Genética del TDAH en la práctica clínica / Genetics of ADHD in clinical practice

Resumen El trastorno por déficit de atención/hiperactividad (TDAH) es un trastorno del neurodesarrollo complejo y heterogéneo desde una perspectiva causal, clínica y pro nóstica. La investigación refleja su carácter multifactorial con un papel destacado de los factores genéticos. Los estudios poblacionales han señalado históricamente la implicación de numerosas variantes genéticas de escaso tamaño de efecto, las cuales por sí mismas apenas incre mentan el riesgo de TDAH y difícilmente justifican su ele vada heredabilidad. Muchas de ellas están presentes en más del 60% de la población general, lo que sugiere su pa pel modulador más que causal. No obstante, gracias a la irrupción de nuevas técnicas genéticas en los últimos 15 años, se están identificando un mayor número de casos con trastornos genéticos (muchos de ellos monogénicos), cuyas variantes genéticas explican por sí mismas la presencia del TDAH. El estudio detallado de los antecedentes personales y familiares, así como una exploración física completa, puede ayudar a identificar algunos de ellos. La identificación de la causa en este conjunto de casos tiene un valor crucial en el asesoramiento clínico, el consejo genético-familiar y la anticipación pronóstica, así como en la realización o evitación de estudios complementarios y en el diseño del plan terapéutico.

Abstract Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous neurodevelopmental disor der from a causal, clinical and prognostic perspective. Research reflects its multifactorial nature with a promi nent role of genetic factors. Population studies have historically pointed to the involvement of numerous genetic variants of small effect size, which hardly by themselves increase the risk of presenting the disorder and hardly justify its high heritability. Many of them are present in more than 60% of the general population, suggesting their modulatory rather than causal role. However, after the irruption of new genetic techniques in the last 15 years, a greater number of cases are be ing identified with genetic disorders (many of them monogenic), whose genetic variants alone explain the presence of ADHD. A detailed study of the personal and family history, as well as a complete physical examination, can help to identify some of them. The identification of the cause in this group of cases has a crucial value in clinical counseling, genetic-familial counseling and prognostic anticipation, as well as in the performance or avoidance of complementary stud ies and in the design of the intervention plan.

Prevalencia de lesiones en mucosa bucal y su relación con condición sistémica, edad y sexo / Prevalence of lesions in the oral mucosa and its relationship with systemic condition, age and gender

Este estudio tiene la finalidad de analizar la prevalencia de variantes de la normalidad y patología en la mucosa de la cavidad bucal por zona anatómica, de una población controlada en una clínica estomatológica universitaria de pregrado en el Estado de México. Se trata de un estudio transversal, descriptivo y observacional de 542 pacientes, de los cuales el 62.7% (340) pertenecen al sexo femenino y 37.3% (202) al masculino; la edad se distribuyó en un rango de dos a 85 años con una media de 28 años y fue categorizada en cinco grupos etarios: 2 a 12, 13 a 18, 19 a 35, 36 a 69 y > 70 años. En este estudio participaron una especialista en patología bucal, un especialista en odontopediatría y una pasante de la licenciatura de estomatología quien fungió como ayudante de investigación. Fueron identificadas 13 variantes de la normalidad y 52 lesiones en total, mismas que son reportadas por zona anatómica, por rangos de edad y por sexo. El número de condiciones y lesiones diagnosticadas por paciente varió de una a cinco en 87.27% y en el restante 12.73% no se detectó ninguna. Las variantes de la normalidad o condiciones más frecuentes fueron lengua fisurada con 12.17%, apéndice mucoso en frenillo vestibular con 11.25% y gránulos de Fordyce con 10.88%. Las lesiones más prevalentes por zona anatómica fueron: nevo intradérmico con 2.39% en labio externo superior e inferior; queilitis simple con 11.43% en la interfase de piel y mucosa de los labios (borde bermellón); úlcera traumática con 3.87% en mucosa labial; absceso de origen dental con 1.42 en encía; frenillo con inserción baja 1.84% en frenillos; úlcera traumática con 5.53% en mucosa bucal; candidiasis atrófica crónica con 5.53% en paladar; amígdalas hipertróficas con 8.11% en zona amigdalina; lengua pilosa con 1.66% en lengua; úlcera traumática con 3.69% en piso de boca; granuloma piógeno con 0.18% en proceso alveolar; y por último, hipertrofia de glándulas salivales labiales con 0.55% asociadas a presencia de aparatología ortodóntica. Finalmente se llevó a cabo una prueba de χ2 de Pearson para establecer correlación entre variables dependientes e independientes, encontrando significancia estadística de p < 0.000 entre lesiones de lengua y condición sistémica y edad en relación a lesiones de lengua, paladar y labios con p < 0.000 (AU)

The purpose of this study is to analyze the prevalence of variants of normality and pathology in the mucosa of the oral cavity by anatomical area in a controlled population in a university undergraduate stomatological clinic in the state of Mexico. This is a cross-sectional, descriptive and observational study of 542 patients, of which 62.7% (340) belonged to the female gender and 37.3% (202) to the male gender, the age was distributed in a range of two to 85 years with a mean of 28 years and was categorized in five age groups: 2 to 12, 13 to 18, 19 to 35, 36 to 69 and > 70 years. A specialist in oral pathology, a specialist in pediatric dentistry and an intern in stomatology who served as a research assistant participated in this study. Thirteen variants of normality and 52 lesions in total were identified and reported by anatomical area, age range and gender. The number of conditions and lesions diagnosed per patient ranged from one to five in 87.27% and none were detected in 12.73% of the population studied. The most frequent variants of normality or conditions were fissured tongue with 12.17%, mucous appendage in the vestibular frenulum with 11.25% and Fordyce granules with 10.88%. The most prevalent lesions by anatomical area were: intradermal nevus with 2.39% in upper and lower external lip; simple cheilitis with 11.43% in the interphase interface of skin and mucosa of the lips (vermilion border); traumatic ulcer with 3.87% in labial mucosa; abscess of dental origin with 1.42 in gingiva; frenulum with low insertion 1.84% in frenulum; traumatic ulcer with 5. 53% in buccal mucosa; chronic atrophic candidiasis with 5.53% in palate; hypertrophic tonsils with 8.11% in tonsillar area; hairy tongue with 1.66% in tongue; traumatic ulcer with 3.69% in floor of mouth; pyogenic granuloma with 0.18% in alveolar process and finally; hypertrophy of labial salivary glands with 0.55% associated with the presence of orthodontic appliances. Finally, a Pearson's χ2 test was carried out to establish correlation between dependent and independent variables, finding statistical significance of p < 0.000 between tongue lesions and systemic condition and age in relation to tongue, palate and lip lesions with a p < 0.000 (AU)

Novas variantes de KPC em isolados do Complexo Klebsiella pneumoniae resistentes à ceftazidima-avibactam / New KPC variants in ceftazidime-avibactam-resistant K. pneumoniae Complex isolates

