Real-life experience with inotersen at CEPARM, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is an inherited, progressive, and fatal disease still largely underdiagnosed. Mutations in the transthyretin (TTR) gene cause the TTR protein to destabilize, misfold, aggregate, and deposit in body tissues, which makes ATTRv a disease with heterogeneous clinical phenotype. OBJECTIVE: To describe the long-term efficacy and safety of inotersen therapy in patients with ATTRv peripheral neuropathy (ATTRv-PN). METHODS: Patients who completed the NEURO-TTR pivotal study and the NEURO-TTR OLE open-label extension study migrated to the present study and were followed-up for at least 18 more months to an average of 67 months and up to 76 months since day 1 of the inotersen therapy (D1-first dose of inotersen). Disease progression was evaluated by standard measures. RESULTS: Ten ATTRv-PN patients with Val30Met mutation were included. The mean disease duration on D1 was of 3 years, and the mean age of the patients was of 46.8 years. During an additional 18-month follow up, neurological function, based on the Neuropathy Impairment Score and the Polyneuropathy Disability Score, functionality aspects (Karnofsky Performance Status), and nutritional and cardiac aspects were maintained. No new safety signs have been noted. CONCLUSION: The treatment with inotersen was effective and well tolerated for the average of 67 months and up to 76 months. Our results are consistent with those of larger phase-III trials.

ANTECEDENTES: Amiloidose hereditária por transtirretina (ATTRv) é uma doença hereditária, progressiva e fatal ainda largamente subdiagnosticada. Mutações no gene transtirretina (TTR) promovem desestabilização, desdobramento, agregação e depósito da proteína TTR em tecidos do corpo, o que faz da ATTRv uma doença de fenótipo clínico heterogêneo. OBJETIVO: Descrever a eficácia e segurança da terapia com inotersena no longo prazo em pacientes com neuropatia periférica ATTRv (ATTRv-PN). MéTODOS: Pacientes que completaram o estudo pivotal NEURO-TTR e o estudo de extensão aberta NEURO-TTR OLE migraram para este estudo e foram acompanhados por no mínimo 18 meses adicionais, em média por 67 meses, e por até 76 meses, desde o dia 1 da terapia com inotersena (D1­primeira dose de inotersena). A progressão da doença foi avaliada por medidas padronizadas. RESULTADOS: Dez pacientes com ATTRv-PN com mutação Val30Met foram incluídos. A duração média da doença no D1 era de 3 anos, e a média de idade dos pacientes era de 46,8 anos. Durante o período de acompanhamento adicional de 18 meses, a função neurológica, baseada no Neuropathy Impairment Score e no Polyneuropathy Disability Score, os aspectos de funcionalidade (Karnofsky Performance Status), nutricional e cardíacos estavam mantidos. Não se observou nenhum novo sinal de segurança. CONCLUSãO: O tratamento com inotersena foi eficaz e bem tolerado por 67 meses em média, e por até 76 meses. Nossos resultados são consistentes com os de estudos maiores de fase III.

Late-onset hereditary ATTR V30M amyloidosis with polyneuropathy: Characterization of Brazilian subjects from the THAOS registry.

BACKGROUND: Despite growing numbers of patients diagnosed with late-onset hereditary ATTR V30M amyloidosis with polyneuropathy (ATTRv-PN), this condition remains poorly characterized in Brazil. OBJECTIVE: Characterize late-onset V30M ATTRv-PN in Brazil. MATERIAL AND METHODS: Demographic and clinical data at the time of enrolment for Brazilian subjects with symptomatic V30M ATTRv-PN were extracted from the ongoing, multinational, longitudinal, observational Transthyretin Amyloidosis Outcomes Survey (THAOS; cut-off date: January 30, 2017). Subjects were divided into those with symptom onset at age <50 years (EO-V30M), and at age ≥50 years (LO-V30M). RESULTS: A total of 96 Val30Met patients were symptomatic. LO-V30M (n = 25, 26.0%) had a longer time to diagnosis (mean 5.1 vs. 2.8 yrs.; p = 0.006) and less frequently positive family history (40% vs. 95.8%; p < 0.0001) than EO-V30M. Clinically, subjects with LO-V30M had more imbalance (92% vs. 54.9%; p = 0.006), deep sensory loss (100% vs. 80%; p = 0.0178), electrocardiogram abnormalities (88.9% vs. 59.4; p = 0.0241), and interventricular septum hypertrophy (69.2% vs. 0%; p < 0001) and less frequently sensory dissociation (12% vs. 74%; p < 0.0001). Also, LO-V30M tended to have more severe mean Neurologic Composite Score (101 vs. 70 pts.; p = 0.1136). CONCLUSIONS: LO-V30M ATTRv-PN is not unusual in Brazil, tending to be more difficult to diagnose and present with a more severe phenotype, with more large nerve fibers and cardiac involvement than EO-V30M. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00628745.

