Recommendations for the classification of germline variants in the exonuclease domain of POLE and POLD1.

BACKGROUND: Germline variants affecting the proofreading activity of polymerases epsilon and delta cause a hereditary cancer and adenomatous polyposis syndrome characterized by tumors with a high mutational burden and a specific mutational spectrum. In addition to the implementation of multiple pieces of evidence for the classification of gene variants, POLE and POLD1 variant classification is particularly challenging given that non-disruptive variants affecting the proofreading activity of the corresponding polymerase are the ones associated with cancer. In response to an evident need in the field, we have developed gene-specific variant classification recommendations, based on the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) criteria, for the assessment of non-disruptive variants located in the sequence coding for the exonuclease domain of the polymerases. METHODS: A training set of 23 variants considered pathogenic or benign was used to define the usability and strength of the ACMG/AMP criteria. Population frequencies, computational predictions, co-segregation data, phenotypic and tumor data, and functional results, among other features, were considered. RESULTS: Gene-specific variant classification recommendations for non-disruptive variants located in the exonuclease domain of POLE and POLD1 were defined. The resulting recommendations were applied to 128 exonuclease domain variants reported in the literature and/or public databases. A total of 17 variants were classified as pathogenic or likely pathogenic, and 17 as benign or likely benign. CONCLUSIONS: Our recommendations, with room for improvement in the coming years as more information become available on carrier families, tumor molecular characteristics and functional assays, are intended to serve the clinical and scientific communities and help improve diagnostic performance, avoiding variant misclassifications.

Características clínicas y demográficas de los niños hospitalizados con infección por SARS-CoV-2

Introducción: en marzo de 2020 se registraron los primeros casos de infección por SARS-CoV-2 en Uruguay y se decretó la emergencia sanitaria. Objetivo: describir las características clínicas demográficas de los menores de 15 años hospitalizados con infección por SARS-CoV-2 en el período 13 de marzo de 2020 al 30 de septiembre de 2021 en el Hospital Pediátrico del Centro Hospitalario Pereira Rossell, centro de referencia público de Uruguay. Metodología: estudio descriptivo, retrospectivo, en el que se describen edad, manifestaciones clínicas, comorbilidades, severidad, tratamiento y evolución. Resultados: se hospitalizaron 207 niños con una frecuencia de 1,6%. La mediana (rango intercuartil) de edad fue 1,5 años (3 meses - 8 años); <1 año 44%; 54% de sexo masculino. Presentaron comorbilidades, 59 niños. Fueron sintomáticos, 71%. De los sintomáticos, presentaron síntomas leves 48%. Las manifestaciones clínicas fueron respiratorias en 96 (65%) y no respiratorias en 51 (fiebre sin foco 15, digestivas 19, exantema viral 3, SIM-Ped S 10 y atípicas 3). Treinta niños ingresaron a unidad de cuidados intensivos (UCI) y tres requirieron ventilación invasiva. Estos pacientes presentaron comorbilidades, tuvieron más días de fiebre y necesitaron oxigenoterapia que los que no requirieron UCI. Un paciente de 2 años con comorbilidades falleció. Conclusión: la frecuencia de hospitalizaciones fue de 1,6%. La mayoría de los niños sintomáticos presentaron formas leves. En los sintomáticos las manifestaciones fueron respiratorias. Los hallazgos en esta serie aportan al conocimiento del comportamiento de la infección por SARS-CoV-2 en niños.

Introduction: in March 2020, the first cases of SARS CoV-2 infection were registered in Uruguay and a health emergency was decreed. Objective: To describe the clinical and demographic characteristics of children under 15 years of age hospitalized with SARS-CoV-2 infection from March 13, 2020, to September 30, 2021, at Pereira Rossell Pediatric Hospital, a public reference center in Uruguay. Method: descriptive, retrospective study describing age, clinical manifestations, comorbidities, severity and treatment. Results: a total of 207 children were hospitalized, with a frequency of 1.6%. The median (interquartile range) age was 1.5 years (3 months - 8 years); <1 year accounted for 44%, and 54% were male. Comorbidities were present in 59 children. 71% of them were symptomatic, and among the symptomatic cases, 48% presented mild symptoms. Clinical manifestations were respiratory in 96 (65%) cases and non-respiratory in 51 (fever without a focus 15, gastrointestinal 19, viral exanthem 3, pediatric inflammatory multisystem syndrome 10, and atypical 3). Thirty patients were admitted to the Intensive Care Unit (ICU), and 3 required invasive ventilation. These patients had comorbidities, more days of fever, and required oxygen therapy compared to those who did not need ICU. One 2-year-old patient with comorbidities died. Conclusion: the hospitalization frequency was 1.6%. Most symptomatic children had mild forms of the disease. Among the symptomatic cases, respiratory manifestations were predominant. The findings from this series contribute to the understanding of the behavior of SARS-CoV-2 infection in children.

