SENTIA: a systematic online monitoring registry for children and adolescents treated with antipsychotics

INTRODUCTION: Despite drastic increases in antipsychotic prescribing in youth, data are still limited regarding their safety in this vulnerable population, necessitating additional tools for capturing long-term, real world data. METHODS: We present SENTIA (SafEty of NeurolepTics in Infancy and Adolescence; https://SENTIA.es), an online registry created in 2010 to track antipsychotic adverse effects in Spanish youth <18 years old currently taking or initiating with any antipsychotic treatment. SENTIA collects information on sociodemographic, diagnostic and treatment characteristics, past personal medical/psychiatric history, healthy lifestyle habits and treatment adherence. Additionally, efficacy and adverse effect data are recorded including the Children’s Global Assessment Scale; Clinical Global Impressions scale for Severity and Improvement, the Safety Monitoring Uniform Report Form, Simpson-Angus Scale, Abnormal Involuntary Movement Scale, vital signs, blood pressure, and EKG. Finally, fasting blood is drawn for hematology, electrolytes, renal, liver and thyroid function, glucose, insulin, lipid, prolactin and sex hormone levels. Initially, a diagnostic interview and several psychopathology scales were also included. Patients are assessed regularly and followed even beyond stopping antipsychotics. RESULTS: Since 01/17/2011, 85 youth (11.5 ± 2.9 (range = 4-17) years old, 70.6% male) have been included at one inaugural center. After a mean duration of 17 ± 11 (range = 1-34) months, 78.8% are still actively followed. For feasibility reasons, the diagnostic interview and detailed psychopathology scales were dropped. The remaining data can be entered in <30 minutes. Several additional centers are currently being added to SENTIA. CONCLUSIONS: Implementation of a systematic online pharmacovigilance system for antipsychotic adverse effects in youth is feasible and promises to generate important information

DSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity

Lung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-α–mediated CD8+-killing and immune-resistant lung tumors to anti–PD-1 treatment. Finally, in a series of lung cancer patients, DSTYK copy number gain predicts lack of response to the immunotherapy. In summary, we have uncovered DSTYK as new therapeutic target in lung cancer. Prioritization of this novel target for drug development and clinical testing may expand the percentage of NSCLC patients benefiting from immune-based treatments.This work was supported by Fundación para la investigación medica aplicada (FIMA), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC; CB16/12/00443), Spanish Association Against Cancer Scientific Foundation (AECC; GCB14-2170), Fundación Ramón Areces, Instituto de Salud Carlos III, and cofunded by the European Union (European Regional Development Fund, “A way to make Europe”; PI19/00098; PI19/00230; PI20/ 00419), Fundación Roberto Arnal Planelles, and International Association for the Study of Lung Cancer (IASLC) Fellowship funding (K. Valencia). M. Echepare was supported by Contratos Predoctorales de Formación en Investigación en Salud (PFIS), Instituto de Salud Carlos III, and co-funded by the European Union (European Social Fund, "Investing in your future"; FI20/00295)

Inhibition of Sema-3A Promotes Cell Migration, Axonal Growth, and Retinal Ganglion Cell Survival

Semaphorin 3A (Sema-3A) is a secreted protein that deflects axons from inappropriate regions and induces neuronal cell death. Intravitreal application of polyclonal antibodies against Sema-3A prevents loss of retinal ganglion cells ensuing from axotomy of optic nerves. This suggested a therapeutic approach for neuroprotection via inhibition of the Sema-3A pathway.Funded by the EU seventh framework program, Grant Agreement #604884.Peer reviewe

Study protocol of psychometric properties of the Spanish translation of a competence test in evidence based practice: The Fresno test

<p>Abstract</p> <p>Background</p> <p>There are few high-quality instruments for evaluating the effectiveness of Evidence-Based Practice (EBP) curricula with objective outcomes measures. The Fresno test is an instrument that evaluates most of EBP steps with a high reliability and validity in the English original version. The present study has the aims to translate the Fresno questionnaire into Spanish and its subsequent validation to ensure the equivalence of the Spanish version against the English original.</p> <p>Methods and design</p> <p>The questionnaire will be translated with the back translation technique and tested in Primary Care Teaching Units in Catalonia (PCTU). Participants will be: (a) tutors of Family Medicine residents (expert group); (b) Family Medicine residents in their second year of the Family Medicine training program (novice group), and (c) Family Medicine physicians (intermediate group). The questionnaire will be administered before and after an educational intervention. The educational intervention will be an interactive four half-day sessions designed to develop the knowledge and skills required to EBP. Responsiveness statistics used in the analysis will be the effect size, the standardised response mean and Guyatt's method. For internal consistency reliability, two measures will be used: corrected item-total correlations and Cronbach's alpha. Inter-rater reliability will be tested using Kappa coefficient for qualitative items and intra-class correlation coefficient for quantitative items and the overall score. Construct validity, item difficulty, item discrimination and feasibility will be determined.</p> <p>Discussion</p> <p>The validation of the Fresno questionnaire into different languages will enable the expansion of the questionnaire, as well as allowing comparison between countries and the evaluation of different teaching models.</p