O Complexo K. pneumoniae (C-Kp) é o principal grupo de bacilos Gram-negativos responsáveis por infecções nosocomiais graves em todo o mundo e o tratamento empírico dessas infecções usualmente inclui os carbapenêmicos. O principal mecanismo de resistência a essa classe de antimicrobianos é a expressão de carbapenemases, e no Brasil, mais frequentemente as do tipo KPC. Em março de 2019 a ceftazidima-avibactam foi disponibilizada para uso clínico no Brasil, sendo amplamente utilizada no tratamento infecções causadas por bacilos gram-negativos produtores de KPC. Diversos países já relataram a presença de K. pneumoniae produtores de KPC resistentes à ceftazidima-avibactam. No entanto, há poucos relatos dessa ocorrência no Brasil. O objetivo deste trabalho foi caracterizar genotipicamente e fenotipicamente isolados do C-Kp produtores de KPC, resistentes à ceftazidima-avibactam. No período de julho/2019 a julho/2021, 46 isolados do C-Kp, um por paciente, foram detectados em diferentes sítios de infecção ou culturas de vigilância de pacientes internados em hospitais privados de seis estados brasileiros. Os isolados tiveram seu genoma completo sequenciado nas plataformas MiSeq e MinION para determinação da variante alélica de blaKPC e avaliação do seu contexto genético. As taxas de resistência ao ertapenem e à ceftazidima-avibactam foram calculadas a partir de banco de dados. A clonalidade dos isolados foi avaliada por PFGE e MLST. A localização plasmidial do gene blaKPC foi confirmada por conjugação e/ou transformação. A concentração inibitória mínima (CIM) para betalactâmicos foi determinada por microdiluição em caldo segundo o BrCAST. Ensaios imunocromatográficos, NG-Test CARBA-5 e O.K.N.V.I. RESIST-5, foram avaliados quanto à sua performance na detecção de variantes KPC. A taxa de resistência ao ertapenem entre isolados do C-Kp aumentou 15,6% em 2019 para 27,3% em 2021. A taxa de resistência à ceftazidima-avibactam entre isolados do C-Kp resistentes ao ertapenem aumentou de 4,2% em 2019 para 17,2% em 2021. Onze isolados apresentaram novas variantes de KPC designadas KPC-103 a KPC-108 e KPC-139 a KPC-143. Os demais isolados apresentavam variantes de KPC já descritas, sendo a KPC-33 a variante mais frequente (36%). Quinze grupos clonais foram identificados, sendo que a maioria dos isolados pertencia ao ST11. O grupo clonal A foi o mais numeroso e pertencia ao ST258. A principal variante detectada nesse grupo foi a KPC-33. Diferentes grupos de incompatibilidade foram identificados em plasmídeos alberguando blaKPC, sendo os grupos IncN (n=12) e IncF, com replicons FII(K)-FIB (n=11), os grupos mais frequentes, seguido de InX3-IncU (n=9) e IncQ1 (n=1). Dos 46 isolados resistentes à ceftazidima-avibactam, 36 foram capazes de transferir o gene blaKPC para cepas receptoras. A maioria dos isolados foi sensível dose padrão ou sensível aumentabdo exposição ao meropenem e apresentaram redução significativa da CIM quando o avibactam foi adicionado ao aztreonam. O NG-Test CARBA-5 detectou 12 das 24 variantes testadas enquanto que o O.K.N.V.I. RESIST-5 detectou apenas nove variantes. A grande diversidade de variantes KPC, e a predominância do grupo clonal ST11, e da KPC- 33 retratam um cenário preocupante no Brasil

The K. pneumoniae Complex (C-Kp) is the main group of gram-negative bacilli responsible for serious nosocomial infections worldwide and the empirical treatment of these infections usually includes carbapenems. The main mechanism of resistance to this class of antimicrobials is the expression of carbapenemases, and in Brazil, more frequently the KPC type. In March 2019, ceftazidime-avibactam was available for clinical use in Brazil, being widely used to treat infections caused by KPC-producing gram-negative bacilli. Several countries have already reported the presence of KPC-producing K. pneumoniae resistant to ceftazidime-avibactam; however, there are few reports of this occurrence in Brazil. This work aimed to genotypically and phenotypically characterize KPC-producing C-Kp isolates resistant to ceftazidimeavibactam. From July 2019 to July 2021, 46 C-Kp isolates, one per patient, were detected in different sites of infection or surveillance cultures from patients admitted to private hospitals in six Brazilian states. The isolates had their complete genome sequenced on the MiSeq and MinION platforms to determine the allelic variant of blaKPC and evaluate its genetic context. Resistance rates to ertapenem and ceftazidime-avibactam were calculated from a database. The clonality of the isolates was evaluated by PFGE and MLST. The plasmid location of the blaKPC gene was confirmed by conjugation and/or transformation. The minimal inhibitory concentrations for beta-lactams were determined by broth microdilution according to BrCAST. Immunochromatographic assays, NG-Test CARBA-5 and O.K.N.V.I. RESIST-5, were evaluated for its performance in detecting KPC variants. The resistance rate to ertapenem among C-Kp isolates increased from 15.6% in 2019 to 27.3% in 2021. The resistance rate to ceftazidime-avibactam among ertapenem-resistant C-Kp isolates increased from 4.2% in 2019 to 17.2% in 2021. Eleven isolates showed new KPC variants designated KPC-103 to KPC-108 and KPC-139 to KPC-143. The remaining isolates presented previously described KPC variants, with KPC-33 being the most common variant (36%). Fifteen clonal groups were identified, with most isolates belonging to ST11. Different incompatibility groups were identified in plasmids harboring blaKPC, with the IncN (n=12) and IncF groups, with FII(K)-FIB(n=11) replicons, being the most frequent groups, followed by InX3-IncU (n= 9) and IncQ1 (n=1). All IncX3-IncU plasmids were approximately 46 kb in size and were identified among isolates belonging to the largest identified clonal group (A) and ST258. The main variant detected in this group was KPC-33. Of the 46 ceftazidime-avibactam-resistant isolates, 36 were able to transfer the blaKPC gene to recipient strains. Most isolates were susceptible standard dose or susceptible increased exposure to meropenem and showed a significant decrease in MIC when avibactam was added to aztreonam. The NG-Test CARBA-5 was able to detect 12 of the 24 variants evaluated while the O.K.N.V.I. RESIST-5 detected only nine variants. The great diversity of KPC variants, the predominance of the ST11 clonal group, and KPC-33 portray a worrying scenario in Brazil

Evaluación de parámetros inflamatorios, trombóticos y variantes genéticas en pacientes con ataque cerebrovascular isquémico que se asisten en un hospital de Uruguay

Introducción: El ataque cerebrovascular es la segunda causa de muerte en adultos en el mundo occidental y una de las principales causas de discapacidad permanente, aumentando su frecuencia con la edad, el 85 % es de tipo isquémico. Objetivos: Analizar parámetros trombofílicos, hipofibrinolíticos y genéticos en pacientes con ataque cerebrovascular isquémico y evaluar la posible asociación de estos con factores de riesgo cardiovascular. Metodología: Se utilizó un cuestionario para evaluar la presencia de factores de riesgo cardiovascular en 114 pacientes incluidos en el estudio con diagnóstico de ataque cerebrovascular isquémico. Proteína C y antitrombina fueron determinados mediante métodos cromogénicos, resistencia a la proteína C activada e inhibidor lúpico mediante métodos coagulométricos y proteína S libre, inhibidor del activador del plasminógeno-1, homocisteína y lipoproteína (a) por métodos inmunoquímicos. Fibrinógeno fue determinado por coagulometría y proteína C reactiva por inmunoturbidimetría, ambos contra un grupo control. Las variantes genéticas factor V Leiden, protrombina G20210A, rs1205 (gen PCR), rs1800779 (gen NOS3) y rs2257073 (gen ASB10) fueron analizadas mediante real-time PCR, comparando los últimos tres con una población de referencia. La alteración de las frecuencias de las variables fue determinada por análisis estadístico chi-cuadrado. Resultados: Tres de los cuatro pacientes jóvenes estudiados presentaron indicadores de trombofilia. El resto de los parámetros alterados fueron homocisteína 30.1% (22.4-39.1), lipoproteína (a) 32.1% (24.1-41.4), inhibidor del activador del plasminógeno-1 36.0% (27.8-45.1), fibrinógeno 12.3% (7.5-19.6) y proteína C reactiva 78.1% (69.6-84.7). Se encontró asociación (p < 0.05) entre ciertos factores de riesgo cardiovascular y los parámetros evaluados como hipertensión/proteína C reactiva, dislipemia/lipoproteína (a), arritmia/lipoproteína (a) y arritmia/fibrinógeno. Para pacientes con ataque cerebrovascular isquémico solo la variante rs1205 mostró una frecuencia más alta del alelo T. Conclusiones: Este estudio revela la importancia de analizar la trombofilia en pacientes jóvenes, especialmente en aquellos sin factores de riesgo cardiovascular, así como el rol de la hipofibrinolisis, inflamación y algunas variantes genéticas en el desarrollo de ataque cerebro vascular isquémico.

