Obstacles in combating multidrug resistant tuberculosis in pediatric patients: a scope review / Obstáculos no combate à tuberculose multidroga resistente em pacientes pediátricos: uma revisão de escopo

Abstract Objectives: to identify the scientific evidence on excessively resistant and multidrug resistant tuberculosis in pediatric patients. Methods: this is a scope review of the literature, with a guiding question: "What is the scientific evidence on multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis in pediatric patients?". The research used the descriptors: "extensively drug-resistant tuberculosis" OR "multidrug-resistant tuberculosis" AND "pediatrics". The research was carried out in a double-blind manner in the following databases of the Medical Literature Analysis and Retrieval System Online, Regional Office for the Western Pacific's Institutional Repository for Information Sharing, Embase/Elsevier and International Clinical Trials Registry Platform, with a temporal cut-off from 2011 to 2021, sending a final synthesized sample of 18 articles, which evaluated the methodological content through the level of evidence. Results: the results show the lack of research with a high level of evidence related to MDR-TB in children, the lack of adequate dosage of second-line drugs for the pediatric population and the importance of drug sensitivity testing for the cases of treatment Conclusions: it was identified that the obstacles to MDR-TB treatment were concentrated in the lack of detailed protocols, safe drug dosages with a low side effect, and mainly in the social health determinants and disease process involving MDR-TB.

Resumo Objetivos: identificar as evidências científicas sobre tuberculose excessivamente resistente e multidroga resistente em pacientes pediátricos. Métodos: trata-se de uma revisão de escopo da literatura, tendo como questão norteadora: "Quais as evidências científicas sobre tuberculose multidroga-resistente (TB-MDR) e tuberculose extensivamente resistente em pacientes pediátricos?" A pesquisa usou os descritores: "tuberculose extensivamente resistente a medicamentos" OR "tuberculose resistente a múltiplos medicamentos" AND "pediatria". A pesquisa foi realizada de modo duplo-cego nas bases de dados Medical Literature Analysis and Retrieval System Online, Regional Office for the Western Pacific's Institutional Repository for Information Sharing, Embase/Elsevier e International Clinical Trials Registry Platform, com um corte temporal de 2011 a 2021, sendo a amostra final sintetizada de 18 artigos, nos quais avaliou-se o conteúdo metodológico por meio do nível de evidência. Resultados: os resultados mostraram a escassez de pesquisas de alto nível de evidência relacionadas à TB-MDR em crianças, ausência de posologia adequada das drogas de segunda linha para o público pediátrico e a importância do teste de sensibilidade a drogas para o tratamento dos casos. Conclusões: identificou-se que os obstáculos do tratamento TB-MDR se concentraram na ausência de protocolos detalhados, de dosagens medicamentosas seguras e com menor efeito colateral, e, principalmente, nos determinantes sociais do processo saúde e doença que envolvem a TB-MDR.

Ketogenic diet in pharmacoresistant epilepsies: a clinical nutritional assessment / Dieta cetogênica na epilepsia fármaco-resistente: avaliação clínica-nutricional

Abstract Background Epilepsies are among the most prevalent chronic neurological diseases, usually beginning in childhood. About 30% of children with epilepsies develop seizures that are difficult to control with medication. Recurrent epileptic seizures hinder diet intake, impairing the nutritional status. Although non-pharmacological interventions (e.g., ketogenic diet therapy) can improve epileptic seizure frequency, few studies analyzed their impact on the nutritional status of children and adolescents with epilepsies. Objective The aim was to evaluate the effects of a ketogenic diet on the nutritional status and clinical course of patients with pharmacoresistant epilepsies. Methods This cross-sectional study included patients under 18 years of age followed up at the Ketogenic Diet Ambulatory Clinic of the Instituto de Medicina Integral Prof. Fernando Figueira between December 2015 and December 2021. Socioeconomic, clinical, nutritional, and laboratory data were collected from medical records at different time points during the ketogenic diet. Results The sample comprised 49 patients aged between 5 months and 17 years (median = 4.4 years), mostly male (62.1%), and from Recife and the metropolitan region (51%). Underweight patients (BMI-for-age) improved their nutritional status in six months. However, patients who were normal weight and overweight maintained their nutritional status. Dyslipidemia was a common and short-term adverse effect. Moreover, the treatment decreased epileptic seizure frequency and antiseizure medication intake. Conclusion The ketogenic diet prevented malnutrition from worsening and reduced epileptic seizures and antiseizure medication intake.

Resumo Antecedentes A epilepsia, uma das doenças neurológicas crônicas mais prevalentes, tem geralmente início na infância. Cerca de 30% das crianças com epilepsia desenvolvem crises de difícil controle medicamentoso. As crises epilépticas recorrentes dificultam a ingestão alimentar, prejudicando o estado nutricional. Intervenções não farmacológicas, como a terapia com dieta cetogênica, podem melhorar a frequência das crises epilépticas, mas existem poucos estudos sobre a repercussão no estado nutricional da criança/adolescente. Objetivo Avaliar o efeito da terapia cetogênica sobre o estado nutricional e a evolução clínica da epilepsia fármaco-resistente. Métodos Estudo tipo corte transversal envolvendo menores de 18 anos acompanhados no Ambulatório de Dieta Cetogênica do Instituto de Medicina Integral Prof. Fernando Figueira entre dezembro de 2015 e dezembro de 2021. Dados socioeconômicos, clínicos, nutricionais e laboratoriais foram coletados nos prontuários dos pacientes em vários momentos da terapia cetogênica. Resultados A amostra foi composta por 49 pacientes com idades entre cinco meses e 17 anos (mediana = 4,4 anos), a maioria do sexo masculino (62,1%) e procedentes de Recife e região metropolitana (51%). Pacientes com baixo peso (de acordo com o IMC para idade) melhoraram seu estado nutricional em seis meses. No entanto, os pacientes com peso adequado e com sobrepeso mantiveram seu estado nutricional. A dislipidemia foi um efeito adverso frequente e de curta duração. Além disso, o tratamento reduziu a frequência de crises epilépticas e a dose de fármacos anticrises. Conclusão A dieta cetogênica preveniu o agravamento da desnutrição e reduziu as crises epilépticas e a dosagem de fármacos anticrises.