Baseline disease characteristics in Brazilian patients enrolled in Transthyretin Amyloidosis Outcome Survey (THAOS).

Transthyretin amyloidosis (ATTR) is characterized by the deposit of mutant or wild-type transthyretin that forms amyloid fibrils, which are extracellularly deposited within tissues and organs. Clinical manifestations of familial amyloid polyneuropathy vary according to the mutation, age at onset and geographical location. This study aimed to describe baseline disease characteristics of Brazilian patients with transthyretin familial amyloid polyneuropathy (ATTR-FAP) enrolled in the Transthyretin Amyloidosis Outcome Survey (THAOS). METHODS: The THAOS is an international, noninterventional, longitudinal, observational, web-based registry designed to characterize ATTR. The outcome measures included demographics (age at symptom onset, gender, time from onset of symptoms to diagnosis, family history), genotype, and clinical characteristics (presence of amyloid deposit, frequency of misdiagnosis, presenting symptomatology). The analysis was conducted in a dataset from Brazilian patients (from November 2008 to January 2016). RESULTS: One hundred and sixty participants (52.5% male) were included in the analysis. The majority of participants (90.6%) reported a positive family history of ATTR-FAP Median age at symptom onset was 32.5 years. Val30Met mutation was found in 91.9%. Misdiagnosis was observed in 26.6% of symptomatic patients. Over one-third (35.3%) of the misdiagnosed patients experienced a delay of more than one year before receiving a correct diagnosis. At presentation, 79.7% of the patients had motor, 87.5% sensory and 93.8% autonomic symptoms. CONCLUSION: ATTR-FAP in Brazil starts early, has a strong family history and the majority has Val30Met mutation. Misdiagnosis is common and the most common presentation is of a sensorimotor and autonomic neuropathy.

Real-life experience with inotersen at CEPARM, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro / Experiência de vida-real com inotersena no CEPARM, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro

Abstract Background Hereditary transthyretin amyloidosis (ATTRv) is an inherited, progressive, and fatal disease still largely underdiagnosed. Mutations in the transthyretin (TTR) gene cause the TTR protein to destabilize, misfold, aggregate, and deposit in body tissues, which makes ATTRv a disease with heterogeneous clinical phenotype. Objective To describe the long-term efficacy and safety of inotersen therapy in patients with ATTRv peripheral neuropathy (ATTRv-PN). Methods Patients who completed the NEURO-TTR pivotal study and the NEURO-TTR OLE open-label extension study migrated to the present study and were followed-up for at least 18 more months to an average of 67 months and up to 76 months since day 1 of the inotersen therapy (D1-first dose of inotersen). Disease progression was evaluated by standard measures. Results Ten ATTRv-PN patients with Val30Met mutation were included. The mean disease duration on D1 was of 3 years, and the mean age of the patients was of 46.8 years. During an additional 18-month follow up, neurological function, based on the Neuropathy Impairment Score and the Polyneuropathy Disability Score, functionality aspects (Karnofsky Performance Status), and nutritional and cardiac aspects were maintained. No new safety signs have been noted. Conclusion The treatment with inotersen was effective and well tolerated for the average of 67 months and up to 76 months. Our results are consistent with those of larger phase-III trials.

