Beckwith-Wiedemann syndrome mimicking the classical form of congenital adrenal hyperplasia in newborn screening.

Beckwith-Wiedemann syndrome (BWS) is a common genetic congenital disease characterized by somatic overgrowth and its broad clinical spectrum includes pre- and post-natal macrosomia, macroglossia, visceromegaly, increased risk of neonatal hypoglycemia, and development of embryonic tumors. BWS occurs due to genetic/epigenetic changes involving growth-regulating genes, located on region 11p15, with an important genotype-phenotype correlation. Congenital adrenal hyperplasia (CAH) comprises a spectrum of autosomal recessive diseases presenting a variety of clinical manifestations due to a deficiency in one of the enzymes involved in cortisol secretion. Early diagnosis based on newborn screening prevents the adrenal crisis and early infant death. However, high 17-hydroxyprogesterone (17-OHP) levels can occur in newborns or premature infants without CAH, in situations of stress due to maternal or neonatal factors. Here, we report new cases of false-positive diagnosis of 21-hydroxylase deficiency during newborn screening - two girls and one boy with BWS. Methylation-specific multiplex ligation-dependent probe amplification revealed a gain of methylation in the H19 differentially methylated region. Notably, all three cases showed a complete normalization of biochemical changes, highlighting the transient nature of these hormonal findings that imitate the classical form of CAH. This report sheds light on a new cause of false-positive 21-hydroxylase deficiency diagnosis during newborn screening: Beckwith-Wiedemann syndrome.

Targeted massively parallel sequencing panel to diagnose genetic endocrine disorders in a tertiary hospital.

OBJECTIVES: To analyze the efficiency of a multigenic targeted massively parallel sequencing panel related to endocrine disorders for molecular diagnosis of patients assisted in a tertiary hospital involved in the training of medical faculty. MATERIAL AND METHODS: Retrospective analysis of the clinical diagnosis and genotype obtained from 272 patients in the Endocrine unit of a tertiary hospital was performed using a custom panel designed with 653 genes, most of them already associated with the phenotype (OMIM) and some candidate genes that englobes developmental, metabolic and adrenal diseases. The enriched DNA libraries were sequenced in NextSeq 500. Variants found were then classified according to ACMG/AMP criteria, with Varsome and InterVar. RESULTS: Three runs were performed; the mean coverage depth of the targeted regions in panel sequencing data was 249×, with at least 96.3% of the sequenced bases being covered more than 20-fold. The authors identified 66 LP/P variants (24%) and 27 VUS (10%). Considering the solved cases, 49 have developmental diseases, 12 have metabolic and 5 have adrenal diseases. CONCLUSION: The application of a multigenic panel aids the training of medical faculty in an academic hospital by showing the picture of the molecular pathways behind each disorder. This may be particularly helpful in developmental disease cases. A precise genetic etiology provides an improvement in understanding the disease, guides decisions about prevention or treatment, and allows genetic counseling.

Minimal intervention procedures: evaluating how much pediatric dentists really know about this field.

The aim of this cross-sectional study was to evaluate how much pediatric dentists know about the noninvasive, micro, and minimally invasive strategies for managing caries lesions in deciduous teeth. An electronic questionnaire was sent to pediatric dentists enrolled in the Regional Board of Dentistry. Information was collected concerning: 1) characteristics of the participants; 2) level of updated knowledge of noninvasive, micro and minimally invasive procedures for caries management in children; 3) agreement to sentences on the indicated procedures. The data were analyzed descriptively and with bivariate tests. Seventy pediatric dentists participated. Results showed high frequency of agreement with sentences on strategies for lesion caries management: 92.8% with the sentence on selective removal of decayed tissue; 90.0% on fluoridated toothpaste (≥1,000 ppm); 84.3% on silver diamine fluoride (SDF); 80.0% on the Hall technique; and 76.9% on the sealing of small dentine lesions. Level of agreement with sentences was not significantly related to variables of time since graduation, degree of updatedness, area of employment, or higher education degree (p > 0.05). A higher score on agreement toward SDF use was accompanied by a greater degree of self-declared updatedness on noninvasive, micro and minimally invasive procedures for caries management in children (rho 0.259; p = 0.031). Pediatric dentists consider themselves updated and agree with the sentences on recommended use of fluoridated toothpaste as of eruption of the first tooth, and on the selective removal of decayed tissue. Disagreement still continues regarding application of SDF to arrest lesion progression, sealing of small dentin lesions, and the Hall technique.

Variants in 46,XY DSD-Related Genes in Syndromic and Non-Syndromic Small for Gestational Age Children with Hypospadias.

Hypospadias is a common congenital disorder of male genital formation. Children born small for gestational age (SGA) present a high frequency of hypospadias of undetermined etiology. No previous study investigated the molecular etiology of hypospadias in boys born SGA using massively parallel sequencing. Our objective is to report the genetic findings of a cohort of patients born SGA with medium or proximal hypospadias. We identified 46 individuals with this phenotype from a large cohort of 46,XY DSD patients, including 5 individuals with syndromic features. DNA samples from subjects were studied by either whole exome sequencing or target gene panel approach. Three of the syndromic patients have 5 main clinical features of Silver-Russell syndrome (SRS) and were first studied by MLPA. Among the syndromic patients, loss of DNA methylation at the imprinting control region H19/IGF2 was identified in 2 individuals with SRS clinical diagnosis. Two novel pathogenic variants in compound heterozygous state were identified in the CUL7 gene establishing the diagnosis of 3M syndrome in one patient, and a novel homozygous variant in TRIM37 was identified in another boy with Mulibrey nanism phenotype. Among the non-syndromic subjects, 7 rare heterozygous variants were identified in 6 DSD-related genes. However, none of the variants found can explain the phenotype by themselves. In conclusion, a genetic defect that clarifies the etiology of hypospadias was not found in most of the non-syndromic SGA children, supporting the hypothesis that multifactorial causes, new genes, and/or unidentified epigenetic defects may have an influence in this condition.

