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Individual, family, economic, and other forms of people suffering impact organizations. Suffering in the workplace is probably a more common occurrence than expected in everyday life, and opposite to health and employee wellbeing. According to the World Health Organization, 300 million people worldwide struggle with depression and close to 800.000 people die due to suicide every year. The European Survey on Working Conditions in the European Union gathers the most varied aspects of working conditions, such as the duration of the working day, relationships between collaborators in organizations, or healthy work habits. Among the results of that survey it is noteworthy that almost half of the close to twenty-two thousand workers surveyed in the 27 member countries stated that they felt uneasiness due to the conditions of their work.

Purpose: Chemotherapy plus anti-EGFR is standard first-line therapy in RAS wild-type (wt) metastatic colorectal cancer (mCRC), but biomarkers of early response are clinically needed. We aimed to define the utility of ctDNA to assess early response in patients with mCRC receiving first-line anti-EGFR therapy. Experimental Design: Prospective multicentric study of tissue patients with RAS wt mCRC treated with first-line chemotherapy plus cetuximab undergoing sequential liquid biopsies. Baseline and early (C3) ctDNA were analyzed by NGS. Trunk mutations were assessed as surrogate marker of total tumor burden. RAS/BRAF/MEK/EGFR-ECD were considered mutations of resistance. ctDNA results were correlated with clinical outcome. Results: One hundred patients were included. ctDNA was detected in 72% of patients at baseline and 34% at C3. Decrease in ctDNA trunk mutations correlated with progression-free survival (PFS; HR, 0.23; P = 0.001). RAS/BRAF were the only resistant mutations detected at C3. An increase in the relative fraction of RAS/BRAF at C3 was followed by an expansion of the RAS clone until PD, and was associated with shorter PFS (HR, 10.5; P < 0.001). The best predictor of response was the combined analysis of trunk and resistant mutations at C3. Accordingly, patients with “early molecular response” (decrease in trunk and decrease in resistant mutations) had better response (77.5% vs. 25%, P = 0.008) and longer PFS (HR, 0.18; P < 0.001) compared with patients with “early molecular progression” (increase in trunk and/or increase in resistant mutations). Conclusions: ctDNA detects early molecular response and predicts benefit to chemotherapy plus cetuximab. A comprehensive NGS-based approach is recommended to integrate information on total disease burden and resistant mutations. See related commentary by Eluri et al., p. 302

BACKGROUND: MicroRNAs (miRs) are frequently altered in colorectal cancer (CRC) and can be used as prognostic factors. OBJECTIVE: To confirm in stage III CRC patients a reported miR signature that was associated to the presence of metastatic disease. To correlate miR expression with microsatellite instability (MSI) and mutations in RAS and BRAF. METHODS: miR-21, miR-135a, miR-206, miR-335 and miR-Let-7a expression was analyzed by RT-qPCR in 150 patients out of the 329 patients used to analyze MSI and RAS and BRAF mutations. Association with disease free survival (DFS) and overall survival (OS) was analyzed. Data was confirmed by a multivariate analysis. RESULTS: MiR-21 high expression (p= 0.034) and miR-335 low expression (p= 0.0061) were significantly associated with MSI-H. A positive trend (p= 0.0624) between miR-135a high expression and RAS mutations was found. Lower miR-21 expression levels are associated with DFS (HR = 2.654, 95% CI: 1.066–6.605, p= 0.036) and a trend with OS (HR = 2.419, 95% CI: 0.749–7.815, p= 0.140). MiR-21 high expression significantly improves DFS of the poor prognosis group (T4 or N2) (p= 0.03). CONCLUSIONS: Association of increased expression of miR-21 and better prognosis in the poor prognostic group may be of interest and could be explored in future prospective clinical trials.

Retrospective studies and meta-analyses suggest that upfront primary tumour resection (UPTR) confers a survival benefit in patients with asymptomatic unresectable metastatic colorectal cancer (mCRC) undergoing chemotherapy, however a consensus of its role in routine clinical practice in the current era of targeted therapies is lacking. This retrospective study aimed to analyse the survival benefit of UPTR in terms of tumour location and mutational status, in patients with synchronous mCRC receiving chemotherapy and targeted therapy.Survival was analysed in a pooled cohort of synchronous mCRC patients treated with a first-line anti-VEGF or anti-EGFR inhibitor in seven trials of the Spanish TTD group, according to UPTR, tumour-sidedness and mutational profiling.Of 1334 eligible patients, 642 (48%) had undergone UPTR. UPTR was associated with significantly longer overall survival (OS; 25.0 vs 20.3 months; HR 1.30, 95%CI 1.15-1.48; p 0.0001). UPTR was associated with significant OS benefit in both left-sided (HR 1.38, 95%CI 1.13-1.69; p = 0.002) and right-sided (HR 1.39, 95%CI 1.00-1.94; p = 0.049) tumours, RASwt (HR 1.29, 95%CI 1.05-1.60; p = 0.016) and BRAFwt (HR 1.49, 95%CI 1.21-1.84; p = 0.0002) tumours, and treatment with anti-EGFRs (HR 1.47, 95%CI 1.13-1.92; p = 0.004) and anti-VEGFs (HR 1.25, 95%CI 1.08-1.44; p = 0.003). Multivariate analysis identified number of metastatic sites, RAS status, primary tumour location and UPTR as independent prognostic factors for OS.Considering the selection bias inherent to this study, our results support UPTR before first-line anti-EGFR or anti-VEGF targeted therapy in right and left-sided asymptomatic unresectable synchronous mCRC patients. RAS/BRAF mutational status may also influence UPTR function.

