Inducción de tolerancia inmune en menores de 18 años con hemofilia A: experiencia en Uruguay, 2009-2020 / Induction of immune tolerance in children of under 18 years of age with hemophilia A: experience in uruguay, 2009-2020 / Indução de tolerância imune em crianças menores de 18 anos com hemofilia A: experiência no uruguai, 2009-2020

Introducción: el desarrollo de inhibidores contra el factor VIII (FVIII) es la complicación más seria del tratamiento en la hemofilia A. La inducción de tolerancia inmune (ITI) permite utilizar nuevamente el concentrado de FVIII para profilaxis o tratamiento. Objetivos: describir la experiencia con la ITI en menores de 18 años con hemofilia A severa (HAS) en un prestador integral de salud pública. Material y métodos: estudio descriptivo, retrospectivo, de menores de 18 años con HAS, concentraciones de inhibidores de FVIII ≥ a 5 UB, a quienes se les realizó ITI y seguimiento completo entre 2009 y 2020. Para la ITI se utilizó concentrado de FVIII derivado plasmático. El beneficio se expresa como la tasa de éxito definido por la negativización del inhibidor. Resultados: se incluyeron seis pacientes. Edad promedio al diagnóstico de inhibidor 2,96 años, luego de 24,4 días de exposición (DDE) a concentrados de FVIII. Media de inicio de ITI 3,76 niños y el tiempo de latencia del diagnóstico de inhibidor y el inicio de la ITI fue de 10,33 meses. El pico máximo del título pre-ITI fue en promedio de 114,7 UB. Cuatro pacientes iniciaron el régimen de ITI con títulos de inhibidor menor a 10 UB. El título del inhibidor se negativizó en 8,2 meses y el porcentaje de recuperación in vivo >65% se logró con una media de 15,7 meses. La ITI fue exitosa en 83% de los casos. Conclusiones: en niños con hemofilia A e inhibidores de alto título, la ITI tiene un elevado éxito, tal como ocurrió en esta serie. Dado que el tiempo de respuesta es variable, la ITI debe ser individualizada.

Introduction: the development of inhibitors against factor VIII is the most serious complication of treatment in hemophilia A. Immune tolerance induction (ITI) enables the factor VIII concentrate to be used again for prophylaxis or treatment. Objectives: describe the experience with ITI in children of under 18 years of age with severe hemophilia A (SAH) in a health care provider. Material and methods: descriptive, retrospective study of children under 18 years of age with SAH, concentrations of FVIII inhibitors ≥ 5BU, who underwent ITI and full follow-up between 2009-2020. For ITI, we used plasma derived FVIII concentrate. The benefit is expressed as the success rate defined by the inhibitor's negativization. Results: 6 patients were included. Mean age at diagnosis of inhibitor 2,96 years, after 24,4 days of exposure (DAE) to FVIII concentrates. Mean ITI onset was 3,76 years and latency time from inhibitor diagnosis and ITI onset was 10,33 months. Maximum peak of the pre ITI title was an average of 114,7 UB. Four patients started the ITI regimen with inhibitors titers less than 10 BU. The inhibitor titer negative in 8,2 months and in vivo recovery rate >65% was achieved with a mean of 15,7 months. The ITI was successful in 83% of the cases. Conclusions: ITI is highly successful in children with hemophilia A and high-titer inhibitors, as this case suggests. Since the response time is variable, the ITI must be individualized.