Introdução: Os primeiros casos de infecção por SARS CoV-2 no Uruguai foram registrados em março de 2020 quando foi decretada a emergência sanitária. Objetivo: descrever as características clínicas e demográficas das crianças menores de 15 anos internadas com infecção por SARS CoV-2 no período 13 de março de 2020 - 30 de setembro de 2021 no Hospital Pediátrico do Centro Hospitalar Pereira Rossell, centro público de referência no Uruguai. Metodologia: estudo descritivo, retrospectivo, incluindo idade, manifestações clínicas, comorbidades, gravidade, tratamento e evolução. Resultados: 207 crianças foram internadas com infecção por SARS CoV-2 correspondendo a frequência de 1,6% do total de crianças hospitalizadas no período estudado. A mediana (intervalo interquartil) de idade foi de 1,5 anos (3 meses - 8 anos) dos quais 44% eram <1 ano 44% e 54% do sexo masculino. 59 crianças apresentaram comorbidades. 71% eram sintomáticas sendo que 48% delas apresentaram sintomas leves. As manifestações clínicas foram respiratórias em 96 (65%) e não respiratórias em 51 (febre sem foco 15, digestiva 19, exantema viral 3, SIM-Ped S 10 e atípico 3). 30 crianças foram internadas na Unidade de Terapia Intensiva e 3 precisaram de ventilação invasiva; esses pacientes apresentavam comorbidades, necessitaram de oxigenoterapia e tiveram mais dias de febre do que aqueles que não necessitaram de UTI. Uma paciente de 2 anos com comorbidades faleceu. Conclusão: a frequência de internações foi de 1,6%. A maioria das crianças sintomáticas apresentou formas leves. Nas sintomáticas as manifestações foram respiratórias. Os achados desta série contribuem para o conhecimento do comportamento da infecção por SARS CoV-2 em crianças.

Ferroelectric, Dielectric and Electromechanical Performance of Ba0.92Ca0.08Ti0.95Zr0.05O3 Ceramics with an Enhanced Curie Temperature.

Ba0.92Ca0.08Ti0.95Zr0.05O3 (BCZT8-5) ceramic materials have been scarcely studied as lead-free piezo/ferroelectrics despite their enhanced Curie temperature (>100 °C) with respect to most studied BCZT compositions. In this work, homogeneous dense BCZT8-5 ceramics with grain size in the range of 20 µm, and optimum ferroelectric, dielectric, and electromechanical performance, were prepared by the mixed oxides route using moderate synthesis (1250 °C-2 h) and sintering (1400 °C-2 h) conditions. Thickness-poled thin disks and monomodal shear plate resonators were used for the determination of piezoelectric coefficients, coupling factors, elastic, and dielectric permittivity coefficients, including all losses, by iterative analysis of impedance curves at resonance. Furthermore, the thermal evolution of the piezoelectric characteristics at resonance was determined to assess the enhanced working range of the ceramics (≈100 °C). Ferroelectric hysteresis loops and strains vs. electric-field butterfly loops were also measured and showed soft behavior with Ec = 2 kV/cm, Pr = 12 µC/cm2 after a maximum applied field of 3 kV was used. The ceramics showed a high endurance of P-E cycles to electrical fatigue up to 107 cycles. Moreover, dielectric properties as a function of temperature were also accomplished and showed nearly normal ferroelectric behavior, characteristic of samples with low crystallographic disorder. Overall, these ceramics showed high sensitivity and higher stability than other currently studied BCZT compositions.

Solid State Processing of BCZT Piezoceramics Using Ultra Low Synthesis and Sintering Temperatures.