A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies.

AIMS: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. METHODS: Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. RESULTS: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. CONCLUSIONS: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

Minimal intervention procedures: evaluating how much pediatric dentists really know about this field

Abstract The aim of this cross-sectional study was to evaluate how much pediatric dentists know about the noninvasive, micro, and minimally invasive strategies for managing caries lesions in deciduous teeth. An electronic questionnaire was sent to pediatric dentists enrolled in the Regional Board of Dentistry. Information was collected concerning: 1) characteristics of the participants; 2) level of updated knowledge of noninvasive, micro and minimally invasive procedures for caries management in children; 3) agreement to sentences on the indicated procedures. The data were analyzed descriptively and with bivariate tests. Seventy pediatric dentists participated. Results showed high frequency of agreement with sentences on strategies for lesion caries management: 92.8% with the sentence on selective removal of decayed tissue; 90.0% on fluoridated toothpaste (≥1,000 ppm); 84.3% on silver diamine fluoride (SDF); 80.0% on the Hall technique; and 76.9% on the sealing of small dentine lesions. Level of agreement with sentences was not significantly related to variables of time since graduation, degree of updatedness, area of employment, or higher education degree (p > 0.05). A higher score on agreement toward SDF use was accompanied by a greater degree of self-declared updatedness on noninvasive, micro and minimally invasive procedures for caries management in children (rho 0.259; p = 0.031). Pediatric dentists consider themselves updated and agree with the sentences on recommended use of fluoridated toothpaste as of eruption of the first tooth, and on the selective removal of decayed tissue. Disagreement still continues regarding application of SDF to arrest lesion progression, sealing of small dentin lesions, and the Hall technique.

Targeted massively parallel sequencing panel to diagnose genetic endocrine disorders in a tertiary hospital

Abstract Objectives To analyze the efficiency of a multigenic targeted massively parallel sequencing panel related to endocrine disorders for molecular diagnosis of patients assisted in a tertiary hospital involved in the training of medical faculty. Material and methods Retrospective analysis of the clinical diagnosis and genotype obtained from 272 patients in the Endocrine unit of a tertiary hospital was performed using a custom panel designed with 653 genes, most of them already associated with the phenotype (OMIM) and some candidate genes that englobes developmental, metabolic and adrenal diseases. The enriched DNA libraries were sequenced in NextSeq 500. Variants found were then classified according to ACMG/AMP criteria, with Varsome and InterVar. Results Three runs were performed; the mean coverage depth of the targeted regions in panel sequencing data was 249×, with at least 96.3% of the sequenced bases being covered more than 20-fold. The authors identified 66 LP/P variants (24%) and 27 VUS (10%). Considering the solved cases, 49 have developmental diseases, 12 have metabolic and 5 have adrenal diseases. Conclusion The application of a multigenic panel aids the training of medical faculty in an academic hospital by showing the picture of the molecular pathways behind each disorder. This may be particularly helpful in developmental disease cases. A precise genetic etiology provides an improvement in understanding the disease, guides decisions about prevention or treatment, and allows genetic counseling.

Gastos com a judicialização de medicamentos: uma revisão integrativa / Expenditure on the judicialization of medicines: An integrating review

A judicialização da saúde é um fenômeno que se iniciou no Brasil após a promulgação da Constituição Federal de 1988, que normatizou a garantia à saúde como um direito social. A quantidade de ações judiciais que requerem do Estado algum insumo ou serviço de saúde vem crescendo a cada ano, o que afeta de forma direta o financiamento da saúde. Por isso, o objetivo deste estudo foi realizar um levantamento bibliográfico acerca dos gastos com a aquisição de medicamentos via demandas judiciais. Para tanto, foi feita uma revisão integrativa a partir de pesquisa nas bases de dados Medline, Lilacs, SciELO e Scopus. Inicialmente, foram encontrados 57 estudos, sendo realizadas a apreciação dos títulos e dos resumos e a análise em pares. Ao final da busca, estaram nove artigos que tinham dados suficientes para o estudo proposto e relação com os critérios de inclusão. Os textos selecionados, em sua maioria, concentraram-se nas regiões Sul e Sudeste do Brasil, tratando principalmente da requisição de medicamentos que atuam no sistema nervoso, mas também de agentes antineoplásicos e imunomoduladores (os mais onerosos). Pôde-se perceber, ainda, que não existe uma padronização na fonte dos dados financeiros e que o gasto com a judicialização dos medicamentos é elevado: tanto os estudos de abrangência municipal e estadual, como o que apenas analisou dados da União, apresentaram valores de R$ 350 mil até R$ 219 milhões. Além disso, observou-se a baixa presença dos medicamentos pedidos judicialmente nas listas oficiais.

The judicialization of health is a phenomenon that began in Brazil after the promulgation of the Federal Constitution of 1988, which standardized the guarantee of health as a social right. The number of lawsuits that require some input or health service from the State has been growing every year, which directly affects health financing. For this reason, the objective of this study was to carry out a bibliographic survey about the expenses with the purchase of medicines via legal demands. To this end, an integrative review was carried out based on research in Medline, Lilacs, Scielo and Scopus databases. Initially, 857 studies were found, with appreciation of titles and abstracts and peer review. At the end of the search, nine articles remained that had sufficient data for the proposed study and relationship with the inclusion criteria. The selected texts were mostly concentrated in the South and Southeast regions of Brazil, dealing mainly with the requisition of medicines that act on the nervous system, but also with antineoplastic and immunomodulatory agents (the most expensive ones). It was also possible to notice that there is no standardization in the source of financial data and that the expense with the judicialization of medicines is high: both the municipal and state studies, as well as the one that only analyzed data from the Union, presented values of R$350 thousand to R$219 million reais. In addition, the low presence of the medicines requested in court was observed in the official lists.

