AVASUS’ Contributions to Promoting Lifelong Learning in Health: Toward Achieving the SDGs and Strengthening Global Health Security

The Virtual Learning Environment of the Brazilian Health System (AVASUS) was developed by the Laboratory for Technological Innovation in Health (LAIS) and the Secretariat of Distance Education (SEDIS) at the Federal University of Rio Grande do Norte (UFRN) in partnership with Brazil’s Ministry of Health (MoH). AVASUS provides open educational resources in the health field and has emerged as the third largest platform for massive health education globally, with more than one million students. Among the various learning pathways AVASUS offers, some specifically focus on meeting the educational needs to address public health emergencies and overlooked health contexts. The main argument in this study is that technology-mediated lifelong learning in health is an effective strategy for achieving the Sustainable Development Goals (SDGs) of the 2030 Agenda. This chapter analyzes the pathways related to COVID-19, syphilis, and prison health, focusing on the contributions towards achieving SDGs 3, 4, 5, 10, 11, 16, and 17 and fulfilling the Global Health Security Agenda. Our analysis revealed two key findings. Lifelong learning in health (i) prompts decision-making on public health policies and (ii) contributes towards implementing the SDGs. Ultimately, AVASUS should be recognized as a tool to improve health services and support policy-making

Análise retrospectiva dos pacientes infectados por RSV na unidade de transplante de medula óssea RSV infection after allogeneic hematopoietic stem cell transplantation (HSCT): analysis of 59 patients transplanted in a single institution

O vírus sincicial respiratório (RSV) é considerado uma causa importante de morbi-mortalidade em pacientes submetidos ao transplante de células-tronco hematopoéticas (TCTH). Mesmo com o uso da ribavirina inalatória (RI), as taxas de mortalidade são de 30% a 40% . O objetivo deste trabalho foi analisar o perfil dos pacientes infectados pelo RSV e a eficácia do tratamento com RI. Realizou-se uma análise retrospectiva de 59 pacientes submetidos ao TCTH com infecção confirmada pelo RSV (métodos de IFI ou PCR) entre 02/1991 e 02/2008. A RI foi administrada por 12 horas, na dose de 5 g diluída 200 ml de água destilada, por cinco dias. Quinze pacientes apresentaram infecções (TRI) do trato respiratório inferior e 44 pacientes apresentaram infecções (TRS) de vias aéreas superiores. No grupo tratado (n=50), quarenta apresentaram infecções no TRS versus dez TRI; no grupo não tratado, quatro TRS versus cinco TRI. Foram constatados vinte óbitos (33,8%), sendo que 13 desses pacientes (65% dos óbitos) tiveram suas mortes relacionadas ao RSV. Dentre estes, nove pacientes foram a óbito antes da instituição da RI como terapia padrão. A sobrevida global (SG) de todos os pacientes foi de 8,3 meses, sendo 66% para o grupo que utilizou RI versus 11,1% no grupo não tratado(p=0,001). No entanto, a SG foi inferior nos pacientes que apresentaram infecções no TRI (37,5%) quando comparadas às infecções do TRS (65,1%), p=0,007. No modelo de regressão de Cox, a única variável independente encontrada foi o tratamento com RI (p=0,001).<br>Respiratory syncytial virus (RSV) causes significant mortality in patients submitted to SCT. Despite the use of ribavirin aerosols (RA), mortality rates are still between 30 and 40% in many centers. The objective of this study was to analyze the clinical course and outcome of 59 patients who developed RSV infections after SCT in a single institution. In this retrospective analysis, the diagnosis of RSV infection was confirmed in 59 patients submitted to HSCT. RA was administrated during 12 hours at a dose of 5g diluted in 200 mL of distillated water, for 5 days. Fifteen patients presented with upper respiratory tract (URT) infection and 44 patients presented with lower respiratory tract (LRT) infection. In the group of patients who received RA (n=50), 40 had URT infections and 10 had LRT infections. In patients who did not receive RA, 3 had URT infections and 6 had LRT infections. Twenty patients died (33.8%) with the main cause of death of 13 patients being RSV infection (all these patients required mechanical ventilation). Nine patients died before RA therapy became standard treatment for RSV (before 1992). The overall survival of patients treated with RA was 66%. However, the overall survival was lower in patients who had LRT infections (37.5%) compared with those who had URT infections (67.5% - p=0.007). In the multivariate analysis, only the use of RA affected overall survival (p=0.001)

A strategy for molecular diagnostics of Fanconi anemia in Brazilian patients

BACKGROUND: Fanconi anemia (FA) is a predominantly autosomal recessive disease with wide genetic heterogeneity resulting from mutations in several DNA repair pathway genes. To date, 21 genetic subtypes have been identified. We aimed to identify the FA genetic subtypes in the Brazilian population and to develop a strategy for molecular diagnosis applicable to routine clinical use. METHODS: We screened 255 patients from Hospital de Clínicas, Universidade Federal do Paraná for 11 common FA gene mutations. Further analysis by multiplex ligation-dependent probe amplification (MLPA) for FANCA and Sanger sequencing of all coding exons of FANCA, -C, and -G was performed in cases who harbored a single gene mutation. RESULTS: We identified biallelic mutations in 128/255 patients (50.2%): 89, 11, and 28 carried FANCA,FANCC, and FANCG mutations, respectively. Of these, 71 harbored homozygous mutations, whereas 57 had compound heterozygous mutations. In 4/57 heterozygous patients, both mutations were identified by the initial screening, in 51/57 additional analyses was required for classification, and in 2/57 the second mutation remained unidentified. We found 52 different mutations of which 22 were novel. CONCLUSION: The proposed method allowed genetic subtyping of 126/255 (49.4%) patients at a significantly reduced time and cost, which makes molecular diagnosis of FA Brazilian patients feasible