Introduction: Stroke is the second cause of death in adults in the Western world and one of the main causes of permanent disability, increasing in frequency with age; 85% are ischemic. Objectives: To analyze thrombophilic, hypofibrinolytic, inflammatory, and genetic parameters in patients with ischemic stroke and evaluate possible associations with vascular risk factors. Methodology: Questionnaires were used to evaluate vascular risk factors in 114 patients included in the study with ischemic stroke diagnosis. Protein C and Antithrombin were determined by chromogenic assays, Activated Protein C Resistance and Lupus Anticoagulant were determined with by coagulometry and Free Protein S, Plasminogen activator inhibitor-1, Homocysteine and Lipoprotein (a) by immunochemistry. Fibrinogen was assayed by coagulometry and C-reactive protein by immunoturbidimetry, both against a control group. Factor V Leiden, Prothrombin G20210A, rs1205 (CRP gene), rs1800779 (NOS3 gene) and rs2257073 (ASB10 gene) genetic variants were analyzed by Real-Time PCR, comparing the last three with a reference population. Alteration frequencies of the variables were determined by chi-square statistical analysis. Results: Three out of four of the young patients studied presented indicators of thrombophilia. The rest of the altered parameters were Homocysteine 30.1% (22.4-39.1), Lipoprotein (a) 32.1% (24.1-41.4), Plasminogen activator inhibitor-1 36.0% (27.8-45.1), Fibrinogen 12.3% (7.5-19.6) and C-reactive protein 78.1% (69.6-84.7). Associations were found (p<0.05) between certain vascular risk factors and parameters evaluated, namely hypertension/C-reactive protein, dyslipidemia/lipoprotein (a), arrhythmia/lipoprotein (a) and arrhythmia/fibrinogen. For ischemic stroke patients only the genetic variant rs1205 showed higher frequency of the T allele. Conclusions: This study reveals the importance of analyzing thrombophilia in young patients, especially those without vascular risk factors, as well as the role of hypofibrinolysis, inflammation and some genetic variants in the development of ischemic stroke.

Introdução: O AVC é a segunda causa de morte em adultos no mundo ocidental e uma das principais causas de incapacidade permanente, aumentando de frequência com a idade; 85% são isquémicos. Metas: Analisar os parâmetros trombofílicos, hipofibrinolíticos e genéticos em pacientes com acidente vascular cerebral isquêmico e avaliar a possível associação com fatores de risco cardiovascular. Metodologia: Um questionário foi utilizado para avaliar a presença de fatores de risco cardiovascular em 114 pacientes incluídos no estudo com diagnóstico de acidente vascular cerebral isquêmico. Proteína C e antitrombina foram determinadas por métodos cromogênicos, resistência à proteína C ativada e inibidor de lúpus por métodos coagulométricos e proteína S livre, inibidor do ativador do plasminogênio-1, homocisteína e lipoproteína (a) por métodos imunoquímicos. O fibrinogênio foi determinado por coagulometria e a proteína C-reativa por imunoturbidimetria, ambos contra um grupo controle. As variantes genéticas fator V Leiden, protrombina G20210A, rs1205 (gene PCR), rs1800779 (gene NOS3) e rs2257073 (gene ASB10) foram analisadas por PCR em tempo real, comparando as três últimas com uma população de referência. As frequências de alteração das variáveis ​​foram determinadas pela análise estatística qui-quadrado. Resultados: Três dos quatro pacientes jovens estudados apresentaram indicadores de trombofilia. O resto dos parâmetros alterados foram homocisteína 30,1% (22,4-39,1), lipoproteína (a) 32,1% (24,1-41,4), inibidor do ativador de plasminogênio-1 36,0% (27,8-45,1), fibrinogênio 12,3% (7,5-19,6) e proteína C reativa 78,1% (69,6-84,7). Foi encontrada associação (p<0,05) entre alguns fatores de risco cardiovascular e os parâmetros avaliados como hipertensão/proteína C reativa, dislipidemia/lipoproteína (a), arritmia/lipoproteína (a) e arritmia/fibrinogênio. Para pacientes com acidente vascular cerebral isquêmico apenas a variante rs1205 apresentou maior frequência do alelo T. Conclusões: Este estudo revela a importância de analisar a trombofilia em pacientes jovens, especialmente aqueles sem fatores de risco cardiovascular, bem como o papel da hipofibrinólise, inflamação e algumas variantes genéticas no desenvolvimento do acidente vascular cerebral isquêmico.

Análisis comparativo de las características clínicas, evolución y mortalidad de pacientes hospitalizados por COVID-19 durante la primera y segunda ola de la pandemia (REGISTRO ECCOVID) / Comparative analysis of clinical characteristics, evolu tion and mortality of hospitalized patients with COVID-19 during the first and second wave of the pandemic (ECCOVID STUDY)

Resumen Introducción : Las características clínicas y evolutivas de los pacientes con diagnóstico de COVID-19 pueden diferir entre las distintas olas de la pandemia. El objetivo de este estudio fue comparar las características clínicas, evolución y mortalidad de pacientes hospitalizados por COVID-19 durante la primera y segunda ola en Argentina. Métodos : Registro multicéntrico y prospectivo de pacientes ≥ 18 años con diagnóstico confirmado de COVID-19 internados en 18 hospitales de Argentina durante la primera (marzo a octubre 2020) y la segunda ola (marzo a julio 2021) de la pandemia. Se compararon variables demográficas, características clínicas, y evolu ción a 30 días. Resultados : Se incluyeron un total de 1691 pacien tes (primera ola n = 809, segunda ola n = 882). Los pa cientes hospitalizados durante la segunda ola tenían mayor edad (mediana 53 años vs. 61 años, p < 0.001), comorbilidades (71% vs. 77%, p = 0.007) y requerimiento de oxígeno (21% vs. 62%, p < 0.001). Durante la hospi talización, los pacientes de la segunda ola requirieron más oxigenoterapia (49% vs. 85%, p < 0.001), asistencia mecánica respiratoria (12% vs. 22%, p <0,001) y presen taron mayor mortalidad (11% vs. 26%, p < 0.001). Compa rando únicamente a los que requirieron oxigenoterapia durante la hospitalización, la mortalidad a los 30 días fue de 20% y 30% p < 0.001 en la primera y segunda ola respectivamente. Conclusión : Comparados con los pacientes interna dos durante la primera ola, los internados durante la segunda ola de SARS-CoV-2 en Argentina presentaron mayor gravedad y mortalidad.

Abstract Introduction : Clinical features and outcomes of SARS-CoV-2 infections may change between different waves of the pandemic. The objective of this study was to compare clinical characteristics and outcomes between two cohorts of patients hospitalized for COVID-19 during the first and second waves in Argentina. Methods : Multicenter and prospective registry of patients ≥18 years old with a confirmed diagnosis of COVID-19 admitted to 18 hospitals in Argentina during the first wave (March to October 2020) and second wave (March to July 2021) of the pandemic. Demographics, clinical characteristics, and outcomes of these patients were compared. Results : A total of 1691 patients were included (first wave n = 809, second wave n = 882). Hospitalized pa tients during the second wave were older (median 53 years vs. 61 years, p < 0.001), had more comorbidities (71% vs. 77%, p=0.007) and required more supplemental oxygen at admission (21% vs 62%, p < 0.001). During hos pitalization, patients of the second wave required more supplemental oxygen (49% vs. 85%, p < 0.001), invasive ventilation (12% vs. 22%, p < 0.001) and had higher 30- day mortality (11% vs. 26%, p < 0.001). Comparing only patients who required supplemental oxygen during hos pitalization, 30-day mortality was 20% and 30% p < 0.001 for the first and second wave, respectively. Conclusion : Compared to patients admitted during the first wave, patients admitted with SARS-CoV2 dur ing the second wave in Argentina were more seriously ill and had a higher mortality.