[Judicialization of access to medicines: analysis of lawsuits in the state of Rio Grande do Norte, Brazil]. / Judicialização no acesso a medicamentos: análise das demandas judiciais no Estado do Rio Grande do Norte, Brasil.

This study aimed to analyze the lawsuits demanding access to medicines in the state of Rio Grande do Norte, Brazil, from 2013 to 2017, describing their sociodemographic, legal, and medical/health characteristics. This was a descriptive study in which the unit of analysis was the individual judicial process for requesting medicines in which the state was the defendant. The data were obtained by consulting the website of the Rio Grande do Norte Court of Justice. A total of 987 suits were analyzed, in which the majority of the plaintiffs were females (58.8%), with a mean age of 48.3 years, and residing in the state's interior (56.9%). The legal aid was predominantly public (52.8%), and 38.1% of the prescriptions originated in the private healthcare sector. Access to the medicines was obtained in 68% of the cases, and the plaintiff was responsible for the purchase in 56.1%, via attachment of public funds. Chronic noncommunicable diseases predominated, as did demands for medicines not supplied by the Brazilian Unified National Health System (SUS). A total of 1,517 medicines were requested, of which 936 (61.7%) were not on the National List of Essential Medicines (Rename). The most frequently demanded drug was insulin glargine (74 case). Of the 10 medicines with the most lawsuits, four were later incorporated by the SUS, featuring insulin analogues. The results showed that legal recourse has been consolidated as a form of access to medicines that have still not been incorporated by the SUS, which can contribute as a form of pressure for such incorporation. The attachment of public funds to comply with these rulings is worrisome for the administration of the SUS, since it jeopardizes the execution of regularly scheduled and budgeted policies in pharmaceutical assistance.

Este trabalho objetivou analisar os processos judiciais que solicitavam medicamentos ao Estado do Rio Grande do Norte, Brasil, no período de 2013 a 2017, descrevendo suas características sociodemográficas, jurídicas e médico-sanitárias. Trata-se de um estudo descritivo, cuja unidade de análise foi o processo judicial individual de solicitação de medicamentos, em que o estado é réu. Os dados foram obtidos por meio de consulta ao sítio eletrônico do Tribunal de Justiça do Estado do Rio Grande do Norte. Foram analisados 987 processos em que a maioria dos autores é do sexo feminino (58,8%), com idade média de 48,3 anos e residentes no interior do estado (56,9%). Houve predomínio de assistência jurídica pública (52,8%) e origem da prescrição no setor privado (38,1%). Em 68% dos casos, houve acesso ao medicamento, sendo o autor responsável pela compra em 56,1% deles, via bloqueio de verbas públicas. As doenças crônicas predominaram, bem como a solicitação de medicamentos não disponibilizados pelo Sistema Único de Saúde (SUS). Foram solicitados 1.517 medicamentos, dos quais 936 (61,7%) não estavam na Relação Nacional de Medicamentos Essenciais (Rename). O medicamento mais solicitado foi a insulina glargina (74 pedidos). Dos 10 medicamentos com maior número de ações judiciais, 4 foram posteriormente incorporados ao SUS, com destaque para as insulinas análogas. Os resultados mostraram que a via judicial tem se consolidado como forma de acesso a medicamentos ainda não incorporados ao SUS, o que pode contribuir como forma de pressão para a incorporação. O bloqueio de verbas públicas para o cumprimento das decisões é preocupante para o gestor do SUS, pois compromete a execução das políticas de assistência farmacêutica programadas.

El objetivo de este estudio fue analizar los procesos judiciales que solicitaban medicamentos al estado de Rio Grande do Norte, Brasil, durante el período de 2013 a 2017, describiendo sus características sociodemográficas, jurídicas y médico-sanitarias. Se trata de un estudio descriptivo, cuya unidad de análisis fue el proceso judicial individual de solicitud de medicamentos, en el que el estado es el acusado. Los datos se obtuvieron a través de la consulta a la página web del Tribunal de Justicia del Rio Grande do Norte. Se analizaron 987 procesos judiciales en los que la mayoría de los autores son del sexo femenino (58,8%), con una edad media de 48,3 años y residentes en el interior del estado (56,9%). Hubo un predominio de asistencia jurídica pública (52,8%) y origen de la prescripción en el sector privado (38,1%). En el 68% de los casos, hubo acceso al medicamento, siendo el autor responsable de la compra en un 56,1% de ellos, vía bloqueo de fondos públicos. Las enfermedades crónicas predominaron, así como la solicitud de medicamentos no puestos a disposición de los pacientes por parte del Sistema Único de Salud brasileño (SUS). Se solicitaron 1517 medicamentos, de los cuales 936 (61,7%) no se encontraban en la Relación Nacional de Medicamentos Esenciales (Rename). El medicamento más solicitado fue la Insulina glargina (74 pedidos). De los 10 medicamentos con mayor número de acciones judiciales, 4 fueron posteriormente incorporados al SUS, destacándose las insulinas análogas. Los resultados mostraron que la vía judicial se ha consolidado como forma de acceso a medicamentos todavía no incorporados al SUS, lo que puede contribuir como forma de presión para su incorporación. El bloqueo de fondos públicos para el cumplimiento de las decisiones es preocupante para el gestor del SUS, puesto que compromete la ejecución de las políticas de asistencia farmacéutica programadas.