Discordancia entre pruebas de susceptibilidad genotípicas y fenotípicas para tuberculosis en Cali, Colombia: un reto en la práctica clínica

Introducción: La detección de patrones de resistencia de Mycobacterium tuberculosis se basa en pruebas de susceptibilidad fenotípicas y genotípicas. Los resultados discordantes entre ellas son un desafío clínico para el manejo de pacientes con tuberculosis resistente a fármacos. Objetivo: Evaluar la concordancia entre pruebas fenotípicas y moleculares en pacientes con tuberculosis resistente a fármacos atendidos en una institución de Cali, Colombia. Materiales y Métodos: Se realizó un estudio transversal en el que se obtuvo el perfil de sensibilidad fenotípico de cultivos de micobacterias y la susceptibilidad genotípica con las pruebas moleculares Xpert-MTB/ RIF® o Genotype-MDRTBplus ®. Se evaluó el porcentaje de resistencia y porcentaje de acuerdo entre los resultados de las pruebas fenotípicas y genotípicas. Se estimó un coeficiente de kappa de Cohen (κ) para cada tipo de resistencia según la prueba utilizada. Resultados: Se incluyeron 30 casos con resultados de pruebas genotípicas y fenotípicas. Las pruebas fenotípicas detectaron resistencia a fármacos de primera línea en 29/30 casos, mientras que las moleculares detectaron la resistencia en todos los casos evaluados. El porcentaje de resistencia a rifampicina detectado entre la prueba fenotípica y Genotype-MDRTBplus ® &e 61,5% (acuerdo global 41,1%, κ = 0,40, p = 0,96), mientras que el porcentaje de resistencia detectado con Xpert-MTB/RIF® fue 100% (acuerdo global 81,82%, κ: 0,00, p < 0,001) para este mismo medicamento. El porcentaje de resistencia a isoniacida detectado entre la prueba fenotípica y Genotype-MDRTBplus ® fue 94,4% (acuerdo global 89,47%, κ: -0,055 p = 0,59). Conclusiones: La discordancia entre los resultados de las pruebas genotípicas y fenotípicas es posible, por lo que es importante usar e interpretar ambos tipos de pruebas de manera complementaria en el diagnóstico de la resistencia a fármacos de primera línea en la infección por M. tuberculosis.

Background: The detection of Mycobacterium tuberculosis resistance patterns is based on phenotypic and genotypic susceptibility tests. The discordant results between them are a clinical challenge for the management of patients with drug-resistant tuberculosis. Aim: To evaluate the concordance between phenotypic and molecular tests in patients with drug-resistant tuberculosis treated in an institution in Cali, Colombia. Methods: A cross-sectional study was conducted. A phenotypic sensitivity profile was obtained from mycobacterial cultures. The genotypic susceptibility was obtained with Xpert-MTB/ RIF® or Genotype-MDRTBplus ®. The percentage of resistance and percentage of agreement between the results of the phenotypic and genotypic tests were evaluated. A Cohen's kappa coefficient (κ) was estimated for each type of resistance according to the test used. Results: A total of 30 cases with both genotypic and phenotypic testing were included. The phenotypic tests detected resistance to first-line drugs in 29/30 cases, while the molecular tests detected resistance in all the cases evaluated. The percentage of resistance detected between Genotype-MDRTBplus® and the phenotypic test for rifampicin was 61.5% (overall agreement 41.1%, κ = 0.40, p = 0.96), while the percentage of resistance detected with XpertMTB/RIF® was 100% (overall agreement 81.82%, κ: 0.00, p < 0.001) for this same drug. Resistance to isoniazid detected by both types of tests was 94.4% (overall agreement 89.47%, κ: -0.055 p = 0.59). Conclusions: Discordance between the results of genotypic and phenotypic tests is possible, so it is important to use and interpret both types of tests in a complementary way in the diagnosis of resistance to first-line drugs in M. tuberculosis infection.

Factores asociados a tuberculosis pre extensamente resistente en pacientes del Hospital Nacional Dos de Mayo, Lima, Perú

Introducción: La resistencia a fármacos antituberculosos está influenciada por las características personales y las condiciones de salud de países en vías de desarrollo. Objetivo: Determinar los factores asociados a TB-pre extensamente resistente (TB-PRE XDR) en pacientes del Hospital Nacional Dos de Mayo (HNDM) entre 2017 y 2019. Pacientes y Método: Se desarrolló un estudio caso control no pareado, definiendo como caso al paciente con TB- PRE XDR y como control al paciente con TB-S. Se recolectaron variables epidemiológicas, clínicas y radiológicas. Resultados: Se analizaron 51 casos y 102 controles. El análisis bivariado determinó como factores con p 51 años (OR: 0,17, IC95%: 0,05-0,51), uso de drogas (OR:2,5, IC95%: 1,1-5,4), antecedente de TB (OR: 20, IC95%: 8,4-47), reclusión previa (OR: 8, IC95%: 2,7-23,8), infección por VIH (OR: 0,2, IC95%: 0,08-1) y uso previo de fármacos antituberculosos (OR: 21, IC95%: 8,8-50). El análisis de regresión logística identificó como factores asociados a TB-PRE XDR al contacto de TB, antecedente de TB, tiempo de enfermedad y uso previo de fármacos antituberculosos. Conclusión: Las medidas para limitar el desarrollo de TB-PRE XDR en pacientes con TB-S deben incidir sobre el antecedente de TB, contacto con TB, tiempo de enfermedad y uso previo de anti-TB no controlados; sin embargo, existen resultados no concluyentes sobre el hábito nocivo y la comorbilidad, siendo necesario más estudios para determinar su influencia como factores asociados identificables.