Purpose:Chemotherapy plus anti-EGFR is standard first-line therapy in RAS wild-type (wt) metastatic colorectal cancer (mCRC), but biomarkers of early response are clinically needed. We aimed to define the utility of ctDNA to assess early response in patients with mCRC receiving first-line anti-EGFR therapy.Experimental Design:Prospective multicentric study of tissue patients with RAS wt mCRC treated with first-line chemotherapy plus cetuximab undergoing sequential liquid biopsies. Baseline and early (C3) ctDNA were analyzed by NGS. Trunk mutations were assessed as surrogate marker of total tumor burden. RAS/BRAF/MEK/EGFR-ECD were considered mutations of resistance. ctDNA results were correlated with clinical outcome.Results:One hundred patients were included. ctDNA was detected in 72% of patients at baseline and 34% at C3. Decrease in ctDNA trunk mutations correlated with progression-free survival (PFS; HR, 0.23; P = 0.001). RAS/BRAF were the only resistant mutations detected at C3. An increase in the relative fraction of RAS/BRAF at C3 was followed by an expansion of the RAS clone until PD, and was associated with shorter PFS (HR, 10.5; P < 0.001). The best predictor of response was the combined analysis of trunk and resistant mutations at C3. Accordingly, patients with “early molecular response” (decrease in trunk and decrease in resistant mutations) had better response (77.5% vs. 25%, P = 0.008) and longer PFS (HR, 0.18; P < 0.001) compared with patients with “early molecular progression” (increase in trunk and/or increase in resistant mutations).Conclusions:ctDNA detects early molecular response and predicts benefit to chemotherapy plus cetuximab. A comprehensive NGS-based approach is recommended to integrate information on total disease burden and resistant mutations.See related commentary by Eluri et al., p. 302

Supplementary Tables 1-8

Influenza virus infection remains a threat to human health since viral hemagglutinins are constantly drifting, escaping infec-tion and vaccine-induced antibody responses. During antigenic drift H3 hemagglutinins have evolved to recognize a2,6 sialylated branched N-glycans with long glycan chains with at least three N-acetyllactosamine units (tri-LacNAc). In this work, we combined glycan arrays and tissue binding analyses with NMR experiments to characterize the interaction of a family of H1 variants, including the one responsible for the last pandemic outbreak. We also analyzed one H6 to understand if the preference for tri-LacNAc motifs is a general trend in recent zoonotic human-type receptor binding adapted viruses. In addition, we developed a new NMR approach to perform competition experiments between glycans with similar compositions and different lengths. Pandemic H1 viruses differ from previous seasonal H1 viruses by a strict preference for a minimum of di-LacNAc structural motif that are in turn present on the ferret upper respiratory tract.

Colorectal cancer consensus molecular subtypes (CMSs) are widely accepted and constitutes the basis for patient stratification to improve clinical practice. We aimed to find whether miRNAs could reproduce molecular subtypes, and to identify miRNA targets associated to the High-stroma/CMS4 subtype. The expression of 939 miRNAs was analyzed in tumors classified in CMS. TALASSO was used to find gene-miRNA interactions. A miR-mRNA regulatory network was constructed using Cytoscape. Candidate gene-miR interactions were validated in 293T cells. Hierarchical-Clustering identified three miRNA tumor subtypes (miR-LS; miR-MI; and miR-HS) which were significantly associated (p < 0.001) to the reported mRNA subtypes. miR-LS correlated with the low-stroma/CMS2; miR-MI with the mucinous-MSI/CMS1 and miR-HS with high-stroma/CMS4. MicroRNA tumor subtypes and association to CMSs were validated with TCGA datasets. TALASSO identified 1462 interactions (p < 0.05) out of 21,615 found between 176 miRs and 788 genes. Based on the regulatory network, 88 miR-mRNA interactions were selected as candidates. This network was functionally validated for the pair miR-30b/SLC6A6. We found that miR-30b overexpression silenced 3′-UTR-SLC6A6-driven luciferase expression in 293T-cells; mutation of the target sequence in the 3′-UTR-SLC6A6 prevented the miR-30b inhibitory effect. In conclusion CRC subtype classification using a miR-signature might facilitate a real-time analysis of the disease course and treatment response.

Airway examination techniques are procedures that can potentially transmit infectious diseases to both patients and healthcare professionals who perform them, by various mechanisms. The pandemic situation due to the COVID-19 disease has practically halted most of the activity of the clinics and laboratories of pulmonary and nasal function, with clear recommendations in this regard. Being already in the early stages after the peak of the pandemic, we still do not know for sure what its consequences will be in the short or long term, since there are important gaps in the knowledge of aspects as fundamental as the transmission mechanisms of the virus, its pathophysiology and immune response or its diagnosis. In this review we will examine the different examination techniques available on the assessment of patients suffering from respiratory allergy, asthma and associated diseases, int the postpandemic momentum, highlighting their possible advantages and disadvantages. For this reason, we wanted to focus on exploring the entire upper and lower airways, from the perspective of the safety of both the healthcare professionals and patients and their specific characteristics. And at the same time we will approach the analysis of the intrinsic value that these interventions provide from the point of view of both diagnosis and management of these patients. The changing situation of this disease may cause some modifications of the assertions presented in this review in the future.While this guidance seeks to ensure a consistent wide approach, some differences in operational details may be applied due to local regulations.

The Rhinitis Control Assessment Test (RCAT) is a patient-based questionnaire that is widely used to evaluate control of rhinitis. Objective: To develop and validate a Spanish version of the RCAT (RCATe).After translation and cultural adaptation of the original RCAT, this multicenter, observational, prospective study evaluated the properties/attributes of the RCATe by assessing its validity, reliability, responsiveness, effect size, minimal important difference and cut point.The recruited sample comprised 252 allergic rhinitis (AR) patients from 27 allergy and otolaryngology departments in hospitals throughout Spain. Significant and strong correlations were found between the RCATe and the total nasal symptom score and the visual analog scale (-0.79 and -0.77, respectively; P.0001). The RCATe revealed significant differences between patients grouped in the different categories of severity or duration of AR (P.001). The internal consistency (Cronbach α) was good (0.84), and the test-retest reliability was moderate (0.54 evaluated by the physician and 0.49 by the patient). The responsiveness to change was high and significant for RCATe (P.0001) and correlated linearly with the improvement in AR. The overall effect size was 1.62. The cut-off point to identify patients with adequate control of AR was20 (area under the receiver operating characteristic curve, 0.746; sensitivity, 58.3%; specificity, 90.9%).The psychometric evaluation and validation of the RCATe indicated good reliability, validity, and responsiveness, thus suggesting that it is effective for measuring control of AR symptoms by Spanish-speaking patients.