Judicialização no acesso a medicamentos: análise das demandas judiciais no Estado do Rio Grande do Norte, Brasil / Judicialization of access to medicines: analysis of lawsuits in the state of Rio Grande do Norte, Brazil / Judicialización en el acceso a medicamentos: análisis de las demandas judiciales en el estado de Rio Grande do Norte, Brasil

Este trabalho objetivou analisar os processos judiciais que solicitavam medicamentos ao Estado do Rio Grande do Norte, Brasil, no período de 2013 a 2017, descrevendo suas características sociodemográficas, jurídicas e médico-sanitárias. Trata-se de um estudo descritivo, cuja unidade de análise foi o processo judicial individual de solicitação de medicamentos, em que o estado é réu. Os dados foram obtidos por meio de consulta ao sítio eletrônico do Tribunal de Justiça do Estado do Rio Grande do Norte. Foram analisados 987 processos em que a maioria dos autores é do sexo feminino (58,8%), com idade média de 48,3 anos e residentes no interior do estado (56,9%). Houve predomínio de assistência jurídica pública (52,8%) e origem da prescrição no setor privado (38,1%). Em 68% dos casos, houve acesso ao medicamento, sendo o autor responsável pela compra em 56,1% deles, via bloqueio de verbas públicas. As doenças crônicas predominaram, bem como a solicitação de medicamentos não disponibilizados pelo Sistema Único de Saúde (SUS). Foram solicitados 1.517 medicamentos, dos quais 936 (61,7%) não estavam na Relação Nacional de Medicamentos Essenciais (Rename). O medicamento mais solicitado foi a insulina glargina (74 pedidos). Dos 10 medicamentos com maior número de ações judiciais, 4 foram posteriormente incorporados ao SUS, com destaque para as insulinas análogas. Os resultados mostraram que a via judicial tem se consolidado como forma de acesso a medicamentos ainda não incorporados ao SUS, o que pode contribuir como forma de pressão para a incorporação. O bloqueio de verbas públicas para o cumprimento das decisões é preocupante para o gestor do SUS, pois compromete a execução das políticas de assistência farmacêutica programadas.

This study aimed to analyze the lawsuits demanding access to medicines in the state of Rio Grande do Norte, Brazil, from 2013 to 2017, describing their sociodemographic, legal, and medical/health characteristics. This was a descriptive study in which the unit of analysis was the individual judicial process for requesting medicines in which the state was the defendant. The data were obtained by consulting the website of the Rio Grande do Norte Court of Justice. A total of 987 suits were analyzed, in which the majority of the plaintiffs were females (58.8%), with a mean age of 48.3 years, and residing in the state's interior (56.9%). The legal aid was predominantly public (52.8%), and 38.1% of the prescriptions originated in the private healthcare sector. Access to the medicines was obtained in 68% of the cases, and the plaintiff was responsible for the purchase in 56.1%, via attachment of public funds. Chronic noncommunicable diseases predominated, as did demands for medicines not supplied by the Brazilian Unified National Health System (SUS). A total of 1,517 medicines were requested, of which 936 (61.7%) were not on the National List of Essential Medicines (Rename). The most frequently demanded drug was insulin glargine (74 case). Of the 10 medicines with the most lawsuits, four were later incorporated by the SUS, featuring insulin analogues. The results showed that legal recourse has been consolidated as a form of access to medicines that have still not been incorporated by the SUS, which can contribute as a form of pressure for such incorporation. The attachment of public funds to comply with these rulings is worrisome for the administration of the SUS, since it jeopardizes the execution of regularly scheduled and budgeted policies in pharmaceutical assistance.

El objetivo de este estudio fue analizar los procesos judiciales que solicitaban medicamentos al estado de Rio Grande do Norte, Brasil, durante el período de 2013 a 2017, describiendo sus características sociodemográficas, jurídicas y médico-sanitarias. Se trata de un estudio descriptivo, cuya unidad de análisis fue el proceso judicial individual de solicitud de medicamentos, en el que el estado es el acusado. Los datos se obtuvieron a través de la consulta a la página web del Tribunal de Justicia del Rio Grande do Norte. Se analizaron 987 procesos judiciales en los que la mayoría de los autores son del sexo femenino (58,8%), con una edad media de 48,3 años y residentes en el interior del estado (56,9%). Hubo un predominio de asistencia jurídica pública (52,8%) y origen de la prescripción en el sector privado (38,1%). En el 68% de los casos, hubo acceso al medicamento, siendo el autor responsable de la compra en un 56,1% de ellos, vía bloqueo de fondos públicos. Las enfermedades crónicas predominaron, así como la solicitud de medicamentos no puestos a disposición de los pacientes por parte del Sistema Único de Salud brasileño (SUS). Se solicitaron 1517 medicamentos, de los cuales 936 (61,7%) no se encontraban en la Relación Nacional de Medicamentos Esenciales (Rename). El medicamento más solicitado fue la Insulina glargina (74 pedidos). De los 10 medicamentos con mayor número de acciones judiciales, 4 fueron posteriormente incorporados al SUS, destacándose las insulinas análogas. Los resultados mostraron que la vía judicial se ha consolidado como forma de acceso a medicamentos todavía no incorporados al SUS, lo que puede contribuir como forma de presión para su incorporación. El bloqueo de fondos públicos para el cumplimiento de las decisiones es preocupante para el gestor del SUS, puesto que compromete la ejecución de las políticas de asistencia farmacéutica programadas.