Introdução: o desenvolvimento de inibidores contra o fator VIII é a complicação mais grave do tratamento da hemofilia A. A indução de tolerância imunológica (ITI) permite que o concentrado de fator VIII seja novamente utilizado para profilaxia ou tratamento. Objetivos: descrever a experiência com ITI em crianças menores de 18 anos com hemofilia A grave (HAS) em um serviço de saúde pública abrangente. Material e métodos: estudo descritivo e retrospectivo de crianças menores de 18 anos com HAS, concentrações de inibidor do FVIII ≥ 5 BU), que realizaram ITI e acompanhamento completo entre 2009-2020. Concentrado de FVIII derivado de plasma foi utilizado para ITI. O benefício é expresso como a taxa de sucesso definida pela negativação do inibidor. Resultados: 6 pacientes foram incluídos. Idade média no diagnóstico do inibidor 2,96 anos, após 24,4 dias de exposição (DDE) a concentrados de FVIII. A média de início da ITI foi de 3,76 crianças e o tempo de latência do diagnóstico do inibidor e início da ITI foi de 10,33 meses. O pico máximo do título pré-ITI foi em média 114,7 BU. Quatro pacientes iniciaram o regime ITI com títulos de inibidor inferiores a 10 BU. O título do inibidor tornou-se negativo em 8,2 meses e a percentagem de recuperação in vivo >65% foi alcançada com uma média de 15,7 meses. O ITI foi bem-sucedido em 83% dos casos. Conclusões: em crianças com hemofilia A e inibidores de títulos elevados, a ITI é altamente bem sucedida, como ocorreu nesta série. Como o tempo de resposta é variável, o ITI deve ser individualizado.

COVID-19 en las embarazadas. Riesgo de las complicaciones durante el embarazo y en el neonato / COVID-19 in pregnant women. Risk of complications during pregnancy and in the newborn

Sobre el tema COVID-19 se han publicado múltiples estudios que reflejan su elevada incidencia, transmisibilidad, morbilidad y mortalidad, con gran repercusión y severidad en los grupos poblacionales de riesgo. El embarazo no escapa a ello, y la inmunosupresión fisiológica que se presenta en esta condición, hace a la gestante y al neonato, ser más susceptibles a las enfermedades infecciosas. El objetivo de esta comunicación es profundizar en la fisiopatología y la repercusión de la enfermedad COVID-19 en las gestantes y el neonato, para mejorar el conocimiento relacionado con el tema, el cual repercutirá en un mejor manejo de estos pacientes. Para ello, se realizó una revisión de investigaciones publicadas en el período comprendido entre enero y diciembre de 2021, en las bases de datos: SciELO, SCOPUS, Medline, Dialnet, Cumed y Lilacs. De los 44 artículos obtenidos inicialmente, 33 cumplieron los criterios de inclusión.

Several studies on COVID-19 have been published reflecting its high incidence, transmissibility, morbidity and mortality, with great repercussions and severity in population groups at risk. Pregnancy does not escape from this, and the physiological immunosuppression that occurs in this condition makes the pregnant woman and the newborn more susceptible to infectious diseases. The objective of this communication is to deepen the pathophysiology and the repercussion of the COVID-19 disease in pregnant women and the newborn in order to improve knowledge related to the subject, which will have an impact on better management of these patients. For this, a review of research published between January and December 2021 was carried out in the databases such as SciELO, SCOPUS, Medline, Dialnet, Cumed and Lilacs. A number of 33 articles met the inclusion criteria from 44 initially obtained.

Rapid flavonoid-focused sub-chemome characterization of Draconis Sanguis using UPLC-Q-TOF-MS in combination with molecular weight imprinting and mass defect filtering / 中国中药杂志

Draconis Sanguis is a precious Chinese medicinal material for activating blood and resolving stasis, and its effective components are flavonoids. However, the structural diversity of flavonoids in Draconis Sanguis brings great challenges to the in-depth chara-cterization of its chemical composition profiles. To clarify the substance basis of Draconis Sanguis, ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was used in this study to acquire MS data of Draconis Sanguis. The molecular weight imprinting(MWI) and mass defect filtering(MDF) were developed for rapid screening of flavonoids in Draconis Sanguis. Full-scan MS and MS~2 were recorded within the mass range m/z 100-1 000 in positive ion mode. Accor-ding to previous literature, MWI was employed to hunt for reported flavonoids in Draconis Sanguis, and the mass tolerance range of [M+H]~+ was set as ±10×10~(-3). A five-point MDF screening frame was further constructed to narrow the screening range of flavonoids from Draconis Sanguis. Combined with diagnostic fragment ions(DFI) and neutral loss(NL) as well as mass fragmentation pathways, 70 compounds were preliminarily identified from the extract of Draconis Sanguis, including 5 flavan oxidized congeners, 12 flavans, 1 dihydrochalcones, 49 flavonoids dimers, 1 flavonoids trimer and 2 flavonoid derivatives. This study clarified the chemical composition of flavonoids in Draconis Sanguis. Moreover, it also showed that high-resolution MS combined with data post-processing methods such as MWI and MDF could achieve rapid characterization of the chemical composition in Chinese medicinal materials.