espanolEl manuscrito de la Biblioteca Nacional de Espana con signatura Mss. 20486 (E-Mn 20486) es una de las cinco fuentes principales que contienen repertorio polifonico del Magnus Liber Organi de Notre Dame. Este codice, de origen y datacion actualmente discutida, contiene una nutrida coleccionde piezas cuyos generos –organum, conductus y motete– se situan en los margenes de la Escuela de Notre Dame, cuyo maximo esplendor tuvo lugar a mediados del siglo XIII en la catedral parisina. El interes de esta fuente reside, ademas, en la influencia del nuevo sistema ritmico-musical cultivado por parte de los compositores parisinos, dando lugar a una estrecha relacion entre el canto y la palabra basada en el uso de pies metricos propios de la lirica clasica. Este articulo estudiara los elementos codicologicos e historicos de mayor importancia de E-Mn 20486, asi como su contenido musical y su posible datacion y procedencia. EnglishThe manuscript of the Biblioteca Nacional de Espana with signature Mss. 20486 (E-Mn 20486) is one of the five main sources that contains polyphonic repertoire of the Magnus Liber Organi of Notre Dame. This codex, whose origin and dating are currently discussed, contains a large collection of pieces whose genres –organum, conductus and motet– are located on the margins of the School of Notre Dame, whose maximum splendor took place in the mid-13th century in the Parisian cathedral. The interest of this source resides, in addition, in the influence of the new rhythmic-musical system cultivated by the Parisian composers, giving rise to a close relation between the song and the word based on the use of metric feet typical of the classical lyric. This paper will study the most important codicological and historical elements of E-Mn 20486, as well as its musical content and its possible dating and provenance.

Freshwater is a strategic natural resource in any region of the world, and this is especially true for the Sub-Saharan Africa region. Sub-Saharan Africa states, where water ecosystems are strategic resources, are oriented towards regional conflict rather than cooperation. However, its fossil fuels—principally, oil and natural gas—have constantly been exposed to scientific scrutiny. To compensate for the scarcity of scientific literature on the issue, the article analyses the role of the unequal distribution of freshwater that has been generating conflicts in Sub-Saharan Africa from the time of decolonization. Next, these conflicts are examined. Recommendations on the non-conflictual use of water are provided.

CONTEXTE : Bien que l’évaluation de l’inflammation bronchique, par expectoration induite, permette d’identifier différents phénotypes, chez les patients asthmatiques, il n’y a que peu d’informations sur le déterminant du pattern d’inflammation bronchique chez les patients présentant un asthme professionnel par sensibilisation. OBJECTIF : Déterminer si le pattern d’inflammation bronchique, déterminé par expectoration induite, permet de définir des phénotypes cliniques distincts. MÉTHODE : Cette étude multicentrique rétrospective a été réalisée auprès de 372 patients, présentant un asthme professionnel diagnostiqué par test d’exposition spécifique, qui étaient recrutés par le biais de la cohorte du groupe European network for Phenotypique of Ocupational Asthma. Chaque patient a bénéficié d’une expectoration induite avant et après test d’exposition spécifique. L’éosinophilie bronchique était définie par un pourcentage d’éosinophiles supérieur ou égal à 3 % dans l’expectoration induite, après test d’exposition spécifique, alors que la neutrophilie bronchique était définie par un pourcentage de neutrophiles supérieur ou égal à 76 %. RÉSULTATS : Au total, 268 (72 %) et 42 patients (11 %) présentaient respectivement une éosinophilie et une neutrophilie bronchique. Les analyses de régression logistique ont mis en évidence une association entre l’éosinophilie bronchique et l’exposition aux agents de haut poids moléculaire (odds ratio [OR], 1,89 ; IC 95 % 1,18–3,04), l’asthme persistant modéré (OR, 3,17 ; IC 95 %, 1,43–7,0) et l’asthme persistant sévère (OR, 2,39 ; IC 95 %, 1,06–5,43). La neutrophilie bronchique était associée à l’âge (OR pour chaque année supplémentaire, 1,04 ; IC 95 % 1,01–1,08), au genre masculin (OR, 2,83 : IC 95 %, 1,14–6,87), à l’asthme persistant léger (OR, 3,26 ; IC 95 %, 1,24–8,88), et à la dysphonie (OR, 2,83 ; IC95 %, 1,14–6,87). CONCLUSIONS : La majorité des patients avec un asthme professionnel par sensibilisation présentait une éosinophilie bronchique post-test d’exposition spécifique. L’éosinophilie et la neutrophilie, dans les expectorations induites, permettaient de définir des phénotypes cliniques différents, notamment en termes de sévérité et selon l’agent causal. [Phenotypes of occupational asthma defined with induced sputum after specific inhalation challenge] RATIONALE : Although the non-invasive assessment of airway inflammation through the induced sputum (IS) technique identified distinct asthma phenotypes, there is few information on the determinants of airway inflammatory pattern in sensitizer-induced occupational asthma (OA). AIM : To investigate whether the pattern of airway inflammation in IS is associated with distinct clinical phenotypes of OA. METHODS : This retrospective multicentric study was conducted among 372 patients with OA confirmed by a positive specific inhalation challenge (SIC) who were recruited in the European network for the Phenotyping of OCupational Asthma cohort (2006–2018). Each patient underwent an analysis of IS before and 24 hours after the SIC. Sputum eosinophilia and neutrophilia were defined by the presence of ≥ 3% eosinophils and ≥ 76% neutrophils in sputum samples collected after the SIC. RESULTS : In total, 268 (72%) and 42 patients (11%) exhibited sputum eosinophilia and neutrophilia, respectively. Multivariate logistic regression analysis revealed that eosinophilia was associated with exposure to a high molecular weight agent (odds ratio [OR], 1.89; 95% CI, 1.18–3.04), moderate asthma (OR, 3.17; 95% CI, 1,43–7.0) and severe asthma (OR, 2.39; 95% CI, 1.06–5.43). Sputum neutrophilia was associated with age (OR for each additional year, 1.04; 95% CI, 1.01–1.08), male gender (OR, 2.74; 95% CI, 1,21–6.8), mild asthma (OR, 3.26; 95% CI, 1.24–8.88), and dysphonia (OR, 2.83; 95% CI, 1.14–6.87). CONCLUSIONS : Sputum eosinophilia post-SIC was predominant in OA patients. Sputum eosinophilia and neutrophilia were associated with distinct clinical phenotypes of OA, especially in terms of causal agents and asthma severity.

