Training of community health agents - a strategy for earlier recognition of mucopolysaccharidoses.

Primary Health Care (PHC) is the gateway for patients in the Brazilian unified health system (Sistema Único de Saúde-SUS), playing an extremely important role in the identification of potential patients with genetic diseases, and referral to specialized and tertiary health services. The PHC is composed of a multidisciplinary team, including the Community Health Agent, who is in direct contact with the community. To implement an educational program aimed at community health agents working in several municipalities in the state of Rio Grande do Sul (RS), Brazil. The training was focused on genetic diseases in general, with a special focus on identifying patients with Mucopolysaccharidosis (MPS). Tests were applied before and after the educational intervention, in order to assess the participants' knowledge on the topic at these two moments. The study covered a total of ten training sessions carried out in eight municipalities in the RS state, training 374 community health agents. The number of correct answers in the pre-test (n = 339) was 8,4 (SD 1.2), while in the post-test (n = 361) it was 9,2 (SD 0.8). Statistical analysis showed that the educational intervention effectively provided information about genetic diseases to the participants. Considering that community health agents are of fundamental importance in the identification and prevention of diseases and in the better navigation of the patients on the SUS, these professionals play a key role in the field of rare genetic diseases, and continuous training strategies should be taken.

Avaliação transversal dos indicadores de saúde do programa nacional de triagem neonatal de um município do Vale do Paranhana / Cross-sectional evaluation of health indicators of the national neonatal screening program in a city of Vale do Paranhana

Objetivo: avaliar indicadores do programa nacional de triagem neonatal (PNTN) e de saúde no município de Rolante, RS, Brasil. Método: estudo transversal, por meio dos prontuários eletrônicos cadastrados entre janeiro de 2017 e julho de 2020. Foi realizado o cálculo dos indicadores do PNTN dos anos de 2017 a 2019, e análise de outras variáveis de saúde como: período e local da coleta, peso e idade de nascimento, idade materna, realização de pré-natal, realização da consulta, resultado do exame e recoleta. Resultado: a cobertura variou entre 201 de 256 (78,5%) e 229 de 272 (84,2%). Das 734 coletas 544 (74,1%) foram realizadas no período de três a cinco dias de vida, preconizado pelo Ministério da Saúde. A mediana da idade do RN na primeira consulta foi superior a 15 dias em todas as doenças triadas, exceto fenilcetonúria e deficiência de biotinidase, no período avaliado. Conclusão: a partir dos resultados foi possível observar que a cobertura do município correspondeu aos dados nacionais e estaduais no período. E, ainda que o percentual de coletas realizadas na data ideal tenha sido alto, a idade preconizada na primeira consulta não foi cumprida na maior parte das patologias

Objective: to evaluate neonatal screening national program (PNTN) and health indicators in the Rolante city, RS, Brazil.Method: cross-sectional study, using electronic medical records registered between January 2017 and July 2020. The calculation of the PNTN indicators from 2017 to 2019 was carried out. And analysis of other health variables such as: period and place of collection, weight and age at birth, maternal age, prenatal care, consultation, test results and collection. Result: coverage ranged from 201 out of 256 (78.5%) to 229 out of 272 (84.2%). Of the 734 collections, 544 (74.1%) were performed within the period of 3 to 5 days of life, recommended by the Ministry of Health. The median age of the NB at the first consultation was greater than 15 days in all screened diseases, except for phenylketonuria and biotinidase deficiency, in the period evaluated.Conclusion: from the results it was possible to observe that the coverage of the municipality corresponded to the national and state data in the period. And even though the percentage of collections carried out on the ideal date was high, the recommended age at the first consultation was not met in most pathologies

Information and Diagnosis Networks - tools to improve diagnosis and treatment for patients with rare genetic diseases.

Brazil is a country of continental dimensions and most genetic services are concentrated in the Southeast and South, including the Medical Genetics Service of the Hospital de Clínicas de Porto Alegre (MGS/HCPA). As many areas on the country do not have adequate medical genetics support, networks were designed to extend the service of the MGS/HCPA reference center. This paper presents the information and diagnosis networks that have their headquarters at MGS/HCPA: SIAT (National Information System on Teratogenic Agents), SIEM (Information Service on Inborn Errors of Metabolism), Alô Genética (Hello Genetics - Medical Genetics Information Service for Primary Health Care Professionals); Rede MPS Brasil (MPS-Mucopolysaccharidosis Brazil Network); Rede EIM Brasil (IEM-Inborn Errors of Metabolism Brazil Network), Rede NPC Brasil (Niemann-Pick C - NPC Brazil Network), Rede DLD Brasil (LSD-Lysosomal Storage Disorders Brazil Network), Rede DXB (MSUD-Maple Syrup Urine Disease Network), RedeBRIM (Brazilian Network of Reference and Information in Microdeletion Syndromes Project), Rede Neurogenética (Neurogenetics Network), and Rede Brasileira de Câncer Hereditário (Brazilian Hereditary Cancer Network). These tools are very useful to provide access to a qualified information and/or diagnostic service for specialized and non-specialized health services, bypassing difficulties that preclude patients to access reference centers.