Study on the sensitivity of a volumetric modulated arc therapy plan verification equipment on multi-leaf collimator opening and closing errors and its gamma pass rate limit / 生物医学工程学杂志

To investigate the γ pass rate limit of plan verification equipment for volumetric modulated arc therapy (VMAT) plan verification and its sensitivity on the opening and closing errors of multi-leaf collimator (MLC), 50 cases of nasopharyngeal carcinoma VMAT plan with clockwise and counterclockwise full arcs were randomly selected. Eight kinds of MLC opening and closing errors were introduced in 10 cases of them, and 80 plans with errors were generated. Firstly, the plan verification was conducted in the form of field-by-field measurement and true composite measurement. The γ analysis with the criteria of 3% dose difference, distance to agreement of 2 mm, 10% dose threshold, and absolute dose global normalized conditions were performed for these fields. Then gradient analysis was used to investigate the sensitivity of field-by-field measurement and true composite measurement on MLC opening and closing errors, and the receiver operating characteristic curve (ROC) was used to investigate the optimal threshold of γ pass rate for identifying errors. Tolerance limits and action limits for γ pass rates were calculated using statistical process control (SPC) method for another 40 cases. The error identification ability using the tolerance limit calculated by SPC method and the universal tolerance limit (95%) were compared with using the optimal threshold of ROC. The results show that for the true composite measurement, the clockwise arc and the counterclockwise arc, the descent gradients of the γ passing rate with per millimeter MLC opening error are 10.61%, 7.62% and 6.66%, respectively, and the descent gradients with per millimeter MLC closing error are 9.75%, 7.36% and 6.37%, respectively. The optimal thresholds obtained by the ROC method are 99.35%, 97.95% and 98.25%, respectively, and the tolerance limits obtained by the SPC method are 98.98%, 97.74% and 98.62%, respectively. The tolerance limit calculated by SPC method is close to the optimal threshold of ROC, both of which could identify all errors of ±2 mm, while the universal tolerance limit can only partially identify them, indicating that the universal tolerance limit is not sensitive on some large errors. Therefore, considering the factors such as ease of use and accuracy, it is suggested to use the true composite measurement in clinical practice, and to formulate tolerance limits and action limits suitable for the actual process of the institution based on the SPC method. In conclusion, it is expected that the results of this study can provide some references for institutions to optimize the radiotherapy plan verification process, set appropriate pass rate limit, and promote the standardization of plan verification.

Research Progress of Regulatory T Cells in the Pathogenesis of Multiple Myeloma --Review / 中国实验血液学杂志

The multiple myeloma (MM), the second most common hematologic malignancy, is malignant proliferative disease of plasma cells. Although the application of many targeted drugs has significantly prolonged the survival time of MM patients, it is still an incurable disease. In recent years, the immunosuppression caused by interaction between tumor microenvironment(TME) and tumor cells has attracted people's attention gradually. As a kind of immunosuppressive cells in TME, regulatory T cells (Treg) play an important role in the progress of MM. Treg is related to the proliferation and metastasis of tumors, and can lead to the progress of MM by promoting the angiogenesis and generating immunosuppressive TME. In this review, we briefly summarized the latest research progress on the impact of Treg on the pathogenesis of MM.

Alergia a la proteína de la leche de vaca; nuevos conocimientos desde una visión multidisciplinaria / Cow's milk protein allergy; new knowledge from a multidisciplinary perspective

En las últimas décadas, se ha observado una mayor prevalencia, persistencia y gravedad de la alergia a la proteína de leche de vaca (APLV). Se han postulado diversas hipótesis respecto a posibles mecanismos responsables, con énfasis en el papel de la microbiota en la inducción y el mantenimiento de la tolerancia inmunitaria, así como la importancia del establecimiento temprano de una microbiota saludable a través de la promoción de la lactancia materna, el parto por vía vaginal, el uso racional de antibióticos e inhibidores de la bomba de protones, junto con la introducción temprana y variada de alimentos. La utilización de probióticos y la inmunoterapia específica para alérgenos (ITA) emergen como las estrategias terapéuticas con más evidencia a favor para la adquisición de tolerancia. El objetivo de esta revisión ha sido describir la información actual respecto a los mecanismos inmunitarios involucrados en la APLV, el papel de la microbiota y las perspectivas futuras en el tratamiento.