Background: Resistance to anti-TB drugs is influenced by personal characteristics and health conditions in developing countries. Aim: To determine the factors associated with pre-extensively drug-resistant tuberculosis (PRE XDR-TB) at Hospital Nacional Dos de Mayo (HNDM) in patients between the 2017 and 2019. Methods: An unpaired case control study was developed; defining as case PRE XDR-TB patient and as control S-TB patient. Epidemiological, clinical and radiological variables were collected. Results: We analyzed 51 cases and 102 controls. The bivariate analysis showed as factors with p 51 years (OR: 0.17, 95% CI: 0.05-0.51), drug use (OR: 2.5, 95% CI: 1.1-5.4), previous history of TB (OR: 20, 95% CI: 8.4-47), previous confinement (OR: 8, 95% CI: 2.7-23.8), HIV infection (OR: 0.2, 95% CI: 0.08-1) and previous use of antiTB drugs (OR: 21, 95% CI: 8.8-50). The logistic regression analysis identified as associated factors with PRE XDR-TB the previous contact with TB, a history of TB, length of illness and previous use of tuberculosis antibiotics. Conclusion: The measures to limit the development of TB-PRE XDR in patients with TB-S must include the previous history of TB, TB contact, length of illness and previous use of uncontrolled antibiotics against TB; however, there are inconclusive results about the harmful habits and comorbidity, requiring more studies to determine their influence as identifiable associated factors.

Ketogenic therapy in childhood and adolescence: recommendations of the Brazilian experts group / Terapia cetogênica na infância e adolescência: recomendações do grupo de especialistas brasileiros

Abstract Ketogenic dietary therapies (KDTs) are a safe and effective treatment for pharmacoresistant epilepsy in children. There are four principal types of KDTs: the classic KD, the modified Atkins diet (MAD), the medium-chain triglyceride (MCT) diet, and the low glycemic index diet (LGID). The International Ketogenic Diet Study Group recommends managing KDTs in children with epilepsy. However, there are no guidelines that address the specific needs of the Brazilian population. Thus, the Brazilian Child Neurology Association elaborated on these recommendations with the goal of stimulating and expanding the use of the KD in Brazil.

Resumo As terapias dietéticas cetogênicas (TDC) são um tratamento seguro e eficaz para epilepsia farmacorresistente em crianças. Existem quatro tipos principais de TDCs: a dieta cetogênica (DC) clássica, a dieta de Atkins modificada (DAM), a dieta de triglicerídeos de cadeia média (DTCM) e a dieta de baixo índice glicêmico (DBIG). O Grupo Internacional de Estudos de Dietas Cetogênicas (International Ketogenic Diet Study Group) propõe recomendações para o manejo da DC em crianças com epilepsia. No entanto, faltam diretrizes que contemplem as necessidades específicas da população brasileira. Assim, a Associação Brasileira de Neurologia Infantil elaborou essas recomendações com o objetivo de estimular e expandir o uso da DC no Brasil.

Dieta cetogénica y su influencia en el tratamiento de la epilepsia refractaria infantil / Ketogenic diet and its influence on the treatment of refractory epilepsy in children / Dieta cetogênica e sua influência no tratamento da epilepsia refratária em crianças

La dieta cetogénica durante muchos años utilizada como una alternativa en el tratamiento para la epilepsia refractaria infantil, que consiste en un alto consumo de grasas, reducidas cantidades de carbohidratos y las cantidades necesarias de proteína que permitan al paciente por medio de la producción de cetonas un correcto y adecuado aporte energético al cerebro y todo el SNC. Objetivo. Describir el uso de la dieta cetogénica en el tratamiento de la epilepsia refractaria infantil para determinar su efectividad en la reducción de convulsiones y mejora en la calidad de vida de los pacientes. Metodología. Se ha realizado una revisión sistemática de la literatura científica para examinar la relación entre la dieta cetogénica y su efecto en el tratamiento de la epilepsia refractaria infantil. Para identificar y seleccionar las fuentes de información, se aplicó la declaración PRISMA y se llevó a cabo una búsqueda bibliográfica exhaustiva en diversas bases de datos electrónicas, incluyendo PubMed, SCOPUS y SCIELO. Se utilizaron términos descriptores específicos como "dieta cetogénica", "influencia", "tratamiento", "epilepsia refractaria" y "niños", así como conectores como AND, OR o NOT para mejorar la precisión de la búsqueda. Conclusión. La dieta cetogénica ha demostrado ser efectiva en el tratamiento de la epilepsia refractaria al reducir en un 50% el número de crisis convulsivas y mejorar la cognición de los pacientes, lo que la convierte en una opción viable para el manejo de esta afección. Sin embargo, es importante tener en cuenta que la dieta cetogénica también puede tener efectos secundarios.

The ketogenic diet has been used for many years as an alternative in the treatment of refractory epilepsy in children, which consists of a high consumption of fats, reduced amounts of carbohydrates and the necessary amounts of protein to allow the patient, through the production of ketones, a correct and adequate energy supply to the brain and the entire CNS. Objective. To describe the use of the ketogenic diet in the treatment of refractory epilepsy in children to determine its effectiveness in reducing seizures and improving the quality of life of patients. Methodology. A systematic review of the scientific literature was conducted to examine the relationship between the ketogenic diet and its effect in the treatment of refractory epilepsy in children. To identify and select sources of information, the PRISMA statement was applied and a comprehensive literature search was conducted in various electronic databases, including PubMed, SCOPUS and SCIELO. Specific descriptor terms such as "ketogenic diet", "influence", "treatment", "refractory epilepsy" and "children" were used, as well as connectors such as AND, OR or NOT to improve search precision. Conclusion. The ketogenic diet has been shown to be effective in the treatment of refractory epilepsy by reducing the number of seizures by 50% and improving patients' cognition, making it a viable option for the management of this condition. However, it is important to keep in mind that the ketogenic diet can also have side effects.