Indicadores de Qualidade na condução de estudos clínicos / Quality indicators in the conduct of clinical studies

Introdução: A geração, análise e difusão de indicadores pertinentes é uma das estratégias fundamentais do processo de gestão de qualidade. Indicadores são mensurações que avaliam direta ou indiretamente os processos e desfechos da assistência ao participante de pesquisa. Padrões rigorosos de qualidade garantirão a validade dos dados obtidos nos estudos clínicos. Métodos: Estudo transversal descritivo e analítico, com dados coletados no Centro de Pesquisa Clínica de um Hospital Universitário, durante Novembro/2016 a Fevereiro/2019 quanto ao tempo de inclusão de dados no electronic case report form (IID), tempo de comunicação de desvios de protocolo ao Comitê de Ética em Pesquisa (ICD), tempo de resposta aos feasibilities recebidos (IRF) e tempo de resposta às pendências de monitoria (IRP). Resultados: Variações substanciais foram encontradas entre os escores de qualidade ao longo de 27 meses. O desempenho geral da equipe do Escritório de Projetos em Pesquisa alcançou a classificação excelente ou satisfatória em 61,40% das observações: 50,87% e 10,52% respectivamente. Entre 38,59% de observações críticas, 17,54% foram expressas pelo IRP, seguido de 12,28% por ICD e 7% atribuído ao IID que não atingiram a meta proposta. Conclusão: O Escritório de Projetos em Pesquisa elencou dois indicadores de qualidade, IID e IRP, que podem melhorar o tempo e a eficácia das entregas propostas da equipe. (AU)

Introduction: The generation, analysis and dissemination of relevant indicators is a fundamental strategy in the quality management process. Indicators are measurements that directly or indirectly evaluate the processes and outcomes of the care provided to research participants. Rigorous quality standards will guarantee the validity of the data obtained in clinical studies. Methods: This descriptive, analytical cross-sectional study collected data at the Clinical Research Center of a University Hospital, covering the period from November 2016 to February 2019, regarding the time of data inclusion in the electronic case report form (IID), communication of protocol deviations to the Research Ethics Committee (ICD), response time to received feasibilities (IRF) and response time to monitoring pending issues (IRP). Results: Substantial variations were found between quality scores in a period of 27 months. The overall performance of the Research Project Office team was excellent or satisfactory in 61.40% of the observations (50.87% and 10.52% respectively). Among critical observations (38.59%), 17.54% were expressed by IRP, 12.28% by ICD and 7% by IID, indicating those that did not reach the proposed target. Conclusions: The Research Project Office has listed two quality indicators, IID and IRP, which can improve the time and effectiveness of team deliveries.(AU)

Immune tolerance induction for laronidase treatment in mucopolysaccharidosis I.

Enzyme replacement therapy (ERT) can produce anti-drug antibody (ADA) responses that reduce efficacy or lead to hypersensitivity reactions. Six patients with severe mucopolysaccharidosis type I (MPS I/Hurler syndrome) who did not receive hematopoietic stem cell transplantation underwent an immunosuppression regimen prior to initiating ERT with laronidase. The primary endpoint for immune tolerance induction was the number of patients with an ADA titer ≤ 3200 after 24 weeks of laronidase at the labeled dose. Cyclosporine levels were measured weekly and doses adjusted to maintain trough levels above 400 mg/mL. A 6-week (Cohort 1) or 12-week (Cohort 2) immune tolerance induction period with cyclosporine (initial dose: 15 or 20 mg/kg/day), azathioprine (initial dose: 2.5 or 5 mg/kg/day) and low-dose laronidase infusions (0.058-0.29 mg/kg/week) was followed by an immune-challenge period with laronidase infusions at the labeled dose (0.58 mg/kg/week) for 24 weeks. Anti-laronidase IgG titers were determined following treatment. There were 147 treatment-emergent adverse events reported, most of which were mild and not related to the study treatment. While there was no evidence of immune tolerance in 3 of 3 patients in Cohort 1, there were some indications of immune tolerance induction in 2 of 3 patients in Cohort 2. Patients with lower ADA titers showed greater reductions in urinary glycosaminoglycan excretion. Routine monitoring of plasma cyclosporine parent-compound levels by high pressure liquid chromatography proved difficult for clinical practice. The evolving clinical management of MPS I and a better understanding of the clinical impact of laronidase-related immunogenicity require reassessment of immune modulation strategies in patients with MPS I receiving laronidase treatment. CLINICAL TRIAL REGISTRATION: NCT00741338.

