Functional and molecular characterization of inherited platelet disorders in the Iberian Peninsula: results from a collaborative study

12 p.-6 tab. Sánchez-Guiu et al.[Background] The diagnostic evaluation of inherited platelet disorders (IPDs) is complicated and time-consuming, resulting in a relevant number of undiagnosed and incorrectly classified patients. In order to evaluate the spectrum of IPDs in individuals with clinical suspicion of these disorders, and to provide a diagnostic tool to centers not having access to specific platelets studies, we established the project “Functional and Molecular Characterization of Patients with Inherited Platelet Disorders” under the scientific sponsorship of the Spanish Society of Thrombosis and Haemostasis.[Patients/methods] Subjects were patients from a prospective cohort of individuals referred for clinical suspicion of IPDs as well as healthy controls. Functional studies included light transmission aggregation, flow cytometry, and when indicated, Western-blot analysis of platelet glycoproteins, and clot retraction analysis. Genetic analysis was mainly performed by sequencing of coding regions and proximal regulatory regions of the genes of interest.[Results] Of the 70 cases referred for study, we functionally and molecularly characterized 12 patients with Glanzmann Thrombasthenia, 8 patients with Bernard Soulier syndrome, and 8 with other forms of IPDs. Twelve novel mutations were identified among these patients. The systematic study of patients revealed that almost one-third of patients had been previously misdiagnosed.[Conclusions] Our study provides a global picture of the current limitations and access to the diagnosis of IPDs, identifies and confirms new genetic variants that cause these disorders, and emphasizes the need of creating reference centers that can help health care providers in the recognition of these defects.Research of the authors’ group is supported by the Instituto de Salud Carlos III (ISCIII, PI10/02594), RECAVA RD12/0042/0050(ISCIII and FEDER), and Fundación Séneca (07703/GERM/07). ISG holds a fellowship from ISCIII (FI10/00535). CGM is supported by the Spanish Plan of Research & Development (BFU2010-15237).Peer reviewe

Post-mortem findings in Spanish patients with COVID-19; a special focus on superinfections

IntroductionWhole-body autopsies may be crucial to understand coronavirus disease 2019 (COVID-19) pathophysiology. We aimed to analyze pathological findings in a large series of full-body autopsies, with a special focus on superinfections. MethodsThis was a prospective multicenter study that included 70 COVID-19 autopsies performed between April 2020 and February 2021. Epidemiological, clinical and pathological information was collected using a standardized case report form. ResultsMedian (IQR) age was 70 (range 63.75-74.25) years and 76% of cases were males. Most patients (90%,) had at least one comorbidity prior to COVID-19 diagnosis, with vascular risk factors being the most frequent. Infectious complications were developed by 65.71% of the patients during their follow-up. Mechanical ventilation was required in most patients (75.71%) and was mainly invasive. In multivariate analyses, length of hospital stay and invasive mechanical ventilation were significantly associated with infections (p = 0.036 and p = 0.013, respectively). Necropsy findings revealed diffuse alveolar damage in the lungs, left ventricular hypertrophy in the heart, liver steatosis and pre-infection arteriosclerosis in the heart and kidneys. ConclusionOur study confirms the main necropsy histopathological findings attributed to COVID-19 in a large patient series, while underlining the importance of both comorbid conditions and superinfections in the pathology

The metabolic co-regulator PGC1α suppresses prostate cancer metastasis

Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α–ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment

Impact of a Primary Care Antimicrobial Stewardship Program on Bacterial Resistance Control and Ecological Imprint in Urinary Tract Infections

Antimicrobial stewardship programs (ASPs) are a central component in reducing the overprescription of unnecessary antibiotics, with multiple studies showing benefits in the reduction of bacterial resistance. Less commonly, ASPs have been performed in outpatient settings, but there is a lack of available data in these settings. We implemented an ASP in a large regional outpatient setting to assess its feasibility and effectiveness. Over a 5-year post-implementation period, compared to the pre-intervention period, a significant reduction in antibiotic prescription occurred, with a reduction in resistance in E. coli urinary isolates. ASP activities also were found to be cost-effective, with a reduction in medication prescription

Caracterización funcional y molecular de trombopatías congénitas= Functional and molecular characterization of inherited platelet disorders