A dieta cetogênica tem sido usada há muitos anos como um tratamento alternativo para epilepsia refratária em crianças, consistindo em um alto consumo de gorduras, quantidades reduzidas de carboidratos e as quantidades necessárias de proteínas para permitir ao paciente, por meio da produção de cetonas, um fornecimento correto e adequado de energia para o cérebro e todo o SNC. Objetivo. Descrever o uso da dieta cetogênica no tratamento da epilepsia refratária em crianças, a fim de determinar sua eficácia na redução das crises e na melhoria da qualidade de vida dos pacientes. Metodologia. Foi realizada uma revisão sistemática da literatura científica para examinar a relação entre a dieta cetogênica e seu efeito no tratamento da epilepsia refratária em crianças. Para identificar e selecionar as fontes de informação, foi aplicada a declaração PRISMA e realizada uma pesquisa abrangente da literatura em vários bancos de dados eletrônicos, incluindo PubMed, SCOPUS e SCIELO. Foram usados termos descritores específicos, como "dieta cetogênica", "influência", "tratamento", "epilepsia refratária" e "crianças", além de conectores como AND, OR ou NOT para melhorar a precisão da pesquisa. Conclusão. A dieta cetogênica demonstrou ser eficaz no tratamento da epilepsia refratária, reduzindo o número de convulsões em 50% e melhorando a cognição dos pacientes, o que a torna uma opção viável para o tratamento dessa condição. Entretanto, é importante observar que a dieta cetogênica também pode ter efeitos colaterais.

Estimulación de nervio vago en epilepsia refractaria y callosotomía previa sin mejoría. Reporte de caso / Vagus nerve stimulation in refractory epilepsy and previous callosotomy without vimprovement. Case report / Estimulação do nervo vago em epilepsia refratária e calosotomia prévia sem melhora. Relato de caso

La epilepsia refractaria tanto generalizada como focal, es una patología sumamente incapacitante, para el tratamiento de la misma se ha establecido a la callosotomía desde hace décadas como primera línea quirúrgica para su control, la cual puede presentar efectos secundarios importantes como síndrome de desconexión y pérdida de memoria, sin embargo, existen pacientes que no responden a la callosotomía y necesitan nuevas líneas de tratamiento, buscando en la estimulación de nervio vago una respuesta a su condición. Descripción del caso de estudio. Se presenta el caso de paciente masculino de 24 años de edad con antecedente patológico de convulsiones tipo tónico clónicas generalizadas confirmadas por video electroencefalograma de 24 horas, de predominio nocturno de 13 años de evolución, es sometido a 2 regímenes farmacológicos antiepilépticos diferentes en un período de 7 años de duración, posteriormente diagnosticado con epilepsia refractaria, por lo que se realiza callosotomía sin control de su cuadro clínico, el mismo año se realiza estimulación de nervio vago, presentando resultados favorables en su evolución. Conclusión. Luego de evidenciar el presente caso de estudio se concluye que el tratamiento de epilepsia refractaria con la colocación de un estimulador de nervio vago izquierdo asociado a un correcto régimen FAE es una alternativa muy eficaz para considerar en estos pacientes.

Refractory epilepsy, both generalized and focal, is an extremely disabling pathology. For its treatment, callosotomy has been established for decades as the first surgical line for its control, which can present important side effects such as disconnection and loss syndrome. by heart, however, there are patients who do not respond to callosotomy and need new lines of treatment, looking for an answer to their condition in vagus nerve stimulation. Description of the case study. We present the case of a 24-year-old male patient with a pathological history of generalized tonic-clonic seizures confirmed by a 24-hour video electroencephalogram, predominantly nocturnal for 13 years, undergoing 2 different antiepileptic pharmacological mechanisms over a period of 7 years in duration, later diagnosed with refractory epilepsy, for which callosotomy was performed without control of its clinical picture, the same year vagus nerve stimulation was performed, presenting favorable results in its evolution. Conclution. After evidencing the present case study, it is concluded that the treatment of refractory epilepsy with the placement of a left vagus nerve stimulator associated with a correct AED regimen is a very effective alternative to consider in these patients.

A epilepsia refratária, tanto generalizada quanto focal, é uma patologia extremamente incapacitante. Para seu tratamento, a calosotomia se estabeleceu há décadas como a primeira linha cirúrgica para seu controle, que pode apresentar importantes efeitos colaterais como desconexão e síndrome de perda., há pacientes que não respondem à calosotomia e precisam de novas linhas de tratamento, buscando resposta para sua condição na estimulação do nervo vago. Descrição do estudo de caso. Apresentamos o caso de um doente do sexo masculino, 24 anos, com antecedentes patológicos de crises tónico-clónicas generalizadas confirmadas por videoeletroencefalograma de 24 horas, predominantemente nocturnas há 13 anos, submetido a 2 mecanismos farmacológicos antiepilépticos diferentes ao longo de 7 anos de duração, posteriormente diagnosticada com epilepsia refratária, para a qual foi realizada calosotomia sem controle de seu quadro clínico, no mesmo ano foi realizada estimulação do nervo vago, apresentando resultados favoráveis em sua evolução. Conclusão. Depois de evidenciar o presente estudo de caso, conclui-se que o tratamento da epilepsia refratária com a colocação de um estimulador de nervo vago esquerdo associado a um esquema correto de DEA é uma alternativa muito eficaz a ser considerada nesses pacientes.

Study of side effect profile of bedaquiline containing regimen among patients with extensively drug-resistant tuberculosis at a nodal drug-resistant center

Background: Extensively drug-resistant tuberculosis (XDR TB) is a type of tuberculosis (TB) characterized by resistance to isoniazid and rifampicin, along with resistance to one of the fluoroquinolones and at least one of the second line injectable drugs. Bedaquiline is a diarylquinoline antimycobacterial agent approved for the treatment of adults with pulmonary multidrug-resistant TB (MDR-TB) and XDR-TB by the food and drug administration. Aim and Objective: The aim of this study was to study the side effect profile of bedaquiline containing regimen among XDR TB patients. Materials and Methods: This study was conducted at outpatient and wards of nodal drug-resistant TB Center, Department of Pulmonary Medicine, SVRRGGH, Tirupati, for a period of 1 year. Forty patients of more than 18 years age and diagnosed with XDR TB were included in the study. Bedaquiline was started and daily monitoring was done with ECG and all organ function tests were repeated every 15 days. Results: All 40 cases were retreatment cases; no new XDR TB case was reported in study period. Most common age group of presentation in our study was 46 to 55 years (32.5%). Gastrointestinal adverse drug reactions were found to be more common (37.5%), cardiovascular QTc changes were observed in 10% of patients, 5% of patients had neurological reactions (Headache), 2.5% of patients had peripheral neuropathy, and 2.5% of patients had arthralgia. Conclusions: Bedaquiline containing regimen is very effective for the treatment of XDR TB cases. The study shows that compliance with this regimen is very good. Bedaquiline has minimal adverse reactions and even these are easily manageable. Bedaquiline has good safety profile and patients have improved quality of life.

