Frequency of polymorphisms in the IKZF1 and CDKN2A/2B genes and descriptive analysis in pediatric patients with acute lymphoblastic leukemia: a multicenter hospital-based prevalence study in Rio De Janeiro.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and B-cell ALL (B-ALL) is the most common subtype. The understanding of ALL has advanced significantly in recent years due to genomic sequencing, which has made it possible to identify genetic variants and detect the association between "single nucleotide polymorphisms" (SNP) and certain diseases. METHODS: We evaluated 126 patients diagnosed with B-ALL in hospitals in Rio de Janeiro. We described the frequency of polymorphisms in the IKZF1, CDKN2A/2B genes, the contribution of these genetic variants in pediatric ALL, and compared them with the general population of Rio de Janeiro. RESULTS: We demonstrated that the SNPs rs3731217, rs4132601, and rs11978267 were more frequent in patients with B-ALL. CONCLUSIONS: These findings contribute to a more complete understanding of B-ALL. They can guide future studies, bringing new perspectives on personalized therapies with reduced side effects and optimization efficacy of B-ALL treatment in children.

Translation, transcultural adaptation and validation to Brazilian Portuguese of tools for adverse drug reaction assessment in children.

BACKGROUND: Children are more vulnerable to adverse drug reactions (ADRs) due to complex changes in the body during the growth process and lack specific pharmacoepidemiologic studies. Causality and Avoidability assessment of ADRs are relevant to clinical guidelines development and pharmacovigilance. This study aimed to translate and transcultural adapt two new tools-Liverpool Causality Assessment Tool (LCAT) and the Liverpool Avoidability Assessment Tool (LAAT)-to Brazilian-Portuguese and evaluate the psychometric properties of these tools to analyse ADRs in Brazilian children. METHODS: The validation of the cross-cultural adaptation of tools was obtained by the functional (conceptual, semantic, operational, and measurement) equivalence between the original and translated versions of each instrument. The translated version of LCAT and LAAT was applied to assessing the twenty-six case reports of suspected adverse drug reactions in a Brazilian teaching paediatric hospital. The inter-rater reliability (a pharmacist and a physician) was evaluated using Cronbach's alpha. The exact agreement percentages (%EA) and extreme disagreement (%ED) were computed. Overall Kappa index was calculated with a 95% confidence interval. RESULTS: There was a need to modify some terms translated into Portuguese for semantic and conceptual equivalence. The Cronbach's alpha coefficient values obtained were 0.95 and 0.85, and the weighted Kappa (95% confidence interval) were 0.82 (0.67-0.97) and 0.68 (0.45-0.91) for LCAT and LAAT, respectively. The Brazilian-Portuguese versions of the LCAT and LAAT showed reliable and valid tools for the diagnosis and follow-up of ADRs in children. CONCLUSION: The methodological approach allowed the translation, transcultural adaptation, and validation to Brazilian-Portuguese of two easy and quick to perform tools for causality and avoidability of ADRs in children by a multidisciplinary expert specialist committee, including the authors of original tools. We believe these versions may be applied by professionals (patient safety teams) and researchers in Brazil in groups or by a single reviewer. TRIAL REGISTRATION: This study was evaluated and approved by the Research Ethics Committee (Instituto de Pediatria e Puericultura Martagão Gesteira - Federal University of Rio de Janeiro - Number: 3.264.238.

Long-Term Outcomes of Childhood Acute Lymphocytic Leukemia Treated with Adapted Berlin-Frankfurt-Münster (BFM) Protocols: A Multicentric Analysis from a Developing Country.

INTRODUCTION: The objective of the current study was to determine the survival probabilities of children and adolescents with acute lymphocytic leukemia treated with adapted Berlin-Frankfurt-Münster (BFM) protocols and compare our results with the original BFM reports. METHODS: This retrospective study included 695 patients up to 19 years old treated with adapted BFM protocols between 1997 and 2018 in four hospitals in Rio de Janeiro. The 1997-2007 and 2008-2018 cohorts were analyzed separately. RESULTS: More than half of the patients were stratified into the high-risk BFM classification. Overall and event-free survivals were, in the 1997-2007 period, respectively, 88% and 80% (BFM standard risk group-SRG), 75% and 67% (intermediate risk group-IRG), and 48% and 33% (high-risk group-HRG). The corresponding numbers for the 2008-2018 period were 93% and 84% (SRG), 75% and 63% (IRG), and 64% and 57% (HRG). In the second period, both the OS (HR = 0.71, p = 0.011) and EFS (HR = 0.62, p < 0.001) were higher. Except for the intermediate-risk group, the latter results are comparable to the BFM. CONCLUSION: The BFM protocol adaptations can be safely implemented in developing countries, accounting for local specificities.

