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BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

To assess myopia progression in Spanish children and whether treatment with low-dose atropine eye drops delays myopia progression and axial elongation.339 eyes of 339 Caucasian patients with myopia, aged 5 to 11 years, were examined. Participants were randomized to a treatment arm, receiving one atropine (0.01%) eye drop/day for two, and an untreated control arm. At the baseline and 2-year follow-up visits, we recorded: spherical equivalent (SE), axial length (AL), mean keratometry (Mean-K) and anterior chamber depth (ACD). We also examined the rate of children with higher myopia progression (change in SE1 D/2 years) and identified risk factors for progression.In 339 eyes of the 339 children (age=7.61; SD 1.70; range 5-11 years), the mean baseline SE was-2.15 (SD 0.62) D, and AL was 24.24 (SD 0.79) mm. After 2 years, higher increases occurred in all variables except ACD in the untreated group vs. the atropine group, respectively: SE (-0.51 (SD 0.39) D vs. -0.76 (SD 0.37) D, P0.001), AL (0.20 (SD 0.20) mm vs. 0.37 (SD 0.27) mm, P0.001) and Mean-K (0.01 (0.28) D vs. 0.09 (0.32) D, P=0.018). Myopia progression was reduced by 32% in the treatment group. There were more progressors1D/2y in the control group: 62/168 (36.9%) vs. 35/171 (20.5%) (P0.001). Atropine was identified as a protective factor against myopia progression (B=1.12; 95% CI= 0.98-1.27; P=0.001).Spanish children showed a low rate of myopia progression. Atropine 0.01% showed a significant effect in slowing the progression of both refractive error and axial elongation.

Canine oral malignant melanoma (COMM) is considered a chemo-resistant cancer with a poor long-term prognosis. The melanoma-associated antigen A (MAGE-A) genes, which belong to the cancer-testis antigen family, are expressed in several different canine cancers but not in normal somatic tissue. This study evaluates the expression of MAGE-A proteins and their prognostic role in COMM. The study was conducted in 2 parts. During the first part, biopsies from oral malignant melanomas from 43 dogs were examined and immunohistochemically assessed for expression of MAGE-A proteins. For the second part, the association between MAGE-A expression and outcome was assessed using follow-up data which was available for 20 dogs whose primary tumour had been controlled with surgery +/- radiation therapy. MAGE-A proteins were expressed in 88.4% (38/43) of oral malignant melanomas and had a predominantly cytoplasmic expression pattern. Immunopositivity was observed in more than 50% of the cells in 21 dogs (48.8%). Immunostaining intensity was classified as weak, moderate and intense in 16 (37%), 16 (37%) and 6 (14%) cases, respectively. No staining for MAGE-A was seen in 5 dogs (11%). Dogs whose COMM had weak MAGE-A staining intensity had a median survival time (MST) of 320 days while this was 129 days for dogs with moderate and intense immunostaining (p = 0.161). Dogs whose COMM had50% of positive staining neoplastic cells had an MST of 141 days and dogs with a staining50% had an MST of 320 days (p = 0.164). MAGE-A expression did not influence survival in our cohort.

En el 2009 un grupo de tareas encabezado por la Sociedad Americana de Enfermedades Infecciosas (IDSA) recomendó niveles de vancomicina entre 15-20 mg/L para asegurar efectividad ante el aumento de las concentraciones mínimas inhibitorias del Staphylococcus aureus resistente a Meticilina (MRSA). No existe evidencia concluyente sobre el impacto de estos nuevos niveles terapéuticos en el riesgo de nefrotoxicidad. Objetivo: determinar si existe una asociación entre los niveles plasmáticos valle de vancomicina y el desarrollo de nefrotoxicidad, independientemente de la presencia o no de otros factores de riesgo para lesión renal. Metodología: se realizó un estudio de cohorte retrospectivo. Se estudiaron pacientes ingresados a UCI del Hospital Santo Tomás, entre el 01 de enero del 2018 y el 31 de diciembre del 2018, que fueron tratados con vancomicina. Se realizó análisis bivariado y multivariante. Resultados: 54 pacientes entraron al análisis; se inició la monitorización de niveles plasmáticos principalmente después de la cuarta dosis (77.78%); 13 pacientes (24.07%) desarrollaron nefrotoxicidad por vancomicina; en el análisis bivariado la única variable con una relación estadísticamente significativa con nefrotoxicidad fue tener niveles valle >15 mg/L (P=0.003). El análisis de regresión logística multivariante mostró que los niveles valle >15 mg/L tienen una asociación estadísticamente significativa con nefrotoxicidad (OR, 15.20 [95% IC, 1.48-156.11]; P=0.022), la cual es independiente de otros confusores. Conclusiones: Los niveles valle de vancomicina >15 mg/L se asociaron de forma independiente a nefrotoxicidad por vancomicina. Se deben realizar estudios prospectivos para definir la asociación de niveles valle de vancomicina con el desarrollo de nefrotoxicidad.