Judicialization of medicines: effectiveness of rights or break in public policies?

OBJECTIVE: To analyze whether lawsuits for medicines filed against the state of Rio Grande do Norte agree with medical-sanitary and pharmaceutical assistance management criteria established by the public policies of access to medicines in force in Brazil. METHODS: This is a descriptive and retrospective study of the individual lawsuits that claimed medicines in the state of Rio Grande do Norte between 2013 and 2017. Information was collected from the procedural documents on the requested medicines, the diagnoses referred and the origin of the medical prescription, in order to analyze medical-sanitary and pharmaceutical assistance management characteristics. RESULTS: We analyzed 987 lawsuits, which requested 1,517 medications. Of these, 60.7% were not part of the National List of Essential Medicines, and, in 75% of the cases, there was a therapeutic alternative in the Brazilian Unified Health System. In 13.6% of the actions, at least one drug was prescribed for off-label use. Prescribers of philanthropic and private services often request medicines not covered by the pharmaceutical care policy. Even judicialized drugs that are part of the national list are constantly requested for non-standard indications. CONCLUSIONS: Court decisions for the supply of medicines violate health rules and make it difficult to manage pharmaceutical assistance, which may weaken the implementation of these policies.

Is Ataxia an Underestimated Symptom of Huntington's Disease?

Background: Huntington's disease (HD) is a progressive disorder characterized by motor, cognitive and psychiatric features. Cerebellar ataxia is classically considered as uncommon in HD clinical spectrum. Objective: To determine the prevalence of cerebellar ataxia in patients with HD, both in the early and in the late stages of HD. Methods: Seventy-two individuals considered eligible were assessed by two trained doctors, applying the Scale for Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS) for ataxia, the Unified Huntington's Disease Rating Scale (UHDRS) and also, Barthel Index (BI), in order to evaluate functional capacity. Results: Fifty-one patients (70.8%) presented with clinical ataxia at the time of examination (mean time of disease was 9.1 years). Six (8.33%) patients presented with cerebellar ataxia as first symptom. When stratified according to time of disease, a decline in the presence of chorea (p = 0.032) and an increase in cognitive deficit (p = 0.023) were observed in the patients as the disease progressed. The presence of ataxia was associated with longer duration of illness and severity of illness (UHDRS) (p < 0.0001), and shorter Barthel (less functionality) (p = 0.001). Conclusions: Cerebellar involvement may play an important role in natural history of brain degeneration in HD. The presence of cerebellar ataxia in HD is relevant and it may occur even in early stages, and should be included as part of the motor features of the disease.

Judicialization of medicines: effectiveness of rights or break in public policies? / Judicialização de medicamentos: efetivação de direitos ou ruptura das políticas públicas?

ABSTRACT OBJECTIVE: To analyze whether lawsuits for medicines filed against the state of Rio Grande do Norte agree with medical-sanitary and pharmaceutical assistance management criteria established by the public policies of access to medicines in force in Brazil. METHODS: This is a descriptive and retrospective study of the individual lawsuits that claimed medicines in the state of Rio Grande do Norte between 2013 and 2017. Information was collected from the procedural documents on the requested medicines, the diagnoses referred and the origin of the medical prescription, in order to analyze medical-sanitary and pharmaceutical assistance management characteristics. RESULTS: We analyzed 987 lawsuits, which requested 1,517 medications. Of these, 60.7% were not part of the National List of Essential Medicines, and, in 75% of the cases, there was a therapeutic alternative in the Brazilian Unified Health System. In 13.6% of the actions, at least one drug was prescribed for off-label use. Prescribers of philanthropic and private services often request medicines not covered by the pharmaceutical care policy. Even judicialized drugs that are part of the national list are constantly requested for non-standard indications. CONCLUSIONS: Court decisions for the supply of medicines violate health rules and make it difficult to manage pharmaceutical assistance, which may weaken the implementation of these policies.

RESUMO OBJETIVO: Analisar se as demandas judiciais por medicamentos movidas contra o estado do Rio Grande do Norte estão de acordo com critérios médico-sanitários e de gestão da assistência farmacêutica estabelecidos pelas políticas públicas de acesso a medicamentos vigentes no Brasil. MÉTODOS: Foi conduzido um estudo descritivo e retrospectivo das ações judiciais individuais que pleiteavam medicamentos no estado do Rio Grande do Norte entre 2013 e 2017. Foram coletadas informações nos autos processuais sobre os medicamentos solicitados, os diagnósticos referidos e a origem da prescrição médica, a fim de se analisar as características médico-sanitárias e de gestão da assistência farmacêutica. RESULTADOS: Foram analisados 987 processos, em que foram solicitados 1.517 medicamentos. Desses, 60,7% não faziam parte do elenco da Relação Nacional de Medicamentos Essenciais, e em 75% dos casos havia alternativa terapêutica no Sistema Único de Saúde. Em 13,6% das ações, ao menos um medicamento foi prescrito para uso off label . Os prescritores dos serviços filantrópicos e privados solicitam frequentemente medicamentos não contemplados pela política de assistência farmacêutica. Mesmo os medicamentos judicializados que fazem parte da relação nacional são constantemente solicitados para indicações não padronizadas. CONCLUSÕES: As decisões judiciais para o fornecimento de medicamentos violam regras sanitárias e dificultam a gestão da assistência farmacêutica, o que pode enfraquecer a execução dessas políticas.