Multisystem inflammatory syndrome drug treatment in countries with different income profiles: a scoping review.

Objective: The purpose of this study was to map and describe the studies that have investigated therapeutic alternatives for the management of paediatric multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. Considering the origin of the studies performed (low-, middle- and high-income countries), a systematic scoping review was conducted with primary studies that reported the use of medications for the treatment of patients with MIS-C. Sources: The searches were performed in MEDLINE, Embase, Lilacs, Epistemonikos, CINAHL, and CENTRAL, in the grey literature (theses and dissertations from CAPES, ProQuest, and PROSPERO) and in clinical trial databases until May 2022. The selection and extraction of studies were performed independently by two reviewers. Summary of the findings: A total of 173 studies were included, most of which were published as case reports or series. No randomized controlled clinical trials (RCTs) were identified. The investigated drugs were immunoglobulins, glucocorticoids, monoclonal antibodies, anticoagulants, and antiplatelet agents. Conclusion: The dosages, when reported, were heterogeneous among the studies. The ethnicity and comorbidity of the participants were poorly reported. Monoclonal antibodies, drugs with higher costs, were mostly described in studies of high-income countries.

Lenalidomide Maintenance and Measurable Residual Disease in a Real-World Multiple Myeloma Transplanted Population Receiving Different Treatment Strategies Guided by Access to Novel Drugs in Brazil.

Despite recent advances in multiple myeloma (MM), the incorporation of novel agents and measurable residual disease (MRD) monitoring in low-income countries remains a challenge. Although lenalidomide maintenance (M-Len) after autologous stem cell transplantation (ASCT) has been associated with improved outcomes and MRD has refined the prognosis of complete response (CR) cases, until now, there have been no data on the benefits of these approaches in Latin America. Here, we evaluate the benefits of M-Len and MRD using next-generation flow cytometry (NGF-MRD) at Day + 100 post-ASCT (n = 53). After ASCT, responses were evaluated based on the International Myeloma Working Group criteria and NGF-MRD. MRD was positive in 60% of patients with a median progression-free survival (PFS) of 31 months vs. not reached (NR) for MRD-negative cases (p = 0.05). The patients who received M-Len continuously had a significantly better PFS and overall survival (OS) than those without M-Len (median PFS: NR vs. 29 months, p = 0.007), with progression in 11% vs. 54% of cases after a median follow-up of 34 months, respectively. In a multivariate analysis, MRD status and M-Len therapy emerged as independent predictors of PFS (median PFS of M-Len/MRD- vs. no M-Len/MRD+ of NR vs. 35 months, respectively; p = 0.01). In summary, M-Len was associated with improved survival outcomes in our real-world MM cohort in Brazil, with MRD emerging as a useful reproducible tool to identify patients at an earlier risk of relapse. The inequity in drug access remains a hurdle in countries with financial constraints, with a negative impact on MM survival.

Prognostic Factors in Children and Adolescents with Lymphomas and Vertical Transmission of HIV in Rio de Janeiro, Brazil: A Multicentric Hospital-Based Survival Analysis Study.

Lymphomas related to HIV are generally aggressive and have a poor prognosis, despite the use of combined antiretroviral therapy (cART) and effective chemotherapy treatment. To determine survival and prognostic factors in children and adolescents living with HIV (CLWH) in Rio de Janeiro (RJ), Brazil, who developed lymphomas, we performed a retrospective and observational study of vertically infected CLWH aged from 0 to 20 incomplete years during1995 to 2018 at five reference centers for cancer and HIV/AIDS treatment. Of the 25 lymphomas, 19 were AIDS-defining malignancies (ADM) and 6 were non-AIDS-defining malignancies (NADM). The 5-year overall survival (OS) and 5-year event-free survival (EFS) probabilities were both 32.00% (95% CI = 13.72-50.23%), and the 5-year disease-free survival (DFS) probability was 53.30% (95% CI = 28.02-78.58%). In the multivariate Cox regression analysis, performance status 4 (PS 4) was considered a poor prognostic factor for OS (HR 4.85, 95% CI = 1.81-12.97, p = 0.002) and EFS (HR 4.95, 95% CI = 1.84-13.34, p = 0.002). For the DFS, higher CD4+ T-cell counts were considered a better prognostic factor (HR 0.86, 95% CI = 0.76-0.97, p = 0.017) in the multivariate Cox regression analysis. This study demonstrates, for the first time, survival and prognostic factors for CLWH who developed lymphomas in RJ, Brazil.