espanolLa insuficiencia cardiaca con fraccion de eyeccion del ventriculo izquierdo reducida (FEVIr) es una entidad al alza, dada su incidencia creciente y el aumento de su supervivencia, lo que hace que cada vez sea una entidad mas frecuente en cualquier consulta. Es importante realizar un adecuado estudio etiologico que permita detectar causas reversibles de disfuncion sistolica. Hoy en dia, la gran mayoria de los casos son secundarios a cardiopatia isquemica, patologia que siempre se debe descartar adecuadamente en este tipo de pacientes. El ecocardiograma sigue siendo la prueba de referencia, si bien la resonancia magnetica, por su precision y por la capacidad de realizar un estudio de caracterizacion tisular, es la prueba mas exacta y que mas informacion aporta. El tratamiento de la IC con FEVIr comprende una compleja medida de terapias no farmacologicas, farmacologicas y de dispositivos implantables. A diferencia de la IC con FEVI preservada, en estos pacientes hay tratamientos que han demostrado mejorar el pronostico de estos en ensayos aleatorizados. Surge entonces la necesidad de realizar un tratamiento individualizado y optimo para cada paciente. A su vez, es importante el adecuado tratamiento de todas las comorbilidades que presentan estos pacientes, ya que pueden influir en una mala evolucion clinica. EnglishHeart failure with reduced left ventricular ejection fraction (rLVEF) is on the increase, given its increasing incidence and improved survival, and is therefore an entity that is increasingly seen in any consultation. An adequate aetiological study is important to detect reversible causes of systolic dysfunction. At present most cases are secondary to ischaemic heart disease, which must always be appropriately ruled out in these types of patients. The echocardiogram is still the benchmark test, although magnetic resonance imaging, due to its precision and ability to provide tissue characterisation, is the most exact test and offers the most information. Treatment of HF with rLVEF comprises a complex array of non-pharmacological, pharmacological, and implantable device therapies. Unlike HF with preserved LVEF, there are treatments that have been shown to improve the prognosis of these patients in randomised clinical trials. The need arises, therefore, for optimal treatment tailored to each patient. In turn, it is important to treat all comorbidities appropriately in these patients, as they could contribute to a poor clinical outcome.

espanolLa insuficiencia cardiaca cronica (ICC) constituye un problema de salud de gran relevancia en nuestro medio, afectando al 1%-2% de la poblacion adulta en paises desarrollados, y cuya prevalencia aumenta por encima del 10% en mayores de 70 anos. El tratamiento de la ICC pretende mejorar la clase funcional, la calidad de vida, prevenir la hospitalizacion y reducir la mortalidad. Es necesaria una distincion importante entre los pacientes con ICC y fraccion de eyeccion del ventriculo izquierdo reducida (ICFEVIr) menor del 40% y aquellos con FEVI en rango medio (ICFEVIm) del 40%-50% o preservada (ICFEVIp) mayor del 50, pues tiene importantes connotaciones en lo referente al tratamiento farmacologico. El abordaje de estos pacientes, particularmente aquellos con una FEVI reducida, es complejo y con frecuencia es necesario el enfoque multidisciplinar en unidades de ICC que aunan distintas especialidades como cardiologia, medicina interna, nefrologia, cirugia cardiaca, rehabilitacion, geriatria y cuidados paliativos. EnglishChronic heart failure (CHF) is a major problem in our setting, affecting 1%-2% of the adult population in developed countries, and whose prevalence exceeds 10% in those over the age of 70. Treatment of CHF aims to improve functional class, quality of life, prevent hospitalisation and reduce mortality. It is important to distinguish patients with CHF and reduced left ventricular ejection fraction (HF with rLVEF less than 40%) from those with mid-range (HF with mLVEF, 40%-50%) or preserved left ventricular ejection fraction (pLVEF, greater than 50%), as there are significant implications for pharmacological treatment. Management of these patients is complex, especially those with reduced LVEF, and often requires a multidisciplinary approach in CHF units that combine different specialties such as cardiology, internal medicine, nephrology, cardiac surgery, rehabilitation, geriatrics, and palliative care.

espanolLas tecnicas de imagen y la medicion de biomarcadores tienen un papel fundamental tanto en el diagnostico inicial del paciente con disnea, en el que se contempla el diagnostico de insuficiencia cardiaca, como en aquellos pacientes ya diagnosticados, en los que se busca identificar la etiologia, establecer un valor pronostico y seleccionar las mejores alternativas terapeuticas de acuerdo con la evidencia actual. EnglishImaging techniques and the measurement of biomarkers play a key role in both the initial diagnosis of the patient with dyspnoea, in which a diagnosis of heart failure is considered, and those already diagnosed with the condition, where the aim is to identify the aetiology, establish a prognostic value, and select the best therapeutic alternatives according to current evidence.

espanolLa insuficiencia cardiaca (IC) con fraccion de eyeccion del ventriculo izquierdo preservada (FEVIp) constituye una causa importante de morbimortalidad en nuestro medio, y su prevalencia esta aumentando a causa del envejecimiento de la poblacion y del aumento de las comorbilidades, con influencia sobre el sistema cardiovascular. Las tasas de mortalidad son cercanas a las de los pacientes con IC y fraccion de eyeccion reducida (FEVIr). La disfuncion diastolica por aumento de la rigidez miocardica constituye la base de esta entidad, al producirse una transmision retrograda de las presiones de llenado al circuito vascular pulmonar y a las camaras derechas. A nivel molecular, se ha descrito un aumento del estado proinflamatorio y protrombotico como origen del problema. El diagnostico supone un autentico reto y no existe un unico metodo validado, habiendose propuesto varias tablas de puntuacion en base a hallazgos clinicos, analiticos, ecocardiograficos y de medicion invasiva de la presion diastolica del ventriculo izquierdo. No existe ningun farmaco que haya demostrado mejorias en la supervivencia o en la disminucion de la tasa de ingresos por IC. El tratamiento se centra en la mejoria de la capacidad funcional y de la calidad de vida, incidiendo en el manejo de las comorbilidades y del estado de volemia. EnglishHeart failure (HF) with preserved left ventricular ejection fraction (PLVEF) is a major cause of morbidity and mortality in our setting, and its prevalence is rising due to the ageing population and increased comorbidities that impact the cardiovascular system. Mortality rates are close to those of patients with reduced ejection fraction (rLVEF). Diastolic dysfunction due to increased myocardial stiffness is the basis of this condition, as there is retrograde transmission of filling pressures to the pulmonary vascular circuit and right chambers. An increased proinflammatory and prothrombotic state has been described as the origin of the problem at the molecular level. Diagnosis is very challenging, and there is no single validated method, several score tables have been proposed based on clinical, laboratory, echocardiographic findings, and invasive measurement of the left ventricle diastolic pressure. No drug has been shown to improve survival or decrease the rate of admissions due to HF. Treatment focusses on improving functional capacity and quality of life, with emphasis on the management of comorbidities and blood volume status.

