Miopatías RYR1 en la infancia: correlación fenotipo-genotipo e incidencia / RYR1 myopathies in childhood: phenotype-genotype correlation and incidence

Introducción: Las miopatías relacionadas con el receptor de rianodina de tipo 1 (RYR1-RM) constituyen la categoría más frecuente de miopatías congénitas. La introducción de técnicas genéticas ha cambiado el paradigma diagnóstico y sugiere la prioridad de estudios moleculares sobre biopsias. Este estudio busca explorar las características clinicoepidemiológicas de pacientes con variantes del gen RYR1 en un hospital pediátrico de tercer nivel con el objetivo de ampliar la comprensión de la correlación genotipo-fenotipo en las RYR1-RM. Pacientes y métodos: Estudio observacional, descriptivo y transversal, de pacientes menores de 14 años con síntomas miopáticos y variantes potencialmente patógenas del gen RYR1 entre enero de 2013 y diciembre de 2023, considerando variables como sexo, edad, desarrollo motor, variantes genéticas, patrón de herencia y otras manifestaciones. Todas las variables fueron tabuladas frente a la variante genética. Resultados: De los nueve pacientes incluidos, la incidencia estimada fue de aproximadamente 1/10.000 nacidos vivos. La mediana en el momento del diagnóstico fue de 6 años, con una variabilidad fenotípica significativa. Se observaron síntomas comunes, como debilidad y retraso del desarrollo motor. Las variantes genéticas afectaron al gen RYR1 de manera diversa, y hubo cinco variantes previamente no descritas. La biopsia muscular se realizó en cinco pacientes, en dos de ellos de tipo miopatía central core; en uno, multiminicore; en uno, desproporción congénita de fibras; y en otro, de patrón inespecífico. Conclusiones: Las RYR1-MR de nuestra serie ofrecieron variabilidad fenotípica y de afectación, con una incidencia en nuestra área de en torno a 1/10.000 recién nacidos. La mayoría de los casos fueron varones, de variantes missense dominantes. Aportamos cinco variantes genéticas no descritas con anterioridad.(AU)

Introduction: Ryanodine receptor type 1-related myopathies (RYR1-RM) represent the most prevalent category of congenital myopathies. The introduction of genetic techniques has shifted the diagnostic paradigm, suggesting the prioritization of molecular studies over biopsies. This study aims to explore the clinical and epidemiological characteristics of patients with RYR1 gene variants in a tertiary pediatric hospital, intending to enhance the understanding of the genotype-phenotype correlation in RYR1-RM. Patients and methods: An observational, descriptive, and cross-sectional study was conducted on patients under 14 years old with myopathic symptoms and potentially pathogenic RYR1 gene variants from January 2013 to December 2023. Variables such as gender, age, motor development, genetic variants, inheritance pattern, and other manifestations were considered. All variables were tabulated against the genetic variant. Results: Of the nine included patients, the estimated incidence was approximately 1 in 10,000 live births. The median age at diagnosis was six years, with significant phenotypic variability. Common symptoms such as weakness and delayed motor development were observed. Genetic variants affected the RYR1 gene diversely, including five previously undescribed variants. Muscle biopsy was performed in five patients, revealing central core myopathy in two, multiminicore in one, congenital fiber-type disproportion in one, and a nonspecific pattern in another.(AU)

[RYR1 myopathies in childhood: phenotype-genotype correlation and incidence]. / Miopatías RYR1 en la infancia: correlación fenotipo-genotipo e incidencia.

INTRODUCTION: Ryanodine receptor type 1-related myopathies (RYR1-RM) represent the most prevalent category of congenital myopathies. The introduction of genetic techniques has shifted the diagnostic paradigm, suggesting the prioritization of molecular studies over biopsies. This study aims to explore the clinical and epidemiological characteristics of patients with RYR1 gene variants in a tertiary pediatric hospital, intending to enhance the understanding of the genotype-phenotype correlation in RYR1-RM. PATIENTS AND METHODS: An observational, descriptive, and cross-sectional study was conducted on patients under 14 years old with myopathic symptoms and potentially pathogenic RYR1 gene variants from January 2013 to December 2023. Variables such as gender, age, motor development, genetic variants, inheritance pattern, and other manifestations were considered. All variables were tabulated against the genetic variant. RESULTS: Of the nine included patients, the estimated incidence was approximately 1 in 10,000 live births. The median age at diagnosis was six years, with significant phenotypic variability. Common symptoms such as weakness and delayed motor development were observed. Genetic variants affected the RYR1 gene diversely, including five previously undescribed variants. Muscle biopsy was performed in five patients, revealing central core myopathy in two, multiminicore in one, congenital fiber-type disproportion in one, and a nonspecific pattern in another. CONCLUSIONS: RYR1-RM in our series exhibited phenotypic and involvement variability, with an incidence in our area of around 1 in 10,000 live births. Most cases were male, with dominant missense variants. We contribute five previously undescribed genetic variants.

TITLE: Miopatías RYR1 en la infancia: correlación fenotipo-genotipo e incidencia.Introducción. Las miopatías relacionadas con el receptor de rianodina de tipo 1 (RYR1-RM) constituyen la categoría más frecuente de miopatías congénitas. La introducción de técnicas genéticas ha cambiado el paradigma diagnóstico y sugiere la prioridad de estudios moleculares sobre biopsias. Este estudio busca explorar las características clinicoepidemiológicas de pacientes con variantes del gen RYR1 en un hospital pediátrico de tercer nivel con el objetivo de ampliar la comprensión de la correlación genotipo-fenotipo en las RYR1-RM. Pacientes y métodos. Estudio observacional, descriptivo y transversal, de pacientes menores de 14 años con síntomas miopáticos y variantes potencialmente patógenas del gen RYR1 entre enero de 2013 y diciembre de 2023, considerando variables como sexo, edad, desarrollo motor, variantes genéticas, patrón de herencia y otras manifestaciones. Todas las variables fueron tabuladas frente a la variante genética. Resultados. De los nueve pacientes incluidos, la incidencia estimada fue de aproximadamente 1/10.000 nacidos vivos. La mediana en el momento del diagnóstico fue de 6 años, con una variabilidad fenotípica significativa. Se observaron síntomas comunes, como debilidad y retraso del desarrollo motor. Las variantes genéticas afectaron al gen RYR1 de manera diversa, y hubo cinco variantes previamente no descritas. La biopsia muscular se realizó en cinco pacientes, en dos de ellos de tipo miopatía central core; en uno, multiminicore; en uno, desproporción congénita de fibras; y en otro, de patrón inespecífico. Conclusiones. Las RYR1-MR de nuestra serie ofrecieron variabilidad fenotípica y de afectación, con una incidencia en nuestra área de en torno a 1/10.000 recién nacidos. La mayoría de los casos fueron varones, de variantes missense dominantes. Aportamos cinco variantes genéticas no descritas con anterioridad.

