Pentraxin 3 Inhibits Complement-driven Macrophage Activation to Restrain Granuloma Formation in Sarcoidosis.

Rationale: Sarcoidosis is a multisystemic inflammatory disease characterized by the formation of granulomas in response to persistent stimuli. The long pentraxin PTX3 (pentraxin 3) has emerged as a component of humoral innate immunity with essential functions in the resolution of inflammation, but its role during granuloma formation is unknown. Objectives: To evaluate PTX3 as a modulator of pathogenic signals involved in granuloma formation and inflammation in sarcoidosis. Methods: Peripheral blood mononuclear cells obtained from patients with sarcoidosis harboring loss-of-function genetic variants and gene-deleted mice were used to assess the role of PTX3 in experimental models of granuloma formation in vitro and in vivo. The identified mechanisms of granulomatous inflammation were further evaluated in tissue and BAL samples and correlated with the disease course. Measurements and Main Results: We have identified a molecular link between PTX3 deficiency and the pathogenic amplification of complement activation to promote granuloma formation. Mechanistically, PTX3 deficiency licensed the complement component C5a-mediated activation of the metabolic checkpoint kinase mTORC1 (mammalian target of rapamycin complex 1) and the reprogramming of macrophages toward increased glycolysis to foster their proliferation and aggregation. This process sustained the further recruitment of granuloma-promoting immune cells and the associated proinflammatory microenvironment and influenced the clinical course of the disease. Conclusions: Our results identify PTX3 as a pivotal molecule that regulates complement-mediated signaling cues in macrophages to restrain granulomatous inflammation and highlight the therapeutic potential of this signaling axis in targeting granuloma formation in sarcoidosis.

Modified Glasgow Prognostic Score predicts survival among advanced non-small cell lung carcinoma patients treated with anti-PD1 agents.

Immune checkpoint inhibitors were approved for advanced nonsmall cell lung cancer (NSCLC) treatment. Despite improved survival, not all patients benefit from these agents. Here, the prognostic impact of pretreatment modified Glasgow Prognostic Score (mGPS) and neutrophil-to-lymphocyte ratio (NLR) was assessed. From 77 patients included, 83.2% received at least one prior systemic therapy. Immune-related adverse events (irAE) occurred in 20 patients. A lower mGPS was associated with higher median overall survival (OS), and a lower Eastern Cooperative Oncology Group (ECOG), irAE and fewer metastatic sites with better survival. A trend towards greater OS and progression-free survival (PFS) was stated among patients with NLR <5. mGPS 0 was associated with better survival; ≥3 metastatic sites with worse PFS and OS; ECOG >2 with worse OS and irAE with better survival. Pretreatment mGPS seems to be useful for predicting survival among advanced NSCLC patients treated with anti-programmed cell death 1 drugs, with ECOG performance status, irAE occurrence, and number of metastatic sites acting as survival predictors.

Non-invasive ventilation in the elderly - never too late!

Dear Editor, Practising evidence-based medicine in an ageing population is challenging. Nevertheless, using age as a diagnostic or therapeutic procedure contraindication is less and less common. Domiciliary non-invasive ventilation (NIV) in chronic respiratory failure patients has been largely used; however, data from older people is scarce...

Today's and tomorrow's imaging and circulating biomarkers for pulmonary arterial hypertension.

The pathobiology of pulmonary arterial hypertension (PAH) involves a remodeling process in distal pulmonary arteries, as well as vasoconstriction and in situ thrombosis, leading to an increase in pulmonary vascular resistance, right heart failure and death. Its etiology may be idiopathic, but PAH is also frequently associated with underlying conditions such as connective tissue diseases. During the past decade, more than welcome novel therapies have been developed and are in development, including those increasingly targeting the remodeling process. These therapeutic options modestly increase the patients' long-term survival, now approaching 60% at 5 years. However, non-invasive tools for confirming PAH diagnosis, and assessing disease severity and response to therapy, are tragically lacking and would help to select the best treatment. After exclusion of other causes of pulmonary hypertension, a final diagnosis still relies on right heart catheterization, an invasive technique which cannot be repeated as often as an optimal follow-up might require. Similarly, other techniques and biomarkers used for assessing disease severity and response to treatment generally lack specificity and have significant limitations. In this review, imaging as well as current and future circulating biomarkers for diagnosis, prognosis, and follow-up are discussed.