Purpose: Stage IS testicular cancer is defined by the persistence of elevated serum tumor markers, including alpha-fetoprotein and/or beta-human chorionic gonadotropin, after orchiectomy without radiological evidence of metastatic disease. Current treatment recommendations include cisplatin based chemotherapy up front but the recommendations are based on limited single center series. Materials and Methods: We retrospectively analyzed clinical and pathological characteristics, and long-term outcomes in 110 patients uniformly treated with primary chemotherapy between 1994 and 2016. The primary objective was to evaluate long-term disease-free survival. We also explored factors associated with the need for additional treatment. Results: The elevated prechemotherapy tumor markers were alpha-fetoprotein in 48% of cases, beta-human chorionic gonadotropin in 14%, and alpha-fetoprotein and beta-human chorionic gonadotropin in 38%. Median alpha-fetoprotein and beta-human chorionic gonadotropin values were 71 ng/ml and 80 mIU/ml, respectively. The IGCCCG (International Germ Cell Cancer Collaborative Group) prognostic classification was good in 94% of cases. Mixed nonseminomatous germ cell tumor was found in 78% of cases. Of the patients 103 achieved a complete response to chemotherapy. In 6 patients radiological signs of progressive disease developed during chemotherapy, while 8 experienced relapse after an initial complete response. At a median followup of 108 months 108 patients were alive and disease-free. Five and 10-year disease-free survival rates were 87% and 85%, respectively. The predominance of embryonal carcinoma in the primary tumor was the only factor associated with the probability of needing additional therapy. Conclusions: Stage IS testicular cancer is more commonly associated with elevated alpha-fetoprotein, an IGCCCG good prognosis and mixed nonseminomatous germ cell tumor. Treatment with cisplatin based chemotherapy leads to cure in most cases. However, a proportion of patients require the integration of additional therapies, including more frequently when embryonal carcinoma is not predominant.

Data regarding management of frail patients with pancreatic ductal adenocarcinoma practice is currently very scarce. Randomized clinical trials usually exclude these subgroup of patients and the majority of the publications only consider chronological age and ECOG performance status for their classification. Therefore, the current available data do not reflect daily clinical practice. Only data from a phase two study (FRAGANCE study), designed to select a tolerable dose-schedule of nab-placitaxel + gemcitabine (Phase one) and to evaluate the efficacy of the selected regimen (Phase two) in patients with ECOG-2 and previously untreated advanced PDAC, are currently available. Management of these particular patients is exceedingly complex and requires collaboration of multidisciplinary teams and intensive support treatment. This article reviews the literature available regarding the management of the so-called frail patients and provide guidance for chemotherapy as well as supportive care treatments.

[Background and objective] Patient-reported outcome measures can provide clinicians with valuable information to improve doctor-patient communication and inform clinical decision-making. The aim of this study was to evaluate the physician-perceived utility of the QLQ-GINET21 in routine clinical practice in patients with gastrointestinal neuroendocrine tumours (GI-NETs). Secondary aims were to explore the patient, clinician, and/or centre-related variables potentially associated with perceived clinical utility., [Methods] Non-interventional, cross-sectional, multicentre study conducted at 34 hospitals in Spain and Portugal (NCT02853422). Patients diagnosed with GI-NETs completed two health-related quality of life (HRQoL) questionnaires (QLQ-C30, QLQ-GINET21) during a single routine visit. Physicians completed a 14-item ad hoc survey to rate the clinical utility of QLQ-GINET21 on three dimensions: 1)therapeutic and clinical decision-making, 2)doctor-patient communication, 3)questionnaire characteristics., [Results] A total of 199 patients at 34 centres were enrolled by 36 participating clinicians. The highest rated dimension on the QLQ-GINET21 was questionnaire characteristics (86.9% of responses indicating “high utility”), followed by doctor-patient communication (74.4%), and therapeutic and clinical decision-making (65.8%). One physician-related variable (GI-NET patient volume > 30 patients/year) was associated with high clinical utility and two variables (older age/less experience treating GI-NETs) with low clinical utility., [Conclusions] Clinician-perceived clinical utility of QLQ-GINET21 is high. Clinicians valued the instruments’ capacity to provide a better understanding of patient perspectives and to identify the factors that had the largest influence on patient HRQoL., This study was sponsored by Ipsen.

This paper describes a text mining approach that utilises the PyLucene search engine and the GrapeNLP grammar engine for extracting links between temperature, humidity and the spread of COVID-19, from a vast collection of scientific publications. The approach was developed in response to a Kaggle challenge from a consortium of research groups to develop text and data mining techniques that can assist the medical community in finding answers to a series of important questions on COVID-19. For this challenge, a large corpus of scientific publications known as the COVID-19 Open Research Dataset (CORD-19) was provided by the consortium. The approach presented in this paper was winner of the competition task of extracting key insights and building summary tables of COVID-19 relevant factors such as temperature and humidity.