In recent decades, a higher prevalence, persistence, and severity of cow's milk protein allergy (CMPA) have been observed. Different hypotheses have been proposed in relation to potential responsible mechanisms, with emphasis on the role of the microbiota in the induction and maintenance of immune tolerance as well as the importance of establishing a healthy microbiota in an early manner through the promotion of breastfeeding, vaginal delivery, rational use of antibiotics and proton pump inhibitors, along with an early introduction of varied foods. The use of probiotics and allergenspecific immunotherapy (AIT) come up as the treatment strategies with the greatest evidence in favor of tolerance acquisition. The objective of this review was to describe the information currently available about the immune mechanisms involved in CMPA, the role of microbiota, and future treatment perspectives.

Aspectos da assistência em pacientes com Doença Falciforme no contexto da pandemia da COVID-19 / Aspects of care in patients with Sickle Cell Disease in the context of the COVID-19 pandemic

Introdução: A pandemia determinada pelo novo coronavírus (SarsCoV-2), doença intitulada COVID-19, atingiu mais de 219 países com grande agravo e impacto à saúde mundial. A infecção pelo vírus desencadeia uma resposta imune explosiva, hiperativada e descontrolada, com manifestações clínicas graves em pessoas com doenças subjacentes. A Doença falciforme (DF), uma condição genética que determina imunosupressão, coloca os pacientes em maior risco de infecções respiratórias e complicações pulmonares dentro do contexto da pandemia. Objetivo: Analisar o impacto da COVID-19 em portadores de DF e propor uma diretriz de atendimento a esta população. Métodos: Trata- se de uma revisão sistemática de literatura onde foram analisados estudos, publicados originalmente em inglês, entre março a dezembro de 2020, tendo como referência as bases de dados MedLine, SciELO e LILACS. A busca foi efetuada mediante a consulta ao MeSH com os descritores "sickle cell disease", "covid-19"e "guideline". Foram identificados 64 artigos a partir da frase de pesquisa. Ao aplicar os critérios de inclusão, 7 artigos foram eleitos para o estudo. Resultados e Conclusão: A infecção pelo novo coronavírus pode precipitar intercorrências em pacientes com DF, como crises vaso-oclusivas e síndrome torácica aguda. Considerando esses dados, os autores formularam uma diretriz para orientação e cuidado aos indivíduos com DF

Introduction: The pandemic caused by the new coronavirus (SarsCoV-2), a disease called COVID-19, has reached more than 219 countries with great damage and impact on global health. The viral infection triggers an explosive, hyperactive and uncontrolled immune response, with severe clinical manifestations in people with underlying diseases. Sickle Cell Disease (SCD), a genetic condition that determines immunosuppression, causes patients a greater risk of respiratory infections and pulmonary complications within the context of the pandemic. Objective: To analyze the impact of COVID-19 in patients with SCD and propose a guideline to care for this population. Methods: This is a systematic literature review where studies were analyzed, originally published in English, between March and December 2020, using the MedLine, SciELO and LILACS databases as references. The search was carried out by consulting the MeSH with the descriptors "sickle cell disease", "covid-19" and "guideline". 64 articles were identified from the search phrase. When applying the inclusion criteria, 7 articles were chosen for the study. Results and Conclusion: The infection with the new coronavirus could cause complications in patients with SCD, such as vaso-occlusive crises and acute chest syndrome. Considering these data, the authors formulated a guideline for guidance and care for individuals with SCD.