The state of the art in telerehabilitation for musculoskeletal conditions.

BACKGROUND: Given the rapid advances in communication technology and the need that emerged from the COVID-19 pandemic, telehealth initiatives have been widely used worldwide. This masterclass aims to provide an overview of telerehabilitation for musculoskeletal conditions, synthesizing the different terminologies used to describe telehealth and telerehabilitation, its effectiveness and how to use it in clinical practice, barriers and facilitators for the implementation in health services, and discuss the need of a curriculum education for the near future. MAIN BODY: Telerehabilitation refers to the use of information and communication technologies provided by any healthcare professionals for rehabilitation services. Telerehabilitation is a safe and effective option in the management of musculoskeletal conditions in different models of delivery. There are many technologies, with different costs and benefits, synchronous and asynchronous, that can be used for telerehabilitation: telephone, email, mobile health, messaging, web-based systems and videoconferences applications. To ensure a better practice of telerehabilitation, the clinician should certify safety and access, and appropriateness of environment, communication, technology, assessment, and therapeutic prescription. Despite the positive effect of telerehabilitation in musculoskeletal disorders, a suboptimal telerehabilitation implementation may have happened due to the COVID-19 pandemic, especially in countries where telehealth was not a reality, and clinicians lacked training and guidance. This emphasizes the need to identify the necessary curriculum content to guide future clinicians in their skills and knowledge for telerehabilitation. There are some challenges and barriers that must be carefully accounted for to contribute to a health service that is inclusive and relevant to health professionals and end users. CONCLUSIONS: Telerehabilitation can promote patient engagement in health care and plays an important role in improving health outcomes in patients with musculoskeletal conditions. Digital health technologies can also offer new opportunities to educate patients and facilitate the process of behavior change to a healthy lifestyle. Currently, the main needs in telerehabilitation are the inclusion of it in health curriculums in higher education and the development of cost-effectiveness and implementation trials, especially in low- and middle-income countries where access, investments and digital health literacy are limited.

Plumbagin reverses proliferation and resistance to apoptosis in experimental PAH.

Like cancer, pulmonary arterial hypertension (PAH) is characterised by a pro-proliferative and anti-apoptotic phenotype. In PAH, pulmonary artery smooth muscle cell (PASMC) proliferation is enhanced and apoptosis suppressed. The sustainability of this phenotype requires the activation of pro-survival transcription factors, such as signal transducer and activator of transcription (STAT)3 and nuclear factor of activated T-cells (NFAT). There are no drugs currently available that are able to efficiently and safely inhibit this axis. We hypothesised that plumbagin (PLB), a natural organic compound known to block STAT3 in cancer cells, would reverse experimental pulmonary hypertension. Using human PAH-PASMC, we demonstrated in vitro that PLB inhibits the activation of the STAT3/NFAT axis, increasing the voltage-gated K(+) current bone morphogenetic protein receptor type II (BMPR2), and decreasing intracellular Ca(2+) concentration ([Ca(2+)](i)), rho-associated coiled-coil containing protein kinase (ROCK)1 and interleukin (IL)-6, contributing to the inhibition of PAH-PASMC proliferation and resistance to apoptosis (proliferating cell nuclear antigen (PCNA), TUNEL, Ki67 and anexine V). In vivo, PLB oral administration decreases distal pulmonary artery remodelling, mean pulmonary artery pressure and right ventricular hypertrophy without affecting systemic circulation in both monocrotaline- and suden/chronic hypoxia-induced PAH in rats. This study demonstrates that the STAT3/NFAT axis can be therapeutically targeted by PLB in human PAH-PASMC and experimental PAH rat models. Thus, PLB could be considered a specific and attractive future therapeutic strategy for PAH.

Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and suppressed apoptosis. This phenotype is sustained by the activation of the Src/signal transducer and activator of transcription 3 (STAT3) axis, maintained by a positive feedback loop involving miR-204 and followed by an aberrant expression/activation of its downstream targets such as Pim1 and nuclear factor of activated T-cells (NFATc2). Dehydroepiandrosterone (DHEA) is a steroid hormone shown to reverse vascular remodeling in systemic vessels. Since STAT3 has been described as modulated by DHEA, we hypothesized that DHEA reverses human pulmonary hypertension by inhibiting Src/STAT3 constitutive activation. Using PASMCs isolated from patients with PAH (n = 3), we demonstrated that DHEA decreases both Src and STAT3 activation (Western blot and nuclear translocation assay), resulting in a significant reduction of Pim1, NFATc2 expression/activation (quantitative RT-PCR and Western blot), as well as Survivin and upregulation of bone morphogenetic protein receptor 2 (BMPR2) and miR-204. Src/STAT3 axis inhibition by DHEA is associated with 1) mitochondrial membrane potential (tetramethylrhodamine methyl-ester perchlorate; n = 150; P < 0.05) depolarization increasing apoptosis by 25% (terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling; n = 150; P < 0.05); and 2) decreased intracellular Ca(2+) concentration (fluo-3 AM; n = 150; P < 0.05) and proliferation by 30% (PCNA). Finally, in vivo similarly to STAT3 inhibition DHEA improves experimental PAH (monocrotaline rats) by decreasing mean PA pressure and right ventricle hypertrophy. These effects were associated with the inhibition of Src, STAT3, Pim1, NFATc2, and Survivin and the upregulation of BMPR2 and miR-204. We demonstrated that DHEA reverses pulmonary hypertension in part by inhibiting the Src/STAT3.

Krüppel-like factor 5 contributes to pulmonary artery smooth muscle proliferation and resistance to apoptosis in human pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced proliferation of pulmonary artery smooth muscle cell (PASMC) and suppressed apoptosis. This phenotype has been associated with the upregulation of the oncoprotein survivin promoting mitochondrial membrane potential hyperpolarization (decreasing apoptosis) and the upregulation of growth factor and cytokines like PDGF, IL-6 and vasoactive agent like endothelin-1 (ET-1) promoting PASMC proliferation. Krüppel-like factor 5 (KLF5), is a zinc-finger-type transcription factor implicated in the regulation of cell differentiation, proliferation, migration and apoptosis. Recent studies have demonstrated the implication of KLF5 in tissue remodeling in cardiovascular diseases, such as atherosclerosis, restenosis, and cardiac hypertrophy. Nonetheless, the implication of KLF5 in pulmonary arterial hypertension (PAH) remains unknown. We hypothesized that KLF5 up-regulation in PAH triggers PASMC proliferation and resistance to apoptosis. METHODS AND RESULTS: We showed that KFL5 is upregulated in both human lung biopsies and cultured human PASMC isolated from distal pulmonary arteries from PAH patients compared to controls. Using stimulation experiments, we demonstrated that PDGF, ET-1 and IL-6 trigger KLF-5 activation in control PASMC to a level similar to the one seen in PAH-PASMC. Inhibition of the STAT3 pathway abrogates KLF5 activation in PAH-PASMC. Once activated, KLF5 promotes cyclin B1 upregulation and promotes PASMC proliferation and triggers survivin expression hyperpolarizing mitochondria membrane potential decreasing PASMC ability to undergo apoptosis. CONCLUSION: We demonstrated for the first time that KLF5 is activated in human PAH and implicated in the pro-proliferative and anti-apoptotic phenotype that characterize PAH-PASMC. We believe that our findings will open new avenues of investigation on the role of KLF5 in PAH and might lead to the identification of new therapeutic targets.

Youngsters' perceptions of the experience of pain and utilisation of over-the-counter pain medication as needed in community: A qualitative study.