Therapies that Have Shown Efficacy Against COVID-19: A Narrative Review / "Terapias que han demostrado eficacia en el COVID-19: una revisión narrativa"

RESUMEN: Antecedentes: La enfermedad por el nuevo coronavirus ha acelerado el desarrollo de pautas terapéuticas para los pacientes en función de su estado de severidad. Hasta la fecha, se han estudiado múltiples fármacos, sin embargo, con el paso del tiempo, solo algunos de los grupos terapéuticos han demostrado ser efectivos y han evidenciado una reducción en la morbimortalidad de los pacientes. Métodos: Se realizó una búsqueda e identificación de artículos publicados en las siguientes bases de datos electrónicas: PubMed, Clinical Key, Web of Science y Scopus para su análisis y selección en inglés y español. La investigación bibliográfica enfatiza la búsqueda de lineamientos actuales sobre el tratamiento de la COVID-19, incluyendo todos los grados de severidad, buscando la efectividad del medicamento. Resultados: Para cada fármaco listado, se describe su farmacodinamia, farmacocinética y recomendaciones generales de uso en pacientes adultos con COVID-19. Conclusiones: Durante la pandemia de COVID-19 se han estudiado numerosos grupos farmacológicos, sin embargo, solo un grupo selecto ha demostrado tener un papel en el tratamiento de la enfermedad. La literatura y las guías respaldan el uso de estos manejos.

ABSTRACT: Background: The new coronavirus disease has accelerated the development of therapeutic guidelines for patients depending on their degree of severity. To date, many drugs have been studied. However, as time passed, only some of these therapeutic groups have been effective and have produced a reduction in patient mortality and morbidity. Methods: A search and identification of articles published in the following electronic databases was carried out: PubMed, Clinical Key, Web of Science, and Scopus; for their analysis and selection in English and Spanish. The literature research emphasizes the search for current guidelines on the treatment of COVID-19, including all degrees of severity, seeking the effectiveness of the medication. Results: For each listed drug, its pharmacodynamics, pharmacokinetics, and general recommendations for use in adult patients with COVID-19, are described. Conclusions: During the COVID-19 pandemic, numerous groups of drugs have been studied, however, only a select group have shown to have a role in the treatment of the disease. The literature and guidelines support the use of these treatments.

Introducción al filtrado, análisis y curación de variantes genéticas en pacientes con Discapacidad Intelectual / Introduction to filtering, analysis and curation of genetic variants in patients with Intellectual Disability

Resumen Actualmente la secuenciación del exoma completo (WES; Whole-exome sequencing) mediante la técnica NGS (Next-generation sequencing) es uno de los estudios genéticos más solicitados dentro del abordaje de pacientes con Discapacidad Intelectual con o sin otras anomalías. Al igual que con otros proce dimientos y estudios clínicos, es conveniente que los médicos prescriptores tengan una comprensión clara de los alcances y limitaciones del uso de WES, del proceso de análisis de las variantes genéticas identificadas, así como de aspectos a evaluar acerca de la calidad y estructura de los informes de los estudios de NGS, con el objetivo de que puedan interpretar mejor los resultados de un estudio y plantear de la mejor manera la correlación de los mismos con la clínica observada.

Abstract Currently, Whole exome sequencing (WES) using NGS (Next-generation sequencing) technology is one of the most requested genetic studies within the approach of patients with intellectual disability with or without other anomalies. As with other procedures and clinical studies, it is convenient for prescribing physicians to have a clear understanding of the scope and limitations of the use of WES, the analysis process of the genetic variants identified, as well as aspects to be evaluated regarding quality and structure of the reports of the NGS studies, with the aim that they can better interpret the results of a study, evaluate its quality, and propose in the best way the correlation of the same with the observed phenotype.

Reclasificación de variante de significancia clínica incierta en un caso de MPS tipo IV-A no clásica

Introducción: La mucopolisacaridosis tipo IV - A (MPS IV-A, Síndrome de Morquio tipo A) es un trastorno hereditario autosómico recesivo y una de las enfermedades lisosómicas comunes, causada por el déficit en la actividad de la hidrolasa lisosómica, N-acetilglucosamina-6-sulfatasa (GALNS) lo cual conlleva a una acumulación de glucosaminoglucanos (GAG) como queratán sulfato (KS) y condroitin-6-sulfato (C6S) en múltiples tejidos. Como en las otras MPS, existen distintos fenotipos, que varían desde formas graves también denominada MPS IV-A clásica hasta formas leves llamada MPS IV-A atenuada o no clásica. Material y métodos: Reporte de caso clínico. Los análisis realizados en aislamientos leucocitarios se realizaron por sedimentación usando Dextran-Heparina, liberando la enzima por sonicación y ajustando la concentración proteica, la valoración enzimática se realizó mediante un ensayo fluorométrico, el análisis de secuencia de los genes de interés se realizó mediante secuenciación de nueva generación (NGS) y el análisis in silico se realizó con herramientas de bioinformáticas para predicción del efecto biológico de la variante. Resultados: Paciente masculino de 12 años con diagnóstico clínico, paraclínico, enzimático y estudio molecular con dos variantes heterocigóticas, una con clasificación de significancia clínica patogénica y la otra con significancia clínica incierta de MPS IV-A, con posterior reclasificación de significancia de acuerdo con las recomendaciones del Colegio Americano de Genética Médica Y Genómica Y La Asociación de Patología Molecular, y su correlación fenotipo, endotipo y genotipo. Conclusiones: La MPS IV-A de manera atenuada representa un reto diagnóstico para profesionales de la salud por lo que es de gran importancia identificar de modo precoz manifestaciones clínicas leves de la enfermedad. A través del uso de herramientas de bioinformática se logró establecer la significancia patogénica de la variante sin sentido c.1088T>C (p. Ile363Thr) y de esta forma se reportarla como variante nueva asociada a MPS IV-A. (provisto por Infomedic International)

Introduction: Mucopolysaccharidosis type IV - A (MPS IV-A, Morquio Syndrome type A) is an autosomal recessive hereditary disorder and one of the common lysosomal diseases, caused by a deficiency in the activity of lysosomal hydrolase, N-acetylglucosamine- 6-sulfatase (GALNS) which leads to an accumulation of glycosaminoglycans (GAGs) such as keratan sulfate (KS) and chondroitin-6-sulfate (C6S) in multiple tissues. As in the other MPS, there are different phenotypes, ranging from severe forms also called classic MPS IV-A to mild forms called attenuated or non-classic MPS IV-A. Material and methods: Clinical case report. The analyzes carried out on leukocyte isolates were carried out by sedimentation using Dextran-Heparin, releasing the enzyme by sonication, and adjusting the protein concentration, the enzymatic assessment was carried out by means of a fluorometric assay, the sequence analysis of the genes of interest was carried out by sequencing of new generation (NGS) and in silico analysis was performed with bioinformatics tools to predict the biological effect of the variant. Results: A 12-year-old male patient with a clinical, paraclinical, and enzymatic diagnosis and molecular study with two heterozygous variants, one with a pathogenic clinical significance classification and the other with uncertain clinical significance of MPS IV-A, with subsequent reclassification of significance according to the recommendations of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, and their phenotype, endotype, and genotype correlation. Conclusions: MPS IV-A in an attenuated manner represents a diagnostic challenge for health professionals, which is why it is of great importance to identify mild clinical manifestations of the disease early. With bioinformatics tools, it was possible to establish the pathogenic significance of the nonsense variant c.1088T>C (p. Ile363Thr) and thus report it as a new variant associated with MPS IV-A. (provided by Infomedic International)

Herramientas ómicas en el diagnóstico de enfermedades ultra-huérfanas: Síndrome de haploinsuficiencia MED13L

Introducción: Las tecnologías de nueva generación han permitido un avance en el diagnóstico y abordaje de enfermedades genéticas ultra-huérfanas ofreciendo mayores posibilidades en tratamiento y consejería genética a las familias. El síndrome de MED13L afecta la proteína MED13L, importante en el desarrollo temprano del corazón, células nerviosas del cerebro y estructuras de la cara. Sus variantes pueden ser las causantes del síndrome de retraso del desarrollo y dismorfia facial con o sin defectos cardíacos. Presentación de caso: Paciente de 4 años, historia de hipotonía generalizada, retraso global del neurodesarrollo, discapacidad cognitiva y rasgos dismórficos, dada la complejidad clínica se realizó secuenciación del exoma clínico completo con análisis de ADN mitocondrial y variación en el número de copias (CNV) con detección de alteración del Gen MED13L variante c.2965C>G (p.Pro989Ala), significado clínico incierto, con posterior implementación de tecnologías de última generación, y reclasificación de la significancia de la variante a patogénica a través del análisis bioinformático, lo cual permitió llegar al origen específico de la patología. Conclusiones: Se resalta la importancia del uso de tecnologías de última generación y herramientas bioinformáticas en el diagnóstico específico de las enfermedades complejas. Las nuevas tecnologías actúan como una herramienta de ayuda para instaurar un protocolo dirigido, un asesoramiento genético y así evaluar el riesgo de heredabilidad, pronóstico y perspectivas terapéuticas de las patologías genéticas ultra-huérfanas. (provisto por Infomedic International)

