano de 49 anos de idade, fumador (15 UMA), com quadro clínico inicial de poliartrite simétrica e aditiva, envolvendo predominantemente as pequenas articulações das mãos, punhos, ombros e tíbio-társicas. O estudo auto-imune revelou positividade para ANA e anticorpo anti-proteína P ribosómica. Foi diagnosticada conectivite indiferenciada e iniciou terapêutica com deflazacorte, naproxeno e hidroxicloroquina. Dois anos após, iniciou dispneia para grandes esforços, sem outros sintomas associados. Realizou tomografia computadorizada torácica de alta resolução, evidenciando zonas difusas com padrão em «vidro despolido». No estudo funcionalrespiratório foi constatado dé- fice da capacidade de difusão. O lavado broncoalveolar (LBA) revelou uma alveolite neutrofílica e eosinofílica (20%), não tendo no entanto sido observada eosinofilia do sangue periférico. O diagnóstico definitivo foi obtido através de biopsia pulmonar cirúrgica, que revelou alterações compatíveis com Pneumonia IntersticialDescamativa (PID). Esta entidade é rara e é referida como uma doença relacionada com o consumo tabágico. Discute-se a eventual associação da PID com as doenças auto-imunes e a eosinofilia no LBA como uma característica de alguns casos com este diagnóstico.A 49 year-old Caucasian male, smoker (15 pack-year), had at the beginning of his disease an additive, symmetric polyarthritis, affecting predominantly the small joints of the hands, wrists, shoulders and tibiotarsal joints. The autoimmune study revealed ANA and anti-ribosomal P protein antibodies positivity. An undifferentiated connective tissue disease was diagnosed and treatment with deflazacort, naproxen and hydroxychloroquine was begun. Two years later, he starts exertional dyspnea, without other respiratory symptoms. A chest high-resolution computerized tomography scan was performed, evidencing diffuse "ground-glass" opacities. Respiratory functional study showed low diffusion capacity. The bronchoalveolar lavage (BAL) revealed a neutrophilic and eosinophilic (20%) alveolitis, which was not associated with peripheral blood eosinophilia. The definitive diagnosis was obtained by a surgical lung biopsy, which showed features consistent with Descamative Interstitial Pneumonia (DIP). This rare entity is referred as a smoke-related disease. The debate about an eventual association of DIP with autoimmune diseases and BAL eosinophilia is discussed by the authors based on the present clinical case features

Cytokine gene polymorphisms in Pigeon Breeder's Disease expression

Background: Exaggerated immunological response to repeated inhalation of organic or chemical dusts may lead to Hypersensitivity Pneumonitis among sensitized individuals. Only a few exposed individuals became ill and disease expression pattern is highly variable which suggest that genetic factors may play a role. Aim: To investigate interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-6, transforming growth factor (TGF)-ß, and IL-10 gene polymorphisms in a cohort of pigeon breeder's disease (PBD) patients in comparison with exposed but healthy controls and the association with different patterns of disease. Methods: We evaluated 40 PBD patients and 70 exposed controls. IFN-γ, TNF-α, IL-6, TGF-ß, and IL-10 polymorphisms were determined by polymerase chain reaction-sequence specific primer amplification. Results: Polymorphism analysis of IFN-γ, TNF-α, IL-6, TGF-ß, and IL-10 genotypes and allele frequencies showed no differences between patients and controls. IFN-γ T/T genotype frequency was increased among patients with chronic presentation (RR=2.33, p=0.047) compared with those with acute/subacute presentation. Also, chronic presenting patients had an increased frequency of IFN-γ T allele (50% vs 22.5%, RR=1.76, p=0.011). No differences were found in TNF-α, IL-6, TGF-ß, and IL-10 genotypes neither allelic frequencies between both groups of patients. IL-6 C/C genotype was more frequent in patients who showed chronic evolution (RR=2.54, p=0.017), when comparing with patients with disease resolution. Conclusion: IFN-γ T/T and the IL-6 C/C genotypes seem to play a role in HP expression due to avian exposure, as their frequencies are increased in chronic presentations or in those with chronic evolution one year after the initial diagnosis, respectively. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (3): e2020004).N. Martins would like to thank the Portuguese Foundation for Science and Technology (FCT-Portugal) for the Strategic project ref. UID/BIM/04293/2013 and “NORTE2020 - Northern Regional Operational Program” (NORTE-01-0145-FEDER-000012) and the Horizon 2020 Program (PTDC/PSI‐GER/28076/2017).info:eu-repo/semantics/publishedVersio

Mortality risk prediction with ILD-GAP index in a fibrotic hypersensitivity pneumonitis cohort

Background: Fibrotic hypersensitivity pneumonitis (fHP) is associated with significant morbidity and mortality. Interstitial lung disease–gender-age-physiology (ILD-GAP) performance in fHP outside the initial cohort was never performed. Aim: To assess the ILD-GAP index’s ability to predict mortality in a Portuguese cohort of patients with fHP and analyse whether other clinical variables add value. Methods: Retrospective analysis of fHP cohort in two Portuguese ILD centres. The baseline ILD-GAP index was calculated. Survival was analysed in months; mortality was the primary outcome. Univariate and multivariate analyses to identify mortality risk factors were performed. Results: A total of 141 patients were included. Fifty-three patients (37.6%) died during the follow-up. The usual interstitial pneumonia (UIP) pattern was found in 49.6%, and their survival was inferior to non-UIP [32 months (interquartile range, IQR = 19, 60) versus 52 months (IQR = 28, 98), p  = 0.048]. Patients with an ILD-GAP index higher than three double their risk of mortality [hazard ratio (HR) = 6.48, 95% confidence interval (CI) = (3.03–13.96)] when compared with the patients with an index between 2 and 3 [HR = 3.04, 95% CI = (1.62–5.71)] adjusting for acute exacerbation history. Even though UIP patients had worse survival, it did not reach statistical significance when UIP pattern was added to this model. Acute exacerbation history was an independent risk factor for mortality; however, ILD-GAP still predicted mortality after adjusting for this factor. PaO 2 and 6-minute walk test desaturation were not significant risk factors. Conclusion: ILD-GAP index is a good predictor for mortality in fHP, even after adjusting for other mortality risk factors