Ensuring the accuracy and completeness of drug labels is a labour-intensive and potentially error prone process, as labels contain unstructured text that is not suitable for automated processing. To address this, we have developed a novel deep learning system that uses a bidirectional LSTM model to extract and structure drug information in a knowledge graph-based embedding space. This allows us to evaluate drug label consistency with ground truth knowledge, along with the ability to predict additional drug interactions. Annotated sentences from 7,117 drug labels sentences were used to train the LSTM model and 1,779 were used to test it. The drug entity extraction system was able to correctly detect relevant entities and relations with a F1 score of 91% and 81% respectively. The knowledge graph embedding model was able to identify inconsistent facts with ground truth data in 76% of the cases tested. This demonstrates that there is potential in building a natural language processing system that automatically extracts drug interaction information from drug labels and embeds this structured data into a knowledge graph embedding space to help evaluate drug label accuracy. We note that the accuracy of the system needs to be improved significantly before it can fully automate drug labeling related tasks. Rather such a system could provide best utility within a human-in-the-loop approach, where operators augment model training and evaluation.

Farmers constitute a large professional group worldwide. In developed countries farms tend to become larger, with a concentration of farm operations. Animal farming has been associated with negative respiratory effects such as work-related asthma and rhinitis. However, being born and raised or working on a farm reduces the risk of atopic asthma and rhinitis later in life. A risk of chronic bronchitis and bronchial obstruction/COPD has been reported in confinement buildings and livestock farmers. This position paper reviews the literature linking exposure information to intensive animal farming and the risk of work-related respiratory diseases and focuses on prevention. Animal farming is associated with exposure to organic dust containing allergens and microbial matter including alive microorganisms and viruses, endotoxins and other factors like irritant gases such as ammonia and disinfectants. These exposures have been identified as specific agents/risk factors of asthma, rhinitis, chronic bronchitis, COPD and reduced FEV1. Published studies on dust and endotoxin exposure in livestock farmers do not show a downward trend in exposure over the last 30 years, suggesting that the workforce in these industries is still overexposed and at risk of developing respiratory disease. In cases of occupational asthma and rhinitis, avoidance of further exposure to causal agents is recommended, but it may not be obtainable in agriculture, mainly due to socio-economic considerations. Hence, there is an urgent need for focus on farming exposure in order to protect farmers and others at work in these and related industries from developing respiratory diseases and allergy.

BACKGROUND Allergic diseases are highly prevalent in industrialized populations. In Spain, children suspected of having an allergic disease are usually referred by their primary care pediatrician to an allergy unit at a general hospital or a children's hospital. We report data from a subanalysis of the pediatric population in Alergologica 2015. METHODS Data were collected from pediatric patients (age, ≤14 years) consulting an allergist for the first time in 2014 and the first quarter of 2015 in order to determine variations compared with data reported in Alergologica 2005. RESULTS Alergologica 2015 included fewer pediatric patients than Alergologica 2005. The study population comprised 481 patients aged ≤14 years from more than 200 centers throughout Spain. Males accounted for 56.5%. Rhinoconjunctivitis was the main reason for consulting an allergist (53.8% vs 46.3% in 2005), followed by asthma (30.2% vs 34.6%), and food allergy (20.0% vs 14.5%). CONCLUSIONS The findings of Alergologica 2015 show a notable increased frequency of allergic rhinitis, drug allergy, and food allergy. The frequency of other allergic conditions remained unchanged, except for asthma, whose frequency decreased, as in adult patients.

Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicular cancer that may contribute to increasing our knowledge about the genetic basis of the disease. Nineteen Spanish families with at least two affected individuals with TGCT were selected. WES was performed on those individuals using an Illumina Hiseq2000 sequencing platform. Data were analyzed under a monogenic and polygenic model of inheritance, and candidate variants were evaluated in a case-control association study performed on 391 Spanish sporadic cases and 1,170 healthy Spanish controls. Results were replicated in a second series consisting of 101 TGCTs from the Cancer Genome Atlas (TGCA) and 27,000 controls from the Exome Aggregation Consortium (ExAC) database. Logistic regression was carried out to analyze the association strength (risk) of candidate variants obtained among cases and controls in different populations. Despite the sample size, we detected a significant earlier age of onset in familial TGCT (28y) than sporadic cases (33y), using a Mann-Whitney U test. We identified significant variants in the comparative study of TGCT cases (391) versus controls (almost 1,170), and three of them [PLEC (OR = 6.28, p = 6.42 × 10-23 ) (p.Arg2016Trp), EXO5 (OR = 3.37, p = 4.82 × 10-09 ) (p.Arg344AlafsTer10) and DNAH7 (OR = 1.64, p = 0.048)] were replicated as potential candidates that may contribute to explaining the genetic basis of TGCT.

SummaryBackground Eosinophils, a central factor in asthma pathogenesis, have the ability to secrete exosomes. However, the precise role played by exosomes in the biological processes leading up to asthma has not been fully defined. Objective We hypothesized that exosomes released by eosinophils contribute to asthma pathogenesis by activating structural lung cells. Methods Eosinophils from asthmatic patients and healthy volunteers were purified from peripheral blood, and exosomes were isolated from eosinophils of asthmatic and healthy individuals. All experiments were performed with eosinophil-derived exosomes from healthy and asthmatic subjects. Epithelial damage was evaluated using primary small airway epithelial cell lines through 2 types of apoptosis assays, that is, flow cytometry and TUNEL assay with confocal microscopy. Additionally, the epithelial repair was analysed by performing wound healing assays with epithelial cells. Functional studies such as proliferation and inhibition-proliferation assays were carried out in primary bronchial smooth muscle cell lines. Also, gene expression analysis of pro-inflammatory molecules was evaluated by real-time PCR on epithelial and muscle cells. Lastly, protein expression of epithelial and muscle cell signalling factors was estimated by Western blot. Results Asthmatic eosinophil-derived exosomes induced an increase in epithelial cell apoptosis at 24 hour and 48 hour, impeding wound closure. In addition, muscle cell proliferation was increased at 72 hours after exosome addition and was linked with higher phosphorylation of ERK1/2. We also found higher expression of several genes when both cell types were cultured in the presence of exosomes from asthmatics: CCR3 and VEGFA in muscle cells, and CCL26, TNF and POSTN in epithelial cells. Healthy eosinophil-derived exosomes did not exert any effect over these cell types. Conclusions and Clinical Relevance Eosinophil-derived exosomes from asthmatic patients participate actively in the development of the pathological features of asthma via structural lung cells.