PURPOSE: Pain is common in youngsters. No matter its nature, youngsters' consideration of pain is complex since its communications vary as a function of several components. The aim of this study is to explore the youngsters' perception linked to their experience of physiological pain at the home/family setting, as well as their experience with the utilisation of over-the-counter pain medication as needed. DESIGN AND METHODS: A qualitative exploratory study was undertaken with 22 youngsters aged 5-17 years old. Semidirected interviews led to the understanding of these components by means of the pain experiences. Thematic analysis allowed the detection of the themes and subthemes emerging from the verbatim collected with the participants. RESULTS: The way pain is described is influenced by the child's development, previous experiences, and the projection of having pain. The pain communication is influenced by the severity perceived, the beliefs of the youngster experiencing pain, the comparison of the pain communication with his brothers and sisters, as well as the anticipated consequences of expressing his pain. The choice of behaviour towards pain is influenced by self-management through nonpharmacological management, with medicines if needed, and by family modelization. PRACTICE IMPLICATIONS: This study confirms that previous pain experiences, beliefs related to pain tolerance and intended reactions of parents exert influence not only on the communication of pain, but also on youngsters' behaviour towards pain. It is important to consider these elements whenever youngsters' pain is evaluated.

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.

Age-related effects of DHEA on peripheral markers of oxidative stress.

Ageing is an inevitable biological process characterized by a general decline in various physiological functions. DHEA and DHEAS levels are maximal between the second and third life decades, then start to decline 2% per year, leaving a residual of 10-20% of the peak production by the eighth decade. Erythrocytes are exposed to frequent oxidative stress due to the oxygen radicals continuously generated by haemoglobin auto-oxidation. We investigated DHEA chronic (10 mg/kg, subcutaneously, for 5 weeks) effects over oxidative stress markers in erythrocytes of male Wistar rats of 3, 13 and 18 month-old. In the 13 month-old group, we found increased lipid peroxidation (LPO), superoxide dismutase (SOD), glutathione-S-transferase and catalase activities when compared to the other age groups. DHEA produced a marked increase in LPO of 13 month-old group when compared to its control. DHEA exerted this pro-oxidant effects in all ages studied, especially in age 13 month-old. It seems that at 13 month-old there would be an important depletion of some specific anti-oxidant in order to determine such susceptibility to DHEA effects. Since this approach allows a minimally invasive assessment, it would be useful as a routine method in human clinical studies investigating DHEA effects during the ageing process.

Invisible work, unseen hazards: The health of women immigrant household service workers in Spain.

BACKGROUND: Household service work has been largely absent from occupational health studies. We examine the occupational hazards and health effects identified by immigrant women household service workers. METHODS: Exploratory, descriptive study of 46 documented and undocumented immigrant women in household services in Spain, using a phenomenological approach. Data were collected between September 2006 and May 2007 through focus groups and semi-structured individual interviews. Data were separated for analysis by documentation status and sorted using a mixed-generation process. In a second phase of analysis, data on psychosocial hazards were organized using the Copenhagen Psychosocial Questionnaire as a guide. RESULTS: Informants reported a number of environmental, ergonomic and psychosocial hazards and corresponding health effects. Psychosocial hazards were especially strongly present in data. Data on reported hazards were similar by documentation status and varied by several emerging categories: whether participants were primarily cleaners or carers and whether they lived in or outside of the homes of their employers. Documentation status was relevant in terms of empowerment and bargaining, but did not appear to influence work tasks or exposure to hazards directly. CONCLUSIONS: Female immigrant household service workers are exposed to a variety of health hazards that could be acted upon by improved legislation, enforcement, and preventive workplace measures, which are discussed.

[Differences in occupational accidents in Spain according to the worker's country of origin]. / Diferencias en los accidentes laborales en España según país de procedencia del trabajador.