Cannabidiol for the treatment of refractory epilepsy in children: a critical review of the literature / Canabidiol para o tratamento de epilepsia refratária em crianças: uma revisão crítica da literatura

Abstract Objective: The aim of this current report was to present a critical review of the use of cannabidiol (CBD) in the treatment of refractory epilepsies in the pediatric population. Data source: Literature review was carried out in the Medline (PubMed), Cochrane, and Scientific Electronic Library Online (SciELO) databases with the descriptors "Cannabidiol" and "Epilepsy." The search was not limited by the date of publication, language, or study design. A total of 69 articles were included in the review. Data synthesis: The efficacy of CBD in treating epileptic seizures has been confirmed by randomized controlled trials for Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. The incidence of side effects reported in subjects of the studies is high. However, most studies indicate a good safety profile and tolerance to the drug, with most of the adverse effects being mild to moderate and transient. Conclusions: There is no consensus on the release of CBD as a therapeutic tool by the drug regulatory agencies worldwide. However, the use of CBD is promising since it has presented satisfactory results in crisis control in well-designed studies. In addition, this drug has a good safety and tolerance profile. However, further studies with a long follow-up period are needed to confirm its usefulness and the long-term safety in pediatric patients.

RESUMO Objetivo: Apresentar uma revisão crítica do uso de canabidiol no tratamento de epilepsias refratárias na população pediátrica. Fontes de dados: Revisão da literatura realizada nas bases de dados Medical Literature Analysis and Retrieval System Online (Medline/PubMed), Cochrane e Scientific Electronic Library Online (SciELO), com os descritores "cannabidiol" e "epilepsy". A busca não foi limitada por data de publicação, idioma ou desenho do estudo. Sessenta e nove artigos foram incluídos na revisão. Síntese dos dados: A eficácia do canabidiol no tratamento de crises epilépticas foi confirmada por ensaios clínicos randomizados para síndrome de Lennox-Gastaut, síndrome de Dravet e complexo de esclerose tuberosa. A incidência de efeitos colaterais relatados nos indivíduos dos estudos é alta. No entanto, a maioria dos estudos indica um bom perfil de segurança e tolerância ao medicamento, com efeitos adversos leves a moderados e transitórios. Conclusões: Não há consenso sobre a liberação do canabidiol como ferramenta terapêutica nas diversas agências reguladoras de medicamentos em todo o mundo. Entretanto, seu uso é promissor, uma vez que apresentou resultados satisfatórios no controle de crises em estudos bem delineados. Além disso, esse medicamento apresenta um bom perfil de segurança e tolerância. No entanto, mais estudos com longo período de acompanhamento são necessários para confirmar sua utilidade e sua segurança em longo prazo em pacientes pediátricos.

Heterogeneidad clínica y molecular en los trastornos asociados con CDKL5 / Clinical and molecular heterogeneity in CDLK5 disorders

Resumen Introducción: El síndrome por deficiencia de CDKL5 es originado por variantes patogénicas en el gen CDKL5, con un espectro clínico variable que va desde pacientes con características del trastorno del espectro autista hasta epilepsia de inicio temprano y refractaria al tratamiento. Inicialmente fue considerado como una forma atípica de síndrome de Rett. Casos clínicos: Presentamos tres pacientes no relacionadas, evaluadas por retraso global del desarrollo y epilepsia refractaria. Los tres casos eran hemicigotos a una variante patógena de CDKL5. En una paciente se realizó panel de 306 genes asociados con epilepsia; en las otras dos se realizó microarreglo genómico comparativo. Las características clínicas y los hallazgos en el electroencefalograma y la resonancia magnética cerebral se han descrito clásicamente en el espectro de manifestaciones de este síndrome. Conclusiones: El síndrome por deficiencia de CDKL5 representa un reto para los médicos, ya que en muchos casos las manifestaciones clínicas y los estudios electroencefalográficos y de neuroimagen pueden ser inespecíficos. Debe sospecharse este síndrome ante la presencia de retraso global del desarrollo, fenotipo conductual autista y epilepsia, asociado o no con dismorfias. Dada la similitud entre diversas encefalopatías epilépticas, se deben solicitar paneles multigénicos que incluyan la secuenciación y el análisis de duplicación/deleción en los que se contemple este gen y sus posibles diagnósticos diferenciales, aunque sin olvidar la utilidad de las técnicas genómicas en casos poco claros.

Abstract Background: CDKL5 deficiency syndrome is caused by pathogenic variants in the CDKL5 gene, with a variable clinical spectrum ranging from patients with characteristics of autism spectrum disorder to early-onset epilepsy refractory to treatment. Initially, until the gene was discovered, it was considered an atypical form of Rett syndrome. This study aimed to describe the clinical and molecular heterogeneity in CDLK5 disorders among three female patients with CDKL5 pathogenic variants. Case reports: We reported three unrelated Mexican female patients evaluated for global developmental delay and epilepsy. All three cases were hemizygotes to a CDKL5 pathogenic variant. In one patient, we performed a 306 gene panel associated with epilepsy. In the other two cases, a human genomic microarray was performed. We describe their clinical features electroencephalogram and brain magnetic resonance evaluations. Conclusions: CDKL5 deficiency syndrome represents a challenge for clinicians since the clinical manifestations, electroencephalographic and neuroimaging studies can be non-specific. This syndrome should be suspected in the presence of global developmental delay, autistic behavioral phenotype and epilepsy, associated or not with dysmorphia. Given the similarity between various epileptic encephalopathies, multigene panels including sequencing and duplication/deletion analysis should be requested in which this gene and its possible differential diagnoses are considered, without forgetting the usefulness of genomic techniques in unclear cases.