Lead-free (Ba0.92Ca0.08) (Ti0.95 Zr0.05) O3 (BCZT) ceramics were prepared by a solid-state route (SSR) using ultra-low synthesis (700 °C/30 min and 700 °C/2 h) and sintering temperatures (from 1150 °C to 1280 °C), due to prior activation and homogenization by attrition milling of the starting high purity raw materials for 6 h before the synthesis and of the calcined powders for 3 h before the sintering. The comparison of the thermal analysis of the mixture of the starting raw materials and the same mixture after 6 h attrition milling allowed to evidence the mechanisms of activation, resulting in a significant decrease of the perovskite formation temperature (from 854 °C down to 582 °C). The secondary phases that limit the functional properties of the ceramic and their evolution with the sintering conditions were analyzed by X-ray diffraction (XRD) and scanning electron microscopy (SEM), which allowed the design of a two-step sintering method to eliminate them. A pure tetragonal BCZT perovskite phase (P4mm, c/a = 1.004) and homogeneous ceramic microstructure was obtained for synthesis at 700 °C for 2 h and sintering with the use of a two-step sintering treatment (900 °C for 3 h and 1280 °C for 6 h). The best electromechanical properties achieved were d33 = 455 pC/N, kp = 35%, Qm = 155.

Brain radiotoxicity-related 15CAcBRT gene expression signature predicts survival prognosis of glioblastoma patients.

BACKGROUND: Glioblastoma is the most common and devastating primary brain cancer. Radiotherapy is standard of care; however, it is associated with brain radiation toxicity (BRT). This study used a multi-omics approach to determine whether BRT-related genes (RGs) harbor survival prognostic value and whether their encoded proteins represent novel therapeutic targets for glioblastoma. METHODS: RGs were identified through analysis of single-nucleotide variants associated with BRT (R-SNVs). Functional relationships between RGs were established using Protein-Protein Interaction networks. The influence of RGs and their functional groups on glioblastoma prognosis was evaluated using clinical samples from the Glioblastoma Bio-Discovery Portal database and validated using the Chinese Glioma Genome Atlas dataset. The identification of clusters of radiotoxic and putative pathogenic variants in proteins encoded by RGs was achieved by computational 3D structural analysis. RESULTS: We identified the BRT-related 15CAcBRT molecular signature with prognostic value in glioblastoma, by analysis of the COMT and APOE protein functional groups. Its external validation confirmed clinical relevance independent of age, MGMT promoter methylation status, and IDH mutation status. Interestingly, the genes IL6, APOE, and MAOB documented significant gene expression levels alteration, useful for drug repositioning. Biological networks associated with 15CAcBRT signature involved pathways relevant to cancer and neurodegenerative diseases. Analysis of 3D clusters of radiotoxic and putative pathogenic variants in proteins coded by RGs unveiled potential novel therapeutic targets in neuro-oncology. CONCLUSIONS: 15CAcBRT is a BRT-related molecular signature with prognostic significance for glioblastoma patients and represents a hub for drug repositioning and development of novel therapies.

Phenotypic and genotypic characterization of oxacillin-susceptible and mecA positive Staphylococcus aureus strains isolated in Uruguay / Caracterización fenotípica y genotípica de cepas de Staphylococcus aureus sensibles a oxacilina y mecA positivas aisladas en Uruguay

Abstract The aim of this study was to characterize phenotypically and genotypically 27 mecApositive Staphylococcus aureus strains with oxacillin MICs of ≤2 g/ml by Vitek 2, isolated indifferent regions of Uruguay. Susceptibility to oxacillin and cefoxitin was studied by gradient dif-fusion, disk diffusion to cefoxitin, and Phoenix and MicroScan systems. PBP2a was determined.SCCmec typing was performed and the isolates were compared by PFGE. Twenty-six isolateswere susceptible to oxacillin; one strain was susceptible to cefoxitin by disk diffusion and 3strains by gradient diffusion. Phoenix and MicroScan panels detected methicillin resistance in25 and 27 strains, respectively. Twenty-six strains tested positive for PBP2a. Twenty-six strainscarried SCCmec V and 24 belonged to pulsotype A. One strain carried SCCmec IV and did notbelong to pulsotype A. Cefoxitin disk diffusion test and PBP2a detection correctly identified 26of these 27 strains as MRSA. PFGE results suggest the dissemination of a cluster of MRSA carryingSCCmec V.