espanolLa insuficiencia cardiaca aguda descompensada es uno de los motivos mas frecuentes de consulta en urgencias. Dada la situacion de compromiso vital que puede llegar a suponer, es importante que se instaure un tratamiento eficaz de la misma de manera paralela al proceso diagnostico. El tratamiento de la congestion es uno de los pilares fundamentales de la misma, ya que esta se encuentra presente en la mayoria de los pacientes. Un adecuado tratamiento diuretico ayudara a mejor la sintomatologia y el pronostico de los pacientes con insuficiencia cardiaca. La hipoperfusion puede aparecer de manera mucho menos frecuente, pero empeora las cifras de mortalidad y el pronostico cuando esta presente, por lo que debe diagnosticarse y tratarse de manera precoz. Otras medidas no farmacologicas, fundamentalmente la oxigenoterapia en todas sus modalidades, son tambien basicas en el tratamiento de estos pacientes. EnglishAcute decompensated heart failure is one of the most frequent reasons for consultation in the emergency department. Because it can be a life-threatening situation, it is important that effective treatment is implemented in tandem with the diagnostic process. Treatment of congestion is one of the mainstays of its treatment, as it is present in most of these patients. Adequate diuretic treatment will help to improve the symptoms and prognosis of patients with heart failure. Hypoperfusion may develop much less frequently, but worsens mortality and prognosis when present, and therefore should be diagnosed and treated promptly. Other non-pharmacological measures, primarily oxygen therapy in all its modalities, are also key in the treatment of these patients.

Acute heart failure (AHF) is an increasingly frequent clinical syndrome in our setting. The heterogeneity of this syndrome, a consequence of multiple pathophysiological mechanisms, makes it difficult to create a consensus protocol for its treatment. There are multiple triggers and hormone amplification mechanisms that can act on a basic anatomical substrate, both of which must be adequately explored to reach an accurate diagnosis that will affect the patient's management and prognosis. As part of diagnosis, the clinical history and physical examination, aimed at detecting signs of congestion (most frequent) or hypoperfusion, remain fundamental tools. In turn, there are traditional complementary tests (plain x-ray, electrocardiogram) and other more advanced tools (heart and lung ultrasound, computed tomography, natriuretic peptides) that are very useful to establish a diagnosis, guide treatment and determine these patients’ prognosis.

espanolLa insuficiencia cardiaca (IC) es un sindrome complejo y heterogeneo, cada vez mas prevalente en la poblacion. Para clasificar el mismo, podemos seguir distintos criterios que posteriormente son importantes a la hora de realizar estudios de investigacion, y que pueden incluir variables clinicas, analiticas y de imagen. Si bien la incidencia de esta enfermedad se encuentra estable o en leve descenso, la prevalencia se muestra al alza por factores como el envejecimiento y la mejora de los tratamientos medicos disponibles. Es importante conocer los distintos factores de riesgo que aumentan la probabilidad de padecerla, asi como las comorbilidades asociadas mas frecuentes, que muchas veces tienen origen y mecanismo fisiopatologicos comunes. Independientemente del origen y de la clasificacion, los pacientes con IC presentan una expectativa de vida y unos indices de calidad disminuida que deben alertarnos sobre la necesidad de una adecuada prevencion, asi como de su diagnostico precoz. EnglishHeart failure (HF) is a complex and heterogenous syndrome that is increasingly prevalent in the population. We can use different criteria to classify it, which are important for subsequent research studies and may include clinical, laboratory and imaging variables. Although the incidence of the disease is stable or slightly declining, its prevalence is rising due to factors such as ageing and the improved medical treatment available. It is important to be aware of the different risk factors that increase the likelihood of developing the disease, and its most common associated comorbidities, which often have a common pathological origin and mechanism. Regardless of the origin and classification, patients with HF have reduced life expectancy and quality indices, which should highlight the need for adequate prevention, and early diagnosis.

The early identification of type 2 diabetic (T2D) patients at risk of developing coronary artery disease (CAD) remains a challenge. The coronary artery calcium score (CACs) is considered the most sensitive tool for assessing CAD risk in diabetic population, and the identification of a more targeted population in which the CACs would be more cost-efficient seems warranted. The accumulation of advanced glycation end products plays an important role in the pathogenesis of cardiovascular disease (CVD) in patients with diabetes. The aim of this study was to evaluate whether the assessment of skin autofluorescence (SAF) could be useful tool to identify those diabetic patients in whom CACs assessment should be prioritized. Prospective case–control study, comprising 156 subjects with T2D with no history of clinical CVD and 52 non-diabetic subjects matched by age. A value of CACs ≥ 400 Agatston Units (AU) was considered as “high CVD risk.” Logistic regression analysis to predict a CACs ≥ 400 AU was performed. Sensibility and specificity were calculated using the optimal cutoff point based on ROC curve. T2D patients had higher value of SAF compared to controls (p = 0.011). Among subjects with diabetes, 122 presented CACs