Background High-dose chemotherapy (HDCT) has been studied in several clinical scenarios in advanced germ cell cancer (GCC). Objective To establish a clinical practice guideline for HDCT use in the treatment of GCC patients. Design, setting, and participants An expert panel reviewed information available from the literature. The panel addressed relevant issues concerning and related to HDCT. The guideline was externally reviewed by two international experts. Results and limitations The efficacy of HDCT has been demonstrated in selected GCC patients. The most conclusive evidence comes from retrospective analyses that need to be interpreted with caution. HDCT can cure a significant proportion of heavily treated GCC patients. When indicated, sequential HDCT with regimens containing carboplatin and etoposide, as well as peripheral stem-cell support, is recommended. There is no conclusive evidence to recommend HDCT as first-line therapy. According to a multinational retrospective pooled analysis, HDCT might be superior to conventional CT as first salvage treatment in selected patients. There is an urgent need for prospective clinical trials addressing the value of HDCT in GCC patients who experience failure on first-line cisplatin-based CT. In patients who progress on conventional-dose salvage CT, HDCT should be considered. Treatment of these patients at experienced centers is strongly recommended. Conclusions It has been demonstrated that HDCT cures selected GCC patients who experience disease progression on conventional rescue regimens. The panel recommends the inclusion of GCC patients in randomized clinical trials including HDCT. Patient summary This consensus establishes clinical practice guidelines for the use and study of high-dose chemotherapy in patients with germ cell cancer.

Background: Chronic spontaneous urticaria (CSU) is a frequent clinical entity that often presents a diagnostic and therapeutic challenge. Objective: To explore the degree of agreement that exists among the experts caring for patients with CSU diagnosis, evaluation, and management. Methods: An online survey was conducted to explore the opinions of experts in CSU, address controversial issues, and provide recommendations regarding its definition, natural history, diagnosis, and treatment. A modified Delphi method was used for the consensus. Results: The questionnaire was answered by 68 experts (dermatologists, allergologists, and primary care physicians). A consensus was reached on 54 of the 65 items posed (96.4%). The experts concluded that CSU is a difficult-to-control disease of unpredictable evolution. Diagnostic testsshould be limited and based on clinical history and should not be indiscriminate. Autoinflammatory syndromes and urticarial vasculitis must be ruled out in the differential diagnosis. A cutaneous biopsy is only recommended when wheals last more than 24h, to rule out urticarial vasculitis. The use of specific scales to assess the severity of the disease and the quality of life is recommended. In patients with severe and resistant CSU, second -generation H1 -antihistamines could be used at doses up to four times the standard dose before giving second-line treatments. Omalizumab is a safe and effective treatment for CSU that is refractory to H1 -antihistamines treatment. In general, diagnosis and treatment recommendations given for adults could be extrapolated to children. Conclusions: This work offers consensus recommendations that may be useful in the management of CSU. (C) 2016 SEICAP. Published by Elsevier Espana, S.L.U. All rights reserved.

This is a post hoc analysis of biomarkers from a large cohort of patients with chemo-naive metastatic colorectal cancer. Both high baseline circulating tumor cell count and RAS mutated were associated with clinical or pathologic features classically associated with poor prognosis. Selection of high- and low-risk populations may help to individualize approaches in the future. Background: Clinicopathologic characteristics and prognostic and predictive factors offer valuable guidance when selecting optimal first-line treatment in patients with metastatic colorectal cancer (CRC). The association between baseline circulating tumor cell (bCTC) count, molecular tumor profile, and clinicopathologic features was analyzed in a chemo-naive metastatic CRC population. Patients and Methods: A total of 1202 patients from the Spanish VISNU-1 (FOLFIRINOX/bevacizumab vs. FOLFOX/bevacizumab) and VISNU-2 (FOLFIRI/bevacizumab vs. FOLFIRI/cetuximab; RAS-wildtype) studies were analyzed for mutational status and bCTC count. The association between clinicopathologic characteristics and bCTC count, mutational status, and microsatellite instability (MSI) was analyzed in 589 eligible patients. Results: Interestingly, 41% of the population studied presented >= 3 bCTC count. bCTC count >= 3 was associated with worse performance status (according Eastern Cooperative Oncology Group scale), stage IV at diagnosis, at least 3 metastatic sites, and elevated carcinoembryonic antigen (CEA) levels; but not with RAS or BRAF mutations or high MSI. BRAFmut (BRAF mutated) tumors were associated with right-sided primary tumors, peritoneum, distant lymph node metastasis, and less frequent liver involvement. RASmut (RAS mutated) was associated with worse performance status; stage IV at diagnosis; right-sided primary tumors; liver, lung, and bone metastases; at least 3 metastatic sites; and elevated CEA, whereas PIK3CAmut (PIK3CA mutated) tumors were associated with right-sided primary tumors, high CEA serum levels, and older age. High MSI was associated with right-sided primary tumors, distant lymph nodes metastasis, and lower CEA levels. Conclusions: In our study, elevated bCTCs and RASmut were associated with clinicopathologic features known to be associated with poor prognosis; whereas the poor prognosis of BRAFmut tumors in chemo-naive metastatic CRC is not explained by associations with poor clinicopathologic prognostic factors, except right-sided primary tumors. (C) 2020 Elsevier Inc. All rights reserved.