First detection of Omicron variant BA.4.1 lineage in dogs, Chile.

SARS-CoV-2's rapid global spread caused the declaration of COVID-19 as a pandemic in March 2020. Alongside humans, domestic dogs and cats are also susceptible to infection. However, limited reports on pet infections in Chile prompted a comprehensive study to address this knowledge gap. Between March 2021 and March 2023, the study assessed 65 pets (26 dogs and 39 cats) from 33 COVID-19+ households alongside 700 nasal swabs from animals in households with unknown COVID-19 status. Using RT-PCR, nasal, fecal, and environmental samples were analyzed for the virus. In COVID-19+ households, 6.06% tested positive for SARS-CoV-2, belonging to 3 dogs, indicating human-to-pet transmission. Pets from households with unknown COVID-19 status tested negative for the virus. We obtained 2 SARS-CoV-2 genomes from animals, that belonged to Omicron BA.4.1 variant, marking the first report of pets infected with this lineage globally. Phylogenetic analysis showed these sequences clustered with human sequences collected in Chile during the same period when the BA.4.1 variant was prevalent in the country. The prevalence of SARS-CoV-2 in Chilean pets was relatively low, likely due to the country's high human vaccination rate. Our study highlights the importance of upholding and strengthening human vaccination strategies to mitigate the risk of interspecies transmission. It underscores the critical role of the One Health approach in addressing emerging zoonotic diseases, calling for further research on infection dynamics and risk factors for a comprehensive understanding.

An environmental analysis of public UAP sightings and sky view potential.

Sightings of unidentified flying objects (UFOs) or unidentified anomalous phenomena (UAP) have been reported throughout history. Given the potential security and safety risks they pose, as well as scientific curiosity, there is increasing interest in understanding what these sighting reports represent. We approach this problem as an important one of the human experience and that can be examined through a geographical lens: what local factors may increase or decrease the number of sighting reports? Using a Bayesian regression method, we test hypotheses based on variables representing sky view potential (light pollution, tree canopy, and cloud cover) and the potential for objects to be present in the sky (aircraft and military installations). The dependent variable includes over 98,000 publicly reported UAP sightings in the conterminous United States during the 20-year period from 2001 to 2020. The model results find credible correlations between variables that suggest people see more "phenomena" when they have more opportunity to. This analysis is one of few investigations of UAP sighting reports at a national scale providing context to help examine individual reports. Given that these objects are labeled unidentifiable in the personal sense, there are many natural and/or human based explanations worth exploring.

Enfermedad neurológica asociada al gen KIF1A: correlación genotipo/fenotipo / KIF1A gene-associated neurological disease: the correlation between genotype and phenotype

Introducción: La encefalopatía KIF1A-associated-neurological-disorder (KAND) es un grupo de patologías neurodegenerativas progresivas de diversa gravedad ocasionadas por mutaciones en el gen KIF1A (kinesin family member 1A) situado en el cromosoma 2q37.3. Dicho gen codifica una proteína de la familia de las cinesinas 3 que participa en el transporte anterógrado de las vesículas presinápticas dependientes del trifosfato de adenosina a través de microtúbulos neuronales. Casos clínicos: Se describen cuatro pacientes, con edades entre 1 y 13 años, con mediana de inicio de los síntomas de cinco meses (rango intercuartílico: 0-11 meses), lo que supone una prevalencia aproximada de 1 de cada 64.000 menores de 14 años para nuestra población pediátrica. Clínicamente, destacaron discapacidad intelectual, hipotonía axial y paraparesia espástica en 4/4, y síntomas cerebelosos en 2/4. Otras manifestaciones fueron incontinencia urinaria, polineuropatía sensitivomotora y alteración conductual. Destaca, en el caso 2, la alteración en el videoelectroencefalograma, que mostraba epilepsia focal con generalización secundaria y focalidad paroxística occipitoparietal posterior derecha con transmisión contralateral. También mostraba crisis oculógiras en supraversión instantáneas pluricotidianas sin correlato electroencefalográfico. Conclusiones: En nuestra serie, la encefalopatía KAND, fenotipo trastorno neurodegenerativo con retraso global del desarrollo, de la marcha y espasticidad progresiva de los miembros inferiores, atrofia cerebelosa y/o afectación de la corteza visual, fue predominante, y en uno de los casos asoció polineuropatía sensitivomotora. La mutación de novo missense fue más frecuente y en tres casos es la primera descripción conocida. Un caso mostraba epilepsia focal y crisis oculógiras no epilépticas.(AU)

Introduction: KIF1A-associated-neurological-disorder (KAND) encephalopathy is a group of progressive neurodegenerative pathologies of varying severity caused by mutations in the KIF1A gene (Kinesin family member 1A) located on chromosome 2q37.3. This gene encodes a protein of the kinesin-3 family that participates in the ATP-dependent anterograde transport of presynaptic vesicles through neuronal microtubules. Case report: Four patients are described, aged 1-13 years, with a median onset of symptoms of 5 months (IQR 0-11 months), which represents an approximate prevalence of 1 per 64,000 children under 14 years of age for our pediatric population. Clinically, intellectual disability (ID), axial hypotonia and spastic paraparesis stood out in 4/4 and cerebellar symptoms in 2/4. Other manifestations were urinary incontinence, sensory-motor polyneuropathy, and behavioral alteration. In case 2, the alteration in the video-EEG stands out, which showed focal epilepsy with secondary generalization and right posterior occipito-parietal paroxysmal focality with contralateral transmission. She also showed instantaneous pluricotidian supraversion oculogyric seizures without EEG correlates. Conclusions: In our series, KAND encephalopathy had a predominant neurodegenerative disorder phenotype with global developmental delay, gait delay, and progressive spasticity of the lower limbs, cerebellar atrophy, and/or involvement of the visual cortex, which in one case was associated with sensory-motor polyneuropathy. The de novo missense mutation was more frequent and in three cases it is the first known description. One case showed focal epilepsy and nonepileptic oculogyric seizures.(AU)

[KIF1A gene-associated neurological disease: the correlation between genotype and phenotype]. / Enfermedad neurológica asociada al gen KIF1A: correlación genotipo/fenotipo.