Because of its impact on social well-being, mental health, and financial security, the COVID-19 health crisis may increase the risk of suicide. This study’s objective was to determine what impact the period of confinement might have had on the incidence of deaths by suicide (DBS) in the Extremadura region (Spain). Cases registered in the Institutes of Legal Medicine and Forensic Science (IMLyCFs) from January 2015 to December 2020 were collected. Intra- and interannual comparisons were made of the suicide rates in the periods of confinement (March–June) and postconfinement (July–October) of 2020 with those of the preceding 5 years. After seasonally adjusting the data by means of a time series analysis, rate ratios (RRs) were calculated together with their 95% confidence intervals (CI). There were no significant differences between the suicide rates of 2020 and the mean of the preceding 5 years (RR = 0.94, CI: 0.56–1.55), and neither did any differences seen in the intra-annual analysis from the period of confinement to postconfinement reach statistical significance (RR = 0.74, CI: 0.45–1.20). It is necessary to strengthen vigilance during and after the crisis and ensure that assistance mechanisms are in place to prevent an increase in suicides.

Resumen Fundamento El examen fisico presenta una rentabilidad limitada en la estimacion de la congestion venosa sistemica y en la prediccion de la mortalidad de los pacientes con insuficiencia cardiaca. Hemos evaluado la utilidad del fragmento amino terminal del peptido natriuretico cerebral (NT-proBNP), del antigeno de cancer 125 (CA125), los hallazgos de la ecografia pulmonar, la estimacion del volumen plasmatico relativo (VPr) y el cociente urea/creatinina, como parametros subrogados de congestion venosa y predictores de mortalidad. Material y metodos Estudio retrospectivo de 203 pacientes ingresados por insuficiencia cardiaca aguda en el servicio de medicina interna de un hospital terciario, con seguimiento monografico en consultas externas entre los anos 2013 y 2018. Los datos clinicos se recogieron de los registros hospitalarios. Las intervenciones terapeuticas se guiaron por el criterio clinico del medico responsable de cada paciente. El desenlace principal fue mortalidad general tras un ano de seguimiento. Resultados La edad media de los pacientes fue 78,8 anos, 47% eran varones. Un total de 130 (65%) pacientes presentaban insuficiencia cardiaca cronica, 51 (26,2%) pacientes se encontraban en clase III-IV de la New York Heart Association y 116 (60%) pacientes presentaban fraccion de eyeccion de ventriculo izquierdo preservada. Durante el seguimiento fallecieron 42 (22%) pacientes. Los valores de NT-proBNP ≥ 3.804 pg/mL (HR 2,78 [1,27-6,08]; p = 0,010) y el VPr ≥ –4,54% (HR 2,74 [1,18-6,38]; p = 0,019) fueron predictores independientes de mortalidad general tras un ano de seguimiento. Conclusiones El NT-proBNP y el VPr son predictores independientes de mortalidad a un ano entre los pacientes ingresados por insuficiencia cardiaca descompensada.

Objetivos: La evaluación de la calidad de vida asociada a distintos tratamientos en pacientes con cáncer de próstata es clave para tomar decisiones terapéuticas informadas. Sin embargo, los resultados en práctica clínica son heterogéneos e insuficientes. Material y métodos: Estudio observacional prospectivo en pacientes que iban a iniciar tratamiento con radioterapia externa o prostatectomía radical laparoscópica (PR) por cáncer de próstata localizado. Se completó el cuestionario de calidad de vida EPIC-CP antes de iniciar el tratamiento (basal) y tras 6, 12 y 24 meses del tratamiento. Resultados: El análisis incluyó 59 pacientes: 34 (58%) se sometieron a prostatectomía radical y 25 (42%) recibieron radioterapia. La calidad de vida media empeoró en los dos grupos de tratamiento y para todos los dominios, observándose un empeoramiento máximo a los 6 meses, recuperándose hasta normalizar las puntuaciones a los 24 meses. A los 6 y 12 meses de tratamiento, el porcentaje de pacientes que experimentó un cambio mínimo relevante en calidad de vida fue significativamente superior en el grupo de PR que en el de radioterapia para los dominios incontinencia y sexual; estas diferencias no se observaron a los 24 meses. Discusión: El cuestionario EPIC-CP permite estimar el cambio mínimo relevante, facilitando así la interpretación clínica de los resultados. Conclusiones: A medio plazo, la PR y la radioterapia externa impactan de una forma distinta en la calidad de vida asociada a la incontinencia y la función sexual. A los 24 meses del tratamiento la calidad de vida se normaliza, independiente del tratamiento elegido.

Objective: Experts recommended that direct discharge without hospitalization (DDWH) for emergency departments (EDs) able to observe acute heart failure (AHF) patients should be 40%, and these discharged patients should fulfil the following outcome standards: 30-day all-cause mortality 40%. Considering DDWH patients altogether, outcomes A/C were above the recommended standards (4.3%/29.4%), while outcome B was nearly met (B = 10.1%). When analyzing individual EDs, 58.1% of them achieved the outcome B standard, while outcomes A/C standards were barely achieved (19.3%/9.7%). We observed clinically relevant linear/quadratic relationships between higher DDWH and worse outcomes B (weighted R-2 = 0.184/0.322) and C (weighted R-2 = 0.430/0.624), but not with outcome A (weighted R-2 = 0.002/0.022). Conclusions: The EDs of this nationwide cohort do not fulfil the standards for AHF patients with DDWH. High DDWH rates negatively impact ED revisit or hospitalization but not mortality. This may represent an opportunity for improvement in better selecting patients for early ED discharge and in ensuring early follow-up after ED discharge. (c) 2020 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.