Introduction: New generation technologies have allowed an advance in the diagnosis and approach of ultra-orphan genetic diseases, to offer greater possibilities in treatment and genetic counseling to families. MED13L syndrome affects the MED13L protein, which is important in early development of the heart, nerve cells in the brain, and structures of the face. Its variants can be the cause of developmental delay syndrome and facial dysmorphia with or without heart defects. Case presentation: 4-year-old patient with history of generalized hypotonia, global neurodevelopmental delay, cognitive disability and dysmorphic features, given the clinical complexity a complete clinical exome sequencing was performed with analysis of mitochondrial DNA and copy number variation (CNV) with detection of alteration of the MED13L gene variant c.2965C>G (p.Pro989Ala), uncertain clinical significance, with subsequent implementation of new generation technologies and reclassification of significance to pathogenic variant through bioinformatic analysis, which allowed reaching the a specific origin of the pathology. Conclusions: The importance of the use of new generation technologies and bioinformatic tools in the specific diagnosis of complex diseases is highlighted. New technologies act as a tool to help establish a targeted protocol, genetic counseling and thus assess the risk of heritability, prognosis, and therapeutic perspectives of ultra-orphan diseases. (provided by Infomedic International)

Germline Mutations Landscape in a Cohort of the State of Minas Gerais, Brazil, in Patients Who Underwent Genetic Counseling for Gynecological and Breast Cancer / Cenário de mutações germinativas em uma coorte do estado de Minas Gerais, Brasil, em pacientes submetidas ao aconselhamento genético para câncer ginecológico e de mama

Abstract Objective The present study evaluated the profile of germline mutations present in patients who underwent genetic counseling for risk assessment for breast cancer (BC), ovarian cancer (OC), and endometrial cancer (EC) with a possible hereditary pattern. Methods Medical records of 382 patients who underwent genetic counseling after signing an informed consent form were analyzed. A total of 55.76% of patients (213/382) were symptomatic (personal history of cancer), and 44.24% (169/382) were asymptomatic (absence of the disease). The variables analyzed were age, sex, place of birth, personal or family history of BC, OC, EC, as well as other types of cancer associated with hereditary syndromes. The Human Genome Variation Society (HGVS) nomenclature guidelines were used to name the variants, and their biological significance was determined by comparing 11 databases. Results We identified 53 distinct mutations: 29 pathogenic variants, 13 variants of undetermined significance (VUS), and 11 benign. The most frequent mutations were BRCA1 c.470_471delCT, BRCA1 c.4675 + 1G > T, and BRCA2 c.2T> G. Furthermore, 21 variants appear to have been described for the first time in Brazil. In addition to BRCA1/2 mutations, variants in other genes related to hereditary syndromes that predispose to gynecological cancers were found. Conclusion This study allowed a deeper understanding of the main mutations identified in families in the state of Minas Gerais and demonstrates the need to assess the family history of non-gynecological cancer for risk assessment of BC, OC, and EC. Moreover, it is an effort that contributes to population studies to evaluate the cancer risk mutation profile in Brazil.

Resumo Objetivo O presente estudo avaliou o perfil de mutações germinativas presentes em pacientes submetidas a aconselhamento genético para avaliação de risco para câncer de mama (CM), câncer de ovário (OC) e câncer de endométrio (CE) com possível padrão hereditário. Métodos Foram analisados os prontuários de 382 pacientes que realizaram aconselhamento genético após consentimento informado. Um total de 55,76% dos pacientes (213/382) eram sintomáticos (história pessoal de câncer), e 44,24% (169/382) eram assintomáticos (ausência da doença). As variáveis analisadas foram idade, sexo, naturalidade, história pessoal ou familiar de CM, OC, CE bem como outros tipos de câncer associados a síndromes hereditárias. As diretrizes de nomenclatura da Human Genome Variation Society (HGVS) foram usadas para nomear as variantes e seu significado biológico foi determinado pela comparação de 11 bancos de dados. Resultados Identificamos 53 mutações distintas: 29 variantes patogênicas, 13 variantes de significado indeterminado e 11 benignas. As mutações mais frequentes foram BRCA1 c.470_471delCT, BRCA1 c.4675 + 1G > T e BRCA2 c.2T > G. Além disso, 21 variantes parecem ter sido descritas pela primeira vez no Brasil. Além das mutações BRCA1/2, foram encontradas variantes em outros genes relacionados a síndromes hereditárias que predispõem a cânceres ginecológicos. Conclusão Este estudo permitiu conhecer melhor as principais mutações identificadas nas famílias do estado de Minas Gerais e demonstra a necessidade de avaliar a história familiar de câncer não ginecológico para avaliação do risco de CM, OC e CE. Além disso, é um esforço que contribui com estudos populacionais para avaliar o perfil de mutações de risco para câncer no Brasil.

Association of Kappa casein gene polymorphism with milk production traits in crossbred dairy cows / Associação do polimorfismo do gene Kappa-caseína com características de produção de leite em vacas leiteiras mestiças

Milk's qualitative and technological properties are greatly affected by genetic polymorphisms in the kappa-casein gene, and their polymorphisms may serve as informative markers of yield and composition. Thus, the objective of this study was to detect kappa-casein (kappa-CN) gene polymorphisms and their association with milk production traits in crossbred dairy cows. One hundred healthy crossbred (Friesian x Jenoubi) dairy animals between three and five years old were sampled for blood and milk during their first lactation. The genomic DNA was extracted from whole blood, and restriction fragment length polymorphism (RFLP-PCR) was used to determine the genotype of the kappa-CN gene. As a consequence of the restriction digestion of this fragment with Hind III, it showed three different restriction patterns: BB (453 base pairs uncut), AB (453, 206, and 225 base pairs), and AA (206 and 225 base pairs). Based on genetic diversity, the AB genotype was the most predominant (n = 67), with a frequency of 0.67. A variant genotype of the kappa-CN gene was associated with milk production traits in crossbred dairy cows. Animals with the AA variant produced a higher milk yield and a higher percentage of fat, casein, protein, and solids not fat (SNF) (P≤0.05) (1.397kg, 0.75%, 0.31%, 0.27%, and 0.68%, respectively) than those with the BB variant. A logistic regression analysis confirmed that the kappa-CN genotypes increase milk yield and casein content. Therefore, genetic variants of the kappa-CN gene could be used as genetic markers for improving milk production traits in dairy cattle.(AU)

As propriedades qualitativas e tecnológicas do leite são muito afetadas por polimorfismos genéticos no gene kappa-caseína e esses polimorfismos podem servir como marcadores informativos de rendimento e composição. Assim, o objetivo deste estudo foi detectar polimorfismos do gene kappa-caseína (kappa-CN) e sua associação com características de produção de leite em vacas leiteiras mestiças. Cem animais mestiços (Freisian x Jenoubi) saudáveis, entre três e cinco anos de idade, foram amostrados durante a primeira lactação para sangue e leite. O DNA genômico foi extraído do sangue total e o polimorfismo dos fragmentos de restrição do DNA genômico (RFLP-PCR) foi usado para determinar o genótipo do gene kappa-CN. Em consequência da digestão de restrição deste fragmento com Hind III, ele apresentou três padrões de restrição diferentes: BB (453 pares de bases não cortadas), AB (453,206 e 225 pares de bases) eAA (206 e 225 pares de bases). Com base na diversidade genética, o genótipo AB foi o mais predominante (n = 67), com frequência de 0,67. Genótipo variante do gene kappa-CN foi associado com características de produção de leite em vacas leiteiras mestiças. Animais com a variante AA tiveram maior produção de leite e maior percentual de gordura, caseína, proteína e sólidos não gordurosos (SNG) (P≤0,05) (l,397kg, 0,75%, 0,31%, 0,27% e 0,68%, respectivamente) do que aqueles com variante BB. Uma análise de regressão logística confirmou que os genótipos kappa-CN aumentam a produção de leite e o teor de caseína. Portanto, variantes genéticas do gene kappa-CN podem ser usadas como marcadores genéticos para melhorar as características de produção de leite em bovinos leiteiros.(AU)