Resumen El objetivo de este estudio fue caracterizar fenotípicamente y genotípicamente 27 cepas de Staphylococcus aureus positivas para mecA y con CIM de oxacilina <2 pg/ml según Vitek 2, obtenidas en diferentes regiones del país. La sensibilidad frente a la oxacilina y la cefoxitina se estudió por difusión en gradiente, por disco-difusión (cefoxitina) y por los sistemas Phoenix y MicroScan. Se analizó la portación de PBP2a, se realizó la tipificación de SCCmec y las cepas se compararon mediante PFGE. Resultaron sensibles a oxacilina por difusión en gradiente 26 cepas; una fue sensible a cefoxitina por disco-difusión y 3 lo fueron por difusión en gradiente. Los sistemas Phoenix y MicroScan detectaron resistencia a meticilina en 25 y 27 cepas, respectivamente. Asimismo, 26 cepas portaban PBP2a y 26 cepas mostraron presencia de SCCmec V, 24 correspondieron al pulsotipo A. Una portaba SCCmec IV y no perteneció al pulsotipo A. La prueba de disco-difusión con cefoxitina y la detección de PBP2a identificaron 26 de 27 cepas como MRSA. La PFGE sugiere la diseminación de un grupo MRSA con SCCmec V. © 2022 Asociación Argentina de Microbiología. Publicado por Elsevier Espana, S.L.U. Este es un artículo Open Access bajo la licencia CC BY-NC-ND (https://creativecommons.org/licenses/by-nc-nd/4.0/).

[Epidemiological and clinical characteristics of children with COVID-19 cared for in a private health provider in Uruguay]. / Características epidemiológicas y clínicas de los niños con COVID-19 asistidos en un prestador de salud privado de Uruguay.

BACKGROUND: After the detection of the first cases of SARS-CoV-2 and the declaration of a health emergency in the country, community transmission of the virus remained low to moderate until November 2020, later becoming medium and high. Children under 15 years of age constitute the least affected group. The diagnosis is confirmed by RT-qPCR. The usefulness of the CT (cycle threshold) is discussed. AIM: To describe the epidemiological and clinical characteristics of children infected with SARS-CoV-2 and the relationship between the CT value and clinical presentation. METHOD: A descriptive, retrospective study was carried out in patients under 16 years of age with SARS-CoV-2 infection, assisted by a health provider in Montevideo between epidemiological week (EW) 3 of2020 and EW 9 of2021. Clinical variables, epidemiological notion, severity and evolution were described. The CT value at diagnosis was recorded and compared with the presence of symptoms. RESULTS: Patients under 16 years of age represented 16.6% of the total infected (794 in 4,792). 70% of the cases occurred between the months of January and February 2021. 67.6% presented intradomiciliary contact. The mean age was 7.5 ± 4.1 years, 51% were male. 55% presented symptoms and 45% were asymptomatic; no significant differences were observed in the mean, mode and age range of both groups. None presented comorbidities. In the group of 440 symptomatic patients, 55% presented fever: 32% associated with other symptoms, mainly upper respiratory symptoms, and 23% as the only symptom. The CT value was obtained in 536 of the 794 patients (67.5%). The mean CT was 29.7+5.8 in the symptomatic group vs. 31.5 ± 5.7 in asymptomatic patients (p > 0.05). Three patients were hospitalized, none required intensive care and none died. CONCLUSIONS: The prevalence and incidence of SARS-CoV-2 infection in children accompany that of adults and the majority had mild or asymptomatic forms, without complications. In this series, the CT value was not different in symptomatic and asymptomatic children. Close household contact was the main source of infection.

Phenotypic and genotypic characterization of oxacillin-susceptible and mecA positive Staphylococcus aureus strains isolated in Uruguay.

The aim of this study was to characterize phenotypically and genotypically 27 mecA positive Staphylococcus aureus strains with oxacillin MICs of ≤2µg/ml by Vitek 2, isolated in different regions of Uruguay. Susceptibility to oxacillin and cefoxitin was studied by gradient diffusion, disk diffusion to cefoxitin, and Phoenix and MicroScan systems. PBP2a was determined. SCCmec typing was performed and the isolates were compared by PFGE. Twenty-six isolates were susceptible to oxacillin; one strain was susceptible to cefoxitin by disk diffusion and 3 strains by gradient diffusion. Phoenix and MicroScan panels detected methicillin resistance in 25 and 27 strains, respectively. Twenty-six strains tested positive for PBP2a. Twenty-six strains carried SCCmec V and 24 belonged to pulsotype A. One strain carried SCCmec IV and did not belong to pulsotype A. Cefoxitin disk diffusion test and PBP2a detection correctly identified 26 of these 27 strains as MRSA. PFGE results suggest the dissemination of a cluster of MRSA carrying SCCmec V.