Drug-Resistant Tuberculosis and COVID-19: A Scoping Review on a New Threat to Antimicrobial Resistance / Tuberculosis Resistente a Medicamentos y COVID-19: Una Revisión de Alcance de una Nueva Amenaza a la Resistencia Antimicrobiana / Tuberculose droga-resistente e COVID-19: revisão de escopo de uma nova ameaça à resistência microbiana a medicamentos

ABSTRACT Objective: To assess the impact of COVID-19 on the morbidity and mortality associated with drug-resistant tuberculosis (DR-TB). Methods: A comprehensive review of articles published in international databases since December 2019 was conducted. The findings are presented in a narrative format, supplemented with tables, diagrams, and a map created using ArcGIS software. Results: Thirty-five studies were selected, highlighting the significant consequences of COVID-19 on TB and DR-TB treatment progress. Four main thematic areas were identified: Clinical and epidemiological aspects of the interaction between COVID-19 and DR-TB; Management of physical resources and the team; Challenges and circumstances; Perspectives and possibilities. Conclusions: This study revealed that the COVID-19 pandemic significantly negatively impacted the control of long-standing diseases like TB, particularly in the context of morbidity and mortality related to DR-TB.

RESUMEN Objetivo: Evaluar el impacto de COVID-19 en la morbilidad y mortalidad asociada con la tuberculosis resistente a medicamentos (DR-TB). Métodos: Se realizó una revisión integral de artículos publicados en bases de datos internacionales desde diciembre de 2019. Los hallazgos se presentaron de forma narrativa, complementados con tablas, diagramas y un mapa creado con el software ArcGIS. Resultados: Se seleccionaron 35 estudios que destacaron las consecuencias significativas de COVID-19 en el progreso del tratamiento de la TB y la DR-TB. Se identificaron cuatro áreas temáticas principales: "Aspectos clínicos y epidemiológicos de la interacción entre COVID-19 y DR-TB", "Gestión de recursos físicos y del equipo", "Desafíos y circunstancias" y "Perspectivas y posibilidades". Conclusiones: Este estudio reveló que la pandemia de COVID-19 tuvo un impacto negativo significativo en el progreso del control de enfermedades antiguas como la TB, especialmente en el contexto de la morbilidad y mortalidad relacionada con la DR-TB.

RESUMO Objetivo: Avaliar o impacto da COVID-19 na morbimortalidade associada à tuberculose resistente a medicamentos (DR-TB). Métodos: Realizou-se uma revisão abrangente de artigos publicados em bases de dados internacionais a partir de dezembro de 2019. As evidências foram apresentadas de maneira narrativa, com o suporte de tabelas, diagramas e um mapa elaborado no software ArcGIS. Resultados: Foram selecionados 35 estudos que destacaram as consequências significativas da COVID-19 nos avanços no tratamento da TB e da DR-TB. Quatro áreas temáticas foram identificadas: "Aspectos clínicos e epidemiológicos da interação entre COVID-19 e DR-TB", "Gestão de recursos físicos e da equipe", "Desafios e circunstâncias" e "Perspectivas e potencialidades". Conclusões: Este estudo evidenciou que a pandemia de COVID-19 teve um impacto negativo significativo na progressão do controle de uma doença ancestral como a TB, especialmente no contexto da morbimortalidade por DR-TB.

New insights on tuberculosis transmission dynamics and drug susceptibility profiles among the prison population in Southern Brazil based on whole-genome sequencing

ABSTRACT Background: The rate of tuberculosis (TB) infection among the prison population (PP) in Brazil is 28 times higher than that in the general population, and prison environment favors the spread of TB. Objective: To describe TB transmission dynamics and drug resistance profiles in PP using whole-genome sequencing (WGS). Methods: This was a retrospective study of Mycobacterium tuberculosis cultivated from people incarcerated in 55 prisons between 2016 and 2019; only one isolate per prisoner was included. Information about movement from one prison to another was tracked. Clinical information was collected, and WGS was performed on isolates obtained at the time of TB diagnosis. Results: Among 134 prisoners included in the study, we detected 16 clusters with a total of 58 (43%) cases of M. tuberculosis. Clusters ranged from two to seven isolates with five or fewer single nucleotide polymorphism (SNP) differences, suggesting a recent transmission. Six (4.4%) isolates were resistant to at least one anti-TB drug. Two of these clustered together and showed resistance to rifampicin, isoniazid, and fluoroquinolones, with 100% concordance between WGS and phenotypic drug-susceptibility testing. Prisoners with clustered isolates had a high amount of movement between prisons (two to eight moves) during the study period. Conclusions: WGS demonstrated the recent transmission of TB within prisons in Brazil. The high movement among prisoners seems to be related to the transmission of the same M. tuberculosis strain within the prison system. Screening for TB before and after the movement of prisoners using rapid molecular tests could play a role in reducing transmission.

Value of rifampicin-resistant real-time fluorescence quantitative nucleic acid amplification detection technology in the fast diagnosis of pulmonary tuberculosis / 中国热带医学