Gastric cancer (GC) is the fifth most common cancer worldwide with a varied geographic distribution and an aggressive behavior. In Spain, it represents the sixth cause of cancer death. In Western countries, the incidence is decreasing slightly, with an increase in gastroesophageal junction adenocarcinoma (GEJA), a different entity that we separate specifically in the guideline. Molecular biology advances have been done recently, but do not yet lead to the choice in treatment approach except in advanced disease with overexpression of HER2. Endoscopic resection in very early stage, perioperative chemotherapy in locally advanced tumors and preliminary immune therapy resulting in advanced disease are the main treatment innovations in the GC/GEJA treatment. We describe the different evidences and recommendations following the statements of the American College of Physicians.

El manuscrito E-Mn 20486 es considerada como una de las principales fuentes con repertorio polifónico del siglo XIII que se conserva en la actualidad. Su importante colección de motetes, organa y contucti nos muestran el desarrollo de la técnica compositiva a varias voces que arrancó a partir de la denominada Escuela de Notre Dame. Uno de los principales estilos es el conductus, heredero del primitivo versus lemosino, en el cual la poesía y la música de nueva creación dan lugar a novedosas piezas en estilo discantus, con interesantes pasajes polifónicos a varias voces, un gran desarrollo musical y temáticas variopintas, yendo de lo sacro a lo profano. En el presente artículo tenemos como objetivo realizar una aproximación a este repertorio copiado en el manuscrito madrileño a través de las alusiones literarias a pasajes bíblicos y a la gran devoción mariana castellana. The manuscript E-Mn 20486 (Madrid Codex or Ma) is considered one of the main sources with a polyphonic repertoire from the thirteenth century that is preserved today. His important collection of motets, organum and contuctus show us the development of the compositional technique for several voices that started from the so-called Notre Dame School. One of the main styles is the conductus, heir to the versus Limousin, in which poetry and newly created music give rise to new pieces in the discantus style, with polyphonic passages in various voices, a great musical development and varied themes, going from the sacred to the profane. In this article we aim to make an approach to this repertoire copied in the aforementioned polyphony manuscript preserved in the Madrid Biblioteca Nacional through textual allusions to biblical passages, knowing its process of adaptation and the differentiation between the practice of the quotation or literary reworking.

Introduction: In colorectal cancer, anti-VEGF agents have demonstrated a survival benefit when combined with chemotherapy. However, development of resistance is very common. One of the mechanisms i...

Metastatic colorectal cancer (mCRC) is a group of distinct diseases, with clinical and molecular differences between right-sided and left-sided tumours driving varying prognosis.Patients withPatients withWe observed significantly improved efficacy outcomes in patients withNCT01161316 and NCT00885885.

Indoxyl sulfate (IxS), a highly albumin-bound uremic solute, accumulates in chronic kidney disease (CKD) due to reduced renal clearance. This study was designed to specifically investigate the role of human serum albumin (HSA) in IxS renal secretion via organic anion transporter 1 (OAT1) in a microfluidic system and subsequently apply quantitative translation of

Summary Background Treatment options for patients with unresectable locally advanced pancreatic cancer are scarce. Results from a subanalysis of the phase 3 MPACT trial in metastatic pancreatic cancer suggested potential activity of nab-paclitaxel plus gemcitabine against locally advanced pancreatic cancer. The objective of this phase 2 trial was to evaluate safety and efficacy of nab-paclitaxel plus gemcitabine in previously untreated locally advanced pancreatic cancer. Methods This international, open-label, multicentre, phase 2 trial (LAPACT) took place at 35 sites in five countries (USA, France, Spain, Canada, and Italy). Patients with Eastern Cooperative Oncology Group performance status of up to 1 underwent six cycles of induction with nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (days 1, 8, and 15 of each 28-day cycle). After induction, patients without progressive disease or unacceptable adverse events were eligible to receive continued therapy per investigator's choice: continued nab-paclitaxel plus gemcitabine, chemoradiation, or surgery. The primary endpoint was time to treatment failure; secondary endpoints were disease control rate, overall response rate, progression-free survival, overall survival, safety, and quality of life. The reported efficacy outcomes were analysed in the intention-to-treat population, and safety outcomes were analysed in the treated population. This trial is registered with ClinicalTrials.gov , NCT02301143 , and EudraCT, 2014-001408-23 and is complete. Findings Between April 21, 2015, and April 26, 2018, 107 patients were enrolled in the study. 106 received the study treatment; one patient enrolled but did not receive treatment. 44 (41%) of 107 enrolled patients discontinued induction; the most common reason for discontinuing induction was adverse events (22 [21%] patients). 62 (58%) of 107 enrolled patients completed induction treatment and 47 (44%) patients subsequently received continued treatment per investigator's choice: 12 (11%) continued nab-paclitaxel plus gemcitabine, 18 (17%) received chemoradiation, and 17 (16%) underwent surgery (seven had R0 resection status, nine had R1). 15 (14%) patients completed induction treatment but did not receive continued treatment. Median time to treatment failure was 9·0 months (90% CI 7·3–10·1); median progression-free survival was 10·9 months (90% CI 9·3–11·6), and median overall survival was 18·8 months (90% CI 15·0–24·0). During induction, 83 patients achieved disease control and the disease control rate was 77·6% (90% CI 70·3–83·5). 36 patients had a best response of partial response; the overall response rate during induction was 33·6% (90% CI 26·6–41·5). The most common treatment-emergent adverse events that were grade 3 or higher in the treated population during induction were neutropenia (35 [33%] of 106 patients), anaemia (12 [11%]), and fatigue (11 [10%]). The most common treatment-emergent serious adverse events during induction were pneumonia (five [5%] patients), pyrexia (five [5%]), and febrile neutropenia (three [3%]). No deaths were caused by treatment-related adverse events during the induction phase, and global quality of life was maintained in most patients. Interpretation The data from this trial support the tolerability and activity of nab-paclitaxel plus gemcitabine for locally advanced pancreatic cancer, and a potential to convert unresectable, locally advanced disease to surgically resectable disease. The safety profile was generally consistent with previous findings. Funding Celgene.