Características epidemiológicas y clínicas de los niños con COVID-19 asistidos en un prestador de salud privado de Uruguay / Epidemiological and clinical characteristics of children with COVID-19 cared for in a private health provider in Uruguay

INTRODUCCIÓN: Tras la detección de los primeros casos de SARS-CoV-2 y declararse la emergencia sanitaria en el país, la transmisión comunitaria del virus se mantuvo baja a moderada hasta noviembre de 2020 pasando luego a ser media y alta. Los niños bajo 15 años de edad constituyen el grupo menos afectado. El diagnóstico se confirma mediante RT-qPCR. La utilidad del CT (cycle threshold) es discutida. Objetivo: Describir las características epidemiológicas y clínicas de los niños infectados con SARS-CoV-2 y la relación entre el valor del CT y la presentación clínica. METODOLOGÍA: Se realizó un estudio descriptivo, retrospectivo, en pacientes bajo 16 años de edad con infección por SARS-CoV-2, asistidos en un prestador de salud de Montevideo entre la semana epidemiológica (S.E.) 3 del 2020 y la SE 9 del 2021. Se describieron variables clínicas, noción epidemiológica, gravedad y evolución. Se consignó el valor del CT al diagnóstico y se comparó con la presencia de síntomas. RESULTADOS: Los pacientes bajo 16 años representaron el 16,6% del total de infectados (794 en 4.792). El 70% de los casos ocurrió entre los meses de enero y febrero de 2021. El 67,6% presentó contacto intradomiciliario. La media de edad fue 7,5 ± 4,1 años, 51% de sexo masculino. Presentaron síntomas 55% y fueron asintomáticos 45%; no se observaron diferencias significativas en la media, moda y rango de edades de ambos grupos. Ninguno presentó comorbilidades. En el grupo de los 440 pacientes sintomáticos, 55% presentaron fiebre: 32% asociada con otros síntomas, principalmente respiratorios altos y 23% como único síntoma. El valor de CT se obtuvo en 536 de los 794 pacientes (67,5%). La media de CT fue 29,7 ± 5,8 en el grupo de sintomáticos vs. 31,5 ± 5,7 en asintomáticos (p > 0,05). Se hospitalizaron tres pacientes, ninguno requirió cuidados intensivos ni falleció. CONCLUSIONES: La prevalencia e incidencia de la infección por SARS-CoV-2 en niños acompañan a la de adultos y la mayoría cursó formas leves o asintomáticas, sin complicaciones. En esta serie, el valor de CT no fue diferente en niños sintomáticos y asintomáticos. El contacto estrecho intradomiciliario fue la principal fuente de infección.

BACKGROUND: After the detection of the first cases of SARS-CoV-2 and the declaration of a health emergency in the country, community transmission of the virus remained low to moderate until November 2020, later becoming medium and high. Children under 15 years of age constitute the least affected group. The diagnosis is confirmed by RT-qPCR. The usefulness of the CT (cycle threshold) is discussed. AIM: To describe the epidemiological and clinical characteristics of children infected with SARS-CoV-2 and the relationship between the CT value and clinical presentation. METHOD: A descriptive, retrospective study was carried out in patients under 16 years of age with SARS-CoV-2 infection, assisted by a health provider in Montevideo between epidemiological week (EW) 3 of2020 and EW 9 of2021. Clinical variables, epidemiological notion, severity and evolution were described. The CT value at diagnosis was recorded and compared with the presence of symptoms. RESULTS: Patients under 16 years of age represented 16.6% of the total infected (794 in 4,792). 70% of the cases occurred between the months of January and February 2021. 67.6% presented intradomiciliary contact. The mean age was 7.5 ± 4.1 years, 51% were male. 55% presented symptoms and 45% were asymptomatic; no significant differences were observed in the mean, mode and age range of both groups. None presented comorbidities. In the group of 440 symptomatic patients, 55% presented fever: 32% associated with other symptoms, mainly upper respiratory symptoms, and 23% as the only symptom. The CT value was obtained in 536 of the 794 patients (67.5%). The mean CT was 29.7+5.8 in the symptomatic group vs. 31.5 ± 5.7 in asymptomatic patients (p > 0.05). Three patients were hospitalized, none required intensive care and none died. CONCLUSIONS: The prevalence and incidence of SARS-CoV-2 infection in children accompany that of adults and the majority had mild or asymptomatic forms, without complications. In this series, the CT value was not different in symptomatic and asymptomatic children. Close household contact was the main source of infection.