Micosis en tiempos de COVID-19 / Mycosis in times of COVID-19

El brote mundial del SARS-CoV-2, descrito a partir del 2019, provocó la pandemia de COVID-19, originando un riesgo para la salud de las personas, una amenaza a la vida y una emergencia de salud pública internacional, que hasta Julio del 2021 no se ha logrado controlar. La coinfección en estos pacientes, por virus, bacterias y hongos, aumenta la dificultad de diagnóstico, tratamiento y pronóstico de la enfermedad. Es importante profundizar los conocimientos sobre el virus SARS-CoV-2 y las coinfecciones que podrían presentarse, en particular, en pacientes con COVID-19 que presentan micosis. El objetivo de esta revisión bibliográfica es, determinar la importancia de las micosis, como enfermedad oportunista, en pacientes con COVID-19. Se realizó una revisión bibliográfica sistemática, en la base de datos "PubMed-NCBI". Se utilizaron las palabras claves: "COVID-19", "SARS-CoV-2", "Coronavirus", "COVID-19 and coinfection", "Mycosis", "Aspergillus spp.", "Candida spp.", "COVID-19 and Aspergillus spp.", "COVID-19 and Candida spp.". Del análisis de la bibliografía, se concluye la importancia de las micosis respiratorias, originadas por diversos hongos en pacientes con COVID-19. Hay poca información del manejo de estas, siendo necesario fortalecer la investigación de la coinfección, para así, mejorar los flujogramas de sospecha clínica, contribuyendo a diagnósticos, tratamientos precisos y fomentar la prevención frente a esta pandemia.

The global outbreak of SARS-CoV-2, described as of 2019 whose expansion caused the COVID-19 pandemic, has created a risk to people's health, presenting itself as a threat to life and an international public health emergency, which to the date cannot be controlled. Coinfection in these patients, by viruses, bacteria and fungi, increases the difficulty of diagnosis, treatment and prognosis of the disease. It's important to deepen the knowledge about the SARS-CoV-2 virus and the co-infections that could occur, in particular, in patients with COVID-19 who present with mycosis. The objective of this bibliographic review is to determine the importance of mycosis, as an opportunistic disease, in patients affected by SARS-CoV-2. A systematic bibliographic review was carried out in the "PubMed-NCBI" database, using the keywords and / or headings: "COVID-19", "SARS-CoV-2", "Coronavirus", "COVID-19 and coinfection" ,"Mycosis", "Aspergillus spp.", "Candida spp." COVID-19 and Aspergillus spp.", "COVID-19 and Candida spp.". From the analysis of the literature, one can conclude the importance of respiratory mycoses, caused by various fungal pathogens in patients with COVID-19. The disease was described in 2019 and there is few a information on cases and their management, making it necessary to strengthen the investigation of coinfection in these patients, in order to improve the flow charts of clinical suspicion, contributing to diagnoses, accurate treatments and promoting prevention against to this pandemic.

Cargas virales en pacientes trasplantados y genotipificación de Citomegalovirus / Viral loads in transplant patients and Cytomegalovirus genotyping

Resumen Objetivo: Determinar el curso de infecciones virales por un periodo de un año, mediante la medición de la carga viral de Adenovirus, virus BK, virus Epstein-Barr, Citomegalovirus y Herpesvirus humano 6, en 30 pacientes del Hospital San Juan de Dios, sometidos a trasplante de riñón o células progenitoras hematopoyéticas. Métodos: Se determinaron las cargas virales en diez muestras de sangre por paciente: una muestra pretransplante, ocho muestras obtenidas cada dos semanas postrasplante y una última muestra a los seis meses posteriores al trasplante. La cuantificación de los virus se realizó por reacción en cadena de la polimerasa en tiempo real y, solo en el caso del Adenovirus, por reacción en cadena de la polimerasa de punto final. También se determinaron los genotipos de Citomegalovirus en los pacientes positivos para este virus, utilizando una reacción en cadena de la polimerasa dirigida al gen de la glicoproteína B y secuenciación de los fragmentos amplificados. Las secuencias obtenidas fueron comparadas y alineadas con una secuencia de referencia, utilizando el programa Clustal Omega. Resultados: Al 77 % de los pacientes se les detectó al menos uno de los cinco virus analizados y el virus con mayor prevalencia fue el Citomegalovirus, con un 57% de positividad del total de la población. El genotipo de Citomegalovirus que más se detectó fue el genotipo 3. Se monitoreó el comportamiento de las cargas virales para cada virus analizado y la proporción de su incidencia entre pacientes masculinos y femeninos. Conclusiones: La cuantificación y caracterización de virus en pacientes de trasplante, permite un mejor manejo clínico del paciente con infecciones oportunistas y también un manejo más adecuado de las terapias farmacológicas.