Erlotinib is a first-generation epithelial growth factor receptor inhibitor used in the treatment of non-small cellular lung cancers. Our previously published method on a Thermo TSQ Quantum Ultra triple quadrupole mass spectrometer for the quantitation of erlotinib, OSI-420, and OSI-413 and some other kinase inhibitors was transferred to a more sensitive Sciex QTRAP5500 system. Both methods showed comparable performance in the previous range (5–5000 and 1–1000 ng/mL for erlotinib and OSI-420) with comparable accuracies and precisions (98.9–106.2 vs 98.7.0–104.0, and 3.7–13.4 vs 4.6–13.2), and a high level of agreement between the methods (R2 = 0.9984 and 0.9951) for the quality control samples. The new system however was also capable of quantifying lower concentrations of both erlotinib and OSI-420 (0.5 and 0.1 ng/mL) with sufficient accuracy and precision. Along with the increased sensitivity we included the semi-quantitative determination of additional erlotinib metabolites M2, M3, M5, M6, M7, M8, M9, M10, M11, M12, M16 (hydroxy-erlotinib), M17, M18, M19, M20, M21 in a 0.1–1000 ng/mL range to the method. With a simple crash, dilute, and shoot sample preparation with acetonitrile and a 4.5 min analytical run time the method outperformed most other published methods in speed and simplicity and was suitable for TDM. Further, enhancement of the understanding of the pharmacokinetics of erlotinib and its metabolites was demonstrated.

Progress in glycoscience is hampered by a lack of well-defined complex oligosaccharide standards that are needed to fabricate the next generation of microarrays, to develop analytical protocols to determine exact structures of isolated glycans, and to elucidate pathways of glycan biosynthesis. We describe here a chemoenzymatic methodology that makes it possible, for the first time, to prepare any bi-, tri-, and tetra-antennary asymmetric N-glycan from a single precursor. It is based on the chemical synthesis of a tetra-antennary glycan that has N-acetylglucosamine (GlcNAc), N-acetyllactosamine (LacNAc), and unnatural Galα(1,4)-GlcNAc and Manβ(1,4)-GlcNAc appendages. Mammalian glycosyltransferases recognize only the terminal LacNAc moiety as a substrate, and thus this structure can be uniquely extended. Next, the β-GlcNAc terminating antenna can be converted into LacNAc by galactosylation and can then be enzymatically modified into a complex structure. The unnatural α-Gal and β-Man terminating antennae can sequentially be decaged by an appropriate glycosidase to liberate a terminal β-GlcNAc moiety, which can be converted into LacNAc and then elaborated by a panel of glycosyltransferases. Asymmetric bi- and triantennary glycans could be obtained by removal of a terminal β-GlcNAc moiety by treatment with β-N-acetylglucosaminidase and selective extension of the other arms. The power of the methodology is demonstrated by the preparation of an asymmetric tetra-antennary N-glycan found in human breast carcinoma tissue, which represents the most complex N-glycan ever synthesized. Multistage mass spectrometry of the two isomeric triantennary glycans uncovered unique fragment ions that will facilitate identification of exact structures of glycans in biological samples.

Neuroendocrine pancreatic tumors (PanNETs) are graded on the basis of their proliferative activity. Cytological samples are commonly the only samples available, but the determination of Ki-67 in cytology and its reliability as a measure of tumor mitotic activity is not well settled. We have retrospectively reviewed all the cases of FNA under EUS control of PanNETs in a 10-year period (2006-2016) in the Hospital Clínico San Carlos (Madrid). We identified 10 PanNET cases with histological correlation. Median age was 49.4 years and the patients were mainly women. PanNETs were located more frequently in the tail of the pancreas, with a median size of 33.8 mm. None of our cases was a grade 3 tumor. The seven grade 1 tumors confirmed in histology had consistent Ki-67 in cytology. In three cases (30 %), there were discrepancies between the Ki-67 index measured in cytology and histology, and the differences ranged from 2 to 15 %; all these cases were grade 2 tumors in histology and were graded as grade 1 tumors in FNA material. Our results are consistent with previous studies which showed understaging when tumor grade was assessed in cytological samples, mainly in G2 tumors. Previous literature has shown that Ki-67 assessment in EUS-FNA samples is a useful tool to rule out G3 tumors, but can be problematic for distinguishing G1 and G2 tumors.

Background Providing adjuvant chemotherapy in locally advanced rectal cancer after neoadjuvant chemoradiation is currently a matter of debate. Recommendations from clinical guidelines range from offering no treatment to oxaliplatin-based combinations. We present a risk-adapted approach based on the response to initial chemoradiation as the strongest prognostic factor for disease-free survival (DFS). Patients and Methods One hundred one patients were treated at a single institution with preoperative long-course radiotherapy plus concurrent fluoropyrimidines. Patients with disease downstaged to pT0-2N0 received adjuvant fluoropyrimidines alone, while the remaining received an oxaliplatin-based combination. The primary study end point was 5-year DFS. Results Overall, the disease of 54 patients was downstaged to pT0-2N0 (53.5%), while that of 47 patients was staged as pT3-4 or N+ (46.5%) after surgery. In the intention-to-treat analysis, 5-year DFS for patients in the good-prognosis group (downstaging to pT0-2 N0) and for those with poor prognosis (pT3-4 or N+) were 79.4% and 66.3%, respectively (hazard ratio, 0.489; P = .043). Downstaging and pN+ were independent prognostic factors for DFS. Conclusion A risk-adapted adjuvant therapy strategy based on pathologic stage after neoadjuvant chemoradiation is feasible and achieves high rates of 5-year DFS. Patients with good prognostic factors can be treated with adjuvant fluoropyrimidines alone, thus permitting the avoidance of oxaliplatin-derived toxicities.