Medical Costs Related to Enzyme Replacement Therapy for Mucopolysaccharidosis Types I, II, and VI in Brazil: A Multicenter Study.

BACKGROUND: Mucopolysaccharidosis (MPS) type I (MPS I), MPS type II (MPS II), and MPS type VI (MPS VI) are lysosomal storage disorders for which enzyme replacement therapy (ERT) is available. OBJECTIVE: The objective of this study was to evaluate the frequency of medical interventions in a cohort of patients with MPS I, II, and VI on ERT to estimate the impact of direct medical costs associated with the treatment of MPS and compare its frequency with that observed among patients not on ERT. METHODS: This was a multicenter study using a retrospective design including a convenience sampling of Brazilian patients with MPS I, II, and VI. Data on the number and type of medical appointments, hospital admissions, medications used, and surgical procedures performed per patient were obtained through a review of medical records, as were data on ERT. These variables were then compared between patients undergoing ERT and those not on ERT. RESULTS: Thirty-four patients (27 on ERT) were included in the study. Overall, between-group differences were found in median absolute frequencies of hospital admissions and surgical procedures per year, both of which were higher in the non-ERT group. Furthermore, we observed a high rate of failure to record medication dosage regimens. CONCLUSIONS: Our findings suggest that Brazilian patients with MPS I, II, and VI who are on ERT undergo fewer medical interventions, which can lead to a reduction in direct medical costs to the publicly funded health care system. The cost of ERT, however, is extremely high and probably outweighs this reduction.

A terapia de reposição enzimática pode mudar a frequência de intervenções médicas na mucopolissacaridose tipo I? Um estudo retrospectivo e exploratório / Can enzyme replacement therapy change the frequency of medical interventions in mucopolysaccharidosis type I? An exploratory retrospective study

Introdução: A mucopolissacaridose tipo I (MPS I) é uma doença lisossômica (DL) para a qual está disponível a terapia de reposição enzimática (TRE) com laronidase. Objetivo: caracterizar o efeito da TRE em pacientes com MPS I avaliados por um único centro de referências para DL a partir da análise da frequência de intervenções médicas. Métodos: Estudo retrospectivo e exploratório com comparações pré e pós-intervenção. O número/ano/paciente de consultas, medicamentos usados, internações, cirurgias e exames realizados, foi obtido por meio de revisão de prontuário médico. Essas variáveis foram, então, comparadas entre dois períodos: pré-TRE e pós-TRE. Resultados: Nove pacientes (graves=3, atenuados=6) foram incluídos no estudo. A mediana de idade de início da TRE foi 9 anos e a mediana de duração da TRE foi 4 anos. Em média, os pacientes realizaram 90% das infusões previstas para o período. Somente o número de cirurgias/ano/paciente foi dependente do tempo de doença (p=0,0004) e da gravidade do fenótipo (p=0,014). Com relação às comparações pré e pós-TRE, as variáveis que apresentaram diferença significativa (média do número/ano/paciente) foram: exames (pré-TRE=10,2±2,7; pós-TRE=22,5±2,1; p=0,005) e internações (pré-TRE=0,05±0,04; pós-TRE=0,30±0,11; p=0,013). Conclusão: Nossos dados sugerem que a TRE não alterou a história natural da MPS I em relação aos desfechos analisados. Este achado pode ser devido à idade relativamente avançada de início do tratamento no nosso centro.