Técnicas de reproducción asistida en personas del mismo sexo y solas por opción: realidad en Chile 2021 / Assisted reproduction techniques in people of the same sex and alone by option: reality in Chile 2021

Resumen El concepto de familia ha cambiado con los años y la constitución de los hogares en Chile ya no es la misma que hace un siglo. Las familias diversas en nuestro país han existido durante toda la vida, pero el conocimiento de cómo se han constituido y la existencia de un catastro en Chile son escasos. El objetivo de esta revisión es mostrar cómo se han constituido las familias diversas en Chile, cómo ha sido el acceso de estas a las técnicas de reproducción asistida, cuál ha sido la política del Estado y las aseguradoras de salud (Fonasa e Isapres) en las coberturas, y qué ha pasado con la legislación a lo largo de los años que ha facilitado la constitución de nuevas familias. Por otra parte, se pretende mostrar cuáles son las barreras al acceso por parte de las familias diversas y la necesidad de una ley de reproducción asistida que permita el acceso a todas las personas independientemente de su estado civil, orientación sexual o identidad de género, y que proteja a todos los nacidos chilenos por igual.

Abstract The image of a typical family has changed in recent years, as the makeup of households in Chile is no longer the same as decades ago. While gender and sexual diverse families in our country have always existed, there is a scarcity of reliable data. We review the evolution of the makeup of these diverse families in Chile and their access to assisted reproduction techniques. We also review national policies and health insurance coverage by both governmental and private carriers (Fonasa and Isapres) and how changes in legislation over the years have facilitated the constitution of these families. We outline barriers to access assisted reproduction techniques and the need for further legislative action to guarantee access to all citizens regardless of their marital status, sexual orientation, or gender identity.

Solving the enigma of POLD1 p.V295M as a potential cause of increased cancer risk.

Germline variants that affect the proofreading activity of polymerases epsilon (POLE) and delta (POLD1) predispose to colorectal adenomas and carcinomas, among other cancers. All cancer-associated pathogenic variants reported to date consist of non-disruptive genetic changes affecting the sequence that codifies the exonuclease domain (ED). Generally, disruptive (frameshift, stop-gain) POLE and POLD1 variants and missense variants outside the ED do not predispose to cancer. However, this statement may not be true for some, very specific variants that would indirectly affect the proofreading activity of the corresponding polymerase. We evaluated, by using multiple approaches, the possibility that POLD1 c.883G>A; p.(Val295Met), -a variant located 9 amino acids upstream the ED and present in ~0.25% of hereditary cancer patients-, affects POLD1 proofreading activity. Our findings show cumulative evidence that support no alteration of the proofreading activity and lack of association with cancer. The variant is classified as likely benign according to the ACMG/AMP guidelines.

[Actinomyces sp. brain abscess: a rare infection in children. A case report]. / Absceso cerebral por Actinomyces sp.: una infección infrecuente en niños. A propósito de un caso.

Despite advances in diagnostic and treatment techniques, intracranial infections remain serious diseases with an estimated incidence of between 0.3 and 1.3 cases/100,000 inhabitants. We present a previously healthy patient with an intraoperative diagnostic of brain abscess, in whom although the culture showed polymicrobial development, Actinomyces sp was presumptively identified in the pathological anatomy. Given this finding, prolonged combined antibiotic therapy was performed with good evolution. Absceso cerebral por Actinomyces sp.: una infección infrecuente en niños. A propósito de un caso Actinomyces sp. brain abscess: a rare infection in children. A case report The presentation of this suppurative process was nonspecific and the contribution of the anatomopathology in the etiological diagnosis was relevant. The identification of an unusual microorganism defined the need to deepen the identification of predisposing factors.

A pesar de los avances en las técnicas de diagnóstico y tratamiento, las infecciones intracraneanas son aún enfermedades graves con una incidencia estimada entre 0,3 y 1,3 casos por cada 100 000 habitantes. Se presenta un paciente previamente sano con un absceso cerebral de diagnóstico intraoperatorio en quien, si bien el cultivo evidenció desarrollo polimicrobiano, se identificó presuntivamente Actinomyces sp. en la anatomía patológica. Dado este hallazgo, se realizó antibioticoterapia combinada prolongada con buena evolución. La presentación de este proceso supurado fue inespecífica y la contribución de la anatomía patológica en el diagnóstico etiológico fue relevante. La identificación de un microorganismo inhabitual definió la necesidad de profundizar en la determinación de factores predisponentes.

Systematic Analysis of FASTK Gene Family Alterations in Cancer.