Resumo Antecedentes Amiloidose hereditária por transtirretina (ATTRv) é uma doença hereditária, progressiva e fatal ainda largamente subdiagnosticada. Mutações no gene transtirretina (TTR) promovem desestabilização, desdobramento, agregação e depósito da proteína TTR em tecidos do corpo, o que faz da ATTRv uma doença de fenótipo clínico heterogêneo. Objetivo Descrever a eficácia e segurança da terapia com inotersena no longo prazo em pacientes com neuropatia periférica ATTRv (ATTRv-PN). Métodos Pacientes que completaram o estudo pivotal NEURO-TTR e o estudo de extensão aberta NEURO-TTR OLE migraram para este estudo e foram acompanhados por no mínimo 18 meses adicionais, em média por 67 meses, e por até 76 meses, desde o dia 1 da terapia com inotersena (D1-primeira dose de inotersena). A progressão da doença foi avaliada por medidas padronizadas. Resultados Dez pacientes com ATTRv-PN com mutação Val30Met foram incluídos. A duração média da doença no D1 era de 3 anos, e a média de idade dos pacientes era de 46,8 anos. Durante o período de acompanhamento adicional de 18 meses, a função neurológica, baseada no Neuropathy Impairment Score e no Polyneuropathy Disability Score, os aspectos de funcionalidade (Karnofsky Performance Status), nutricional e cardíacos estavam mantidos. Não se observou nenhum novo sinal de segurança. Conclusão O tratamento com inotersena foi eficaz e bem tolerado por 67 meses em média, e por até 76 meses. Nossos resultados são consistentes com os de estudos maiores de fase III.

Perfil para empreendedorismo e inovação de graduandos em um curso de enfermagem / Profile for entrepreneurship and innovation of undergraduates in a nursing course / Perfil de emprendimiento e innovación de los estudiantes de la carrera de enfermería

Introdução: A enfermagem necessita aprender a inovar e a empreender, acompanhando o desenvolvimento tecnológico e a globalização. Objetivo: Analisar o perfil empreendedor e inovador entre graduandos de um curso de enfermagem. Método: Estudo transversal, descritivo e quantitativo, realizado com 161 graduandos do primeiro ao quarto anos, por meio de um questionário autoaplicável sobre perfil empreendedor, sendo dividido em três perfis: A: Não possui características empreendedoras, B: Possui chance de adquirir as características empreendedoras e C: Possui características empreendedoras. Resultados: A maioria dos graduandos apresentou comportamento participativo no trabalho em equipe, tomada de decisão e considerou ter um pouco de criatividade. O comportamento omisso foi sobre atitude após o término do ensino médio e diante de imprevistos que acontecem no cotidiano. O comportamento de apenas cumprir ordens foi em relação à economia, mundo dos negócios e sobre a percepção de si próprio. Não houve diferença significante entre os quatro anos, a maioria apresentou chance de se tornar um empreendedor, necessitando melhorar e desenvolver essas habilidades. Conclusão: Os graduandos devem adquirir conhecimento sobre empreendedorismo e inovação, pois esses conteúdos podem influenciar, direcionar e preparar melhor o enfermeiro para dar maior visibilidade e atender aos novos espaços da profissão.(AU)

Introduction: Nursing needs to learn to innovate and undertake, accompanying technological development and globalization. Objective: To analyze the entrepreneurial and innovative profile among undergraduates of a nursing course. Method: Cross-sectional, descriptive and quantitative study, conducted with 161 undergraduate students from the first to the fourth years, through a self-administered questionnaire on entrepreneurial profile, being divided into three profiles B: Has a chance to acquire the entrepreneurial characteristics and C: Has entrepreneurial characteristics. Results: Most of the students presented participatory behavior in teamwork, decision making and considered having a little creativity. The omissive behavior was about attitude after the end of high school and before unforeseen events that happen in everyday life. The behavior of just following orders was in relation to the economy, the business world and the perception of oneself. There was no significant difference between the four years, most had a chance to become an entrepreneur, needing to improve and develop these skills. Conclusion: Graduates should acquire knowledge about entrepreneurship and innovation, because these contents can influence, direct and better prepare the nurse to give greater visibility and meet the new spaces of the profession.(AU)

Introdución: La enfermería necesita aprender a innovar y emprender, siguiendo el desarrollo tecnológico y la globalización. Objetivo: Analizar el perfil emprendedor e innovador de los estudiantes de graduación de un curso de enfermería. Método: Estudio transversal, descriptivo y cuantitativo, con 161 estudiantes de grado de primero a cuarto año, a través de un cuestionario autoadministrado sobre perfil emprendedor, dividido en tres perfiles: A: No tiene características empreendedoras, B: Tiene oportunidad de adquirir características emprendedoras y C: Tiene características emprendedoras. Resultados: La mayoría de los estudiantes universitarios mostró un comportamiento participativo en el trabajo en equipo, la toma de decisiones y consideró tener un poco de creatividad. El comportamiento omitido fue sobre la actitud después de terminar la escuela secundaria y ante los imprevistos que suceden en la vida cotidiana. El comportamiento de solo seguir órdenes estaba en relación con la economía, el mundo de los negocios y sobre la autopercepción. No hubo diferencia significativa entre los cuatro años, la mayoría tenía posibilidades de convertirse en emprendedores, necesitando mejorar y desarrollar estas habilidades. Conclusión: Los estudiantes de grado deben adquirir conocimientos sobre emprendimiento e innovación, ya que estos contenidos pueden influir, orientar y preparar mejor a los enfermeros para dar mayor visibilidad y conocer los nuevos espacios de la profesión.(AU)