Carcinoma de células escamosas em língua pós-transplante de medula óssea por Anemia de Fanconi

Anemia Fanconi (AF) é uma síndrome autossômica recessiva, caracterizada por pancitopenia progressiva com hipoplasia de MO, em associação com várias anormalidades constitucionais, tendo como único recurso terapêutico com possibilidade potencial de cura o transplante de medula óssea, e sendo tais pacientes propensos ao desenvolvimento de malignidades hematológicas e carcinoma de células escamosas (CEC) em diversos locais: reto, vagina, cérvice, esôfago, cavidade bucal, faringe ou pele, mas especialmente em cabeça e pescoço. Relatamos aqui três casos de pacientes portadores de AF, que após TMO desenvolveram CEC em língua. Além disso, mencionamos fatores de risco relatados para tal evento, como diagnóstico de AF, condicionamento pré-transplante (quimioterápicos e irradiação), terapia com drogas imunossupressoras para tratamento de doença enxerto contra hospedeiro (DECH) aguda ou crônica, sexo e idade avançada. Além do que, discorremos sobre a existência de três mecanismos postulados que predispõem indivíduos com AF ao desenvolvimento de neoplasia: (1) defeito na reparação do DNA; (2) defeito na detoxificação de radicais de oxigênio; e (3) imunodeficiência.<br>Fanconi's Anemia, first described in 1927, is a rare autonomic recessive disease characterized by progressive pancytopenia, congenital malformations, spontaneous or chemically induced chromosome breakage and increased incidence of leukemia and other cancers. The onset of bone marrow hypoplasia and its hematological manifestations is usually in the 3 - 7 year age range. The disease has traditionally been managed clinically through administration of blood products, treatment of infections and prolonged administration of androgens, growth factors and more recently with gene therapy. The value of bone marrow transplantation in correcting the hematological manifestations of Fanconi's anemia has been established. Alkilanting agents and radiation have been utilized as a conditioning regimen in bone marrow transplantation for Fanconi's anemia, but these patients are particularly hypersensitive to these agents and its toxicity is the main cause of mortality and morbidity. Bone marrow transplantation is at the moment the only therapeutic modality able to bring hematological cure. Fanconi's anemia patients are particularly susceptible to the development of hematological malignancies and squamous cell carcinoma in the epithelium of the rectum, vagina, cervix, esophagus, oral cavity, pharynx or skin in general but more frequently on the head and neck; probably not only because the basic cellular defect but also because of the conditioning regimen. We report on three cases of Fanconi's anemia patients developing squamous cell carcinoma of the tongue after bone marrow transplantation. Furthermore, there is mention of the risk factors linked in an event, such as the diagnosis of Fanconi's anemia, pre-transplant conditioning regimen that usually includes alkylating agents and irradiation; immunosuppressive prophylactic therapy for acute and chronic graft-versus-host-disease, gender and age. Additionally, we discussed the existence of three postulated mechanisms that make individuals with Fanconi's anemia susceptible to the development of neoplasias: (1) deficiency in the DNA repair system, (2) deficiency in oxygen radical detoxification; and (3) immunodeficiency

Reversible posterior leucoencephalopathy syndrome associated with bone marrow transplantation Leucoencefalopatia posterior reversível associada a transplante de medula óssea

Reversible posterior leucoencephalopathy syndrome (RPLS) has previously been described in patients who have renal insufficiency, eclampsia, hypertensive encephalopathy and patients receiving immunosuppressive therapy. The mechanism by which immunosuppressive agents can cause this syndrome is not clear, but it is probably related with cytotoxic effects of these agents on the vascular endothelium. We report eight patients who received cyclosporine A (CSA) after allogeneic bone marrow transplantation or as treatment for severe aplastic anemia (SSA) who developed posterior leucoencephalopathy. The most common signs and symptoms were seizures and headache. Neurological dysfunction occurred preceded by or concomitant with high blood pressure and some degree of acute renal failure in six patients. Computerized tomography studies showed low-density white matter lesions involving the posterior areas of cerebral hemispheres. Symptoms and neuroimaging abnormalities were reversible and improvement occurred in all patients when given lower doses of CSA or when the drug was withdrawn. RPLS may be considered an expression of CSA neurotoxicity.<br>A síndrome de leucoencefalopatia posterior reversível (SLPR) tem sido descrita em pacientes com insuficiência renal, eclâmpsia, encefalopatia hipertensiva e em pacientes que recebem terapia imunossupressora. O mecanismo pelo qual os agentes imunossupressores podem causar a síndrome ainda não são conhecidos, porém estão provavelmente relacionados aos efeitos citotóxicos destes agentes no endotélio vascular. Relatamos oito pacientes que receberam ciclosporina A (CSA) após transplante de medula óssea alogênico ou para tratamento de anemia aplástica severa e que desenvolveram a SLPR. Os sinais e sintomas mais comuns foram convulsões e cefaléia. A disfunção neurológica ocorreu simultaneamente ou precedida por elevação da pressão arterial sistêmica e disfunção renal aguda em seis pacientes. O exame de tomografia computadorizada do crânio demonstrou a presença de áreas de baixos valores de atenuação na distribuição da substância branca, envolvendo áreas posteriores de ambos os hemisférios cerebrais. O quadro clínico e as anormalidades tomográficas foram reversíveis; a melhora ocorreu em todos os pacientes em que as doses de CSA foram reduzidas ou quando a droga foi retirada. A SLPR pode ser considerada uma expressão de neurotoxicidade da CSA

Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency

BACKGROUND:Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE:Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS:In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS:Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS:Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management