The FASTK family of proteins have been recently reported to play a key role in the post-transcriptional regulation of mitochondrial gene expression, including mRNA stability and translation. Accumulated studies have provided evidence that the expression of some FASTK genes is altered in certain types of cancer, in agreement with the central role of mitochondria in cancer development. Here, we obtained a pan-cancer overview of the genomic and transcriptomic alterations of FASTK genes. FASTK, FASTKD1, FASTKD3 and FASTKD5 showed the highest rates of genetic alterations. FASTK and FASTKD3 alterations consisted mainly of amplifications that were seen in more than 8% of ovarian and lung cancers, respectively. FASTKD1 and FASTKD5 were the most frequently mutated FASTK genes, and the mutations were identified in 5-7% of uterine cancers, as well as in 4% of melanomas. Our results also showed that the mRNA levels of all FASTK members were strongly upregulated in esophageal, stomach, liver and lung cancers. Finally, the protein-protein interaction network for FASTK proteins uncovers the interaction of FASTK, FASTKD2, FASTKD4 and FASTKD5 with cancer signaling pathways. These results serve as a starting point for future research into the potential of the FASTK family members as diagnostic and therapeutic targets for certain types of cancer.

Determination of the PIC700 Ceramic's Complex Piezo-Dielectric and Elastic Matrices from Manageable Aspect Ratio Resonators.

Achieving good piezoelectric properties, such as the widely reported d33 charge coefficient, is a good starting point in establishing the potential applicability of piezoceramics. However, piezoceramics are only completely characterized by consistent piezoelectric-elastic-dielectric material coefficient matrices in complex form, i.e., including all losses. These matrices, which define the various alternative forms of the constitutive equations of piezoelectricity, are required for reliable virtual prototyping in the design of new devices. To meet this need, ten precise and accurate piezoelectric dielectric and elastic coefficients of the material, including all losses, must be determined for each alternative. Due to the difficulties arising from the coupling of modes when using the resonance method, this complete set of parameters is scarcely reported. Bi0.5Na0.5TiO3-based solid solutions are already commercially available in Europe and Japan. Here, we report a case study of the determination of these sets of material coefficients (diα, giα, eiα and hiα; sE,Dαß and cE,Dαß; εTik and εSik; and ßTik and ßSik), including all losses, of the commercial PIC700 eco-piezoceramic. Plate, disk, and cylinder ceramic resonators of a manageable aspect ratio were used to obtain all the material coefficients. The validation procedure of the matrices is also given by FEA modeling of the considered resonators.

Cyclic Mechanical Fatigue Lifetime of Bi0.5Na0.5TiO3-Based Eco-Piezoceramics.

The mechanical strength and cyclic fatigue behavior of PIC700 commercial eco-piezoceramic disks are investigated under biaxial loading on unpoled and poled samples. The bending strength of unpoled samples was higher than those of poled ones. Fatigue tests were conducted under a load ratio of 10 at a frequency of 20 Hz with a sinusoidal waveform. The curve fitting for the S-N fatigue diagram is used to predict the lifetime of these eco-piezoceramics and describe their fatigue behavior. It was also found that the unpoled samples exhibited higher fatigue resistance than the poled ones. The fatigue limit of maximum load for ten million cycles of unpoled and poled samples was estimated to be 160 and 135 MPa, respectively. The detailed observations of the fatigue fracture surfaces by scanning electron microscopy (SEM) indicated that a wavy surface with a mixture of transgranular and intergranular fractures occurred preferentially in the case of the poled material. On the other hand, transgranular fractures seem to be predominant in the unpoled samples. It appears that the poling process causes the change in failure characteristics due to domain orientation that leaves an anisotropic stress field in the material. The poled ceramics possess a local stress concentration created by the orientation under the electric poling field of the 90° ferroelectric-ferroelastic domains. Under this local stress concentration, a microstructural degeneration is induced by domain switching under the cyclic load that accelerates crack growth, thereby reducing fatigue lifetime.

MgNb2 O6 Modified K0.5 Na0.5 NbO3 Eco-Piezoceramics: Scalable Processing, Structural Distortion and Complex Impedance at Resonance.