@#Abstract: Objective　To evaluate the value and significance of rifampicin-resistant real-time fluorescence quantitative nucleic acid amplification detection technology (GeneXpert MTB/RIF) in the diagnosis of pulmonary tuberculosis. 　　Methods　The clinical data of 228 patients with suspected pulmonary tuberculosis, who admitted to Hebei Chest Hospital from January 2018 to December 2019, were analyzed retrospectively. The sputum was collected for GeneXpert MTB/RIF, sandwich cup liquid-based bacterial acid-fast staining smear microscopy (referred to as “sandwich cup method”) and Loop-Mediated isothermal amplification (referred to as “LAMP method”) and the results were statistically analyzed by SPSS 17.0 software. Results　Among the 228 patients with suspected cases, 200 cases were clinically diagnosed as pulmonary tuberculosis and 28 were non-tuberculosis. The positive detection rate of GeneXpert MTB/RIF (81.0%, 162/200) was significantly higher than that of sandwich cup method (62.5%, 125/200) and LAMP method (72.5%,145/200) (χ2=16.885, 4.049, P<0.05). Taking clinical diagnosis as gold standard, the sensitivity of GeneXpert MTB/RIF (80.00%,160/200) was significantly higher than that of sandwich cup method (60.00%, 120/200) and LAMP method (70.50%, 141/200) (χ2=19.048, 4.846, P<0.05). The diagnostic consistency of GeneXpert MTB/RIF (K=0.73) was higher than that of sandwich cup method (K=0.39) and LAMP method (K=0.56). Conclusions The GeneXpert MTB/RIF detection method is rapid and simple, and can diagnose pulmonary tuberculosis rapidly and simultaneously detect rifampicin resistance of Mycobacterium tuberculosis with high sensitivity. It has high clinical value for early diagnosis of pulmonary tuberculosis and guidance of treatment in general and specialized hospitals.

Influencing factors of blood infection and death risk of Acinetobacter baumannii in elderly patients / 公共卫生与预防医学

Objective To investigate the death prognosis and risk factors of extensively drug-resistant Acinetobacter baumannii in hospitalized elderly patients with hematological infection, so as to facilitate clinical prevention and treatment. Methods The elderly (> 80 years old) hospitalized patients with hematological infection in our hospital from 2015 to 2021 were selected for analysis. Firstly, 314 patients with extensively drug-resistant Acinetobacter baumannii hematological infection were distinguished by etiological analysis. A total of 98 cases of death were detected during hospitalization (later referred to as the observation group). By comparing with the surviving patients (216 cases) (later referred to as the control group), the general data of patients with XDRAB infection were collected, and the risk of death and its influencing factors were analyzed. Results In the study, the proportion of patients in the observation group who used catheters was higher, the catheter retention time was longer, the acute physiology and chronic health status II scores were higher, and the proportion of patients who lost self-care ability was also higher. Conclusion The death of blood borne infection of extensively drug-resistant Acinetobacter baumannii in elderly patients is affected by many factors. Among them, patients who use catheters for a long time, have poor self-care ability and lose self-care ability have a higher risk of death, which is worthy of clinical attention.

Serotypes and drug resistance of salmonella in commercial food in Pudong New Area from 2020 to 2022 / 上海预防医学

ObjectiveTo understand the serotype distribution and drug resistance of salmonella contaminated in commercially available food. MethodsSalmonella detection， including the serotypes， was conducted in food products sold in Pudong New Area from 2020 to 2022. The antimicrobial susceptibility test of 15 antibiotics was conducted by the broth microassay. ResultsA total of 118 salmonella strains were detected in 2 497 pieces of food， with a total detection rate of 4.7%. The dominant detection categories were poultry meat， livestock meat and aquatic products. The 118 salmonella strains could be divided into 24 serotypes， Salmonella enteritidis （26.4%）， Salmonella Typhimurium （16.2%） and Salmonella delpy （14.4%） were the main dominant types. Salmonella had the highest resistance rate to ampicillin （63.6%）， followed by tetracycline， chloramphenicol， cotrimoxazole and nalidixic acid. Among the three dominant serotypes， the multidrug resistance rate of Salmonella typhimurium was the highest （89.5%）， followed by Salmonella delpy （70.6%） and Salmonella enteritidis （61.3%）. ConclusionLivestock， poultry meat， and aquatic products are seriously contaminated by salmonella with diverse serotypes. The livestock meat is mainly contaminated by Salmonella typhimurium and Salmonella delpy， and the poultry meat is mainly contaminated by Salmonella enteritidis. The drug resistance spectrum is wide and the multi-drug resistance rate is high. Different from the livestock and aquatic isolates， poultry meat-derived strains have high tolerance to ampicillin， nalidixic acid and polymyxin， and carry certain potential food safety risks.

Effect of Inhibiting SIX1 Expression on Drug-resistance of Acute Myeloid Leukemia Cell Line HL-60/ADR Cells / 中国实验血液学杂志

OBJECTIVE@#To establish HL-60 cells and adriamycin resistant HL-60 cells (H-60/ADR) in which the expression of homologous box gene 1 (SIX1) was inhibited, and investigate the effect of inhibiting the expression of SIX1 on the drug resistance.@*METHODS@#Lentivirus was used to transfect HL-60 and HL-60/ADR cells, and the cell lines stably inhibiting the expression of SIX1 were screened by puromycin. CCK-8 assay was used to detect the proliferation ability of cells in each group, apoptosis kit was used to detect the cell apoptosis, and real-time quantitative PCR was used to detect the expression level of drug-resistant related genes.@*RESULTS@#HL-60 and HL-60/ADR stably transfected cell lines with down-regulation of SIX1 expression were successfully constructed. Compared with control group, the inhibition of SIX1 expression significantly inhibited the proliferation of HL-60 and HL-60/ADR cells (P <0.05), increased the apoptosis rate (P <0.05), and the sensitivity of cells to adriamycin increased after inhibition of SIX1 expression.@*CONCLUSION@#Inhibition of SIX1 expression can improve cell sensitivity to adriamycin, and its role in reversing drug resistance may be related to the promotion of apoptosis gene expression.

Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs

A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with β-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4-512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C β-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of β-lactamase-producing MDR Gram-negative bacterial infections.