L-asparaginase doses number as a prognostic factor in childhood acute lymphoblastic leukemia: A survival analysis study.

BACKGROUND: The survival of children with acute lymphoblastic leukemia (ALL) has improved due to changes in the treatment and the disease diagnosis. A significant advance was the incorporation of asparaginase. However, hypersensitivity reactions are a common cause of early discontinuation of this drug. AIM: The proposed study aims to evaluate early interruptions and the influence of the number of asparaginase doses effectively administered on the prognosis of patients with ALL. METHODS AND RESULTS: An observational cohort study was carried out, with retrospective data collection, in medical records. The prognostic variables indicated in the protocol applied were used, and the principal outcomes were 5 years event-free survival (EFS) and 5 years of overall survival (OS) probability. Statistical analyzes were performed using SPPS 20.0 and R. In Cox's proportional hazards model for EFS and OS, variables of prognostic importance (n = 126 children) were: high-risk group (HGR), by the protocol classification, and less than 10 doses of asparaginase. The increased risk of events and death in HGR, who did less than 10 doses, was 3.6 and 7 times, respectively. The study did not show statistical significance for the number of asparaginase doses in patients who were not at high risk. CONCLUSIONS: We demonstrated that the early interruption of asparaginase treatment could negatively impact the prognosis of patients with ALL, especially HGR, reinforcing the need for careful diagnosis of reactions and the availability of alternative types of asparaginase.

The growth and development of research on personality disorders: A bibliometric study.

This study objective was to investigate publication trends on personality disorders (PD) and to identify patterns of historical development. Publication rates were determined using the Results by Year Timeline feature of PubMed. Time series autoregressive integrated moving average models were used to analyse the publication rates for PDs in quinquennial periods beginning in 1980 and ending in 2019 and to predict the number of publications in the 2024-2029 period. More than 300 articles on antisocial and borderline PD are being published each year, and the models suggest an accelerating growth rate. Approximately 100 articles are being published on average every year on schizotypal PD, and the regression model indicates linear growth in the near future. The mean number of publications per year for obsessive-compulsive, narcissistic and avoidant PDs is in the range of 10-30 with the corresponding models indicating linear growth. Fewer than 10 articles are being published each year on dependent, paranoid, histrionic and schizoid PD, whereas dependent PD shows modest growth and paranoid PD rates tended to stability, histrionic and schizoid PD exhibit declining rates. Personality disorders are a group of conditions with diverse etiological, prognostic, therapeutic, legal, research, social and cultural implications that influence publication rates.

Incidence and Clinical Description of Lymphomas in Children and Adolescents with Vertical Transmission of HIV in Rio de Janeiro, Brazil, in Pre- and Post-Combined Antiretroviral Therapy Eras: A Multicentric Hospital-Based Survival Analysis Study.

The incidence of cancer in children living with HIV (CLWH) is high and lymphomas are the most common type of cancer in this population. The combined antiretroviral therapy (cART) changed the natural history of HIV infection. To determine the incidence and profile of these CLWH malignancies in Rio de Janeiro (RJ), Brazil, we conducted a retrospective and observational study of vertically infected CLWH, ranging from 0−20 incomplete years, from 1995 to 2018, at five reference centers. The study period was divided into three eras in accordance with the widespread use of cART in Brazil. 1306 patients were included. Of the 25 lymphomas found, 19 were AIDS-defining malignancies (ADM); 6 were non-AIDS-defining malignancies (NADM). The incidence rate (IR) of lymphoma developing was 1.70 per 1000 children-year (95% CI 1.09−2.50). ADM development IR decreased from 2.09−1.75−0.19 per 1000 children-year (p < 0.001) through cART eras. Cumulative Nelson−Aalen hazards of developing ADM over a 20-year period were 3.73% in the Early-cART era, 3.07% in the Mid-cART era, and 0.32% in the Late-cART era (p = 0.013). This study demonstrates the IR of lymphoma in CLWH in RJ, Brazil, as well as the benefit of cART in reducing ADM and death occurrence in the Post-cART era.

Flow Cytometry Immunophenotyping for Diagnostic Orientation and Classification of Pediatric Cancer Based on the EuroFlow Solid Tumor Orientation Tube (STOT).