Ganho de Conhecimento no Internato Médico em Psiquiatria Não Reduz Estigmatização dos Transtornos Mentais / Increased Knowledge among Psychiatric Medical Interns does not Reduce the Stigmatization of Mental Disorders

RESUMO Introdução Considerando a prevalência dos transtornos mentais, é essencial que qualquer médico seja capaz de prestar assistência qualificada e humanizada a pessoas em sofrimento psíquico. No entanto, o usual estigma e a falta de conhecimento no manejo das doenças mentais por parte dos médicos podem representar uma barreira de acesso e ineficiência importante enfrentada pelos pacientes no sistema de saúde. Objetivo Estimar o ganho de aprendizado percebido e a redução de estigma em relação a pessoas portadoras de esquizofrenia por estudantes de Medicina após a exposição ao estágio obrigatório no internato numa escola médica pública no Distrito Federal. Método Estudo quasi-experimental para avaliação de impacto de programa educacional durante o internato médico em saúde mental. A amostra consistiu em 35 estudantes do último ano do curso de Medicina. Foram aplicados questionários para aferição do grau e tipificação do estigma em relação à esquizofrenia e à autopercepção sobre manejo de medicamentos e sobre tratamento de doenças psiquiátricas. Os instrumentos utilizaram uma escala do tipo Likert de três pontos para aferição dos resultados. Os questionários foram aplicados imediatamente antes e após a exposição ao programa educacional, que teve duração de quatro semanas. Os valores médios de autopercepção e estigma foram comparados entre os dois momentos empregando-se o teste t de Student emparelhado. Resultados Não houve mudança significativa do grau de estigmatização nas dimensões avaliadas (estereótipo total, p = .230; preconceito percebido, p = .172; distância social, p = .209; direitos civis, p = .837). Quanto à autopercepção de conhecimento, os valores médios do número de resposta igual a 3 e a soma no momento pós- são significativamente maiores que no momento pré- (p = .007 e p < .0001, respectivamente). Os ganhos não se mostraram associados significativamente com as variáveis demográficas. Conclusão A despeito do ganho em conhecimento, a imersão em saúde mental no internato do curso de Medicina ao longo de quatro semanas não se mostrou eficaz para mudança no estigma. É possível que a curta duração da intervenção implique contato insuficiente com o portador de doença mental para redução do estigma. Sugerimos a realização de novos trabalhos com ampliação da amostra e com desenhos experimentais.

ABSTRACT Introduction Considering the high prevalence of mental illnesses, it is essential for any physician to offer proper treatment and attention to people with these disorders. Nevertheless, the usual stigma and lack of knowledge regarding the management of mental disorders on the part of physicians can represent a significant barrier to treatment and inefficiency faced by patients in the health care system. Objective This study aimed to measure the gain of psychiatric knowledge and the reduction in the stigmatization of people with schizophrenia by medical students after exposure to the compulsory internship program at a public medical school in the Federal District. Methods Quasi-experimental study to evaluate the impact of the training program during medical internship in the final year of undergraduate medical training. The sample was 35 final-year medical students. Questionnaires were applied to measure the degree and type of stigma in relation to schizophrenia and self-perception regarding the drug management and treatment of psychiatric diseases. A three-point Likert scale was used to measure the results. The questionnaires were applied immediately before and after exposure to the four-week training program. The medical values of self-perception and stigma were compared between two moments using the Student's t test. Results: There was no statistically significant difference found between stigmatization before and after the intervention (total stereotype, p = 0.230; perceived prejudice, p = 0.172; social distance, p = 0.209; civil rights, p = 0.837). Regarding self-perception of knowledge, the number of items reaching total confidence and the mean values after the training were significantly improved (p = 0.007 and p < 0.0001, respectively). There was no correlation with sociodemographic characteristics. Conclusion Despite the knowledge gain, medical students failed to show any improvement in the degree of stigma held after immersion in a 4-week practical psychiatric training program. The short duration of the intervention might have meant that the students' contact with patients was insufficient to reduce stigma. More studies are needed with larger groups and experimental designs.

Avaliação da satisfação de usuários a partir da Carta SUS, no Rio Grande do Norte, Brasil / Evaluation of user satisfaction from the Carta SUS, in Rio Grande do Norte, Brazil

RESUMO Objetivou-se analisar a satisfação dos usuários e a caracterização dos serviços de atendimento hospitalar e ambulatorial do Sistema Único de Saúde (SUS). Realizou-se um estudo transversal analítico por meio de dados de usuários que responderam ao instrumento Carta SUS entre 2012 e 2013, no estado do Rio Grande do Norte, no qual foi avaliada a qualidade da estrutura física, da equipe de saúde e do tratamento ofertado. Dos 17.333 usuários que responderam à Carta SUS no período estudado, 62,3% eram mulheres e 62,4% tinham acima de 40 anos. A maior parte dos atendimentos (56,8%) foi realizada na capital e em serviços públicos (70,3%). Os usuários apresentaram-se satisfeitos com os serviços, com um percentual que variou de 79 a 90%, de acordo com as regiões de saúde. Os homens e as pessoas com mais de 60 anos avaliaram mais positivamente os serviços; a alta complexidade e os serviços da capital tiveram melhores resultados (p≤0,001), assim como as unidades privadas. Ressaltam-se a importância da avaliação em saúde e a relevância de se analisar, divulgar e dar continuidade ao instrumento Carta SUS, com vistas a subsidiar mais estudos e reflexões sobre a qualidade dos serviços.