Nephrotoxicity caused by polymyxin in the treatment of drug-resistant Gram-negative bacterial infections：a meta-analysis / 中国药房

OBJECTIVE To evaluate the incidence of nephrotoxicity in patients with drug-resistant Gram-negative bacterial infections after the use of polymyxin， and to provide evidence-based reference for clinical rational drug use. METHODS PubMed， Embase， Web of Science， the Cochrane Library， Wanfang database， CNKI， VIP and SinoMed were searched to collect randomized controlled trials （RCTs） or cohort studies about the polymyxin （trial group） versus other antibiotics （control group） or polymyxin B （trial group） versus polymyxin E （control group）. After literature screening， data extraction and quality evaluation， RevMan 5.4.1 software was used for meta-analysis. RESULTS A total of 37 studies were included， including 4 RCTs and 33 cohort studies， with a total of 5 871 patients. The meta-analysis results showed that in RCT [RR＝2.64，95%CI （1.43，4.87），P＝0.002] and in cohort studies [RR＝1.59， 95%CI （1.27， 1.98）， P＜0.000 1]， the incidence of nephrotoxicity in the trial group was significantly higher than control group. The results of the subgroup analysis of cohort studies showed that the incidence of nephrotoxicity in the trial group （receiving polymyxin） was significantly higher than control group （receiving new β-lactam and β-lactamase inhibitors and tigecycline）； when Kidney Disease Improving Global Outcomes （KDIGO）， renal replacement therapy or 0.5 times increase in serum creatinine were used as the standard of nephrotoxicity， the incidence of nephrotoxicity in the trial group was significantly higher than the control group （P＜0.05）. The incidence of nephrotoxicity in patients receiving polymyxin E was significantly higher than those using polymyxin B [RR＝0.57， 95%CI （0.39，0.84）， P＝0.005]. CONCLUSIONS In the treatment of drug-resistant Gram-negative bacteria infections， the incidence of nephrotoxicity caused by polymyxin is relatively high. The TYU108F）； incidence of nephrotoxicity caused by polymyxin E is higher than polymyxin B.

Efficacy and safety evaluation of the regimen containing Bedaquiline in elderly patients with drug-resistant pulmonary tuberculosis / 中华老年医学杂志

Objective:To evaluate the efficacy and adverse reactions of the regimen containing Bedaquiline in elderly patients with multi-drug resistant tuberculosis.Methods:From March 2019 to June 2022, patients with multi-drug resistant pulmonary tuberculosis admitted to Anhui Chest Hospital were randomly divided into two groups: the observation group was given a treatment containing Bedaquiline, and the control group was given a treatment without Bedaquiline.Patients were also divided into elderly patients(age ≥60 years old)and non-elderly patients(age <60 years old)according to age.Sputum culture conversion, lesion absorption and adverse reactions were compared between the observation group and the control group in general, elderly and non-elderly patients, respectively.Results:A total of 170 cases were collected, including 79 in the observation group and 91 in the control group.Sputum culture conversion: The sputum culture conversion rates of observation groups in general, non-elderly and elderly patients were better than that of control groups at the 3rd month after treatment(the general, 96.2% vs.75.8%, χ2=14.001, P<0.001; the non-elderly, 94.9% vs.82.1%, χ2=4.675, P=0.031; the elderly, 100.0% vs. 65.7%, χ2=8.771, P=0.003), and at the 6th month, the rates of overall observation group was better than that of control group(98.7% vs.92.3%, χ2=3.895, P=0.048); the rates of non-elderly and elderly observation group and control group were all greater than 90%, with no statistical significance( P>0.05). Lesion absorption: Overall and non-elderly observation groups were better than control group in lesion absorption at the 3rd month(the general, 84.8% vs.68.1%, χ2=12.962, P=0.002; the non-elderly, 88.1% vs.71.4%, χ2=9.832, P=0.007; and the 6th month(the general, 88.6% vs.76.9%, χ2=14.888, P=0.001; the non-elderly, 89.8% vs.82.1%, χ2=8.618, P=0.013). The focal absorptivity of senile observation group at the end of March and June were 75.0% and 85.0%, respectively, both better than control group, but the difference was not statistically significant( P>0.05). Adverse reactions: Overall and non-senile observation groups had longer QT interval than control groups( P<0.05), but no patients stopped bedaquiline because of this, and there was no significant difference in QT interval between the two groups( P>0.05). Conclusions:In elderly patients with multi-drug resistant pulmonary tuberculosis, early sputum culture conversion turns fast after treatment with Bedaquiline, which has good therapeutic effect, good tolerance and controllable adverse reactions.

Clinical features of an outbreak of extensive drug resistant typhoid fever / 中华传染病杂志

Objective:To analyze the clinical features of an outbreak of extensive drug resistant typhoid fever, and to provide experience for the diagnosis and treatment of drug resistant typhoid fever.Methods:Seven patients with confirmed diagnosis of extensive drug resistant typhoid fever who visited Beijing You′an Hospital, Capital Medical University, from January 27 to February 15, 2022 were included. The clinical characteristics, drug sensitivity tests, consultation and treatment history and prognosis of the patients were analyzed through descriptive study.Results:Of the seven extensive drug resistant typhoid fever patients, three were male and four were female, one of whom was pregnant (at 32-week gestation), aged (29.8±6.8) years, with a range of 22 to 42 years. There were seven cases with fever, and the course of fever ranged from six to 20 days. There were five cases with diarrhea and lack of typhoid-specific manifestations such as rose spot, apathetic facial expression and relatively slow pulse. Four cases were complicated with intestinal bleeding and six cases developed liver function injury. Six cases had loss or decrease in eosinophil ratio and two cases had decreased white blood cell count. The results of drug susceptibility tests showed that seven strains of Salmonella typhi were resistant to chloramphenicol, ampicillin, sulfamethoxazole-trimethoprim, quinolones, ceftriaxone, cefepime, ceftazidime, cefuroxime, and sensitive to carbapenem antibiotics, tigecycline and piperacillin/tazobactam. All seven cases had a history of antimicrobial use before admission. One case was administered with intravenous ceftizoxime for seven days after admission. After discharge, cefixime was administered orally for seven days. Six patients were given intravenous piperacillin sodium/tazobactam sodium for 14 days. All blood/fecal cultures were negative and the patients were cured and discharged. During the follow-up, one patient developed splenic abscess. All the seven patients were residents of the same apartment in Beijing City, and there were water cuts and turbid odors in the incubation period, which were considered as typhoid fever outbreak caused by waterborne transmission. Conclusions:With the use of antimicrobial agents, the typical clinical manifestations of typhoid fever are absent, and the drug resistance rates to quinolone and third-generation cephalosporins increase. Appropriate antimicrobial agents should be selected and the anti-infection course should be prolonged.