Early diagnosis of pediatric cancer is key for adequate patient management and improved outcome. Although multiparameter flow cytometry (MFC) has proven of great utility in the diagnosis and classification of hematologic malignancies, its application to non-hematopoietic pediatric tumors remains limited. Here we designed and prospectively validated a new single eight-color antibody combination-solid tumor orientation tube, STOT-for diagnostic screening of pediatric cancer by MFC. A total of 476 samples (139 tumor mass, 138 bone marrow, 86 lymph node, 58 peripheral blood, and 55 other body fluid samples) from 296 patients with diagnostic suspicion of pediatric cancer were analyzed by MFC vs. conventional diagnostic procedures. STOT was designed after several design-test-evaluate-redesign cycles based on a large panel of monoclonal antibody combinations tested on 301 samples. In its final version, STOT consists of a single 8-color/12-marker antibody combination (CD99-CD8/numyogenin/CD4-EpCAM/CD56/GD2/smCD3-CD19/cyCD3-CD271/CD45). Prospective validation of STOT in 149 samples showed concordant results with the patient WHO/ICCC-3 diagnosis in 138/149 cases (92.6%). These included: 63/63 (100%) reactive/disease-free samples, 43/44 (98%) malignant and 4/4 (100%) benign non-hematopoietic tumors together with 28/38 (74%) leukemia/lymphoma cases; the only exception was Hodgkin lymphoma that required additional markers to be stained. In addition, STOT allowed accurate discrimination among the four most common subtypes of malignant CD45- CD56++ non-hematopoietic solid tumors: 13/13 (GD2++ numyogenin- CD271-/+ nuMyoD1- CD99- EpCAM-) neuroblastoma samples, 5/5 (GD2- numyogenin++ CD271++ nuMyoD1++ CD99-/+ EpCAM-) rhabdomyosarcomas, 2/2 (GD2-/+ numyogenin- CD271+ nuMyoD1- CD99+ EpCAM-) Ewing sarcoma family of tumors, and 7/7 (GD2- numyogenin- CD271+ nuMyoD1- CD99- EpCAM+) Wilms tumors. In summary, here we designed and validated a new standardized antibody combination and MFC assay for diagnostic screening of pediatric solid tumors that might contribute to fast and accurate diagnostic orientation and classification of pediatric cancer in routine clinical practice.

Risk factors for the development of hospital-acquired pediatric venous thromboembolism-Dealing with potentially causal and confounding risk factors using a directed acyclic graph (DAG) analysis.

INTRODUCTION: Hospital-acquired venous thromboembolism (HA-VTE) in children comprises multiple risk factors that should not be evaluated separately due to collinearity and multiple cause and effect relationships. This is one of the first case-control study of pediatric HA-VTE risk factors using a Directed Acyclic Graph (DAG) analysis. MATERIAL AND METHODS: Retrospective, case-control study with 22 cases of objectively confirmed HA-VTE and 76 controls matched by age, sex, unit of admission, and period of hospitalization. Descriptive statistics were used to define distributions of continuous variables, frequencies, and proportions of categorical variables, comparing cases and controls. Due to many potential risk factors of HA-VTE, a directed acyclic graph (DAG) model was created to identify confounding, reduce bias, and increase precision on the analysis. The final model consisted of a DAG-informed conditional logistic regression. RESULTS: In the initial conventional univariable model, the following variables were selected as potential risk factors for HA-VTE: length of stay (LOS, days), immobility, ICU admission in the last 30 days, LOS in ICU, infection, central venous catheter (CVC), number of CVCs placed, L-asparaginase, heart failure, liver failure, and nephrotic syndrome. The final model using the set of variables selected by DAG analysis revealed LOS (OR = 1.106, 95%CI = 1.021-1.198, p = 0.013), L-asparaginase (OR = 26.463, 95%CI = 1.609-435.342, p = 0.022), and nephrotic syndrome (OR = 29.127, 95%CI = 1.044-812.508, p = 0.004) as independent risk factors for HA-VTE. CONCLUSION: The DAG-based approach was useful to clarify the influence of confounders and multiple causalities of HA-VTE. Interestingly, CVC placement-a known thrombotic risk factor highlighted in several studies-was considered a confounder, while LOS, L-asparaginase use and nephrotic syndrome were confirmed as risk factors to HA-VTE. Large confidence intervals are related to the sample size; however, the results were significant.

The clinical and molecular diagnosis of childhood and adolescent pulmonary tuberculosis in referral centers.