INTRODUCTION: KIF1A-associated-neurological-disorder (KAND) encephalopathy is a group of progressive neurodegenerative pathologies of varying severity caused by mutations in the KIF1A gene (Kinesin family member 1A) located on chromosome 2q37.3. This gene encodes a protein of the kinesin-3 family that participates in the ATP-dependent anterograde transport of presynaptic vesicles through neuronal microtubules. CASE REPORT: Four patients are described, aged 1-13 years, with a median onset of symptoms of 5 months (IQR 0-11 months), which represents an approximate prevalence of 1 per 64,000 children under 14 years of age for our pediatric population. Clinically, intellectual disability (ID), axial hypotonia and spastic paraparesis stood out in 4/4 and cerebellar symptoms in 2/4. Other manifestations were urinary incontinence, sensory-motor polyneuropathy, and behavioral alteration. In case 2, the alteration in the video-EEG stands out, which showed focal epilepsy with secondary generalization and right posterior occipito-parietal paroxysmal focality with contralateral transmission. She also showed instantaneous pluricotidian supraversion oculogyric seizures without EEG correlates. CONCLUSIONS: In our series, KAND encephalopathy had a predominant neurodegenerative disorder phenotype with global developmental delay, gait delay, and progressive spasticity of the lower limbs, cerebellar atrophy, and/or involvement of the visual cortex, which in one case was associated with sensory-motor polyneuropathy. The de novo missense mutation was more frequent and in three cases it is the first known description. One case showed focal epilepsy and nonepileptic oculogyric seizures.

TITLE: Enfermedad neurológica asociada al gen KIF1A: correlación genotipo/fenotipo.Introducción. La encefalopatía KIF1A-associated-neurological-disorder (KAND) es un grupo de patologías neurodegenerativas progresivas de diversa gravedad ocasionadas por mutaciones en el gen KIF1A (kinesin family member 1A) situado en el cromosoma 2q37.3. Dicho gen codifica una proteína de la familia de las cinesinas 3 que participa en el transporte anterógrado de las vesículas presinápticas dependientes del trifosfato de adenosina a través de microtúbulos neuronales. Casos clínicos. Se describen cuatro pacientes, con edades entre 1 y 13 años, con mediana de inicio de los síntomas de cinco meses (rango intercuartílico: 0-11 meses), lo que supone una prevalencia aproximada de 1 de cada 64.000 menores de 14 años para nuestra población pediátrica. Clínicamente, destacaron discapacidad intelectual, hipotonía axial y paraparesia espástica en 4/4, y síntomas cerebelosos en 2/4. Otras manifestaciones fueron incontinencia urinaria, polineuropatía sensitivomotora y alteración conductual. Destaca, en el caso 2, la alteración en el videoelectroencefalograma, que mostraba epilepsia focal con generalización secundaria y focalidad paroxística occipitoparietal posterior derecha con transmisión contralateral. También mostraba crisis oculógiras en supraversión instantáneas pluricotidianas sin correlato electroencefalográfico. Conclusiones. En nuestra serie, la encefalopatía KAND, fenotipo trastorno neurodegenerativo con retraso global del desarrollo, de la marcha y espasticidad progresiva de los miembros inferiores, atrofia cerebelosa y/o afectación de la corteza visual, fue predominante, y en uno de los casos asoció polineuropatía sensitivomotora. La mutación de novo missense fue más frecuente y en tres casos es la primera descripción conocida. Un caso mostraba epilepsia focal y crisis oculógiras no epilépticas.

Waning and boosting of antibody Fc-effector functions upon SARS-CoV-2 vaccination.

Since the emergence of SARS-CoV-2, vaccines targeting COVID-19 have been developed with unprecedented speed and efficiency. CoronaVac, utilising an inactivated form of the COVID-19 virus and the mRNA26 based Pfizer/BNT162b2 vaccines are widely distributed. Beyond the ability of vaccines to induce production of neutralizing antibodies, they might lead to the generation of antibodies attenuating the disease by recruiting cytotoxic and opsonophagocytic functions. However, the Fc-effector functions of vaccine induced antibodies are much less studied than virus neutralization. Here, using systems serology, we follow the longitudinal Fc-effector profiles induced by CoronaVac and BNT162b2 up until five months following the two-dose vaccine regimen. Compared to BNT162b2, CoronaVac responses wane more slowly, albeit the levels remain lower than that of BNT162b2 recipients throughout the entire observation period. However, mRNA vaccine boosting of CoronaVac responses, including response to the Omicron variant, induce significantly higher peak of antibody functional responses with increased humoral breadth. In summary, we show that vaccine platform-induced humoral responses are not limited to virus neutralization but rather utilise antibody dependent effector functions. We demonstrate that this functionality wanes with different kinetics and can be rescued and expanded via boosting with subsequent homologous and heterologous vaccination.

NEUROENDOCRINE PEPTIDES IN THE PATHOGENESIS OF COLORECTAL CARCINOMA.