Apresentações atípicas do câncer de boca / Atypical presentations of oral cancer

O câncer de cavidade oral ocupa a décima sexta colocação entre as principais neoplasias malignas no mundo, sendo no Brasil a oitava mais comum. Estimam-se no país cerca de 15.100 novos casos no triênio de 2023 a 2025, e o CEC representa aproximadamente 90% desses casos. O CEC de boca pode apresentar-se de forma histológica variante, já bem descrita na literatura. O que os trabalhos ainda não consideram é uma descrição mais específica das suas apresentações clínicas variantes. Por esse motivo, esse trabalho teve como objetivo propor uma classificação clínica que possa ser aplicada por profissionais envolvidos no diagnóstico de câncer de boca e que possa contribuir para um diagnóstico mais inicial da doença. O estudo foi feito em 3 etapas: 1- foram fornecidas fotografias dos casos de CEC de boca do ACCC, da UFPB e da UERJ e separadas em convencional ou atípicos, todos os casos atípicos foram classificados em subtipos (papiliforme, fenda, verrucoso, vegetante, nódulo, pregas ou massa tumoral) pelos pesquisadores FAA e NFM, 2- através de um formulário online com as fotografias de todos os casos os avaliadores puderam classificá-los em convencionais ou atípicos, e quando atípicos agrupa-los de acordo com os subtipos citados e 3- os pesquisadores se reuniram para comparar e discutir as respostas dos formulários. Além disso foram coletadas informações dos prontuários dos pacientes. Como resultados obtivemos 422 casos, dos quais 316 são convencionais e 106 atípicos. Dentre os atípicos 18 foram classificados como Papiliforme, 29 em Fenda, 13 em Nódulo, 21 Vegetante, 3 Verrucoso, 4 em Pregas e 18 em Massa Tumoral. Ao avaliar os dados coletados, homens foram a maioria, com média de idade acima de 60 anos em ambos os grupos. No grupo atípicos menos pacientes eram tabagistas e apresentaram tempo de queixa até 2 meses a mais que no convencional. A localização mais comum das lesões foi em borda de língua no grupo convencional e assoalho nos atípicos. O principal fator que difere os dois grupos é o fumo que não aparece como um fator de risco determinante para o desenvolvimento da lesão nos atípicos. Na classificação dos CECs atípicos os subtipos mais frequentes foram Fenda e Vegetante. O diagnóstico do CEC convencional foi realizado de forma mais assertiva que se comparado ao CEC atípicos pelos especialistas

Oral cavity cancer ranks sixteenth among the main malignant neoplasms in the world, being the eighth most common in Brazil. Around 15,100 new cases are estimated in the country in the three-year period from 2023 to 2025, and SCC (squamous cell carcinoma) represents approximately 90% of these cases. Oral SCC can present in a histologically variant form, which has already been well described in the literature. What works still do not consider is a more specific description of their variant clinical presentations. For this reason, this work aimed to propose a clinical classification that can be applied by professionals involved in the diagnosis of oral cancer and that can contribute to a more initial diagnosis of the disease. The study was carried out in 3 stages: 1- photographs were provided of the cases of mouth SCC at the ACCC, UFPB and UERJ and separated into conventional or atypical, all atypical cases were classified into subtypes (papilliform, cleft, verrucous, vegetative , nodule, folds or tumor mass) by the FAA and NFM researchers, 2- through an online form with photographs of all cases, the evaluators were able to classify them as conventional or atypical, and when atypical, group them according to subtypes cited and 3- the researchers met to compare and discuss the responses on the forms. In addition, information was collected from the patients' medical records. As a result, we obtained 422 cases, of which 316 are conventional and 106 are atypical. Among the atypical cases, 18 were classified as Papilliform, 29 as Cleft, 13 as Nodule, 21 Vegetative, 3 Verrucous, 4 as Folds and 18 as Tumor Mass. When evaluating the collected data, men were the majority, with a mean age above 60 years in both groups. In the atypical group, fewer patients were smokers and had complaints for up to 2 months longer than in the conventional group. The most common location of the lesions was on the tongue edge in the conventional group and on the buccal floor in the atypical group. The main factor that differentiates the two groups is smoking, which does not appear as a determining risk factor for the development of lesions in atypical patients. In the classification of atypical SCCs, the most frequent subtypes were Cleft and Vegetative. The diagnosis of conventional SCC was performed more assertively than when compared to atypical SCC by specialists

Actualización en fibrosis quística estándares de atención para pacientes con diagnóstico de fibrosis quística con terapia moduladora: informe de la Sociedad Europea de Fibrosis Quística 2023 / Standards of care for patients with a diagnosis of cystic fibrosis who are on modulator therapy: report of the European Fibrosis Cystic Society 2023

La fibrosis quística ha entrado en la era de la terapia específica con los moduladores, útiles en variantes genéticas definidas por estudio molecular, con resultados clínicos exitosos. Este es un resumen de la publicación reciente de la Sociedad Respiratoria Europea que establece los estándares de cuidado para los pacientes que reciben este tratamiento.

Cystic fibrosis has entered the era of specific therapy called modulators, useful in genetic variants defined by molecular study, with successful clinical results. This is a summary of the recent publication of the European Respiratory Society that establishes the standards of care for patients receiving this treatment.

Clinical and genetic study of developmental and epileptic encephalopathy in argentinean pediatric patients / Estudio clínico y genético de encefalopatía epiléptica y del desarrollo en pacientes pediátricos argentinos

Abstract Introduction: The aim of this study was to extend our knowledge of the genetic background of Argentinean pediatric patients with developmental and epileptic encephalopathy (DEE) applying a next generation sequencing (NGS) panel. Methods: Thirty one patients with DEE were studied, including these phenotypes: Dravet syndrome (n:7), Dravet like syndrome (n:3), West syndrome (WS) (n:6), WS that evolved to Lennox-Gastaut syndrome (LGS) (n:4), epilepsy of infancy with migrating focal seizures (n:2), continuous spikes and waves during slow sleep evolving to LGS (n:1), LGS (n:1), myoclonic status in non-progressive encephalopathy (n:1), myoclonic atonic epilepsy (n:1), epileptic encephalopathy with multifocal spikes (n:1) and unclassified epileptic encephalopathy (n:4). Fifty-two genes frequently associated with DEE were studied by NGS in genomic DNA from peripheral blood. Results: Relevant variants were detected in 12 cases; 6 novel pathogenic or likely pathogenic variants, 6 previously reported as pathogenic and 1 variant of unknown sig nificance. Single-nucleotide heterozygous variants were identified in the SCN1A (5), GABRG2 (1), STXBP1 (2) genes, a mosaic variant in SCN2A (1) and a homozygous variant in SCN1B (1). Additionally, a heterozygous deletion involving the SCN1A, SCN2A and SCN3A genes (1), and the most frequent triplet repeat expansion in the ARX gene (1) were detected. Discussion: Genetic diagnosis was made in 39% of patients. We emphasize the importance of considering mosaic variants, copy number variants and hereditary forms when designing and interpreting molecular studies, to optimize diagnosis and management of patients. Approximately 42% of the de tected variants were novel, expanding the knowledge of the molecular basis of DEEs in Latin-American patients.