INTRODUCTION: The diagnostic accuracy of Xpert MTB/RIF (Xpert) in pulmonary tuberculosis (PTB) in children is lower than in adults. In Brazil, the diagnosis of PTB is based on a diagnostic score system (DSS). This study aims to study the role of Xpert in children and adolescents with PTB symptoms. METHODS: cross-sectional study was conducted in 3 referral centers to TB. Children and adolescents (0-19 years old) whose respiratory samples were submitted to Xpert were included. Statistical analysis (bivariate and logistic regression) to assess the simultaneous influence of TB-related variables on the occurrence of Xpert detectable in TB cases was done. To evaluate the agreement or disagreement between Xpert results with acid-fast bacillus (AFB) and cultures, κ method was used (significancy level of 5%). RESULTS: Eighty-eight patients were included in the study and PTB occurred in 43 patients (49%) and Xpert was detectable in 21 patients (24%). Adolescents and positive culture results were independent predictive variables of Xpert positivity. DSS sensitivity compared with the final diagnosis of TB was 100% (95% CI, 88.1-100%), specificity was 97.2% (95% CI, 85.5-99.9%). The accuracy of the method was 98.5% (95% CI, 91.7-99.9%). CONCLUSIONS: Xpert contributed to diagnosis in 9% of patients with AFB and in culture negative cases. DSS indicated relevance for this diagnostic approach of intrathoracic TB (ITB) in reference centers for presenting data both with high sensitivity and specificity.

The Utility of the Liverpool Adverse Drug Reaction Assessment Tools in the Evaluation of Chemotherapy-Induced Nausea and Vomiting in Children / Utilidade das Ferramentas de Avaliação de Reações Adversas a Medicamentos de Liverpool na Análise de Náuseas e Vômitos Induzidos por Quimioterapia em Crianças / La Utilidad de las Herramientas de Evaluación de Reacciones Adversas a Medicamentos de Liverpool en la Evaluación de Náuseas y Vómitos Inducidos por Quimioterapia en Niños

Introduction: Chemotherapy-induced nausea and vomiting (CINV) are common adverse drug reactions (ADR) experienced by children undergoing treatment for cancer. New paediatric ADR Assessment Causality and Avoidability tools (LCAT and LAAT) of Liverpool are suitable for categorizing factors related to ADR prevention and improving patient care. Still, no studies to date have compared the utility and results of its application for CINV in countries with different levels of development. Objective: To investigate the utility of the Liverpool Adverse Drug Reaction Causality and Avoidability Assessment Tools (LCAT and LAAT) in assessing CINV in children. Method: Prospective observational study of CINV assessment in children aged 4 to 16 years from Alder Hey Children's Hospital (Liverpool, UK) and "Instituto de Puericultura e Pediatria Martagão Gesteira" (Rio de Janeiro, Brazil). Children (helped by the parents) completed a symptom diary during chemotherapy and for 24 hours after treatment. Information regarding underlying diagnosis, past medical history, and medications administered was collected from the patient record. Case reports were prepared, and the temporal relationship between nausea and vomiting and exposure to chemotherapy, including any strategy to prevent CINV, was recorded. The causality and avoidability were assessed with LCAT and LAAT, respectively. Results: There were 26 reports of CINV in 36 chemotherapy cycles. The causality assessment was 'definite' for 24 cases. Twenty ADRs were deemed 'definitely avoidable' and four 'not avoidable'. Selection of inappropriate therapeutic options and non-administration of antiemetic were the most common factors observed in the hospitals studied. Conclusion: The LCAT and LAAT were helpful for assessing CINV in children in two different hospitals.

Introdução: Náuseas e vômitos induzidos por quimioterapia (NVIQ) são reações adversas a medicamentos (RAM) comuns em crianças em tratamento oncológico. Novas ferramentas de Avaliação de Causalidade e Evitabilidade de RAM de Liverpool (LCAT e LAAT) foram validadas e auxiliam a categorização de fatores de risco. Contudo, até o momento, nenhum estudo comparou a utilidade e os resultados de sua aplicação para NVIQ em países com diferentes níveis de desenvolvimento. Objetivo: Investigar a utilidade da LCAT e LAAT na avaliação de NVIQ. Método: Estudo observacional prospectivo com crianças de 4 a 16 anos do Alder Hey Children's Hospital (Liverpool, Reino Unido) e do Instituto de Puericultura e Pediatria Martagão Gesteira (Rio de Janeiro, Brasil). As crianças (ajudadas pelos pais) preencheram um diário de sintomas durante e até 24 horas após administração da quimioterapia. Informações sobre diagnóstico subjacente, história médica pregressa e medicamentos administrados foram coletadas do prontuário do paciente. Relatos de casos foram preparados e a relação temporal entre náuseas e vômitos e exposição à quimioterapia, incluindo qualquer estratégia para prevenir NVIQ, foi registrada para análise da causalidade e evitabilidade com o auxílio de LCAT e LAAT, respectivamente. Resultados: Houve 26 notificações de NVIQ em 36 ciclos de quimioterapia. A causalidade foi 'definida' para 24 casos. Foram consideradas 'definitivamente evitáveis' 20 RAM e 'não evitáveis', quatro. A seleção de opções terapêuticas inadequadas e a omissão de antieméticos foram os principais problemas evitáveis. Conclusão: O LCAT e o LAAT foram úteis para avaliar NVIQ em crianças em dois hospitais diferentes