Colorectal carcinoma (CRC) is the third most frequent neoplasm worldwide and the second leading cause of mortality. Neuroendocrine peptides such as glucagon, bombesin, somatostatin, cholecystokinin, and gastrin as well as growth factors such as platelet-derived growth factor, epidermal growth factor, insulin-like growth factor, and fibroblast growth factor have been postulated as being involved in carcinogenesis. The fact that these neuroendocrine peptides are involved in the development of CRC through the activation of growth factors that stimulate a series of molecular pathways that activate oncogenic signaling mechanisms is emphasized in this review. Peptides such as CCK1, serotonin, and bombesin have been found to be over-expressed in human tumor tissues. Meanwhile, the expression of peptides such as GLP2 has been seen mainly in murine models. The information contained in this review provides a better understanding of the role these peptides play in the pathogenesis of CRC for basic and clinical science studies.

Implementación del uso del SPECT portátil para valoración de márgenes quirúrgicos en cáncer de mama con indicación de ROLL. Primeros resultados / Implementation of the use of SPECT-portable for evaluation of surgical margins in breast cancer with indication of ROLL: First results

Objetivo principal: comparar la efectividad para la comprobación de márgenes quirúrgicos entre SPECT portátil y la mamografía de la pieza (RxM). Objetivo secundario: estandarizar un protocolo preintraquirúrgico mediante SPECT portátil y evaluar el tiempo requerido en el uso de esta técnica. Material y métodos Estudio longitudinal prospectivo con 36 pacientes (39 lesiones) diagnosticadas de cáncer de mama con criterios para realización SNOLL/ROLL. Se realiza en estudio prequirúrgico de la lesión tumoral, tras la administración ecoguiada de [99mTc]Tc-nanocoloides de albúmina/[99mTc]Tc-macroagregados de albúmina, en la lesión tumoral. Mediante SPECT portátil se obtienen imágenes híbridas (óptico + SPECT) e imágenes de navegación en 3D con sonda gamma. En quirófano se obtienen 4-5 imágenes con SPECT portátil, I) sobre piel para localización tumoral II) tras exposición de lecho para guía de resección, III) del lecho tras exéresis, IV y V) a la pieza quirúrgica. Se decide ampliación o no de márgenes considerando tres criterios: a) actividad residual (cps) en bordes de resección del lecho; b) análisis visual de la captación en la pieza; c) una distancia mínima de 10mm de los bordes de la pieza hasta el centro de mayor captación, más el radio de la lesión. En este estudio se valora la concordancia de: la medición de la profundidad entre ecografía y SPECT portátil en el estudio prequirúrgico; los márgenes quirúrgicos entre SPECT portátil vs. RxM, teniendo de técnica de referencia anatomía patológica (AP); del tiempo quirúrgico empleado con SPECT portátil (AU)

Objectives Main objective: To compare the effectiveness for checking surgical margins between SPECT-portable and mammography of the piece (RxM). Secondary objective: To standardize a pre-operative protocol using SPECT-portable and to evaluate the time required in the use of this technique. Material and method Prospective longitudinal study with 36 patients (39 lesions) diagnosed with breast cancer (CM) with criteria for SNOLL/ROLL. A pre-surgical study of the tumor lesion was performed, after the eco-guided administration of 99mTc-nanocolloids of albumin/99mTc-macroaggregates of albumin, in the tumor lesion. Hybrid images (optical+SPECT) and 3D navigation images with gamma probe are obtained using freehandSPECT. In the operating room, 4–5 images are obtained with freehandSPECT, (I) on skin for tumor location, (II) after exposure of surgical bed for resection guide, (III) of the surgical bed after exeresis, (IV and V) the anterior–posterior and lateral surface of the surgical specimen. The three criteria to decide to extend the margins are: (a) residual activity (cps) at the edges of the surgical bed resection; (b) visual analysis of the uptake in the specimen; (c) a minimum distance of 10mm from the edges of the specimen to the center of greatest uptake, plus the radius of the lesion. We study the concordance of: the depth measurement between ultrasound and freehandSPECT; the surgical margins between freehandSPECT vs. mammography of the specimen (RxM), considering anatomical pathology (AP) as the gold standard technique as reference; surgical time used with freehandSPECT and RxM. Results Intraoperative localization was performed in all cases. False negative (FN: no detection margin affected) with freehandSPECT: 9 margins; with RxM: 8 (AU)

Diagnóstico incidental del cáncer de vejiga en España. Estudio observacional a nivel nacional / Incidental diagnosis of bladder cancer in a national observational study in Spain

Introducción El cáncer de vejiga (CV) es una neoplasia frecuente en España. Los objetivos de este estudio fueron: identificar la proporción de pacientes diagnosticados de CV de forma incidental o tras la presentación de síntomas en un periodo contemporáneo en España; comparar las características demográficas, clínicas y patológicas entre estos grupos. Métodos El presente fue un análisis retrospectivo de un estudio observacional multicéntrico realizado en 26 hospitales del Sistema Nacional de Salud español, incluyendo a todos los nuevos diagnósticos de CV en 2011. El estudio representó 21,5% de la población española y los hospitales fueron seleccionados de forma proporcional a las regiones españolas para asegurar una muestra representativa. Los pacientes fueron categorizados según el diagnóstico de cáncer incidental o tras la presentación sintomática y se analizaron las características demográficas, patológicas y clínicas basales. Resultados En los 26 hospitales españoles incluidos en el estudio, se diagnosticaron 2.472 casos de CV, de los cuales 308 (12,5%) fueron diagnosticados de forma incidental y 2.164 (87,5%) tras la presentación de síntomas. No se observaron diferencias entre los pacientes diagnosticados incidentalmente frente a los sintomáticos en términos demográficos o de comorbilidades evaluadas. En comparación con los tumores de vejiga con diagnostico posterior a la presentación de síntomas, los diagnósticos incidentales tenían más probabilidades de ser tumores papilares, significativamente más pequeños y de tener una citología positiva/sospechosa. Además, los tumores de vejiga diagnosticados incidentalmente tenían menos probabilidades de ser músculo-invasivos (11,7 vs. 25%, p < 0,01) y de ser agresivos en el estudio patológico, con 33,6% de grado 3 vs. 50,1% (p < 0,01). Conclusiones Identificamos un porcentaje significativo (12,5%) de nuevos diagnósticos de CV realizados de forma incidental en una muestra representativa de la población española (AU)