Background. Immunotherapy represents one of the fundamental treatments in the management of some types of cancer, especially malignant melanoma. Toxicity derived from increased immune system activity can manifest in multiple organs and systems. We present a case of hematological toxicity, manifested as hemophagocytic syndrome (HPS), which was successfully treated with an anti-interleukin-6 antibody (tocilizumab). Case Report. This case presents a 75-year-old woman diagnosed with metastatic choroidal melanoma, refractory to several lines of treatment. After the failure of the previous lines, ipilimumab was started. After the third dose, she developed grade 2 thrombocytopenia and anemia accompanied by elevated levels of ferritin, triglycerides, and decreased fibrinogen. Hemophagocytosis was observed in the bone marrow biopsy, and a PET-CT showed splenomegaly with increased metabolism. Treatment was based on high doses of corticosteroids and tocilizumab. Four days after the start of treatment, progressive clinical and analytical improvement was observed, achieving total remission of the condition. Discussion. HPS induced by immunotherapy is due to an immunorelated cytokine storm syndrome (CSS). The administration of the anti-interleukin-6 receptor antibody drug acted on this cytokine cascade, leading to stabilization and subsequent remission. For this reason, the use of tocilizumab should be part of the immunotherapy-induced HPS treatment algorithm.

This article is part of the thesis: Analysis of genetic variants associated with response to bisoprolol in patients with acute coronary syndrome with percutaneous coronary intervention with stent, within the doctoral program in Pharmacy at the University of Granada, to whom we thank for their collaboration. We would like to thank Dr. T. Eschenhagen and Dr. K. Kontula for sharing with us detailed information from their articles [16,22] which have allowed us to perform the meta-analysis., β-blockers are commonly prescribed to treat multiple cardiovascular (CV) diseases, but, frequently, adverse drug reactions and intolerance limit their use in clinical practice. Interindividual variability in response to β-blockers may be explained by genetic differences. In fact, pharmacogenetic interactions for some of these drugs have been widely studied, such as metoprolol. But studies that explore genetic variants affecting bisoprolol response are inconclusive, limited or confusing because of mixed results with other β-Blockers, different genetic polymorphisms observed, endpoint studied etc. Because of this, we performed a systematic review in order to find relevant genetic variants affecting bisoprolol response. We have found genetic polymorphism in several genes, but most of the studies focused in ADRB variants. The ADRB1 Arg389Gly (rs1801253) was the most studied genetic polymorphism and it seems to influence the response to bisoprolol, although studies are inconclusive. Even, we performed a meta-analysis about its influence on systolic/diastolic blood pressure in patients treated with bisoprolol, but this did not show statistically significant results. In conclusion, many genetic polymorphisms have been assessed about their influence on patients´ response to bisoprolol and the ADRB1 Arg389Gly (rs1801253) seems the most relevant genetic polymorphism in this regard but results have not been confirmed with a meta-analysis. Our results support the need of further studies about the impact of genetic variants on bisoprolol response, considering different genetic polymorphisms and conducting single and multiple SNPs analysis, including other clinical parameters related to bisoprolol response in a multivariate study.

Background Adoptive immunotherapy with tumour-infiltrating lymphocytes (TIL) may benefit from the use of selective markers, such as PD-1, for tumour-specific T-cell enrichment, and the identification of predictive factors that help identify those patients capable of rendering tumour-reactive TILs. We have investigated this in ovarian cancer (OC) patients as candidates for TIL therapy implementation. Methods PD-1− and PD-1+ CD8 TILs were isolated from ovarian tumours and expanded cells were tested against autologous tumour cells. Baseline tumour samples were examined using flow cytometry, multiplexed immunofluorescence and Nanostring technology, for gene expression analyses, as well as a next-generation sequencing gene panel, for tumour mutational burden (TMB) calculation. Results Tumour-reactive TILs were detected in half of patients and were exclusively present in cells derived from the PD-1+ fraction. Importantly, a high TIL density in the fresh tumour, the presence of CD137+ cells within the PD-1+CD8+ TIL subset and their location in the tumour epithelium, together with a baseline T-cell-inflamed genetic signature and/or a high TMB, are features that identify patients rendering tumour-reactive TIL products. Conclusion We have demonstrated that PD-1 identifies ovarian tumour-specific CD8 TILs and has uncovered predictive factors that identify OC patients who are likely to render tumour-specific cells from PD-1+ TILs.

Molecular epidemiology of circulating clinical isolates is crucial to improve prevention strategies. The Spanish Working Group on multidrug resistant tuberculosis (MDR-TB) is a network that monitors the MDR-TB isolates in Spain since 1998. The aim of this study was to present the study of the MDR-TB and extensively drug-resistant tuberculosis (XDR-TB) patterns in Spain using the different recommended genotyping methods over time by a national coordinated system. Based on the proposed genotyping methods in the European Union until 2018, the preservation of one method, MIRU-VNTR, applied to selected clustered strains permitted to maintain our study open for 20 years. The distribution of demographic, clinical and epidemiological characteristics of clustered and non-clustered cases of MDR/XDR tuberculosis with proportion differences as assessed by Pearson's chi-squared or Fisher's exact test was compared. The differences in the quantitative variables using the Student's-t test and the Mann-Whitney U test were evaluated. The results obtained showed a total of 48.4% of the cases grouped in 77 clusters. Younger age groups, having a known TB case contact (10.2% vs 4.7%) and XDR-TB (16.5% vs 1.8%) were significantly associated with clustering. The largest cluster corresponded to a Mycobacterium bovis strain mainly spread during the nineties. A total of 68.4% of the clusters detected were distributed among the different Spanish regions and six clusters involving 104 cases were grouped in 17 and 18 years. Comparison of the genotypes obtained with those European genotypes included in The European Surveillance System (TESSy) showed that 87 cases had become part of 20 European clusters. The continuity of MDR strain genotyping in time has offered a widespread picture of the situation that allows better management of this public health problem. It also shows the advantage of maintaining one genotyping method over time, which allowed the comparison between ancient, present and future samples. The molecular methods applied in this work were supported by the Carlos III Health Institute in the context of two consecutive Grants FIS15/0317 and 18/0336 and JC was awarded a scholarship by the Government of Aragon / European Social Fund, “Building Europe from Aragon”. Sí