Introducción: Las náuseas y vómitos inducidos por quimioterapia (NVIQ) son reacciones adversas a medicamentos (RAM) comunes en niños en tratamiento oncológico. Nuevas herramientas de Evaluación de Causalidad y Evitabilidad de RAM de Liverpool (LCAT y LAAT) han sido validadas y ayudan en la categorización de factores de riesgo. Sin embargo, ningún estudio ha comparado su utilidad y resultados para evaluación de NVIQ en países con diferentes niveles de desarrollo. Objetivo: Investigar la utilidad de LCAT y LAAT en la evaluación de NVIQ. Método: Estudio observacional prospectivo con niños de 4 a 16 años del Alder Hey Children's Hospital (Liverpool, Reino Unido) y del Instituto de Pediatría Martagão Gesteira (Río de Janeiro, Brasil). Los niños (ayudados por los padres) completaron un diario de síntomas durante y hasta 24 horas después de la quimioterapia. La información sobre el diagnóstico subyacente, la historia médica previa y los medicamentos se recopiló de la historia clínica médico del paciente. Se prepararon informes de casos y se registró la relación temporal entre las RAM y la exposición a la quimioterapia, incluyendo cualquier estrategia para prevenir NVIQ, para análisis de causalidad y evitabilidad con LCAT y LAAT, respectivamente. Resultados: Hubo 26 notificaciones de NVIQ en 36 ciclos de quimioterapia. La causalidad fue "definida" para 24 casos. Fueron consideradas "definitivamente evitables" 20 RAM y "no evitables", cuatro. La selección de opciones terapéuticas inadecuadas y la omisión de antieméticos fueron los principales problemas evitables. Conclusión: LCAT y LAAT fueron útiles para evaluar NVIQ en niños en dos hospitales diferentes

CHILDREN WITH MULTIPLE CONGENITAL DEFECTS: WHAT ARE THE LIMITS BETWEEN THERAPEUTIC OBSTINACY AND THE TREATMENT OF UNCERTAIN BENEFIT? / CRIANÇAS COM MÚLTIPLAS MALFORMAÇÕES CONGÊNITAS: QUAIS SÃO OS LIMITES ENTRE OBSTINAÇÃO TERAPÊUTICA E TRATAMENTO DE BENEFÍCIO DUVIDOSO?

OBJECTIVE: Therapeutic approach of children with multiple malformations poses many dilemmas, making it difficult to build a line between the treatment of uncertain benefit and therapeutic obstinacy. The aim of this paper was to highlight possible sources of uncertainty in the decision-making process, for this group of children. CASE DESCRIPTION: An 11-month-old boy, born with multiple birth defects and abandoned by his parents, has never been discharged home. He has complex congenital heart disease, main left bronchus stenosis and imperforate anus. He is under technological support and has gone through many surgical procedures. The complete correction of the cardiac defect seems unlikely, and every attempt to wean the ventilator has failed. COMMENTS: The first two main sources of uncertainty in the management of children with multiple birth defects are related to an uncertain prognosis. There is a lack of empirical data, due to the multiple possibilities of anatomic or functional organ involvement, with few similar cases described. Prognosis is also unpredictable for neuro-developmental evolution, as well as the capacity for the development and regeneration of other organs. Another source of uncertainty is how to qualify the present and future life as worth living, by weighing the costs and benefits. The fourth source of uncertainty is who has the decision: physicians or parents? Finally, if a treatment is defined futile then, how to limit support? No single framework exists to help these delicate decision-making processes. We propose, then, that physicians should be committed to develop their own perception skills in order to understand patient's manifestations of needs and family values.