Introduction Bladder cancer (BC) is a common malignancy in Spain. The aims of this study were: to identify the proportion of patients diagnosed with BC incidentally or after symptomatic presentation in a contemporary period in Spain; to compare demographic, clinical, and pathologic characteristics between these groups. Methods This was a retrospective analysis of a multi-centre observational study of 26 hospitals in the Spanish National Health System of all BCs newly diagnosed in 2011. The study represented 21.5% of the Spanish population and hospitals were selected in proportion to Spain's regions to ensure a representative sample. Patients were categorized by whether the cancer was diagnosed incidentally or after symptomatic presentation and baseline demographic, pathologic, and clinical characteristics were analyzed. Results 2472 were newly diagnosed with BC at the 26 participating Spanish hospitals with 308 (12.5%) of cases diagnosed incidentally and 2164 (87.5%) diagnosed after symptomatic presentation. No differences were observed between patients diagnosed incidentally vs. symptomatically in terms of demographics or measured co-morbidities. Compared to symptomatically diagnosed bladder tumours, those diagnosed incidentally were more likely to have a papillary appearance, to be significantly smaller, and less likely to have positive/suspicious cytology. Additionally, incidentally diagnosed bladder tumours were less likely to be muscle-invasive (11.7% vs. 25.0%, P < .01) nor aggressive at pathology, with 33.6% Grade 3 compared to 50.1%, (P < .01). Conclusions We identified a significant percentage (12.5%) of new bladder cancer diagnosis made incidentally in a representative sample of the Spanish population. These tumours exhibited less aggressive pathologic characteristics than their symptomatic counterparts (AU)

[Congenital myotonia. Incidence and presentation of a series of cases]. / Miotonía congénita. Incidencia y presentación de una serie de casos.

INTRODUCTION: Myotonia congenita is the most common form of genetic myotonia and is caused by mutations in the CLCN1 gene. It can be inherited in an autosomal dominant or recessive manner. We present a series of cases to update its incidence in our environment, to describe its phenotype in relation to the genotype found, and we also review the mutations found, among which we provide a new, undescribed alteration. CASES REPORT: The medical records of patients with a diagnosis of congenital myotonia studied and followed up in the pediatric neurology section in a tertiary hospital between the years 2015-2020 were reviewed. Demographic variables (age, sex), disease course (age of onset, symptoms and signs, time elapsed until diagnosis, clinical evolution), family history and evaluation of response to treatment were collected. Five cases with a clinical diagnosis of myotonia congenita were identified (three with Becker's disease and two with Thomsen's disease). The incidence in relation to the number of births is estimated at 1:15,000 newborns for cases with the Becker phenotype and 1:21,000 newborns for the Thomsen phenotypes. We found a probably pathogenic mutation not previously described (CLCN1: c.824T> C). CONCLUSIONS: the approximate incidence in our environment was higher than previously known and we describe a new, undescribed mutation: c.824T> C with pathogenicity predictors that behaved like a Becker recessive phenotype but with an earlier debut.

TITLE: Miotonía congénita. Incidencia y presentación de una serie de casos.Introducción. La miotonía congénita es la forma más común de miotonía de causa genética y se produce por mutaciones en el gen CLCN1. Puede heredarse de manera autosómica dominante o recesiva. Presentamos una serie de casos para actualizar su incidencia en nuestro medio, para describir su fenotipo en relación con el genotipo encontrado y, además, revisamos las mutaciones encontradas, entre las que aportamos una nueva alteración no descrita. Casos clínicos. Se revisaron las historias clínicas de pacientes con diagnóstico de miotonía congénita estudiados y seguidos en la consulta de neurología pediátrica en un hospital de tercer nivel entre los años 2015 y 2020. Se recogieron variables demográficas (edad y sexo), curso de la enfermedad (edad de inicio, síntomas y signos, tiempo transcurrido hasta el diagnóstico y evolución clínica), antecedentes familiares y evaluación de la respuesta al tratamiento. Se identificaron cinco casos con diagnóstico clínico de miotonía congénita (tres con enfermedad de Becker y dos con enfermedad de Thomsen). La incidencia en relación con el número de nacimientos la estimamos en 1:15.000 recién nacidos para los casos con fenotipo Becker y en 1:21.000 recién nacidos para los fenotipos Thomsen. Hallamos una mutación probablemente patogénica no descrita previamente (CLCN1: c.824T>C). Conclusiones. La incidencia aproximada en nuestro medio fue superior a la previamente conocida y describimos una nueva mutación no descrita: c.824T>C, con predictores de patogenicidad, que se comportó como un fenotipo recesivo Becker, pero con inicio más temprano.

Miotonía congénita. Incidencia y presentación de una serie de casos / Congenital myotonia. Incidence and presentation of a series of cases

Introducción: La miotonía congénita es la forma más común de miotonía de causa genética y se produce por mutaciones en el gen CLCN1. Puede heredarse de manera autosómica dominante o recesiva. Presentamos una serie de casos para actualizar su incidencia en nuestro medio, para describir su fenotipo en relación con el genotipo encontrado y, además, revisamos las mutaciones encontradas, entre las que aportamos una nueva alteración no descrita. Casos clínicos. Se revisaron las historias clínicas de pacientes con diagnóstico de miotonía congénita estudiados y seguidos en la consulta de neurología pediátrica en un hospital de tercer nivel entre los años 2015 y 2020. Se recogieron variables demográficas (edad y sexo), curso de la enfermedad (edad de inicio, síntomas y signos, tiempo transcurrido hasta el diagnóstico y evolución clínica), antecedentes familiares y evaluación de la respuesta al tratamiento. Se identificaron cinco casos con diagnóstico clínico de miotonía congénita (tres con enfermedad de Becker y dos con enfermedad de Thomsen). La incidencia en relación con el número de nacimientos la estimamos en 1:15.000 recién nacidos para los casos con fenotipo Becker y en 1:21.000 recién nacidos para los fenotipos Thomsen. Hallamos una mutación probablemente patogénica no descrita previamente (CLCN1: c.824T>C). Conclusiones: La incidencia aproximada en nuestro medio fue superior a la previamente conocida y describimos una nueva mutación no descrita: c.824T>C, con predictores de patogenicidad, que se comportó como un fenotipo recesivo Becker, pero con inicio más temprano.(AU)

