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.

Retrograde inhibition of hyperactive central pathways in nociplastic pain / Inibição retrógrada das vias centrais hiperativas nas dores nociplásticas

ABSTRACT BACKGROUND AND OBJECTIVES: Nociplastic pain occurs due to a combination of hyperexcitability and decreased inhibitory activity in the central nervous system, responsible for a state of amplification of different stimuli, present in many chronic disorders. Among them: fibromyalgia, chronic migraine, irritable bowel syndrome, myofascial pain syndrome and complex regional pain syndrome. Often, several of these diseases are associated. Nociplastic pain therapy is a challenge in clinical practice, since most traditional treatments are not effective in controlling symptoms, often causing difficulty in adherence or even interruption of treatment due to undesirable adverse effects. The objective of this article was to demonstrate the importance of identifying the presence of nociplastic pain in the patient's condition, and also the pathophysiological mechanisms involved. Thus, due to retrograde neuromodulation, a unique feature of the endocannabinoid system until now, evaluate the use of pharmaceutical grade medicines based on the cannabis plant as an adjunct in the therapy of pain and other symptoms associated with this disorder. CONTENTS: This article was addressed the pathophysiology of nociplastic pain, the physiology to the endocannabinoid system, the cannabis plant with its components and its use as an adjuvant medication in the multimodal treatment of nociplastic pain (due to retrograde neuromodulation), based on published scientific articles between 1981 and 2022. CONCLUSION: Although the scientific evidence supporting the use of medical cannabis in nociplastic pain therapy is insufficient so far, it can and should be considered as a possible adjuvant medication in multimodal pain therapy, always on an individual basis, when recommended treatments fail or are not tolerated.

RESUMO JUSTIFICATIVA E OBJETIVOS: A dor nociplástica ocorre por uma combinação de hiperexcitabilidade e diminuição da atividade inibitória no sistema nervoso central, responsável por um estado de amplificação de estímulos diversos, presente em muitas doenças crônicas. Entre essas doenças estão: fibromialgia, migrânea crônica, síndrome do intestino irritável, síndrome dolorosa miofascial e síndrome de dor complexa regional. Frequentemente, várias dessas doenças se apresentam associadas. A terapia da dor nociplástica é um desafio na prática clínica, uma vez que a maioria dos tratamentos tradicionais não são eficazes no controle dos sintomas, causando muitas vezes dificuldade de adesão ou até mesmo interrupção do tratamento, devido aos efeitos adversos indesejáveis. O objetivo deste artigo foi demonstrar a importância da identificação da presença da dor nociplástica no quadro do paciente, e do conhecimento dos mecanismos fisiopatológicos envolvidos. Dessa forma, devido à neuromodulação retrógrada, característica exclusiva do sistema endocanabinoide até o momento, avaliar a utilização de fármacos de grau farmacêutico à base da planta cannabis como coadjuvante na terapia da dor e dos outros sintomas associados a essa doença. CONTEÚDO: Este artigo abordou a fisiopatologia da dor nociplástica, a fisiologia do sistema endocanabinoide, a planta cannabis com seus componentes e sua utilização como medicação coadjuvante no tratamento multimodal da dor nociplástica (decorrente da neuromodulação retrógrada), com base em artigos científicos publicados entre 1981 e 2022. CONCLUSÃO: Apesar das evidências científicas que apoiam o uso da cannabis medicinal na terapia da dor nociplástica serem insuficientes até o momento, ela pode e deve ser considerada como um possível fármaco coadjuvante na terapia multimodal da dor, sempre de forma individualizada, quando os tratamentos preconizados falharem ou não forem tolerados.

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.

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.

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...

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.

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.

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

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 and 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

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 of the 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

[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.

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.

Adult congenital heart disease outpatient clinic. descriptive analysis of a 12-year experience in Brazil

Abstract 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.

Indoor radon in Spanish workplaces. A pilot study before the introduction of the European Directive 2013/59/Euratom / Radón interior en puestos de trabajo en España. Un estudio piloto antes de la introducción de la Directiva Europea 2013/59/Euratom

Objective: To explore whether there is a possible problem regarding indoor radon concentration surpassing the new European Directive 2013/59/Euratom threshold in Spanish workplaces. We also aim to find out whether radon concentration might be associated with certain characteristics of workplaces. Method: We performed a cross-sectional study to measure indoor radon concentrations in Spanish workplaces including five different sectors (education, public administration, the health sector, the tourist sector and the private sector). To be measured, the workplace should be occupied permanently by at least one worker. Alpha-track type radon detectors were placed for at least three months and read at the Galician Radon Laboratory at the University of Santiago de Compostela. A descriptive analysis was performed on radon distribution by sector, building characteristics and number of workers affected. Results: We faced enormous difficulties in finding volunteers for this study. Galicia and Madrid had the highest number of measurements. Of a total of 248 measurements, 27% had concentrations above 300 Bq/m3. Median radon concentration was 251 Bq/m3 in Galicia, followed by Madrid, with 61.5 Bq/m3. Forty-six percent of the workplaces measured in Galicia had radon concentrations higher than 300 Bq/m3 followed by 10.6% in Madrid. Nineteen percent of all workers were exposed to more than 300 Bq/m3 and 6.3% were exposed to radon concentrations higher than 500 Bq/m3. Conclusion: Indoor radon exposure might be a relevant problem in Spanish workplaces and the number of affected workers could be high. The prevalence of workers exposed to high radon concentrations probably depends on the geographical area