OBJETIVO: A abordagem terapêutica de crianças com múltiplas malformações inclui muitos dilemas, tornando difícil diferenciar um tratamento de benefício duvidoso da obstinação terapêutica. O objetivo deste artigo foi destacar as possíveis fontes de incerteza no processo de tomada de decisão para esse grupo de crianças. DESCRIÇÃO DO CASO: Lactente de 11 meses de idade, que nasceu com múltiplas malformações congênitas e foi abandonado por seus pais, nunca recebeu alta hospitalar. Ele tem cardiopatia congênita cianótica, estenose do brônquio fonte esquerdo e imperfuração anal. Passou por muitos procedimentos cirúrgicos e permanece sob suporte tecnológico. A correção total do defeito cardíaco parece improvável, e todas as tentativas de desmame do ventilador falharam. COMENTÁRIOS: As duas principais fontes de incerteza no processo de tomada de decisão para crianças com múltiplos defeitos congênitos estão relacionadas ao prognóstico incerto. Dados empíricos escassos são por conta das múltiplas possibilidades de envolvimento (anatômico ou funcional) de órgãos, com poucos casos semelhantes descritos na literatura. O prognóstico é também imprevisível para a evolução da capacidade cognitiva e para o desenvolvimento de outros órgãos. Outra fonte de incertezas é como qualificar uma vida como valendo a pena ser vivida, ponderando custos e benefícios. A quarta fonte de incerteza é quem tem a decisão: os médicos ou os pais? Finalmente, se um tratamento é definido como fútil, então, como limitar o suporte? Na ausência de um método universal para essa tomada de decisão, ficamos com a responsabilidade dos médicos em desenvolver suas habilidades de percepção das necessidades dos pacientes e dos valores familiares.

Analysis of the Economic Impact of Cardiovascular Diseases in the Last Five Years in Brazil.

Background: There is growing concern about the economic impact of cardiovascular diseases (CVD) in Brazil and worldwide. Objective: To estimate the economic impact of CVD in Brazil in the last five years. Methods: The information to estimate CVD costs was taken from national databases, adding the direct costs with hospitalizations, outpatient visits and benefits granted by social security. Indirect costs were added to the calculation, such as loss of income caused by CVD morbidity or mortality. Results: CVD mortality accounts for 28% of all deaths in Brazil in the last five years and for 38% of deaths in the productive age range (18 to 65 years). The estimated costs of CVD were R$ 37.1 billion in 2015, a 17% increase in the period from 2010 to 2015. The estimated costs of premature death due to CVD represent 61% of the total cost of CVD, Direct costs with hospitalizations and consultations were 22%, and costs related to the loss of productivity related to the disease were 15% of the total. Health expenditures in Brazil are estimated at 9.5% of GDP and the average cost of CVD was estimated at 0.7% of GDP. Conclusion: CVD costs have increased significantly in the last five years. It is estimated that CVD costs increase as the Brazilian population ages and the prevalence of CVD increases.

Fundamento: Existe uma preocupação crescente com o impacto econômico das doenças cardiovasculares (DCV) no Brasil e no mundo. Objetivo: Estimar o impacto econômico das DCV no Brasil nos últimos cinco anos. Métodos: As informações para estimar os custos em DCV foram retiradas de bancos de dados nacionais, somando os custos diretos com hospitalizações, atendimentos ambulatoriais e benefícios concedidos pela previdência. Custos indiretos foram acrescidos ao cálculo, como a perda de renda causada pela morbidade ou pela mortalidade da DCV. Resultados: A mortalidade por DCV representa 28% do total de óbitos ocorridos no Brasil nos últimos cinco anos e atinge 38% dos óbitos na faixa etária produtiva (18 a 65 anos). Os custos estimados por DCV foram de R$ 37,1 bilhões de reais no ano de 2015, um aumento percentual de 17% no período de 2010 a 2015. Os custos estimados pela morte prematura por DCV representam 61% do total de custo por DCV, os custos diretos com internações e consultas foram de 22% e os custos pela perda da produtividade relacionados à doença foram de 15% do total. Os gastos com saúde no Brasil são estimados em 9,5% do PIB e o custo médio das DCV foi estimado em 0,7% do PIB. Conclusão: Os custos com DCV vêm aumentando significativamente nos últimos cinco anos. Estima-se que os custos por DCV aumentem à medida que a população brasileira envelhece e que a prevalência de DCV aumenta.

Reactions related to asparaginase infusion in a 10-year retrospective cohort.