In this work, piezoceramics of the lead-free composition K0.5 Na0.5 NbO3 with an increasing amount of MgNb2 O6 (0, 0.5, 1, 2 wt.%) were prepared through conventional solid-state synthesis and sintered in air atmosphere at 1100 °C. The effect of magnesium niobate addition on structure, microstructure and piezoelectric properties was evaluated. The ceramics maintain the orthorhombic Amm2 phase for all compositions, while an orthorhombic Pbcm secondary phase was found for increasing the concentration of MgNb2 O6 . Our results show that densification of these ceramics can be significantly improved up to 94.9 % of theoretical density by adding a small amount of magnesium-based oxide (1 wt.%). Scanning electron microscopy morphology of the 1 wt.% system reveals a well-packed structure with homogeneous grain size of ∼2.72 µm. Dielectric and piezoelectric properties become optimal for 0.5-1.0 wt.% of MgNb2 O6 that shows, with respect to the unmodified composition, either higher piezoelectric coefficients, lower anisotropy and relatively low piezoelectric losses (d33 =97 pC N-1 ; d31 =-36.99 pC N-1 and g31 =-14.04×10-3  mV N-1 ; Qp (d31 )=76 and Qp (g31 )=69) or enhanced electromechanical coupling factors (kp =29.06 % and k31 =17.25 %).

A Virtual Instrument for Measuring the Piezoelectric Coefficients of a Thin Disc in Radial Resonant Mode.

In this paper, we describe and present a Virtual Instrument, a tool that allows the determination of the electromechanical, dielectric, and elastic coefficients in polarised ferroelectric ceramic discs (piezoceramics) in the linear range, including all of the losses when the piezoceramics are vibrating in radial mode. There is no evidence in the recent scientific literature of any automatic system conceived and implemented as a Virtual Instrument based on an iterative algorithm issued as an alternative to solve the limitations of the ANSI IEEE 176 standard for the characterisation of piezoelectric coefficients of thin discs in resonant mode. The characterisation of these coefficients is needed for the design of ultrasonic sensors and generators. In 1995, two of the authors of this work, together with other authors, published an iterative procedure that allowed for the automatic determination of the complex constants for lossy piezoelectric materials in radial mode. As described in this work, the procedures involved in using a Virtual Instrument have been improved: the response time for the characterisation of a piezoelectric sample is shorter (approximately 5 s); the accuracy in measurement and, therefore, in the estimates of the coefficients has been increased; the calculation speed has been increased; an intuitive, simple, and friendly user interface has been designed, and tools have been provided for exporting and inspecting the measured and processed data. No Virtual Instrument has been found in the recent scientific literature that has improved on the iterative procedure designed in 1995. This Virtual Instrument is based on the measurement of a unique magnitude, the electrical admittance (Y = G + iB) in the frequency range of interest. After measuring the electrical admittance, estimates of the set of piezoelectric coefficients of the device are obtained. The programming language used in the construction of the Virtual Instrument is LabVIEW 2019®.

A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases.

DNA-Damage Response (DDR) proteins are crucial for maintaining the integrity of the genome by identifying and repairing errors in DNA. Variants affecting their function can have severe consequences since failure to repair damaged DNA can result in cells turning cancerous. Here, we compare germline and somatic variants in DDR genes, specifically looking at their locations in the corresponding three-dimensional (3D) structures, Pfam domains, and protein-protein interaction interfaces. We show that somatic variants in metastatic cases are more likely to be found in Pfam domains and protein interaction interfaces than are pathogenic germline variants or variants of unknown significance (VUS). We also show that there are hotspots in the structures of ATM and BRCA2 proteins where pathogenic germline, and recurrent somatic variants from primary and metastatic tumours, cluster together in 3D. Moreover, in the ATM, BRCA1 and BRCA2 genes from prostate cancer patients, the distributions of germline benign, pathogenic, VUS, and recurrent somatic variants differ across Pfam domains. Together, these results provide a better characterisation of the most recurrent affected regions in DDRs and could help in the understanding of individual susceptibility to tumour development.

FEA Study of Shear Mode Decoupling in Nonstandard Thin Plates of a Lead-Free Piezoelectric Ceramic.

The finite-element analysis (FEA) is used in this work to study the impedance curves and modes of motion at resonance of nonstandard shear plates, thickness poled, and longitudinally excited. An ecological, lead-free, piezoelectric ceramic of ( 1-x )(Bi0.5Na0.5)TiO3- x BaTiO3 with x =0.06 (BNBT6) composition is studied. The FEA modeling is based on the full matrix of the material coefficients. These are obtained from complex impedance measurements on two-thickness poled resonators. A study as a function of the variations of the dimensions of the plate was accomplished ( t = thickness for poling and L and w = lateral dimensions, where w is the distance between electrodes for the electrical excitation). We aimed to a further understanding, and, thus, the ability to control, the coupling of the main shear resonance and the lateral modes. The use of uncoupled shear modes to obtain the material parameters is a key issue for their determination as complex quantities, thus considering all material losses, electromechanical, dielectric, and elastic.