Introduction: Myotonia congenita is the most common form of genetic myotonia and is caused by mutations in the CLCN1 gene. It can be inherited in an autosomal dominant or recessive manner. We present a series of cases to update its incidence in our environment, to describe its phenotype in relation to the genotype found, and we also review the mutations found, among which we provide a new, undescribed alteration. Cases report: The medical records of patients with a diagnosis of congenital myotonia studied and followed up in the pediatric neurology section in a tertiary hospital between the years 2015-2020 were reviewed. Demographic variables (age, sex), disease course (age of onset, symptoms and signs, time elapsed until diagnosis, clinical evolution), family history and evaluation of response to treatment were collected. Five cases with a clinical diagnosis of myotonia congenita were identified (three with Becker’s disease and two with Thomsen’s disease). The incidence in relation to the number of births is estimated at 1:15,000 newborns for cases with the Becker phenotype and 1:21,000 newborns for the Thomsen phenotypes. We found a probably pathogenic mutation not previously described (CLCN1: c.824T> C). Conclusions: the approximate incidence in our environment was higher than previously known and we describe a new, undescribed mutation: c.824T> C with pathogenicity predictors that behaved like a Becker recessive phenotype but with an earlier debut.(AU)

Implementation of the use of SPECT-portable for evaluation of surgical margins in breast cancer with indication of ROLL: First results.

OBJECTIVES: Main objective: To compare the effectiveness for checking surgical margins between SPECT-portable and mammography of the piece (RxM). SECONDARY OBJECTIVE: To standardize a pre-operative protocol using SPECT-portable and to evaluate the time required in the use of this technique. MATERIAL AND METHODS: Prospective longitudinal study with 36 patients (39 lesions) diagnosed with breast cancer (CM) with criteria for SNOLL/ROLL. A pre-surgical study of the tumor lesion was performed, after the eco-guided administration of 99mTc-nanocolloids of albumin/99mTc-macroaggregates of albumin, in the tumor lesion. Hybrid images (optical + SPECT) and 3D navigation images with gamma probe are obtained using freehandSPECT. In the operating room, 4-5 images are obtained with freehandSPECT, (I) on skin for tumor location, (II) after exposure of surgical bed for resection guide, (III) of the surgical bed after exeresis, (IV and V) the anterior-posterior and lateral surface of the surgical specimen. The three criteria to decide to extend the margins are: (a) residual activity (cps) at the edges of the surgical bed resection; (b) visual analysis of the uptake in the specimen; (c) a minimum distance of 10 mm from the edges of the specimen to the center of greatest uptake, plus the radius of the lesion. We study the concordance of: the depth measurement between ultrasound and freehandSPECT; the surgical margins between freehandSPECT vs. mammography of the specimen (RxM), considering anatomical pathology (AP) as the gold standard technique as reference; surgical time used with freehandSPECT and RxM. RESULTS: Intraoperative localization was performed in all cases. False negative (FN: no detection margin affected) with freehandSPECT: 9 margins; with RxM: 8. True positive (TP: detection margin affected) with freehandSPECT: 5 margins, with RxM: 6. True negative (TN: consider free margin when healthy) with freehandSPECT: 213 margins; with RxM: 196. Negative predictive value (NPV: probability of negative margin on unaffected part) with freehandSPECT: 95.9%, with RxM: 96.07%. Specificity with freehandSPECT: 96.8%, with RxM: 97%. The concordance of surgical bed margins between freehandSPECT and RxM: 94.5%. Between freehandSPECT and AP: 93.1%. Between RxM and PA: 93.5%, being all statistically significant (p-value <0.000), so we can affirm that both techniques are related or dependent on the reference technique, the PA. Degree of correlation between SPECT-portable and low PA (Kappa index: 0.34, 95% CI [0.22-0.47], and between RxM and moderate PA (Kappa index: 0.42, 95% CI [0.29-0.56], p-value <0.001. Comparison of the successes and failures of both techniques (SPECT-portable and RxM) and PA: Distribution χ2: 0.023 with degree of freedom 1, with value <0.05, so we can affirm that both techniques are similar, since there are no significant statistical differences. Median total OR time: 60.25 min (30-145). Mean freehandSPECT OR time: 5 scans = 10 min. CONCLUSIONS: There are no statistically significant differences in the probability to rule out affective margins that require a second surgery between both techniques (SPECT-portable and RxM) so, the technique performed with SPECT-Portable is a useful and effective procedure, which requires specific training with an optimized and multidisciplinary protocol. The time spent with SPECT-portable is feasible for daily practice.

Waning and boosting of functional humoral immunity to SARS-CoV-2.

Since the emergence of the SARS-CoV-2 virus, we have witnessed a revolution in vaccine development with the rapid emergence and deployment of both traditional and novel vaccine platforms. The inactivated CoronaVac vaccine and the mRNA-based Pfizer/BNT162b2 vaccine are among the most widely distributed vaccines, both demonstrating high, albeit variable, vaccine effectiveness against severe COVID-19 over time. Beyond the ability of the vaccines to generate neutralizing antibodies, antibodies can attenuate disease via their ability to recruit the cytotoxic and opsinophagocytic functions of the immune response. However, whether Fc-effector functions are induced differentially, wane with different kinetics, and are boostable, remains unknown. Here, using systems serology, we profiled the Fc-effector profiles induced by the CoronaVac and BNT162b2 vaccines, over time. Despite the significantly higher antibody functional responses induced by the BNT162b2 vaccine, CoronaVac responses waned more slowly, albeit still found at levels below those present in the systemic circulation of BNT162b2 immunized individuals. However, mRNA boosting of the CoronaVac vaccine responses resulted in the induction of significantly higher peak antibody functional responses with increased humoral breadth, including to Omicron. Collectively, the data presented here point to striking differences in vaccine platform-induced functional humoral immune responses, that wane with different kinetics, and can be functionally rescued and expanded with boosting.