Prevalence of enteropathogenic viruses and molecular characterization of group A rotavirus among children with diarrhea in Dar es Salaam Tanzania

Different groups of viruses have been shown to be responsible for acute diarrhea among children during their first few years of life. Epidemiological knowledge of viral agents is critical for the development of effective preventive measures, including vaccines. In this study we determined the prevalence of the four major enteropathogenic viruses - rotavirus, norovirus, adenovirus and astrovirus - was determined in 270 stool samples collected from children aged 0 - 60 months who were admitted with diarrhea in four hospitals in Dar es Salaam, Tanzania, using commercially available ELISA kits. In addition, the molecular epidemiology of group A rotavirus was investigated using reverse transcriptase multiplex polymerase chain reaction (RT-PCR). At least one viral agent was detected in 87/270 (32.2%) of the children. The prevalence of rotavirus, norovirus, adenovirus and astrovirus was 18.1%, 13.7%, 2.6% and 0.4%, respectively. In most cases (62.1%) of viruses were detected in children aged 7-12 months. The G and P types (VP7 and VP4 genotypes respectively) were further investigated in 49 rotavirus ELISA positive samples. G9 was the predominant G type (81.6%), followed by G1 (10.2%) and G3 (0.2%). P[8] was the predominant P type (83.7%), followed by P[6] (0.4%) and P[4] (0.2%). The following G and P types were not detected in this study population; G2, G4, G8 G10, P[9], P[10] and P[11]. The dominating G/P combination was G9P[8], accounting for 39 (90.7%) of the 43 fully characterized strains. Three (6.1%) of the 49 rotavirus strains could not be typed. Nearly one third of children with diarrhea admitted to hospitals in Dar es Salaam had one of the four viral agents. The predominance of rotavirus serotype G9 may have implication for rotavirus vaccination in Tanzania

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non–Small Cell Lung Carcinoma: the ROSING Study

Introduction: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data. Methods: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific). Results: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively). Conclusions: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm

Biological properties of extracellular vesicles and their physiological functions

María Yáñez-Mó#, Pia R.-M. Siljander#, Zoraida Andreu, Apolonija Bedina Zavec, Francesc E. Borràs, Edit I. Buzas, Krisztina Buzas, Enriqueta Casal, Francesco Cappello, Joana Carvalho, Eva Colás, Anabela Cordeiro-da Silva, Stefano Fais, Juan M. Falcon-Perez, Irene M. Ghobrial, Bernd Giebel, Mario Gimona, Michael Graner, Ihsan Gursel, Mayda Gursel, Niels H. H. Heegaard, An Hendrix30, Peter Kierulf, Katsutoshi Kokubun, Maja Kosanovic, Veronika Kralj-Iglic, Eva-Maria Krämer-Albers, Saara Laitinen, Cecilia Lässer, Thomas Lener, Erzsébet Ligeti, Aija Linē, Georg Lipps, Alicia Llorente, Jan Lötvall, Mateja Manček-Keber, Antonio Marcilla, Maria Mittelbrunn, Irina Nazarenko, Esther N.M. Nolte-‘t Hoen, Tuula A. Nyman, Lorraine O'Driscoll, Mireia Olivan, Carla Oliveira, Éva Pállinger, Hernando A. del Portillo, Jaume Reventós, Marina Rigau, Eva Rohde, Marei Sammar, Francisco Sánchez-Madrid, N. Santarém1, Katharina Schallmoser, Marie Stampe Ostenfeld, Willem Stoorvogel, Roman Stukelj, Susanne G. Van der Grein, M. Helena Vasconcelos, Marca H. M. Wauben and Olivier De WeverIn the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells.While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.Peer reviewe

Surveillance of Human Calicivirus in Spain

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