INTRODUCTION: Although it is an essential component of the treatment of acute lymphoid leukemia in children, asparaginase causes adverse reactions that sometimes make it impossible to use it fully. Hypersensitivity reactions are the most frequent and may lead to early discontinuation of treatment. The present study aimed to investigate suspicions of adverse reactions during the infusion of asparaginase in a pediatric cohort. METHODS: A retrospective observational study was carried out at a university pediatric institute in the state of Rio de Janeiro. Information regarding clinical features and characteristics of adverse reactions was collected from hospital medical records. Suspicions of adverse reactions were classified regarding causality and severity. RESULTS: Seventy-three suspicions of adverse reactions were recorded during asparaginase infusion in 72 children in the study period. Allergic hypersensitivity reactions were suspected in 60.5% of the cases. Of these, 25% of the reactions occurred during induction and 61.1% in concomitant use with vincristine, findings that diverge from other studies. High-risk classification and younger age were considered risk factors for these reactions. A total of 72.4% of the reactions were classified as grade 1 or 2, which suggest that not all are related to antibody formation; this highlights the importance of differential diagnosis with other reactions, such as non-allergic hypersensitivity and hyperammonemia. CONCLUSION: The implementation of the differential diagnosis of reactions related to infusion of asparaginase with ammonia dosage and classification of the grade of reactions is crucial to facilitate the identification and proper management of each type of reaction.

[Profile of clinical trials enrolling Brazilian children]. / Perfil dos ensaios clínicos envolvendo crianças brasileiras.

This study aimed to characterize the clinical trials with medicines enrolling Brazilian children and adolescents, registered in the databases of Clinical Trials and the Brazilian Clinical Trials Network (ReBEC) from 1994 to 2014. Only 462 clinical trials enrolled Brazilian children and adolescents. There was an increase in registrations beginning in 2003, with an important drop in 2011. Among these trials, 35.5% were hosted in Brazil. The international clinical trials were mostly conducted by North American companies. In both cases, multinational industry was the principal source of funding. The clinical trials were predominantly phase III with injectable and solid oral pharmaceutical forms of antiviral drugs. Domestic clinical trials showed wider variation in the pharmaceutical forms and higher percentage of liquid formulations, when compared to the international trials. In addition to heavy external dependence for conducting clinical trials, the study emphasized the challenge for pediatric care in Brazil, which presents epidemiological peculiarities in an environment prone to the use of unlicensed medicines for children.

Abandonment of Treatment for Latent Tuberculosis Infection and Socioeconomic Factors in Children and Adolescents: Rio De Janeiro, Brazil.

BACKGROUND: Routine data on the use of isoniazid preventive therapy (IPT) in children and adolescents are scarce in high tuberculosis (TB) burden countries. OBJECTIVE: To describe the factors related to abandonment of IPT in children and adolescents with latent tuberculosis infection (LTBI) receiving routine care. METHODS: Retrospective (2005-2009) descriptive study of 286 LTBI cases with indication of IPT and serviced at a pediatric hospital in the State of Rio de Janeiro, Brazil. Survival analysis of the risk of abandonment of IPT over six months was performed, including multivariate analysis using the Cox proportional hazards model. RESULTS: Out of the 245 cases of LTBI included, 62 abandoned IPT (25.3%; 95% CI: 20%-31%). On multivariate analysis, the variables related to the IPT abandonment hazard ratio were the Human Development Index (HDI) (hazard ratio-HR: 0.004; 0.000-0.569) of the place of residence and the contact with adults that were not undergoing anti-TB treatment (HR: 7.30; 1.00-53.3). CONCLUSION: This study reveals the relevance of the relation of abandonment of IPT to the socioeconomic conditions at the place of residence and poor adherence to the active TB treatment. Educational measures to stimulate preventive treatment of child contacts and curative treatment of index cases should target the full familial setting.

Recombinant L-Asparaginase from Zymomonas mobilis: A Potential New Antileukemic Agent Produced in Escherichia coli.

L-asparaginase is an enzyme used as a chemotherapeutic agent, mainly for treating acute lymphoblastic leukemia. In this study, the gene of L-asparaginase from Zymomonas mobilis was cloned in pET vectors, fused to a histidine tag, and had its codons optimized. The L-asparaginase was expressed extracellularly and intracellularly (cytoplasmically) in Escherichia coli in far larger quantities than obtained from the microorganism of origin, and sufficient for initial cytotoxicity tests on leukemic cells. The in silico analysis of the protein from Z. mobilis indicated the presence of a signal peptide in the sequence, as well as high identity to other sequences of L-asparaginases with antileukemic activity. The protein was expressed in a bioreactor with a complex culture medium, yielding 0.13 IU/mL extracellular L-asparaginase and 3.6 IU/mL intracellular L-asparaginase after 4 h of induction with IPTG. The cytotoxicity results suggest that recombinant L-asparaginase from Z. mobilis expressed extracellularly in E.coli has a cytotoxic and cytostatic effect on leukemic cells.

Correction: Recombinant L-Asparaginase from Zymomonas mobilis: A Potential New Antileukemic Agent Produced in Escherichia coli.

[This corrects the article DOI: 10.1371/journal.pone.0156692.].