EXPRESSION OF CHEMOKINE (C-C MOTIF) RECEPTOR 7 IN PROSTATE CANCER TISSUE OF YOUNG PATIENTS AND IN METASTATIC CANCER CELLS.

BACKGROUND: Chemokine (C-C motif) receptor 7 (CCR7) is a chemokine receptor involved in the carcinogenesis of several types of tumors due to its promoting action in epithelial-mesenchymal transition events, invasion, angiogenesis and metastasis. However, its role in prostate cancer (PCa) remains unclear. AIM: To evaluate CCR7 expression by immunohistochemistry in prostate tumors from young patients and to determine the possible relationship with the clinicopathological characteristics. MATERIALS AND METHODS: We analyzed retrospectively paraffin-embedded tissue sections from 23 young PCa (≤ 55 years old) patients and evaluated the transcriptomic expression in the TCGA database. RESULTS: Expression of CCR7 was observed in 15 cases (65%). The tissue samples from younger patients (≤ 50 years) were mostly positive in 72.7% (8/11) of cases. High grade GS (≥ 3) tumors were CCR7-positive in 71% cases. The malignant cells present in lymph nodes were CCR7 positive in 100% cases. The bioinformatic analysis showed a high CCR7 expression associated with the presence of metastasis (FC = 2.6, p = 0.03) in the Cancer Genome Atlas (TCGA) PCa cohort (PRAD). CONCLUSION: We showed that CCR7 expression in tumors from young patients is associated with the early onset of the disease and could also be related to lymph node metastasis.

Delphi consensus on recommendations for the treatment of spinal muscular atrophy in Spain (RET-AME consensus).

INTRODUCTION: Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a biallelic mutation of the SMN1 gene, located on the long arm of chromosome 5, and predominantly affects the motor neurons of the anterior horn of the spinal cord, causing progressive muscle weakness and atrophy. The development of disease-modifying treatments is significantly changing the natural history of SMA, but uncertainty remains about which patients can benefit from these treatments and how that benefit should be measured. METHODOLOGY: A group of experts specialised in neurology, neuropediatrics, and rehabilitation and representatives of the Spanish association of patients with SMA followed the Delphi method to reach a consensus on 5 issues related to the use of these new treatments: general aspects, treatment objectives, outcome assessment tools, requirements of the treating centres, and regulation of their use. Consensus was considered to be achieved when a response received at least 80% of votes. RESULTS: Treatment protocols are useful for regulating the use of high-impact medications and should guide treatment, but should be updated regularly to take into account the most recent evidence available, and their implementation should be assessed on an individual basis. Age, baseline functional status, and, in the case of children, the type of SMA and the number of copies of SMN2 are characteristics that should be considered when establishing therapeutic objectives, assessment tools, and the use of such treatments. The cost-effectiveness of these treatments in paediatric patients is mainly influenced by early treatment onset; therefore, the implementation of neonatal screening is recommended. CONCLUSIONS: The RET-AME consensus recommendations provide a frame of reference for the appropriate use of disease-modifying treatments in patients with SMA.

Andersen-Tawil syndrome: Overlapping clinical features with Noonan syndrome?

Andersen-Tawil syndrome (ATS) and Noonan syndrome (NS) are both autosomal dominantly inherited disorders that share anomalies in the same body systems, i.e. cardiovascular system, skeleton, growth, and face morphology. Here we report a patient meeting clinical diagnostic criteria for NS in whom no variant in one of the genes known to cause NS was found and a pathogenic variant in KCNJ2 (c.653G > C, p.(Arg218Pro)) was demonstrated. Because of manifestations typical for NS and previously not described in ATS (broad neck, low hairline and pectus excavatum), this may indicate there is a phenotypical overlap between ATS and NS, although we cannot exclude that the patient has an additional, hitherto undetected variant in another gene that explains the NS features. Further studies into a functional relation between KCNJ2 and the RAS/MAPK pathway are needed to determine this further.

Echographic findings in ectopic intrathyroidal thymic tissue in children. A systematic review.

Intrathyroidal ectopic thymic tissue (IETT) is an indulgent, unusual entity and is part of the differential diagnosis of thyroid nodules in the pediatric population. Because of the low prevalence of IETT, the diagnosis may be difficult. Awareness of this diagnosis is definitive to avoid surgical interventions. The aim of this study was to review the literature on the echographic characteristics of IETT. We conducted a search of Ovid, PubMed and the virtual health library. A total of 619 patients with a mean age of 6.2 years old were included. IETT was located in the lower portion of both of the thyroidal lobes in 556 children, the echographic shape was reported for 173 patients, with the fusiform shape as the most representative, the appearance of the IETTs was reported for 121 patients, the most common was the hypoechogenic pattern with multiple internal echogenic foci. The average lesion diameter was 5.53 mm, and Doppler findings reported a hipovascular pattern in 56% of the lesions. In conclusion, IETT is an infrequent entity; nonetheless, it must be considered in the differential diagnosis of neck nodules in children and should be study and follow with echography to avoid unnecessary surgery.

Síndrome de Joubert: incidencia y descripción clinicorradiológica de una serie genotipada de siete casos / Joubert syndrome: incidence and clinicoradiological description of a genotyped series of seven cases