Background: Mucopolysaccharidosis type I (MPSI) is a lysosomal disorder (LSD) which can be treated with enzyme replacement therapy (ERT) with laronidase. Aim: To describe the effect of ERT on MPSI patients evaluated at a single referral center for LSD by assessing the frequency of medical interventions. Methods: An exploratory, retrospective study with pre- and post-intervention assessments. We reviewed medical records to collect data on the number of medical appointments/year/patient, medications used, hospital admissions, surgeries, and exams performed. These variables were then compared between the pre- and the post-ERT periods.Results: Nine patients (severe=3; attenuated=6) were included in the study.The median age for the start of ERT was 9 years, and the median time on ERT was 4 years. On average, patients received 90% of the infusions predicted for the study period. Only the number of surgeries/year/patient was found to be dependent on length of disease (p=0.0004) and on severity of phenotype (p=0.014). Regarding pre- and post-ERT comparisons, there was a significant difference (mean number/year/patient in exams (pre-ERT, 10.2±2.7; post-ERT, 22.5±2.1; p=0.005) and hospital admissions (pre-ERT, 0.05±0.04; post-ERT, 0.30±0.11; p=0.013). Conclusion: Our data suggest ERT didn’t alter the natural history of MPSI the outcomes assessed in this study. This may be due to the relatively advanced age of patients when they started treatment at our Center.

Recomendações para o processo de obtenção do consentimento na pesquisa com seres humanos realizada no Hospital de Clínicas de Porto Alegre: [revisão] / Hospital de Clínicas de Porto Alegre directives for the informed consent process in human experimentation: [review]

São apresentadas recomendações institucionais para o processo de consentimento em pesquisas envolvendo seres humanos, especialmente para a elaboração e aplicação do Termo de Consentimento Livre e Esclarecido. Estas recomendações visam esclarecer os pesquisadores, com ênfase nos critérios utilizados pelo Comitê de Ética em Pesquisa do Hospital de Clínicas de Porto Alegre na avaliação de projetos, sobre aspectos fundamentais que devem ser levados em consideração quando da elaboração e obtenção do consentimento de potenciais participantes de um projeto de pesquisa.

Institutionals directives are proposed for the informed consent process in research involving human beings, especially for the development and implementation of the Informed Consent Form. These recommendations aim to clarify the researchers, using the Research Ethics Committee of Hospital de Clinicas de Porto Alegre in project review, on key aspects that must be taken into account when preparing and obtaining the consent of the prospects participants in a research project.

[Enzyme replacement therapy for mucopolysaccharidoses I, II and VI: recommendations from a group of Brazilian F experts]. / Terapia de reposição enzimática para as mucopolissacaridoses I, II e VI: recomendações de um grupo de especialistas brasileiros.

Mucopolysaccharidoses (MPS) are rare genetic diseases caused by deficiency of specific lysosomal enzymes that affect catabolism of glycosaminoglycans (GAG). Accumulation of GAG in various organs and tissues in MPS patients results in a series of signs and symptoms, producing a multisystemic condition affecting bones and joints, the respiratory and cardiovascular systems and many other organs and tissues, including in some cases, cognitive performance. So far, eleven enzyme defects that cause seven different types of MPS have been identified. Before introduction of therapies to restore deficient enzyme activity, treatment of MPS focused primarily on prevention and care of complications, still a very important aspect in the management of these patients. In the 80's treatment of MPS with bone marrow transplantation/hematopoietic stem cells transplantation (BMT/HSCT) was proposed and in the 90's, enzyme replacement therapy (ERT),began to be developed and was approved for clinical use in MPS I, II and VI in the first decade of the 21st century. The authors of this paper are convinced that a better future for patients affected by mucopolysaccharidoses depends upon identifying, understanding and appropriately managing the multisystemic manifestations of these diseases. This includes the provision of support measures (which should be part of regular multidisciplinary care of these patients) and of specific therapies. Although inhibition of synthesis of GAG and the recovery of enzyme activity with small molecules also may play a role in the management of MPS, the breakthrough is the currently available intravenous ERT. ERT radically changed the setting for treatment of mucopolysaccharidosis I, II and VI in the last decade., Benefits can even be extended soon to MPS IV A (ERT for this condition is already in clinical development), with prediction for treatment of MPS III A and the cognitive deficit in MPS II by administration of the enzyme directly into the central nervous system (CNS). A large number of Brazilian services, from all regions of the country, already have experience with ERT for MPS I, II and VI. This experience was gained not only by treating patients but also with the participation of some groups in clinical trials involving ERT for these conditions. Summing up the three types of MPS, more than 250 patients have already been treated with ERT in Brazil. The experience of professionals coupled to the data available in international literature, allowed us to elaborate this document, produced with the goal of bringing together and harmonize the information available for the treatment of these severe and progressive diseases, which, fortunately, are now treatable, a situation which bring new perspectives for Brazilian patients, affected by these conditions.

Intrathecal administration of recombinant human N-acetylgalactosamine 4-sulfatase to a MPS VI patient with pachymeningitis cervicalis.