Introducción Los trastornos plaquetarios congénitos son un grupo heterogéneo de enfermedades raras que se caracterizan por alterar la producción/función plaquetaria, dando lugar a diátesis hemorrágica. A pesar de que estas enfermedades son muy conocidas, la identificación temprana y la caracterización de los pacientes sigue siendo difícil debido a la heterogeneidad clínica y de laboratorio; la falta de especificidad y la complejidad de los ensayos de la función plaquetaria; el gran número de genes causales; y la ausencia de correlación genotipo-fenotipo. Los proyectos multicéntricos sobre estos trastornos, guías consenso para el diagnóstico y redes de centros de referencia, podrían ayudar a abordar este problema. Objetivos 1. Facilitar el acceso al diagnóstico funcional y molecular de trastornos plaquetarios congénitos, para la comunidad médica de la Península Ibérica, promoviendo y apoyando la formación de un proyecto de colaboración para el reclutamiento y estudio de pacientes con un diagnóstico previo o con sospecha clínica de estos trastornos. 2. Realizar una evaluación cuantitativa de diátesis hemorrágica en los pacientes por medio de una escala común de sangrado. 3. Completar un análisis detallado y estandarizado de la función plaquetaria en los pacientes reclutados, con el objetivo de confirmar o descartar el diagnóstico funcional. 4. Lograr un diagnóstico molecular en los individuos con un diagnóstico funcional confirmado. 5. Establecer las posibles relaciones entre fenotipo clínico y/o de laboratorio y genotipo. Métodos En cinco años, 70 pacientes (no emparentados) con sospecha de trastorno plaquetario congénito, se remitidos desde hospitales de España y Portugal. Las características clínicas y manifestaciones hematológicas fueron evaluadas mediante una escala de sangrado. Se caracterizó el fenotipo plaquetario mediante un hemograma y un frotis; test PFA-100; ensayos de agregación plaquetaria; evaluación de los receptores de superficie plaquetarios y el estado de activación y secreción de gránulos por citometría de flujo; en algunos casos se realizó el ensayo de retracción del coágulo, la absorción/liberación de serotonina-14C, y microscopía electrónica. Se estudió en paralelo un control extraído a la vez que el paciente y un voluntario sano extraído en el momento del estudio. El análisis genético consistió, principalmente, en la secuenciación de regiones codificantes de los genes de interés. Resultados y Conclusiones 1. Hemos promovido un proyecto de colaboración para promocionar el diagnóstico funcional y molecular de pacientes con sospecha clínica de trastornos plaquetarios congénitos. Esto ha permitido el diagnóstico de un elevado número de pacientes. 2. Esta tesis comprende el estudio de 70 pacientes, siendo la cohorte de pacientes con sospecha clínica de trastornos plaquetarios congénitos más extensa de la Península Ibérica. 3. Nuestro estudio demuestra que mientras que una estrategia para el envío de muestras de sangre a una instalación distante puede no ser ideal y supone limitaciones técnicas, es válido para la identificación funcional de los pacientes con fenotipos severos. 4. En el 67% de los casos remitidos, se confirmó el diagnóstico, mientras que en el 33% restante no se ratificó la sospecha clínica. 5. El 40% de los pacientes obtuvo un diagnóstico a nivel molecular, el 28,8% con TG, y el 17,7% con SBS. La caracterización molecular de estos pacientes reveló 22 mutaciones, 11 fueron descritas aquí por primera vez. 6. Se identificaron dos nuevas variantes de SCH. Describimos por primera vez un caso de la forma severa de la enfermedad debido a una mutación missense en homocigosis. 7. Se describe el segundo caso de la caracterización molecular de un paciente con SHP en España, mediante secuenciación directa de gen HPS1. También se describió una mutación en el gen HPS7 en otro paciente, empleando el mapeo de marcadores microsatélites para detectar el gen candidato para secuenciación. 8. El análisis de otros casos con sospecha de trastornos plaquetarios congénitos, confirmó el diagnóstico molecular de CAMT, THC2 y MYH9-RD en 5 pacientes 9. El estudio del paciente con trombocitopenia crónica y tendencia hemorrágica leve, puso de manifiesto la primera evidencia de un autoanticuerpo IgM que causa la activación y agregación de plaquetas autólogas y alogénicas dependiente de temperatura, vía GPVI. En resumen, esta Tesis destaca la necesidad de mejorar el diagnóstico de los trastornos plaquetarios congénitos a nivel funcional y molecular. Se debe considerar el establecimiento de criterios estandarizados para evitar la heterogeneidad entre las distintas instalaciones, y la creación de centros de referencia para colaborar y favorecer el diagnóstico correcto de estas enfermedades. Introduction Inherited platelet disorders (IPDs) comprise a heterogeneous group of rare diseases characterized by abnormalities of platelet production or function giving rise to lifelong bleeding diathesis. Despite a century of research on IPDs, early identification and characterization of affected patients remain a challenge due to: heterogeneity of clinical and laboratory presentation; lack of specificity and complexity of platelet function assays; large number of causative genes; and absence of genotype-phenotype correlations. Multicenter projects on IPDs, consensus guides for diagnosis, and reference centers networks, could help to overcome this challenge. Objectives 1. To facilitate access to the specialized functional and molecular diagnosis of IPDs, for the medical community of the Iberian Peninsula, by promoting and initiating a collaborative project for the recruitment and study of patients with a previous diagnosis or clinical suspicion of either inherited thrombocytopenias or congenital disorders of platelet function. 2. To perform a quantitative re-evaluation of bleeding diathesis in the recruited patients by means of a common bleeding scale. 3. To complete a detailed and standardized analysis of platelet function in the samples from recruited patients, aiming to confirm or discard a functional diagnosis. 4. To achieve a molecular diagnosis in the individuals with a confirmed laboratory diagnosis. 5. To establish potential relationships between clinical and/or laboratory phenotype and genotype, in different types of IPDs. Methods In five years, seventy unrelated patients with suspected IPD were referred from hospitals of Spain and Portugal. Clinical features were assessed by their hematological and bleeding manifestations graded by a unique simple scale. We received blood samples and performed a platelet phenotype characterization including: full blood count and film examination; PFA-100 tests; light transmission aggregation (LTA); flow cytometry assessment of surface receptors, activation status and granule secretion; and in some cases clot retraction assay, 14C-serotonin uptake/release, and electron microscopy. A patient´s parallel control and a healthy volunteer freshly extracted were studied in parallel. Genetic analysis was mainly performed by sequencing of coding regions of the genes of interest. Results and Conclusions 1. The collaborative project promoted through this Thesis has permitted the accurate diagnosis of a high number of patients that will benefit from more specific medical management. 2. This Thesis comprises the largest cohort of patients with IPDs ever investigated in the Iberian Peninsula. 3. Our study demonstrates that despite a strategy for sending blood samples to a distant facility may not be ideal and not free of technical limitations, it is valid for functional identification of patients with severe phenotypes. 4. The clinical diagnosis of an IPD was confirmed in 67% of the 70 cases referred, while in the remaining 33% was not. Thus, our study demonstrates that correct diagnosis of IPDs may not be straightforward even for severe disorders and supports the benefit of specialized platelet laboratories for the diagnostic confirmation in these patients. 5. A high percentage of patients (40%) achieved a diagnosis at a molecular level, 28.8% with GT, and 17.7% with BSS. The molecular characterization of patients with GT revealed sixteen mutations along both genes encoding for the IIb3 receptor, 8 not reported previously. In the case of BSS, six mutations were identified, 3of them firstly described in this study. 6. We identified two new variants of CHS in this study. Noteworthy, we describe for the first time a case of a severe infant-onset CHS due to a homozygous missense mutation. 7. We characterized at the molecular level the second case of HPS-1 in Spain. A novel mutation in the HPS7 gene was identified in another HPS patient following autozygosity mapping using microsatellite markers to identify the candidate gene for Sanger sequencing. 8. Other cases with IPDs attained a molecular diagnosis of CAMT, THC2, and MYH9-RD. 9. The study of a patient with lifelong chronic thrombocytopenia and mild bleeding tendency, provided the first evidence of an IgM autoantibody causing temperature-dependent activation and aggregation of autologous and allogeneic platelets, through interaction with the platelet collagen receptor GPVI. In summary, this Thesis highlights the need to improve the diagnosis of IPDs at the level of the functional and by molecular analysis. Standardized criteria for diagnosis of IPDs would overcome the present heterogeneity between facilities, and the creation of reference centers should be considered to help healthcare providers in the diagnosis of these disorders