Summary Aim: The objective of this study was to determine the course of viral infections during a period of one year, by measuring viral loads for Adenovirus, BK virus, Epstein-Barr virus, Cytomegalovirus and Human herpesvirus 6, in 30 patients from the San Juan de Dios National Hospital, undergoing kidney or hematopoietic progenitor cell transplants. Methods: Viral loads were determined in ten blood samples from each patient: a pre- transplant sample, eight samples obtained at two-week intervals post-transplant and one last sample at six months post-transplant. Viral quantification was performed by real-time polymerase chain reaction and, only for Adenovirus, by end-point polymerase chain reaction. Also, Cytomegalovirus genotypes were determined in patients that tested positive for this virus, by polymerase chain reaction directed towards the glycoprotein B gene and sequencing of the amplified fragments. These sequences were compared and aligned with a reference sequence, using the Clustal Omega Program. Results: The results of the study indicated that 77% of the patients had at least one of the five viruses detected and the virus with the highest prevalence was Cytomegalovirus, exhibiting 57% positivity in the total population studied. The most frequent Cytomegalovirus genotype detected was genotype 3. The viral load behavior was monitored for each virus analyzed as well as the incidence proportion between male and female patients. Conclusions. Viral quantification and characterization in transplant patients allows for better clinical management of patients with opportunistic infections and also a better management of pharmacological therapies.

Papel de la alimentación en la respuesta a infecciones respiratorias altas en atletas de élite / Role of nutrition in the response to upper respiratory infections in elite athletes

Las infecciones de las vías respiratorios altas (IVRA), son debilitantes para el potencial deportivo de los atletas de élite. El ejercicio físico activa múltiples vías moleculares y bioquímicas relacionadas con el sistema inmune, sensibles a influencias nutricionales. Sobre este contexto, la inmunonutrición está adquiriendo una nueva dirección orientada a conseguir el equilibrio inmunológico, contraponiéndose con algunas de las teorías que han sentado las bases de la inmunología del ejercicio durante las últimas décadas. Objetivo. Investigar los aspectos nutricionales que puedan mejorar la respuesta inmunológica en deportistas de elite. Estudiar los posibles beneficios del equilibrio inmunológico para mejorar el rendimiento, analizar los factores nutricionales que contribuyan al equilibrio de la respuesta inmunológica y extrapolar la evidencia actual en recomendaciones prácticas de alimentación/suplementación para mejorar la homeostasis de la respuesta inmunológica en atletas de élite, teniendo en cuenta las limitaciones existentes.Resultados. La evidencia científica apunta que se puede potenciar el equilibrio inmunológico y la respuesta inmune a través de la modificación de factores nutricionales. Dentro de los cuales, la vitamina D, los probióticos, la vitamina C y el cinc son los que cuentan con mayor evidencia. Conclusión. Los avances científicos resultan prometedores y de interés para los atletas de élite, debido a que pueden disminuir la incidencia de IVRA, mejorando el éxito deportivo de los mismos. Se requieren más estudios para su validación y aplicación(AU)

Upper respiratory tract infections (URTI) are debilitating for the athletic potential of elite athletes. Physical exercise in elite athletes activates multiple molecular and biochemical pathways related to the immune system, which, at the same time, are sensitive to nutritional influences. Based on this context, immunonutrition is taking a new direction aimed at achieving the immunological balance. Objective. To investigate the nutritional aspects that can improve the immune response in elite athletes. To study the potential benefits of immune balance to improve performance, to analyse nutritional factors that contribute to the balance of the immune response and to extrapolate current evidence into practical dietary/supplementation recommendations to improve the homeostasis of the immune response in elite athletes, considering existing limitations. Results. Scientific evidence suggests that immune balance and immune response can be enhanced through the modification of nutritional factors. Among which, vitamin D, probiotics, vitamin C and zinc are the micronutrients with most evidence. Conclusion. Scientific advances in this field are promising and of great interest to elite athletes since it could decrease the incidence of URTI and, as a consequence, it could improve their sporting success. However, more studies are still required for its validation and application(AU)