ABSTRACT The purpose of this study was to analyze user satisfaction and the characterization of the hospital and outpatient services of the Unified Health System (SUS). A cross-sectional analytical study was performed using user data that responded to the Carta SUS instrument between 2012 and 2013, in the state of Rio Grande do Norte, in which the quality of the physical structure, the health team and the treatment offered. Of the 17.333 users who answered the SUS Charter in the period studied, 62.3% were women and 62.4% were over 40 years old. Most of the attendances (56.8%) were held in the capital and in public services (70.3%). The users were satisfied with the services, with a percentage that ranged from 79 to 90%, according to the health regions. Men and people over 60 evaluated services more positively; the high complexity and the services of the capital had better results (p≤0.001), as well as the private units. The importance of health evaluation and the relevance of analyzing, disseminating and giving continuity to the SUS Charter instrument is emphasized, with a view to subsidizing further studies and reflections on the quality of services.

Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study.

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.

Gastos públicos com medicamentos judicializados no Rio Grande do Norte nos anos de 2016 e 2017 / Public expenditures with legalized medicines in Rio Grande do Norte in the years 2016 and 2017

A judicialização da saúde é um fenômeno que se iniciou no Brasil após a Constituição Federal de 1988. Esse tipo de ação judicial vem crescendo em quantidade a cada ano e solicita desde leitos de terapia intensiva até medicamentos. Quando tem como parte requerida o Poder Público acaba por afetar de forma direta o financiamento da saúde pública. Por isso, os processos de judicialização de medicamentos atingem diversas políticas públicas de saúde, principalmente, as políticas de acesso a medicamentos, e de financiamento. O objetivo deste artigo é caracterizar as demandas judicias por medicamentos no Estado do Rio Grande do Norte em relação ao aspecto financeiro nos anos de 2016 e 2017. Trata-se de um estudo misto, pois foram elaborados uma revisão integrativa sobre os gastos com a judicialização de medicamentos, e um estudo descritivo de caráter exploratório sobre os gastos públicos com medicamentos judicializados no Estado do Rio Grande do Norte. O primeiro estudo analisou 857 artigos científicos, ao final foram incluídos 9 artigos, dos quais todos pesquisaram processos judiciais brasileiros, na sua maioria com concentraram nas regiões sul e sudeste do Brasil, e configurou gastos entre 350 mil a 219 milhões de reais, onde a parte requerida podiam ser municípios, estados ou União. No segundo estudo foram analisados 370 processos judiciais individuais dos anos de 2016 e 2017, solicitando medicamentos, movidos no Estado do Rio Grande do Norte. Os valores gastos com a judicialização de medicamentos nesses anos foram de R$ 10.687.951,09. Foram requeridos 572 medicamentos, estando 61,36% deles fora da Relação Nacional de Medicamentos (RENAME) e o tipo de medicamento mais demandado foram os agentes antineoplásicos e imunomoduladores (24,13%). A compra foi realizada pelo paciente em 75,81% dos casos a partir da liberação de alvará judicial. Assim, a judicialização de medicamentos em um estado de pequeno porte ocasiona iniquidades no acesso dos usuários do Sistema Único Saúde aos medicamentos e no financiamento da Assistência Farmacêutica (AU).

The judicialization of health is a phenomenon that began in Brazil after the Federal Constitution of 1988. This type of lawsuit has been growing in quantity every year and requests from beds of intensive therapy to medicines. When it has as requested the Public Power ends directly affect the financing of public health. For this reason, the processes of judicialization of medicines reach several public health policies, mainly the policies of access to medicines, and of financing. The objective of this article is to characterize the legal claims for medicines in the State of Rio Grande do Norte in relation to the financial aspect in the years 2016 and 2017. This is a mixed study, since an integrative review was elaborated on the expenses with the judicialization of drugs, and an exploratory descriptive study on the public expenditures with judicialized medicines in the State of Rio Grande do Norte. The first study analyzed 857 scientific articles, at the end of which 9 articles were included, all of which investigated Brazilian judicial processes, most of them concentrated in the southern and southeastern regions of Brazil, and set up expenditures between 350,000 and 219 million reais. The second study analyzed 370 individual lawsuits in 2016 and 2017, requesting medicines, moved in the State of Rio Grande do Norte. The amounts spent on the judicialization of medicines in these years were R $ 10,687,951.09. 572 drugs were required, 61.36% of which were outside National Drug List (RENAME) and the most demanded type of drug were antineoplastic agents and immunomodulators (24.13%). The purchase was made by the patient in 75.81% of the cases from the release of a court order. Thus, the judicialization of medicines in a small state causes iniquities in the access of users of the Brazilian Health System (SUS) to medicines and in the financing of Pharmaceutical Assistance (AU).

Polylactic/polyglycolic acid copolymer is a good carrier for bmp-2 on bone regeneration? / Copolímero do ácido polilático/poliglicólico é um bom carreador para bmp-2 na regeneração óssea?

The aim of this work was to evaluate the role of polylactic /polyglycolic acid copolymer as carrier for BMP-2 on bone regeneration in rat calvarium. Forty five adult male rats underwent 5-mm critical defects in bone calvaria to be divided into three groups according to the filling materials: Control-blood clot; PLGA-polylactic acid Polyglycolic/copolymer; PLGA + BMP-2 -polylactic acid Polyglycolic/copolymer associated with BMP-2. Sacrifice of animals occurred at 5, 15 and 30 days after surgery The evaluation of new bone formation was obtained by histomorphometry, while OPG and RANKL proteins were observed by immunohistochemistry. Statistical analysis was performed by means of nonparametric tests based on quantitative variables of independent samples. Considering the amount of newly formed bone, significant difference was detected between PGLA (178,2±137,5µm) and the other groups, at day 30. In PLGA + BMP-2 and control groups, the expression of RANKL was prevalent on the OPG in the periods of 15 and 30 days, suggesting a favorable condition for bone reabsorption in these periods. Therefore, immunoexpression of RANKL and OPG and bone formation observed in different groups and periods of analysis showed that the polylactic/polyglycolic acid copolymer does not act as a good carrier for BMP-2.