OBJECTIVE: Compare the occupational accidents between autochthonous and immigrant workers in Spain. MATERIAL AND METHODS: Data were obtained from the Spanish Survey of Working Conditions. Nationality was considered as an explicative variable, and the country of origin was regrouped according to the Human Development Index-HDI. Occupational accidents were the outcome. Other variables included were sociodemographic and employment conditions. Prevalences were calculated as well as simple and adjusted odds ratio (OR) (logistic regression) with a 95% confidence interval (CI 95%). RESULTS: The prevalence of occupational accidents was 12.7% (women, 11.1%) for workers from low HDI countries and 10.3% (women, 8.1%) for Spaniards. A higher risk of occupational accidents was observed among women from low HDI countries compared to Spaniards (adjusted OR 1.66; 95%CI 1.21-2.28). DISCUSSION: It is necessary to conduct a more thorough causal analysis of occupational accidents among immigrants in order to identify risk factors and strengthen prevention and control strategies.

Adult Congenital Heart Disease Outpatient Clinic. Descriptive Analysis of A 12-Year Experience in Brazil.

OBJECTIVE: Description of adult congenital heart disease (CHD) outpatient characteristics has not been reported and several aspects regarding these patients require attention. We describe the 12-year experience of a Brazilian unit. METHODS: The main characteristics of 1168 patients were reviewed annotating for each patient age, gender, city of residence, main diagnosis, functional class at last examination, defect complexity and in-hospital referral pattern. RESULTS: Increasing workload was documented. Among the CHD patients, 663 (57%) were between 14 and 30 years old and 920 (79%) lived in the referral region. Referrals were made by hospital cardiologists for 611 (52%) patients, while 519 (45%) were referred by pediatric cardiologists. Regarding CHD severity, 637 (55%) had a defect of mild complexity. Of the patients analyzed, 616 (53%) had undergone an intervention, mainly atrial septal defect (ASD) closure, correction of tetralogy of Fallot, ventricular septal defect (VSD) closure and relief of coarctation of the aorta (CoAo). The main diagnosis of the 552 (47%) patients not submitted to an intervention were ASD, VSD, aortic stenosis, complex CHD and pulmonary stenosis. Regarding functional class, 1016 (87%) were in class I and 280 (24%) were lost to follow-up. Seventy-three patients had died, mainly due to cardiac death. CONCLUSION: In a unit were complex pediatric congenital heart surgery started twenty years ago, an increasing adult CHD workload was documented. Referral came predominantly from cities around the unit, most patients had low complexity defects and were in functional class I, a significant loss of follow-up was documented, and the death of patients was mainly due to the heart defect.

[Transcultural adaptation and validation of the Organizational Performance Metric safety culture questionnaire]. / Adaptación transcultural y validación del cuestionario de cultura preventiva Organizational Performance Metric.

OBJECTIVE: Safety positive performance indicators (PPI) reflect key aspects of safety culture; some of them also have predictive validity for occupational injuries. This is the case of the Organizational Performance Metric (OPM), developed by the Canadian Institute for Work & Health (IWH), a short, widely validated international English language questionnaire. The objective of this study was to obtain a transculturally adapted Spanish language version ofthe OPM, and to analyze its statistical reliability, validity and internal consistency. METHOD: After a translation and back translation process was performed by an expert panel, 478 questionnaires were completed in Navarra, Spain. We calculated the Cronbach alpha coefficient, bivariate correlations and the intra-class correlation coefficient (ICC) and performed exploratory factorial analysis of all eight items. RESULTS: Data show the new tool has high reliability (Cronbach alpha==0.863) and internal validity (ICC=0.842). The factorial analysis confirmed a single latent factor among the eight items of the questionnaire. CONCLUSIONS: the adapted questionnaire (OPM-Esp) constitutes a valid instrument for use as an indicator of safety performance in Spanish companies. Its brevity and simplicity make it especially useful in the work environment. Its ability to predict occupational injuries should be tested in the Spanish context.