Introducción: El síndrome de Joubert se produce por una alteración de las proteínas ciliares esenciales para la estructura y la función de neuronas y órganos como los riñones, el hígado, la retina y el oído. Se conocen unas 34 mutaciones en la actualidad. Objetivo: Calcular la incidencia/prevalencia y describir el fenotipo/genotipo y las alteraciones clinicorradiológicas de esta ciliopatía en nuestra área de salud. Pacientes y métodos: Revisamos las historias clínicas con diagnóstico de síndrome de Joubert en los últimos 10 años para recoger el fenotipo, las características radiológicas y las manifestaciones extraneurológicas en relación con la alteración genética detectada. Resultados: Se incluyeron siete casos, de los cuales cinco eran varones (6-17 años). Presentaban seis mutaciones diferentes. Fue constante la hipotonía, los dedos finos/largos y el retraso en el desarrollo psicomotor. Presentaban rasgos dismórficos, retraso mental, apraxia ocular y nistagmo indistintamente, 3/7; apnea/hiperpnea neonatal, 2/7; hipoplasia de vermis, 7/7; síndrome del molar, 6/7; elongación-adelgazamiento de los pedúnculos cerebelosos, 2/7; estrechez en la unión pontomesencefálica, 6/7, y fastigio del IV ventrículo alto, 4/7. Entre las complicaciones somáticas había: retinopatía, 2/7; coloboma retiniano, 1/7; fibrosis hepática, 1/7; nefronoptisis, 1/7, y quiste renal 1/7. Conclusiones: La incidencia del síndrome de Joubert fue de al menos 1/20.000 recién nacidos/año. Las alteraciones radiológicas pontomesencefálicas y pedunculares fueron constantes. La hipotonía, el retraso psicomotor y los dedos finos/largos afectaron a todos los casos.(AU)

Introduction: Joubert syndrome is produced by an alteration of the ciliary proteins essential for the structure and function of neurons and organs such as the kidneys, liver, sight, and hearing. Some 34 mutations are currently known. Objective: Calculate the incidence / prevalence, describe the phenotype / genotype and radiological alterations of this ciliopathy in our health area. Patients and methods: We reviewed the medical records with a diagnosis of Joubert Syndrome in the last 10 years to collect phenotype, radiological characteristics, and extra-neurological manifestations in relation to the genetic alteration detected. Results: 7 cases were included: 5 children (6 -17 years). They had 6 different mutations. Hypotonia, thin / long fingers and delayed psychomotor development were constant. They presented dysmorphic features, mental retardation, ocular apraxia, and nystagmus indistinctly in 3/7; Neonatal apnea/hyperpnea 2/7; hypoplasia of vermis 7/7; Molar syndrome was evident in 6/7 and in 2/7 there was elongation-thinning of cerebellar peduncles. Pontomesencephalic junction tightness 6/7; fastigium of the IV ventricle high in 4/7. Among the somatic complications, retinopathy 2/7, retinal coloboma 1/7, liver fibrosis 1/7, nephronoptysis 1/7 and renal cyst 1/7. Conclusions: The incidence of Joubert syndrome was at least 1 / 20,000 newborns / year. The pontomesencephalic and peduncular radiological alterations were constant. Hypotonia, psychomotor retardation, and thin / long fingers affected all cases.(AU)

[Joubert syndrome: incidence and clinicoradiological description of a genotyped series of seven cases]. / Síndrome de Joubert: incidencia y descripción clinicorradiológica de una serie genotipada de siete casos.

INTRODUCTION: Joubert syndrome is produced by an alteration of the ciliary proteins essential for the structure and function of neurons and organs such as the kidneys, liver, sight, and hearing. Some 34 mutations are currently known. OBJECTIVE: Calculate the incidence / prevalence, describe the phenotype / genotype and radiological alterations of this ciliopathy in our health area. PATIENTS AND METHODS: We reviewed the medical records with a diagnosis of Joubert Syndrome in the last 10 years to collect phenotype, radiological characteristics, and extra-neurological manifestations in relation to the genetic alteration detected. RESULTS: 7 cases were included: 5 children (6 -17 years). They had 6 different mutations. Hypotonia, thin / long fingers and delayed psychomotor development were constant. They presented dysmorphic features, mental retardation, ocular apraxia, and nystagmus indistinctly in 3/7; Neonatal apnea/hyperpnea 2/7; hypoplasia of vermis 7/7; Molar syndrome was evident in 6/7 and in 2/7 there was elongation-thinning of cerebellar peduncles. Pontomesencephalic junction tightness 6/7; fastigium of the IV ventricle high in 4/7. Among the somatic complications, retinopathy 2/7, retinal coloboma 1/7, liver fibrosis 1/7, nephronoptysis 1/7 and renal cyst 1/7. CONCLUSIONS: The incidence of Joubert syndrome was at least 1 / 20,000 newborns / year. The pontomesencephalic and peduncular radiological alterations were constant. Hypotonia, psychomotor retardation, and thin / long fingers affected all cases.

TITLE: Síndrome de Joubert: incidencia y descripción clinicorradiológica de una serie genotipada de siete casos.Introducción. El síndrome de Joubert se produce por una alteración de las proteínas ciliares esenciales para la estructura y la función de neuronas y órganos como los riñones, el hígado, la retina y el oído. Se conocen unas 34 mutaciones en la actualidad. Objetivo. Calcular la incidencia/prevalencia y describir el fenotipo/genotipo y las alteraciones clinicorradiológicas de esta ciliopatía en nuestra área de salud. Pacientes y métodos. Revisamos las historias clínicas con diagnóstico de síndrome de Joubert en los últimos 10 años para recoger el fenotipo, las características radiológicas y las manifestaciones extraneurológicas en relación con la alteración genética detectada. Resultados. Se incluyeron siete casos, de los cuales cinco eran varones (6-17 años). Presentaban seis mutaciones diferentes. Fue constante la hipotonía, los dedos finos/largos y el retraso en el desarrollo psicomotor. Presentaban rasgos dismórficos, retraso mental, apraxia ocular y nistagmo indistintamente, 3/7; apnea/hiperpnea neonatal, 2/7; hipoplasia de vermis, 7/7; síndrome del molar, 6/7; elongación-adelgazamiento de los pedúnculos cerebelosos, 2/7; estrechez en la unión pontomesencefálica, 6/7, y fastigio del IV ventrículo alto, 4/7. Entre las complicaciones somáticas había: retinopatía, 2/7; coloboma retiniano, 1/7; fibrosis hepática, 1/7; nefronoptisis, 1/7, y quiste renal 1/7. Conclusiones. La incidencia del síndrome de Joubert fue de al menos 1/20.000 recién nacidos/año. Las alteraciones radiológicas pontomesencefálicas y pedunculares fueron constantes. La hipotonía, el retraso psicomotor y los dedos finos/largos afectaron a todos los casos.