Resumen Introducción: El objetivo del estudio fue ampliar el conocimiento de las bases moleculares de las encefalopatías epilépticas y del desarrollo (EED) en pacientes pediátricos argentinos aplicando un panel de secuenciación de nueva generación (NGS). Métodos: Se analizaron 31 pacientes con los fenotipos clínicos de síndrome de Dra vet (n:7), síndrome símil Dravet (n:3), síndrome de West (SW) (n:6), SW que evoluciona a síndrome de Lennox Gastaut (SLG)(N:4), epilepsia de la infancia con crisis focales migratorias (n:2), actividad de punta onda continua durante el sueño que evolucionan a SLG (n:1), SLG (n:1), encefalopatía no progresiva con estatus mioclónico (n:1), epilepsia mioclónica atónica (n:1), encefalopatía epiléptica con espigas multifocales (n:1) y encefalopatía epiléptica indeterminada (n:4). Se estudiaron los 52 genes más frecuentemente asociados a EED a través de NGS, en ADN extraído de sangre periférica. Resultados: Se identificaron variantes relevantes en 12 casos, de las cuales 5 fueron nuevas y 6 previamente reportadas como patogénicas o posiblemente patogénicas, mien tras que una variante fue clasificada como de significado incierto. Variantes heterocigotas, de nucleótido único, se identificaron en los genes SCN1A (5), GABRG2 (1), STXBP1 (2), una variante en mosaico en SCN2A (1) y otra homocigota en SCN1B (1). Además, se detectó una deleción que involucra a los genes SCN1A, SCN2A y SCN3A (1) y la expansión de repeticiones de tripletes más frecuente en el gen ARX (1). Discusión: Se alcanzó el diagnóstico molecular en el 39% de los pacientes. Remarcamos la importancia de considerar variantes en mosaico, variantes en el número de copias y formas heredadas al momento de diseñar e interpretar los estudios moleculares, de tal forma de optimizar el diagnóstico y seguimiento de los pacientes con EED. Cabe destacar, que el 42% de las variantes detectadas fueron nuevas, ampliando nuestro conocimiento sobre las bases mole culares de las EED en población latino americana.

Variantes de la normalidad del crecimiento infantil versus fallo de medro

Introducción: El fallo de medro es la incapacidad de un niño menor de 3 años de conseguir un desarrollo y crecimiento óptimo. A menudo es confundido con las variantes normales del crecimiento y desarrollo infantil. Objetivo: Examinar las variantes normales del crecimiento infantil y diferenciarlas del verdadero fallo de medro. Métodos: Se localizaron y seleccionaron estudios relevantes en las bases electrónicas Medline, Biblioteca Virtual de Salud, Google Académico, SciELO y en libros digitales. Para la búsqueda se emplearon los vocablos: fallo de medro, variantes de la normalidad del crecimiento y desarrollo infantil. Se hallaron 89 artículos publicados entre 2005-2020 sobre temáticas afines, se escogieron 41 que conformaron la muestra. Análisis y síntesis de la información: Se actualizaron diferentes aspectos del fallo de medro: definición, clasificación, criterios diagnósticos, factores de riesgo, causas potenciales, evaluación diagnóstica y conducta. Se examinaron las características clínicas de las variantes de la normalidad del crecimiento y desarrollo infantil que permiten diferenciarlas del fallo de medro. Conclusiones: El retardo constitucional del crecimiento y desarrollo, la talla baja familiar, la talla baja idiopática, la prematuridad, el crecimiento intrauterino retardado, la delgadez y el catch-down, constituyen variantes normales del crecimiento infantil que se diagnostican erróneamente como fallo de medro y genera medicalización injustificada, gastos innecesarios en análisis complementarios y angustia familiar. Diferenciar estas entidades del fallo de medro permitiría enfocar las acciones de salud hacia objetivos más concretos y ofrecer a cada niño un tratamiento individualizado de acuerdo a su condición real de salud.

Introduction: Failure to thrive is the inability of a child under 3 years of age to achieve optimal development and growth. It is often confused with the normal variants of child growth and development. Objective: To examine the normal variants of infant growth and differentiate them from true failure to thrive. Methods: Relevant studies were located and selected in the electronic databases Medline, Virtual Health Library, Google Scholar, SciELO and in digital books. For the search, the words used were: failure to thrive, variants of the normality of growth and child development. 89 articles published between 2005-2020 on related topics were found; 41 were chosen and made up the sample. Analysis and synthesis of information: Different aspects of failure to thrive were updated: definition, classification, diagnostic criteria, risk factors, potential causes, diagnostic evaluation and behavior. The clinical characteristics of the variants of the normality of child growth and development that allow them to be differentiated from the failure of growth were examined. Conclusions: Constitutional growth and development retardation, family short stature, idiopathic short stature, prematurity, delayed intrauterine growth, thinness and catch-down were normal variants of infant growth that are erroneously diagnosed as failure to thrive and generate unjustified medicalization, unnecessary expenses in complementary tests and family anguish. Differentiating these entities from the failure to thrive would allow health actions to focus on more specific objectives and offer each child an individualized treatment according to their real health condition.

Variantes da neurose tipo / Variations of type neurosis / Variantes de la névrose type

Na obra de Sigmund Freud, é possível localizarmos outra teoria da neurose que não está ancorada na existência de sintomas oriundos do processo defensivo próprio ao recalque, como pudemos verificar na constituição da neurose de caráter e das neuroses atuais. A evidência de tal problemática, presente já na elaboração teórica freudiana, nos leva à atualidade de nossa clínica. Na prática psicanalítica contemporânea, nos deparamos, cada vez mais, com fenômenos sintomáticos que não correspondem a sintomas propriamente ditos. O fenômeno da obesidade para alguns sujeitos evidencia uma forma de defesa inconsciente primária, mais arcaica, sem a produção de conflito psíquico e não sendo possível a satisfação da pulsão por meio do sintoma. A obesidade pode ser localizada como uma variante da neurose.

In Sigmund Freud's work it is possible to locate another theory of neurosis that is not anchored in the existence of symptoms arising from the defensive process at work in repression, as we could see in the constitution of the character neurosis and in the current neuroses. The evidence of such a problem, already present in the Freudian theoretical preparation, takes us to the present day of our clinic. In contemporary psychoanalytic practice, we are increasingly faced with symptomatic phenomena that do not correspond to symptoms themselves. The phenomenon of obesity for some subjects is evidence of a primary, more archaic form of unconscious defense, without the production of psychic conflict, and in which it is not possible to satisfy the drive through the symptom. Obesity can be located as a variant of neurosis.

Il est possible de localiser, dans l'œuvre de Sigmund Freud, une autre théorie de la névrose qui n'est pas ancrée dans l'existence de symptômes issus du processus défensif propre au refoulement, comme nous avons pu vérifier dans la constitution de la névrose de caractère et des névroses actuelles. L'évidence d'une telle problématique, présente déjà dans l'élaboration théorique freudienne, nous conduit à l'actualité de notre clinique. Dans la pratique psychanalytique contemporaine, nous sommes confrontés, de plus en plus, à des phénomènes symptomatiques qui ne correspondent pas à des symptômes proprement dits. Le phénomène de l'obésité pour certains sujets met en évidence une forme de défense inconsciente primaire, plus archaïque, sans la production de conflit psychique, n'étant pas possible la satisfaction de la pulsion par le symptôme. L'obésité peut être localisée comme une variante de la névrose

Variations in the origin of the superior laryngeal artery and their clinical significance: a case report with a proposal for a new classification / Variaciones en el origen de la arteria laríngea superior y su significado clínico: reporte de un caso con una nueva propuesta de clasificación

SUMMARY: The superior laryngeal artery is the primary vessel providing the blood supply to the larynx. Commonly, it is derived from the superior thyroid artery. Different variations in the origin have been described in the current literature; knowledge of such variations is crucial for various surgical interventions of the larynx and surgical procedures in the lateral region of the neck regarding the carotid triangle. It should be noted that radiological studies, such as selective angiography of the thyroid gland, can also be misleading in cases of variations. Herein, we describe a case of bilateral superior laryngeal artery originating directly from the external carotid artery of the neck. The arteries at first have a transverse course and then pierce through the thyrohyoid membrane alongside internal laryngeal nerves. Moreover, we also review the known variations in the origin of the superior laryngeal artery and propose a new classification of all known variations.