Functional and molecular characterization of inherited platelet disorders in the Iberian Peninsula: results from a collaborative study

Abstract Background: The diagnostic evaluation of inherited platelet disorders (IPDs) is complicated and time-consuming, resulting in a relevant number of undiagnosed and incorrectly classified patients. In order to evaluate the spectrum of IPDs in individuals with clinical suspicion of these disorders, and to provide a diagnostic tool to centers not having access to specific platelets studies, we established the project "Functional and Molecular Characterization of Patients with Inherited Platelet Disorders" under the scientific sponsorship of the Spanish Society of Thrombosis and Haemostasis

Presentació de comunicacions sobre educació i comunicació

Presentació de les diferents comunicacions a les 'IV Jornades Internacionals de Comunicació i Societat", vinculades amb diferents temàtiques relacionades amb Educació i Comunicació. Comunicacions presentades: "Educació en comunicació: bon camí per al canvi social" de Xavier Serra Besalú, professor de l'IES Salvador Espriu de Salt; "Gent del barri: narrativas audiovisuals per repensar Poblenou" de Gemma Paricio i Pera del departament de Didàctiques de la UAB i professora de l'IES Euclides a Pineda de Mar; "Aprender comunicando: experiencia docente" de Sera Sánchez i Eulàlia Guiu de la Facultat d'Educació i Psicologia de la UdG; "Teacher 2020: the discussion on complex projects through media" de Jonas Norgaard de l'Aalbor Universitet i de Mariona Masgrau de la UdG; "Els nous mitjans: una oportunitat per actuar com emirecs i un instrument per educar en la diversitat" de les periodistes Anna Flotats i Mònica Roca; "Los proyectos musicales: la búsqueda del bienestar en contextos de diversidad" de Diego Calderón del departament de Didàctiques de la UB; "Ficción televisiva y cuestiones sociales: análisis del feedback de las internautas" de Charo Lacalle: "Public communication education and extension: civic skills to talk and act on polis" de Guilherme Fráguas i "Temporada 4 projecte d'edu-comunicació sexual" d'Alfredo Cohen de l'Associació Cultural elParlant