Baseline disease characteristics in Brazilian patients enrolled in Transthyretin Amyloidosis Outcome Survey (THAOS) / Características da polineuropatia amiloidotica familiar ligada à transtirretina em pacientes brasileiros participantes do "Transthyretin Amyloidosis Outcome Survey (THAOS)"

ABSTRACT Transthyretin amyloidosis (ATTR) is characterized by the deposit of mutant or wild-type transthyretin that forms amyloid fibrils, which are extracellularly deposited within tissues and organs. Clinical manifestations of familial amyloid polyneuropathy vary according to the mutation, age at onset and geographical location. This study aimed to describe baseline disease characteristics of Brazilian patients with transthyretin familial amyloid polyneuropathy (ATTR-FAP) enrolled in the Transthyretin Amyloidosis Outcome Survey (THAOS). Methods: The THAOS is an international, noninterventional, longitudinal, observational, web-based registry designed to characterize ATTR. The outcome measures included demographics (age at symptom onset, gender, time from onset of symptoms to diagnosis, family history), genotype, and clinical characteristics (presence of amyloid deposit, frequency of misdiagnosis, presenting symptomatology). The analysis was conducted in a dataset from Brazilian patients (from November 2008 to January 2016). Results: One hundred and sixty participants (52.5% male) were included in the analysis. The majority of participants (90.6%) reported a positive family history of ATTR-FAP Median age at symptom onset was 32.5 years. Val30Met mutation was found in 91.9%. Misdiagnosis was observed in 26.6% of symptomatic patients. Over one-third (35.3%) of the misdiagnosed patients experienced a delay of more than one year before receiving a correct diagnosis. At presentation, 79.7% of the patients had motor, 87.5% sensory and 93.8% autonomic symptoms. Conclusion: ATTR-FAP in Brazil starts early, has a strong family history and the majority has Val30Met mutation. Misdiagnosis is common and the most common presentation is of a sensorimotor and autonomic neuropathy.

RESUMO Amiloidose ligada à transtirretina (ATTR) é caracterizada por depósito de transtirretina que forma fibrilas amiloides, que são depositadas extracelularmente dentro de tecidos e órgãos. As manifestações clínicas de polineuropatia amiloidótica familiar (ATTR-PAF) variam de acordo com a mutação, idade de início e localização geográfica. Este estudo tem como objetivo descrever as características dos pacientes com ATTR no Brasil, com base nos dados coletados no THAOS. Métodos: THAOS é um registro internacional longitudinal observacional desenhado para caracterizar ATTR. As medidas de desfecho incluíram dados demográficos (idade do início dos sintomas, gênero, tempo do início dos sintomas até diagnóstico, histórico familiar), genotipagem e características clínicas (presença de depósito amiloide, frequências de diagnósticos errôneos, sintomatologia presente). Esta analise foi conduzida com dados de pacientes brasileiros registrados no THAOS de Novembro 2008 a Janeiro de 2016. Resultado: Cento e sessenta pacientes (52,5% homens) foram incluídos na análise. Na maioria dos casos (90,6%) observou-se história familiar positiva de ATTR-FAP A idade média de inicio dos sintomas foi 32,5 anos. A mutação Val30Met foi encontrada em 91,9%. Erros diagnósticos foram observados em 26,6% dos casos sintomáticos. Aproximadamente um terço dos pacientes diagnosticados erroneamente tiveram atraso de mais de um ano para receber um diagnostico correto. No momento do diagnóstico 79,7% dos pacientes possuíam sintomas motores, 87,5% sintomas sensitivos e 93,8% sintomas autonômicos. Conclusão: No brasil a ATTR-FAP tem início precoce, historia familiar fortemente positiva e em sua maioria são portadores da mutação Val30Met. Erros diagnósticos são comuns e a apresentação mais comum é polineuropatia sensitivo-motora com disautonomia.