OBJETIVO: Los Indicadores Positivos de Esfuerzo Preventivo (IPEP) reflejan aspectos centrales de la cultura preventiva; existen evidencias respecto a la validez predictiva de algunos de estos respecto a los accidentes de trabajo. Éste es el caso del Organizational Performance Metric (OPM) desarrollado por el Institute for Work & Health (IWH) de Canadá, cuestionario en inglés, corto y ampliamente validado internacionalmente. El objetivo es obtener una versión adaptada transculturalmente de la herramienta OPM, traducida al castellano y analizar su fiabilidad estadística, validez y consistencia interna. MÉTODO: Tras un proceso de traducción y retro traducción con un panel de expertos, se cumplimentaron en Navarra, España, 478 cuestionarios. Se calculó el estadístico alfa de Cronbach, las correlaciones bivariadas, el índice de correlación intraclase (ICC) y un análisis factorial exploratorio a los ocho ítems que lo forman. RESULTADOS: el análisis muestra una alta fiabilidad (alfa de Cronbach=0,863) y validez interna(ICC=0,842) de la herramienta. El análisis factorial confirma un único factor latente entre los ocho ítems del cuestionario. CONCLUSIONES: El cuestionario obtenido (OPM-Esp) constituye un instrumento válido como indicador positivo de esfuerzo preventivo para las empresas españolas. Su reducido tamaño y fácil aplicación lo hacen especialmente útil en el ámbito laboral. Su predictibilidad respecto a los accidentes de trabajo deberá valorarse para el entorno español.

Effects of neonatal handling on social memory, social interaction, and number of oxytocin and vasopressin neurons in rats.

Early-life environmental events can induce profound long-lasting changes in several behavioral and neuroendocrine systems. The neonatal handling procedure, which involves repeated brief maternal separations followed by experimental manipulations, reduces stress responses and sexual behavior in adult rats. The purpose of this study was to analyze the effects of neonatal handling on social behaviors of male and female rats in adulthood, as manifest by the results of social memory and social interaction tests. The number of oxytocin (OT) and vasopressin (VP) neurons in the paraventricular (PVN) and supraoptic (SON) nuclei of hypothalamus were also analyzed. The results did not demonstrate impairment of social memory. Notwithstanding, handling did reduce social investigative interaction and increase aggressive behavior in males, but did not do so in females. Furthermore, in both males and females, handling was linked with reduced number of OT-neurons in the parvocellular region of the PVN, while no differences were detected in the magnocellular PVN or the SON. On the other hand, handled males exhibited increased number of VP-neurons in the magnocellular zone of the PVN. We may conclude that the repeated brief maternal separations can reduce affiliative social behavior in adult male rats. Moreover, the disruption of the mother-infant relationship caused by the handling procedure induced long-lasting morphological changes in critical neuroendocrine areas that are involved in social bonding in mammals.

[Occupational health of immigrant workers in Spain [ITSAL Project]: key informants survey]. / Condiciones de trabajo y salud en inmigrantes (Proyecto ITSAL): entrevistas a informantes clave.

OBJECTIVE: To describe the characteristics, working conditions, and occupational health situation of immigrant workers in Spain through key informants. METHOD: We performed a qualitative, exploratory and descriptive study using indepth interviews carried out in 2006. Organizations and associations working with immigrant collectives in Alicante, Barcelona, Huelva, Madrid and Valencia were identified and the most representative and accessible entities in each location were selected. Fortythree interviews were performed with key informants from 34 different organisms. A narrative content analysis was performed. RESULTS: Informants described difficulties in having health problems recognized as workrelated, due to irregular and precarious employment, employers' and insurance companies' reluctance, and immigrants' lack of knowledge. Informants coincided in reporting that the occupational risks for immigrant workers did not differ from those affecting Spanish workers in the same occupations and circumstances. However, exposure to occupational risks was exacerbated in immigrants because of their greater presence in unqualified jobs and their economic need to prolong working hours. Immigrants had little knowledge of their occupational health and safetyrelated rights, although some informants detected an increase in empowerment in this area, mostly through greater participation in trade unions. CONCLUSIONS: This first step allowed us to identify some of the general factors influencing the health and safety of immigrant workers in Spain. This information will be used in a longterm, ongoing research project [Project Immigration, Work and Health (Proyecto Inmigración, Trabajo y Salud [ITSAL]), which aims to evaluate occupational health problems in inmigrants working in Spain through both qualitative and quantitative methods.