O objetivo deste estudo foi avaliar o copolímero do ácido polilático/poliglicólico como carreador para BMP-2 na regeneração óssea da calvária de ratos. Foram utilizados 45 ratos adultos machos. Defeitos ósseos críticos de 5mm de diâmetro foram realizados com uma broca trefina na calvária dos animais. Os animais foram divididos em três grupos, de acordo com o material de notas para preenchimento dos defeitos: Controle - coágulo; PLGA - copolímero ácido polilático/poliglicólico; PLGA + BMP-2 - copolímero do ácido polilático/poliglicólico associado a BMP-2. O sacrifício ocorreu aos 5, 15 e 30 dias após a cirurgia. A avaliação da neoformação óssea foi obtida por histomorfometria, enquanto a análise de marcação para as proteínas OPG e RANKL foi observada por imunohistoquímica. Análises estatísticas foram realizadas por meio de testes não paramétricos de variáveis quantitativas em amostras independentes. Com relação à quantidade de tecido ósseo neoformado, observou-se diferença estatística significante entre o grupo PLGA (178,2±137,5µm) e os demais, no período de 30 dias. Nos grupos PLGA+BMP-2 e Controle, a marcação de RANKL foi predominante sobre a marcação de OPG nos períodos de 15 e 30 dias, evidenciado uma condição favorável para a reabsorção óssea nestes períodos. Portanto, a marcação de RANKL e OPG, e a formação óssea observada nos diferentes grupos e tempos de análise mostrou que o copolímero de ácido polilático/poliglicólico não atua como um bom carreador para BMP-2.

Critérios de normalidade dos testes de resolução temporal: random gap detection test e gaps-in-noise / Normality tests of temporal resolution: random gap detection test and gaps-in-noise

OBJETIVO: avaliar a resolução temporal em indivíduos audiologicamente normais entre 20 e 60 anos. MÉTODOS: 40 indivíduos de ambos os sexos, de 20 aos 60 anos de idade, divididos em quatro grupos etários contendo 10 indivíduos em cada grupo: Grupo I de 20 a 30 anos; Grupo II de 31 a 40 anos; Grupo III de 41 a 50 anos e Grupo IV de 51 a 60. Todos foram submetidos a procedimentos que fazem parte da rotina audiológica para caracterizar a audição periférica, e central com destaque nos testes de resolução temporal com tons puros, o Randon-gap-detection-test, e com ruído o Gaps-in-noise. RESULTADOS: os valores médios obtidos para o limiar de detecção de gap no teste Gaps-in-noise encontram-se em torno de seis milissegundos para os grupos 1 e 2 e de oito, nos grupos 3 e 4. Verificou-se limiar de detecção de gap obtido no teste Random-gap-detection-test com valor médio de 10 milissegundos para os grupos 1 e 2 e entre 10 e 15ms nos grupos 3 e 4. CONCLUSÃO: a habilidade de resolução temporal piora com o aumento da idade. Os valores de normalidade dos testes com segmentos de ruído (teste GIN - Gaps In Noise) e tom puro (teste RGDT - Random Gap Test Detection) são crescentes de acordo com a faixa etária avaliada. .

PURPOSE: to evaluate temporal resolution of normal hearing individuals from 20 years old to 60 years old. METHODS: individuals of both genders from 20 to 60 years old have been separated by age in four groups of ten individuals per group. Group I: from 20 years old to 30 years old. Group II: from 31 years old to 40 years old. Group III: from 41 years old to 50 years old. Group IV: from 51 years old to 60 years old. All individuals were submitted to procedures of audiological routine in order to evaluate the central and peripheral hearing. After those tests, they were included in the sample and submitted to temporal resolution tests: Randon-gap-detection-test and Gaps-in-noise. RESULTS: the average values obtained for the gap detection threshold on Gaps-in-noise were around 6ms at Group I and II. For the Group III and IV these values were around 8ms. Regarding the gap detection threshold obtained on Random-gap-detection-test the average values were 10ms at Group I and II. At Group III and IV these values were between 10ms and 15ms. CONCLUSION: the temporal resolution ability worsens with increasing age. The normal values of tests with noise segments (GIN - Gaps in Noise) and pure tone (RGDT - Random Gap Detection Test) are increasing according to age range studied. .

White Matter Atrophy in Patients with Mesial Temporal Lobe Epilepsy: Voxel-Based Morphometry Analysis of T1- and T2-Weighted MR Images.

Introduction. Mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis is highly refractory to clinical treatment. MRI voxel-based morphometry (VBM) of T1-weighted images has revealed a widespread pattern of gray matter (GM) and white matter (WM) atrophy in MTLE. Few studies have investigated the role of T2-weighted images in revealing WM atrophy using VBM. Objectives. To compare the results of WM atrophy between T1- and T2-weighted images through VBM. Methods. We selected 28 patients with left and 27 with right MTLE and 60 normal controls. We analyzed T1- and T2- weighted images with SPM8, using VBM/DARTEL algorithm to extract maps of GM and WM. The second level of SPM was used to investigate areas of WM atrophy among groups. Results. Both acquisitions showed bilateral widespread WM atrophy. T1-weighted images showed higher sensibility to detect areas of WM atrophy in both groups of MTLE. T2-weighted images also showed areas of WM atrophy in a more restricted pattern, but still bilateral and with a large area of superposition with T1-weighted images. Conclusions. In MTLE, T1-weighted images are more sensitive to detect subtle WM abnormalities using VBM, compared to T2 images, although both present a good superposition of statistical maps.