RESUMEN: La arteria laríngea superior es el vaso principal que proporciona el suministro de sangre a la laringe. Comúnmente, se deriva de la arteria tiroidea superior. Han sido descritas diferentes variaciones en su origen y el conocimiento de éstas resulta crucial para las intervenciones quirúrgicas realizadas en la laringe, como también en los procedimientos quirúrgicos que se llevan a cabo en la región lateral del cuello, respecto al triángulo carotídeo. Cabe señalar que los estudios radiológicos, como la angiografía selectiva de la glándula tiroides, también pueden ser engañosos en casos de variaciones anatómicas. Aquí, describimos un caso de arteria laríngea superior bilateral que se originaba directamente de la arteria carótida externa. Las arterias al inicio tenían un curso transversal y luego atravezaban la membrana tirohioidea junto con los nervios laríngeos internos. Revisamos también las variaciones conocidas en el origen de la arteria laríngea superior y proponemos una nueva clasificación de todas las variaciones conocidas.

El enigma del coronavirus - Nuevas subvariantes de subvariantes del SARSCoV-2 - COVID-19 y embarazo ¿Existe algún lado bueno de la pandemia?

Desde fines del año 2020 se previó que el coronavirus SARS-CoV-2 se quedaría con nosotros de manera indefinida, pero había la esperanza que pudiéramos combatirla en algún momento con efectividad, de manera que no produjera la enfermedad severa y la muerte que veíamos en esos momentos. La pandemia ha continuado con este coronavirus que se modifica continuamente para ingresar con más facilidad al organismo humano. La variante ómicron infecta preferentemente las vías respiratorias superiores. Y algunas de sus mutaciones parecen afectar partes de la proteína de la espiga que se unen a la ACE2. Una de las últimas subvariantes de las variantes, la BA.212.1 infecta con mayor rapidez a un mayor número de personas, aunque los casos de infección severa y muertes han disminuido considerablemente. A continuación, se presenta un resumen de lo que se ha conocido en este primer trimestre del año 2022 sobre las particularidades del virus, la forma de infectar y sus consecuencias, la protección de la vacunación, lo nuevo sobre la gestante y su recién nacido y si existe algún lado bueno sobre la ocurrencia de la pandemia COVID-19.

Since the late 2020's it was anticipated that the SARS-CoV-2 coronavirus would stay with us indefinitely, but there was hope that we would be able to combat it at some point effectively so that it would not produce the severe illness and death that we were seeing at that time. The pandemic has continued with this coronavirus continually modifying itself to enter the human body more easily. The Omicron variant preferentially infects the upper respiratory tract. And some of its mutations appear to affect parts of the spike protein that bind to ACE2. One of the latest subvariants of the variants, BA.212.1, infects more people more rapidly, although cases of severe infection and deaths have declined considerably. The following is a summary of what has been known in this first quarter of the year 2022 about the particularities of the virus, how it infects and its consequences, the protection of vaccination, what's new about the pregnant woman and her newborn, and whether there is any good side to the occurrence of the COVID-19 pandemic.

Escala de preocupación por el contagio de una variante de la COVID-19 (EPCNVCov-19)

RESUMEN Introducción: Desde el inicio de la pandemia por la COVID-19, se han documentado diversas variantes del virus, lo cual ha provocado preocupación en la población. Objetivos: Analizar las propiedades psicométricas de una escala de preocupación por el contagio de una variante de la COVID-19 (EPCNVCov-19). Métodos: Se realizó un estudio instrumental, que adaptó 5 preguntas de tipo Likert de una escala previamente validada (EPCov-19), se aplicó de forma virtual a 407 personas (56,5 % mujeres) de diversos departamentos en el Perú. Para analizar la evidencia de validez de contenido se empleó el coeficiente V de Aiken, el análisis de la estructura interna a través del análisis factorial confirmatorio, la confiabilidad fue estimada mediante el coeficiente Omega. Además, se hizo los análisis de invarianza por género y validez convergente y discriminante. Resultados: La EPCNVCov-19 se adaptó en tiempo y contexto, los ítems recibieron una valoración satisfactoria de los expertos (coeficiente V de Aiken > 0,70). Con los índices de bondad de ajuste se confirmó la estructura unidimensional de la escala (χ2 = 9,36, gl = 5, p= 0,09; CFI = 0,999; TLI = 0,999; RMSEA = 0,046 [IC90 % 0,00 - 0,092] y SRMR = 0,015). El análisis de invarianza muestra que la EPCNVCov-19 puede ser utilizada en individuos de ambos sexos. La escala presenta una aceptable confiabilidad (ω > 0,8). Asimismo, se alcanzó evidencias de validez convergente y discriminante. Conclusión: La EPCNVCov-19 es una medida breve válida, confiable e invariante según sexo en la población peruana.

ABSTRACT Introduction: Since the beginning of the COVID-19 pandemic, several variants of the virus have been documented, generating greater concern among the population. Objective: To analyze the psychometric properties of a scale of concern about the contagion of a variant of COVID-19 (EPCNVCov-19). Methods: An instrumental study, which adapted 5 Likert-type questions from a previously validated scale (EPCNVCov-19), was conducted and applied virtually to 407 people (56.5 % women) from different departments in Peru. To analyze the evidence of content validity, the Aiken V coefficient was used, the analysis of internal structure through confirmatory factor analysis, and reliability was estimated by means of the Omega coefficient. In addition, analyses of invariance by gender and convergent and discriminant validity were performed. Results: The EPCNVCov-19 was adapted in time and context, and the items received a satisfactory rating from the experts (Aiken's V coefficient > 0.70). With the goodness-of-fit indices, the unidimensional structure of the scale was confirmed (χ2 = 9,36, df = 5, p = 0,09; CFI = 0,999; TLI = 0.999; RMSEA = 0.046 [CI90 % 0.00 - 0.092] and SRMR = 0.015). The invariance analysis shows that the EPCNVCov-19 can be used in individuals of both sexes. Conclusion: The scale presents acceptable reliability (ω > 0,8). Likewise, evidence of convergent and discriminant validity was achieved. In conclusion, the EPCNVCov-19 is a valid, reliable and sex-invariant brief measure in the Peruvian population.

Germline pathogenic variants in Mexican patients with hereditary triple-negative breast cancer / Variantes patóge nas de línea germinal en mexicanas con cáncer de mama triple negativo hereditario

Abstract: Objective: Describe the prevalence of breast cancer (BC)-associated germline pathogenic variants (PVs) among Mexican patients with triple-negative BC (TNBC). Materials and methods: The spectrum of PVs identified among patients with TNBC who were enrolled in a prospective registry and underwent genetic testing was analyzed. Results: Of 387 patients with invasive TNBC and a median age at diagnosis of 39 years (range 21-72), 113 (29%) were carriers of PVs in BC-susceptibility genes: BRCA1 (79%), BRCA2 (15%), and other (6%: ATM, BRIP1, PALB2, PTEN, RAD51C, and TP53). PV carriers were younger at BC diagnosis (37 vs. 40 years, p=0.004) than non-carriers. Conclusion: A large proportion of TNBC in Mexican patients is associated with germline PVs, the vast majority in BRCA. The incremental yield of PVs in other BC-susceptibility genes was modest, and a stepwise approach starting with BRCA testing may be justified if it is more cost-effective than multigene panel testing.

Resumen: Objetivo: Describir la prevalencia de variantes patógenas (VPs) germinales en genes asociados con cáncer de mama (CM) en pacientes mexicanos con CM triple negativo (CMTN). Material y métodos: Se analizó el espectro de VPs identificadas en pacientes con CMTN que fueron incluidos prospectivamente en un registro y se realizó un estudio genético. Resultados: Se analizó un total de 387 pacientes con una mediana de edad al diagnóstico de 39 años; 113 (29%) eran portadores de VPs en genes de susceptibilidad a CM: BRCA1 (79%), BRCA2(15%), y otros (6%: ATM, BRIP1, PALB2, PTEN, RAD51C y TP53). Los portadores de VPs eran más jóvenes al diagnóstico de CM (37 vs. 40 años, p=0.004). Conclusiones: Existe una alta prevalencia de VPs en pacientes mexicanos con CMTN y la mayoría se encuentra en genes BRCA. La realización de pruebas genéticas se puede optimizar mediante la adopción de un proceso escalonado para la detección de VPs.