Diagnostic yield and safety of transbronchial cryobiopsy in sarcoidosis.

INTRODUCTION: Transbronchial lung cryobiopsy (TBLC) is an endoscopic technique proven to be useful in diagnostic approach to interstitial lung disease (ILD), but its role in sarcoidosis is not fully established. The aim of the present study was to assess the diagnostic yield of TBLC in sarcoidosis and its safety profile. METHODS: Retrospective analysis of patients, evaluated in a tertiary hospital ILD outpatient clinic, who underwent TBLC in the diagnostic work-up. TBLC was performed in accordance with the 2018 expert statement from the Cryobiopsy Working Group. RESULTS: 32 patients were included (mean±sd age 47.7±12.6 years, 59.4% male) and divided into three groups: highly likely sarcoidosis (n=21), possible sarcoidosis (n=6) and unlikely sarcoidosis (n=5). A mean of 2.8±0.8 TBLCs were performed. The definitive diagnosis was established by TBLC in 20 out of 27 patients with suspected sarcoidosis. Two patients were diagnosed with sarcoidosis by other methods performed afterwards. TBLC leaded to other diagnosis as well, such as fungal infection (n=1), hypersensitivity pneumonitis (n=1) and silicosis (n=3), making the diagnostic yield for suspected sarcoidosis of TBLC of 92.6%. TBLC was also able to show compatible histological features in five patients whom sarcoidosis was not previously considered. The complications reported overall were pneumothorax in five (15.6%) patients and moderate bleeding in one (3.1%) case. CONCLUSION: In this cohort, TBLC was a safe, reliable and useful procedure in sarcoidosis diagnosis. These results suggest that TBLC can be used successfully in those cases where a definitive diagnosis could not be reached with the usual and less-invasive diagnostic tools.

Targeted Gene Next-Generation Sequencing Panel in Patients with Advanced Lung Adenocarcinoma: Paving the Way for Clinical Implementation.

Identification of targetable molecular changes is essential for selecting appropriate treatment in patients with advanced lung adenocarcinoma. Methods: In this study, a Sanger sequencing plus Fluorescence In Situ Hybridization (FISH) sequential approach was compared with a Next-Generation Sequencing (NGS)-based approach for the detection of actionable genomic mutations in an experimental cohort (EC) of 117 patients with advanced lung adenocarcinoma. Its applicability was assessed in small biopsies and cytology specimens previously tested for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutational status, comparing the molecular changes identified and the impact on clinical outcomes. Subsequently, an NGS-based approach was applied and tested in an implementation cohort (IC) in clinical practice. Using Sanger and FISH, patients were classified as EGFR-mutated (n = 22, 18.8%), ALK-mutated (n = 9, 7.7%), and unclassifiable (UC) (n = 86, 73.5%). Retesting the EC with NGS led to the identification of at least one gene variant in 56 (47.9%) patients, totaling 68 variants among all samples. Still, in the EC, combining NGS plus FISH for ALK, patients were classified as 23 (19.7%) EGFR; 20 (17.1%) KRAS; five (4.3%) B-Raf proto-oncogene (BRAF); one (0.9%) Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2); one (0.9%) STK11; one (0.9%) TP53, and nine (7.7%) ALK mutated. Only 57 (48.7%) remained genomically UC, reducing the UC rate by 24.8%. Fourteen (12.0%) patients presented synchronous alterations. Concordance between NGS and Sanger for EGFR status was very high (κ = 0.972; 99.1%). In the IC, a combined DNA and RNA NGS panel was used in 123 patients. Genomic variants were found in 79 (64.2%). In addition, eight (6.3%) EML4-ALK, four (3.1%), KIF5B-RET, four (3.1%) CD74-ROS1, one (0.8%) TPM3-NTRK translocations and three (2.4%) exon 14 skipping MET Proto-Oncogene (MET) mutations were detected, and 36% were treatable alterations. Conclusions: This study supports the use of NGS as the first-line test for genomic profiling of patients with advanced lung adenocarcinoma.