Resumen La presente investigación se desarrolló en la Unidad Educativa Salcedo, cantón el cual lleva su mismo nombre, ubicado en la provincia de Cotopaxi, Ecuador. Este trabajo presenta resultados de un análisis basado en la pedagogía constructivista del proceso de enseñanza-aprendizaje, cuyo propósito fue tener una visión clara sobre el tipo de metodología utilizada dentro del aula de clases por parte de las maestras y los maestros. Se pudo verificar que este interviene de manera significativa al ejecutar algunos cambios, de la misma forma que elementos y técnicas son los más apropiados para lograr un mejor conocimiento en el alumnado. Se contó con la participación de docentes de noveno año de Educación General Básica, del período académico 2019 – 2020, en las asignaturas esenciales del tronco común en el currículo educativo ecuatoriano (Matemáticas, Lengua y Literatura, Ciencias Naturales y Estudios Sociales), donde se pudo detectar distintos problemas de aprendizaje como distracción, aburrimiento, falta de interés, entre otros, lo cual dificultaba su aprendizaje; posteriormente, se efectuaron medidas correctivas. Para este análisis se utilizó un enfoque de estudio cualitativo con un diseño de investigación-acción. Además, se elaboraron entrevistas al cuerpo docente mediante un formulario online de Google, las cuales permitieron diagnosticar el conocimiento a nivel teórico de la pedagogía constructivista, lo que a su vez se corroboró con una ficha de observación donde se pudo constatar cómo son las clases de cada docente sin previo aviso. Los resultados más relevantes indican que el profesorado, en teoría, conoce los conceptos de la pedagogía constructivista, sin embargo, al momento de trasladarlos al aula, ello no se evidencia, por lo que se recomienda a las autoridades capacitación continua, el dialogo con el personal docente para que utilicen el modelo constructivista, que usen nuevas formas de enseñanza dentro del aula de clases y rompan el temor que tienen para aplicarlo. Abstract This study was conducted at the Salcedo Educational Unit, in the province of Cotopaxi, Ecuador and is based on a constructive pedagogy analysis of teaching and learning. The objective of the study was to observe the different types of methodologies teachers use in classrooms and, as we corroborated, their impact on change and the elements and techniques which are essential to helping students achieve better knowledge acquisition. Participants included Ninth grade Basic General Education Teachers for the 2019-2020 academic year, responsible for teaching the essential core subjects of the Ecuadorian Educational Curriculum (Mathematics, Language and Literature, Natural Sciences and Social Studies). If learning weaknesses were detected, such as distraction, boredom or lack of interest, which hindered learning, corrective measures were then taken. The study was based on a qualitative approach with an action-research design. Teachers were interviewed using an online Google form, allowing us to gauge their theoretical knowledge of constructivist pedagogy. Observation of the teachers while in class was then carried out to corroborate their knowledge and performance. It was noted, that many of these results noted in the theoretical evaluation were not applied in the classroom, which emphasizes the need for further training and open dialogues with the teachers. It is recommended that school authorities provide continuous training and discussions with the teaching staff so that they may be able to use the constructivist mode in class, learn new teaching techniques and be less fearful of applying them in the classroom.

We observed a severe case of cerebral toxoplasmosis in a 22-year-old woman diagnosed with dermatomyositis in 2016 in Venezuela, and treated with rituximab and azathioprine. The patient met clinical and microbiological criteria. Treatment with pyrimethamine and sulfadiazine was initiated, and the patient was discharged. She was rehospitalized with signs and symptoms of a manic episode. During hospitalization, the patient developed acute kidney injury related to sulfadiazine crystalluria. Finally, acute kidney injury was resolved and the patient was successfully discharged.

Resumen Introduccion A pesar de los avances en el diagnostico y el tratamiento, la insuficiencia cardiaca (IC) sigue teniendo una alta morbimortalidad. El tratamiento de las comorbilidades y la educacion sanitaria se han demostrado eficaces, asi como la atencion multidisciplinar, en unidades especializadas, aunque ello implica un esfuerzo organizativo y estructural no siempre disponible. Presentamos los resultados de una consulta ambulatoria simple, centrada en la atencion monografica a la IC. Pacientes y metodos La consulta incluyo a pacientes dados de alta tras una hospitalizacion (ingreso indice) por descompensacion de IC en el servicio de Medicina Interna. El seguimiento se realizo por internistas con especial dedicacion (no exclusiva) en IC y una enfermera con dedicacion compartida. El seguimiento consistio en visitas fijas 1, 3, 6 y 12 meses tras el alta, mas visitas a demanda en caso de necesidad. Resultados Se incluyo a 250 pacientes con un seguimiento minimo de un ano. La disminucion de los ingresos y las visitas a Urgencias por IC fue del 56 y el 61% (p Conclusion Un modelo sencillo basado en la atencion monografica a la IC es eficaz en la reduccion de reingresos y la optimizacion del tratamiento. La carencia de recursos asistenciales no deberia suponer un obstaculo para una atencion monografica a pacientes con IC.