Objetivo: Explorar si podría existir un problema en cuanto a la concentración de radón en los puestos de trabajo en España por superación del umbral propuesto por la nueva Directiva Europea 2013/59/Euratom. También se pretende conocer si la concentración de radón puede estar asociada a las características de los puestos de trabajo. Método: Estudio transversal en seis regiones y diferentes sectores (educación, administración pública, sanitario, turístico y privado). El puesto de trabajo medido debía ser ocupado de manera permanente por al menos un trabajador. Los detectores de radón de tipo alfa-track estuvieron colocados al menos 3 meses y fueron revelados en el Laboratorio de Radón de Galicia, de la Universidad de Santiago de Compostela. Se realizó un análisis descriptivo de la concentración de radón por sector, por características de los edificios y por número de trabajadores afectados. Resultados: Hubo dificultades para encontrar voluntarios para este estudio. Galicia y Madrid tuvieron el mayor número de mediciones. Se midieron 248 lugares de trabajo, con el 27% por encima de los 300 Bq/m3. La concentración mediana fue de 251 Bq/m3 en Galicia, seguida de Madrid con 61,5 Bq/m3. El 46% de los puestos de trabajo en Galicia tenían concentraciones mayores de 300 Bq/m3, y el 10,6% en Madrid. El 19% de los trabajadores estuvieron expuestos a más de 300 Bq/m3 y el 6,3% a más de 500 Bq/m3. Conclusión: La exposición a radón podría ser un problema de salud relevante en los lugares de trabajo en España. El número de trabajadores expuestos parece elevado. La prevalencia de trabajadores afectados depende del área geográfica

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.

Indoor radon in Spanish workplaces. A pilot study before the introduction of the European Directive 2013/59/Euratom.

OBJECTIVE: To explore whether there is a possible problem regarding indoor radon concentration surpassing the new European Directive 2013/59/Euratom threshold in Spanish workplaces. We also aim to find out whether radon concentration might be associated with certain characteristics of workplaces. METHOD: We performed a cross-sectional study to measure indoor radon concentrations in Spanish workplaces including five different sectors (education, public administration, the health sector, the tourist sector and the private sector). To be measured, the workplace should be occupied permanently by at least one worker. Alpha-track type radon detectors were placed for at least three months and read at the Galician Radon Laboratory at the University of Santiago de Compostela. A descriptive analysis was performed on radon distribution by sector, building characteristics and number of workers affected. RESULTS: We faced enormous difficulties in finding volunteers for this study. Galicia and Madrid had the highest number of measurements. Of a total of 248 measurements, 27% had concentrations above 300 Bq/m3. Median radon concentration was 251 Bq/m3 in Galicia, followed by Madrid, with 61.5 Bq/m3. Forty-six percent of the workplaces measured in Galicia had radon concentrations higher than 300 Bq/m3 followed by 10.6% in Madrid. Nineteen percent of all workers were exposed to more than 300 Bq/m3 and 6.3% were exposed to radon concentrations higher than 500 Bq/m3. CONCLUSION: Indoor radon exposure might be a relevant problem in Spanish workplaces and the number of affected workers could be high. The prevalence of workers exposed to high radon concentrations probably depends on the geographical area.

DHEA Treatment Effects on Redox Environment in Skeletal Muscle of Young and Aged Healthy Rats.

BACKGROUND: Dehydroepiandrosterone (DHEA) is an important precursor of active steroid hormone, produced abundantly by the adrenal cortex with an age-dependent pattern. OBJECTIVE: We investigated whether chronic DHEA administration impacts on redox status and on Akt protein activation in skeletal muscle during the aging process (3 and 24 months-old rats). METHODS: Rats received one weekly dose/5 weeks of DHEA (10 mg/kg) or vehicle. Gastrocnemius muscle was removed to evaluate glutathione system, hydrogen peroxide, antioxidant enzymes, and expression of Akt kinase protein. RESULTS: In the 3-months-old rats DHEA induced an increase in hydrogen peroxide when compared both to its control (276%) and the 24-months-old DHEA group (485%). Moreover, in the 24- months-old rats DHEA caused an increase in GSSG (41 and 28%), a decrease in reduced-GSH (55 and 51%), and a more oxidized redox status (reduction in GSH/GSSG ratio, 47 and 65 %) when compared to 3-month-old DHEA and to 24-months-old control groups, respectively. Both older groups had increased G6PDH (2.7 fold) and GST (1.7 fold) activities when compared to younger groups, independently of any DHEA treatment. However, there was no modulation of Akt protein (phosphorylated/total isoform). CONCLUSION: The results show that chronic DHEA administration to 3 and 24-months-old rats may not present positive effects regarding the redox environment in skeletal muscle without modulation of pro-survival Akt kinase. Due to the large-scale self-administration of DHEA as an "anti-aging" dietary supplement, it is crucial to investigate its molecular mechanisms over oxidative stressinduced related diseases.