In mucopolysaccharidosis VI, or Maroteaux-Lamy syndrome, deficiency of N-acetylgalactosamine 4-sulfatase leads to storage of glycosaminoglycans (GAGs) and MPS VI patients often develop spinal cord compression during the course of the disease due to GAG storage within the cervical meninges, requiring neurosurgical intervention, as intravenous (IV) enzyme replacement therapy (ERT) is not expected to cross the blood-brain barrier. We report the use of intrathecal (IT) recombinant human N-acetylgalactosamine 4-sulfatase (arylsulfatase B, or ASB) in a MPS VI child with spinal cord compression whose parents initially refused the surgical treatment. Assessments were performed at baseline, with clinical, neurological and biochemical evaluations, urodynamic studies and MRI of the CNS. Changes on these parameters were evaluated after IT infusions of ASB administered monthly via lumbar puncture (LP) in a IV ERT naive patient. To our knowledge, this was the first MPS VI patient who received IT ERT. Despite significant urodynamic improvement and some neurological amelioration, the patient developed worsening of walking capacity. After IV ERT was started, the patient presented with a generalized hypotonia and a life-saving surgical fixation of the neck was then performed. The results observed on this MPS VI patient suggest that instability of the cervical vertebrae could be unmasked by IV ERT as joint storage is reduced, and the decrease in neck stiffness and stability could confound the expected improvement of SCC manifestations following IT ERT. The study of further patients, if possible in a clinical trial setting, is needed to evaluate the potential of a non-surgical IT ERT treatment of SCC for MPS VI.

Terapia de reposição enzimática para as mucopolissacaridoses I, II e VI: recomendações de um grupo de especialistas brasileiros / Enzyme replacement therapy for mucopolysaccharidoses I, II and VI: recommendations from a group of Brazilian F experts

As mucopolissacaridoses (MPS) são doenças genéticas raras causadas pela deficiência de enzimas lisossômicas específicas que afetam o catabolismo de glicosaminoglicanos (GAG). O acúmulo de GAG em vários órgãos e tecidos nos pacientes afetados pelas MPS resulta em uma série de sinais e sintomas, integrantes de um quadro clínico multissistêmico que compromete ossos e articulações, vias respiratórias, sistema cardiovascular e muitos outros órgãos e tecidos, incluindo, em alguns casos, as funções cognitivas. Já foram identificados 11 defeitos enzimáticos que causam sete tipos diferentes de MPS. Antes do advento de terapias dirigidas para a restauração da atividade da enzima deficiente, o tratamento das MPS tinha como principal foco a prevenção e o cuidado das complicações, aspecto ainda bastante importante no manejo desses pacientes. Na década de 80 foi proposto o tratamento das MPS com transplante de medula óssea/transplante de células tronco hematopoiéticas (TMO/TCTH) e na década de 90 começou o desenvolvimento da Terapia de Reposição Enzimática (TRE), que se tornou uma realidade aprovada para uso clínico nas MPS I, II e VI na primeira década do século 21. Os autores deste trabalho têm a convicção de que um melhor futuro para os pacientes afetados pelas MPS depende da identificação, compreensão e manejo adequado das manifestações multissistêmicas dessas doenças, incluindo medidas de suporte (que devem fazer parte da assistência multidisciplinar regular destes pacientes) e terapias específicas...

Mucopolysaccharidoses (MPS) are rare genetic diseases caused by deficiency of specific lysosomal enzymes that affect catabolism of glycosaminoglycans (GAG). Accumulation of GAG in various organs and tissues in MPS patients results in a series of signs and symptoms, producing a multisystemic condition affecting bones and joints, the respiratory and cardiovascular systems and many other organs and tissues, including in some cases, cognitive performance. So far, eleven enzyme defects that cause seven different types of MPS have been identified. Before introduction of therapies to restore deficient enzyme activity, treatment of MPS focused primnarily on prevention and care of complications, still a very important aspect in the management of these patients. In the 80's treatment of MPS with bone marrow transplantation/hematopoietic stem cells transplantation (BMT/HSCT) was proposed and in the 90's, enzyme replacement therapy (ERT),began to be developed and was approved for clinical use in MPS I, II and VI in the first decade of the 21st century. The authors of this paper are convinced that a better future for patients affected by mucopolysaccharidoses depends upon identifying, understanding and appropriately managing the multisystemic manifestations of these diseases. This includes the provision of support measures (which should be part of regular multidisciplinary care of these patients) and of specific therapies...