Background Despite advances in the diagnosis and treatment of heart failure (HF), the condition still has high morbidity and mortality. Health education and the treatment of comorbidities have been shown to be effective, as has multidisciplinary care in specialized units, although this involves organizational and structural efforts that are not always feasible. We present the results of a simple outpatient consultation, focused on the specialized care of HF. Patients and methods The consultation included patients discharged after hospitalization (index hospitalization) for decompensated HF from an internal medicine department. The follow-up was conducted by internists especially dedicated (not exclusively) to HF and a nurse partially dedicated to HF. The follow-up consisted of fixed visits 1, 3, 6 and 12 months after the discharge, with more visits on demand if needed. Results A total of 250 patients were included with a minimum follow-up of 1 year. The reduction in hospitalisations and emergency department visits was 56% and 61% (p Conclusion A simple model based on a specialized care consultation for HF is effective in reducing readmissions and optimizing the treatment. The lack of healthcare resources should not be an obstacle for specialized care for patients with HF.

La violencia es un fenómeno social que se encuentra en todos los ámbitos de la vida humana. Las violencias de género e intrafamiliares siguen siendo un problema de salud pública grave en nuestro contexto latinoamericano y también a nivel mundial. Este problema sigue siendo foco de interés durante la crisis sanitaria que se vive debido a la pandemia por COVID-19. En el presente artículo se realiza una revisión bibliográfica que permite reflexionar sobre estos tipos de violencia en la situación actual generada por el COVID-19.

Objective The severity of breakthrough cancer pain (BTcP) impacts patients' quality of life, increases the risk of anxiety and depression, lowers functional capacities, and may lead to poor compliance with cancer treatments. The aim of the current study was to assess, in a real-life setting, patient satisfaction with a fentanyl-pectin-nasal-spray (FPNS) for BTcP management in head and neck (H&N) cancer patients treated by radiotherapy. Materials and Methods This non-interventional, prospective study was conducted in 92 adult H&N-cancer patients undergoing radiotherapy and who started FPNS treatment for BTcP. Throughout the radiotherapy period, the patients completed self-diaries to assess their BTcP episodes, FPNS use, satisfaction on FPNS efficiency (primary outcome), tolerability and ease of use. Results Prior to FPNS treatment, 86% of the patients were experiencing ≤4 BTcP episodes/day. During the radiotherapy period, the BTcP episodes were treated with a median dose of 100µg of FPNS. Patients were "satisfied/very-satisfied" with the efficiency (73% of assessments), ease of use (87% of assessments) and tolerability (87% of assessments) of FPNS. In total, 27% of patients reported at least one adverse event related to FPNS and 4% of patients discontinued treatment due to adverse events. None of the adverse events were serious. Patient quality of life was maintained throughout the radiotherapy period. Conclusion This study showed, in a real-life setting, that a clear majority of H&N cancer patients treated with FPNS for BTcP throughout radiotherapy expressed satisfaction with this analgesic treatment.

Patients with primary immunodeficiency disease (PID) have an increased risk of experiencing physical activity limitations, social difficulties, and psychological problems due to their chronic condition. Evaluation of their health-related quality of life (HRQOL) and fatigue is crucial in these patients to help understand their complex disease and provide adequate medical care. In this study, we evaluated HRQOL and fatigue in pediatric and young adult patients with PID attending our center. Participants completed the Pediatric Quality of Life Inventory (PedsQL), version 4.0, and the PedsQL multidimensional fatigue module, standard version. Fifty-three PID patients were recruited (age range: 2–23 years). The mean HRQOL score obtained was 66.61 (SD: 18.73) out of 100, and the emotional and work/school dimensions were the ones most highly affected. There were no significant differences in reported quality of life between patients and their caregivers. The mean patient-reported fatigue value was 68.81 (SD: 17.80) out of 100, and the rest-related dimension was the one most highly affected. In the caregivers’ assessment, general fatigue was the most highly affected dimension. The results of this study show that quality of life is poor and fatigue measures are considerably increased in our young adult and pediatric patients with PIDs. These findings can indicate areas requiring more intensive interventions, and they will serve as a basis for comparison of future results.

Objective To evaluate the level of compliance to the clinical practice guidelines (CPG) recommendations for the diagnosis and monitoring of the main chronic vascular complications of patients with type2 diabetes (DM2) in Primary Care (PC). Material and methods A retrospective cross-sectional descriptive study was conducted on patients aged 18years and over and consecutively selected in PC. Patient data were obtained by direct interview and access to the computerised history, and recording the clinical and analytical variables of interest. The determination and recording of urine microalbumin (MALB), glomerular filtration rate (GFR), foot examination (pulse palpation, monofilament or tuning fork), and electrocardiogram (ECG), if performed annually, and the eye fundus (FO) every two years. Results A total of 1,420 patients were included, of which 55.8% were male. The mean age (SD) was 70.6 (10.8) years and the mean onset of the diabetes was 9.3 (6.2) years. The mean BMI (kg /m2) was 30.1 (5.4) in females and 29.5 (4.7) in males (P=.023), and a mean HbA1c (%) of 6.9 (1.2). Good metabolic control of DM was achieved in 63.0% (95%CI: 60.4-65.5). In the last two years, 976 (68.7%; 95%CI: 66.2-71.1) patients had an eye fundus examination. The urine microalbumin had been performed on 1,228 patients (86.5%; 95%CI: 84.6-88.2). The mean glomerular filtration rate was performed on 1,391 patients (98.0%; 95%CI: 97.1-98.6), the foot pulses examination on 626 (44.1%; 95%CI: 41.5-46.7), and the neurological examination on 473 patients (33.3%; 95%CI: 30.8-35.8). Conclusions The results of the present study indicate that the presence of retinopathy or neuropathy is not explored in a significant percentage of patients with DM2. Only seven out of ten patients have been screened for retinopathy, one in three had a neurological examination, and only one in four have all the scans recommended by the CPG.

COVID-19-specific vaccines are efficient prophylactic weapons against SARS-CoV-2 virus. However, boosting innate responses may represent an innovative way to immediately fight future emerging viral infections or boost vaccines. MV130 is a mucosal immunotherapy, based on a mixture of whole heat-inactivated bacteria, that has shown clinical efficacy against recurrent viral respiratory infections. Herein, we show that the prophylactic intranasal administration of this immunotherapy confers heterologous protection against SARS-CoV-2 infection in susceptible K18-hACE2 mice. Furthermore, in C57BL/6 mice, prophylactic administration of MV130 improves the immunogenicity of two different COVID-19 vaccine formulations targeting the SARS-CoV-2 spike (S) protein, inoculated either intramuscularly or intranasally. Independently of the vaccine candidate and vaccination route used, intranasal prophylaxis with MV130 boosted S-specific responses, including CD8+-T cell activation and the production of S-specific mucosal IgA antibodies. Therefore, the bacterial mucosal immunotherapy MV130 protects against SARS-CoV-2 infection and improves COVID-19 vaccines immunogenicity., CF was supported by AECC Foundation (INVES192DELF) and is currently funded by the Miguel Servet program (ID: CP20/00106) (ISCIII). IH-M receives the support of a fellowship from la Caixa Foundation (ID 100010434, fellowship code: LCF/BQ/IN17/11620074) and from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 713673. AJ-C is a postgraduate fellow of the City Council of Madrid at the Residencia de Estudiantes (2020–2021). GD is supported by an European Molecular Biology Organization (EMBO) Long-term fellowship (ALTF 379-2019). This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. Project number 892965. OL and JA-C acknowledge Comunidad de Madrid (Tec4Bio-CM, S2018/NMT-4443, FEDER). Work in OL laboratory was funded by CNIO with the support of the projects Y2018/BIO4747 and P2018/NMT4443 from Comunidad de Madrid and co-funded by the European Social Fund and the European Regional Development Fund. The CNIO is supported by the Instituto de Salud Carlos III (ISCIII). Work at CNB and CISA is funded by the Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII), Fondo COVID-19 grant COV20/00151, and Fondo Supera COVID-19 (Crue Universidades-Banco Santander) (to JG-A). Work in the DS laboratory is funded by the CNIC; by the European Research Council (ERC-2016-Consolidator Grant 725091); by Agencia Estatal de Investigación (PID2019-108157RB); by Comunidad de Madrid (B2017/BMD-3733 Immunothercan-CM); by Fondo Solidario Juntos (Banco Santander); by a research agreement with Inmunotek S.L.; and by Fundació La Marató de TV3 (201723). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MICINN, and the Pro CNIC Foundation.

Background Previous studies have shown that prophylactic implantable cardioverter-defibrillators (ICD) in patients with symptomatic severe systolic dysfunction reduce all-cause mortality. However, their benefit in patients with severe systolic dysfunction of non-ischemic origin is not so clear, and is currently under debate. Methods/Aim We retrospectively reviewed all consecutive patients with nonischemic dilated cardiomyopathy (NICM) who underwent prophylactic ICD implantation between 2008 and 2020 in two tertiary centers. Our main goal was to identify predictors of appropriate ICD therapies (ATP and/or shocks) in this cohort of patients. Results A total of 224 patients were included, median age 62.7 years, 73.7% men. During a median follow-up of 51 months, 61 patients (27.2%) required appropriate ICD intervention, 7 patients (3.1%) presented inappropriate shocks and 11 (4.9%) had device infection. Patients that received appropriate ICD therapies, as compared to those who did not, were more frequently men (86.9% vs 68.7%, p=0.006) and were significantly younger (median age 58.7 years, IQR 53.0–64.8 vs 63.7, IQR 57.0–69.8; p=0.02). Left ventricular end diastolic volume (LV-EDV) and left ventricular end systolic volume (LV-ESV) were both significantly higher in this subgroup of patients (median LVEDV 100 ml/m2 vs 86, p=0.0106; median LVESV 72.2 ml/m2 vs 60.9, p=0.0467). A trend towards lower LVEF was also noted, but it did not reach statistical significance (26% vs 29%, p=0.077). Regarding ECG previous to implant, patients that required ICD intervention presented more frequently complete right bundle branch block (RBBB) (14.8% vs 4.3%, p=0.007). On the other hand, left bundle branch block (LBBB) was more frequent in those patients who did not receive ICD intervention during follow-up (47.2% vs 26.2%, p=0.005). Table 1 summarizes baseline characteristics and results. In a multivariate Cox regression analysis, RBBB (HR 3.9, CI 95% 1.9–8.0, p Conclusion RBBB and male sex may help identify patients with NICM at high-risk of ventricular arrhythmias requiring ICD intervention. Funding Acknowledgement Type of funding sources: None. Baseline characteristics and resultsKaplan-Meier curves